Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619001218189p
Ethics application status
Submitted, not yet approved
Date submitted
16/08/2019
Date registered
3/09/2019
Date last updated
15/09/2020
Date data sharing statement initially provided
3/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Volumetric Modulated Arc Therapy (VMAT) Irradiation in Skin Cancer Incidence Prevention
Scientific title
Volumetric Modulated Arc Therapy (VMAT) Irradiation in Skin Cancer Incidence Prevention: A randomised, open-label, single arm, phase II, controlled trial
Secondary ID [1] 297830 0
Nil
Universal Trial Number (UTN)
U1111-1230-8218
Trial acronym
VMAT-SCIP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
basal cell carcinoma 312199 0
squamous cell carcinoma 314168 0
keratotic skin lesions 314169 0
Condition category
Condition code
Cancer 310744 310744 0 0
Non melanoma skin cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Volumetric modulated arc therapy (VMAT) irradiation.

VMAT will be deliver a total dose of 45 Gy in 25 fractions (1.8 Gy per fraction per day). Only one of two legs of an individual participant will receive VMAT treatment. The untreated leg will serve as the comparator/control.

The treatment will occur in two separate segments. The first segment will deliver 10-12 radiation fractions over 2 - 2.5 weeks. This will be followed by a mandatory mid-treatment break of at least 2 weeks (extended up to 4 weeks if necessary). The second treatment segment will deliver the remainder of the 25 fractions (13 - 15 fractions, depending on the number of prior fractions delivered) over 2.5 - 3 weeks. The delivery of each daily fraction will take approximately 20 minutes. Treatments will occur only on weekdays between 9 am - 5 pm. Qualified radiation therapists will administer the intervention.

The overall treatment period will last no longer than 10 weeks.

The GenesisCare Skin Cancer Reference Group will oversee the quality assurance of the VMAT within the trial to ensure the safety and consistency of radiotherapy delivery at treatment site. Prior to inclusion in the trial, individual centres will demonstrate they have robust procedures in place to ensure the appropriate VMAT guidelines are met.
Patient specific pre-treatment quality assurance (QA) is required for all VMAT cases and must show a pass result before delivery of the first fraction. In vivo dosimetry is required for all VMAT limb cases and should be performed at or before fraction three to verify that the delivered dose is within 10% of the prescription dose
Intervention code [1] 314067 0
Prevention
Comparator / control treatment
Each participant will have only one leg treated with VMAT. The untreated leg will serve as the comparator/control.
Control group
Active

Outcomes
Primary outcome [1] 319593 0
Number of incident histologically proven BCC, SCC and keratotic lesions on the irradiated and control legs of patients with a past history of one or more histologically proven keratinocyte cancers (BCC or SCC) on the lower limbs as assessed by clinical examination.
Timepoint [1] 319593 0
24 months after completion of radiation therapy
Secondary outcome [1] 368813 0
The time from the end of study treatment to the first histologically proven BCC or SCC on the irradiated and control legs of patients with a past history of one or more histologically proven keratinocyte cancers (BCC or SCC) on the lower limbs as assessed by clinical examination.
Timepoint [1] 368813 0
Follow up visits at 28 days, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months after completion of radiation therapy
Secondary outcome [2] 368814 0
To evaluate the tolerability and feasibility of VMAT irradiation, as determined by adverse events and number of patients completing treatment, to the lower limb (to a skin surface area of >50 cm^3) for patients with a past history of one or more histologically proven keratinocyte cancers (BCC or SCC) on the lower limbs.

Participants will be queried on any adverse events by the clinical team at each of the associated visits listed. Additionally, participants are advised to contact the medical team at any time if they are feeling unwell.

Two separate questionnaires (The Dermatology Life Quality Index (DLQI) and a lymphoedema-specific questionnaire) will determine the impact of treatment on the quality of life of the participants. The DLQI questionnaire is a standard, validated instrument designed for routine clinical use. The lymphoedema-specific questionnaire was designed by the ALERT (Australian Lymphoedema Education, Research and Treatment) team at MQ Health, Macquarie University, for the assessment of the impact of lymphoedema on patients' quality of life.

Additionally, a pain of skin assessment will be conducted and this will be participant-reported and clinician recorded.

Limb assessments will be performed at each of the following visits in order to determine any toxicities associated with the VMAT treatment. These include:
1. The skin condition will be scored according to CTCAE terms for dermatitis radiation, superficial fibrosis, skin ulceration and lymphoedema.
2. Measurement of limb circumference - this will be performed in order to measure oedema volume which is a potential side effect of radiation treatment
3. A skin infection assessment will be carried out according to CTCAE
4. Leg circulation will be assessed by looking for signs of pitting oedema, leg ulcer or intermittent claudication, lower limb pulse palpation

Eastern Cooperative Oncology Group (ECOG) performance status - This scale describes a patient's level of functioning in terms of their ability to care for themselves, daily activity and physical ability. The scale is used to define the population of patients to be studied in the trial and to track changes in a patient’s level of functioning as a result of treatment during the trial
Timepoint [2] 368814 0
Mid-treatment visit (2 - 2.5 weeks after treatment commencement)
End of treatment visit (10 weeks after treatment commencement) and
Follow up visits at 28 days, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months after completion of radiation therapy
Secondary outcome [3] 368815 0
The Dermatology Quality of Life Index (DLQI) 12 and 24 months after radiation treatment compared to the DLQI at baseline for patients with a past history of one or more histologically proven keratinocyte cancers (BCC or SCC) on the lower limbs as provided by the participant and assessed by the medical team.
Timepoint [3] 368815 0
Baseline
Follow up visits at 12 months and 24 months after completion of radiation therapy
Secondary outcome [4] 368816 0
The pain of skin NCI CTCAE measure at baseline, during radiation treatment and at follow-up points for the irradiated and control legs for patients with a past history of one or more histologically proven keratinocyte cancers (BCC or SCC) on the lower limbs as reported by the participant and recorded by the medical team.
Timepoint [4] 368816 0
At baseline,
Mid-treatment visit (2 - 2.5 weeks after treatment commencement)
End of treatment visit (10 weeks after treatment commencement) and
During all follow up visits at 28 days, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months after completion of radiation therapy
Secondary outcome [5] 373957 0
The incidence and functional impact of lymphoedema following VMAT treatment for field cancerisation of the lower limb (determined by limb circumference measurements/volume calculation) as assessed by clinical examination.
This is a composite outcome.
Timepoint [5] 373957 0
Baseline,
Mid-treatment visit (2 - 2.5 weeks after treatment commencement)
End of treatment visit (10 weeks after treatment commencement) and
During all follow up visits at 28 days, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months after completion of radiation therapy
Secondary outcome [6] 373958 0
The mutation load of the skin of the radiated leg six months after radiation treatment with the mutation load of the control leg for patients with a past history of one or more keratinocyte cancers (BCC or SCC) on the lower limbs. This will be achieved by performing target sequencing of 153 oncogenes of skin biopsies taken at baseline and at six months after radiation treatment. The mutation load will be compared to the germline DNA of saliva samples obtained six months after radiation treatment.

This will be achieved through standard laboratory practices.
Timepoint [6] 373958 0
Follow up visit 6 months after radiotherapy
Secondary outcome [7] 373959 0
To evaluate proliferative potential and senescence of dermal fibroblasts in the skin of the radiated leg six months after radiation treatment with the mutation load of the control leg for patients with a past history of one or more keratinocyte cancers (BCC or SCC) on the lower limbs.
This is a composite outcome.
Timepoint [7] 373959 0
Follow up visit 6 months after radiotherapy

Eligibility
Key inclusion criteria
1. Aged 70 years or older.

2. Has provided written Informed Consent for participation in this trial.

3. Past history of two or more keratinocyte cancers (BCC or SCC) with at least one on lower limbs, Histologically confirmed disease OR past history of one or more keratinocyte cancers and multiple keratotic lesions on the lower limbs.

4. Life expectancy greater than three years.

5. Willing to use adequate contraception measures (both in vivo and in vitro) during and for six months after radiation treatment for participants who will engage in the conception of a child.

6. Available for follow-up for two years.
Minimum age
70 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous radiotherapy to either lower limb.

2. Previous field treatment (e.g. Fluorouracil (5-FU), Aldara Picato Photodynamic therapy) to area to be treated in past 12 months.

3. Chronic lymphoedema with pitting oedema, peripheral vascular disease in the form of intermittent claudication or critical ischaemia.

4. Chronic leg ulcer.

5. Relapsing leg cellulitis.

6. Active/untreated keratinocyte cancer (i.e. invasive BCC or SCC) on legs at the time of enrolment.

7. Patients with clinical evidence of metastatic disease from any primary cancer.

8. Solid organ transplant recipient

9. Genetic conditions predisposing to malignancies such as Gorlin Syndrome, Gardner’s syndrome and Fanconi Anaemia.

10. Use of any other systemic cancer therapeutic with significant cutaneous adverse reaction: Fluorouracil (5FU) based chemotherapeutics, epidermal growth factor receptor (EGFR) inhibitors,
immune checkpoint inhibitors, sorafenib, sunitinib and other tyrosine kinase inhibitors. (Patient’s will be considered eligible if they have a 28 day wash out period if these therapeutics are in use)

11. Connective tissue disorders: systemic lupus erythematosus, scleroderma.

12. Known radiation hypersensitivity syndrome and ataxia telangiectasia.

13. Radiosensitising medication including methotrexate

14. Any other condition as defined by the investigator which significantly impact the patient’s involvement and suitability in this study

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The legs will be randomised for treatment based on the selection with a computer program.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated using randomly sized blocks. No stratification is planned.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
It is assumed that across 58 patients there will be around seven SCC on the treated legs and around 22 SCC on the untreated legs in the 2-year follow-up period. For BCC, it is assumed across the 58 patients that there will be around 22 on the treated legs and 65 on the untreated legs. Counts of BCC/SCC follow a Poisson distribution. The above rates assume that for both BCC and SCC there is a 3-fold reduction for treated legs compared to untreated.

With a two-sided alpha set at 0.05, 58 patients provide a power of 80% to detect a 3-fold reduction in SCC and over 99% to detect a 3-fold reduction in BCC.

Sample size calculations were performed using PASS version 16.0.4.

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
Unable to establish an agreement on contracts
Date of first participant enrolment
Anticipated
1/04/2020
Actual
Date of last participant enrolment
Anticipated
3/05/2021
Actual
Date of last data collection
Anticipated
1/05/2023
Actual
Sample size
Target
58
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 14567 0
Princess Alexandra Hospital - Woolloongabba
Recruitment postcode(s) [1] 27582 0
4102 - Woolloongabba
Recruitment postcode(s) [2] 27584 0
4101 - South Brisbane

Funding & Sponsors
Funding source category [1] 302352 0
Commercial sector/Industry
Name [1] 302352 0
Varian
Country [1] 302352 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
GenesisCare
Address
41-43 Bourke Road, Alexandria,
NSW 2015
Country
Australia
Secondary sponsor category [1] 303656 0
None
Name [1] 303656 0
Address [1] 303656 0
Country [1] 303656 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 303026 0
Metro South Health Human Research Ethics (HREC) Office
Ethics committee address [1] 303026 0
Ethics committee country [1] 303026 0
Australia
Date submitted for ethics approval [1] 303026 0
14/08/2019
Approval date [1] 303026 0
Ethics approval number [1] 303026 0
Ethics committee name [2] 304179 0
Metro South Ethics Committee
Ethics committee address [2] 304179 0
Ethics committee country [2] 304179 0
Australia
Date submitted for ethics approval [2] 304179 0
14/08/2019
Approval date [2] 304179 0
11/10/2019
Ethics approval number [2] 304179 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 92214 0
Dr Andrew Potter
Address 92214 0
GenesisCare,
St Andrew's Hospital, 352 South Terrace,
Adelaide, SA 5000
Country 92214 0
Australia
Phone 92214 0
+61 8 82286700
Fax 92214 0
Email 92214 0
[email protected]
Contact person for public queries
Name 92215 0
Sophie Mepham
Address 92215 0
GenesisCare,
Level 5, 126 Wellington Parade,
East Melbourne,
VIC 3002
Country 92215 0
Australia
Phone 92215 0
+61 409 612 302
Fax 92215 0
Email 92215 0
[email protected]
Contact person for scientific queries
Name 92216 0
Kiarash Khosrotehrani
Address 92216 0
The University of Queensland Diamantina Institute
Faculty of Medicine
Level 7, 37 Kent St
Translational Research Institute (TRI)
Woolloongabba, QLD 4102
Country 92216 0
Australia
Phone 92216 0
+61 7 334 66077
Fax 92216 0
Email 92216 0
[email protected]

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.