Melanoma Sentinel Node

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MELANOMA

Sentinel Lymph Node Evaluation:

Update

Kim James Charney, MD



Conflict of Interest

None



Objectives

Sentinel lymph node (SLN) biopsy conceptand technique

Impact of SLN metastasis on recurrence andsurvival in melanoma

Implication of isolated SLN tumor cells inmelanoma

SLN tumor burden

Necessity of completion lymph node

dissection (CLND) Candidates for SLN biopsy



Stage I & II

85% of newly diagnosed patients



Surgical Management of Stage I and II

Goals

Accurate Staging

Assess risk for recurrence Recommendation for therapy

Durable Local/Regional Control

Cure

Minim ize Morb idi ty



Stage I and II Primary MelanomaComponents of Treatment

Wide Excision

Margins appropriate for thickness

Regional Nodes?



Lymph Node Involvement and

Melanoma

Regional nodes, most common site of first

recurrence

>50% chance for distant relapse

15-50% chance for in-basin failure after lymph node

dissection for palpable disease



Approach to the Clinically Negative

Regional Basin

Observation-----------------------Therapeutic Dissection

ELND Intermediate thickness

Selective lymphadenectomy Lymphatic mapping and sentinel lymph node biopsy

Only pt’s with metastases are dissected



Morton, DL, et al. Arch Surg . 1992; 127:392-399



Sentinel Node BiopsyPublished Findings

SLN identification rate: 99% Dual modality technique

Blue dye

Radio-colloid injections and gamma probe

Accurately stages regional nodal basin Concomitant ELND:FNR < 5%

Follow-up of SLN-neg. patients: ~3% will develop nodaldisease

Facilitates the use of sensitive pathologic techniques



Sentinel Node Biopsy

Goals

Improve disease outcome for node positive

patients

Regional control

Survival

Prevent the development of clinical nodal involvement

Minimally invasive approach to nodal staging



StagingPrognostic Relevance



2010 AJCC StagingChanges

Stage I and II (clinically localized) Thickness

Ulceration

Mitotic Rate >1/mm2

SLN status?

Stage III (regional) Nodes

In-transit disease

Ulceration

Stage IV (distant) Site

LDH



0 1 2 3 4 5 6 7 8

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

9 10 11 1312 14 15

(1)

(3)(5)

(7)

Survival, years

P r o p o r t i o n S u r v i v

i n g

(2)

(4)

(6)

(8)

Balch CM, et al. J Clin Oncol . 2001;19(16):3622-3634.

Non-ulcerated

Ulcerated

AJCC MELANOMA STAGING DATABASESurvival Curves for Stage I & II

Ia

Ib

IIa

IIb

IIc



Incidence of SLN MetastasesMDACC Database

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 21.22.01-4.00 310 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.



2008 AJCC Melanoma Database Stage I

Survival Rates for T1 Patients (0.01-1.00 mm)

According to MR (per mm2)

Survival Rate

Thickness MR 5-Year 10-Year n

(mm)

0.01-0.50 <1.0 99% 97% 1,194

0.01-0.50 >1.0 97% 95% 327

0.51-1.00 <1.0 98% 93% 1,472

0.51-1.00 >1.0 94% 87% 1,868

2009 staging rule: T1b melanomas defined as

≤1.0 mm with ulceration or >1 mitosis / mm2

The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010)

published by Springer Science and Business Media LLC, www.springerlink.com.



Impact of MR on SLN Positivity

Currently, the T1b designation is used for staging interms of survival

Is not itself a criterion to perform SLNB

Evolving data suggests that MR may be predictive of

occult regional nodal disease

Andtbacka RH et al: SLNB in thin melanoma

Suggests that SLNB is appropriate for patients with T1b

melanomas, including those defined by MR

Await publication of a larger analysis of patients with

thin melanoma

Andtbacka RH, Gershenwald JE. JNCCN. 2009;7:308-317.



Prognostic Factors Influencing

Disease-Specific Survival _____________________________________________________________________________

Multiple covariate

Prognostic Factor Univariate Hazard Ratio p-value

Age NS - NS

Sex NS - NS

Axial location .03 - NSTumor thickness <.0001 1.1 .04

Clark level > III .001 2.3 .01

Ulceration <.0001 3.3 <.0001

SLN status <.0001 6.5 <.0001

_____________________________________________________________________________

Several large single institution and multi-center databases provide consistent findings



Disease-Specific Survival by

SLN Status

Morton DL, et al. N Engl J Med. 2006; 355: 1307-1317

Most powerful predictor of survival



Does early treatment of lymph node

disease improve survival?



Randomized Surgical Trials Comparing

ELND vs. Nodal Observation

Pt’s. Thickness Site

WHO Program

Trial #1 533 All Extremities

Trial #14 227 >1.5mm Trunk

Mayo Clinic 171 All Extremities

Trunk

Intergroup Melanoma Trial 737 1-4mm All

Not all patients benefit



Long Term Results of ELND Trials

2 contemporary ELND trials with survival benefits for patients with

microscopic disease



Survival According to Status of Regional Nodes

Cascinelli. Lancet 1998

German Retrospective Review



German Retrospective Review

Impact of Sentinel Node Biopsy on Survival

for Node-Positive Patients

Kretschmer et al, Eur J Cancer . 2004; 212-218.

SLNE: Sentinel Lymph Node positive Elective node dissection

DLND: Delayed Lymph Node Dissection



ELND Trial OutcomesConclusions

No overall survival benefit

Early dissection has no impact on the natural history of primary

melanoma

Incidence of node positive patients too low to adequately test the

hypothesis

Survival benefit observed in the node positive and other stratified

subgroups



MSLT-I: Immediate vs. Delayed CLND

for Nodal MetastasesBiopsy-proven Melanoma > 1mm

Randomized

60% 40%

WEX + SNB WEX + Watch & Wait Observation

A: Comparison of al l randomized patients

SN(-) SN(+) Nodal

Recurrence

Observation Immediate CLND Delayed CLND

B: Comparison of randomized patients with

SN occult vs. palpable nodal metastases




MSLT-15-year Survival Benefit Estimates

Based on previous trial observations

WHO: 20% survival advantage in the microscopic node positive

German multi-center trial: 15% benefit in SLN positive group

Assuming 20% incidence of node positivity

Overall 3%-4% survival benefit






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

• Median follow-up 59.8 months

• 26.8% patients on observation arm with relapse at any

site

• 20.7% patients on sentinel node biopsy arm with

relapse at any site

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

Impact of Sentinel Node Biopsy on

Relapse-Free Survival



MSLT-I: Immediate vs. Delayed CLND

for Nodal MetastasesBiopsy-proven Melanoma > 1mm

Randomized

60% 40%

WEX + SNB WEX + Watch & Wait Observation

A: Comparison of al l randomized patients

SN(-) SN(+) Nodal

Recurrence

Observation Immediate CLND Delayed CLND

B: Comparison of randomized patients with

SN occult vs. palpable nodal metastases




Stage Progression to More Advanced Nodal Disease

Among “Watch and Wait” Patients vs. SNB

0

1

2

3

4

Rx

0%

10%

20%

30%

40%

50%

60%

70%

% S

N B ( + ) o r N o d a l R

e c u r .

M

e a n # P o s .

N o d e s

1.6

SNB

3.4

Watch

N1 N2 N3

> 4 Nodes

67%

41%

28%

32%

5%

27%

SNB

Watch

SNB

Watch

SNB

Watch

1 Node 2-3 Nodes

AJCC N Stage

P=0.0001



Randomizat ion

SLNB OBS

P= 0.004multivariate model adjusted for known prognostic factors

+ - - +

Early TLND

72% 5-year survival

Delayed TLND

52% 5-year survival

MSLT-I: Impact of Sentinel Node Biopsy on

Survival for Node-Positive PatientsA ll 2001 Patien ts




MSLT-1 Node + SubgroupsReasons for Survival Differences

False positive SLN's

SLN group prognostically more favorable

Early dissection prevents regional progression and

distant dissemination



False Positive SLN?



Incidence of SN Metastases at SNB vs. Clinical Nodal

Recurrence following “Watch and Wait”

0.0%

10.0%

20.0%

30.0%

40.0%

1.2-3.5 >3.5 Overall

SNB

Watch

% N

o d e ( + ) o r N o d a

l R e c u r r e n c e

Breslow Thickness (mm)

P=0.8329

16.2 16.4

35.2 35.5

19.8 20.3



Cumulative Incidence of Regional

Node Metastasis

Morton et al. N Engl J Med. 2007;356:418-421



AJCC 2009 Stage III Changes

Concept of ITCs as node-negative disease [N0(i+)] no longer used

Scheri et al: 214 SLN+ patients, 57 had ITCs (≤ 0.2 mm) CLND 6 (12%) additional + nodes, 5-yr melanoma-specific survival LOWER

in ITC+ patients than SLN- patients (89% vs 94%, P =.02)

Akkooi et al: 388 SLN+ patients, 40 (10%) had metastases <0.1 mm 1 (3%) with additional + nodes, 5-yr OS 91% = to SLN- patients

Bottom line: It remains unclear whether ITCs in the regional

nodes are of clinical significance BUT, concept of “clinically insignificant nodal disease” unproven

Scheri RP et al. Ann Surg Oncol. 2007;14:2861-2866.

van Akkooi ACJ et al. Ann Surg. 2008;248:949-955.



Microscopic metastases will become

Macroscopic



Do the AJCC staging criteria apply to

patients with microscopic SLN tumor

burden?

R i d AJCC St i S t



Revised AJCC Staging System

Stage III Changes

Independent Prognostic Factors

AJCC Cox Model – 1151 Stage III Patients

Variable Chi Square P-Value Risk Ratio

Number of (+) 57.6 <0.00001 1.26

Nodes

Tumor Burden 40.3 <0.00001 1.79

Ulcer + 23.3 <0.00001 1.58

6th Edition - 2002

Balch CM et al. J Clin Oncol. 2001; 19(16):3622-3634.



Disease-Specific Survival Total # Positive NodesSLN Positive Patients Only

Gershenwald JE et al. WHO 6th World Congress on Melanoma; September 2005; Vancouver, BC.



Disease-Specific Survival by Ulceration

SLN Positive Patients Only

Gershenwald et al, Ann Surg Oncol. 2000;7:160



Di S ifi S i l b T B d



Disease-Specific Survival by Tumor Burden

Largest Focus SLN-Positive Patients Only

Gershenwald JE et al. WHO 6th World Congress on Melanoma; September 2005; Vancouver, BC.



Survival According to Tumor Burden in

SLN’s

Ross MI. New AJCC Recommendations for Melanoma Staging. Presented at: 33rd ESMO Congress Satellite

Symposium: Current Trends in Melanoma Management ; September 14, 2008; Stockholm, Sweden.



Prognostic Factors Influencing DSS

SNL Positive Patients Only

Multiple covariate

Prognostic Factor Hazard Ratio p-value

Ulceration 2.04 .01

Total Positive Nodes

1 1.0 -

2 1.46 .25

3+ 2.10 .045

Largest SLN metastatic focus

< 2mm 1.0 -

>2 & < 8mm 2.51 .004

> 8mm 2.91 .01



Copyright ©2004 American Cancer Society

From Balch, C. M. et al.

CA Cancer J Clin 2004;54:131-149.

Fifteen-year Survival Curves for the Stage Groupings of Patients with RegionalMetastatic Melanoma (Stage III)



Completion Node Dissection for

Positive Sentinel Nodes:Is i t necessary?

Staging

Survival

Regional Control



Regional Recurrence After Surgery

Alone

Regional

Reference Failure Rate

Fuhrmann,2001 28%

Kretschmer, 2001 34%Lee, 2000 30% Weighted average:

Shen, 2000 14%

Hughes, 2000 25% 692 failures/3350 patients=

Monsour, 1993 52%

Miller, 1992 12% 21%

O’Brien, 1991 24%

Calabro, 1989 17%

Bowsher, 1986 15%

Byers, 1986 16%



Risk Factors for Regional Recurrence

After Surgery Alone

Regional

Characteristic Failure Rate References

Extracapsular extension 31% - 63% Lee, Calabro, Shen, Monsour

>4 involved lymph nodes 22% - 63% Lee, Calabro, Miller, Kretschmer

Lymph node >3 cm 42% - 80% Lee

Cervical ln location 33% - 50% Lee, Bowsher, Monsour

30% - 50% if high-risk features present



In-Basin FailureSelective Lymphadenectomy vs. ELND

(Node Positive Only)

0

1

2

3

4

56

7

8

9

ELND SLN

Slingluff, 1994 MDACC Study, 2003

% N

o d a l F

a i l u r e



Rational For Completion Dissection

Avoid the development of palpable nodal disease

- residual microscopic disease in non-sentinel nodes

Staging- total number of nodes involved prognostically relevant

- may influence recommendations for adjuvant therapy

Incidence of non-sentinel node involvement under-estimated

- based on routine pathologic techniques



Reasons Against Routine Use of

Completion Dissections

Incidence of non-sentinel node involvement is only 10%-20%

- unnecessary cost and morbidity in patients without additional

microscopic disease

No proven survival benefit for node dissection

Incidence of nodal failure after SLN biopsy



A selective approach to completion

dissection is rational.



Recommendations

CLND for a positive SLN is the standard of care

Omission of CLND should only occur as part of a

clinical trial



SLN BiopsyIndispensable Staging Procedure?

Effectively identifies microscopic disease/Promotes early node

dissection

survival benefit

optimizes regional control

Identifies patients who benefit most with adjuvant therapy

Facilitates careful pathologic scrutiny

Node negative patients spared toxicity

Critical prognostic information

Stratification criteria for clinical trials



Candidates for SLN Biopsy

Incidence of Positive SLN:



Incidence of Positive SLN:

AJCC Stage Grouping

0

10

20

30

40

50

60

P e r c e n t P o s i t i v e S L N

3.9%

11.4%

22.1%

35.3%

55.4%

Ia Ib IIa IIb IIc

AJCC Stage



Melanoma Lymphatic MappingPreoperative Eligibility

Primary tumor criteria

> 1mm Breslow thickness

< 1mm MR: present (Ib)

Ulceration (Ib)

Clark Level IV/V Vertical growth phase?

Age?

After a wide excision?

Ambiguous diagnosis of melanocytic lesion?

Pure Desmoplastic melanoma?

National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for

Melanoma. V1.2010

Balch CM et al. J Clin Oncol. 2009;27(6):6199-6206.



Who Should Undergo SLNB?

National Comprehensive Cancer Network, 2011 Consider SLNB for high risk Ia melanoma

Discuss and offer SLNB for stage Ib, stage II CM

SLNB important staging tool, but impact on overall survival

unclear

AJCC Recommendations Microstaging of all primary melanomas

Pathologic nodal staging for stage Ib-IIc

National Comprehensive Cancer Network Clinical Practice Guidelinesin Oncology Melanoma. V. 3.2011

AJCC Cancer Staging Manual, Seventh Edition (2010) publishedby Springer Science and Business Media LLC, www.springerlink.com.



SLN Biopsy

Standard of Care?

Discuss with patients:

accuracy of SLN biopsy

predicted risk for microscopic nodal disease

potential risks and benefits

how the information will impact therapy

Currently offered as standard of care for patientswith Ib-IIc and selectively for Ia.



Thank You



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