Sentinel Lymph Node Biopsy Versus Axillary Clearance in Operable ...
Sentinel Lymph Node Biopsy Versus Axillary Clearance in Operable ...
Sentinel Lymph Node Biopsy Versus Axillary Clearance in Operable ...
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<strong>Sent<strong>in</strong>el</strong> <strong>Lymph</strong> <strong>Node</strong> <strong>Biopsy</strong><br />
<strong>Versus</strong><br />
<strong>Axillary</strong> <strong>Clearance</strong><br />
<strong>in</strong> <strong>Operable</strong> Breast Cancer<br />
Dr Neil R Wetzig May 2005
RACS Section of Breast Surgery<br />
- 32 Centres Australia & New Zealand<br />
A Multicentre Randomised<br />
Controlled Trial<br />
NHMRC Cl<strong>in</strong>ical Trials Centre<br />
- Sydney, NSW<br />
PARTICIPANTS
Royal Adelaide Hospital (SA)<br />
Westmead Hospital (NSW)<br />
Royal Melbourne Hospital (Vic)<br />
North Shore Hospital (NZ)<br />
Nambour Hospital (Qld ( Qld)<br />
Waikato Hospital (NZ)<br />
Pr<strong>in</strong>cess Alexandra Hospital (Qld ( Qld)<br />
Mater Hospitals (Qld ( Qld)<br />
Wesley Hospital (Qld ( Qld)<br />
St Andrews Hospital (SA)<br />
Sir Charles Gard<strong>in</strong>er Hospital (WA)<br />
Coff Harbour Based Hospital<br />
Bar<strong>in</strong>ga Private Hospital (NSW)<br />
Concord Hospital (NSW)<br />
PARTICIPANTS<br />
Palmerston North Hospital (NZ)<br />
Strathfield Private Hospital (NSW)<br />
Royal Women’s Hospital (Vic)<br />
Western Breast Cl<strong>in</strong>ic (SA)<br />
St V<strong>in</strong>cent’s Hospital (NSW)<br />
Queen Elizabeth Hospital (SA)<br />
St V<strong>in</strong>cent’s Mater Hospital (NSW)<br />
Middlemore Hospital (NZ)<br />
Nepean Hospital (NSW)<br />
Royal Pr<strong>in</strong>ce Alfred Hospital (NSW)<br />
Lismore Base Hospital<br />
St V<strong>in</strong>cent’s Private Lismore<br />
Geelong Hospital<br />
Gold Coast Hospital<br />
St John of God Hospital Murdoch<br />
St V<strong>in</strong>cent’s Hospital<br />
Auckland Hospital
Study Chair:<br />
Deputy Study Chair:<br />
Management Committee<br />
CTC: Study Coord<strong>in</strong>ator:<br />
Surgeons:<br />
Pathologist:<br />
Data Manager<br />
Nuclear Medic<strong>in</strong>e:<br />
Consumer Representatives:<br />
Trial Statistician:<br />
Cl<strong>in</strong>ical Epidemiologist:<br />
Cl<strong>in</strong>ical Trialist:<br />
A/Prof Grantley Gill<br />
Dr Neil Wetzig<br />
Burcu Cakir<br />
Xanthi Cosk<strong>in</strong>as<br />
Mr John Coll<strong>in</strong>s<br />
Prof David Gillett<br />
Dr James Kollias<br />
Dr Owen Ung<br />
Dr Michael Bilous<br />
A/Prof Roger Uren<br />
Avis MacAphee (BCNA)<br />
Leonie Young (ANZ BCTG)<br />
Mr Val Gebski<br />
Dr Mart<strong>in</strong> Stockler<br />
Prof John Simes
AIMS & OBJECTIVES<br />
To determ<strong>in</strong>e whether breast cancer<br />
outcomes follow<strong>in</strong>g<br />
sent<strong>in</strong>el node biopsy are<br />
equivalent to those follow<strong>in</strong>g<br />
axillary clearance<br />
with reduced morbidity
Inclusion Criteria:<br />
All women with operable <strong>in</strong>vasive breast<br />
cancer < 3cm <strong>in</strong> diameter (<strong>in</strong> whom<br />
axillary stag<strong>in</strong>g is required as part of<br />
their treatment)<br />
Patient Consent
ELIGIBILITY:<br />
Invasive Cancer<br />
Primary Tumour<br />
LYMPHATIC MAPPING - Technique<br />
Comb<strong>in</strong>ed Method<br />
<strong>Lymph</strong>osc<strong>in</strong>tigraphy Preoperatively<br />
40-80 mbq Tc 99 antimony colloid<br />
Peritumoral <strong>in</strong>jection with massage<br />
Patent blue <strong>in</strong>jected <strong>in</strong> OR<br />
Gamma Probe<br />
Patent Blue Dye alone<br />
(if nuclear medic<strong>in</strong>e not available)
ACCREDITATION OF CENTRE<br />
Completion of 20 consecutive cases of<br />
SNB reviewed by management committee<br />
(>90% success)<br />
SITE VISIT :<br />
External review of nuclear medic<strong>in</strong>e facility<br />
External review of operative technique
PATHOLOGICAL ASSESSMENT OF<br />
THE SENTINEL NODE<br />
<strong>Sent<strong>in</strong>el</strong> node is sliced <strong>in</strong>to 2mm slices<br />
4 step sections from each slice<br />
Sections sta<strong>in</strong>ed for H&E and CAM 5.2
PATHOLOGICAL ASSESSMENT OF<br />
THE SENTINEL NODE<br />
AXILLARY CLEARANCE – s<strong>in</strong>gle section on each non-sent<strong>in</strong>el node<br />
(H&E)<br />
SENTINEL NODE BIOPSY – multiple sections on SN (H&E and IHC)
Endpo<strong>in</strong>ts<br />
FOLLOW UP & ASSESSMENT<br />
At 1, 6 and 12 months<br />
Annually thereafter<br />
• Disease Status – axillary recurrence and DFS<br />
• Arm volume<br />
• Quality of life (global and arm symptoms)<br />
-- BIBCQ, EORTC, QLQ-C30, QLQ QLQ-C30, C30, QLM-B23 QLM QLM-B23 B23
MORBIDITY AND QUALITY OF LIFE<br />
Objective Outcomes<br />
Arm swell<strong>in</strong>g and numbness<br />
Shoulder movement (goniometer)<br />
Seroma rate, <strong>in</strong>fection<br />
Hospital stay and number of surgical episodes<br />
Self Assessed<br />
• Subjective arm symptoms<br />
• Quality of Life <strong>in</strong>struments<br />
- Body Image after Breast Cancer Qu (BIBCQ);<br />
- EORTC Core Quality of Life Qu (QLQ-C30) (QLQ (QLQ-C30) C30)<br />
- EORTC Breast Module (QLM-B23)<br />
(QLM (QLM-B23) B23)
Trial Commenced May 2001<br />
Stage 1:<br />
– 150 Patients to assess Study Procedures<br />
(Optimisation<br />
Optimisation of Outcome Measures) (1 year)<br />
Stage 2:<br />
– 1100 Patients over 5 year period<br />
(Comparison of treatments)
To 18th April 2005:<br />
1080 Patients randomised<br />
Recruitment Ceased<br />
32 centres<br />
as of<br />
57 Surgeons<br />
6 th May 2005<br />
Total Accrual 1088
No. of patients recruited<br />
1100<br />
1000<br />
900<br />
800<br />
700<br />
600<br />
500<br />
400<br />
300<br />
200<br />
100<br />
0<br />
Jun-01<br />
Oct-01<br />
Feb-02<br />
Jun-02<br />
Oct-02<br />
SNAC Recruitment<br />
Feb-03<br />
Jun-03<br />
Oct-03<br />
Feb-04<br />
Jun-04<br />
Oct-04<br />
Feb-05<br />
Jun-05<br />
Oct-05<br />
Actual accrual<br />
Target accrual<br />
Feb-06<br />
Jun-06<br />
Oct-06
RACS SNAC TRIAL<br />
First 150 patients<br />
NSW 29 19%<br />
QLD 52 35%<br />
SA 48 32%<br />
VIC 16 11%<br />
WA 5 3%<br />
NZ 0<br />
Recruitment by State<br />
Total to 8.4.05<br />
NSW 238 22%<br />
QLD 274 25%<br />
SA 204 19%<br />
VIC 94 10%<br />
WA 70 6%<br />
NZ 199 18%
35%<br />
30%<br />
25%<br />
20%<br />
15%<br />
10%<br />
5%<br />
0%<br />
RACS SNAC TRIAL<br />
Recruitment by State<br />
NSW QLD SA NZ WA VIC<br />
First 150<br />
Apr-05
SUCCESSFUL RECRUITMENT<br />
A RACS study conducted by surgeons<br />
Informed Consent Workshops<br />
Regular newsletters for participants<br />
Supported by NHMRC, NBCF, DHAC and state<br />
cancer councils and other organizations
-ve SNB<br />
349<br />
SNB Alone<br />
540<br />
RANDOMISATION<br />
1080<br />
+ve SNB<br />
151 (28%)<br />
AC<br />
SNB +AC<br />
540<br />
SN Not Found<br />
24 (4%)<br />
AC<br />
14.6 + 7.1
PROJECT STATISTICS :<br />
(CRF’s )<br />
Number Entered Clean<br />
CRF Retrieval 14894 98% 89%<br />
QOL Retrieval 18695 98% 96%<br />
% of Patients at<br />
each stage of FU<br />
1 month FU 1070 99%<br />
6 month FU 1024 95%<br />
1 year FU 878 81%<br />
2 year FU 519 48%<br />
3 year FU 131 12%<br />
(N= 1080)
STUDY VARIABLES<br />
MEAN + SD<br />
Age 58.0yr + 10.2<br />
Weight 72.4kg + 15.7<br />
Tumour Diameter 16.1mm + 9.0<br />
Equally distributed between both arms<br />
14.6 + 7.1
STUDY VARIABLES (N= 974)<br />
Symptomatic 412 42%<br />
Screen detected 559 57%<br />
Palpable 548 56%<br />
Impalpable 426 44%<br />
Method of Diagnosis<br />
Number %<br />
FNA Cytology 354 36%<br />
Core <strong>Biopsy</strong> 524 54%<br />
Open <strong>Biopsy</strong> 92 9.6%<br />
Equally distributed between both arms
Tumor Grade<br />
STUDY VARIABLES<br />
High 233 25%<br />
Moderate 392 41%<br />
Low 302 32%<br />
<strong>Lymph</strong>atic Invasion<br />
772<br />
161<br />
Equally distributed between both arms<br />
(N= 974)<br />
Number %<br />
No 757 80%<br />
Yes 178 19%<br />
EIC Positive<br />
82 %<br />
17 %<br />
No 772 82%<br />
Yes 161 17%
Equally<br />
distributed<br />
between<br />
both arms<br />
STUDY VARIABLES (N=869)<br />
Surgery for Primary Tumour<br />
Number %<br />
WLE (wide local excision) 622 66%<br />
WLE & Re-excision 138 15%<br />
Mastectomy 47 5%<br />
Completion Mastectomy 62 6%
Total Number = 991<br />
LYMPHATIC MAPPING & SN DETECTION - Results<br />
SNB + AC SNB<br />
• <strong>Lymph</strong>osc<strong>in</strong>tigraphy Used 90% 90%<br />
• SN Detected <strong>Lymph</strong>osc<strong>in</strong>tography 86% 84%<br />
• Gamma Probe 90% 90%<br />
• Detected as “Hot” by Gamma Probe 96% 94%<br />
• Blue Dye Used 99% 99%<br />
• Detected by Blue Dye 85% 85%<br />
• Blue Dye only 8.7%
SN DETECTION - Results<br />
Total Number = 991<br />
SNB + AC SNB<br />
• SNB Attempted 100% 100%<br />
• SN Identified 99.7% 96%<br />
• SN Removed 99.7% 96%
SENTINEL LYMPH NODE SITES<br />
Axilla 694 91%<br />
Internal Mammary 46 6%<br />
Intra-mammary 3 2%<br />
Other 5 3 -<br />
50<br />
28<br />
41<br />
91 %<br />
6 %<br />
2 %<br />
< 1 %<br />
8.8%<br />
5.0%<br />
6.1%
Number of Positive<br />
<strong>Node</strong>s <strong>in</strong> <strong>Axillary</strong><br />
<strong>Clearance</strong><br />
LYMPH NODES<br />
N = 567 <strong>in</strong>cludes those with<br />
positive SN who went on to AC<br />
1 -<br />
2 -<br />
>3 -<br />
50<br />
28<br />
41<br />
MEAN +<br />
<strong>Lymph</strong> <strong>Node</strong>s <strong>in</strong> AC specimen 14.6 + 7.1<br />
Number %<br />
0 - 448 79%<br />
1 - 50 8.8%<br />
2 - 28 5.0%<br />
>3 - 41 6.1%<br />
8.8%<br />
5.0%<br />
6.1%
<strong>Sent<strong>in</strong>el</strong><br />
<strong>Node</strong>s<br />
DIAGNOSTIC ACCURACY OF SNB<br />
ALL Patients with SNB + AC<br />
<strong>Node</strong>s <strong>in</strong> Axilla<br />
Positive Negative Total<br />
Positive 49 84 133<br />
Negative 11 337 348<br />
Total 60 421 481
PERFORMANCE STATISTICS :<br />
(N= 489)<br />
% of Total Tumour size 19% 54% 20% 7%<br />
Tumour size All 3cm<br />
Sensitivity 92% 100% 93% 88% 94%<br />
Specificity 100% 100% 100% 100% 100%<br />
False Neg 8% 0% 7% 12% 4%<br />
False Pos 0% 0% 0% 0% 0%<br />
+ve Predictive 100% 100% 100% 100% 100%<br />
-ve Value 96% 100% 97% 92% 90%<br />
Control Arm only
OTHER FACTORS<br />
SNB + AC SNB<br />
Operative Duration 1.5 hrs 1.2hrs<br />
Duration Hospital Stay 2.8 days 1.8 days<br />
91 %<br />
6 %<br />
Duration of Dra<strong>in</strong> 7.1 days 4.2 days<br />
1 -<br />
2 -<br />
>3 -<br />
50<br />
28<br />
41<br />
2 %<br />
< 1 %<br />
No of Cases per Institut’n 2 (0.2%) - 150 (14.2%)<br />
8.8%<br />
5.0%<br />
No of Cases per Surgeon 1 (0.1%) - 108 (10.2%)<br />
6.1%
Rapid recruitment<br />
CONCLUSIONS<br />
Recruitment has now closed<br />
Accurate performance of SNB across multiple centres<br />
Satisfactory compliance with randomised treatments<br />
Outcomes for quality of life, arm symptoms and<br />
recurrence free survival to be determ<strong>in</strong>ed
Supported by :<br />
MBF<br />
DHAC<br />
RACS SNAC TRIAL<br />
FUNDING<br />
• WESLEY RESEARCH INSTITUTE<br />
• ESA INTERNATIONAL<br />
• BREAST CANCER ASSOC of QLD<br />
• TYCO<br />
•ASTRA ZENECA<br />
National Breast Cancer Foundation<br />
NHMRC
<strong>Sent<strong>in</strong>el</strong> <strong>Lymph</strong> <strong>Node</strong> <strong>Biopsy</strong><br />
<strong>Versus</strong><br />
<strong>Axillary</strong> <strong>Clearance</strong><br />
<strong>in</strong> <strong>Operable</strong> Breast Cancer<br />
Dr Neil R Wetzig May 2005