““It’s not the size of the dog in It’s not the size of the dog in a fight, it’s the size of the a fight, it’s the size of the

fight in the dog” fight in the dog” – – Mark Twain Mark Twain 19011901

Past, Present and FutureDr. Leena Rahmat

Our PatientOur Patient

64 year old lady

Presented to a primary hospital with a pigmented lesion on

the back of her neck

Pathology:

“Superficial spreading melanoma

Clark’s II

Breslow 0.42mm

No Lymphovascular invasion

No ulceration

Evidence of regression”

Palpable lymph nodes in

anterior and posterior

chain of neck

Upon examinationUpon examination

Multiple LNs in anterior & posterior triangles of neck on left side, largest 2.5cm in lower neck.

Wider excision

&

Biopsy of

palpable lymph node

Skin re-excision:

No evidence of residual melanoma. Dermal

fibrosis and mild chronic inflammation

consistent with previous surgery

Lymph node, left posterior triangle:Sections show a lymph node with evidence of metastatic melanoma confirmed with immunohistochemistry

PET scan

“Metastatic lymphadenopathy left supraclavicular region & left side of neck extending to level 2”

“Physiological activity on right consistent with brown fat. No definitively metabolically active or metastatic lymph nodes on the right.”

Extended left sided radical neck Extended left sided radical neck dissectiondissection

Sacrificed/Excised

• Internal Jugular Vein• Accessory nerve• Sternocleidomastoid

muscle• Skin• Lymph nodes

Level 1-5 dissectionIVJ obliterated

Review post surgeryReview post surgery

Pathology:

• 56 of 58 lymph nodes identified show evidence of metastatic melanoma

• Extensive lymphovascular invasion in surrounding fibroadipose tissue

Clinical:

Palpable node on right side of neck

Melanoma regressionMelanoma regression

“Spontaneous regression occurs when a primary or secondary tumour regresses, or dies, in the absence of treatment capable of causing tumour destruction”

RegressionRegression

• 5-8% of patients with melanoma metastases have no detectable primary lesions

• 50% of excised melanomas demonstrate focal regression

• Regression of metastases occurs in just 0.25% of cases

RegressionRegression

• There is a significant increase in the number of T-cells infiltrating regressing melanomas

• Metastatic lesions do not contain mRNA for cytokines involved in T-cell activation

• This suggests that T-cells in metastasis are not actively secreting immunoenhancing cytokines

Regression & marginsRegression & margins

There is no evidence that tumours with regression should have larger margins

Primary melanoma with regression: Implications for management

K. Morris, K. Busam and M. S. Brady

Department of Surgery & Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA

Vol 23 Jun 2005 No. 16S

The presence of regression in a primary melanoma does not warrant adjustment of current treatment recommendations.

We found no evidence that these patients are at higher risk for local or regional nodal recurrence.

Regression & SLNBRegression & SLNB

• Regression does not influence nodal positivity

• There is no evidence that regression should influence the decision to perform SLNB

Regression & prognosisRegression & prognosis

• It has been proposed that regression improves, reduces or has no affect on prognosis

• There is no difference in survival of patients with regression compared to those without

• However regression does affect the reliability of depth if regression is present

Primary Cutaneous Melanoma with Regression Does not Require a Lower Threshold for Sentinel Lymph Node Biopsy

Katherine T. Morris, MD1, Klaus J. Busam, MD2, Suzannah Bero, PA1, Ami Patel, BS1 and Mary S. Brady, MD, FACS1 ..

Department of Surgery & Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA

Vol 15 Mar 2008 Pages 316-322

The median Breslow depth for the 344 patients with RG was 1.1 mm versus 1.5 mm for 1,005 patients with no regression (NRG) (P < 0.005).

The presence of histological RG in a primary melanoma predicts neither SLN positivity when stratified by Breslow depth nor increased risk of

recurrence when compared with melanomas with NRG

• >85% with stage 4 disease have metastases confined to a single organ

• Immunotherapy may control occult systemic metastases

• Radiotherapy may provide palliation• Currently surgery offers the only significant

chance of 5 year survival• Patient selection is crucial

Stage 4 diseaseStage 4 disease

24 months24 months 26-41%26-41%

28 months28 months29%29%

20.4 months20.4 months21%21%

Median SurvivalMedian Survival5 Year Survival5 Year Survival

MetastasectomyMetastasectomy

• Cryosurgical ablation

• Radiofrequency ablation

• Combination Chemotherapy

• Immunotherapy – IFN & IL-2

Non resectable lesionsNon resectable lesions

ImmunotherapyImmunotherapy

IFN-α• Response rate of 10-15% in

metastatic disease• Adjuvant therapy for stage II/

III• Many trials underpowered,

heterogeneous populations, wide variety of doses & Rx schedules

• Data pending in 3000 of the 6000 patients participating in adjuvant trials

• Meta-analysis has demonstrated no significant impact on overall survival but has an affect on relapse free survival

IL-2• RCT

• Combination with IFN for intermediate & high risk primary melanoma

• Better tolerated but no definitive survival benefit

PREDICT studyStudy of Serum Biomarkers for Prediction of Response to

Interferon Therapy in Patients With Melanoma

Objectives• Generate a comprehensive multiplexed array of

melanoma-associated serological markers and validate it using serum samples from patients with melanoma and healthy control participants.

• Determine changes in the profile of serological markers induced by interferon-alfa 2b (IFN-α2b) therapy.

• Define panels of serological markers with prognostic and predictive power for IFN-α2b therapy responses in patients with melanoma.

PREDICT Trial

Predictive gene signature for REsponse to recMAGE-A3 in unresecteD metastatIc CuTaneous melanoma

Study Design

• Assess clinical activity of recMAGE-A3 + AS15 (Adjuvant Systems) in pts with unresectable MAGE-A3-positive metastatic melanoma

Antigen-Specific Cancer Immunotherapy (ASCI)

Tumour antigens +

Adjuvant systems -->

trigger a specific immune

response to eliminate

tumour cells

Objective

• Delay disease progression or shrink existing tumour

• 1 year overall survival in gene signature positive pts

(predicted survival is 71% for MAGE-A3 positive pts)

Study Design

No control arm- Therapeutic trial

About 60 centres in Europe & U.S.

110 patients

10 pts in Ireland (2 pts per centre)

4 cycles of treatment

24 doses over 48 months

Study Design

Biopsy Tumour staging

ASCI q 2/52

ASCI q 3/52

ASCI q 6/52

4 ASCI q 4/124 ASCI q 6/12

Conc. visit

F/U visit

Inclusion Criteria

• Unresectable stage III or IV M1a melanoma

• MAGE-A3 positive (fresh tissue sample)

• Performance status of 0/1 (ECOG)

• Fully recovered from previous interventions (biopsy/treated or resected melanoma)

• Informed consent

SummarySummary

0.4mm melanoma demonstrating regression

•Heavy nodal burden and poor prognosis

•The evidence reports that regression does not affect nodal positivity or prognosis