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 ~ 70% of newly dx. pt’s with melanoma have thin melanomas

Surgical Management of Stage I and II Goals Accurate Staging Assess risk for recurrence Recommendation for therapy Durable Local/Regional Control Cure Minimize Morbidity The challenges for staging are to assess for recurrence. For that, we need relevant prognostic factors. We need to target at-risk populations and facilitate rational treatment utilizing appropriate modalities. Optimize chance for cure. Offer useful trial stratification criteria

Stage I and II Primary Melanoma Components of Treatment Wide Excision Margins appropriate for thickness Regional Nodes? Whether or not to evaluate clinically negative lymph 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 The natural history of melanoma…. Before the widespread use of SLNB, regional nodes were the most common site of initial recurrence. Once regional nodes become palpable… These are reasons to understand and treat LN’s early

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 80% of patients undergoing ELND do not have + lymph nodes and do not benefit (over treats 80%). Selective lymphadenectomy. Minimizes development of clinical nodal disease and spares node-negative pt’s morbidity of a formal lymph node dissection. A rational alternative to the two prior popularized approaches of ELND or nodal observation.

Lymphatic mapping with sentinel lymphadenectomy has become the standard approach to intermediate thickness melanoma at most melanoma centers worldwide. 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 SLND combined with ELND

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? Stage III (regional) Nodes In-transit disease Stage IV (distant) Site LDH These are the prognostic factors that influence the various stages of melanoma. Thickness remains the single most powerful predictor of survival and mitotic rate replaces Clark Level. Mitotic rate is an independent predictor of outcome. Mitotic rate trumps ulceration in staging. How important is the SLN status in pt’s. with clinically negative LN’s?

AJCC MELANOMA STAGING DATABASE Survival Curves for Stage I & II 1.0 (2) (4) (6) (8) 0.9 (1) Ia 0.8 Ib 0.7 (3) 0.6 (5) IIa (7) Proportion Surviving 0.5 IIb 0.4 The concept of primary tumor ulceration was incorporated into the 6th edition of the AJCC 2002, for the first time, as primary tumor ulceration was found to worsen survival at all tumor thicknesses. Clinical staging, not path staging. The 15-year survival curves of 14,914 patients with localized melanoma are stratified here by tumor thickness and the presence of ulceration. It is evident that the survival rates for patients with ulcerated tumors are proportionately lower than for patients with nonulcerated tumors of similar thickness. In addition, the survival rates of those with ulcerated tumors of a given thickness are strikingly similar to those of patients with thicker, nonulcerated tumors. Stage I and II melanoma patients. This group, from a prognostic perspective is very heterogeneous, composed of subgroups with survival estimates ranging from 40% to 95%. Some of the prognostic heterogeneity is resolved by the predominant prognostic factors of thickness and ulceration status, the combination of which identifies 5 prognostic groups. The current criteria, although improved, have limitations. 0.3 IIc 0.2 Non-ulcerated Ulcerated 0.1 1 2 3 4 5 6 7 8 9 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 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 Thickness remains a powerful predictor of survival. Ulceration influences whether disease is found in the SLN Ulceration predicts a higher incidence of positive SLN’s-----predictive of a metastatic phenotype 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. MR was included in the 2008 AJCC staging. Increased MR is significantly associated with decreasing 5 and 10 year survival rates. MR is an independent predictor of outcome. Analysis showed that the most significant survival differences were seen in those with thin melanomas < 1 mm in depth according to MR. For patients with melanomas with mitoses < 1/mm2, survival was significantly higher than for those patients with 1 or more mitoses/mm2, who also appear to be at increased risk of LN met’s.. This change in the staging rule may impact performance of SLNB on pt’s who are now upstaged to T1b by virtue of MR. While it is estimated that <10% of primary tumors <1mm in depth have ulceration, as many as 30-40% may be associated with a MR of 1 or more/mm2.

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. 24 studies analyzing predictors of SLNB in thin melanoma were analyzed and in those that assessed MR, it was shown that higher MR strongly correlated with SLN positivity.

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 Numerous studies have shown that SLN positivity is the most important prognostic factor and is associated with significantly reduced disease-free and over all survival for patients with melanoma of various thicknesses.

Disease-Specific Survival by SLN Status Most powerful predictor of survival Among pt’s with intermediate-thickness mels., the 5-year survival rate was 90% with a negative SN but 72% with a positive SN. Disease-free survival (A) and disease-specific survival (B) were significantly better for patients with a negative SLN biopsy (each P <.0001). SLN status is the most powerful prognostic factor for death from melanoma: 5-year melanoma-specific mortality of 28% for SLN+ vs. 10% for SLN- (P<.001) Not perfect. Some pt’s have pure hematogenous spread. Some were missed by SLN technique. 5-year survival in SLN+ = 72%. 5-years survival in SLN- = 92%. 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 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 Until recently, pathological nodal status in patients with melanoma could be assessed only by elective lymph node dissection (ELND). After four prospective randomized trials failed to demonstrate a survival benefit for ELND, the procedure was felt to have no therapeutic benefit to patients with melanoma. Critics concluded that early tx. of nodal mets. has little impact on disease progression. However, because only the 20% pt’s. who harbored clinically occult nodal disease could potentially benefit from ELND, the trials were underpowered to detect a survival difference.

Long Term Results of ELND Trials 2 contemporary ELND trials with survival benefits for patients with microscopic disease In contrast to the ELND trials, analyses limited to pt’s. with nodal disease have shown a survival benefit from early lymph node dissection.

Survival According to Status of Regional Nodes A potential outcome benefit for early therapeutic LND was suggested in a randomized trial of ELND vs. observation conducted by the WHO Pt’s. with >1.5mm were randomized to ELND vs. observation. No overall survival benefit, but group with positive nodes in the ELND (immediate CLND) arm had a 48% 5-yr survival compared with group with positive nodes in the observation arm (delayed CLND), who had a 27% 5-yr. survival (P=.04). The data must be interpreted with caution, and can at best only be considered suggestive. There was a 20% improvement in survival. Cascinelli. Lancet 1998

Kretschmer et al, Eur J Cancer. 2004; 212-218. German Retrospective Review Impact of Sentinel Node Biopsy on Survival for Node-Positive Patients Retrospective study, multicenter. Compared survival of SLN pt’s vs. TLND pt’s. 3 year overall survival: 80% SLND vs. 67.6% TLND was statistically significant. 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 Older studies suggested no benefit, but the trials were underpowered. However, lymph node dissection is curative for some patients with nodal metastases, including those with stage III disease. In addition, the best predictor of outcome is tumor burden as measured by the number of positive nodes. Thus, early removal of lymph nodes seems to be a more rational approach than waiting until the patient develops multiple nodal involvement and bulky disease.

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 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 2001 patients from 18 centers world wide with a median f/u of 59.5 months. Developed in 1994. All conclusions of the 3rd interim report of the MSLT-I trial have recently been confirmed by Leiter, Tuebingen, Germany, Ann Surg Oncol, Jan. 2010. They concluded that SLND reduced subsequent regional LN mets. and improved disease-free survival, while overall survival remained unaffected. SLND reduced distant metastases and improved overall survival in the subgroup of pt’s with regional LN involvement. 4th interim report: decreased overall recurrence by 25%. Median f/u 6.4 years. Primary end point. Secondary end point.

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 Similar trial design limitations exist in the MSLT-1, which was developed in 1994. Based on observation of the previous trials, that approx. 15%-20% of micro. + pt’s. actually benefit from an early LND (i.e. about 80% of SLN+ pt’s in the CLND group will have no additional non-sentinel nodal ds., in other words you have already diluted the potential benefit to 20% of the patients), a survival advantage of no more than 3%-4% would be expected for the overall SLN bx. group compared to the overall observation group. The trial did not have sufficient power to detect such a survival benefit.

Latest update (1/11) of MSLT-I=3. 5% overall survival advantage Latest update (1/11) of MSLT-I=3.5% overall survival advantage. Approaching statistical significance. Why was there no difference in the overall group comparisons? There is absence of nodal disease in the majority of patients. As with any targeted therapy, if over 80% of patients do not demonstrate the responding phenotype, it is extremely difficult to demonstrate an overall survival improvement. No significant melanoma specific survival advantage. 5-year survival WLE-86%, WLE+SLNB-87% Melanoma-specific survival, ess, no difference in the two groups, survival differences may emerge with longer follow-up of the MSLT-1, 87.1% vs. 86.6%. But the two more recent ELND trials showed that with increasing f/u, survival differences increased as more events occurred in the observation group than in the immediate ELND group. It therefore seems appropriate to speculate that greater survival differences may emerge with longer follow-up of the MSLT-1. Conclusion: SLN- patients are similar to the observation group who have no recurrence, i.e. same survival. 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 Quality-of-life studies have repeatedly shown that cancer patients assign importance to disease-free survival, even without a demonstrated impact on overall survival. 4th interim analysis: DFS is improved for intermediate and thick; not thin. 4th interim report= 6.4 years Possible psychological benefit of being ds. free; avoid morbidity of surgical procedures for resection of recurrent t ds. 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 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 2001 patients from 18 centers world wide with a median f/u of 59.5 months. Developed in 1994. All conclusions of the 3rd interim report of the MSLT-I trial have recently been confirmed by Leiter, Tuebingen, Germany, Ann Surg Oncol, Jan. 2010. They concluded that SLND reduced subsequent regional LN mets. and improved disease-free survival, while overall survival remained unaffected. SLND reduced distant metastases and improved overall survival in the subgroup of pt’s with regional LN involvement. 4th interim report: decreased overall recurrence by 25%. Median f/u 6.4 years. Primary end point. Secondary end point.

Stage Progression to More Advanced Nodal Disease Among “Watch and Wait” Patients vs. SNB Mean # Pos. Nodes 67% 3.4 SNB P=0.0001 Watch 41% Watch 32% 28% 1.6 27% Watch SNB SNB Watch Nodal observation allows tumor cells in regional nodes to increase in size and spread to additional nodes. There is progression to a more advanced stage if nodes are left intact. The average number of total involved nodes after CLND in the SLNB arm was 1.6 compared with 3.4 after delayed CLND in the observation are. This suggests a clinical benefit if tumor burden correlates with survival, regional control, or both. 5% SNB 1 Node 2-3 Nodes > 4 Nodes N1 N2 N3 AJCC N Stage

multivariate model adjusted for known prognostic factors MSLT-I: Impact of Sentinel Node Biopsy on Survival for Node-Positive Patients All 2001 Patients Randomization SLNB OBS Average 1.6 positive nodes Average 3.4 positive nodes + - - + Early TLND 72% 5-year survival 5 year survival was significantly higher after immed. CLND for SN+ than delayed CLND for clinical nodal recurrence (72% vs., 52%; P=0.004) All conclusions of the 3rd interim report of the MSLT-I trial have recently been confirmed by Leiter, Tuebingen, Germany, Ann Surg Oncol, Jan. 2010. They concluded that SLND reduced subsequent regional LN mets. and improved disease-free survival, while overall survival remained unaffected. SLND reduced distant metastases and improved overall survival in the subgroup of pt’s with regional LN involvement. 4th interim report-reduced distant recurrence 48%. 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 32

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 #34 Some have suggested small volume of ds. in the SLN was clinically irrelevant-would have never progressed, and therefore should be considered “falsely positive”. There has never been any proof of inconsequential metastasis. Some have suggested survival differences , thus far observed among the node + groups-explained by differences in their constellation of prognostic factors. While these criticisms should be considered, it is also logical to conclude that the pt’s. in the two subgroups were similar and that micro. met’s. would most likely have progressed----

False Positive SLN? HMB-45. Argument that ITC’s are not clinically relevant.

Incidence of SN Metastases at SNB vs Incidence of SN Metastases at SNB vs. Clinical Nodal Recurrence following “Watch and Wait” 35.2 35.5 P=0.8329 % Node (+) or Nodal Recurrence 19.8 20.3 16.2 16.4 Breslow Thickness (mm)

Cumulative Incidence of Regional Node Metastasis Projected at 8 years. This confirms that sentinel node biopsy identifies patients who would require a complete node dissection. Nodal mets. were identified in 19% of SLNB pt’s. while nodal recurrence developed in 18% of WEO pt’s. Micro mets. grow to palpable LN’s 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. Rotterdam criteria. Recent data from the Netherlands suggests that ITC’s (<0.1mm) in sentinel lymph nodes do not impart a worse prognosis than completely negative nodes. However, pt’s with such minimal disease are also the most likely to have their disease progression arrested by the SLND itself. Absence of recurrence among these pt’s may be evidence of therapeutic efficacy, rather than clinical insignificance.

Microscopic metastases will become Macroscopic Micro mets. grow to palpable LN’s

Do the AJCC staging criteria apply to patients with microscopic SLN tumor burden? The established stage III factors of number of positive nodes and primary tumor ulceration are also important prognostic risk factors for the SLN+ (microscopic) cohort.

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 What influences overall survival. Among pt’s. with nodal metastases (stage III, the number of metastatic nodes and clinical nodal status (nonpalpable vs. palpable) are the most important predictors of survival, followed by the presence or absence of primary tumor ulceration 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 Ulceration-a phenotype or morphologic surrogate for molecular mechanisms that we do not yet understand. Tumor cells probably gain access to either the lymphatic vessels or the hematogenous vessels at the local tumor environment, which is why ulceration is predictive of both lymph node metastases and distant disease in patients without positive nodes. Gershenwald et al, Ann Surg Oncol. 2000;7:160

Attempts to look at tumor burden in SLN’s Newer discriminates of tumor burden at the microscopic level have all been reported as powerful independent predictors of survival and represent the third factor relevant in this group.

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 Volume is a good predictor of outcome. 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 Such prognostic classifications may have important implications in the design of future randomized systemic adjuvant trials and help in the risk benefit analysis when making individual decisions to pursue adjuvant systemic therapy. Tumor burden is most important.

Fifteen-year Survival Curves for the Stage Groupings of Patients with Regional Metastatic Melanoma (Stage III) The stage III pt. population is also very heterogeneous, exhibiting survival rates ranging from 13% to 69% as predicted by the number of positive nodes, the burden of disease in the nodes (microscopic vs. macroscopic), and primary tumor ulceration. As a result of the routine use of SLNB, the percentage of stage III pt’s. with microscopic nodal ds. is increasing. There is significant prognostic heterogeneity within this favorable group as well. The 5-year survival of this group overall is ~70% but ranges from 40% to 90%. 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 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% Rates of nodal relapse reported range from 9% to 36% after TLND for gross disease.

Risk Factors for Regional Recurrence After Surgery Alone 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 Depending on the amount of gross disease relapse rates may be as high as 63%.

In-Basin Failure Selective Lymphadenectomy vs In-Basin Failure Selective Lymphadenectomy vs. ELND (Node Positive Only) % Nodal Failure Evidence for better regional control is indirect. No study directly answers the question of better regional control, and there is no comparative high-level data in terms of regional failure between SLNB followed by immediate CLND vs. delayed CLND. However, almost 3 decades of evidence exists regarding the regional failure rate after delayed CLND and immediate CLND (ELND or after a positive SLNB). Rates of nodal relapse are in the range of 0% to 10%. With the wide spread use of SLNB, the regional node basin is no longer the most common initial site of clinical recurrence. Slingluff, 1994 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 Important points: -SLN- is not a guarantee of cure. 10% died from melanoma in the first 5 years postsurgery in the SLN- group and 17% relapsed -SLN status was a strong and reliable predictor of outcome and could be relied on to make important treatment recommendations, specifically, whether to consider adjuvant treatment. -Node positive pts. fared sign. better with immediate CLND after SLNB than with delayed CLND after nodal recurrence. -SNB reduces anxious anticipation of recurrence because it optimally stages early melanoma

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 #2. May be that the SLN is the only node with disease. #2. No longer true.

A selective approach to completion dissection is rational. Assessment of risk for non-sentinel node metastases.

STANDARD TREATMENT Recommendations CLND for a positive SLN is the standard of care Omission of CLND should only occur as part of a clinical trial The prospective, randomized MSLT-II trial will look at the therapeutic impact of a CLND. STANDARD TREATMENT

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% 35.3% Percent Positive SLN 22.1% The likelihood of regional nodal involvement increases with increasing tumor thickness. 11.4% 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. Clark IV is now Ia, but increased risk of positive SLN’s. Can have VGP without increased MR. But, cannot have increased MR without VGP.

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