Métastases hépatiques du cancer colorectal : Point de vue du radiothérapeute 26ème Congrès de la SMC Tanger 28.04.2018

INTRODUCTION Amélioration du pronostique du CCR M+ Survie médiane 2 ans Amélioration des thérapies systémiques+++ Réponse complète rx = >80% de rechutes locales Benoist JCO 2006 Chirurgie des M+ hépatique améliore le pronostique (Survie à 5 ans = 30-40%) Mets non résécables dans 80-90% des cas Small R, Isr Med Assoc 2007 CT = 10 à 30% deviennent résécables Kemeny N, Oncology 2006

Radiosensitivity of liver mets based on primary Radiosensitive Radioresistant Ahmed KA, IJROBP 2016

SBRT vs RFA 161 pts 282 CCR liver mets (112 RFA vs 170 SBRT) Primitif CCR : 40% (RFA) / 20% (SBRT) Median FU : 24.6 mos Tox G3+ 4SBRT vs 3 RFA (NS) SBRT meilleure si T>2cm Jackson WC, IJROBP 2018

Schémas 50Gy / 10fx (43%) BED10= 75 Gy 60Gy/3fx (19%) BED10= 180 Gy 99.5% PTV = IDL 80% (75-85) Minimum PTV dose 90% BED10= 75 Gy BED10= 180 Gy BED10= 48-85.5 Gy BED10= 43.2-151 Gy BED10= 115.5-132 Gy Jackson WC, IJROBP 2018

Résultats de la SBRT hépatique Mahadevan 25-427 Majorité CCR 14 à 75Gy 1 à 6 séances 0-3% G3 0 G4+ Suivi 1 à 2 ans CL>70%

Single dose Heidelberg Stanford Phase I Phase I/II N= 26 (19 w/ liver mets) 18 to 30Gy Med FU = 18 mos No DLT (1 acute G2 = duodenal ulcer and 2 late duodenal ulcer) 1-y LC 77% 1-y and 2-y OS = 62 and 49% Phase I/II N= 37 Liver mets = 55 14 to 26Gy / 1fx 1-y LC 67% 22-26Gy (80%) 14-20Gy (0%) Herfarth KK, JCO 2001 Goodman KA, IJROBP 2010

Fractionated SBRT Liver mets 45Gy/3fx (BED10= 112.5Gy) 2-y LC = 79% 1 death (hepatic failure), 1 colonic perforation, 2 duodenal ulcers No tracking/gating (Large PTV margins) Hoyer M, Acta Oncol 2006

University of Colorado Phase I N= 18 1-3 Liver mets <6cm 36 to 60Gy / 3Fx No DLT Phase II N= 47 (63 liver mets) 38 had 60Gy/3fx Med FU 16 mos 1-y / 2-y in-field LC = 95% /92% 100% if <3cm 1G3+ (2%) / No G4+ Schefter TE, IJROBP 2005 Rusthoven KE, JCO 2009

University of Colorado (Phase I/II) Favorable histology = 15CRC/23 (65%) Rusthoven KE, JCO 2009

University of Texas southwestern Phase I dose escalation 30Gy/3fx - 2-y LC 56% (NoG3+) 50Gy/5fx – 2-y LC 89% (No G4+ - 1G3 liver enzyme) 60Gy/5fx – 2-y LC 100% (No G3+) Dose-response relationship betwwen 30Gy and 60Gy (p=0.009) Rule W, Timmerman R, Ann Surg Oncol 2011

Ultra high dose (University of Milan, Italy) 76 liver mets 75Gy/ 3fx (BED10=262.5Gy) Med FU = 12 mos LC = 95%, 2-y OS 70% Scorsetti M, IJROBP 2013

CRC Liver Mets : Prognosticators on LC 3 institutions 1 to 4 liver mets N= 65 (102 lesions = 100% CRC) 72% ≥ 1 CT before SBRT, 42% had ≥2 CT regimen Predictors of LC on MVA: Total dose (> vs < 42Gy) Dose /fx BED (< vs >75Gy) LC> 90% if 46-52Gy/3fx Recommendation = 48+Gy /3fx N of chemo regimen (NS) 90% LC BED 117Gy Chang DT, Cancer 2011

CRC Liver Mets: Prognosticators on OS Active non-liver disease (p=0.046) Local failure (p=0.06) N of chemo regimen (NS) Chang DT, Cancer 2011

CRC & Liver Mets : Phases I + II N= 60 82% previous CT, 23% previous liver tx, 38% extrahepatic disease Median n of GTV = 1 (1-6) Median target size= 6cm (4.5-21) Median min GTV dose = 37.6 (22.7-62.1) / 6 fx over 2w median FU= 28.1 mos 1-y and 4-y LC = 49.8% and 26.2% 1-y and 4-y LC = 65.0% and 49.8% if BED>75Gy (>45Gy/6fx) McPartlin A, IJROBP 2017

CRC & Liver Mets : PMH Experience McPartlin A, IJROBP 2017

The international multi-institutional RSSearch® Patient Registry 427 pts 568 liver Mets 25 academic and community-based Median FU 14 mos n Median OS (mos) 1-y OS CRC 189 27 76.4% Breast 42 21 66.4% Gynae 26 25 81.3% Lung 52 10 50% Other GI 33 61% Pancreas 20 6 18% Other 65 Mahadevan A, Radiat Oncol 2018

Effet dose/volume <40cm3 ≥40cm3 Mahadevan A, Radiat Oncol 2018

CRC & Liver Mets : LC predicts OS!! McPartlin A, IJROBP 2017

CONCLUSIONS Option thérapeutique ablative et conservatrice pour les M+ non résécables Contrôle local en SBRT >80% et relié à la survie Modélisation de l’effet dose/volume permet d’établir les schémas thérapeutiques efficaces T>3cm efficacité >RFA mais BED >117Gy Toxicités minimes+++ Intérêt de combiner thérapies systémiques?