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melanoma-specific survival if they had SLNB and EPLND. The hazard ratio was 0.67 (P = 0.04), when only melanomas of intermediate thickness are considered—there was no difference between arms for thicker melanomas. The analysis of a small subset, the possibility of subtle ascertain-ment bias, and the borderline statistical signifi cance of this finding casts doubt on this conclusion.

From this study one cannot conclude that no patient with primary melanoma would benefit from a SLN-directed EPLND. One can only say that no benefit could be detected in a well-designed and meticu-lously executed randomized study of 1,661 patients. To determine more precisely if EPLND can affect survival, MSLT-2 will assess patients who are already defined to have nodal involvement by a positive SLN and they will be randomly assigned to EPLND or ultrasound monitoring and observation. Yet, without the results of that study, one must ask, how has SLNB become the standard of care for inter mediate thick-ness melanomas? Guidelines for the staging and therapy of melanoma that include SLNB have been widely accepted in the USA, Canada, Europe, Australia, and New Zealand.6 These guidelines go beyond the current British recommendation that this surgery is a “staging procedure… that … has no proven therapeutic value”.7 Nodal staging has been advocated by some because of the availability of adjuvant interferon-α (IFN) for patients with nodal involvement, yet IFN has not been shown to clearly improve survival of patients with melanoma either.8 So, an expensive procedure that costs approximately US$10,000–$15,0009 and without a proven survival benefit is being used to justify the use of a toxic adjuvant that also has no clear survival benefit. Such recommendations cannot represent the best data-driven use of our healthcare dollars. The best current evidence of whether to perform SLNB when a patient and their doctor are faced with a new diagnosis of primary melanoma is provided by the definitive result of MSLT1: “No significant treatment-related difference in the 10-year melanoma-specific survival rate was seen in the overall study population…”.5 Certainly, there is prognostic information in a SLNB, and its use in defining patients for research studies is justifiable. Yet, without additional data showing that it can improve survival, it must be considered an expensive and optional staging tool and understood as such by patients considering this procedure.

Surgery Branch, Center for Cancer Research, National Cancer Institute, CRC Room 3-5952, 9000 Rockville Pike, Bethesda, MD 20892, USA (J.C.Y., R.M.S., S.A.R.). Correspondence to: S.A.R. sar@mail.nih.gov

Competing interestsThe authors declare no competing interests.

1. Morton, D. L. et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch. Surg. 127, 392–399 (1992).

2. Veronesi, U. et al. Inefficacy of immediate node dissection in stage 1 melanoma of the limbs. N. Engl. J. Med. 297, 627–630 (1977).

3. Balch, C. M. et al. Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Ann. Surg. Oncol. 7, 87–97 (2000).

4. Morton, D. L. et al. Sentinel-node biopsy or nodal observation in melanoma. N. Engl. J. Med. 355, 1307–1317 (2006).

5. Morton, D. L. et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N. Engl. J. Med. 370, 599–609 (2014).

6. Fong, Z. V. & Tanabe, K. K. Comparison of melanoma guidelines in the U.S.A., Canada, Europe, Australia and New Zealand: a critical appraisal and comprehensive review. Br. J. Dermatol. 170, 20–30 (2014).

7. Marsden, J. R. et al. Revised UK guidelines for the management of cutaneous melanoma 2010. Br. J. Dermatol. 163, 238–256 (2010).

8. Kirkwood, J. M. et al. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin. Cancer Res. 10, 1670–1677 (2004).

9. Agness, D. M. Cost-effectiveness of sentinel lymph node biopsy in thin melanomas. Surgery 134, 542–547 (2003).

MELANOMA

MSLT‑1—putting sentinel lymph node biopsy into contextVernon K. Sondak and Jonathan S. Zager

The MSLT-1 study compared sentinel lymph node biopsy (SLNB) with nodal observation in patients with localized cutaneous melanoma. The final results of the trial—conducted from 1994 to 2002—strongly support using SLNB in staging patients with melanomas ≥1.0 mm in thickness, but the optimal staging approach for thinner melanomas is unanswered. Sondak, V. K. & Zager, J. S. Nat. Rev. Clin. Oncol. 11, 246–248 (2014); published online 15 April 2014; doi:10.1038/nrclinonc.2014.66

Sentinel lymph node biopsy (SLNB) for the surgical staging of clinically node-negative cutaneous melanoma, which was intro-duced by Morton et al. in 1992,1 has been broadly accepted worldwide, albeit with some islands of controversy.2 Two large pro-spective evaluations of SLNB were carried out in the years following its i ntroduction —the Sunbelt Melanoma Trial,3 which involved over 3,600 patients with melano-mas ≥1.0 mm undergoing SLNB, and the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1).4,5 MSLT-1 is the only randomized trial of SLNB ever conducted; it randomly assigned 2,001 patients in a 60:40 ratio to either SLNB or nodal obser-vation. Patients with positive nodes (found at SLNB or upon recurrence) underwent radical lymphadenectomy. The primary end point was melanoma-specific survival, with secondary end points including relapse-free survival (RFS) and melanoma-specific survival for the subset of node-positive patients. Outcomes in patients with posi-tive sentinel nodes, who underwent early

lymphadenectomy, were compared with outcomes in those who underwent delayed lymphadenectomy at the time of nodal relapse. Results of 1,661 patients with mela-nomas ≥1.2 mm in t hickness were included in the final report.

Supporting a wealth of other data, the MSLT-1 trial confirmed that sentinel node status is the most important prognostic factor for clinically localized melanomas ≥1 mm in thickness. A positive sentinel node was detected in about 20% of patients, and approximately 5% of patients with a nega-tive SLNB developed nodal recurrence. RFS was signifi cantly improved in the SLNB arm, largely due to a much lower rate of regional nodal recurrence than noted in the obser-vation arm. However, melanoma-specific survival was not significantly different for

‘‘…this finding is more than sufficient to justify routine use of the procedure’’

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SLNB and observation (81.4% versus 78.3% respectively, P = 0.18). Among patients with a positive node, distant metastasis- free and melanoma- specific survi val rates were improved for patients with intermediate- thickness melanoma (defined as 1.2–3.5 mm in the study’s pri mary stratum or as 1.0– 4.0 mm in keep ing with standard staging cri-teria, which is provided in the study’s sup-plementary material) who were randomly assigned to undergo SLNB, but there were no signifi cant differences between the two arms in those patients with thick (in this case >3.5 mm) node- positive melanoma. RFS for patients with thick melanomas was significantly improved in the SLNB arm, largely due to many fewer nodal recurrences in that arm. The finding that both distant metastasis- free survival and melanoma- specific survival were significantly impro-ved for patients with intermediate-thickness melanoma randomly assigned to undergo SLNB suggests that early diagnosis and surgical treatment of node-positive mela-noma can improve o utcomes dramatically.5

Morbid ity of l ymphadenectomy—e specially l ymphoedema—was less among patients undergoing early lymphadenectomy after a positive SLNB compared with those under-going later l ymphadenectomy at the time of recurrence.6

Of note, the primary analysis group for MSLT-1 was the stratum of patients with melanomas between 1.2 and 3.5 mm thick-ness, as these patients were considered to have the greatest chance for demon strating an improved outcome for early inter vention in node-positive cases. This indeed proved to be the case: although the prognostic signifi cance and improvement in RFS were maintained in patients with thicker mela-nomas, there were no significant differ-ences in distant metastasis-free survival and melanoma- specific survival for node-positiv e patients with melanomas >3.5 mm thick. While this observation supports the long-held view that patients with node- positive thick melanomas have such a high risk for occult distant metastasis that early surgical intervention offers limited poten-tial to impact survival,7 the very high risk

of posi tive nodes and the short disease-free inter val before nodes became palpable on the observation arm (median time 9.2 months for melanomas >3.5 mm),5 combined with the significantly improved RFS after SLNB in these patients, argues strongly for routine use of SLNB in clinically node-negative patients with thick melanomas.

However, does early lymphadenec-tomy for sentinel node-positive patients really improve survival for patients with intermediate- thickness melanoma or is this finding an artefact of the study design? ‘Attribution bias’ is a factor to consider in this regard, as all patients with a positive senti nel node are identified early in the intervention arm, whereas node-positive patients on the observation arm are only identified after a period of follow-up. Some patients with very late nodal relapse in the observation group, as well as those who never have nodal relapse owing to ante-cedent distant metastasis or intercurrent death, will not be properly counted, poten-tially making the node- positive patients in the observation arm seem to fare worse than is actually the case. There is no easy way to address this issue, but the MSLT-1 investigators attempt to do so with post‑hoc simulation- based analysis, which is unsatis-fying at best. The 10-year follow-up and relatively low numbers of patients on the observation arm who died from other causes or were lost to follow-up do provide some degree of reassurance but, in the end, we must recognize that this study can do nothing more than suggest that early diagnosis and surgical treatment of node-positive intermediate-thickness melanoma might improve survival, it can never prove that point. Given the other benefits of SLNB for our patients with intermediate-thickness and thick melanomas, this finding is more than sufficient to justify routine use of the procedure.

Nevertheless, there are two major areas of controversy that the MSLT-1 trial does not help us address. Thin melanomas, those with a thickness ≤1 mm, have an incidence of sentinel node metastasis <10% but account for a large percentage of newly diagnosed melanoma cases.8 Patients with melanomas <1 mm thick were excluded from the MSLT-1 trial (and the Sunbelt Melanoma Trial as well) so we are left with retrospective studies and extrapolation to guide us in managing this important population. Nonetheless, there does seem to be the gradual emer-gence of a consensus that most patients with clinically node-negative melanomas

0.76–1.00 mm in thickness should be con-sidered for SLNB, but few if any patients with lesions thinner than 0.76 mm are good candidates for the procedure.9 Available evi-dence supports the staging value of SLNB for patients with melanomas 0.76–1.00 mm in thickness; however, at present, little is known about how RFS and survival out-comes for patients with node- positive thin melanoma are influenced by routine use of SLNB in this population.

The second controversial area is the manage ment of the sentinel node-positive lymphatic basin; specifically: is completion of lymph node dissection routinely, selec-tively, or never required for the benefits of SLNB to be realized? As both MSLT-1 and the Sunbelt Melanoma Trial required routine completion lymphadenectomy for senti-nel node-positive cases, current practice guidelines recommend routine completion lymphadenectomy.10 Another randomized trial, MSLT-2, will attempt to address this issue. MSLT-2 accrued 1,937 patients with positive sentinel nodes who were randomly assigned to either completion lymphadenec-tomy or nodal observation with ultrasono-graphy surveillance of the at-risk nodal basin (Mark B. Faries, personal communi-cation). Results from this trial are likely to be years away, meaning that patients and sur-geons will struggle with this issue for some time to come.

Although published over two decades after the original published description of SLNB, the final results of the MSLT-1 random ized trial represent one of the most significant contri butions ever made to our understanding of the surgical management of melanoma. These results clearly help put SLNB into perspective, and define the potential benefits patients can expect from the procedure while challenging us all to further improve on the staging and treat-ment of node-positive m elanoma in the decades ahead.

Department of Cutaneous Oncology, Moffitt Cancer Center, and Departments of Oncologic Sciences and Surgery, University of South Florida, Morsani College of Medicine, 12902 Magnolia Drive, Tampa, FL 33612, USA (V.K.S., J.S.Z.). Correspondence to: V.K.S. vernon.sondak@moffitt.org

Key point

The final MSLT-1 trial results strongly support the use of sentinel lymph node biopsy in staging patients with melanomas ≥1.0 mm in thickness, but the optimal approach to the staging of thinner melanomas remains unanswered.

‘‘…is completion of lymph node dissection routinely, selectively, or never required for the benefits of SLNB to be realized?’’

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Competing interestsV.K.S. is a consultant for Bristol–Myers Squibb, Glaxo Smith-Kline, Merck, Navidea, Novartis and Provectus. J.S.Z. is a consultant for Amgen and Delcath Systems.

1. Morton, D. L. et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch. Surg. 127, 392–399 (1992).

2. Thomas, J. M. Prognostic false-positivity of the sentinel node in melanoma. Nat. Clin. Pract. Oncol. 5, 18–23 (2008).

3. McMasters, K. M. et al. Lessons learned from the Sunbelt Melanoma Trial. J. Surg. Oncol. 86, 212–223 (2004).

4. Morton, D. L. et al. Sentinel-node biopsy or nodal observation in melanoma. N. Engl. J. Med. 355, 1307–1317 (2006).

5. Morton, D. L. et al. Final report of sentinel-node biopsy versus nodal observation in melanoma. N. Engl. J. Med. 370, 599–609 (2014).

6. Faries, M. B. et al. The impact on morbidity and length of stay of early versus delayed complete

lymphadenectomy in melanoma: results of the Multicenter Selective Lymphadenectomy Trial (I). Ann. Surg. Oncol. 17, 3324–3329 (2010).

7. Balch, C. M. The role of elective lymph node dissection in melanoma: rationale, results, and controversies. J. Clin. Oncol. 6, 163–172 (1988).

8. Han, D. et al. Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. J. Clin. Oncol. 31, 4387–4393 (2013).

9. Gershenwald, J. E., Coit, D. G., Sondak, V. K. & Thompson, J. F. The challenge of defining guidelines for sentinel lymph node biopsy in patients with thin primary cutaneous melanomas. Ann. Surg. Oncol. 19, 3301–3303 (2012).

10. Wong, S. L. et al. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J. Clin. Oncol. 30, 2912–2918 (2012).

MELANOMA

MSLT‑1—SNB is a biomarker, not a therapeutic interventionAlexander C. J. van Akkooi and Alexander M. M. Eggermont

The final analysis of the MSLT-1 trial confirms that sentinel lymph node biopsy (SNLB) does not improve survival in patients with melanoma >1 mm thickness. Subgroup analyses remain inconclusive. SNLB provides prognostic information for adjuvant therapy decisions, as recent data indicate that adjuvant therapies are effective in patients with positive sentinel nodes with an ulcerated primary.

van Akkooi, A. C. J. & Eggermont, A. M. M. Nat. Rev. Clin. Oncol. 11, 248–249 (2014); published online 8 April 2014; doi:10.1038/nrclinonc.2014.64

Changes in the management of cuta neous melanoma, the malignancy with the fastest rising incidence in the world, are occurring at all stages of the disease.1 The most impor-tant prognostic bio markers for patients with primary stage I or stage II mela nomas are Breslow thickness, ulceration, mitotic index and microscopic nodal status, which is detected by sentinel lymph node biopsy (SLNB).2 The prognosis of patients with microscopic sentinel node involvement is very heterogeneous and correlates closely with tumour load in the sentinel node.3 Depending on tumour load, the prog-nosis ranges from negative sentinel nodes to palpable macroscopic disease.3 Sentinel node-positivity is considered a biomarker for the likelihood of systemic micro-metastatic disease, and can thus provide clinical guidance for adjuvant therapy decisions.4 The management of primary melanomas and the role of SLNB have been much debated over the past decade.

The final, 10-year results of the Multicentre Selective Lymphadenectomy Trial-1 (MSLT-1) have been published, shortly after the demise of the much respected and beloved Donald Morton, the princi-pal investigator and pioneer of SLNB.5 The question addressed in this trial is whether SLNB—and, in the instance of sentinel node-positivity, a completion lymph node dissection (CLND)—can improve survival in the patient popu lation with primary melanomas >1 mm thickness, in particular in patients with melanomas of intermediate thickness (1.2–3.5 mm).

The MSLT-1 was well designed with a primary end point of melanoma-specific survival (MSS) and secondary end points of disease-free survival (DFS), survival of

senti nel node-positive patients versus sen-tinel node-negative patients and the inci-dence of nodal metastases in both groups.5 The authors clearly define the target popu-lation: patients with inter mediate thick-ness melanoma (Breslow thickness of 1.20–3.50 mm), but also provide an extra post‑hoc analyses of patients with Breslow thickness of 1.00–4.00 mm and outcome in thick melanomas >4.00 mm. The study required a sample size of 900 patients with inter mediate thickness melanomas to detect a 10% difference in survival, with 90% power and a 5% type 1 error rate, which was achieved with an accrual of 1,270 patients in the intermediate-thickness group. Interim analysis revealed a higher proportion of low-risk patients and, thus, accrual was increased to 1,200 patients after re-calculation for power analysis.2

Patients were randomly assigned in a 60:40 fashion to SLNB or nodal observa-tion, resulting in 770 patients undergoing SLNB and 500 patients undergoing nodal observation. Both intention-to-treat and per-protocol analyses were conducted, but did not show any differences to each other. The respective 10-year melanoma-specific survival rates were 81.4% in the SLNB group compared with 78.3% in the obser-vation group (HR 0.84, 95% CI 0.64–1.09; P = 0.18).5 Therefore, we must conclude that SLNB-based management does not improve survival in melanoma. For melanomas >4 mm, any hint of an impact on survival was completely absent (HR 1.12, 95% CI 0.76–1.67; P = 0.56).

Multiple subgroup analyses were pre-sented to try to identify a beneficial effect for SLNB. The subgroup analysis of patients with a positive sentinel node (10-year MSS 62.1%) in the interventional arm com-pared with patients with palpable posi-tive lymph-nodes in the observation arm (10-year MSS 41.5%) indicate a significant benefit for those patients staged by SLNB (HR 0.56, P = 0.006). The authors justify this subgroup analysis on the grounds of the obvious ration ale to compare these two node- positive groups. However, the bio-logical rationale would be to include the false-negative sentinel node patients who develop a nodal recurrence in this analysis. This analysis showed a reduced effect of SLNB on survival (56.4% versus 41.5%; HR 0.67, 95% CI 0.46–0.97; P = 0.04).5 Inclusion of prognostically false positive SNLB cases will further reduce any survival differences between the two arms. These patients have a good prognosis, which is comparable to

‘‘SLNB status is a biomarker with all the caveats that come with a biomarker’’

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