Nodal Treatment in Melanoma: Snow to MSLT-II

Nodal Treatment in Melanoma: Snow to MSLT-II Mark B. Faries, MD, FACS Director, Donald L. Morton Melanoma Research Program Program Director, JWCI Complex General Surgical Oncology Fellowship Director, Therapeutic Immunology February 27, 2016

Outline History Elective Node Dissection Sentinel Lymph Node MSLT-I Indications (Thin/Thick) RT-PCR evaluation of SLN Nodal Ultrasound Completion Node Dissection

Herbert Lumley Snow, MD

Elective Lymph Node Dissection A radical cure is alone thus rendered possible in the more common instance of the more common forms of Cancer. It was, and It is essential to remove, whenever possible, those lymph glands which first receive the infective protoplasm, and bar its entrance into the blood, before they have undergone increase in bulk. This is Anticipatory Gland-Excision, a simple common-sense measure, adding nothing to the gravity of a surgical operation, while most materially enhancing its efficacy..

Elective Lymph Node Dissection: WHO #14 All (>1.5mm)

Elective Lymph Node Dissection: WHO #14 All (>1.5mm) 1.5-4.0mm >4.0mm

Elective Lymph Node Dissection: Intergroup Balch, Ann Surg Oncol, 2000

Intergroup ELND: Subgroups 1-2 mm Age < 60 Limb Melanoma Non-ulcerated

Problem: Identification of patients

Problem: Identification of patients 80% of patients undergoing ELND had negative nodes Others have concomitant systemic spread not cured by ELND

Problem: Identification of patients 80% of patients undergoing ELND had negative nodes Others have concomitant systemic spread not cured by ELND Only a subset can benefit from nodal surgery

History of the Sentinel Node Concept Rudolph Virchow

History of the Sentinel Node Concept Rudolph Virchow Leonard R. Braithwaite, FRCS (1923) glans sentinel Upper abdominal node trapping bacterial from the ileum/cecum

History of the Sentinel Node Concept Rudolph Virchow Leonard R. Braithwaite, FRCS (1923) glans sentinel Upper abdominal node trapping bacterial from the ileum/cecum Joseph Weinberg (1950/1951) Blue dye injection for stomach/lung

Donald L. Morton, MD

Lymphoscintigraphy for Nodal Irradiation

Lymphoscintigraphy for Melanoma

Lymphoscintigraphy for Melanoma Cutaneous Lymphoscintigraphy Tc 99m Human Serum Albumin

Dermal Lymphatics

Intraoperative Identification

Multicenter Selective Lymphadenectomy Trials

MSLT-I: Trial Design Melanoma >1 mm or > Clark IV (primary analysis 1.2-3.5 mm)

MSLT-I: Trial Design Melanoma >1 mm or > Clark IV (primary analysis 1.2-3.5 mm) Randomization Wide excision alone 40% 60% Wide excision + SLN

MSLT-I: Trial Design Melanoma >1 mm or > Clark IV (primary analysis 1.2-3.5 mm) Randomization Wide excision alone 40% 60% Wide excision + SLN CLND for Recurrence No recurrence: observation

MSLT-I: Trial Design Melanoma >1 mm or > Clark IV (primary analysis 1.2-3.5 mm) Randomization Wide excision alone 40% 60% Wide excision + SLN SLN + SLN - CLND for Recurrence No recurrence: observation

MSLT-I: Trial Design Melanoma >1 mm or > Clark IV (primary analysis 1.2-3.5 mm) Randomization Wide excision alone 40% 60% Wide excision + SLN SLN + SLN - CLND for Recurrence Immediate CLND No recurrence: observation Observation

MSLT-I: Trial Design Melanoma >1 mm or > Clark IV (primary analysis 1.2-3.5 mm) Randomization DSS: Primary Endpoint DFS: Secondary Endpoint Wide excision alone 40% 60% Wide excision + SLN SLN + SLN - CLND for Recurrence Immediate CLND No recurrence: observation Observation

MSLT-I: Trial Design Melanoma >1 mm or > Clark IV (primary analysis 1.2-3.5 mm) Randomization DSS: Primary Endpoint DFS: Secondary Endpoint Wide excision alone 40% 60% Wide excision + SLN SLN + SLN - Occult Stage III CLND for Recurrence Immediate CLND No recurrence: observation Observation

MSLT-I prognosis

Staging vs. ELND or Clin Exam

SLN: Learning Curve

SLN Biopsy and Disease-Free Survival: MSLT-I

SLN Biopsy and Disease-Free Survival: MSLT-I Intermediate Thickness (1.2-3.5mm)

SLN Biopsy and Disease-Free Survival: MSLT-I Intermediate Thickness (1.2-3.5mm) Thick ( 3.5mm)

Delayed treatment metastatic spread within the regional nodal basin

Mean # Pos. Nodes Delayed treatment metastatic spread within the regional nodal basin 3.5 3.3 ± 0.5 3 2.5 2 1.5 1 1.4 ± 0.1 SNB Watch & Wait 0.5 0 Immediate CLND Delayed CLND

Impact of Clinical Recurrence: Morbidity MSLT-I

Number of Nodes Removed Lymphedema by Extent of Dissection 19.6 21.2 14.9 14.2 Lymphedema No Lymphedema p=0.61 p=0.35

Number of Nodes Removed Lymphedema by Extent of Dissection 19.6 21.2 40 35 30 36.4% 34.2% 14.9 14.2 Lymphedema 25 20 21.4% 22.6% Immediate No Lymphedema 15 Delayed 10 p=0.61 p=0.35 5 0 Superficial Superficial and Deep

Survival (%) Overall Melanoma Related Survival (Breslow 1.20 3.5mm) Final Dataset 100 SNB 75 50 0 HR: 0.84 P=0.18, 95% CI (0.64-1.09) Group OBS SNB # Event / Total N 97 / 500 125 / 770 Estimate S(t) ± SE 5-year 10-year 85.7 ± 1.6 % 78.3 ± 2.0% 86.6 ± 1.3 % 81.4 ± 1.5 % 2 4 6 8 10 12 Time (years) OBS

MSLT-I: Trial Design Melanoma >1 mm or > Clark IV (primary analysis 1.2-3.5 mm) Randomization DSS: Primary Endpoint DFS: Secondary Endpoint Wide excision alone 40% 60% Wide excision + SLN SLN + SLN - Occult Stage III CLND for Recurrence Immediate CLND No recurrence: observation Observation

Survival (%) Morton A 50 Year Odyssey 111509 53 Melanoma Specific Survival Node+ (1.2-3.5mm) Final Dataset 100 Group # Event / Estimate S(t) ± SE % Total N 5-year 10-year OBS, had nodal recur. 48/87 57.5 ± 5.4 41.5 ± 5.6 SNB+ 70 / 193 69.8 ± 4.4 62.1 ± 4.8 75 SNB+ 50 25 0 0 HR: 0.56 95% C.I. (0.37, 0.84) Log Rank P=0.006 OBS 2 4 6 8 10 12 Time (years)

MSLT-I: Trial Design Melanoma >1 mm or > Clark IV (primary analysis 1.2-3.5 mm) Randomization DSS: Primary Endpoint DFS: Secondary Endpoint Wide excision alone 40% 60% Wide excision + SLN SLN + SLN - Occult Stage III CLND for Recurrence Immediate CLND No recurrence: observation Observation

Factor (%) Patient Characteristics by Intent to Treat Randomization All Strata mm Years 70 60 50 40 30 20 10 0 Female SNB Watch and Wait Male Gender Ext H/N Trunk Site III IV V Clark N=1973 NS Yes No? Ulceration 3.5 2.5 1.5 0.5 0 Mean Median Breslow 60 50 40 30 20 10 0 Mean Age Median

Cumulative Incidence of Nodal Metastases Detected by Sentinel Node Biopsy or by Nodal Observation Breslow 1.2-3.5 mm Breslow > 3.5 mm

Latent Subgroup Analysis

Survival (%) Morton A 50 Year Odyssey 111509 58 Melanoma Specific Survival Node+ (1.2-3.5mm) Final Dataset 100 Group # Event / Estimate S(t) ± SE % Total N 5-year 10-year OBS, had nodal recur. 48/87 57.5 ± 5.4 41.5 ± 5.6 SNB+ 70 / 193 69.8 ± 4.4 62.1 ± 4.8 75 SNB+ 50 25 0 0 HR: 0.56 95% C.I. (0.37, 0.84) Log Rank P=0.006 OBS 2 4 6 8 10 12 Time (years)

Patient Selection for SLNB

Thin melanoma and SLND Does a positive SLN matter in thin melanoma?

Thin melanoma and SLND Does a positive SLN matter in thin melanoma? Wong, et al. [Ann Surg Oncol, 2006]

Thin melanoma and SLND Does a positive SLN matter in thin melanoma? Wong, et al. [Ann Surg Oncol, 2006] No deaths in SLN+ patients with thin lesions

Thin melanoma and SLND Does a positive SLN matter in thin melanoma? Wong, et al. [Ann Surg Oncol, 2006] No deaths in SLN+ patients with thin lesions BUT:

Thin melanoma and SLND Does a positive SLN matter in thin melanoma? Wong, et al. [Ann Surg Oncol, 2006] No deaths in SLN+ patients with thin lesions BUT: N=8 Median f/u = 25 months (median time to recurrence = 45 months)

Thin melanoma and SLND 31 of 631 (5%) positive

Melanoma-specific Survival Thin melanoma and SLND 31 of 631 (5%) positive

Thin melanoma: SLN / Prognosis

Survival Probability Node-Positive Thin Melanoma Outcomes Penn JWCI SLN + Penn JWCI Nodal recurrence Months

NCCN: SLN and Thin Melanoma Stage IA (<0.75 mm, thick, no ulceration, mitotic rate <1/mm 2 ) Stage IB (<0.75 mm thick with ulceration and/or mitotic rate >1/mm 2 )

NCCN: SLN and Thin Melanoma Stage IA (<0.75 mm, thick, no ulceration, mitotic rate <1/mm 2 ) Stage IB (<0.75 mm thick with ulceration and/or mitotic rate >1/mm 2 ) Usually No

NCCN: SLN and Thin Melanoma Stage IA (<0.75 mm, thick, no ulceration, mitotic rate <1/mm 2 ) Stage IB (<0.75 mm thick with ulceration and/or mitotic rate >1/mm 2 ) Usually No In general, SLNB is not recommended for primary melanoma <0.75 mm thick unless there is significant uncertainty about the adequacy of microstaging. Stage IA (0.76-1.0 mm thick, no ulceration, mitotic rate <1/mm 2 ) Discuss and Consider Stage IB (0.76-1.0 mm thick, with ulceration or mitotic rate >1/mm 2 ) Discuss and Offer In patients with thin melanomas (<1.0 mm), apart from primary tumor thickness, there is little consensus as to what should be considered high-risk features for a positive SLN. Conventional risk factors for a positive SLN, such as ulceration, high mitotic rate, and lymphovascular invasion (LVI) are very uncommon in melanoma <0.75 mm thick.

SLN Selection: Thin Sentinel node studies Clinical recurrence studies Author <0.76 0.76-1.00 <1.00 Factors Bedrosian* 1/40 (2.5%) 3/31 (9.7%) 4/71 (5.6%) VGP, no other Bleicher 2/118 (1.7%) 6/154 (3.9%) 8/272 (2.9%) Age, incomplete bx Jacobs 1/NR 1/NR 2/63 (3.2%) Kesmodel 1/91 (1.1%) 8/90 (8.9%) 9/181 (5.0%) MR, Br, gender Lowe 2/NR 1/NR 3/46 (6.5%) Clark >III Nahabedian 0/NR 2/NR 2/24 (8.3%) Oliveira Filho NR NR 6/77 (7.8%) ulceration, MR, VGP Puleo NR 20/409 (4.9%) NR None predictive Wong 0/109 8/114 (7.0%) 8/223 (3.6%) None predictive Stitzenberg 3/NR 3/NR 6/146 (4.1%) None predictive Herschko 2/NR 3/NR 5/64 (7.8%) Age Morton NR NR 238/1979 (12.0%) Kalady NR NR 38/1082 (3.5%) Massi** 8/174 (4.6%) 17/113 (15%) 25/287 (8.7%) TIL Karakousis 21/684 (3.1%) 17/198 (8.6%) 38/882 (4.3%) male,<60,axial Corsetti 0/NR 5/NR 5/68 (7.4%) med TTR 52mo Schmidt-Wendtner 37/2301 (1.6%) NR NR male, ALM or LMM McKinnon NR NR NR TTR 49.8mo Woods 5/400 (1.3%) NR NR 2.8% total recur Naruns 28/649 (4.3%) NR NR male, regression TOTAL 102/4526(2.3%) 59/965 (6.1%) 372/5178 (7.2%) * These patients also in Kesmodel, not duplicated in total figures. ** up to 1.5 mm included, not included in total figures.

Predictors 10.0 8.0 Breslow 6.0 4.0 2.0 0.0 0.01-0.25 0.26-0.50 0.51-0.75 0.76-0.99

Predictors 10.0 8.0 Breslow 7.0 6.0 5.0 Clark 6.0 4.0 4.0 2.0 3.0 2.0 1.0 0.0 0.01-0.25 0.26-0.50 0.51-0.75 0.76-0.99 0.0 I II III IV V UNK

Predictors 10.0 8.0 6.0 Breslow 7.0 6.0 5.0 4.0 Clark 10.0 8.0 6.0 Ulceration 4.0 2.0 3.0 2.0 1.0 4.0 2.0 0.0 0.01-0.25 0.26-0.50 0.51-0.75 0.76-0.99 0.0 I II III IV V UNK 0.0 Yes No Unknown

Predictors 10.0 8.0 6.0 Breslow 7.0 6.0 5.0 4.0 Clark 10.0 8.0 6.0 Ulceration 4.0 2.0 3.0 2.0 1.0 4.0 2.0 0.0 0.01-0.25 0.26-0.50 0.51-0.75 0.76-0.99 0.0 I II III IV V UNK 0.0 Yes No Unknown 5.0 4.0 3.0 2.0 1.0 Gender 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Primary Site 0.0 Female Male 0.0 Extremity Head/neck Trunk

Predicted probabilities of Nodal Recurrence Breslow Age Sex % node recurrence <0.5 >70 female 0.1 <0.5 >70 male 0.4 <0.5 50-70 female 0.3 <0.5 50-70 male 0.9 <0.5 <50 female 0.6 <0.5 <50 male 2.1 0.51-0.75 >70 female 0.5 0.51-0.75 >70 male 1.7 0.51-0.75 50-70 female 1.2 0.51-0.75 50-70 male 4.1 0.51-0.75 <50 female 2.9 0.51-0.75 <50 male 9.2 0.76-0.99 >70 female 1.0 0.76-0.99 >70 male 3.4 0.76-0.99 50-70 female 2.5 0.76-0.99 50-70 male 8.1 0.76-0.99 <50 female 5.8 0.76-0.99 <50 male 17.4

Thick Melanoma? Likelihood of systemic metastasis high at presentation Too late to prevent spread

Prognosis: Thick?

Survival (%) Prognosis: Thick? 100 >3.5mm (n=173) MSLT-I 1 75 Sentinel Node (-) 50 Sentinel Node (+) 25 Group # Event / N Estimated S(t) SE 5-Year 10-Year Log Rank: P=0.016 0 Node(-) Node(+) 36 / 116 28 / 57 70.0 4.5 60.6 6.6 62.8 5.3 41.4 8.0 Cox Multivar: RR 1.82 95% C.I. (1.11-2.98) 0 20 40 60 80 100 120 140 Time (Months)

False Negative SLN

False Negative SLN Ann Surg Oncol. 2016;23:1012-1018.

False Negative SLN: Surgeon 10 9 8 7 6 LITR Excluded 5 4 3 2 1 0 Ann Surg Oncol. 2016;23:1012-1018.

False Negative SLN <4 mm >4 mm Ann Surg Oncol. 2016;23:1012-1018.

Smallest Metastases

Isolated Tumor Cells Satzger, Am J Pathol 2007

Isolated Tumor Cells: Submicromets Too small to matter Ann Surg, 2008

Isolated Tumor Cells: Submicromets Too small to matter Ann Surg, 2008 Eur J Cancer, 2010

Isolated Tumor Cells: Submicromets Unless it does matter

Isolated Tumor Cells: Submicromets Truly determining size may be a problem

Isolated Tumor Cells: Submicromets Truly determining size may be a problem 20 patients with <0.1 mm SLN metastases

Isolated Tumor Cells: Submicromets Truly determining size may be a problem 20 patients with <0.1 mm SLN metastases Additional sections cut: upstaged in Max size: 8/20 Tumor penetrative depth: 8/20 Intranodal location: 6/20

2009 AJCC TNM Staging System AJCC 6 th edition cut off N1 at 0.2mm

2009 AJCC TNM Staging System AJCC 6 th edition cut off N1 at 0.2mm AJCC 7 th edition: There is no lower threshold of tumor burden used to define the presence of regional nodal metastasis. Specifically, as a result of the consensus that volumes of regional metastatic tumor <0.2mm in diameter are clinically important, nodal tumor deposits of any size are to be included in staging nodal disease. An evidenced-based lower threshold of clinically insignificant nodal metastases has not been defined. Gershenwald et al, Ann Surg Oncol, 2010

Nodal Ultrasound

Pre-operative Morton Nodal ACS 100410 Ultrasound 111

Pre-SLN Ultrasound 325 patients 6 (1.8%) of patients avoided SLN biopsy due to US findings Sensitivity 33.8% Specificity 85.7% 400 patients peripheral perfusion, loss of central echoes, balloon shape 82% sensitivity, PPV 52%

Morton ACS 100410 113 Pre-operative Nodal Ultrasound MSLT-II: Nodal Ultrasound Criteria Either 1 or 2 of the following: Length: Depth ration <2 Hypoechoic center Failure to identify nodal hilar vessel Focal rounded area of low level echoes with increased vascularity in that area

MSLT-II Screening Morton ACS 100410 Phase: 114 Baseline Nodal Ultrasound Screening Phase Ultrasound (US) n=2964 Baseline US+ n=109 (3.7%) Baseline US n=2855 (96.3%) Updated from: Thompson JF, et al Society of Surgical Oncology, 2011

MSLT-II Screening Morton ACS 100410 Phase: 115 Baseline Nodal Ultrasound Screening Phase Ultrasound (US) n=2964 Baseline US+ n=109 (3.7%) Baseline US n=2855 (96.3%) SLND Path+ n=49 SLND Path n=60 Updated from: Thompson JF, et al Society of Surgical Oncology, 2011

MSLT-II Screening Morton ACS 100410 Phase: 116 Baseline Nodal Ultrasound Screening Phase Ultrasound (US) n=2964 Baseline US+ n=109 (3.7%) Baseline US n=2855 (96.3%) SLND Path+ n=49 SLND Path n=60 SLND Path+ n=558 SLND Path n=2297 Updated from: Thompson JF, et al Society of Surgical Oncology, 2011

Pre-SLN Ultrasound Preoperative ultrasound assessment of sentinel nodes in melanoma patients does not provide reliable staging. Updated from: Thompson JF, et al Society of Surgical Oncology, 2011

Pre-SLN Ultrasound Preoperative ultrasound assessment of sentinel nodes in melanoma patients does not provide reliable staging. 49 (1.7%) True Positives (558 False Negative) Sensitivity was 8.1% Specificity 97.5% Negative Predictive Value: 80.5% Median area for US detected metastases = 4.80mm 2 Median overall SLN metastasis area = <0.5mm 2 Sensitivity doubles (13% 23%) after first 100 cases Sensitivity and PPV increase with increasing tumor thickness SLN excision may be therapeutic (i.e. no need to proceed to CLND) Updated from: Thompson JF, et al Society of Surgical Oncology, 2011

Follow-up Ultrasound

Completion Node Dissection

MSLT-II: Is CLND necessary in SN(+) LN basins? 79-88% of patients have Negative NSN nodes in CLND specimen MSLT-I JWCI Cochran # SN(+) Stain CLND(+) n (%) 187 322 90 H&E H&E IHC 22 (11.8%) 39 (12.1%) 19 (21.1%) NSN(-) % 88% 88% 79%

Survival Probability Disease Specific Survival 1.0 0.8 Group 5-Year DSS SLN+ NSLN- 77.8% SLN+ NSLN+ 46.4% 0.6 SLN+ NSLN- 0.4 0.2 SLN+ NSLN+ 0 P<0.0001 0 24 48 72 96 120 144 168 192 216 240 Disease Specific Survival (Months) Leung et al, PSCA, 2013

Equipoise: Advantages Potential removal of more cancer (10-20%) Complete Staging Information Clinical trial eligibility? Disadvantages Additional surgery Larger incision JP drain Potential complications: Lymphedema Disease may already be systemic Ultrasound may pick up any recurrence at an early time point

Is CLND necessary in SN(+) LN basins? p=0.07

Is CLND necessary in SN(+) LN basins? RFS MSS Multivariable: HR 1.51, p=0.09

Regional recurrence CLND-HR 0.46, 95% CI 0.24-0.86, p=0.016 Age 65 y- HR 2.17, 95% CI 1.12-4.02, p=0.013

Melanoma-specific survival

Subgroup Analysis

DeCOG CLND Trial 1,258 patients melanoma and positive SLNB. (2006 2014) 483 (39%) agreed to randomization (Missed accrual goals.) 241 patients underwent observation only 242 received CLND.

DeCOG CLND Trial 1,258 patients melanoma and positive SLNB. (2006 2014) 483 (39%) agreed to randomization (Missed accrual goals.) 241 patients underwent observation only 242 received CLND. Mean follow-up: 34 months. Improved regional nodal recurrence No significant treatment-related difference in the 5-year RFS (P = 0.72), DMFS (P= 0.76) MSS (P = 0.86) In this early analysis of trial results, no survival benefit was achieved by CLND in melanoma patients with positive SLNB. A subsequent analysis three years after inclusion of the last patient is planned.

MSLT-II: Trial Design Melanoma >1.2 mm or > Clark IV, n=3500 Melanoma: + SLN (Outside Center) n=700

MSLT-II: Trial Design Melanoma >1.2 mm or > Clark IV, n=3500 LM/SL: standard and molecular assessment Melanoma: + SLN (Outside Center) n=700 -

MSLT-II: Trial Design Melanoma >1.2 mm or > Clark IV, n=3500 LM/SL: standard and molecular assessment Melanoma: + SLN (Outside Center) n=700 + -

MSLT-II: Trial Design Melanoma >1.2 mm or > Clark IV, n=3500 LM/SL: standard and molecular assessment Melanoma: + SLN (Outside Center) n=700 + - Observation

MSLT-II: Trial Design Melanoma >1.2 mm or > Clark IV, n=3500 LM/SL: standard and molecular assessment Melanoma: + SLN (Outside Center) n=700 + - Observation Randomization n=1926

MSLT-II: Trial Design Melanoma >1.2 mm or > Clark IV, n=3500 LM/SL: standard and molecular assessment Melanoma: + SLN (Outside Center) n=700 + - Observation Randomization n=1926 Stratification: MSLT-I Center Breslow Ulceration SLN H&E vs. PCR

MSLT-II Accrual: Complete

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