Improved effectiveness of stereotactic radiosurgery in large brain metastases by individualized isotoxic dose prescription: an in silico study

INTRODUCTION: In large brain metastases (BM) with a diameter of more than 2 cm there is an increased risk of radionecrosis (RN) with standard stereotactic radiosurgery (SRS) dose prescription, while the normal tissue constraint is exceeded. The tumor control probability (TCP) with a single dose of 15 Gy is only 42%. This in silico study tests the hypothesis that isotoxic dose prescription (IDP) can increase the therapeutic ratio (TCP/Risk of RN) of SRS in large BM. MATERIALS AND METHODS: A treatment-planning study with 8 perfectly spherical and 46 clinically realistic gross tumor volumes (GTV) was conducted. The effects of GTV size (0.5–4 cm diameter), set-up margins (0, 1, and 2 mm), and beam arrangements (coplanar vs non-coplanar) on the predicted TCP using IDP were assessed. For single-, three-, and five-fraction IDP dose–volume constraints of V(12Gy) = 10 cm(3), V(19.2) (Gy) = 10 cm(3), and a V(20Gy) = 20 cm(3), respectively, were used to maintain a low risk of radionecrosis. RESULTS: In BM of 4 cm in diameter, the maximum achievable single-fraction IDP dose was 14 Gy compared to 15 Gy for standard SRS dose prescription, with respective TCPs of 32 and 42%. Fractionated SRS with IDP was needed to improve the TCP. For three- and five-fraction IDP, a maximum predicted TCP of 55 and 68% was achieved respectively (non-coplanar beams and a 1 mm GTV-PTV margin). CONCLUSIONS: Using three-fraction or five-fraction IDP the predicted TCP can be increased safely to 55 and 68%, respectively, in large BM with a diameter of 4 cm with a low risk of RN. Using IDP, the therapeutic ratio of SRS in large BM can be increased compared to current SRS dose prescription.