““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