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

• Sponsor: University Hospital Schleswig-Holstein (Other)
• Overall Status: Completed
• CT.gov ID: NCT03070431
• Collaborator: (none)
• Enrollment: 44
• Location: 1
• Arm: 1
• Actual Duration (Months): 25.4
• Patients Per Site Per Month: 1.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Spinal Cord Compression Due to Metastasis to Spine	Radiation: High-precision RT 5x5 Gy in 1 week	N/A

Detailed Description

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.

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.

Patient Registration:

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:

• A sample size of at least 40 eligible patients is needed to estimate the probability of

LPFS at 6 month with adequate precision, based on the following assumptions:

• 6-month LPFS can be assumed to be 87%

• 6-month LPFS is to be estimated with a precision of plus/minus 20 percentage points expressed as the half length of the associated two-sided confidence interval with a confidence coefficient of 95%.

• The power -i.e. the probability to obtain this precision, should be at least 80%

• Confidence limits are used as the approach for sample size. Assuming that roughly 10% of enrolled patients will not be eligible for efficacy analysis due to early lost-to-follow-up or due to premature discontinuation of high-precision RT, a total of 44 patients should be enrolled in the prospective part of the trial.

• The aim of the confirmatory study is to compare the prospectively collected data with a historical, propensity-score matched cohort collected up to the time of data analysis. Assuming for simplicity and conservative power calculation that this comparison could be conducted with a simple Pearson-Chi-Square test using a two-sided significance level of 5% (10%), a power of 79% (86%) is reached, if 40 patients are treated with high-precision RT and roughly 400 patients of the historical control group qualify for Propensity-Score adjusted comparison and assuming that the expected 6-month LPFS are 87% and 67%, respectively. Taking into account that the more sophisticated propensity-score adjusted statistical analysis will increase statistical power, the power for treatment arm comparison reached with 40 eligible patients in the prospective part of the study can be assumed to be at least 80%.

Primary endpoint:

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).

Secondary endpoints:

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 Design

• Study Type: Interventional
• Actual Enrollment: 44 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Single arm studySingle arm study
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: High-precision Radiotherapy of Motor Deficits Due to Metastatic Spinal Cord Compression
• Actual Study Start Date: Jan 15, 2017
• Actual Primary Completion Date: Feb 28, 2019
• Actual Study Completion Date: Feb 28, 2019

Arms and Interventions

Arm	Intervention/Treatment
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.	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

Outcome Measures

Primary Outcome Measures

1. 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 [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.

Secondary Outcome Measures

1. Number of Participants Showing Improvement of Motor Deficits Following Radiotherapy (Best Response) [up to 6 months following radiotherapy]

   Motor function was evaluated using the following scale. Improvement of motor function was defined as a decrease of at least 1 point. 0 = Normal strength = Ambulatory without aid = Ambulatory with aid = Not ambulatory = Complete paraplegia [Tomita T, et al., Acta Radiol Oncol 1983;22:135-143.]

2. Number of Participants Showing Improvement of Sensory Function Following Radiotherapy (Best Response) [up to 6 months following radiotherapy]

   Sensory function was evaluated with the following scale, modified in accordance to the classification of the American Spinal Injury Association. 0 = Absent = Impaired = Normal 9 = Cannot be assessed [Baskin DS. Spinal cord injury. In Evans RW (Ed.), Neurology and trauma, WB Saunders, Philadelphia;1996, pp. 276-299.]

3. Number of Participants Showing Improvement of Sphincter Dysfunction Following Radiotherapy (Best Response) [up to 6 months following radiotherapy]

   Sphincter dysfunction was rates as yes (presence of sphincter dysfunction) or no (absence of sphincter dysfunction).

4. Number of Participants Who Were Alive at 3 Months Following Radiotherapy Without Deterioration of Motor Function During (or Directly Following) Radiotherapy and Freedom From In-field Recurrence of Metastatic Spinal Cord Compression Following Radiotherapy [3 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. The values of 3-month LPFS were estimated using the Kaplan-Meier method.

5. Number of Participants Who Were Alive at 6 Months Following Radiotherapy [6 months after the end of radiotherapy]

   Overall Survival (OS) was defined as freedom from death of any cause. Time to death 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 OS were estimated using the Kaplan-Meier method.

6. Number of Participants Who Experienced Relief of Pain at 1 Month Following Radiotherapy Compared to Baseline [Evaluation at 1 month following radiotherapy]

   Vertebral pain was measured with a numeric self-rating scale ranging from 0 (no pain) to 10 (worst pain). Pain relief was defined as improvement (=decrease of pain) by at least 2 points without increase of analgesics. Patients with baseline-scores of 0-1 points were not included, since improvement by 2 points was not possible.

7. Number of Participants Who Experienced Relief of Distress at 1 Month Following Radiotherapy Compared to Baseline [Evaluation at 1 month following radiotherapy]

   Distress (as an indicator of impairment of quality of life) was measured with the distress-thermometer. the patients rated their level of distress on a scale ranging from 0 (no distress) to 10 (extreme distress). Patients rated the distress they experienced during the last week and stated the reasons for distress from a list of items. An improvement (lower score) by 2 points was considered a clinically relevant relief of distress. Patients with baseline-scores of 0-1 points were not included, since improvement by 2 points was not possible.

8. Number of Participants Experiencing at Least One Grade >=2 Radiotherapy-related Toxicity [during radiotherapy and up to 6 months following radiotherapy]

   Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) (version 4)

9. Number of Participants Who Were Able to Walk Following Radiotherapy [up to 6 months following radiotherapy]

   Ambulatory status was assessed using the following scoring system: 0=Normal strength Ambulatory without aid Ambulatory with aid Not ambulatory A patient with a score equal to or less than 2 is considered "able to walk". Both participants that could and could not walk prior to radiotherapy have been included in this assessment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Motor deficits of the lower extremities resulting from MSCC, which have persisted for no longer than 30 days

• Confirmation of diagnosis by magnetic resonance (MR) imaging (computed tomography (CT) allowed)

• Age 18 years or older

• Written informed consent

• Capacity of the patient to contract

Exclusion Criteria:

• Previous RT or surgery of the spinal areas affected MSCC

• Symptomatic brain tumor or symptomatic brain metastases

• Metastases of the cervical spine only

• Other severe neurological disorders

• Pregnancy, lactation period

• Indication for decompressive surgery of affected spinal areas

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Radiation Oncology, University of Lübeck and University Medical Center Schleswig-Holstein, Ratzeburger Allee 160, 23562 Lübeck, Germany	Lubeck Hansestadt		Germany	23562

Sponsors and Collaborators

• University Hospital Schleswig-Holstein

Investigators

• Principal Investigator: Dirk Rades, Professor, Radiation Oncology, University of Lübeck, Lübeck, Germany

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - May 6, 2019

More Information

Publications

None provided.

• Responsible Party: Prof. Dirk Rades, MD, Professor Dr. med., University Hospital Schleswig-Holstein
• ClinicalTrials.gov Identifier: NCT03070431
• Other Study ID Numbers: PRE-MODE
• First Posted: Mar 3, 2017
• Last Update Posted: Mar 3, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Prof. Dirk Rades, MD, Professor Dr. med., University Hospital Schleswig-Holstein: spinal cord compression, radiotherapy
• Additional relevant MeSH terms: Spinal Cord Compression

Study Results

Participant Flow

Arm/Group Title	High-precision RT 5x5 Gy in 1 Week
Arm/Group Description	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. 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
Period Title: Overall Study
STARTED	44
COMPLETED	40
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	High-precision RT 5x5 Gy in 1 Week
Arm/Group Description	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. 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
Overall Participants	44
Age, Customized (Count of Participants)
<=65 years	30 68.2%
>=66 years	14 31.8%
Sex: Female, Male (Count of Participants)
Female	16 36.4%
Male	28 63.6%
Race/Ethnicity, Customized (Count of Participants)
caucasian	44 100%
other	0 0%
Region of Enrollment (Count of Participants)
Germany	20 45.5%
Spain	12 27.3%
Slovenia	9 20.5%
Georgia	3 6.8%
primary tumor type (Count of Participants)
breast cancer	9 20.5%
prostate cancer	3 6.8%
myeloma/lymphoma	5 11.4%
lung cancer	13 29.5%
other tumors	14 31.8%
interval from tumor diagnosis to MSCC (Count of Participants)
<=15 months	23 52.3%
>15 months	21 47.7%
number of involved vertebrae (Count of Participants)
1-2	30 68.2%
>=3	14 31.8%
other bone metastases (Count of Participants)
no	10 22.7%
yes	34 77.3%
visceral metastases (Count of Participants)
no	16 36.4%
yes	28 63.6%
time developing motor deficits (Count of Participants)
1-7 days	14 31.8%
8-14 days	10 22.7%
>14 days	20 45.5%
ambulatory status (Count of Participants)
not ambulatory	18 40.9%
ambulatory	26 59.1%
Eastern Cooperative Oncology Group performance score (Count of Participants)
ECOG 1-2	20 45.5%
ECOG 3-4	24 54.5%
motor function (Count of Participants)
ambulatory without aid	15 34.1%
ambulatory with aid	12 27.3%
not ambulatory	15 34.1%
complete paraplegia	2 4.5%
sensory function (Count of Participants)
absent	0 0%
impaired	17 38.6%
normal	23 52.3%
unclear	4 9.1%
sphincter dysfunction (Count of Participants)
no	37 84.1%
yes	6 13.6%
unclear	1 2.3%
Distress (measured with the distress-thermometer) (Count of Participants)
0-1 points	1 2.3%
2-4 points	11 25%
5-7 points	15 34.1%
8-10 points	16 36.4%
not available	1 2.3%
Pain (measured with a numeric self-rating scale) (Count of Participants)
0-1 points	8 18.2%
2-4 points	11 25%
5-7 points	14 31.8%
8-10 points	11 25%

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	6 months after the end of radiotherapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High-precision Radiotherapy 5x5 Gy in 1 Week
Arm/Group Description	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. High-precision radiotherapy 5x5 Gy in 1 week: Patients included in this study will receive a high-precision radiotherapy with 5x5 Gy in 1 week
Measure Participants	40
Number (95% Confidence Interval) [percentage of participants]	95.0 215.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	High-precision Radiotherapy 5x5 Gy in 1 Week
	Comments	historical control group treated with 5 x 4 Gy
	Type of Statistical Test	Superiority
	Comments	It was assumed that radiotherapy with 5x4 Gy results in 6-month LPFS of 67% and an increase by 20% is clinically relevant when using 5x5 Gy. For comparison of 5x5 Gy and a historical control (5x4 Gy), it was assumed that it can be performed with a simple Pearson-Chi-Square test (2-sided significance level of 5%, power of 79%) if 40 patients treated with 5x5 Gy and 400 patients of the control group qualified for Propensity-Score adjusted comparison, assuming 6-month LPFS rates of 87% and 67%.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	20
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		In a prospective study, 6-month LPFS rates were 86% after longer-course (mainly 3Gyx10) and 67% after short-course radiotherapy (mainly 4Gyx5) [Rades D, et al., Int J Radiat Oncol Biol Phys 2009;73:228-34.]. For sample size calculations, it was assumed that conventional radiotherapy with 4Gyx5 results in 6-month LPFS of 67% and that an increase by 20% is clinically relevant and realistic with 5Gyx5. A sample size of 40 eligible patients was required for the phase 2 trial assuming that that 6-month LPFS would be 87% and estimated with a precision of +/-20% expressed as the half length of the associated two-sided confidence interval (95%), and power of >=80%. For comparison of phase 2 cohort and historical control group, it was assumed that this could be performed with a simple Pearson-Chi-Square test using a two-sided significance level of 5% (10%) and a power of 79% (86%) if 40 patients received 5Gyx5 and N=400 of the control group qualified for Propensity-Score adjusted comparison.

2. Secondary Outcome

Title	Number of Participants Showing Improvement of Motor Deficits Following Radiotherapy (Best Response)
Description	Motor function was evaluated using the following scale. Improvement of motor function was defined as a decrease of at least 1 point. 0 = Normal strength = Ambulatory without aid = Ambulatory with aid = Not ambulatory = Complete paraplegia [Tomita T, et al., Acta Radiol Oncol 1983;22:135-143.]
Time Frame	up to 6 months following radiotherapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High-precision RT 5x5 Gy in 1 Week
Arm/Group Description	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. 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
Measure Participants	40
improvement of motor function	24 54.5%
no improvement of motor deficits	16 36.4%

3. Secondary Outcome

Title	Number of Participants Showing Improvement of Sensory Function Following Radiotherapy (Best Response)
Description	Sensory function was evaluated with the following scale, modified in accordance to the classification of the American Spinal Injury Association. 0 = Absent = Impaired = Normal 9 = Cannot be assessed [Baskin DS. Spinal cord injury. In Evans RW (Ed.), Neurology and trauma, WB Saunders, Philadelphia;1996, pp. 276-299.]
Time Frame	up to 6 months following radiotherapy

Outcome Measure Data

Analysis Population Description

Patients who had sensory deficits prior to the start of radiotherapy.

Arm/Group Title	Patients With Sensory Deficits at Baseline
Arm/Group Description	Patients who had sensory deficits prior to the start of radiotherapy.
Measure Participants	16
improvement of sensory deficits	8 18.2%
no improvement of sensory deficits	8 18.2%

4. Secondary Outcome

Title	Number of Participants Showing Improvement of Sphincter Dysfunction Following Radiotherapy (Best Response)
Description	Sphincter dysfunction was rates as yes (presence of sphincter dysfunction) or no (absence of sphincter dysfunction).
Time Frame	up to 6 months following radiotherapy

Outcome Measure Data

Analysis Population Description

Patients who had a sphincter dysfunction prior to the start of radiotherapy.

Arm/Group Title	Patients With Sphincter Dysfunction at Baseline
Arm/Group Description	Patients who had a sphincter dysfunction prior to the start of radiotherapy.
Measure Participants	6
improvement	2 4.5%
no improvement	2 4.5%
post-treatment assessment not available	2 4.5%

5. Secondary Outcome

Title	Number of Participants Who Were Alive at 3 Months Following Radiotherapy Without Deterioration of Motor Function During (or Directly Following) Radiotherapy and Freedom From In-field Recurrence of Metastatic Spinal Cord Compression Following Radiotherapy
Description	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. The values of 3-month LPFS were estimated using the Kaplan-Meier method.
Time Frame	3 months after the end of radiotherapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High-precision RT 5x5 Gy in 1 Week
Arm/Group Description	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. 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
Measure Participants	40
Number (95% Confidence Interval) [percentage of participants]	95 215.9%

6. Secondary Outcome

Title	Number of Participants Who Were Alive at 6 Months Following Radiotherapy
Description	Overall Survival (OS) was defined as freedom from death of any cause. Time to death 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 OS were estimated using the Kaplan-Meier method.
Time Frame	6 months after the end of radiotherapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High-precision RT 5x5 Gy in 1 Week
Arm/Group Description	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. 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
Measure Participants	40
Number (95% Confidence Interval) [percentage of participants]	45.0 102.3%

7. Secondary Outcome

Title	Number of Participants Who Experienced Relief of Pain at 1 Month Following Radiotherapy Compared to Baseline
Description	Vertebral pain was measured with a numeric self-rating scale ranging from 0 (no pain) to 10 (worst pain). Pain relief was defined as improvement (=decrease of pain) by at least 2 points without increase of analgesics. Patients with baseline-scores of 0-1 points were not included, since improvement by 2 points was not possible.
Time Frame	Evaluation at 1 month following radiotherapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With a Pain Score of >1 at Baseline
Arm/Group Description	Patients who had a pain score of >1 prior to the start of RT and were evaluable for pain relief at 1 month following RT.
Measure Participants	21
pain relief	13 29.5%
no pain relief	8 18.2%

8. Secondary Outcome

Title	Number of Participants Who Experienced Relief of Distress at 1 Month Following Radiotherapy Compared to Baseline
Description	Distress (as an indicator of impairment of quality of life) was measured with the distress-thermometer. the patients rated their level of distress on a scale ranging from 0 (no distress) to 10 (extreme distress). Patients rated the distress they experienced during the last week and stated the reasons for distress from a list of items. An improvement (lower score) by 2 points was considered a clinically relevant relief of distress. Patients with baseline-scores of 0-1 points were not included, since improvement by 2 points was not possible.
Time Frame	Evaluation at 1 month following radiotherapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients With a Distress Score of >1 at Baseline
Arm/Group Description	Patients who had a distress score of >1 prior to the start of RT and were evaluable for relief of distress at 1 month following RT.
Measure Participants	24
relief of distress	13 29.5%
no relief of distress	11 25%

9. Secondary Outcome

Title	Number of Participants Experiencing at Least One Grade >=2 Radiotherapy-related Toxicity
Description	Toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) (version 4)
Time Frame	during radiotherapy and up to 6 months following radiotherapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High-precision RT 5x5 Gy in 1 Week
Arm/Group Description	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. 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
Measure Participants	40
toxicity	4 9.1%
no toxicity	36 81.8%
toxicity	1 2.3%
no toxicity	39 88.6%

10. Secondary Outcome

Title	Number of Participants Who Were Able to Walk Following Radiotherapy
Description	Ambulatory status was assessed using the following scoring system: 0=Normal strength Ambulatory without aid Ambulatory with aid Not ambulatory A patient with a score equal to or less than 2 is considered "able to walk". Both participants that could and could not walk prior to radiotherapy have been included in this assessment.
Time Frame	up to 6 months following radiotherapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High-precision RT 5x5 Gy in 1 Week
Arm/Group Description	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. 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
Measure Participants	40
able to walk following radiotherapy	33 75%
not able to walk following radiotherapy	7 15.9%

Adverse Events

Time Frame	during the period of radiotherapy and up to 6 months during the period of follow up
Arm/Group Title	High-precision RT 5x5 Gy in 1 Week
Arm/Group Description	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. 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
All Cause Mortality
	High-precision RT 5x5 Gy in 1 Week
	Affected / at Risk (%)	# Events
Total	22/40 (55%)
Serious Adverse Events
	High-precision RT 5x5 Gy in 1 Week
	Affected / at Risk (%)	# Events
Total	5/40 (12.5%)
Cardiac disorders
Heart failiure	1/40 (2.5%)	1
Infections and infestations
Systemic aspergillosis	1/40 (2.5%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonia	1/40 (2.5%)	1
Unknown death (shortness of breath)	1/40 (2.5%)	1
Vascular disorders
Pulmonary embolism	1/40 (2.5%)	1
Other (Not Including Serious) Adverse Events
	High-precision RT 5x5 Gy in 1 Week
	Affected / at Risk (%)	# Events
Total	10/40 (25%)
Gastrointestinal disorders
Nausea	10/40 (25%)	17
Diarrhea	7/40 (17.5%)	13
General disorders
Fatigue	2/40 (5%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.