Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000831987
Ethics application status
Approved
Date submitted
11/06/2020
Date registered
21/08/2020
Date last updated
6/06/2023
Date data sharing statement initially provided
21/08/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
Magnetic Sentinel Lymph Node Mapping in Oral Squamous Cell Carcinoma: A Phase I Feasibility and Validity Clinical Trial
Scientific title
Magnetic Sentinel Lymph Node Mapping in Oral Squamous Cell Carcinoma: A Phase I Feasibility and Validity Clinical Trial
Secondary ID [1] 301483 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Oral Cancer 317813 0
Condition category
Condition code
Cancer 315872 315872 0 0
Head and neck

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients undergoing surgery to remove a proven T1-T2 oral squamous cell carcinoma (SCC) and associated elective neck dissection (END).

Patients will receive a single dose of MagTrace or FerroTrace magnetic tracer (Endomag, Cambridge UK or Ferronova, Adelaide Australia). FerroTrace will be used on the first patient, and thereafter the selected tracer will be at the discretion of the principal investigator. The tracer will be delivered via intra-oral sub mucosal injection around the tumour in 5 injections at 12-, 3-, 6-, and 9- o’clock positions around the periphery of the tumour and then another injection deep to the tumour. The total dose for the first injection will be 0.5ml (5 x 100ul), and if this injection volume is not sufficient to demonstrate feasibility to locate the sentinel nodes in surgery, the dose will be increased at the discretion of the principal investigator, but to no more than 2ml (5 x 400ul).

Patients will undergo MRI prior to and then following tracer injection to localize lymph nodes (LNs) with tracer uptake and assess tracer distribution within nodes. Areas of low signal intensity thought to represent putative SLNs will be documented. The first patient will undergo the MRI both the day before and the day of surgery. Subsequent patients will have the MRI timing decided at the discretion of the principal investigator.

Surgical resection of the oral cancer will be carried out prior to treatment of the neck. Prior to surgical removal of neck nodes, the hand-held magnetometer probe will be used to conduct an initial detection survey of the entire cervical lymph node basin to identify the areas of increased magnetic activity representing putative SLNs. The probe, in conjunction with pre-operative imaging, will be used to find the putative SLN, which will be identified if the magnetic reading exceeds 3 standard deviations above the mean normal tissue background count and/or if the node demonstrates a colour change to black/brown due to the stain of the tracer. If more than 4 LNs meet these criteria, at least 4 SLNS with the highest magnetic activity will be excised and denoted putative SLNs. After removal of all SLNs meeting these criteria, the magnetometer probe will be placed back within the nodal basin to ensure that no substantial residual magnetic activity remains.

After removal of all sentinel lymph nodes (SLNs), all participants will undergo a planned END. Lymph node levels I, II (including IIB), III and IV will be removed at the discretion of the surgeon and following hospital protocols. Bilateral neck dissections will be performed when primary lesions involve the midline or in the case of tumours less than 1 cm from the midline with evidence of contralateral drainage on pre-operative serial MRI at the discretion of the surgeon and following clinical team consensus.

All SLNs will be labeled individually according to the surgical location. These will be fixed in formalin and cut in a transverse fashion along the long axis every 2mm. Slides from these sections will undergo initial evaluation by means of standard hematoxylin-eosin (H&E) staining. SLNs with findings of metastases on H&E assessment will be deemed positive nodes. SLNs that are negative for metastases on H&E assessment will be further evaluated with immunohistochemical staining for pancytokeratin markers. Non-SLNs in the END will undergo routine histopathological analysis with H&E staining of a single section carried out along the longitudinal axis of the node. Putative SLNs will undergo Prussian blue staining to identify presence of magnetic particles.

We will evaluate the feasibility and safety of the new technology. Data surrounding timings of tracer injection and flow to first and second echelon nodes will be collected to optimize timing of surgery. SLN detection rate will be recorded and tabulated for each patient and we will also record the rate of SLN detection per node, malignancy detection rate in participants, and the negative predictive value (NPV), ie. whether a negative SLN will predict negativity of the other cervical LNs.




Intervention code [1] 317793 0
Diagnosis / Prognosis
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 324078 0
1. Feasibility - Composite primary outcome
- Dosing of tracer
- Optimum timing of MRI and surgery post-tracer injection
- Duration of imaging and assessment of flow to second echelon nodes
- Duration of surgery

For each dosing of tracer, the feasibility of detecting sentinel nodes on MRI, the timing of MRI, and the feasibility and time to detect sentinel nodes in surgery will be assessed. It will either be feasible or not.

The patient record forms record all data required to determine these endpoints (dose, MRI images at each timepoint with the radiologists assessment, magnetometer probe signals for every node invivo and exvivo).
Timepoint [1] 324078 0
At time of hospital discharge. Within 1 week post surgery
Primary outcome [2] 324079 0
SLN detection rate - Composite primary outcome
- SLN detection rate per patient
- SLN detection rate per node (determined from MRI radiology assessment and confirmed with magnetometer probe signal)
- SLN malignancy detection rate (determined from H&E staining)
Negative predictive value (NPV) of SLNB
- Defined as the proportion of participants who are negative with respect to other cervical LNs among the participants who are classified as SLN negative
The pathology records are used to determine these end-points.
Timepoint [2] 324079 0
At time of pathological assessment of Sentinel Lymph Node biopsy, as well as of all non Sentinel Lymph Node biopsies. Within 1 week post-surgery
Primary outcome [3] 324080 0
Risk profile - Composite primary outcome
- Rate of general peri-operative complications (as recorded in the patients medical records and including seroma's, wound infections etc)
- Rate of marginal mandibular nerve weakness (a complication specific to this procedure(determined from clinical assessment)
- Skin staining (determined from clinical assessment)
- Tracer clearance (determined by follow up MRI as assessed by the radiologist)
These risks will be assessed by the investigators during clinical followup at the 3 month and 6 month MRI scans.
Timepoint [3] 324080 0
3 months and 6 months post-surgery
Secondary outcome [1] 383694 0
Feasibility of pre-operative MRI
- Feasibility of MRI following tracer injection for pre-operative SLN localization

The outcome will be assessed by a subjective analysis of the MRI image by the radiology co-investigator, assessing whether the resolution and distribution of the Tracer on the MRI is sufficient to identify the sentinel nodes
Timepoint [1] 383694 0
At the time of preoperative MRI
Secondary outcome [2] 383695 0
Surgeon Learning curve
- Change in surgeon SLN detection sensitivity, NPV and FNR with number of procedures performed
The outcome will be assessed by analysis of pathology records.
Timepoint [2] 383695 0
At the time of surgery
Secondary outcome [3] 384996 0
Potential role of MRI and magnetic tracer for non-invasive identification of LN metastases

The outcome will be assessed by a subjective analysis of the MRI image by the radiology co-investigator, assessing whether the resolution and distribution of the Tracer on the MRI is sufficient to potentially diagnose metastasis in tumour.
Timepoint [3] 384996 0
At the time of preoperative MRI
Secondary outcome [4] 384997 0
Surgeon Learning curve
- Change in time from skin Incision to node detection with number of procedures performed

The outcome will be assessed by recording time from skin incision to node detection for each procedure, and analysis of patient records.
Timepoint [4] 384997 0
At the time of surgery

Eligibility
Key inclusion criteria
- Age 18 or older
- Willing to provide informed consent
- ECOG status 0-2
- Biopsy proven T1-T2 oral SCC (tongue, RMT, buccal mucosa, FOM, hard palate)
- Clinically and radiologically N0 neck on contrast enhanced CT or gadolinium enhanced MRI +/- (USS or FDG PET)
- No distant metastases
- Primary tumours amenable to surgical resection


Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Serious medical comorbidities or other contraindications to surgery +/- adjuvant therapy
- Advanced T-stage primary tumour (>T2)
- Primary tumours not amenable to surgical resection
- Previous HNSCC
- Previous head and neck radiotherapy at any time
- Lip involvement
- Allergy or Intolerance to iron oxide or dextran compounds
- Metal implant close to site of sentinel lymph node
- Iron overload disorder
- Standard contraindications to MRI scanning
- Pregnant or lactating women

Study design
Purpose of the study
Diagnosis
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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
2/07/2020
Date of last participant enrolment
Anticipated
31/12/2021
Actual
25/03/2022
Date of last data collection
Anticipated
1/01/2022
Actual
30/09/2022
Sample size
Target
16
Accrual to date
Final
15
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 16857 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 30506 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 305921 0
Government body
Name [1] 305921 0
NHMRC Development Grant
Country [1] 305921 0
Australia
Primary sponsor type
Hospital
Name
Central Adelaide Local Health Network trading as Royal Adelaide Hospital
Address
CALHN Research Office
RAH Clinical Trial Centre
Wayfinder 3D460.02
Level 3, Royal Adelaide Hospital
Port Road, Adelaide SA 5000
Country
Australia
Secondary sponsor category [1] 306377 0
None
Name [1] 306377 0
Address [1] 306377 0
Country [1] 306377 0
Other collaborator category [1] 281358 0
Other Collaborative groups
Name [1] 281358 0
Dr Jones & Partners Medical Imaging, South Australian Medical and Health Research Institute
Address [1] 281358 0
2 North Terrace,
Adelaide SA 5000
Country [1] 281358 0
Australia
Other collaborator category [2] 281359 0
University
Name [2] 281359 0
University of Adelaide
Address [2] 281359 0
Adelaide SA 5005
Country [2] 281359 0
Australia
Other collaborator category [3] 281360 0
University
Name [3] 281360 0
University of South Australia
Address [3] 281360 0
MM Building,
Mawson Lakes Blvd
Mawson Lakes SA 5095
Country [3] 281360 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306170 0
Central Adelaide Local Health Network Human Research Ethics Committee (CALHN HREC)
Ethics committee address [1] 306170 0
Ethics committee country [1] 306170 0
Australia
Date submitted for ethics approval [1] 306170 0
27/04/2020
Approval date [1] 306170 0
08/05/2020
Ethics approval number [1] 306170 0
HREC/19/CALHN/44

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

Contacts
Principal investigator
Name 102958 0
Dr Andrew Foreman
Address 102958 0
Royal Adelaide Hospital
Port Road, Adelaide SA 5000
Country 102958 0
Australia
Phone 102958 0
+61 8 8222 7158
Fax 102958 0
Email 102958 0
[email protected]
Contact person for public queries
Name 102959 0
Giri Krishnen
Address 102959 0
Royal Adelaide Hospital
Port Road, Adelaide SA 5000
Country 102959 0
Australia
Phone 102959 0
+61 8 8222 7158
Fax 102959 0
Email 102959 0
[email protected]
Contact person for scientific queries
Name 102960 0
Giri Krishnen
Address 102960 0
Royal Adelaide Hospital
Port Road, Adelaide SA 5000
Country 102960 0
Australia
Phone 102960 0
+61 8 8222 7158
Fax 102960 0
Email 102960 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
SourceTitleYear of PublicationDOI
EmbasePreclinical feasibility of robot-assisted sentinel lymph node biopsy using multi-modality magnetic and fluorescence guidance in the head and neck.2022https://dx.doi.org/10.1002/hed.27177
Dimensions AINanoparticles Targeted to Fibroblast Activation Protein Outperform PSMA for MRI Delineation of Primary Prostate Tumors2023https://doi.org/10.1002/smll.202204956
N.B. These documents automatically identified may not have been verified by the study sponsor.