1. Liver directed therapy – when and how? V. Heinemann Department of Oncology and Comprehensive Cancer Center University of Munich, Germany

2. …resection or ablation (either alone or in combination with resection) should be reserved for patients with disease that is completely amenable to local therapy.

3. Group 3 Group 1 Scenarios for Locoregional Therapy Group 2 probably never resectable asymptomatic slowly progressing primarily resectable metastases 2a potentially resectable metastasen 2b: symtomatic, rapidly progressive + limited extrahepatic metastais

4. Multidisciplinary Decision Making Staging CT MRT US PET Surgery Locoregional treatment Multidisciplinary tumor board (TB) Conversion chemotherapy Secon- dary Surgery Palliative chemotherapy TB

5. Indications for a Non-Surgical Approach Comorbidity Size or location of metastatic lesion Inadequate volume of liver after surgery Combination with surgery in bilobar or extrahepatic disease Early recurrence with small lesions after resection Patient wish

6. RFA versus Resection Aloia TA, et al. Arch Surg 2006 Gravante G, et al. J Gastrointest Surg 2011 Wu Y-Z, et al. World J Gastroenterol 2011 Patients with solitary colorectal liver metastases Analysis of a prospective database RFA Resection OS DFS Local recurrence-free Message: RFA clearly inferior to resection

7. Hammill CW, et al. Surgical Oncology 2011 Retrospective review of patients after laparoscopic RFA technically resectable vs non-resectable 5-year survival of resectable patients 48.7%

8. n=226 Liver mets < 3cm OS PFS

9. OS PFS n=70 Liver mets > 3cm

10. EORTC Phase II Systemic Chemo +/- RFA in non-resectable pts 1st randomized study on the efficacy of RFA 119 patients randomized Chemo: FOLFOX4 over 6 months primary endpoint: 30-mo OS >38% for the combined group Ruers T, et al. Ann Oncol 2012 PFS OS + RFA ChemoChemo + RFA PFS (mo)9.916.8 OS (mo)40.545.3 30-mo-OS (%)5862

11. High risk of biliary injury in the demarcated area Limitation of RFA Hammill CW, et al. Surgical Oncology 2011

12. Radiotherapy Very limited database (mostly cohort studies) Recommendation only in selected cases where surgery is not an option: –3D conformal radiation –stereotactic body radiosurgery (SBRT) –intensity modulated radiotherapy (IMRT) –robotic radiosurgery (RRS) Possible –1-3 metastases –maximum lesion size (3-6cm) depends on method used –dose: 1 x 20-26 Gy; 3 x 12.5 Gy etc. Van der Pool AEM, Br J Surg 2010

13. Advantages over RFA –Proximity to large vessels not limiting (no heat-sink effect) –Heat injury of major bile ducts not limiting –Treatment of central lesions possible Disadvantages –Less feasible for treatment of multiple lesions –Cost Stereotactic Body Radiation (SBRT) Van der Pool AEM, Br J Surg 2010

14. Robotic Radiosurgery vs RFA: Local DFS matched pairs analysis of 60 mCRC patients with unresectable liver metastasis Stinzing S, et al. WCGIC, PD0021 Median follow-up 20.1 (RRS) and 24.6 months (RFA) RFARRS 12-mo local DFS64%85% 24-mo local DFS60%80%

15. How to Treat Recurrent Hepatic Metastases after Partial Hepatectomy ? Risk of hepatic recurrence >60% Surgery remains the first choice of treatment RFA or Radiation: small liver remnant, small central lesion Van der Pool AEM, et al. J Gastrointest Surg 13: 890, 2009  51 pts with hepatic recurrence  70% surgery; 20% RFA; 10% radiation  5-year OS 35%  Morbidity 16%, mortality 0% Clinical study

16. Treatment Algorithm for Recurrent Hepatic Metastases After Hepatic Resection Recurrent liver metastases Disease-free interval < 6 months Disease-free interval > 6 months CTx Small liver remnant YesNo resection Metastases nearby biliary ducts/vessels Yes SRx No RFA Van der Pool AEM J Gastrointest Surg 2009

17. Intraarterial Hepatic Therapy Options  hepatic arterial infusion (HAI)  drug-eluting beads (DEB-TACE)  radioembolization (SIRT) Contraindications  poor liver function  hyperbilirubinemia  portal occlusion  extensive extrahepatic disease

18. Mocellin S, et al. JCO 25: 5649, 2007 Overall survival: HAI versus systemic Chemotherapy Meta-Analysis of HAI in non resectable Liver metastasis

19. Conclusion Currently available evidence does not support the clinical or investigational use of fluoropyrimidine-based HAI alone for the treatment of patients with unresectable CRC liver metastases, at least as a first-line therapy.

20. TACE with Irinotecan Loaded Beads (DEBIRI)  Open label study of mCRC pts with LLD after failure of standard therapy  N = 55  DEBIRI (drug-eluting beads: irinotecan)  Median irinotecan dose 100 mg (range 100-200 mg)  Median number of total treatments: 2 (range 1-5)  Lack of biliary toxicity  ORR: 65% at 3 mo  DFS: 11 months  OS: 19 months Martin RCG, et al. Ann Surg Oncol 2011

21. DEBIRI-TACE vs FOLFIRI DEBIRI-TACE vs FOLFIRI after failure of at least 2 lines of chemotherapy DEBIRI-TACEFOLFIRI syst n3638 ORR70%20% PFS7.5 mo3.1 mo OS23 mo16 mo 2-year OS38%18% DEBIRI: 2 courses of TACE at 1 month intervals FOLFIRI:8 courses iv at 2-wk intervals Fiorentini G, et al. ESMO 2010; #588 see also Anticancer Res 2012

22. Radioembolization (SIRT) Yttrium-90 labelled microspheres –mean diameter 32 µm –beta 0.93 MeV –half life of activity: 2.7 days –mean tissue penetration 2.5 mm –radiation dose in tumor 100-1,000+ Gy –dose: 1.2-2.4 GBq (according to shunt)

23. SIRT + 5-FU vs 5-FU in mCRC Salvage Therapy SIRT + 5-FU vs 5-FU in mCRC Salvage Therapy TTP in the liver: primary endpoint Hendlisz A, et al. J Clin Oncol 2010

24. SIRT + Chemotherapy Lim L, et al. BMC Cancer 2005 Van Hazel et al. J Clin Oncol 2009 van Hazel 200421 SIRT + 5FU/FA 5FUFA 90% 0% 18.6 mo 3.6 mo 29.4 mo 12.8 mo Sharma 200720SIRT + FOLFOX490%9.3nr 1st line InvestigatornTreatmentORRTTP/PFSSurvival Lim 200530SIRT (+ 5FU) 70% 33%5.3 monr van Hazel 200925SIRT + irinotecan48%6.0 mo12.2 mo 2nd-line or 3rd line

25. Liver-dominant metastasis Tumor resectable? Resection 10–20% chemo-refractory? 1 st -line chemotherapy 2 nd -line chemotherapy n th -line chemotherapy <20% Integration of SIRT into the Algorithm of mCRC-Therapy Kennedy AS et al. ICACT 2008. + SIRT SIRT supportive therapy?

26. 1st-Line SIRT + FOLFOX: Randomised Study SIRFLOX Study – International, multicentre RCT (n=518) FOXFIRE Study – UK, multicentre RCT Planned combined analysis Recruit: non- resectable liver- dominant mCRC Stratification: extrahepatic metastasis extent of liver involvement bevacizumab use Institution RANDOMIZERANDOMIZE FOLFOXm (+Bev) FOLFOXm (+Bev) + SIRT SIRFLOX and FOXFIRE study design PFS = primary endpoint Bevacizumab not started unti cycle 4

27. SIRFLOX Trial Limited extrahepatic metastasis of the lung and/or lymph nodes –up to five small pulmonary metastases (<1cm) –one single pulmonary lesion (≤1.7cm) –involvement of lymph nodes in one single anatomic area (<2cm)

28. Conclusions Primary Surgery remains the standard in resectable disease Conversion chemotherapy is the treatment of choice in potentially resectable disease (group II) RFA may be an alternative to resection in pts with solitary small lesions Radiation is a promising approach, but requires more data Hepatic arterial treatment with DEB-TACE or SIRT represent options for salvage therapy in experienced centres

29. Diagnosis of mCRC Multidisciplinary tumor board (TB) R0-resection possible no contra- indications resection contra- indications RFA / RS R0-resection not likely conversion therapy TB resection not resectable, disseminated disease systemic chemotherapy multi-organ metastasis liver-dominant metastasis systemic chemotherapy resection RFA / RS SIRT DEB-TACE HAI Treatment algorithm for liver directed therapy intra-arterial salvage therapy