-: Welcome to the talk on the evaluation
of the axillary nodal basin
and the lymph node involvement
in patients with invasive breast carcinoma.
And we shall discuss the current consensus,
the opinion of the experts
as to how to evaluate the axillary lymph nodes
in patients with carcinoma of the breast
and what are its pitfalls
and how can we overcome
or circumvent the current issues.
Lord Moynihan, a famous surgeon in Britain,
stated that surgery of the malignant disease
is not the surgery of the organs,
it is actually the anatomy of the lymphatic system.
And with this, assured in an era
of radical lymph node dissection,
also called block dissection.
We hear of William Stewart Halsted
performing the first radical hosted mastectomy
where he removed the entire axillary nodal basin
started way back in 1882.
Then came George Washington Crile,
starting the radical neck dissection in patients
with, had a neck cancers in 1906.
And a year later, Ernest Miles in London
performing the first rectal cancer
in the form of abdominal perineal resection,
where again, he performed clearance of all the lymph nodes
located in the pelvis in the juxtaposition
of the rectum and anus.
Very soon surgeons and their patients realized
that there were issues related to radical block dissection,
such as pain due to cutting of the sensory nerves,
paraesthesia or anesthesia.
Again, due to unnecessary dividing or removing
the sensory nerve endings located in the nodal basin.
Lymph nodes are essential for drainage of the lymph
from the organs and removal of these lymph nodes
and lymphatics leads to collection of fluid
in the tissues or organs called lymphoedema.
So in radical mastectomy,
we saw a lot of women developing lymphoedema
of the upper arm in 10 to 30% of patients.
And similarly in patients undergoing radical dissection
of other organs had collection of lymph.
Wound infection was fairly common
and this would lead to breakdown of the skin wound
and surgical site infection.
Moreover, it was realized that in patients
where lymph nodes were negative for metastasis,
this operation was futile and totally unnecessary.
Let us now come to the valuation
of the axillary lymph nodes in patients
with invasive breast carcinoma.
In this cartoon, we are trying to show you
the primary tumour,
where lymphatics from the organ,
in this case, the breast parenchyma carry the lymph
along with the tumour cells to the first station
or first echelon of the lymph nodes
located low down in the axilla.
They are called the level I nodes.
Actually they are the pectoral nodes located just lateral
to the pectoralis major and minor muscles.
And it has been found that about 90% of these nodes
are located between the pectoral muscles and a vein,
which is tributary of the axillary vein.
This vein is called the lateral thoracic vein.
So 90% of those nodes are located in this area
between the lateral thoracic vein
and the lateral margin of the pectoral muscles
from the efferent of these nodes emanate
and go to higher echelon nodes called the second echelon
or second station nodes.
From there the efferent will carry the lymph
and the tumour cells to the higher order nodes
and this will then continue.
This anatomical presentation, again, demonstrates
the presence of very rich lymphatic plexus
in the breast parenchyma and in the overlying skin
and the nipple-areolar complex.
All these lymphatics converge to a set of nodes
located between the pectoralis major
and the lateral thoracic vein.
And these actually serve as the sentinel nodes
as we will discuss later.
And these lymph nodes then go to the,
they carry the lymph to the higher echelon nodes,
which are then located behind the pectoralis minor muscle,
which are called level II nodes.
And from there the efferent arise going
to higher order nodes located above
and medial to the pectoralis minor muscle
called level III or apical axillary nodes.
Why do we need to evaluate axillary nodes
in patients with breast carcinoma?
Well, in patients with invasive breast cancer,
we need to stage the presentation
and get some idea about the prognosis of the patient.
Therefore, we need to know how many nodes
are involved in patients with breast carcinoma.
And the adjuvant therapy is decided by the oncologist
to a large extent, based on the presence
of the lymph node metastasis in the axilla.
In patients where lymph nodes are already involved,
the best treatment is offered in the form
of axillary lymph node dissection, ALND.
So it is both diagnostic as well as therapeutic role
in patients with invasive breast carcinoma
in patients who present with large in-situ
breast carcinoma or DCIS.
And if we have decided to treat this lady
by operation of mastectomy,
we need to evaluate the first order nodes
called the sentinel lymph node biopsy.
Because if there is a focus of invasion
or microinvasion within this area of DCIS,
then again, we need nodal evaluation
for deciding further adjuvant therapy.
Axillary nodal spread was evaluated extensively
by a large number of NSABP trials in America.
The notable among these is the NSABP-B04,
the first breast cancer trial started
by great oncologist Dr. Bernard Fisher in America.
It was found that in women where there was no clinically
palpable lymph node clinically and zero disease,
30 to 40% patients actually harboured
microscopic foci of cancer in their nodes.
So as high as 30 to 40% patients actually harbour
microscopic foci of cancer cells
within the axillary nodes in women
who have no palpable lymph nodes.
And this was the data of NSABP-B04
where 362 women were randomized
either to receive radical mastectomy,
which was the standard of care in those days.
40% had microscopic cancer in the axillary nodes
and assuming a similar proportion will have this
in the other group.
The other group was treated by total mastectomy,
removal of the entire breast with no further therapy
or the third group, which had total mastectomy
followed by radiotherapy.
And there only 2.9% patients developed
axillary recurrence as opposed to women
who had total mastectomy,
where 19% developed axillary recurrence.
So please note that from 40% of the microscopic cells
demonstrated in radical mastectomy arm,
only half developed axillary recurrence clinically,
if we left all the axillary nodes inside to in the body.
So perhaps the body's immune system,
the T lymphocytes and the cytotoxic T cells
were effective and natural killer cells
were effective in killing these microscopic tumour cells.
And if we offered radiotherapy in the post-op period,
only 2.9% developed metastasis in the axilla,
other cells were effectively controlled by radiotherapy.
So what we conclude from this B04 trial
that of those 40% which are present in microscopic form
within the axilla in clinical indicative axilla,
about 20% that is only of these 20%,
only half present clinically.
And of those only 3% remain active after radiotherapy,
i.e. 5/6ths, that is majority of the clinically
active nodes can be controlled by appropriate radiotherapy.
Does it help to remove impalpable nodes in women
presenting with negative axilla?
A meta-analysis was carried out way back in 1999
by surgeon Orr and he demonstrated
that there was a minimal, about 5.4% survival benefit
in women who underwent prophylactic axillary dissection
compared to none.
However, this was an initial study
before adjuvant systemic therapy
was offered to most women.
And in the long term,
it has been found that there's no benefit
even among these patients
with prophylactic axillary lymph node dissection.
So the message is that if patient has no palpable
lymph nodes, prophylactic axillary node dissection
is not beneficial.
Dr. Mona Sanghani and her group carried out
a meta-analysis and found the impact
of axillary lymph node dissection on breast cancer
outcomes in women presenting
with clinically negative axilla.
And this was a meta-analysis published
in Cancer Journal way back in 2009.
And it was observed that no survival benefit
accrues by performing prophylactic axillary node dissection
versus just observing these women.
This is, mind you, women who have screen detected
breast cancer.
So message is that survival is not improved
by performing prophylactic lymph node dissection
if patient presents with clinically negative axilla.
So surgeons tried to evaluate the axilla
by some minimal access approach.
And this was the study by Sir APM Forrest
way back in Cardiff in 1967 in Wales in United Kingdom.
He performed a study called pectoral node biopsy
or axillary sampling published in 1982.
And in this study,
they performed the mastectomy and a small incision
in the dissection in the axilla removing four nodes
from the axilla, lower part of the axilla
called the pectoral node biopsy.
So this is perhaps the beginning of minimal access approach
to evaluating the axilla in women
who had clinically negative axilla.
And four nodes were removed,
starting from the lower part of the axilla.
The advantage is that skip metastases in axilla
is very low in the tune of 5% or so.
Now we come to the concept of sentinel lymph node biopsy.
If you see to visit the queen,
Her Majesty the Queen of England and go to London
and go in front of the Buckingham Palace
where the Queen lives,
you don't just barge in.
You ask the guard, is Her Majesty inside?
If she is, then you go inside and bow down to her
and pay your respect and tribute.
However, if the guard says,
no, Her Majesty is not inside.
Then you don't fiddle around there.
Similarly, if you want to meet your professor,
your chairman of the department
and you go to the office of your department,
the surgery office, you ask the guard
standing in front of the office.
Have you seen my chairman, my professor inside?
If the guard says no, then you don't waste
your time there.
You don't fiddle around.
And the guard is right.
The guard is right because there is no backdoor entry.
So we apply the same concept to the axilla.
So on the gateway of the axilla,
somewhere here on the gateway of the axilla
is a standing guard, a lymph node like a guard,
like a guard is standing on the gateway of the axilla.
And the guard knows if the cancer has gone through it.
So we ask the guard, have you seen cancer going inside?
If the guard says yes,
then we go inside the axilla and clear all the nodes.
If the guard says no, and guard is right
because there is no backdoor entry,
backdoor entry means that there's no skip metastases,
exceedingly rare.
Then we don't fiddle around with these nodes
that mother nature has produced for some purpose.
The purpose is that to drain the lymph,
the lymph from not only the torso,
the breast and the pectoral region of the torso,
but also the lymph from the upper limb.
There is a common pathway shared by these nodes,
though the lymphatics from the upper arm
and lymphatics of the breast,
both share a common pathway in the form of these nodes.
And if we remove these node unnecessarily,
there'll be a concomitant lymphedema.
And in order to avoid this,
we have now embarked on the concept
of sentinel lymph node biopsy.
Sentinel means the guard.
So, again, let us explain this process
from the primary tumour lymphatics carry the tumour cells
to the first station nodes.
Majority of these are located between the pectoral muscle
and the lateral thoracic vein.
Some lymphatics will go to other set of nodes as well.
And from there, the second order nodes will carry the lymph.
And if tumour cells are present in it,
the tumour cells as well to the second station nodes,
they are located behind the pectoralis minor.
They are called level II nodes.
So these are level I nodes lateral to the pectoralis minor,
level II nodes behind the pectoralis minor
and level III or the apical nodes located high up
in the axilla above and medial to pectoralis minor muscle.
This muscle is the pectoralis minor muscle.
The lymph from efferent of the apical nodes
is then taken by the axillary or subclavian lymph trunk
to the junction of the internal jugular vein
on the left side and the subclavian vein
at the jugular subclavian angle
near the junction of thoracic duct.
And this is also joined by a lymph trunk
from the jugular chain, the jugular lymph trunk.
And this is the thoracic duct,
which is carrying the lymph from the,
practically whole of the body,
first below the diaphragm through the thoracic duct
and it is joined by the bronchomediastinal trunk
on the left side.
On the right side,
the jugular lymph trunk will join the subclavian lymph trunk
at, again, the jugular subclavian angle.
And this is how the tumour cells will enter
into the venous circulation from the lymphatics.
So the sentinel means a guard and one who keeps a vigil
or a watch like a sentry.
So this is the first station node located
in the axillary nodal basin
and it may be a cluster of nodes.
It may be more than one node,
and it is defined as a node,
which is either hot on isotope uptake
or blue if we have injected blue dye
or fluorescent if we have injected a fluorescent dye
such as indocyanine green or fluorescein
or any node, which is palpable in the axilla
will also be called a sentinel node.
So sentient node is defined as a hot, blue, fluorescent,
or a palpable node,
or sometimes you will not see any blue colour node,
but you will see a blue colour lymphatic entering
into a node.
That node should also be defined as a sentinel node.
So it may be a cluster of nodes and all such nodes
which carry these features should be removed
as part of sentinel node biopsy.
Dr. Krishna Clough, a famous breast surgeon
in Paris described anatomical classification
of the location of the sentinel nodes in the axilla.
This was published in a famous article
in British Journal of Surgery.
And he found that in women who presented
with T1 or T2 tumours with clinical negative axilla,
86% of these were located in the,
this quadrangular area.
Pectoralis minor here.
This is the lateral thoracic vein, lateral thoracic vein.
And this is the intercostobrachial nerve.
So if you divide this area of the lower axilla
into four quadrants, based on axillary vein here,
lateral thoracic vein here,
and intercostobrachial nerve here.
So you get the area A which harbours
the majority of the nodes,
area B above the intercostobrachial nerve.
Again, medial to the lateral thoracic vein, 11% nodes.
C and D constitute only 1.8%.
So a very small fraction of the sentinel nodes
will be located lateral to the lateral thoracic vein.
So during dissection,
if we are not able to find any hot or blue node
look into this area,
the area between the pectoralis muscle
and the lateral thoracic vein.
Majority of those nodes, sentinel nodes
will be located in this area.
So how do we perform sentinel node biopsy?
We can use a number of dyes,
such as methylene blue dye or isosulphane blue dye.
We can use isotopes attached to a large particulate matter,
such as sulphur colloid, albumin or antimony.
And usual radio isotope tracer used
is technetium-99 which emits gamma rays,
which can be picked up by a gamma detector
or a Geiger Muller counter probe.
Fluorescent dyes used in breast cancer
are fluorescein, sodium and indocyanine green.
A combination of two tracers,
one blue dye and one isotope or fluorescent dye
has been found to have an yield of 95-100%.
So nearly all the sentinel loads can be picked up
or identified if we use a combination of two tracers,
one colour dye and one isotope or a fluorescent dye.
So this is an example of the operative field
where we have injected the blue dye,
and you can see the blue colour sentinel node here.
From this node is emerging the efferent
which is entering into the second station,
a second echelon node.
So the sentinel node biopsy,
and then we'll send these,
both these nodes to our pathologist
for evaluation and presence of any metastasis.
Sentinel node biopsy reliably predicts
the axillary nodal involvement in invasive breast cancer
because it permits our pathologist to have a focus approach
evaluating only one or two nodes.
At the All Indian Institute of Medical Sciences
in New Delhi, we evaluated our first 500 cases in 2005.
Mind you, we started our sentinel node program in 1999
after one of our surgeons Dr. V. Seenu
learned the technique from the master
in Santa Monica in California, by Dr. Armando Giuliano.
So learning from Dr. Armando Giuliano,
the word master of sentinel node biopsy,
we started our initial validation program.
The validation means that you perform
the sentinel node biopsy and then follow the removal
of rest of the axillary nodes,
and then send as two separate samples.
Sentinel node as one sample or in one specimen bottle
and the rest of axillary nodes will be sent separately
and as a separate specimen.
And then you evaluate how many times you found
the cancer cells in the sentinel nodes
and in the rest of the axilla.
And this is how you calculate the diagnostic indices
for sentinel node mapping in the form of identification,
the sensitivity and the false negative rate.
So we achieved reasonable identification of 91%
with a combination of blue dye
and isotope technetium sulphur colloid.
With the overall accuracy of 97%,
sensitivity of 91%, false negative of 8%.
So which was similar to the global standard,
since then we are offering this technique
for the treatment of women presenting
with early breast cancer as a therapeutic modality.
So see, these are some of our publications.
I leave it for you to go through
and peruse at your leisure time.
One of the professors, Dr. Seenu also carried out
randomized trial to evaluate two different types
of blue dyes namely methylene blue,
which is very affordable and has less side effects
compared to the expensive blue dye that is patent blue.
And so as a randomized trial,
two armed randomized trial,
half the women randomized to receive methylene blue
along with isotope and other half, well, offered
the sentinel node mapping with patent blue
and isotope was the same technetium sulphur colloid
in both the arms.
So we found that 97% of women,
we were able to identify sentinel node biopsy
in the methylene group arm,
and 86.6% in the patent blue arm.
So almost similar with no statistical difference
between the two groups.
Sentinel node positive patients were 32%
in the methylene group arm
and 20.87 in the patent blue arm.
Again, hardly any difference between the two groups,
total number of sentinel nodes identified
with the methylene blue was with the mean of 2.73,
and a standard vision of 1.7.
Again, very similar 2.55 is the mean with patent blue,
with a standard division of 1.7.
So we could identify the blue sentinel nodes
with the help of methylene blue,
which was exactly similar to that achieved
by patent blue violet.
So since then we are using methylene blue
in our study and we are popularizing the use
of methylene blue in the low and middle income
Asian countries because it is easily available
and quite affordable compared to more expensive patent blue.
So axillary sampling is another alternative
to evaluate axillary node involvement
in patients presenting with clinically negative axilla
where we dissect a block of tissue
located between the pectoralis major muscle
and latissimus dorsi located
below the intercostobrachial node.
So lower part of the level one tissue is dissected,
look lying below the intercostobrachial nerve.
And this block of tissue is then sent
for evaluation of any involvement,
based on that we can perform the axillary node dissection
if the nodes are involved.
We should learn how a pathologist in his laboratory
evaluates these sentinel nodes.
So this will be based on the size of the node involved.
If the node measures less than 5 millimeter in size,
very tiny, small node,
then they will just bisect it
and make it into two halves
and then both halves will be evaluated
by histological evaluation.
If the node measures more than 4 millimeter
in it's longest dimension,
then we will make slices of 2 millimeter each.
So this is a 2 millimeter slice
and such slices will be made.
The idea of making 2 millimeter slices,
the fact that a macro-metastases in the sentinel node
is defined as a tumour focus,
measuring more than 2 millimeter in diameter.
This is a macro-metastases,
so it's more than 2 millimeter.
So if you cut 2 millimeter slices of a node,
you will capture this macro-metastases,
if not here, at least here.
So that's the logic behind slicing the node,
which is larger than 4 millimeter in dimension
at 2 millimeters diameter slices.
If the focus in the node is less than 2 millimeter
measuring between 0.2 millimeter to 2 millimeter,
we call it micro-metastases.
Micro-metastasis 0.2 to two millimeter in diameter.
So more than 2 millimeter would be called macro-metastases,
less than 2 up to 0.2 will be called micro-metastases.
And what do we call if we have any tumour cell
or a group of cells measuring less than 0.2 millimeter.
So they'll be called isolated tumour cells.
They're scattered here and there within the lymph node.
And sometimes they may not be visible to the usual
pathologist eye on hematoxylin and eosin stain,
such as in this staining of hematoxylin and eosin.
Then we use a special stain called pancytokeratin
or CK-19 staining.
The breast cancer cells are derived from epithelial cells
from the ducts or the lobules.
Epithelial cells have cytokeratin as their cytoskeleton.
So presence of a cell containing cytokeratin positive
molecule indicates the presence of epithelial cells
within the lymph node.
Lymph node is a mesodermal structure and no cytokeratin
is present within the lymph node.
So presence of cytokeratin positive cells
is indicative of metastases of the epithelial cell origin.
And the isolated tumour cells can also be discerned
or delineated using these special cytokeratin stain,
which are missed by conventional staining
of hematoxylin and eosin.
One of the earliest large randomized trial
evaluating the role of sentinel node mapping
in women presenting with early breast cancer
in clinically negative axilla was published
by Dr. Robert Mansel, professor of surgery
at Cardiff Breast Unit.
And he published it as the name ALMANAC Trial,
ALMANAC Trial with Professor Robert Mansel
as the PI was published way back in 2006
in Journal of National Cancer Institute, JNCI
where thousand women from across various breast centers
in Britain were randomized either to receive
sentinel node mapping or full axillary treatment
in the form of either four node sampling
or axillary node dissection.
And it was observed at the end of one year,
the occurrence lymphoedema was only 5% in patients
who had sentinel load mapping
compared to 13% women following full axillary dissection.
The incidence of sensory loss was only in the tune of 11%
in women undergoing sentinel node mapping
compared to 31% of sensory loss in women
having full axillary dissection.
Thus the relative risk of lymphoedema
was reduced to one-third or 0.3 by performing
sentinel node mapping.
Similarly, the risk of sensory loss was also reduced
to 0.3 or one-third by performing sentinel node mapping
compared to full axillary dissection.
Since then a large number of trials have been published
in the literature.
And this is a summary of a systematic review
published in Journal of American Medical Association,
JAMA in 2013 where long-term adverse outcomes
associated with different axillary operations
are published.
The lymphedema marker in the tune of 10 to 20% patients
in different series in women who had undergone
full axillary node dissection
compared only to 5 to 7% women where only
sentinel node mapping was carried out.
So 10 to 20% with full ALND and 5 to 7%
with sentinel node mapping,
the quality-of-life reduction due to various symptoms,
frozen shoulder, difficulty in movement of the arm,
pain in the shoulder area, pain in the upper arm
was noticed about one-third of the patients.
35% had reduction in these scores of the quality-of-life
compared to only 23% women who had a reduction
in the quality-of-life scores if they had their axilla
assessed by sentinel node mapping.
The arm pain, and the numbness was also nearly one-third,
only 11% women after sentinel node mapping
compared to 31% in those who had full
axillary node dissection.
So we can notice that all the major adverse effects
of full axillary node dissection can be minimized
by carrying out this minimally invasive approach
that is sentinel node mapping in women
with early breast cancer and clinically negative axilla.
What is the impact of sentinel node mapping
on axillary recurrence is listed on this table data
from large centers, from Milan, Milan Institute of Oncology.
In women who had sent negative sentinel node mapping
with a follow up of 38 months.
Local recurrence was only 0.3% in the axilla.
In the Memorial Sloan Kettering data from New York,
women who had negative sentinel node biopsy,
again with a 31 month follow up,
we had 0.12% of the local recurrence in the axilla.
Similar another study by Moffitt,
women who had negative sentinel node up to 60 month
follow up only 0.26%.
So extremely low recurrence is observed in the axilla
if sentinel node biopsy is negative.
What happens if we have positive nodes?
Well, there is one such study and mind you here,
patients decided, patient choice was that in spite
of a positive sentinel node,
they will not have further axillary surgery.
And we have to honor patients desires
in deciding the treatment for patients with breast cancer.
It was observed that if they had micro-metastases again,
the axillary recurrence occurred in the tune of 0.3%,
very similar to the negative sentinel node mappings
indicating that presence of micro-metastases in the axilla
in the sentinel node probably has the same impact
as the negative sentinel node mapping.
If they had macro-metastases then axillary recurrence
was slightly higher, again, less than 1%, 0.7%.
So even with positive sentinel node, small numbers,
small tumour burden in the axilla,
we have extremely low recurrence within the axilla.
So what are the options available to a surgeon
if sentinel node biopsy is reported as positive?
Well, we have the three options,
either perform just observation
and provide all the adjuvant therapy
decided by the oncologist
in the form of radiation therapy,
adjuvant chemotherapy, hormone therapy,
or other targeted therapy.
Or we perform
a full completion axillary lymph node dissection.
And the third option is that offer radiotherapy
to the axilla and two trials have tested this hypothesis.
One has already completed,
the AMAROS trial in Europe and England
and the POSNOC trial, which is an ongoing study
in Britain.
A large multicenter study evaluated the role
of sentinel node biopsy versus axillary node dissection
in women where sentinel node biopsy reported
presence of only micro-metastases.
And it was observed that in women,
where the sentinel node is harboring
only micro-metastases there is no deterioration
in the disease-free survival.
The disease-free survival was 84% versus 88%,
whether you perform the axillary node dissection or not.
So the conclusion is that disease-free survival biopsy
with micro-metastases alone,
it is safe if we leave the axilla untouched
and offer other forms of adjuvant therapy.
If we have macro-metastases,
then what to do has been addressed by this large trial
known as American College of Surgeons Oncology Group
or ACOSOG Z-0011 trial
with the principal investigator being Dr. Giuliano,
Armando Giuliano.
And this is the famous Z-0011 trial,
women with T1 or T2 tumour clinical negative axilla
were offered breast conservation.
And if sentinel node were positive,
up to two positive macro-metastases sentinel node,
then they were randomized either to have full ALND,
axillary dissection,
only observation of the axilla
with systemic adjuvant therapy.
So the trial started way back in 1999
and finished recruitment in 2004,
165 investigators from 177 institutions
took part in this study and the target
was to accrue 1900 patients,
but the trial ended prematurely with only 891 patients.
And this is the breakup of the outcome reported
by Dr. Giuliano, axillary recurrence occurred
in 0.9% women who had sentinel node biopsy alone,
as opposed to 0.5% following full axillary node dissection.
The adverse events were much less in the form
of lymphoedema, shoulder disfunction, et cetera.
Only 25% in sentinel node group
and 70% in axillary node dissection.
Overall survival 92% in the sentinel node arm,
91.8% exactly similar survival in both the groups.
And the slide shows the inclusion criteria
for women aged 80 and above,
T1 and T2 tumour clinically negative,
no evidence of metastases.
Sentinel node had to have macro-metastases
either reported at frozen
or touch preparation or HNE staining.
And treatment has to be in the form of lumpectomy
with negative margins.
Patients having mastectomy or no radiation therapy
were excluded and patients with large tumours
were also excluded.
So this is the consort flow diagram for women
who had undergone the Giuliano Z-0011 trial,
445 patients recruited in the ALND arm
and 446 in the sentinel node biopsy arm.
And then with the intention to treat sample,
we evaluated 388 patients in the ALND arm,
425 patient in the sentinel node biopsy arm.
So this is the age distribution and clinical parameters.
They were all balanced within the two groups,
type of carcinoma, histologically infiltrating
ductal carcinoma in the majority of women
in both the groups, almost similar distribution.
Chemotherapy was offered nearly to the same
proportion of women
and so is true for patient receiving endocrine therapy.
The locoregional recurrence was reported
as a long-term outcome of this trial
way back in 2016 in Annals of Surgery.
And here is the result,
at nine years of follow up
women undergoing ALND had local recurrence of 5.8%.
And in the sentinel node group,
local recurrence of 3.8%,
regional recurrences 0.5 here and 1.5 here,
so almost similar recurrences.
At the cumulative 10 year local recurrence
as reported here,
the blue bar represents the data
from women undergoing ALND
and the maroon bar represents the data
for women undergoing sentinel node biopsy.
So the cumulative local recurrence occurred in 5.8%
following ALND and 3.8% following sentinel node biopsy,
no statistical difference on the P value.
Cumulative regional recurrence or CRR
occurred 0.5% in ALND group
and 1.5% in sentinel node, slightly higher
P value, slightly more than 0.5,
so not attaining a statistical significance.
Cumulative loco-regional recurrence that is taken
local plus the regional together,
6.3% in the ALND arm vs 5.8% in sentinel node biopsy.
Again, no statistical difference.
If we take the overall survival with the purple line
representing the data from women undergoing
axillary node dissection and the green line representing
those who had axillary radiotherapy.
Again, there's no difference.
These two curves almost overlap till the very end.
And then there is bit of divarication at the end
of the follow up.
Disease-free survival, again, the two lines,
the purple line representing the axillary node dissection
data and the green line representing the information
from those having axillary radiotherapy,
the two lines almost overlap each other.
So what to do after mapping axilla,
offer radiotherapy or surgery to the axilla
has been addressed in this trial called AMAROS.
AMAROS is an acronym for this,
After Mapping Axilla: Radiotherapy or Surgery.
And this was a EORTC Breast Cancer Group trial
with Dr. Rutgers from Netherlands as the PI
and Professor Robert Mansel
as the PI from the United Kingdom.
Eligibility criteria, T1, T2 tumours
up to 5 centimeter in size,
clinically negative undergoing either breast conservation
or mastectomy, any age and with prior informed consent
were included.
Patient with multicentric disease,
neoadjuvant chemotherapy was an exclusion criteria
and presence of prior malignancies.
So 4823 patients were registered,
of these 4806 were randomly assigned
either to have axillary lymph node dissection
or to only axillary radiotherapy.
And this is the final sample,
which was analyzed by intention-to-treat analysis,
744 after sentinel node
and 681 were axillary node positive sentinel node mapping.
The axillary recurrence in the women
undergoing ALND was exactly similar
to those where axillary nodes were treated
by axillary radiotherapy.
The blue line and the red line overlap
from the beginning down to the end of the follow up.
Axillary recurrence rate was noted
in 4 out of 744 women undergoing ALND 0.43%
versus those having axillary radiotherapy, 1.19%,
no statistical difference.
Significant difference was observed with the survival curve
line overlapping exactly till the very end of the follow up.
Women having micro-metastases, axillary clearance
occurs in exceedingly low proportion of women 0.2%
if you have micro-metastases
and if you do not offer any further therapy, only 1.9%.
Presence of macro-metastases as shown in Z-11 trial,
0.5% of axillary clearance, 0.9% after observation
of axilla alone.
In the AMAROS trial we observe that radiotherapy
in the axilla has a recurrence rate of only 1.2%
as opposed to 0.4% with axillary clearance.
POSNOC trial is ongoing with Dr. Amit Goyal
as the PI in UK.
Here, T1 in T2 tumours with clinically
and negative and no metastases,
N0 and M0 patients are being evaluated.
Ultrasound axilla is performed to exclude those
who have suspicious nodes and if the nodes are negative,
then they are being randomized to sentinel node biopsy.
And breast cancer is being treated either
by wide local excision or mastectomy.
So both lumpectomy and mastectomy patients are being
included in this trial.
The trial is ongoing and we are waiting
for the final results to be published.
So the ASCO guidelines published in 2016
suggests that if the sentinel node is negative,
do not carry out any axillary node dissection.
If you have 1-2 positive macro-metastases
sentinel node and patient is having breast conservation
surgery, again no axillary dissection is recommended.
If you have positive sentinel nodes
and patient is having mastectomy,
axillary node should be performed.
Patients with large tumours, T3 and T4 tumors,
or those presenting with the inflammatory breast carcinoma,
recommendation is perform full axillary node dissection.
There is no role of breast conservation
and no role of sentinel node mapping
in these patients with advanced cancers.
What to do if patient has advanced cancer
and we offer primary systemic chemotherapy
or neoadjuvant chemotherapy
has been addressed in this trial.
False negative rate has been found to be very high
if you remove less than three nodes, up to 20%
with a single agent.
And if you use dual tracers,
it can be brought to 10%.
So if more than three nodes are removed,
false negative rate can be reduced to less than 10%.
So now we have observed an era
of de-escalation of axillary surgery
in the form of use of biomarkers to assist
the systemic therapy and not the axillary node involvement.
Sentinel node concept is now being used
more and more in evaluating the axillary nodal
involvement and deciding further adjuvant systemic therapy
in women with low burden of axillary disease.
Two European trials are on way.
One is SOUND trial in Italy
where patients are being evaluated
where no axillary surgery is carried out.
And similar trial in Germany called INSEMA trial
is evaluating 5940, large number of patients
being evaluated where sentinel node versus no axillary
surgery
is being carried out.
Let us appreciate various pitfalls and shortcomings
associated with axillary nodal assessment in patients
with breast cancer.
Most important fact to appreciate is the issue
of sentinel node biopsy in patients suffering
from locally advanced breast cancer.
Current data does not support the use
of sentinel node mapping in patients
who present with initial advances stage
of disease in the breast
in the form of large tumours.
More than 5 centimeter in size that is T3 tumours
and T4 tumours that is tumours involving the skin
of the breast and underlying chest wall.
And also the patients with inflammatory breast cancer.
In all these situations,
some authors have attempted to carry out
sentinel node mapping,
but have reported very high and unacceptable levels
of false negativity with sentinel node mapping.
Hence it has not been accepted as a standard of care
for patients either with locally advanced breast cancer
or with inflammatory breast cancer.
We should also appreciate that we do not have very solid
evidence in support of performing sentinel node mapping
after initial neoadjuvant chemotherapy
for women presenting with locally advanced breast cancer.
Moreover, there is the need for training surgeons,
pathologist, operative room associated personnel
like scrub nurse and nuclear medicine physicians
in obtaining optimal results of sentinel node mapping.
And of course there is a need of providing
radio-isotope injection to the patient
and the need of radioactivity detection gamma probe,
which is very expensive.
So what is the way ahead?
What can we do to circumvent these problems and issues?
Obviously there is need of more research in this area.
We have to train our surgeons and other associated personnel
in the performance of sentinel node mapping
and in ultrasound evaluation of the axillary nodes.
One alternative to the use of radioactive tracer
in performance of sentinel node mapping,
maybe a fluorescent dye such as fluorescein
or indocyanine green in combination
with blue dye methylene blue.
In order to develop this fluorescence
based sentinel node mapping technique
research was carried out
at the Advanced Center for Training Research
& Education in Cancer,
research wing of Tata Memorial Center in Mumbai,
in short it is called ACTREC.
ACTREC serves as a bridge between the basic sciences
and clinical oncology.
A research project was undertaken in the name
of Fluorescent Dye Guided Sentinel Node Mapping
and Raman spectroscopic assessment
of sentinel node biopsy in patients
with breast cancer.
Fluorescein sodium solution was used
to identify the sentinel nodes.
At this time there was only one study
reporting the role of fluoroscein sodium
in sentinel node mapping for patients
with colorectal cancers.
Group of workers in Michigan State University
led by Dan et. Al., had performed initial study
on 120 patients with colorectal cancer.
And they had shown that fluoroscein sodium
could actually replace the gold standard
being used at that time that is lymphazurin
and isosulphane blue.
So we carried out a study at ACTREC
where a combination of fluorescein sodium,
methylene blue and radio tracer technetium
tagged to albumin was used.
Blue dye helps in identification
of the dermal lymphatic plexus very nicely.
The fluorescent lymphatics can be nicely visualized
using blue light of 480 nanometer wavelength.
Bilateral mammary crease incision helps
in identifying the lymphatics travelling
from the nipple-areolar complex and dermal lymphatics
of the breast.
If an incision is placed along this lateral mammary crease,
dissection deep to the axillary facia
then reveals these shiny fluorescent lymph nodes
and lymphatics, which are then dissected
and the blue and fluorescent nodes are removed.
In this patient we were able to identify
four nodes in such manner.
The initial results of this study using a combination
of fluorescein, methylene blue and radio tracer
was quite encouraging.
And based on that,
we evaluated its results
at the Tata Memorial Hospital in Mumbai.
We obtained acceptable identification
of lymph nodes with fluorescein in 92% of patients
as opposed to identification
with technetium sulphur colloid in 96% of patients.
We achieved a false negative rate of 8.3%
when we used the combination of the traces.
This result was presented
in the San Antonio Breast Cancer Symposium.
Based on these encouraging results
we then embarked upon a randomized trial
with non-inferiority hypothesis
at the All India Institute of Medical Sciences, New Delhi.
This is an ongoing trial.
And so far we have achieved an identification
of sentinel nodes when we use the combination
of fluorescein and methylene blue in 84% of patients,
which is similar to that achieved
by combination of radio tracer with methylene blue.
These results have been presented
in the San Antonio Breast Cancer Symposium.
This technique has also been validated
by a group of breast surgeons
led by professor Gaurav Agarwal
who's an eminent breast surgeon
at the Sanjay Gandhi Memorial Post Graduate Institute
in Lucknow.
They have achieved an identification
with fluorescein and methylene blue
in 95% of patients achieving a sensitivity of 93%
and a false negative of 6.3%.
Based on these results,
we could suggest that a combination
of fluorescein and methylene blue could perhaps
be adopted world over because it is offering
an affordable low-cost, effective
and safe alternative to the conventional combination
of radioactive tracer along with the blue dye.
In conclusion, we will submit
that patients with invasive breast cancer
presenting with a clinical negative axilla,
an ultrasound evaluation of the axilla
should be carried out, any suspicious node
should be biopsied, if found positive
should proceed to performing
axillary lymph node dissection or ALND.
However, if patient has both clinically
and sonographically negative axilla
or if the biopsy of the suspected node is negative,
we should proceed with sentinel node biopsy
in patients where histological examination
of sentinel node reveals presence
of macro-metastases in up to two sentinel lymph nodes.
Axillary radiotherapy can be offered as a viable option
to full axillary dissection where we find
three or more sentinel nodes positivity
revealing macro-metastases perhaps
axillary lymph node dissection is the best
therapeutic option based on current evidence.
For women presenting with locally advanced breast cancer
or those who are coming after neoadjuvant chemotherapy
and with inflammatory breast cancer,
axillary sampling or full axillary dissection
remains the most effective and safe option
for dealing with axillary lymph node metastasis.
The future lies in training the surgeons and pathologists
in performing and evaluating sentinel lymph nodes
and generating level one robust evidence
in favour of axillary sentinel node biopsy
based on fluorescent dye fluorescein sodium.
Thank you very much.