High-precision Radiotherapy of Motor Deficits Due to Metastatic Spinal Cord Compression

This is a multinational, multicenter study (single arm) supplemented by a comparison to a historical, propensity score matched control group (superiority study).

A total of 44 patients (40 patients + 10% for potential drop-outs) who will receive modern high-precision radiotherapy (RT) treatment for the metastases on their vertebral bodies are planned to take part in the clinical study. The historical control group treated with 5x4 Gy of conventional RT between 2001 and 2016 consists of more than 500 patients The primary aim of this study is to investigate the local progression-free survival (LPFS) of metastatic spinal cord compression (MSCC) after 5x5 Gray (Gy) of high-precision RT and to demonstrate that this regimen results in significantly better 6-month LPFS than conventional RT with 5x4 Gy. For the high-precision RT volumetric modulated arc therapy (VMAT), stereotactic body radiotherapy (SBRT) is allowed for treatment of patients with involvement of only one vertebra, if the required constraints can be met. LPFS is defined as freedom from progression of motor deficits during RT and freedom from an in-field recurrence of MSCC (i.e. freedom from motor deficits due to a recurrence of MSCC in the previously irradiated parts of the spine) following RT. The LPFS rate will be assessed 6 months after the end of RT.

In patients treated with RT alone for MSCC, conventional RT with 10x3 Gy in 2 weeks results in similar motor function but significantly better LPFS than conventional RT with 5x4 Gy in 1 week. Since patients with MSCC are often significantly impaired, a RT regimen with an overall treatment time of only 1 week would be preferable if it resulted in similar LPFS as 10x3 Gy in 2 weeks. This may be achieved with 5x5 Gy in 1 week, since the equivalent dose in 2 Gy fractions (EQD2) with respect to tumor cell kill of 5x5 Gy and 10x3 Gy are similar. The tolerance dose of the spinal cord, 5x5 Gy can be safely administered with high-precision RT such as VMAT (or SBRT). Therefore, the present study investigates the LPFS after high-precision RT with 5x5 Gy in 1 week. To demonstrate superiority the patients of this study will be compared to a historical control group receiving conventional RT with 5x4 Gy in 1 week. If superiority regarding LPFS can be shown for high-precision RT with 5x5 Gy, patients with MSCC would benefit from this regimen, since they can achieve high LPFS rates with an RT regimen lasting only 1 week (5x5 Gy) instead of 2 weeks (10x3 Gy). This study aims to make a significant contribution to the most appropriate RT schedule for patients with MSCC.

In accordance with a previous study assessing local control of MSCC, the following patient characteristics will be recorded to allow adequate comparison with the historical, propensity-score matched control group:

• Age (2 groups, depending on median age)
• Gender
• Type of primary tumor (breast cancer vs. prostate cancer vs. myeloma/lymphoma vs. lung cancer vs. other tumors)
• Interval from tumor diagnosis to MSCC (≤15 months vs. >15 months)
• Number of involved vertebrae (1-2 vs. ≥3)
• Other bone metastases at the time of RT (no vs. yes)
• Visceral metastases at the time of RT (no vs. yes)
• Time developing motor deficits prior to RT (1-7 days vs. 8-14 days vs. >14 days)
• Ambulatory status prior to RT (no vs. yes)
• Eastern Cooperative Oncology Group (ECOG) performance score (1-2 vs. 3-4) Study arm: 5x5 Gy of high-precision RT in 1 week Historical control: 5x4 Gy of conventional RT in 1 week Follow-up directly and at 1, 3 and 6 months following RT RT is administered as high-precision RT with 25.0 Gy in 1 week, i.e. with 5.0 Gy per fraction on 5 days per week (representing an EQD2 of 43.8 Gy for radiation myelopathy). An EQD2 of 45 Gy is estimated to be associated with a risk of radiation-related myelopathy of 0.03% and is therefore considered safe. The clinical target volume (CTV) includes the vertebral and soft tissue tumor as seen on the planning computed tomography and diagnostic MR-imaging, the spinal canal, the width of the involved vertebrae, and half a vertebra above and below those vertebrae involved by MSCC. The planning target volume (PTV) should include the CTV plus 0.8 cm and should be covered by the 95%-isodose. The maximum relative dose allowed to the spinal cord is 101.5% of the prescribed dose (representing an EQD2 of 44.9 Gy for radiation myelopathy). This maximum dose is estimated to be associated with a risk of radiation-related of <0.03% and is, therefore, also considered safe. Both the EQD2 of the prescribed dose (41.7 Gy) and the EQD2 of the maximum dose (43.8 Gy) are well below the tolerance dose of bone. In accordance with the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) data, the mean doses EQD2 for esophagus, heart and lung must be <34 Gy, <26 Gy and ≤7 Gy, respectively. Taking into account a radiation regimen of five fractions, the corresponding mean doses per fraction are 4.5 Gy, 3.8 Gy and 1.54 Gy, respectively. MSCC may affect single or multiple spinal sites. All sites need to be treated with high-precision RT following the dose prescriptions and constraints given above.