Trial Review

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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
14/01/2024
Date data sharing statement initially provided
18/12/2018
Date results information initially provided
9/01/2023
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
0.5-15 cubic cm will receive 20 Gy in 1 fraction
6.0-15 cubic cm will receive 27 Gy in 3 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 totalling up to 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.

Beam Arrangement and Technique Selection
(i) Treatment Modality
BrainLab Elements™ and Varians HyperArc TM are both novel radiotherapy planning software designed solely for the planning of multiple brain metastases simultaneously. Internal algorithms within the software analyse predefined target and critical structure proximity and dose constraints, structure priority, size and shape, and work to construct a plan that best achieves the dosimetry that matches all the input parameters. BrainLab Elements™ and Varians HyperArc TM Planning software both employ dynamic high definition multi-leaf collimators (HD-MLC) to create tight margins around identified targets. This creates dose distributions with steep dose gradients, greatly minimising dose to the normal healthy surrounding tissues and structures.
At the discretion of the investigator and as per local policy, BrainLab iPlan™ RT Dose and Varian Eclipse may be utilised in planning of isolated metastases using single isocentre per target and non-coplanar dynamic arcs techniques if required to achieve optimal plan and OAR constraints.

(ii) Number of treatment arcs and arrangement
To facilitate treatment efficiency and to meet predefined dose constraints, TPS software automatically places a single virtual isocentre and utilises multiple dynamic arcs at multiple (non-coplanar) table angles (maximum 10 arcs at 5 table positions). 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
Three months post-treatment, compared to baseline
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.
Secondary outcome [6] 405602 0
Neurocognitive functioning as measured by the Hopkins Verbal Learning Test (HVLT)
Timepoint [6] 405602 0
Six months post-treatment, compared to baseline
Secondary outcome [7] 405603 0
Assessment of visual attention and task switching assessed by the Symbol Digit Modality Task (SDMT).
Timepoint [7] 405603 0
Assessed at baseline, 3 months, 6 months post treatment.
Secondary outcome [8] 405604 0
Dose delivered to the hippocampus assessed by dose volume histogram metrics from the radiotherapy treatment planning system. Metrics will include: the minimum, maximum and mean dose delivered to the hippocampus, as well as the D40 (dose delivered to 40% of the hippocampus). Dose will be reported in Gray.
Timepoint [8] 405604 0
Assessed at time of treatment planning.
Secondary outcome [9] 405605 0
Assessment primary attention, capacity and working memory assessed by the Digit Span test.
Timepoint [9] 405605 0
Assessed at baseline, 3 months, 6 months post treatment.
Secondary outcome [10] 405606 0
Assessment of verbal fluency, language and executive function assessed by the Controlled Oral Word Association Test (COWAT).
Timepoint [10] 405606 0
Assessed at baseline, 3 months, 6 months post treatment.
Secondary outcome [11] 405607 0
Assessment of executive function and processing speed assessed by the Trails Making Task.
Timepoint [11] 405607 0
Assessed at baseline, 3 months, 6 months post treatment.
Secondary outcome [12] 405608 0
Assessment of mood assessed by the Depression, Anxiety and Stress Scale (DASS-21).
Timepoint [12] 405608 0
Assessed at baseline, 3 months, 6 months post treatment.
Secondary outcome [13] 405609 0
Assessment of selective attention and cognitive flexibility as assessed by the Victoria Stroop Task.
Timepoint [13] 405609 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 or three fraction treatment and <35cc for fractionated treatment (five fractions).
• 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
Sex
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 primary endpoint of patients’ neurocognitive functioning (HVLT) at 3 months compared with baseline will be assessed using a non-inferiority analysis based upon a paired samples t-test. A nonparametric Wilcoxon paired samples test, as employed in RTOG 0933, will be undertaken if the assumptions of the above test are not met. Time to event analysis will employ Kaplan-Meier survival analysis, while other primary and secondary endpoints will be examined using methods appropriate for repeated measurements over time.
Non-inferiority analyses will be one-tailed, with alpha or statistical significance set to p < 0.025. All other statistical tests will be two-tailed, with alpha set to p < 0.05, and 95% confidence intervals reported where appropriate.

Recruitment
Recruitment status
Stopped early
Data analysis
Data collected is being analysed
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
Actual
11/09/2015
Date of last participant enrolment
Anticipated
30/09/2024
Actual
29/06/2022
Date of last data collection
Anticipated
30/04/2025
Actual
Sample size
Target
54
Accrual to date
Final
30
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 hospital [3] 21596 0
Icon Cancer Centre Greenslopes - Greenslopes
Recruitment hospital [4] 21597 0
Icon Cancer Centre Geelong - Waurn Ponds
Recruitment postcode(s) [1] 10229 0
3121 - Richmond
Recruitment postcode(s) [2] 36517 0
3216 - Waurn Ponds
Recruitment postcode(s) [3] 36516 0
4120 - Greenslopes
Recruitment postcode(s) [4] 25209 0
7000 - Hobart

Funding & Sponsors
Funding source category [1] 291955 0
Charities/Societies/Foundations
Name [1] 291955 0
Epworth Medical Foundation
Country [1] 291955 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Icon Cancer Foundation
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 brain (memory and cognitive) function. This study is for patients who are are aged 18 years or above and have been diagnosed with 3-10 cerebral metastases, i.e. the cancer has spread to three or more spots on the brain.

All participants in this study will receive a new treatment called Hypofractionated Stereotactic Radiotherapy. This is highly focused radiation given in one to five treatments. Robotic targeting is used to avoid important parts of the normal brain. Whereas previous treatment for multiple sites of cancer within the brain has involved giving radiation to the whole brain, this treatment will allow for targeted treatment of just the affected areas. In this way, the dose of radiation delivered to key areas of the brain involved with memory function can be minimised.

All participants will be monitored throughout treatment for safety. At the beginning of the study, and then at 3 and 6 months following treatment, patients will be asked to undergo MRI scans to assess disease control, have assessments of neurocognitive function by a trained neuropsychologist, and complete quality of life questionnaires. 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 Kevin So
Address 57714 0
Icon Cancer Centre Richmond
Level 4, 32 Erin St
Richmond VIC 3121
Country 57714 0
Australia
Phone 57714 0
+61 3 99368269
Fax 57714 0
Email 57714 0
kevin.so@icon.team
Contact person for public queries
Name 57715 0
Dr Lloyd Smyth
Address 57715 0
Icon Group, Level 1/22 Cordelia St, South Brisbane QLD 4101
Country 57715 0
Australia
Phone 57715 0
+61 7 3737 4500
Fax 57715 0
Email 57715 0
research.iit@icon.team
Contact person for scientific queries
Name 57716 0
Dr Kevin So
Address 57716 0
Icon Cancer Centre Richmond
Level 4, 32 Erin St
Richmond VIC 3121
Country 57716 0
Australia
Phone 57716 0
+61 3 99368269
Fax 57716 0
Email 57716 0
kevin.so@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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.