Melanoma 10/12/18 Justin J. Baker, M.D.

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1 Objectives Review Incidence Risk Factors for Development Detection 10/12/18 Justin J. Baker, M.D. Treatment of Surgery Medicine Radiation What is Incidence Cancer of Melanocytes Melanocytes are normal pigment cells Live at the bottom of the epidermis Arises due to genetic mutations Siegel et al. Cancer Statistics 2018, CA Cancer J Clin, 2018; 68: 7 30 Incidence Incidence 91,270 new cases in US deaths from melanoma in US 2018 Among White Americans incidence increasing 2.7% per year 1420 new cases in Minnesota in 2018 Siegel et al. Cancer Statistics 2018, CA Cancer J Clin, 2018; 68: 7 30 Siegel et al. Cancer Statistics 2018, CA Cancer J Clin, 2018; 68: 7 30 AllinaHealthSystems 1

2 UV radiation Sun Exposure Tanning Bed Risk Factors for Skin Type Age Gender Personal History Large # Benign Nevi Family history/genetics Role of Skin Type on Risk Recent Advances in the Biology, Therapy and Management of, Lester Davids, 2013 UV Exposure Causes Cancer Initial Presentation Recent Advances in the Biology, Therapy and Management of, Lester Davids, 2013 Detecting Diagnosis Asymmetry Color Border Diameter Biopsy Excisional biopsy, full thickness Gives true depth All decision making based on depth Evolution AllinaHealthSystems 2

3 Two ways to measure tumor thickness Stage Breslow Thickness Measures the distance in mm melanoma invaded into the dermis Used in the AJCC staging of T Stage Thickness 1 <=1mm mm mm 4 >4mm Clark s Level Is not the same as Stage Describes the anatomical level of invasion into the skin Stage 1 Less than 2mm thickness no lymph nodes Stage 2 Greater than 2mm thickness no lymph nodes Stage 3 Any thickness positive lymph nodes or in transit or satellite metastasis Stage 4 Distant metastasis Treatment Historical Margins Surgery Primary treatment in stage I IIIB Medicine Radiation Wide Local Excision/Radical Excision 4 5 cm Margins Two Key trials changed this WHO trial Intergroup trial Intergroup study WHO study Multicenter Randomized Controlled Trial Randomized patients 1 4 mm thickness 2 cm 4 cm yr Overall Survival 79.5% 83.7% 10yr Overall Survival 70% 77% Local Recurrence 1.7% 0.8% Balch et al. Ann Surg; 218; 3: , Balch et al. Ann Surg Onc; 8; 2: Multicenter Randomized Controlled Trial Early 1980 s Randomized patients <2 mm 1 cm 3 cm yr Overall Survival 87.2% 85.1% Local Recurrence 2.6% 0.98% <=1mm 1.6% 0.6% mm 4.2% 1.5% Cascinelli, Sem Surg Onc, 14: AllinaHealthSystems 3

4 Current Recommendations In Situ 0.5 cm 1 cm margins <1 mm thickness 1 cm margins 1 2 mm thickness 1 2 cm margins >2 mm thickness 2 cm margins Margins are Surgical and not Pathological No recommendation regarding depth of excision Most feel going to muscle fascia layer is best Ways to Repair the Damage Primary Often has to be longer than wide Skin Grafts Secondary Intention Local Tissue Rearrangements Flaps Distant Tissue Flaps/Free Flaps NCCN Guidelines Tiny bean shaped glands located throughout the body Normal part of the lymphatic system Important part of the immune system Filter lymph fluid; catching viruses/bacteria/unknown materials Lymph Nodes niaid.nih.gov Historical Lymph Node Management Surgical resection for patients with large palpable Lymph Nodes Elective node dissection 4 Clinical trials studied effect of Elective Node Dissection None showed improvement in survival High risk of complications meded.ucsd.edu Sentinel Lymph Node Biopsy In 1992 Donald Morton described the Sentinel Lymph Node technique in humans Arch Surg Apr;127(4):392-9 MSLT I Intermediate Thickness Identifies the first draining Lymph Node of an area of skin lymph node most likely to contain melanoma 500 patients WLE alone No Difference in Overall Survival 764 patients WLE + SLN bx Closer examination of the lymph node under the microscope than traditionally done Thinner sections Special stains 422 Remain under observation 78 patients with nodal recurrence and delayed LND 122 SLN Positive Immediate LND 642 SLN Negative 5 yr Survival 52.4% 5 yr Survival 72.3% 26 false negativesdeveloped node recurrence and had delayed LND AllinaHealthSystems 4

5 MSLT - II 1755 patients with a positive SLN Medical Treatment of Chemotherapy 824 Completion LND 931 Observation with Ultrasound & Delayed LND if needed Interferon -2b Dacarbazine Ontak Penginterferon -2b Vemurafenib Nivolumab Ipilimumab Pembrolizumab Dabrafenib+trametinib 86% 3 yr melanoma specific survival, 92% 3 yr regional control, 24 % lymphedema 86% 3 yr melanoma specific survival, 77% 3 yr regional control, 6% lymphedema Talimogene laherparepvec Interleukin-2 Dabrafenib Cobimetinib+vemurafenib Trametinib Domingues et al., Immuno Targets and Therapy, 2018:7, Chemotherapy Darcarbazine Standard chemotherapy for metastatic melanoma Complete response rate <5% 5 yr survival rates 2 6% Only chemotherapy to show any survival advantage Interferon Cytokine released by leukocytes Activates the immune system Used as adjuvant treatment in stage IIB and III Reduces risk of recurrence Improves survival Low numbers of patients will respond Ulceration predicts response Side Effects: fatigue, muscle aches, flu like symptoms IL 2 Cytokine that increases T cells Approved for metastatic melanoma Complete response in 4% of patients Toxic side effects Hypotension, tachycardia, arrhythmias, multisystem organ failure gp100 vaccine Ontak gp100 Ipilimumab CD86 CD80 Durvalumab CK-301 Avelumab Atezolizumab PD-L1 PD-L2 Tregs CTLA-4 CD28 CD80 PD-1 Toll-like mdc receptor 8 Resiquimob Interferon -2b/ Penginterferon -2b CTLA-4 CD28 TCR Toll-like receptor 7 pdc B7 B7 MHC Talimogene laherparepvec MHC Tumor antigen Tumor cell Nivolumab CD122 CD25 Pembrolizumab C Dendritic TCR Interleukin-2 cell CAR T Cell CAR-T cell Domingues et al., Immuno Targets and Therapy, 2018:7, AllinaHealthSystems 5

6 CTLA 4 Inhibitory checkpoint of the immune system Blocking this will enhance the immune system Ipilimumab Anti CTLA 4 monoclonal antibody Approved for adjuvant stage III and stage IV melanoma Improves survival Adverse events are immunogenic Dermatitis, colitis, hepatitis, etc PD 1/PD L1 Act to suppress the immune system Nivolomab Anti PD 1 monoclonal antibody Approved for adjuvant stage III and stage IV melanoma Improves survival Side effects: much less than ipilimumab Pembrolizumab T VEC Genetically modified herpes simplex virus Injected directly in melanoma Only replicates in melanoma cells, causes cell lysis and release of tumor specific antigens Approved for unresectable stage III and stage IV melanoma Side effects: fever, fatigue, nausea Cell signaling pathways 40 70% of melanoma will have mutations in key pathways Cause an oncogenic mutation Turns on cell division/replication Bevacizumab Imatinib Receptor Sunitinib CKIT tyrosine kinases VEGFR Dasatinib (ErbB2) (ErbB4) Nilotinib Extracellular GRB2 SOS Intracellular RAS PI-103 Vemurafenib BKM120 PI3K BRAF GSK Dabrafenib INCB IPI-549 Trametinib ASN003 MEK1/2 AKT MK2206 Cobimetinib ERK Everolimus mtor Temsirolimus MITF Ribociclib Transcription Abemaciclib CDK4/6 factors Palbociclib SHR6390 Nucleus Domingues et al., Immuno Targets and Therapy, 2018:7, BRAF Activating mutation causing increased growth and proliferation Vemurafenib BRAF inhibitor Approved for stage III and IV melanoma Improved Survival Adverse reactions: athralgias, fatigue, GI, headache, rash, photosensitivity, hyperkeratosis, warts, SCC, BCC Dabrafenib Resistance develops AllinaHealthSystems 6

7 Radiation MEK Downstream driver oncogene of BRAF Trametinib MEK1/2 inhibitor Improved survival Side Effects: diarrhea, edema, fatigue nausea Largely used for metastatic disease or Palliation Many additional targeted therapies in the pipeline Incidence has increased Conclusion Thank You Questions Limit sun exposure especially sun burns ABCDE of detection Diagnose with Excisional Biopsy Surgery is initial treatment of choice Medical options have increased in number and efficacy over last 5 10 years AllinaHealthSystems 7