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.

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.

Hypofractionated Stereotactic Ablative Radiotherapy for Recurrent or Oligometastatic Tumours in Children and Young Adults.

AIMS: Cancer remains a leading cause of death in children and adolescents in the developed world. Despite advances in oncological management, rates of primary treatment failure remain significant. Radiation of recurrent or metastatic disease improves survival in adults but there is little data to support clinical decision making in the paediatric/teenage and young adult population. MATERIALS AND METHODS: We present a retrospective case series of 14 patients treated with stereotactic ablative body radiotherapy or stereotactic radiosurgery at The Royal Marsden Hospital from September 2011 to December 2015. Eligible patients were aged <25 years, with Lansky/Karnofsky performance status ≥60 with confirmed relapsed or metastatic tumour in fewer than three sites. Follow-up was in accordance with standard clinical care and included regular outpatient review and radiological surveillance. Local control, progression-free survival and overall survival are presented. RESULTS: Data for 14 patients with 18 treated lesions were included. The median patient age was 15 years (range 5-20 years). Nine patients were treated for local recurrence and five for metastatic lesions. All patients had already undergone multiple previous treatments. Eleven patients had undergone previous radiotherapy. The median interval between the completion of initial radiotherapy and reirradiation was 29.0 months (range 0.2-49.5 months). The median follow-up was 3.4 years (range 0.28-6.4 years). The 1-year local control rate was 78.6% and the 2-year local control rate was 57.1%. Overall median survival was 58.4 months (95% confidence interval 33.8-82.9 months). Cumulative biologically effective doses (BED) over 200 Gy were associated with late toxicity (P = 0.04). CONCLUSION: Radical doses of short-course hypofractionated radiotherapy can achieve excellent local control and may contribute to the prolongation of overall survival. There is a need for prospective trials exploring the use of ablative radiotherapy in metastatic disease in paediatric/teenage and young adult patients in order to establish safe and effective treatment schedules.

Duration of antibiotic therapy in hospitalised patients with community-acquired pneumonia.

Recent guidelines suggest that duration of antibiotic therapy for hospitalized patients with community-acquired pneumonia (CAP) can be reduced by individualising treatment based on patient's clinical response. However, the degree of application of this principle in clinical practice is unknown. Duration of therapy was analysed in patients identified from the Community-Acquired Pneumonia Organization database and evaluated with respect to severity of the disease on admission and time to clinical stability (TCS). Among the 2,003 patients enrolled, mean duration of total antibiotic therapy was 11 days. Neither the pneumonia severity index (r(2) = 0.005) nor the CRB-65 (r(2) = 0.004) scores were related to total duration of therapy. Duration of intravenous antibiotic therapy was related to TCS (r(2) = 0.198). Conversely, TCS was not related to duration of either oral (r(2) = 0.014) or total (r(2) = 0.02) antibiotic therapy. Neither TCS nor other characteristics were found to be significantly associated with duration of total therapy by logistic regression analysis (r(2)<0.09). The individualised approach suggested by recent guidelines has not been adopted in current clinical practice. Duration of therapy is not influenced by either the severity of disease at the time of hospitalisation or the clinical response to therapy.

Appreciation of medical treatments through confidence intervals.

The typical way of judging about either the efficacy of a new treatment or, on the contrary, the damage of a pollutant agent is through a test of hypothesis having its ineffectiveness as null hypothesis. This is the typical operational field of Kolmogorov's statistical framework where wastes of data (for instance non significant deaths in a polluted region) represent the main drawback. Instead, confidence intervals about treatment/pollution effectiveness are a way of exploiting all data, whatever their number is. We recently proposed a new statistical framework, called Algorithmic Inference, for overcoming crucial difficulties usually met when computing these intervals and abandoning general simplifying hypotheses such as errors' Gaussian distribution. When effectiveness is expressed in terms of regression curves between observed data we come to a learning problem that we solve by identifying a region where the whole curve lies with a given confidence. The approach to inference we propose is very suitable for identifying these regions with great accuracy, even in the case of nonlinear regression models and/or a limited size of the observed sample, provided that a normally powered computing station is available. In the paper we discuss this new way of extracting functions from the experimental data and drawing conclusions about the treatments originating them. From an operational perspective, we give the general layout of the procedure for computing confidence regions as well as some applications on real data.

Model of gas exchange and diffusion in legume nodules : I. Calculation of gas exchange rates and the energy cost of N2 fixation.

A mathematical model is described which allows the estimation of rates of O2, CO2, N2, and H2 exchange from legume nodules under steady state conditions of N2 fixation. Calculated rates of gas exchange under defined conditions of nodule size, relative growth rate (RGR), specific total nitrogenase activity (TNA), nitrogenase electron allocation coefficient (EAC), uptake-hydrogenase activity (HUP) and nature of the N export product compared favorably with experimentally-obtained rates reported in the literature. Therefore the model was used to predict the effects of varying each of these nodule characteristics on the rates of gas exchange, and on the apparent respiratory cost (CO2/NH3) and sucrose cost (sucrose consumed/NH3) of N2 fixation.The model predicted that, all other characters being equal, ureide-producing nodules would consume 8% less sucrose per N fixed than asparagine-producing nodules, but would display an apparent respiratory cost which would be 5% higher than that in asparagine-producing nodules. In both ureide-producing and asparagine-producing nodules, the major factor affecting the apparent respiratory cost of N2 fixation was predicted to be EAC, followed by TNA, nodule RGR and nodule size. The relative importance of HUP in improving the apparent respiratory cost of N2 fixation was predicted to be largely dependent upon its potential role in the regulation of EAC.

Model of gas exchange and diffusion in legume nodules : II. Characterisation of the diffusion barrier and estimation of the concentrations of CO2, H 2 and N 2 in the infected cells.

The rates of nodule O2, CO2, N2 and H2 exchange calculated in the previous modeling study (D.B. Layzell et al., 1987, Planta 173, 117-127) were combined with information on the diffusion characteristics of each gas, and the structural characteristics of soybean nodules, to produce a comprehensive mathematical model of nodule structure and function. The model assumed that an aqueous barrier to gas diffusion exists in the nodule cortex which may be regulated to maintain an O2 concentration of 10 nM in the centre of the infected cells of the central zone. The model was used to predict the concentration of N2, CO2 and H2 in the infected cells as the physical and physiological characteristics of the nodule were varied. The model predicted that (a) the diffusion barrier may be represented by plugs of water in the intercellular spaces of a layer of cells between the inner and outer cortex, the depth of which may be varied to vary the resistance of the barrier; (b) facilitated diffusion of O2 by oxyleghemoglobin is essential to the regulation of free O2 concentration in the infected cells; (c) the diffusion barrier is less effective in regulating CO2 flux than the fluxes of other gases with the result that the total gas pressure in the central zone is less than atmospheric pressure; (d) concentrations of N2 and HCO 3 (-) in the infected cells are saturating with respect to nitrogenase activity and phosphoenolpyruvate carboxylase activity respectively and (e) under atmospheric conditions the concentration of H2 in the infected cells is similar to, or greater than the K i . (H2) for N2 fixation, which may account for values of nitrogenase electron allocation coefficient below 0.75.

The effect of several intertrial intervals on the 1 Hz interference effect.

Experiments were conducted to evaluate the effect of two intertrial intervals of 1-Hz brain stimulation on kindling behavior induced by 60Hz sine wave stimulation. In two experiments, the effective threshold intensity (ETI) to elicit a convulsion was determined on four separate occasions with 5 days of daily trials between determinations. On each day experimental rats were stimulated with 1-Hz current on the first and third trials for 120 seconds duration and with 60-Hz current for 30 seconds on the second trial (1-60-1 group). A second group was stimulated with 60-Hz-current on each trial (60-60-60 group). A third group received no stimulation on Trials 1 and 3 and 60-Hz current on Trial 2 (X-60-X group). In Experiment 1, the intertrial interval was 3 hours; a 24 hour interval was used in Experiment 2. The results were similar in both experiments. For the 1-60-1 group, there was a steady increase in the intensity required to elicit a convulsion shown with 60-Hz current from EtI1 to ETI4. However, the 24 hour interval produced a lesser effect than did 3 hour interval (or the 1 hour interval used in previous experiments). Rats in the other groups maintained relatively stable values from ETI1 to ETI1, with a slight decline occurring. Suppression of convulsive behaviour on daily trials was present with the 1-60-1 groups, and nonexistent with the other groups.

Interference effect of 3 Hz brain stimulation on kindling behavior induced by 60 Hz stimulation.

Experiments were conducted to evaluate the effect of 3 Hz brain stimulation on kindling behavior induced by 60 Hz sine waves stimulation. In Experiment 1, 12 rats were subjected to 40 or 60 convulsion trials with 60 Hz stimulation and then given 36 trials of 3 Hz stimulation. When these rats were stimulated again with 60 Hz sine wave current at the same brain site, none of the rats showed a convulsion in nine test trials. The intensity of stimulation had to be increased on test trial 10 to elicit convulsions for each rat. Of 10 rats in two control groups, only 1 did not convulse during the nine test trials. In Experiment 2 the effective threshold intensity (ETI) to elicit a convulsion was determined on five separate occasions with 10 days of daily trials between determinations. On each day experimental rats were stimulated with 3 Hz current on the first and third trials and with 60 Hz current on the second trial (3-60-3 group). A steady increase in the intensity required to elicit a convulsion with 60 Hz current from ETI1 to ETI5 resulted. Rats stimulated only with 60 Hz sine waves on the second trial each day (X-60-X grou,) maintained relatively stable values from ETI1 to ETI5. In the four, 10-day blocks of trials, convulsions were suppressed in 20% to 80% of the trials over the 10 day period for the 3-60-3 group, with the greatest effect occurring after about 4 days of stimulation. This suppressive effect was prominent both with rats that were at the convulsion stage prior to the first application of 3 Hz stimulation and with rats that were at preconvulsion stages. In Experiment 3 the permanency of the suppressive effect was evaluated. Eight suppressed rats from the experimental group in Experiment 2 and 4 control rats were stimulated for 90 trials over 30 days with 60 Hz current, and ETI values were determined after each set of six trials. Four of the 8 experimental rats were convulsing at ETI1 within 20 days.