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: Non-central Nervous System Group.

AIMS: The UK Proton Overseas Programme (POP) was launched in 2008. The Proton Clinical Outcomes Unit (PCOU) warehouses a centralised registry for collection, curation and analysis of all outcomes data for all National Health Service-funded UK patients referred and treated abroad with proton beam therapy (PBT) via the POP. Outcomes are reported and analysed here for patients diagnosed with non-central nervous system tumours treated from 2008 to September 2020 via the POP. MATERIALS AND METHODS: All non-central nervous system tumour files for treatments as of 30 September 2020 were interrogated for follow-up information, and type (following CTCAE v4) and time of onset of any late (>90 days post-PBT completion) grade 3-5 toxicities. RESULTS: Four hundred and ninety-five patients were analysed. The median follow-up was 2.1 years (0-9.3 years). The median age was 11 years (0-69 years). 70.3% of patients were paediatric (<16 years). Rhabdomyosarcoma (RMS) and Ewing sarcoma were the most common diagnoses (42.6% and 34.1%). 51.3% of treated patients were for head and neck (H&N) tumours. At last known follow-up, 86.1% of all patients were alive, with a 2-year survival rate of 88.3% and 2-year local control of 90.3%. Mortality and local control were worse for adults (≥25 years) than for the younger groups. The grade 3 toxicity rate was 12.6%, with a median onset of 2.3 years. Most were in the H&N region in paediatric patients with RMS. Cataracts (30.5%) were the most common, then musculoskeletal deformity (10.1%) and premature menopause (10.1%). Three paediatric patients (1-3 years at treatment) experienced secondary malignancy. Seven grade 4 toxicities occurred (1.6%), all in the H&N region and most in paediatric patients with RMS. Six related to eyes (cataracts, retinopathy, scleral disorder) or ears (hearing impairment). CONCLUSIONS: This study is the largest to date for RMS and Ewing sarcoma, undergoing multimodality therapy including PBT. It demonstrates good local control, survival and acceptable toxicity rates.

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.

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.

Hypofractionated Radiotherapy in Oesophageal Cancer for Patients Unfit for Systemic Therapy: A Retrospective Single-Centre Analysis.

AIMS: Chemoradiotherapy (CRT) is established as a superior treatment option to definitive radiotherapy in the non-surgical management of oesophageal cancer. For patients precluded from CRT through choice or comorbidity there is little evidence to guide delivery of single-modality radiotherapy. In this study we outline outcomes for patients unfit for CRT who received a hypofractionated radiotherapy (HRT) regimen. MATERIALS AND METHODS: A retrospective UK single-centre analysis of 61 consecutive patients with lower- or middle-third adenocarcinoma (OAC; 61%) or squamous cell carcinoma of the oesophagus managed using HRT with radical intent between April 2009 and 2014. Treatment consisted of 50 Gy in 16 fractions (n = 49, 80.3%) or 50-52.5 Gy in 20 fractions (n = 12, 19.7%). Outcomes were referenced against a contemporaneous comparator cohort of 80 (54% OAC) consecutive patients managed with conventionally fractionated CRT within the same centre. RESULTS: Three-year and median overall survival were, respectively, 56.9% and 29 months with HRT compared with 55.5% and 26 months for CRT; adjusted hazard ratio 0.79 (95% confidence interval 0.48-1.28). Grade 3 and 4 toxicity rates were low at 16.4% (n = 10) for those receiving HRT and 40.2% (n = 32) for the CRT group. In patients with OAC, CRT delivered superior overall survival (hazard ratio 0.46; 95% confidence interval 0.25-0.85) and progression-free survival (hazard ratio 0.45; 95% confidence interval 0.23-0.88) when compared with HRT. CONCLUSIONS: The HRT regimen described here was safe and tolerable in patients unable to receive CRT, and delivered promising survival outcomes. The use of HRT for the treatment of oesophageal cancer, both alone and as a sequential or concurrent treatment with chemotherapy, requires further study. New precision radiotherapy technologies may provide additional scope for improving outcomes in oesophageal cancer using HRT-based approaches and should be evaluated.

Analysis of a National Programme for Selective Internal Radiation Therapy for Colorectal Cancer Liver Metastases.

AIMS: Patients with chemotherapy-refractory colorectal cancer liver metastases have limited therapeutic options. Selective internal radiation therapy (SIRT) delivers yttrium 90 microspheres as a minimally invasive procedure. This prospective, single-arm, observational, service-evaluation study was part of National Health Service England Commissioning through Evaluation. METHODS: Patients eligible for treatment had histologically confirmed carcinoma with liver-only/liver-dominant metastases with clinical progression during or following oxaliplatin-based and irinotecan-based chemotherapy. All patients received SIRT plus standard of care. The primary outcome was overall survival; secondary outcomes included safety, progression-free survival (PFS) and liver-specific PFS (LPFS). RESULTS: Between December 2013 and March 2017, 399 patients were treated in 10 centres with a median follow-up of 14.3 months (95% confidence interval 9.2-19.4). The median overall survival was 7.6 months (95% confidence interval 6.9-8.3). The median PFS and LPFS were 3.0 months (95% confidence interval 2.8-3.1) and 3.7 months (95% confidence interval 3.2-4.3), respectively. During the follow-up period, 143 patients experienced an adverse event and 8% of the events were grade 3. CONCLUSION: Survival estimates from this pragmatic study show clinical outcomes attainable in the National Health Service comparable with previously published data. This study shows the value of a registry-based commissioning model to aid national commissioning decisions for highly specialist cancer treatments.

The Road Map for National Health Service Proton Beam Therapy.

Proton Beam Therapy is one of the key elements in a major improvement in access to advanced radiotherapy in the UK. An overseas programme has treated significant numbers of children and young adults and skull base tumours since 2008. A major government investment has resulted in building two proton centres in England sited in academic major cancer centres. A weak evidence base for most adult indications means that the NHS will use clinical trials and studies to explore the future role of Protons.

Caution is required in the implementation of 90-day mortality indicators for radiotherapy in a curative setting: A retrospective population-based analysis of over 16,000 episodes.

BACKGROUND: 90-day mortality (90DM) has been proposed as a clinical indicator in radiotherapy delivered in a curative setting. No large scale assessment has been made. Its value in allowing robust comparisons between centres and facilitating service improvement is unknown. METHODS: All radiotherapy treatments delivered in a curative setting over seven years were extracted from the local electronic health record and linked to cancer registry data. 90DM rates were assessed and factors associated with this outcome were investigated using logistic regression. Cause of death was identified retrospectively further characterising the cause of 90DM. RESULTS: Overall 90DM was 1.25%. Levels varied widely with diagnosis (0.20-5.45%). Age (OR 1.066, 1.043-1.073), year of treatment (OR 0.900, 0.841-0.969) and diagnosis were significantly associated with 90DM on multi-variable logistic regression. Cause of death varied with diagnosis; 50.0% post-operative in rectal cancer, 40.4% treatment-related in head and neck cancer, 59.4% disease progression in lung cancer. CONCLUSION: Despite the drive to report centre level comparative outcomes, this study demonstrates that 90DM cannot be adopted routinely asa clinical indicator due to significant population heterogeneity and low event rates. Further national investigation is needed to develop a meaningful robust indicator to deliver appropriate comparisons and drive improvements in care.

Superiority of Deformable Image Co-registration in the Integration of Diagnostic Positron Emission Tomography-Computed Tomography to the Radiotherapy Treatment Planning Pathway for Oesophageal Carcinoma.

AIMS: To investigate the use of image co-registration in incorporating diagnostic positron emission tomography-computed tomography (PET-CT) directly into the radiotherapy treatment planning pathway, and to describe the pattern of local recurrence relative to the PET-avid volume. MATERIALS AND METHODS: Fourteen patients were retrospectively identified, six of whom had local recurrence. The accuracy of deformable image registration (DIR) and rigid registration of the diagnostic PET-CT and recurrence CT, to the planning CT, were quantitatively assessed by comparing co-registration of oesophagus, trachea and aorta contours. DIR was used to examine the correlation between PET-avid volumes, dosimetry and site of recurrence. RESULTS: Positional metrics including the dice similarity coefficient (DSC) and conformity index (CI), showed DIR to be superior to rigid registration in the co-registration of diagnostic and recurrence imaging to the planning CT. For diagnostic PET-CT, DIR was superior to rigid registration in the transfer of oesophagus (DSC=0.75 versus 0.65, P<0.009 and CI=0.59 versus 0.48, P<0.003), trachea (DSC=0.88 versus 0.65, P<0.004 and CI=0.78 versus 0.51, P<0.0001) and aorta structures (DSC=0.93 versus 0.86, P<0.006 and CI=0.86 versus 0.76, P<0.006). For recurrence imaging, DIR was superior to rigid registration in the transfer of trachea (DSC=0.91 versus 0.66, P<0.03 and CI=0.83 versus 0.51, P<0.02) and oesophagus structures (DSC=0.74 versus 0.51, P<0.004 and CI=0.61 versus 0.37, P<0.006) with a non-significant trend for the aorta (DSC=0.91 versus 0.75, P<0.08 and CI=0.83 versus 0.63, P<0.06) structure. A mean inclusivity index of 0.93 (range 0.79-1) showed that the relapse volume was within the planning target volume (PTVPET-CT); all relapses occurred within the high dose region. CONCLUSION: DIR is superior to rigid registration in the co-registration of PET-CT and recurrence CT to the planning CT, and can be considered in the direct integration of PET-CT to the treatment planning process. Local recurrences occur within the PTVPET-CT, suggesting that this is a suitable target for dose-escalation strategies.

Wide Variation in the Use of Radiotherapy in the Management of Surgically Treated Rectal Cancer Across the English National Health Service.

AIMS: Radiotherapy is an important treatment modality in the multidisciplinary management of rectal cancer. It is delivered both in the neoadjuvant setting and postoperatively, but, although it reduces local recurrence, it does not influence overall survival and increases the risk of long-term complications. This has led to a variety of international practice patterns. These variations can have a significant effect on commissioning, but also future clinical research. This study explores its use within the large English National Health Service (NHS). MATERIALS AND METHODS: Information on all individuals diagnosed with a surgically treated rectal cancer between April 2009 and December 2010 were extracted from the Radiotherapy Dataset linked to the National Cancer Data Repository. Individuals were grouped into those receiving no radiotherapy, short-course radiotherapy with immediate surgery (SCRT-I), short-course radiotherapy with delayed surgery (SCRT-D), long-course chemoradiotherapy (LCCRT), other radiotherapy (ORT) and postoperative radiotherapy (PORT). Patterns of use were then investigated. RESULTS: The study consisted of 9201 individuals; 4585 (49.3%) received some form of radiotherapy. SCRT-I was used in 12.1%, SCRT-D in 1.2%, LCCRT in 29.5%, ORT in 4.7% and PORT in 2.3%. Radiotherapy was used more commonly in men and in those receiving an abdominoperineal excision and less commonly in the elderly and those with comorbidity. Significant and substantial variations were also seen in its use across all the multidisciplinary teams managing this disease. CONCLUSION: Despite the same evidence base, wide variation exists in both the use of and type of radiotherapy delivered in the management of rectal cancer across the English NHS. Prospective population-based collection of local recurrence and patient-reported early and late toxicity information is required to further improve patient selection for preoperative radiotherapy.

Preoperative radiotherapy combined with 5 days per week capecitabine chemotherapy in locally advanced rectal cancer.

There is increasing evidence supporting the use of preoperative chemoradiotherapy in patients with locally advanced rectal cancer in an attempt to facilitate complete surgical resection with clear margins. We describe our experience of using a 5-day per week regime of preoperative capecitabine chemoradiotherapy. Between November 2004 and September 2006, 70 patients with MRI-defined locally advanced rectal cancer were selected for treatment. Capecitabine was given at a dose of 900 mg m(-2) for 5 days per week combined with 45 Gy of radiotherapy in 25 doses. This regime was well tolerated with 89% of our patients receiving the full dose of chemotherapy and 96% receiving the full dose of radiotherapy. Ninety-three per cent proceeded to macroscopically complete surgical resection. The pathological complete response rate was 9.2% with a node-negative rate of 66%. A negative circumferential margin was achieved by 79% of the patients who underwent resection. Compared to studies using a 7-day per week capecitabine schedule, our results show increased compliance and less dose reductions with comparable pathological outcome.

The clinical implications of the collapsed cone planning algorithm.

AIMS: The accuracy of computer treatment planning systems is important in achieving clinically acceptable dose distributions. The pencil beam (PB) algorithm on Helax-TMS is currently used for all clinical treatment planning at the two centres involved in this study. However, it has been shown that the Helax-TMS collapsed cone (CC) algorithm is more accurate in regions of heterogeneity, such as the thorax, and head and neck. The aim of this study was to show the actual dose delivered to the patient when treating with a Helax-TMS PB plan, by using the corresponding Helax-TMS CC plan as the reference standard. MATERIALS AND METHODS: Thirty PB treatment plans (for lung and oesophageal treatments) were recalculated using the CC algorithm, and plans were then compared. RESULTS: The number of monitor units required to deliver the prescription dose differed between algorithms, by up to 3.4%. In most cases, the CC algorithm calculated more monitor units than the PB, indicating under-dosage at the prescription point during treatment. The dose distributions also seemed less homogeneous when calculated using the CC algorithm. The minimum dose to the planning target volume (PTV) was lower than the PB plan suggested in every case, by up to 23.2%. ICRU homogeneity requirements (i.e. a minimum 95% of the prescription dose in the PTV) were not met in any of the cases. Even with some attempts at optimisation, conformance to these requirements was difficult. CONCLUSION: The CC algorithm has several factors limiting its suitability for routine clinical use. However, it is an important milestone in radiotherapy treatment planning, and should be used to show expected changes in computer planned dose distributions with new accurate dose algorithms. It is worthwhile considering dose homogeneity requirements well before the advent of anticipated Monte Carlo-based models.