Sentinel Node Alphabet Soup: MSLT-1, DeCOG-SLT, MSLT-2, UNC David W. Ollila MD James and Jesse Millis Professor of Surgery University of North Carolina, Chapel Hill Disclosures: None July 15, 2018
AJCC 8 th Edition 2018 Gershenwald et al., 2017 2
Comparisons of 7 th vs. 8th Balch, JCO 2009 Gershenwald et al.,2017 3
Comparisons of 7 th vs. 8th Balch, JCO 2009 Gershenwald et al.,2017 4
Comparisons of 7 th vs. 8th Balch, JCO 2009 Gershenwald et al.,2017 5
MSLT-1: Immediate vs. Delayed CLND Nodal Metastases Melanoma 1.2-3.5mm Randomized WEX + SNB 60% WEX + Watch & Wait Observ. 40% SN(-) SN(+) Nodal Recurrence Observation Immediate CLND Delayed CLND Overall Survival p=ns Morton, NEJM 2006 6
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Morton, NEJM 2006 8
MSLT-1: Immediate vs. Delayed CLND Nodal Metastases Melanoma 1.2-3.5mm Randomized WEX + SNB 60% WEX + Watch & Wait Observ. 40% SN(-) SN(+) Nodal Recurrence Observation Immediate CLND Delayed CLND Mean # Nodes 4.3 1.4 3.3 5 year Melanoma Survival: 90.2% 72.3% 52.4% HR 2.48; p<0.001 HR 0.51; p<0.001 Morton, NEJM 2006 9
Morton, NEJM 2006 Patients with T2/T3 melanomas and nodal metastases derive a 20% absolute survival advantage with a SN procedure and CLND as compared to watchful waiting CAVEAT: DSMB advised release of data to physicians and public because multiple endpoints had been reached, but not overall survival 10
Standard of care for patients with T2 or T3 melanoma No survival advantage 1/2008 24% False-positivity 1/2008 11
Demonstrating Biology Metastatic melanoma cells, regardless of the size of the cluster, have biologic relevance Ollila et al., JACS 2009 Society of Surgical Oncology Position Statement Annals of Surgical Oncology 2012 12
Recurrence and Death events for each tumor burden group (n=578) Tumor Burden N (% ) Recurrence n(%) Distance Recurrence n(%) Death n(%) Node 488 (84%) 56 (11%) 35 (7%) 52 (11%) negative <0.1mm 33 (6%) 8 (24%) 5 (15%) 5 (15%) 0.1-1.0mm 27 (5%) 10 (37%) 6 (22%) 6 (22%) >1.0mm 30 (5%) 21 (70%) 14 (47%) 12 (40%) Ollila et al., JACS 200913
MSLT-1: Immediate vs. Delayed CLND Nodal Metastases Melanoma 1.2-3.5mm Randomized WEX + SNB 60% WEX + Watch & Wait Observ. 40% SN(-) SN(+) Nodal Recurrence Observation Immediate CLND Delayed CLND Overall Survival: p=ns Morton, NEJM 2014 14
MSLT-1: Immediate vs. Delayed CLND Nodal Metastases Melanoma 1.2-3.5mm Randomized WEX + SNB 60% WEX + Watch & Wait Observ. 40% SN(-) SN(+) Nodal Recurrence Observation Immediate CLND Delayed CLND Mean # Nodes 4.3 1.4 3.3 10 year Melanoma Survival: 85.1% 62.1% 33.5% HR 3.09; p<0.001 HR 0.51; p<0.001 Morton, NEJM 2014 15
MSLT-1: Immediate vs. Delayed CLND Nodal Metastases Melanoma 1.2-3.5mm Randomized WEX + SNB 60% WEX + Watch & Wait Observ. 40% SN(-) SN(+) Nodal Recurrence Observation Immediate CLND Delayed CLND Mean # Nodes 4.3 1.4 3.3 10 year Melanoma Survival: 85.1% 62.1% 33.5% HR 3.09; p<0.001 HR 0.51; p<0.001 Morton, NEJM 2014 16
DeCOG-SLT and MSLT-2 SN+ Immediate CLND Active Surveillance: Ultrasound Leiter U et al., Lancet Oncol. 2016 Faries MB et al., NEJM 2017 17
DeCOG-SLT: Results Distant Metastasis-Free Survival Overall Survival Recurrence-Free Survival HR P-value HR P- HR P-value value Obs vs LND 1.19 0.43 1.02 0.95 0.96 0.83 Tumor load in 2.33 < 0.0001 2.96 <0.001 3.03 < 0.0001 SLN ( 1 m v > 1) Tumor thickness 3.06 < 0.0001 3.46 < 0.001 3.03 < 0.0001 ( 2 mm vs > 2) Ulceration (y/n) 1.35 0.20 1.2 0.48 1.24 0.28 # SLNs + (1 vs 1.15 0.75 1.69 0.23 1.14 0.73 2) IFN therapy (y/n) 0.99 0.98 0.83 0.46 0.87 0.46 Median follow-up was 35 months 18 Leiter U et al., Lancet Oncol. 2016
DeCOG-SLT: Results Distant Metastasis-Free Survival Overall Survival Recurrence-Free Survival HR P-value HR P- HR P-value value Obs vs LND 1.19 0.43 1.02 0.95 0.96 0.83 Tumor load in 2.33 < 0.0001 2.96 <0.001 3.03 < 0.0001 SLN ( 1 m v > 1) Tumor thickness 3.06 < 0.0001 3.46 < 0.001 3.03 < 0.0001 ( 2 mm vs > 2) Ulceration (y/n) 1.35 0.20 1.2 0.48 1.24 0.28 # SLNs + (1 vs 1.15 0.75 1.69 0.23 1.14 0.73 2) IFN therapy (y/n) 0.99 0.98 0.83 0.46 0.87 0.46 Median follow-up was 35 months 19 Leiter U et al., Lancet Oncol. 2016
DeCOG-SLT: Results Distant Metastasis-Free Survival Overall Survival Recurrence-Free Survival HR P-value HR P- HR P-value value Obs vs LND 1.19 0.43 1.02 0.95 0.96 0.83 Tumor load in 2.33 < 0.0001 2.96 <0.001 3.03 < 0.0001 SLN ( 1 m v > 1) Tumor thickness 3.06 < 0.0001 3.46 < 0.001 3.03 < 0.0001 ( 2 mm vs > 2) Ulceration (y/n) 1.35 0.20 1.2 0.48 1.24 0.28 # SLNs + (1 vs 1.15 0.75 1.69 0.23 1.14 0.73 2) IFN therapy (y/n) 0.99 0.98 0.83 0.46 0.87 0.46 Median follow-up was 35 months 20 Leiter U et al., Lancet Oncol. 2016
DeCOG-SLT: Results A: Distant Metastasis-Free Survival B: Overall Survival C: Recurrence-Free Survival Leiter U et al., Lancet Oncol. 2016 21
DeCOG-SLT: Results A: Distant Metastasis-Free Survival B: Overall Survival C: Recurrence-Free Survival Leiter U et al., Lancet Oncol. 2016 22
DECOG: Conclusion A: Distant Metastasis-Free Survival B: Overall Survival Active ultrasound surveillance appears a reasonable alternative for T1,T2 N1 melanoma C: Recurrence-Free patients Survival with SN metastasis < 1mm Leiter U et al., Lancet Oncol. 2016 23
DeCOG-SLT and MSLT-2 SN+ Immediate CLND Active Surveillance: Ultrasound Leiter U et al., Lancet Oncol. 2016 Faries MB et al., NEJM 2017 24
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MSLT-2 Results (n=1755) Overall Survival: CLND vs Observation 86±1% vs 86±1%,p=0.42 n=1934 ITT n=1755 per protocol Median: 43 months Disease-free Survival: CLND vs. observation 68±1% vs 63±1%,p=0.05 26 Faries MB et al., NEJM 2017
MSLT-2 Results (n=1755) Overall Survival: CLND vs Observation 86±1% vs 86±1%,p=0.42 n=1934 ITT n=1755 per protocol Median: 43 months Disease-free Survival: CLND vs. observation 68±1% vs 63±1%,p=0.05 Nonsentinel node metastases, identified in 11.5% of the patients in the dissection group, were an independent prognostic factor for recurrence (HR 1.78; p=0.005). Faries MB et al., NEJM 2017 27
MSLT-2 Results (n=1755) Overall Survival: CLND vs Observation 86±1% vs 86±1%,p=0.42 n=1934 ITT n=1755 per protocol Median: 43 months Disease-free Survival: CLND vs. observation 68±1% vs 63±1%,p=0.05 28 Faries MB et al., NEJM 2017
MSLT-2 Conclusions Overall Survival: CLND vs Observation 86±1% vs 86±1%,p=0.42 n=1934 ITT n=1755 per protocol Median: 43 months Immediate CLND increased the rate of regional control and provided prognostic information but did not increase melanoma-specific survival in patients with SN metastases Disease-free Survival: CLND vs. observation 68±1% vs 63±1%,p=0.05 Faries MB et al., NEJM 2017 29
Comparisons CLND DeCOG-SLT MSLT-2 UNC DeCOG SLT (n = 240) MSLT II (n=824) UNC (n=209) Breslow Depth (mm) median (range) 2.4 (1.6 4.0) 2.1 (0.34 28.0) 2.4 (0.5 15.0) mean Not Available 2.76 3.1 p= 0.036 Ulceration n(%) present 90 (38) 316 (38.3) 86(41) absent 150 (63) 508(61.7) 123(59) p = NS p = NS SLN Met n(%) <=1mm 153 (63) 378 (46) 114 (54.6) >1mm 62 (26) 188 (23) 87 (41.6) size unknown 25(10) 258 (31) 8 (3.8) p=0.002 p=0.01 Total # SLN + n(%) 1 222 (93) 678 (82) 167 (80) > 1 16 (7) 148 (18) 42 (20) unknown 2 (1) p<0.001 p = NS NSLN n(%) positive 43(18) x(11.5) 40 (22) negative 138 (58) 141 (78) unknown 59 (25) p = NS p<0.001 Time to Follow up (months) median (range) 33 (17 50) 43 40(6 196) 30
Comparisons CLND DeCOG-SLT MSLT-2 UNC DeCOG SLT (n = 240) MSLT II (n=824) UNC (n=209) Breslow Depth (mm) median (range) 2.4 (1.6 4.0) 2.1 (0.34 28.0) 2.4 (0.5 15.0) mean Not Available 2.76 3.1 p= 0.036 Ulceration n(%) present 90 (38) 316 (38.3) 86(41) absent 150 (63) 508(61.7) 123(59) p = NS p = NS SLN Met n(%) <=1mm 153 (63) 378 (46) 114 (54.6) >1mm 62 (26) 188 (23) 87 (41.6) size unknown 25(10) 258 (31) 8 (3.8) p=0.002 p=0.01 Total # SLN + n(%) 1 222 (93) 678 (82) 167 (80) > 1 16 (7) 148 (18) 42 (20) unknown 2 (1) p<0.001 p = NS NSLN n(%) positive 43(18) x(11.5) 40 (22) negative 138 (58) 141 (78) unknown 59 (25) p = NS p<0.001 Time to Follow up (months) median (range) 33 (17 50) 43 40(6 196) 31
Comparisons CLND DeCOG-SLT MSLT-2 UNC DeCOG SLT (n = 240) MSLT II (n=824) UNC (n=209) Breslow Depth (mm) median (range) 2.4 (1.6 4.0) 2.1 (0.34 28.0) 2.4 (0.5 15.0) mean Not Available 2.76 3.1 p= 0.036 Ulceration n(%) present 90 (38) 316 (38.3) 86(41) absent 150 (63) 508(61.7) 123(59) p = NS p = NS SLN Met n(%) <=1mm 153 (63) 378 (46) 114 (54.6) >1mm 62 (26) 188 (23) 87 (41.6) size unknown 25(10) 258 (31) 8 (3.8) p=0.002 p=0.01 Total # SLN + n(%) 1 222 (93) 678 (82) 167 (80) > 1 16 (7) 148 (18) 42 (20) unknown 2 (1) p<0.001 p = NS NSLN n(%) positive 43(18) x(11.5) 40 (22) negative 138 (58) 141 (78) unknown 59 (25) p = NS p<0.001 Time to Follow up (months) median (range) 33 (17 50) 43 40(6 196) 32
UNC Overall Survival Kaplan Meier method disease specific survival SN metastases <=1mm vs >1mm. Log-rank tests performed to 5 yr survival <=1mm = 84% 5 yr survival >1mm = 41% 33
UNC Overall Survival 34
Comparisons CLND DeCOG-SLT MSLT-2 UNC DeCOG SLT (n = 240) MSLT II (n=824) UNC (n=209) Breslow Depth (mm) median (range) 2.4 (1.6 4.0) 2.1 (0.34 28.0) 2.4 (0.5 15.0) mean Not Available 2.76 3.1 p= 0.036 Ulceration n(%) present 90 (38) 316 (38.3) 86(41) absent 150 (63) 508(61.7) 123(59) p = NS p = NS SLN Met n(%) <=1mm 153 (63) 378 (46) 114 (54.6) >1mm 62 (26) 188 (23) 87 (41.6) size unknown 25(10) 258 (31) 8 (3.8) p=0.002 p=0.01 Total # SLN + n(%) 1 222 (93) 678 (82) 167 (80) > 1 16 (7) 148 (18) 42 (20) unknown 2 (1) p<0.001 p = NS NSLN n(%) positive 43(18) x(11.5) 40 (22) negative 138 (58) 141 (78) unknown 59 (25) p = NS p<0.001 Time to Follow up (months) median (range) 33 (17 50) 43 40(6 196) 35
UNC Approach 2018 SN indications: T1a: No T1b: Yes T2/T3: SOC T4a/b: Offer routinely after PET/CT CLND vs US surveillance T1/T2, SN met < 1mm: Offer active surveillance T1/T2, SN met > 1mm: Tilt towards CLND T3/T4, SN+: CLND + systemic therapy 36
Final Thoughts Gershenwald et al.,2017 37
AJCC March Melanoma 22, 2019 8 th Edition Newly created international database housed: MD Anderson 1998+ Stages I-III N > 49,000 patients US, Australia, Europe (Italy, Greece, Spain) Additional sites onboarding for planned tool development Thirteenth Given the unprecedented changes in the still rapidly evolving landscape of the management of patients with stage IV melanoma, the Melanoma Expert Panel concluded that it was premature to embark on a broad-based analytic initiative involving data from patients with stage IV disease Gershenwald et al., CA Cancer J Clin. Dec 2017 38
Thank you Nancy Thomas Ben Schmidt Surg Onc Fellow UNC Dermatology & Skin Cancer Center NC Cancer Hospital 39
Adjuvant Ipilimumab in Stage III Melanoma IIIa=186 IIIb=420 IIIc=345 OS due 4-2018 EORTC 18071 NCT00636168, n=951 Eggermont Lancet Oncol 2015 40
UNC Disease Specific Survival Kaplan Meier method depicting disease specific survival grouped by patients with melanoma sentinel lymph node metastases <=1mm vs >1mm. Log-rank tests performed to compare groups. 5 year survival <=1mm = 87% 5 year survival >1mm = 54% Events: death with disease present 41
Types of Recurrence Local Regional Distant <=1mm n(%) 3 (3) 13 (11) 19 (17) median time to recurrence (months) 10.7 20.5 20.5 >1mm n(%) 0 (0) 26 (30) 19 (22) median time to recurrence (months) 0 9.7 9.5 42
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New World Order: 8 th Edition AJCC Melanoma Staging System David W. Ollila MD James and Jesse Millis Distinguished Professor of Surgery University of North Carolina, Chapel Hill Disclosures: None May 14, 2018
Melanoma Staging Principle communication tool Clinician patient Clinician clinician Registry reporting Risk stratification defines groups of patients Treatment recommendations often stage-based Development of prognostic models and clinical tools Clinical trial eligibility, stratification, analysis 2
AJCC Melanoma Staging System 7 th Edition 8 th Edition Charles Balch Jeff Gershenwald Richard A. Scolyer MIA 3 CA Cancer J Clin. 2017 Nov;67(6):472-492
AJCC Melanoma 8 th Edition Chair: Jeff Gershenwald Vice Chair: Richard Scolyer Statistician: Ken Hess Expert Panel:» 25 other members worldwide Jeff Gershenwald Ken Hess 8th edition 4
AJCC Melanoma 8 th Edition Newly created international database housed: MD Anderson 1998+ Stages I-III N > 49,000 patients US, Australia, Europe (Italy, Greece, Spain) Additional sites onboarding for planned tool development Gershenwald et al., CA Cancer J Clin. Dec 2017 5
Gershenwald et al., CA Cancer J Clin. Dec 2017 6
International Melanoma Pathology Study Group Meet at UCSF(Nov 2015) prior to AJCC F2F Pathology staging issues discussed/voted AJCC pathologists took consensus to F2F Phil LeBoit Ray Barnhill Richard Scolyer Alistair Cochran 7
2010 AJCC T Classification 7 th Edition Stage Breslow Thickness (mm) Definition T1 1.00 a: No ulceration and <1 mitosis/mm 2 b: Ulceration or >1 mitosis/mm 2 T2 1.01-2.00 a: No ulceration b: Ulceration T3 2.01-4.00 a: No ulceration b: Ulceration T4 > 4.00 a: No ulceration b: Ulceration Balch, Gershenwald, Soong, et al. JCO 2009
Primary Tumor (T) - AJCC 8 th Edition Gershenwald et al., CA Cancer J Clin. Dec 2017 9
Primary Tumor (T) - AJCC 8 th Edition Gershenwald et al., CA Cancer J Clin. Dec 2017 10
Melanoma Institute Australia Data: n=6270 11
Richard A. Scolyer MIA Richard A. Scolyer MIA 12
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Primary Tumor (T) - AJCC 8th Edition Tumors >1mm: Impracticality/imprecision measurements to nearest 0.01mm Recorded to nearest 0.1mm (not 0.01mm) Tumors 1mm: May be measured to nearest 0.01mm Reported rounded to the nearest 0.1mm 0.75mm to 0.84mm reported 0.8mm (T1b) 1.04mm reported 1.0mm (T1b) Gershenwald et al., CA Cancer J Clin. Dec 2017
Primary Tumor (T) - AJCC 8th Edition Tumors >1mm: Impracticality/imprecision measurements to nearest 0.01mm Recorded to nearest 0.1mm (not 0.01mm) Tumors 1mm: May be measured to nearest 0.01mm Reported rounded to the nearest 0.1mm 0.75mm to 0.84mm reported 0.8mm (T1b) 1.04mm reported 1.0mm (T1b) Implications for sentinel node procedure
Melanoma Specific Survival T category T stage group Gershenwald et al., CA Cancer J Clin. Dec 2017 16
Occasional Difficulties in Staging Difficulty in determining Breslow thickness?ulceration vs trauma vs artefact What is a microsatellite? What happened to mitotic rate? 17
Difficulty in determining Breslow thickness H & E S100 Courtesy of Richard A. Scolyer MIA 18
Include Periadnexal Extension? Richard A. Scolyer MIA NO NO 19
Ulceration Courtesy of Richard A. Scolyer20 MIA
Ulceration Distinguish true ulceration from artefact Presence of fibrin or granulation tissue useful Iatrogenic vs non-iatrogenic may be difficult Courtesy of Richard A. Scolyer21 MIA
AJCC 7th edition: Microsatellites DEF: tumor nest >0.05mm in diameter that is separated by normal dermis from the main invasive component of melanoma by a distance of >0.5mm Problem: what appears a microsatellite on 1 section may be contiguous with primary on levels Balch, Gershenwald, Soong, et al. JCO 2009 22
AJCC 7 th edition: Microsatellites DEF: tumor nest >0.05mm in diameter that is separated by normal dermis from the main invasive component of melanoma by a distance of >0.5mm Problem: what appears a microsatellite on 1 section may be contiguous with primary on levels Balch, Gershenwald, Soong, et al. JCO 2009 23
AJCC 8 th edition: Microsatellites Microscopic metastasis adjacent/deep to 1 0 Identified on path exam primary tumor site Must be discontinuous from the primary Not separated only by fibrosis or inflammation No minimal size or distance from primary Balch, Gershenwald, Soong, et al. JCO 2009 24
AJCC 8 th Edition N-category Regional nodes Non-nodal regional disease In-transits (ITM) Satellites Microsatellites Microsatellites/satellites/ITM grouped together for staging purposes Gershenwald et al., CA Cancer J Clin. Dec 2017 25
Tumor Mitotic Rate (TMR) TMR: strongly independent prognostic factor Prognostic across as a continuous variable Removed as T1 staging criterion in 8 th ed» Fewer melanomas with TMR=0 after 7 th AJCC edition» Erroneously: only prognostic 0 vs 1 Record TMR in all T1-T4 primary melanomas Gershenwald et al., CA Cancer J Clin. Dec 2017 26
Melanoma Specific Survival TMR *mitotic rate, mitoses/mm 2 Gershenwald et al., CA Cancer J Clin. Dec 2017 27
MSS:T- and N-categories N1+ 28 Gershenwald et al., CA Cancer J Clin. Dec 2017
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MSS according to Stage III Groups 8 th Edition international melanoma database Melanoma-Specific Survival Probability 0.0 0.2 0.4 0.6 0.8 1.0 IIIA: N = 1006, 5yr = 93%, 10yr = 88% IIIB: N = 1170, 5yr = 83%, 10yr = 77% IIIC: N = 2201, 5yr = 69%, 10yr = 60% IIID: N = 205, 5yr = 32%, 10yr = 24% 0.0 0.2 0.4 0.6 0.8 1.0 4 stage groups Significant heterogeneity Substage stratification: both T- and N-category criteria Tumor thickness Ulceration # LNs Microsat/ITM/satellites 0 1 2 3 4 5 6 7 8 9 10 Years Since Diagnosis Gershenwald et al., CA Cancer J Clin. Dec 2017 30
Comparisons of 7 th vs. 8th Balch, JCO 2009 Gershenwald et al.,2017 31
Comparisons of 7 th vs. 8th Balch, JCO 2009 Gershenwald et al.,2017 32
Comparisons of 7 th vs. 8th Balch, JCO 2009 Gershenwald et al.,2017 33
T category Summary: T Stage Breslow, Ulceration T stage group Gershenwald et al., CA Cancer J Clin. Dec 2017 34
Summary: Stage III Melanoma-Specific Survival Probability 0.0 0.2 0.4 0.6 0.8 1.0 IIIA: N = 1006, 5yr = 93%, 10yr = 88% IIIB: N = 1170, 5yr = 83%, 10yr = 77% IIIC: N = 2201, 5yr = 69%, 10yr = 60% IIID: N = 205, 5yr = 32%, 10yr = 24% 0.0 0.2 0.4 0.6 0.8 1.0 0 1 2 3 4 5 6 7 8 9 10 Years Since Diagnosis Gershenwald et al., CA Cancer J Clin. Dec 2017 35
AJCC 8th Edition: Factors NOT Included Primary tumour mitotic rate Level of invasion TILs Lymphovascular invasion Neurotropism SNs: Max dimension-largest deposit Extranodal extension in + nodes Richard A. Scolyer MIA 36
AJCC Melanoma 8 th Edition Newly created international database housed: MD Anderson 1998+ Stages I-III N > 49,000 patients US, Australia, Europe (Italy, Greece, Spain) Additional sites onboarding for planned tool development Gershenwald et al., CA Cancer J Clin. Dec 2017 37
AJCC Melanoma 8 th Edition Newly created international database housed: MD Anderson 1998+ Stages I-III N > 49,000 patients US, Australia, Europe (Italy, Greece, Spain) Additional sites onboarding for planned tool development Given the unprecedented changes in the still rapidly evolving landscape of the management of patients with stage IV melanoma, the Melanoma Expert Panel concluded that it was premature to embark on a broad-based analytic initiative involving data with stage IV melanoma Gershenwald et al., CA Cancer J Clin. Dec 2017 38
AJCC March Melanoma 22, 2019 8 th Edition Newly created international database housed: MD Anderson 1998+ Stages I-III N > 49,000 patients US, Australia, Europe (Italy, Greece, Spain) Additional sites onboarding for planned tool development Thirteenth Given the unprecedented changes in the still rapidly evolving landscape of the management of patients with stage IV melanoma, the Melanoma Expert Panel concluded that it was premature to embark on a broad-based analytic initiative involving data from patients with stage IV disease Gershenwald et al., CA Cancer J Clin. Dec 2017 39
Thank you Nancy Thomas Richard Scolyer AJCC Data UNC Dermatology & Skin Cancer Center NC Cancer Hospital 40