What are the indications for sentinel lymph node biopsy?

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ASCO/SSO Guidelines on Sentinel Node Biopsy Do They Represent the Gold Standard?

NO! Vernon K. Sondak, MD Chair, Department of Cutaneous Oncology Moffitt Cancer Center Tampa, Florida 2013 HemOnc Today Melanoma Conference New York, New York March 22, 2013

Department of Cutaneous Oncology

Disclosures • Dr. Sondak is a consultant to Merck and Navidea (Neoprobe)

Department of Cutaneous Oncology

Sentinel Node Biopsy for Melanoma Evidence Based Guidelines or Personalized Care?

Department of Cutaneous Oncology

SENTINEL LYMPH NODE BIOPSY FOR MELANOMA AMERICAN SOCIETY OF CLINICAL ONCOLOGY AND SOCIETY OF SURGICAL ONCOLOGY JOINT CLINICAL PRACTICE GUIDELINE

Wong et al. J Clin Oncol 2012;30:2912 and Ann Surg Oncol 2012;19:3301

Limitations of the Literature • Only one randomized clinical trial that addresses whether patients with melanoma managed using SLN biopsy have better clinical outcomes than those managed any other way – Multicenter Lymphadenectomy Trial I (MLST I)

• Systematic review, by necessity, included observational studies – Cohort studies (SLN biopsy with or without CLND)

• Significant variability across studies (e.g., in techniques used)

www.asco.org/guidelines/snbmelanoma

MSLT-1 Randomized Sentinel Node Biopsy Trial

2006 – Fourth interim analysis, first publication 2010 – Fifth interim analysis, presented at SSO 2013 – Final analysis, submitted for publication to NEJM

Morton et al. N Engl J Med 2006;355:1307* *1.2 – 3.5 mm Primaries

Clinical Questions 1. What are the indications for sentinel lymph node biopsy? 2. What is the role of completion lymph node dissection?

www.asco.org/guidelines/snbmelanoma

CLINICALLY NODE-NEGATIVE MELANOMA

Evidence Based Guidelines for Sentinel Node Biopsy TUMOR <1 mm 1-4 mm >4 mm Any positive nodes

SURGERY No SLN Bx* Recommend SLN Bx SLN Bx May Be Recommended Complete LN dissection

* Selected patients with melanomas <1mm may be considered for SLN Bx ASCO/SSO Joint Guidelines on Sentinel Node Biopsy for Melanoma

Department of Cutaneous Oncology

Impact of Tumor Thickness on Sentinel Node Status Moffitt Cancer Center Experience 2075 patients 30.4%

% of patients with a positive sentinel node

35 30

22.7%

25 20 15

10.0%

10 5

<1%

3.4%

0 <0.76

0.76-1.0

1-2.0

2-4.0

Breslow thickness (mm) Department of Cutaneous Oncology

>4

Recommendation 1 • What are the indications for sentinel lymph node biopsy? Intermediate-thickness melanomas (1 to 4 mm Breslow) SLN biopsy is recommended to patients with intermediatethickness cutaneous melanomas of any anatomic site. Routine use of SLN biopsy in this population provides accurate staging, with acceptable FNR. FNR: false-negative rate

(emphasis added)

www.asco.org/guidelines/snbmelanoma

Impact of Sentinel Node Status on DiseaseFree and Melanoma-Specific Survival

HR=3.04

HR=2.48

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

Sentinel node biopsy differentiates between a ~50% or a 20% risk of relapse and death at 10 years

MSLT-1 Randomized Trial 4th Interim Analysis

Impact of Sentinel Node Status on DiseaseFree and Melanoma-Specific Survival •

1.2 – 3.5 mm Primaries 10-year melanoma-specific survival •

•

•

84.7% if the sentinel node was negative 60.9% if the sentinel node was positive (p<0.0001)

Hazard ratio for death 3.19 * Primary stratum – initially reported in NEJM 2006 Sentinel node biopsy reliably predicts recurrence and death at 5 and 10 years for intermediate thickness primary melanomas

Morton et al. Ann Surg Onc 2010;17(supp 1):S22

MSLT-1 Results UPDATE

Cumulative Incidence of Nodal Metastases

31 of 153 positive nodes missed = 10-year false negative rate 20.3%

734 of 765 sentinel node negative patients correctly classified = 95.9%

Sentinel node biopsy identifies the overwhelming majority of patients who would require a complete node dissection anyway, with a low rate of nodal failure in sentinel node-negative patients

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

My Recommendation • What are the indications for sentinel lymph node biopsy? Intermediate-thickness melanomas (1 to 4 mm Breslow) SLN biopsy is indicated for patients with intermediate-thickness cutaneous melanomas of any anatomic site. Routine use of SLN biopsy in this population provides reliable staging information with few nodal recurrences among sentinel node-negative patients. Department of Cutaneous Oncology

Recommendation 1 • What are the indications for sentinel lymph node biopsy? Thick melanomas (T4; >4 mm Breslow thickness) While there are few studies focusing specifically on patients with thick melanomas, the use of SLN biopsy in this population may be recommended for staging purposes and to facilitate regional disease control.

(emphasis added)

www.asco.org/guidelines/snbmelanoma

MSLT-1 Randomized Trial 4th Interim Analysis

Impact of Sentinel Node Status on DiseaseFree and Melanoma-Specific Survival •

>3.5 mm Primaries (33% node +) 10-year melanoma-specific survival •

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•

62.8% if the sentinel node was negative 41.4% if the sentinel node was positive (p=0.0162)

Hazard ratio for death 1.82 Sentinel node biopsy still predicts recurrence and death for thick primary melanomas, and for nodepositive cases the time to nodal recurrence is short!

Morton et al. Ann Surg Onc 2010;17(supp 1):S22

My Recommendation • What are the indications for sentinel lymph node biopsy? Thick melanomas (>4 mm Breslow) SLN biopsy is indicated for patients with thick cutaneous melanomas of any anatomic site. Routine use of SLN biopsy in this population provides reliable staging information, but patients with negative nodes are still at substantial risk of recurrence. Department of Cutaneous Oncology

Recommendation 1 • What are the indications for sentinel lymph node biopsy? Thin melanomas (T1; <1 mm Breslow thickness) There is insufficient evidence to support routine SLN biopsy for patients with thin melanoma, although it may be considered in selected cases with high risk features, when the benefits of pathologic staging may outweigh the potential risks of the procedure. Such risk factors may include ulceration or mitotic rate ≥1/mm2, especially in the subgroup of patients with Breslow thickness 0.75 mm to 0.99 mm. (emphasis added) www.asco.org/guidelines/snbmelanoma

THIN CLINICALLY NODE-NEGATIVE MELANOMA

Does Sentinel Node Status Predict Prognosis in Thin Melanoma? •

<1.2 mm Primaries (n=139, 10% node +) 5-year melanoma-specific survival •

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•

10-year melanoma-specific survival •

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•

96.0% if the sentinel node was negative 92.3% if the sentinel node was positive 92.7% if the sentinel node was negative 69.2% if the sentinel node was positive (p=0.0649)

Hazard ratio for death 4.06 Analyze your data too early and conclude there is little or no impact of micrometastatic disease Morton et al. Ann Surg Onc 2010;17(supp 1):S22

A Positive SLN Takes Many Years to Impact Melanoma-Specific Survival In T1 Melanoma

p<0.001 for +SLN vs -SLN

Wright et al. Arch Surg 2008;143:892

My Recommendation • What are the indications for sentinel lymph node biopsy? Thin melanomas (<1 mm Breslow) Selecting patients with melanomas <1mm for SLN Bx should be personalized based on likelihood of long-term survival to benefit from the information, the relative risk of the procedure, and the yield of positive SLN (5% or more for a patient at low risk from the procedure, 10% or more for a patient at slightly higher risk). SLN Bx is not indicated for patients with cutaneous melanomas <0.76 mm in the absence of very specific criteria.

Department of Cutaneous Oncology

THIN CLINICALLY NODE-NEGATIVE MELANOMA

Evidence Based Personalized Surgical Guidelines TUMOR <1 mm ABSOLUTE:

SURGERY No SLN Bx unless: Ulcerated primary Obvious residual tumor >1mm Thickness >0.75 plus either RELATIVE: Mitotic rate >0 or Patient <70 years of age NOT Positive deep biopsy margin AN INDICATION: Clark’s level IV-V Regression Selecting patients with melanomas <1mm for SLN Bx should be personalized based on likelihood of longterm survival, yield, and risk of the procedure Department of Cutaneous Oncology

Recommendation 2 • What is the role of completion lymph node dissection? CLND is recommended for all patients with a positive SLN biopsy. CLND achieves regional disease control, although whether or not CLND following a positive SLN biopsy improves survival is the subject of the ongoing Multicenter Selective Lymphadenectomy Trial II (MSLT II).

(emphasis added)

www.asco.org/guidelines/snbmelanoma

My Recommendation • What is the role of completion lymph node dissection? LND is indicated for all patients with clinically positive nodes, and CLND is the standard of care recommendation for all patients with a positive SLN biopsy. Before we abandon LND for patients with positive sentinel nodes, we must be sure longterm recurrence and death rates are not adversely impacted. Clinical trial participation should be strongly encouraged for properly selected patients interested in avoiding CLND. Department of Cutaneous Oncology

NODE-POSITIVE MELANOMA

Evidence Based Personalized Surgical Guidelines NODES N1-2a N1-2b N3, extranodal extension Unknown primary

SURGERY LND or MSLT-2 trial LND LND with consideration of postoperative radiation Treat as known primary

Selecting patients with positive nodes for observation of the nodes instead of LND should be personalized NCCN Guidelines for Cutaneous Melanoma based on likelihood recurrence (not yield) and risk of Morton et of al, N Engl J Med 2006;355:1307 the procedure ifOncol doneClin now vs at recurrence Rao et al, Surg N Am 2011;20:115 Department of Cutaneous Oncology

Multicenter Selective Lymphadenectomy Trial-II

Can complete lymph node dissection be avoided in some patients with positive sentinel nodes?

Are the ASCO/SSO Evidence Based Guidelines for Sentinel Node Biopsy the Gold Standard?

• Sentinel node biopsy widely accepted worldwide, but indications in thin melanomas and role of CLND, especially for smallvolume nodal disease and for positive in transit nodes, remains controversial • The ASCO/SSO guidelines add an important degree of objective support for the procedure, but are not the “Gold Standard”  Clearly our patients require personalized care Department of Cutaneous Oncology