August 22, 2011 — Sentinel lymph node biopsy (SLNB) "should be performed" in patients with melanoma of the head and neck for the same indications for which it is used in melanoma of the trunk and extremities, concludes a new paper published online in Cancer.
However, a critic of the procedure says that this study and others have not convincingly proven that there is a therapeutic advantage from early vs delayed lymphadenectomy in melanoma in general. In the absence of that evidence, "the technique represents excessive and unnecessary surgery," says J. Meirion Thomas, MS, from the Royal Marsden Hospital and Imperial College in London, the United Kingdom.
"Currently the only proven benefit of SLNB in melanoma is as a prognostic tool," Dr. Thomas told Medscape Medical News.
The results of the new study from the University of Michigan Comprehensive Cancer Center assert the prognostic value of the procedure in patients with head and neck cancer.
Led by Audrey B. Erman, MD, the study authors conducted a chart review of 353 patients from their center, which is the largest single-center series of patients with head and neck melanoma.
The goal of the study was "to demonstrate that SLNB accuracy and prognostic value in the head and neck region are comparable to other sites," write Dr. Erman and colleagues. SLNB has emerged as a widely used staging procedure for cutaneous melanoma, they point out. "However, debate remains around the accuracy and prognostic implications of SLNB for cutaneous melanoma arising in the head and neck, as previous reports have demonstrated inferior results to those in nonhead and neck regions," they explain.
The study "puts forward powerful data indicating that SLN status is highly prognostic in the head and neck region," say the authors. They also report that they found that SLNB to be as accurate in the head and neck region as it is in other parts of the body.
With regard to prognostic value of SLNB in the head and neck region, the investigators found that, on multivariate analysis, the hazard ratio was 4.23 (P < .0001) for positive SLN status and decreased recurrence-free survival and 3.33 (P < .0001) for positive SLN status and decreased overall survival.
At the University of Michigan, a positive SLN status for head and neck melanomas is an important clinical consideration and is used to direct management, say the authors.
"Patients with a positive SLNB received recommendation for completion lymphadenectomy followed by referral to medical oncology for consideration of adjuvant therapy, including high-dose interferon alfa-2b or clinical trials. Patients with a negative SLNB were followed clinically for recurrence," they write.
But Dr. Thomas does not endorse this approach.
"With regard to adjuvant therapy and/or clinical trials, there is no other example in medicine where patients undergo an invasive surgical procedure in order to qualify for adjuvant therapy or entry into adjuvant trials. What price have these 353 patients paid for the prognostic information provided?" he asks about SLNB.
Data on Feasibility, Safety, Accuracy
In their study, the authors reviewed patients who underwent SLNB for cutaneous melanoma of the head and neck at the University of Michigan from 1997 to 2007.
Patients underwent preoperative lymphoscintigraphy 2 to 4 hours before surgery. Nodal basin radioactivity was measured with handheld gamma probes. Incisions 1 to 3 cm long were made directly over sites of highest radioactivity. In addition to radioactivity level, the surgeons also used intradermal blue dyes to locate the SLN. "Lymph node removal continued until the operative bed emitted < 10% of the ex vivo count of the highest emitting lymph node and until any blue dyed or suspicious appearing nodes were removed," explain the authors.
They found that none of the 353 patients sustained permanent nerve injuries from the procedure, and all but 1 patient had a sentinel lymph node identified. In other words, the procedure was safe and feasible, say the authors. This conclusion is supported by the literature, they add.
About one fifth (n = 69; 19.6%) of the patients had at least 1 sentinel node positive for cancer, and all but 1 patient went on to receive a complete dissection to remove additional lymph nodes.
Seventeen patients (25%) in this "completion lymphadenectomy group" (n = 68) had at least 1 positive non-SLN, report the authors.
That means that the majority of this group — 51 patients — had no further lymph node involvement, points out Dr. Thomas. "I would argue, of course, that all 353 patients had an unnecessary SLNB procedure but undeniably the 51 patients had unnecessary completion lymphadenectomy because they had no positive nonsentinel nodes in the lymphadenectomy specimen," he said.
The study authors also report that, overall, there was a false-negative rate of 14.8%.
However, the authors say that only 12 patients had recurrence first in the regional basin alone (the area of the sentinel node). In other words, a negative SLNB that failed regionally — in the absence of a local or in-transit recurrence — occurred in only 4.2% of cases. This percentage, which is called a "false-omission" rate, is similar to what was found in studies of sentinel lymph node biopsy used for melanomas in other parts of the body, and thus SLNB in the head and neck region is similarly accurate, the authors say.
But Dr. Thomas suggests that distinguishing between false-negative and false-omission rates is a kind of smoke-screen.
"Both terms are euphemisms for the failure of the technique, meaning that the surgeon took out the wrong node for whatever reason," he says.
Survival Advantage Questioned
The most important issue in analyzing SLNB in melanoma — for all body regions — is whether its use improves outcome, suggests Dr. Thomas.
In a related matter, surgeons need to know what the meaning of a false-negative test result is. This was the subject of recent letters from Dr. Thomas and other commentators in the August 11 edition of the New England Journal of Medicine.
The letter writers were responding to a case study that concluded that a patient with cutaneous melanoma was a good candidate for SLNB. Each of the 3 letters questioned the value of the procedure.
Dr. Thomas wrote that 2 major clinical trials "give conflicting findings with respect to the consequences of a false-negative test."
The Sunbelt Melanoma Trial showed no survival difference between patients with positive sentinel nodes and those with false-negative sentinel nodes, even though the latter group had a greater nodal tumor burden, he writes. "This finding suggests that the timing of lymphadenectomy may not be important," said Dr. Thomas.
In contrast, the Multicenter Selective Lymphadenectomy Trial I (MSLT-1) suggests that patients with positive sentinel nodes had a 20% survival advantage at 5 years over patients with false-negative sentinel nodes, he writes.
"How accurate is this test for individual patients...?," asks Dr. Thomas in his letter, in which he cites a 13% false-negative rate for the procedure.
Dr. Thomas also has questioned the results of MSLT-1. In a published paper (J Plast Reconstr Aesthet Surg. 2009;62:442-446) he has asserted that a fourth interim analysis of MSLT-I "supports the hypothesis that prognostic false-positivity is the explanation for the large survival advantage claimed for patients having early lymphadenectomy versus delayed lymphadenectomy."
The concept of false-positivity — where disease is present in the lymph nodes but does not seem destined to affect progression — and its importance has been part of an ongoing debate in SLNB for breast cancer as well, as reported by Medscape Medical News.
However, Dr. Thomas says that his analyses have made him a marked man in his field.
"As a result of publishing this paper [on MSLT-1], I have been effectively ostracized by the melanoma/SLNB community. I have never been invited to speak as a member of faculty at any melanoma meeting since 2006. The protagonists of SLNB in melanoma have a powerful hold on many journals and regularly censor my work. All this because I question the efficacy of the procedure and its benefit to patients," he said.
However, things may be changing. "I have been invited to debate SLNB in melanoma with Vernon Sondak [of H. Lee Moffitt Cancer Center in Tampa, Florida] at the next meeting of the College of Pathologists in Dallas in September."
The authors have disclosed no relevant financial relationships.
Cancer. Published online July 19, 2011.
However, a critic of the procedure says that this study and others have not convincingly proven that there is a therapeutic advantage from early vs delayed lymphadenectomy in melanoma in general. In the absence of that evidence, "the technique represents excessive and unnecessary surgery," says J. Meirion Thomas, MS, from the Royal Marsden Hospital and Imperial College in London, the United Kingdom.
"Currently the only proven benefit of SLNB in melanoma is as a prognostic tool," Dr. Thomas told Medscape Medical News.
The results of the new study from the University of Michigan Comprehensive Cancer Center assert the prognostic value of the procedure in patients with head and neck cancer.
Led by Audrey B. Erman, MD, the study authors conducted a chart review of 353 patients from their center, which is the largest single-center series of patients with head and neck melanoma.
The goal of the study was "to demonstrate that SLNB accuracy and prognostic value in the head and neck region are comparable to other sites," write Dr. Erman and colleagues. SLNB has emerged as a widely used staging procedure for cutaneous melanoma, they point out. "However, debate remains around the accuracy and prognostic implications of SLNB for cutaneous melanoma arising in the head and neck, as previous reports have demonstrated inferior results to those in nonhead and neck regions," they explain.
The study "puts forward powerful data indicating that SLN status is highly prognostic in the head and neck region," say the authors. They also report that they found that SLNB to be as accurate in the head and neck region as it is in other parts of the body.
With regard to prognostic value of SLNB in the head and neck region, the investigators found that, on multivariate analysis, the hazard ratio was 4.23 (P < .0001) for positive SLN status and decreased recurrence-free survival and 3.33 (P < .0001) for positive SLN status and decreased overall survival.
At the University of Michigan, a positive SLN status for head and neck melanomas is an important clinical consideration and is used to direct management, say the authors.
"Patients with a positive SLNB received recommendation for completion lymphadenectomy followed by referral to medical oncology for consideration of adjuvant therapy, including high-dose interferon alfa-2b or clinical trials. Patients with a negative SLNB were followed clinically for recurrence," they write.
But Dr. Thomas does not endorse this approach.
"With regard to adjuvant therapy and/or clinical trials, there is no other example in medicine where patients undergo an invasive surgical procedure in order to qualify for adjuvant therapy or entry into adjuvant trials. What price have these 353 patients paid for the prognostic information provided?" he asks about SLNB.
Data on Feasibility, Safety, Accuracy
In their study, the authors reviewed patients who underwent SLNB for cutaneous melanoma of the head and neck at the University of Michigan from 1997 to 2007.
Patients underwent preoperative lymphoscintigraphy 2 to 4 hours before surgery. Nodal basin radioactivity was measured with handheld gamma probes. Incisions 1 to 3 cm long were made directly over sites of highest radioactivity. In addition to radioactivity level, the surgeons also used intradermal blue dyes to locate the SLN. "Lymph node removal continued until the operative bed emitted < 10% of the ex vivo count of the highest emitting lymph node and until any blue dyed or suspicious appearing nodes were removed," explain the authors.
They found that none of the 353 patients sustained permanent nerve injuries from the procedure, and all but 1 patient had a sentinel lymph node identified. In other words, the procedure was safe and feasible, say the authors. This conclusion is supported by the literature, they add.
About one fifth (n = 69; 19.6%) of the patients had at least 1 sentinel node positive for cancer, and all but 1 patient went on to receive a complete dissection to remove additional lymph nodes.
Seventeen patients (25%) in this "completion lymphadenectomy group" (n = 68) had at least 1 positive non-SLN, report the authors.
That means that the majority of this group — 51 patients — had no further lymph node involvement, points out Dr. Thomas. "I would argue, of course, that all 353 patients had an unnecessary SLNB procedure but undeniably the 51 patients had unnecessary completion lymphadenectomy because they had no positive nonsentinel nodes in the lymphadenectomy specimen," he said.
The study authors also report that, overall, there was a false-negative rate of 14.8%.
However, the authors say that only 12 patients had recurrence first in the regional basin alone (the area of the sentinel node). In other words, a negative SLNB that failed regionally — in the absence of a local or in-transit recurrence — occurred in only 4.2% of cases. This percentage, which is called a "false-omission" rate, is similar to what was found in studies of sentinel lymph node biopsy used for melanomas in other parts of the body, and thus SLNB in the head and neck region is similarly accurate, the authors say.
But Dr. Thomas suggests that distinguishing between false-negative and false-omission rates is a kind of smoke-screen.
"Both terms are euphemisms for the failure of the technique, meaning that the surgeon took out the wrong node for whatever reason," he says.
Survival Advantage Questioned
The most important issue in analyzing SLNB in melanoma — for all body regions — is whether its use improves outcome, suggests Dr. Thomas.
In a related matter, surgeons need to know what the meaning of a false-negative test result is. This was the subject of recent letters from Dr. Thomas and other commentators in the August 11 edition of the New England Journal of Medicine.
The letter writers were responding to a case study that concluded that a patient with cutaneous melanoma was a good candidate for SLNB. Each of the 3 letters questioned the value of the procedure.
Dr. Thomas wrote that 2 major clinical trials "give conflicting findings with respect to the consequences of a false-negative test."
The Sunbelt Melanoma Trial showed no survival difference between patients with positive sentinel nodes and those with false-negative sentinel nodes, even though the latter group had a greater nodal tumor burden, he writes. "This finding suggests that the timing of lymphadenectomy may not be important," said Dr. Thomas.
In contrast, the Multicenter Selective Lymphadenectomy Trial I (MSLT-1) suggests that patients with positive sentinel nodes had a 20% survival advantage at 5 years over patients with false-negative sentinel nodes, he writes.
"How accurate is this test for individual patients...?," asks Dr. Thomas in his letter, in which he cites a 13% false-negative rate for the procedure.
Dr. Thomas also has questioned the results of MSLT-1. In a published paper (J Plast Reconstr Aesthet Surg. 2009;62:442-446) he has asserted that a fourth interim analysis of MSLT-I "supports the hypothesis that prognostic false-positivity is the explanation for the large survival advantage claimed for patients having early lymphadenectomy versus delayed lymphadenectomy."
The concept of false-positivity — where disease is present in the lymph nodes but does not seem destined to affect progression — and its importance has been part of an ongoing debate in SLNB for breast cancer as well, as reported by Medscape Medical News.
However, Dr. Thomas says that his analyses have made him a marked man in his field.
"As a result of publishing this paper [on MSLT-1], I have been effectively ostracized by the melanoma/SLNB community. I have never been invited to speak as a member of faculty at any melanoma meeting since 2006. The protagonists of SLNB in melanoma have a powerful hold on many journals and regularly censor my work. All this because I question the efficacy of the procedure and its benefit to patients," he said.
However, things may be changing. "I have been invited to debate SLNB in melanoma with Vernon Sondak [of H. Lee Moffitt Cancer Center in Tampa, Florida] at the next meeting of the College of Pathologists in Dallas in September."
The authors have disclosed no relevant financial relationships.
Cancer. Published online July 19, 2011.
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