1. Role of Interventional Radiology in a Gastrointestinal Tumor Service
Anastasia Balius, MD
Interventional Radiology
UTMCK
October 23, 2011

2. Hepatocellular Carcinoma
Approximately 24,120 persons diagnosed with liver or intrahepatic bile duct cancer in the US in 20101
18,910 deaths from those cancers during that year1
Incidence has risen significantly in developed countries in the past two decades2
Increased prevalence of hepatitis B and C
1American Cancer Society. Statistics last revised 7/7/10
2Ince N, Wands JR. The increasing incidence of heaptocellular carcinoma. N Engl J Med 1999;340: .

3. Risk Factors Same as those for Cirrhosis Hepatitis B/C
Inherited errors of metabolism
Autoimmune hepatits
Non -alcoholic steatohepatitis [NASH]
Excessive alcohol intake
Environmental exposure to aflatoxin 3

4. Hepatocellular Carcinoma (HCC)
With definitive treatment 5 year survival is over 50%1
For all stages combined, 5 year survival is approximately 10%1
Only 10-15% of patients are candidates for curative therapy2,3
Surgical resection or transplant
1American Cancer Society. Statistics last revised 8/16/10
2Llovet JM. Treatment of hepatocellular carcinoma. Curr Treat Options Gastroenterol. 2004;7:
3Kanematsu T, Furui J, Yanaga K, et al. A 16-year experience in performing hepatic resection in 303 patients with hepatocellular carcinoma. J Vasc Interv Radiol 1995; 6:71–74.

5. Metastatic Colorectal Cancer (mCRC)
5 year survival for stage IV colorectal cancer is 6%1
Liver is most frequent site of metastases
Approximately 60% of patients with mCRC will eventually have liver as predominant site of disease2
Surgical resection is treatment of choice
5 year survival rates after resection >50%3,4
Feasible in <20% of patients2
1American Cancer Society. Statistics last revised 3/2/2011
2Sasson AR, Sigurdson ER. Surgical treatment of liver metastases. Semin Oncol. 2002;29:
3Choti MA, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002;235:
4Pawlik TM, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg. 2005;241: , discussion

6. NCCN Categories of evidence
Category 1: The recommendation is based on high-level evidence (eg randomized controlled trials) and there is uniform NCCN consensus
Category 2A: The recommendation is based on lower- level evidence and there is uniform NCCN consensus
Category 2B: The recommendation is based on lower- level evidence and there is non uniform NCCN consensus (but no major disagreement)
Category 3: The recommendation is based on any level of evidence but reflects major disagreement
All recommendations are Category 2A unless otherwise noted

7. Treatment of HCC HCC confirmed
Potentially resectable or transplantable, operable by performace status or comorbidity
HCC
confirmed
Multidisciplinary Evaluation
H+P
Hepatitis Panel
Bilirubin, transaminases, alk phos, LDH
PT /INR, albumin, protein, BUN, Cr
CBC, platelets
AFP
Chest imaging
Bone scan as indicated
Metastatic disease
Inoperable by performance status or comorbidity, local disease only
Unresectable

8. Treatment of HCC
For patients with an estimated FLR/total liver volume ratio below recommended values who are otherwise suitable candidates for liver resection, pre-operative portal vein embolization (PVE) should be considered
NCCN Practice Guidelines in Oncology – v , Hepatobiliary Cancers.

9. Treatment of HCC Clinical presentation Surgical Assessment Treatment
Child’s A, B
No portal hypertension
Suitable tumor location
Adequate liver reserve
Suitable liver remnant
Resection, if feasible (preferred)
or locoregional
therapy
Potentially resectable or transplantable
UNOS criteria
Patient has a tumor <5 cm in dm or 2-3 tumors < 3 cm each
No macrovascular involvement
No extrahepatic disease
These patients may be resected if transplantation not feasible
Liver Transplant

10. Child-Pugh Score
Clinical/Biochemical Parameters
Points for Increasing Abnormality 1 2 3
Encephalopathy (grade)
None
1-2
3-4
Ascites
Slight
Moderate
Albumin (g/dL)
>3.5
<2.8
Prothrombin time
Prolonged (sec)
1-4
4-6
>6
Bilirubin (mg/dL)
- for primary biliary
cirrhosis
2-3
4-10
>3
>10
Class A = 5-6 points; Class B = 7 -9 points; Class C = points

11. Treatment of HCC Clinical Presentation Treatment Options:
Sorafenib (Child-Pugh Class A [Category 1] or B)
Clinical Trial
Locoregional Therapy
RT (conformal or sterotactic) (category 2B)
Supportive Care
Inoperable by performance status or comorbity, local disease only
Sorafenib (Child-Pugh Class A [Category 1] or B) Or
Supportive Care
Clinical trial
Metastatic disease

12. Locoregional Therapy Ablation Embolization
Tumor and margin of normal tissue should be treated
Tumors < 3 cm; lesions between 3-5 cm should be treated in combination with embolization
Arterial blood supply to the tumor must be able to be isolated without non-target embolization
Relatively contraindicated with bilirubin >3 mg/dL
Contraindicated with main PV thrombosis (relative) or Child-Pugh Class C (absolute)

13. Treatment of HCC Inadequate hepatic reserve Transplant
Tumor location
Transplant
Meets UNOS criteria?
Not a transplant candidate
Unresectable
Options:
Sorafenib (Child-Pugh Class A [Category 1] or B)
Chemotherapy + RT only in the context of a clinical trial
Clinical trial
Locoregional therapy
RT (conformal or sterotactic) (category 2B)
Supportive care
Systemic or intra-arterial chemotherapy in clinical trial
Extensive liver tumor burden

14. Treatment of mCRC
When hepatic disease is not optimally resectable based on insufficient remnant liver volume, approaches utilizing preoperative portal vein embolization1 or staged liver resection can be considered
NCCN Practice Guidelines in Oncology – v , Colon Cancer
1Covey AM, et al. Combined portal vein embolization and neoadjuvant chemotherapy as a treatment strategy for resectable hepatic colorectal metastases. Ann Surg Mar;247(3):451-5.

15. Treatment of mCRC
Ablative techniques may be considered alone or in conjuction with resection. All original sites of disease need to be amenable to ablation or resection.
Some institutions use arterially directed embolic therapy in highly select patients with chemotherapy resistant/refractory disease without obvious systemic disease, with predominent hepatic metastases (category 3)

16. Interventional Radiology’s Role
Supportive procedures for the oncology patient
Determination of disease
Facilitation of definitive surgical treatment
Treatment of non-surgical candidates

18. Determination of Disease
AFP and ultrasound are used as screening for HCC
Additional imaging is indicated in the setting of a rising serum AFP or identification of a liver mass nodule on US

19. Determination of Disease
Three different modalities
Triphasic helical CT
Triphasic dynamic contrast enhanced MRI
Contrast enhanced U/S

20. Determination of Disease
Nodules 1 to 2 cm in size need to demonstrate classic arterial enhancement with two different diagnostic techniques
Nodules > 2 cm need demonstrate classic arterial enhancement with only one diagnostic technique
Nodules < 1 cm should be re-evaluated every 3 to 4 months until fit into a size criteria
If nodules are non-diagnostic on imaging, tissue sampling is needed

21. Facilitation of Definitive Surgical Treatment
Portal Vein Embolization Transplant “Bridge”

22. Portal Vein Embolization (PVE)
In primary or secondary hepatic malignancy, extended hepatectomies provide a chance of cure1
Morbidity and mortality of such procedures are considerable2
Volume and function of the liver remnant is a major risk factor for perioperative complications3,4
1Vauthey JN, et al. Is extended hepatectomy for hepatobiliary malignancy justified? Annals of Surgery May; 239(5):722-30; discussion 30-2
2Jarnagin WR, et al. Improvement in perioperative outcome after hepatic resection: analysis of 1,803 consecutive cases over the past decade. Annals of Surgery Oct;236(4): ; discussion-7..
3Abdalla EK, et al. Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg Jun:137(6):675-80; discussion 80-1
4Vauthey JN, et al. Standardized measurement of the future liver remnant prior to extended liver resection: methodology and clinical associations. Surgery May;127(5):512-9

23. Portal Vein Embolization
PVE induces hypertrophy in the non- embolized liver segments
Increase in volume and function of future liver remnant (FLR)
Decreases risk of post-operative hepatic insufficiency
Abdalla EK, et al. Portal vein embolization: rationale, technique and future prospects. The British Journal of Surgery Feb;88(2):165-75
Makuuchi M, et al. Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery May;107(5):521-7

24. PVE Normal underlying liver1 Chemotherapy induced liver injury2
FLR should be 20-25% of total liver volume (TLV)
Chemotherapy induced liver injury2
FLR should be >30% of TLV
Chronic liver disease (cirrhosis or severe fibrosis)2
FLR should be >40%
1Abdalla EK, et al. Extended hepatectomy in patients with hepatobiliary malignancies with and without preoperative portal vein embolization. Arch Surg Jun;137(6):675-80; discussion 80-1.
2Azoulay D, et al. Percutaneous portal vein embolization increases the feasibility and safety of major liver resection for hepatocellular carcinoma in injured liver. Annals of Surgery Nov;232(5):

25. PVE Contraindications
Extrahepatic metastases
Overt portal hypertension
Tumor invasion of the portal vein
Tumor invasion of the FLR
Biliary obstruction
Renal insufficiency
Uncorrectable coagulopathy

26. Couinaud Classificiation

27. Hepatic Anatomy

28. Hepatic Anatomy

29. PVE Performed under conscious sedation 2 standard approaches
Percutaneous ipsilateral
Percutaneous contralateral
Wide array of embolic agents
Coils, amplatzer plugs
Particles
Absolute alcohol
Fibrin glue
N-BCA (n-butyl cyanoacrylate)

32. Complications Bleeding (0.2 – 1/6%)
Pneumothorax
Sepsis
Liver abscess (0.3%)
Portal hypertension resulting in esophageal variceal hemorrhage
Migration of embolic material ( %)
Portal vein thrombosis of FLR (<1%)
Portal vein dissection
Intraparenchymal injury
Transient liver failure (3.2%)
Di Stefano DR, et al. Preoperative percutaneous portal vein embolization: evaluation of adverse events in 188 patients. Radiology Jul;188(1):73-7
Kodama Y, et al. Complications of percutaneous transhepatic portal vein embolization. J Vasc Interv Radiol Dec;13(12):1233-7

33. Outcomes Average expected growth of FLR = 8-27%1
75% of growth occurs in first 3 weeks post- PVE2
Failure to hypertrophy >5% following PVE is associated with a significantly higher risk of major complications, hepatic insufficiency, and increased 90-day mortality2
1Abulkhir A, et al. Preoperative portal vein embolization for major liver resection: a meta-analysis. Ann Surg Jan;247(1):49-57
2Ribero D, et al. Portal vein embolization before major hepatectomy and its effects on regeneration, resectability, and outcome. The British Journal of Surgery Nov;94(11):

34. Facilitation of Definitive Surgical Treatment
Locoregional treatment of HCC as a “bridge” to liver transplantation1,2
Radiofrequency ablation3,4
Chemoembolization5
Radioembolization
1Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:
2Llover JM, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:
3Pompili M, et al. Percutaneous ablation procedures in cirrhotic patients with hepatocellular carcinoma submitted for liver transplantation: assessment of efficacy at explant analysis and of safety for tumor recurrence. Liver Transpl. 2005;11:
4Mazzaferro V, et al. Radiofrequency ablation of small hepatocellular carcinoma in cirrhotic patients awaiting liver transplantation: a prospective study. Ann Surg. 2004;240:
5Richard HM, 3rd, et al. Hepatic arterial complications in liver transplant recipients treated with pretransplantation chemoembolization for hepatocellular carcinoma. Radiology. 2000;214:

35. Treatment of Nonsurgical Candidates
Ablative techniques
Radiofrequency ablation
Microwave ablation
Alcohol ablation
Arterial embolization
Trans-arterial embolization (TAE)
Trans-arterial chemoembolization (TACE)
Trans-arterial radioembolization or Selective Internal Radiation Therapy (SIRT)
Combination therapy

36. Patient Work-up Laboratory studies Cross-sectional imaging (CT/MRI)
CBC, Chem 7, PT/PTT, liver function tests, tumor markers
Cross-sectional imaging (CT/MRI)
Childs class
Performance status
ECOG/Karnofsky
Staging
Consent with emphasis on palliation and management of expectations

37. Alcohol versus RFA
RFA was shown to be superior to PEI with respect to complete response rate1
RFA demostrated a lower rate of recurrence2,3
Overall survival higher for RFA2,3
Fewer treatment sessions for RFA3
1Brunello F, et al. Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: A randomized controlled trial. Scand J Gastroenterol. 2008;43:
2Lin SM, et al. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma <4 cm. Gastroenterology. 2004;127:
3Shiina S, et al. A randomized controlled trial of radiofrequency ablation with ethanol injection for small hepatocellular carcinoma. Gastroenterology. 2005;129:

38. RFA vs. Ethanol Injection
Survival rate
Author
Treatment
Complete Resonse
2-yr local progression
2 yr
3 yr P
Lencioni , 20031
PEI (n=50)
82%
38%*
88% NA
RFA (n=52)
95%
4%*
96% NS
Lin, 20042
PEI, low dose (n=52)
45%
61%
50%
PEI, high dose (n=52)
92%
33%
63%
55%
18%
74%
<.05
Shiina, 20053
PEI (n=114)
100%
11%
RFA (n=118) 2%
90%
80%
1Lencioni R, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radiofrequency ablation versus percutaneous ethanol injection. Radiology 2003;228:
2Lin SM, et al. Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma < or = 4 cm. Gastroenterology 2004;127:
3Shiina S, et al. A randomized controlled trial of radiofrequency ablation versus ethanol injection for small hepatocellular carcinoma. Gastroenterology. 2005;129:

39. Local recurrence rates for HCC
More recent study found <3% of patients with single HCC tumor < 2 cm had recurrent disease at 31 months after repeated application of RFA1
1Livraghi T, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice? Hepatology. 2008;47:82-89. 18

40. Long-Term Survival Survival Rate (%) Author and Year
Patient Characteristics
Pt #
1 yr
3 yr
5 yr
Lencioni, 2005
Child A, 1 HCC <5cm or 3 <3cm
144
100 76 51
Child A, 1 HCC <5 cm
116 89 61
Child B, 1 HCC <5 cm or 3 <3 cm 43 46 31
Tateishi, 2005
Naive patients
319 95 78 54
Non-naïve patients
345 92 62 38
Cabassa, 2006 59 94 65
Choi, 2007
Child A, 1 HCC <5cm or 3 <3 cm
359 NA 64
Child B, 1 HCC <5cm or 3 <3 cm
160 49
Lencioni R, et al. Early-stage hepatocellular carcinoma in cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology 2005;234:
Tateishi R, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma. Cancer 2005;103:
Cabassa P, et al. Radiofrequency ablation of hepatocellular carcinoma: long-term experience with expandable needle electrodes. AJR 2006;185:S
Choi D, et al. Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment: long-term results and prognostic factors in a large singe-institution series. Eur Radiol 2007;17:

41. Radiofrequency Ablation vs. Resection
RFA compared to liver resection in a prospective randomized controlled study
Patients with solitary HCC <5 cm in dm
No differences in recurrence-free survival or overall survival were found when treatment arms were compared.
Chen MS, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg. 2006;243:

42. Microwave Ablation
In moderately or poorly differentiated HCC, overall survival was significantly better than with PEI1
In study of 234 pts, 3 yr and 5 yr survival rates were 73% and 57%2
In the one randomized trial comparing microwave and radiofrequency ablation, no statistically significant differences were observed in the efficacy of the two techniques3
1Seki T, et al. Percutaneous microwave coagulation therapy for patients with small hepatocellular carcinoma: comparison with percutaneous ethanol therapy. Cancer 1999;85:
2Dong B, et al. Percutaneous sonographically guided microwave coagulation therapy for hepatocellular carcinoma: results in 234 patients. AJR 2003;180:
3Shibata T, et al. Small hepatocellular carcinoma: comparison of radio-frequency ablation and percutaneous microwave coagulation therapy. Radiology 2002;223:

43. RFA for mCRC Author Patients Metastases Size (cm) Local contol
Survival
Solbiati
117
179 ;
61%
3 yr: 46%
Gillams 20042
167
354
1-12; mean, 3.9
74.9%
5 yr: 26%
Jakobs 20063 68
183
; mean, 2.2
82%
3 yr: 68%
Lencioni 20054
423
543
; mean 2.7
85.4%
3 yr: 47%
5 yr: 24%
Sorensen 20075
102
332
3 yr: 64%
5 yr: 44%
1Solbiati L, et al. Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: long-term results in 117 patients. Radiology 2001 Oct;221(1):
2Gillams AR, Lees WR. Radio-frequency ablation of colorectal metastases in 167 patients. Eur Radiol 2004;14:
3Jakobs TF, et al. Radiofrequency ablation of colorectal liver metastases: mid-term results in 68 patients. Anti-cancer Res 2006;26:
4Lencioni R, et al. Percutaneous radiofrequency ablation of hepatic colorectal metastases: technique, indications, results and new promises. Invest Radiol 2004;39:
5Sorensen SM, et al. Radiofrequency ablation of colorectal liver metastases: long-term survival. Acta Radiol 2007;48:

44. RFA versus resection of mCRC
A number of retrospective studies have compared RFA and liver resection in the tx of liver mets1-3, although RFA has not been well studied in this setting
In retrospective studies comparing RFA and liver resection in liver mets RFA has been inferior to resection with respect to rates of local recurrence and 5-year overall survival4
Patient selection bias, technological limitations of RFA or both?2
1Hur H, et al. Comparative study of resection and radiofrequency ablation in the treatment of solitary colorectal liver metastases. Amer J Surg. 2009;197:
2Gleisner AL, et al. Colorectal liver metastases: recurrence and survival following hepatic resection, radiofrequency ablation, and combined resection-radiofrequency ablation. Arch Surg. 2008;143:
3Reuter NP, et al. Radiofrequency ablation vs. resection for hepatic colorectal metastasis: therapeutically equivalent? J Gastrointest Surg. 2009;13:
4Abdalla EK. Commentary: Radiofrequency ablation for colorectal liver metastases: do not blame the biology when it is the technology. Amer J Surg. 2009;197:

45. Radiofrequency Ablation
Electrode probes deliver an alternating high-frequency electrical current (460 to 500 kHz)
Ion agitation is converted by friction into heat
Tissue temperature is increased
Cellular death occurs via thermal coagulation necrosis

46. Technique Re-identify lesion under CT or US
Choose appropriate access site
Plan approach
Place probes
12 to 16 minute ablation
Tract ablation

47. Considerations “Heat sink” effects Compromised sphincter of Oddi
Levaquin and flagyl prep
Adjacent structures
Diaphragm
Abdominal wall
Capsule
Bowel
Size

48. Development of Ablated Region
After 24 to 48 hours, necrotic lesion forms reaching maximum size by 7 days
Ablated lesion may exhibit an increase in size up to 3 months post ablation1
Ablated tissue will be replaced by scar or reabsorbed
Treated area will not enhance on follow up imaging2
Most residual viable tumor is evident at 1-3 months after ablation3
1McDougal WS, et al; J Urol 2005; 174:61-63
2Kawamoto, et al; Radiographics 2007; 27:
3Gervais, et al; AJR 2005; 185:64-71

49. Complications Hemorrhage1 Pneumo/Hydrothorax Abscess Sepsis
Hemoperitoneum
Hemothorax
Hemobilia
Pneumo/Hydrothorax
Abscess
Sepsis
Liver Failure2
Tumor seeding
Skin Burn
Damage to surrounding structures
Pain in a dermatomal/ diaphragmatic distribution
Post ablation syndrome
1Goto E et al. J Clin Gastroenterol 2009 Oct 3 [Epub ahead of print}
2Kong WT, et al. World J Gastroenterol 2009 Jun 7; 15(21):2651-6 11

50. Complication Rate Mortality rate ranges from 0.1% to 0.5%
Most common causes of death were sepsis and hepatic failure
Major complication rate ranges from 2.2% to 3.1%
Minor complication rate ranges from 5% to 8.9%
Most common complications were intraperitoneal bleeding, hepatic abscess, bile duct injury, hepatic decompensation, and grounding pad burns
Rhim H. Complications of radiofrequency ablation in hepatocellular carcinoma. Abdom Imaging 2005 Jul-Aug; 30 (4):
Livraghi T, et al. Treatment of focal liver tumors with percutaneous radiofrequency ablation: complications encountered in a multicenter study. Radiology 2003;26:
De Baere T, et al. Adverse events during radiofrequency treatment of 582 hepatic tumors. AJR 2003;181:
Bleicher RJ, et al. Radiofrequency ablation in 447 complex unresectable liver tumors: lessions learned. Ann Surg Oncol 2003;10:52-58. 12

51. Tumor seeding Uncommon late complication
Subcapsular location and poor degree of differentiation seem to be at a higher risk1
Incidence of 0.5% in HCC patients in both a multicenter and single institution series2,3
Tract ablation used routinely to prevent
1Llovet JM, et al. Barcelona Clinic Liver Cancer (BCLC) Group. Increased risk of tumor seeding after percutaneous radiofrequency ablation for single hepatocellular carcinoma. Hepatology 2001;33:
2Livraghi T, et al. Treatment of focal liver tumors with percutaneous radiofrequency ablation: complications encountered in a multicenter study. Radiology 2003;26:
3Lencioni R, et al. Early-stage hepatocellular carcinoma in cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology 2005;234:

52. Post RFA Syndrome Analagous to post embolization syndrome
Defined as low grade fever and flu-like symptoms within the first hours lasting approximately one week
Fever usually peaks on day 3
Flu-like symptoms peak on day 5 14

53. Wah, et al; Radiology 2005; 237:1097-1102
Post RFA Syndrome
Incidence of 37% in liver ablation
95% of patients had symptoms but not complete syndrome
Size of treated lesion doesn’t correlate with incidence or severity
Number of ablations (>3) correlates with increased symptoms
Wah, et al; Radiology 2005; 237: 15

54. Overall RFA Complication Rates
Tissue
# patients
Complications
Mortality rates
Liver
2300 [1]
382 [2]
2.2% 8%
0.3%
0.1%
Kidney
54 sessions [3] 7% 0%
Bone
43 [4]
Lung
26 [5]
10%
1. Livraghi T et al. Treatment of Focal Liver Tumors with Percutaneous Radiofrequency Ablation: complications encountered in a multicenter study. Radiology 2003; 226:
2. Curley S et al. Early and late Complications after Radiofrequency Ablation of malignant Liver Tumors in 608 Patients. Annals of Surgery, Vol 239, No4 April 2004
3. Gervais DA et al, renal Cell Carcinoma: Clinical Experience and Technical Success with Radio-frequency Ablation of 42 tumors. Vascular and Interventional Radiology
4. Goetz et al. Percutaneous image-guided radiofrequency ablation of painful metastases involving bone: a multi center study. J Clin Oncol Jan 15;22 (2):300-6
5. Lee et al. Percutaneous Radiofrequency Ablation for inoperable NSC Lung Cancer and matastases: Preliminary report. Radiology, January 2004

55. Follow-up imaging
Post ablation hypoattenuation is greater than original lesion initially, then a decrease in size will be seen
HCC
mCRC
Contrasted CT or MRI in 1 month to detect new lesions
CT/MRI every 3 months with tumor markers
PET may be useful in detecting residual tumor or relapse1,2,3
Contrasted CT or MRI in 1 month
CT/MRI every 3 months until one year
Enhancement in HCC pt = residual disease/recurrence
1Akhurst T, et al. Positron emission tomography imaging of colorectal cancer. Semin Oncol 1999;26:
2Fong Y, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230:
3Anderson GS, et al. FCG positron emission tomography in the surveillance of hepatic tumors treated with radiofrequency ablation. Clin Nucl Med 2003;28*:

56. Intra-arterial therapy HCC
The panel recommends that patients with unresectable/inoperable disease who are eligible to undergo embolization therapy and have tumor lesions > 5 cm should be treated using arterial embolic approaches (chemoembolization, bland embolization, radioembolization)
Those patients with lesions 3-5 cm can be considered for combination therapy with ablation and arterial embolization
NCCN Practice Guidelines in Oncology – v , Hepatobiliary Cancers

57. Intra-arterial Therapy mCRC
Arterially-directed embolic therapy is considered category 3
Specifically, highly select patients with chemotherapy resistant/refractory disease, without obvious systemic disease, with predominant hepatic metastases
Radioembolization with yttrium-90 microspheres is the only technique specifically mentioned
NCCN Practice Guidelines in Oncology – v , Colon Cancer

58. Intra-arterial Therapy Options
At this point, institution and physician preference determines technique(s) preferred

59. Catheter is placed via a transfemoral approach with tip within the selected hepatic artery

60. Tumors receive 80- 100% of their blood supply from hepatic artery
Intra-arterial administration exploits the dual blood supply of the liver
Tumors receive % of their blood supply from hepatic artery
Normal liver receives > 75% of its blood supply from portal vein
Breedis C, Young G. The blood supply of neoplasms in the liver. Am J Pathol. 1954;30:

61. Bland Embolization of HCC
Retrospective analysis
1-, 2-, and 3-year survival rates of 66%, 46%, and 33% were observed
Survival rates increased to 84%, 66% and 51% when only the subgroup of patients w/o extrahepatic spread or portal vein involvement by tumor was considered1
1Maluccio MA, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2008;19:

62. Bland Embolization of HCC
Predictors of poor prognosis on multivariate analysis
Tumor size >5 cm
5 or more tumors
Extrahepatic disease
Portal vein occlusion was not found to be an independent predictor of survival
Maluccio MA, et al. Transcatheter arterial embolization with only particles for the treatment of unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2008;19:

63. Bland vs. Chemo-embolization of HCC
Only one study directly comparing the two therapies
Pt randomized to TAE, TACE, supportive care
This was stopped early when a demonstrable benefit was shown between chemoembolization and supportive care arms
Due to early termination, lack of power to detect a difference in TACE and TAE
Llovet JM, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomixed controlled trial. Lancet 2002;359((9319):

64. Chemoembolization of HCC
Barcelona Multicenter Study1
Hong Kong (Single Center) Study2
112 patients with unresectable HCC
85% had hepatitis C
Randomized to blandembolization, chemoembolizaiton, or conservative management
Primary endpoint was survival
80 patients with unresectable HCC
80% had hepatitis B
Randomized to chemoembolization or conservative management
Primary endpoint was survival
1Llovet JM, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomixed controlled trial. Lancet 2002;359((9319):
2Lo CM, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35(5):

65. Chemoembolization of HCC
Barcelona Study
Hong Kong Study
Survival in CE group
1 yr = 82%
2 yr = 63%
Survival in bland embolization group
1 yr = 75%
2 yr = 50%
Survival in conservative therapy group
1 yr = 63%
2 yr = 27%
Survival in CE group
1 yr = 57%
2 yr = 31%
Survival in conservative therapy group
1 yr = 32%
2 yr = 11%

66. Chemoembolization of HCC
In both studies, patients in the chemoembolization group were half as likely to die during the trial than patients in the conservative therapy group
For the Barcelona study:
OR = 0.45
95% CI 0.25 – 0.81
For the Hong Kong study:
OR = 0.5
95% CI 0.31 – 0.81

67. Chemoembolization of HCC
Survival rates in both the CE and control groups were lower in the Hong Kong study than in the Barcelona study
Higher proportion of Okunda stage II disease
Patients with portal vein invasion not excluded

68. Chemoembolization of HCC
Only independent predictor of survival was treatment allocation1
Benefit of chemoembolization was independent of tumor size, stage or presenting symptom2
When portal vein invasion present, however, no benefit to chemoembolization seen
1Llovet JM, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomixed controlled trial. Lancet 2002;359((9319):
2Lo CM, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002;35(5):

69. Bland/Chemo-embolization of mCRC
Randomized study comparing TAE with TACE demonstrated no advantage of one technique over the other
Salman HS, et al. Randomized phase II trial of embolization therapy versus chemoembolization therapy in previously treated patients with colorectal carcinoma metastatic to the liver. Clin Colorectal Cancer 2002;2:

70. Drug eluting beads in HCC
Objective response rate by imaging (EASL criteria) ranged from 60 to 90%1,2
Survival rates appear improved over those with conventional TACE3
93% at 6 months to 89% at 2 years1,2
Significantly lower serum levels of chemotherapy drug4
1Kettenbach J, et al. Drug-loaded microspheres for the treatment of liver cancer: review of current results. Cardiovasc Intervent Radiol 2008;31:
2Malagari K, et al. Transarterial chemoembolization of unresectable heptaocellular carcinoma with drug eluting beads: Results of an open-label study of 62 patients. Cardiovasc Intervent Radiol 2008;31:
3Dhanasekaran R, et al. Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC) J. Surg. Oncol. 2010; 101:
4Varela M, et al. Chemoembolization of Hepatocellular carcinoma with drug eluting beads: Efficacy and doxorubicin pharmcokinetics. J Hepatol 2007;46:

72. DEB for mCRC
In study of 55 patients, survival rate of 78% at 18 months1
Patients thought to have less side effects from the beads than from traditional TACE
Easier to infuse
More study is needed
1Martin RCG, et al. Transarterial chemoembolisation (TACE) using irinotecan-loaded beads for the treatment of unresectable metastases to the liver in patients with colorectal cancer: an interim report. World Journal of Surgical Oncology 2009, 7:80

73. Chemoembolization Pt Selection
Is patient eligible for hepatic resection?
Is patient eligible for ablation?
Liver dominant disease
Hepatocellular carcinoma
Metastatic colorectal carcinoma
Intrahepatic cholangiocarcinoma
Metastatic neuroendocrine tumors
Rarely, ocular melanoma, sarcoma, pancreas, breast, lung

74. Chemoembolization Work-up
Cross-sectional imaging (MR/CT)
Assessment of performance status (ECOG or Karnofsky)
Childs class
Tumor stage
Laboratory studies (CBC, Chem 7, PT/PTT, liver function tests, tumor markers)

75. Relative Contraindications
Biliary obstruction
High risk of infection of obstructed segments1
Without intact sphincter of Oddi
Increased risk of abscess2
Portal vein occlusion
Liver infarction
Elevated bilirubin
Liver failure
11Song SY, et al. Liver abscess after transcatheter oily chemoembolization for hepatic tumors: incidence, predisposing factors and clinical outcome. J Vasc Interv Radiol 2001;12:
2Kim W, Clark TWI, Baum RA, et al. Risk factors for liver abscess formation after hepatic chemoembolization. J Vasc Interv Radiol 2001; 12:965–968. .

76. Relative Contraindications
Biliary obstruction
Percutaneous catheter drainage1
Without intact sphincter of Oddi
Night before bowel prep and prophylactic antibiotics2
Portal vein occlusion
Segmental or subsegmental embolization
Limit chemotherapy3
Document sufficient hepatic collaterol flow4
Elevated bilirubin
Superselective embolization
1Song SY, et al. Liver abscess after transcatheter oily chemoembolization for hepatic tumors: incidence, predisposing factors and clinical outcome. J Vasc Interv Radiol 2001;12:
2Geschwind JF, Kaushik S, Ramsey DE, et al. Influence of a new prophylactic antibiotic therapy on the incidence of liver abscesses after chemoembolization treatment of liver tumors. J Vasc Interv Radiol 2002; 13:1163–1166.
3Kiely JM, et al. Chemoembolization in patients at high risk: results and complications. J Vasc Interv Radiol 2006;17:47-53.
4Pentecost MJ, et al. Hepatic chemoembolization: safety with portal vein thrombosis. J Vasc Interv Radiol 1993;4:

77. Prep for Sphincter of Oddi disfunction
Oral levaquin 500 mg daily two days before and for seven days following the procedure
Oral Flagyl 500 mg twice daily two days before and for seven days following the procedure

78. High risk of acute hepatic failure and post procedural mortality post TACE
>50% of liver volume replaced by tumor
LDH >425 IU/L
AST (SGOT) > 100 IU/L
Bilirubin >2 mg/dL
Individual abnormalities of these four parameters have not been shown to predict adverse outcomes of chemoembolization
Charnsangavej, C. Chemoembolization of liver tumors. Semin Invest Radiol 1993;10:
Berger DH, Carrasco CH, Hohn DC, et al. Hepatic artery chemoembolization or embolization for primary and metastatic liver tumors: post-treatment management and complications. J Surg Oncol 1995; 60:116 –121.
Brown DB, Fundakowski CE, Lisker-
Melman M, et al. Comparison of
MELD and Child-Pugh scores to predict
survival after chemoembolization
for hepatocellular carcinoma. J Vasc Interv
Radiol 2004; 15:1209 –1218.

79. Side effects Post embolization syndrome in 80-90% of patients
Pain, fever, nausea, vomitting
Severity varies
PCA and liberal use of antiemetics as well as good pre-procedure medication regimen
Leung DA, Goin JE, Sickles C, et al. Determinants of postembolization syndrome after hepatic chemoembolization. J Vasc Interv Radiol 2001; 12:321–326.

80. 30 day mortality ranges from 1 – 4%
Complications
Serious event = 3-7%
Other complications (<1% incidence each)
Hepatic insufficiency/infarction
Hepatic abscess
Tumor rupture
Chemical cholecystitis
Non-target embolization to the bowel
Renal insufficiency
anemia
30 day mortality ranges from 1 – 4%
Sakamoto I, et al. Complications associated with transcatheter embolization for hepatic tumors. Radiographics 1998;18:
Gates J, et al. Chemoembolization of hepatic neoplasms: safety, complications and when to worry. Radiographics 1999;19:

81. Major complications Specific Major Complication Reported Rate (%))
Liver failure
2.3
Abscess with functional sphincter of Oddi
<1
Post-embolization syndrome requiring extended stay or readmission
4.6
Abscess with biliary-enteric anastamosis/biliary stent/sphincterotomy 25
Surgical cholecystitis
Biloma requiring perutaneous drainage
Pulmonary arterial oil embolus
Gastrointestinal hemorrhage/ulceration
Iatrogenic dissection preventing treatemtn
Death within 30 days 1
Daniel B. Brown, et al. Quality Improvement Guidelines for Transhepatic Arterial Chemoembolization, Embolization, and Chemotherapeutic Infusion for Hepatic Malignancy. J Vasc Interv Radiology July 2009 ;20(7) Supplement:S219-S226.e10

82. Pre-procedure orders IV normal saline 500 cc bolus then 200cc/hr
Rocephin 1 gm IV
Diphenhydramine 50 mg IV
Dexamethazone 10 mg IV
Ondansetron 24 mg IV
Pepcid 20 mg IV
Dilaudid PCA

83. Post procedure orders Patient controlled anesthesia
Ondansetron 8 mg q8h IV, PRN nausea
Tylenol 650 mg q4h po, PRN fever
Augmentin 875mg one PO BID x seven days. or if allergic to PCN: Cipro 500mg one PO bid x seven days.

84. Follow up Labs in three weeks to assess for continued eligibility
Repeat CT or repeat treatment in 4 weeks

85. Discharge Augmentin or Ciprofloxacin
Fevers < 103o are normal in the first week and do not require cultures

86. Radioembolization or Selective Internal Radiation Therapy (SIRT)
This technique selectively targets a very high radiation dose to all tumors (average dose of Gy) within the liver, regardless of their cell of origin, number, size or location while at the same time maintaining a low radiation dose to the normal liver tissue (<40 Gy)

87. Radiation in HCC
Traditional radiation therapy in management of unresectable HCC demonstrated palliation of symptoms in >50% of patients and 20% signficant tumor shrinkage
Risk of radiation induced liver toxicity after uniform whole liver radiation to 30 Gy (<dose required to eradicate tumor) delivered over 3 weeks was 5%
Sakamoto I, et al. Complications associated with transcatheter embolization for hepatic tumors. Radiographics 1998;18:
Gates J, et al. Chemoembolization of hepatic neoplasms: safety, complications and when to worry. Radiographics 1999;19:

88. SIR-Spheres mean diameter 35 μm
SIR-Sphere size is small enough to gain entry into tumor nodules but too large to pass through the end capillary bed into the venous circulation
Tumor vessels 25μm -75μm
End arterioles 8 μm
SIR-Spheres mean diameter 35 μm

89. Regulatory Status
In US, regulated under the pre-market approval regulations (21 CFR Part 814)
FDA approval March 2002
Unresectable metastatic liver tumors from primary colorectal cancer together with adjuvant intra-hepatic chemotherapy with FUDR
In Europe and UK, Europe and UK regulated under the Active Implantable Medical Device Directive (90/385/EEC)
CE Mark approval October 2002
Primary and secondary (metastatic) liver cancer

90. Radioembolization in HCC
Partial response rate of 42.2% in phase 2 study of 108 patients with unresectable HCC with/without portal vein thrombosis
More study is needed
Kulick LM, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology. 2008;47:71-81

91. Patient Selection Unresectable primary hepatic malignancy: Hepatoma
Unresectable metastatic disease:
Colorectal
Breast
Pancreatic
Carcinoid
Neuroendocrine
Cholangiocarcinoma

92. Patient Selection
Tumor board/ multidisciplinary team determination that patient has unresectable liver tumor with a life expectancy > 3 months
ECOG 0,1,2
Karnofsky score of 60% or higher

93. Patient Work-up CT/MRI/PET imaging to confirm
liver dominant disease + no CNS mets
tumoral/nontumoral volume
patent portal vein
Adequate synthetic and excretory liver function
Total bilirubin < 2.0mg/dL
Serum albumin > 3.0g/dL
Patient may be on systemic chemotherapy except except Capecitabine, Avastin, Erbitux
Trials in progress to determine safety in conjunction with Capecitabine, Avastin, Erbitux
No history of external beam radiation to the liver

94. Patient Work-up Two absolute contraindications
reflux into arteries that supply the gastroduodenal region
can result in gastritis, pancreatitis, gastric ulceration
exaggerated hepatopulmonary shunting (lung shunt > 20%)
can result in radiation pneumonitis
To address these issues, a pre-treatment diagnostic hepatic angiogram is performed

95. Pre-treatment hepatic arteriogram
Ability to coil embolize GDA and RGA and others as necessary to prevent reflux into arteries in the gastroduodenal region
Pre-treatment hepatic arteriogram
Hepatic Arteries
Right Gastric Artery
Gastroduodenal Artery

96. After coil embolization, injection of 5-6 mCi of Tc-99m labeled MAA as a microsphere surrogate into the hepatic arterial territory to assess extent of hepatopulmonary shunting 19

97. Reduce implanted activity for lung shunting > 10%
Lung shunt fraction
Reduce implanted activity by
0 – 10%
No reduction required
11 – 15%
Reduce by 20%
16 – 20%
Reduce by 40%
> 20%
Do not treat

98. Implanted activity calculation for a whole liver treatment from the proper hepatic artery
1) Activity (GBq) = BSA*-0.2 +
2) Reduce implanted activity for lung shunting as described
3) Reduce implanted activity for special cases
CRLMs – heavy pre-treatment with systemic chemotherapy
HCC - cirrhosis
Tumor volume
Tumor volume + normal liver volume
*BSA = Body Surface Area

99. SIR-Spheres Meds Rocephin 1gm IV pre procedure. No home antibiotics.
PPI or any H2 blocker one week before and for 4 weeks after.
Medrol dose pack if not diabetic (script written at discharge).
Ketorolac 10mg PO q 4-6 hours PRN pain x 5 days after treatment.
Ondansetron 8mg PO q 8 hours PRN N/V. or Promethazine 25mg tablets, one PO q 6hours PRN N/V.

100. Radiation Safety Exposure Ward
Bremsstrahlung is typically 15 uSv per Gbq at 15cm from the patient’s right side (initially)
Ward
Outpatient procedure
No pregnant women, children (‘three feet for three days’)
Nursing from left hand side of patient
Shielding unnecessary
No special handling required for blood, body fluids, urine

101. Complications to be aware of…
Postembolization syndrome – may occur in as many as 50% pts; not as severe as that observed with TACE and is usually dominated by fatigue and constitutional symptoms
Gastrointestinal ulceration – incidence minimized with coil embolization of right gastric, etc.
Pancreatitis – incidence minimized with coil embolization of gastro-duodenal artery
Radiation pneumonitis – incidence practically zero with routine work-up and Tc99 lung shunt study
Radiation hepatitis (RILD) – increased risk in patients with cirrhosis and reduced liver reserve
Radiation Cholecystitis – clinically relevant radiation cholecystitis requiring cholecystectomy is not common but does occur

102. Questions?
Anastasia Balius, MD Interventional Radiology