EORTC 1208 MINITUB: Prospective Registry on Sentinel Node (SN) Positive Melanoma patients with minimal SN Tumor Burden who undergo Completion Lymph Node Dissections (CLND) or Nodal Observation

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EORTC 1208MINITUB Prospective Registry on
Sentinel Node (SN) Positive Melanoma patients
with minimal SN Tumor Burden who undergo
Completion Lymph Node Dissections (CLND) or
Nodal Observation

• Study coordinator Alexander van Akkooi
  (Rotterdam, NL)

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Overview

• Background and introduction
• RCTs on ELND
• MSLT-1 final results NEMJ 2014
• SN Tumor Burden Retrospective EORTC data
• Study objectives
• Trial design
• History and current status
• Feasibility assessment

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Elective Lymph Node Dissection (ELND)

• 4 RCTs
• WHO study, 267 vs. 286, Veronesi et al. (NEJM
  1977)
• No Survival Benefit
• Sim et al. (Cancer 1978)
• Immediate (n54), delayed (3 months) (n56), no
  (n63)
• No Survival Benefit

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Elective Lymph Node Dissection (ELND)

• WHO study, 122 vs. 118, Cascinelli et al. (Lancet
  1998)
• No Survival Benefit (62 vs. 51, P 0.09)
• Possible benefit for Node Pos pts
• ELND pos vs. OBS pos (P 0.04)
• Intergroup Trial, 379 vs. 361, Balch et al. (Ann
  Surg Oncol 2000)
• No Survival Benefit (77 vs. 73, P 0.12)
• Non-Ulcerated (84 vs. 77, P 0.03)
• T2 (86 vs. 80, P 0.03)
• Extremity (84 vs. 78, P 0.05)
• Sentinel Node Hypothesis

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Sentinel Node (SN) Hypothesis

• ELND could not detect survival benefit due to
• Small benefit 5 10
• Potential dilution by thin (T1) and thick (T4)
  melanomas
• Seldom metastases / often haematogenous
• Potential dilution by N- neg pts
• Cannot benefit from ELND
• Thus
• Identification of clinically occult metastases
• All SNs progress to clinical node metastases
• Intermediate thickness (T2 - T3)

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Final Results MSLT-1
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MSLT-1
Morton et al. NEJM 2014
Calculated Sample Size 900, Increased to 1200
after interim results
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Primary End-Point MSS
Morton et al. NEJM 2014
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DFS
Secondary End-Point SN vs. OBS Local /
In-transit 7.0 vs. 6.4 Nodal 4.9 vs.
14.6 Distant 13.9 vs. 11.2
Morton et al. NEJM 2014
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Subgroup Analysis
Subgroup Analysis SN pos vs. OBS node pos HR
0.56 P0.006
Morton et al. NEJM 2014
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New type of Subgroup Analysis

• Accelerated-failure-time latent-subgroup analysis
  showed a clear survival benefit
• Estimated effect
• DFS 1.17 (P lt 0.001) Survival increase 3.2 x
• DMFS 0.73 (P 0.04) Survival increase 2.1 x
• MSS 0.68 (P 0.05) Survival increase 2.0 x

Morton et al. NEJM 2014
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Altstein et al. Statistics in Medicine 2011
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New type of Subgroup Analysis

• Accelerated-failure-time latent-subgroup analysis
  showed a clear survival benefit
• Non-validated statistical hypothesis
• Developed on MSLT-1 interim data
• Cannot be used as validation!!

Morton et al. NEJM 2014, Altstein et al.
Statistics in Medicine 2011
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Nodal Positivity Rate
Still 2.4 difference after 10-years in Nodal
Positivity between SLNB and OBS Difference is
less than after 5-years Quite a significant
difference based on total of nodal positivity
Morton et al. NEJM 2014
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Prognostic False Positivity?
87 / 500 node positive in OBS-arm 17.4 17.4
out of 770 patients 134 patients 134 31 False
negatives 103 should be SN 122 SN pos 103
19 patients too many node pos pts in SN-arm 19 /
122 15.6 False Positive
based on J.M. Thomas, Nat Clin Pract Oncol 2008
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Hypothetical Causes of Prognostic False Positivity

• Develop distant visceral metastases and die
  before developing clinically relevant nodal
  disease
• Incorrect diagnosis of metastasis in case of
  benign capsule nevi
• Minimal SN Tumor Burden
• Might never progress, merely antigen presentation

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Prognostic Heterogeneity

• 5-year Survival of SN 56 75
• Depending on
• Median Breslow thickness of population
• Ulcerated Melanomas
• How extensive Pathological Sampling SN

van Akkooi et al. Nat Rev Clin Oncol 2010
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Difference in Biology not all SN positive
patients are the same
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Minimal SN tumor burden Rotterdam criteria
0.1-1.0 mm
gt 1.0 mm
lt 0.1 mm
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Microanatomic Location

• Microanatomic location of the metastasis within
  the lymph node
• Subcapsular
• Combined
• Parenchymal
• Multifocal
• Extensive

Dewar et al. J Clin Oncol 2004
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SN Tumor Burden - Survival

• 5-year survival1
• 0.1 mm 92
• 0.1 1.0 mm 74
• gt 1.0 mm 59
• Subcapsulair 81
• Non-subcapsulair 66
• Inter-Observer Reproducibility2 ICC (1 max)
• Size 0.88
• Infiltration from capsule 0.83
• Surface area in mm2 0.73
• SN Involved 0.68
• Micro-anatomic Location 0.50
• Extracapsular Extension 0.39

1. van der Ploeg et al. J Clin Oncol 2011
2. Murali et al. Cancer 2009

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Study rationale

• 20 NSN but 100 receives CLND!
• Issues
• Morbidity ?
• Chronic Lymph Edema
• Nerve Damage
• Wound infection
• No clear therapeutic benefit of CLND
• Which SN positive patients might safely be spared
  CLND?
• Patient with minimal SN tumor burden at the
  moment both options (CLND or not) are performed
  in Europe (no accepted standard of care)

• Studies
• Balimoria et al. 2008
• 50 of SN pts in USA CLND, 50 no CLND
• Regardless of SN Tumor Burden
• Pasquali et al. 2012
• Heterogenous treatment of SN pts in Europe, USA
  Australia
• Already low frequency of CLND in minimal SN Tumor
  Burden pts

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Study Objective
To analyze if patients with T2-T3 primary tumor
and minimal SN tumor burden managed by only
serial nodal observation, have a 5-year DMFI
comparable to the ones who had CLND based on
historical data (5-year MSS rate 87) Note
patients with T1 and T4 with a minimal Tumor
Burden will be registered in the study for
descriptive analyses only (distinct prognosis and
clinical characteristics)
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Minimal SN Tumor Burden EORTC 1208

• Any SUB-micrometastasis with a maximum diameter lt
  0.1 mm, regardless of the site (Rotterdam
  criteria)
• or
• Metastases solely confined to the subcapsular
  (Dewar criteria) space and largest metastasis
  with a maximum diameter 0.4 mm (Rotterdam
  criteria)

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Main eligibility criteria

• Age gt 18 years
• Histological evidence of T2-T3 primary cutaneous
  melanoma
• Note patients with T1 and T4 with a minimal
  Tumor Burden will be registered in the study for
  descriptive analyses only
• Patients with minimal SN tumor burden
• Note If there is more than 1 metastatic SN, the
  patient will be still eligible provided that all
  involved SN have minimal tumor burden, regardless
  of the amount of positive SNs and the interested
  basin
• Absence of clinically apparent metastatic disease
  at the time of or before undergoing a SN
  procedure

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Main eligibility criteria

• No previous history of melanoma
• No history of any other malignancy from which the
  patient has been disease-free for less than 5
  years, except for non-melanoma skin cancer (Basal
  Cell Carcinomas or Squamous Cell Carcinomas) and
  in situ cervical cancer
• No previous SN procedure for locally recurrent
  melanoma or uncertain malignant disease, such as
  atypical Spitz tumor/naevi

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• Primary endpoint
• Distant Metastasis Free Interval (DMFI) time
  from SN positive biopsy until distant metastasis
• Secondary endpoints
• Regional Control Rate rate of lymph node
  dissection in the same basin where the SN was
  previously removed
• Relapse Free Interval (RFI) time from SN
  positive biopsy until first relapse regional or
  distant metastasis or death due to melanoma
• Melanoma Specific Survival (MSS) time from SN
  positive biopsy until death due to melanoma
• Overall survival (OS) time from SN positive
  biopsy until death due to any cause
• Morbidity (wound infection , lymphedema and
  neurologic damage )

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Study Design

• Prospective observational study
• H0 5-year DMFI rate 80
• H1 5-year DMFI rate 87
• If out of 243 patients with a minimum follow-up
  of 5 years, no more than 38 (15.7) patients
  develop a DMet within 5-years (so that at least
  205 (84.3) patients are DM-free at 5 years),
  then one may reject the null hypothesis at
  alpha0.05, and beta0.10 (90 statistical
  power).
• Total number of patients to be registered is 260
  (24317 drop outs)
• Additionally, 26 pts with T2-T3 minimal TB who
  will undergo CLND will be registered and
  evaluated (comparison dataset 10 of sample
  size)
• Additionally, 50 T1 T4 patients with minimal
  TB will be registered/evaluated (descriptive
  analysis 20 of sample size)
• Accrual 5 years Follow-up 10 years

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Study Flow Chart
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Assessments
Assessment Enrollment Years 1 2 Years 1 2 Years 1 2 Years 1 2 Years 1 2 Years 1 2 Years 3 - 5 Years 3 - 5 Years 3 - 5 Years 3 - 5 Years 3 - 5 Years 3 - 5 Years 6 10
Month T0 4 8 12 16 20 24 30 36 42 48 54 60 Once a year
History Physical X X X X X X X X X X X X X X
Chest X-ray X X X X X X X
Ultrasound Liver X I I I I I I I I I I I I I
Ultrasound of Lymph Nodes C A A A A A A A A A A A A A
CT-thorax/ abdomen, CT/MRI brain, PET-scan I I I I I I I I I I I I I
Serum for TR X X X X X X
Plasma for TR X X X X X X
Recommended C Only for Centers performing
regular lymph node ultrasound examinations I If
indicated by symptoms
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Study history MINITUB

• 2008 ExCo decision
• No RCT, but Registry study
• EORTC would NOT become sponsor
• EORTC would let MG conduct the study
• Supported the idea, but it did not fit EORTC HQ
  philosophy as official EORTC study
• September 2013
• 9 participating Centers of which 4 recruiting
• 35 patients included (FPI 31-7-2009)
• T1 2 (6.7)
• T2 8 (26.7)
• T3 13 (43.3)
• T4 3 (10)
• Unknown 4 (13.3)

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Current Status

• Sponsorship Issues
• Sites requested a central sponsor / legal
  contracts
• MG cannot take this role / become sponsor
• No single investigator / site will take this role
  for all sites
• Individual sites sometimes difficult to be
  sponsor at own site
• 2012 Exco Revision
• Exco endorsement (EORTC 1208)
• EORTC will act as study sponsor insurance
• Fee per patient included into registry

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Feasibility
Country Institname Investigator eligible patients/year Real Expected/year
Belgium Antwerp University Hospital Pol Specenier 8 1 - 2
Belgium Leuven Marguerite Stas 10 20 3 - 5
Denmark Odense Bastholt / Gad 3 - 5 3 - 5
France LILLE MORTIER 15 22 3 5
France CHU de Nice Lacour 2 2
France IGR Villejuif/Paris Sud Robert / Eggermont 15 3
Germany University Medical Center Mannheim Jochen Utikal 5 10 1 2
Germany Charité University Medicine Berlin Voit 12 2 3
Germany Mainz Dr. Carmen Loquai 5 10 1 2
Germany Heidelberg Jessica Hassel 15 3
Italy IEO Milano Testori 15 3
Italy national cancer institute naples italy mozzillo n 15 3
Slovenia Ljubljana Hocevar 10 2
Spain "Virgen de la Arrixaca" University Hospital Antonio Piñero-Madrona 4 4
Spain Hospital Clinic Susana Puig 4 4
Switzerland Centre Hospitalier Universitaire Vaudois Dr Maurice MATTER 2 3 2 3
Switzerland Zurich Daniela Mihic - Probst ? ?
Portugal Lisbon (CUF Descoberatas) Joao Silva 5 2
The Netherlands Radboud University Nijmegen MC J.J. Bonenkamp 20 2 3
The Netherlands Netherlands Cancer Institute J.A. van der Hage 15 20 4 5
The Netherlands Erasmus MC Daniel den Hoed A. van Akkooi 4 - 5 4 5
United Kingdom Guy's and St Thomas' NHS Foundation Trust Jenny L C Geh 6 6
United Kingdom St. George's Hospital Barry Powell 10 10
United Kingdom Cambridge Dr Pippa Corrie 8 2
United Kingdom Salisbury Lorna Burrows 15 3
United Kingdom Whiston Hospital philip brackley 10 2
Conservative Estimate 75 pts / years
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MSLT-2 EORTC 1208
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Please Consider us

• Feasibility is clear yes we can!
• Need for sufficient centers, as events are
  somewhat rare
• Please consider participation into EORTC 1208
• Thank You!

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Join us at EORTC Melanoma GroupFall 2014
Meeting Rotterdam
October 16 - 18
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Thank you
Contacts