352 - The Effect of Tumor Biological Effective Dose (BED) on Stereotactic Body Radiotherapy (SBRT) Outcomes for Locally Advanced Cholangiocarcinoma (CCA): An Analysis of the ABC-07 Randomized Trial

D. Brand^1,2, J. Valle³, H. Wasan⁴, M. Harrison⁵, H. Moremont⁶, P. Manoharan⁷, G. Radhakrishna⁷, D. Eaton⁸, T. Adedoyin⁹, K. M. Mak⁹, N. Hava⁹, S. Shelly⁹, M. Rashid⁹, A. Lopes⁹, J. Bridgewater¹⁰, and M. A. Hawkins^1,2; ¹Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom, ²Department of Radiotherapy, University College London Hospitals NHS Foundation Trust, London, United Kingdom, ³The Cholangiocarcinoma Foundation, Lehi, UT, ⁴Hammersmith Hospital, Imperial College, London, United Kingdom, ⁵Mount Vernon Centre for Cancer Treatment, Mount Vernon Hospital, Rickmansworth Road, Northwood, United Kingdom, ⁶AMMF - The Cholangiocarcinoma Charity, Essex, United Kingdom, ⁷The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom, ⁸RTTQA Group, London, United Kingdom, ⁹Cancer Research UK & UCL Cancer Trials Centre, London, United Kingdom, ¹⁰University College London Cancer Institute, London, United Kingdom

Purpose/Objective(s): 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. Materials/

Methods: 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 (a/ß=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.
Results: 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).
Conclusion: 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).