The Surgical Oncologists Role in Primary and Metastatic Melanoma

Department of Cutaneous Oncology
The Surgical Oncologists Role in Primary and
Metastatic Melanoma
Jonathan S. Zager, MD, FACS
Director of Regional Therapies
Professor of Surgery
Cutaneous Oncology Program
Moffitt Cancer Center

Disclosures
• Medical Advisory Board Member Delcath
• Grant funding Delcath Systems
• PI on clinical trials - Delcath
• Consultant for Amgen
• PI on clinical trials – Amgen
• Consultant for Castle Biosciences
• PI on clinical trials – Castle Biosciences
• PI on clinical trials - Provectus

Surgical Treatment of
Primary Cutaneous Melanoma
Wide Excision +/- SLNB
Thickness
(mm)
Excision
margin (cm)
(from scar or
pigment)
SLNB?
In situ 0.5 to 1.0 No
≤ 1.0 1.0 At Moffitt if >
0.76mm
1.01 – 2.0 1.0 – 2.0 Yes
>2.01 2.0 Yes
Recommendations from National Comprehensive Cancer
Network (NCCN)
Margins may be modified to accommodate individual
anatomic, functional, or aesthetic considerations

Sentinel Lymph Node Biopsy

Summary - Benefits of SLN Biopsy
• Early therapeutic node dissection
 survival benefit
 regional control
• Careful pathologic scrutiny
 node negative patients spared toxicity
 node positive patients offered treatment
• Stratification criteria for clinical trials
• 17% of patients (overall) will have a positive sentinel node
• Identification of ‘unexpected’ drainage patterns in 5-15% of patient

Lymphoscintigraphy

Unpredictable Drainage

First SLN

MSLT-1 RANDOMIZED TRIAL FINAL ANALYSIS
Melanoma-Specific Survival By Nodal
Status
Intermediate Thickness1.0-4.0 mm
Morton et al. N Engl J Med 2014;370:599

MSLT-1 RANDOMIZED TRIAL FINAL ANALYSIS
Melanoma-Specific Survival Node-Positive
Intermediate Thickness 1.2-3.5 mm
Supplement to Morton et al. N Engl J Med 2014;370:599
DOI: 10.1056/NEJMoa1310460
1.2-3.5 mm
Morton et al. N Engl J Med 2014;370:599

Special Situations
• MMIS  Marginal contoured excision
• Desmoplastic Melanoma
• Thin Melanoma
• Thick Melanoma

Marginal contoured excision of melanoma in situ
-consider anatomical structures

-consider aesthetic lines

Moffitt Experience
• 127 patients, median age 68,
• Head and neck MMIS
• Excise ≈ 5 mm margins from tumor site
• 22% had (+) margins initially, had additional
margin excised
• 3 patients (2.4%) had local recurrence with (-)
margins
In literature 7-20%
• 6 patients had (+) final margins and no recurrence
3 at ciliary margin, 1 at vestibular skin nose,
2 refused further excision

Thin Melanoma
• Good prognosis for most patients with thin
melanoma (T1, ≤1 mm): 10-year survival ~90%
• Subset of thin melanoma patients do poorly
with 5-10% developing regional recurrences
• Sentinel lymph node biopsy (SLNB) widely
recommended for melanomas >1 mm
• SLNB for melanomas ≤1 mm is debated
• Several high-risk factors for nodal disease in
thin melanomas reported with no consensus

Han et al JCO 2013

Han et al Ann Surg Onc 2012

p<0.01 for Node Recur. vs. -SLNB
p=0.1 for Node Recur. vs. +SLNB
p=0.53 for +SLNB vs. -SLNB
Overall median follow-up: 2.1 years
Thin melanoma
Thin melanomas have a significant risk for a
positive SLN, particularly those ≥0.76 mm (8.4%)
although no survival impact was seen for a
positive SLN

Thick Melanoma
• Fair prognosis for most patients with thick
melanomas with 40 -70% 5 year survival
• Sentinel lymph node biopsy (SLNB) widely
recommended for melanomas >1 mm
• SLNB for melanomas > 4 mm is debated
• Several high-risk factors for nodal disease
in thick melanomas reported with no
consensus

Yamamoto et al Cancer. 2015

• Entire Cohort 42.5 mo
• SLN negative 82.4 mo
• SLN positive 41.2 mo
• Clinically positive 26.8 mo
P<0.0001

Conclusions
• With an acceptably low false-negative
rate, patients with thick melanoma and a
negative SLNB appear to have
significantly prolonged RFS, DSS, and OS
compared with those with a positive SLNB.
• Therefore, SLNB should be considered as
indicated for patients with thick, clinically
lymph node-negative melanoma

Desmoplastic Melanoma
• Desmoplastic melanoma (DM) represents ~4 %
of all primary cutaneous melanomas and is
characterized by a paucicellular proliferation of
malignant spindled melanocytes within an
abundant collagenous/myxoid
(‘‘desmoplastic’’) stroma.
• Usually found on the head and neck of older
males and often presents as a thicker tumor
compared with nondesmoplastic melanoma
(non-DM)

Pure vs Mixed Desmoplastic
Melanoma
• In 2004, Busam et al. proposed subdividing DM into pure and
combined variants based on extent of desmoplasia.
• In 2005, Hawkins et al. renamed the combined variant as the
‘‘mixed’’ subtype.
• Pure DM was defined by a predominance of stromal fibrosis
with >90 % desmoplasia.
• Mixed DM was characterized by desmoplasia in < 90 % but
>10 % of the tumor, with the remainder consisting of a
conventional melanoma pattern of epithelioid and/or spindle
areas without a significant stromal component.
Busam et al Am J Surg Pathol 2004
Hawkins et al. Ann Surg Oncol 2005

Han et al PLoS One 2015

Han et al Ann Surg Onc 2013

Conclusions
• The overall risk for SLN metastasis for DM
is 13.7 % and is significantly higher for
mixed (24.6 %) compared with pure (9.0
%) DM.
• We believe that these rates are sufficient
to justify consideration of SLNB for both
histologic variants, especially since
detection of SLN disease appears to
predict a higher risk for melanoma-related
death.

Stage III Melanoma
• Characterized by presence of nodal
metastasis
With or without in-transit/satellite lesions
Microscopic Vs. Macroscopic Disease
• Confers significantly worse prognosis
Stage dependent stage IIIA>IIIB>IIIc

Stage III Melanoma
• National Cancer Comprehensive Network
Currently recommends CLND for all positive
SLNB
Exceptions:
Enrollment into a clinical trial
Severe comorbidities precluding surgery
• Prior to Surgical Intervention
Evaluation of Distant Disease
PET/CT or CT N/C/A/P
MRI or CT of the Brain

Stage III Melanoma
4 Significant Prognostic Factors:
1. # of Metastatic Lymph Nodes
2. Microscopic vs. Macroscopic Tumor in
Lymph Nodes
3. Presence of in-transit or satellite metastasis
Represent dissemination of tumor through
lymphatic channels
4. Presence of Ulceration in Primary Tumor

Treatment of Stage III Melanoma
Completion Lymph Node Dissections
• Considered Standard of Care:
• 3 Level Axillary Node Dissection
• Superficial Groin +/- Pelvic Node
Dissection
Robotic, minimally invasive
• Modified Radical Neck Dissection
Superficial Parotidectomy
Posterolateral Neck Dissection

Intransit Metastases –
A Spectrum of Disease that is Difficult to Treat
• Surgical Resection
• Systemic therapy
Immunotherapy
Targeted therapy
• Intralesional injections
• Radiotherapy
• Clinical trials
• Amputation
• Chemotherapy – systemic
• HILP
• ILI

Isolated Limb Infusion
• Minimally invasive
technique
• Can be used to treat
locally recurrent and
metastatic melanoma
isolated to one limb
• Percutaneously
introduced catheters
• Chemotherapy infused
for 30 minutesThompson et al 1998

Hand Pumped
Heating Source
Temp Probes
DP Pulse
Tourniquet
Circuit/ Catheters

Initial Moffitt Experience
> 70% ORR
Wong et al Ann Surg Onc 2013

Intralesional Therapy for Melanoma
• BCG
• IL-2
• TVEC
• PV-10
• Electrochemotherapy
• Topical Diphencyprone

Andtbacka et al JCO 2015

Waterfall Plot Best Tumor Response
TVEC
GM CSF

Duration of Response

Overall Survival

Overall Survival
Stage IIIb/c M1a Stage M1b/c

Case 1

BEFORE TVEC

AFTER TVEC (~6 months)

Case 2:
72 year old Male
Stage IIIB
3 months of treatment
Biopsy of residual pigment was
consistent with path CR

Pre Treatment

After TVEC (4 months)
Residual Pigment Biopsied – Path CR

After 4 Months Treatment
Path CR

Case 3
94 year old female
Stage IIIB
3 months of treatment
Biopsy of Residual Pigment Revealed
Path CR

PRETREATMENT
5 X, NODULE OF PIGMENTED
CELLS SURROUNDED BY

10X, VIABLE
TUMOR CELLS
PRETREATMENT

SOX10, SHOWING
NICE NUCLEAR
POSITIVITY IN
VIABLE CELLS, ALL
THE BROWN ARE
THE
MELANOPHAGES
PRETREATMENT

Post Treatment - 3 Months
Path CR

POST TREATMENT
H&E, 40 x, showing clumps of
melanin-laden macrophages

POST TREATMENT
Sox10 showing
negative nuclear
staining in
pigmented cells
(contrast with
positive internal

Visceral Responses

Conclusions
• WLE and SLNB should be considered SOC for
primary melanomas >1.0mm (0.76 at Moffitt)
• SLNB should be offered to patients with select
thin, thick and desmoplastic melanomas
• CLND is considered SOC – until results of
MSLT-2 are published
• ILI and intralesional injections are useful
therapeutic tools for treating unresectable in-
transit melanoma

Thank You

Treatment Options for Liver Metastases
• Surgical resection
• TACE
• HAI
• RFA
• Cryotherapy
• Yttrium beads
• XRT
• Systemic Therapy
Immunotherapy, BRAF,MEK
• Isolated Hepatic Perfusion
• Chemosaturation Therapy/PHP

Chemosaturation/PHP
Isolation of
Liver for
Regional Tx
Saturation
of Liver with
Melphalan
Extracorporeal
Filtration and Veno-
Veno Bypass

Main Principle is
Saturation and Isolation of the Liver
• IVC venogram
• Back filling of hepatic
veins
Left usually does not
fill
• No leak around
cranial balloon into
right atrium

Moffitt PHP Experience
• 18 pts received 57 PHP treatments
A 19th patient had a PHP aborted due to anatomical
constraints and inability to seat balloon in IVC/atrial
border
Median age at first PHP was 60.5 (range, 37-77 years)
Median 3 PHPs (range, 1-6)
1/2 of patients had regional or systemic therapy before
PHP
Breakdown of histology:
Ocular melanoma N=13
Cutaneous melanoma N=3
Melanoma Unknown Primary N=1
Leiomyosarcoma N=2

Responses
17 evaluable for response
At least 6 weeks – 1st follow up scan
Median follow up was 12.5 months (range, 0.4 – 61.4 months)
Responses (based on RECIST)
5.9% (1/17) Complete response
 path confirmed
41.2% (7/17) Partial response (> 30% response)
47.1% (8/17) Stable disease (-20% to 30% response)
5.9% (1/17) Progressive disease (> -20% progression)
94.1% disease control (16 of 17 patients had stable disease
or a PR/CR)
Median hepatic progression free survival is 347 days

Pt # Sex Age Primary # of
PHPs
hPFS (days)
**=ongoing
Response by
RECIST
(% change)
Follow up
(months)
OS (months)
after DX of
Metastases
1-MLD F 69 Sarcoma 4 678 - 13.0 (SD) 39.6 54.5
2-DD F 55 Ocular 3 407 - 62.1 (PR) 34.8 45.3
3-SD F 68 Ocular 1 0 + 82.8 (PD) 5.8 7.7
4-CL M 77 Ocular 3 224 - 38.6 (PR) 7.5 12.4
5-RR F 47 Cutaneous 4 248 - 11.1 (SD) 8.3 10.9
6-RR M 73 Ocular 3 510 - 91.0 (PR) 23.6 24.5
7-RS M 65 Cutaneous 2 1848 - 43.6 (PR) 61.4 62.8
8-KVP F 59 MUP 3 178 - 4.0 (SD) 36.2 70.4
9-AV F 51 Cutaneous 1 118 - 8.1 (SD) 4.4 10.3
10-AM F 62 Ocular 4 356 - 78.3 (PR) 19.5 21.2
11-JK M 37 Ocular 5 441 - 90.2% (PR) 22.2 25.2
12-KW F 48 Ocular 6 953 ** - 83.8% PATH CR 23.6 23.6
13-DC F 67 Ocular- 5 823** - 73.5 (PR) 22.3 31.3
14-JH M 37 Sarcoma- 6 430 ** - 26.9 (SD) 11.2 36.4
15-SF F 43 Ocular- 4 225 ** +6.5 (SD) 4.2 24.4
16-MK M 64 Ocular- 2 154 ** -25.5% (SD) 2.7 13.4
17-MD F 39 Ocular- 1 56 ** +7.5% (SD) 0.4 21.4
18-PS M 65 Ocular 1 37** NA 1.2 3.7

Waterfall Plot by Tumor Type
-100
-80
-60
-40
-20
0
20
40
60
80
100
%ChangefromBaseline
Best Overall Response
Ocular Melanoma
Unknown Primary
Melanoma
Cutaneous Melanoma
Sarcoma

Foster MF et al JSO 2013

June 4th 2012
April 13th 2012

Toxicity
• Mainly hematological
• Vast majority treated as outpatient
• 1 PE – asymptomatic found on follow up scans
• Did have 2 cardiac events (2/57 =3.5%) on table
1 before Melphalan was give – V Tach –
procedure aborted – patient left hospital day 1
without sequelae
1 after protamine reversal – Cardiac arrest –
patient left hospital day 2 without sequelae

Summary
• Regional therapies and intralesional injections
are efficacious therapeutic modalities for
treatment of intransit metastases
• PHP and ILI are effective intra-arterial therapies
for metastatic melanoma in a limb or the liver
• Combination therapies with systemic therapies
might be the best strategy
• Which comes first systemic or regional remains
to be seen and is the focus of ongoing research

Future Directions- Current and
Planned Clinical Trials
• Ipilimumab and ILI
• Ipilimumab and TVEC
• Pembrolizumab and ILI
• Pembrolizumab and TVEC
• Pembrolizumab and PV-10
• TVEC and Surgery (neodadjuvant)
• Phase II shedding TVEC (safety and efficacy)
• Phase III PHP (vs BAC regional or systemic)

Topical Diphencyprone (DPCP) Cream
• John Thompson and colleagues at
Melanoma Institute of Australia
• Induces immune modulation through
TH17 lymphocyte activation
• Sensitization period of 2 weeks,
then 0.005% increased to 0.01%
once per week, within 1 month no
viable melanoma identified
• Phase II study at Moffitt being
planned (melanoma, CTCL, KA) Martiniuk et al J Drugs Dermatol. 2010

Ablative Immunotherapy with PV-10

Intralesional Therapy PV-10
# of Pts - ORR CR PFS/ Duration of
Response/
Survival
Disease
Control
Rate
CR/PR/SD
Bystander
Effect?
Adverse
Events
PHASE II-
80 stage
III/ IV
49% 24% 8.2 months overall,
11.7 months for
those with CR
71% (22%
SD)
37% ORR
of
bystander
lesions
seen in
injected
responders
Local,
mild to
moderate
pain at
site,
ulceration
• Injection of a dye - Rose Bengal (PV-10) a xanthene dye used for liver
function studies and in ophthalmology exams for decades
• IL PV-10 has been shown to induce regression of treated melanoma and
non treated “bystander” subcutaneous and visceral metastases in phase I
and II studies
•Presented at ASCO and Int’l Melanoma Congress 2010 (Agarwala et al.)

PV-10
Subject 0001: Male, age 78, Stage IIIB (N2c) since 1992, multiple Sx of mets since
2005
Single treatment with 2.0 mL PV-10 to 10 lesions; 1 untreated bystander lesion
CR of Target and Bystander Lesions at Week 52
Week 52Day 7 Week 4Pre-Rx
Phase II Study PV-10

PV-10
Subject 0014: Male, age 48, Stage IIIB (N2c) since 2008, Sx of 1O and mets
Single treatment with 1.3 mL PV-10 to 10 lesions; 1 untreated bystander
lesion (B1)
CR of Target and Bystander Lesions at Week 24
Week 24Day 1 Week 4Pre-Rx
B1
Phase II Study PV-10

Response at 3 Months by Burden of
Disease.
Complete
Response
Partial
Response
Stable
Disease
Progressive
Disease
P-value
BOD
High n= 100 24 (24%) 23 (23%) 14 (14%) 39 (39%)
0.002
Low n= 60 30 (50%) 14 (23%) 2 (3.3%) 14 (23.3%)
Muilenburg Ann Surg Onc 2015
• Increased overall response rate
•73.3% (Low BOD) vs. 47% (High BOD)
• A significantly improved complete response rate
•50% (Low BOD) vs. 23% (High BOD)
• A significant improvement in median overall PFS
•6.9 months (Low BOD) vs. 3.8 months (High BOD)

PhaseIIIStudy.PingpanketalASO2015

0
2
4
6
8
10
12
14
16
18
20
22
24
0 50 100 150 200 250 300 350
WBCCount(K/uL)
Time (days)
White Blood Cells
JH
MK
SF
MD
KW

25
30
35
40
45
50
0 50 100 150 200 250 300 350
Hematocrit(%)
Time (days)
Hematocrit
JH
MK
SF
MD
KW

50
100
150
200
250
300
350
400
450
500
550
0 50 100 150 200 250 300 350
PLTCount(x10^9/L)
Time (days)
Platelets
JH
MK
SF
MD
KW

-consider aesthetic units

Histological Classification
Superficial spreading
Nodular melanoma
Lentigo maligna melanoma
Acral lentiginous melanoma
Desmoplastic melanoma
Amelanotic Melanoma

Prognosis
Clinicopathological factors (primary tumor)
Tumor thickness*
Ulceration*
Mitotic Rate*
Lymphovascular Invasion*
Location
Age
* Pathological characteristics

Prognosis
• Factors related to Nodal Metastasis
 - Number of lymph nodes involved
 - Tumor burden in lymph nodes involved
 Microscopic disease - from sentinel lymph node biopsy
 Mactoscopic Disease – clinically obvious/ radiological obvious

The Surgical Oncologists Role in Primary and Metastatic Melanoma

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