MSLT-1

Published

Morton DL, et al. "Multicenter Selective Lymphadenectomy Trial". The New England Journal of Medicine. 2014. 370(7):599-609.
PubMed • Full text • PDF

Clinical Question

Among patients undergoing wide excision for melanoma, does sentinel lymph node biopsy with reflex completion lymphadenectomy improve melanoma-specific survival compared with nodal observation?

Bottom Line

Among patients undergoing wide excision for melanoma, staging based on sentinel lymph node biopsy improves disease-free survival compared to nodal observation. Further, in intermediate-thickness melanomas, sentinel lymph node biopsy provides useful prognostic information, and may prevent local nodal recurrence.

Major Points

Sentinel lymph node biopsy (SLNB) is a minimally invasive staging procedure performed at initial wide excision of melanoma, often using dual methylene blue dye and lymphoscintigraphy with an intraoperative gamma probe. SLNB provides crucial prognostic information to stratify patients with melanoma in the absence of clinically apparent nodal disease. This final report of the MSLT-I study provided data supporting routine use of SLNB over observation for selected patients with melanoma.

The Multicenter Selective Lymphadenectomy Trial (MSLT-I) sought to investigate the benefit of SLNB compared with nodal observation in patients with majority intermediate (1.2-3.5 mm) and thick melanomas (>3.5 mm), which are more likely to have subclinical nodal involvement than thin melanomas (<1.2 mm). Patients were randomized to wide excision plus SLNB, in which reflex completion lymph node dissection (CLND) was performed for patients with a positive SLNB, or to wide excision plus nodal observation, in which CLND was performed only at the time of nodal recurrence. The primary endpoint was melanoma-specific survival, and was no difference between groups at 10 years of follow-up (81% vs. 78%). Disease-free survival, a key secondary endpoint, was extended by SLNB compared to nodal observation in both intermediate thickness melanomas (71% vs. 65%) and thick melanomas (51% vs. 41%). Patients with a positive SLNB had inferior outcomes compared to those with a negative SLNB, with 10-year melanoma-specific survival of 62% vs. 85% in the intermediate thickness group, and 48% vs. 65% among patients with thick melanomas.

Although SLNB did not demonstrate an effect on the primary endpoint of melanoma-specific survival, MSLT-I showed that SLNB provides prognostic value at the time of wide excision, and also impacts disease-free survival. The follow-up MSLT-II trial randomized patients with a positive SLNB to either immediate CLND or to nodal observation, and showed no improvement in melanoma-specific survival.

Guidelines

NCCN Cutaneous Melanoma Guidelines (Version 1.2024, adapted)

• Stage IB (T1b) disease: Discuss and consider SLNB
• Stage IB (T2a) or II (T2b or higher): Discuss and offer SLNB

Design

• Phase 3, multicenter, randomized controlled trial
• N=2,001 patients
• Setting: Multiple clinical centers in the US and globally
• Enrollment: 1994-2002
• Mean follow-up: 10 years
• Analysis:
  • Parallel per-protocol and intention-to-treat analysis
  • Kaplan-Meier method to estimate 5-year and 10-year rates of melanoma-specific and disease-free survival
• Primary endpoint: Melanoma-specific survival at 10 years
• Secondary endpoints: Disease-free survival, survival with tumor-positive or tumor-negative sentinel nodes, and the incidence of sentinel node metastases

Population

Inclusion Criteria

• Age 18 to 75 years
* Primary melanomas of the head and neck, extremities, trunk, sole of foot, palm of hand, or subungal
• Breslow thickness ≥1.00mm AND Clark level III
• Any Breslow thickness AND Clark level IV or V

Exclusion Criteria

• Primary melanomas of the ear
• Entered trial no more than 10 weeks after skin biopsy
• Lymphatic mapping/sentinel lymph node biopsy performed within 12 weeks of diagnosis
• History of prior operative procedure disruptive of lymphatic drainage from primary site, including prior wide excision of the primary with shortest margin ≥1.5 cm
• History of melanoma or other invasive malignancy within 5 ears of diagnosis
• Life expectancy <10 years
• Primary or secondary immune deficiency
• Pregnancy

Baseline Characteristics

From the intermediate thickness melanoma, biopsy group.

• N=770
• Male sex 58%
• Age (mean±SD) 52±13.7 years
• Primary melanoma location
  • Arm or leg 46.5%
  • Other site 53.5%
• Breslow thickness (mean±SD): 1.98±0.63mm
• Clark level
  • III 43.5%
  • IV 55.4%
  • V 1.0%
• Ulceration
  • Present 26.8%
  • Absent 65.3%
  • Unknown 7.9%
• Nodal metastasis- 16.0% (122/765)
• Site of first recurrence
  • Nodal 38(4.9%)
  • Distant 107 (13.9%)
  • Local/intratransit 54(7.0%)
• No recurrence 571 (74.2%)

Interventions

• Wide excision margins recommended as 2-3 cm for intermediate (1.2-3.5 mm) and thick melanomas (>3.5 mm)
• Randomization to one of two groups:
  • Biopsy group: Wide excision of the primary melanoma plus SLNB
    • If positive SLNB identified, immediate CLND was completed
  • Observation group: Wide excision for the primary melanoma plus nodal surveillance
    • If nodal metastasis occurs during surveillance, CLND was performed
• Postoperative surveillance: clinical examination, lab surveillance, chest radiography
  • Years 0-2: q3 months
  • Year 3: q4 months
  • Years 4-5: q6 months
  • Years 6-10: Annual
• Site-specific PET scans, nodal ultrasound, melanoma markers (S-100, LDH)

Outcomes

Comparisons are biopsy group vs. observation group.

Primary Outcomes

Melanoma specific survival

Intermediate thickness melanoma: 81.4±1.5% vs. 78.3±2.0%(HR 0.84; 95% CI 0.64-1.09; P=0.18)

Thick melanoma: 58.9±4.1% vs. 64.4±4.6%(HR 1.12; 95% CI 0.76-1.67; P=0.56)

Secondary Outcomes

Disease-free survival

Intermediate thickness melanoma: 71.3±1.8% vs. 64.7±2.3%(HR 0.76; 95% CI 0.62-0.94; P=0.01)

Thick melanoma: 50.7±4.0% vs. 40.5±4.7%(HR 0.70; 95% CI 0.50-0.96; P=0.03)

Melanoma specific-survival rate

Comparisons are SLNB positive vs. SLNB negative.

Intermediate thickness melanoma: 62.1±4.8% vs. 85.5±1.5%(HR 3.09; 95% CI 2.12-4.49; P<0.001)

Thick melanoma: 48.0±7.0% vs. 64.6±4.9%(HR 1.75; 95% CI 1.07-2.87; P=0.03)

Nodal metastasis in observation group

Intermediate thickness melanomas 17.4% (87/500), estimated 10-year cumulative incidence 19.5% (median 19.2 months, 95% CI 13.6-24.1)

Thick melanoma 37.6% (44/117), estimated 10-year cumulative incidence = 41.4% (median 9.2 months, 95% CI 6.4-12.2)

Nodal metastasis in biopsy group

Intermediate-thickness melanoma 16.0% (122/765)

Thick melanoma 32.9% (57/173)

Nodal metastasis in biopsy group among patients initially with no evidence of disease

Intermediate-thickness melanoma 4.8% (31/643)

Thick melanoma 10.3% (12/116)

Survival Comparisons

'Comparisons are biopsy vs. observation groups.

Melanoma-specific survival rate, with nodal metastases

Intermediate thickness melanoma: 62.1±4.8% vs. 41.5±5.6% (HR death from melanoma 0.56; 95% CI 0.37-0.84, P=0.006)

Thick melanoma: 48.0±7.0% vs. 45.8±7.8% (HR death from melanoma 0.92; 95% CI 0.53-1.60, P=0.78)

Melanoma-specific survival rate, without nodal metastases

Intermediate Thickness Melanoma: 88.0±1.4% vs. 86.6±1.8% (HR death from melanoma 0.89; 95% CI 0.61-1.29,P=0.54)

Thick Melanoma: 69.8±5.0% vs. 76.1±5.2% (HR death from melanoma 1.18; 95% CI 0.63-2.18,P=0.61)

Distant disease-free survival

Comparisons are immediate versus delayed CLND.

Intermediate thickness melanoma: 54.8±4.8% vs. 35.6±5.4% (HR distant metastasis 0.62; 95% CI 0.42-0.91, P=0.0.02)

Thick Melanoma: 45.3±6.9% vs. 43.8±7.7%(HR distant metastasis 0.96; 95% CI 0.56-1.64, P=0.88)

Subgroup Analysis

Latent-subgroup statistical methods to estimate the treatment effect of sentinel lymph node biopsy with immediate lymphadenectomy in the subgroup of patients with nodal metastasis, for intermediate thickness melanoma.

Disease-free survival

Estimated treatment effect = 1.17 (P<0.001)

Distant disease-free survival

Estimate treatment effect = 0.73 (P=0.04)

Melanoma-specific survival

Estimated treatment effect = 0.68 (P=0.05)

Adverse Events

Wound separation

3.3% (1.2% SLNB, 3.0% CLND) vs. 3.5%

Seroma/Hematoma

4.4% (5.5% SLNB, 23.1% CLND) vs. 2.8%

Infection

8.3%(4.6% SLNB, 15.8% CLND) vs. 8.4%

Skin graft failure

2.2% vs. 1.8%

Total AEs

13.8% (10.1% SLNB, 37.2% CLND) vs. 13.9%

• Regional complications
  • Leg edema 8
  • Thrombophlebitis 7
• Systemic Complications
  • Pulmonary 7
  • Urinary 3
  • Other 4
• Methylene urticaria 0.17% (2/1173)
• Intermediate thickness cohort increased to 1200 patients because of lower than anticipated event rates

Criticisms

• Overall concerns of overstating purported therapeutic benefit of CLND, especially in light of subsequent MSLT-II trial failing to demonstrate melanoma-specific survival among patients with sentinel-node metastases with CLND compared to nodal observation
• The benefits of improved regional control could in theory be gained by lymphadenectomy at recurrence without costing the patient any survival time, and perhaps delaying or avoiding consequences of immediate lymphadenectomy
• Post-randomization subgroup analysis between the biopsy and observation nodal metastatic groups, reported as a statistically significant difference in intermediate thickness melanomas with disease specific survival, may be methodologically unsound due to confounding factors (non-random comparison groups)
• Lymph node involvement definition inconsistently applied between the two arms of the study

Funding

• National Cancer Institute Grant 29605 to Dr. Don Morton
• Australian and New Zealand Melanoma Trials Groups contributed funding
• Dr. Thompson discloses payment from advisory board positions and/or travel fees from GlaxoSmithKline, Roche and Provectus
• Dr. Kashani-Sabet discloses fees for service on advisory boards from Merck and Myriad Genetics, honoraria and grant support from Merck, holding stock in Melanoma Diagnostics, and holding a patent on the molecular classification of melanoma (patent no. 8492102), which has been licensed to Myriad Genetics.