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Trial registered on ANZCTR


Registration number
ACTRN12615001202550
Ethics application status
Approved
Date submitted
2/09/2015
Date registered
5/11/2015
Date last updated
18/12/2018
Date data sharing statement initially provided
18/12/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Study to assess the neurological and cognitive effects of using Hypofractionated Stereotactic Radiotherapy used to treat multiple (3-10) brain metastases.
Scientific title
A Phase II Prospective Trial of Stereotactic Hypofractionated Radiation for Multiple (3-10) cerebral metastases including Neurological and Cognitive assessment
Secondary ID [1] 286832 0
Nil known
Universal Trial Number (UTN)
Trial acronym
SHRINC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neurocognitive impairment 295211 0
Condition category
Condition code
Cancer 295461 295461 0 0
Any cancer
Cancer 296360 296360 0 0
Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Prescription Dose Per Site
Stereotactic radiotherapy over 5-6 days or stereotactic radiosurgery over 1-2 days will be performed using planning software which allows for the planning and treatment of multiple (3-10) cerebral metastases. Dose prescription and fractionation schedules will be based on metastases’ size, location and previous surgery. For each metastatic site identified, 98.5% of the defined PTV volume must be covered by the appropriate dose. All prescribed doses per lesion classification are outlined below:

PTV* (total) -Total Dose (Gy) to 80% IDL* - Fractions
0.5-4.0 cubic cm will receive 20 Gy in 1 fraction
4.0-15 cubic cm will receive 35 Gy in 5 fractions
Brainstem/basal ganglia will receive 36 Gy in 6 fractions
Resection Cavity 0.5-4.0 cubic cm will receive 20 Gy in 1 fraction
Resection cavity >4.1 cubic cm will receive 35 Gy in 5 fractions

*PTV = Planning target volume / IDL = Isodose level

Dose prescriptions
All fractionation is based on the prescription dose covering >98.5% of the PTV. Dose-fractionation has been designed to provide similar efficacy in terms of tumour control with increasing fractionation based on volume (PTV), and to provide maximum safety in terms of late reactions such as tumour necrosis and symptomatic cerebral oedema.

For participants prescribed hypofractionated dose regimes, it is expected that treatments will be delivered daily totaling 5 fractions per week according to departmental policies, except where interruptions to treatment schedule are unavoidable due to public holidays or any other reason. If an interruption in treatment is needed due to an adverse event, the cause and nature shall be documented and scored using the per-protocol CTCAE v4.03, with treatment to resume as soon as is clinically feasible. Any other alternative events that result in treatment interruptions should also be documented.

Planning System Requirements
The computerised planning system should have the following minimum capabilities:
- Provides a 3D dose calculation algorithm (e.g. convolution / superposition algorithm) capable of performing calculations that account for variations in scatter in the presence of 3D CT defined heterogeneities.
- Can provide dose calculation grid spacing of 1x1x1mm.
- Can provide digitally reconstructed radiographs (DRRs) with superimposed target volume, critical structure contours and treatment aperture.
For the purposes of this study, BrainLab Elements (Trademark) Brain Metastases Planning system (Version 1.0) (BrainLab AG, Germany) utilizing iPlan Pencil Beam Convolution RT Dose (Verision 4.5.3) (6MV photons) will be employed, using a calculation grid size resolution of 1mm or finer to ensure the accuracy of dose distribution calculated.

Beam Arrangement and Technique Selection
(i) Treatment Modality
BrainLab Elements (Trademark) Automatic Brain Metastases Planning program (BrainLab AG, Germany) is a novel radiotherapy planning software that was designed solely for the treatment of numerous brain metastases simultaneously. Internal algorithms within the software will analyse predefined target and critical structure proximity and dose constraints, structure priority, size and shape, and work in reverse to construct a plan that best achieves the dosimetry that matches all the input parameters (i.e. inverse-planned). Radiotherapy planning with BrainLab Elements (Trademark) Automatic Brain Metastases Planning software and the use of dynamic Micro-multi-Leaf Collimators (mMLCs) to create tight margins around identified targets allows for dose distributions with steep dose gradients that greatly minimise dose to the normal healthy surrounding tissues and structures.

(ii) Number of treatment arcs and arrangement
In order to make treatment sessions exponentially faster, and to meet predefined dose constraints, BrainLab Elements (Trademark) Automatic Brain Metastases Planning (BrainLab AG, Germany) software will automatically place a single virtual isocentre and utilise a number of dynamic arcs at multiple table angles (non-coplanar) (maximum 10 arcs at 5 table positions) respectively. Arcs will rotate backward and forward at the same couch position to ensure adequate coverage of metastases that may be occluding one another.
Intervention code [1] 291990 0
Treatment: Other
Intervention code [2] 292945 0
Treatment: Devices
Comparator / control treatment
Single arm interventional study. No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 295190 0
Neurocognitive functioning as measured by the Hopkins Verbal Learning Test (HVTL)
Timepoint [1] 295190 0
Measured at baseline, then at three and six months post treatment.
Secondary outcome [1] 315007 0
Local control as measured by MRI scans.
Timepoint [1] 315007 0
Undertaken at the time of neurocognitive assessment with local control assessed in terms of complete or partial response, stable or progressive disease. Measured at baseline, then at three and six months post treatment.
Secondary outcome [2] 315008 0
Treatment-related toxicity as measured by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03)
Timepoint [2] 315008 0
Measured daily during radiation therapy and at 3 month follow-up visit.
Secondary outcome [3] 315009 0
Quality of Life (QoL) as measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) instrument.
Timepoint [3] 315009 0
Administered at baseline, 3 months and 6 months post treatment.
Secondary outcome [4] 315010 0
Performance in activities of daily living (ADL) as measured by the Barthel ADL index.
Timepoint [4] 315010 0
Measured at baseline, three and six months post treatment.
Secondary outcome [5] 317157 0
Overall survival as predicted from using the Disease Specific-Graded Prognostic Assessment
Timepoint [5] 317157 0
Assessed at baseline, 3 months, 6 months post treatment.

Eligibility
Key inclusion criteria
• Pathological evidence of a known non-haematological malignancy within 5 years of enrolment.
• Three to ten metastatic brain lesions or surgical cavities which correlate with the confirmed non-haematological malignancy.
• Total Planning Target Volume <15cc for single fraction treatment and <35cc for fractionated treatment
• Largest single Planning Target Volume of unresected disease <10cc
• Largest single Planning Target Volume of a resection cavity <15 cc
• Age >18years
• Participants 60 years of age or older must nominate a friend or relative whom will participate in the cognitive decline questionnaire sub-study.
• Must be sufficiently proficient in English to complete neuropsychology tests
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Cognitive impairment which may interfere with ability to participate in the neurocognitive assessments
• Untreated clinically significant hydrocephalus
• Haematological, Small cell, Germ Cell malignancy or unknown primary tumour
• Leptomeningeal disease
• Multiple new cranial nerve deficits in the absence of overt intracranial disease
• Prior cranial irradiation which would compromise safety if overlapped with protocol treatment
• Contra-indication for MRI and gadolinium contrast use:
o Participants with a known risk of poor renal function must have an estimated Glomerular Filtration Rate >50 millilitres per minute
o Known hypersensitivity to Gadolinium contrast
o Non-MRI compatible VP shunt/surgical apparatus
o Pacemaker/cardiac defibrillator not MRI compatible
• Contra-indications to steroid support (e.g. active peptic ulceration or previous steroid psychosis)

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
N/A
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Descriptive statistics such as means/medians and standard deviations, interquartile ranges (the difference between the 25th and 75th percentiles) will be reported. The nonparametric Wilcoxon paired samples test will be employed to compare patients’ neurocognitive functioning (HVLT) between baseline and 3 months, and baseline and 6 months evaluations as described in the Radiation Therapy Oncology Group (RTOG) trial, "A Phase II Trial of Hippocampal Avoidance During Whole Brain Radiotherapy for Brain Metastases--RTOG CCOP Study - RTOG 0933". Time to event analysis will employ the Kaplan-Meier method as described by Armitage (2002). Secondary endpoints will be examined using methods appropriate for repeated measures such as generalized estimating equation or mixed models.

RTOG 0933 was based on the Wilcoxon paired sample test with alpha =0.05(one-sided) noting a total of 51 eligible patients would ensure 80% statistical power to detect a 15% average relative loss in delayed recall at 4 months. Assuming 20% of patients would be unable to complete the evaluation at 3 or 6 months and 10% protocol deviation by requiring further intervention prior to further assessment, 73 patients, conservatively rounded to 75 patients would be required.

Unless otherwise specified, 0.05 statistical significance and 95% confidence intervals will be employed throughout.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
TAS,VIC
Recruitment hospital [1] 12768 0
Icon Cancer Centre Richmond - Richmond
Recruitment hospital [2] 12769 0
Icon Cancer Centre Hobart - Hobart
Recruitment postcode(s) [1] 10229 0
3121 - Richmond
Recruitment postcode(s) [2] 25209 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 291955 0
Hospital
Name [1] 291955 0
Integrated Clinical Oncology Network Pty Ltd (ICON)
Address [1] 291955 0
Level 1, 22 Cordelia Street
South Brisbane QLD 4101
Country [1] 291955 0
Australia
Primary sponsor type
Hospital
Name
Integrated Clinical Oncology Network Pty Ltd (ICON)
Address
Level 1, 22 Cordelia St
South Brisbane QLD 2101
Country
Australia
Secondary sponsor category [1] 290621 0
None
Name [1] 290621 0
None
Address [1] 290621 0
None
Country [1] 290621 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293451 0
Epworth HealthCare Human Research Ethics Committee
Ethics committee address [1] 293451 0
Pelaco Building One
21–31 Goodwood Street
Richmond VIC 3121
Ethics committee country [1] 293451 0
Australia
Date submitted for ethics approval [1] 293451 0
25/03/2015
Approval date [1] 293451 0
06/05/2015
Ethics approval number [1] 293451 0
676-15
Ethics committee name [2] 302222 0
Monash Health Human Research Ethics Committee
Ethics committee address [2] 302222 0
246 Clayton Road
Clayton VIC 3168
Ethics committee country [2] 302222 0
Australia
Date submitted for ethics approval [2] 302222 0
17/10/2018
Approval date [2] 302222 0
10/12/2018
Ethics approval number [2] 302222 0
RES-18-0000644A

Summary
Brief summary
The purpose of this study is to investigate whether improved radiation planning technology that conforms to the shape and size of the cancer, can be used to treat multiple sites of cancer within the brain, and at the same time protect and preserve your brain (memory and cognitive) function.

Who is it for? You may be eligible to join this study if you are aged 18 years or above and have been diagnosed with 3-10 measurable cerebral metastases, i.e. your cancer has spread to three or more spots on the brain.

Study details: All participants in this study will receive a new treatment called Hypofractionated Stereotactic Radiotherapy. This is highly focused radiation given in one or a few (5-6) treatments. Robotic targeting is used to avoid important parts of the normal brain. Where previous treatment for multiple sites of cancer within the brain has involved giving radiation to the whole brain, this treatment will allow us to treat multiple areas at the same time. The aim is to avoid the use of whole brain radiation that can affect the memory structures within the brain such as the hippocampus, thus preserving brain (memory and cognitive) function. The trial will use software called "BrainLab Elements (Trademark)". This software will help the radiation oncologist to plan and deliver the radiotherapy treatment. All participants will be monitored throughout treatment for safety. They will also be asked to undergo MRI scans and complete some questionnaires at the start of the study and at 3 and 6 months after treatment to assess neurocognitive functioning, disease response, and quality of life. We estimate that this study will contribute further to the research into using radiotherapy to control cancers that have spread to the brain, while minimising the effects on brain function.
Trial website
Trial related presentations / publications
Public notes
The Brainmet Elements (Trademark) software which is being used in this trial has been provided by Brainlab AG, Heimstetten, Germany

Contacts
Principal investigator
Name 57714 0
Dr Michael Dally
Address 57714 0
Icon Cancer Centre Richmond
Level 4, 32 Erin St
Richmond VIC 3121
Country 57714 0
Australia
Phone 57714 0
+61399368277
Fax 57714 0
Email 57714 0
Michael.Dally@icon.team
Contact person for public queries
Name 57715 0
Ms Skye Nolan
Address 57715 0
Icon Cancer Centre Richmond
Level 4, 32 Erin St
Richmond VIC 3121
Country 57715 0
Australia
Phone 57715 0
+61399368277
Fax 57715 0
Email 57715 0
Skye.Nolan@icon.team
Contact person for scientific queries
Name 57716 0
Dr Michael Dally
Address 57716 0
Icon Cancer Centre Richmond
Level 4, 32 Erin St
Richmond VIC 3121
Country 57716 0
Australia
Phone 57716 0
+61399368277
Fax 57716 0
Email 57716 0
Michael.Dally@icon.team

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable