NSABP B-32 TRIAL

1. NSABP B-32
Prof. S. Subbiah et al

2. Background
 The goals of axillary-lymph-node dissection (ALND) are to maximize survival,
provide regional control and stage the patient.
 However, this procedure has substantial side-effects.
 The purpose of the B-32 trial is to establish whether sentinel-lymph-node (SLN)
resection can achieve the same therapeutic goals as conventional ALND but
with reduced morbidity
Prof. S. Subbiah et al

3. Background
 Extensive information was available for long term outcomes of ALND
 The overall magnitude of improved survival in RCTs was about 5%
 Bland et al analysed a large database of 500,000 patients –
85% vs 66% 10 year OS
 Lymphadenectomy is therapeutic and diagnostic
 With this search began for that subset of patients who would not benefit from
axillary dissection
 Justification for conducting the clinical trial – remarkable accuracy of SLN
technology
Prof. S. Subbiah et al

4.  A core group pf surgeons performed site visits and provided personal training for all enrolled
surgeons to ensure quality control
 Surgeon was required to perform 5 prerandomisation SLB procedures before entering into trial
 These were evaluated for protocol compliance and accuracy of data maintenance
Prof. S. Subbiah et al

5.  Protocol compliance analysis
 Basic details, Procedural data, pathology data
 815 training cases
 70% surgeons completed training in 5 cases
 30 % required additional training before entering the trial
 Sentinel nodes were identified in 96.2% cases with false negative rate of 6.7% with
protocol adherence of more than 95%
 All the surgeons were audited during initial at least 20 cases after they were enrolled
into trial
Prof. S. Subbiah et al

6. A Description of the Trial
Prof. S. Subbiah et al

7. May 1999 and February 2004
5611 women with operable primary invasive breast cancer with
clinically negative nodes
 Group 1-SLB f/b immediate conventional ALND
 Group 2-SLB without ALND (if SLN were negative on cytology & histological examination) (ALND was
performed if no SLN were identified or if they were positive)
233 surgeons from 80 institutions in the USA and Canada
The randomisation was stratified according to
 age at entry (≤49 years or ≥50 years);
 surgical treatment plan (lumpectomy or mastectomy)
 clinical tumour size (≤2 cm, 2.1-4.0 cm, or >4 cm).
Prof. S. Subbiah et al

8. Aims & objectives
 Primary
 Overall survival, disease free survival
 Designed to detect 2% survival difference between the groups
 Regional recurrence rates
 Evaluation of morbidity profile
 Secondary
 Accuracy
 Technical success
Prof. S. Subbiah et al

9.  Between 30 min and 8 h before surgery, 1 millicurie (mci) of unfiltered
technetium-99m sulphur colloid in a total volume of 8 mL of normal saline
was injected into the breast circumferentially above, below, and on each
side of the tumour or biopsy cavity in four evenly divided injections.
 An additional injection of 0.2 mci in 0.05 mL of normal saline was injected
into the skin over the tumour.
 Hand-held gamma detector to identify hot spots.
 A hot spot was defined as a discrete area of radioactivity separate from
the injection site.
 An ex-vivo count of more than 25 in 10 s is defined as hot or
radioactive; a count of 25 or less in 10 s is defined as not hot.
Prof. S. Subbiah et al

10.  5 ml of undiluted isosulfan blue was injected into the breast
circumferentially around the tumour and the breast was
gently massaged for 5 min.
 Radio active nodes were removed until the bed count was less
than 10% of the hottest ex-vivo SLN.
 Blue-stained nodes were removed and deemed SLNs
regardless of radioactive counts.
 Nodes that were hard and highly suspicious for metastatic
tumour were also removed and defined as SLNs irrespective
of radioactivity or blue-dye staining.
Prof. S. Subbiah et al

11.  SLNs removed from patients in group 2 were assessed intraoperatively using
imprint or scrape and smear cytology.
 All SLNs were subsequently sent for HPE
 IHC staining was reserved only for confirmation of suspected metastases
Prof. S. Subbiah et al

12. Secondary endpoints - accuracy and technical success
Prof. S. Subbiah et al

13.  Technical success, defined as the ability to identify and remove at least one SLN,
was 97.3% (2672 of 2746) in group 1 and 97% (2707 of 2790) in group 2
 The mean numbers of SLNs removed were 2.9 and 2.8 for groups 1 and 2
respectively.
 Of 5379 patients with SLNs, 694 (26%) in group1 & 696 (25.7%) in group 2 were
sentinel node positive
Prof. S. Subbiah et al

14. Selected factors and technical success
Prof. S. Subbiah et al

15. Prof. S. Subbiah et al

16. SLN location and character
 98% of SLN are located in level 1&2
of axilla.
 Less than 1% of SLNs were found
outside axilla
 Most of SLNB specimens were both
blue and hot(65%)
 3.9% palpable only
Prof. S. Subbiah et al

17. Accuracy of SLNB
 Out of 1928 patients classified as SLN neg 1853 were confirmed to be negative by ALND
 75 patients who were SLN negative were node positive in subsequent ALND
 Overall accuracy - 97.1%
 Negative predictive value - 96.1%
 Sensitivity - 90.2%
 False negative rate - 9.8%
 Several variables were assessed for possible association with false-negative rates
Prof. S. Subbiah et al

18. Prof. S. Subbiah et al

19.  In 61.4% positive SLN patients in group 1, positive SLNs were the only nodes
positive in final HPE
 38.6% patients had non-sentinel node positivity
Prof. S. Subbiah et al

20. Intraoperative cytology
 2697 patients in group 2 had complete set of data on introp
cytology and subsequent HPE
 Overall accuracy was 89.7%
 The negative predictive value was 88.1%.
 The positive predictive value was 97.5%
 The false-negative rate was high at 38.6%
 Sensitivity was 61.4%
 Only 11 of the 2003 patients deemed to have negative nodes on
histological examination were classified as having positive nodes on
intraoperative cytology.
Prof. S. Subbiah et al

21. Allergy
 Allergic reactions were associated with blue dye injections.
 0.4 % (n=25) had grade 1 or 2 allergic reactions.
 0.2% (n=12) had grade 3 or 4 allergic reactions.
 No deaths due to allergic reactions were reported.
Prof. S. Subbiah et al

22. NSABP- B 32
 The trail was powered to test a difference in survival of 2% between the two groups
for the SLN-negative patients at 5 years
Prof. S. Subbiah et al

23. Trial Profile
Prof. S. Subbiah et al

24. Clinical characteristics
Prof. S. Subbiah et al

25. Death
 Mean follow up 95.6 months
 309 deaths reported (140+169)
109
Breast cancer
recurrence
7
Contralateral
breast cancer
84
Second cancer
109
Other causes
Prof. S. Subbiah et al

26. Among the deaths due to breast cancer recurrence
 15 were after a local recurrence (eight in group 1 and seven in group 2)
 10 after regional recurrence (three in group 1 and seven in group 2)
 84 after systemic recurrence (39 in group 1 and 45 in group 2)
Prof. S. Subbiah et al

27. Overall survival
 5-year Kaplan-Meier estimates
for overall survival were 96.4%
(95% CI 95.6–97.2) in group 1
and 95.0% (94.0–96.0) in
group 2
 8-year estimates were 91.8%
(90.4–93.3) for group 1 and
90.3% (88.8–91.8) for group 2
Prof. S. Subbiah et al

28. Disease-free survival
 No substantial differences are
evident across sites
 The trial validates that when SLN
is negative, nodal recurrences do
not differ significantly between
patients who have axillary
dissection or SLN resection only.
Prof. S. Subbiah et al

29. Disease-free Survival
 5-year Kaplan-Meier estimates
for disease-free survival were
89.0% (95% CI 87.6–90.4) in
group 1 and 88.6%(87.2–90.0)
in group 2
 the 8-year estimates were
82.4% (80.5–84.4) in group 1
and 81.5% (79.6–83.4) in
group 2
Prof. S. Subbiah et al

30. Overall survival, disease-free survival, and
regional control were all statistically
equivalent in SLN-negative patients who
had an ALND or SLN surgery alone
Prof. S. Subbiah et al

31. Non sentinel node positivity
 Group 1, 75 patients had positive non sentinel nodes
 71 received systemic adjuvant therapy
 The outcome of these 75 patients was not worse than that of
the group as a whole (mean yearly mortality 0.99% [95% CI
0.32–2.30] vs 1.02% [0.85–1.19],respectively), even though
they were node-positive.
 In group 2, a similar subset of non-SLN-positive patients can
be expected-it did not alter the survival
Prof. S. Subbiah et al

32. Morbidity
Patient-reported outcomes and morbidity related to range of motion, edema, pain, and sensory
defects are lower in the SLN group than in the ALND group
Prof. S. Subbiah et al

33.  3year post procedure morbidity between the groups were compared
 Included
 Objective shoulder abduction assessments
 Baseline, 1wk, 2wk, 3wk &6m
 Objective arm volume assessments
 Baseline, every 6m till 3years
 Subjective assessments if numbness and tingling
 Baseline, every 6m till 3years
Prof. S. Subbiah et al

34.  Residual shoulder morbidity was defined as >5% difference in abduction at
baseline and at 6m
 Residual arm volume morbidity was defined as >5% difference in volume between
baseline and at 36m
 Residual arm numbness and tingling was defined as presence of the same at 36m
Prof. S. Subbiah et al

35.  ALND fared worse in all 3 categories
 More with dominant arm and radiation therapy&/or chemotherapy
Prof. S. Subbiah et al

36. Conclusion
When the SLN is negative, SLN surgery alone
with no further ALND is an appropriate, safe,
and effective therapy for patients with breast
cancer with favourable morbidity profile.
Prof. S. Subbiah et al

37. Safe reduction of surgery
Landmark surgical trials
 NSABP B-06
 NSABP B-32
Prof. S. Subbiah et al

38. Follow up results
 At 10 years there continues to be no significant differences in OS and DFS between
SNR and SNR + AD in pts with negative SN.(OS - 87.8% for SNR alone and 88.9%
for SNR + AD, DFS - 76.9% for both)
 The relative increase in risk of DFS and OS for pts with occult SN metastases
remains stable.
Prof. S. Subbiah et al

39. To summarise
 Successful identification of SLN
 Presence of pre-incision hot spot is strong indicator of successful identification SLN
 Identification of extra axillary SLN is possible without undue morbidity
 More the number of SLN, less is the false negative rate
 Lateral quadrant lesion or h/o incision biopsy can increase the false negative rates
 Any palpable node is likely to harbour metastasis
 Imprint cytology has high false negative rates
When the SLN is negative, SLN surgery alone with no further
ALND is an appropriate, safe, and effective therapy for patients
with breast cancer with favourable morbidity profile
Prof. S. Subbiah et al

40. Thank you
Prof. S. Subbiah et al