Jayant S Vaidya What is the best way to treat the axilla? 19th century 21st century The background picture won a prize among 180 contestants at UCL for ‘research image as art’ Jayant S Vaidya MBBS MS DNB FRCSGlag PhD FRCS(Gen Surg)

of axillary sampling procedures For Axillary Sampling …with a choice of flavours… Clearance 4-node Sample Blue dye guided Sample Sentinel Node biopsy for… A CHOICE of axillary sampling procedures

Once upon a time….. Tata Memorial Cancer Centre Axillary Clearance

Middlesex Hospital, University College London Axillary Clearance Sentinel Node Biopsy

Axillary Clearance Axillary Sample – Sentinel Node Biopsy Ninewells Hospital, University of Dundee Axillary Clearance Sunshine in Oct Axillary Sample – best of both worlds Sentinel Node Biopsy Snowshine in Feb

False negative rate The chance of missing a positive axilla Could cause harm by Axillary relapse Missed opportunity to institute systemic adjuvant therapy

How Much?

Mathematical Model

Mathematical Model

The mathematical model - the known facts (NSABP B-32) trial False negative rate (FNR) SEER dataset Estimated node positivity (ENP) www.adjuvantonline.com Benefit from chemotherapy in ER negative women This would be similar to additional benefit of chemotherapy in ER positive women on top of hormone therapy

The mathematical model - the known facts NSABP B-04 (Fisher, 2002) 50% of involved nodes cause local recurrence Overview (Peto R, 2004) 20% of local recurrence translates into mortality (for example, if LR increases by 10% the mortality increases by 2%) Thus, if 10% of patients have untreated axillary disease, 5% will have local recurrence 1% more will die as a consequence.

Mathematical Model Age 60 years Grade 1 0.5cm ER negative Estimated Node Positivity (ENP) = 10%

The 10-Year mortality risk 1 to 3 - Node positive women Node negative women 3% 1 to 3 - Node positive women 13%

The Benefit from adjuvant chemotherapy (reduction in 10 year mortality) If Node negative (adjuvantonline.com) 0.8% If (1 to 3) Node positive 3.4%

Difference in benefit “if NN” vs. “if NP” is 3.4% minus 0.8% = 2.6%

Let us assume the False Negative Rate of SNB is 9.7%

Mathematical Model Actual (chance of )False Negative axilla in this patient undergoing SNB is = AFN = FNR x ENP e.g., if FNR =9.7% and ENP is 10% AFN= 1%

Increased mortality due to axillary recurrence Mathematical Model Actual chance of missing a positive axilla in this patient is (AFN=ENP x FNR) 1% Increased mortality due to axillary recurrence 1/10th of 1% = 0.1%

Mathematical Model Actual chance of missing a positive axilla in this patient is (AFN=ENP x FNR) 1% Increased mortality due to “no chemotherapy” = 2.4% times D (diff. in benefit in NN and NP) = 1% x 2.6% = 0.02%

Unsuspected harm in this SNB-negative woman (60yrs, 1 Unsuspected harm in this SNB-negative woman (60yrs, 1.5cm, Grade I, ER-ve) because of omitting chemotherapy on assumption that she is node negative Increased Mortality due to axillary recurrence + Increased mortality due to “no chemotherapy” 0.1% + 0.02% = 0.12%

Tweak… Increase False Negative Rate to 20% 100%

Unsuspected harm in this SNB-negative woman (60yrs, 0 Unsuspected harm in this SNB-negative woman (60yrs, 0.5cm, Grade i, ER-ve) because of omitting chemotherapy on assumption that she is node negative (FNR=20%) Increased Mortality due to axillary recurrence + Increased mortality due to “no chemotherapy” 0.2% + 0.05% = 0.25%

Unsuspected harm in this SNB-negative woman (60yrs, 0 Unsuspected harm in this SNB-negative woman (60yrs, 0.5cm, Grade i, ER-ve) because of omitting chemotherapy on assumption that she is node negative (FNR=100%) Increased Mortality due to axillary recurrence + Increased mortality due to “no chemotherapy” 1% + 0.26% = 1.26%

False negative rate does not matter…

But…

More Tweaks… Increase tumour size and grade Size 2cm Grade 2

Unsuspected harm in this SNB-negative woman (60yrs, 2 cm, Grade ii, ER-ve) because of omitting chemotherapy on assumption that she is node negative (FNR=9.7%) Increased Mortality due to axillary recurrence + Increased mortality due to “no chemotherapy” 0.29% + 0.11% = 0.4%

Unsuspected harm in this SNB-negative woman (60yrs, 2 cm, Grade ii, ER-ve) because of omitting chemotherapy on assumption that she is node negative (FNR=20%) Increased Mortality due to axillary recurrence + Increased mortality due to “no chemotherapy” 0.6% + 0.22% = 0.82%

Unsuspected harm in this SNB-negative woman (60yrs, 1 Unsuspected harm in this SNB-negative woman (60yrs, 1.5cm, Grade I, ER-ve) because of omitting chemotherapy on assumption that she is node negative (FNR=100%) Increased Mortality due to axillary recurrence + Increased mortality due to “no chemotherapy” 3% + 1.11% = 4.11%

Tweaks… Increase tumour size, grade and reduce age Size 2cm Grade 3

Unsuspected harm in this SNB-negative woman (40yrs, 2 cm, Grade iii, ER-ve) because of omitting chemotherapy on assumption that she is node negative (FNR=9.7%) Increased Mortality due to axillary recurrence + Increased mortality due to “no chemotherapy” 0.34% + 0.22% = 0.56%

Unsuspected harm in this SNB-negative woman (40yrs, 2 cm, Grade iii, ER-ve) because of omitting chemotherapy on assumption that she is node negative (FNR=9.7%) Increased Mortality due to axillary recurrence + Increased mortality due to “no chemotherapy” 0.34% + 0.22% = 0.56%

Unsuspected harm in this SNB-negative woman (40yrs, 2 cm, Grade iii, ER-ve) because of omitting chemotherapy on assumption that she is node negative (FNR=20%) Increased Mortality due to axillary recurrence + Increased mortality due to “no chemotherapy” 0.7 + 0.46% = 1.16%

Unsuspected harm in this SNB-negative woman (60yrs, 1 Unsuspected harm in this SNB-negative woman (60yrs, 1.5cm, Grade I, ER-ve) because of omitting chemotherapy on assumption that she is node negative (FNR=100%) Increased Mortality due to axillary recurrence + Increased mortality due to “no chemotherapy” 3.5% + 2.31% = 5.81%

We need to inform our patients and take a shared decision about using Sentinel Node Biopsy?

p < 0.0001 p = 0.30 NSABP B-32 Smoothed Technical Failure Rates 15 10 p < 0.0001 Percentage Technical Failure 5 50 100 150 Surgeon Case Number NSABP B-32 Smoothed False Negative Rates 60 40 p = 0.30 Percentage False Negative 20 50 100 150 Surgeon Case Number

We need to accept that this 10% false negative rate is not a correctable technical error It is an indicator of the biological behaviour of breast cancer

“barking dogs do not bite” but the dog doesn’t know that

SNB is appealing because it is precise and logical But breast cancer doesn’t know the rules!

In 10% of cases tumour skips the sentinel lymph node

Is there an alternative?

There is an alternative

Replace “dogma” with “informed choice”

Breast conservation (466) Edinburgh Studies Prof Bob Steele, Mr Udi Chetty, Sir Patrick Forrest and colleagues Mastectomy (417) Breast conservation (466) 4- node sample RANDOMISATION Axillary clearance Outcome- local relapse, survival and morbidity

Technical Success Sample Clearance (202) (199) Mean Number 4.8 20.6 (202) (199) Mean Number 4.8 20.6 Positive 85(42%) 80 (40%) Failure 1 0

False negative rate In 135 patients, randomisation was done after sampling N Positive Additional Positive Sample only 68 26 (38%) - Sample +Clearance 67 26 (39%) 0

Overall Survival

Axillary Recurrence

Arm Oedema

the Edinburgh technique 4-node sample the Edinburgh technique Near 100% detection rate Near 0% false negative rate Low morbidity Survival and local relapse equivalent

4-node sample - Other benefits No need of costly equipment No need of Nuclear medicine and ARSAC No need of radiation protection Needs proper surgical training

Study of biology of Biological tissues are NOT contaminated with radiation So can be stored in tissue bank for further study – e.g., gene microarray analysis. RADIATION HAZARD

Applying the Mathematical model to 4 node sampl e FNR = 0% Effect of mortality = 0 Effect of local recurrence = 0

Node positivity in trials of SNB 26% On average, 1 in 4 patients have a second operation

Patient Choice A. ¾ chance of an unnecessary axillary procedure, but the full treatment is completed in one operation (AC) B. ¼ chance of 2nd operation + 1/10 chance of a missed positive node (SNB) C. ¼ chance of a 2nd procedure + 0 chance of a missed positive node (AS)

What is the right way? INFORMED CHOICE AND PATIENT SELECTION Those with high risk of nodal metastasis= Axillary clearance Those with medium risk of nodal metastasis = Axillary sample Those with low risk of nodal metastasis = Sentinel node biopsy (don’t bother about FNR)

REMEMBER WHEN YOU VOTE If you Vote for the action then you are voting for a choice – surgeon choice and patient choice- in different ways of sampling the axilla – Clearance-Sample-SNB If you Vote against the action then you are voting against such an informed and wise choice – and NOT for Sentinel node biopsy.

Remember VOTING AGAINST this action is NOT the same as to VOTING FOR SNB So if you believe that SNB is A right way then you should vote FOR the action

Vote for choice If you wish to just replace the dogma of Axillary clearance to the dogma of Sentinel node biopsy Vote against the action If you believe that Surgeons and Patients should be allowed to make an informed choice Vote for the action