Whole Breast Irradiation: Class vs. Hypofractionation

Whole Breast Irradiation: Class vs. Hypofractionation Kyung Hwan Shin, MD, PhD. Dept. of Radiation Oncology, Seoul National University Hospital 2018. 4. 6. GBCC

Treatment Trends of Early Breast Cancer Less surgery lumpectomy vs mastectomy sentinel LNB vs axillary dissection Less radiation partial breast irradiation vs whole breast irradiation omitting RT (old age) hypofractionation Less chemotherapy determining who doesn t benefit from chemo by molecular subtypes or alternative molecular profiling schema (Oncotype-DX, Mammaprint, PAM50, etc)

Whole breast radiotherapy 50 Gy / 25 fx (± boost) - the most world wide frequent schedule - has been considered as standard fractionation

Prospective randomized trials comparing Lumpectomy Alone vs. with WBRT Trial N F/U (yr) op Breast recurrence (%) BCS BCS + RT % reduction Sweden 381 10 Q 24 9 63 Milan III 579 10 Q 24 6 75 NSABP-B06 1262 20 L 39 14 64 Ontario 837 7.6 L 35 11 69 Scottish 585 7.7 L 25 5 80 England 399 >5 L 35 13 63 Finland 152 6.7 L 18 8 56 NSABP-B21 1009 8 L 16.5 2.8* 83 * Patients received tamoxifen

EBCTCG, Meta-analysis EBCTCG Lancet 378:1707-16, 2014

Post-operative Breast Irradiation Daily fractional dose (Gy) RT Volume Total RT duration Conventional whole breast 1.8-2.0 Gy Whole breast 6-7 weeks Accelerated whole breast (AWBI) (Hypofractionated) 2.6-3.3 Gy Whole breast 3-4 weeks Accelerated partial breast (APBI) 3.8 bid-6 Gy qd Partial breast 1 week

Adjuvant radiation therapy options after breast conserving surgery

Post-operative Breast Irradiation Daily fractional dose (Gy) RT Volume Total RT duration Conventional whole breast 1.8-2.0 Gy Whole breast 6-7 weeks Accelerated whole breast (AWBI) (Hypofractionated) 2.6-3.3 Gy Whole breast 3-4 weeks Accelerated partial breast (APBI) 3.8 bid-6 qd Gy Partial breast 1 week

Hypofractionated RT 1) Shorter total treatment time 2) More convenient for patient ( time and money ) 3) Less resource intensive At least treatment outcome, normal tissue effect and cometic outcome should be non-inferior to standard fractionation.

RCT s: Treatment Scheme Fisher et al. J Clin Oncol 2014;32:2894-2901.

Equivalent local control to standard fractionation Total dose(gy) / fractionation Daily dose /total weeks 5yr local recurrence (%) 10yr local recurrence (%) RMH/GOC 50/25 39/13 42.9/13 2Gy/5wks 3Gy/5wks 3.3Gy/5wks 12.1 14.8 9.6 START A 50/25 39/13 41.6/13 2Gy/5wks 3Gy/5wks 3.2Gy/5wks 3.4 4.4 3.1 6.7 8.1 5.6 START B 50/25 40/15 2Gy/5wks 2.67Gy/3wks 3.3 2.2 5.2 3.8 Canadian 50/25 42.5/16 2Gy/5wks 2.66Gy/3.5wks 3.2 2.8 6.7 6.2

Cumulative risk of LR Overall Survival Whelan TJ, NEJM 362:513-20, 2010

Canadian Trial: Late Toxicity Whelan et al. N Engl J Med 2010;362:513-520.

Canadian Trial: Cosmesis Whelan et al. N Engl J Med 2010;362:513-520.

Cumulative risk of LRR Disease Free Survival Haviland JS, Lancet Oncol 14:1086-94, 2013

Late normal tissue effect and cosmetic factors START A START B 40Gy/15fx seems gentler than 50Gy/25fx. Haviland JS, Lancet Oncol 14:1086-94, 2013

Late adverse effects of START-A, B START-A (%) START-B (%) 50Gy 41.6Gy 39Gy Total 50Gy 40Gy Total Symptomatic rib fracture Symptomatic lung fibrosis Ischemic heart disease (left sided) 0.7 1.1 1.2 1.0 1.5 2.2 1.9 0.8 1.2 1.1 1.0 1.7 1.7 1.7 0.5 0.1 0.5 0.4 0.5 0.4 0.4 Haviland JS, Lancet Oncol 14:1086-94, 2013

Meta-analysis a) LR (p = 0.74) b) LRR (p = 0.32) c) Cancer-related mortality (p = 0.97) BCRT 162:409-417, 2017

a) Risk of acute toxicity (p = 0.0003) b) Cosmesis (p=0.55) BCRT 162:409-417, 2017

Linear-Quadratic (LQ) model for radiotherapy S=e - D- D2

Survival / ratio linear ( ) and the quadratic ( ) component of cell killing are equal. D= D 2 D D 2 Dose / ratio: shape of cell survival curve, BED (biological effective dose)

Therapeutic ratio of tumor and normal tissue 2 Gy 4 Gy Daily dose Tumor SF Normal tissue SF Therapeutic ratio 2Gy More kill Less damage better 4Gy Less kill More damage poorer

α/β ratio of Breast α/β ratio, Gy Conventional Tumor Normal tissue effect 10 3 In vitro human breast ca. cell lines 4 *Locoregional tumor control Change in photographic breast appearance 4.6 3.4 *Bentzen SM. Lancet Oncol 9:331-41, 2008

α/β ratio of breast cancer (from 4 key randomized trials) Outcome RMH/GOC RMH/GOC + START A (5yr) START A (10yr F/U) RMH/GOC + START A (10yr) Local Recurrence Breast appearance (Any change) Breast Induration 4.0 4.1 4.0 3.5 3.6 3.6 3.5 3.1 3.1 4.0 Telangiectasia 5.1 3.8 cf. (α/β ratio 10 for other tumor tissues) Kim et al. ROJ 2016

Breast cancer 2 Gy 3 Gy α/β ratio of breast cancer: 4.6 Gy breast normal tissue: 3.4 Gy Breast cancer is as sensitive to fraction size as the dose-limiting normal tissues.

Actually, EQD2 of AWBI was less than conventional regimen Benjamin D Smith, ASTRO 2017

All three regimens on flat part of dose-response curve for local control Either extra 5 Gy is not needed, or shorter treatment course compensated for less dose due to less repopulation 40 Gy/15 fx confers lower normal tissue dose leading to less late toxicity Benjamin D Smith, ASTRO 2017

Kim KS, Shin KH et al, Radiat Oncol J 34:81-87, 2016

Issues to be solved Regional nodal irradiation Tumor bed boost Heart DCIS Biologic subtype Tumor grade

Regional nodal irradiation and boost RMH/GOC START A START B Canadian No. of pts 1410 2236 2215 1234 Age <50 yrs 30.3% 23% 21% 25% Stage T1-3N0-1 T1-3N0-1 T1-3N0-1 T1-2N0 pn0 40% 69% 74% 100% HG III - 28% 23% 19% BCS 100% 85% 92% 100% CTx 13.9% 35% 22% 11% RNI 21% 14% 7% 0% Boost 75% 61% 39% 0% Boost dose 14 Gy/7fx 10 Gy/5fx 10 Gy/5fx - Holloway CL. The breast 19:163-7, 2010

Arm and Shoulder effects in START Trials - Regional Nodal Irradiation Haviland et al. Radiother Oncol 2018;126:155-162.

PMRT Phase II Trial Khan et al. J Clin Oncol 2018;126:155-162.

Heart Major coronary events increased linearly with mean heart dose Darby SC. NEJM 368(11):987-998, 2013

Heart Hypofractionated adjuvant RT did not significantly increase the risk of cardiac mortality. Marhin W. IJROBP 69:483-9, 2007

DCIS, retrospective data. Conventional 50Gy/25fx (n=104) AWBI 42.4Gy/16fx or 40Gy/16fx+12.5Gy boost (n=162) Williamson D. Radiot Oncol 95:317-320, 2010

Loco-regional relapse free survival after BCS Basal HER2 Breast cancer is known to have heterogeneous subtypes Different α/β ratio (cell survival curve) between subtypes? Voduc, JCO 28:1684, 2010

Molecular subtype Canadian trial Bane AL, Ann Oncol, 25: 993,2014

Tumor grade Whelan TJ, NEJM 362:513, 2010 Central Path Review (N=989 of 1234 enrolled patients) Bane AL, Ann Oncol, 25: 993,2014

START Trials: Subgroup Analysis Haviland et al. Lancet Oncol 2013;14:1086-1094.

Korean Data

JY Kim, KH Shin. IJROBP 87:1037-1042, 2013

Comparison with other studies This study START A START B Canadian Patient, n 276 2236 2216 1234 Stage T1-2 N0-1 T1-3aN0-1 T1-3aN0-1 T1-2 N0 Median F/U 4.9 years 5.1 years 6 years 12 years Dose schedule 39 Gy / 13 F + 9 Gy / 3F (Boost) A : 39 Gy / 13F B : 41.6 Gy / 13F C : 50 Gy / 25F A : 40 Gy / 15 F B : 50 Gy / 25F A : 42.5 Gy / 16 F B : 50 Gy / 25F Boost RT 100% 61% 43% 0% Results 5-year LRR - 1.4% 5-year LRR - 39 Gy : 5.2% - 41.6 Gy : 3.5% - 50 Gy : 3.6% 5-year LRR - 40 Gy : 2.2% - 50 Gy : 3.3% 10-year LRR - 42.5 Gy : 6.2% - 50 Gy : 6.7%

This study This study

Cosmesis RMH/GOC START A START B Canadian Total dose(gy) / fractionation 50/25 39/13 42.9/13 50/25 39/13 41.6/13 50/25 40/15 50/25 42.5/16 Excellent/Good Cosmesis or no change (%) (5 year) 60.4 54.3 69.7 59.0 58.1 65.9 58.8 64.5 79.2 77.9 This study 39/13+boost 9/3 80.2 (3 year)

Skin toxicity Total dose(gy) / fractionation Moderate /Marked Induration (%) 5 yr 10 yr Skin toxicity (%) 5 yr 10 yr RMH/GOC 50/25 39/13 42.9/13 23 36 36 51 16 28 12 18.1 13 18 5.6 12 START A 50/25 39/13 41.6/13 1.0 1.09 0.69 (HR) 1.0 0.83 0.63 START B 50/25 40/15 1.0 0.83 (HR) 1.0 0.76 Canadian 50/25 42.5/16 6.1 10.4 4.7 11.9 3.3 7.7 3.2 8.9 This study 39/13+boost 9/3 2.7 (3yr) Grade 1 (3yr) Hyperpigmentation 1.8 breast pain 7.1 induration 2.7

Retrospective Data in Korea 2007-2010 pt1-2n0-1 breast-conserving surgery hypofractionated RT: 39 Gy/13fx + 9-12 Gy/3-4fx @ National Cancer Center conventional RT: 50.4 Gy/28fx + 9-14 Gy/5-7fx @ Seoul National University Hospital 379 patients in each group Lee et al. Medicine(Baltimore) 2016;95:e3320.

Lee et al. Medicine(Baltimore) 2016;95:e3320.

BCS+RT, 2007-2010 pt1-2n0-1m0 AWBI (39Gy+ boost, NCC) n=330 CWBI (50.4Gy+boost, SNUH) n=330 S-W Lee, KH Shin. Oncotarget 7:81888-98, 2016

Hazard ratios for IBTR

Skin toxicities

ASTRO Guideline [2011] 50 yrs or older at diagnosis pt1-2n0 breast-conserving surgery w/o systemic chemotherapy acceptable dose heterogeneity 50 Gy/25 fx in 5 wks 42.5 Gy/16 fx in 3 wks Smith et al. Int J Radiat Oncol Biol Phys 2011;81:59-68.

According to Period Medicare + Medicaid data: 65 yr & BCS + WBRT Gillespie et al. Int J Radiat Oncol Biol Phys 2016;96:251-258.

According to Chemotherapy NCDB data: 50 yr & pt1-2n0 & WBRT alone Diwanji et al. Breast Cancer Res Treat 2017;165:445-453.

ASTRO Guideline [2018] Original WBI guideline was published in 2011. In June 2015, the Guidelines Subcommittee formed a work group to evaluated the guideline for updating. The proposal to develop a new guideline was approved by the ASTRO Board of Directors in October 2015. Not yet published

www.rcr.ac.uk, Nov. 2016

There is no indication to use more than 15 fractions for the breast, chest wall or nodal areas. Strong support (70-90% support) DCIS, regional nodal irradiation : favor hypofx www.rcr.ac.uk, Nov. 2016

Looking to the future, why consider conventionally fractionated breast radiotherapy at all? At present, there are more limited data available on tumor control and toxic effects outcomes with hypofractionated irradiation for patients with ductal carcinoma in situ and for patients receiving regional nodal irradiation. Nonetheless, the mounting evidence supporting hypofractionation can no longer be ignored. With comparable tumor control, lower costs, and reduced morbidity, hypofractionation should be strongly considered for the majority of patients with earlystage disease. JAMA Oncol J 1:941-942, 2017

Patterns of Care Survey in Korea Shared decision (N=11) No (N=41) Yes (N=23) Physician s choice (N=12) Unpublished data

Patient preference Hoopes DJ et al. 1,807 patients respond 10% 62% 28% IJROBP 82:674-681, 2011

RCT s: Treatment Scheme Fisher et al. J Clin Oncol 2014;32:2894-2901.

SNUH AWBI: Scheme Conventional RT 60.4 Gy / daily dose 1.8Gy / 33 fractions /6.6 weeks Whole breast (28 fx) week 1 2 3 4 5 6 7 Tumor bed boost (5 fx) Hypofractionated RT 50.1 Gy / daily dose 2.7 Gy / 19 fractions / 3.8 weeks Whole breast (15 fx) week 0 1 2 3 Tumor bed boost (4 fx)

Thank you