1. Residents’ Journal Club Giao Q. Phan, M.D. September 4, 2014

2. 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) Overall Survival Years Veronesi – NEJM (1977) 553 Pts. with stage I-II limb 1  randomized (1967-1974):  Elective node dissection  Observation  Dissection if develops palpable mets

3. 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%

4. Early days of sentinel LN biopsy Described by UCLA surgical oncology group Radioactive colloid gold 198 Au  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

5. 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

6. 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

7. Results: Recurrences P <0.001

8. Survival: SLN+ vs. SLN- SLN(-) SLN(+) Disease-Free Survival Melanoma-Specific Survival P < 0.001

9. Survival: SLNB vs. Observation Disease-Free Survival Melanoma-Specific Survival Obsrv SLNB P = 0.009 P = 0.58

10. Survival: Pts without nodal mets Melanoma-Specific Survival (%) Observation SLNB

11. Survival: Pts with nodal mets Melanoma-Specific Survival (%) 1: +SLN  immed dissn 2: Any node mets (1+4) 3: Obs  node mets  dissn 4: False (-)SLN  node mets

12. 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%

13. 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

14. 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

15. 10-year follow-up of prior data New data on 314 pts. with >3.5 mm Breslow-depth

16. Survival (10-yrs): SLNB vs. Obs: 1.2-3.5mm Disease-Free Survival Melanoma-Specific Survival P = 0.01 Obsrv SLNB P = 0.18

17. Survival (10-yrs): SLNB vs. Obs: >3.5mm Disease-Free Survival Melanoma-Specific Survival P = 0.03 Obsrv SLNB P = 0.56

18. Survival (10-yrs): Prognostic Indicators

19. 10-yrs incidence node mets: 1.2 -3.5mm

20. 10-yrs incidence node mets: >3.5mm

21. 10-yr MSS: Subgroup analyses: 1.2-3.5mm P < 0.001 P < 0.006

22. 10-yr MSS: Subgroup analyses: >3.5mm P = 0.004 P = NS ! P = 0.09

23. 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 1 st five years]

24. 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.

25. 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!!!!

26. 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