Surgical Issues in Melanoma Mark B. Faries, MD, FACS Director, - - PowerPoint PPT Presentation

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*

* Wong CK, Dermatologica 141: 215, 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)

Randomized Trials: <2 mm

French Cooperative Group

(n=326)

Swedish Melanoma Trial Group

(n=989)

WHO #10

(n= 712) 8 vs. 3 local recurrences (NS) < 2 mm 2 cm 5 cm 1cm 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

DFS

Randomized Trials: Intergroup

1-4 mm

• n=468
• Median follow up >10 years
• 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

2 cm 4 cm

Randomized Trials: UK Trial

• n=900

> 2 mm

Thomas et al. NEJM 2004

1cm 3 cm

Sweden

2 cm 4 cm

• n = 936 pts

Gillgren et al, Lancet, November 2011

Answer Key: Current (NCCN) Recommendations

Melanoma-in-situ 5 mm 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) Wide excision alone Wide excision + SLN SLN + SLN - Observation Immediate CLND CLND for Recurrence Randomization No recurrence:

• bservation

40% 60%

MSLT-I prognosis

SLN Biopsy and Disease-Free Survival: MSLT-I

Intermediate Thickness (1.2-3.5mm) Thick (≥3.5mm)

0.5 1 1.5 2 2.5 3 3.5 Immediate CLND Delayed CLND

Delayed treatment  metastatic spread within the regional nodal basin Mean # Pos. Nodes

Watch & Wait SNB

1.4 ± 0.1 3.3 ± 0.5

Impact of Clinical Recurrence: Morbidity

MSLT 1

Overall Melanoma Related Survival

(Breslow 1.20 – 3.5mm) Final Dataset

Time (years) Survival (%)

25 50 75 100 2 4 6 10 8 12

SNB OBS

HR: 0.84 P=0.18, 95% CI (0.64-1.09)

81.4 ± 1.5 % 86.6 ± 1.3 % 125 / 770 SNB 78.3 ± 2.0% 85.7 ± 1.6 % 97 / 500 OBS 10-year 5-year Estimate S(t) ± SE # Event / Total N Group

MSLT-I

Melanoma >1 mm or > Clark IV (primary analysis 1.2-3.5 mm) Wide excision alone Wide excision + SLN SLN + SLN - Observation Immediate CLND CLND for Recurrence Randomization No recurrence:

• bservation

DSS: Primary Endpoint DFS: Secondary Endpoint Occult Stage III 40% 60%

Morton A 50 Year Odyssey 111509

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Melanoma Specific Survival – Node+

(1.2-3.5mm) Final Dataset

Time (years) Survival (%) 25 50 75 100 2 4 6 10 8 12

HR: 0.56 95% C.I. (0.37, 0.84) Log Rank P=0.006

SNB+ OBS

62.1 ± 4.8 69.8 ± 4.4 70 / 193 SNB+ 41.5 ± 5.6 57.5 ± 5.4 48/87 OBS, had nodal recur. 10-year 5-year Estimate S(t) ± SE % # Event / Total N Group

Latent Subgroup Analysis

Morton A 50 Year Odyssey 111509

26

Melanoma Specific Survival – Node+

(1.2-3.5mm) Final Dataset

Time (years) Survival (%) 25 50 75 100 2 4 6 10 8 12

HR: 0.56 95% C.I. (0.37, 0.84) Log Rank P=0.006

SNB+ OBS

62.1 ± 4.8 69.8 ± 4.4 70 / 193 SNB+ 41.5 ± 5.6 57.5 ± 5.4 48/87 OBS, had nodal recur. 10-year 5-year Estimate S(t) ± SE % # Event / Total N Group

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

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

Breslow

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 I II III IV V UNK

Clark

0.0 1.0 2.0 3.0 4.0 5.0 Female Male

Gender

0.0 1.0 2.0 3.0 4.0 5.0 <30 30-39 40-49 50-59 60-69 >=70

Age

0.0 2.0 4.0 6.0 8.0 10.0 Yes No Unknown

Ulceration

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Extremity Head/neck Trunk

Primary Site

Predicted probabilities of Nodal Recurrence

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 >70 50-70 <50 Female Male <0.50 0.51-0.75 0.76-0.99

Concordance index = 0.79

CLND: Rationale and Data

79-88% of patients have Negative NSN nodes in CLND specimen

MSLT2:

Is CLND necessary in SN(+) LN basins?

# SN(+) CLND(+) n (%) Stain H&E H&E IHC 22 (11.8%) 39 (12.1%) 19 (21.1%) 187 322 90 MSLT-I JWCI Cochran 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

• 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

DeCOG Trial: Discussion/Conclusions

MSLT-II and MILND

MSLT II: Trial Design

Melanoma >1.2 mm or > Clark IV, n=3500 Immediate CLND Nodal Ultrasound Recur No Recur Observation Delayed CLND Randomization n=1926 Observation LM/SL: standard and molecular assessment

+

• Observation

Melanoma: + SLN (Outside Center) n=700 Stratification: MSLT1 Center Breslow Ulceration SLN H&E vs. PCR

64

Accrual: Complete

200 400 600 800 1000 1200 1400 1600 1800 2000 1 2 3 4 5 6 7 8 9 10 All North Am Europe Australia Target

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Morton SSO PI MSLT-II 5Mar11 45

MSLT-II Possible Outcomes

Minimally Invasive: MILND

Minimally Invasive: MILND

Minimally Invasive: MILND

Minimally Invasive: MILND

Minimally Invasive: MILND

Distant Metastases

• It’s too late for surgery, a local therapy
• Surgery is morbid and complicated
• Risk/Benefit Ratio very high

Surgery for Metastatic Melanoma:

Heresy?

Korn et al. J Clin Oncol. Feb 1 2008, 527-34.

Meta-analysis of Phase 2 Trials

Korn et al. J Clin Oncol. Feb 1 2008, 527-34.

Better Staging

• CT scanning

Circa 1990 2003 2008

Stratification Factors

• Site of metastasis:

M1a: soft-tissue & nodal mets M1b: visceral mets

• # individual lesions: 1, 2-3, 4-5

BCG + Canvax. BCG + Placebo

Randomize N=496

Resection of Metastatic Lesions

Vaccines: CancerVax

AJCC Stage IV Melanoma

0.0 0.2 0.4 0.6 0.8 1.0 12 24 36 48 60 72 84 96 108 120 132

BCG/Pl BCG/Cv

MMAIT-IV Overall Survival (Intent To Treat) Overall Survival

Time (months)

HR=1.18 P=0.245 Survival at 5 years Median Survival (months) 45% 39 Placebo CanvaxinTM

BCG + CanvaxinTM n=246 BCG + Placebo n=250

40% 32

Morton ACS 100410

58

Stage IV Metastasis Location

P=0.153 HR=1.37 43% 52% Survival at 5 years 36 60 Median Survival (months) Canvaxin Placebo 100 80 60 40 20 12 24 36 48 60 72 84 % Survival Time (months) BCG + CanvaxinTM n=107 BCG + Placebo n=108 P=0.728 HR=1.06 36% 39% Survival at 5 years 29 32 Median Survival (Months) Canvaxin Placebo 100 80 60 40 20 12 24 36 48 60 72 84 % Survival Time (months) BCG + CanvaxinTM n=138 BCG + Placebo n=138

Soft Tissue Visceral

JWCI Metastasectomy Series

Lung

Tafra, J Thorac CV Surg, 1995

P<0.00 1

Surgical, n=58 Non-surgical, n=1020

Months

Overall Survival

Liver

Faries, J Am Coll Surg, 2014

Small Bowel

Ollila, Arch Surg 1996

Wood, Ann Surg Oncol, 2001

Solid Organ Adrenal

Flaherty, Am Surg, 2015

Median OS 9.4 months Median OS 29.2 months

Surgery No Surgery

p < .001

Trial Patient Outcomes Over the Years

175 200 225 250 275 475 500

MMAIT Vax (Surgery)

Korn et al. J Clin Oncol. Feb 1 2008, 527- 34.

Ipi + DITC Ipi +/- gp100 vemurafenib Ipi/PD-1 combo BRAF/MEK combo PD-1

SWOG JWCI Vax Phase 2

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

4-5 Mets (reference) 1 Met: HR=0.537, p=0.0214 2-3 Mets: HR=0.591, p=0.0664

Number of Metastases

Not competition, but collaboration

• Neoadjuvant trials

– Biomarker development

• Adjuvant Surgery

– Consolidation – Selective resection

Metastasectomy: Consolidation

P<0.00 1

Surgical, n=58 Non-surgical, n=1020

Months

Overall Survival

Liver

Faries, J Am Coll Surg, 2014

Stabilization on Prior Therapy

p=0.01 Yes, n=20 No, n=33 Months Melanoma-Specific Survival

Faries, et al, JACS, 2014

Metastasectomy: Selective Resection

Adrenal

Flaherty, Am Surg, 2015

Median OS 9.4 months Median OS 29.2 months

Surgery No Surgery

p < .001

Treatment Approach Median Survival (mos.) Overall Survival (p value) Curative Surgery No Surgery 41.9 9.4 0.0007 Non-Curative Surgery No Surgery 14.5 9.4 0.023

Curative Surgery Non-Curative Surgery No Surgery

+ = Censored

Flaherty et al, Am Surg, 2014

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

Thank you