Whole Brain Radiotherapy Versus Volumetric Modulated Arc Therapy for Brain Metastases (Amadeus)

May 19, 2020 updated by: British Columbia Cancer Agency

A Randomized Phase II Study of 20 Gy in 5 Fractions Whole Brain Radiotherapy Versus 15 Gy in 1 Fraction Volumetric Modulated Arc Therapy for One to Ten Brain Metastases

Patients with brain metastases with expected life expectancy of 3-6 months are typically treated with radiotherapy to the whole brain giving a dose of 20 Gy over a 5 day period. This study will compare this with volumetric modulated arc therapy (VMAT) which is capable of delivering 15 Gy in one single session to identified disease within the brain but sparing the normal surrounding brain tissue. Primarily the study will assess whether it is possible to recruit sufficient patient numbers to a trial of this type. It will also compare effectiveness, side effects and quality of life between the two treatment methods.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This is a Phase II prospective clinical trial. Pre treatment evaluations include estimation of life expectancy, Creatinine (GFR) and MRI brain with contrast. An assessment of cognitive function using Montreal Cognitive Assessment questionnaire, assessment of daily living activities using the Modified Barthel's index and quality of life assessment using EORTC QLQ-PAL-15 & BN-20 questionnaires will be performed in clinic. Karnofsky Performance Status will also be assessed by the clinician. If all assessments are within the eligibility criteria then the patient can be recruited. Before treatment begins a history documenting baseline symptoms using NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 and a neurological examination documenting baseline deficits must be obtained.

If patient is randomized to standard treatment of whole brain radiotherapy (WBRT) then subjects will have a non-contrast CT scan using a slice thickness of 2.5 mm or less to plan radiotherapy. If patient are randomized to single fraction radiotherapy then a contrast CT will be used as this aids in identifying metastatic tumours within the brain. Also for the single fraction arm if a contrast-enhanced diagnostic MRI was obtained ≤ 10 days before the CT planning scan, with a single-plane high-resolution sequence or low-resolution sequences in two planes, it can be used for treatment planning. If the contrast-enhanced diagnostic MRI was obtained > 10 days before the CT planning scan or there is no diagnostic MRI, the subject requires a gadolinium-enhanced, high-resolution MRI sequence for fusion in the treatment planning system. During treatment, patients will have daily online cone beam CT scans to apply setup corrections to ensure treatment accuracy. To ensure minimal movement during radiotherapy all subjects will be immobilized lying on their back in a plastic headshell with an integrated bite block.

For subjects in the single-fraction arm that are not requiring steroids before radiotherapy, dexamethasone 8 mg 1 hour before the radiotherapy and for 5 days afterwards is required. For subjects in the single-fraction arm that are requiring corticosteroids for symptom management before radiotherapy, dexamethasone 8 mg before treatment and 8 mg 2 times daily for 2 days is required. Beginning three days after radiotherapy, a taper back to the pre-radiotherapy dose can be done swiftly over 4-6 days. However, for subjects who have been on dexamethasone for more than 2 weeks at this time point, slow tapering from the pre-radiotherapy dose using decrements of 0.5 - 2 mg every 3-5 days should be used to prevent a hypocortisolemia. For subjects in the 5-fraction arm, corticosteroids will be prescribed according to the preference of the treating radiation oncologist. Anti-sickness medication and steroids will be prescribed are required before each fraction in both arms.

Following therapy completion, all patients will be seen at 6 weeks, 3, 6, 9 and 12 months. At each visit history and neurological examination will be performed. Cognitive Function, Karnofsky Performance Status, Quality of life and Adverse Events will all be assessed and recorded. Activities of Daily Living and steroid use will be assessed by telephone consultation every 4 weeks (monthly) for 1 year. Steroid use will be confirmed by evaluating the pharmacy prescription database.

Patients will have contrast-enhanced MRI brain at every time point with a creatinine 1 week before each MRI to ensure safety of intravenous contrast administration. Steroid use will be recorded in a patient diary for first 6 weeks post treatment and monthly by telephone discussion.

Study Type

Interventional

Enrollment (Actual)

20

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 4E6
        • British Columbia Cancer Agency

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age ≥ 18
  • Pathologically confirmed solid malignancy
  • 1-10 brain or brainstem metastases on MRI with a maximum of 4 cm diameter
  • Documented extracranial disease
  • Anticipated median survival 3-6 months (Graded Prognostic Assessment: Appendix I)
  • Available for regular clinical and imaging follow up (< 1 hour from a cancer centre)
  • Montreal Cognitive Assessment score ≥ 20 (Appendix II)
  • Karnofsky Performance Score (KPS) ≥ 70 (Appendix III)
  • Barthel Activities of Daily Living score ≥ 90 (Appendix IV)
  • Able to complete EORTC quality of life questionnaires (Appendix V)

Exclusion Criteria:

  • A metastasis located within 5 mm of the optic nerves or optic chiasm
  • Requiring craniotomy to relieve mass effect
  • Cytotoxic systemic therapy administered within one week before radiotherapy or planned within one week after radiotherapy
  • Neurological decline since starting corticosteroids
  • Metastatic germinoma, small cell carcinoma, multiple myeloma, lymphoma or leukaemia
  • Systemic lupus erythematosis, scleroderma, or other connective tissue disorders not in remission
  • Multiple sclerosis
  • Glomerular Filtration Rate < 45 ml/minute
  • Contra-indications to MRI
  • Pregnancy
  • AST, ALT or Bilirubin > 3 times upper limit of normal
  • Haemorrhagic Metastases

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Whole-brain radiotherapy

All subjects will have a non-contrast CT scan using a slice thickness of 2.5mm or less.

The Brain contour will be generated using the segmentation wizard and edits as required.

PTV_Brain is an expansion of the Brain by 5mm. 99% of PTV_Brain is to be covered by 95% of 20 Gy in 5 fractions using 6-10 MV photons in a parallel-opposed pair lateral beam arrangement.
Radiation: Whole-brain radiotherapy
Whole brain radiotherapy delivering 20 Gy in five fractions to brain metastases
Experimental: Single-fraction radiotherapy
Immobilized in the mask, the subject will be imaged for radiotherapy planning with a CT slice thickness of 1.25 mm or less and an axial resolution of < 0.7 mm (CT field of view < 35 cm). Subjects that require contrast with GFR 45-59 will have pre-hydration, contrast dose modification and/or Mucomyst administration to preserve renal function, according to standard practice for radiological imaging at the institution.
Radiation: Single-fraction radiotherapy
Volumetric modulated arc therapy (VMAT) delivering 15 Gy in one fraction to brain metastases

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Accrual
Time Frame: 8 months
The time of accrual of 20 subjects will be recorded in months from the official study opening at each cancer centre until the 20th patient is accrued. The rate of accrual will be calculated by dividing the number of patients by the number of months it took to accrue them
8 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intracranial disease control
Time Frame: 3 months
All subjects who complete radiotherapy and have imaging at 6 weeks will be considered evaluable for response. Those who exhibit objective disease progression on imaging before 6 weeks will also be considered evaluable for response.
3 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Compare the use of corticosteroids
Time Frame: Every 4 weeks for 1 year
The subjects' use of corticosteroids will be recorded in a diary for the first 6 weeks and assessed monthly with phone follow-up. The amount and pattern of corticosteroid use will be compared between the two arms of the study.
Every 4 weeks for 1 year
Compare the incidence of retreatment with cranial radiotherapy
Time Frame: 3 months
Subjects with new brain metastases can be treated in a number of ways if their performance status remains good. If 3 months have passed since their initial treatment and there are 1-10 new metastases, subjects can receive the study treatment with 15 Gy in 1 fraction again. However, if the new brain metastases are detected within 3 months or there are more than 10 new brain metastases, subjects must have WBRT, rather than treatment to the metastases alone. Subjects with progression or relapse of a treated brain metastasis can be considered for surgery, retreatment with radiosurgery or retreatment with WBRT. Subjects with poor performance status should be considered for best supportive care.
3 months
Compare the incidence of acute and late side effects
Time Frame: 6 weeks, 3 months, 6 months, 9 months, 12 months
The study will use the descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) for grading of acute and late side effects. The incidence of the various side effects will be compared between the two arms.
6 weeks, 3 months, 6 months, 9 months, 12 months
Compare the time to decline in activities of daily living using the Modified Barthel Index
Time Frame: Every 4 weeks for 1 year
The Modified Barthel index will be administered at baseline and at each follow-up visit. The scores will be recorded and analysed. The minimum clinically important difference for this scale is 10 points.
Every 4 weeks for 1 year
Compare the time to decline in Karnofsky Performance Status < 70
Time Frame: 6 weeks, 3 months, 6 months, 9 months, 12 months
The KPS will be recorded at each clinic visit. The patient will be regarded as having had a decline in KPS when it falls below 70, at which time subjects are no longer independent.
6 weeks, 3 months, 6 months, 9 months, 12 months
Compare the time to decline in cognition
Time Frame: 6 weeks, 3 months, 6 months, 9 months, 12 months
The MoCA questionnaire will be administered at baseline and at each follow-up visit (Appendix II). The score will be recorded and analysed. A decline in MOCA score of 3 is considered to be clinically significant.
6 weeks, 3 months, 6 months, 9 months, 12 months
Time to decline in quality of life
Time Frame: 6 weeks, 3 months, 6 months, 9 months, 12 months
The EORTC QLQ-PAL-15 will be administered at baseline and at each follow-up visit. The EORTC BN-20 (brain-specific) quality of life questionnaire will be administered at baseline and at each follow-up visit. The quality of life questionnaire scores will be recorded and analysed.
6 weeks, 3 months, 6 months, 9 months, 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

British Columbia Cancer Agency

Investigators

  • Principal Investigator: Nichol Alan, MD, British Columbia Cancer Agency

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2014

Primary Completion (Actual)

May 18, 2020

Study Completion (Actual)

May 18, 2020

Study Registration Dates

First Submitted

August 15, 2014

First Submitted That Met QC Criteria

August 18, 2014

First Posted (Estimate)

August 20, 2014

Study Record Updates

Last Update Posted (Actual)

May 20, 2020

Last Update Submitted That Met QC Criteria

May 19, 2020

Last Verified

May 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H14-02032

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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