1. Best Practice for Breast Radiotherapy: 2015 Clinical Oncology Audit Conference Royal College Radiologists Suzy Cleator: Consultant Clinical Oncologist, Imperial College Healthcare NHS Trust

2. Focus on Breast Adjuvant Radiotherapy (invasive disease) Best practice defined by: Acceptable Local control – other factors: Patient population (screening vs symptomatic) Selection for breast conserving radiotherapy Quality of radiology Quality of pathology Quality of systemic therapy Quality/ appropriate selection of Surgery (nipple/ skin preservation/ margins) Radiotherapy Minimizing toxicity: Cardiac Musculoskeletal Cosmetic Second malignancy Brachial plexopathy Avoiding unnecessary radiotherapy/ technology: Avoid unnecessary radiotherapy – elderly, postmastectomy Avoid inappropriate hyperfractionation/IMRT/boosts

3. Most centres cannot quote their local control rate ‘Contemporary’ UK local control rates captured by the UK START Trial Measuring Local Control

4. START Trial; local control 17 centres for START-A and 23 for START-B Patients were recruited after complete excision of primary invasive breast cancer (pT1–3a, pN0–1, M0) Boost (10Gy in 5f) – no effect on local control/ cosmetic result (61% patients overall)

5. Local Recurrence Rates have Fallen

6. Do what was done in the START trial! CT-planned 3D conformal Use whole breast radiotherapy post breast conservation Apply boosts as indicated Don’t miss the tumour bed – clips, appropriate use of shielding ? Appropriate use of bolus post-mastectomy Good set up – individual and departmental Start within a time window How to achieve good local control (from radiotherapy)

7. Rationale: > 90% of recurrences are adjacent to primary site Late toxicity relates to treated volume Reduction in poor cosmesis, chest wall discomfort, second malignancy Smaller volumes allow for acceleration and hypofractionation But: It is not going to be more effective than WBRT It needs to be at least equivalent It should be better than surgery alone Not all partial breast irradiation is the same Whole breast vs Partial Breast

8. Intra-operative TARGIT: Intraoperative single treatment 50 kV (“soft”) x-rays (photons) Dedicated machine (Intrabeam) 20 Gy at the surface of the applicator 5-6 Gy at 1 cm NICE-approved ……for now Mammosite: Afterloading catheters Placed intra- or post-operatively 2 balloon sizes, cavity is stretched over surface 34 Gy at 1 cm in 10 # (BD) 5/7 Intra-operative Electrons: EIO Milan Dedicated theatre Linac Post quadrantectomy & SNB Initially developed as a boost In phase III trial as sole therapy (ELIOT) 21 Gy as a single fraction to 90% isodose (calculated to be 56 Gy equivalent) External Beam Conformal/ IMRT Partial Breast Radiotherapy – techniques

9. TARGIT Very short follow-up (median follow-up of 2 years and 5 months) Clearly not effective for pts not on endocrine therapy Trend towards increased risk LR in TARGIT arm – no impact on OS expected TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same LR expected from no radiotherapy : 2·1% (1·1–4·2) versus 1·1% (0·5– 2·5; p=0·31) What happens when pts complete endocrine therapy? Well tolerated (as is external beam RT) Partial Breast Radiotherapy – long term data ELIOT 10 year results poor (not published) At medium follow-up of 5·8 years, 35 (4.4%) patients in the IORT and 4 (0.4%) patients in the external RT group had an IBTR (p<0·0001 Most recurrences near tumour bed HDR Brachytherapy Budapest Trial 258 patients randomized Partial breast RT delivered by electrons in 30% cases 10yr LR was 5.9% vs 5.1% in PBI and WBI arms, respectively (p = 0.77) rate of excellent-good cosmetic result was 81% in the PBI, and 63% in the control group (p < 0.01) External Beam Results pending: NSABP-B-39/RTOG -0413: 4,300 participants randomly assigned to WBI or APBI using 3D-CRT or balloon-catheter or interstitial brachytherapy IMPORT low Lancet Oncology, 2013 Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial. Veronesi U et al.

10. EORTC “boost versus no boost” trial 5318 patients with no tumour at margin Whole breast 50 Gy in 25# (2 Gy) ± 16 Gy boost in 8# or implant (9%) 20 year recurrence 13% (no boost) vs. 9% (boost) HR 0·65 (99% CI 0·52–0·81, p<0·0001) Age  40 local relapse 36% (NB) 24.4%(B), p=0.003 Age 41-50 local relapse 19.4%(NB) 13.5%(B), p=0.007 Age 51-60 local relapse 13.2%(NB) 10.3%(B) NS Age >60 local relapse 12.7%(NB) 9.7%(B) NS Young age most important risk factor for local recurrence Cosmetic results not as good in boost arm No impact on overall survival Use of Boosts Whole-breast irradiation with or without a boost for patients treated with breast-conserving surgery for early breast cancer: 20- year follow-up of a randomised phase 3 trial. Bartelink H et al. Lancet Oncology 2015

11. Facilitate accurate localization for tumour bed boost Avoid mis-placement of tangents No evidence of clip migration Help with treatment verification LCA audit: Clinical findings alone were used to define tumour bed in 2/180 (1.1%) cases and CT abnormality alone in 14/180 (7.7%) cases. Clips were inserted and used in 164/180 (91.2%) cases. The median number of clips inserted was 5 (minimum 2) - S Dadhania, S Cleator. Use of Clips

12. Variation in use: 1035 responses to survey- Vu T et al, Clin Oncol 2007 642 from the Americas - 82% use bolus 327 from Europe - 31% 66 from Australasia - 65% - (P < 0.0001) Variation in the schedule of application every day [33%] alternate days [46%]) < 1 cm [35%] > or = 1 cm [48%]) Adds to toxicity: Retrospective cohort study of 254 patients treated with adjuvant postmastectomy radiotherapy, 1993 -2003 (Tieu M, Int Radiat Oncol Biol Phys, 2011) 143 patients received radiotherapy with whole chest wall bolus 88 patients with parascar bolus 23 with no bolus. Twenty patients did not complete radiotherapy because of acute skin toxicity: 17 in the whole chest wall bolus group (12%) 2 in the parascar bolus group (2%) 1 in the group not treated with bolus (4%) On multivariate analysis, whole chest wall bolus and chemotherapy were found to be significant predictors for early cessation of radiotherapy resulting from acute skin toxicity 19 chest wall failures 13 in the whole chest wall bolus group (9%) 4 in the parascar bolus group (4.5%) 2 in the no-bolus group (9%) On multivariate analysis, lymphovascular invasion and failure to complete radiotherapy because of acute skin toxicity were associated with chest wall recurrence Appropriate Use of Bolus

13. Monitor set-up CFD: Central Flash distance CLD: Central Lung Distance ICM: Inferior Central-axis Margin CFD CLD ICM Systematic and random errors evaluated following method described in BIR publication “Geometric Uncertainties in Radiotherapy Treatment Planning”

14. Breast Set-up Audit - Results Ruth McLauchlan, Anne-Maree Thoi, Susan Cleator, Mary-Ann Carmichael Dept. Radiation Physics and Radiobiology, Imperial College Healthcare NHS Trust, London, UK.

15. Window for Radiotherapy 18 050 women ≥ 65 with stage 0-II breast cancer diagnosed in 1991- 2002 who received, BCS, RT but no chemotherapy (SEER database) Interval between surgery and starting RT of > 6 weeks associated with increased likelihood of local recurrence hazard ratio 1.19, 95% confidence interval 1.01 to 1.39, P=0.033 Continuous relationship association hazard ratio 1.005 per day, 1.002 to 1.008, P=0.004) intervals over six weeks were associated with a 0.96% increase in recurrence at five years (P=0.026).

16. Start Times

17. Avoid use of 50Gy in ‘START Trial’ population Avoid cardiac toxicity Avoid increasing risk of second malignancy Avoid boost were not necessary Avoid radiotherapy where possible PRIME2 population Low-risk post-mastectomy patients Employ IMRT to minimize dose to normal tissues in complex cases How to deliver safe radiotherapy

18. Avoid 50Gy in 25f in low/ moderate risk patients

19. Avoid cardiac toxicity 2158 women undergoing RT to breast 1958- 2001 (Sweden/ Denmark) Included 963 with major coronary events, 1205 controls Mean dose to whole heart and to LAD estimated from RT charts CT of women with typical anatomy used to reconstruct individual dosimetry Overall mean heart dose 6.6 Gy (L) 2.9 Gy (R) Rate of major coronary event increased linearly with mean dose to heart by 7.4% per Gy started within first 5 years

20. Cardiac Avoidance Not needed for all Shielding Partial Breast Radiotherapy IMRT Prone radiotherapy Breath-hold End inspiratory gating Deep inspiratory breath hold ABC Gating Voluntary breathold

21. Thirteen studies comprising 762,468 breast cancer patients included in meta-analysis ≥ 5yrs after breast cancer diagnosis radiotherapy was significantly associated with an increased risk of second non-breast cancer RR 1.12 (95% confidence interval [CI] 1.06–1.19) second cancer of the lung RR 1.39 (95% CI 1.28–1.51) esophagus RR 1.53 (95% CI 1.01–2.31) second sarcomas RR 2.53 (95% CI 1.74–3.70) The risk increased over time, and was highest 15 or more years after breast cancer diagnosis for second lung RR 1.66 (95% CI 1.36–2.01) and second esophagus cancer RR 2.17 (95% CI 1.11–4.25) Second lung cancer after radiotherapy for breast cancer is associated with the delivered dose to the lung (Grantzau T et al. Risk of second primary lung cancer in women after radiotherapy for breast cancer. Radiother Oncol 2014;111:366–73) It has been estimated by Hall et al., that IMRT would almost double the incidence of second cancers compared to conventional 3DCRT (Hall EJ, Wuu CS. Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 2003;56:83–8) Avoid second malignancy

22. Cumulative incidence of severe fibrosis at 20 years 5·2% (99% CI 3·9–6·4) in the boost group versus 1·8% (1·1–2·5) in the no boost group (p<0·0001). S The cumulative incidence of any degree of fibrosis (minor, moderate, or severe) 71·4% (69·0–73·7) versus 57·2% (54·6–59·8; p<0·0001). Avoid boost where possible

23. Consider with-holding radiotherapy in PRIME2 population Several randomized studies CALBG PRIME 2 March 2015, Lancet (Kunkler et al) >65 yrs, ER pos, node neg Median F/U 5 yrs, IBR was 1·3% vs 4·1% (p=0·0002) HR for IBR, 5·19 (95% CI 1·99-13·52; p=0·0007) ASCO endorse withholding of radiotherapy in elderly low risk (has not been adopted) More work needed to selection of patients at very low risk of recurrence; Canadian LUMINA study (NCT01791829)

24. Many of the trials were undertaken decades ago Management of axilla was often suboptimal Contemporary series suggest risk of LR low if 1-3 LN positive Contemporary series suggest risk of LR low if T3N0 Current ASCO and LCA guidance: RT of T3/ T4 RT if >3LN positive/ single LN mass≥3cm Awaiting results from SUPREMO study Post mastectomy, RT vs no RT, intermediate risk cases Select patients carefully post-mastectomy

25. EBCTCG, post mastectomy RT, Lancet 2014

27. Medial tumours Unusual chest anatomy Internal mammary irradiation Dose homogeneity for whole breast RT can usually be achieved by CT forward planned IMRT (extra segments) Employ IMRT when indicated

28. Clear guidance/ gold standard: Set up Use of clips Appropriate fractionation Timeliness Controversial: Use of boosts Post mastectomy radiotherapy For the future: Use of cardiac sparing radiotherapy (mean cardiac dose) ???LOCAL CONTROL………….. What can be measured