Breast cancer: Clinical evidence of new treatments Aero academy Conference Innovation and Safety Patients Come First January 26 & 27, 2018 Lisbon, Portugal
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Focus on: 1. Hypofractionation 2. PMRT and RNI 3. Biology
1. Hypofractionation a parallel standard
Review and meta-analysis 13 randomized trials 8189 patients, early stage pt1 pt2, pn0 Age > 50 years No concomitant chemotherapy No study designd for boost (0 74%) Hypofractionation versus standard High homogeneity in dose distribution strongly recommended (ASTRO ± 7%) Valle LF et al, Breast Cancer Res Treat 2017
Local Failure Review and meta-analysis No difference in: Local Failure, Locoregional Failure LocoRegional Failure, and Breast Cancer Specificity Mortality Breast Cancer Mortality Acute toxicity Hypofractionation better in acute toxicity Poor cosmesis No difference in cosmetic outcome Valle LF et al, Breast Cancer Res Treat 2017
The winner is: START B (Haviland et al. 2013) 10 y IBR 10 y OS Cosmesis 50 Gy in 25 fr (5 wks) 2.0 Gy/fr 40 Gy in 15 fr (3 wks) 2.67 Gy/fr 5.5% 89% 45.3% 4.3% 92% 37.9% Equivalent local control Survival benefit Better cosmesis
UK IMPORT LOW Trial 2,018 patients, 2007-2010, randomised in 3 arms 1) Control WBI 40Gy 2) Reduced Dose WBI 36 Gy + 4 Gy PBI 3) PBI Only 40 Gy 1) IBTR Control 1.1% 2) IBTR Reduced Dose 0.2% 3) IBTR PBI only 0.5% Equivalent or fewer adverse effects in 2)&3) WBI: Whole Breast Irradiation PBI: Partial Breast Irradiation IBRT: Ipsilateral Breast Tumor Recurrence Coles CE et al. Lancet 2017
Hypofractionation Open question How can we integrate the boost?
Boost: Cochrane Database, 2017 LC better (HR 0.64, Qe low) OS equal (HR 1.04, Qe moderate) DFS equal (HR 0.94, Qe low) Late toxicity equal (Qe very low) Cosmesis by panel worse (Qe low) Cosmesis by physicians equal (Qe low) Subgroup > 40 y HR 0.65 = to 40 y 5 randomised controlled trials of 8325 patients
IMRT: Concomitant Boost & Hypo Whole breast 2.67 Gy x 15 Boost area only 3.2 Gy x 15
Hypofractionation Open question How can we integrate hypofractionaction and lymphatic irradiation?
Locoregional hypofractionated EBRT at IEO 3 WEEKS, 2.67 Gy/fractions
RNI & hypofractionation: ongoing trials DBCCG (40 Gy/15 fx vs 50 Gy/25 fx) 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 fx of 2.7 Gy each In 2 studies IMN irradiation is also investigated Sub-study UK FAST-Forward (40 Gy/15 fx/ 3 weeks versus 27 Gy/5fx/5days or 26 Gy/5fx/5days)
2. PMRT and RNI an emerging standard PMRT: Post Mastectomy Radiation Therapy RNI: Regional Nodal Irradiation
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 Regional Node Irradiation SLN biopsy + When????
60 x 1000 50 40 30 20 26.9% 28.7% 40.5% 10 0 2000 2007 2011 SEER data 2000-2011, Fraiser LL et al, JAMA Oncol 2016 NCDB data 2003-2012, Ohri N et al, Cancer 2017
EORTC phase III trial 22922/10925 4004 patients 1996 to 2004 Distant Disease Free Survival No IM-MS Irradiation R IM-MS irradiation (50Gy) Overall Survival Poortmans PM et al, N Engl J Med 2015
5-year results WBI WBI + RNI P value Patient Eligibility: NCIC-CTG - MA-20 LR Control 94.5% 96.8% 0.020 1) 1-3 LN+ or >4+ LN+ DFS 84% 90% 0.003 2) Lumpectomy Distant DFS* 87% 92.4% 0.002 3) > 10 nodes dissected 4) >1 of the following (with High Risk LN-) OS 90.7% 92.3% 0.070 Grade 3 histology Lymphedema 4.1% 7.3% 0.004 ER-negative disease >G2 toxicity LymphoVascular 0.2% space Invasion 1.3% (LVI) 0.010 Whelan TJ et al, N Engl J Med, 2015
Quality Assurance in pathology Country Reported Reviewed Reported Reviewed G 3 (%) G 3 (%) LVI (%) LVI (%) UK 54.6 42.4 41.2 15.1 Netherlands 52.0 39.6 28.4 19.5 China 26.8 45.0 31.7 28.6 Total 52.7 41.9 39.3 15.1 N negative G3 Reported G3 Reviewed LVI Reported LVI Reviewed 87.4 64.2 38.2 9.9 Supremo/ Big 2.04 Breast Cancer Res Treat 2017
Volume 34 Number 36 December 20, 2016 Journal of Clinical Oncology ASCO Special Article Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update Recht A, Comen EA, Fine RE, Fleming GF, Hardenbergh PH, Ho AY, Hudis CA, Hwang ES, Kirshner JJ, Morrow M, Salerno KE, Sledge GW Jr, Solin LJ, Spears PA, Whelan TJ, Somerfield MR, Edge SB. PMRT/RNI versus no RT The panel found insufficient evidence to endorse any specific model or to unambiguosly define specific patients subgroups to which PMRT should not be administered The panel recommends treatment generally be administered to both the IMNs and the supraclavicular-axillary apical nodes in addition to the CW or reconstructed breast when PMRT is used for patients with N+
De-escalating and escalating treatments St.Gallen International Expert Consensus Conference 2017 Post-mastectomy Radiotherapy (PMRT) Regional Node Irradiation (RNI) *Consider omitting RT in women with pt1-pt2, pn1 (1-3), and favorable biological profile **PMRT in patients with pt3 or 4 or more positive lymph nodes *Consider omitting RNI in N1 (1-3 positive lymph nodes) in the absence of adverse clinical factors **RNI in N1 cancers and adverse clinical features ( 40 years, low or negative estrogen receptor, G3, extensive lympho-vascular invasion) or >3 positive nodes *De-escalation; **Escalation Curigliano G et al, 28:1700-12, Ann Oncol 2017
PMRT and RNI Open question Could RT substitute surgery in axillary treatment?
Lymphedema Chronic pain, functional impairment, psychological distress, poor QoL B/CW + SC + PAB B/CW + SC No RT B/CW only
AMAROS (EORTC) trial 1425 patients with N+, 744 ALND and 681 ART Axillary relapse: - 0.54% (4 patients) in the surgery group - 1.03% (7 patients) in the RT group - No differences in OS and DFS At 5-years Lymphedema: ART 13.6% vs ALND 28.0% (p<0.0001) Arm circumference increase >10%: ART 5.9% vs ALDN 13.1% (p<0.0009) Donker M et al, Lancet Oncol 2014
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 differences in OS and DFS Any clinical sign of toxicity at 1-year: 15.3% ALND 4.7% RNI Savolt A et al, Eur J Surg Oncol 2017
PMRT and RNI Open question Could avoid to increase toxicity?
60 x 1000 50 40 30 31.9% 20 10 0 14.8% 2000 2011 SEER data 2000-2011, Fraiser LL et al, JAMA Oncol 2016
Implant Sparing Irradiation (ISI) CTV excluding implant
Goal: Heart Dose Zero Deep Inspiration Breath Hold (DIBH) Respiratory gating Prone position (large breast) Partial Breast RT Protontherapy IMRT
Comparison of heart dose 3DCT For-IMRT Inv-IMRT HT VMAT Heart Dmax Dmean 46.04 4.39 45.22 4.38 37.90 8.36 27.21 4.13 36.60 9.24 LAD Dmax Dmean 45.01 16.42 44.38 16.22 39.49 15.11 11.10 3.42 32.77 17.99 Haciislamoglu E et al, Phys Med 2015, modified Heart Ideal mean median range 3D-CRT Dmean < 5 Gy 4.57 4.70 2-11.3 Tomo Direct Dmean < 3,2 Gy 1.4 0.7 0.2-14 IEO data, 2016
3. Biology How can we move to it?
BCS. LR and molecular subtype Braunstein LZ et al, Breast Cancer Res Treat 2017
Something new from biology? Luminal A High radiosensivity Low LRR rate Local pattern of recurrence To discuss: omission of RT, dose de-escalation, PBI Non-Luminal A Intermediate/low/very low radiosensivity Intermediate/high/very high LRR rate Local, regional and distant pattern of recurrence To discuss: dose escalation, regional node RT, chemoradiation, new fractionation 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
Highlights Adjuvant RT maximizes LR control, with positive impact on survival and quality of life Hypofractionation is becoming a parallel standard Regional node irradiation and PMRT are extending their indications Optimization of high precision techniques will allow to maximize effectiveness, and minimize toxicities Better understanding of tumour biology, and translation in clinics, will allows to personalize treatment and realize a true adaptive RT to most patients
Thank you very much for your attention!!!! roberto.orecchia@ieo.it