Dose response relation for optic nerve atrophy at low-dose rate brachytherapy of uveal melanoma

Dose-response relationships for optic neuropathy and optic nerve atrophy after brachytherapy for posterior uveal melanoma were poorly defined from previous studies. Here, the outcome differences were analyzed in dependence on dosimetric factors, the applicator type, and tumor dependent variables.

Primary objective was to evaluate the association of applied dose and on-set of optic nerve atrophy after brachytherapy for posterior uveal melanoma in order to allow risk estimation for new patients.

This retrospective study was performed at a single high volume centre for ocular oncology. Patients receiving brachytherapy with Ruthenium-106 applicators for posterior uveal melanoma with a maximum distance between optic nerve and the nearest tumor margin of 4 optical disc diameters and follow-up with fundus photographs were included. The dose distribution at the optic nerve was reconstructed from the fundus photographs at latest follow-up and the dose-distribution of the applicator using a dedicated software. A first mask with important structural elements such as optic nerve, macula, tumor and vessels was first superimposed on the fundus photograph and adapted to the real contours. In a second step, an applicator contour mask was adapted to the radiation scar in order to calculate the dose distribution in all structures. Dose-response relations were obtained by weighted logistic regression.

The maximum dose at the optic disc (OD_max) in this group of 109 patients ranged from 5.8 Gy - 242.2 Gy, median 48.7 Gy. Optic nerve atrophy was observed in 29patients. Median time to radiation induced optic nerve atrophy was 18months. Using weighted logistic regression, the dependence of optic nerve atrophy on OD_max was significant (p = 0.0001, chi²-test). There was a considerable interobserver variability in OD_max values (p < 0.02, signed rank test). An additional factor influencing the dose-response was the applicator type (p = 0.0315, chi²-test). The OD_max for a probability of optic nerve atrophy of 50 % (ED50) were 77.6 Gy ± 7.0 Gy for patients treated with notched COB applicators and 53.2 Gy ± 8.2 Gy for patients with other applicators. Including the applicator type, the area under ROC curve reached a value of 0.857 (95 %-CI: 0.793-0.921) for the logistic model with OD_max. The ED50 for optic nerve neuropathy, classified as grade ≥ 1 toxicity, was estimated to be 46.9 Gy ± 4.1 Gy for the maximum dose at the optic disc.

Significant dose-response curves were found for optic nerve atrophy at low dose rate brachytherapy. A standard position of COB applicators was identified that allows estimation of the dose-response relation from the scleral dose of the applicator for risk estimation without fundus photographs. This larger data set enhances the knowledge of dose-response relationships for irradiation near the optic nerve.