Nodal Treatment in Melanoma: Snow to MSLT-II

Transcription

1 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

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

3 Herbert Lumley Snow, MD

4 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..

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

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

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

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

9 Problem: Identification of patients

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

11 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

12 History of the Sentinel Node Concept Rudolph Virchow

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

14 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

15 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 Gould (1960) Parotid tumor upper neck LN

16 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 Gould (1960) Parotid tumor upper neck LN Cabanas (1977) Penile carcinoma Superficial groin LN

17 Donald L. Morton, MD

18 Lymphoscintigraphy for Nodal Irradiation

19 Lymphoscintigraphy for Melanoma

20 Lymphoscintigraphy for Melanoma Cutaneous Lymphoscintigraphy Tc 99m Human Serum Albumin

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25 Dermal Lymphatics

26 Dermal Lymphatics

27 Intraoperative Identification

28 Intraoperative Identification

29 Multicenter Selective Lymphadenectomy Trials

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

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

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

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

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

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

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

37 MSLT-I prognosis

38 MSLT-I prognosis

39 MSLT-I prognosis

40 MSLT-I prognosis

41 Staging vs. ELND or Clin Exam

42 SLN: Learning Curve

43 SLN Biopsy and Disease-Free Survival: MSLT-I

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

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

46 Delayed treatment metastatic spread within the regional nodal basin

47 Mean # Pos. Nodes Delayed treatment metastatic spread within the regional nodal basin ± ± 0.1 SNB Watch & Wait Immediate CLND Delayed CLND

48 Impact of Clinical Recurrence: Morbidity MSLT-I

49 Number of Nodes Removed Lymphedema by Extent of Dissection Lymphedema No Lymphedema p=0.61 p=0.35

50 Number of Nodes Removed Lymphedema by Extent of Dissection % 34.2% Lymphedema % 22.6% Immediate No Lymphedema 15 Delayed 10 p=0.61 p= Superficial Superficial and Deep

51 Survival (%) Overall Melanoma Related Survival (Breslow mm) Final Dataset 100 SNB HR: 0.84 P=0.18, 95% CI ( ) Group OBS SNB # Event / Total N 97 / / 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 % Time (years) OBS

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

53 Survival (%) Morton A 50 Year Odyssey Melanoma Specific Survival Node+ ( mm) Final Dataset 100 Group # Event / Estimate S(t) ± SE % Total N 5-year 10-year OBS, had nodal recur. 48/ ± ± 5.6 SNB+ 70 / ± ± SNB HR: % C.I. (0.37, 0.84) Log Rank P=0.006 OBS Time (years)

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

55 Factor (%) Patient Characteristics by Intent to Treat Randomization All Strata mm Years Female SNB Watch and Wait Male Gender Ext H/N Trunk Site III IV V Clark N=1973 NS Yes No? Ulceration Mean Median Breslow Mean Age Median

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

57 Latent Subgroup Analysis

58 Survival (%) Morton A 50 Year Odyssey Melanoma Specific Survival Node+ ( mm) Final Dataset 100 Group # Event / Estimate S(t) ± SE % Total N 5-year 10-year OBS, had nodal recur. 48/ ± ± 5.6 SNB+ 70 / ± ± SNB HR: % C.I. (0.37, 0.84) Log Rank P=0.006 OBS Time (years)

59 Patient Selection for SLNB

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

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

62 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

63 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:

64 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)

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

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

67 Thin melanoma: SLN / Prognosis

68 Thin melanoma: SLN / Prognosis

69 Thin melanoma: SLN / Prognosis

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

71 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 )

72 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

73 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.

74 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 ( mm thick, no ulceration, mitotic rate <1/mm 2 )

75 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 ( mm thick, no ulceration, mitotic rate <1/mm 2 ) Discuss and Consider

76 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 ( mm thick, no ulceration, mitotic rate <1/mm 2 ) Stage IB ( mm thick, with ulceration or mitotic rate >1/mm 2 ) Discuss and Consider

77 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 ( mm thick, no ulceration, mitotic rate <1/mm 2 ) Discuss and Consider Stage IB ( mm thick, with ulceration or mitotic rate >1/mm 2 ) Discuss and Offer

78 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 ( mm thick, no ulceration, mitotic rate <1/mm 2 ) Discuss and Consider Stage IB ( 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.

79 SLN Selection: Thin Sentinel node studies Clinical recurrence studies Author < <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.

80 Predictors Breslow

81 Predictors Breslow Clark I II III IV V UNK

82 Predictors Breslow Clark Ulceration I II III IV V UNK 0.0 Yes No Unknown

83 Predictors Breslow Clark Ulceration I II III IV V UNK 0.0 Yes No Unknown Gender Female Male

84 Predictors Breslow Clark Ulceration I II III IV V UNK 0.0 Yes No Unknown Gender Primary Site 0.0 Female Male 0.0 Extremity Head/neck Trunk

85 Predictors Breslow Clark Ulceration I II III IV V UNK 0.0 Yes No Unknown Gender Primary Site Age 0.0 Female Male 0.0 Extremity Head/neck Trunk 0.0 < >=70

86 Predicted probabilities of Nodal Recurrence Breslow Age Sex % node recurrence <0.5 >70 female 0.1 <0.5 >70 male 0.4 < female 0.3 < male 0.9 <0.5 <50 female 0.6 <0.5 <50 male >70 female >70 male female male <50 female <50 male >70 female >70 male female male <50 female <50 male 17.4

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

88 Prognosis: Thick?

89 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= Node(-) Node(+) 36 / / Cox Multivar: RR % C.I. ( ) Time (Months)

90 False Negative SLN

91 False Negative SLN Ann Surg Oncol. 2016;23:

92 False Negative SLN Ann Surg Oncol. 2016;23:

93 False Negative SLN Ann Surg Oncol. 2016;23:

94 False Negative SLN Ann Surg Oncol. 2016;23:

95 False Negative SLN: Surgeon LITR Excluded Ann Surg Oncol. 2016;23:

96 False Negative SLN <4 mm >4 mm Ann Surg Oncol. 2016;23:

97 Smallest Metastases

98 Isolated Tumor Cells Satzger, Am J Pathol 2007

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

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

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

102 Isolated Tumor Cells: Submicromets Unless it does matter

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

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

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

106 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

107 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

108 2009 AJCC TNM Staging System AJCC 6 th edition cut off N1 at 0.2mm

109 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

110 Nodal Ultrasound

111 Pre-operative Morton Nodal ACS Ultrasound 111

112 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%

113 Morton ACS 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

114 MSLT-II Screening Morton ACS 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

115 MSLT-II Screening Morton ACS 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

116 MSLT-II Screening Morton ACS 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

117 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

118 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% Updated from: Thompson JF, et al Society of Surgical Oncology, 2011

119 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 Updated from: Thompson JF, et al Society of Surgical Oncology, 2011

120 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

121 Follow-up Ultrasound

122 Completion Node Dissection

123 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 (%) H&E H&E IHC 22 (11.8%) 39 (12.1%) 19 (21.1%) NSN(-) % 88% 88% 79%

124 Survival Probability Disease Specific Survival Group 5-Year DSS SLN+ NSLN- 77.8% SLN+ NSLN+ 46.4% 0.6 SLN+ NSLN SLN+ NSLN+ 0 P< Disease Specific Survival (Months) Leung et al, PSCA, 2013

125 Survival Probability Disease Specific Survival Group 5-Year DSS SLN+ NSLN- 77.8% SLN+ NSLN+ 46.4% 0.6 SLN+ NSLN SLN+ NSLN+ 0 P< Disease Specific Survival (Months) Leung et al, PSCA, 2013

126 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

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

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

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

130 Regional recurrence CLND-HR 0.46, 95% CI , p=0.016 Age 65 y- HR 2.17, 95% CI , p=0.013

131 Melanoma-specific survival

132 Subgroup Analysis

133 Subgroup Analysis

134

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

136 DeCOG CLND Trial 1,258 patients melanoma and positive SLNB. ( ) 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

137 DeCOG CLND Trial 1,258 patients melanoma and positive SLNB. ( ) 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.

138

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

140 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 -

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

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

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

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

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

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

147 MSLT-II: Trial Design Melanoma >1.2 mm or > Clark IV, n=3500 LM/SL: standard and molecular assessment Melanoma: + SLN (Outside Center) n= Observation Randomization n=1926 Stratification: MSLT-I Center Breslow Ulceration SLN H&E vs. PCR Immediate CLND Nodal Ultrasound Recur No Recur Observation Delayed CLND Observation

148 MSLT-II Accrual: Complete

149 Thank You