MELANOMA Sentinel Lymph Node Evaluation: Update Kim James Charney, MD

Conflict of Interest
None

Objectives

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 & 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 Minimize Morbidity

Stage I and II Primary Melanoma

Components 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 pts with metastases are dissected

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

Sentinel Node Biopsy

Published 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 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

Staging
Prognostic Relevance

2010 AJCC Staging

Changes

Stage I and II (clinically localized)

Thickness Ulceration Mitotic Rate >1/mm2 SLN status? Nodes In-transit disease Ulceration Site LDH

Stage III (regional)

Stage IV (distant)

AJCC MELANOMA STAGING DATABASE

Survival Curves for Stage I & II
1.0 0.9 0.8
(2) (3) (5) (7) (1)

Ia Ib

Proportion Surviving

0.7
(4)

0.6 0.5 0.4 0.3 0.2 0.1

Non-ulcerated

IIa
(6)

IIb IIc

(8)

Ulcerated

10 11 12 13 14 15

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

Incidence of SLN Metastases

MDACC Database
Tumor Thickness (mm) < 1.00 1.01-2.00 2.01-4.00 4.01+ Total Total No. Patients (N) 326 490 310 190 1316 Positive SLN non-Ulcerated (%) 3.9 10.8 23.1 34.2 11.9

All (%) 4.2 11.4 28.5 45.5 17.4

ulcerated (%) 12.5 21.2 37.0 55.4 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 (mm) 0.01-0.50 0.01-0.50 0.51-1.00 0.51-1.00

MR

5-Year

10-Year

<1.0 >1.0 <1.0 >1.0

99% 97% 98% 94%

97% 95% 93% 87%

1,194 327 1,472 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 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 Disease-Specific Survival

_____________________________________________________________________________
Multiple covariate Prognostic Factor Univariate Hazard Ratio p-value

Age NS NS Sex NS NS Axial location .03 NS Tumor 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

Most powerful predictor of survival

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

Does early treatment of lymph node disease improve survival?

Randomized Surgical Trials Comparing ELND vs. Nodal Observation

Pts. WHO Program Trial #1 Trial #14 Mayo Clinic Thickness Site

533 227 171

All >1.5mm All

Extremities Trunk Extremities Trunk All

Intergroup Melanoma Trial

737

1-4mm

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

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

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

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

ELND Trial Outcomes

Conclusions

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 Metastases

Biopsy-proven Melanoma > 1mm Randomized 60% 40%

WEX + SNB WEX + Watch & Wait Observation A: Comparison of all randomized patients

SN(-)

SN(+)

Nodal Recurrence Delayed CLND B: Comparison of randomized patients with SN occult vs. palpable nodal metastases

Observation

Immediate CLND

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

MSLT-1
5-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

Impact of Sentinel Node Biopsy on Relapse-Free Survival

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

MSLT-I: Immediate vs. Delayed CLND for 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 Delayed CLND B: Comparison of randomized patients with SN occult vs. palpable nodal metastases

Observation

Immediate CLND

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

Stage Progression to More Advanced Nodal Disease Among Watch and Wait Patients vs. SNB
70%
3.4 67% SNB P=0.0001

60%
% SNB (+) or Nodal Recur.

Watch

50%
41%

Mean # Pos. Nodes

40% 30%

Watch
28%

32% 27% Watch SNB Watch

1.6 SNB

20% 10%
5% SNB

0%
Rx

1 Node N1

2-3 Nodes N2

> 4 Nodes N3

AJCC N Stage

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

All 2001 Patients
Randomization SLNB OBS

Early TLND 72% 5-year survival

Delayed TLND 52% 5-year survival

P= 0.004
multivariate model adjusted for known prognostic factors
Morton DL, et al. N Engl J Med. 2006; 355: 1307-1317

MSLT-1 Node + Subgroups

Reasons 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
% Node (+) or Nodal Recurrence
40.0%
35.2 35.5

P=0.8329

30.0%

19.8

20.3

20.0%

16.2

16.4

SNB Watch

10.0%

0.0% 1.2-3.5 >3.5 Overall

Breslow Thickness (mm)

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?

Revised AJCC Staging System Stage III Changes

Independent Prognostic Factors AJCC Cox Model 1151 Stage III Patients

Variable Number of (+)

Chi Square 57.6

P-Value <0.00001

Risk Ratio 1.26

Nodes
Tumor Burden Ulcer + 40.3 23.3 <0.00001 <0.00001 1.79 1.58

6th Edition - 2002

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

Disease-Specific Survival Total # Positive Nodes

SLN 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

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 SLNs

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

Prognostic Factor Ulceration Total Positive Nodes 1 2 3+ Largest SLN metastatic focus < 2mm >2 & < 8mm > 8mm Multiple covariate Hazard Ratio p-value 2.04 .01 1.0 1.46 2.10 1.0 2.51 2.91 .25 .045 .004 .01

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

From Balch, C. M. et al. CA Cancer J Clin 2004;54:131-149.

Copyright 2004 American Cancer Society

Completion Node Dissection for Positive Sentinel Nodes:

Is it necessary?

Staging Survival Regional Control

Regional Recurrence After Surgery Alone

Reference
Fuhrmann,2001 Kretschmer, 2001 Lee, 2000 Shen, 2000 Hughes, 2000 Monsour, 1993
Miller, 1992 OBrien, 1991 Calabro, 1989 Bowsher, 1986 Byers, 1986

Regional Failure Rate

28% 34% 30% 14% 25% 52%
12% 24% 17% 15% 16%

Weighted average: 692 failures/3350 patients=

21%

Risk Factors for Regional Recurrence After Surgery Alone

Characteristic
Extracapsular extension >4 involved lymph nodes Lymph node >3 cm Cervical ln location

Regional Failure Rate

31% - 63% 22% - 63% 42% - 80% 33% - 50%

References
Lee, Calabro, Shen, Monsour Lee, Calabro, Miller, Kretschmer Lee Lee, Bowsher, Monsour

30% - 50% if high-risk features present

In-Basin Failure
Selective Lymphadenectomy vs. ELND (Node Positive Only)
9 8 7 6 5 4 3 2 1 0 ELND
Slingluff, 1994

% Nodal Failure

SLN
MDACC Study, 2003

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 Biopsy
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 Biopsy

Incidence of Positive SLN: AJCC Stage Grouping

55.4%

60
Percent Positive SLN

50 40 30 20
11.4% 22.1% 35.3%

10 0

3.9%

Ia

Ib

IIa

IIb

IIc

AJCC Stage

Melanoma Lymphatic Mapping

Preoperative 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 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 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 patients with Ib-IIc and selectively for Ia.

Thank You