BA Guadagnolo

DL Morton

Kelly M. McMasters

M Vries de

MS Sabel

SL Wong

SR Martinez

English

PubMed

Crossref

Why Does No One Want to Perform Lymph Node Dissection Anymore?

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EDITORIAL
Why Does No One Want to Perform Lymph Node Dissection
Anymore?
Kelly M. McMasters, MD, PhD
Department of Surgery, University of Louisville School of Medicine, James Graham Brown Cancer Center, Louisville, KY
The truth is rarely pure and never simple.
Oscar Wilde
It is error only, and not truth, that shrinks from
inquiry.
Thomas Paine
In seeking absolute truth we aim at the unattainable
and must be content with broken portions.
William Osler
In this issue of Annals of Surgical Oncology, Kingham
et al. from Memorial Sloan-Kettering Cancer Center
present their single-institution retrospective experience of
melanoma patients who did not undergo completion lymph
node dissection (CLND) for a tumor-positive sentinel
lymph node (SLN).1 Of 313 patients who had a tumor-
positive SLN, 271 underwent CLND and 42 did not. Of the
42 patients who did not undergo CLND, 5 did not do so
because they were found to have stage IV disease on fur-
ther workup, leaving 37 patients who should reasonably
have considered CLND. The nodal recurrence rates were
no different in the no-CLND group (7%) versus the CLND
group (6%). Because the disease-free and disease-specific
survival rates were similar between the groups, the authors
question the value of CLND.
We must recognize the limitations of this study. It is a
small, retrospective review from a single institution. The
groups are not well balanced in terms of clinicopathologic
factors. Patients in the no-CLND group versus the CLND
group were older (median age, 70 vs. 56 years, P \ .01),
more often had lower-extremity melanomas (40% vs. 13%,
P \ .01), and had a trend toward thicker (3.5 vs. 2.8 mm,
P \ .06), more often ulcerated (62 vs. 44%, P = .09)
melanomas.1 Why did the patients not undergo CLND in
this study? In 33% of cases, it seems that the surgeon
essentially talked the patient out of having a CLND.
Although patient refusal was cited as the most common
reason for failure to perform CLND (45%), it is likely that
the surgeon’s opinion strongly influenced the patients’
decisions in these cases as well. The patients who chose to
forego CLND did not do so for random reasons; selection
bias is a major drawback of this study. In my experience,
most patients choose CLND if recommended by their
surgeon. So what does this study really tell us? I believe it
tells us that the experienced melanoma surgeons at
Memorial Sloan-Kettering Cancer Center were very good
at selecting patients who were unlikely to have nodal
recurrence and/or were very likely to develop distant
metastatic disease, and thus were unlikely to benefit from
CLND. It does not tell us that CLND is of no value.
The authors cite population studies that indicate that
only 50–69% of melanoma patients in the United States
who have a tumor-positive SLN undergo CLND. So why
are surgeons so reluctant to perform CLND these days? To
address this question, we must consider the reasons for
performing CLND. There are two goals: regional disease
control and cure. The patients who undergo CLND for a
tumor-positive SLN fall into three camps: (1) those who do
not need CLND because they do not have, and never will
have, additional nodal disease; (2) those who will not
benefit from CLND because they are going to die of distant
metastatic disease or because their disease will recur in the
regional nodes, despite the best possible lymph node dis-
section; and (3) those who have nonsentinel node
metastases for whom CLND will prevent regional nodal
recurrence and, in some cases, result in cure. The third
camp undoubtedly represents the smallest group. The
article by Kingham et al. implies that the third camp does
 Society of Surgical Oncology 2009
Published Online: 26 November 2009
K. M. McMasters, MD, PhD
e-mail: kelly.mcmasters@nortonhealthcare.org
Ann Surg Oncol (2010) 17:358–361
DOI 10.1245/s10434-009-0837-2
not even exist, but I suggest that the preponderance of
evidence, imperfect as it may be, suggests that regional
lymphadenectomy provides regional disease control for
most and cures some fraction of patients. The problem is
that until we are able to predict accurately which patients
belong to each of these three camps, we are left with a
decision to perform potentially morbid lymphadenectomy
knowing that it can only benefit a minority of patients.
The question of whether CLND improves disease-free
and overall survival is the subject of the ongoing Multi-
center Selective Lymphadenectomy Trial (MSLT) II,
conducted by Dr. Donald Morton and colleagues. Kingham
et al. conclude, however, that until the results of MSLT II
are available, ‘‘nodal observation may be a reasonable
alternative to the informed patient who does not want to
participate in MSLT II or who does not have access to
participation in MSLT II.’’ I would suggest that this is too
bold a conclusion to draw from a retrospective study of 37
patients that has the limitations described above.
REGIONAL DISEASE CONTROL
First, what is the risk of regional nodal recurrence if
CLND is not performed? In two large prospective ran-
domized trials, the Sunbelt Melanoma Trial and the MSLT
I trial, the rate of positive nonsentinel nodes among
patients who underwent CLND for a tumor-positive SLN
was 16%.2 In a retrospective multi-institutional study by
Wong et al. of 134 SLN-positive patients who did not
undergo CLND, regional nodal recurrence was a compo-
nent of first recurrence in 15% of patients.3 Overall, 41% of
patients experienced regional nodal metastasis as a com-
ponent of their recurrence; undoubtedly some of these
patients eventually underwent therapeutic lymphadenec-
tomy for control of regional nodal disease as well. Wong
et al. reported a statistically insignificant trend toward
decreased nodal recurrence-free survival in the group of
patients who did not undergo CLND but no difference in
overall survival compared to a contemporary series of
patients who underwent CLND.3 Therefore, we can rea-
sonably conclude from these data that the risk of
developing clinically apparent and meaningful regional
nodal recurrent disease as the first site of recurrence is at
least 15%; the fact that only 5% of patients in the study of
Kingham et al. developed nodal metastasis as the first site
of recurrence is likely not generalizable to the entire pop-
ulation of patients with tumor-positive SLN.1
Next, we must ask the question: does CLND for patients
with a tumor-positive SLN improve regional disease con-
trol? In MSLT I, the rate of regional nodal recurrence after
CLND was 4.2%.2 In the Sunbelt Melanoma Trial, it was
4.9% (unpublished data). This is much lower than the 15%
rate of regional nodal recurrence as a site of first metastasis
and 41% overall regional nodal recurrence rate in the study
by Wong et al.3 In retrospective studies of therapeutic
lymphadenectomy for clinically detectable (palpable)
metastases, the rate of regional nodal recurrence ranges
from 14 to 52% overall, and from 31 to 63% in high-risk
groups with extracapsular extension, multiple positive
nodes, nodal metastasis C3 cm in size, or cervical nodal
basin location.4 On the basis of these comparisons of data
from prospective and retrospective data, which have
obvious limitations, one would conclude that CLND for
patients with tumor-positive SLN is an excellent strategy
for achieving regional disease control. Although some have
suggested that patients with a tumor-positive SLN who do
not undergo CLND can be followed by ultrasound exam-
ination of the regional nodal basin to detect nodal disease
before it becomes bulky and difficult to control, this
strategy remains unproven. Those of us who are called
upon try to achieve regional disease control once it has
been lost understand the nature of the intense pain and
suffering it can cause. Hence, achieving regional disease
control is a laudable surgical goal; we as surgeons should
remember our solemn obligation to achieve it. Until final
results of MSLT II are available, we will not be able to
determine with greater-level evidence the effect of CLND
on regional disease control. Until that time, the best evi-
dence we have suggests that CLND is effective at
achieving regional disease control in most patients.
CURE
Surgeons, by definition, are locoregional disease control
specialists. All we can do is resect the cancer, wherever we
may find it, locally or regionally. To the extent that we cure
any patients, it is because they do not already have distant
metastatic disease at the time we resect their local and
regional disease. Resection of stage IV melanoma, when
possible, also results in 5-year survival rates of up to 40%.5
Do we cure patients with regional nodal metastases by
lymphadenectomy? The answer is a resounding yes. Even
before the advent of SLN biopsy, we cured approximately
one-third of patients with regional nodal disease by thera-
peutic lymphadenectomy. Given that there are no
universally accepted effective adjuvant therapies that
improve overall survival (even high-dose interferon alfa-2b
therapy is controversial), and given that there are no sys-
temic therapies for stage IV melanoma that have been
shown to improve overall survival, surgical resection of all
sites of disease is still the best thing we can do for mela-
noma patients with every stage of disease.
MSLT I (which randomized patients to SLN biopsy vs.
no SLN biopsy) showed no benefit in terms of overall
Why Does No One Want to Perform CLND? 359
survival, likely because only a minority of patients (16%)
had tumor-positive SLN and could be potentially helped by
removal of regional lymph nodes.2 However, considering
only the node-positive subgroups, the 5-year survival rate
for patients with tumor-positive SLN who underwent
CLND was 72.3 vs. 52.4% for patients who did not
undergo SLN biopsy and who developed palpable nodal
disease (hazard ratio .51; 95% confidence interval, .32–.81;
P = .004). Similarly, in the Sunbelt Melanoma Trial, the
5-year overall survival rate for patients with tumor-positive
SLN who underwent CLND was 67% (unpublished data).
Therefore, we cure most patients with stage III disease
these days by early detection and aggressive surgical
resection of nodal metastases. Whether or not we cure the
same number of patients if we eliminated routine CLND
remains to be seen. However, it is predictable that even if
MSLT II (which randomizes patients with a tumor-positive
SLN to CLND vs. no CLND) demonstrates a difference in
survival, it will be quite small, because only 16% of
patients are expected to have nonsentinel node metastases
and could potentially be helped by lymphadenectomy.
WHY DO SURGEONS NOT WANT TO PERFORM
CLND ANYMORE?
Yes, I have had some patients who chose not to undergo
CLND, and in most of those cases, I influenced their
decision. Usually this was in older patients with other
comorbidities, for whom a 15% or so risk of regional nodal
recurrence was less than their risk of dying of other
problems within the next few years. Why did I even per-
form SLN biopsy for these patients? Because, for patients
with high-risk primary melanomas, SLN biopsy alone does
provide a measure of regional disease control. Most
patients with tumor-positive SLN (84% from MSLT I and
Sunbelt Melanoma Trial data) have no additional nodes
detected via CLND. We must recognize, however, that
routine histopathology of nodes in the CLND specimen
may miss small foci of metastatic disease that may become
clinically apparent at a later date. Nevertheless, most
patients will not benefit from CLND. Given the risk/benefit
ratio, I think it is sometimes appropriate to suggest that
CLND should be avoided. However, this is only in a small
fraction of patients with extenuating circumstances. Most
patients, however, do not want to leave cancer behind, and
they want to do everything possible to prevent recurrence.
For which other diseases do we deliberately perform less
than an R0 resection when it easily can be achieved? How
is this different from what surgical oncologists do for other
diseases? I would argue that the risk/benefit ratio for
CLND for melanoma is more favorable than that of radical
resections for pancreatic cancer, esophageal cancer, locally
advanced stomach cancer, etc. Even a 15% risk of nodal
recurrence (which is the minimum estimate I would use) is
too high for most patients.
Surgeons do not want to perform and patients do not
want to undergo CLND because of the morbidity of these
procedures. Until such time as we have an accurate way to
determine which SLN-positive patients have a minimal risk
of nonsentinel node metastases, it is difficult to balance the
benefits and risks of lymphadenectomy when only a
minority of patients can potentially benefit from this pro-
cedure. However, in a study comparing patients who
underwent inguinal lymph node dissection for a tumor-
positive SLN versus palpable nodal metastases, Sabel et al.
showed that patients with palpable nodal disease had a
significantly greater number of involved nodes (3.0 vs.
1.96, P = .0013), more often had more than four involved
nodes (29 vs. 9%, P \ .001), and had a greater incidence of
extranodal extension (47 vs. 5%, P \ .001).6 An under-
appreciated reason to perform CLND for positive SLN, as
opposed to waiting to see if the patients develop clinically
evident disease, involves the role of adjuvant radiotherapy.
In many centers, despite limited data to support its use, the
finding of involved nodes of[3 cm in size, multiple tumor-
positive nodes, or extracapsular extension is an indication
for adjuvant radiotherapy.4 There can be no question that
radiotherapy to regional nodal basins adds additional
morbidity and contributes to lymphedema. In the study of
Sabel et al., wound complications (28 vs. 14%, P = .02)
and lymphedema (41 vs. 24%, P = .025) were signifi-
cantly greater among patients with palpable nodal disease
versus those with a positive SLN. However, regional nodal
recurrence was not significantly greater in patients with
clinically palpable disease (13 vs. 9%, P = not significant),
although the authors note that this result was possibly the
result of the significantly greater rate of distant recurrence
(49 vs. 18%, P \ .001) and death (48 vs. 21%) in patients
with palpable disease versus a positive SLN, respectively.
In virtually all cases, regional nodal recurrence after lym-
phadenectomy was associated with development of distant
metastatic disease.6 Given the fact that the morbidity, at
least for groin dissection, is significantly greater for
patients who undergo therapeutic lymphadenectomy for
palpable disease versus CLND for microscopically positive
SLN, is it not perhaps a better strategy to perform CLND
when we find tumor-positive SLN? 6
How morbid is regional lymphadenectomy anyway? Is it
as bad as we think? A study by de Vries et al. that exam-
ined quality of life (QoL) in melanoma patients who
underwent SLN biopsy alone (with tumor-negative nodes)
or SLN biopsy plus CLND provides some intriguing
results.7 The study included patients with axillary and
inguinal SLN biopsy and CLND. Surprisingly, the overall
group of patients reported better overall QoL than a
360 K. M. McMasters
German norm group. Furthermore, this study did not con-
firm the hypothesis that patients in the CLND group had
lower QoL scores than patients who only underwent SLN
biopsy. Interestingly, the group that underwent axillary
lymphadenectomy reported greater problems than those
who underwent inguinal lymph node dissection.7 We all
know that lymphadenectomy is associated with morbidity,
including lymphedema, but this study suggests that overall,
the effect on QoL is not clinically meaningful—at least, it
is not as devastating as some of us imagine. The unan-
swered question is whether, to patients, the utility of
preventing nodal recurrence exceeds the potential negative
impact of lymphadenectomy on QoL. Given these data, the
choice between CLND and leaving behind nodal disease
that will become clinically apparent in at least 15% of
patients seems easier.
FINAL THOUGHTS
Would we cure the same number of patients if we did
not perform CLND? Perhaps, but do we want to make this
assumption on the basis of nonrandomized retrospective
data subject to selection bias? I don’t. The study of mela-
noma is rife with examples of nonrandomized dogma that
evaporates in the face of randomized controlled trials. If
not for randomized trials, we would still be performing 5-
cm-margin-wide local excisions, elective lymph node dis-
sections, adjuvant hyperthermic limb perfusions, routine
biochemotherapy for patients with stage IV disease, and we
would still be conducting interminable phase II studies of a
variety of melanoma vaccines that have since been shown
to be ineffective, if not harmful. Perhaps the conclusions I
draw by comparison of randomized, nonrandomized, and
retrospective data about the value of CLND are similarly
flawed; I hope MSLT II will tell us the answer. Until then,
the elusive truth remains uncertain—but an excellent topic
for editorialists.
REFERENCES
1. Kingham TP, Panageas KS, Ariyan CE, et al. Outcome of patients
with a positive sentinel lymph node who do not undergo
completion lymphadenectomy. Ann Surg Oncol. (in press).
2. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or
nodal observation in melanoma. N Engl J Med. 2006;355:1307–17.
3. Wong SL, Morton DL, Thompson JF, et al. Melanoma patients
with positive sentinel nodes who did not undergo completion
lymphadenectomy: a multi-institutional study. Ann Surg Oncol.
2006;13:809–16.
4. Guadagnolo BA, Zagars GK. Adjuvant radiation therapy for high-
risk nodal metastases from cutaneous melanoma. Lancet Oncol.
2009;10:409–16.
5. Martinez SR, Young SE. A rational surgical approach to the
treatment of distant melanoma metastases. Cancer Treat Rev.
2008;34:614–20.
6. Sabel MS, Griffith KA, Arora A, et al. Inguinal node dissection for
melanoma in the era of sentinel lymph node biopsy. Surgery.
2007;141:728–35.
7. de Vries M, Hoekstra HJ, Hoekstra-Weebers JE. Quality of life
after axillary or groin sentinel lymph node biopsy, with or without
completion lymph node dissection, in patients with cutaneous
melanoma. Ann Surg Oncol. 2009;16:2840–7.
Why Does No One Want to Perform CLND? 361


A rational surgical approach to the treatment of distant melanoma metastases. Cancer Treat Rev.

Adjuvant radiation therapy for highrisk nodal metastases from cutaneous melanoma. Lancet Oncol.

Inguinal node dissection for melanoma in the era of sentinel lymph node biopsy.

Melanoma patients with positive sentinel nodes who did not undergo completion lymphadenectomy: a multi-institutional study. Ann Surg Oncol.

MortonDL,ThompsonJF,CochranAJ,etal.Sentinel-nodebiopsyor nodal observation in melanoma.

Outcome of patients with a positive sentinel lymph node who do not undergo completion lymphadenectomy. Ann Surg Oncol.

Quality of life after axillary or groin sentinel lymph node biopsy, with or without completion lymph node dissection, in patients with cutaneous melanoma. Ann Surg Oncol. 2009;16:2840–7. Why Does No One Want to Perform CLND?

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