Letter Regarding Editorial by Samuel Zagarella
American Journal of Dermatopathology, vol. 43, pp. 539–541
Abstract
To the Editor: The recent editorial from Zagarella1 regarding the utility of sentinel lymph node (SLN) biopsy in melanoma offers several unique opinions and perspectives. However, SLN biopsy is considered a part of the standard of care recommended in all national and professional association melanoma treatment guidelines, which in turn are based on extensive and systematic reviews of the literature regarding nodal staging. Given that there are numerous factors to consider for SLN biopsy, of which only a few are mentioned in the editorial, we felt it was important to have experts in the field provide additional views and commentary. The editorial discusses rival hypotheses of melanoma progression, which characterize lymph nodes as incubators or markers for metastasis. The reality of metastasis is undoubtedly more complex than can be accurately represented by a simple version of either model. Although it is an interesting topic, we do not feel it is directly clinically relevant and defer consideration to other forums. However, the editorial has 3 central clinical assertions that are much more immediately troubling: first, that SLN biopsy is not an important staging tool, second that SLN biopsy does not have therapeutic value, and third, that the availability of new adjuvant therapies is not a rationale for SLN staging. The inconsistency of these assertions with current recommended standard treatment suggests that a comparison of the data cited in the editorial with that which is available in the published literature would be useful. Regarding the staging utility of SLN biopsy, there are few things in medicine with a stronger evidence base. The editorial suggests SLN provides no staging value when tumor thickness is taken into account. Three sources are cited for this, one of which is a review with no primary data,2 one of which actually concludes the SLN status is necessary for optimal staging,3 and one that is a somewhat underpowered, single institution study.4 The last report actually finds a hazard ratio for SLN metastasis on multivariable analysis of 1.53, with a P-value of 0.067. By contrast, the published literature in support of a strong, independent prognostic value of the SLN status in staging is extensive. This includes data derived from innumerable large institutional and multicenter series examining thin,5–9 intermediate thickness and thick melanomas,8,10–20 multiple prospective clinical trials,21,22 and the analysis of over 43,000 patients with complete staging in the most recent update of the American Joint Commission on Cancer melanoma staging system.23 This new system does not discount primary tumor thickness, as is suggested in the editorial, but incorporates it into generating the Stage III substages. Importantly, the overwhelming preponderance of data that supports the use of SLN biopsy are not mentioned or addressed in the editorial. Regarding the therapeutic value of SLN biopsy, the editorial discounts the importance of disease-free survival as an endpoint, suggesting that in the first Multicenter Selective Lymphadenectomy Trial (MSLT-I) it was a post-randomization subgroup analysis. It was not. In fact, it was the first prespecified secondary endpoint of the study, was considered in the entire trial population and demonstrated a reduction in overall recurrence by about a quarter.22 Although nodal recurrences in the control arm could be treated with delayed surgery in many cases, such delayed surgery was accompanied by a greater risk of postoperative morbidity in terms of lymphedema.24 We have now found, through MSLT-II that about 3 quarters of patients with nodal metastases can have all of that disease eradicated with the SLN biopsy alone and never require completion dissection.25 Thus, most patients with nodal metastases achieve durable regional disease control after an outpatient lymph node biopsy procedure. The therapeutic value of achieving regional disease control by such a minimally invasive procedure should not be underestimated and should be accurately reflected in the editorial. The editorial is both incomplete and factually incorrect regarding adjuvant therapy. The piece conflates the 2 categories of revolutionary new medical therapies (immune vs. targeted) and discounts the possibility of overall survival benefit. However, data have already been reported from 3 independent adjuvant trials that included stage IIIA melanoma, all of which showed a benefit from treatment.26–28 The piece also seems to imply that all SLN positive melanomas are stage IIIA, when in fact they can be any of the stage III substages. It states without comment that the COMBI-AD trial did not show a survival benefit that “reached the nominated significance level.” However, that analysis showed a hazard ratio of 0.57 with a P-value of 0.0006, which is important qualifying information regarding this interim analysis that probably should have been included in any editorial comment.27 The editorial states that trial was heavily skewed to unresectable patients. Unresectable patients were, in fact, excluded from the trial. Multiple other trials with demonstrated overall survival benefit including the EORTC 18071 study (ipilimumab vs. placebo)26 and E1609 (ipilimumab vs. interferon)29 and that head-to-head comparisons of CTLA-4 blockade to PD-1 blockade show the superiority of the latter30 are not acknowledged or discussed and represent concerning omissions. Finally, the EORTC 1325/Keynote 054 showed a 43% reduction in the risk of melanoma recurrence or death compared with placebo and included stage IIIA patients.28 Other errors in the editorial include misinterpretation of lymphedema data from MSLT-II. The 6% rate that is quoted includes patients who underwent delayed complete lymph node dissection in the observation arm.25 Ultrasound is suggested as an adequate replacement for SLN biopsy, but analysis of the MSLT-II screening phase demonstrates sensitivity of only 6.6% in that setting.31 In addition, the sensitivity and specificity of SLN biopsy are miscalculated in the editorial, based on an assertion that if a patient does not die of melanoma, a metastasis found in a SLN is a false-positive.32 This definition of false-positive is incorrect, as a test that diagnoses cancer is not invalidated if that disease is subsequently cured. SLN biopsy is not appropriate for every patient, and we and others continue to work to refine selection criteria. Similarly, it is likely that adjuvant therapy will be indicated for some node-negative patients but demonstrating that benefit requires accurate staging, which is impossible without SLN biopsy. To continue the remarkable progress in treatment that we have enjoyed in the current era, we need to accept the things we now know to be true, honestly take stock of the things we do not yet understand, and continue to produce primary data through research that advances our patients' best interests.
Authors 18
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Mark B. Faries corresponding
Cedars-Sinai Medical Center · Angeles Clinic and Research Institute
Affiliation as printed
The Angeles Clinic and Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
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Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale"
Affiliation as printed
Unit of Melanoma, Istituto Nazionale Tumori IRCCS Fondazione Pascale, Napoli, Italy
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The Netherlands Cancer Institute
Affiliation as printed
Netherlands Cancer Institute, Amsterdam, Netherlands
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University of California, Los Angeles
Affiliation as printed
University of California Los Angeles, Los Angeles, CA
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Affiliation as printed
Winship Cancer Institute of Emory University School of Medicine, Atlanta, GA
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Affiliation as printed
Peter MacCallum Cancer Centre, Melbourne, Australia
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Leiden University Medical Center
Affiliation as printed
Division of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
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Cedars-Sinai Medical Center · Angeles Clinic and Research Institute
Affiliation as printed
Cutaneous Oncology Program, The Angeles Clinic and Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA
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Oregon Health & Science University
Affiliation as printed
Oregon Health Science University, Portland, OR
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Hospital of the University of Pennsylvania
Affiliation as printed
Hospital of the University of Pennsylvania, Philadelphia, PA
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California Pacific Medical Center
Affiliation as printed
California Pacific Medical Center, San Francisco, CA
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Oregon Health & Science University
Affiliation as printed
Oregon Health Science University, Portland, OR
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Marc D. Moncrieff corresponding
Norfolk and Norwich University Hospital
Affiliation as printed
Norfolk and Norwich University Hospital, Norwich, United Kingdom
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The Netherlands Cancer Institute
Affiliation as printed
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
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Policlinico San Matteo Fondazione
Affiliation as printed
Fondazione IRCCS Policlinico San Matteo, Divisione di Dermatologia, Pavia, Italy
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The Netherlands Cancer Institute
Affiliation as printed
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands
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Dartmouth–Hitchcock Medical Center
Affiliation as printed
Department of Surgery, Professor of Surgery, Geisel School of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH
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Jonathan S. Zager corresponding
University of South Florida · Moffitt Cancer Center
Affiliation as printed
Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL
Department of Oncological Sciences, University of South Florida Morsani School of Medicine, Tampa, FL
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