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

• ClinicalTrials.gov Identifier: NCT03070431
• Recruitment Status: Completed
• First Posted: March 3, 2017
• Results First Posted: March 3, 2020
• Last Update Posted: March 3, 2020
• Sponsor: University Hospital Schleswig-Holstein
• Information provided by (Responsible Party): Prof. Dirk Rades, MD, University Hospital Schleswig-Holstein

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Spinal Cord Compression Due to Metastasis to Spine
• Intervention: Radiation: High-precision RT 5x5 Gy in 1 week
• Enrollment: 44

Participant Flow

Recruitment Details
Pre-assignment Details

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
Reason Not Completed
Withdrawal by Subject	2
Lost to Follow-up	2

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 Number of Baseline Participants		44
Baseline Analysis Population Description		[Not Specified]
Age, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Age	Number Analyzed	44 participants
	<=65 years	30 68.2%
	>=66 years	14 31.8%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	Female	16 36.4%
	Male	28 63.6%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	caucasian	44 100.0%
	other	0 0.0%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	44 participants
Germany		20 45.5%
Spain		12 27.3%
Slovenia		9 20.5%
Georgia		3 6.8%
primary tumor type; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 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; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	<=15 months	23 52.3%
	>15 months	21 47.7%
number of involved vertebrae; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	1-2	30 68.2%
	>=3	14 31.8%
other bone metastases; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	no	10 22.7%
	yes	34 77.3%
visceral metastases; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	no	16 36.4%
	yes	28 63.6%
time developing motor deficits; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	1-7 days	14 31.8%
	8-14 days	10 22.7%
	>14 days	20 45.5%
ambulatory status; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	not ambulatory	18 40.9%
	ambulatory	26 59.1%
Eastern Cooperative Oncology Group performance score [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	ECOG 1-2	20 45.5%
	ECOG 3-4	24 54.5%
		[1] Measure Description: Performance status was rated with the Eastern Cooperative Oncology Group (ECOG), ranging from 0 to 5 (lower grade=better performance status). 0: Fully active without restrictions.; Restricted in physically strenuous activity; ambulatory and able to perform light or sedentary work.; Ambulatory and capable of all self-care; unable to work; up and about >50% of hours awake.; Capable of limited self-care; confined to bed/chair >50% of hours awake.; Completely disabled. Totally confined to bed or chair.; Dead. [Oken et al., Am J Clin Oncol 1982;5:649-55.]
motor function; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 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; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	absent	0 0.0%
	impaired	17 38.6%
	normal	23 52.3%
	unclear	4 9.1%
sphincter dysfunction; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	no	37 84.1%
	yes	6 13.6%
	unclear	1 2.3%
Distress (measured with the distress-thermometer) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	0-1 points	1 2.3%
	2-4 points	11 25.0%
	5-7 points	15 34.1%
	8-10 points	16 36.4%
	not available	1 2.3%
		[1] Measure 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. [Holland JC, et al. J Natl Comp Cancer Network 2013;11:190-209.]
Pain (measured with a numeric self-rating scale) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants
	0-1 points	8 18.2%
	2-4 points	11 25.0%
	5-7 points	14 31.8%
	8-10 points	11 25.0%
		[1] Measure Description: Pain was measured with a numeric self-rating scale ranging from 0 (no pain) to 10 (worst pain).

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
Overall Number of Participants Analyzed	40
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	95.0; (81.5 to 98.7)

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	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	20
	Estimation Comments	[Not Specified]
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
Overall Number of Participants Analyzed	40
Measure Type: Count of Participants; Unit of Measure: Participants
improvement of motor function	24 60.0%
no improvement of motor deficits	16 40.0%

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.
Overall Number of Participants Analyzed	16
Measure Type: Count of Participants; Unit of Measure: Participants
improvement of sensory deficits	8 50.0%
no improvement of sensory deficits	8 50.0%

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.
Overall Number of Participants Analyzed	6
Measure Type: Count of Participants; Unit of Measure: Participants
improvement	2 33.3%
no improvement	2 33.3%
post-treatment assessment not available	2 33.3%

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
Overall Number of Participants Analyzed	40
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	95; (82 to 99)

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
Overall Number of Participants Analyzed	40
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	45.0; (26.7 to 57.6)

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.
Overall Number of Participants Analyzed	21
Measure Type: Count of Participants; Unit of Measure: Participants
pain relief	13 61.9%
no pain relief	8 38.1%

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.
Overall Number of Participants Analyzed	24
Measure Type: Count of Participants; Unit of Measure: Participants
relief of distress	13 54.2%
no relief of distress	11 45.8%

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
Overall Number of Participants Analyzed		40
Measure Type: Count of Participants; Unit of Measure: Participants
grade 2-3 toxicity	toxicity	4 10.0%
	no toxicity	36 90.0%
grade 3 toxicity	toxicity	1 2.5%
	no toxicity	39 97.5%

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
Overall Number of Participants Analyzed	40
Measure Type: Count of Participants; Unit of Measure: Participants
able to walk following radiotherapy	33 82.5%
not able to walk following radiotherapy	7 17.5%

Adverse Events

Time Frame	during the period of radiotherapy and up to 6 months during the period of follow up
Adverse Event Reporting 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
All-Cause Mortality
	High-precision RT 5x5 Gy in 1 Week
	Affected / at Risk (%)
Total	22/40 (55.00%)
Serious Adverse Events
	High-precision RT 5x5 Gy in 1 Week
	Affected / at Risk (%)	# Events
Total	5/40 (12.50%)
Cardiac disorders
Heart failiure * 1	1/40 (2.50%)	1
Infections and infestations
Systemic aspergillosis * 1	1/40 (2.50%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonia * 1	1/40 (2.50%)	1
Unknown death (shortness of breath) * 1	1/40 (2.50%)	1
Vascular disorders
Pulmonary embolism * 1	1/40 (2.50%)	1
1 Term from vocabulary, CTCAE v4.03; * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	High-precision RT 5x5 Gy in 1 Week
	Affected / at Risk (%)	# Events
Total	10/40 (25.00%)
Gastrointestinal disorders
Nausea * 1	10/40 (25.00%)	17
Diarrhea * 1	7/40 (17.50%)	13
General disorders
Fatigue * 1	2/40 (5.00%)	3
1 Term from vocabulary, CTCAE 4.03 (MedDRA); * Indicates events were collected by non-systematic assessment

Limitations and 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.

Results Point of Contact

• Name/Title: Prof. Dr. med. Dirk Rades
• Organization: Department of Radiation Oncology, University of Lübeck, Lübeck, Germany
• Phone: 0049 451 500 ext 45400
• EMail: rades.dirk@gmx.net

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Rades D, Cacicedo J, Conde-Moreno AJ, Segedin B, Lomidze D, Ciervide R, Hollaender NH, Schild SE. Comparison of 5 × 5 Gy and 10 × 3 Gy for metastatic spinal cord compression using data from three prospective trials. Radiat Oncol. 2021 Jan 7;16(1):7. doi: 10.1186/s13014-020-01737-7.

Rades D, Cacicedo J, Conde-Moreno AJ, Segedin B, But-Hadzic J, Groselj B, Kevlishvili G, Lomidze D, Ciervide-Jurio R, Rubio C, Perez-Romasanta LA, Alvarez-Gracia A, Olbrich D, Doemer C, Schild SE, Hollaender NH. Precision Radiation Therapy for Metastatic Spinal Cord Compression: Final Results of the PRE-MODE Trial. Int J Radiat Oncol Biol Phys. 2020 Mar 15;106(4):780-789. doi: 10.1016/j.ijrobp.2019.11.401. Epub 2019 Dec 5.

Rades D, Cacicedo J, Conde-Moreno AJ, Doemer C, Dunst J, Lomidze D, Segedin B, Olbrich D, Holländer NH. High-precision radiotherapy of motor deficits due to metastatic spinal cord compression (PRE-MODE): a multicenter phase 2 study. BMC Cancer. 2017 Dec 4;17(1):818. doi: 10.1186/s12885-017-3844-x.

• Responsible Party: Prof. Dirk Rades, MD, University Hospital Schleswig-Holstein
• ClinicalTrials.gov Identifier: NCT03070431
• Other Study ID Numbers: PRE-MODE
• First Submitted: February 27, 2017
• First Posted: March 3, 2017
• Results First Submitted: January 30, 2020
• Results First Posted: March 3, 2020
• Last Update Posted: March 3, 2020