MELANOMAMELANOMA

Sentinel Lymph Node Evaluation: Sentinel Lymph Node Evaluation: UpdateUpdate

Kim James Charney, MDKim James Charney, MD

Conflict of InterestConflict of Interest

NoneNone

ObjectivesObjectives

Sentinel lymph node (SLN) biopsy concept and technique

Impact of SLN metastasis on recurrence and survival in melanoma

Implication of isolated SLN tumor cells in melanoma

SLN tumor burden Necessity of completion lymph node

dissection (CLND) Candidates for SLN biopsy

Stage I & IIStage I & II

85% of newly diagnosed patients

Surgical Management of Stage I and IISurgical Management of Stage I and IIGoals

Accurate Staging Assess risk for recurrence Recommendation for therapy

Durable Local/Regional Control Cure Minimize Morbidity

Stage I and II Primary MelanomaStage I and II Primary MelanomaComponents of Treatment

Wide Excision

Margins appropriate for thickness

Regional Nodes?

Lymph Node Involvement and Lymph Node Involvement and MelanomaMelanoma

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 Approach to the Clinically Negative Regional BasinRegional 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 BiopsySentinel 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 nodal

disease Facilitates the use of sensitive pathologic techniques

Sentinel Node BiopsySentinel Node BiopsyGoalsGoals

Improve disease outcome for node positive patients

Regional control Survival

Prevent the development of clinical nodal involvement

Minimally invasive approach to nodal staging

StagingStagingPrognostic Relevance

2010 AJCC Staging2010 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

00 11 22 33 44 55 66 77 88

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

99 1010 1111 13131212 1414 1515

(1)(1)

(3)(3)

(5)(5)

(7)(7)

Survival, yearsSurvival, years

Pro

po

rtio

n S

urv

ivin

gP

rop

ort

ion

Su

rviv

ing

(2)(2)

(4)(4)

(6)(6)

(8)(8)

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

Non-ulcerated

Ulcerated

AJCC MELANOMA STAGING DATABASEAJCC MELANOMA STAGING DATABASESurvival Curves for Stage I & II

Ia

Ib

IIa

IIb

IIc

Incidence of SLN MetastasesIncidence 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 21.2

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.

2008 AJCC Melanoma Database Stage I2008 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 PositivityImpact of MR on SLN Positivity Currently, the T1b designation is used for staging in

terms 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 Prognostic Factors Influencing Disease-Specific SurvivalDisease-Specific Survival

_____________________________________________________________________________

Multiple covariate

Prognostic Factor Univariate Hazard Ratio p-value

Age NS - NSSex NS - NSAxial location .03 - NSTumor thickness <.0001 1.1 .04Clark level > III .001 2.3 .01Ulceration <.0001 3.3 <.0001SLN status <.0001 6.5 <.0001____________________________________________________________________________

_

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

Disease-Specific Survival by Disease-Specific Survival by SLN StatusSLN 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 Randomized Surgical Trials Comparing ELND vs. Nodal ObservationELND vs. Nodal Observation

Pt’s. Thickness Site

WHO ProgramTrial #1 533 All ExtremitiesTrial #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 TrialsLong Term Results of ELND Trials

2 contemporary ELND trials with survival benefits for patients with microscopic disease

Survival According to Status of Regional NodesSurvival According to Status of Regional Nodes

Cascinelli. Lancet 1998

German Retrospective ReviewGerman Retrospective Review

Impact of Sentinel Node Biopsy on Survival Impact of Sentinel Node Biopsy on Survival for Node-Positive Patientsfor Node-Positive Patients

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

SLNE: Sentinel Lymph Node positive Elective node dissection DLND: Delayed Lymph Node Dissection

ELND Trial OutcomesELND 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 MSLT-I: Immediate vs. Delayed CLND for Nodal Metastasesfor Nodal Metastases

Biopsy-proven Melanoma > 1mm

Randomized

60% 40%

WEX + SNB WEX + Watch & Wait Observation

A: Comparison of all randomized patients

SN(-) SN(+) Nodal

Recurrence

Observation Immediate CLND Delayed CLND

B: Comparison of randomized patients with

SN occult vs. palpable nodal metastases

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

MSLT-1MSLT-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

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

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

Impact of Sentinel Node Biopsy on Impact of Sentinel Node Biopsy on Relapse-Free SurvivalRelapse-Free Survival

MSLT-I: Immediate vs. Delayed CLND MSLT-I: Immediate vs. Delayed CLND for Nodal Metastasesfor Nodal Metastases

Biopsy-proven Melanoma > 1mm

Randomized

60% 40%

WEX + SNB WEX + Watch & Wait Observation

A: Comparison of all randomized patients

SN(-) SN(+) Nodal

Recurrence

Observation Immediate CLND Delayed CLND

B: Comparison of randomized patients with

SN occult vs. palpable nodal metastases

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

Stage Progression to More Advanced Nodal Disease Stage Progression to More Advanced Nodal Disease Among “Watch and Wait” Patients vs. SNBAmong “Watch and Wait” Patients vs. SNB

0

1

2

3

4

Rx0%

10%

20%

30%

40%

50%

60%

70%

% S

NB

(+) o

r Nod

al R

ecur

.

M

ean

# P

os. N

odes

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

Randomization

SLNB OBS

P= 0.004 multivariate model adjusted for known prognostic factors

+ - - +

Early TLND72% 5-year survival

Delayed TLND52% 5-year survival

MSLT-I: Impact of Sentinel Node Biopsy on MSLT-I: Impact of Sentinel Node Biopsy on Survival for Node-Positive PatientsSurvival for Node-Positive Patients

All 2001 PatientsAll 2001 Patients

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

MSLT-1 Node + SubgroupsMSLT-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?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

od

e (+

) o

r N

od

al R

ecu

rren

ce

Breslow Thickness (mm)

P=0.8329

16.2 16.4

35.2 35.5

19.8 20.3

Cumulative Incidence of Regional Cumulative Incidence of Regional Node MetastasisNode Metastasis

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

AJCC 2009 Stage III ChangesAJCC 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 regionalnodes 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 Microscopic metastases will become MacroscopicMacroscopic

Do the AJCC staging criteria apply to Do the AJCC staging criteria apply to patients with microscopic SLN tumor patients with microscopic SLN tumor

burden?burden?

Revised AJCC Staging SystemRevised AJCC Staging SystemStage III ChangesStage 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 NodesDisease-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 UlcerationDisease-Specific Survival by UlcerationSLN Positive Patients Only

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

Disease-Specific Survival by Tumor BurdenDisease-Specific Survival by Tumor BurdenLargest Focus SLN-Positive Patients OnlyLargest 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 Survival According to Tumor Burden in SLN’sSLN’s

Ross MI. New AJCC Recommendations for Melanoma Staging. Presented at: 33rd ESMO Congress SatelliteSymposium: Current Trends in Melanoma Management; September 14, 2008; Stockholm, Sweden.

Prognostic Factors Influencing DSS Prognostic Factors Influencing DSS SNL Positive Patients OnlySNL Positive Patients Only

Multiple covariatePrognostic Factor Hazard Ratio p-value Ulceration 2.04 .01

Total Positive Nodes 1 1.0 -2 1.46 .253+ 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 Regional Metastatic Melanoma (Stage III)

Completion Node Dissection for Completion Node Dissection for Positive Sentinel Nodes:Positive Sentinel Nodes:

Is it necessary?Is it necessary?

Staging Survival Regional Control

Regional Recurrence After Surgery Regional Recurrence After Surgery AloneAlone

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 Risk Factors for Regional Recurrence After Surgery AloneAfter 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 FailureIn-Basin FailureSelective Lymphadenectomy vs. ELND

(Node Positive Only)

0

1

2

3

4

5

6

7

8

9

ELND SLN

Slingluff, 1994 MDACC Study, 2003

% N

odal

Fa

ilure

Rational Rational ForFor Completion Dissection 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 Reasons AgainstAgainst Routine Use of Routine Use of Completion DissectionsCompletion 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 A selective approach to completion dissection is rational.dissection is rational.

RecommendationsRecommendations

CLND for a positive SLN is the standard of care

Omission of CLND should only occur as part of a clinical trial

SLN BiopsySLN BiopsyIndispensable Staging Procedure?Indispensable 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 BiopsyCandidates for SLN Biopsy

Incidence of Positive SLN:Incidence of Positive SLN:AJCC Stage GroupingAJCC Stage Grouping

0

10

20

30

40

50

60

Per

cen

t P

osi

tive

SL

N

3.9%

11.4%

22.1%

35.3%

55.4%

Ia Ib IIa IIb IIc

AJCC Stage

Melanoma Lymphatic MappingMelanoma 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?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 Guidelines in Oncology Melanoma. V. 3.2011 AJCC Cancer Staging Manual, Seventh Edition (2010)

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

SLN BiopsySLN BiopsyStandard of Care?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 patients with Ib-IIc and selectively for Ia.

Thank YouThank You