BREAST CANCER CONTROVERSIES This house believes that Chieti

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

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SURGERY Hypofractionation - Definition Ø Larger doses of radiation per treatment fraction delivering a full course of treatment over a shorter period of time compared to conventional fractionation Ø Conventional fraction: 1. 8 – 2. 0 Gy per day Ø Hypofractionation: 2. 25 per day 20 Gy (SBRT)

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

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

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

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

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY 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 Safety and Efficacy 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.

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Safety and Efficacy • 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.

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Safety and Efficacy Ø 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

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Safety and Efficacy Ø 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

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

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Safety and Efficacy Florence University experience Ø 539 pts treated between 1997 and 2003 Ø p. T 1 is (9%), p. T 1 (79%) or p. T 2 (12%) Ø Median age : 59 years Ø Median FU : 4. 3 years Ø p. N+: 20% (p. N 1 -3: 14, 5%; p. N >3: 5, 3%) Ø Delivered breast RT dose : 44 Gy/16 fx (2. 75/fx) Ø 48% : 10 Gy boost

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Safety and Efficacy Florence University experience Results: Ø 1, 8% of patients had breast replace (LRR) Ø No patients developed nodal recurrence MARGIN AGE TAMOXIFEN LATE TOXICITY LRR p value POSITIVE 7% 0, 05 NEGATIVE 1, 7% ≤ 40 11% > 40 1, 5% YES 0, 5% NO 5, 3% G 2 21 G 3 2, 5% 0, 04 0, 001

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

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Which patients obtain equivalent results from HF-WBI and CF-WBI? v 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.

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Which patients obtain equivalent results from HF-WBI and CF-WBI? v T STAGE § p. T 1, p. T 2: 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. § p. T 3, p. T 4: treated with mastectomy, there were few data from the randomized trials to determinate the appropriateness in this group¹. YES MASTECTOMY NO HP-WBI 1. ASTRO, 2011 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

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Which patients obtain equivalent results from HF-WBI and CF-WBI? v N STAGE § The majority of women treated on analyzed trials had nodenegative disease. The evidence most strongly supports the use of HF-WBI in women with stage p. N 0 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.

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Which patients obtain equivalent results from HF-WBI and CF-WBI? v 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 HFWBI for women treated with neoadjuvant chemotherapy, because such patients were not included in these trials. ASTRO, 2011

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Which patients obtain equivalent results from HF-WBI and CF-WBI? v LACK OF adequate RT DOSE distribution § Patients with larger breasts § Significant post-operative edema § Chest wall separation ″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. ″ AIRO, 2013

HYPO-FRACTIONATED IRRADIATION AFTER CONSERVING SUGERY Summary NCCN 2016 AIOM 2015 AIRO 2013 ASTRO 2011 ESMO 2015 ST. GALLEN / / ≥ 50 / p. T T 1 -2 T 1 -2 p. N N 0 N 0 N 0 / / NO NO / NO 2015 CONSERVING SURGERY AGE Chemotherapy

ACCELERATED PARTIAL BREAST IRRADIATION

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

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

ACCELERATED PARTIAL BREAST IRRADIATION

ACCELERATED PARTIAL BREAST IRRADIATION

ACCELERATED PARTIAL BREAST IRRADIATION ASTRO RECOMMENDATIONS

ACCELERATED PARTIAL BREAST IRRADIATION APBI versus WBI

ACCELERATED PARTIAL BREAST IRRADIATION

ACCELERATED PARTIAL BREAST IRRADIATION TARGIT-A TRIAL: Results

ACCELERATED PARTIAL BREAST IRRADIATION launched in Spring 2013, Trial ongoing

ACCELERATED PARTIAL BREAST IRRADIATION 2006 -2011 2135 patients 3 D-CRT APBI 38, 5 Gy in 10 fractions twice daily WBI 42, 5 Gy in 16 fractions or 50 Gy in 25 fractions ±boost Canada, 2013 ü>40 yrs üInvasive or in situ üT≤ 3 cm üNode negative üMargin negative üNo BRCA 1/2

ACCELERATED PARTIAL BREAST IRRADIATION RAPID TRIAL: Results Median Follow-up: 36 months APBI WBI 3 year adverse cosmesis 29% 17% P < 0, 001 Grade 3 toxicities 1, 4% 0%

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

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

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

ACCELERATED PARTIAL BREAST IRRADIATION Results Median Follow up: 5 years • All the IBTR were ER+ , G 2, small ductal invasive BC( mean size 9, 8 mm) • The acute and chronic toxicity and cosmetic outcome of APBI were significantly better

ACCELERATED PARTIAL BREAST IRRADIATION

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

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

ACCELERATED PARTIAL BREAST IRRADIATION 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<3 cm • 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 3 D CRT (NOT IMRT) • Twice daily for 10 fractions over 5 -7 days • No data available yet

ACCELERATED PARTIAL BREAST IRRADIATION B-39/0413 Protocol design

ACCELERATED PARTIAL BREAST IRRADIATION

ACCELERATED PARTIAL BREAST IRRADIATION

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