Dermatology Online Journal

Still Debating Sentinel Lymph Node Biopsy?
Barbara Burrall¹, Vijay Khatri²
Dermatology Online Journal 7(2): 1

1. Melanoma Clinic, Department of Dermatology, University of California Davis, and Mather VA Medical Center 2. Surgical Oncology, University of California Davis

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Abstract

Controversy still surrounds the recommendation for performing sentinel node biopsy (SLNB) in patients with primary melanoma 1mm or greater in thickness, but why? In the absence of widespread, metastatic disease, nodal status is the single most important prognostic factor which determines likelihood of survival. It allows early therapeutic removal of micrometastatic lymph node disease and identifies patients who are eligible for Interferon alfa-2b adjuvant therapy. SLNB is a requirement for current clinical trials.

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In the past sixty years melanoma has increased in frequency by a factor of about 15. [1] Approximately 51,400 new cases are expected in 2001 and 7800 will die this year. [2] Furthermore, deaths from melanoma, the fifth most common cancer, are generally at an earlier age than deaths due to most other cancers. [3,4,5] These statistics speak for the crucial role of the dermatologist who will usually be making the diagnosis and determining initial work up and treatment. It is imperative for dermatologists to be familiar with the most current information concerning staging, prognosis and treatment.

For this reason, the wide and rapid dissemination of information made possible by utilizing on-line capabilities is essential to allow the updating of publications which are already becoming outdated when published, particularly when the subject concerns crucial topics such as SLNB, melanoma staging and treatment. [6] Correctly, the authors state that SLNB is highly accurate. When the SLNB is negative, the predictive value for the rest of the nodal basin approaches 98% or better. [7,8,9] However, concerns regarding the lack of qualified surgeons to perform the procedure reliably are overstated; a reference is cited from 1992. [10] Training in this procedure has blossomed over the past decade allowing access to reliable SLNB for both melanoma and breast cancer patients in most areas of the U.S. Further, most agree that this outpatient procedure produces little morbidity. Mild to moderate lymphedema developed in only 1.7% of patients evaluated at Massachusetts General Hospital and some of these had potential contributing causes. [11] For these reasons SLNB has been accepted as the standard method of nodal staging for melanoma at most major U.S. medical centers. [12]

McMasters [12] recently, concisely discussed the four major benefits obtained from SLNB which are summarized here:

• Accurate staging (required for prognostic assessment).
• Identification of early nodal micrometastasis to direct therapeutic lymph node dissection.
• Identification of patients who may benefit from adjuvant Interferon alpha-2b treatment.
• Definition of homogeneous patient populations for clinical trials.

SLNB is a requirement for most recently designed clinical trials, but even if a patient has no interest in entering a clinical trial, the first three benefits are sufficiently compelling to recommend SLNB. These three will be discussed further.

Accurate staging-prognosis

In 1999, Gershenwald published the results of a multicenter study which showed SLNB-determined nodal status to be the most important predictor of survival in melanoma stage I and II patients. [9] The hazard ratio for survival with a positive SLNB was 6.53 as compared to 1.62 for tumor ulceration and 1.23 for tumor thickness. This level of prognostic information cannot be approximated even by combining other prognostic data concerning the primary tumor. The three-year disease specific survival for negative and positive SLNB patients was 96.8% and 69.9%, respectively. Approximately 20% of patients with tumor thickness 1.0 mm or 1.5 mm to 4.0 mm will have occult nodal disease as assessed either by SLNB or by later development of clinical nodal involvement. [9, 13,14] Further, 34.4% of those with tumors thicker than 4 mm had a positive SLNB. [9] But even these patients with thick tumors are not homogeneous. A highly significant difference in 3 year disease free survival of patients with thick melanomas has been shown between SLNB positive and negative patients (37% vs. 73%). [15] For patients with melanomas with thickness of 1 mm or greater, patients and physicians need to have this crucial information which allows assignment of such disparate prognoses. In patients with tumors thinner than 1 mm, but which exhibited ulceration or were Clark¹s level IV, a positive SLNB was identified in 4.7%. [9] Further investigation on the utility of SNLB in these patients is underway.

Currently there is no reliable way to non-invasively evaluate lymph node involvement for staging or prognosis. Positron emission tomography (PET) has been reported to identify melanoma metastases as small as 3 mm in diameter and has been used as an adjunct in staging. However, earlier this year Acland et al. reported upon a group of 50 melanoma patients who underwent both PET scanning and SLNB. [16] Fourteen of these patients (28%) had a positive SLNB and none of these were detected by the PET scans. Their conclusion is that SLNB is the only reliable way to identify regional nodal micrometastases.

Identification of patients for therapeutic lymph node dissection

The value of elective lymph node dissection (ENLD) has been long debated. Experienced surgeons have observed that a proportion of stage III (node positive) patients appear to be cured by lymphadenectomy . [12] In SLNB-positive patients with tumors thinner than 3 mm, one investigation found no additional positive nodes when complete lymphadenectomy was subsequently performed, though complete lymphadenectomy is recommended currently after positive SLNB. [17] In addition, the most recent analysis of prognostic factors in melanoma patients has shown a five fold difference in 5 year survival for defined subgroups of stage III patients. [18] In these patients, the lymph node tumor burden (microscopic vs. macroscopic) is the best predictor of prognosis. Hence, it would seem that removing involved nodes early before they become palpable would result in a more favorable outcome. [12] Nevertheless, three randomized trials showed no survival benefit for ELND. One must consider that in two of these, patients were not stratified for important prognostic factors. [14,19,20] In addition, of these two studies, one was made up in large part by women with melanomas of the lower extremity who are known to have a generally favorable prognosis. One of these had a patient population that was really too small to allow reliable data interpretation. [19] It is also important to note that nodal dissections in two of three were entirely undirected by lymphoscintigraphy to ensure that the correct basin was dissected. In the third of the studies (WHO #14), only patients entered into the later part of the study were given nodal dissections directed by lymphoscintigraphy. The patients in this study had truncal melanomas which may exhibit an unpredictable drainage pattern in up to 32%. [21] Therefore it is entirely likely that in many of these patients, the wrong nodal basin was dissected. Balch has critiqued these studies in detail. [22] Still, in the third study, though the overall benefit of ENLD was not significant when all patients with tumors thicker than 1.5 mm were considered, the benefit was very significant when only those patients who actually had nodal metastases were considered. [23] The five year survival rate was 48.2% in patients who had immediate (ENLD) showing occult metastases versus 26.6% in those in whom node dissection was delayed until the appearance of overt regional metastases. The possible crux of the problem with showing increased survival after ELND, is that, as mentioned above, only about 20% of patients with intermediate thickness melanoma have subclinical nodal metastases. [9,13,14] Hence, approximately 80% could not possibly benefit from ENLD. [12] In spite of this, the 10 year survival results in the fourth randomized ELND trial, the Intergroup Melanoma Surgical Trial, for tumors of intermediate thickness (1 mm to 4 mm) still showed significant reductions in the mortality rates for patients with non-ulcerated tumors, tumors with thickness between 1 and 2 mm, and limb tumors of 30%, 30% and 27%, respectively. [14] These combined findings certainly justify Cascinelli's conclusion that SLNB could become the tool for identifying patients with occult nodal metastases who could derive survival benefit from therapeutic node dissection. [23] Final proof of survival benefit or lack thereof will await the completion of the Multicenter Selective Lymphadenectomy Trial (MSLT) headed by Dr. Donald Morton.

Identification of patients for adjuvant treatment with Interferon alfa-2b

High dose Interferon alfa-2b was approved in 1996 by the U.S. Food and Drug Administration for adjuvant therapy in melanoma patients with thick tumors (greater than 4 mm) or with stage III (nodal) disease. The approval was based on the results of the Eastern Cooperative Oncology Group (ECOG) trial E1684. [24] Both the relapse-free survival (RFS) and the overall survival (OS) were significantly improved compared to those seen in patients who did not receive this treatment. The estimated 5 year survival was 46% with high dose interferon alfa-2b versus 37% with observation only. The follow up study, E1690, caused some confusion. Though RFS was still significantly improved with treatment, the study failed to demonstrate benefit in overall survival. [25] Interestingly, the OS for the interferon arm was comparable to that in the original trial, but the observation arm fared much better than in E1684. Kirkwood postulated that this was a result of the cross-over design of the second study. [26] Patients who were originally in the observation arm often later received Interferon alfa-2b after relapse was noted. Significant difficulty with interpretation of either of these studies stems from the fact that SLNB was not widely accepted and many of the patients with thick melanomas did not undergo nodal staging. Furthermore, these patient populations were different and were not stratified with respect to prognostic factors such as ulceration and number of positive nodes which are now known to be important. The most recent high dose interferon trial (E1694), in which high dose Interferon alfa-2b therapy was compared to treatment with the ganglioside, GM2 vaccine (GMK), included more thorough stratification criteria. The highly significant benefit in both RFS and OS of high dose interferon over GMK forced closure of the study at a median follow-up of 16 months. [26] Analysis of the data indicated a 52% increase in the hazard of death for the GMK-treated patients. Though there is significant morbidity associated with high dose Interferon alfa-2b and some uncertainty as to the magnitude of the overall benefit, a recent multidisciplinary consensus panel utilizing the RAND/UCLA Appropriateness Method judged this therapy to be appropriate for patients with regional nodal and/or in-transit metastasis and for node-negative patients with thick primary melanomas (>4mm). [27] Appropriate staging with SNLB allows melanoma patients to have this option as well as options for a variety of adjuvants and vaccines currently under investigation.

In summary, the reasons for recommending SLNB have become compelling. This minimally invasive and highly accurate procedure allows appropriate regional nodal staging and is the most important prognostic factor in determining survival. Early detection of nodal micrometastases allows prompt therapeutic lymph node dissection which not only provides local control, but may enhance survival. Additionally, SLNB provides identification of patients who are eligible for Interferon alfa-2b adjuvant therapy. In addition, the information that the study provides is so important to stratification of patients for clinical trials that without it they would not be eligible for inclusion in most, even if they desired. Our melanoma patients deserve the benefits SLNB can provide.

Author's note: The updated version of the American Joint Committee on Cancer Staging System for cutaneous melanoma has been published. [28]

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