Download Sentinel node: Next Level questions

The Sentinel Node:
1) Neoadjuvant Chemotherapy
2) Ipsilateral Breast Cancer Recurrence
EJW 2006
Basic Concepts
Sentinel node (SLN) “biopsy” has been demonstrated to be remarkably
accurate in evaluating the axilla for nodal metastases. It is at least as
good for axillary assessment as axillary lymph node dissection (ALND)
and probably superior.[1] In the past, standard pathology evaluation of
ALND nodes resulted in a 7-20% false negative result when re-evaluated
by serial sectioning.[2,3] SLN evaluation yields a 5-6% false negative
rate. In “early” breast cancer, and even after neoadjuvant chemotherapy,
studies show that when the sentinel node is positive it is the only positive
lymph node about 50% of the time.[4,5] That fact may explain why
standard evaluation tends to miss more positive axillary states than the
more intensive study of the SLN.
Additionally, long term follow-up of sentinel node negative patients
with no ALND has recurrence rates of 1.5% or less.[6] From an axillary
risk standpoint, even with a positive sentinel node and standard BCT Rx,
axillary recurrence is rare.[7,8]
Survival after negative SLN treated with adjuvant Rx is superior to
historical NSABP series with node negative standard ALND with
adjuvant Rx, suggesting that missed positive nodes in old studies lead to
errors in stage and prognosis. Improved data on modern SLN studies
leads to more accurate classification.[9]
Moreover, there is abundant data from randomized studies suggesting
that axillary node dissection, per se, provides no benefit to overall
survival.[10-15] This may be especially true in the setting of BCT where
chemotherapy and radiation therapy functionally target any “missed”
axillary disease.[16-22] The recent development of multigene assays
capable of predicting pCR may further limit the need for axillary
dissection to those proven to be at high risk of incomplete
response.[23,24] These studies were performed on RNA obtained by
FNA of the tumor.
Therefore SLN (selective sentinel-lymphadenectomy) is
extraordinarily useful in obtaining needed information for treatment
planning while minimizing risk and morbidity.
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Sentinel node: Next Level questions
There are new settings (previously thought to be contraindications) in which
sentinel node evaluation may be useful.
• Peri- neoadjuvant chemotherapy, (i.e. post or pre neoadjuvant.)
• Ipsilateral breast tumor recurrence (IBTR) with prior axillary
interventions.
Post Neo-adjuvant Chemotherapy Axillary Node Issues
Neoadjuvant chemotherapy has become increasingly used in the setting of
more advanced local disease. Originally used in inflammatory breast cancer,
it has been recently extended to locally advanced non-inflammatory cases in
the hope of reducing subsequent mortality as yet with no proof in that
application. Trends suggesting benefit in overall survival were noted in nine
year follow-up in the B-18 trials for pre-menopausal patients, but worsened
survival was noted in post-menopausal patients, and the net effect was no
overall change in survival.[25] (These issues may prove to be very different
with her-2-neu positive patients treated with herceptin.)[26] Many studies
show an approximate 25% complete pathologic response (cPR) to neo
adjuvant chemotherapy. That response predicts for a better longterm
outcome. However, recent evidence suggests that gene expression profiles
of the tumor will allow accurate prediction of cPR, possibly eliminating the
need for the clinical “test”.[24] Certainly a significant number of patients
can be converted to BCT rather than mastectomy by neoadjuvant
chemotherapy, though there can be substantial theoretical questions about
this approach, (e.g., does the known increase risk for local recurrence after
conversion to BCT contribute to decreased overall survival and cancel the
benefit of neoadjuvant treatment?)[27-32]
With the increased frequency of neoadjuvant therapy there has not been a
standard approach to the axillary nodes. It would be appropriate to consider
some standards.
The fundamental question underlying this analysis will be:
“What do we want to know and why do we think we want to know it”
• Is sentinel node ID possible in this setting?
• Is the sentinel node concept meaningful in this setting? I.e. => (Will it
change therapy/ Surgery, Chemo or Rad Rx?)
• Does a positive sentinel node imply additional positive nodes?
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Can ALND be avoided if SLN Negative?
Should the approach for clinical N0 be different from N1/N2 patients?
Should SLN BX be done pre Neoadj Rx (instead of or in addition to)
Should a positive sentinel node in the Axillary Node Dissection Group
lead to more detailed study of additional nodes? If a sentinel node is
positive, added levels used to evaluate non-sentinel nodes may result in ~
20% positive non-sentinel node? (Will evidence of additional positive
nodes change Rx.)
• In ALND patients, it is the sentinel node “positive” by SLN protocol,
remainder “negative” by standard protocol that may be significant. If the
sentinel node is not identified the positive status may be missed, since it
may be the only positive node 50% of the time. If ALND “only” without
SLN ID then may miss metastases at only two levels per node. SLN the
Only + node ~30-50%[33,34]
Other Issues
• Sentinel node count may be lower post neoadjuvant Rx[35]
• What is the correlation between in breast CPR and nodal CPR. Can true
CPR in the axilla be based on “standard pathology” of a standard ALND?
Axillary Nodes After Neoadjuvant ChemoRx
•
Le Bouedec, Geissler, et al
2006[36]
74 pts T1T2T3N0N1 POST neo
SLN 68/74 (92%) then ALND
Mets in 30/68 (44%) i.e. Neg 56%
False neg 14% But if clinically neg N0 pre RX then accuracy 100% and
FN 0%
In 32 N1 patients accuracy 83% FN 25%
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Reitsamer, Peintinger, et al (2003)[33]
30 Patients Stage II or III, Rx Neoadj Chemo
Attempted SLN with completion ALND
SLN 26 of 30 (86.7%) (could not ID SLN in 4 (13.3%)
SLN accurate 25 of 26 (96.2%)
11 pts Neg SLN and Neg ALND
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3
• 6 pts Pos SLN and Pos ALND
• 8 pts SLN pos and the only Pos node (~30%)
• 1 pt false-neg (1/15 = 6.7%)
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Cohen, Breslin, et al (2000)[37]
38 pts, stage II or III treated with neoadjuvant chemo
SLN attempted then ALND
If SLN neg then all other nodes 3 add’l levels + IHC
SLN ID in 31 (82%) and accurate 28 (90%)
3 False neg
4 of 20 “neg” SLN with add’l studies + for occult mets (20%)
Kinoshita, Takasugi, et al, 2006[38]
Post neo 77 pts Stage II and III
Clinically node neg post Rx
SLN then ALND
SLN ID 72 of 77 (93.5%)
69 of 72 accurate (95.8%)
3 of 27 False Neg (11%)
Mamounas, Brown et al
NSABP B-27[34]
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428 pts
SLN then ALND
SLN ID 89% with isotope
+SLN the only + node in 56% (70 of 125)
Of 218 Neg SLN nonsent + 15 => False neg 11%
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Kuerer, Sahin, et al (1999)[39]
191 pts “cyto +” ALN => neoadj chemo
Surgery ALND
43 pts ALND “neg” re-eval confirmed Neg (add’l 1112 sections/half IHC)
=>43 of 191 “+” converted to neg (23%) by neoadj chemo
Of those 43, 11 were N1 and 32 were N2
If Converted to Neg: 5 yr surv = 87%
If Residual Positive: 5 yr surv = 51%
If Occult Positive (10%): 5 yr = 75%
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• Proposed: maybe consider SLN
POST-NEO PTS
SLN
SLN ID
False Neg
SLN
Accurate
Le Bouedec 74 PTs
2006
SL/ALND
68
(92%)
14%
If cN0 pre
0%
83%
100%
Reitsamer
30
2003
SLN/ALND
Cohen
38
2000
SLN/ALND
26
86%
25/26
96%
31
82%
28/30
90%
Kinoshita
77
2006
SLN/ALND
B-27
428
72/77
93%
3/27
11%
89%
11%
SLN only+
8/30
30%
72/77
96%
70/125
56%
SLN before Neo adjuvant
Van Rijk, Nieweg, et al 2006[40]
• Reviewed 18 studies SLN after neoRX, SLN ID 89%, FN 10%
Then studied:
• SLN in 25 T2 preRX
• if pre SLN + then ALND after neoadj
• 10 pos SLN=>post Rx ALND=> 4 pts addl nodes pos in compl ALND
• 14 SLN Neg pts=> no completion ALND =>no recurrence 18 mo
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Kahn, Sabel, et al 2005[41]
91 patients pre neo axillary staging
Pre neo SLN Bx path Neg 58% (53 pts)
Pre neo Pos by US FNA or SLN 42% (38 pts)
These 38 pts then Neo=>then ALND
33 of these SLN attempted, found 32 (97%)
33% of these Node Negative on ALND
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• Residual disease 22 patients
• “False negative” 1 pt (4.5%)
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Cox,Cox, et al., 2006[16]
89 pts (42 palp or image+ histo proven; 47 cN0)
47 cN0 SLN preRX
82 of 89 + nodes
7 (8%) of 89 neg SLN=>no completion ALND (no recurrence in25 mo)
24 (27%) pCR axilla; 26% grp 1 and 33% grp 2
Demonstrated improved prognosis, avoided ALND 15%, improved
staging 53%
Comparison
Jones, Zabicki, et al., 2005[42]
• SLN ID rates better pre than post 100% vs 80.6%
• Recommend SLN in cN0 pre Rx and question its use post neo
Proposed
• If accuracy is important to the overall treatment planning and
sequencing, then pre-treatment workup requires staging the axilla. If
clinically + or US + then Bx; if cN0 and US/N0 Then SLN Bx pretreatment
• If pre-treatment SLN is negative (with good mapping and careful
assessment), then leave the axilla alone post treatment.
• If pre-treatment SLN or US/FNA are positive, then post treatment
ALND with SLN ID.
• If post treatment axillary status is important in defining added
treatment then repeat SLN and complete ALND with additional levels
in non-SLNs if the SLN is positive.
Next Question: IBTR
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The increased use of breast conservation therapy will continue to increase
the number of patients who present with ipsilateral “in-breast” recurrence
(perhaps as high as 1-2% per year). In this setting prior axillary
interventions (ALND or SLN Bx) have generally been performed. These
“recurrences” represent both true recurrences (same site) and new primaries.
In many of these patients the implication of node metastases, or lack thereof,
should be equivalent to the original setting. If knowledge of the nodal status
is therapeutically important, then reassessment is required. This may be
particularly important in “late” recurrences that are more likely to be true
new primaries. A number of studies have looked at the question of “repeat
nodal evaluations”.
Dinan, Nagle, et al 2005[43]
• 16 pts second IBTR
• Lymphoscintigraphy pos 69%
• Ipsi ax, contra ax, supraclav (ipsi and contra)
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Intra, Trifiro, et al, 2005[44]
79 pts recurrent disease prior SLN 18 pts cN0 ~ 26 mo after initial Dx/Rx
Pre op ID SLN 100% with lymphoscintigrapy and SLN removed average
1.3
SLN pos in 2 patients
At 12 mo no recurrences in pts SLN Neg w/o ALND
Re-operative SLN
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Taback, Nguyen, et al 2006[45]
15 pts prior Rx BCT with IBTR and prior SLN or ALND
Preop Lymphoscintig + 11 (73%)
3 contralat ax, 5 ipsilat ax, 2 IM, 2 SC, 2 Intra pect
Intraop ID 11 of 14, Mets in 3; 2 contralat ax and 1 ipsilat ax
Individual Reports
• Milardovic 2006 Epigastric node[46]
• Jackson 2006 IBTR prior neg now Pos SLN single pt[47]
• Agarwal 2005 Two pts prior BCT with ALND => IBTR => SLN
contralateral +. SLN neg X 2[48]
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Newman 2006[49]
• 14 LRR (10 previous ALND, 2 SLN, 2 no ax surg)
• SLN ID 90% no mets, non ipsilat drainage in 65%
Proposed
• With IBTR and prior Ax RX SLN ID (a neo-SLN) is possible ~ 70%
of the time, but the potential sites are many. Therefore
lymphoscintigraphy and planning SLN Bx are justified if a change in
therapy would occur; e.g. 1) If a positive ipsi- or contra- lateral
axillary neo-SLN would then lead to ALND. 2) If a positive neo-SLN
would lead to an increase in Chemo Rx or Rad Rx. (For internalmammary and supraclavicular nodes minimal data is available, but
Chemo or Radiation are probably the only useful interventions if
nodes are proven positive.)
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