1

SENTINEL LYMPH NODE BIOPSY IN EARLY STAGE BREAST CANCER

A Technology Assessment

INTRODUCTION

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.

BACKGROUND

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

2

cases and 14% of all cancer deaths in women.1

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

3

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.

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

4

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 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.

5

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 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

6

TECHNOLOGY ASSESSMENT (TA)

TA Criterion 1: The technology must have final approval from the appropriate 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 2: The scientific evidence must permit conclusions concerning the effectiveness of the technology regarding health

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 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

7

Figure 1: Selection of studies for inclusion in review

Level of Evidence: 1 and 2 TA Criterion 2 is met.

TA Criterion 3: 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

587 potentially relevant references screened

115 abstracts for assessment

37 references on 10 randomized

trials included in the assessment

plus 2 systematic reviews

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

8

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.

9 Table 1: M

ethodological Quality O

f The Random

ized Trials Com

paring Sentinel Lymph N

ode Biopsy to Axillary D

issection Study

Random

ization Allocation

concealment

Groups

comparable

Blinding Follow

-up > 80%

Intention to

treat analysis Q

uality

Purushotham 2005

49 U

K 3 Centers

Yes Yes

Yes N

o Yes

Yes Fair

Goyal 2007

28,29,31,37-

39,47,48 U

K

ALMAN

AC

Yes Yes

Yes N

o Yes

Yes Fair

Helm

s 200841

Germ

any KiSS

Yes N

R

NR

N

o N

o N

o Poor

Zavagno 200830,58,60

Italy 18 Centers

GIVO

M

Yes Yes

Yes N

o Yes

NR

Fair

Canavase 2009

27 Italy Single C

enter

Yes Yes

Yes N

o Yes

Yes Fair

Gill 2009

26,33,34,50,52,57 Australia / N

Z SN

AC

Yes Yes

Yes N

o Yes

Yes Fair

Veronesi 201053-55

Italy Multicenter

Yes Yes

Yes N

o Yes

No

Fair

Fougo 201132

Portugal Single

Center

Yes Yes

Yes N

o Yes

Yes Fair

Giuliano 2011

35,36,46 U

SA

ACO

SOG

-Z0011

Yes Yes

Yes N

o Yes

Yes Fair

Krag 2010, Weaver

201112,25,40,42-45,56

US, C

anada N

SAB

P-B32

Yes

Yes Yes

No

Yes Yes

Fair

10 Table 2: C

haracteristics Of The R

andomized Trials C

omparing Sentinel Lym

ph Node Biopsy to Axillary D

issection *C

olloid radiolabeled with technetium

Study

N

SLNB

technique SLN

Evaluation

Inclusion criteria

Exclusion criteria

Enroll period

FU

(years) Age, years

Tumor

size Prim

ary outcom

e Purushotham

200549

UK 3 C

enters

298 Blue dye

+ Album

in*

H&E

+

cytokeratin IH

C

IBC < 3 cm

C

N-

Multifocal

Prior BC Tx

Pregnant

1999-2003

1 58

1.6 cm

Morbidity, Q

OL

Goyal 2007

28,29,31,37-

39,47,48 U

K

ALMAN

AC

1031 Blue dye

+ Album

in*

H&E

IBC

any size C

N-

Age < 80 y

Multifocal

Prior BC Tx

Pregnant

1999-2003

1.5 58

75% ≤ 2

cm

Morbidity, Q

OL

Helm

s 200841

Germ

any KiSS

181 Blue dye

+ Album

in*

NR

IBC

< 2.5 cm

CN

- N

R

2000-2002

0.9 58

71% T1

Morbidity

Zavagno 200830,58,60

Italy 18 Centers

GIVO

M

749 Album

in* H

&E

+ cytokeratin

IHC

IBC ≤ 3 cm

C

N-

Age ≤ 80 y

Multifocal

Prior BC Tx

Pregnant

1999-2004

4.6 58

81% T1

DFS

Canavase 2009

27 Italy Single C

enter

248 Blue dye

+ Album

in*

H&E

+

cytokeratin IH

C

IBC < 3 cm

C

N-

Age 18-75

Multifocal

Prior BC Tx

1998-2001

5.5 58

81% T1

DFS

Gill 2009

26,33,34,50,52,57 Australia / N

Z SN

AC

1088 Blue dye

+ Antim

ony*

H&E

+

cytokeratin IH

C

IBC < 3 cm

C

N-

Age ≥ 18

Multifocal

Prior BC Tx

2001-2005

1 M

edian 50-69

Median

1-2 cm

Morbidity

Veronesi 201053-55

Italy Multicenter

532 Album

in* H

&E

+ cytokeratin

IHC

IBC ≤ 2 cm

C

N-

Age 40-75 y

Multifocal

Prior BC Tx

Pregnant

1998-1999

7.9 56

Median

1.1-1.5 cm

Morbidity

Fougo 201132

Portugal Single

Center

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, m

orbidity

Giuliano 2011

35,36,46 U

SA

891 Blue dye

+ H

&E

IBC ≤ 5 cm

C

N-

≥ 3 + nodes M

atted 1999-2004

6.3 55

1.7 cm

OS

11 Study

N

SLNB

technique SLN

Evaluation

Inclusion criteria

Exclusion criteria

Enroll period

FU

(years) Age, years

Tumor

size Prim

ary outcom

e AC

OSO

G-Z0011

RI

Age ≤ 80 y nodes

Extranodal dz

Krag 2010, Weaver

201112,25,40,42-45,56

US, C

anada N

SAB

P-B32

5611 Blue dye

+ Sulfur*

H&E

IBC

any size C

N-

Age ≥ 18

Prior BC Tx

1999-2004

8.0 25%

< 50

84% ≤

2.0 cm

OS

12 Table 3: Prim

ary Outcom

es In The Random

ized Trials Com

paring Sentinel Lym

ph Node B

iopsy to Axillary Dissection

Study

Group

N

Success SLN

B

Sensitivity N

odes rem

oved Pathologically node positive

Locoregional recurrence

Disease Free

Survival

Overall

survival

Purushotham 2005

49 U

K 3 Centers

SLNB

AD

143

155

94%

NA

N

R

N

R

36%

N

R

NR

NR

NR

NR

NR

NR

G

oyal 200728,29,31,37-

39,47,48 U

K

ALMAN

AC

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

Helm

s 200841

Germ

any KiSS

SLNB

AD

NR

NR

NR

NR

NR

3 21

NR

NR

NR

NR

NR

NR

NR

NR

Zavagno 2008

30,58,60 Italy 18 C

enters G

IVOM

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

C

anavase 200927

Italy Single Center

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 G

ill 200926,33,34,50,52,57

Australia / NZ

SNA

C

SLNB

AD

544

544

95%

94%

94.5%

1.8 16

31%

28%

NR

NR

NR

NR

NR

NR

Veronesi 2010

53-55 Italy M

ulticenter

SLNB

AD

268

264

100%

100%

91%

1.7 26

36%

35%

2.2% 10 y

2.2% N

S

89.9%

10 y

88.8%

0.52

93.5%

10 y

89.7%

0.15 Fougo 2011

32 SLN

B

57 99%

N

R

1.7 37%

0%

6 y

NR

100%

13 Study

Group

N

Success SLN

B

Sensitivity N

odes rem

oved Pathologically node positive

Locoregional recurrence

Disease Free

Survival

Overall

survival

Portugal Single

Center

AD

49

N

R

0%

N

S

N

R

6 y

94%

.006 G

iuliano 201135,36,46

USA

AC

OSO

G-Z0011

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 Krag 2010, W

eaver 2011

12,25,40,42-45,56 U

S, Canada

NSA

BP

-B32

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

14 Table 4: Q

uality of Life Outcom

es In The Random

ized Trials Com

paring Sentinel Lym

ph Node B

iopsy to Axillary Dissection

Study

Group

N

Lymphedem

a Serom

a Sensory

Neuropathy

Shoulder R

OM

Pain

Quality of life

Purushotham 2005

49 U

K 3 Centers

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 2007

28,29,31,37-

39,47,48 U

K

ALMAN

AC

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 SLN

B group at 1 year

Helm

s 200841

Germ

any KiSS

SLNB

AD

NR

NR

P<0.001 for arm

volume

favoring SLN

B

NR

P<0.001

favoring SLN

B

P=0.006 favoring SLN

B

P<0.001 favoring SLN

B

NR

Zavagno 200830,58,60

Italy 18 Centers

GIVO

M

SLNB

AD

345

352

OR

0.48 (0.3-0.8) p=0.01

NR

O

R 0.51 (0.4-

0.7) p < 0.001 O

R 0.55 (0.3-

0.9) p=0.016 O

R 0.74 (0.5-

1.1) p=0.11 N

o significant differences

Canavase 2009

27 Italy Single C

enter

SLNB

AD

124

124

NR

N

R

NR

N

R

NR

N

R

Gill 2009

26,33,34,50,52,57 Australia / N

Z SN

AC

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

SN

AC

study specific scale 4.4 vs. 7.0, p<0.001

Veronesi 201053-55

Italy Multicenter

SLNB

AD

268

264

0%

2 y

12%

NR

NR

1%

2 y

68%

N

R

0%

2 y

21%

NR

8%

2 y

39%

NR

NR

Fougo 201132

Portugal Single C

enter

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

15 Study

Group

N

Lymphedem

a Serom

a Sensory

Neuropathy

Shoulder R

OM

Pain

Quality of life

Giuliano 2011

35,36,46 U

SA

ACO

SOG

-Z0011

SLNB

AD

446

445

6%

1+ y

19%

0.0001

6%

0.1 y

14%

0.0001

9%

1+ y

39%

0.0001

NR

N

R

NR

Krag 2010, Weaver

201112,25,40,42-45,56

US, C

anada N

SAB

P-B32

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 m

onths

Significant early, but no difference at

1 year

16

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 immunohistochemistry (IHC) staining for cytokeratin to increase the sensitivity

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

17

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 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.

18

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

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

19

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 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

20

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 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

21

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 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

22

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 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.

23

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 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

24

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 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 met

TA Criterion 4: The technology must be as 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

25

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

TA Criterion 4 is met

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

26

RECOMMENDATION

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.

October 17, 2012

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

Assessment Forum.

27

RECOMMENDATIONS OF OTHERS

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

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) 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 oncologists, nuclear medicine physicians, pathologists and

medical oncologists.

The physician guidelines cana be found at

28

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)

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

American College of Surgeons (ACS) ACS was invited to provide an opinion on this technology and to send a

representative to the CTAF public meeting.

American Society of Breast Surgeons (ASBS) ASBC was invited to provide an opinion on this technology and to send a

representative to the CTAF public meeting.

Association of Northern CA Oncologists (ANCO)

ANCO was invited to provide an opinion on this technology and to send a

representative to the CTAF public meeting.

Society of Nuclear Medicine and Molecular Imaging (SNMMI) SNMMI was invited to provide an opinion and to send a representative to the

CTAF public meeting.

29

Society of Surgical Oncology (SSO) SSO was invited to provide an opinion on this technology and to send a

representative to the CTAF public meeting.

30

ABBREVIATIONS

CTAF California Technology Assessment Forum

AJCC: American Joint Committee on Cancer

TNM: Tumor, Node, Metastasis staging system

NSABP: National Surgical Adjuvant Breast and Bowel Project Protocol

cm: Centimeters

AD: Axillary Lymph Node Dissection

EBCTCG: Early  Breast  Cancer  Trialist’s  Collaborative  Group

ASCO: American Society of Clinical Oncology

DARE Database of Abstracts of Reviews of Effects

FDA: US Food and Drug Administration

OS: Overall Survival

DFS: Disease-Free Survival

ALMANAC: Axillary Lymphatic Mapping Against Nodal Axillary Clearance

KiSS: This is a metastasis suppressor gene.

RCT Randomized Controlled Trial

NS Not significant

CI Confidence Interval

NR Not reported

HR Hazard ratio

OR Odds ratio

US United States

IHC: Immunohistochemistry

IBC: Inflammatory Breast Cancer

GIVOM: Gruppo Interdisciplinare Veneto di Oncologia Mammaria

H&E: Hematoxylin and Eosin

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

SNAC: Sentinel Node versus Axillary Clearance

31

UK: United Kingdom

US: United States

NZ: New Zealand

A: Technitium-99 labeled albumin colloid

Ant: Technitium-99 labeled antimony colloid

S: Technitium-99 labeled sulfur colloid

RI: Radioisotope at discretion of individual sites

32

REFERENCES

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-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

33

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.

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

34

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.

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

35

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 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.

36

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.

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

37

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.

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.

38

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.

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.