Single vs Multiple-Fraction Therapy in Treating Patients With Previously Irradiated Painful Bone Metastases

• Sponsor: NCIC Clinical Trials Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00080912
• Collaborator: National Cancer Institute (NCI) (NIH), Radiation Therapy Oncology Group (Other), Trans Tasman Radiation Oncology Group (Other), Cancer Research UK (Other), Assistance Publique - Hôpitaux de Paris (Other)
• Enrollment: 850
• Locations: 12
• Arms: 2
• Actual Duration (Months): 120.3
• Patients Per Site: 70.8
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. It is not yet known whether single-fraction (single-dose) re-irradiation therapy is as effective as multiple-fraction (many small doses of radiation therapy) re-irradiation therapy in relieving bone pain caused by bone metastases.

PURPOSE: This randomized phase III trial is studying single-dose radiation therapy to see if it works as well as multiple-dose radiation therapy in treating patients previously irradiated with painful bone metastases.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Cancer; Pain	Radiation: radiation therapy	N/A

Detailed Description

OBJECTIVES:

Primary

• Compare pain relief in patients undergoing single-fraction vs multiple-fraction re-irradiation of painful bone metastases at 2 months after treatment.

Secondary

• Compare overall pain relief in patients treated with these regimens.

• Compare time to pain progression in patients treated with these regimens.

• Assess relationship between response to initial radiation and pain relief after re-irradiation in these patients.

• Compare changes in functional interference after re-irradiation using the Brief Pain Inventory in patients treated with these regimens.

• Compare quality of life of patients treated with these regimens (patients in Canada, France, the Netherlands, and patients registered through RTOG).

• Determine characteristics of non-responders (to both initial and re-irradiation) among patients treated with these regimens.

• Monitor the incidence of acute severe radiation-related side effects in patients treated with these regimens.

• Monitor the incidence of in-field pathological fractures and spinal cord compression in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to response to initial radiotherapy (yes vs no), initial fractionation (single fraction vs multiple fraction), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive single-fraction radiotherapy (8Gy) on day 1.

• Arm II: Patients receive multiple-fraction radiotherapy (to a total of 20Gy) over 5 days or over 8 days if re-irradiation of the spine and/or whole pelvis is involved AND prior initial radiotherapy was given in multiple fractions.

At least 4 weeks after the first re-treatment, patients in both arms may receive a second re-treatment at the discretion of the treating oncologist.

Patients complete a Brief Pain Inventory questionnaire at baseline, on days 7 and 14, monthly during months 1-6, and at months 9 and 12. Acute Toxicities are assessed on days 7 and 14. Quality of Life is assessed at baseline and then monthly during months 1-6 for patients from participating groups.

Patients are followed for up to 1 year.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A total of 850 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 850 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III International Randomized Trial Of Single Versus Multiple Fractions For Re-Irradiation Of Painful Bone Metastases
• Actual Study Start Date: Jan 7, 2004
• Actual Primary Completion Date: Apr 10, 2013
• Actual Study Completion Date: Jan 16, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive single-fraction radiotherapy (8 Gy) on day 1.	Radiation: radiation therapy; Given in a single fraction or multiple fractions
Active Comparator: Arm II Patients receive multiple-fraction radiotherapy (to a total of 20 Gy) over 5 days or over 8 days if re-irradiation of the spine and/or whole pelvis is involved AND prior initial radiotherapy was given in multiple fractions.	Radiation: radiation therapy; Given in a single fraction or multiple fractions

Outcome Measures

Primary Outcome Measures

1. Pain Relief Measured by the Brief Pain Inventory at 2 Months After Treatment [2 months]

   The primary endpoint of this study is Overall Response Rate (complete response and partial response) at two months after the first fraction of re-irradiation. A complete response was defined as a Brief Pain Inventory worst-pain score of zero with no associated increase in daily oral morphine equivalent. A partial response was defined as pain that persisted after treatment, either with a worst-pain score reduction of 2 or more and no increase in daily oral morphine equivalent consumption, or no increase in pain and a reduction in daily oral morphine equivalent consumption of at least 25%.

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed malignancy

• Diagnosis by needle biopsy, bone marrow biopsy, cytology, or surgical biopsy or resection

• Bone metastases at clinically painful areas confirmed by any of the following:

• Plain radiographs

• Radionuclide bone scans

• CT scans

• Magnetic resonance imaging

• Worst pain score of ≥ 2/10 using the baseline Brief Pain Inventory

• Pain arising from previously irradiated metastases and not from progressive disease in adjoining or remote areas

• Initial radiotherapy field is reproducible for re-irradiation

• Current treatment field for palliative radiotherapy must be the same size or smaller than the initial treatment field

• No clinical or radiological evidence of pathological fractures in the target site extremities.

• No radiological evidence of high-risk lesions for pathological fractures in the extremities (lytic lesions > 3cm or > 50% cortical erosion of bone diameter) if target site AND patient is a candidate for surgical intervention.

• No clinical or radiological evidence of spinal cord compression at target site.

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Karnofsky 50-100%

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Not specified

Other

• Not pregnant or nursing

• Fertile patients must use effective barrier contraception

• Able and willing to complete quality of life questionnaire in English, French, Dutch, or Spanish (if randomized by Canadian, Dutch, French or RTOG centre)

• Must be accessible for treatment follow-up

• Informed consent

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• Not specified

Radiotherapy

• See Disease Characteristics

• No more than 1 prior course of radiotherapy to the target site

• No prior radiotherapy dose ≥ 24 Gy in 6 fractions, 27 Gy in 8 fractions, or 30 Gy in 10 fractions to the spine or any part of the pelvis encompassing small or large bowel and/or the rectum, if these sites are being treated on study

• Initial doses of 24 Gy in 6 fractions, 27 Gy in 8 fractions or 30 Gy in 10 fractions to the acetabulum or hip and proximal femur allowed as long as the medial field border of the initial treatment did not cross midline

• No prior radiotherapy dose > 30Gy in 10 fractions to the ribs or extremities if these sites are being treated on study

• More than 30 days since prior strontium chloride Sr 89

• More than 30 days since prior half-body radiotherapy, including the current re-irradiation field

• At least 4 weeks since initial radiotherapy

Surgery

• No prior palliative surgery in treatment area

• No concurrent surgical intervention on treatment area

Other

• No prior participation on this protocol

• No plan to make an immediate change in analgesic regimen

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
2	The Vitalite Health Network - Dr. Leon Richard	Moncton	New Brunswick	Canada	E1C 8X3
3	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8V 5C2
4	Cancer Centre of Southeastern Ontario at Kingston	Kingston	Ontario	Canada	K7L 5P9
5	Grand River Regional Cancer Centre	Kitchener	Ontario	Canada	N2G 1G3
6	Thunder Bay Regional Health Science Centre	Thunder Bay	Ontario	Canada	P7B 6V4
7	Odette Cancer Centre	Toronto	Ontario	Canada	M4N 3M5
8	Univ. Health Network-Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
9	CHUM - Hopital Notre-Dame	Montreal	Quebec	Canada	H2L 4M1
10	McGill University - Dept. Oncology	Montreal	Quebec	Canada	H2W 1S6
11	Centre hospitalier universitaire de Sherbrooke	Sherbrooke	Quebec	Canada	J1H 5N4
12	Allan Blair Cancer Centre	Regina	Saskatchewan	Canada	S4T 7T1

Sponsors and Collaborators

• NCIC Clinical Trials Group
• National Cancer Institute (NCI)
• Radiation Therapy Oncology Group
• Trans Tasman Radiation Oncology Group
• Cancer Research UK
• Assistance Publique - Hôpitaux de Paris

Investigators

• Study Chair: Edward LW Chow, MD, Toronto Sunnybrook Regional Cancer Centre
• Study Chair: William F. Hartsell, MD, Advocate Good Samaratin Cancer Centre
• Study Chair: Daniel Roos, MD, Royal Adelaide Hospital Cancer Centre
• Study Chair: Yvette von der Linden, Radiotherapeutic Institution Friesland
• Study Chair: Peter Hoskin, Mount Vernon Cancer Centre

Study Documents (Full-Text)

None provided.

More Information

Publications

• Chow E, Hoskin PJ, Wu J, Roos D, van der Linden Y, Hartsell W, Vieth R, Wilson C, Pater J. A phase III international randomised trial comparing single with multiple fractions for re-irradiation of painful bone metastases: National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) SC 20. Clin Oncol (R Coll Radiol). 2006 Mar;18(2):125-8. Review.

• Responsible Party: NCIC Clinical Trials Group
• ClinicalTrials.gov Identifier: NCT00080912
• Other Study ID Numbers: SC20; CAN-NCIC-SC20; RTOG-0433; TROG-03.08; CDR0000357423; NCT00797173
• First Posted: Apr 8, 2004
• Last Update Posted: Apr 14, 2020
• Last Verified: Apr 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 NCIC Clinical Trials Group: bone metastases; pain
• Additional relevant MeSH terms: Neoplasm Metastasis

Study Results

Participant Flow

Arm/Group Title	Single-fraction	Multiple-fraction
Arm/Group Description	Patients receive single-fraction radiotherapy (8 Gy) on day 1. radiation therapy: Given in a single fraction or multiple fractions	Patients receive multiple-fraction radiotherapy (to a total of 20 Gy) over 5 days or over 8 days if re-irradiation of the spine and/or whole pelvis is involved AND prior initial radiotherapy was given in multiple fractions. radiation therapy: Given in a single fraction or multiple fractions
Period Title: Overall Study
STARTED	425	425
COMPLETED	425	425
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Single-fraction	Multiple-fraction	Total
Arm/Group Description	Patients receive single-fraction radiotherapy (8 Gy) on day 1. radiation therapy: Given in a single fraction or multiple fractions	Patients receive multiple-fraction radiotherapy (to a total of 20 Gy) over 5 days or over 8 days if re-irradiation of the spine and/or whole pelvis is involved AND prior initial radiotherapy was given in multiple fractions. radiation therapy: Given in a single fraction or multiple fractions	Total of all reporting groups
Overall Participants	425	425	850
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64.6	65.3	65.1
Sex: Female, Male (Count of Participants)
Female	181 42.6%	167 39.3%	348 40.9%
Male	243 57.2%	256 60.2%	499 58.7%

Outcome Measures

1. Primary Outcome

Title	Pain Relief Measured by the Brief Pain Inventory at 2 Months After Treatment
Description	The primary endpoint of this study is Overall Response Rate (complete response and partial response) at two months after the first fraction of re-irradiation. A complete response was defined as a Brief Pain Inventory worst-pain score of zero with no associated increase in daily oral morphine equivalent. A partial response was defined as pain that persisted after treatment, either with a worst-pain score reduction of 2 or more and no increase in daily oral morphine equivalent consumption, or no increase in pain and a reduction in daily oral morphine equivalent consumption of at least 25%.
Time Frame	2 months

Outcome Measure Data

Analysis Population Description

Intend to treat (ITT) population

Arm/Group Title	Single-fraction	Multiple-fraction
Arm/Group Description	Patients receive single-fraction radiotherapy (8 Gy) on day 1. radiation therapy: Given in a single fraction or multiple fractions	Patients receive multiple-fraction radiotherapy (to a total of 20 Gy) over 5 days or over 8 days if re-irradiation of the spine and/or whole pelvis is involved AND prior initial radiotherapy was given in multiple fractions. radiation therapy: Given in a single fraction or multiple fractions
Measure Participants	425	425
Number (95% Confidence Interval) [percentage of participants]	28.0 6.6%	32.0 7.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Single-fraction, Multiple-fraction
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	The original sample size was determined based on the non-inferiority. The original sample size is based on assumption of response rate on the multiple fraction arm is 70%, 260 patients were required in each treatment arm to have 80% power to exclude, with a one sided alpha of 0.05, a response rate of 60% or less in the single fraction radiation group (non-inferiority margin =10%). Given an inevaluability rate of 30%, 850 patients (425 for each treatment arm) were randomized to the study.
Statistical Test of Hypothesis	p-Value	0.03
	Comments	p-value is for one-sided non-inferiority test
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	4.0
	Confidence Interval	(1-Sided) 95%; to 9.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	The upper limit of one-sided 95% CI for the response rate difference was 9.2%, which was below the pre-specified 10% non-inferiority boundary

Adverse Events

Time Frame	8.2 years
Arm/Group Title	Single-fraction		Multiple-fraction
Arm/Group Description	Patients receive single-fraction radiotherapy (8 Gy) on day 1. radiation therapy: Given in a single fraction or multiple fractions		Patients receive multiple-fraction radiotherapy (to a total of 20 Gy) over 5 days or over 8 days if re-irradiation of the spine and/or whole pelvis is involved AND prior initial radiotherapy was given in multiple fractions. radiation therapy: Given in a single fraction or multiple fractions
All Cause Mortality
	Single-fraction		Multiple-fraction
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	227/425 (53.4%)		220/425 (51.8%)
Serious Adverse Events
	Single-fraction		Multiple-fraction
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/425 (0.2%)		0/425 (0%)
Cardiac disorders
Cardiac ischemia/infarction	1/425 (0.2%)		0/425 (0%)
Other (Not Including Serious) Adverse Events
	Single-fraction		Multiple-fraction
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/425 (0%)		0/425 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.