INTRAARTERIAL TREATMENT OF COLORECTAL LIVER METASTASES. Dr. Joan Falcó Interventional Radiology UDIAT. Hospital Universitari Parc Taulí

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1 INTRAARTERIAL TREATMENT OF COLORECTAL LIVER METASTASES Dr. Joan Falcó Interventional Radiology UDIAT. Hospital Universitari Parc Taulí

2 STRATEGIES FOR CRLM LIVER METASTASES Extended indications Resectable 20-30% 10-20% Non resectable 80-90% 70-80% Surgery 20-40% Optimizing Chemotherapy Loco-regional therapies 2

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4 80 PERCUTANEOUS TREATMENTS TIMELINE 90 RADIOEMBOLIZATION (TARE) HAI 80 TAE 85 TACE-LIPIODOL in HCC >90 TACE HCC highly developed >2010 DEBIRI-M1 INTRAARTERIAL CHEMOTHERAPY HAI TAE c-tace TACE DEBIRI RADIOEMBOLIZATION

5 80 PERCUTANEOUS TREATMENTS TIMELINE 90 RADIOEMBOLIZATION (TARE) HAI 80 TAE 85 TACE-LIPIODOL in HCC >90 TACE HCC highly developed >2010 DEBIRI-M1 INTRAARTERIAL CHEMOTHERAPY HAI TACE DEBIRI

6 1. Colorectal cancer (CRC): Liver is ussually the 1st site of mets. Hematogenic spread: Portal vein liver lung other organs 2. Vascularization: CRLM: Almost exclusively by hepatic artery Normal liver: Preferentially by portal vein 3. Increased exposure to chemotherapy of liver VASC. METS HEPATIC ARTERY >95% HEPATIC ARTERY PORTAL VEIN NORMAL LIVER PORTAL VEIN 80% HEPATIC ARTERY 20%

7 1. Placement of a permanent catheter in gastroduodenal artery Surgical vs.endovascular 2. Oclusion of gastrointestinal branches with coils 3. Redistribution of hepatic flow through common hepatic artery TOTAL PARENQUIMAL SATURATION RIGTH AND LEFT HEPATIC A. LEFT GASTRIC A. GASTRODUODENAL A. COMMON HEPATIC A.

8 HEPATICO-MESENTERIC TRUNK

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10 28 patients ORR: 64% 5 Surgical resections PFS: 27 months HAI oxaliplatin and IV LV5FU2 is feasible, safe, and shows promising activity after systemic chemotherapy failure, allowing surgical resection of initially unresectable CRLM in 18% of patients.

11 16 patients, with missing metastases( ) 12 patients received oxiloplatin HAI pre or post-operative. In 10 (61%), missing LMs not reapear Mean follow-up 51 months (24-90) 3-year survival: 94% Adjuvant HAI was significantly correlated with the definitive eradication of missing LMs (P <.01).

12 Kemeny et al., 2009 N: 49. Sistemic chemotherapy(irinotecan/oxaliplatin) + HAI(FUDR) 73% >5 lesions, 98% Bilobar disease, 86% >6 segments afected Results: ORR 92% 47% Resection (57% in chemo-naive) Median survival 50,8 M 35 M

13 Diagnosis of CRLM Resectable Unresectable Neo-adjuvant/ Pre-operative therapy Potentially resectable HAI First-line HAI Surgery Adjuvant therapy Missing metastases HAI Second-line HAI Third-line HAI Fourth-line

14 Chemoembolization with drug-eluting beads preloaded with irinotecan Round and calibrate particulate of PVA Hidrophilic coating µ DC Bead before Irinotecan loading More recently DEBIRI M 1 ( µ) Max. Load 50mg /ml Irinotecan Loading by ion exchange Pharmacy preparation Time to complete charge about 2 hours Charged spheres stability 14 days DC Bead after Irinotecan loading

15 PROOF OF CONCEPT Intraarterial Debiri produce a High intratumoral levels, and negligible plasmatic levels, with a constant and sustained release of Irinotecan. Forni et al. 1994

16 Unresectable, liver only or liver-dominant metastases With no response to chemotherapy. <60% hepatic involvement Portal patency ECOG < 2 Expected survival>3 meses Liver tests INR <1.3 Tot. Bil. <2mg/100ml Serum transaminases (AST & ALT) 5 x ULN Special attention Previous history of biliary tree surgery.

17 1 vial per session (100mg Irinotecan) Lobar embolization prefered* PARAGON II STUDY * Lobar injection of DEBIRI should be prefered to a selective injection because some nodules are not visible at imagery and therefore may not be treated if the catheterization is too selective Jones et al. HPB 2012

18 1 vial per session (100mg Irinotecan) Lobar embolization prefered* Unilobar disease 2 treatments at 3-4 weeks interval. Bilobar disease 4 treatments at.2-3 weeks intervals

19 1. PROSPECTIVE STUDY PHASE II. TACE DEBIRI in patients with CRLM, refractory to chemotherapy. (n=82 ) 185 treatments SAFETY AND TOLERABILITY MAJOR COMPLICATIONS: 0% (1 caso de pancreatitis). MINOR COMPLICATIONS: - Post-embolitzation syndrome: Fever 80% Abdominal pain, 40% Hypertension 12% Nausea 27% Asthenia 70% Diarrhea 14% RESULTS ORR (mrecist): 80% >50% CEA 75%. ALIBERTI : TACE using irinotecan-eluting beads is well tolerated and a feasible and effective PALLIATIVE therapy in pretreated patients

20 Fiorentini et al. Anticancer research PROSPECTIVE TRIAL PHASE III. TACE DEBIRI (36) vs. FOLFIRI (38) (n=74) 2 years SURVIVAL RR (mrecist) ACUTE TOXICITY LATE TOXICITY IMPROVEMENT QOL COST (Euros) DEBIRI 56% 78% 80% 25% 65% 4500 FOLFIRI 32% 20% 20% 70% 25% Procedures 60% 50% 40% 30% 20% DEBIRI FOLFIRI 56% DEBIRI 22 months (95% CI 21-23) FOLFIRI15 months (95% CI 12-18) p = (log rank test) 10% 0% 32% Pain Vomiting and Nausea Fever Asthaenia Diarrhoaea Leucopaenia Anemia Alopecia DEBIRI could reach the goal to increase MEDIAN SURVIVAL by 43% at 2 years compared to FOLFIRI chemotherapy.

21 3. Randomized phase II Clinical Trial of Irinotecan Drug Eluting Beads with simultaneous FOLFOX/ Bevacizumab for patients with irressecable colorectal liver-limited metastasis. Prospective, multiinstitutional, phase II clinical trial. N=70 patients 30 Patients Control arm FOLFOX +/- Bevacizumab vs. 40 ( ) patients Treatment arm FOLFOX- DEBIRI +/- Bevacizumab Chemo-naive population, Liver dominant disease 80% Liver replacement by tumor 60% Standard chemotherapy at day 0, 14 and 7, 21 for DEBIRI. Bevacizumab to the discretion of medical oncologist Robert Martin C. G. Cancer 2015

22 No significant diferences about dose delay, dose-limiting toxicity No significant diferences between treatment groups among chemotherapy-specific adverse events Improvement hepatic PFS (17 mo vs. 12 mo.) No diferences in overall PFS. More durable ORR in pacients downsized to resection (35% vs. 6%) DEBIRI represents a less toxic, less expensive, and more convenient treatment alternative to other regional hepatic artery therapies. Robert Martin C. G. Cancer 2015

23 Adjuvant treatment after hepatic resection. Decrease recurrences Missing metastases First line treatment in unresectable CRLM patient. Convert to resectability. In further line as a salvage treatment. Allow chemotherapy holidays.

24 HAI performed at Highly specialized centers, can improve survival. Need for high skilled team. DEBIRI represents a simple, effective, and confident technique in delivering a high intratumoral dose of Irinotecan. Good tolerance, low systemic toxicity, and low rate morbidity in suitable candidates. Effective in 2 ond line and further. Response rate 70-80% in no responders DEBIRI in combination with systemic chemotherapy in first line therapy are promising, but Prospective clinical data are lacking, and outcomes relating to survival have yet to be established in large-scale Phase III trials.

25 Thank You!