An Analysis on Local Control of Chemoradiation Therapy for Locally Advanced Pancreatic Cancer Using a Biophysical Model

Abstract

Chemoradiotherapy (CRT) has played a key role in the treatment of unresectable locally advanced pancreatic cancer (LAPC). This work aims to analyze published clinical data on CRT for LAPC and to estimate a set of plausible radiosensitivity parameters that may be used to help design new radiation treatment schemes. A thorough literature search from 1996 to 2016 yielded a total of 51 clinical studies on CRT for LAPC using different radiation fractionation regimens ranging from conventional fractionation to stereotactic body radiotherapy (SBRT). Among these studies, 38 (total # of patients: 1270) reported tumor control data. These 38 studies were categorized into 5 groups in this analysis: (1) 12 SBRT studies (RT fraction dose d ≥ 3 Gy) with gemcitabine (GEM) based chemotherapy ; (2) 9 conventional RT fractionation (1.8 Gy ≤ d < 3 Gy) studies with GEM; (3) 11 conventional RT fractionation (1.8 Gy ≤ d < 3 Gy) studies with 5-FU or other agents based chemotherapy; (4) 3 RT alone studies; and (5) 3 Carbon-ion RT studies. A modified linear-quadratic tumor control probability model (mLQ-TCP) that considers Poisson TCP model, RT fractionation dependent biologically effective dose (BED), and tumor repopulation, was used to fit the TCP data reported in the selected studies. The mLQ-TCP model includes 4 radiobiologic parameters: α, α/β, the tumor doubling time Td, the initial tumor clonogenic cell number N0. A chemotherapy factor (fc) is used to account for the combined effect of chemotherapy on BED. In addition, radiosensitivity parameter α is assumed to have a Gaussian distribution (σα) to account for the inhomogeneity of tumor radiosensitivity that may be correlated with the tumor histopathological grades. A large spread of TCP as a function of BED was observed. For the SBRT group, there is clear correlation between TCP and BED, which can be fitted by the mLQ-TCP model with the fitting parameters as: α = 0.29 Gy-1, σα = 0.12, Td = 42 days, N0 = 1.44 x 107, fc = 1.40 with fixed parameters of α/β = 10 Gy. The goodness of this fit was χ2/dof = 2.3. By varying α and σα and keeping the other parameters fixed, we obtained the upper and lower TCP-BED limit curves, with α = 0.24 Gy-1, σα = 0.12 for lower limit and α = 0.32 Gy-1, σα = 0.04 for the upper limit. These ranges of α and σα parameters are consistent with those reported for different tumor grades. According to the model calculation, 14.9 Gy and 10.9 Gy per fraction are needed to achieve 95% LC for a 3-fraction and 5-fraction SBRT, respectively. The tumor control rate is clearly related to radiation dose in SBRT for LAPC based on the clinical studies reported so far, which can be described by the mLQ-TCP model. A plausible set of radiosensitivity parameters along with their ranges were obtained, which may be used to help develop more effective fractionation schemes accounting for different pancreatic tumor grades.