Dr. Thompson is Professor of Melanoma and Surgical Oncology, Sydney Medical School, The University of Sydney, and Senior Surgeon, Melanoma Institute Australia, Sydney.
John F. Thompson, MD, FRACS, FACS
IN THE MID-1990s, the surgical management of patients presenting with primary cutaneous melanomas changed forever when the sentinel lymph node biopsy technique was introduced by Dr. Donald Morton and colleagues at the John Wayne Cancer Institute in Los Angeles.1 This technique was rapidly taken up by melanoma surgeons worldwide, and a long-running and unresolved debate about the role of elective regional lymph node dissection at the same time as wide excision of the primary melanoma became irrelevant. However, important new questions arose: When was it appropriate (or inappropriate) to offer sentinel lymph node biopsy? And if metastatic melanoma was found in a sentinel lymph node, was an immediate completion lymph node dissection necessary?
Having developed the sentinel lymph node concept and introduced the sentinel node biopsy technique, Dr. Morton sought to obtain rigorous scientific evidence to confirm or refute the value of sentinel node biopsy and completion lymph node dissection in those found to be sentinel node–positive, to answer the two important new questions previously mentioned. To do this, he initiated two large international, multicenter randomized controlled trials: the first and second Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II).
MSLT-I and MSLT-II
IN MSLT-I, 2,001 patients were randomized to receive nodal observation or sentinel lymph node biopsy, with completion lymph node dissection in those found to be sentinel node–positive. The final results of this trial, reported in 2014,2 showed conclusively that sentinel node status (positive or negative) gave important prognostic information for patients with primary melanomas of all Breslow thicknesses and was a reliable indicator of the status of the entire lymph node field. For those with intermediate-thickness melanomas (1.2–3.5 mm), there was a substantial improvement in survival in patients who had a positive sentinel node removed, then a completion lymph node dissection, compared with patients in the observation arm, who had no initial sentinel node biopsy and a therapeutic lymph node dissection when recurrence became clinically apparent at a later date. As well as having worse survival, the latter group had substantially greater morbidity.
“These updated ASCO/SSO guidelines provide an evidence-based framework for providing advice to patients who present with a primary cutaneous melanoma and those whose regional nodes are found to contain metastatic disease.”— John F. Thompson, MD, FRACS, FACS
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In MSLT-II, 1,934 patients with sentinel lymph node–positive disease were randomized to receive observation or completion lymph node dissection. The initial results of MSLT-II, reported in 2017, indicated there was no additional survival benefit achieved by completion lymph node dissection in sentinel node–positive patients, although disease-free survival was improved and the problems associated with clinical regional node recurrence were greatly reduced.3 These results were comparable to the initial results reported for the 473-patient German DeCOG study, which had a similar design and similar objectives.4
Initial Set of Guidelines
IN 2012, an initial set of guidelines for sentinel lymph node biopsy and the management of regional lymph nodes in patients with clinically node-negative disease who presented with a primary cutaneous melanoma was developed and published jointly by ASCO and the Society of Surgical Oncology (SSO).5 In late 2017, an updated set of evidence-based ASCO/SSO guidelines, published by an expert international panel of surgical oncologists, medical oncologists and pathologists, who had been assigned the task of examining all available new evidence and reviewing the guidelines accordingly.6,7 The update was based on a systematic literature review, which included the three large prospective randomized trials mentioned above, supplemented by evidence from nine new observational studies and two other systematic reviews.
Highlights of Updated Guidelines
THE UPDATED ASCO/SSO guidelines addressed the two fundamentally important questions described previously that confront clinicians treating patients who present with a primary cutaneous melanoma and which were addressed in both MSLT-I and MSLT-II: What are the indications for sentinel lymph node biopsy, and what is the role of completion lymph node dissection in sentinel node–positive patients?
The evidence-based recommendations of the ASCO/SSO expert panel are outlined in the summary that accompanies this commentary, in this issue of The ASCO Post. In brief, the guidelines recommend sentinel lymph node biopsy for all patients with intermediate-thickness melanomas (1–4 mm) and state that it should also be considered in patients with American Joint Committee on Cancer (AJCC) T1b melanomas (0.8–1 mm or < 0.8 mm with ulceration) and T4 melanomas (> 4 mm). Routine sentinel node biopsy was not recommended for T1a melanomas (< 0.8 mm, nonulcerated).
The ASCO/SSO guidelines in relation to completion lymph node dissection recommended a discussion be had with each patient who is found to have sentinel node–positive disease, with an explanation that both completion lymph node dissection and careful observation are options, with due consideration of clinicopathologic factors that may indicate a lower or higher risk, as discussed in the guidelines, and also with consideration of the social and geographic circumstances of the individual patient. The guidelines emphasized that the initial findings of the MSLT-II and DeCOG studies, indicating no overall benefit for completion lymph node dissection, may not be directly transferable to everyday practice, when patients may be unable or unwilling to attend frequent follow-up or when high-quality nodal ultrasonography as part of their follow-up evaluation is not available.
These updated ASCO/SSO guidelines offer an evidence-based framework for providing advice to patients who present with a primary cutaneous melanoma and those whose regional nodes are found to contain metastatic disease.
“The requirement for accurate staging to select patients appropriately for these costly and sometimes toxic adjuvant systemic therapies cannot be overemphasized.”— John F. Thompson, MD, FRACS, FACS
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Need for Accurate Nodal Staging
THE FUNDAMENTAL importance of sentinel node biopsy for staging was emphasized by the melanoma expert group of the AJCC that undertook the most recent revision of the Eighth Edition of the AJCC Cancer Staging Manual.8,9 Also, in relation to staging, it is important to note that if completion lymph node dissection is not performed in sentinel node–positive patients, no additional staging information is obtained, because the number of positive nonsentinel lymph nodes remains unknown, and nonsentinel node status has been shown to be a valuable additional prognostic factor. The
need for accurate nodal staging of patients with melanoma is today more important than ever, as clinical trial evidence accumulates showing adjuvant systemic therapies improve disease-free and overall survival.10,11 The requirement for accurate staging to select patients appropriately for these costly and sometimes toxic adjuvant systemic therapies cannot be overemphasized. ■
DISCLOSURE: Dr. Thompson reported no conflicts of interest.
REFERENCES
1. Morton DL, Wen DR, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392-399, 1992.
2. Morton DL, Thompson JF, Cochran AJ, et al: Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 370:599-609, 2014.
3. Faries MB, Thompson JF, Cochran AJ, et al: Completion dissection or observation for sentinel-node metastasis in melanoma. N Engl J Med 376:2211-2222, 2017.
4. Leiter U, Stadler R, Mauch C, et al: Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): A multicentre, randomised, phase 3 trial. Lancet Oncol 17:757-767, 2016.
5. Wong SL, Balch CM, Hurley P, 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.
6. Wong SL, Faries MB, Kennedy EB, et al: Sentinel lymph node biopsy and management of regional lymph nodes in melanoma: American Society of Clinical Oncology and Society of Surgical Oncology clinical practice guideline update. Ann Surg Oncol 25:356-377, 2018.
7. Wong SL, Faries MB, Kennedy EB, et al: Sentinel lymph node biopsy and management of regional lymph nodes in melanoma: American Society of Clinical Oncology and Society of Surgical Oncology clinical practice guideline update. J Clin Oncol 36:399-413, 2018.
8. Amin MB, Edge S, Greene F, et al: AJCC Cancer Staging Manual. 8th Edition. Switzerland, Springer, 2017.
9. Gershenwald JE, Scolyer RA, Hess KR, et al: Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 67:472-492, 2017.
10. Long GV, Hauschild A, Santinami M, et al: Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med 377:1813-1823, 2017.
11. Weber J, Mandala M, Del Vecchio M, et al: Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 377:1824-1835, 2017.
