[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.

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.

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.

A replicated association between polymorphisms near TNFα and risk for adverse reactions to radiotherapy.

BACKGROUND: Response to radiotherapy varies between individuals both in terms of efficacy and adverse reactions. Finding genetic determinants of radiation response would allow the tailoring of the treatment, either by altering the radiation dose or by surgery. Despite a growing number of studies in radiogenomics, there are no well-replicated genetic association results. METHODS: We carried out a candidate gene association study and replicated the result using three additional large cohorts, a total of 2036 women scored for adverse reactions to radiotherapy for breast cancer. RESULTS: Genetic variation near the tumour necrosis factor alpha gene is shown to affect several clinical endpoints including breast induration, telangiectasia and overall toxicity. In the combined analysis homozygosity for the rare allele increases overall toxicity (P=0.001) and chance of being in the upper quartile of risk with odds ratio of 2.46 (95% confidence interval 1.52-3.98). CONCLUSION: We have identified that alleles of the class III major histocompatibility complex region associate with overall radiotherapy toxicity in breast cancer patients by using internal replication through a staged design. This is the first well-replicated report of a genetic predictor for radiotherapy reactions.

Temozolomide responsiveness in aggressive corticotroph tumours: a case report and review of the literature.

Pituitary carcinoma occurs in ~0.2% of resected pituitary tumours and carries a poor prognosis (mean survival <4 years), with standard chemotherapy regimens showing limited efficacy. Recent evidence suggests that temozolomide (TMZ), an orally-active alkylating agent used principally in the management of glioblastoma, may also be effective in controlling aggressive/invasive pituitary adenomas/carcinomas. A low level of expression of the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) predicts TMZ responsiveness in glioblastomas, and a similar correlation has been observed in the majority of aggressive pituitary adenomas/carcinomas reported to date. Here, we report a case of a silent pituitary corticotroph adenoma, which subsequently re-presented with Cushing's syndrome due to functioning hepatic metastases. The tumour exhibited low immunohistochemical MGMT expression in both primary (pituitary) and secondary (hepatic) lesions. Initial TMZ therapy (200 mg/m² for 5 days every 28 days-seven cycles) resulted in marked clinical, biochemical [>50% fall in adrenocorticotrophic hormone (ACTH)] and radiological [partial RECIST (response evaluation criteria in solid tumors) response] improvements. The patient then underwent bilateral adrenalectomy. However, despite reintroduction of TMZ therapy (further eight cycles) ACTH levels plateaued and no further radiological regression was observed. We review the existing literature reporting TMZ efficacy in pituitary corticotroph tumours, and highlight the pointers/lessons for treating aggressive pituitary neoplasia that can be drawn from experience of susceptibility and evolving resistance to TMZ therapy in glioblastoma. Possible strategies for mitigating resistance developing during TMZ treatment of pituitary adenomas/carcinomas are also considered.

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.

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.

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.

Dose-volume population histogram: a new tool for evaluating plans whilst considering geometrical uncertainties.

We present a method to incorporate geometrical uncertainties into dose-volume histogram evaluation: the dose-volume population histogram (DVPH). For each dose-volume point, the probability of the plan DVH meeting the constraint is calculated. The use of DVPH for the target shows that the minimum dose to the PTV might not be representative of the minimum dose to the CTV considering geometrical uncertainties when the PTV extends into the build-up region. For OARs, the DVH obtained from DVPH with 90% confidence level is found to be different to the planning organ at risk volume (PRV) DVH recommended by ICRU 62, especially for parallel organs.

The optimization of intensity modulated radiotherapy in cases where the planning target volume extends into the build-up region.

A common clinical problem in IMRT, especially when treating head and neck cases, is that the clinical target volume (CTV) stops short of the skin surface, whilst the margin for geometric uncertainties may take the planning target volume (PTV) to the skin surface or beyond. In these cases, optimization leads to over-dosing of the skin, unless the planner resorts to procedural tricks to avoid this, such as the use of pretend bolus or reduction of the PTV followed by adding 'flash' after optimization. This paper describes a method of avoiding the need for these tricks by using a multiple-isocentre CTV-based objective function. This enables plans to be produced that will give good coverage of the CTV for all the geometrical uncertainties that would have been covered by the PTV without causing the problem of over-dosing the skin. Eight isocentre shifts, equally distributed on the surface of a sphere with a radius equal to the CTV-PTV margin, are shown to be adequate for the optimization process. The resulting fluence maps are much simpler than those resulting from PTV optimization and will therefore be simpler to deliver. The method also permits better sparing of organs at risk such as the spinal cord.

Imaging regional variation of cellular proliferation in gliomas using 3'-deoxy-3'-[18F]fluorothymidine positron-emission tomography: an image-guided biopsy study.

AIM: To compare regional variations in uptake of 3'-deoxy-3'- [(18)F]-fluorothymidine (FLT) images using positron-emission tomography (PET) with measures of cellular proliferation from biopsy specimens obtained by image-guided brain biopsies. MATERIALS AND METHODS: Fourteen patients with a supratentorial glioma that required an image-guided brain biopsy were imaged preoperatively with dynamic PET after the administration of FLT. Maps of FLT irreversible uptake rate (K(i)) and standardized uptake value (SUV) were calculated. These maps were co-registered to a gadolinium-enhanced T1-weighted spoiled gradient echo (SPGR) sequence that was used for biopsy guidance, and the mean and maximum K(i) and SUV determined for each biopsy site. These values were correlated with the MIB-1 labelling index (a tissue marker of proliferation) from these biopsy sites. RESULTS: A total of 57 biopsy sites were studied. Although all measures correlated with MIB-1 labelling index, K(i)(max) provided the best correlation (Pearson coefficient, r=0.68; p<0.001). In low-grade gliomas the K(i)(mean) (+/-SD) was significantly higher than in normal tissue (3.3+/-1.7x10(-3)ml(plasma)/min/ml(tissue) versus 1.2+/-0.7x10(-3)ml(plasma)/min/ml(tissue); p=0.001). High-grade gliomas showed heterogeneous uptake with a mean K(i) of 7.7+/-4x10(-3)ml(plasma)/min/ml(tissue). A threshold K(i)(mean) of 1.8x10(-3) differentiates between normal tissue and tumour (sensitivity 84%, specificity 88%); however, the latter threshold underestimated the extent of tumour in half the cases. SUV closely agreed with K(i) measurements. CONCLUSION: FLT PET is a useful marker of cellular proliferation that correlates with regional variation in cellular proliferation; however, it is unable to identify the margin of gliomas.

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.

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.

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.

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.

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.

Practical issues in the implementation of image-guided radiotherapy for the treatment of prostate cancer within a UK department.

AIMS: To study the feasibility of using implanted gold seeds in combination with a commercial software system for daily localisation of the prostate gland during conformal radiotherapy, and to assess the effect this may have on departmental workload. MATERIALS AND METHODS: Six patients had three gold radio-opaque seeds implanted into the prostate gland before starting a course of radiotherapy. The seeds were identified on daily portal images and an automated online system provided immediate vector analysis of discrepancies between the planned and actual daily position of the intraprostatic seeds. In total, 138 interfractional displacements were analysed. The workload impact for the department was assessed using the basic treatment equivalence model, by comparing measurements of daily treatment session durations with a control group of patients receiving standard conformal radiotherapy, matched for treatment complexity. RESULTS: No acute complications of seed insertion were observed. A number of developmental issues required solutions to be identified before clinical implementation was possible. The standard deviations of the set-up and organ motion systematic errors in the left-right, superior-inferior and anterior-posterior directions were 2.4, 3.0 and 2.5 mm, respectively. The standard deviations of the set-up and organ motion random errors calculated were 2.5, 2.9 and 3.7 mm. The mean treatment session duration with this daily prostate localisation system was increased by 3 min compared with matched controls using standard imaging practice. If all radical prostate patients in our department were to receive image-guided radiotherapy in this way, this would increase machine workload time by 2.2 h/day. CONCLUSIONS: The implementation of this image-guided system is feasible. No additional linear accelerator modification is required and standard imaging devices can be used. It would be a useful addition to any department's image-guided radiotherapy developmental strategy.

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.

The genomics revolution and radiotherapy.

The expansion of our knowledge through the Human Genome Project has been accompanied by the development of new high-throughput techniques, which provide extensive capabilities for the analysis of a large number of genes or the whole genome. These assays can be carried out in various clinical samples at the DNA (genome), RNA (transcriptome) or protein (proteome) level. There is a belief that this genomic revolution, i.e. sequencing of the human genome and developments in high-throughput technology, heralds a future of personalised medicine. For clinical oncology, this progress should increase the possibility of predicting individual patient responses to radiotherapy. This review highlights some of the work involving sparsely ionising radiation and the new technologies.