Computer simulation of cytotoxic and vascular effects of radiosurgery in solid and necrotic brain metastases

Purpose: Solid and necrotic brain tumors respond to radiosurgery, although necrotic lesions often contain a significant proportion of hypoxic cells wh ich cannot become reoxygenated during the short overall treatment time of s ingle dose application. In addition to the direct cytotoxic action, delayed vascular occlusion followed by ischemic tumor cell death could contribute to the effect of radiosurgery. Materials and methods: In order to determine the impact of the two possible effects on tumor response, a 3-dimensional computer simulation was develop ed and fitted to response data obtained from 90 patients who were treated b y LINAC radiosurgery for 1-3 brain metastases with median marginal doses of 20 Gy, Complete response rates were as follows: small, solid lesions (diam eter 0.4-1 cm), 52% (12/23); large solid lesions (1.1-5.2 cm), 28% (17/60); large necrotic lesions, 12% (6/50). The 3-dimensional computer model simul ated the growth of small, solid, and large, solid or necrotic tumors situat ed in a vascularized stroma. Oxygen supply, tumor cell division (cell cycle time 5 days), neovascularization. tumor cell kill by single dose irradiati on (linear-quadratic model, alpha/beta = 10 Gy: oxygen enhancement ratio 3. 0) and time-dependent vascular occlusion (alpha/beta = 3 Gy) were modeled b y Monte-Carlo simulation techniques. Results: In the presence of neovascularization, solid tumors with a hypoxic fraction of 1-2% developed, Without neoangiogenesis, central necrosis occu rred, and tumors had a hypoxic fraction of 20-25%. Assuming a pure cytotoxi c effect of radiosurgery, neither the dose-response relationship for the so lid lesions of different size nor that for the large lesions with solid or necrotic appearance could be reproduced for any given level of radiosensiti vity. This was only possible by introducing a vascular effect that led to t he occlusion of greater than or equal to 99% of the vessels at the border o f the target volume within 1 year after irradiation. In the presence of the vascular effect, the apparent radiosensitivity of the tumor cells was incr eased by 50-100%. Calculations of the dose-equivalent for the Vascular effe ct show that it contributes 19-33% of the overall effect of single dose rad iosurgery. Conclusion: This simulation study suggests that the therapeutic effect of s ingle radiosurgery in malignant brain tumors cannot be understood without t he consideration of vascular effects. The computer model might serve as a b asis far exploring new treatment modalities that modify both cytotoxic and vascular effects of radiosurgery. Published by Elsevier Science Ireland Ltd .