SENTINEL LYMPH node (SLN) biopsy has become

COMMENTARY Sentinel Lymph Node Biopsy for Melanoma: Controversy Despite Widespread Agreement By Kelly M. McMasters, Douglas S. Reintgen, Merrick I. Ross, Jeffrey E. Gershenwald, Michael J. Edwards, Arthur Sober, Neil Fenske, Frank Glass, Charles M. Balch, and Daniel G. Coit Abstract: Although sentinel lymph node (SLN) biopsy for melanoma has been adopted throughout the United States and abroad as a standard method of determining the pathologic status of the regional lymph nodes, some controversy still exists regarding the validity and utility of this procedure. SLN biopsy is a minimally invasive procedure, performed on an outpatient basis at the time of wide local excision of the melanoma, with little morbidity. Numerous studies have documented the accuracy of this procedure for identifying nodal metastases. There are four major reasons to perform SLN biopsy. First, SLN biopsy improves the accuracy of staging and provides valuable SENTINEL LYMPH node (SLN) biopsy has become widely accepted as a minimally invasive method of staging the regional lymph nodes for melanoma. Recently, it has been suggested that this procedure is highly controversial 1,2 ; however, this is a controversy about which there is widespread agreement. SLN biopsy has been adopted as the standard method of nodal staging for melanoma at nearly every major medical center in the United States. Furthermore, the World Health Organization has issued a statement indicating that SLN biopsy should be considered standard of care for patients with melanoma. 3 We believe that there are four major reasons to perform SLN biopsy. All of them involve the critically important issue of accurate staging. First, SLN biopsy improves the accuracy of staging and provides valuable prognostic information for patients and physicians to guide subsequent treatment decisions. Second, SLN biopsy facilitates early therapeutic lymph node dissection for those patients with nodal metastases. Third, SLN biopsy identifies patients who are candidates for adjuvant therapy with interferon alfa-2b. Fourth, SLN biopsy identifies homogeneous patient populations for entry onto clinical trials of novel adjuvant therapy agents. PROGNOSTIC INFORMATION FOR PATIENTS AND PHYSICIANS Morton et al 4 first demonstrated the feasibility and accuracy of SLN biopsy for nodal staging of patients with melanoma. The low false-negative rate of SLN biopsy for melanoma has been confirmed in additional studies from other institutions, not only by comparing SLN biopsy prognostic information for patients and physicians to guide subsequent treatment decisions. Second, SLN biopsy facilitates early therapeutic lymph node dissection for those patients with nodal metastases. Third, SLN biopsy identifies patients who are candidates for adjuvant therapy with interferon alfa-2b. Fourth, SLN biopsy identifies homogeneous patient populations for entry onto clinical trials of novel adjuvant therapy agents. Overall, the benefit of accurate nodal staging obtained by SLN biopsy far outweighs the risks and has important implications for patient management. J Clin Oncol 19:2851-2855. 2001 by American Society of Clinical Oncology. results to completion lymphadenectomy specimens, but also by long-term follow-up to determine recurrence in undissected nodal basins after a negative SLN biopsy. 5-14 SLN status is the most important predictor of survival of patients with melanoma. In fact, in the report by Gershenwald et al, 14 the hazard ratio for survival associated with a positive SLN was 6.53, much greater than that for any other prognostic factor (Table 1). No combination of prognostic factors of the primary tumor can provide this prognostic information. This nodal staging information serves two purposes. First, it identifies a population of patients with a relatively favorable prognosis for which adjuvant therapy may not be necessary. Second, it identifies a high-risk population of patients who may benefit from additional From the Department of Surgery, University of Louisville, James Graham Brown Cancer Center; Center for Advanced Surgical Technologies at Norton Healthcare; and the Alliant Community Trust Fund, Louisville, KY; University of South Florida, Moffitt Cancer Center, Tampa, FL; The American Society of Clinical Oncology, Alexandria, VA; The Johns Hopkins University, Baltimore, MD; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Harvard University, Boston, MA; and Memorial Sloan-Kettering Center, New York, NY. Submitted November 15, 2000; accepted March 5, 2001. Address reprint requests to Kelly M. McMasters, MD, PhD, University of Louisville-James Graham Brown Cancer Center, 529 S Jackson St, Louisville, KY 40202; email: kelly.mcmasters@ nortonhealthcare.org. 2001 by American Society of Clinical Oncology. 0732-183X/01/1911-2851 Journal of Clinical Oncology, Vol 19, No 11 (June 1), 2001: pp 2851-2855 2851

2852 Table 1. Prognostic Factors Relative to Disease-Specific Survival* Disease-Specific Survival Prognostic Factor Hazard Ratio 95% CI P Age 1.01 0.98-1.01.57 Sex 1.11 0.45-1.82.78 Tumor thickness 1.23 1.10-1.38.0004 Clark level III 2.32 1.03-5.23.04 Axial location 1.72 0.85-3.45.13 Ulceration 1.62 0.85-3.08.14 SLN status 6.53 3.39-12.58.00001 *Table adapted with permission from Gershenwald et al. 14 therapy. This information is immediately worthwhile in guiding patients to make appropriate choices regarding additional treatment and has important implications for patient follow-up. It has been suggested that, unless SLN biopsy can be shown to improve overall survival for patients with melanoma, it is not valuable. 1,2 An ongoing study, the Multicenter Selective Lymphadenectomy Trial (MSLT) by Morton et al, 15 will address the impact of SLN on survival. While we await the results of this study, we believe that even if SLN biopsy in and of itself does not improve survival, it has inherent value and should be continued until or unless another less invasive staging test with similar predictive value is developed. SLN biopsy is a diagnostic staging test. We do not impose the burden of therapeutic efficacy on other diagnostic staging tests in oncology, including computed tomography scan, magnetic resonance imaging, positron emission tomography scan, or for that matter, axillary lymph node dissection for breast cancer. SLN biopsy is minimally invasive, is performed at the same time as the wide local excision of the primary melanoma, and has been shown to be cost effective and less morbid compared with elective lymph node dissection. 16,17 That is not to say that this test should be over-utilized. SLN biopsy is appropriate for patients with a significant risk of nodal metastasis, including those with melanomas 1.0 mm Breslow thickness or greater. 4-15 SLN biopsy for melanomas less than 1.0 mm Breslow thickness with poor prognostic features (eg, ulceration and Clark s level IV) may be appropriate and requires further investigation. IDENTIFICATION OF PATIENTS WHO MAY BENEFIT FROM EARLY THERAPEUTIC LYMPH NODE DISSECTION Before the advent of SLN biopsy, the pathologic nodal status of patients with melanoma was known only after elective lymph node dissection. However, four prospective randomized trials have failed to demonstrate an overall survival benefit for patients who undergo elective lymph node dissection. 18-22 This has led to the common misconception that lymphadenectomy offers no therapeutic benefit for patients with melanoma. However, the important distinction between elective and therapeutic lymph node dissection is often overlooked or obscured. Lymph node dissection is curative for some patients with nodal metastases. A substantial and reproducible fraction of stage III melanoma patients is cured by lymphadenectomy, and this was true long before any adjuvant therapy was available. Furthermore, in patients with positive nodes, tumor burden as measured by the number of positive nodes has been consistently the best predictor of outcome. Therefore, it makes intuitive sense that early removal of lymph nodes should be better than waiting until the patient develops multiple positive nodes with bulky, palpable disease. Why, then, has there been no survival benefit in the trials of elective lymph node dissection? The answer has to do with the fact that with elective lymph node dissection, the majority of patients do not have cancer in the lymph nodes. As an example, consider the Intergroup Melanoma Trial of elective lymph node dissection. In that study, patients with intermediate thickness melanoma were randomized to observation versus elective lymph node dissection. 21,22 The hypothesis was that early lymph node dissection while the patients had subclinical nodal metastasis would improve survival compared with waiting until the patients developed palpable nodal metastases. Overall, 20% of the patients in the observation arm developed positive lymph nodes. Therefore, 80% of the patients had no potential or real therapeutic benefit from early lymph node dissection. Let s consider that elective lymph node dissection imparts a survival advantage similar to other forms of adjuvant therapy, approximately 25% to 50% reduction in the relative risk of death. This is similar to the magnitude of benefit of adjuvant therapy in breast cancer, colon cancer, and so on. Because elective lymph node dissection could only potentially benefit the patients who have cancer in the lymph nodes, at best one quarter to one half of the 20% of patients with positive nodes, or 5% to 10% of patients overall, could be expected to be cured as a result of elective lymph node dissection. Any survival benefit in favor of elective lymph node dissection in randomized trials is diluted by the majority of patients with negative nodes. None of the prospective trials had adequate statistical power to detect this small benefit of elective lymph node dissection in the overall patient population studied. In fact, the 10-year follow-up results that have recently been published for the Intergroup Melanoma Trial demonstrate a 4% overall survival advantage in favor of elective lymph node dissection, although this did not reach statistical significance. 21,22 However, certain prospectively stratified

2853 Table 2. Subgroup Analysis of the Intergroup Melanoma Surgical Trial* Subgroup 10-Year Survival (%) P Reduction in Risk of Death (%) Absolute Difference Relative Difference Nonulcerated melanoma Nodal observation 77 ELND 84.03 7 30 Breslow thickness 1.0 to 2.0 mm Nodal observation 80 ELND 86.03 6 30 Extremity melanoma Nodal observation 78 ELND 84.05 6 27 All patients Nodal observation 73 ELND 77.12 4 15 Abbreviation: ELND, elective lymph node dissection. *Table adapted with permission from Balch et al. 21 subgroups of patients, most notably those with nonulcerated melanomas, did benefit from elective lymph node dissection. The magnitude of the benefit in these subgroups of patients was equivalent to that which we would expect based on the above calculations (Table 2). Although retrospective subgroup analysis of clinical trials is always subject to criticism, it is important to point out that patients in this study were prospectively stratified by tumor thickness, anatomic site, and ulceration, and these analyses were planned during the design of the trial. Another crucial piece of evidence regarding the value of early lymph node dissection versus delayed dissection for palpable disease is derived from the World Health Organization Programme 14 Trial of elective lymph node dissection for patients with truncal melanomas. 20 Overall, there was no difference in survival for the two randomized arms (nodal observation v elective lymph node dissection). However, when the survival of the patients with positive lymph nodes, either detected histologically at elective lymph node dissection or by palpation in the observation arm is evaluated, quite a different picture emerges. The overall survival of patients with nodal micrometastases removed at elective lymph node dissection was significantly greater than that of patients who underwent lymphadenectomy for palpable lymph nodes in the observation arm (48% v 27% 5-year survival, respectively, P.04). 20 This difference is significant both statistically and, more important, clinically, despite the relatively small numbers of patients in each subgroup. Therefore, if occult micrometastatic disease can be accurately identified, the data from the Intergroup Melanoma Trial and the World Health Organization Programme 14 trial suggest that early therapeutic lymph node dissection may improve survival. Certainly there is no evidence that patients who undergo delayed lymph node dissection at the time of palpable recurrence have a better prognosis than those who undergo lymphadenectomy when they have microscopic nodal metastases. Therefore, the available evidence suggests that early therapeutic lymph node dissection for microscopic nodal disease may be superior to delayed lymph node dissection once the patients develop palpable nodal disease. 23,24 The problem with elective lymph node dissection is that the procedure is applied indiscriminately to all patients who have clinically negative lymph nodes. Therefore, the majority of patients (without nodal metastases) are subjected to the morbidity of lymphadenectomy without any therapeutic benefit. The ideal situation would be to identify the patients with positive lymph nodes for therapeutic lymph node dissection and spare the rest the need for complete lymph node dissection. This is the advantage of SLN biopsy. When SLN biopsy is performed for patients with melanomas 1.0 mm Breslow thickness, 20% or more will be found to have positive SLNs when careful pathologic analysis is performed. 4-15 Therefore, at least 20% of patients are identified as candidates for additional therapy, which includes therapeutic lymph node dissection. Importantly, patients harboring occult metastatic disease are offered an early therapeutic lymph node dissection, not an elective lymph node dissection. The 80% of patients who have negative SLN are spared the need for lymph node dissection and have undergone a procedure that amounts to little more than a lymph node biopsy performed on an outpatient basis at the time of the wide local excision of the melanoma. IDENTIFICATION OF PATIENTS WHO ARE CANDIDATES FOR ADJUVANT INTERFERON ALFA-2B THERAPY Interferon alfa-2b therapy has been approved by the Food and Drug Administration for adjuvant therapy of high-risk melanoma patients. The vast majority of these high-risk melanoma patients are those with positive lymph nodes. This indication for interferon alfa-2b is based on the the Eastern Cooperative Oncology Group Trial E1684, which demonstrated a disease-free and overall survival benefit for treatment with interferon. 25 However, a follow-up study, E1690, confirmed a disease-free survival benefit, but did not demonstrate an overall survival benefit for patients treated with high-dose interferon alfa-2b. 26 This has generated some controversy regarding the overall benefit of interferon alfa-2b therapy for adjuvant treatment of high-risk melanoma. Part of the explanation for a lack of an overall

2854 survival benefit in the E1690 study for high-dose interferon is related to the fact that the observation group had substantially better overall survival than the patients in the observation group in the E1684 study. However, in the E1690 study there was somewhat of a cross-over effect; patients in the observation group in the E1690 study were more likely to receive interferon alfa-2b and other salvage therapies than patients in the interferon-treated group (J. Kirkwood, unpublished data). How can the results of E1684 and E1690 be reconciled? Both studies concluded that high-dose interferon imparts a significant disease-free survival advantage; however, an overall survival advantage was demonstrated only in E1684. Therefore, it is clear that high-dose interferon alfa-2b has activity against melanoma. The advantages in terms of disease-free survival are not disputed. The impact on overall survival remains to be clearly defined. To add further support for adjuvant high-dose interferon alfa-2b therapy, the results of the Eastern Cooperative Oncology Group study E1694 have been presented recently (J. Kirkwood, unpublished data). In this study, 774 high-risk melanoma patients were randomized to receive adjuvant high-dose interferon alfa-2b versus a GM2 ganglioside vaccine. The study was stopped early by the data-monitoring committee based on a planned interim analysis that showed superiority of interferon alfa-2b in terms of both disease-free and overall survival. This study adds important new evidence confirming a beneficial impact of high-dose interferon alfa-2b in melanoma. The goal that lies ahead is to identify the patient populations that benefit most from this therapy. IDENTIFICATION OF HOMOGENEOUS PATIENT POPULATIONS FOR CLINICAL TRIALS OF ADJUVANT THERAPY A significant concern regarding the E1684 and E1690 studies is that very heterogeneous patient populations were studied. The vast majority of patients had palpable nodal disease either synchronous with the primary tumor or recurrent at some time after the primary tumor had been previously excised. Very few patients (12% in E1684% and 11% in E1690) had microscopically positive lymph nodes. These studies were performed before the wide-spread acceptance of SLN biopsy for nodal staging. Whereas, in E1684, pathologic nodal staging by elective lymph node dissection was required, only a few patients in the E1690 study who were staged as T4N0 actually underwent nodal staging with SLN biopsy. As SLN biopsy has become a standard practice in most major medical centers throughout the country, few patients with bulky palpable nodal disease are seen any longer, suggesting that the spectrum of stage III melanoma has changed. The vast majority of stage III patients are now represented by those patients who have microscopically positive nodes detected at SLN biopsy, most frequently a single positive sentinel node. Therefore, the patients with stage III disease currently identified by SLN biopsy represent a significantly different population than that studied in E1684 and E1690. The heterogeneity of the patients entered onto these two studies certainly confounds the interpretation of the results. Therefore, one of the major goals of SLN biopsy is to identify homogeneously staged patient populations for entry onto clinical trials. Only by entry of patients with similar prognoses will meaningful interpretation of adjuvant therapy results be possible. As a result of a major effort on the part of the American Joint Committee on Cancer Melanoma Task Force, major changes in the staging system for melanoma have been proposed. 27,28 These new changes incorporate several important independent prognostic factors that were not taken into account in these two trials. For instance, the number of positive lymph nodes was not a stratification criterion in E1684, although it is now known to be an important prognostic factor. 27,28 Furthermore, it is now known that tumor ulceration is such an important independent prognostic factor that it may be used to upstage patients in each T category of the new American Joint Committee on Cancer staging system. 27,28 Not only is ulceration an important prognostic factor for patients with node-negative melanoma, but it retains its prognostic significance for patients with positive lymph nodes. Therefore, a relatively minor imbalance in ulceration between treatment arms could result in significant differences in survival. Ulceration was not a stratification factor in either E1684 or E1690. This underscores the importance of stratifying patients in clinical trials not only by Breslow thickness, but also by the number of positive lymph nodes and the presence of ulceration. In conclusion, SLN biopsy is a diagnostic staging test to determine the pathologic status of the regional lymph nodes and accurately identifies the presence of nodal metastasis. The presence of a positive SLN is the single most important prognostic factor in determining the likelihood of survival. As such, patients should be offered the option of SLN biopsy, when appropriate, to determine the status of the regional lymph nodes. This provides the opportunity for early therapeutic lymph node dissection, for which there is evidence of benefit in node-positive patients. Furthermore, those patients identified with positive SLNs are then eligible for adjuvant therapy with interferon alfa-2b, which is still the only Food and Drug Administration approved adjuvant therapy for melanoma and is consid-

2855 ered by many to be the standard of care and the reference treatment against which all other adjuvant therapies should be compared. The value of SLN biopsy for identifying homogeneous patient populations for entry into clinical trials of novel adjuvant agents cannot be underestimated. Only by identifying populations of patients with similar prognosis will we be likely to develop more effective adjuvant therapies. 1. Otley CC, Zitelli JA: Review of sentinel lymph node biopsy and systemic interferon for melanoma: Promising but investigational modalities. Dermatol Surg 2000 26:177-180 2. Thomas JM, Patocskai EJ: The argument against sentinel node biopsy for malignant melanoma: Its use should be confined to patients in clinical trials. BMJ 321:3-4, 2000 3. WHO declares lymphatic mapping to be the standard of care for melanoma. Oncology 13:288, 1999 4. Morton DL, Wen DR, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392-399, 1992 5. Morton DL, Wen DR, Foshag LJ, et al: Intraoperative lymphatic mapping and selective cervical lymphadenectomy for early-stage melanoma of the head and neck. J Clin Oncol 11:1751-1756, 1993 6. Ross MI, Reintgen D, Balch CM: Selective lymphadenectomy: Emerging role for lymphatic mapping and sentinel node biopsy in the management of early stage melanoma. Semin Surg Oncol 9:219-223, 1993 7. Reintgen D, Cruse CW, Wells K, et al: The orderly progression of melanoma nodal metastases. Ann Surg 220:759-767, 1994 8. Miliotes G, Albertini J, Berman C, et al: The tumor biology of melanoma nodal metastases. Am Surg 62:81-88, 1996 9. Gershenwald JE, Colome MI, Lee JE, et al: Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol 16:2253-2260, 1998 10. Albertini, JJ, Cruse CW, Rapaport D, et al: Intraoperative radiolymphoscintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg 223:217-224, 1996 11. Essner R, Bostick PJ, Glass EC, et al: Standardized probedirected sentinel node dissection in melanoma. Surgery 127:26-31 2000 12. Gershenwald JE, Tseng CH, Thompson W, et al: Improved sentinel lymph node localization in patients with primary melanoma with the use of radiolabeled colloid. Surgery 124:203-210, 1998 13. Essner R, Conforti A, Kelley MC, et al: Efficacy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as a therapeutic procedure for early-stage melanoma. Ann Surg Oncol 6:442-449, 1999 14. Gershenwald JE, Thompson W, Mansfield PF, et al: Multiinstitutional melanoma lymphatic mapping experience: The prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17:976-983, 1999 15. 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Sim FH, Taylor WF, Ivins JC, et al: A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Cancer 41:948-956, 1978 20. Cascinelli N, Morabito A, Santinami M, et al: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: A randomized trial WHO Melanoma Programme. Lancet 351:793-796, 1998 21. Balch CM, Soong S-J, Bartolucci AA, et al: Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 224:255-266, 1996 22. Balch CM, Soong S, Ross MI, 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): Intergroup Melanoma Surgical Trial. Ann Surg Oncol 2000 7:87-97 23. Reintgen DS: Emerging evidence for a survival benefit associated with regional lymph node dissection for melanoma. Ann Surg Oncol 7:75-76, 2000 24. Reintgen DS: Regional nodal surgery for melanoma impacts recurrence rates and survival. Ann Surg Oncol 7:80-81, 2000 25. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14:7-17, 1996 26. Kirkwood JM, Ibrahim J, Sondak V, et al: High- and low-dose interferon alpha-2b in high-risk melanoma: First analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18:2444-2458, 2000 27. Buzaid AC, Ross MI, Balch CM, et al: Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system. J Clin Oncol 15:1039-1051, 1997 28. Balch CM, Buzaid AC, Atkins MB, et al: A new American Joint Committee on Cancer staging system for cutaneous melanoma. Cancer 88:1484-1491, 2000