Originally published as JCO Early Release 10.1200/JCO.2008.19.5586 on November 17 2008

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In Reply:

Jeffrey E. Gershenwald, Robert H. I. Andtbacka, Merrick I. Ross

Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX

We appreciate the interest by van Akkooi et al in our study¹ and the opportunity to respond to their correspondence by addressing the questions raised. Among our large cohort of patients who had at least one histologically positive sentinel lymph node (SLN), we used multiple measures of SLN microscopic tumor burden to comprehensively assess in both univariate and multivariate models patients who may be at low as well as high risk of having non-SLN involvement in their complete therapeutic lymph node dissection (cTLND) specimen. SLN tumor burden was assessed by the diameter of the largest SLN metastatic focus, SLN tumor square area, the number of SLN metastatic foci, the microanatomic location of SLN metastasis (subcapsular, intramedullary, or both), and the presence or absence of microscopic extracapsular extension. Tumor square area was calculated as the sum of the cross-sectional products of all SLN deposits. While all aforementioned measures of tumor burden were included in the multivariate analysis and found to be independent predictors of non-SLN involvement, the largest metastatic focus was chosen for our working model based on the potential for easy widespread applicability and its association with the highest odds ratio among the various measures of tumor burden examined.

We agree with van Akkooi et al that tumor square area is challenging to accurately measure (as has been noted by others)²; these data were presented as part of a comprehensive analysis of predicting non-SLN involvement using multiple measures of tumor burden. In fact, we used recursive partitioning methodologies to identify multiple cutoff points for each measure of SLN microscopic tumor burden. While van Akkooi et al have employed single cutoff point univariate approaches (eg, 0.1 or 0.2 mm) to interrogate this important clinical issue, our analysis provides a comprehensive range of SLN tumor burden thresholds that facilitate identification of patients not only with low-risk of harboring non-SLN involvement but also those patients at significant risk of non-SLN involvement (ie, up to 50%), and provides the melanoma community with data to further elucidate the significant heterogeneity of non-SLN involvement among patients harboring SLN metastases. While these lower cutoff points may be potentially useful in helping to define those patients at lowest risk for harboring non-SLN metastases, it is also potentially limiting; the multivariate modeling we report comprehensively addresses these important questions.

van Akkooi et al provide a table that summarizes, albeit in a distilled format, the results of select studies in which SLN microscopic tumor burden was assessed in melanoma patients to determine its association with risk of non-SLN involvement in the cTLND specimen and alternatively, in some studies, survival. However, the extremely limited annotation of the data in the table and, in particular, its inclusion of survival end points that were not at all a theme of our manuscript, prohibit comment; the table is at significant risk of misinterpretation and is therefore not appropriate to discuss further in this forum.

A decision to not perform cTLND at this time should be made cautiously. Predictions regarding non-SLN involvement are based almost exclusively on routine evaluation of the cTLND specimen and may therefore underestimate the incidence of clinically relevant microscopic non-SLN disease. Before elimination of cTLND can be advocated in patients with limited melanoma micrometastasis, prospective clinical trials designed to assess the long-term safety of omitting formal cTLND with respect to survival and locoregional control in low-risk groups are needed. The ongoing Multicenter Selective Lymphadenectomy Trial II,³ which compares cTLND with close observation with sonography and clinical examination for patients with a positive SLN, should provide valuable information about which patients might be spared a cTLND.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

NOTES

published online ahead of print at www.jco.org on November 17, 2008.

REFERENCES

1. Gershenwald JE, Andtbacka RH, Prieto VG, et al: Microscopic tumor burden in sentinel lymph nodes predicts synchronous nonsentinel lymph node involvement in patients with melanoma. J Clin Oncol 26:4296-4303, 2008[Abstract/Free Full Text]

2. Scolyer RA, Murali R, Satzger I, et al: The detection and significance of melanoma micrometastases in sentinel nodes. Surg Oncol 17:165-174, 2008[CrossRef][Medline]

3. Morton DL: Sentinel node mapping and an International Sentinel Node Society: Current issues and future directions. Ann Surg Oncol 11:137S-143S, 2004[Free Full Text]

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