Nabil Wasif MD, MPH Associate Professor of Surgery

Mayo Clinic in Arizona

Disclosures

Relevant Financial Relationship(s) None

Off Label Usage

None

Learning Objectives

• Discuss controversies in surgical margins for melanoma excision

• Examine the indications for sentinel node biopsy for melanoma

• Discuss controversies in the management of node positive melanoma

• Analyze the role of surgery for stage IV melanoma

Centrifugal lymph permeation

Surgical Margins in Melanoma

Surgical Margins in Melanoma

Balch CM, Houghton AN, Sober AJ, Soong S. Cutaneous Melanoma. St Louis QMP 1998

Randomized trials on Surgical Margins

WHO Intergroup Swedish European UK

# patients 612 740 989 326 900

Thickness <2 mm 1-4 mm 0.8-2 mm <2.1 mm >2 mm

Median f/u 7.5 years 10 years 11 years 16 years 5 years

Margins 1 cm vs 3 cm 2 cm vs 4 cm 2 cm vs 5 cm 2 cm vs 5 cm 1 cm vs 3 cm

LRR 9% vs 9% 2.5% vs 3.5% 1% 13% vs 20% HR 1.26

DFS 82% vs 84% 80% 85% vs. 83% NS

OS 90% vs 90% 70% vs 77% 85% 87% vs 86% NS

Conclusion 1 cm for <1 mm 2 cm for 1-4 mm

2 cm for > 0.8 mm

2 cm for < 2.1 mm

1 cm NOT for >2 mm

Current Guidelines for Surgical Margins of Excision

Controversies • There has never been a comparison of 1 vs. 2cm for

intermediate and thick melanomas • 1cm margin for all?

• None of the randomized trials showed any difference in survival or local recurrence

• What about Mohs surgery?

Mohs surgery for H&N Melanoma

Zitelli. J Am Acad Dermatol. 2005 Jan;52(1):92-100

• Not randomized

• Used historical controls

Mohs surgery for melanoma • No randomized trials • National Comprehensive Cancer Network (NCCN)

does not make any recommendations • Journal of the American Academy of Dermatology

(JAAD) takes a pass on the issue

• Reasonable to use for tricky anatomic locations • Also reasonable for melanoma in situ

Courtesy of JC Martinez, MD.

Should All Melanomas Undergo

SLNB? Tumor Total No. Positive SLN Thickness Patients All Non-Ulcerated

Ulcerated (mm) (N) (%) (%) (%) < 1.00 326 4.2 3.9 12.5 1.01-2.00 490 11.4 10.8 21.2 2.01-4.00 310 28.5 23.1 37.0 4.01+ 190 45.5 34.2 55.4 Total 1316 17.4 11.9 37.0

Ross, MI. Clin Cancer Res. 2006;12: 2312s-2319s.

Incidence of Positive SLN: AJCC Stage Grouping

0

10

20

30

40

50

60

Perc

ent P

ositi

ve S

LN

3.9%

11.4%

22.1%

35.3%

55.4%

Ia Ib IIa IIb IIc

AJCC Stage

Guidelines for SLNB for Melanoma SSO/ASCO and NCCN published guidelines

Intermediate thickness melanoma

• Recommended for Breslow thickness 1-4 mm of any anatomic site

Thick melanomas

• May be recommended for staging and to facilitate regional disease control >4 mm melanomas

Thin melanomas

• Insufficient evidence to support routine SLNB for melanomas <1 mm in Breslow thickness, although it may be considered in high-risk patients

Coit DG, et al. Melanoma clinical practice guidelines in oncology. J Natl Compre Cancer Netw. 2012;10:366-400.

Morton DL, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609. doi: 10.1056/NEJMoa1310460.

Breslow thickness: - 1.2 – 3.5 mm - >3.5 mm

Efficacy and Value of SLNB: Multi-center Selective Lymphadenectomy Trial - I

Randomization: - WLE and observe - WLE and SLNB

1661 randomized - 1347 intermediate - 314 thick

• Within SLNB group,melanoma specific survival differed significantly between positive and negative SLN patients in both intermediate and thick groups

Morton DL, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609. doi: 10.1056/NEJMoa1310460.

SLN status most powerful predictor of survival

Significant prognostic value for evaluating SLN status for intermediate group

Morton DL, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609. doi: 10.1056/NEJMoa1310460.

5-year disease-free survival 73.1% vs 78.3%, p=0.009

• Median follow-up 59.8 months

• However no difference in melanoma specific survival was seen between the two arms at 5 years

86.6% vs. 87.1, p = 0.58

Morton et al. N Engl J Med. 2006;355:1307

Impact of Sentinel Node Biopsy on Relapse-Free Survival

SLNB for Thin Melanoma

• 70% of newly diagnosed melanomas are ≤1 mm and have 10-year survival rates of ~90%

• Controversy exists • Subset of thin melanoma patients do poorly with 5-

10% developing regional recurrences and these patients may benefit from nodal staging

• Low incidence of nodal metastasis • Uncertain prognostic value

• Several high-risk factors for nodal disease in thin melanomas reported with no consensus

AAD Guidelines for SLN Biopsy • Status of SLN is most important prognostic indicator for disease-

specific survival in patients with primary cutaneous melanoma; impact of SLNB on overall survival remains unclear.

• SLNB is not recommended for patients with melanoma in situ or T1a melanoma.

• SLNB should be considered in patients with melanoma >1 mm in tumor thickness.

• In patients with T1b melanoma 0.76-1.00 mm in tumor thickness, SLNB should be discussed

• In T1b melanoma, with tumor thickness ≤0.75 mm, SLNB should generally not be considered, unless other adverse parameters in addition to ulceration or increased mitotic rate are present, such as angiolymphatic invasion, positive deep margin, or young age

Strength of Recommendations: B Level of Evidence: I,II,III

• SLN positivity more common in the younger patients • Elderly have a higher incidence of in-transit

metastases

Lymph Node Status and Age

SLN+

<70 years

>70 years

P value

Entire Cohort

15%

11%

0.02

T1/T2 T3/T4

9%

33%

6%

18%

0.02

MacDonald JB, J Cancer, 2011;2:538-543

Deep Positive Margins on Initial Biopsy

• Retrospective analysis of 609 patients

• 60% had a positive margin • Shave (81%) vs. Punch (64%) or Excision (23%)

• 39% were found to have residual disease at excision

• Only 10% of patients had a T category upstage at excision

• No difference in overall or disease free survival

• Change in surgical management should be based upon clinical judgment Egnatios GL, Am J Surg;2011:202:771-778

Desmoplastic Melanoma

• DM is a biologically distinct form of melanoma • Higher incidence of local recurrence • Very low risk of regional metastasis

• Mayo Arizona 0/35 SLN+ • Overall thickness greater than other cutaneous

melanomas • Lymph node staging may be avoided in this

subgroup of patients

Wasif N, J Surg Oncol, 2011;103:158-62

• Gene Sequencing and Prediction of Nodal Status

• Noninvasive gene expression profile (GEP) test

• AAD 2014 and ASCO 2105

• Prediction of metastatic risk in patients with negative SLNB

• Improves risk stratification independent of SLN and ulceration

Should Any Melanoma Undergo SLNB?

Surgical Management of Positive SLNB

• Approximately 15-20% of patients with +SLNB have additional disease

• Patients with minimal sentinel node tumor burden appear to have outcomes similar to sentinel node negative patients

• Only 2% patients with subcapsular metastases (<0.1 mm) had additional positive nodes and 10-year MSS of 95%

• No clear survival benefit for CLND

Van der Ploeg, J Clin Oncol 2011

White, Ann Surg 2002

Prognostic Impact of Positive Lymph Nodes

Does Every Positive SLN Case Require CLND? MSLT-II

Morton DL, et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242:302-11; discussion 311-3.

• 80-85% of positive SLN cases with no additional nodal metastasis outside of SLN disease

• 70-80% of positive SLN patients only have 1 node with metastasis

Surgical Resection for Stage IV melanoma

• Multiple series indicate 15-28% 5-year survival can be achieved in a small proportion of highly selected patients with a few sites of distant metastases that can be completely resected.

• For isolated GI metastases, can reach up to 40% with surgical resection alone.

• Recent multicenter SWOG study had similar results – 25% 5-year survival, median survival of 21 months

Surgical Resection for Stage IV melanoma

Currently, randomized trial comparing surgery to best medical therapy.

Surgical Resection for Stage IV melanoma

Wasif N et al. Does metastasectomy improve survival in patients with Stage IV melanoma? A cancer registry analysis of outcomes. J Surg Oncol. 2011

• Margins • Melanoma in situ and thick melanoma

• SLNB • Thin and thick melanoma

• Positive SLNB • Completion dissection

• Surgery for Stage IV melanoma • In select cases

Summary