In 2000, Reintgen, et al.,⁸³ in an article titled, "In support of sentinel node biopsy as a standard of care for patients with malignant melanoma," said this about the issue of END: "There is emerging evidence that at least in some groups of the melanoma population, such as those with intermediate thickness melanoma (tumor thickness between 1 and 4.0 mm), including an ELND [elective node dissection] in the primary surgical treatment may improve survival . . . In lieu [sic] of the evidence accumulating that ELND may provide a survival benefit, one can assume that the only patients whom ELND may possibly benefit are those with nodal metastases. With lymphatic mapping and sentinel lymph node biopsy, there is a less morbid method to judge nodal status. In this way the more radical surgery (complete lymph node dissection) can be applied in a selective fashion, only to those patients with a positive SLN." In support of their position, Reintgen and coauthors cited data supplied by the Intergroup Melanoma Trial under the direction of Balch and collaborators.³¹ In that report, however, there was no increase in survival overall; there was, however, some apparent advantage for certain sets of patients. That benefit accrued only to patients whose melanoma was not ulcerated, measured 1–2 mm in thickness, or arose on an extremity. There was no benefit if the melanoma were ulcerated, measured between 2 and 4.0 mm, or occurred on a trunk, head, or neck. That such extensive analysis of sets may result in incorrect inferences was acknowledged by Balch and his group in 1996 when they made this telling comment: "Third, subgroup analysis can yield false-positive conclusions." Furthermore, the results of the analysis of sets are in conflict, and it is not clear which one of those results, if any, should prevail in the final analysis. The authors attempt to resolve the conundrum by citing ulceration of a melanoma as the most important factor for selecting patients for END, but they did that without any effort at reasoned substantiation. Parenthetically, it is difficult to conceive of ulceration as an important gauge of prognosis when trauma, rather than the malignant neoplastic process itself, may be the sole cause of it.

Kirkwood,⁸⁴ in 1998, made this indicting comment: "Compared with node dissection [END], sentinel lymph-node mapping and selective lymphadenectomy directed by isotopic lymphoscintigraphy and blue-dye lymphography identify lymph-node metastases more precisely, with less surgical morbidity, with shorter hospital stays, and more cheaply, so it is increasingly being adopted despite unproven therapeutic value."

Otley,⁸⁵ in 2000, wrote insightfully about the matter in these words: " . . . without definite evidence of efficacy from elective lymphadenectomy, the ability of sentinel lymph node biopsy to identify candidates for effective adjuvant surgical therapy remains unfounded." Kirkwood and Otley are correct; all randomized trials that deal with the subject of END have failed to demonstrate a whit of benefit from the procedure.

Also in 2001, Coldiron⁸⁶ shared the view that END should not be recommended as treatment for patients with melanoma and this is how he expressed it: "At best, the benefit of ELND is arguable, and is certainly a weak foundation on which to build a new approach to the treatment of melanoma."

In conclusion, there is no evidence whatsoever, not a scintilla, that lends credence to the proposition that END should be the standard of care for any patient with melanoma; in fact, it should not be used routinely even in patients who have had a SNB that produced a SN replete with cells of melanoma. END, and any modification of it, must be abandoned now and should be referred to only in historical context as a relic, a useless technique that, from the outset, was illogical and, therefore, not only an exercise in futility, but one that actually was harmful to some patients.

Reintgen, et al.⁸³ confronted the matter of whether any decision about treatment should be predicated on information gained from SNB. They stated their opinion thus: "Adjuvant therapy with interferon alfa-2b has been shown to provide a survival benefit to those patients with stage 3 melanoma [nodal metastases] . . . This trial [ECOG 1684] was the basis of the FDA approval of the drug as the first effective adjuvant therapy for 'high risk for recurrence' melanoma patient in December, 1995." Despite this claim by Reintgen and collaborators, no adjuvant medical therapy, including interferon alfa-2b, has been proven to be effective for ridding a patient of metastases of melanoma. Moreover, interferon at high doses is accompanied by many effects that at best are unpleasant in the extreme and at worst are fatal. In actuality, every patient in the trial cited by Reintgen and coworkers experienced side effects so disabling that not a single one of them could complete the entire protocol without the need for reducing the dosage of the drug. The evidence for and against interferon as being an efficacious adjuvant therapy, as well as the opinions of a variety of persons considered to be expert about the subject, are laid out in Section 6 of this work. Just as is the case for END, there is not a jot of evidence that supports the contention that use of interferon should be the standard of care. Assessment further of interferon alfa-2b in clinical trials in the future only can be of dubious value and, if the best interest of patients is to be guiding, should not be undertaken at all.

The issue of benefit of SNB in regard to prognosis was raised by Reintgen, et al.⁸³ as follows: " . . . [This issue] arises in discussing the significance of nodal staging and missed micrometastatic[sic] disease . . . " Those coworkers then made this observation: "There is evidence to suggest that it [metastasis discovered by virtue of SNB] is clinically relevant disease . . . Nodal staging of melanoma patients with the SLN biopsy procedure will be a significant advanced [sic] for clinical trial work." Of course metastases of melanoma are of crucial importance because they are harbingers of death, in time, from the effects of them. It is conceivable that SNB could have value in clinical trials designed to test new and innovative adjuvant medical therapies for patients with known metastasis of melanoma, but in the setting of routine clinical practice, SNB cannot have merit because no effective treatment is available currently for metastases of melanoma. In addition, it has been established solidly that 11–12%^50,51,71 of patients whose SN seems not to harbor cells of melanoma nonetheless develop signs later of indubitable metastasis of melanoma and patients whose SN harbors cells of melanoma may die within a year or they may survive for decades. In short, prognostications in regard to an individual patient with metastasis of melanoma are pure guess and profit no one, not least the patient.

Because no reliably effective therapy is available currently for metastases of melanoma, research directed to that end must be unrelenting. SNB could play a role in that endeavor were it used to define a set of patients with metastasis of melanoma in whom experimental adjuvant therapy might be administered after approval by agencies that monitor ethical aspects of such treatment.

In 1999, Morton and Chan,⁸⁸ pioneers of SNB and for years irrepressible advocates of it, actually called into question the worth of SNB as standard of care. This is how they said it: "Until this trial [comparing wide local excision only versus wide local excision, lymphatic mapping, SNB and removal of the nodal basin] is complete, lymphatic mapping/sentinel lymphadenectomy, as with any other technique, should be undertaken under the auspices of a clinical trial." Morton has expressed that same sentiment elsewhere.^70,87

In the not too distant future, molecular biologic techniques that are invasive minimally may be employed to identify those patients who have metastases of melanoma not apparent clinically, thereby obviating any need for SNB. That idea, propounded in an editorial in 2000 by Thomas and Patocskai,⁸⁹ was voiced by them thus: "If no survival advantage is shown for sentinel node biopsy and selective completion lymph node dissection, it could be replaced by newer techniques, including molecular reverse transcriptase polymerase chain reaction . . . These techniques could become the methods of choice for the early detection of metastatic disease."

Reintgen, et al.⁸³ ended their piece with these lines: "Lymphatic mapping and SLN [sic] has been supported to be the standard of care by the World Health Organization and is the standard of care for many national trials (Sunbelt Melanoma Trial) in the country . . . With world organizations endorsing the procedure and the stronger evidence that surgery and interferon alpha-2b may provide a survival benefit to patients with Stage 3 melanoma, it becomes difficult to not offer the procedure to patients."

Coldiron,⁸⁶ in a letter to the editor that appeared in the January issue of Dermatologic Surgery for 2001, wrote about the matter trenchantly thus: "In summary, it should be made clear to the patient that sentinel node biopsy is an evolving technique that has no proven survival benefit . . . Patients should know that a negative sentinel node is not a promise of cure and there is little effective adjunctive therapy if they have metastatic disease." Coldiron made crystal clear his opinion that SNB should be utilized only in clinical trials and should not be the standard of care.

Other authors, however, continue to blare the claim that the World Health Organization advocates SNB as the standard of care. Connelly⁹⁰ in a letter to the editor of Dermatologic Surgery and the Journal of the American Academy of Dermatology⁹¹ made it obvious beyond doubt that no official support has been given by the World Health Organization to the notion of SNB as standard of care for patients with melanoma. This is the intriguing story as told by Connelly⁹⁰ and repeated here in its entirety:

To the Editor:

Recently in this journal, Reintgen, et al.¹ stated in summary that Lymphatic mapping and sentinel lymph node biopsy (SLNB) has been supported to be the standard of surgical care by the World Health Organization (WHO) and is the standard of care for many of the national trials (Sun Belt Melanoma Trial) in the country. The authors repeat their claim in another paragraph that this world organization has endorsed these procedures. In another journal, Reintgen, et al. again summarize their position by stating that "2 months ago the WHO issued a consensus statement stating that lymphatic mapping and SLNB biopsy should be considered the standard of care for patients with melanomas thicker than 1.0 mm² [sic]. These statements were made without reference in both articles.

I have previously requested a reference from Dr. Reintgen's office documenting a WHO Consensus Statement and was provided with a copy of a news bulletin that appeared in the journal Oncology². This news brief attributed announcement of such a consensus statement to Dr. Natale Cascinelli, president of WHO Melanoma Program⁴. Unable to find the published form of such an important consensus statement, I called Dr. Cascinelli in Milan, Italy on 10/23/00. He said that there is no such consensus statement or WHO Standard of Care designation and that he was merely expressing his personal opinion during his presentation entitled "An overview on sentinel lymph node dissection" at a Paris oncology conference.

I contacted the editorial director of Oncology and asked her about the source of the news brief. She informed me that the news brief was a press release sent to Oncology by the Neoprobe Corporation. This press release was reprinted without editing or confirmation. Neoprobe Corporation is a maker of intraoperative lymphatic mapping supplies. Neoprobe Corporation has repeated this misrepresentation in their federally required Security and Exchange Commission Form 10-K/A.

This misrepresentation has also been repeated by others in a free Schering Corporation-sponsored color glossy booklet mailed to all US dermatologists⁴. It is likely that this misrepresentation has been presented to physicians across the country in both seminars, SLNB training sessions, and visits by Neoprobe Corporation representatives.

Since this misrepresentation seems to be central to or at least important to the argument for SLNB by Reintgen, et al., I believe that immediate correction is essential. To allow this misrepresentation to remain and even be perpetuated has direct consequences for both practicing physicians and patients. Finally, I question the authors' statement that SLNB is the standard of care for many of the national trials (Sun Belt Melanoma Trial) in the country. Perhaps I am missing something important here. Are trials not clinical experiments to determine efficacy? How can something still in clinical trials be considered standards of care? Perhaps the authors meant that SNLB is a normal part of the protocol for their ongoing studies.

THOMAS J. CONNELLY, MD

Stuart, Florida

In rebuttal to the assertions of Connelly, Reintgen, et al.³⁹ offered these arguments: "Standards of care are defined by community practice, at least in the medico-legal world. They are established and changed when there is compelling data (usually from national trials) to suggest that patients' lives will be impacted by the therapy . . . Of course, the only people that ELND could possibly benefit are those with nodal metastases . . . With this surgical strategy [SNB] only those patients with documented metastases undergo the more radical complete node dissection . . . the adjuvant therapy [interferon] can be applied in a selective fashion and clinical trial work will be much more interpretable . . . Already physicians have been sued successfully by not offering some kind of a nodal staging procedure for patients with melanoma so that Stage III disease [metastasis in nodes] can be identified and the survival benefit of adjuvant alfa-2b at least offered to the patient . . . Standards of care are only changed by community practice, where there is compelling evidence of a patients' benefit."

But it has been demonstrated compellingly and beyond doubt that SNB contributes no benefit at all to a patient with melanoma metastatic to a node or beyond it, and that no effective therapy is available now for a patient whose SN is proven to contain cells of melanoma. The evidence to which Reintgen and collaborators refer has been discussed, debated, and decimated. That SNB has been employed as vehicle to litigation successfully against a physician does not justify use of it. Manipulation efficaciously of the legal system by lawyers for plaintiffs and by physicians masquerading as authentic experts for plaintiffs rewards plaintiffs unjustly and wrongly. SNB benefits only the physician who performs it, not patients.

In regard to advantage taking by physicians in the matter of SNB, Coldiron⁸⁶ wrote this: "It is hard to argue for the performance of a six to 10 thousand dollar procedure, to allow earlier detection of metastatic disease, if there is nothing available that will improve the patient's survival." Connors, et al.⁹² agreed and put it this way: "For now, it may be best to view the SLN biopsy for what it was originally designed to be: an accurate prognostic tool for patients with melanoma who are at risk for micrometastatic disease and for identifying patients for randomized trials. Nothing more." In 2000, Otley⁸⁵ concurred with Coldiron and Connors, et al. in these lines: "In the absence of randomized, controlled data, sentinel lymphadenectomy cannot be considered a therapeutic standard of care."

Also in 2000, Thomas and Patocskai⁸⁹ resisted the surge to making SNB the standard of care by opining that enthusiasm for SNB should be dampened, a sentiment expressed thus: "Sentinel node biopsy has been enthusiastically adopted into clinical practice without a clear understanding of its benefit, which is often assumed rather than proved . . . Until the answers to important questions of efficacy are obtained, those responsible for health service funding should control clinical enthusiasm by refusing to underwrite the costs of sentinel node biopsy unless all patients who undergo the procedure are entered into clinical trials."

Morton and Chan⁸⁷ expressed their reservations about the place of SNB in regard to standard of care as follows: "Although LM/SL/SCLND [sentinel node biopsy and node dissection] has been determined by expert consensus opinion to be an option in the standard of care of melanoma, it has not been validated by a randomized trial using endpoints of overall and disease-free survival; therefore, caution must be exercised in regard to its therapeutic use."

In 2000, Eggermont⁴¹ on review of the subject of adjuvant therapy for melanoma and the role of lymphatic mapping for SN, concluded with this thought: "In the absence of a standard adjuvant therapeutic regimen of proven efficacy for lymph node positive patients, the value of the sentinel node procedure is limited to providing us with the best staging system to perform clean phase III trials to discover an effective adjuvant systemic therapy." Eggermont echoed the opinion that if SNB has any role in medicine, that role should be limited to clinical trials and, apart from that, it has no place in the practice of medicine.

In the issue of the Journal of the American Academy of Dermatology⁹³ for October 2001, guidelines were set forth for the care of patients with melanoma. In the process of formulating those guidelines, an opportunity was given to the entire membership of the American Academy of Dermatology (AAD) to review those policies and make comments about them. Ultimately the guidelines were approved by the Board of Directors of the AAD, but only after the proposals had been sent back to the committee following several contentious sessions given to consideration of them. The panel of "experts" had only this brief statement to make regarding SNB: "The value of sentinel lymph node biopsy is undetermined at this time, and the issue is not addressed in this guideline." The panel did not consider SNB to be standard of care, a reasonable decision in the context of no evidence that therapeutic benefit derives from it. Several members of the Board of Directors, notably A. B. Ackerman and C. Cockerell, had resisted vehemently for more than a year much that had been recommended by the committee as "guidelines." Although many changes were effectuated by virtue of the efforts of those two dermatologists/dermatopathologists, many other matters in dispute eventually were approved by the Board of Directors, to the evident dissatisfaction of the opponents. In the case of SNB, those two were outspoken and averred that SNB had no value to a patient and that the AAD should say so. The committee declined to recommend guidelines for the employment of END, but the very omission of it implies that in their view the procedure has yet to be vindicated.

Dubois, et al.⁹⁴ in 2001, set forth indications for SNB and recommended the use of it. This is what they said: "As the results of the literature review show, no trial has definitively demonstrated a survival benefit in the use of SLN biopsy. Despite this lack of evidence, the panel clearly delineated patients for whom the procedure was appropriate, inappropriate, and uncertain using a risk-benefit metric." Curiously, those authors acknowledged that no evidence exists on behalf of the position that patients derive any benefit from SNB, and yet they had no hesitation in recommending use of that procedure. Ironically, the article appeared in a section of the journal titled, "Evidence-based dermatology: Original contribution."

Our own review of what has been published about the subject of SNB leads us to conclude that the procedure has no chance of surviving the test of time because it has no worth. That being the case, it surely should not be the standard of care. If for political and financial reasons SNB does become the standard of care, it is only a matter of time before it will come to the same ignoble end as prophylactic tonsillectomy and adenoidectomy, radical mastectomy, and wide and deep excision for primary cutaneous melanoma. If melanoma is to be cured, that can be accomplished only by extirpation of the neoplasm before it has given rise to metastases. Once there is metastasis, nothing effective can be done for it as of now.