Surgical Issues in Melanoma Mark B. Faries, MD, FACS Director, Donald L. Morton Melanoma Research Program Director, Surgical Oncology Training Program Professor of Surgery John Wayne Cancer Institute
Surgical Issues • Margins • How narrow? • Sentinel Lymph Node Biopsy • Who • Why • Completion Lymph Node Dissection • Why? • Why not? • Metastatic Disease (Stage IV) • Where does surgery fit?
Margin Recommendations:pre-1970* 2 cm – Cooling (1966) 5 cm – Hadley (1907) Raven (1953) Petersen (1962) Olsen (1966) 8 cm – Pack (1953) 15 cm – Petersen (1962) “As wide as possible” - Veronesi (1966) * Wong CK, Dermatologica 141: 215, 1970
Randomized Trials: <2 mm DFS French Cooperative Group (n=326) < 2 mm Swedish Melanoma Trial Group (n=989) 2 cm 5 cm WHO #10 (n= 712) 1cm 8 vs. 3 local recurrences (NS) 3 cm Khayat et al, Cancer , 2003 Apr; 97(8): 1941-6 Cohn-Cedermark, Cancer , 2000; 89: 1495 Veronesi U, Arch Surg, 1991 Apr; 126(4): 438-441
Randomized Trials: Intergroup • n=468 • Median follow up >10 years 2 cm 1-4 mm 4 cm • No difference in local recurrence • 2.6% (4cm) vs. 2.1% (2cm) • Skin grafts 46% (4cm) vs. 11% (2cm) • Risk of LR based on primary tumor
Randomized Trials: UK Trial Sweden • n=900 • n = 936 pts 1cm 2 cm 3 cm 4 cm > 2 mm Gillgren et al, Lancet, November 2011 Thomas et al. NEJM 2004
Answer Key: Current (NCCN) Recommendations 5 mm Melanoma-in-situ Breslow <1mm 1 cm Breslow 1.01-2mm 1-2 cm Breslow 2.01-4mm 2 cm Breslow >4mm 2 cm
Clinical vs. Pathological Margins
Lymph Node Treatment
Lymph Node Treatment
Regional Lymph Nodes
Elective Lymph Node Dissection: WHO #14 All (>1.5mm) 1.5- 4.0mm >4.0mm
Intergroup ELND: Overall Survival Balch, Ann Surg Oncol , 2000
Sentinel Node
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
MSLT-I Melanoma >1 mm or > Clark IV (primary analysis 1.2-3.5 mm) Randomization Wide excision alone 40% 60% Wide excision + SLN SLN - SLN + Immediate CLND CLND for Recurrence No recurrence: Observation observation
MSLT-I prognosis
SLN Biopsy and Disease-Free Survival: MSLT-I Thick (≥3.5mm) Intermediate Thickness (1.2-3.5mm)
Delayed treatment metastatic spread within the regional nodal basin 3.5 3.3 ± 0.5 Mean # Pos. Nodes 3 2.5 2 Watch & 1.4 ± 0.1 1.5 Wait SNB 1 0.5 0 Immediate CLND Delayed CLND
Impact of Clinical Recurrence: Morbidity MSLT 1
Overall Melanoma Related Survival (Breslow 1.20 – 3.5mm) Final Dataset 100 SNB Survival (%) 75 OBS HR: 0.84 50 P=0.18, 95% CI (0.64-1.09) Group # Event / Estimate S(t) ± SE Total N 5-year 10-year 25 OBS 97 / 500 85.7 ± 1.6 % 78.3 ± 2.0% 86.6 ± 1.3 % 81.4 ± 1.5 % SNB 125 / 770 0 0 2 4 6 8 10 12 Time (years)
MSLT-I Melanoma >1 mm or > Clark IV (primary analysis 1.2-3.5 mm) DSS: Primary Endpoint DFS: Secondary Endpoint Randomization Wide excision alone 40% 60% Wide excision + SLN SLN - SLN + Occult Stage III Immediate CLND CLND for Recurrence No recurrence: Observation observation
24 Melanoma Specific Survival – Node+ Morton A 50 Year Odyssey 111509 (1.2-3.5mm) Final Dataset Group # Event / Estimate S(t) ± SE % Total N 5-year 10-year OBS, had nodal recur. 48/87 57.5 ± 5.4 41.5 ± 5.6 100 SNB+ 70 / 193 69.8 ± 4.4 62.1 ± 4.8 75 SNB+ Survival (%) 50 OBS HR: 0.56 25 95% C.I. (0.37, 0.84) Log Rank P=0.006 0 0 2 4 6 8 10 12 Time (years)
Latent Subgroup Analysis
26 Melanoma Specific Survival – Node+ Morton A 50 Year Odyssey 111509 (1.2-3.5mm) Final Dataset Group # Event / Estimate S(t) ± SE % Total N 5-year 10-year OBS, had nodal recur. 48/87 57.5 ± 5.4 41.5 ± 5.6 100 SNB+ 70 / 193 69.8 ± 4.4 62.1 ± 4.8 75 SNB+ Survival (%) 50 OBS HR: 0.56 25 95% C.I. (0.37, 0.84) Log Rank P=0.006 0 0 2 4 6 8 10 12 Time (years)
Selection for SLN: Thick Melanoma? Overall Survival
Thin Melanoma? Melanoma-specific Survival
Node-Positive Thin Melanoma: Outcomes
Thin Melanoma SLN predictors Problems: – SLN population is selected – SLN has false negatives – SLN has shorter follow up – Use clinical nodal recurrence instead
Predictors 10.0 7.0 10.0 Clark Ulceration Breslow 6.0 8.0 8.0 5.0 6.0 6.0 4.0 3.0 4.0 4.0 2.0 2.0 2.0 1.0 0.0 0.0 0.0 I II III IV V UNK Yes No Unknown 0.01-0.25 0.26-0.50 0.51-0.75 0.76-0.99 Primary Site 5.0 5.0 Gender Age 4.0 4.0 4.0 3.5 3.0 3.0 3.0 2.5 2.0 2.0 2.0 1.5 1.0 1.0 1.0 0.5 0.0 0.0 0.0 Extremity Head/neck Trunk Female Male <30 30-39 40-49 50-59 60-69 >=70
Predicted probabilities of Nodal Recurrence Predicted % Breslow Age Sex node recurrence >70 50-70 <50 <0.5 >70 female 0.1 <0.5 >70 male 0.4 Male Female <0.5 50-70 female 0.3 <0.5 50-70 male 0.9 <0.50 0.51-0.75 0.76-0.99 <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 Concordance index = 0.79 0.76-0.99 <50 male 17.4
CLND: Rationale and Data
MSLT2 : Is CLND necessary in SN(+) LN basins? 79-88% of patients have Negative NSN nodes in CLND specimen CLND(+) NSN(-) # SN(+) Stain n (%) % MSLT-I 187 22 (11.8%) H&E 88% JWCI 322 39 (12.1%) H&E 88% Cochran 90 19 (21.1%) IHC 79%
Equipoise: ? Disadvantages Advantages • Additional surgery • Potential removal of – Larger incision more cancer (10-20%) – JP drain • Complete Staging • Potential Information complications: – Lymphedema • Clinical trial eligibility • Disease may already be systemic • Ultrasound may pick up any recurrence at an early time point
Is CLND necessary in SN(+) LN basins? RFS MSS Multivariable: HR 1.51, p=0.09
JWCI Retro Data
DeCOG Trial • Randomized 1:1 to CLND or observation • Powered to detect 10% absolute survival difference with 80% power • No Head/Neck Melanomas • Median Breslow 2.4 mm • About 2/3 of patients’ SLN disease <1 mm
DeCOG Trial: Discussion/Conclusions • Better nodal recurrence rate (14.6 vs 8.3%) • Not better MSS “Based on our findings, complete lymphadenectomy cannot be recommended in melanoma patients with micro- metastases.” • Difficult recruitment - High refusal/dropout • Did not achieve target accrual -Decreased statistical power • Follow up <3 years
MSLT-II and MILND
MSLT II: Trial Design Melanoma >1.2 mm or > Clark IV, n=3500 LM/SL: standard and molecular assessment Melanoma: + SLN - + Observation (Outside Center) n=700 Stratification: MSLT1 Center Breslow Randomization n=1926 Ulceration SLN H&E vs. PCR Immediate CLND Nodal Ultrasound No Recur Recur Observation Delayed CLND Observation
64
Accrual: Complete 2000 1800 All North Am 1600 Europe Australia 1400 Target 1200 1000 800 600 400 200 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 0 1 2 3 4 5 6 7 8 9 10
MSLT-II Possible Outcomes Morton SSO PI MSLT-II 5Mar11 45
Minimally Invasive: MILND
Minimally Invasive: MILND
Minimally Invasive: MILND
Minimally Invasive: MILND
Minimally Invasive: MILND
Distant Metastases
Surgery for Metastatic Melanoma: Heresy? • It’s too late for surgery, a local therapy • Surgery is morbid and complicated • Risk/Benefit Ratio very high
Meta-analysis of Phase 2 Trials Korn et al. J Clin Oncol . Korn et al. J Clin Oncol . Feb 1 2008, 527-34. Feb 1 2008, 527-34.
Better Staging 2008 • CT scanning 2003 Circa 1990
Vaccines: CancerVax AJCC Stage IV Melanoma Resection of Metastatic Lesions Stratification Factors • Site of metastasis : M1a: soft-tissue & nodal mets M1b: visceral mets • # individual lesions : 1, 2-3, 4-5 Randomize N=496 BCG + Canvax. BCG + Placebo
MMAIT-IV Overall Survival (Intent To Treat) 1.0 Canvaxin TM Placebo Median Survival (months) 32 39 0.8 Survival at 5 years Overall Survival 40% 45% 0.6 BCG + Placebo n=250 0.4 BCG + Canvaxin TM n=246 0.2 HR=1.18 P=0.245 BCG/Pl BCG/Cv 0.0 0 12 24 36 48 60 72 84 96 108 120 132 Time (months)
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