Breast cancer. (early and advanced) Radiotherapy

Transcription

1 Breast cancer (early and advanced) Radiotherapy

2 Need for RT. ESTRO-HERO estimation Tumor site RT courses 2012 Increase in number 2025 Increase in rate (%) Breast 396,891 40, Lung 315,197 56, Prostate 243,669 59, Head&Neck 108,194 13, Rectum 99,493 18, Lymphoma 74, Others. Borras JM et al, Radiother Oncol 2016

3 The role of RT after BCS RT is standard treatment after BCS Breast RT prevents up to 7-8 LRRs every 100 patients (factor of 3-4) and up to 2 breast cancer deaths. A tumor bed boost is strongly recommended in younger patients Older patients, with ER+ tumor, or other favorable features (luminal A), could avoid breast RT, but long term-data are still lacking

4 5-y Local Relapse (LR) Rates after BCS + RT IEO Milan : from 8.5% to 19.7% BCS + EBRT (50+10 Gy) 2784 pts b/n LF at 5-y: 1.1% (Ann Oncol, 2010) : from 2.8% to 5.7% IEO Milan ELIO T trial BCS + EBRT 601 pts b/n : from 1.0% to 0.4% LF at 5-y: 0.4% (Lancet Oncol, 2013)

5 Equivalence of hypofractionated WBI with conventionally fractionated WBI for patients who satisfy all these criteria ASTRO evidence-based guidelines, IJROBP, 81: 59-68, years or older at diagnosis T1-2 N0 pathological stage and BCS No systemic chemotherapy Technical recommandation: Within the breast along the central axis, the Min Dose is no less than 93% and the Max Dose is no greater than 107% of the prescription dose

6 HYPOFRACTIONATION Schedules The WINNER is : START B (Haviland et al. 2013) 40 Gy/15 fractions/3 weeks: (2.66 Gy each) Equivalent local control (50Gy/25/5) Better cosmesis Survival benefit

7 Statistical advantage for all age groups Less advantage in patients >60 years No effect on OS Extra dose could be avoided in most patients > years WBI with or w/out boost (EORTC randomised trial) 20-year IBTR rate: 16.4% in no boost group vs 12.00% in boost group H Bartelink et al, Lancet Oncol 2015

8 Concomitant Boost & Hypo Whole breast 2.66 Gy x 15 Additional daily dose 0.54 Gy Boost area only 3.2 Gy x 15

9 PRIME II randomized trial, WBI vs no WBI 1326 women 65 years with low-risk cancer ER +, N0, <3 cm size, clear margin All received HT, randomly assigned to WBI or not Regional recurrence 1.5% vs 0.5% Distant recurrence 1.0% vs 0.5% Contralateral cancer 0.7% vs 1.5% New non-breast cancer 4.3% vs 3.7% Ipsilateral Recurrence Rate at 5-y: 1.3% vs 4.1% (p=0.0002) Hazard risk 5.19% Kunkler IH et al, Lancet Oncol 2015

10 LUMINA Canada IDEA USA PRECISION Boston New clinical studies - Luminal A, IDC, Ki-67 not >13% - Age 60 years - Stage I, pn0, G1/2, no EIC & LVI - Low Oncotype-DX, RS ( 18) - Age years - Stage I, pn0 - Low Risk PAM50 score - Age years - Stage I, pn0, G1-2

11 PBI: Treatment Modalities Interstitial BRT Low dose-rate High dose-rate Intracavitary Therapy Orthovoltage (Intrabeam) Intraoperative electrons Baloon BRT (Mammosite) Xoft system WBH External-Beam RT - 3D-CRT/mixed beam - IMRT/V-MAT/Helical - Radiosurgery - Protons Brachytherapy NYU MGH Intrabeam IORT 58

12 PBI ASTRO & ESTRO guidelines Smith BD, ASTRO IJROBP 2009 Age at 50 years DCIS allowed Correa C, ASTRO, Pract Radiat Oncol 2016 Polgar C, ESTRO Radiother Oncol 2010

13 The role of RT after Mastectomy PMRT is standard treatment in patients with a LRR risk 30%, independently from breast reconstruction This group includes T3/T4 ( 5 cm), axillary N+, unfavorable pathological features (G3, high Ki- 67, ER/PgR -, HER2 +++, Triple Negative,.) PMRT can improve overall survival because LRR rates are substantially reduced (factor 3)

14 PMRT/RNI versus no RT No subgroups in which PMRT should be omitted For patients with N+, in addition to CW or reconstructed breast, RT should be administered to both IMNs and SC-axillary apical nodes

15 How to integrate Radiotherapy and Breast Reconstructive Surgery? Timing SEER data Fraiser LL et al, JAMA Oncol 2016 Breast reconstruction increased from 14.8% in 2000 to 31.9% in 2011 overall overall PMRT increased from 24.7% in 2000 to 30.0% in 2011

16 Implant Sparing Irradiation (ISI) CTV excluding implant

17 Radiation Therapy before or after... Total complication rate was significantly higher for implant reconstruction after RT (48.7%), than before (19.6%) The same for revision surgery, with higher rate of reconstruction complication after RT (42.4%), than before (8.5%) For the group with a reconstruction after RT, fibrosis occurred more frequently with an implant (20.8%), than with an autologous reconstruction (2.7%) Berbers J et al, Eur J Cancer, 2014

18 Regional Node Irradiation When? More than 4 +ve nodes Well established indication From 1 to 3 +ve nodes Emerging indication in HR group Internal Mammary Chain Positive trials in HR group SLN biopsy +???

19 NCIC - CTG - MA-20 Whelan TJ et al, N Engl J Med, year results WBI WBI + RNI P value LR Control 94.5% 96.8% DFS 84% 90% Distant DFS* 87% 92.4% OS 90.7% 92.3% Lymphedema 4.1% 7.3% >G2 toxicity 0.2% 1.3% 0.010

20 Internal Mammary Chain RT vs not EORTC phase III trial 22922/10925 Poortmans PM, NEJM 2015 Distant Disease-Free Survival Overall Survival

21 LR hypofractionated EBRT 3 WEEKS, 2.67 Gy/fractions

22 RNI & hypofraction: ongoing trials DBCCG (40 Gy/15 fr vs 50 Gy/25 fr) 2000 pts, pt1-3, pn0-3, BCS or PMRT endpoints: late effects and tumor control Other similar trials in USA, France, and Egypt with 15/16 fr of 2.7 Gy each In 2 studies IMN irradiation is also investigated Sub-study UK FAST-Forward (40 Gy/15 fr/3 weeks versus 27 Gy/5fr/5days or 26 Gy/5fr/5days)

23 AMAROS (EORTC) trial 1425 patients with N+, 744 ALND and 681 ART Intention to treatment study (85% received treatment) Median follow-up 6.1 years Axillary relapse: % (4 patients) in the surgery group % (7 patients) in the RT group - No differences in OS and DFS Significantly less rate of lymphedema at 5-y: 13.6% vs 28.0% Donker M et al, Lancet Oncol 2014

24 OTOASOR trial 2106 patients with N+, 1054 ALND and 1052 ART Axillary relapse: - 2.0% in the surgery group - 1.7% in the RT group - No difference in OS and DFS Savolt A et al, Eur J Surg Oncol 2017 Any clinical sign of toxicity at 1-y 15.3% ALND 4.7% RNI

25 POSNOC SINODAR ONE SENOMAC SOUND INSEMA BOOG NSABP B-51 Alliance A11202 Ann Surg 2017 Axillary dissection Sentinel Node biopsy only Axillary RT Axillary RT + RNI No treatment

26 RT is generally very well tolerated Acute side effects are quite common, selflimiting, and resolve within 4-6 weeks. Skin reactions and fatigue are the most frequent How toxicities The most common late toxicities are not can be reduced? frequent and consist of persistent breast edema, hyperpigmentation, and fibrosis Lymphedema, radiation pneumonitis and cardiac morbidity are very uncommon, but can have significant health consequences

27 LATE Edema Peeling Dystrophy or atrophy Hypo or hyper pigmentation Teleangectasia Skin thickening Skin reactions Breast edema Fibrosis (with nipple and/or breast displacement)

28 Late toxicity Breast IMRT resulted in fewer changes in breast appearance at 5 y

29 Lymphedema B/CW + SC + PAB No RT B/CW + SC B/CW only 1476 women (1501 breasts) Prospective arm volume measurement Pre- and post-operative Perometer Lymphedema defined as a 10% increase in arm volume occurring >3 months post-operatively

30 Irradiation of the left breast Coronary Artery Disease Distribution and extent is related to areas and dose of radiation Left-sided BC have risk of stenosis at the mid/distal LAD arteries and distal diagonal branches No differences in cardiovascular disease were found at 10 years; however if regional LNI gains in prominence, these data may need to be re-examinated at longer-term

31 Studies Up to 10 ys ys ys >20 ys Years Cardiac mortality in irradiated/control group In subsequent studies, increased cardiac mortality was no longer observed

32 Rate of major coronary events according to mean radiation dose to the heart Mean dose Hazard R 0-5 Gy Gy 1.32 > 15 Gy 1.63 RT increased the rate of major coronary events by 7.4% per Gy, with no apparent threshold. The hazard risk doubled in patients received CT and RT

33 Geometrical difficulties in field junction Right coronary artery Left anterior descending artery (LAD) Left circumflex artery Left anterior descending artery (LAD) Cardiac toxicity is mainly due to macrovascular damage, and particularly to the left anterior descending (LAD) artery

34 Goal: Cardiac exposure as close to zero to ZERO as possible IMRT Deep Inspiration Breath Hold (DIBH) technique Respiratory gating technique Prone position (large breast) Partial Breast Irradiation (PBI) Proton therapy

35 DIBH Technique Statistically significant reduction in the mean heart and LAD artery dose Mean heart dose from Gy to Gy (38-67%) Mean LAD artery dose from Gy to Gy (5.9-71%) Free breathing Deep inspiration

36 Take Home Message (I) RT remains a standard in most breast cancer. The number of patients will increase and more cases are expected for RT in More tailored radiation treatments are needed in the era of personalised medicine, with a great attention to QoL aspects Modern RT techniques has shown to be able to increase the homogeneity of the dose distribution in the target and to reduce the dose to the OARs

37 Take Home Message (II) Using these technics, RT will improve effectiveness and reduce side effects These characteristics allow to face the new challenges of breast RT in hypofractionaction, locoregional treatment, breast reconstruction, and special cases Biology driven indications will ensure in the future a real tailored RT treatment to the breast cancer patients

38 BCS. LR and molecular subtype Braunstein LZ et al, Breast Cancer Res Treat 2017

39 Something of new from biology? Luminal A High radiosensitivity Low LRR rate Local pattern of recurrence To discuss: omission of RT, dose de-escalation, PBI Non-Luminal A Intermediate/low/very low radiosensitivity Intermediate/high/very high LRR rate Local, regional and distant pattern of recurrence To discuss: dose escalation, regional node RT, chemoradiation, new fractionaction Leonardi MC.Orecchia R et al, From technological advances to biological understanding: the main steps toward high-precision RT in breast cancer. The Breast 2016 Orecchia R, Tailoring radiotherapy according to cancer subtypes. The Breast 2017

40 Thank You very much!!!!