NEWS & VIEWS 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 ascertainment bias, and the borderline statistical significance 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 meticulously 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 intermediate 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. 246 | MAY 2014 | VOLUME 11
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. [email protected]
4.
Competing interests The authors declare no competing interests.
6.
1.
2.
3.
Morton, D. L. et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch. Surg. 127, 392–399 (1992). Veronesi, U. et al. Inefficacy of immediate node dissection in stage 1 melanoma of the limbs. N. Engl. J. Med. 297, 627–630 (1977). 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).
5.
7.
8.
9.
Morton, D. L. et al. Sentinel-node biopsy or nodal observation in melanoma. N. Engl. J. Med. 355, 1307–1317 (2006). Morton, D. L. et al. Final trial report of sentinelnode biopsy versus nodal observation in melanoma. N. Engl. J. Med. 370, 599–609 (2014). 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). Marsden, J. R. et al. Revised UK guidelines for the management of cutaneous melanoma 2010. Br. J. Dermatol. 163, 238–256 (2010). 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). 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 context Vernon 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 introduced by Morton et al. in 1992,1 has been broadly accepted worldwide, albeit with some islands of controversy.2 Two large prospective evaluations of SLNB were carried out in the years following its introduction —the Sunbelt Melanoma Trial, 3 which involved over 3,600 patients with melanomas ≥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 observation. 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 relapsefree survival (RFS) and melanoma-specific survival for the subset of node-positive patients. Outcomes in patients with positive 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 melanomas ≥1.2 mm in thickness were included in the final report.
‘‘
…this finding is more than sufficient to justify routine use of the procedure
’’
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 negative SLNB developed nodal recurrence. RFS was significantly improved in the SLNB arm, largely due to a much lower rate of regional nodal recurrence than noted in the observation arm. However, melanoma-specific survival was not significantly different for www.nature.com/nrclinonc
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS 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.
SLNB and observation (81.4% versus 78.3% respectively, P = 0.18). Among patients with a positive node, distant metastasis-f ree and melanoma-specific survival rates were improved for patients with intermediate- thickness melanoma (defined as 1.2–3.5 mm in the study’s primary stratum or as 1.0– 4.0 mm in keeping 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 significant differences between the two arms in those patients with thick (in this case >3.5 mm) node-p ositive 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-f ree 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 melanoma can improve outcomes dramatically.5 Morbidity of lymphadenectomy—especially lymphoedema—was less among patients undergoing early lymphadenectomy after a positive SLNB compared with those undergoing later lymphadenectomy 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 thickness, as these patients were considered to have the greatest chance for demonstrating an improved outcome for early intervention in node-positive cases. This indeed proved to be the case: although the prognostic significance and improvement in RFS were maintained in patients with thicker melanomas, there were no significant differ ences in distant metastasis-free survival and melanoma-specific survival for nodepositive 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 potential to impact survival,7 the very high risk
of positive nodes and the short disease-free interval 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 lymphadenectomy for sentinel node-positive patients really improve survival for patients with intermediate-t hickness 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 sentinel 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, potentially making the node-p ositive 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 nodepositive 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 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
sentinel node-positive patients versus sentinel node-negative patients and the incidence of nodal metastases in both groups.5 The authors clearly define the target population: patients with intermediate thickness 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 intermediate 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 observation, 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 observation 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 presented 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 compared with patients with palpable positive 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 rationale to compare these two node-p ositive groups. However, the biological 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 www.nature.com/nrclinonc
© 2014 Macmillan Publishers Limited. All rights reserved
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. [email protected]
4.
Competing interests The authors declare no competing interests.
6.
1.
2.
3.
Morton, D. L. et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch. Surg. 127, 392–399 (1992). Veronesi, U. et al. Inefficacy of immediate node dissection in stage 1 melanoma of the limbs. N. Engl. J. Med. 297, 627–630 (1977). 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).
5.
7.
8.
9.
Morton, D. L. et al. Sentinel-node biopsy or nodal observation in melanoma. N. Engl. J. Med. 355, 1307–1317 (2006). Morton, D. L. et al. Final trial report of sentinelnode biopsy versus nodal observation in melanoma. N. Engl. J. Med. 370, 599–609 (2014). 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). Marsden, J. R. et al. Revised UK guidelines for the management of cutaneous melanoma 2010. Br. J. Dermatol. 163, 238–256 (2010). 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). 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 context Vernon 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 introduced by Morton et al. in 1992,1 has been broadly accepted worldwide, albeit with some islands of controversy.2 Two large prospective evaluations of SLNB were carried out in the years following its introduction —the Sunbelt Melanoma Trial, 3 which involved over 3,600 patients with melanomas ≥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 observation. 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 relapsefree survival (RFS) and melanoma-specific survival for the subset of node-positive patients. Outcomes in patients with positive 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 melanomas ≥1.2 mm in thickness were included in the final report.
‘‘
…this finding is more than sufficient to justify routine use of the procedure
’’
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 negative SLNB developed nodal recurrence. RFS was significantly improved in the SLNB arm, largely due to a much lower rate of regional nodal recurrence than noted in the observation arm. However, melanoma-specific survival was not significantly different for www.nature.com/nrclinonc
© 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS 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.
SLNB and observation (81.4% versus 78.3% respectively, P = 0.18). Among patients with a positive node, distant metastasis-f ree and melanoma-specific survival rates were improved for patients with intermediate- thickness melanoma (defined as 1.2–3.5 mm in the study’s primary stratum or as 1.0– 4.0 mm in keeping 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 significant differences between the two arms in those patients with thick (in this case >3.5 mm) node-p ositive 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-f ree 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 melanoma can improve outcomes dramatically.5 Morbidity of lymphadenectomy—especially lymphoedema—was less among patients undergoing early lymphadenectomy after a positive SLNB compared with those undergoing later lymphadenectomy 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 thickness, as these patients were considered to have the greatest chance for demonstrating an improved outcome for early intervention in node-positive cases. This indeed proved to be the case: although the prognostic significance and improvement in RFS were maintained in patients with thicker melanomas, there were no significant differ ences in distant metastasis-free survival and melanoma-specific survival for nodepositive 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 potential to impact survival,7 the very high risk
of positive nodes and the short disease-free interval 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 lymphadenectomy for sentinel node-positive patients really improve survival for patients with intermediate-t hickness 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 sentinel 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, potentially making the node-p ositive 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 nodepositive 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 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
sentinel node-positive patients versus sentinel node-negative patients and the incidence of nodal metastases in both groups.5 The authors clearly define the target population: patients with intermediate thickness 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 intermediate 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 observation, 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 observation 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 presented 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 compared with patients with palpable positive 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 rationale to compare these two node-p ositive groups. However, the biological 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 www.nature.com/nrclinonc
© 2014 Macmillan Publishers Limited. All rights reserved
