Regional therapy options for tumors include embolization (bland, chemo, radio) and ablation (radiofrequency, cryo). Embolization is useful for colorectal cancer, hepatocellular carcinoma, cholangiocarcinoma, and neuroendocrine metastases. Chemoembolization is palliative for primary and metastatic liver cancer. It provides a survival benefit compared to best supportive care alone in salvage patients. Radioembolization also prolongs survival compared to supportive care. Transarterial chemoembolization improves survival for unresectable cholangiocarcinoma and hepatocellular carcinoma compared to systemic therapy or supportive care alone.

1. Regional Therapy for Tumors
By:
Emil Cohen, MD
Center Radiology
cohenemil@gmail.com

2. Objectives
• Familiarize the audience with various
options available for loco-regional
treatment of tumors
• Gain input about needs and gaps in
treatment of the oncology patients

3. Objectives
• Familiarize the audience with various
options available for loco-regional
treatment of tumors
•Embolization
•Bland
•Chemo
•Radio
•Ablation
•Radiofrequency
•Cryo

4. Options for Liver Disease

5. What Cancers to Consider
• Colorectal
• Hepatocellular carcinoma
• Intrahepatic cholangiocarcinoma
• Neuroendocrine metastases

6. When to Consider
• Colorectal
– After failure of first line
– Chemo-Holiday
• Hepatocellular Carcinoma
– List for transplant or resection
– Give regional therapy
– Ablation if possible/necessary
• Intrahepatic Cholangiocarcinoma – First Line
• Neuroendocrine tumors – failure of sandostatin;
preferably before 50% of liver replaced

7. Background
• Liver metastases from colon and neuroendocrine tumors
is common; overall liver is the most common site for
metastatic disease
• In colon cancer, liver only metastatic disease is seen in
approximately 30% of the patients
Sasson AR, Sigurdson ER Surgical treatment of liver metastases. Semin
Oncol. 2002 Apr;29(2):107-18
• Primary liver cancer (HCC or Cholangiocarcinoma) is
one of the most common tumors worldwide(5th
worldwide)
Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer
burden:GLOBOCAN 2000. Int J Cancer 2001;94:153-156
– This is predominantly due to endemic Hep B in southeast asia
– Growing numbers of Hep C in the Europe and remainder of the
world

8. Cholangiocarcinoma
• Increase in the rate of intrahepatic
cholangiocarcinoma (more than doubled)
Shaib YH, Davila JA, McGlynn K, El-Serag HB. Rising incidence of intrahepatic
cholangiocarcinoma in the United States: a true increase?
J Hepatol. 2004 Mar;40(3):472-7.
• Decrease in the rate of extrahepatic
cholangiocarcinoma
– More cholecystectomies

9. Background
• Trans-arterial chemo-embolization (TACE)
is primarily a palliative therapy
• Proven therapy in primary and liver
dominant metastatic disease

10. Background
• Survival rates for untreated liver metastases is
poor being approximately about a year
• Systemic chemotherapy is an option for most
tumors except for HCC.
• Review of literature demonstrated a significant
benefit of chemoembolization with doxirubicin or
cisplatin
Llovet et al Systematic review of randomized trials for
unresectable hepatocellular carcinoma: Chemoembolization
improves survival. Hepatology. 2003 Feb;37(2):429-42

11. Relative Contraindications
• Total bilirubin > 4
• Albumin < 2
• Creatinine > 1.7
• Encephalopathy
• Biliary colonization with gut flora (risk of abscess
formation as high as 40%)
• PV thrombosis**, Hopkins study demonstrated
no additional risk, other similar studies have
followed
Georgiades CS et al. Safety and efficacy of transarterial
chemoembolization in patients with unresectable hepatocellular
carcinoma and portal vein thrombosis. J Vasc Interv Radiol.
2005 Dec;16(12):1653-9.

12. Complications
• Hemorrhage
• Liver Failure
• Liver Abscess
• Renal Failure
• Allergic Reaction to contrast
• Non-target embolization

13. Pre-procedure imaging
evaluation

14. Pre-procedure planning
Baseline CT and/or MRI to be within 30
days of treatment

15. What to look for
• Hyperenhancing lesion + washout is
diagnostic for HCC and no biopsy is
necessary
• Size and location of mets – most of the
disease must be within the liver

16. HCC reading a good path book

17. HCC reading a good path book

18. Imaging and Treatment Options
• Resection
• Radiofrequency Ablation
– location, location, location, size
• Chemo-Embolization
• Transplant
– one lesion under 5 cm
– 3 lesions each no more than 3 cm
• Vascular invasion

19. Pre procedure labs
• Metabolic panel
• Liver Function test
• Coagulation profile

20. Why it works?
• Dual Blood Supply of the normal liver
parenchyma:
– 70-80% from portal circulation
– 10-20%Hepatic Artery
• Tumor blood supply:
– Tumors >3 mm derive >90% of blood supply from
artery
– Micro analysis of tumor vessels reveals tumor arterial
vascularity to be at least 5x normal liver parenchyma

21. Anatomical consideration
• On Pre-procedure imaging assess hepatic
arterial supply (20% variant anatomy)
• Risk of non-target embolization; no
deaths (as of 2003) recorded from non-
target chemo-embolization
• Radio-embolization non-target
embolization is potentially fatal (less than
2%)

22. Procedure
• Administer chemotherapy (50-75 mg
Doxorubicin, 10 mg Cisplatin, 50 mg
Mitomycin)
• Lipiodol 1-5 ml vs 10-30 ml; concentrates
chemotherapy but washes out over the
course of a few weeks
• +/- lidocaine
• Achieve a pruned tree appearance not a
complete stasis

24. Day of Treatment
Day of Treatment

25. Pre vs. Post Treatment

26. Neuroendocrine Metastases

27. Neuroendocrine Mets
• Treat only after failure of sandostatin
• Category 2B recommendation from NCCN

28. Hepatocellular Carcinoma
(HCC)

29. Do not recommend following
NCCN guidelines for
screening or biopsy, use
UNOS instead

30. Problems with NCCN guidelines
for HCC
• Recommend US screening (sensitivity is
60-80% at best)
• Over-biopsy with risk of underdiagnosis
since false negatives are common with
biopsies
• Requires two tests, may delay care

31. UNOS imaging criteria

32. HCC
• Screen with CT or MRI once cirrhotic
• US sensitivity 60-80%
• Milan Criteria
• Childs A/B Treat
• Childs C – Meaningful treatment or
palliation

33. Treatment for HCC
• Transplantation
• Resection
• Radiofrequency Ablation
• Chemoembolization (conventional or drug
eluting beads)
• Radioembolization
– Portal or hepatic vein invasion
• External beam radiation (SBRT) combined
with TACE

34. Treatment for HCC
• RFA 80-95% cure rates for tumors up to 3
cm
• 60-77% response rate for TACE (CR, PR,
SD). CR less than 2% of patients.
• SBRT 60% infield response rate in non-
operable patients

35. DEB for Unresectable HCC
• 173 HCC patients not suitable for curable treatments
were prospectively enrolled (mean age 70.4 ± 7.4 years)
• Diameter was 7.6 ± 2.1 cm.
• Included single and multifocal disease
• Overall survival at 1, 2, 3, 4, and 5 years was 93.6, 83.8,
62, 41.04, and 22.5 %,
• Higher rates achieved in Child class A compared with
Child class B patients (95, 88.2, 61.7, 45, and 29.4 % vs.
91.5, 75, 50.7, 35.2, and 12.8 %).
• Mean overall survival was 43.8 months (range 1.2–64.8)
Malagari, K. et al. Chemoembolization With Doxorubicin-Eluting Beads for Unresectable
Hepatocellular Carcinoma: Five-Year Survival Analysis. CardioVascular and
Interventional Radiology 35, 1119–1128 (2012).

36. Cholangiocarcinoma

37. Treatment
• Surgery is the only curative option
– 10-15% Present early enough
– 46% Recurrence rate
– 3 month survival after non-curative resection
• No evidence for systemic adjuvant therapy
• Hepatic arterial port (case series)
– Cisplatin
Yang, J. & Yan, L.-N. Current status of intrahepatic cholangiocarcinoma. World J
Gastroenterol 14, 6289–6297 (2008).

38. Treatment Options for Non-
Resectable Tumors
• Systemic Chemotherapy
• Intra-arterial chemo
• Radiation Therapy
• Regional Therapy
– TACE
– Radioembolization
• Combination of Above

39. Systemic
• Median survival: 11.7 months in cisplatin–
gemcitabine group
• Randomized study of 410 patients to
gemcitabine vs cisplatin-gemcitabine
• 81% SD+PR
Valle, J. et al. Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. New
England Journal of Medicine 362, 1273–1281 (2010).

40. TACE
• Median Survival 20 months
• 62 Patients treated
• 76% SD+PR
• No 30 day mortality
Kiefer, M. V. et al. Chemoembolization of intrahepatic cholangiocarcinoma with
cisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol: a 2-center study.
Cancer (2010).doi:10.1002/cncr.25625

41. TACE
• Hopkins study with smaller patient set (24)
• Traditional TACE
• Median Survival 23 Months
Burger, I. et al. Transcatheter arterial chemoembolization in unresectable
cholangiocarcinoma: initial experience in a single institution. J Vasc Interv Radiol 16, 353–361
(2005).

42. Radioembolization
• 25 patients
• 9.3 months median survival
Saxena, A., Bester, L., Chua, T. C., Chu, F. C. & Morris, D. L. Yttrium-90 radiotherapy for
unresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this novel
treatment option. Ann. Surg. Oncol. 17, 484–491 (2010).

43. Radioembolization
• 24 patients
• 48 treatments
• 14.9 months median survival
Ibrahim, S. M. et al. Treatment of unresectable cholangiocarcinoma using yttrium-90
microspheres: results from a pilot study. Cancer 113, 2119–2128 (2008).

44. DEB TACE
• 24 patients half of whom had failed
resection and/or RFA
• 17.5 month median survival
Schiffman, S. C. et al. Precision Hepatic Arterial Irinotecan Therapy in the Treatment of
Unresectable Intrahepatic Cholangiocellular Carcinoma: Optimal Tolerance and Prolonged
Overall Survival. Annals of Surgical Oncology 18, 431–438 (2010).

45. Note on Perihilar
Cholangiocarcinoma
• Analysis of patients who underwent
transplant after external radiation (99%),
brachytherapy (75%), radio-sensitizing
therapy (98%), and/or maintenance
chemotherapy (65%)
• 65% rate of recurrence-free survival after
5 years
Murad, S. D. et al. Efficacy of Neoadjuvant Chemoradiation, followed by Liver Transplantation,
for Perihilar Cholangiocarcinoma at 12 US Centers. Gastroenterology
(2012).doi:10.1053/j.gastro.2012.04.008

46. Colorectal Metastases

47. Treatment options
• Resection
• Resection
• Resection
• RFA
• Systemic Chemo FOLFOX
• What then?
– FOLFIRI
– Cetuximab

48. Let’s compare
• EPIC trial
• Second line therapy: cetuximab (400 mg/m(2) day 1
followed by 250 mg/m(2) weekly) plus irinotecan (350
mg/m(2) every 3 weeks)
• Median survival 10-10.7 months
• Progression free survival (PFS): 4.0 months
• PFS: 4.0 (cetuximab + irinotecan) vs. 5.5 months
(radioembolization)
• Median survival: 10.7 vs. 11 months with conventional
TACE (salvage , usually sicker, patients)
Sobrero, A. F. et al. EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and
Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer. JCO 26, 2311–2319 (2008).

49. Irinotecan DEB (DEBIRI)
• April 2012 Phase III research
• 74 patients randomly assigned to FOLFIRI
or DEBIRI
• Endpoints : Survival (Primary)
• Median survival 22 vs 15 months
• Progression free survival 7 vs 4 months
• Quality improvement of life 8 vs 3 months
Fiorentini, G. et al. Intra-Arterial Infusion of Irinotecan-Loaded Drug-Eluting Beads (DEBIRI) Versus
Intravenous Therapy (FOLFIRI) for Hepatic Metastases from Colorectal Cancer: Final Results of a Phase III
Study. Anticancer Res 32, 1387–1395 (2012).

50. Salvage Patients for
Radioembolization
• Compared with BSC alone,
radioembolization prolonged survival
(median, 8.3 vs. 3.5 months; P < 0.001)
with a hazard ratio of 0.3 (95% confidence
interval, 0.16-0.55; P < 0.001) in a
multivariate Cox proportional hazard
model.
Seidensticker, R. et al. Matched-Pair Comparison of Radioembolization Plus Best Supportive
Care Versus Best Supportive Care Alone for Chemotherapy Refractory Liver-Dominant Colorectal
Metastases. CardioVascular and Interventional Radiology 35, 1066–1073 (2011).

51. Conventional Chemoembolization
• Many case series, no randomized studies
• 121 patients (lipiodol, CAM)
• Median survival was 33 months from diagnosis of the primary colon
cancer, 27 months from development of liver metastases, and 9
months from chemoembolization.
• Survival was significantly better when chemoembolization was
performed after first- or second-line systemic therapy (11-12
months) than after third- to fifth-line therapies (6 months) (P = .03).
• Presence of extrahepatic metastases did not adversely affect
survival (P = .48).
• Chemoembolization provided local disease control of hepatic
metastases after 43% of treatment cycles. Median survival was 27
months overall, and 11 months when initiated for salvage after
failure of second-line systemic therapy.
Albert, M. et al. Chemoembolization of colorectal liver metastases with cisplatin, doxorubicin,
mitomycin C, ethiodol, and polyvinyl alcohol. Cancer (2010).

52. Renal Cell Carcinoma

53. Renal Ablation
• Cryo is preffered
• Embolize tumors more than 3 cm in
diameter
• Recent meta analysis of cryo-ablation and
RFA of 457 patients 89-90% efficacy for
tumors less than 4 cm in size
• No significant difference between
complication rates (salt, grain of)
El Dib, R., Touma, N. J. & Kapoor, A. Cryoablation vs radiofrequency ablation for the treatment of renal
cell carcinoma: a meta-analysis of case series studies. BJU Int. 110, 510–516 (2012).

54. Bony Metastases

55. Metastatic Disease to Bones
• Several small case series until 2011
• 309 embolization in 243 patients
• 50% reduction in pain score for an average of 8
months
• Adverse events (87 patients):
– Postembolization syndrome
– ischemic pain at the site of embolization
– paresthesias
– skin breakdown
– subcutaneous necrosis
Rossi, G. et al. Selective Embolization with N-butyl Cyanoacrylate for Metastatic Bone Disease. Journal of
Vascular and Interventional Radiology 22, 462–470 (2011).

56. Summary
• Please consider regional therapy for:
– Intrahepatic cholangiocarcinoma
– HCC
– Painful bone metastases (radiation first)
• Think about it for
– Second line or at least salvage for
• Colorectal cancer
– Renal cell carcinoma