EORTC 1208EORTC 1208MINITUBMINITUB: :

Prospective Registry on Prospective Registry on Sentinel Node (SN) Positive Melanoma patients with Sentinel Node (SN) Positive Melanoma patients with

minimal SN Tumor Burden minimal SN Tumor Burden who undergo who undergo

Completion Lymph Node Dissections (CLND) or Completion Lymph Node Dissections (CLND) or Nodal ObservationNodal Observation

Study coordinator: Alexander van Akkooi (Rotterdam, NL)

1. Background and introduction

a) RCT’s on ELND

b) MSLT-1; final results NEMJ 2014

c) SN Tumor Burden Retrospective EORTC data

2. Study objectives

3. Trial design

4. History and current status

5. Feasibility assessment

OverviewOverview

2

4 RCT’s

• WHO study, 267 vs. 286, Veronesi et al. (NEJM 1977) No Survival Benefit

• Sim et al. (Cancer 1978) Immediate (n=54), delayed (=3 months) (n=56), no

(n=63) No Survival Benefit

Elective Lymph Node Dissection (ELND)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

Elective Lymph Node Dissection (ELND)Elective Lymph Node Dissection (ELND)

• 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)

Sentinel Node (SN) HypothesisSentinel Node (SN) Hypothesis

Final Results MSLT-1Final Results MSLT-1

MSLT-1MSLT-1

Calculated Sample Size = 900, Increased to 1200 after interim results

Morton et al. NEJM 2014

Primary End-Point: MSSPrimary End-Point: MSS

Morton et al. NEJM 2014

DFSDFS

Secondary End-Point

SN vs. OBSLocal / In-transit 7.0% vs. 6.4%Nodal 4.9% vs. 14.6%Distant 13.9% vs. 11.2%

Morton et al. NEJM 2014

Subgroup Analysis

Subgroup Analysis

SN pos vs. OBS node pos HR 0.56P=0.006

Morton et al. NEJM 2014

New type of Subgroup Analysis

Accelerated-failure-time latent-subgroup analysis showed a clear survival benefit:

Estimated effect:

•DFS 1.17 (P < 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

Altstein et al. Statistics in Medicine 2011

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!!

New type of Subgroup Analysis

Morton et al. NEJM 2014, Altstein et al. Statistics in Medicine 2011

Nodal Positivity Rate

Morton et al. NEJM 2014

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

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

Hypothetical Causes of Prognostic False Positivity

1. Develop distant visceral metastases and die before developing

clinically relevant nodal disease

2. Incorrect diagnosis of metastasis in case of benign capsule nevi

3. Minimal SN Tumor Burden

• Might never progress, merely antigen presentation

Prognostic HeterogeneityPrognostic 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

Difference in Biologynot all SN positive patients are the same

> 1.0 mm< 0.1 mm

Minimal SN tumor burdenRotterdam criteria

0.1-1.0 mm

MicroanatomicLocation

• Microanatomic location of the metastasis within the lymph node

Subcapsular Combined Parenchymal Multifocal Extensive

Dewar et al. J Clin Oncol 2004

SN Tumor Burden - SurvivalSN Tumor Burden - Survival

1) van der Ploeg et al. J Clin Oncol 2011

2) Murali et al. Cancer 2009

5-year survival5-year survival11

≤ ≤ 0.1 mm 0.1 mm 92%92%0.1 – 1.0 mm 74%> 1.0 mm 59%

Subcapsulair 81%Non-subcapsulair 66%

Inter-Observer ReproducibilityInter-Observer Reproducibility22 ICC (1 = ICC (1 = max)max)

1. Size 0.882. Infiltration from capsule 0.833. Surface area in mm2 0.734. % SN Involved 0.685. Micro-anatomic Location 0.506. Extracapsular Extension 0.39

~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)

Study rationale

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

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)

Study Objective

Minimal SN Tumor Burden – EORTC 1208

• Any SUB-micrometastasis with a maximum diameter < 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)

Main eligibility criteria

• Age > 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

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

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 %)

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 alpha=0.05, and beta=0.10 (90% statistical power).

Total number of patients to be registered is 260 (243+17 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

Study Design

Study Flow Chart

Assessment Enrollment Years 1 – 2 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

Assessments

* RecommendedC Only for Centers performing regular lymph node ultrasound examinationsI If indicated by symptoms

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%)

Study history: MINITUB

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

Current Status

FeasibilityCountry Institname Investigator # eligible

patients/year Real Expected/year

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

Conservative Estimate = 75 pts / years

MSLT-2 MSLT-2 EORTC 1208EORTC 1208

Feasibility is clear; yes we can!

Need for sufficient centers, as events are somewhat rare

Please consider participation into EORTC 1208

Thank You!

Please Consider us

Join us at: EORTC Melanoma GroupFall 2014 Meeting – Rotterdam

October 16 - 18

Thank youThank you

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