melanoma sentinel lymph node evaluation: update kim james charney, md
TRANSCRIPT
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