MSLT-2

Clinical Question

What is the value of completion lymph node dissection for patients with melanoma with sentinel-node metastases?

Bottom Line

Completion lymph-node dissections at the time of the primary operation was found to improve local disease control as well as aiding in prognostication. There was no increase in survival from melanoma in patients with sentinel node metastases.

Major Points

Melanoma is staged at the time of its surgical excisions using a sentinel lymph node biopsy (SLNB). This minimally invasive technique is performed with methylene blue dye and/or lymphoscintigraphy with intra-operative gamma probe analysis. SLNB is important in the prognostication of melanoma. Clinically in patients with positive SLNB a completion lymph node dissection (CLND) is performed at the time of the SLNB with the goal of local disease control. These patients may also receive adjuvant medical therapies. There is currently no evidence regarding the utility of immediate CLND. This procedure is not without risks, specifically including infection, seroma, wound separation, and lymphedema.

The Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1) confirmed that SLNB is an important part in the treatment of patients with melanoma. . The MSLT-1 trial demonstrated that pathologic analysis of sentinel lymph nodes was the most important factor for prognostication of melanoma, and that patients who had a sentinel lymph node biopsy had a decreased rate of recurrence of melanoma when compared to patients who had wide excision with no nodal biopsy. Sentinel lymph node biopsy was found to be associated with improved 10 year melanoma specific survival (62% Biopsy with nodal involvement vs 41.5% observation with nodal involvement, P = 0.006) as well as 10 year distant disease free survival (54.8% Biopsy with nodal involvement vs. 35.6% observation with nodal involvement, P=0.002) in patents with intermediate-thickness melanoma (1.2-3.5-mm Breslow depth).

The MSLT-2 trial demonstrated that CLND offers local disease control, but does not increase disease-specific survival rates in patients with melanoma with sentinel lymph node metastases.

Guidelines

NCCN guidelines (Version 2.2019)

• Recommend SLNB be offered to patients with disease > stage 1B (>1mm thick or 0.76-1.00mm thickness with ulceration, mitotic rate ≥ 1 mm^2).

Society for Surgical Oncology (SSO) and American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines, Published December 13, 2017

• SLNB recommended for melanomas with Breslow thickness 1.0-4mm (T2, T3)
• SLNB may be offered for melanomas with Breslow thickness >4mm (T4)

Design

• Phase III parallel arm, multicenter randomized control trial
• N=1934
  • CLND (n=967)
  • Nodal Observation (n=967)
• Setting: International, 63 centers
• Enrollment: September 2004-September 2022
• Mean follow-up: 10 years
• Analysis: Intention-to-treat and Per-protocol
• Primary outcome: 10 year melanoma-specific survival

Population

Inclusion Criteria

• Ability to provide informed consent
• 18-75 years old
• Primary cutaneous melanoma (head, neck, trunk, extremity, scalp, palm, sole, and subungual).
• Clear margins following WLE.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Life expectancy of at least 10 years from the time of diagnosis, (excluding melanoma diagnosis) as determined by the P
• Willing to return for follow up examinations and procedures
• Randomization and/or CLND within 120 days of diagnostic biopsy
• Have a melanoma-related tumor-positive sentinel node (SN), determined by either of the following methods:
  • Diagnosis of tumor-positive SN by MSLT-II center institutional pathologist by either H and E or IHC (using S-100, Mart-1, and HMB-45)
  • Diagnosis of tumor-positive SN by RT-PCR analysis performed at JWCI, provided the primary melanoma is one of the following:
    • Breslow thickness of 1.20 mm or greater and Clark Level III
    • Clark Level IV or V, regardless of Breslow thickness
    • Ulceration, regardless of Breslow thickness or Clark level

Exclusion Criteria

• Previous or concurrent invasive melanoma.
• Primary melanoma of the eye, ears, mucous membranes or internal viscera
• Physical, clinical, radiographic or pathologic evidence of satellite, in-transit, regional, or distant metastatic disease
• Other solid tumor or hematologic malignancy during the past 5 years (excluding T1 skin lesions of squamous cell carcinoma, basal cell carcinoma, or uterine cervical cancer).
• Skin grafts, tissue transfers or flaps
• Allergy to vital blue dye or any radiocolloid.
• Inability to localize 1-2 SN drainage basins
• CLNDs or SLs (before evaluation of the current melanoma) that may have altered the lymphatic drainage pattern from the primary cutaneous melanoma to a potential LN basin.
• Organic brain syndrome or significant impairment of basal cognitive function or any psychiatric disorder
• Melanoma-related operative procedures not corresponding to criteria described in the protocol
• Primary or secondary immune deficiencies or known significant autoimmune disease
• History of organ transplantation
• Immunosuppressive agents (excluding topical or inhaled steroids) at any time during study participation or within 6 months prior to enrollment
• Pregnant or lactating women
• Participation in concurrent therapy protocols of alternative local nodal basin therapies that might confound analysis

Baseline Characteristics

From the CLND group

• Demographics: Male sex 57.0%, median age 53.3 (18-76)
• Smoking Status
  • Never: 59.3%
  • Former: 22.7&
  • Current: 18.0%
  • Missing: 2.48%
• Median Breslow (mm): 2.10 (0.34-28.0_
  • <1.50 mm: 29.0%
  • 1.50-3.50 mm: 39.2%
  • >3.50 mm: 21.8%
• Primary Site:
  • Extremity: 40.7%
  • Head/Neck: 13.7%
  • Trunk: 45.6%
• Ulceration
  • Absent: 63.0%
  • Present: 37.0%
• Number of Postive Sentinle Lymph Node (SLN)
  • 0: 11.7%
  • 1: 71.2%
  • 2: 14.2%
  • 3: 1.9%
  • >3: 1.0%
• Mean SLN metastasis: 1.06 mm
• Median SLN metastasis: 0.59 mm
• SLN Metastasis Size
  • <0.1 mm: 5.4%
  • 0.1-1 mm: 39.2%
  • >1 mm: 21.4%
• Received adjuvant therapy: 8.1%
  • Missing in 69 patients

Interventions

• Participants were randomized to group:
  • Ultrasound Observation Group - Monitoring with serial nodal ultrasound of SLND positive basin. If recurrence detected, subject has CLND.
  • CLND -completion lymphadenectomy node dissection of lymph node basin with positive node

Outcomes

Comparisons CLND vs. observation except where specified.

Primary Outcomes

3 year melanoma-specific survival

'86±1.3% vs. 86±1.2%; P=0.42 by the log-rank test'

3 year melanoma-specific survival, after adjustment for prognostic factors

'Hazard ratio for death, 1.08; 95% confidence interval [CI], 0.88 to 1.34; P=0.42'

3 year disease free survival, after adjustment for prognostic factors

'68±1.7% vs. 63±1.7%; P=0.05 by the log-rank test'

Secondary Outcomes

Rate of disease control in regional nodes at 3 years

92±1.0% vs. 77±1.5%; P<0.001 by the log-rank test

Rate of nodal recurrence in patents with sentinel node metastases

Hazard ratio, 0.31; 95% CI, 0.24 to 0.41; P<0.001

Prognostic Factors

CLND Group

Sex: male vs. female,

Hazard ratio, 1.13 (0.80-1.59); 95% CI; P=0.50

Observation Group

Sex: male vs. female,

Hazard ratio, 1.41 (0.98-2.05); 95% CI; P=0.07

CLND Group

Age per 1 year increase:

Hazard ratio, 1.00 (0.99-1.01); 95% CI; P=0.93

Observation Group

Age per 1 year increase:

Hazard ratio, 1.01 (0.99-1.02); 95% CI; P=0.15

CLND Group

Breslow thickness <1.50 mm

Hazard ratio, 1.00; 95% CI

Observation Group

Breslow thickness <1.50 mm

Hazard ratio, 1.00; 95% CI

CLND Group

Breslow thickness 1.50-3.50 mm

Hazard ratio, 1.64 (0.96-2.79); 95% CI, P=0.07

Observation Group

Breslow thickness 1.50-3.50 mm

Hazard ratio, 2.46 (1.34-4.53); 95% CI, P=0.004

CLND Group

Breslow thickness >3.50 mm

Hazard ratio, 3.82 (2.19-6.66); 95% CI, P<0.001

Observation Group

Breslow thickness >3.50 mm

Hazard ratio, 4.32 (2.31-8.09); 95% CI, P<0.001

CLND Group

Ulceration: present vs. absent

Hazard ratio, 1.97 (1.40-2.77); 95% CI, P<0.001

Observation Group

Ulceration: present vs. absent

Hazard ratio, 2.17 (1.55-3.05); 95% CI, P<0.001

CLND Group

Melanoma in arm or leg

Hazard ratio, 1.00; 95% CI

Observation Group

Melanoma in arm or leg

Hazard ratio, 1.00 (1.40-2.77); 95%

CLND Group

Melanoma in head or neck

Hazard ratio, 0.81 (0.44-1.48); 95% CI, P=0.49

Observation Group

Melanoma in head or neck

Hazard ratio, 1.60 (0.96-2.66); 95% CI, P=0.07

CLND Group

Melanoma in trunk

Hazard ratio, 1.26 (0.89-1.77); 95% CI, P=0.19

Observation Group

Melanoma in trunk

Hazard ratio, 1.05 (0.74-1.49); 95% CI, P=0.80

CLND Group

1 positive sentinel node

Hazard ratio, 1.00, 95% CI

Observation Group

1 positive sentinel node

Hazard ratio, 1.00, 95% CI

CLND Group

2 positive sentinel nodes

Hazard ratio, 1.08 (0.71-1.62), 95% CI, P=0.73

Observation Group

2 positive sentinel nodes

Hazard ratio, 1.27 (0.87-1.84), 95% CI, P=0.21

CLND Group

≥ 3 positive sentinel nodes

Hazard ratio, 1.17 (0.61-2.24), 95% CI, P=0.64

Observation Group

≥ 3 positive sentinel nodes

Hazard ratio, 2.01 (0.82-4.95), 95% CI, P=0.13

CLND Group

postive vs. negative non senintel node

Hazard ratio, 1.78 (1.19-2.67), 95% CI, P=0.005

Adverse Events

Lymphedema

24,1% vs. 6.3%; P<0.001

Criticism

• The patients selected for this trial may not be generalizable. Patients included in the trial had a lower burden of disease than those in previous retrospective studies. 70% of patients only had 1 sentinel node involved and 12% of patients had only molecular findings of melanoma as determined by RT-PCR. In the general population, who may have more significant disease burden, there may be an increase in local lymph node involvement, which may coincide with a survival decrease in patients who did not undergo CLND. .
• While there may be advantages to performing CLND in terms of prognosis and regional disease control, there is also significant morbidity associated with the procedure.
• This trial protocol specified that patients indicated that patients had 140 days after sentinel node biopsy to be randomized. This prolonged time period has been criticized for being excessive in terms of length of time for management of positive sentinel nodes in melanoma. .

Funding

• National Cancer Institute (CA189163 and CA29605)
• Borstein Family Foundation
• Amyx Foundation
• Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
• John Wayne Cancer Institute Auxiliary
• Dr. Faries receives fees for his role on an advisory board for myriad Genetic Laboratories, Amgen, and Immune Design
• Dr. Thompson receives fees for serving on the board for GlaxoSmithKline, Bristol-Myers Squibb, and Provectus Biopharmaceuticals
• Dr. Drummer receives consulting fees from Novartis, Bristol-Myers Squibb, Roche, Takeda, Pierre Fabre, Merck Sharp and Dohme, and Amgen
• Dr. Wright received a grant from Roche
• Dr. Hsueh receives lecture fees from Amgen and Castle Biosceinces
• Dr. MacKenzie-Ross received fees for being on the advisory board of Amgen
• Dr. Johnson received a grant from Incyte and fees for serving on an advisory board from Bristol-Myers Squibb and Genoptix
• Dr. Terheyden received honoraria and travel funding from Bristol-Myers Squibb and Roche and honoraria from Merck and Novartis
• Dr. Gershenwald received fees for serving on an advisory board from Merck and Castle Biosciences
• Dr. McMasters received fees for serving on the board of directors from Provectus Biopharmaceuticals and fees for serving on an advisory board and equity interest from Elucida Oncology
• Dr. Barth, holds a pending patent on systems and methods for guiding tissue resection (patent no. US 14/919,411)
• Dr. Hoon holds an issued patent on detection of micrometastasis of melanoma and breast cancer in paraffin-embedded, tumor-draining lymph nodes by means of multimarker quantitative reverse-transcriptase–polymerase-chain-reaction assay (patent no. US 7910295)