Assessment of pain relief and sensory dysfunction outcomes after CyberKnife radiosurgery for trigeminal neuralgia using detailed radiobiologic dose modeling: Results from a retrospective study on large international patient cohort

Introduction: To evaluate clinical outcomes and identify patient- and treatment-related predictors of pain relief onset, long-term pain control, and sensory dysfunction in patients with medically refractory trigeminal neuralgia (TN) treated with CyberKnife radiosurgery (CKRS), incorporating radiobiologic modeling of delivered doses. Methods: A retrospective study was performed across five international institutions, analyzing 560 TN patients treated with CKRS between 2009 and 2024. Demographic, clinical and dosimetric data were collected. Pain and sensory dysfunction outcomes were evaluated using the modified Barrow Neurological Institute Pain Intensity (mBNI-PIS) and Facial Numbness Scales (BNI-FNS), respectively. Logistic regression and Cox proportional hazards models were used to identify predictors of pain relief, latency, long-term pain control, and facial numbness risk. Biological effective dose (BED) distributions were calculated accounting for sublethal DNA damage repair and treatment delivery timelines; retreatments were excluded. Results: Pain relief (defined as BNI-PIS I-IIIa) was achieved in 92% of patients with a median latency of 12-weeks (range: 0 – 76 weeks). The median follow-up was 50 months (range: 6 – 175 months). Actuarial freedom-from-pain rates were 85%, 78%, 68% and 58% at 12-, 24-, 60- and 120-months, respectively. Bothersome and severely bothersome facial numbness occurred in 5% and 1% of patients, respectively, while an additional 21% experienced non-bothersome numbness. Multivariate analysis identified older age, higher target maximum dose and BED (>1607 Gy2.47) values, and shorter beam-on- and treatment-time as predictors of early pain relief (< 30-days), whereas neurovascular conflict (NVC) predicted delayed response. Older age and NVC were also associated with pain control maintenance. Multiple sclerosis predicted both reduced treatment response and increased pain recurrence risk. Maximum target dose of 77 Gy, and integral BED of 59 mJ2.47 (corresponding to a target volume of 47 mm3) were independently associated with a 10% hypoesthesia risk. Conclusion: CKRS provides high pain relief onset (92%) and durable pain control (68% at 60-months) in TN patients, with low bothersome (5%) and severely bothersome (1%) facial numbness rates. The identified dosimetric thresholds offer practical guidance for optimizing treatment planning while balancing hypoesthesia risk.