Sentinel Lymph Node Biopsy (SNLB) in Early Stage Breast Cancer

1

TITLE:TITLE:TITLE:TITLE: Sentinel Sentinel Sentinel Sentinel Lymph Lymph Lymph Lymph Node BiopsyNode BiopsyNode BiopsyNode Biopsy (SNLB)(SNLB)(SNLB)(SNLB) in Early Stage in Early Stage in Early Stage in Early Stage

Breast CancerBreast CancerBreast CancerBreast Cancer

AUTHOR:AUTHOR:AUTHOR:AUTHOR: Jeffrey A. Tice, MDJeffrey A. Tice, MDJeffrey A. Tice, MDJeffrey A. Tice, MD

AssociateAssociateAssociateAssociate Professor of MedicineProfessor of MedicineProfessor of MedicineProfessor of Medicine

Division of General Internal Division of General Internal Division of General Internal Division of General Internal MedicineMedicineMedicineMedicine

Department of MedicineDepartment of MedicineDepartment of MedicineDepartment of Medicine

University of California San FranciscoUniversity of California San FranciscoUniversity of California San FranciscoUniversity of California San Francisco

PUBLISHER:PUBLISHER:PUBLISHER:PUBLISHER: California Technology Assessment ForumCalifornia Technology Assessment ForumCalifornia Technology Assessment ForumCalifornia Technology Assessment Forum

DATE OF DATE OF DATE OF DATE OF

PUBLICATION:PUBLICATION:PUBLICATION:PUBLICATION: October 17October 17October 17October 17, 2012, 2012, 2012, 2012

PLACE OF PLACE OF PLACE OF PLACE OF

PUBLICATION:PUBLICATION:PUBLICATION:PUBLICATION: San Francisco, CASan Francisco, CASan Francisco, CASan Francisco, CA

2

SENTINEL SENTINEL SENTINEL SENTINEL LYMPH LYMPH LYMPH LYMPH NODE BIOPSY IN NODE BIOPSY IN NODE BIOPSY IN NODE BIOPSY IN EARLY STAGE BREAST CANCEREARLY STAGE BREAST CANCEREARLY STAGE BREAST CANCEREARLY STAGE BREAST CANCER

A Technology Assessment

INTRODUCTIONINTRODUCTIONINTRODUCTIONINTRODUCTION

The California Technology Assessment Forum (CTAF) was asked to assess the

evidence for the use of sentinel node biopsy during surgical resection of early stage

breast cancer. The standard approach to the surgical evaluation of breast cancer has

been to do an axillary lymph node dissection, but this procedure is associated with a

significant risk for lifelong symptoms in the ipsilateral arm including lymphedema, pain,

neuropathy, and decreased range of motion. Despite the lack of clinical trial evidence,

the trend among surgeons has been to remove the first lymph nodes draining the breast

and only performing axillary node dissection if the so-called sentinel node contains

metastatic breast cancer. Several large randomized trials have recently published their

primary results.

BACKGROUNDBACKGROUNDBACKGROUNDBACKGROUND

Breast Cancer

Cancer of the breast is the most common form of cancer in women. Every

American woman is estimated to have a one in eight chance of developing breast

cancer at some time during her life. In 2012, there will be an estimated 226,870 new

cases of invasive breast cancer in the United States and an estimated 39,510 deaths

from this cancer.1 This represents approximately 29% of all new cancer cases and 14%

of all cancer deaths in women.1

3

The staging system of the American Joint Committee on Cancer (AJCC)2 defines

Stage I, II, and IIIA invasive breast cancer as early stage breast cancer. In the TNM

(Tumor Node Metastasis) staging system for breast cancer, stage T1 refers to

carcinomas 2.0 cm or less in greatest dimension; stage T2 refers to tumors more than

2.0 cm, but not more than 5.0 cm in greatest dimension; stage T3, to tumors more than

5.0 cm in greatest dimension; and stage T4, to tumors of any size that have direct

extension to chest wall or skin. Stage N0 refers to tumors without regional lymph node

metastasis and N1 refers to tumors with ipsilateral metastases to mobile level I or II

axillary lymph nodes. N2 refers to tumors with ipsilateral metastases to fixed or matted

level I or II axillary lymph nodes. N3 refers to tumors with ipsilateral metastases to level

III axillary lymph nodes, internal mammary lymph nodes or supraclavicular lymph

nodes. M0 refers to tumors without distant metastases and M1 to distant metastases.

The stages of breast cancer are defined below.

• Stage 0 - Carcinoma in situ

• Stage I – T1 N0.

• Stage IIA – T1 N1 or T2 N0

• Stage IIB – T2 N1, or T3 N0.

• Stage IIIA – T1-2 N2 or T3 N1-2

• Stage IIIB – T4 N0-2

• Stage IIIC – Any T N3

• Stage IV – Any T, Any N M1

Treatment of early stage breast cancer

Nodal status used to be one of the most important prognostic factors in breast

4

cancer.3 For example, the five year survival for localized breast cancer is 99%, but for

patients with positive lymph nodes it is only 84%.4 Lymph node status is also an

important determinant of the treatment offered for breast cancer. In almost all cases,

treating physicians will offer systemic chemotherapy to patients with positive lymph

nodes, but not to patients with small, node negative cancers with other favorable

tumor characteristics.5

Staging and risk assessment have important limitations. Patients with the same

stage breast cancer can have markedly different responses to therapy and long-term

outcomes.6,7 The majority of women with hormone receptor positive, node negative

breast cancer have no evidence of breast cancer recurrence after ten years of follow-

up, even if they are classified in a higher risk group using standard clinical

measurements. In the NSABP-20, a randomized trial of women with estrogen receptor

positive, lymph node negative breast cancer less than five cm in diameter, 83% of

women treated with tamoxifen alone were disease free at ten years.8 However, many

patients with early stage breast cancer are treated with chemotherapy in the United

States.

Sentinel Lymph Node Biopsy (SLNB)

Traditionally, axillary lymph node dissection (AD) is done as part of the standard

treatment for early stage breast cancer. Identifying the number and location of axillary

lymph nodes that contain metastatic disease provides important staging information

and influences treatment decisions as described above. In addition, removal of the

affected lymph nodes may help to reduce the risk for recurrence of breast cancer in the

axilla and to reduce the risk for later metastatic recurrence.

5

However, axillary lymph node dissection can cause significant morbidity. The

disruption of the lymphatic system in the axilla can cause significant lymphedema in

the ipsilateral arm. In addition, women may experience long-term sensory loss, pain,

and a decrease in the range of motion of the affected arm. The majority of women with

early breast cancer do not have lymph node involvement; so axillary lymph node

dissection puts them at risk for complications with no benefits.

Surgeons developed sentinel lymph node biopsy to identify women who may not

need further axillary node dissection.9,10 Theoretically, tumor cells should travel along

lymph channels near the primary tumor and spread to one or more proximal lymph

nodes before spreading to additional lymph nodes deeper in the drainage system. The

sentinel node is any node that directly drains the primary tumor. Thus, there can be

more than one sentinel node. If the first or sentinel lymph nodes do not contain tumor,

then theoretically the remainder of the lymph system should be free from cancer and

complete axillary lymph node dissection can be avoided.

Surgeons use two classes of tracers to identify the sentinel lymph nodes: blue dyes

and radioactive colloid. One or both of these are injected either around the tumor or in

the subareolar region of the affected breast.9,10 The tracers travel along the lymphatic

channels draining the breast to the axilla enabling the surgeon to identify the sentinel

node. The tracer should not be injected directly into the tumor or into the tumor cavity

if lumpectomy has already been performed because the lymphatic system may be

disrupted or occluded in those locations. Comparative studies suggest that sentinel

nodes are identified more frequently with radioactive colloid than with blue dye and

that the combination of both agents is associated with a higher sensitivity for the

6

detection of nodes with metastatic disease.11-14

Isosulfan blue dye is the recommended dye. The surgeon injects about five cc of

dye at the time of surgery.9,10 The surgeon then massages the breast for about five

minutes to dilate the lymphatic ducts and enhance drainage of the dye into the axilla. A

small inferior incision is made in the axilla and the region is carefully inspected for blue

lymphatic vessels leading to blue lymph nodes. The most blue node and the node

closest to the tumor are usually removed. Finally, the axilla is inspected and palpated

for additional suspicious lymph nodes and those are removed.

A number of different radioactive colloids have been studied.9,10 In the United

States, Technetium-labeled sulfur is most commonly used. In Europe, Technetium-

labeled albumin is commonly used; Technetium-labeled antimony is also used. Prior to

skin incision, a hand-held gamma probe is used to locate radioactively “hot” spots in

the axilla. During surgery, an incision is made at the hot spot and the gamma probe

guides the surgeon to the sentinel node or nodes.

Early studies found that these techniques identify a sentinel node in between 92%

and 98% of patients15,16 and there is 97% to 100% concordance between the SLNB and

AD.9,17-19 The primary concern with SLNB is false negatives: patients that have no

metastases found on SLNB, but do have positive lymph nodes on AD. These patients

may be at higher risk for local recurrence and a meta-analysis performed by the Early

Breast Cancer Trialist’s Collaborative Group has documented that better local control

eventually leads to fewer deaths from breast cancer.20 A systematic review of 69 studies

performed in 2004 as part of guideline development for ASCO found that the false

negative rate (1-sensitivity) ranges from 0% to 15%.13 More importantly, observational

7

studies have reported very low rates of axillary recurrence following a negative sentinel

lymph node biopsy.21

The detection of sentinel nodes is a technically difficult procedure with a significant

learning curve. The American Society of Breast Surgeons has published guidelines on

credentialing criteria and recommend a minimum of 20 procedures either proctored or

with axillary dissection prior to performing SLNB alone.22

TECHNOLOGY ASSESSMENT TECHNOLOGY ASSESSMENT TECHNOLOGY ASSESSMENT TECHNOLOGY ASSESSMENT (TA)(TA)(TA)(TA)

TA Criterion 1:TA Criterion 1:TA Criterion 1:TA Criterion 1: The technology must have final approval from the appropriate The technology must have final approval from the appropriate The technology must have final approval from the appropriate The technology must have final approval from the appropriate

government regulatory bodies.government regulatory bodies.government regulatory bodies.government regulatory bodies.

Sentinel lymph node biopsy (SLNB) is a procedure and therefore not under the

purview of the U.S. Food and Drug Administration (FDA). However, equipment

including instrumentation, assays, etc. used to perform SLNB are under FDA oversight

TA Criterion 1 is met.TA Criterion 1 is met.TA Criterion 1 is met.TA Criterion 1 is met.

TA Criterion 2:TA Criterion 2:TA Criterion 2:TA Criterion 2: The scientific evidence must permit conclusions concerning The scientific evidence must permit conclusions concerning The scientific evidence must permit conclusions concerning The scientific evidence must permit conclusions concerning

the effectiveness of the technology regarding health the effectiveness of the technology regarding health the effectiveness of the technology regarding health the effectiveness of the technology regarding health

outcomes.outcomes.outcomes.outcomes.

The Medline database, Embase, Cochrane clinical trials database, Cochrane reviews

database and the Database of Abstracts of Reviews of Effects (DARE) were searched

using the key words “sentinel lymph node” OR “sentinel node” AND “breast neoplasms”

OR “breast cancer.” The search was performed for the period from 1945 through

September 2012. The bibliographies of systematic reviews and key articles were

8

manually searched for additional references. The abstracts of citations were reviewed

for relevance and all potentially relevant articles were reviewed in full. We included all

randomized trials in women with invasive breast cancer that compared sentinel lymph

node biopsy to axillary lymph node dissection.

The search identified 587 potentially relevant studies (Figure 1). After elimination of

duplicate and non-relevant references the search identified two systematic reviews23,24

and 37 articles describing ten randomized trials. 12,25-60

FFFFigure 1: Selection of studies for inclusion in reviewigure 1: Selection of studies for inclusion in reviewigure 1: Selection of studies for inclusion in reviewigure 1: Selection of studies for inclusion in review

Level of Evidence: 1 and 2Level of Evidence: 1 and 2Level of Evidence: 1 and 2Level of Evidence: 1 and 2

TA Criterion 2 is met.TA Criterion 2 is met.TA Criterion 2 is met.TA Criterion 2 is met.

587 potentially relevant references screened

115 abstracts for assessment

37 references on 10 randomized

trials included in the assessment

56 studies for full text review

194 duplicate citations excluded 278 excluded: not randomized; reviews, abstracts only; other interventions

59 studies excluded (Editorials, reviews, abstracts, no

clinical outcomes)

17 studies excluded: no primary data, reviews

9

TA Criterion 3:TA Criterion 3:TA Criterion 3:TA Criterion 3: The technology must improve net health outcomes.The technology must improve net health outcomes.The technology must improve net health outcomes.The technology must improve net health outcomes.

The two most important outcomes in cancer are overall survival (OS) and disease-

free survival (DFS). Because early stage breast cancer has such a long natural history

and the majority of women do well, large randomized trials with long follow-up are

needed to demonstrate the equivalence of these outcomes in patients managed with

SLNB to patients managed with AD. One of the potential early indicators of worse

outcome with SLNB would be recurrence in the ipsilateral axilla, so the rate of

locoregional recurrence is also an important outcome. Most locoregional recurrence

occurs in the first five years after diagnosis, but DFS requires up to eight years follow-

up to assess differences and ten to fifteen year follow-up is needed for OS. Finally, the

primary reason for doing SLNB is to reduce the morbidity associated with AD, so

important secondary outcomes are the rates of lymphedema, pain, neuropathy, and

reduced range of motion in the ipsilateral arm.

Randomized controlled trials

The initial results of ten randomized trials have been published. The methodologic

quality of the studies is summarized in Table 1 and the characteristics of the studies are

summarized in Table 2. The primary benefits are summarized in Table 3 and the harms

in Table 4. The individual studies are described below.

10

Table 1: Methodological Quality Of The Randomized Trials Comparing Sentinel Lymph Node Biopsy to Axillary Dissection

Study Randomization Allocation concealment

Groups comparable

Blinding Follow-up > 80%

Intention to treat analysis

Quality

Purushotham 200549 UK 3 Centers

Yes Yes Yes No Yes Yes Fair

Goyal 200728,29,31,37-

39,47,48 UK ALMANAC


Helms 200841 Germany KiSS

Yes NR NR No No No Poor

Zavagno 200830,58,60 Italy 18 Centers GIVOM

Yes Yes Yes No Yes NR Fair

Canavase 200927 Italy Single Center


Gill 200926,33,34,50,52,57 Australia / NZ SNAC


Veronesi 201053-55 Italy Multicenter

Yes Yes Yes No Yes No Fair

Fougo 201132 Portugal Single Center


Giuliano 201135,36,46 USA ACOSOG-Z0011


11

Study Randomization Allocation concealment

Groups comparable

Blinding Follow-up > 80%

Intention to treat analysis

Quality

Krag 2010, Weaver 201112,25,40,42-45,56 US, Canada NSABP-B32

Yes

Yes Yes No Yes Yes Fair

12

Table 2: Characteristics Of The Randomized Trials Comparing Sentinel Lymph Node Biopsy to Axillary Dissection *Colloid radiolabeled with technetium

Study

N SLNB technique

SLN Evaluation Inclusion criteria

Exclusion criteria

Enroll period

FU (years)

Age, years

Tumor size

Primary outcome


298 Blue dye +

Albumin*

H&E +

cytokeratin IHC

IBC < 3 cm CN-

Multifocal Prior BC Tx Pregnant

1999-2003

1 58 1.6 cm Morbidity, QOL

Goyal 200728,29,31,37-

39,47,48 UK ALMANAC

1031 Blue dye +

Albumin*

H&E IBC any size CN-

Age < 80 y


1999-2003

1.5 58 75% ≤ 2 cm

Morbidity, QOL


181 Blue dye +

Albumin*

NR IBC < 2.5 cm CN-

NR 2000-2002

0.9 58 71% T1 Morbidity


749 Albumin* H&E +

cytokeratin IHC

IBC ≤ 3 cm CN-

Age ≤ 80 y


1999-2004

4.6 58 81% T1 DFS


248 Blue dye +

Albumin*

H&E +

cytokeratin IHC

IBC < 3 cm CN-

Age 18-75

Multifocal Prior BC Tx

1998-2001 5.5 58 81% T1 DFS


1088 Blue dye +

Antimony*

H&E +

cytokeratin IHC

IBC < 3 cm CN-

Age ≥ 18

Multifocal Prior BC Tx

2001-2005

1 Median 50-69

Median 1-2 cm

Morbidity


532 Albumin* H&E +

cytokeratin IHC

IBC ≤ 2 cm CN-

Age 40-75 y


1998-1999 7.9 56 Median 1.1-1.5 cm

Morbidity


166 Blue dye +

Sulfur*

H&E IBC ≤ 3 cm CN-

Age 18-80 y

Prior Tx Pregnant

2001-2003

6.0 54 NR Axillary recurrence, morbidity

13


891 Blue dye + RI

H&E IBC ≤ 5 cm CN-

Age ≤ 80 y

≥ 3 + nodes Matted nodes

Extranodal dz

1999-2004

6.3 55 1.7 cm OS


5611 Blue dye +

Sulfur*

H&E IBC any size CN-

Age ≥ 18

Prior BC Tx 1999-2004

8.0 25% < 50

84% ≤ 2.0 cm

OS

14

Table 3: Primary Outcomes In The Randomized Trials Comparing Sentinel Lymph Node Biopsy to Axillary Dissection

Study

Group N Success SLNB

Sensitivity Nodes removed

Pathologically node positive

Locoregional recurrence

Disease Free Survival

Overall survival


SLNB

AD

143

155

94% NA NR

NR

36%

NR

NR

NR

NR

NR

NR

NR

Goyal 200728,29,31,37-

39,47,48 UK ALMANAC

SLNB

AD

515

516

98% 93% 2

15

26%

23%

0.2% 1 y

0.8% NS

NR

NR

1.5% 1 y

1.5% NS


SLNB

AD

NR

NR

NR

NR

NR 3

21

NR

NR

NR

NR

NR

NR

NR

NR


SLNB

AD

345

352

95%

95%

83% 1.6

NR

30%

27%

4.6% 5 y

0.9% NR

87.6% 5 y

89.9% 0.77

94.8% 5 y

95.5%

NS


SLNB

AD

124

124

99% 77% 1.8

14.5

29%

30%

0.8% 1 y

0.8% NS

94.5% 1 y

89.8% 0.72

97.2% 1 y

97.2%

0.70


SLNB

AD

544

544

95%

94%

94.5% 1.8

16

31%

28%

NR

NR

NR

NR

NR

NR


SLNB

AD

268

264

100%

100%

91% 1.7

26

36%

35%

2.2% 10 y

2.2% NS

89.9% 10 y

93.5% 10 y

15

Study

Group N Success SLNB

Sensitivity Nodes removed

Pathologically node positive

Locoregional recurrence

Disease Free Survival

Overall survival

88.8% 0.52

89.7% 0.15


SLNB

AD

57

49

99% NR 1.7 37%

NR

0% 6 y

0% NS

NR

NR

100% 6 y

94% .006


SLNB

AD

446

445

100%

100%

NA 2

17

100% by design

100% by design

1.6% 5 y

3.1% 0.11

83.9% 5 y

82.2% 0.14

92.5% 5 y

91.8% 0.25


SLNB

AD

2804

2807

97%

97%

90% 2.8 26%

28%

3.1% 8 y

3.1% NS

88.6% 5 y

89.0% NR

95.0% 5 y

96.4%

0.12

Table 4: Quality of Life Outcomes In The Randomized Trials Comparing Sentinel Lymph Node Biopsy to Axillary Dissection

Study

Group N Lymphedema Seroma Sensory Neuropathy

Shoulder ROM

Pain Quality of life


SLNB

AD

143

155

OR 0.36 (0.2-0.9) p=0.03

14% 1 y

21% 0.10

66% 1 y

84% 0.001

-6.7% 1 y

-13% 0.04

NR Better early, but no difference at 1 year

Goyal 200728,29,31,37-39,47,48 UK ALMANAC

SLNB

AD

515

516

5% 1 y

13% 0.001

NR 11% 1 y

31% 0.001

Loss in AD arm, p 0.004

Slightly higher in SLNB group at 1

year

16

Study

Group N Lymphedema Seroma Sensory Neuropathy

Shoulder ROM

Pain Quality of life


SLNB

AD

NR

NR

P<0.001 for arm volume

favoring SLNB

NR P<0.001 favoring SLNB

P=0.006 favoring SLNB

P<0.001 favoring SLNB

NR


SLNB

AD

345

352

OR 0.48 (0.3-0.8) p=0.01

NR OR 0.51 (0.4-0.7) p < 0.001

OR 0.55 (0.3-0.9) p=0.016

OR 0.74 (0.5-1.1) p=0.11

No significant differences


SLNB

AD

124

124

NR NR NR NR NR NR


SLNB

AD

544

544

2.8% 1 y

4.2% 0.002

17% 1 y

36% 0.0001

NR 2.5% 1 y

4.4% 0.02

SNAC study specific scale 4.4 vs. 7.0,

p<0.001


SLNB

AD

268

264

0% 2 y

12% NR

NR 1% 2 y

68% NR

0% 2 y

21% NR

8% 2 y

39% NR

NR


SLNB

AD

57

49

7% 4 y

38% 0.001

NR 11% 4 y

62% 0.001

4% 4 y

23% 0.005

5% 4 y

15% 0.18

NR


SLNB

AD

446

445

6% 1+ y

19% 0.0001

6% 0.1 y

14% 0.0001

9% 1+ y

39% 0.0001

NR NR NR


SLNB

AD

2804

2807

8% 3 y

14% 0.001

NR 7.5% 3 y

30% 0.001

16% 0.5 y

22% 0.001

No significant difference

after 6 months

Significant early, but no difference at 1

year

17

Summarizing the trials

Table 1 summarizes the quality of the published randomized trials. All of the

studies suffer from lack of blinding to randomization assignment. This could lead to

differences in co-interventions, such as the use of radiation therapy or the use of

adjuvant chemotherapy, which may impact breast cancer mortality. It also could impact

the patient’s self-assessment of ipsilateral arm symptoms and quality of life. Overall the

quality of the trials was fair.

Table 2 highlights the heterogeneity of the patient populations studied, the

techniques used for the identification of the sentinel lymph node, and the

histopathology used to identify cancer in the sentinel nodes. Most of the trials included

patients with IBC ≤ 3 cm with clinically negative axillary lymph nodes. Two of the trials

included only patients with smaller tumors41,54 and two of the trials enrolled patients

with tumors of any size.38,42 The studies generally excluded patients with multifocal

disease and prior breast cancer treatment because of the potential for poor localization

of sentinel nodes and pregnant women due to potential toxicity from both the dye and

the radiation. Most of the studies began enrollment in 1999 or 2000, but only half of

the studies have reported outcomes through five or more years.

The majority of the trials used both blue dye and a radioactive colloid to identify

the sentinel nodes, but two of the trials only used radiolabeled albumin colloid.54,60 Of

note (see Table 3), the two trials that did not use blue dye successfully identified

sentinel nodes in about the same proportion of subjects as the other studies, but the

sensitivity of the sentinel nodes for detection of metastatic disease found with axillary

dissection was low in the GIVOM study.60 In addition, many of the studies used

18

immunohistochemistry (IHC) staining for cytokeratin to increase the sensitivity for

metastatic disease when examining pathologic slides. However, the clinical importance

of metastatic disease identified solely using IHC remains controversial. Most of the

larger, commonly cited studies only classified sentinel nodes as positive or negative for

metastatic breast cancer based on hematoxylin and eosin (H&E) stains including the

NSABP-B32 study, the ACOSOG-Z0011 study, and the ALMANAC study.

There are two other differences in the design of the trials that are not highlighted

in Table 2. First, one study randomized patients to either axillary dissection without

prior SLNB or to SLNB with AD for subjects with a positive sentinel node.49 This design

does not allow for the calculation of the sensitivity of SLNB or the false positive rate (1-

sensitivity) - there is no group of subjects that randomly was chosen to receive both AD

and SLNB. Another study (ACOSOG Z0011)35 performed SLNB on all potential subjects,

but only randomized patients with one or two positive sentinel lymph nodes to AD or

no AD. As opposed to the other trials that examined the utility of AD in patients with

negative sentinel lymph nodes, the primary research question in the Z0011 trial was

whether AD improved patient outcomes in sentinel node positive patients. Because all

of the subjects in the trial were node positive, they would be expected to have a higher

incidence of recurrence and a lower DFS than a study population that included both

sentinel node negative and positive patients. Finally, most of the trials compared the

outcomes of the SLNB group to the AD group as randomized. However, the NSABP

B32 trial42, which was by far the largest and highest quality study, directly compared

the outcomes of the subjects with negative sentinel nodes in the SNLB and AD groups

rather than including subjects with positive sentinel nodes in their analyses. Thus, they

were evaluating whether the outcomes of patients with negative sentinel nodes without

19

AD were equivalent to those of patients with negative sentinel nodes treated with AD.

Because all of the reported outcomes for subjects in the NSABP B32 trial were in

sentinel node negative patients, their recurrence rates should be lower than those

observed in studies including subjects with both positive and sentinel nodes.

Table 3 summarizes the primary outcomes of the study. Surgeons successfully

identified sentinel nodes in 94% to 100% of the study subjects in all studies as had been

described in prior observational studies. However, the sensitivity varied significantly

between studies. Two of the Italian studies had unacceptably high false negative rates

(sensitivity < 90%). In the GIVOM trial30,58,60, the sensitivity of SLNB was 83%. This may

explain the higher locoregional recurrence in this study (4.6% in SLNB group versus

0.9% in AD group, p not reported), although this did not result in significant differences

in five year disease free survival or overall survival. In the second Italian trial, the 77%

sensitivity was not associated with a trend towards greater locoregional recurrence or

lower DFS, though the follow-up may have been too short at one year.

As expected, the number of lymph nodes removed was much lower with SLNB than

with AD (approximately 2 versus 16). About 30% of the randomized subjects had

positive lymph nodes by SLNB or AD. There were no significant differences in DFS or

OS in any of the studies. Trends towards better outcomes favored the SLNB group as

often as they favored the AD group. See the Tables and the discussion of the larger

individual trials below for more detail.

Table 4 summarizes the outcomes in the arm ipsilateral to the primary breast

cancer and the overall quality of life outcomes. Unfortunately, there are no standard

objective or subjective assessments for lymphedema, neuropathy associated with

20

axillary dissection, shoulder range of motion or function, and pain. Each study used

different measures. However the trends consistently favored SLNB for all ipsilateral arm

outcomes. For example, in the NSABP-B32 trial, 8% of the SLNB group reported

lymphedema at the 3-year follow-up compared to 14% of the AD group (p<0.001).

Short term surgical outcomes such as seroma formation, wound infection, and hospital

length of stay were all significantly shorter in the SLNB group. This likely explains why

quality of life outcomes were better in the SLNB group over the first three to six

months of follow-up, although the differences tended to disappear by one year. Many

of the self-reported outcomes could represent measurement bias because of lack of

blinding – patients randomized to the SLNB group may have expected better

outcomes. However many of the studies also estimated arm volume by measuring arm

circumference and measures shoulder range of motion as objective outcomes

supporting the subjective self-reported outcomes.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B32

The NSABP B32 study randomly assigned 5,611 patients to SLNB with AD only if the

sentinel nodes were positive (SLNB group) or to SLNB plus AD (AD group).12,22,25,40,42-

45,56 The study was designed as an equivalence trial with overall survival in subjects with

negative sentinel nodes pre-specified as the primary outcome. It was powered to

detect a difference in overall survival at five years of follow-up with a difference of 2%

or less considered equivalent. Patients with any size tumor were eligible, but the large

majority (85%) had tumors ≤ 2 cm. At the time of the primary analysis, the median

follow-up was eight years and all randomized patients had more than five years of

follow-up.42 There were 2,011 patients in the SLNB group with negative sentinel nodes

21

and 1,975 patients in the AD group with negative sentinel nodes. At five years, the OS

was 95.0% in the SLNB group and 96.4% in the AD group (p=0.12). Similarly the five-

year DFS was 88.6% in the SLNB group and 89.0% in the AD group (p=NR). At eight

years, the OS was 90.3% and 91.8% in the two groups and the DFS was 81.5% and

82.4%. The number of locoregional recurrences were nearly identical during follow-up:

63 (3.1%) in the SLNB group and 62 (3.1%) in the AD group. There was a non-significant

trend towards more recurrences in the SLNB group (14 recurrences versus 8

recurrences, p = 0.22). There were allergic reactions reported by 46 patients (0.8%)

primarily due to the blue dye.

The NSABP B32 trial measured arm volume every six months for three years.25 Arm

volume differences of greater than 10% were still present in 7.5% of the SLNB group

and 14.3% of the AD group (p<0.001). Shoulder abduction deficits of greater than 10%

were most common one week following surgery (41% SLNB group, 75% AD group,

p<0.001), but were still significantly different when last assessed at six months (5.7%

versus 9.0%, p < 0.001). Self-reported numbness and tingling were less common in the

SLNB group at all time points through three years (p<0.001). A subgroup of 749

patients enrolled in the trial completed a series of questionnaires on arm symptoms,

activity limitations, and quality of life at baseline, one and three weeks, and then every

six months through three years.45 There were significant differences in favor of the

SLNB group in self-reported restrictions in occupational activities, recreational activities,

and overall quality of life from one week to six months after surgery, but the scores

were nearly identical in the two groups at twelve months and later.

This trial provides the strongest evidence for the use of SNLB in patients with early

22

stage breast cancer who do not appear to have lymph node metastases on clinical

examination. It is a large randomized trial administered by an organization with a long

track record in performing high quality randomized trials. Follow-up was 99.9%

complete through a median of eight years. There were non-significant trends towards

lower disease free and overall survival at five and eight years of follow-up. The follow-

up is long enough and the trial large enough to detect clinically important differences

in disease free survival: at eight years the absolute difference in disease free survival

was less than 1%. There was also less surgical morbidity in the SLNB group and their

quality of life was better during the six months following surgery. The lack of blinding

may have contributed to some of the difference in self-reported outcomes, but is

unlikely to explain the objective measures of arm volume and shoulder mobility.

The Veronesi et al Italian Study53-55

The other trial with long follow-up (median 7.9 years) published their 10-year

estimates for DFS and OS in 2010.55 As in the NSABP B32, the investigators randomized

532 patients with invasive breast cancers ≤ 2cm to either SLNB with AD only if the

sentinel nodes were positive (SLNB group) or to SLNB plus AD (AD group). However,

the investigators in this Italian study compared all patients as randomized, not just the

patients with negative sentinel nodes. The 10-year locoregional recurrence rate was

2.2% in both arms. The trends in 10-year DFS (89.9% versus 88.8%, p=0.52) and 10-year

OS (93.5% versus 89.7%, p=0.15) both favored the SLNB group.

The American College of Surgeons Oncology Group (ACOSOG) Z0011 Trial35,36,46

The ACOSOG Z0011 trial complements the NSABP B32 trial. Investigators noted

23

that observational studies documented that the sentinel nodes were the only positive

lymph nodes following axillary dissection in about half of patients and that their was

excellent local control in patients with early stage breast cancer and one or two positive

sentinel nodes.9,61. In Z0011, the investigators randomized 821 patients with T1 or T2

invasive breast cancer, no palpable adenopathy, and one or two positive sentinel lymph

nodes to either no further nodal dissection (SLNB group) or standard axillary dissection

(AD group). All patients underwent lumpectomy, tangential whole-breast irradiation,

and appropriate systemic therapy. The trial was designed to enroll 1,900 women in

order to demonstrate equivalence in overall survival, but closed early due to lower than

expected mortality in both groups of the study. After a median follow-up of 6.3 years,

the trends in five year DFS (83.9% versus 82.2%, p NR) and five year OS (92.5% versus

91.8%, p NR) both favored the SLNB group. Locoregional recurrence was also lower in

the SLNB group (1.6% versus 3.1%, p=0.11). The hazard ratio (HR) for OS was 0.79 (95%

confidence interval 0.56 to 1.10). The HR for DFS, which is likely more relevant after this

relatively short follow-up period, was 0.82 (95% confidence interval 0.58 to 1.17).

As expected, surgical morbidity was lower in the SLNB group. These included

wound infection at 30 days (3% versus 8%, p=0.0016), axillary seromas (6% versus 14%,

p=0.001), paresthesias at one year (9% versus 39%, p<0.001), lymphedema at one year

by self report (6% versus 19%, p<0.001), and lymphedema at one year by arm

measurements (6% versus 11%, p=0.079).

Harms

The primary harms specific to SLNB include allergic reactions to the blue dye,

radiation exposure from the radiolabeled colloid, and false negatives. False negatives

24

may lead to understaging and undertreatment of women with node positive breast

cancer that would have been discovered on standard axillary lymph node dissection.

This would potentially lead to higher rates of locoregional recurrence and lower rates

of disease-free and overall survival. Those outcomes were described earlier in the

assessment. The radiation dose is negligible in comparison with the radiation therapy

used for breast cancer following lumpectomy. Allergic reactions are potentially serious,

but relatively uncommon. As documented above in the B32 trial, they occur in less than

1% of all women receiving blue dye for sentinel node mapping.42 Of the 46 allergic

reactions documented in the B32 trial only 10 were grade 4 reactions and 3 were grade

3.

Other systematic reviews and meta-analyses.

The search identified two relatively recent systematic reviews and meta-

analyses.23,24 The first, by Kell et al, identified seven randomized trials including 9,608

patients. They found no difference in the rate of axillary node positivity between SLNB

and AD (OR 1.00, 95% CI 0.95 to 1.17, p=0.96). However, there were significantly fewer

morbidities with SLNB including infection (OR 0.58, 95% CI 0.42-0.80, p=0.001), seroma

(OR 0.40, 95% CI 0.31-0.51, p=0.007), arm swelling (OR 0.30, 95% CI 0.14-0.66,

p=0.003), and numbness (OR 0.24, 95% CI 0.10-0.59, p=0.002).

The second meta-analysis, by Wang et al, focused more on OS, DFS, and

locoregional recurrence. There were no significant differences between SLNB and AD in

OS (HR 1.07, 95% CI 0.90-1.27), DFS (HR 1.00, 95% CI 0.88-1.14), or regional lymph node

recurrence (OR 1.65, 95% CI 0.77-3.6). The trend in regional lymph node recurrence was

concerning, but there was also significant heterogeneity in meta-analysis of this

25

outcome. There was minimal, non-significant heterogeneity for OS and DFS. They also

noted unequivocally fewer morbidities following SLNB including lymphedema,

paresthesias, and seroma formation.

Summary

There are ten published randomized trials comparing SLNB to AD in early stage

breast cancer. Six of the ten have published their five to ten year outcome data, which

should be long enough to see any important trends in DFS, though perhaps not in OS.

There were no significant differences in DFS or OS between the two groups in any of

the studies with some studies showing trends favoring SLNB and others favoring AD.

These differences likely represent random variation. The summary estimates from the

published meta-analyses also suggest no important differences in DFS between SLNB

and AD. These data are still somewhat immature for a disease like early stage breast

cancer, which has a long natural history. At least one of the four studies that has not

published their long-term outcomes data has presented their data at an international

meeting. Additional follow-up from all of the randomized trials will help to better

delineate the role of SLNB. The results of the NSABP B32 trial, in conjunction with the

remaining studies support the use of SLNB for early stage breast cancer, though AD

should still be strongly considered in patients with positive sentinel nodes. The

ACOSOG Z0011 trial suggests that AD may be optional for patients with one or two

positive sentinel nodes. However, the trial recruitment was stopped early and it is the

only trial with data on this topic.

The ten randomized trials and the meta-analyses unequivocally demonstrate fewer

post-surgical morbidities with SLNB. There are short term quality of life benefits from

26

an easier recovery from surgery and long-term benefits in terms of lymphedema,

neuropathy and range of motion of the arm.

Thus, there is solid evidence with reasonably long-term follow-up demonstrating

that patients treated with SLNB have similar breast cancer outcomes as those treated

with AD and unequivocal evidence that the morbidity is less with SLNB.

TA Criterion 3 is TA Criterion 3 is TA Criterion 3 is TA Criterion 3 is metmetmetmet

TA Criterion 4:TA Criterion 4:TA Criterion 4:TA Criterion 4: The technology must be as The technology must be as The technology must be as The technology must be as beneficial as any established alternatives.beneficial as any established alternatives.beneficial as any established alternatives.beneficial as any established alternatives.

The accepted alternative to SLNB is AD. All of the trials described under TA

Criterion 3 compared SLNB to AD. The trials demonstrated equivalent OS, DFS, and

locoregional relapse rates through a median of eight years of follow-up in the largest

trial. In addition, SLNB causes less harm than AD.

TA Criterion 4 is metTA Criterion 4 is metTA Criterion 4 is metTA Criterion 4 is met

TA Criterion 5:TA Criterion 5:TA Criterion 5:TA Criterion 5: The improvement must be attainable outside of the The improvement must be attainable outside of the The improvement must be attainable outside of the The improvement must be attainable outside of the

investigational setting.investigational setting.investigational setting.investigational setting.

Several of the randomized clinical trials trained physicians to perform SLNB at

more than one hundred sites.43,46 In early breast cancer, sentinel lymph node biopsy is

more commonly performed than axillary dissection in the United States and is widely

used around the world. Thus, there is ample real world evidence that SLNB is a

procedure that can be learned by many surgeons. However, it is not a straightforward

surgery. There have been a number of studies evaluating the learning curve for

27

performing sentinel lymph node biopsy.29,40,43,45,62,63 Most agree that a training manual

with detailed descriptions of the technique, intra-operative proctoring by a surgeon

experienced in the technique, and between 20 and 40 cases are needed for proficiency.

The American Society of Breast Surgeons guidelines should be used to credential

surgeons prior to performing SLNB alone.22

TA Criterion 5 is met TA Criterion 5 is met TA Criterion 5 is met TA Criterion 5 is met

RECOMMENDATIONRECOMMENDATIONRECOMMENDATIONRECOMMENDATION

It is recommended that use of sentinel lymph node biopsy meets CTAF TA Criterion

1 through 5 for safety, effectiveness and improvement in net health outcomes for

women with clinically node negative invasive breast cancer.

The CTAF Panel voted nine in favor of the recommendation as written with none

opposed.

October 17October 17October 17October 17, 2012, 2012, 2012, 2012

This is the first review of this technology by the California Technology Assessment

Forum.

28

RECOMMENDATIONS OF OTHERSRECOMMENDATIONS OF OTHERSRECOMMENDATIONS OF OTHERSRECOMMENDATIONS OF OTHERS

Blue Cross Blue Shield Association (BCBSA)Blue Cross Blue Shield Association (BCBSA)Blue Cross Blue Shield Association (BCBSA)Blue Cross Blue Shield Association (BCBSA)

No assessments on this technology were found on the BCBSA TEC website.

Canadian Agency for Drugs and Technologies in Health (CADTH)Canadian Agency for Drugs and Technologies in Health (CADTH)Canadian Agency for Drugs and Technologies in Health (CADTH)Canadian Agency for Drugs and Technologies in Health (CADTH)

No reports on this technology were found on the CADTH website.

National Institute for Health and Clinical Excellence (NICE)National Institute for Health and Clinical Excellence (NICE)National Institute for Health and Clinical Excellence (NICE)National Institute for Health and Clinical Excellence (NICE)

NICE published its guideline on breast cancer in February 2009: NICE Clinical

Guideline 80 - Early and locally advanced breast cancer: - diagnosis and treatment.

The guideline states that “Minimal surgery, rather than lymph node clearance, should

be performed to stage the axilla for patients with early invasive breast cancer and no

evidence of lymph node involvement on ultrasound or a negative ultrasound-guided

needle biopsy. Sentinel lymph node biopsy (SLNB) is the preferred technique….SNLB

should be performed by a team that is validated in the use of the technique.“

National Comprehensive Cancer Network (NCCN)National Comprehensive Cancer Network (NCCN)National Comprehensive Cancer Network (NCCN)National Comprehensive Cancer Network (NCCN)

NCCN has an extensive guideline for physicians (The NCCN Guideline 3.2012:

Invasive Breast Cancer) and a version written for patients (The NCCN Guideline for

Patients 2.2011: Breast Cancer). These guidelines offer extensive and detailed

information on the recommended use of SNLB and treatment recommendations based

on the patient’s clinical history of breast cancer, current clinical status, and SNLB

findings. The guideline emphasizes that SNLB should be performed by a team with

documented experience in SNLB and the team should include the surgeons, radiation

29

oncologists, nuclear medicine physicians, pathologists and medical oncologists.The

physician guidelines cana be found at

http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. The patient

guideline can be found at http://www.nccn.com/files/cancer-

guidelines/breast/index.html#/66/.

Centers for Medicare and Medicaid Services (CMS)Centers for Medicare and Medicaid Services (CMS)Centers for Medicare and Medicaid Services (CMS)Centers for Medicare and Medicaid Services (CMS)

There is no National Coverage Determination code (NCD) for SNLB for breast

cancer. Coverage is based on Local Coverage Determination (LCD).

Agency for Healthcare Research and QualityAgency for Healthcare Research and QualityAgency for Healthcare Research and QualityAgency for Healthcare Research and Quality (AHRQ)(AHRQ)(AHRQ)(AHRQ)

No reports on this technology were found at the AHRQ website.

American College of SurgeonsAmerican College of SurgeonsAmerican College of SurgeonsAmerican College of Surgeons (ACS)(ACS)(ACS)(ACS)

ACS provided an opinion on this technology. ACS did not send a representative to

the CTAF public meeting.

American Society of Breast SurgeonsAmerican Society of Breast SurgeonsAmerican Society of Breast SurgeonsAmerican Society of Breast Surgeons (ASBS)(ASBS)(ASBS)(ASBS)

ASBS provided an opinion on this technology. ASBS did not send a representative

to the CTAF public meeting.

Association of Northern CA Oncologists (ANCO)Association of Northern CA Oncologists (ANCO)Association of Northern CA Oncologists (ANCO)Association of Northern CA Oncologists (ANCO)

ANCO did not provide an opinion on this technology. ANCO did not send a

representative to the CTAF public meeting.

30

Society of Nuclear Medicine and Molecular Imaging (SNMMI)Society of Nuclear Medicine and Molecular Imaging (SNMMI)Society of Nuclear Medicine and Molecular Imaging (SNMMI)Society of Nuclear Medicine and Molecular Imaging (SNMMI)

SNMMI provided an opinion on this technology. SNMMI did not send a

representative to the CTAF public meeting.

Society of Surgical OncologySociety of Surgical OncologySociety of Surgical OncologySociety of Surgical Oncology (SSO)(SSO)(SSO)(SSO)

SSO did not provide an opinion on this technology nor send a representative to

the CTAF public meeting.

31

ABBREVIATIONSABBREVIATIONSABBREVIATIONSABBREVIATIONS

A: Technitium-99 labeled albumin colloid

AD: Axillary Lymph Node Dissection

ALMANAC: Axillary Lymphatic Mapping Against Nodal Axillary Clearance

Ant: Technitium-99 labeled antimony colloid

AJCC: American Joint Committee on Cancer

ASCO: American Society of Clinical Oncology

ACOSOG: The American College of Surgeons Oncology Group (ACOSOG)

BC: Breast Cancer

TNM: Tumor, Node, Metastasis staging system

NSABP: National Surgical Adjuvant Breast and Bowel Project Protocol

cc: Cubic centimeters

CI Confidence Interval

cm: Centimeters

CTAF California Technology Assessment Forum

DARE Database of Abstracts of Reviews of Effects

DFS: Disease-Free Survival

Dz: Disease

EBCTCG: Early Breast Cancer Trialist’s Collaborative Group

FDA: US Food and Drug Administration

GIVOM: Gruppo Interdisciplinare Veneto di Oncologia Mammaria

H&E: Hematoxylin and Eosin

HR Hazard ratio

IBC: Inflammatory Breast Cancer

32

IHC: Immunohistochemistry

KiSS: This is a metastasis suppressor gene.

NR Not reported

NS Not significant

NSABP: National Surgical Adjuvant Breast and Bowel Project

NZ: New Zealand

OR Odds ratio

OS: Overall Survival

QOL: Quality of Life

RCT Randomized Controlled Trial

RI: Radioisotope at discretion of individual sites

S: Technitium-99 labeled sulfur colloid

SNAC: Sentinel Node versus Axillary Clearance

Tx: Treatment

UK: United Kingdom

US: United States

33

REFERENCESREFERENCESREFERENCESREFERENCES

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. Jan-Feb 2012;62(1):10-29.

2. Singletary SE, Allred C, Ashley P, et al. Revision of the American Joint Committee on Cancer staging system for breast cancer. Journal of clinical oncology : official

journal of the American Society of Clinical Oncology. Sep 1 2002;20(17):3628-3636.

3. Mustafa IA, Cole B, Wanebo HJ, Bland KI, Chang HR. Prognostic analysis of survival in small breast cancers. Journal of the American College of Surgeons.

May 1998;186(5):562-569.

4. DeSantis C, Siegel R, Bandi P, Jemal A. Breast cancer statistics, 2011. CA Cancer J

Clin. Nov-Dec 2011;61(6):409-418.

5. NCCN. Breast Cancer. Practice Guidelines in Oncology - v3.2012. 2012.

6. Carlson RW, Brown E, Burstein HJ, et al. NCCN Task Force Report: Adjuvant Therapy for Breast Cancer. J Natl Compr Canc Netw. Mar 2006;4 Suppl 1:S1-26.

7. Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol. Oct 2005;16(10):1569-1583.

8. Fisher B, Jeong JH, Bryant J, et al. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet. Sep 4-10 2004;364(9437):858-868.

9. Albertini JJ, Lyman GH, Cox C, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA. Dec 11 1996;276(22):1818-1822.

10. McMasters KM, Tuttle TM, Carlson DJ, et al. Sentinel lymph node biopsy for breast cancer: a suitable alternative to routine axillary dissection in multi-

34

institutional practice when optimal technique is used. J Clin Oncol. Jul 2000;18(13):2560-2566.

11. Cody HS, 3rd, Fey J, Akhurst T, et al. Complementarity of blue dye and isotope in sentinel node localization for breast cancer: univariate and multivariate analysis of 966 procedures. Ann Surg Oncol. Jan-Feb 2001;8(1):13-19.

12. Krag DN, Anderson SJ, Julian TB, et al. Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. Lancet Oncology. 2007;8(10):881-888.

13. Lyman GH, Giuliano AE, Somerfield MR, et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer. J Clin Oncol. Oct 20 2005;23(30):7703-7720.

14. Takei H, Suemasu K, Kurosumi M, et al. Added value of the presence of blue nodes or hot nodes in sentinel lymph node biopsy of breast cancer. Breast

Cancer. 2006;13(2):179-185.

15. Kern KA. Sentinel lymph node mapping in breast cancer using subareolar injection of blue dye. J Am Coll Surg. Dec 1999;189(6):539-545.

16. Rubio IT, Korourian S, Cowan C, Krag DN, Colvert M, Klimberg VS. Sentinel lymph node biopsy for staging breast cancer. Am J Surg. Dec 1998;176(6):532-537.

17. Krag D, Weaver D, Ashikaga T, et al. The sentinel node in breast cancer--a multicenter validation study. N Engl J Med. Oct 1 1998;339(14):941-946.

18. Veronesi U, Paganelli G, Galimberti V, et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet.

Jun 28 1997;349(9069):1864-1867.

19. Veronesi U, Paganelli G, Viale G, et al. Sentinel lymph node biopsy and axillary dissection in breast cancer: Results in a large series. Journal of the National

Cancer Institute. 1999;91(4):368-373.

35

20. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. Dec 17 2005;366(9503):2087-2106.

21. van der Ploeg IM, Nieweg OE, van Rijk MC, Valdes Olmos RA, Kroon BB. Axillary recurrence after a tumour-negative sentinel node biopsy in breast cancer patients: A systematic review and meta-analysis of the literature. European

journal of surgical oncology : the journal of the European Society of Surgical

Oncology and the British Association of Surgical Oncology. Dec 2008;34(12):1277-1284.

22. American Society of Breast Surgeons. Consensus statement for performing sentinel lymph node dissection in breast cancer. 2005. https://http://www.breastsurgeons.org/statements/PDF_Statements/SLN_Dissection.pdf. Accessed September 23, 2012.

23. Kell MR, Burke JP, Barry M, Morrow M. Outcome of axillary staging in early breast cancer: a meta-analysis. Breast Cancer Res Treat. Apr 2010;120(2):441-447.

24. Wang Z, Wu LC, Chen JQ. Sentinel lymph node biopsy compared with axillary lymph node dissection in early breast cancer: a meta-analysis. Breast Cancer Res

Treat. Oct 2011;129(3):675-689.

25. Ashikaga T, Krag DN, Land SR, et al. Morbidity results from the NSABP B-32 trial comparing sentinel lymph node dissection versus axillary dissection. Journal of

Surgical Oncology. 2010;102(2):111-118.

26. Bochner MA, Kollias J, Gill PG, Farshid G, Dodd TJ. Implication of intraoperative sentinel node imprint cytology for consent in the SNAC trial. ANZ Journal of

Surgery. 2004;74(3):105-107.

27. Canavese G, Catturich A, Vecchio C, et al. Sentinel node biopsy compared with complete axillary dissection for staging early breast cancer with clinically negative lymph nodes: Results of randomized trial. Annals of Oncology.

2009;20(6):1001-1007.

36

28. Clarke D, Khonji NI, Mansel RE. Sentinel node biopsy in breast cancer: ALMANAC trial. World Journal of Surgery. 2001;25(6):819-822.

29. Clarke D, Newcombe RG, Mansel RE. The learning curve in sentinel node biopsy: the ALMANAC experience. Annals of surgical oncology : the official journal of the

Society of Surgical Oncology. 2004;11(3 Suppl):211S-215S.

30. Del Bianco P, Zavagno G, Burelli P, et al. Morbidity comparison of sentinel lymph node biopsy versus conventional axillary lymph node dissection for breast cancer patients: Results of the sentinella-GIVOM Italian randomised clinical trial. European Journal of Surgical Oncology. 2008;34(5):508-513.

31. Fleissig A, Fallowfield LJ, Langridge CI, et al. Post-operative arm morbidity and quality of life. Results of the ALMANAC randomised trial comparing sentinel node biopsy with standard axillary treatment in the management of patients with early breast cancer. Breast Cancer Research and Treatment. 2006;95(3):279-293.

32. Fougo JL, Dinis-Ribeiro M, Araujo C, et al. Impact of lymphadenectomy on axillary recurrence and morbidity of the upper limb in breast cancer patients with negative sentinel node. A prospective randomised study. Cirugia Espanola.

2011;89(5):307-316.

33. Gill G. Sentinel-lymph-node-based management or routine axillary clearance? One-year outcomes of sentinel node biopsy versus axillary clearance (SNAC): A randomized controlled surgical trial. Annals of Surgical Oncology.

2009;16(2):266-275.

34. Gill PG. Sentinel lymph node biopsy versus axillary clearance in operable breast cancer: The RACS SNAC trial, a multicenter randomized trial of the Royal Australian College of Surgeons (RACS) Section of Breast Surgery, in collaboration with the National Health and Medical Research Council Clinical Trials Center. Annals of surgical oncology : the official journal of the Society of

Surgical Oncology. 2004;11(3 Suppl):216S-221S.

35. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A

37

randomized clinical trial. JAMA - Journal of the American Medical Association.

2011;305(6):569-575.

36. Giuliano AE, McCall L, Beitsch P, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: The American college of surgeons oncology group z0011 randomized trial. Annals of Surgery. 2010;252(3):426-432.

37. Goyal A, Newcombe RG, Chhabra A, Mansel RE. Factors affecting failed localisation and false‚Äênegative rates of sentinel node biopsy in breast cancer‚Äê‚Äêresults of the ALMANAC validation phase. Breast Cancer Research

and Treatment. 2006(2):203‚Äê208. http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/040/CN-00576040/frame.html.

38. Goyal A, Newcombe RG, Chhabra A, Mansel RE. Morbidity in breast cancer patients with sentinel node metastases undergoing delayed axillary lymph node dissection (ALND) compared with immediate ALND. Annals of Surgical Oncology.

2008;15(1):262-267.

39. Goyal A, Newcombe RG, Mansel RE, et al. Sentinel lymph node biopsy in patients with multifocal breast cancer. European journal of surgical oncology : the

journal of the European Society of Surgical Oncology and the British Association

of Surgical Oncology. 2004(5):475‚Äê479. http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/370/CN-00482370/frame.html.

40. Harlow SP, Krag DN, Julian TB, et al. Prerandomization Surgical Training for the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial: a randomized phase III clinical trial to compare sentinel node resection to conventional axillary dissection in clinically node-negative breast cancer. Ann

Surg. Jan 2005;241(1):48-54.

41. Helms G, Kuhn T, Moser L, Remmel E, Kreienberg R. Shoulder-arm morbidity in patients with sentinel node biopsy and complete axillary dissection--data from a prospective randomised trial. Eur J Surg Oncol. Jul 2009;35(7):696-701.

38

42. Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol. Oct 2010;11(10):927-933.

43. Krag DN, Ashikaga T, Harlow SP, et al. Surgeon training, protocol compliance, and technical outcomes from breast cancer sentinel lymph node randomized trial. Journal of the National Cancer Institute. 2009(19):1356‚Äê1362. http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/637/CN-00718637/frame.html.

44. Krag DN, Julian TB, Harlow SP, et al. NSABP-32: Phase III, randomized trial comparing axillary resection with sentinal lymph node dissection: a description of the trial. Annals of surgical oncology : the official journal of the Society of

Surgical Oncology. 2004;11(3 Suppl):208S-210S.

45. Land SR, Kopec JA, Julian TB, et al. Patient-reported outcomes in sentinel node-negative adjuvant breast cancer patients receiving sentinel-node biopsy or axillary dissection: National Surgical Adjuvant Breast and Bowel Project phase III protocol B-32. Journal of Clinical Oncology. 2010;28(25):3929-3936.

46. Lucci A, McCall LM, Beitsch PD, et al. Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group trial Z0011. Journal of Clinical Oncology. 2007;25(24):3657-3663.

47. Mansel RE, Fallowfield L, Kissin M, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: The ALMANAC trial. Journal of the National Cancer Institute. 2006;98(9):599-609.

48. Mansel RE, Goyal A, Newcombe RG, et al. Internal mammary node drainage and its role in sentinel lymph node biopsy: The initial ALMANAC experience. Clinical

Breast Cancer. 2004;5(4):279-284.

49. Purushotham AD, Upponi S, Klevesath MB, et al. Morbidity after sentinel lymph node biopsy in primary breast cancer: Results from a randomized controlled trial. Journal of Clinical Oncology. 2005;23(19):4312-4321.

39

50. Smith MJ, Gill PG, Wetzig N, et al. Comparing patients' and clinicians' assessment of outcomes in a randomised trial of sentinel node biopsy for breast cancer (the RACS SNAC trial). Breast Cancer Research and Treatment.

2009;117(1):99-109.

51. Sola M, Alberro JA, Fraile M, et al. Complete Axillary Lymph Node Dissection Versus Clinical Follow-up in Breast Cancer Patients with Sentinel Node Micrometastasis: Final Results from the Multicenter Clinical Trial AATRM 048/13/2000. Ann Surg Oncol. Sep 7 2012.

52. Ung OA. Australasian experience and trials in sentinel lymph node biopsy: The RACS SNAC trial. Asian Journal of Surgery. 2004;27(4):284-290.

53. Veronesi U, Paganelli G, Viale G, et al. Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of a randomised controlled study. Lancet

Oncology. 2006;7(12):983-990.

54. Veronesi U, Paganelli G, Viale G, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. New England

Journal of Medicine. 2003;349(6):546-553.

55. Veronesi U, Viale G, Paganelli G, et al. Sentinel lymph node biopsy in breast cancer: Ten-year results: Of a randomized controlled study. Annals of Surgery.

2010;251(4):595-600.

56. Weaver DL, Ashikaga T, Krag DN, et al. Effect of occult metastases on survival in node-negative breast cancer. New England Journal of Medicine. 2011;364(5):412-421.

57. Wetzig NR, Gill PG, Ung O, et al. Participation in the RACS sentinel node biopsy versus axillary clearance trial. ANZ Journal of Surgery. 2005;75(3):98-100.

58. Zavagno G, De Salvo GL, Scalco G, et al. A randomized clinical trial on sentinel lymph node biopsy versus axillary lymph node dissection in breast cancer: Results of the sentinella/GIVOM trial. Annals of Surgery. 2008;247(2):207-213.

59. Zavagno G, Del Bianco P, Koussis H, et al. Clinical impact of false-negative sentinel lymph nodes in breast cancer. European Journal of Surgical Oncology.

2008;34(6):620-625.

40

60. Zavagno G, Meggiolaro F, Bozza F, et al. Sentinel lymph node biopsy in breast cancer: The GIVOM experience in Veneto, Italy. Tumori. 2002;88(3):S52-S54.

61. Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Annals of Surgery. Sep 1994;220(3):391-398; discussion 398-401.

62. Mahajna A, Hershko DD, Israelit S, Abu-Salih A, Keidar Z, Krausz MM. Sentinel lymph node biopsy in early breast cancer: The first 100 cases performed in a teaching institute. Israel Medical Association Journal. 2003;5(8):556-559.

63. Rodier JF. Learning of sentinel node biopsy in invasive breast cancer multicentric study on behalf of the National Federation of French comprehensive cancer center. Medecine Nucleaire. 2001;25(9):523-525.

Sentinel Lymph Node Biopsy (SNLB) in Early Stage Breast Cancer

Documents

Transcript of Sentinel Lymph Node Biopsy (SNLB) in Early Stage Breast Cancer