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Dr. Leena Rahmat

“It’s not the size of the dog in a fight, it’s the size of the fight in the dog” – Mark Twain 1901 Past, Present and Future. Dr. Leena Rahmat. Our Patient. 64 year old lady Presented to a primary hospital with a pigmented lesion on the back of her neck Pathology:

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Dr. Leena Rahmat

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  1. “It’s not the size of the dog in a fight, it’s the size of the fight in the dog” – Mark Twain 1901Past, Present and Future Dr. Leena Rahmat

  2. Our 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”

  3. Upon examination Palpable lymph nodes in anterior and posterior chain of neck Multiple LNs in anterior & posterior triangles of neck on left side, largest 2.5cm in lower neck.

  4. Wider excision & Biopsy of palpable lymph node

  5. 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

  6. 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.”

  7. Extended left sided radical neck dissection Level 1-5 dissection IVJ obliterated Sacrificed/Excised • Internal Jugular Vein • Accessory nerve • Sternocleidomastoid muscle • Skin • Lymph nodes

  8. Review 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

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

  10. Regression • 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

  11. Regression • 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

  12. Regression & margins There is no evidence that tumours with regression should have larger margins

  13. Primary melanoma with regression: Implications for management 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. 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

  14. Regression & SLNB • Regression does not influence nodal positivity • There is no evidence that regression should influence the decision to perform SLNB

  15. Regression & 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

  16. Primary Cutaneous Melanoma with Regression Does not Require a Lower Threshold for Sentinel Lymph Node Biopsy Vol 15 Mar 2008 Pages 316-322 The median Breslow depth for the 344 patients withRG 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 melanomapredicts neither SLN positivity when stratified by Breslow depthnor increased risk of recurrence when compared with melanomaswith NRG 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

  17. Stage 4 disease • >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

  18. Metastasectomy 5 Year Survival Median Survival 21% 20.4 months 29% 28 months 26-41% 24 months

  19. Non resectable lesions • Cryosurgical ablation • Radiofrequency ablation • Combination Chemotherapy • Immunotherapy – IFN & IL-2

  20. Immunotherapy • IFN-α • Response rate of10-15% in metastatic disease • Adjuvant therapy for stage II/ III • Many trials underpowered, heterogeneous populations, wide variety ofdoses &Rx schedules • Datapending 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

  21. PREDICT study • Study 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.

  22. PREDICT Trial • Predictive gene signature for REsponse to recMAGE-A3 in unresecteDmetastatIc CuTaneous melanoma

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

  24. Antigen-Specific Cancer Immunotherapy (ASCI) Tumour antigens + Adjuvant systems --> trigger a specific immune response to eliminate tumour cells

  25. 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)

  26. Study Design No control arm- Therapeutic trial About 60 centres in Europe & U.S. 110 patients 10 pts in Ireland (2 pts per centre)

  27. Study Design 4 cycles of treatment 24 doses over 48 months

  28. 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

  29. Summary 0.4mm melanoma demonstrating regression • Heavy nodal burden and poor prognosis • The evidence reports that regression does not affect nodal positivity or prognosis

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