Surgical Management of Malignant Melanoma - uphs.upenn.edu · Surgical Management of Malignant Melanoma Giorgos C. Karakousis, M.D. Associate Professor of Surgery Division of Endocrine

Surgical Management of Malignant Melanoma

Giorgos C. Karakousis, M.D.Associate Professor of Surgery

Division of Endocrine and Oncologic SurgeryUniversity of Pennsylvania School of Medicine

Surgery for Melanoma

Background

• 91,270 cases of melanoma estimated in 2018*• 9,320 melanoma related deaths*• Majority of patients (~85%+) present with clinical Stage I

and II disease• Definitive surgical management of these patients

involves wide excision ± sentinel lymph node (SLN) biopsy

Surveillance and Epidemiology and End Results Program (SEER)


EARLY STAGE DISEASE(CLINICAL STAGE I, II)

Early Stage Melanoma: Margins of Wide ExcisionSurgery for Melanoma

Lens et al. Arch Surg 2007; 142 (9): 885-890

*No difference in survival based on margin excision*Borderline significance in loco-regional recurrence rate in UK trial

Margins of Wide Excision: NCCN guidelinesSurgery for Melanoma

Tumor Thickness Recommended Clinical MarginsIn situ 5 mm≤1.0 mm 1 cm1.01-2.0 mm 1-2 cm2.01-4 mm 2 cm> 4 mm 2 cm

NCCN guidelines Version 2.2014

SLN Biopsy: History

• Lymphoscintigraphy described as early as the 1950s and was used to stage carcinomas of the penis

• The technique was presented for use in melanoma by Morton at the World Health Organization’s International Conference of Melanoma in 1989

• Presented at the Society of Surgical Oncology 1991

• Original report by Morton et al published in 1992 of 223 patients with vital blue dye alone

• In 1993 both Morton and Alex and Krag described the technique with radiotracer and gamma probe localizer

Don Morton, MDJWCI


SLN Biopsy Procedure

•Injection of the melanoma biopsy site with Technetium Tc 99 [99mTc] sulfur colloid

•Lymphoscintigraphy

•Injection with 1% Isosulfan (Lymphazurin) blue dye intra-operatively

•Use of the hand-held gamma probe to identify “hot nodes”

•Removal of all blue nodes and “hot nodes” until radiotracer counts are <10% of the hottest node in the basin

•WE of the primary melanoma

Elias et al. Arch Surg 2004; 139 (4): 400-404


SLN Biopsy: Why do it and for which patients

Why?

For whom?

PrognosisRegional controlTherapy?

Patients with T2-T4 (≥1.00 mm)Patients with T1 melanomas?


Morbidity of SLN biopsy

Lymphedema rates ~5% Infection <5%Hematoma < 5%Seroma 5-10%Parasthesias 5-10%Anaphylaxis from dye injection <<1%


SLN biopsy and prognosis: MSLT-1

MSLT1 (N=1,327)WE alone + observation

WE, SLN biopsy(1.2 – 3.5 mm thickness

melanomas)

Morton et al. NEJM 2006; 335 (13): 1307-1317

72.3%

90.2%

p<0.001

SLN positivity rate:16.0%


SLN biopsy and therapeutic effect?: MSLT-1

Subgroup (SG) 1: +SLN2: SG 1+ SG 43: clinical nodal recurrence during observation4: nodal recurrence after - SLN

Morton et al. NEJM 2006; 335 (13): 1307-1317

72.3%52.4%

Mean LN #

1.4

3.3


SLN biopsy and therapeutic effect?: MSLT-1Surgery for Melanoma

Morton et al NEJM 2014

Among patients with nodal metastases, those who underwent SLN biopsy with immediate lymphadenectomy demonstrated improved survival in intermediate thickness group but not thick group.

Outcomes of Thin Melanoma Patients undergoing SLN biopsy

P<0.0001

SLN +

Clinical Nodal Recurrence

}SLN +

}CNR

Surv

ival

Pr

obab

ility

Months

JWCI

JWCIPenn

Penn

SLN +

Clinical Nodal Recurrence

Months P<0.0001

Karakousis, Faries et al Ann Surg Onc 2016

SLN Biopsy in Melanoma

5 yr 10 yr

SLN+ 88% 84%

CNR 72% 49%

SLN biopsy and T1 melanomas

• SLN biopsy is prognostic for intermediate thickness melanomas and there is an appreciable incidence of SLN positivity (15-20%) to justify the procedure in this group, but how about for patients with T1 melanomas?


SLN biopsy in T1 melanomas: NCCN guidelinesSurgery for Melanoma

• Stage IA (<0.8 mm*)

• Stage IB<0.8 mm ulcerated or 0.8-1.0 mm ± ulceration)

• Stage IB (T2a) or Stage II

• * high mitotic count, transected specimen, LVI, younger age

Version 2.2018

WE alone

WE, discuss and consider SLN

WE, discuss and offer SLN

https://www.nccn.org/professionals/physician_gls/pdf/melanoma.pdf

SLN biopsy ASCO/SSO guidelinesSurgery for Melanoma

Wong et al JCO 2018

SLN biopsy in T1 melanomas: Penn ExperienceSurgery for Melanoma

Bartlett, Karakousis et al Ann Surg Onc 2014

SLN biopsy in T1 melanomas: Penn ExperienceSurgery for Melanoma

Bartlett, Karakousis et al Ann Surg Onc 2014

Predictors of LN positivity in patients with Thin Melanoma

Sinnamon, Karakousis et al JAMA Derm 2017

NCDB database• T1 melanomas≥0.5mm

who had nodal evaluation

• 8,772• Thickness, ulceration,

mitoses, Clark level, LVI, age


SLN biopsy in T1 melanomasSurgery for Melanoma

Cordeiro et al, Ann Surg Onc 2016

Systematic review and Meta-analysis of 60 studies

Thin Melanomas with + deep margin SLN Biopsy in Melanoma

Multivariate Analysis

2.7% 0.32%

≤0.75 mm+DM -DM

p=0.02

SLN biopsy in T4 melanomas

•SLN positivity rates are high, but so is potential risk of distant (beyond regional nodes) disease

•Should other staging modalities be used prior to SLN biopsy?

•Is it prognostic in this group?


SLN biopsy in T4 melanomas: staging modality

Maubec et al. Melanoma Res 2007; 17 (3): 147-154

Prospective Study

N=25

Primary Melanoma Non-Palpable Regional Nodal Disease

Palpable Regional Nodal Disease

0/2 0/6Sensitivity: 0%

Specificity: 92%

4/4

Distant Metastases

0

3 patients had PET avid distant lesions that upon biopsy did not demonstrate metastatic disease


SLN biopsy in T4 melanomas: prognostic value

Gajdos et al. Cancer 2009; 115 (24): 5752-60



STAGE III DISEASE

Completion lymphadenectomy or not for +SLNSurgery for Melanoma

Incidence of finding additional non-sentinel nodes on completion lymphadenectomy for a + SLN is approximately 15-20%

Various factors may help to predict which patients are at risk for harboring additional metastatic disease in the non-sentinel nodes

Disease in the non-sentinel nodes may portend a worse prognosis

Completion lymphadenectomy has been the standard approach for patients with + SLN, but this has recently changed

Predictors of non-sentinel LN positivitySurgery for Melanoma

Van der Ploeg et al. JCO 2011; 29 (16): 2206-14

Prognosis of patients with non-SLN+Surgery for Melanoma

Ariyan et al. Ann Surg Onc 2009; 16: 186-190

66 mo

34 mo

p=0.04104 mo

36 mo

P<0.001

2 nodes +

DECOG study

Leiter et al. Lancet Oncology 2016; 17 (6): 757-67


DECOG study


Distant metastasis free survival

Overall survival


MSLT2 StudySLN Biopsy in Melanoma

Faries et al NEJM 2017

MSLT2 StudySLN Biopsy in Melanoma

Faries et al NEJM 2017

ASCO/SSO guidelines 2018

Wong et al JCO 2018


DECOG study



Adjuvant therapy (stage III)SLN Biopsy in Melanoma

Drug Indications ImpactDabrafenib/Trametinib SLN+ >1mm

BRAF V600 activating mutation

RFS

Ipilimumab (10 mg/kg) *seems greatest benefit in high nodal burden disease

RFS, OS

Nivolumab IIIB/C/IV RFS High dose Interferon DFS

In-transit diseaseSurgery for Melanoma

Courtesy of Dr. D.L. Fraker

Patient with extensive in transit melanoma of the distal left leg

•In-transit disease is defined by the presence of metastatic melanoma deposits beyond 2 cm from the primary melanoma but not in the immediate draining regional nodal basin•Incidence of in-transit disease in patients with Stage I and II melanoma is estimated at 2-11%•Factors associated with the development of in-transit disease include tumor thickness, nodal metastases, female gender, lower extremity site

Isolated limb perfusion (ILP) Surgery for Melanoma

ILP

•ILP is a technique that involves surgical isolation of the vessels to an extremity for the administration of chemotherapeutics at doses much higher than could be given systemically.

Complete response after ILPSurgery for Melanoma

Pre-ILP Post-ILP

Courtesy of Dr. D.L. Fraker

TNF+ melphalan

Complete response after ILPSurgery for Melanoma

Sanki et al. Curr Prob Surgery 2011; 48: 371-430

Morbidity of ILP procedureSurgery for Melanoma

Grade Reaction

I No visible reaction

II Mild erythema or edema

III Considerable erythema/edema with some skin blistering

IV Extensive epidermolysis with deep tissue damage and functional disturbance and threatened or actual compartment syndrome

V Reaction necessitating amputation

Wieberdunk classification system

Wieberdink et al. Eur J Cancer Clin Oncol 1982; 18 (10): 905-10

30-92%

35-40%

<5%

<5%

Isolated limb infusionSurgery for Melanoma

ILI

•ILI is a technique developed in the early 1990s at the Sydney Melanoma Unit as a less costly method for administering regional therapy by percutaneous approach

Beasley et al. J Am Coll Surgeons2009; 208 (5): 706-15

Comparison of ILP to ILISurgery for Melanoma

ILP ILIAccess of vessels to the extremity

surgical percutaneous

Need for perfusionist yes no

Perfusion/Infusion timeOR Time

~60-90 min4+hrs

~30 min1-1.5 hrs

Cost > <Response rates*

CROR

50.4%79.4%

33%64%

Regional toxicity ≈ ≈

Beasley et al. J Am Coll Surgeons2009; 208 (5): 706-15

STAGE IV DISEASE



Outcomes of surgery for Stage IV melanoma

Ollila et al. Lancet Oncology 2006; 7: 919-24


Randomized phase III Canvaxin trial

496 randomized patientsPatients were eligible with up to 3 distant melanoma metastases5 year survival in the surgery + placebo group was 44.9% compared to 39.6% in the surgery + Canvaxingroup

Morton et al. 59th SSO symposium 2006

Surgery for Melanoma SWOG Phase II trial: Patient characteristics

Sosman et al. Cancer 2011; 117: 4740-46


Sosman et al. Cancer 2011; 117: 4740-46

Median RFS : 5 months

Relapse free survival (RFS) Overall survival

Results of SWOG Phase II trial

Surgery for Melanoma Surgery in the era of emerging new therapies

Targeted therapies:BRAF inhibitor)/MEK inhibitor

Immunotherapy:Ipilimumab (anti-CTLA4 therapy)PD-1 inhibitorTVEC (talimogene laherparepvec)

Summary

• WE ± SLN biopsy remains standard treatment for early stage melanoma

• SLN biopsy is safe procedure and appears to be prognostic across melanoma tumor thickness

• The therapeutic value of SLN biopsy in patients with melanoma has not been established

• SLN biopsy should be discussed and offered in patients with intermediate depth melanoma


Summary

• SLN biopsy should not be routinely offered in all patients with T1 melanomas (5% or less likelihood of SLN positivity), but should be considered in those >0.8 mm in depth or ulcerated or with other adverse tumor characteristics

• Completion lymph node dissection or close observation are options for patients with positive SLN

• Melphalan ILP and ILI are useful techniques for treating patients with locally advanced melanoma with in-transit disease

• Metastatectomy in selected patients with stage IV melanoma is associated with favorable outcomes


Documents

Surgical Management of Malignant Melanoma - uphs.upenn.edu · Surgical Management of Malignant Melanoma Giorgos C. Karakousis, M.D. Associate Professor of Surgery Division of Endocrine