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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02220491
Recruitment Status : Active, not recruiting
First Posted : August 20, 2014
Last Update Posted : January 18, 2018
Information provided by (Responsible Party):
British Columbia Cancer Agency

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Brain Metastases Radiation: Single-fraction radiotherapy Radiation: Whole-brain radiotherapy Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : October 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

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

Primary Outcome Measures :
  1. 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

Secondary Outcome Measures :
  1. 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.

Other Outcome Measures:
  1. 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.

  2. 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. 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.

  4. 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.

  5. 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. 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.

  7. 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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02220491

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Canada, British Columbia
British Columbia Cancer Agency
Vancouver, British Columbia, Canada, V5Z 4E6
Sponsors and Collaborators
British Columbia Cancer Agency
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Principal Investigator: Nichol Alan, MD British Columbia Cancer Agency

Karnofsky DA, Burchenal JH. The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod CM, editor. Evaluation of Chemotherapeutic Agents. Columbia University Press; 1949. p. 196.

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Responsible Party: British Columbia Cancer Agency Identifier: NCT02220491     History of Changes
Other Study ID Numbers: H14-02032
First Posted: August 20, 2014    Key Record Dates
Last Update Posted: January 18, 2018
Last Verified: January 2018

Additional relevant MeSH terms:
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Neoplasm Metastasis
Brain Neoplasms
Neoplastic Processes
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases