Trial Information

Clinical Trial of Sentinel Node Biopsy Versus Axillary Sampling in Women With Clinically Node Negative Operable Breast Cancer

Axillary node dissection in operable breast cancer provides an accurate way of staging the
disease. With increased popularity of screening and earlier diagnosis, most women do not
harbor axillary metastases, in which case, axillary lymph node dissection could be avoided.
Sentinel node biopsy (SNB) gained rapid popularity because the technique could predict the
presence of metastases in downstream lymph nodes, so that surgery and its associated
morbidity could be safely avoided. SNB can be performed with injection of isosulphan blue
subdermally and peritumorally alone or in combination with radio-guidance with technetium-99
labeled colloid injection. Radio-guided SNB is superior to the blue dye in identifying the
SN, and a combined technique is still better. However, it failed to accomplish its objective
in a proportion of cases where the sentinel node could not be identified even with expensive
gadgetry like gamma probes. An overview of sentinel node studies showed that the node was
found in only 85-90% of patients and the overall sensitivity in correctly predicting the
negative axilla by sentinel node biopsy was only 94%. There was a false negative rate of
6.2% wherein the sentinel node was reported negative in presence of metastasis to
non-sentinel nodes in axilla.

Axillary sampling was a forerunner to the targeted sentinel node biopsy. The main objective
of axillary sampling at that time was to detect a positive axilla. More recently it is being
tested as an accurate predictor of axillary status for absence of metastasis.

There is a definite learning curve in SNB with higher non-detection rates and false negative
rate in the earlier phases of the study compared to the later part. This learning curve is
absent in axillary sampling, which requires no specialized training or expensive equipment
and has a 100% detection rate. The mean number of sentinel nodes that were identified, as
reported in various SNB studies, was 2.13 (with a range of mean numbers of SN dissected
being 1.3-3.1). The actual range of number of sentinel nodes dissected was 1 - 8, which is
quite comparable to the average 4 -5 nodes that are required to be sampled for accurately
predicting the axilla. Badwe and Mittra have concluded that sentinel node biopsy is
expensive and is driven by lure for technology and fashion, and has little advantage over
axillary node sampling in predicting a negative axilla.

There is a validation study of lower axillary sampling versus total axillary clearance
reported by Steele et al in 1985 with a sensitivity of 100% and an accuracy of 99.5%. The
more recent validation study of 5-node axillary sampling compared to level I-II dissection
was reported from Stockholm on 416 operable breast cancer patients. The noteworthy finding
was that in this study node sampling had a 100% yield, 97.3% sensitivity and a negative
predictive value of 98.5% with a false negative rate of 2.7% in predicting the axilla. The
comparative figures for SNB in the world overview are 94% sensitivity, 97% negative
predictive value and a false negative rate of 6.5%.

Preliminary studies of SNB and axillary sampling at TMH Sentinel node biopsy by Isosulphan
blue injection was performed as a validation pilot study at the Breast unit in TMH between
April 1999 to November 2000 in 100 women with clinically node negative operable breast
cancer. SN was found in 77% cases with a false negative rate of 16.6% and sensitivity of
76.1%. The procedure had a negative predictive value of 90.4% cases in predicting the rest
of the axilla. The number of sentinel nodes dissected was 1-6 with an average of 1.4.

Axillary sampling was subsequently performed as a pilot study between May 2001 to August
2002 in 97 women with a similar clinical stage as above. Nodes were found in all patients
(100%) in level I with a false negative reporting in 11% cases, sensitivity of 88.9%,
negative predictive value of 100% and an average of 4 nodes dissected (range from 1-9).

In developing countries with limited resources, it may not be feasible for every institution
to acquire a gamma probe. Axillary sampling may thus be a comparably cheaper and practical
alternative to SNB. Axillary sampling and sentinel node biopsy should, however, be compared
with respect to the resultant morbidity and false negative rates before adopting either
method as standard clinical practice.

The Nottingham group have recently published the results of a prospective study to find out
the value of adding SNB to 4-node axillary sampling (4NAS) within the same patient. Two
hundred patients were accrued and 4NAS was found to have a lower false negative rate
compared to SNB. We propose to compare the two procedures in a clinical trial with a
comparison of respective false negative rates and sensitivity as the immediate end points.

Methodology:

Eligible women will be recruited in the study after obtaining an informed consent and
centrally registered at the Clinical Research Secretariat at the Tata Memorial Hospital,
Mumbai.

The radiolabeled Tc-99 colloid or phytate (500 Mbq) will be injected into the primary tumor
2 hours before surgery. A localized scintiscan will then be performed to confirm the
radiolabeling of the sentinel node before surgery and for documentation. Isosulphan blue dye
will be injected subdermal (0.5ml) over the tumor and intraparenchymal (3-4ml) towards the
axilla 10-15mins before incision.

Axillary sampling will be performed first. A 2 cm incision will be made in the middle third
of the proposed axillary clearance incision below the axillary hairline. All axillary fat
and tissue in an area of 2cm diameter will be dissected out. The anterior limit of
dissection is the posterior border of pectoralis major, the posterior limit of dissection is
the anterior border of latissimus dorsi muscle, upper limit of dissection is the
intercostobrachial nerve, and base is serratus anterior muscle on lateral chest wall. In
those cases that undergo a mastectomy, the tissue in the axillary tail will be identified
first and then removed as specified above.

After completion of sampling procedure, the remaining axillary tissue will be checked for
any other node showing a blue discoloration or radioactivity and the same will be documented
as found outside of axillary sampling. Axillary clearance will then be separately completed
in all patients by standard technique after extending the incision without waiting for the
frozen section report.