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Time to Re-Evaluate Sentinel Node Biopsy in Melanoma Post-Multicenter Selective Lymphadenectomy Trial

Royal Marsden Hospital, London, United Kingdom

To the Editor:

A surgical procedure without a survival advantage may be untenable if it is associated with a serious iatrogenic risk. A recent article in the Journal of Clinical Oncology by Pawlik et al¹ refutes the observation made by several European authors that lymphadenectomy for melanoma in sentinel node (SN) –positive patients is associated with an increased incidence of in-transit metastasis (ITM)—a condition which itself is associated with an ominous prognosis.² The authors provide a comprehensive and accurate review of the European case, but conclude that any increased incidence of ITM is explained by the biology of melanoma and not by the consequences of performing lymphadenectomy while melanoma cells are still in-transit from the primary site to that lymph node basin. In other words, because SN-positive patients have a worse prognosis than SN-negative patients, this eminent multinational authorship explains that any increased incidence of ITM is permissible and indeed is to be expected. To some extent their argument is correct because increasing tumor thickness and ulceration are risk factors both for SN-positivity and for ITM. However, this does not entirely explain the magnitude of the risk. Our literature overview³ suggested that the incidence of ITM in SN-positive patients after lymphadenectomy may be greater than four times the incidence expected in patients undergoing wide local excision alone. In support of their argument, Pawlik et al¹ quote Dr Donald Morton’s oral presentation of the results of the Multicenter Selective Lymphadenectomy Trial (MSLT-1) in Los Angeles in December 2004 which showed that the incidence of ITM in the control and test arms were similar. In that presentation, Dr Morton also suggested a 16% overall survival advantage at five years for the test arm (SN-positive patients undergoing lymphadenectomy). That calculation was based on an invalid, selection of patients after random assignment. Following a statistical challenge, it was conceded that MSLT-1 showed no overall survival advantage (87% v 86% five-year survival, P = .4).

Whatever the truth about the incidence of ITM, there are other important and better defined disadvantages to the SN-biopsy procedure in melanoma. First, there is no overall survival advantage to early lymphadenectomy, and the claimed disease-free survival is an artifact. Inevitably, there will be fewer nodal recurrences in the test arm of MSLT-1 (the most common site of first recurrence in this cohort of patients) because all SN-positive patients were treated by lymphadenectomy at the outset. Therefore, the only way to estimate disease-free survival in MSLT-1 would be to exclude nodal recurrence from the analysis and to compare only the incidence of regional non-nodal and distant recurrences.

Second, the SN-biopsy procedure is championed as the best staging method for primary cutaneous melanoma, but how accurate is SN-status as a prognostic tool? We know that approximately 13% of SN-negative patients will experience a recurrence somewhere by 3 years after surgery.⁴ Of greater concern is the risk of prognostic false-positivity leading to unnecessary lymphadenectomy, a matter which is rarely discussed. One error in the SN biopsy theory is that all positive SNs would inevitably have progressed to overt nodal disease if lymphadenectomy had not been performed. There is now strong evidence that this is not the case and that some micrometastases in the SN (often clumps of cells in the peripheral sinuses) are destined either for destruction by host-immune processes or for dormancy. The evidence for this statement relates to the spectrum of prognosis relative to the tumor burden within the SN.^5-8 For example, Starz et al⁵ have suggested that only deposits greater than 1 mm are of adverse prognostic significance. Similarly, Spanknebel et al⁸ have shown that micrometastases identifiable only by immunohistochemistry may carry no adverse prognostic significance. Reverse-transcriptase polymerase chain reaction alone is likely to increase false-positivity further. Therefore, some tiny deposits of melanoma so avidly sought, may be prognostically irrelevant and lead to unnecessary lymphadenectomy and possibly to unnecessary adjuvant therapy. Another measure of prognostic false-positivity comes from nonrandomized studies comparing the survival of patients who are SN-positive and undergo early lymphadenectomy with the survival of patients following delayed lymphadenectomy for palpable nodal metastatic disease. Kretschmer et al⁹ reported a 12% survival advantage at 5 years for early lymphadenectomy while Morton et al in their matched pair analysis¹⁰ reported a survival advantage of 22%, 32%, and 37% at five, 10, and 15 years, respectively. How can these large survival advantages be reconciled with the lack of any survival advantage in the defining randomized trial (MSLT-1)? Prognostic false-positivity within the SN can be the only explanation.

Third, there is no evidence that adjuvant chemotherapy, immunotherapy, or biologic therapy can benefit SN-positive patients although knowledge of SN-status may be necessary in the future for entry onto studies of novel adjuvant therapies.

For these reasons the SN biopsy procedure cannot be considered as standard of care. Physicians have a responsibility to explain the meaning of SN-status to patients in its detailed entirety as well as the complexities of the arguments both for and against the procedure.

Author’s Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Pawlik TM, Ross MI, Thompson JF, et al: The risk of in-transit metastasis in patients with cutaneous melanoma undergoing sentinel lymph node biopsy. J Clin Oncol 23:4588-4590, 2005[Free Full Text]

2. 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[Abstract/Free Full Text]

3. Thomas JM, Clark MA: Selective lymphadenectomy in sentinel node-positive patients may increase the risk of local/in-transit recurrence in malignant melanoma. Eur J Surg Oncol 30:686-691, 2004[CrossRef][Medline]

4. Gershenwald JE, Thomson W, Mansfield PF, et al: Multi-institutional 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[Abstract/Free Full Text]

5. Starz H, Siedlecki K, Balda BR: Sentinel lymphonodectomy and S-classification: A successful strategy for better prediction and improvement of outcome of melanoma. Ann Surg Oncol 11:162S-168S, 2004 (suppl 3)[CrossRef][Medline]

6. Carlson GW, Murray DR, Lyles RH, et al: The amount of metastatic melanoma in a sentinel lymph node: Does it have prognostic significance? Ann Surg Oncol 10:575-581, 2003[CrossRef][Medline]

7. Ranieri JM, Wagner JD, Azuaje R, et al: Prognostic importance of lymph node tumor burden in melanoma patients staged by sentinel node biopsy. Ann Surg Oncol 9:975-981, 2002[CrossRef][Medline]

8. Spanknebel K, Coit DG, Bieligk SC, et al: Characterisation of micrometastastic disease in melanoma sentinel lymph nodes by enhanced pathology: Recommendations for standardizing pathologic analysis. Am J Surg Pathol 29:305-317, 2005[CrossRef][Medline]

9. Kretschmer L, Hilgers R, Mohrle M, et al: Patients with lymphatic metatasis of cutaneous malignant melanoma benefit from sentinel lymphonodectomy and early excision of their nodal disease. Eur J Cancer 40:212-218, 2004[CrossRef][Medline]

10. Morton DL, Hoon DS, Cochran AJ, et al: Lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: Therapeutic utility and implications of nodal microanatomy and molecular staging for improving the accuracy of detection of nodal micrometastases. Ann Surg 238:538-549, 2003[Medline]

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