High-precision Radiotherapy of Motor Deficits Due to Metastatic Spinal Cord Compression (PRE-MODE)
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|ClinicalTrials.gov Identifier: NCT03070431|
Recruitment Status : Completed
First Posted : March 3, 2017
Results First Posted : March 3, 2020
Last Update Posted : March 3, 2020
|First Submitted Date ICMJE||February 27, 2017|
|First Posted Date ICMJE||March 3, 2017|
|Results First Submitted Date ICMJE||January 30, 2020|
|Results First Posted Date ICMJE||March 3, 2020|
|Last Update Posted Date||March 3, 2020|
|Actual Study Start Date ICMJE||January 15, 2017|
|Actual Primary Completion Date||February 28, 2019 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Number of Participants Who Were Alive at 6 Months After Radiotherapy Without Deterioration of Motor Function During (or Directly After) Radiotherapy and Freedom From In-field Recurrence of Metastatic Spinal Cord Compression Following Radiotherapy [ Time Frame: 6 months after the end of radiotherapy ]
Local Progression Free Survival (LPFS) was defined as freedom from progression of motor deficits during or one month following radiotherapy and freedom from in-field recurrence of metastatic spinal cord compression (MSCC) following radiotherapy. An in-field recurrence was defined as a recurrence of MSCC associated with motor deficits in the region of the spinal cord that had been previously irradiated for MSCC. In case of clinical suspicion of sich a recurrence, a spinal MRI was performed to confirm the diagnosis. Time to in-field recurrence was calculated from the last day of radiotherapy, and the patients were followed for a maximum of 6 months after the end of radiotherapy. The values of 6-month LPFS were estimated using the Kaplan-Meier method.
|Original Primary Outcome Measures ICMJE
||Superiority in local progression-free survival at 6 months following radiotherapy [ Time Frame: 6 months after the end of radiotherapy ]
Local progression-free survival (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. LPFS time will be calculated from the last day of the radiotherapy treatment. LPFS will be regularly assessed clinically ( physical examination). In case of a suspected recurrence of MSCC (i.e. progression of existing or development of new motor deficits), a spinal MR-imaging will be performed to confirm or exclude an in-field recurrence of MSCC. In case of progression of existing or development of new motor deficits between two regular follow-up visits, spinal MR-imaging will be performed at any time. The number of MR-imaging sessions is minimized to clinically relevant situations, since patients with MSCC are often quite debilitated.
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||High-precision Radiotherapy of Motor Deficits Due to Metastatic Spinal Cord Compression|
|Official Title ICMJE||High-precision Radiotherapy of Motor Deficits Due to Metastatic Spinal Cord Compression|
|Brief Summary||The major goal of this clinical study is to investigate to which extent high-precision radiotherapy (RT) with modern techniques can prevent progression or recurrence of motor deficits (weakness) of the legs following RT. In addition, it will be evaluated to which extent RT can lead to improvement of motor function, ambulatory status, sensory function and sphincter dysfunction, to pain relief and to improvement in quality of life, side effects and overall survival. For this purpose 44 patients who will receive modern high-precision RT treatment for the metastases on their vertebral bodies will be included into this phase 2 study. The results of the high-precision RT with a treatment of 5x5 Gray (Gy) in 1 week will be compared to data of a historical control group. The data set of the historical control group consists of more than 500 patients who received conventional RT with 5x4 Gy. The data collected in 1 week treatment will be compared. It is intended to show superiority regarding the local progression-free survival (LPFS) for the high-precision RT when compared with the conventional RT.|
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:
It is recommended that the patients receive concomitant treatment with dexamethasone during the period of radiotherapy if indicated.
Quality assurance plan:
Monitoring: The Centre for Clinical Trials Lübeck will conduct clinical on-site monitoring at the German sites according to Good Clinical Practice and written standard operating procedures (SOPs) to ensure the patients' rights and safety as well as the reliability of trial results.
The frequency of monitoring visits per site will be defined depending on the recruitment rate and the quality of data.
The patients were assigned 2 code numbers, the number of the contributing center plus a patient identification number starting with 001 and chronologically ongoing.
Coordination and supervision of the inclusion of the patients will be performed by the Department of Radiation Oncology of the University of Lübeck, Germany.
Sample size calculation:
The primary goal of this study is to assess high-precision RT with 5x5 Gy in 1 week with respect to 6-month LPFS and to demonstrate that this rate is superior to conventional RT with 5x4 Gy with respect to LPFS of MSCC (hypothesis).
With respect to tumor cell kill, the EQD2 of 5x5 Gy is similar to the EQD2 of 10x3 Gy (31.3 Gy vs. 32.5 Gy) and higher than the EQD2 of 5x4 Gy (23.3 Gy) . In a previous prospective non-randomized study, the 6-month LPFS rates were 86% after longer-course RT and 67% after short-course RT, respectively (p=0.034). In that study, 95 of 117 patients (81%) in the longer-course RT group had received 10x3 Gy, and 91 of 114 patients (80%) in the short-course RT group had received 5x4 Gy. Thus, assuming - for the present study - that conventional RT with 5x4 Gy in fact results in a 6-month LPFS rate of 67%, an increase by roughly 20 percentage point is considered to be clinically minimal relevant and even appears to be realistic when applying high-precision RT with 5x5 Gy.
The sample size is chosen to obtain prospective data that can be interpreted on its own and to allow for comparison with historical data:
The primary endpoint (LPFS of MSCC) will be evaluated based on the sample size calculations. The evaluation will be performed in those patients, who are available for assessment of the primary endpoint and have received at least 80% of the planned RT dose. Due to the open nature of the study, a blind data review is not necessary. The safety population includes all patients who have received at least 1 fraction of high-precision RT.
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. Deterioration of motor deficits during RT will be counted as LPFS of 0 months. Freedom from an in-field recurrence following RT will be referenced from the last day of RT. LPFS rates will be calculated for each potential prognostic factor using the Kaplan-Meier method. Differences between the Kaplan-Meier curves will be calculated with the log-rank test (univariate analysis). Factors that achieve significance (p<0.05) or show a trend (p<0.06) on univariate analysis will be additionally included in a multivariate analysis (Cox proportional hazards model).
The comparison of the high-precision RT group and the conventional RT group with respect to their effect on motor function and sensory function (improvement, no further progression, deterioration) will be evaluated with the ordered logit model adjusted for propensity score, because the data for the impact of RT on motor and sensory function are ordinal (-1 = deterioration, 0 = no further progression, 1 = improvement). An improvement or deterioration of the motor function will be defined as a change of at least 1 point on a 5-point scale. Post-RT ambulatory and sphincter dysfunction rates will be compared between both groups with the Chi-square test stratified for propensity score. Effect of RT on motor function, post-RT ambulatory rates, sensory function and sphincter dysfunction will be evaluated directly after RT and at 1, 3 and 6 months following RT in those patients who are alive and available for assessment. P-values of <0.05 are considered significant.
Overall survival (OS) will be counted from the last day of RT. OS rates will be calculated with the Kaplan-Meier-method. Differences between Kaplan-Meier curves will be analyzed with the log-rank test. Again, p-values of <0.05 are considered significant. Factors that achieve significance or show a trend (p<0.06) on univariate analysis will be included in a multivariate analysis (Cox proportional hazards model). The analysis of OS will be conducted in the intent-to-treat population.
Data regarding pain, quality of life and toxicity will only be assessed in the study group.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
Single arm studyMasking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Spinal Cord Compression Due to Metastasis to Spine|
|Intervention ICMJE||Radiation: High-precision RT 5x5 Gy in 1 week
Patients included in this study will receive a high-precision radiotherapy with 5x5 Gy in 1 week
|Study Arms ICMJE||Experimental: High-precision RT 5x5 Gy in 1 week
Patients with motor deficits of the lower extremities due to metastatic spinal cord compression (MSCC) will receive 5x5 Gy of high-precision RT in 1 week.
Intervention: Radiation: High-precision RT 5x5 Gy in 1 week
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Actual Study Completion Date ICMJE||February 28, 2019|
|Actual Primary Completion Date||February 28, 2019 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Germany|
|Removed Location Countries|
|NCT Number ICMJE||NCT03070431|
|Other Study ID Numbers ICMJE||PRE-MODE|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Prof. Dirk Rades, MD, University Hospital Schleswig-Holstein|
|Study Sponsor ICMJE||University Hospital Schleswig-Holstein|
|Collaborators ICMJE||Not Provided|
|PRS Account||University Hospital Schleswig-Holstein|
|Verification Date||February 2020|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP