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Radiotherapy for CCA remains an area of research. ABC-07 [ISRCTN: 10639376] is a randomized trial (1:2 randomization) for newly diagnosed, inoperable, locally advanced CCA (n = 69), comparing 8 cycles of Gemcitabine/Cisplatin (GC) vs 6 cycles GC plus SBRT to the tumor (50 Gy in 5 fractions (Fr)). The primary endpoint of improving progression free survival was not met. Here, we examine the influence of BED, alongside patient and cancer variables, on disease outcomes. 45 patients were randomized to SBRT, of which 41 received SBRT. The protocol specified longer fractionation (67.5 Gy in 15 Fr) for larger tumors (>6cm, max 12cm) or inclusion of nodal disease. Reduced dose thresholds (45 Gy then 40 Gy in 5 Fr; 58.1 Gy then 45 Gy in 15 Fr) were specified to meet mean liver dose constraints. PTV D95% values (min dose (Gy) to 95% of planning target volume (PTV)) were extracted from DICOM plans and converted to BED (α/β = 10Gy) (termed PTV_D95%BED). Other predictor variables included were: age, performance status (PS), female sex, biliary stent in-situ, T-stage (3-4 vs 1-2), N-stage (1 vs 0), distal CCA (dCCA), PTV Volume (PTV_vol). PTV D95% association with overall survival (OS), progression free survival (PFS) and time to local progression (TLP) was initially tested by univariate Cox and visualized by Kaplan-Meier. Multivariate Cox models were fitted for each endpoint, fitting PTV_D95%BED and other predictor variables, using backward stepwise selection using p<0.2. For TLP, as all variables removed, p<0.3 was used instead. PTV volumes were median 65cc (range 21.5 – 498cc). PTV_D95%BED doses were median 72 Gy (IQR 57 – 100 Gy BED). Planned fractionation was 5 Fr (n = 30) or 15 Fr (n = 11). PTV volume vs PTV_D95%BED showed no correlation = -0.0003. By univariate Cox, PTV_D95%BED did not meet p<0.05 threshold against OS (HR 0.989, P = 0.36), PFS (HR 0.982, P = 0.068) or TLP (HR 0.980, P = 0.26). Multivariate model selected variables were: OS model: PS (HR 0.3, p 0.02), N-stage (HR 2.1, p 0.13), PTV_vol (HR 0.98, p 0.037); PFS model: D95%BED (HR 0.98, p 0.047), age (HR 0.96, p 0.054), PTV_vol (HR 0.997, p 0.17); Local progression model: D95%BED (HR 0.96, p 0.14), age (HR 0.94, p 0.18), dCCA (HR 0.27, p 0.25), T-stage3/4 (HR 2.5, p 0.24), PTV_vol (HR 0.995, p 0.21). We believe this phase II prospectively collected trial data shows a signal of dose effect in subsequent CCA outcomes. There appears to be no correlation with patient or cancer related variables. Models for prediction of tumor coverage should be incorporated into treatment pathway diagnostics; enabling selection of best candidates for SBRT. Better understanding of tumor biology would also aid in selecting patients where local control is more critical (i.e. lower metastatic propensity). [ABSTRACT FROM AUTHOR]

The FLASH effect, defined as normal tissue sparing while maintaining tumor control with ultra-high dose rate (UHDR) irradiation, has been demonstrated preclinically in different tumor sites and normal tissues. As we approach the next phase of clinical testing, optimizing a clinical study design is of paramount importance incorporating available preclinical data and considering technological constraints. The purpose of this study is to provide recommendations on the prerequisites, study design, and endpoints for next clinical trials that will explore the clinical potential of proton (p) FLASH. We hypothesized that consensus would be reached for the optimal patient population and other clinical and biological domains but not for the technical delivery of pFLASH. Delphi methodology was used to develop expert consensus. An international expert group was composed using predefined expertise criteria consisting of 21 clinicians, medical physicists and biologists, well balanced in professions and across Europe versus North America. Statements on preclinical and technical prerequisites and clinical trial design were scored on a 5-point Likert scale or as multiple choice in 2 online questionnaire rounds. To reach consensus, an agreement from at least 66% of the entire group was needed. Strong consensus required ≥80% agreement. Response rates were 100% in both questionnaire rounds. For the design of the next pFLASH trials, consensus was achieved that adult patients only should be included with a minimal expected overall survival of 1 year in a palliative setting or, preferably, with oligometastatic disease treated with ablation. It was strongly agreed that the FLASH effect should first be studied as a single treatment modality with toxicity reduction as primary endpoint. Consensus was that ex vivo experiments cannot substitute the need for in vivo data proving reduction of normal tissue toxicity and isoeffectiveness in tumor response before starting a clinical trial in a specific treatment site. Consensus was reached on the use of clinical target and organs at risk constraints, minimum pencil beam dose rates, dose rate optimization, accuracy and evaluation and quality assurance. No consensus was reached on use of single versus multiple beams, single versus multiple fractions and minimum fractionation dose. This Delphi study resulted in an international multidisciplinary expert consensus and recommendations on requirements for preclinical evidence, technical developments, quality assurance and study design for the next clinical trials investigating the clinical value of pFLASH. There is a need for additional data regarding fractionation and FLASH treatment planning. Results of this study can be used to develop a roadmap for future clinical trials. [ABSTRACT FROM AUTHOR]