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Trial registered on ANZCTR


Registration number
ACTRN12614000721606
Ethics application status
Approved
Date submitted
12/06/2014
Date registered
8/07/2014
Date last updated
9/01/2023
Date data sharing statement initially provided
11/09/2019
Date results information initially provided
18/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of Groin Lymphadenectomy Extent For metastatic Melanoma
Scientific title
Inguinal or Ilio-inguinal Lymphadenectomy for patients with metastatic melanoma to groin lymph nodes and no evidence of pelvic disease on PET/CT Scan - A randomised phase III trial to evaluate survival, morbidity, and quality of life ( 01.12 EAGLE FM Trial)
Secondary ID [1] 284747 0
MASC 01.12
Secondary ID [2] 284933 0
NCT02166788 (Clintrials.gov Trial Registry Number)
Universal Trial Number (UTN)
Trial acronym
EAGLE FM
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic melanoma 292114 0
Condition category
Condition code
Cancer 292446 292446 0 0
Malignant melanoma
Surgery 292505 292505 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Inguinal Lymphadenectomy (IL) is removal of the easily accessible superficial groin lymph nodes (LNs) and has a median LN retrieval of 11 whereas with Ilio-inguinal Lymphadenectomy (I-IL) there is removal of the same superficial groin LNs but also combined with the more surgically complex removal of the ipsilateral pelvic LN. About twice as many LN are removed with I-IL compared to IL. The approximate duration of both procedures is 3 hours.

Arm 1: Inguinal Lymphadenectomy
Arm 2: Ilio-inguinal Lymphadenectomy
Intervention code [1] 289533 0
Treatment: Surgery
Comparator / control treatment
Neither of the 2 arms in the study is a comparator or control arm. Currently surgeons have polarised opinions on whether to perform a limited or more extensive lymphadenectomy, with strong arguments made for each option by respected experts. To date there is no high level evidence to show either is superior.
Control group
Active

Outcomes
Primary outcome [1] 292306 0
Disease Free Survival following lymphadenectomy. This outcome will be assessed using the time interval to the first sign of histologically confirmed melanoma recurrence.
Timepoint [1] 292306 0
60 Months
Secondary outcome [1] 308690 0
Overall Survival
Timepoint [1] 308690 0
Within the 10 year follow up
Secondary outcome [2] 308778 0
Distant Disease Free Survival. This outcome will be assessed using the time interval to histologically confirmed metastatic recurrence.
Timepoint [2] 308778 0
Within the 10 year follow up
Secondary outcome [3] 308779 0
Regional Recurrence-Free Survival. This outcome will be assessed using the time interval to histologically confirmed metastatic recurrence.
Timepoint [3] 308779 0
Within the 10 year follow up
Secondary outcome [4] 308780 0
Morbidity differences including lymphoedema, and short and long term surgical related morbidities. Adverse events and lymphoedema questionnaires will assess all events.

For purposes of the evaluation, major surgical complications may include any of the following:

*Seroma/Haematoma requiring intervention beyond aspiration up to and including 3 times
*Haemorrhage requiring return to the operating theatre or transfusion >2 units of packed cells
*Post-operative wound healing complications that require debridement, formal reconstruction or further surgery to attain wound closure.
*Post-operative infection requiring admission for intravenous antibiotics; or requiring incision and drainage as well as antibiotics as an outpatient
*Wound necrosis/healing problems delaying skin healing by more than 3 weeks
*Chronic pain requiring medication >12 weeks post-operatively
*A prolonged admission (>10 days) after nodal surgery due to complications related to the regional operation
*Demonstrated motor nerve damage
*Subcutaneous tissue fibrosis – clearly noticeable compared to “normal” to surgeon > 6 months after surgery
*Thrombophlebitis requiring intravenous antibiotics at an intravenous site
*Urinary Tract Infection, Urinary Retention
*Percutaneous or open pelvic drain replacement required in the post-operative period
*Cardiac complications requiring monitoring > 12 hours or a other cardiac intervention or introduction of new cardiac medication
*DVT / pulmonary embolus
*Lymphoedema defined as a volume change of greater than 10% compared to the unaffected limb OR a lymphoedema index change of 10 points on bioimpedance
*Other significant complications should be reported

The LYMQOL-LEG questionnaire is a validated condition-specific QoL assessment tool which can be used for lymphoedema of the limbs both in clinical assessment and as an outcome measure.
Timepoint [4] 308780 0
Within 120 days of surgery and within the 10 year follow up
Secondary outcome [5] 308781 0
Quality of Life. This outcome will be assessed by using EORTC QLQ-C30.
Timepoint [5] 308781 0
Within the 10 year follow up. Quality of Life (QOL) will be collected regularly throughout the study during Baseline, every 3 months between Baseline to Year 2, every 6 months between Year 2 to Year 5, and annually between Year 5 to Year 10.
Secondary outcome [6] 308782 0
Sensitivity / specificity and PPV and NPV of PET/CT and CT scan for pelvic disease
Timepoint [6] 308782 0
Within the 10 year follow up
Secondary outcome [7] 308783 0
Resource use and utility based QOL. A health resource questionnaire and the EORT EQ 5D 5L will be used throughout the study to assess this outcome.
Timepoint [7] 308783 0
at 60 months
Secondary outcome [8] 308784 0
Provide a resource of tissue and blood for evaluation of biological markers predictive of outcome in resected stage III disease
Timepoint [8] 308784 0
Within the 10 year follow up

Eligibility
Key inclusion criteria
Patients may be included in the study only if they meet all of the following criteria:
1. Must be 15 and above.
2. Have primary cutaneous melanoma or if the patient presents with stage III melanoma with no known primary tumour then a thorough search for the primary should be documented (including perineal and perianal areas)
3. Life expectancy of at least 10 years from the time of diagnosis, not considering the melanoma in question, as determined by the PI
4. Must have one or multiple inguinal node(s) involved, histologically or cytologically proven as metastatic melanoma. This can can be detected:
a. At the time of diagnosis;
b. Or by Ultrasound detection;
c. Or later after relapse when no Sentinel Node Biopsy (SNB) was performed at the time of primary tumour management;
d. Or as a result of SNB;
e. Or at the time of regional recurrence after “false negative” SNB;
f. Absent distant disease clinically and on PET/CT scan. (Patients must have NO further distant disease or visceral metastases)
6. ECOG performance status must be between 0 to 2 at randomisation
7. Whole body PET/CT scan, specifically stating there is NO evidence of pelvic lymph node involvement prior to randomisation and a CT Brain or MRI Brain scan. Scans must be performed within 6 weeks prior to randomisation.
8. Able to provide written, informed consent
9. Willing to return to the centre for follow up examinations and procedures, as outlined in the protocol.
10. All patients must be randomised and undergo lymphadenectomy surgery no more than 120 days following diagnosis of inguinal LN involvement
Minimum age
15 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded from the study for any of the following reasons:
1. Distant metastatic disease on clinical examination or staging imaging (CT/MRI brain or whole body PET/CT scan). Scans must be performed within 6 weeks prior to randomisation
2. Pelvic LN involvement on SNB or PET/CT scan suggestive of metastatic disease in the pelvis – criteria for diagnosis include normal size or enlarged lymph nodes (> 1 cm) with increased FDG activity on PET (SUV >3). If there are enlarged, necrotic lymph nodes FDG activity on PET is not required to be present. If unsure central review should be sought.
3. Bilateral inguinal lymph node involvement
4. Patients with a history of major pelvic surgery and / or regional radiotherapy at any time in the past
5. Requiring planned radiotherapy following surgery due to macroscopic, bulky and matted nodes.
6. Unfit for General Anaesthesia
7. Melanoma-related operative procedures not corresponding to criteria described in the protocol
8. Patients with prior cancers, except:
a. those with a thin <=1 mm, regionally unrelated melanoma > 5 years ago
b. Those with a good prognosis regionally unrelated cancer (>90% probability of 10 years disease specific survival)
c. Other cancers diagnosed more than five years ago with no evidence of disease recurrence within this time
d. Successfully treated basal cell and squamous cell skin carcinoma
e. Carcinoma in-situ of the cervix
f. 1 episode of in transit melanoma > 3 years ago
9. A medical or psychiatric condition that compromises ability to give informed consent or complete the protocol
10. Positive urine pregnancy test for women of childbearing potential (+/-7 days of randomisation onto the trial)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation of treatment will be performed centrally, and sites will be notified as to which arm treatment the patient was allocated.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This is a randomised controlled clinical trial.
This study will use a Permuted block randomisation method for the allocation of subjects into different groups.
Patients will be randomised 1:1 using a Randomisation system to either IL or I-IL. Randomisation will be stratified by the following factors:
1. Centre
2. Gender
3. Age (less than or equal to 40 years old; 41-64 years old; or greater than or equal to 65 years old)
4. Macroscopic (clinical) vs microscopic (subclinical - detected by SNB) LN involvement
5. Extracapsular spread (ECS) vs No ECS
6. Primary melanoma (Known vs Unknown Primary)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
A total of 634 patients accrued in 5 years and each individual followed up for a mandatory 5 years for the primary endpoint provides >80% power to demonstrate non-inferiority of IL compared with I-IL for DFS following lymphadenectomy at the 5% significance level, with a non-inferiority margin of 7%. The basis of this calculation is that if 50% of patients in the I-IL group experience a recurrence of melanoma at 2 years, a margin of non-inferiority of 7% dictates that we accept a maximum of 57% of patients in the IL group that experience a recurrence of melanoma at two years. This corresponds to a hazard rate in the I-IL of 0.03 and a hazard ratio of equivalence of 1.22. A non-inferiority log-rank test with an overall sample size of 634 subjects (317 in each group) achieves 80% power at a 0.05 significance level.

An intention to treat analysis will be used. Time to event analyses (DFS, DDFS, OS) will be conducted with log-rank tests and the Kaplan-Meier method. Proportions will be compared with the Chi-square test. Exploratory analyses investigating the adjusted hazard ratios for I-IL v IL arms will be conducted with the Cox proportional hazards model.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/08/2014
Actual
2/03/2015
Date of last participant enrolment
Anticipated
31/12/2019
Actual
15/10/2019
Date of last data collection
Anticipated
31/12/2029
Actual
Sample size
Target
634
Accrual to date
Final
101
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,VIC
Recruitment hospital [1] 2614 0
The Poche Centre, Melanoma Institute Australia - North Sydney
Recruitment hospital [2] 3605 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [3] 3606 0
Mater Private Hospital - South Brisbane
Recruitment hospital [4] 6643 0
Sydney Adventist Hospital - Wahroonga
Recruitment hospital [5] 6644 0
Westmead Hospital - Westmead
Recruitment hospital [6] 7045 0
Calvary Public Hospital ACT - Bruce
Recruitment hospital [7] 12214 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 24393 0
2050 - Camperdown
Recruitment postcode(s) [2] 14264 0
2065 - Wollstonecraft
Recruitment postcode(s) [3] 14267 0
2076 - Wahroonga
Recruitment postcode(s) [4] 14268 0
2145 - Westmead
Recruitment postcode(s) [5] 14773 0
2617 - Bruce
Recruitment postcode(s) [6] 14265 0
3000 - Melbourne
Recruitment postcode(s) [7] 14266 0
4101 - South Brisbane
Recruitment outside Australia
Country [1] 8216 0
Brazil
State/province [1] 8216 0
Sao Paulo
Country [2] 8217 0
Italy
State/province [2] 8217 0
Padua
Country [3] 8218 0
Netherlands
State/province [3] 8218 0
Groningen, Nijmegen
Country [4] 8219 0
Slovenia
State/province [4] 8219 0
Ljubljana
Country [5] 8220 0
United Kingdom
State/province [5] 8220 0
Norfolk, London, St Helens

Funding & Sponsors
Funding source category [1] 289407 0
Charities/Societies/Foundations
Name [1] 289407 0
Friends of the Mater Foundation
Country [1] 289407 0
Australia
Funding source category [2] 290982 0
Charities/Societies/Foundations
Name [2] 290982 0
Cancer Council NSW
Country [2] 290982 0
Australia
Funding source category [3] 290983 0
Charities/Societies/Foundations
Name [3] 290983 0
Melanoma Institute Australia
Country [3] 290983 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Melanoma and Skin Cancer Trial
Address
Level 2, 553 St Kilda Road, Melbourne, Victoria 3004
Country
Australia
Secondary sponsor category [1] 288090 0
Charities/Societies/Foundations
Name [1] 288090 0
Melanoma Institute Australia
Address [1] 288090 0
40 Rocklands Road North Sydney NSW 2060
Country [1] 288090 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297898 0
Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 297898 0
Research Development Office
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Ethics committee country [1] 297898 0
Australia
Date submitted for ethics approval [1] 297898 0
16/05/2014
Approval date [1] 297898 0
25/09/2014
Ethics approval number [1] 297898 0
HREC/14/RPAH/229

Summary
Brief summary
This study aims to determine optimum surgical management of patients with melanoma spread to their groin lymph nodes.

Who is it for?
You may be eligible to join this study if you are aged 15 years or above and have been diagnosed with primary cutaneous melanoma or stage III melanoma with metastases (i.e. tumour spread) in the groin area.

Study details
Participants in this study will be randomly (by chance) allocated to one of two surgery types. Participants in one group will be undergo Inguinal Lymphadenectomy (IL), which is removal of the easily accessible superficial groin lymph nodes (LNs) and has a median LN retrieval of 11. Participants in the other group will undergo Ilio-inguinal Lymphadenectomy (I-IL) which involves removal of the same superficial groin LNs but also combined with the more surgically complex removal of the ipsilateral pelvic LN. About twice as many LN are removed with I-IL compared to IL. Currently surgeons have polarized opinions as to whether to perform a limited or more extensive lymphadenectomy and there is no evidence of which is the best option.

Participants will be followed-up for a period of up to 10 years in order to evaluate disease response, survival and quality of life outcomes. The results of this study may standardise care globally, lead to better cancer outcomes, reduce surgical morbidity and reduce economic burden for the health sector.
Trial website
https://www.masc.org.au/active-trials-closed-for-recruitment/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 49006 0
A/Prof Andrew Spillane
Address 49006 0
Melanoma Institute Australia
The Poche Centre
40 Rocklands Road
North Sydney NSW 2060 Australia
Country 49006 0
Australia
Phone 49006 0
+61 2 9911 7200
Fax 49006 0
+61 2 9954 9435
Email 49006 0
andrew.spillane@melanoma.org.au
Contact person for public queries
Name 49007 0
Mrs Gabrielle Byars
Address 49007 0
Melanoma and Skin Cancer Trials
553 St Kilda Road, Melbourne, Victoria 3004
Country 49007 0
Australia
Phone 49007 0
+61 3 9903 9022
Fax 49007 0
Email 49007 0
hello@masc.org.au
Contact person for scientific queries
Name 49008 0
Prof Andrew Spillane
Address 49008 0
Melanoma Institute Australia
The Poche Centre
40 Rocklands Road
North Sydney NSW 2060 Australia
Country 49008 0
Australia
Phone 49008 0
+61 2 9911 7200
Fax 49008 0
Email 49008 0
andrew.spillane@melanoma.org.au

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.