High-precision radiotherapy of motor deficits due to metastatic spinal cord compression (PRE-MODE): a multicenter phase 2 study

Abstract

BackgroundFor metastatic spinal cord compression (MSCC), conventional radiotherapy with 10 × 3 Gy in 2 weeks results in better local progression-free survival (LPFS) than 5 × 4 Gy in 1 week. Since patients with MSCC are often significantly impaired, an overall treatment time of 1 week would be preferable if resulting in similar outcomes as longer programs. This may be achieved with 5 × 5 Gy in 1 week, since the biologically effective dose is similar to 10 × 3 Gy. It can be expected that 5 × 5 Gy (like 10 × 3) Gy results in better LPFS than 5 × 4 Gy in 1 week.Methods/DesignThis phase 2 study investigates LPFS after high-precision RT with 5 × 5 Gy in 1 week. LPFS is defined as freedom from both progression of motor deficits during RT and new or progressive motor deficits dur to an in-field recurrence of MSCC following RT. Considering the tolerance dose of the spinal cord, 5 × 5 Gy can be safely administered with high-precision radiotherapy such as volumetric modulated arc therapy (VMAT) or stereotactic body radiotherapy (SBRT). Maximum dose to the spinal cord should not exceed 101.5% of the prescribed dose to keep the risk of radiation myelopathy below 0.03%. Primary endpoint is LPFS at 6 months following radiotherapy; secondary endpoints include motor function/ability to walk, sensory function, sphincter dysfunction, LPFS directly and 1 and 3 months following radiotherapy, overall survival, pain relief, quality of life and toxicity. Follow-up visits will be performed directly and at 1, 3 and 6 months following radiotherapy. After completion of this phase 2 study, patients will be compared to a historical control group receiving conventional radiotherapy with 5 × 4 Gy in 1 week. Forty-four patients will be included assuming 5 × 5 Gy will provide the same benefit in LPFS when compared to 5 × 4 Gy as reported for 10 × 3 Gy.DiscussionIf superiority regarding LPFS is shown for high-precision radiotherapy with 5 × 5 Gy when compared to conventional radiotherapy with 5 × 4 Gy, patients with MSCC would benefit from 5 × 5 Gy, since high LPFS rates could be achieved with 1 week of radiotherapy instead of 2 weeks (10 × 3 Gy).Trial registrationclinicaltrials.gov NCT03070431. Registered 27 February 2017.

Radiotherapy for metastatic spinal cord compression with increased radiation doses (RAMSES-01): a prospective multicenter study

“…Propensity score techniques will be applied to reduce confounding due to differences between the historical control group and prospective trial data [14]. The inclusion and exclusion criteria are almost identical to those of a previous trial investigating 5x5Gy of precision radiotherapy of MSCC [11]. Only the inclusion criteria are supplemented by favorable survival prognosis (defined as 36–45 points on a survival score) [1, 2].…”

“…This maximum dose is estimated to be associated with a risk of radiation-related myelopathy of < 0.2% [9]. Both the EQD2 of the prescribed dose (45.1Gy) and the EQD2 of the maximum dose (46.1Gy, α/β = 2.5Gy) are below the tolerance dose of bone of 52Gy [9, 11]. The mean doses (EQD2) for esophagus, heart and lung must be <34Gy, <26Gy and ≤ 7Gy [9].…”

“…However, this way of assessment was selected, since the primary endpoint LPFS included no progression of motor deficits during radiotherapy (=immediate response), which would ideally be assessed directly after the end of radiotherapy. Motor function will be evaluated with a 5-point scale [11, 18]. Sensory function will be assessed as absent, impaired or normal, sphincter dysfunction as yes or no [19].…”

“…It is estimated that 235 patients will qualify for the control group. To reduce the risk of hidden selection biases, a propensity score approach including 10 potential prognostic factors will be used for comparisons between the prospective cohort and the historical control group [7, 11].…”

“…Increase of the dose for MSCC is limited by the radiation tolerance of the spinal cord [9, 10]. With precision radiotherapy techniques such as volumetric modulated arc therapy (VMAT) and stereotactic body radiotherapy (SBRT), radiation doses can be further increased than with conventional radiotherapy [11].…”