Clinical trial NCT02166788: Evaluation of Groin Lymphadenectomy Extent For Metastatic Melanoma
Official 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 (EAGLE FM)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastatic Melanoma to the Groin Lymph Nodes
Keywords: metastatic melanoma
groin lymph nodes
surgery
lymphadenectomy
Lead sponsor: Melanoma and Skin Cancer Trials Limited
Sponsor class: OTHER
Collaborators: name: Cancer Council New South Wales
name: Melanoma Institute Australia
First posted: 2014-06-18
Enrollment: 634
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: BACKGROUND: Spread of metastatic melanoma to the groin lymph nodes (LN) is a common event affecting about 350 people a year in Australia. Globally it has been shown that patients with involved groin LN, without proven pelvic LN disease on imaging receive 1 of 3 management strategies in equal proportions - inguinal lymphadenectomy (IL); ilio-inguinal lymphadenectomy (I-IL); or variable use of either depending on circumstances. Different experts have strong and polarised opinions favouring either IL or more extensive I-IL with existing cases series reporting conflicting data on best cancer outcomes. No high level evidence proves which operation is best. HYPOTHESIS: There will be no significant difference in DFS between patients having IL or I-IL, conditional on PET/CT scan showing no evidence of pelvic disease at the time of diagnosis of groin LN metastatic melanoma. AIMS: To provide a rational evidence base for management for melanoma to the groin LNs by randomly assessing the effect of each operation on DFS, distant DFS, overall survival (OS), morbidity - including early complications and longer-term rates of lymphedema as well as comprehensively assessed QOL. Also to clarify the reliability of PET/CT scans for staging pelvic LNs and evaluate any health economic benefits of I-IL over IL. TARGET POPULATION: To recruit 634 patients in 5 years. DESIGN: An Australian led, international, multi-centre, non-inferiority, phase III, prospective, randomised clinical trial comparing IL or I-IL for patients with metastatic melanoma to groin LNs and no evidence of pelvic disease on PET/CT. ENDPOINTS: DFS, Distant DFS, OS and QOL at 5 years. Accuracy of PET/CT for pelvic LN metastases.

OUTCOMES: International standardization of care, improved cancer outcomes, improved QOL for patients with groin metastatic melanoma. Proof of principle about extent of surgery when PET/CT is clear in adjacent LN areas, leading to clinical trials investigating management of other lymph node fields.

Detailed description: Background and Rationale

Spread of metastatic melanoma to the groin lymph nodes (LN) is a common event for patients with melanoma. In melanoma treatment centres around the world, patients without demonstrated pelvic LN disease receive 1 of 3 strategies of management in relatively equal proportions (Pasquali, Spillane et al. 2012):

i. Inguinal Lymphadenectomy (IL) ii. Ilio-inguinal Lymphadenectomy (I-IL) iii. Variable use of either IL or I-IL surgery.

Some larger melanoma centres have an institutional policy that all patients have either IL or I-IL for metastatic inguinal node involvement. Nearly all centres would agree that patients with pelvic LN involvement without distant metastatic disease should have I-IL.

Study Objectives This study aims to provide a more rational evidence base for appropriate management for metastatic melanoma in the groin LNs, through assessing the effect of the addition of ipsilateral pelvic lymphadenectomy on patient disease-free survival (DFS), distant disease-free survival (DDFS), overall survival (OS), morbidity, and quality of life. In addition, the study will clarify the reliability of PET (Positron Emission Tomography) / CT (Computed Tomography) scans for staging pelvic LNs, clarify morbidity differences between the operations in a balanced cohort, evaluate any health economic benefits of I-IL over IL and provide a tissue and serum resource to be used to identify biological markers of recurrence and progression after inguinal metastases.

Study Hypothesis There will be no significant difference in DFS between patients having IL or I-IL, conditional on PET/CT scan showing no evidence of pelvic disease at the time of diagnosis of groin LN metastatic melanoma.

Study Population The aim is to recruit 634 patients in 5 years who are 15 years or older with cytologically or histologically confirmed metastatic melanoma in inguinal LNs (H\&E \& IHC); specifically with no evidence of pelvic node involvement or distant spread of melanoma clinically or on PET/CT staging scans. To be eligible patients must have an Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 at randomisation.

Study Treatments Eligible patients will be randomised 1:1 to undergo an IL or I-IL.

Study Design This is an international, multi-centre, phase III, non-inferiority, prospective, randomised clinical trial.

Eligibility criteria: 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:

   * At the time of diagnosis;
   * Or by Ultrasound detection;
   * Or later after relapse when no Sentinel Node Biopsy (SNB) was performed at the time of primary tumour management;
   * Or as a result of SNB;
   * Or at the time of regional recurrence after "false negative" SNB;
5. 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

Exclusion Criteria:

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:

   * those with a thin \<=1 mm, regionally unrelated melanoma \> 5 years ago
   * those with a good prognosis regionally unrelated cancer (\>90% probability of 10 years disease specific survival)
   * other cancers diagnosed more than five years ago with no evidence of disease recurrence within this time
   * successfully treated basal cell and squamous cell skin carcinoma
   * carcinoma in-situ of the cervix
   * 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)

Primary outcomes:
measure: The primary endpoint of the study will be Disease Free Survival following lymphadenectomy, assessed after 60 months of follow-up.
timeFrame: 60 Months
Secondary outcomes:
measure: Overall Survival
timeFrame: 0 - 120 months
measure: Distant Disease Free Survival
timeFrame: 0 - 120 Months
measure: Regional Recurrence Free Survival
timeFrame: 0 - 120 Months
measure: Morbidity differences
timeFrame: Up to 120 days from lymphadenectomy, and from 0 - 120 months
measure: Quality Of Life
timeFrame: 0 - 120 Months
measure: Sensitivity / specificity and positive predictive value and negative predictive value of PET/CT for pelvic disease at diagnosis of groin LN involvement by melanoma.
timeFrame: 0 - 120 Months
measure: Resource use and utility based Quality Of Life
timeFrame: 0 - 60 Months
Other outcomes:
Locations:
city: Canberra
country: Australia
facility: Calvary Public Hospital Bruce
state: Australian Capital Territory
city: North Sydney
country: Australia
facility: Melanoma Institute Australia - The Poche Centre
state: New South Wales
city: Sydney
country: Australia
facility: Sydney Adventist Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Mater Hospital Brisbane
state: Queensland
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Barretos
country: Brazil
facility: Hospital de Câncer de Barretos
state: SP
city: Sao Paulo
country: Brazil
facility: A.C. Camargo Cancer Center
state: SP
city: Padova
country: Italy
facility: Veneto Institute of Oncology - IOV
state: Veneto
city: Nijmegen
country: Netherlands
facility: Radboud University Nijmegen Medical Center
state: Gelderland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Ljubljana
country: Slovenia
facility: Institute of Oncology Ljubljana
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospital
state: Norfolk
city: London
country: United Kingdom
facility: Guy's and St Thomas's Hospitals
city: London
country: United Kingdom
facility: St George's Hospital
city: St Helens
country: United Kingdom
facility: St Helen's and Knowsley Teaching Hospitals
Study officials:
affiliation: The University of Sydney, Northern Clinical School
name: Andrew Spillane
role: PRINCIPAL_INVESTIGATOR
References: