Residents’ Journal ClubGiao Q. Phan, M.D.September 4, 2014

Melanoma

• Having metastases to regional nodes is the most important prognostic indicator in early-stage melanoma.

• Elective (complete) node dissection was previously routinely used to stage (& possibly improve survival)

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Years

Veronesi – NEJM (1977)

•553 Pts. with stage I-II limb 1 randomized (1967-1974):

Elective node dissection Observation Dissection if

develops palpable mets

Survival: All stages

Balch et al. JCO 2001;19:3635-48

5-Year Survival Stage I = ~ 94%Stage II = ~ 68%Stage III = ~ 45%Stage IV = ~ 10%

Early days of sentinel LN biopsy

• Described by UCLA surgical oncology group • Radioactive colloid gold 198Au lymphoscintigraphy

Elective LN dissection as “gold standard”

Holmes (UCLA) – Ann Surg (1977)•57 Pts. with injected with radioactive colloid gold

Elective node dissection 17 found to have LN mets

LN mets occur only at area seen by colloid gold

MSLT-1: Multicenter Selective Lymphadenectomy Trial

• To study the usefulness of SLNB in identifying pts with clinically occult metastases

• To evaluate the clinical effect of immediate complete lymphadenectomy

• 1269 Melanoma pts. with Breslow depth 1.2 mm - 3.5 mm enrolled from 1994 to 2002

Methods• Randomize 60:40 WLE & SLNB

Node dissection immediately if SLNs were (+) for mets

WLE & post-op observation Node dissection if nodal recurrence found later

• Primary endpoint Melanoma-specific survival (MSS): Survival until death from

melanoma

• Secondary endpoints Disease-free survival (DFS): Time until recurrence MSS and DFS: (+)SLN mets vs. (-)SLN mets MSS and DFS: (+)LN mets vs. (-)LN mets

• Stratified for: Breslow thickness, site of primary

Results: Recurrences

P <0.001

Survival: SLN+ vs. SLN-

SLN(-)

SLN(+)

Disease-Free Survival Melanoma-Specific Survival

P < 0.001 P < 0.001

Survival: SLNB vs. Observation

Disease-Free Survival Melanoma-Specific Survival

ObsrvSLNB

P = 0.009 P = 0.58

Survival: Pts without nodal mets

Mel

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ObservationSLNB

Survival: Pts with nodal mets

Mel

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Sp

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(%)

1: +SLN immed dissn2: Any node mets (1+4)3: Obs node mets dissn4: False (-)SLN node mets

Summary

• SLNB with “immediate” node dissection if SLN+ improves disease-free survival compared to observation with “delayed” dissection when clinically detected.

5-year DFS: 78% vs. 73%; P = 0.009

• SLNB does not improve melanoma-specific survival (i.e., overall survival) compared to observation w/ “delayed” dissection.

5-year MSS: 87% vs. 87%

• SLN+ pts. have worse prognosis than SLN- pts.

5-year DFS: 53% vs. 83%

5-year MSS: 72% vs. 90%

Summary

• ~16% patients with Breslow-depth 1.2mm to 3.5m had nodal metastases during mean follow-up of 5 years (both arms).

• Pts with nodal mets: SLNB pts. had less tumor burden (+1.4 LNs) compared to Obs pts (+3.3 LNs) progression with delay

• Pts with nodal mets: 5-year MSS higher with SLNB vs. Obs.

72% vs. 52%; P = 0.0004

Sub-group analysis; unplanned comparison

Their conclusion (& limitations)

• SLNB has staging and prognostic value in patients with intermediate-thickness melanoma and, coupled with immediate complete lymphadenectomy, improves survival among patients with tumor positive SLN.

Unplanned subgroup analysis

Ascertainment bias/selection bias, i.e., pts known to have +SLN may have been treated/evaluated differently

• 10-year follow-up of prior data• New data on 314 pts. with >3.5 mm Breslow-depth

Survival (10-yrs): SLNB vs. Obs: 1.2-3.5mm

Disease-Free Survival Melanoma-Specific Survival

P = 0.01

ObsrvSLNB

P = 0.18

Survival (10-yrs): SLNB vs. Obs: >3.5mm

Disease-Free Survival Melanoma-Specific Survival

P = 0.03

ObsrvSLNB

P = 0.56

Survival (10-yrs): Prognostic Indicators

10-yrs incidence node mets: 1.2 -3.5mm

10-yrs incidence node mets: >3.5mm

10-yr MSS: Subgroup analyses: 1.2-3.5mm

P < 0.001

P < 0.006

10-yr MSS: Subgroup analyses: >3.5mm

P = 0.004

P = NS !

P = 0.09

Summary

• No major changes in findings compared to earlier report

• SLNB with “immediate” node dissection if SLN+ improves disease-free survival compared to observation with “delayed” dissection when clinically detected SLNB--but does not improve melanoma-specific survival (i.e., overall survival) compared to observation w/ “delayed” dissection.

• ~20% intermediate-thickness melanoma develop nodal mets

• ~42% thick melanoma develop nodal mets

• The majority of recurrences happen within the first 5 years

[Closer follow-up &/or scans for high-risk patients within the 1st five years]

Their conclusion (& limitations)• “Biopsy-based staging of intermediate-thickness or thick melanoma provides important prognostic information & identifies patients with

nodal metastases who may benefit from immediate complete lymphadenectomy.”• “Biopsy-based management prolongs DFS for all and prolongs MSS for patients with nodal metastases from intermediate-thickness

melanomas.”

Unplanned subgroup analysis

“A separate analysis of pts. with node+ disease is justified by the obvious biologic rationale (i.e., only patients with nodal disease can benefit from nodal intervention)”.

Latent-group analysis (stats method) was used to correct ascertainment bias.

PROs• The best prognostic indicator• Simple procedure, minimal side effects• Important for entry into adjuvant clinical trials• Personalization of follow-up schedule depending on risks• Early surgery/close follow-up can prevent bulky recurrence &

subsequent difficult surgery

CONS• Costs: $10K - $15K (surgeon, OR, nuclear medicine, etc.)

• Diagnostic, not therapeutic

• Lack of effective adjuvant therapy despite knowing pt. has higher recurrence risks – psychological impact on patient

Interferon alpha-2B (regular & pegylated) is the ONLY drug FDA-approved for adjuvant tx: Increases disease-free survival but not overall survival; 1-year of tx; many sx’s

Need more clinical trials for this!!!!

Next step: MSLT-2

• Since the majority of completion lymphadenectomies for +SLN are negative for further LN mets, is completion lymphadenectomy necessary?

• Randomize“Standard” therary: Completion node dissection

Close observation & followup (w/ U/S, P.E.)

• Follow for MSS and DFS

• Trial in follow-up period

• Any guess????

• In the meantime: ASCO/SSO consensus: Completion node dissection is standard & should be discussed with patient