INTERVENTIONELLE RADIOLOGIE

INTERVENTIONELLE RADIOLOGIE JENS RICKE

CLOCC STUDY Ruers et al. J Clin Oncol 33, 2015 (suppl; abstr 3501) Patients with unresectable CRC liver metastases N=152 Randomization RF + Systemic treatment ± resection if an option Systemic treatment ± resection if an option

RADIOFREQUENCY ARM RF + Systemic (N=57) Treatment by RF 30 (52.6%) RF + resection* 27 (47.4%) RF procedure laparotomy 51 (89.5%) Type of resection (N=27) laparoscopically 1 (1.8%) percutaneously 4 (7.0%) unknown 1 (1.8%) atypical resection or wedge 16 (59.3%) 2 or more segments 11 (40.7%) Mean time in hospital 4.8 days *1 patient with resection only Ruers et al. J Clin Oncol 33, 2015 (suppl; abstr 3501)

TREATMENT INFORMATION Treatment received Assigned Treatment Folfox Folfox + bev RF only No treatment Resection RF + Systemic (N=60) 43 72% 8 13% 6* 10% 3** 5% Systemic (N=59) 46 78% 13 22% 0 0% 7*** 12% * 6 patients with RF only: : progression (2), intercurrent death (1), RF/surgery complications (3) ** 3 patients with no treatment: refusal, no treatment data received, bone metastases at baseline *** 1 patient was resectable on initial CT imaging (ineligible) Ruers et al. J Clin Oncol 33, 2015 (suppl; abstr 3501)

OVERALL SURVIVAL 100 90 80 70 60 50 40 30 20 10 0 Median (95% CI) 40.54 (27.50, 47.67) Systemic (Months) 45.60 (30.32, 67.75) RF+Systemic 8-year OS (95% CI) 8.9% ( 3.3, 18.1) Systemic 35.9% (23.8, 48.2) RF+Systemic HR = 0.58, 95% CI (0.38-0.88), P = 0.010 (Log-rank test) 0 2 4 6 8 10 12 (years) O N Number of patients at risk : Treatment 53 59 43 21 11 4 2 Systemic 39 60 44 28 21 19 9 RF+Systemic Ruers et al. J Clin KLINIKUM Oncol DER 33, UNIVERSITÄT 2015 MÜNCHEN (suppl; abstr 3501)

Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

Lethal tumor load Baseline tumor load Deepness of response PFS No tumor shrinkage OS PFS Tumor shrinkage PFS Time under treatment

VORTRAGSSTRUKTUR Der Werkzeugkasten ( LAT ) Ablative Techniken Locoregionäre Techniken Patientenselektion Tumorentität Tumorbiologie Kurative Intention oder Debulking? Oder Palliation?

FIGURE 1: TOOLBOX OF ABLATIVE TREATMENTS Van Cutsem E, KLINIK Cervantes UND A, POLIKLINIK Arnold D FÜR et al, RADIOLOGIE ESMO Consensus 2016 Online Ann Oncol, July 2016

Local and ablative treatment (including surgery) recommendation 15: local ablation techniques. In patients with unresectable liver metastases only, or OMD, local ablation techniques such as thermal ablation or high conformal radiation techniques (e.g. SBRT, HDR-brachytherapy) can be considered. The decision should be taken by an MDT based on local experience, tumour characteristics and patient preference [IV, B]. In patients with lung only or OMD of the lung, ablative high conformal radiation or thermal ablation may be considered if resection is limited by comorbidity, the extent of lung parenchyma resection, or other factors [IV, B]. Van Cutsem E, Cervantes A, Arnold D et al, ESMO Consensus 2016 Online Ann Oncol, July 2016

LOKALE KONTROLLE NACH RESEKTION UND RFA Tanis Eur J Cancer 2014

LOKALREZIDIVE PER GRUPPE RFA: lesion size > 30 mm (n = 6/28, 21.4%) 30 mm (n = 4/139, 2.9%) Resektion: <30 mm was 6.2% (n = 6/97) No recurrences >30 mm (n = 0/13) Tanis Eur J Cancer 2014

Welsh et al. Surgical Oncol 2008

CT-BRACHYTHERAPIE: LEBER, LUNGE, RETROPERITONEAL, MESENTERIAL,

Deutsche Akademie für Mikrotherapie

CUP, NN-Metastase: Progress unter 1st-line-CTx; 6 Monats-F/U CRC NN-METASTASE: STABIL IN 2ND-LINE, CHEMO-PAUSE; 12 MONATS-F/U

Prospektiv randomisierte Dosisfindung Primärer Endpunkt: lokale Kontrolle Sekundärer Endpunkt: Gesamtüberleben, Tumorgröße 5 15cm FFLP >90% nach 12 Mon. (>20Gy single fraction) Ricke et al. Int J Radiat Oncol Biol Phys 2010

LOCAL CONTROL AFTER CT-BRACHYTHERAPY CRC: 80-90% (12 months, 2-15cm) 1,2 Breast: >95% (12 months, 3-12cm) 3,4 Cholangiocellular/Adenoca: >80% 5,6 HCC: >90% (12 months, 5-15) 7, 8 GIST/Sarkoma: 80% 9 Melanoma: >80% 10 1,2 Collettini 2014, Ricke 2010 3,4 Collettini 2014, Wieners 2011 5,6 Kamphues 2012, Schnapauff 2012 7,8 Collettini 2012, Mohnike 2010 9 Bretschneider 2015 (in press) KLINIKUM DER UNIVERSITÄT MÜNCHEN 10 KLINIK Bretschneider UND POLIKLINIK FÜR 2015 RADIOLOGIE

COMBINED ANALYSIS OF: Professor Ricky Sharma Chair of Radiation Oncology, University College London, United Kingdom on behalf of the FOXFIRE, SIRFLOX and FOXFIRE-Global Investigators

PATIENT CHARACTERISTICS Characteristic Chemo (n = 549) Chemo+SIRT (n = 554) Median age in years (range) 63 (23 89) 63 (28 90) Male 65.8% 65.5% WHO performance status 0 63.2% 36.4% 63.9% 35.7% 1 Extra-hepatic metastases 34.8% 35.9% >25% liver involvement 30.6% 32.3% Intent to treat with biologicals 54.5% 53.8% Synchronous presentation with liver mets 86.5% 87.2% Primary tumour in situ 55.0% 50.2%

1.00 OVERALL SURVIVAL Chemo (N=1103) Chemo+SIRT Proportion Alive Proportion Alive 0.75 0.50 0.25 0.00 No. at Risk Chemo Chemo+SIRT 1.00 0.75 0.50 0.25 0.00 1.00 0.75 0.50 Chemo Chemo+SIRT 0 12 24 36 48 60 Time 0.25 from Randomisation (months) 0 12 24 36 48 60 549 419 242 88 33 12 554 417 247 91 35 17 Time from Randomisation (months) No. at Risk 0.00 Chemo 549 419 242 88 33 12 Chemo+SIRT 554 417 247 91 35 17 No. at Risk Chemo Chemo+SIRT Chemo Chemo+SIRT 0 12 24 36 48 60 Time from Randomisation (months) n Events Median 549 411 23.3 months 554 433 22.6 months HR: 1.04 (95% CI: 0.90 1.19) p=0.609 549 419 242 88 33 12 554 417 247 91 35 17

Cumulative incidence Cumulative incidence LIVER-SPECIFIC PROGRESSION-FREE SURVIVAL First radiological progression within the liver HR 0.51 (95% CI 0.43-0.62) p<0.001 First progression extrahepatic or death without radiological progression having been documented HR 1.76 (95% CI 1.47-2.11) p<0.001 Time from Randomisation (months) Time from Randomisation (months) Patients in the Chemotherapy + SIRT arm had a lower risk of progression in the liver as a first event and a higher risk of non-liver progression as a first event

TREATMENT EFFECT ON OS WITHIN SUBGROUPS

Probability of Overall Survival Overall Survival for SF and FF-G Patients with Left-Sided Primary Tumours 1.0 0.8 0.6 0.4 Censored n Median Survival (95% CI) Chemo + SIRT 264 24.6 months (22.3 26.7) Chemo 276 26.6 months (24.8 29.9) Hazard Ratio 1.12 (0.92 1.36) p=0.279 0.2 0.0 0 12 24 36 48 60 72 84 96 Time from Randomization (months) At Risk (n) 264 199 130 47 20 12 2 0 276 223 150 54 22 7 2 1 0

Probability of Overall Survival Overall Survival for SF and FF-G Patients with Right-Sided Primary Tumours 1.0 0.8 0.6 0.4 n Median Survival (95% CI) Chemo + SIRT 98 22.0 months (18.9 25.6) Chemo 81 17.1 months (13.9 19.9) Hazard Ratio 0.64 (0.46 0.89) p=0.007 0.2 Censored 0.0 0 12 24 36 48 60 72 84 96 Time from Randomization (months) At Risk (n) 98 78 43 14 5 3 1 1 81 51 15 6 2 1 0 0 The treatment interaction by location for Overall Survival was highly KLINIKUM DER UNIVERSITÄT MÜNCHEN significant (Chi-square: 9.49; p=0.002; HR: 0.548 [0.37 0.80])

REsect: Blinded assessment of surgical resectability of previously unresectable colorectal cancer liver metastases following chemotherapy±y90-radioembolization Benjamin Garlipp Peter Gibbs Guy van Hazel Rohan Jeyarajah Robert Martin Christiane Bruns Hauke Lang Derek Manas Giuseppe Maria Ettorre Fernando Pardo Vincent Donckier Christoph Benckert Thomas van Gulik Diane Goéré Michael Schön Johann Pratschke Wolf Bechstein Shola Adeyemi Max Seidensticker

Results A total of 472 patients with similar baseline characteristics were evaluable (mfolfox n=228; mfolfox + SIRT n = 244). Characteristic FOLFOX (±bev) alone (n=228 a ) FOLFOX (±bev) + SIRT (n=244 a ) BSA, m 2 (SD) 1.87 (0.207) 1.87 (0.215) Mean (SD) estimated tumor burden, % 17.6 (15.3) b 18.3 (16.6) c Mean (SD) number of baseline hepatic target lesions 3.8 (1.2) b 3.8 (1.3) Patients with extra-hepatic metastases, n (%) 91 (39.9) 99 (40.6) Primary tumor in situ, n (%) 103 (45.2) 108 (44.3) a Number of patients with parameter unless stated otherwise; b n=227; c n=243

Results Of patients deemed unresectable at baseline, 31.2% in the FOLFOX+SIRT arm vs. 22.7% in the FOLFOX arm were converted to resectability (p<0.0001)

Hepatology 2013

Sekundäre Resektabilität nach RE 120 100 80 60 40 20 p<0,001 29 % 61% RE PVE 0 PVE hat eine höhere Induktionskapazität... Aber was ist mit der Tumorkontrolle? Garlipp, Seidensticker, Hepatology 2013

INCLUSION CRITERIA Treatment failure w/ liver metastases of CRC Min. post 2 nd line CTx (5-FU/FA, Oxaliplatin, Irinotecan) and 1 monoclonal antibody (Erbitux/Avastin) >20% tumor load No relevant extrahep. manifestations Karnofsky 60%

SIRT VS. BSC Median 5,5 vs. 2,1 months; p<0,001 Control SIRT Seidensticker R, Cardiovasc Intervent Radiol. 2012 Oct;35(5):1066-73

J Vasc Interv Radiol 2012; 23:96 105

EXCLUSION CRITERIA FOR RE (ALL PATIENTS)

OVERALL SURVIVAL NACH RE, N=224 (CRC)

PATIENT CHARACTERISTICS Sex (f/m) 58 / 1 Mean Age (y, range) 57,4 (32-80) Age ( vs. >60y) 37 / 22 Estrogen Receptor (pos/neg) 46 / 13 Progesteron Receptor (pos/neg) 34 / 25 In sum: Hormone Receptor (pos/neg) 49 / 10 Her2 neu (pos (triple)/neg) 20 / 39 Grading (1 / 2 / 3), 8 missing 4 / 26 / 21 45 (0-335,4) Median time from first diagnosis to liver metastases (months, range) Median time from first diagnosis liver metastases to first treatment in interventional radiology (months, range) 22 (1-294) Mean number of liver metastases (n, range) 13 (1-88) Mean maximum diameter of liver metastases (cm, range) 4,9 (1-14) Mean tumor load (%, range) 8,2 (0,1-51,4) Prior Chemotherapy (without hormones) (yes/no) 54 / 5 median lines (range) 2 (0-8) Seidensticker BMC Cancer 2015

PATIENT CHARACTERISTICS Other prior treatments (for metastases) (yes/no) 40 / 19 detailed** surgery (for metastasis) 19 radiotherapy 20 Bisphophonates 24 Extrahepatic metastases (yes/no) 29 / 30 site detailed** bones only 19 bones 24 pulmonary 6 lymphatic nodes (others than axillary) 4 peritoneal 1

GESAMTÜBERLEBEN AB LOKALABLATIVER THERAPIE Median overall survival Months 95% CI From first diagnosis 127,9 87,1-168,7 From first diagnosis liver metastases 56,3 44,5-67,9 From first treatment in Radiology 21,9 11,1-32,6

MULTIVARIAT: EINFLUß AUF GESAMTÜBERLEBEN Variable set Hazard ratio 95% CI p-value Extrahepatic metastases (yes/no) 0,57 0,21-1,60 0,286 Bone metastases only (yes/no) 0,91 0,39-2,10 0,82 Tumor load ( vs. < 2%) 4,32 1,63-11,44 0,003 Lines of chemotherapy ( vs. < 3) 1,57 0,73-3,38 0,244 CEA ( vs. < 6,2U/mL) 1,78 0,68-4,66 0,242 Under local control in FU (yes/no) 0,38 0,16-0,88 0,025 Best response overall (OR, RECIST) 5,88 2,27-15,27 < 0,001

69 YEARS, GOOD PS Insuline-secreting pancreatic NET 08/2009, Pancreas resection, hemihepatectomy Recurrence after Surgery, Octreotide, DOTATATE, Everolimus, Y90-Radioembolisation Intermittent severe hypoglycemia Continuous glucose infusion

MRI PRE BRACHY

CONTINUOUS GLUCOSE INFUSION 40 GRAMS GLUCOSE/HOUR 8 weeks hospital stay, ECOG 0 (!)

IBT IN 2 SESSIONS, 2 WEEKS INTERVAL

NORMALIZED GLUCOSE LEVELS WITHOUT SUBSTITUTION, 1 WEEK AFTER 2ND SESSION OF IBT Home at last!

SYNOVIAL SARKOMA, 34Y MALE Left lower extremity 2009 Repeated tumor resections 2015: systemic therapy w/ Ifosfamid/Cisplatin, Yondelis, no response Progressive inflow congestion 12/15 Weight loss 10kg in 4 months Fatigue Grade 3 09.12.2015 V. cava superior

Synovial sarkoma, 34y male

SYNOVIAL SARKOMA, 34Y MALE 09.12.2015 V. cava superior 12.01.2016 V. cava superior

TAKE HOME Der interdisziplinäre Werkzeugkasten ist entscheidend! Keine örtliche oder Größenlimitation Die onkologische Überlegung führt Klein = thermisch oder SBRT, groß = IR & Strahlentherapie Diffus = locoregionär (derzeit nur Radioembolisation) oder in Kombination mit Resektion (CLOCC) Patientenselektion Tumorbiologie < biologisches Verhalten Kurativ und palliativ Immer multidisziplinär und potentiell kombiniert konzipiert

DANKE! JENS.RICKE@MED.UNI-MUENCHEN.DE GOOGLE: RADIOLOGIE LMU