1. Interventional Oncology vs. Liver Tumors: What’s in the quiver?
Howard M. Richard, III, MD
1. Explain the various modalities utilized in the treatment of liver tumors2. Discuss the nature of clinical evidence for the various interventional oncology options for treating liver tumors3. Discuss the rationale for choosing between the various options based on the varied clinical presentations of liver tumors

2. Disclosures
None

3. Overview
Explain the various modalities utilized in the treatment of liver tumors
Discuss the nature of clinical evidence for the various interventional oncology options for treating liver tumors
Discuss the rationale for choosing between the various options based on the varied clinical presentations of liver tumors

4. History Liver resection for cure
Only 20% of patients are candidates for curative resection
Liver transplant
Scarcity of livers > up to 30% of candidates will have disease progression and fall off transplant list
Liver resection
Lobectomy, segmentectomy...

5. Resection for cure Milan criteria for liver transplantation
One lesion smaller than 5cm
Three lesions smaller than 3cm
No extra-hepatic disease
No vascular invasion
Partial liver resection
Functional liver remnant

6. Resection for cure
26% functional liver reserve for patients with normal liver function
40% high grade steatosis and after oxaliplatin- or irinotecan-based neoadjuvant chemotherapy
>50% of the total liver volume for cirrhotic
26.6% of the total functional liver volume in patients with normal liver parenchyma [2]. The safe margin increases to 40% in patients with high-grade steatosis and after oxaliplatin- or irinotecan-based neoadjuvant chemotherapy, and the safe margins are >50% of the total liver volume for cirrhotic livers [2, 3].

7. Pathology Primary Secondary Hepatocellular carcinoma
Colorectal liver (most common)
Neuroendocrine
Carcinoid
Breast, melanoma, etc...

8. Modalities Resection Resection after down-staging Palliative
Bridging treatment
Prior to OLT or hepatectomy
Resection after down-staging
Portal vein embolization
Palliative
Ablation
Embolization
Adjuvant medications

9. Resection for cure Extended resection Staged resection
Preoperative portal vein embolization to increase future remnant liver volume
Resection combined with tumor ablation

10. Portal vein embolization
Patients with marginal or insufficient functional liver reserve
Ipsilateral hepatic atrophy
Contralateral hepatic hypertrophy
In non cirrhotic patients % hypertrophy of contralateral lobe
Portal-vein embolizationIn some cases, the resection of one or more hepatic metastases is technically feasible, yet cannot be performed because the amount of liver tissue remaining after resection would be too small. To minimize the risk of postoperative hepatic insufficiency, ipsilateral hepatic atrophy and contralateral hepatic hypertrophy can be induced preoperatively by selective embolization of the hepatic portal vein, or else by ligation of the branch of the portal vein that leads to the hepatic lobe containing the metastasis. Portal-vein embolization should always be considered when the residual hepatic volume without it would be less than 30% of the normal size of the liver, and when at least two contiguous hepatic segments are free of metastases. For technical surgical reasons, the left lateral segments 2 and 3 are particularly suitable for this approach. As long as the liver is not cirrhotic, portal-vein embolization results in a 40% to 60% hypertrophy of the contralateral hepatic lobe. It remains unclear at present whether the stimulus to hypertrophy that portal-vein embolization provides might also accelerate the growth of tumor nodules (16, e35). In any case, the data regarding morbidity, mortality, and long-term survival are comparable to those of standard hepatic resections (16, e36– e39).

11. Portal vein embolization
Ipsilateral access into portal veins
Limits any iatrogenic damage to the eventually resected portion of the liver

12. Portal vein embolization
PVA
N-butyl cyanoacrylate
Fibrin glue/Lipiodol
Gelfoam and thrombin
Coils
Gentamycin
Ethanol
Nearly every commercially available embolic agent has been used for PVE, including N-butyl cyanoacrylate; fi- brin glue with Lipiodol; absolute ethanol; coils; and a mixture of Gelfoam, thrombin, contrast material, Lipiodol, and gentamicin with varying results.

13. Portal vein embolization
Can increase the size of the liver remnant %
More effective in enlarging the left lobe
Using Ethanol requires balloon occlusion

14. Ablation Thermal Chemical Irreversible Electroporation
RF, Laser, Microwave, HiFUS, Cryo
Chemical
Alcohol, acetic acid, other
Irreversible Electroporation

15. Ablation Thermal vs Non thermal Thermal Non thermal RFA is predominant
Laser, Microwave, HiFUS, and Cryo are much less popular
Non thermal
Ethanol is inexpensive
Proven inferior to RFA
IRE is emerging as an option

16. Embolization Bland Chemoinfusion Chemoembolization Radio embolization
Adjuvant medications

17. Bland embolization Concept of hepatic arterial embolization 1950s
Tumors derive 90% of blood from hepatic artery while portal vein provides majority of flow to liver
Goal is terminal arterial blockade
40 um particles optimally block tumor neo- vascular network

18. Bland embolization Fistulas allow systemic non-target embolization
Tumor ischemia > Hypoxia
Stimulation of angiogenesis
Up-regulate pro-angiogenic factors
Provide mechanism for resisting apoptosis
Associated with metastasis
Poor outcomes

19. Bland embolization Benefits Disadvantages Inexpensive Repeatable
Non target embolization of gallbladder, pancreatitis, liver failure
Liver abscess

20. Chemo infusion Infuse drug alone no embolization
Infuse chemotherapeutics with first pass hepatic metabolism
Maximize tumor exposure to drug
Minimize systemic toxicity

21. Chemo infusion
First premise > liver can clear the drug at first pass even at high dose
Second premise > increased drug concentration in liver leads to increased response
Third premise > regional drug delivery leads to decreased systemic exposure to drug

22. Chemo infusion Colorectal cancer
Floxuridine FUDR
Increase response rate when compared to systemic chemo
Usual referral is for patients who progress on traditional chemo
HCC no improvement in survival when compared to systemic chemo

23. Chemo embolization
Drugs and Gelfoam embolization introduced in the 1970s by Yamada
Currently defined as
Infusion of a mixture of chemotherapeutics with or without iodized oil followed by particle embolization
Purpose
Prevent washout of drug
Induce tumor ischemia

24. Chemo embolization Higher local drug concentrations
Lower systemic drug exposure
Compared to systemic treatment
Lipiodol is believed to increase intra-tumoral retention of the chemotherapeutics
Worldwide > single agent Doxyrubicin
US > Doxyrubicin, Cisplatin and Mitomycin C

25. Chemo embolization 2002 Lo and Llovet reported RCT vs HCC
Survival benefit for TX of HCC
When compared to standard supportive treatment
2006 Geschwind reported RCT vs CRC
Survival benefit for TX of CRC
Effective in generating tumor response
Neuroendocrine, breast, cholangiocarcinoma...

26. Chemo embolization 2009 Vogl retrospective TACE with
Mitomycin C vs Mitomycin C and Gemcitabine for neuroendocrine liver mets
Combination therapy
Improved local control
Improved five year survival

27. Chemo embolization Breast cancer mets to liver Sarcoma mets to liver
Local control can be established
Sarcoma mets to liver
Significant tumor necrosis
Improved survival

28. Drug eluting Beads Chemoembolization with special beads
Load PVA based beads with various types of chemo and deliver to hepatic artery
Once on location, beads release drug
Sustained and controlled release
Improve local delivery and minimize systemic exposure

29. Drug eluting beads DC beads Biocompatibles 100-300 Yellow 300-500 Blue
Red

30. Drug eluting beads Quadraspheres Biosphere/Meritt
Beads swell upon exposure to ionic fluids
Conforms to vessels
Studies as a bland agent
Can absorb Doxyrubicin

31. Drug eluting beads Doxyrubicin-capable or DC beads
Load with doxyrubicin 25mg/ml by immersion in drug solution for minutes.
Requires drug compounding in the pharmacy
DC beads have been loaded with Irinotecan for use against colorectal liver mets
Quadraspheres can be loaded with Doxyrubicin

32. Drug eluting beads Tumor response rates for DC beads vs HCC
10-20% total response
40-60% partial response rates
Irinotecan vs CRC mets
19 month overall survival in patients who had progressed on systemic chemo
Safe and effective
Expensive

33. Radio embolization

34. Yttrium-90 microsphere Glass sphere
Yttrium-89 is converted to Yttrium-90
Beta decay to Zirconium-90

35. 100 Gy HCC study Objectives:
Define activity of Yttrium-90 microspheres in previously untreated patients with HCC
Evaluate treatment response and survival of patients treated with Yttrium-90 microspheres
Survival benefit
Dancey, JE, Shepherd, FA, Paul, K, Sniderman, KW, Houle, S, Gabrys, J, Hendler, AL, & Goin, JE. Treatment of Nonresectable Hepatocellular Carcinoma with Intrahepatic 90 Y-Microspheres
J Nucl Med 2000; 41:

36. 100 Gy HCC study Survival of Patients Receiving TheraSphere
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
DAYS
> 104 Gy (N = 10)
Median Survival = 635 days
< 104
Gy (N = 10)
Median Survival = 323 days
Survival of Patients Receiving TheraSphere
By Liver Dose

37. TheraSphere®
Glass

38. SIR-Spheres Initially developed in 1990 35 micron spheres
Impregnated with yttrium-90 
Particles emit beta radiation
The original concepts underpinning the core technology which has been commercialised by SIRTeX Medical was initially developed by Dr Bruce Gray and the Cancer Research Institute Inc (CRI) and have been published in the scientific literature. The CRI is an independently incorporated research institute, founded in and has undertaken many research programs investigating cancer over the past decade.
Resin

39. SIR Sphere Characteristics
35 μm
100% ß emitter
MeV
Half-life of 64.2 h
2.5 mm av (max 11)
Glass/Ceramic matrix
SIR-Spheres® is a therapeutic radioactive implant, comprised of beta-emitting yttrium-90 microspheres. The microspheres are approximately 35 microns. The average penetration of the beta particles in tissue is 2.4 mm. The microspheres are suspended in sterile, pyrogen-free water for injection. The vials are shipped in lead shields for radiation protection.

40. SIR-Spheres Selective Internal Radiation
Particles lodge in capillaries of tumor
Size and number of tumors does not matter

41. SIR-Spheres 90Y-microspheres do not undergo any biologic degradation
Activity decays to infinity at a mean life of d
Beta particle decay
average range in tissue is 2.5 mm
with a maximum range of < 11mm
RADIATION DOSIMETRY90Y, a pure beta emitter, decays to stable zirconium 90 with a physical half-life of 64.2 hours (2.68 days). The average energy of the beta emissions from 90Y is MeV. The average range of the radiation in tissue is 2.5 mm, with a maximum range of less than 1 cm. A 1-GBq (27-mCi) dose of 90Y per kilogram of tissue gives an initial radiation dose of 13 Gy (1,297 rad) per day. The mean life of 90Y is 3.85 days. Thus, the radiation dose delivered by 90Y over complete radioactive decay starting at an activity level of 1 GBq (27 mCi) per kilogram of tissue is 50 Gy (5,000 rad).

42. Trans-Arterial Hepatic LDR Brachytherapy
TARGETED DELIVERY
LETHALITY

43. Radioembolization Response rate 90% *
Falling tumor markers and serial 3-monthly CT scans
HCC can be down-staged to OLT, resection or ablation
Increased survival, tumor response time and time to progression when compared to 5-FU vs CRC
Hepatogastroenterology Mar-Apr;48(38): Related Articles, Links
Selective internal radiation therapy (SIRT) with 90Yttrium microspheres for extensive colorectal liver metastases. Stubbs RS, Cannan RJ, Mitchell AW. Wakefield Clinic for Gastrointestinal Diseases, Private Bag 7909, Wellington, New Zealand. BACKGROUND/AIMS: SIRT (selective internal radiation therapy) is a new modality for the treatment of nonresectable liver tumors which has been reported to achieve high response rates. We report our initial experience in patients with extensive colorectal liver metastases. METHODOLOGY: Thirty-eight (38) patients were treated with SIRT between February 1997 and November Liver involvement was < 25% in 19 patients, 25-50% in 9 and > 50% in 10. Patients received 90Yttrium microspheres into the hepatic artery via an arterial port and subsequent 4-weekly cycles of hepatic artery chemotherapy with 5-fluorouracil. RESULTS: SIRT was well tolerated and no treatment-related mortality was observed. Responses to SIRT as indicated by falling tumor markers and serial 3-monthly computed tomography scans were seen in over 90% of patients. Estimated survival at 6, 12 and 18 months was 70%, 46% and 46%, respectively, and was principally determined by the development of extrahepatic metastases. CONCLUSIONS: SIRT is well tolerated in patients with extensive colorectal liver metastases and achieves encouraging liver tumor responses, which are well maintained by hepatic artery chemotherapy. The modality warrants wider use and investigation.
* Hepatogastroenterology Mar-Apr;48(38):333-7.

44. Dose Distribution and Effect
MAA
PET After TheraSphere®
PET Before TheraSphere®

45. Adjuvant chemotherapy
Sorafenib (Nexavar, Bayer)
MultiKinase inhibitor (anti VEGF)
Can be used to decrease intratumoral arteriovenous fistulas and enable SIR
Bevacizumab (Avastin, Genentech)
Monoclonal antibody to vascular endothelial growth factor
Augments efficacy of TACE vs HCC

46. Discussion Radioembolization vs HCC Radioembolization vs CRC
Treatment can down stage patients to become eligible for transplant, resection or ablation
Radioembolization vs CRC
Compared to hepatic artery chemotherapy
Decreased time to progression
Increased survival
Radioembolization vs neuroendocrine
Increased survival compared to systemic treatment

47. Discussion Lo and llovet RCT for HCC DEB vs embolization
Chemoembolization is superior to best supportive care
DEB vs embolization
DEB is superior to bland embolization
Longer time to progression

48. Discussion DEB vs chemoembolization
DEB higher rate of response
DEB fewer adverse events
DEB has yet to show a survival benefit
Radioembolization vs Chemoembolization
SIR better at downstaging HCC
SIR less toxicity
SIR has yet to show survival benefit

49. Discussion
Surgery compared to embolization and ablation for HCC up to 7cm
Five year survival 56 to 54%
Chemoembolization vs CE and ablation for HCC 3-5cm
CE & RFA is more effective
Radio embolization & 5-FU vs 5-FU for CRC
SIR & 5-FU is well tolerated, improved time to progression

50. Conclusions
Ablation with RFA is choice for small tumors when surgery or transplantation is not feasible
IRE is a choice when ablation target is adjacent to large vessels (Heat Sink) or central bile ducts
Ethanol or cryoablation can be used if target is in sensitive location ie. Near the dome of the diaphragm or heart

51. Conclusions
Chemoembolization is standard for intermediate/ advanced unresectable HCC
CE can help select patients for OLT (bridge)
Combination of CE and Ablation is effective with limited toxicity
Drug eluting bead will replace oil based chemoembolization

52. Conclusions Y-90 is safe and effective as outpatient TX Y-90 for HCC
Downstaging / bridging to transplantation or resection
Portal vein thrombosis
Advanced disease

53. Decisions decisions Milan criteria for resection Few lesions
If close consider portal vein embolization, CE, SIR
Few lesions
Ablation
Moderate disease CE
Extensive disease
SIR