Hot topics in breast radiotherapy Mark Beresford

Current issues Axillary radiotherapy/no surgery AMAROS trial Intraoperative RT

AMAROS trial: After Mapping of the Axilla: Radiotherapy Or Surgery?

Axillary treatment Within 12 weeks for both groups Surgery (AND): levels I, II and preferably III Post-op RT allowed if >4 LNs and more than 1 level involved Radiotherapy: 50Gy/25# Large anterior field with smaller PA field Non-inferiority endpoint

Results (ASCO 2013) 4,806 patients Median fu 6.1 years +ve LNs (60% macromets) in: 744 AND 681 RT 5-year axillary recurrence rates after –ve SLNB = 0.8%

5 year - survival rates OS ALND 93.27% RT 92.53% (p=0.3386) DFS ALND 86.90% RT 82.65% (p=0.1788)

Other effects Lymphoedema more after AND vs RT 1 year (40% vs 22%, p<0.0001) 5 years (28% vs 14%,p<0.0001) Non-significant trend to more shoulder impairment after RT

Axillary radiotherapy as an alternative to axillary surgery- other studies Trial DesignNo. Patients Median Follow-up Regional Relapse Rates Referen ce T1-2 cN0 >50 years Non-randomised Axillary radiotherapy (RT) vs. Axillary lymph node dissection (ALND) 180 RT 341 ALND 7.2 years1.1% RT 1.5% ALND spruit Stage I or II Non-randomised Axillary radiotherapy (RT) vs. Axillary lymph node dissection (ALND) 229 RT 782 ALND 111 months (RT) 79 months (ALND) 1.3% RT 0.9% ALND chua cN0 Wide local excision + RT to breast/axilla/SCF 105 RT41 months 0 isolated axillary recurrence 1.9% axillary recurrence with distant metastases Hoebers Randomised Lumpectomy + axillary RT vs. Lumpectomy +ALND (level I/II) 332 RT 326 ALND 15 years Axillary node relapses: 3% RT 1% ALND (P=0.04) No overall survival difference at 15 years Louis- Sylvestre

Issues Extranodal extension Increased risk of regional recurrence? Conflicting studies May not be independent predictor from number of nodes Indicator for systemic treatment? Neoadjuvant chemotherapy Down-staging of axilla by treatment Approx 2/3 of SLN +ve at baseline are still +ve at surgery Can we rely on –ve SLNB?

Nodal RT fields Need for PA field given depths of LNs? CT study: mean depths of the level I-III axillary nodes were 4.6, 5.1 and 3.6cm respectively (Goodman et al, 2001) Standard tangential breast radiotherapy fields include some nodes All level 1 nodes included and 50% of level 2 (Goodman et al, 2001) 55% (range 23-87%) of the level I-II axillary lymph node volume encompassed by 95% isodose line (Reed et al, 2005) Sentinel node marker clips at time of biopsy fall within tangential fields in 34 of 36 cases (Chung 2002)

Intra-operative radiotherapy Improvements in the MDT approach have dramatically improved outcomes for women with breast cancer Absolute long-term risk of local relapse following BCS and radiotherapy is very low Hypothesis that specific subgroups with predicted low risk of recurrence could be treated with partial breast radiotherapy or avoid radiotherapy completely, with acceptable long-term recurrence rates and minimal side effects

TARGIT (Vaidya et al, Lancet 2014) 1:1 ratio to receive single dose intra-op RT or whole-breast RT 1721 vs 1730 pts If adverse pathology in IORT group, went on to EBRT Median fu 2 yrs 5 months 5-year local recurrence: 3·3% (95% CI 2·1-5·1) for TARGIT 1·3% (0·7-2·5) for EBRT (p=0·042) Breast cancer mortality was similar (2·6% [1·5-4·3] for TARGIT vs 1·9% [1·1-3·2] for EBRT; p=0·56) Fewer non-breast-cancer deaths with TARGIT (1·4% [0·8-2·5] vs 3·5% [2·3-5·2]; p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers

ELIOT The only other large randomised IORT trial 1305 patients were randomised (654 to external radiotherapy and 651 to intraoperative radiotherapy) Medium follow-up of 5.8 years The 5-year event rate for ipsilateral breast tumour recurrence 4.4% (35 patients, 95% CI 2.7–6.1) in the intraoperative radiotherapy group 0.4% (4 patients, 95% CI 0.0–1.0) in the external radiotherapy group HR 9.3 [95% CI 3.3–26.3] Local recurrence rates continued to rise in a linear fashion for both study arms for those patients follow up beyond 5 years

PRIME II: no radiotherapy? Published in abstract form 1479 good prognosis breast cancer patients defined as aged ≥65 years with primary invasive cancer ≤3cm, grade 1/2, node negative with clear margins following BCS Early results shows 1.3% and 4.1% local relapse rates by 5 years with and without radiotherapy 10-year data will be presented in due course

Concerns Median follow up is only 2 years 5 months does not represent a true 5-year local recurrence rate also be note these patients with lower risk of recurrence have a linear risk of local recurrence, which can rise steadily year on year Intrabeam device delivers a very low (?subtherapeutic) dose (5 Gy) compared to standard EBRT, and to just a 1 cm rim around the tumour bed Results from Intrabeam may be closer to the recurrence risk following no radiotherapy at all. True 5-year recurrence rates with TARGIT may mirror the results from PRIME II