Sentinel lymph node (SLN) biopsy has become a common
procedure in melanoma and has been endorsed by professional guidelines.
It is considered to be a minimally invasive and highly
accurate procedure that allows for appropriate regional nodal staging
and identification of patients without nodal metastases.
However, in a feature
published online January 8 in
BMJ, freelance journalist Ingrid Torjesen, from
London, United Kingdom, describes SLN biopsy as an "expensive and
invasive
procedure" and reports that thousands of melanoma patients
around the world are having it done despite a lack of clear evidence
that it will improve outcomes.
She focuses on the Multicenter Selective Lymphadenectomy
Trial (MSLT-I), which was designed to determine the ability of SLN
biopsy to identify patients with clinically occult nodal
metastases and to evaluate the effectiveness of immediate completion
lymph node dissection (CLND) in patients with positive SLNs.
The 5-year follow-up of the MSLT-I, published in 2006 (
N Engl J Med. 2006;355:1307-1317), failed to show a
survival advantage from SLN biopsy. However, it did confirm that SLN
biopsy was highly
accurate in identifying positive nodes in patients with
melanomas 1.2 to 3.5 mm thick, and that SLN biopsy followed by CLND
was associated with prolonged disease-free survival.
In addition, clinically node-negative patients with SLN metastases who underwent CLND had significantly better melanoma-specific
5-year survival rates than those who had delayed CLND for clinically detected nodal relapse.
SLN biopsy is now commonly used in Australia, Canada, the United States, and Western Europe, but is not routinely used in
the United Kingdom.
A
guideline issued
jointly by the American Society of Clinical Oncology (ASCO) and the
Society of Surgical Oncology (SOS) recommends SLN biopsy
for patients with melanomas of intermediate thickness. The
procedure has also been endorsed by the American Joint Committee
on Cancer as a valuable staging procedure for those at risk
of developing clinically occult nodal metastases.
Why No Interim Results?
In her report, Torjesen states that the results of the
MSLT-I were controversial, and that critics said it was not surprising
"to see an improved disease-free survival in the biopsy arm
[because] patients whose disease was most likely to progress had
had their regional nodes removed."
She notes that the fourth interim analysis of the MSLT-I data (showing 7-year follow-up data), which was expected in 2008,
and the fifth and final analysis (with 10-year data), expected in 2011, will settle the question once and for all.
So why haven't they been published, Torjesen asks.
"A minimum of 10 years of follow-up is required to see the
full benefit of the technique," said Alistair Cochran, MD, MB ChB,
distinguished professor of pathology, laboratory medicine,
and surgery at the University of California Los Angeles School
of Medicine.
"The 10-year data have been analyzed and are being prepared for submission, hopefully within the next month or so," Dr. Cochran
told
Medscape Medical News.
Dr. Cochran was involved in developing the technique, is a coauthor of the ASCO/SOS guidelines, and has worked with Donald
Morton, MD, lead author of the MSLT-I.
Sandra Wong, MD, associate professor of surgery at the University of Michigan Health Systems in Ann Arbor, and lead author
of the ASCO/SOS guidelines, agrees. "In a lot of studies, the follow-up time just isn't long enough," she told
Medscape Medical News. "Melanoma is not like a lot of other cancers, where you start seeing recurrences within the first 2 years. I have patients
who are a decade out and they are having a recurrence. It's just a very different disease process," she explained.
Lacking Balance
Dr. Cochran pointed out that Torjesen relies heavily on
comments from J. Meiron Thomas, MS, FRCP, FRCS, who is a consultant
surgeon at the Royal Marsden Hospital London and chair of
surgical oncology at Imperial College, London, United Kingdom.
Dr. Thomas has been very vocal in his criticism of SLN
biopsy and has published maybe 15 or 16 papers on the subject, Dr.
Cochran explained. "This is a picture of a tennis match....
We publish something and then Dr. Thomas prints a rebuttal. We
have eventually left him to it and figured time will tell,"
he noted.
"I don't know if bias is the right word, but the paper seems to only represent 1 side of the debate," said Dr. Wong. "That
side is a very minority opinion, and Dr. Thomas is a vocal critic," she added.
Dr. Wong noted that when "we try to set up debates at national meetings, we can never get anyone to take the con side. Not
even a 'soft' con."
This report is not offering any new information or insight,
said Daniel Coit, MD, a surgical oncologist at Memorial Sloan-Kettering
Cancer Center in New York City. It "is really just a rehash
of arguments and commentaries that have been made for quite some
time," he explained.
Dr. Coit emphasized Donald Morton, who introduced the
technique and who has, so to speak, the biggest stake in it "is the
one person who has done more than anyone else to critically
evaluate the technique, with these 2 large randomized prospective
trials.... While there are many critics — and Steve
Rosenberg [mentioned in the report] and Meiron Thomas have an absolute
right to interpret the data of others — neither has actually
created any data of their own to contribute to this," he explained.
"It is very easy to take pot shots, but very hard to create new data," Dr. Coit added. "And Don Morton has created a wealth
of data."
All of the arguments made in the report are cogent. "This is not a procedure that affects survival, it is a procedure that
provides important prognostic information," he noted.
"As a society, we have to decide if we want to pay for it, just as we decide if we are going to pay for CT scans or PET scans,"
Dr. Coit added.
Professional Advancement and Company Profits?
Torjesen implies that the uptake of SLN biopsy has been
largely driven by professional advancement and commercial profit.
She states that "whole professional careers and businesses
have been built on sentinel node biopsy for melanoma. Professional
pride and company profits are now at stake."
Dr. Cochran explained that it is highly doubtful that the
use of SLN biopsy has been endorsed simply to advance careers or
to generate profit. "I don't think that the popularity of
the technique can be put down to the commercialization," he said.
"I'm sure that there is some money to be made, but nothing
like the money that can be made by pharmaceutical companies from
some of their new drugs."
Dr. Wong agrees that there is some cost associated with the procedure, but it is not very expensive overall and not a huge
profit maker. "It's not like chemotherapy or using excessive imaging," she noted.
"If you're really cynical, you can say that if melanoma
surgeons stopped doing this, they would lose a large part of their
practice," she added. "But that's cynical because this is a
procedure that can help overall survival or help make an accurate
diagnosis," she said.
Harms of Overtreatment
Torjesen raises concerns about overtreatment in her report.
"It is generally accepted that only 20% of patients who have sentinel
node biopsy will have positive sentinel nodes, and only 20%
of those will have metastatic disease in the nonsentinel nodes,"
she states. "Therefore, 96% of patients who have sentinel
node biopsy will have unnecessary surgery," she writes.
Dr. Cochran agrees that the prophylactic removal of lymph
nodes can cause serious morbidity, but pointed out that some people
can be saved by it. "The other alternative is to watch and
wait, but we've found that the number of involved lymph nodes in
patients who have been observed is about 3 times as high as
those treated with sentinel node biopsy," he said. "We know that
with time, the disease progresses. I think most physicians
are uncomfortable with letting things be and letting nature take
its course," he explained.
Dr. Cochran added that at some point it will be possible to tell which patients with a positive SLN have metastatic disease,
"but we are not there yet."
It is hoped that the follow-up MSLT-II will answer some of those questions. That study is also being run by Dr. Morton, and
will evaluate the potential benefits of regional lymphadenectomy for melanoma patients with positive sentinel nodes.
The MSLT-II will establish whether "every patient with a positive SLN needs a full dissection," said Dr. Wong.
If lymph node surgery in melanoma is ultimately scaled back,
it would not be without precedent. In recent years, surgical
oncologists have learned that not all women with positive
sentinel axillary lymph nodes need completion dissection. The
Z0011 trial,
conducted by the American College of Surgeons Oncology Group, showed
that women with minimal lymph node involvement did
not suffer from inferior survival when they only underwent
sentinel node biopsy and did not undergo completion dissection.
In addition, new agents have been shown to be very effective
in metastatic disease; that's why the staging is so important,
Dr. Wong explained. "You may have a patient who walks in
with a stage I melanoma clinically, but may actually be a stage III
once we do the procedure. If we lose these data, we won't
know which patients will benefit from these new treatments," she
noted.
In general, the jury is still out as far as SLN biopsy goes.
"But everyone is doing it, and I don't think there is too much
debate," Dr. Wong said. "It is hard to tell a patient that
you don't want to do it if they are in the 1 to 4 mm stage. They
want to know."
Dr. Coit agrees. "I don't think any clinicians regularly using this procedure propose it to patients as anything other than
a method that will provide more information on how likely melanoma is to occur," he said.
The main question right now is which patients are least
likely to benefit from the procedure, he added. "We are taking a long
hard look at who this prognostic information will likely
help, this procedure will help, but also who it will not be of benefit
to."
Medscape Medical News requested a comment on this report from
BMJ, but had not received a response by press time.
BMJ. 2013;346:e8645.
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