Radiotherapy for Metastatic Spinal Cord Compression with Increased Doses: Final Results of the RAMSES-01 Trial

Abstract

To investigate the outcomes of precision-radiotherapy (RT) with 15 × 2.633 Gy (EQD2 = 41.6 Gy for tumor cell kill, α/β = 10 Gy) or 18 × 2.333 Gy (EQD2 = 43.2 Gy) in patients with metastatic spinal cord compression (MSCC) and favorable survival prognoses (>35 points on a validated survival score). In addition, these patients were compared to a historical control group of patients with favorable prognoses treated with 10 × 3 Gy (EQD2 = 32.5 Gy). In a multi-center phase 2 study (RAMSES-01), patients with MSCC and favorable survival prognoses receiving 15 × 2.633 Gy or 18 × 2.333 Gy of precision-RT alone (no upfront surgery) were mainly evaluated for local progression-free survival (LPFS), defined as no deterioration of motor function during RT and no in-field recurrence of MSCC following RT, at 12 months (primary endpoint). Secondary endpoints included improvement of motor and sensory functions, post-RT ambulatory status, relief of pain and distress, toxicity, and survival (OS). The maximum relative doses allowed to the spinal cord were 101.5 % of the prescribed dose for 18 × 2.333 Gy and 101.2% for 15 × 2.633 Gy, respectively (both representing an EQD2 of 46.6 Gy for myelopathy, α/β = 2 Gy). In addition, the RAMSES-cohort was compared to a historical control group (N = 266) irradiated with 10 × 3 Gy (propensity score adjusted Cox regression). In the RAMSES-cohort, 50 (of 62 planned) patients were evaluable for LPFS and included in the analyses. Since OS was worse than expected, a new survival score was developed, which was more precise in predicting OS than a previous tool. As a consequence, the RAMSES-trial, which was based on the previous score, was terminated. In the 50 patients included so far, 12-month rates of LPFS and OS were 97.6% and 69.9%, respectively. Improvement of motor function occurred in 28 patients (56.0%), and 47 patients (94.0%) were ambulatory following RT. Within 3 months following RT, 12 of 21 patients (57.2%) with pre-RT sensory deficits improved, 38 of 45 patients (84.4%) with pre-RT pain experienced at least partial relief, and 39 of 50 patients (78.0%) reported relief of distress. Ten of 50 patients (20.0%) experienced grade 2 toxicities (mainly esophagitis/dysphagia) and another two patients (4.0%) grade 3 toxicities (1 diarrhea, 1 esophagitis). After propensity score adjustment, the RAMSES-cohort showed significantly better LPFS than the control group (hazard ratio = 0.125, 95% confidence interval = 0.016 - 0.962, p = 0.046) and a strong trend regarding improvement of motor function (hazard ratio = 1.943, 95% confidence interval = 0.981 - 3.850, p = 0.057). Post-RT ambulatory rates (p = 0.56) and OS rates (p = 0.62) were not significantly different. Precision-RT with 15 × 2.633 Gy or 18 × 2.333 Gy was sufficiently well tolerated and resulted in significantly better long-term LPFS than 10 × 3 Gy in patients with MSCC and favorable survival prognoses. Thus, the dose-fractionation regimens of the RAMSES-01 trial appear preferable for these patients.