| Summary: | 博士 === 國立臺灣大學 === 電機工程學研究所 === 93 === Radiotherapy has been one of the most important treatment modalities in cancer patients. The scientific method to estimate the risk of radiation-induced organ complication is using the dose-volume data from the computerized treatment planning system to perform calculations with certain thresholds and criteria. The current commonly used dosimetric parameters have the defects of non-volumetric criteria and the lack of volume effect integrated into the radiation-related organ damage. Normal tissue complication probability (NTCP) model has been proposed as a more comprehensive way to calculate the risk of complication by the use of the serial dose-volume data with a few parameters to weigh the risk between low-dose and high-dose damage. In our past patients with radiation-induced liver disease (RILD) after three-dimensional conformal radiotherapy (3DCRT), we found that the NTCP was more useful than the conventionally used parameters. However, the risk of RILD in Taiwan seemed underestimated with the NTCP model parameters developed in the Unites States. This means the tolerance of liver to radiation for patients in Taiwan different from the patients’ tolerance in the western countries, and the indication of generating the unique model parameters based on the biological features of RILD in Taiwanese patients.
Our first step was to establish the biology-integrated NTCP in the two different databases, 89 patients with hepatocellular carcinoma (HCC) and 62 patients with gastric carcinoma (GC) undergoing 3DCRT. Hepatitis B viral (HBV) carriers have been the unique feature of Taiwanese patients in their liver tolerance as compared to the western countries. We first used the three-parameter Lyman NTCP model to recalculate the NTCP of RILD in 89 HCC patients by their original dose-volume data retrieved from the conformal design of 3DCRT. Logistic regression was used for significant factors of RILD. Maximal likelihood analysis was conducted to obtain the best estimates of NTCP model parameters based on the true occurrence of RILD in 17 of 89 HCC patients. In multivariate analysis, HBV carrier remained statistically significant as the susceptible factor to RILD. The best estimates of NTCP parameters (n, m, TD50(1)) were 0.35, 0.39, and 49.4 Gy. The parameters specifically estimated from HBV carriers were 0.26, 0.40, and 50.0 Gy, as compared to 0.86, 0.31, and 46.1 Gy for non-carrier patients. The main difference in volume effect parameter (n) between the two subgroups indicated the impact of this biological factor (HBV carrier) on modeling NTCP. The second step was to apply the Lyman NTCP model in 62 GC patients. HBV carrier status was the only independent factor associated with RILD. The parameters (n, m, TD50(1)) specifically estimated from HBV carriers were 0.11, 6.88, and 20.5 Gy, as compared to 1.99, 0.09, and 21.5 Gy for non-carrier patients. The difference in volume effect parameter similarly described the biological integration of HBV carrier into the NTCP model. The third step was to use the four-parameter parallel-architecture NTCP model, specifically designed for the organ with parallel feature like liver, in a combined group of 151 patients with either HCC or GC. HBV carrier was the only independent factor with statistically significant susceptibility to RILD in multivariate test. The NTCP model parameters, mean functional reserve (v50), width of functional reserve distribution ( ), dose at which half of liver subunits are damaged (d1/2), slope parameter for subunit dose response (k), were 0.54, 0.14, 50Gy, 0.13 (whole group); 0.53, 0.07, 50Gy, 4.6 10-7 (HBV carriers); 0.59, 0.12, 25Gy, 59.8 (non-HBV carriers), respectively. The main difference in slope parameter demonstrated the biological influence of HBV carrier on RILD. The threshold effect of fraction of liver damaged (f) became evident after integrating biological factor (HBV carrier) into the modeling process.
We concluded the effectiveness of the two NTCP models in RILD, and the unique importance of HBV carrier in estimating the two NTCP model parameters. It is emphasized that physical and mathematical NTCP methods should be cautiously used with appropriate integration of biological factors. The biology integrated NTCP models are extremely important for HBV carrier patients undergoing 3DCRT or the other new technology of radiotherapy to the liver. Such importance of biological factor in radiation-induced liver damage also implies the corresponding biological pathogenesis and warrants the ongoing basic cellular or molecular research on RILD.
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