SUPREMO  

Selective Use of Postoperative Radiotherapy

aftEr MastectOmy 

       

           

MRC SUPREMO(BIG 2-04) 

  Selective Use of Postoperative Radiotherapy aftEr MastectOmy

Phase III randomised trial of chest wall RT in intermediate- risk breast cancer

Kunkler I, Canney P, Price A,Prescott R, Hophood P,Dixon J, Sainsbury R,Aird E, Thomas G,Bowman A,Thomas J, Bartlett J,Dunlop

J, Denvir M,McDonagh T,Russell N

 

Background:Trials of postmastectomy RT

• Danish and Canadian trials 9-10% survival benefit at 10 yrs from addition of RT to systemic therapy (Overgaard 97,99;Ragaz 97)

• PMRT standard for T3 and =/> 4 N+

• Role of PMRT in 1-3 N+ research priority of NIH (2000)

• Weighting of risk factors (N+, grade, LVI) in selecting patients for PMRT unclear

Trials of PMRT in premen1-3 N++ adjuvant CMFchemo

(Fowble,1999)

Trial No Redn

LRR

OS %

C

OS%

C+RT

P

value

Int

(yr)

B.C 183 23% 48 64 0.06 15act

Den’k

pre

1061 23% 54 62 - 10act

Glas

pre

141 NS 84 78 .40 5act

Dana 83 3% 85 77 >.05 4.4me

Whelan & Levine,JNCI Jan 2005

• Level I evidence needed to assess PMRT in 1-3 N+

• Currently limited to subgroup analysis

• New RCTs needed to address the issue

Effects of RT on breast cancer mortality and all cause mortality after breast conserving / mastectomy and axillary clearance (EBCTCG; Lancet 2005;366:2087-2106

Oxford overview 2006; RT trials and breast cancer mortality at 20 yr, mastectomy & axillary

clearance by nodal statusBreast camortality (%)

Breast camortality(%)

20 yr gain/loss(%)

Path nodal status

No RT RT

pNO 28.7 30.2 -1.6 NS

pN1-3 54.2 47.7 +6.42p=0.002

pN =/>4N+ 81.5 70.8 +10.72p=0.0008

Interpretation of Overview of RT trials

• Older radiotherapy techniques• Loco-regional rather than local RT• CMF rather than anthracycline systemic

therapy• Improved survival of EPI-CMF vs CMF• Absolute risk of LRR after Mx and systemic

therapy may be lower• Surgery, radiotherapy and systemic therapy

not quality assured

PMRT 1-3 N+ with 8 or more nodes DBCG 82b,c trial

Overgaard et al,Radiother Oncol,2007

RT No RT p value

LRR 4% 27% <0.001

Overall

survival

57% 48% 0.03

0.73 -1.381.005YES

0.250.70 -0.890.7913NO

p95% CIOdds

ratio

No of

studies

Anthracycline

use

Whelan et al JCO 2000 2000;18:1220-29

Overall and relapse free survival NEAT trial

(Poole et al,NEJM,2006

Eligibility criteria

1. pT1, pN1, M0 or pT2, pN0-1 M0 histologically confirmed invasive breast cancer.

2. Unifocal invasive breast cancer or multifocal breast cancer if at least a 2cm focus of invasive breast cancer

3. Fit for adjuvant chemotherapy (if indicated), adjuvant endocrine therapy (if indicated) and postoperative irradiation

4. Undergone simple mastectomy (with minimum of 1mm clear margin) and an axillary staging procedure

1. If axillary node clearance node positive (1-3 positive nodes) then an axillary node clearance (minimum of 10 nodes removed) should have been performed.

2. Axillary node negative status can be determined on the basis of either axillary node clearance, or axillary node sampling or sentinel node biopsy T2NO tumours are eligible with grade III histology and/or lymphovascular invasion

5. Written informed consent

Exclusion criteria

1. Any pT0, pN0-1, or pT1, pN0 or pT3 or pT42. Patients who have undergone neoadjuvant systemic therapy.3. Previous or concurrent malignant other than non melanomatous skin

cancer and cancer in situ of the cervix4. Male sex 5. Pregnancy6. Bilateral breast cancer7. Known BRCA1 and BRCA2 carriers8. Not fit for surgery, radiotherapy or adjuvant systemic therapy9. Internal mammary nodes positive on sentinel node scintigraphy10. Unable or unwilling to give informed consent 

Randomisation in SUPREMO

Chest wall irradiation

Vs

No chest wall irradiation

Endpoints for SUPREMO:

Primary: overall survivalSecondary:• Disease free survival• Acute and late morbidity• Quality of life• Cost effectiveness (cost per life year)• Molecular markers of local relapse and

radiosensivity

Powering of the trial

3500 patients (1750 per arm) for 80% power to detect a statistically significant difference at the 5% level if the true rates of survival at 5 years are 75% and 79%

(ie 4% difference)

Need 794 events (deaths)

Biological,cardiac, QL and health economic substudies

15 October 2001 Dr John BartlettGlasgow University

Tissue Microarray construction

Removal of coreRemoval of corefrom donor blockfrom donor blockleaves block intactleaves block intact

Recipient block actsRecipient block actsas micro “tumour as micro “tumour bank” for researchbank” for research

Multiple sectionsMultiple sectionsallow study ofallow study ofcomplex pathwayscomplex pathways

Beam’s eye view of medial tangential

field

Maximum Heart Distance (MHD)

Heartcontour

Breastcontour

From: C. Hurkmans, NKI

TRANS-SUPREMO

• Archiving of tumour for future analysis for molecular markers of radiation sensitivity

Proteins which may affect local relapse

• Proteins involved in:• Signal• Transduction• Adhesion and invasiveness• Apoptotic pathways

Late cardiac morbidity (EBCTCG,Lancet 2000;355:1757-1770)

• Breast cancer mortality reduced by 13%

• Increase in annual mortality rate from other causes by 21%

• Increase primarily due to excess deaths from cardiovascular causes

• Cardiac effects may not emerge until 15 yrs after treatment

field

Maximum Heart Distance (MHD)

Heartcontour

Breastcontour

SUPREMO collaboration 136 centres in 24 countries

Acknowledgements

ISD Clinical Trials Team, NHS Scotland