ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12616000645459

Ethics application status

Approved

Date submitted

9/05/2016

Date registered

18/05/2016

Date last updated

21/01/2024

Date data sharing statement initially provided

11/04/2019

Type of registration

Retrospectively registered

Titles & IDs

Public title

A prospective audit of sentinel node biopsy for vulval carcinoma in Australia and New Zealand

Scientific title

Prospective collection of clinical data following sentinel node biopsy for vulval carcinoma in Australia and New Zealand

Secondary ID [1]

nil known

Universal Trial Number (UTN)

U1111-1182-6358

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Vulval carcinoma

Condition category

Condition code

Cancer

Other cancer types

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Prior to the operation and following application of emlar cream, 0.2-0.6 ml of 60-MBq technetium-99m–labeled nanocolloid (or similar) is injected by the surgeon intradermally in 4 locations around the primary tumour (0.05 ml each in each site) or clearly identifiable scar from recent excision biopsy. XRay pictures are then taken over the next 2 1/2 hours to identify the first appearing persistent focal accumulation or sentinel node. The site of the sentinel node is marked on the overlying skin.
On the day or the afternoon after the injection of the radioactive tracer, following induction of anesthesia for surgery, approximately 0.5-1.0 ml of the blue dye (eg. Patente blue-V) is injected intradermally on the same 4 locations around the primary tumor approximately 5-10 minutes prior to the surgical procedure. The surgical procedure starts with identification and removal of the sentinel nodes. During the operation a handheld gamma-ray-detection probe is used to confirm the marked area of greatest activity in the groin. A small skin incision is made at the marked spot and a sentinel node excision biopsy is performed using the handheld gamma-ray detector and by dissection of blue-stained lymph vessels. Sentinel nodes are sent to the pathologist. Subsequently resection of the vulvar lesion is performed.
Participation in this study is entirely voluntary. If women do not wish to take part in this study, they will receive one standard management of early vulval carcinoma which is wide excision or vulvectomy and removal of all groin nodes.

Intervention code [1]

Treatment: Surgery

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Recurrence in a groin with negative sentinel node as assessed clinically and entered on CRF

Timepoint [1]

at the time of recurrence and/or 24 months after surgery.

Secondary outcome [1]

Node positivity rate as assessed and entered on CRF

Timepoint [1]

At time of sentinel node procedure and surgery

Secondary outcome [2]

Disease recurrence at other sites as assessed clinically and entered on CRF

Timepoint [2]

At time of recurrence and/or at 3, 12, 24, 36, 48, and 60 months after surgery

Secondary outcome [3]

number of sentinel nodes detected using gamma-ray probe

Timepoint [3]

at the beginning of the surgical procedure

Secondary outcome [4]

Morbitity as assessed clinically and entered on CRF

Timepoint [4]

At 3, 12, 24, 36, 48, and 60 months after surgery

Secondary outcome [5]

length of Hospital stay after surgery

Timepoint [5]

at 3 months and entered on CRF

Secondary outcome [6]

Utility of immunohistochemistry stains entered onto CRF

Timepoint [6]

At final data analysis

Eligibility

Key inclusion criteria

.1. Able to give informed consent.
2. Early vulval carcinoma confirmed histologically (unifocal, invasive squamous cell carcinoma less than 4cm in greatest dimension - not including insitu component)
3. Depth of invasion greater than 1mm

Minimum age

18 Years

Maximum age

No limit

Sex

Females

Can healthy volunteers participate?

Key exclusion criteria

1. Tumour involves urethra, anus or middle 1/3 of vagina.
2. Reconstruction of the vulva using a flap has been performed with removal of the
primary lesion .
3. Clinical evidence of groin node metastasis.(palpation, imaging , FNA)
4. Prior history of SCC of the genital tract, anus, or lower body.
5. Prior groin node dissection

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)

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

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Statistical Considerations.
The following matters are taken into consideration.
a) Vulval carcinoma is a rare disease.
b) GROINSS study revealed a recurrence rate of 2.3% following negative sentinel nodes.
c) Expected node positivity rate between 10 and 30%
d) A groin recurrence rate of greater than 5% in women with negative sentinel nodes would be considered unacceptable.
e) Recruitment will continue until 31 August 2024. The study follow up period will continue for a minimum of 24 months (and up to 60 months) post-surgery for each woman.
Statistical review by Biostatistician Elisabeth Wells, Public Health and General Practice, University of Otago – Christchurch is reproduced below:

Sample Size for Frequency in a Population
________________________________________
Population size(for finite population correction factor or fpc)(N): 1000000
Hypothesized % frequency of outcome factor in the population (p): 3%+/-2
Confidence limits as % of 100(absolute +/- %)(d): 2%
Design effect (for cluster surveys-DEFF): 1

Sample Size(n) for Various Confidence Levels

Confidence Level(%) Sample Size
95% 280
80% 120
90% 197
97% 343
99% 483
99.9% 788
99.99% 1101

Equation
Sample size n = [DEFF*Np(1-p)]/ [(d2/Z21-a/2*(N-1)+p*(1-p)]

Results from OpenEpi, Version 2, open source calculator--SSPropor
http://www.openepi.com/SampleSize/SSPropor.htm

It would be prudent to plan the study to allow for the possibility that centres may differ somewhat, because of differences in treatment regimes or in the characteristics of patients. The statistical impact of clustering within centres is captured by the DEFF (design effect) which is the ratio of the variance of an estimate from a complex sample compared with that from a simple random sample.
DEFF = 1 + (m-1)p where m is the average cluster size (n per centre), and
p(rho) is the coefficient of intra-class correlation
Let m=13 and
p=.03 (a lowish value as patient within a centre would not be expected to be much more similar to each other than to patients at other centres)
DEFF = 1 + (13-1)*.03 = 1.36
Therefore the number required for the 95% CI to be below 5% would be 280*1.36 = 380.

Recruitment

Recruitment status

Stopped early

Data analysis

Data collected is being analysed

Reason for early stopping/withdrawal

Lack of funding/staff/facilities
Other reasons/comments

Other reasons

The Primary endpoint of the study was cancer recurrence in a groin with "negative sentinel groin nodes" after 24 months of follow up, A groin recurrence rate of greater than 5% in women with negative sentinel nodes would be considered unacceptable.

Power analysis had provided a total recruitment target of at least 280 women (95% CI to be below 5%). However, an ideal target of 380 women was set to allow for the possibility that recruitment centres may differ somewhat, because of differences in treatment regimens or in the characteristics of patients (Statistical considerations detailed above).

Power analysis included an allowance of 30% of women having positive sentinel nodes and a recurrence rate of 2.3%. Ultimately, the proportion of women excluded from primary analysis due to a positive sentinel node (22%) was lower than the predicted upper estimate (30%) and the groin recurrence rate in women with a negative node (1%) was well below the undesirable level of 5% (p 0.001).

The study had already run for longer than initially forecast (including a period of non-recruitment for a pathology protocol audit) and funding was at an end.

Ultimately, 316 women were recruited. While recruitment did not meet the ideal target of 380, it exceeded the minimum recruitment target of 280.

Due to the reasons outlined above, it was decided to cease recruitment on 31st December 2023.

Date of first participant enrolment

Anticipated

Actual

20/12/2010

Date of last participant enrolment

Anticipated

31/08/2024

Actual

28/11/2023

Date of last data collection

Anticipated

28/11/2025

Actual

Sample size

Target

380

Accrual to date

Final

316

Recruitment in Australia

Recruitment state(s)

NSW,QLD,TAS,WA,VIC

Recruitment hospital [1]

Westmead Hospital - Westmead

Recruitment hospital [2]

The Royal Women's Hospital - Parkville

Recruitment hospital [3]

Royal Hobart Hospital - Hobart

Recruitment hospital [4]

St John of God Hospital, Subiaco - Subiaco

Recruitment hospital [5]

Mater Private Hospital - South Brisbane

Recruitment hospital [6]

John Hunter Hospital - New Lambton

Recruitment postcode(s) [1]

4101 - South Brisbane

Recruitment postcode(s) [2]

2305 - New Lambton

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Christchurch

Country [2]

New Zealand

State/province [2]

Otago

Country [3]

New Zealand

State/province [3]

Wellington

Country [4]

New Zealand

State/province [4]

Auckland

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Otago Christchurch

Address [1]

Private Bag 4711
Christchurch 8140

Country [1]

New Zealand

Funding source category [2]

Other

Name [2]

Robert McClelland Trust Board

Address [2]

Estate of Robert McClelland
C/- Public Trust Charitable Services, Private Bag 17906, Greenlane, Auckland. 1546

Country [2]

New Zealand

Funding source category [3]

Charities/Societies/Foundations

Name [3]

GRACI Foundation (The Gynaecological Cancer Research Trust)

Address [3]

PO Box 36665, Merivale, Christchurch. 8146

Country [3]

New Zealand

Funding source category [4]

Charities/Societies/Foundations

Name [4]

Australian Society of Gynaecologic Oncologists (ASGO)

Address [4]

ASGO Secretariat
c/o YRD Event Management
PO Box 717, Indooroopilly, QLD 4068, AUSTRALIA

Country [4]

Australia

Primary sponsor type

University

Name

University Of Otago Christchurch

Address

Private Bag 4711
Christchurch 8140

Country

New Zealand

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

HDEC Multi-region ethics Committee

Ethics committee address [1]

PO Box 5013
Wellington 6145

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

01/06/2010

Approval date [1]

31/08/2010

Ethics approval number [1]

MEC/10/07/063

Summary

Brief summary

This study aims to prospectively collect clinical data following sentinel node biopsy for vulval carcinoma in Australia and New Zealand. You may be eligible to join this study if you are a female aged 18 years or above with histologically confirmed, unifocal invasive squamous cell carcinoma of vulva less than 4cm in greatest dimension. 
Women in Australia and New Zealand women with early vulval cancer will be offered sentinel node procedures in place of groin node dissection. 
On the day before or the morning of your operation, you will have a small injection of a radioactive marker into the skin next to the cancer. A local anaesthetic cream will be used to reduce any discomfort from this injection. Pictures will then be taken over the next 2 1/2 hours to see which glands the marker has spread to. The marker will also help us find the ‘sentinel nodes’ during your operation.
Either on the afternoon after the injection or the next day you will have your operation as planned by your doctor. Whilst you are asleep we will inject some blue dye around the cancer which will also help us to identify the sentinel glands. During the 60 minute operation we will remove the cancer. We will identify and remove the sentinel lymph gland(s) from one or both groins. When sentinel nodes in one or two groins can not be identified a full removal of the groin nodes (lymphadenectomy) on either one or both sides will be performed. The gland(s) will be sent to the laboratory for detailed assessment by the pathologist. 
Follow up clinical data will be collected from your clinical records at 3, 12, and 24 months after surgery (and at, 36, 48, and 60 months where possible), from information obtained when you attend outpatients clinic. 
The majority of women with early vulval carcinoma do not have groin node metastasis and these women are unlikely to benefit from groin node dissection. The use of sentinel node dissection is safe and should be part of the standard treatment for women with early stage vulvar cancer.

Trial website

Trial related presentations / publications

Sykes PH. et al. (2015) Abstract presentation at  ANZGOG Annual Scientific Meeting. Groin Recurrence Following Negative Sentinel Node Biopsy. A report from the “Prospective Audit of Sentinel Node Biopsy for Vulval Cancer in Australia and New Zealand” Sykes PH et al. (2016) Abstract presentation at ASGO Annual Scientific Meeting. The crucial nature of pathology in sentinel node biopsy procedures for vulvar cancer.

Public notes

Contacts

Principal investigator

Name

A/Prof Peter Hugh Sykes

Address

Department of O & G
University of Otago - Christchurch
2 Riccarton Avenue
Private Bag 4711
Christchurch 8140

Country

New Zealand

Phone

+64 3 364 4630

Fax

+64 3 364 4634

peter.sykes@otago.ac.nz

Contact person for public queries

Name

Dianne Harker

Address

Dept O & G
University of Otago - Christchurch
Christchurch Women's Hospital
2 Riccarton Avenue
Private Bag 4711
Christchurch 8140

Country

New Zealand

Phone

+64 3 364 4624

Fax

+64 3 364 4634

dianne.harker@otago.ac.nz

Contact person for scientific queries

Name

Peter Sykes

Address

Dept O & G
University of Otago - Christchurch
Christchurch Women's Hospital
2 Riccarton Avenue
Private Bag 4711
Christchurch 8140

Country

New Zealand

Phone

+64 3 364 4630

Fax

+64 3 364 4634

peter.sykes@otago.ac.nz

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

We did not indicate that we would be sharing IPD when we applied for ethical approval for our study. There are no plans for IPD sharing.

What supporting documents are/will be available?

Doc. No.	Type	Email
7715	Study protocol	peter.sykes@otago.ac.nz
7716	Informed consent form	peter.sykes@otago.ac.nz
7717	Ethical approval	peter.sykes@otago.ac.nz

Results publications and other study-related documents

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No additional documents have been identified.

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