Proton Beam Therapy in the Reirradiation Setting of Brain and Base of Skull Tumour Recurrences.

The therapeutic management of local tumour recurrence after a first course of radical radiotherapy is always complex. Surgery and reirradiation carry increased morbidity due to radiation-induced tissue changes. Proton beam therapy (PBT) might be advantageous in the reirradiation setting, thanks to its distinct physical characteristics. Here we systematically reviewed the use of PBT in the management of recurrent central nervous system (CNS) and base of skull (BoS) tumours, as published in the literature. The research question was framed following the Population, Intervention, Comparison and Outcomes (PICO) criteria: the population of the study was cancer patients with local disease recurrence in the CNS or BoS; the intervention was radiation treatment with PBT; the outcomes of the study focused on the clinical outcomes of PBT in the reirradiation setting of local tumour recurrences of the CNS or BoS. The identification stage resulted in 222 records in Embase and 79 in Medline as of March 2023. Sixty-eight duplicates were excluded at this stage and 56 were excluded after screening as not relevant, not in English or not full-text articles. Twelve full-text articles were included in the review and are presented according to the site of disease, namely BoS, brain or both brain and BoS. This review showed that reirradiation of brain/BoS tumour recurrences with PBT can provide good local control with acceptable toxicity rates. However, reirradiation of tumour recurrences in the CNS or BoS setting needs to consider several factors that can increase the risk of toxicities. Therefore, patient selection is crucial. Randomised evidence is needed to select the best radiation modality in this group of patients.

Assessing Equity of Access to Proton Beam Therapy: A Literature Review.

Proton beam therapy (PBT) is one of the most advanced radiotherapy technologies, with growing evidence to support its use in specific clinical scenarios and exponential growth of demand and capacity worldwide over the past few decades. However, geographical inequalities persist in the distribution of PBT centres, which translate into variations in access and use of this technology. The aim of this work was to look at the factors that contribute to these inequalities, to help raise awareness among stakeholders, governments and policy makers. A literature search was conducted using the Population, Intervention, Comparison, Outcomes (PICO) criteria. The same search strategy was run in Embase and Medline and identified 242 records, which were screened for manual review. Of these, 24 were deemed relevant and were included in this analysis. Most of the 24 publications included in this review originated from the USA (22/24) and involved paediatric patients, teenagers and young adults (61% for children and/or teenagers and young adults versus 39% for adults). The most reported indicator of disparity was socioeconomic status (16/24), followed by geographical location (13/24). All the studies evaluated in this review showed disparities in the access to PBT. As paediatric patients make up a significant proportion of the PBT-eligible patients, equity of access to PBT also raises ethical considerations. Therefore, further research is needed into the equity of access to PBT to reduce the care gap.

Outcomes of Patients Treated in the UK Proton Overseas Programme: Central Nervous System Group.

AIMS: In 2008, the UK National Health Service started the Proton Overseas Programme (POP), to provide access for proton beam therapy (PBT) abroad for selected tumour diagnoses while two national centres were being planned. The clinical outcomes for the patient group treated for central nervous system (CNS), base of skull, spinal and paraspinal malignancies are reported here. MATERIALS AND METHODS: Since the start of the POP, an agreement between the National Health Service and UK referring centres ensured outcomes data collection, including overall survival, local tumour control and late toxicity data. Clinical and treatment-related data were extracted from this national patient database. Grade ≥3 late toxicities were reported following Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 definition, occurring later than 90 days since the completion of treatment. RESULTS: Between 2008 and September 2020, 830 patients were treated within the POP for the above listed malignancies. Overall survival data were available for 815 patients and local control data for 726 patients. Toxicity analysis was carried out on 702 patients, with patients excluded due to short follow-up (<90 days) and/or inadequate toxicity data available. After a median follow-up of 3.34 years (0.06-11.58), the overall survival was 91.2%. The local control rate was 85.9% after a median follow-up of 2.81 years (range 0.04-11.58). The overall grade ≥3 late toxicity incidence was 11.97%, after a median follow-up of 1.72 years (0.04-8.45). The median radiotherapy prescription dose was 54 GyRBE (34.8-79.2). CONCLUSIONS: The results of this study indicate the safety of PBT for CNS tumours. Preliminary clinical outcomes following PBT for paediatric/teen and young adult and adult CNS tumours treated within the POP are encouraging, which reflects accurate patient selection and treatment quality. The rate of late effects compares favourably with published cohorts. Clinical outcomes from this patient cohort will be compared with those of UK-treated patients since the start of the national PBT service in 2018.

Effect of Race and Ethnicity on Risk of Radiotherapy Toxicity and Implications for Radiogenomics.

AIMS: Patient factors affect the risk of radiotherapy toxicity, but many are poorly defined. Studies have shown that race affects cancer incidence, survival, drug response, molecular pathways and epigenetics. Effects on radiosensitivity and radiotherapy toxicity are not well studied. The aim of the present study was to identify the effects of race and ethnicity on the risk of radiotherapy toxicity. MATERIALS AND METHODS: A systematic review was carried out of PubMed, Ovid Medline and Ovid Embase with no year limit. PRISMA 2020 guidelines were followed. Two independent assessors reviewed papers. RESULTS: Of 607 papers screened, 46 fulfilled the inclusion criteria. Papers were published between 1996 and 2021 and involved 30-28,354 individuals (median 433). Most involved patients with prostate (33%), breast (26%) and lung (9%) cancer. Both early and late toxicities were studied. Some studies reported a higher risk of toxicity in White men with prostate cancer compared with other races and ethnicities. For breast cancer patients, some reported an increased risk of toxicity in White women compared with other race and ethnic groups. In general, it was difficult to draw conclusions due to insufficient reporting and analysis of race and ethnicity in published literature. CONCLUSIONS: Reporting of race and ethnicity in radiotherapy studies must be harmonised and improved and frameworks are needed to improve the quality of reporting. Further research is needed to understand how ancestral heritage might affect radiosensitivity and risk of radiotherapy toxicity.

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.

A Novel Model and Infrastructure for Clinical Outcomes Data Collection and Their Systematic Evaluation for UK Patients Receiving Proton Beam Therapy.

AIMS: To establish an infrastructure for sustainable, comprehensive data collection and systematic outcomes evaluation for UK patients receiving proton beam therapy (PBT). MATERIALS AND METHODS: A Proton Outcomes Working Group was formed in 2014 to develop a national minimum dataset for PBT patients and to define a clinically integrated informatics solution for data collection. The Christie Proton Beam Therapy Centre formed its Proton Clinical Outcomes Unit in 2018 to collect, curate and analyse outcomes data prospectively for UK-treated patients and retrospectively for UK patients referred abroad for PBT since 2008 via the Proton Overseas Programme (POP). RESULTS: A single electronic form (eForm) was developed to capture the agreed data, using a data tree approach including conditional logic: data items are requested once, further questions depend on previous answers and are sensitive to tumour site and patient pathway time point. Relevant data automatically populate other forms, saving time, prompting completeness of clinical assessments and ensuring data consistency. Completed eForm data populate the electronic patient record and generate individualised outputs, including consultation letters, treatment summary and surveillance plans, based on organs at risk irradiated, age and sex. All data regarding POP-treated patients are verified and migrated into the system, ensuring that patient data, whether overseas or UK treated, are consistently recorded. The eForm utilises a 'user friendly' web portal interface, the Clinical Web Portal, including clickable tables and infographics. Data items are coded to a universally recognised standard comparable with other data systems. Patient-reported outcomes are also integrated, highlighting significant toxicities and prompting a response. Outcomes data can be correlated with dosimetric DICOM data to support radiation dose modelling. CONCLUSION: Outcomes data from both POP-treated and The Christie-treated patients support long-term care, allow evaluation of PBT efficacy and safety, assist future selection of PBT patients and support hypothesis generation for future clinical trials.

A Predictive Model for Reactive Tube Feeding in Head and Neck Cancer Patients Undergoing Definitive (Chemo) Radiotherapy.

AIMS: Careful management of a patient's nutritional status during and after treatment for head and neck squamous cell cancers (HNSCC) is crucial for optimal outcomes. The aim of this study was to develop a model for stratifying a patient's risk of requiring reactive enteral feeding through a nasogastric tube during radiotherapy for HNSCC, based on clinical and treatment-related factors. MATERIALS AND METHODS: A cohort of consecutive patients treated with definitive (chemo)radiotherapy for HNSCC between January 2016 and January 2018 was identified in the institutional electronic database for retrospective analysis. Patients requiring enteral feeding pretreatment were excluded. Clinical and treatment data were obtained from prospectively recorded electronic clinical notes and planning software. RESULTS: Baseline patient characteristics and tumour-related parameters were captured for 225 patients. Based on the results of the univariate analysis and using a stepwise backwards selection process, clinical and dosimetric variables were selected to optimise a clinically predictive multivariate model, fitted using logistic regression. The parameters found to affect the probability, P, of requiring a nasogastric feeding tube for >4 weeks in our clinical multivariate model were: tumour site, tumour stage (early T0/1/2 stage versus advanced T3/T4 stage), chemotherapy drug (none versus any drug) and mean dose to the contralateral parotid gland. A scoring model using the regression coefficients of the selected variables in the clinical multivariate model achieved an area under the curve (AUC) of 0.745 (95% confidence interval 0.678-0.812), indicating good discriminative performance. Internal validation of the model involved splitting the dataset 80:20 into training and test datasets 10 times and assessing differences in AUC of the model fitted to these. CONCLUSIONS: We developed an easy-to-use prediction model based on both clinical and dosimetric parameters, which, once externally validated, can lead to more personalised treatment planning and inform clinical decision-making on the appropriateness of prophylactic versus reactive enteral feeding.

Skin Toxicity Profile of Photon Radiotherapy versus Proton Beam Therapy in Paediatric and Young Adult Patients with Sarcomas.

AIMS: Radiotherapy is key in the management of patients with both Ewing sarcoma and rhabdomyosarcoma. However, there is little evidence in the literature with regards to radiation-induced skin toxicities (RISTs) for patients treated with conventional radiotherapy with X-rays (XRT) or proton beam therapy (PBT) for these two conditions. In the present study we evaluated acute and late RIST in patients treated within European protocols with either PBT or XRT, taking both clinical and dosimetric variables into consideration. MATERIALS AND METHODS: This was a retrospective analysis of 79 paediatric/young adult patients treated with radical radiotherapy (with XRT or PBT) and concurrent chemotherapy. In all cases, radiotherapy was given in conventional fractionation (1.8 Gy/fraction). Acute and late RISTs were registered according to the Radiation Therapy Oncology Group (RTOG) scoring system. RESULTS: With regards to acute RIST, 47.9% (23/48) of XRT patients and 48.4% (15/31) of PBT patients had acute grade 2/3 toxicity. When it comes to late RIST, 17.5% (7/40 with known toxicity profile) of XRT patients and 29.0% (9/31) of PBT patients had grade 1/2 toxicity. This difference of -11.5% (95% confidence interval -31.2 to 7.9%) in grade 1/2 toxicity between XRT and PBT was not statistically significant (P = 0.25). Regardless of the radiotherapy technique, V30Gy seems a good predictor of acute RIST. Moreover, for the same value of V30Gy, patients who receive PBT may have a higher risk of moderate-severe acute RIST. Perhaps due to the small sample, definitive conclusions on the predictive factors of late RIST could not be drawn. CONCLUSIONS: No clinically meaningful differences in acute and late RIST were observed between PBT and XRT subgroups. Systematic differences in the modelling of the build-up region may exist between XRT and PBT algorithms, which could make the comparison of dose metrics between techniques potentially biased. A more comprehensive analysis of dosimetric data on larger patient cohorts is needed to elucidate the most relevant skin dose metrics. Dose-effect models of RIST for this unique patient population would be an invaluable tool in radiotherapy plan optimisation.

Comparing Proton to Photon Radiotherapy Plans: UK Consensus Guidance for Reporting Under Uncertainty for Clinical Trials.

In the UK, the recent introduction of high-energy proton beam therapy into national clinical practice provides an opportunity for new clinical trials, particularly those comparing proton and photon treatments. However, comparing these different modalities can present many challenges. Although protons may confer an advantage in terms of reduced normal tissue dose, they can also be more sensitive to uncertainty. Uncertainty analysis is fundamental in ensuring that proton plans are both safe and effective in the event of unavoidable discrepancies, such as variations in patient setup and proton beam range. Methods of evaluating and mitigating the effect of these uncertainties can differ from those approaches established for photon therapy treatments, such as the use of expansion margins to assure safety. These differences should be considered when comparing protons and photons. An overview of the effect of uncertainties on proton plans is presented together with an introduction to some of the concepts and terms that should become familiar to those involved in proton therapy trials. This report aims to provide guidance for those engaged in UK clinical trials comparing protons and photons. This guidance is intended to take a pragmatic approach considering the tools that are available to practising centres and represents a consensus across multidisciplinary groups involved in proton therapy in the UK.

In Silico Models of DNA Damage and Repair in Proton Treatment Planning: A Proof of Concept.

There is strong in vitro cell survival evidence that the relative biological effectiveness (RBE) of protons is variable, with dependence on factors such as linear energy transfer (LET) and dose. This is coupled with the growing in vivo evidence, from post-treatment image change analysis, of a variable RBE. Despite this, a constant RBE of 1.1 is still applied as a standard in proton therapy. However, there is a building clinical interest in incorporating a variable RBE. Recently, correlations summarising Monte Carlo-based mechanistic models of DNA damage and repair with absorbed dose and LET have been published as the Manchester mechanistic (MM) model. These correlations offer an alternative path to variable RBE compared to the more standard phenomenological models. In this proof of concept work, these correlations have been extended to acquire RBE-weighted dose distributions and calculated, along with other RBE models, on a treatment plan. The phenomenological and mechanistic models for RBE have been shown to produce comparable results with some differences in magnitude and relative distribution. The mechanistic model found a large RBE for misrepair, which phenomenological models are unable to do. The potential of the MM model to predict multiple endpoints presents a clear advantage over phenomenological models.

Autosegmentation of the rectum on megavoltage image guidance scans.

Autosegmentation of image guidance (IG) scans is crucial for streamlining and optimising delivered dose calculation in radiotherapy. By accounting for interfraction motion, daily delivered dose can be accumulated and incorporated into automated systems for adaptive radiotherapy. Autosegmentation of IG scans is challenging due to poorer image quality than typical planning kilovoltage computed tomography (kVCT) systems, and the resulting reduction of soft tissue contrast in regions such as the pelvis makes organ boundaries less distinguishable. Current autosegmentation solutions generally involve propagation of planning contours to the IG scan by deformable image registration (DIR). Here, we present a novel approach for primary autosegmentation of the rectum on megavoltage IG scans acquired during prostate radiotherapy, based on the Chan-Vese algorithm. Pre-processing steps such as Hounsfield unit/intensity scaling, identifying search regions, dealing with air, and handling the prostate, are detailed. Post-processing features include identification of implausible contours (nominally those affected by muscle or air), 3D self-checking, smoothing, and interpolation. In cases where the algorithm struggles, the best estimate on a given slice may revert to the propagated kVCT rectal contour. Algorithm parameters were optimised systematically for a training cohort of 26 scans, and tested on a validation cohort of 30 scans, from 10 patients. Manual intervention was not required. Comparing Chan-Vese autocontours with contours manually segmented by an experienced clinical oncologist achieved a mean Dice Similarity Coefficient of 0.78 (SE < 0.011). This was comparable with DIR methods for kVCT and CBCT published in the literature. The autosegmentation system was developed within the VoxTox Research Programme for accumulation of delivered dose to the rectum in prostate radiotherapy, but may have applicability to further anatomical sites and imaging modalities.

Mechanistic modelling supports entwined rather than exclusively competitive DNA double-strand break repair pathway.

Following radiation induced DNA damage, several repair pathways are activated to help preserve genome integrity. Double Strand Breaks (DSBs), which are highly toxic, have specified repair pathways to address them. The main repair pathways used to resolve DSBs are Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). Cell cycle phase determines the availability of HR, but the repair choice between pathways in the G2 phases where both HR and NHEJ can operate is not clearly understood. This study compares several in silico models of repair choice to experimental data published in the literature, each model representing a different possible scenario describing how repair choice takes place. Competitive only scenarios, where initial protein recruitment determines repair choice, are unable to fit the literature data. In contrast, the scenario which uses a more entwined relationship between NHEJ and HR, incorporating protein co-localisation and RNF138-dependent removal of the Ku/DNA-PK complex, is better able to predict levels of repair similar to the experimental data. Furthermore, this study concludes that co-localisation of the Mre11-Rad50-Nbs1 (MRN) complexes, with initial NHEJ proteins must be modeled to accurately depict repair choice.

Radiogenomics in the Era of Advanced Radiotherapy.

Most radiogenomics studies investigate how genetic variation can help to explain the differences in early and late radiotherapy toxicity between individuals. The field of radiogenomics in photon beam therapy has grown rapidly in recent years, carving out a unique translational discipline, which has progressed from candidate gene studies to larger scale genome-wide association studies, meta-analyses and now prospective validation studies. Genotyping is increasingly sophisticated and affordable, and whole-genome sequencing may soon become readily available as a diagnostic tool in the clinic. The ultimate aim of radiogenomics research is to tailor treatment to the individual with a test based on a combination of treatment, clinical and genetic factors. This personalisation would allow the greatest tumour control while minimising acute and long-term toxicity. Here we discuss the evolution of the field of radiogenomics with reference to the most recent developments and challenges.

Clinically relevant nanodosimetric simulation of DNA damage complexity from photons and protons.

Relative Biological Effectiveness (RBE), the ratio of doses between radiation modalities to produce the same biological endpoint, is a controversial and important topic in proton therapy. A number of phenomenological models incorporate variable RBE as a function of Linear Energy Transfer (LET), though a lack of mechanistic description limits their applicability. In this work we take a different approach, using a track structure model employing fundamental physics and chemistry to make predictions of proton and photon induced DNA damage, the first step in the mechanism of radiation-induced cell death. We apply this model to a proton therapy clinical case showing, for the first time, predictions of DNA damage on a patient treatment plan. Our model predictions are for an idealised cell and are applied to an ependymoma case, at this stage without any cell specific parameters. By comparing to similar predictions for photons, we present a voxel-wise RBE of DNA damage complexity. This RBE of damage complexity shows similar trends to the expected RBE for cell kill, implying that damage complexity is an important factor in DNA repair and therefore biological effect.

[Target volume concepts in radiotherapy and their implications for imaging]. / Zielvolumenkonzepte in der Strahlentherapie und ihre Bedeutung für die Bildgebung.

CLINICAL ISSUE: Successful radiotherapy requires precise localization of the tumor and requires high-quality imaging for developing a treatment plan. STANDARD TREATMENT: Irradiation of the tumor region, including a safety margin. TREATMENT INNOVATIONS: The target volume consists of the gross tumor volume (GTV) containing visible parts of the tumor, the clinical target volume (CTV) covering the GTV plus invisible tumor extensions, and the planning target volume (PTV) to account for uncertainties. The non-GTV parts of the CTV are based on historical patient data. The PTV margins are based on a calculation of possible uncertainties during planning, setup, or treatment. Normal tissue deserves the identical care in contouring, since its tolerance may limit the tumor dose, taking into account the contours of organs at risk. Serial risk organs benefit from defining a planning organ of risk volume (PRV) to better limit the dose delivered to them. DIAGNOSTIC WORK-UP: The better the imaging, the more reliable the definition of the GTV and treatment success will be. Multiple imaging sequences are desirable to support the delineation of the tumor. They may result in different CTVs that, depending on their tumor burden, may require different doses. PERFORMANCE: The definition of standardized target volumes according to the ICRU reports 50, 62, and 83 forms the basis for an individualized radiation treatment planning according to unified criteria on a high-quality level. ACHIEVEMENTS: Radio-oncology is by nature interdisciplinary, the diagnostic radiologist being an indispensable team partner. A regular dialogue between the disciplines is pivotal for target volume definition and treatment success. PRACTICAL RECOMMENDATIONS: Imaging for target volume definition requires highest quality imaging, the use of functional imaging methods and close cooperation with a diagnostic radiologist experienced in this field.

Tumour Volume and Dose Influence Outcome after Surgery and High-dose Photon Radiotherapy for Chordoma and Chondrosarcoma of the Skull Base and Spine.

AIMS: To evaluate the long-term outcomes of patients with chordoma and low-grade chondrosarcoma after surgery and high-dose radiotherapy. MATERIALS AND METHODS: High-dose photon radiotherapy was delivered to 28 patients at the Neuro-oncology Unit at Addenbrooke's Hospital (Cambridge, UK) between 1996 and 2016. Twenty-four patients were treated with curative intent, 17 with chordoma, seven with low-grade chondrosarcoma, with a median dose of 65 Gy (range 65-70 Gy). Local control and survival rates were calculated using the Kaplan-Meier method. RESULTS: The median follow-up was 83 months (range 7-205 months). The 5 year disease-specific survival for chordoma patients treated with radical intent was 85%; the local control rate was 74%. The 5 year disease-specific survival for chondrosarcoma patients treated with radical intent was 100%; the local control rate was 83%. The mean planning target volume (PTV) was 274.6 ml (median 124.7 ml). A PTV of 110 ml or less was a good predictor of local control, with 100% sensitivity and 63% specificity. For patients treated with radical intent, this threshold of 110 ml or less for the PTV revealed a statistically significant difference when comparing local control with disease recurrence (P = 0.019, Fisher's exact test). Our data also suggest that the probability of disease control may be partly related to both target volume and radiotherapy dose. CONCLUSION: Our results show that refined high-dose photon radiotherapy, following tumour resection by a specialist surgical team, is effective in the long-term control of chordoma and low-grade chondrosarcoma, even in the presence of metal reconstruction. The results presented here will provide a useful source for comparison between high-dose photon therapy and proton beam therapy in a UK setting, in order to establish best practice for the management of chordoma and low-grade chondrosarcoma.