Disclosures. SLNB for Melanoma 25/02/2014 SENTINEL LYMPH NODE BIOPSY FOR MELANOMA: CURRENT GUIDELINES AND THEIR CLINICAL APPLICATION

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8 th Canadian Melanoma Conference February 22, 2014 Rimrock Resort Hotel, Banff, Alberta SENTINEL LYMPH NODE BIOPSY FOR MELANOMA: CURRENT GUIDELINES AND THEIR CLINICAL APPLICATION

1 8 th Canadian Melanoma Conference February 22, 2014 Rimrock Resort Hotel, Banff, Alberta SENTINEL LYMPH NODE BIOPSY FOR MELANOMA: CURRENT GUIDELINES AND THEIR CLINICAL APPLICATION Christopher Bichakjian, MD Associate Professor Cutaneous Surgery and Oncology University of Michigan Disclosures I do not have any relationships with industry. SLNB for Melanoma 1

2 SLNB for Melanoma Historical perspective Snow H. Lancet. 1892;2:872 4 Snow H. Lancet. 1892;2:

The danger lies in the diffusion of malignant cell particles from this primary focus;

Palpable enlargement of these glands is unfortunately but a late symptom of deposit

1892;2:872 4 We further see the paramount importance of securing, whenever possible, the

1907;1;927,996 Elective Complete Lymph Node Dissection 1892 Dr. Herbert Snow 1907 Dr.

3 The danger lies in the diffusion of malignant cell particles from this primary focus; these always implicate the nearest lymph glands which intercept them for a time. Palpable enlargement of these glands is unfortunately but a late symptom of deposit therein; Snow H. Lancet. 1892;2:872 4 We further see the paramount importance of securing, whenever possible, the perfect eradication of those lymph glands which will necessarily be first infected; Lancet. 1907;1;927,996 Elective Complete Lymph Node Dissection 1892 Dr. Herbert Snow 1907 Dr. William Handley removal of 2 inches of subcutaneous tissue to muscle fascia with radical removal of lymph nodes. Guided surgical nodal treatment of melanoma for nearly a century 3

Multicenter Selective Lymphadenectomy Trial (MSLT I) Morton DL, et al. N Engl J Med.

4 Dr. Donald Morton Introduced preoperative and intraoperative lymphatic mapping and sentinel lymphadenectomy in early 1990s as a minimally invasive alternative to routine elective complete lymph node dissection. Multicenter Selective Lymphadenectomy Trial (MSLT I) Morton DL, et al. N Engl J Med. 2014;370(7): SLNB for Melanoma Current Rationale for SLNB Sentinel Lymph Node Biopsy Status of SLN is most important prognostic indicator for disease specific survival in patients with primary cutaneous melanoma 4

SLNB Staging and Prognosis 88 93% 50 67% 85.1 62.1 Gershenwald JE, et al. J Clin Oncol. 1999;17:976 83 Morton DL, et al. N Engl J Med.

Cancer. 2009;15:5752 60 Accuracy and Prognostic Value of SLNB in the Head and Neck Erman AB, et al. Cancer. 2012;118:1040 7 353 patients 352 SLNs identified (99.

5 SLNB Staging and Prognosis 88 93% 50 67% Gershenwald JE, et al. J Clin Oncol. 1999;17: Morton DL, et al. N Engl J Med. 2014;370(7): Survival of Melanoma > 4mm by Sentinel Lymph Node Status SLN SLN SLN+ SLN+ Overall Survival Distant Disease Free Survival Gajdos C, et al. Cancer. 2009;15: Accuracy and Prognostic Value of SLNB in the Head and Neck Erman AB, et al. Cancer. 2012;118: patients 352 SLNs identified (99.7%) 19.6% positivity 25% additional positive nonsentinel nodes Patients with local control and SLNB 4.2% failed regionally SLN status most prognostic predictor of recurrence free and overall survival 5

SLNB Regional Control Macroscopic Microscopic IHC Postoperative

Palpable Disease ILND for positive SLNB (132) ILND for clinical

0013 4 positive nodes 9% 29% <0.001 Extranodal 5% 47% <0.

6 SLNB Regional Control Macroscopic Microscopic IHC Postoperative Complications after Inguinal Lymph Node Dissection for + SLNB vs Palpable Disease ILND for positive SLNB (132) ILND for clinical disease (80) P value # positive nodes positive nodes 9% 29% <0.001 Extranodal 5% 47% <0.001 extension Wound 14% 28% 0.02 complication lymphedema 24% 41% ILND inguinal lymph node dissection; SLNB sentinel lymph node biopsy Sabel MS, et al. Surgery. 2007;141: SLNB for Merkel Cell Carcinoma 6

7 SLNB Impact on Survival Multicenter Selective Lymphadenectomy Trial 1 (MSLT 1) Largest, multi continent, randomized trial comparing SLNB versus nodal observation in melanoma. Final report with 10 year follow up published last week. Study underpowered to detect significant treatment related difference in 10 year melanoma specific survival in overall study population. Morton DL, et al. N Engl J Med. 2014;370(7): SLNB Impact on Survival Multicenter Selective Lymphadenectomy Trial 1 (MSLT 1) 10 year disease free survival significantly improved in SLNB group. For patients with intermediate depth melanoma and nodal metastases, SLNB based management significantly improved 10 year distant diseasefree survival and melanoma specific survival. Cumulative rates of nodal metastases in both groups very similar. Morton DL, et al. N Engl J Med. 2014;370(7): SLNB for Melanoma Global Guidelines for SLNB 7

AAD Melanoma Guidelines of Care Biopsy Pathology Report Staging Workup and Follow up Surgical Management Nonsurgical Treatments Sentinel Lymph Node Biopsy Bichakjian CK, et al. J Am Acad Dermatol.

Cancer Council Australia European Dermatology Forum (EDF); European Association of Dermato Oncology (EADO); European Organization for Research and Treatment of Cancer (EORTC) European Society for

8 AAD Melanoma Guidelines of Care Biopsy Pathology Report Staging Workup and Follow up Surgical Management Nonsurgical Treatments Sentinel Lymph Node Biopsy Bichakjian CK, et al. J Am Acad Dermatol. 2011;65: Melanoma Treatment Guidelines American Academy of Dermatology (AAD) National Comprehensive Cancer Network (NCCN) Cancer Care Ontario (CCO) British Association of Dermatologists (BAD) Cancer Council Australia European Dermatology Forum (EDF); European Association of Dermato Oncology (EADO); European Organization for Research and Treatment of Cancer (EORTC) European Society for Medical Oncology (ESMO) Cancer Care Ontario SLNB provides good staging and prognostic information and potentially improved locoregional control. (Based on the evidence review in the Clinical Practice Guidelines for the Management of Melanoma in Australia and New Zealand 2008) Wright F, et al. Clin Oncol. 2011;23(9):

Clinical Practice Guidelines for the Management of Melanoma in Australia and New Zealand SLN status provides accurate prognostic information for disease free and overall survival for melanomas stage

9 Clinical Practice Guidelines for the Management of Melanoma in Australia and New Zealand SLN status provides accurate prognostic information for disease free and overall survival for melanomas stage T1b or greater. Patients with melanoma >1.0 mm should be given the opportunity to discuss SLNB. SLNB should be performed only, following discussion of options, in a unit with access to appropriate surgical, nuclear medicine, and pathology services. Australian Cancer Network Melanoma Guidelines Revision Working Party. Clinical Practice Guidelines for the Management of Melanoma in Australia and New Zealand. Cancer Council Australia and Australian Cancer Network, Sydney and New Zealand Guidelines Group, Wellington (2008) British Association of Dermatologists SLNB can be considered in stage IB melanoma and upwards in Specialist Skin Cancer Multidisciplinary Teams. Patients should be introduced to the concept of SLNB as a staging procedure but should also understand that it has no proven therapeutic value. Surgical risks of SLNB, the possibility of failure to find a SLN, and of a false negative result, should also be explained. Marsden JR, et al. Br J Dermatol. 2010;163: European Dermatology Forum European Association of Dermato Oncology European Organization for Research and Treatment of Cancer SLNB has been established as a valuable staging tool. Positivity rate for melanomas <1 mm is so low that it is normally not recommended, although some centres take additional poor prognostic features into account. Seems appropriate to concentrate SLNB in larger centres where experience can be acquired. Garbe C, et al. Eur J Cancer. 2012;48:

European Society for Medical Oncology SLNB in melanoma >1 mm and/or ulceration is necessary for precise staging. SLNB has no proven effect on overall survival.

2012;23 (Sup 7):vii86 91 American Academy of Dermatology Status of SLN is most important prognostic indicator for diseasespecific survival; impact on survival remains unclear.

10 European Society for Medical Oncology SLNB in melanoma >1 mm and/or ulceration is necessary for precise staging. SLNB has no proven effect on overall survival. SLNB should be carried out only by skilled teams in experienced centers. Dummer R, et al. Ann Oncol. 2012;23 (Sup 7):vii86 91 American Academy of Dermatology Status of SLN is most important prognostic indicator for diseasespecific survival; impact on survival remains unclear. SLNB not recommended for in situ or T1a melanoma. SLNB should be considered for melanoma >1 mm. In T1b, mm, SLNB should be discussed; in T1b 0.75 mm, SLNB should generally not be considered, unless other parameters are present. Bichakjian CK, et al. J Am Acad Dermatol. 2011;65: National Comprehensive Cancer Network SLNB is an important staging tool; the impact on overall survival is unclear. SLNB should be discussed and offered for melanoma >1 mm. In general, SLNB not recommended for 0.75 mm. Other than thickness, little consensus what other conventional features predict SLN positivity in melanoma <1 mm. Coit DG, et al. J Natl Compr Canc Netw. 2013;11:

11 NCCN EORTC CCO SLNB BAD AAD CCA SLNB for Melanoma Clinical Implications and Real Decisions Case 1 56 y/o healthy male Ulcerated nodular melanoma, right upper back 2.8 mm Breslow thickness 5 mitoses/mm2 IIB (T3b N0 M0) WLE wide local excision; SLNB sentinel lymph node biopsy 11

12 2010 AJCC T Classification T Classification Thickness (mm) Ulceration Status/Mitoses T1 1.0 a: w/o ulceration and <1 mitosis/mm 2 or 1 mitosis/ mm 2 T a: w/o ulceration T a: w/o ulceration T4 > 4.0 a: w/o ulceration Balch CM, et al. AJCC Cancer Staging Manual p Case 2 64 y/o healthy female Non ulcerated superficial spreading melanoma, left forearm 0.6 mm Breslow thickness 0 mitoses/mm2 IA (T1a N0 M0) WLE wide local excision 2010 AJCC T Classification T Classification Thickness (mm) Ulceration Status/Mitoses T1 1.0 a: w/o ulceration and <1 mitosis/mm 2 or 1 mitosis/ mm 2 T a: w/o ulceration T a: w/o ulceration T4 > 4.0 a: w/o ulceration Balch CM, et al. AJCC Cancer Staging Manual p

Cases 3 & 4 24 y/o healthy female Ulcerated superficial spreading melanoma, left shoulder 0.

Ulceration Status/Mitoses T1 1.0 a: w/o ulceration and <1 mitosis/mm 2 or 1 mitosis/ mm 2 T2 1.01 2.

AJCC Cancer Staging Manual. 2009. p. 325 44.

13 Cases 3 & 4 24 y/o healthy female Ulcerated superficial spreading melanoma, left shoulder 0.92 mm Breslow thickness 3 mitoses/mm2 IB (T1b N0 M0) 39 y/o healthy male Non ulcerated superficial spreading melanoma, right shoulder 0.82 mm Breslow thickness 1 mitosis/mm2 IB (T1b N0 M0) 2010 AJCC T Classification T Classification Thickness (mm) Ulceration Status/Mitoses T1 1.0 a: w/o ulceration and <1 mitosis/mm 2 or 1 mitosis/ mm 2 T a: w/o ulceration T a: w/o ulceration T4 > 4.0 a: w/o ulceration Balch CM, et al. AJCC Cancer Staging Manual p SLNB Thin Melanoma 24 retrospective studies reporting SLNB for melanoma 1.0 mm Breslow depth: 1.0 mm: 184/3635 (5.1%) mm: 72/1166 (6.2%) 0.75 mm: 22/829 (2.7%) AJCC survival T1aN0M0: 5 year survival rate: 97% 10 year survival rate: 93% Andtbacka RH, et al. J Natl Compr Canc Netw. 2009;7: Balch CM, et al. J Clin Oncol 2009;27:

14 Survival Curves by Number of Mitoses/mm2 Thompson J F et al. JCO 2011;29: by American Society of Clinical Oncology Age and Mitotic Rate as Predictors of SLN Positivity UM Experience Breslow Depth held constant at 1.0 mm 429 patients Sondak VK, et al. Ann Surg Oncol. 2004;11: Azzola MF, et al. Cancer. 2003;97: SLNB Thin Melanoma Melanoma Institute Australia (SMU) Retrospective review 1mm patients SLN positivity rate 6.7% Only factors associated with SLN positivity: Breslow thickness (p = 0.012) Lymphovascular invasion (p = 0.018) Mitotic rate significant predictor of survival, but not SLN positivity Murali R, et al. Ann Surg. 2012;255:

15 Patients Preferences Adjuvant chemotherapy in early breast cancer. What makes it worthwhile? Half judged 1 day or 0.1% sufficient to make adjuvant chemotherapy worthwhile Disconnect between patient and provider preferences Duric V, et al. Ann Oncol. 2005;16: Duric V, et al. Lancet Oncol. 2001;2:691 7 SLNB for Melanoma Future Role of SLNB 15

New Systemic Therapies for Melanoma Anti CTLA4 mab

BRAF inhibitors vemurafenib dabrafenib MAPK kinase

Melanoma Determine need for adjuvant therapy?

16 New Systemic Therapies for Melanoma Anti CTLA4 mab ipilimumab Anti PD1 mab nivolumab lambrolizumab BRAF inhibitors vemurafenib dabrafenib MAPK kinase (MEK) inhibitor trametinib Future Role for SLNB in Melanoma Determine need for adjuvant therapy? Determine type of adjuvant therapy? Melanoma the unlikely poster child for personalized cancer care. Smalley KS, Sondak VK. N Engl J Med. 201o; 363(9):

Translating Evidence into Practice: Primary Cutaneous Melanoma Guidelines. Sentinel Lymph Node Biopsy

American Academy of Dermatology 2018 Annual Meeting San Diego, CA, February 17, 2018 Translating Evidence into Practice: Primary Cutaneous Melanoma Guidelines. Sentinel Lymph Node Biopsy Christopher Bichakjian,