1. BREAST CANCER CONTROVERSIES This house believes that… BREAST CANCER CONTROVERSIES This house believes that… Chieti, 27 June, 2016 Hypo-fractionated irradiation and Partial Breast Irradiation are recommended after breast conserving surgery D. Genovesi U.O.C. Radioterapia Oncologica Chieti

2. HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SURGERY  Larger doses of radiation per treatment fraction delivering a full course of treatment over a shorter period of time compared to conventional fractionation  Conventional fraction: 1.8 – 2.0 Gy per day  Hypofractionation: 2.25 per day 20 Gy (SBRT) Hypofractionation - Definition

3. Standard breast cancer treatment includes conserving surgery with negative margins followed by Whole Breast Irradiation (WBI). Conventional fraction (CF-WBI): 50 Gy (2 Gy x 25 fractions) +/- lumpectomy cavity boost (10 Gy, 2 Gy x 5 fractions) Hypofractionation (HF-WBI): 42,5 Gy (2.66 Gy x 16 fractions), 40 Gy (2,66 Gy x 15 fractions) Breast Cancer Applications HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SURGERY 1W 2W 3W 4W 5W CONVENTIONAL HYPOFRACTIONATION

4. HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Rationale and Radiobiology At α /ß= 2, BED and EQD2 values are equivalent for regimens that have been demonstrated in randomized trials to have clinically equivalent normal tissue effects.

5. Rationale and Radiobiology HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Yarnold et al. hypotesis: Hypofractionated radiation therapy reduce cancer cell growth that occurs overnight and during weekends. Approximately 0,6 Gy of daily radiotherapy dose is wasted during the 5 week treatment schedules to compensate for cancer cells growing. “Shorter schedules may be more effective against breast cancer recurrence.”

6. Safety and Efficacy HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Four randomized trials : RMH/COG START A START B Canadian A total of 7,095 patients Median follow up: ~ 10 years Endpoints : Local control Cosmesis Distant recurrence Late toxicity ASTRO, 2011

7. Safety and Efficacy CONCLUSION: 42.5 Gy in 16 daily fractions delivered over 3 weeks provided equivalent local control, survival, cosmetic outcome, and normal tissue toxicity compared to 50 Gy in 25 daily fraction over 5 weeks. HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY

8. Safety and Efficacy HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Meta-analysis: 29 full text articles from 19 trial Total of 12,447 patients There is no significant difference in overall survival, disease free survival and distant metastasis rate between HF ( 2.5-3 Gy per fraction) and CF.

9. Safety and Efficacy HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Cosmetic: NO difference Photographic changes in breast appearance: HFRT significantly decrease moderate/marked photographic changes in the 2.5-3 Gy fraction subgroup Grade 2/3 acute skin reaction: HFRT significantly decrease grade 2/3 acute skin reaction in the 2.5-3 Gy fraction subgroup.

10. Safety and Efficacy HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY  START A trial The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet, 2008

11. Safety and Efficacy HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY  START B trial The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet, 2008

12. Safety and Efficacy HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Florence University experience

13. Safety and Efficacy HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY  539 pts treated between 1997 and 2003  pT1is (9%), pT1 (79%) or pT2 (12%)  Median age : 59 years  Median FU : 4.3 years  pN+: 20% (pN1-3: 14,5%; pN >3: 5,3%)  Delivered breast RT dose : 44 Gy/16 fx (2.75/fx)  48% : 10 Gy boost Florence University experience

14. Safety and Efficacy HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Florence University experience Results:  1,8% of patients had breast replace (LRR)  No patients developed nodal recurrence LRRp value MARGIN POSITIVE 7%0,05 NEGATIVE 1,7% AGE≤ 4011%0,04 > 401,5% TAMOXIFENYES0,5%0,001 NO5,3% LATE TOXICITY G221 G32,5%

15. HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Which patients obtain equivalent results from HF-WBI and CF-WBI? ASTRO Guidelines, 2011

16. HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Which patients obtain equivalent results from HF-WBI and CF-WBI?  AGE Canadian trial stratified patients by age ( younger than 50 years vs 50 years and older.)  The risk of ipsilateral tumor recurrence is particularly high for younger women (≤ 40).  The reason are not fully understood. Probably the sensitivity of breast cancer to radiation therapy may vary with age.

17. HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Which patients obtain equivalent results from HF-WBI and CF-WBI?  T STAGE  pT1, pT2: HP-WBI is equivalent to CF-WB¹.  CDIS: a meta-analysis of observational series found no difference in local recurrence rates between hypofractionated and 5 weeks RT- course².  pT3, pT4: treated with mastectomy, there were few data from the randomized trials to determinate the appropriateness in this group¹. YES MASTECTOMY NO HP-WBI 2. Nilsson C, Valachis A. The role of boost and hypofractionation as adjuvant radiotherapy in patients with DCIS: a meta-analysis of observational studies. Radiother Oncol. 2015 1. ASTRO, 2011

18. HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Which patients obtain equivalent results from HF-WBI and CF-WBI?  N STAGE  The majority of women treated on analyzed trials had node-negative disease. The evidence most strongly supports the use of HF-WBI in women with stage pN0 breast cancer. ¹  Regarding safety, Powell et al reported that a higher dose/day fractionation schedule increased the brachial plexopathy rate from 1% to 6%. ²  A single case of brachial plexopathy (0.1% of cases) was reported with the use of 41.6 Gy/13 fx in the START A trial. N POSITIVE NO HP-WBI 1. NCCN, 2016 2. Powell S, Cooke J, Parsons C. Radiation-induced brachial plexus injury: follow-up of two different fractionation schedules. Radiother Oncol. 1990.

19. HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Which patients obtain equivalent results from HF-WBI and CF-WBI?  CHEMOTHERAPY  Retrospective studies have not shown that chemotherapy increased the risk of side effects attributable to HF-WBI, but the numbers of patients in these studies were small and follow-up limited.  No recommendation can be rendered with respect to use of HF-WBI for women treated with neoadjuvant chemotherapy, because such patients were not included in these trials. ASTRO, 2011

20. HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Which patients obtain equivalent results from HF-WBI and CF-WBI?  LACK OF adequate RT DOSE distribution  Patients with larger breasts  Significant post-operative edema  Chest wall separation AIRO, 2013 ″ Volume mammario importante definito come distanza tra gli ingressi dei due campi tangenziali maggiore di 25 cm, a causa della difficoltà ad ottenere una distribuzione omogenea della dose e conseguente maggiore probabilità di tossicità. ″

21. HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY NCCN 2016 AIOM 2015 AIRO 2013 ASTRO 2011 ESMO 2015 ST.GALLEN 2015 CONSERVING SURGERY AGE//≥ 50 / pTT1-2 pNN0 Chemotherapy //NO / Summary

22. ACCELERATED PARTIAL BREAST IRRADIATION

23. CRITICAL QUESTIONS  Can less than the entire breast be treated? If so, for which types of cases?  Which portion of the breast?  How big a margin?  External beam vs brachytherapy?  Which patients may be the most appropriate for APBI?

24. ACCELERATED PARTIAL BREAST IRRADIATION Twin rationale: 1) 76-90% of local recurrence occurs close to the tumor bed 2) Ipsilateral breast recurrences in other areas than the tumor bed ("elsewhere relapse") occurred in 3-4% of the cases. Veronesi U, et al. NEJM 2002; 347:1227-32 End points: Ipsilateral breast tumour rate( IBTR) Overall survival (OS) Acute and late side effects Cosmetic outcomes

25. ACCELERATED PARTIAL BREAST IRRADIATION

27. ASTRO RECOMMENDATIONS

28. ACCELERATED PARTIAL BREAST IRRADIATION APBI versus WBI

29. ACCELERATED PARTIAL BREAST IRRADIATION

30. TARGIT-A TRIAL: Results

31. ACCELERATED PARTIAL BREAST IRRADIATION launched in Spring 2013, Trial ongoing

32. ACCELERATED PARTIAL BREAST IRRADIATION 2006-2011 2135 patients 3D-CRT APBI 38,5 Gy in 10 fractions twice daily WBI 42,5Gy in 16 fractions or 50Gy in 25 fractions ±boost Canada, 2013 >40yrs Invasive or in situ T≤3 cm Node negative Margin negative No BRCA 1/2

33. ACCELERATED PARTIAL BREAST IRRADIATION RAPID TRIAL: Results Median Follow-up: 36 months APBIWBI 3 year adverse cosmesis29%17% P < 0,001 Grade 3 toxicities1,4%0%

34. ACCELERATED PARTIAL BREAST IRRADIATION ELIOT TRIAL 2000-2007 1305 patients 654 patients 3D-CRT 50Gy/25 fractions + BOOST 10Gy 651 patients IOERT 21 Gy single fraction Italy  48-75 yrs  T<2,5 cm Lancet Oncol 2013; 14: 1269-77

35. ACCELERATED PARTIAL BREAST IRRADIATION ELIOT TRIAL : Results Median Follow-up : 5,8 years Overall survival at 5 years did not differ between the two groups

36. ACCELERATED PARTIAL BREAST IRRADIATION  >40 yrs  Invasive ca  T≤25mm 2005-2013 520 patients 260 patients APBI: IMRT 30Gy tumor bed 6Gy/fraction 260 patients WBI 50Gy in 25 fractions + BOOST 10Gy

37. ACCELERATED PARTIAL BREAST IRRADIATION Results Median Follow up: 5 years All the IBTR were ER+, G2, small ductal invasive BC( mean size 9,8 mm ) The acute and chronic toxicity and cosmetic outcome of APBI were significantly better

38. ACCELERATED PARTIAL BREAST IRRADIATION

39.  APBI is only a suitable option and should only be considered in patients with early-stage breast cancer based on consensus statements  The main questions about safety and efficacy of APBI can only be answered in the ongoing randomized clinical trials. ACCELERATED PARTIAL BREAST IRRADIATION FUTURE DIRECTIONS

40. GEC – ESTRO : ONGOING TRIAL 2004-2009 1233 patients WBI 50 Gy/ 25fractions +/- BOOST Interstitial Brachytherapy 32 Gy in 8 fractions HDR 30 Gy in 7 fractions HDR 50 Gy PDR >40 years Stages 0-II (T ≤3cm) DCIS or invasive adenocarcinoma Node negative or micrometastasis Margin 2 mm Accrual completed, results awaited ACCELERATED PARTIAL BREAST IRRADIATION

41. NSABP B-39/RTOG 0413 trial : ONGOING Phase III randomized comparison of whole breast vs. Short-course partial breast XRT Stage 0,I, or II with T<3cm No more than 3 histologically positive nodes Pos-surgical CT evaluations of lumpectomy cavity Defined ratios of partial-breast to whole breast volumes Either interstitial catheters, Mamma Site or 3D CRT (NOT IMRT) Twice daily for 10 fractions over 5-7 days No data available yet

42. ACCELERATED PARTIAL BREAST IRRADIATION B-39/0413 Protocol design

43. ACCELERATED PARTIAL BREAST IRRADIATION

45. GRAZIE PER L’ATTENZIONE