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) As wide as possible - Veronesi (1966) 15 cm Petersen (1962) * Wong CK, Dermatologica 141: 215, 1970
Randomized Trials: <2 mm French Cooperative Group (n=326) DFS < 2 mm 2 cm Swedish Melanoma Trial Group (n=989) 5 cm 1cm 3 cm WHO #10 (n= 712) 8 vs. 3 local recurrences (NS) 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 1-4 mm 2 cm 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 3 cm 2 cm 4 cm > 2 mm Thomas et al. NEJM 2004 Gillgren et al, Lancet, November 2011
Answer Key: Current (NCCN) Recommendations Melanoma-in-situ Breslow <1mm Breslow 1.01-2mm Breslow 2.01-4mm Breslow >4mm 5 mm 1 cm 1-2 cm 2 cm 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 - CLND for Recurrence Immediate CLND No recurrence: observation Observation
MSLT-I prognosis
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 3.5 3.3 ± 0.5 Mean # Pos. Nodes 3 2.5 2 1.5 1 0.5 1.4 ± 0.1 SNB Watch & Wait 0 Immediate CLND Delayed CLND
Impact of Clinical Recurrence: Morbidity MSLT 1
Overall Melanoma Related Survival (Breslow 1.20 3.5mm) Final Dataset Survival (%) 100 75 50 25 0 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 SNB
MSLT-I 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
Morton A 50 Year Odyssey 111509 24 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 Survival (%) 75 50 25 0 0 HR: 0.56 95% C.I. (0.37, 0.84) Log Rank P=0.006 OBS SNB+ 2 4 6 8 10 12 Time (years)
Latent Subgroup Analysis
Morton A 50 Year Odyssey 111509 26 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 Survival (%) 75 50 25 0 0 HR: 0.56 95% C.I. (0.37, 0.84) Log Rank P=0.006 OBS SNB+ 2 4 6 8 10 12 Time (years)
Selection for SLN: Thick Melanoma? Overall Survival
Melanoma-specific Survival Thin Melanoma?
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 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 Gender 4.0 3.5 Primary Site 5.0 4.0 Age 3.0 3.0 2.5 3.0 2.0 2.0 1.5 2.0 1.0 1.0 0.5 1.0 0.0 Female Male 0.0 Extremity Head/neck Trunk 0.0 <30 30-39 40-49 50-59 60-69 >=70
Predicted probabilities of Nodal Recurrence >70 50-70 <50 Female Male <0.50 0.51-0.75 0.76-0.99 Concordance index = 0.79 Breslow Age Sex Predicted % 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
CLND: Rationale and Data
MSLT2: 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%
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? 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 micrometastases. 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 (Outside Center) n=700 + - Observation Randomization n=1926 Stratification: MSLT1 Center Breslow Ulceration SLN H&E vs. PCR Immediate CLND Nodal Ultrasound Recur No Recur Observation Delayed CLND Observation
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Accrual: Complete 2000 1800 1600 1400 All North Am Europe Australia Target 1200 1000 800 600 400 200 0 02005 1 2006 2 2007 3 2008 4 2009 5 2010 6 2011 7 2012 8 2013 9 2014 10
MSLT-II Possible Outcomes Morton SSO PI 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 et al. J Clin Oncol. Feb Feb 11 2008, 527-34.
Better Staging 2008 CT scanning Circa 1990 2003
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) Overall Survival 1.0 0.8 0.6 0.4 0.2 Median Survival (months) Survival at 5 years Canvaxin TM Placebo 32 39 40% 45% BCG + Placebo n=250 BCG + Canvaxin TM n=246 0.0 HR=1.18 P=0.245 BCG/Pl BCG/Cv 0 12 24 36 48 60 72 84 96 108 120 132 Time (months)
Morton ACS 100410 58 Stage IV Metastasis Location Soft Tissue Visceral 100 Placebo Median Survival (months) 60 Survival at 5 years 52% Canvaxin 36 43% 100 Placebo Median Survival (Months) 32 Survival at 5 years 39% Canvaxin 29 36% 80 80 % Survival 60 40 BCG + Placebo n=108 BCG + Canvaxin TM n=107 % Survival 60 40 BCG + Placebo n=138 BCG + Canvaxin TM n=138 20 HR=1.37 P=0.153 20 HR=1.06 P=0.728 0 0 12 24 36 48 60 72 84 Time (months) 0 0 12 24 36 48 60 72 84 Time (months)
JWCI Metastasectomy Series Lung Small Bowel Adrenal Surgery No Surgery Median OS 29.2 months Tafra, J Thorac CV Surg, 1995 Liver P<0.00 1 Ollila, Arch Surg 1996 Solid Organ Median OS 9.4 months p <.001 Flaherty, Am Surg, 2015 Overall Survival Surgical, n=58 Non-surgical, n=1020 Months Faries, J Am Coll Surg, 2014 Wood, Ann Surg Oncol, 2001
Trial Patient Outcomes Over the Years Ipi/PD-1 combo BRAF/MEK combo SWOG PD-1 vemurafenib JWCI Vax Phase 2 MMAIT Vax (Surgery) Ipi + DITC Ipi +/- gp100 175 200 225 250 275 475 500 Korn et al. J Clin Oncol. Feb 1 2008, 527-34.
Selection! Selection! Selection! Surgery is not appropriate for all patients. True predictive factors are not available Factors for post-resection prognosis are available (TVDT, DFI, Prior Stage III) prognostic predictive
Selection Factors Number of Metastases 1 Met: HR=0.537, p=0.0214 4-5 Mets (reference) 2-3 Mets: HR=0.591, p=0.0664
Not competition, but collaboration Neoadjuvant trials Biomarker development Adjuvant Surgery Consolidation Selective resection
Metastasectomy: Consolidation Liver Stabilization on Prior Therapy P<0.00 1 Melanoma-Specific Survival Overall Survival Surgical, n=58 Non-surgical, n=1020 Months Faries, J Am Coll Surg, 2014 Yes, n=20 No, n=33 p=0.01 Months Faries, et al, JACS, 2014
Metastasectomy: Selective Resection Adrenal Surgery No Surgery Curative Surgery Non-Curative Surgery No Surgery Median OS 29.2 months Median OS 9.4 months p <.001 Flaherty, Am Surg, 2015 + = Censored Treatment Approach Curative Surgery No Surgery Median Survival (mos.) 41.9 9.4 Overall Survival (p value) 0.0007 Flaherty et al, Am Surg, 2014 Non-Curative Surgery No Surgery 14.5 9.4 0.023
Ipilimumab with resection 5 year MSS Med. MSS (months) p-value Ipi after Resection 61% (CI 21-62%) 60 0.37 Ipi before Resection 42% (CI 30-82%) 47 p=0.37
Resection following Ipilimumab: Resection for: n 5 year MSS Isolated Persistent Disease 7 69% (CI 21-91%) Symptomatic 7 53% (CI 17-79%) Progressive 10 14%(0.7-47%)
Unresectable
Percutaneous Hepatic Perfusion
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