This is a general overview of options available to patients with liver dominant metastatic disease as well other focal areas of disease which may benefit from services provided by an interventional radiologist
What Cancers to Consider• Colorectal• Hepatocellular carcinoma• Intrahepatic cholangiocarcinoma• Neuroendocrine metastases
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
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
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
Background• Trans-arterial chemo-embolization (TACE) is primarily a palliative therapy• Proven therapy in primary and liver dominant metastatic disease
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
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.
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
Pre procedure labs• Metabolic panel• Liver Function test• Coagulation profile
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
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%)
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
Do not recommend following NCCN guidelines for screening or biopsy, use UNOS instead
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
HCC• Screen with CT or MRI once cirrhotic• US sensitivity 60-80%• Milan Criteria• Childs A/B Treat• Childs C – Meaningful treatment or palliation
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
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
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 UnresectableHepatocellular Carcinoma: Five-Year Survival Analysis. CardioVascular andInterventional Radiology 35, 1119–1128 (2012).
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) – CisplatinYang, J. & Yan, L.-N. Current status of intrahepatic cholangiocarcinoma. World JGastroenterol 14, 6289–6297 (2008).
Systemic • Median survival: 11.7 months in cisplatin– gemcitabine group • Randomized study of 410 patients to gemcitabine vs cisplatin-gemcitabine • 81% SD+PRValle, J. et al. Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. NewEngland Journal of Medicine 362, 1273–1281 (2010).
TACE • Median Survival 20 months • 62 Patients treated • 76% SD+PR • No 30 day mortalityKiefer, M. V. et al. Chemoembolization of intrahepatic cholangiocarcinoma withcisplatinum, doxorubicin, mitomycin C, ethiodol, and polyvinyl alcohol: a 2-center study.Cancer (2010).doi:10.1002/cncr.25625
TACE • Hopkins study with smaller patient set (24) • Traditional TACE • Median Survival 23 MonthsBurger, I. et al. Transcatheter arterial chemoembolization in unresectablecholangiocarcinoma: initial experience in a single institution. J Vasc Interv Radiol 16, 353–361(2005).
Radioembolization • 25 patients • 9.3 months median survivalSaxena, A., Bester, L., Chua, T. C., Chu, F. C. & Morris, D. L. Yttrium-90 radiotherapy forunresectable intrahepatic cholangiocarcinoma: a preliminary assessment of this noveltreatment option. Ann. Surg. Oncol. 17, 484–491 (2010).
Radioembolization • 24 patients • 48 treatments • 14.9 months median survivalIbrahim, S. M. et al. Treatment of unresectable cholangiocarcinoma using yttrium-90microspheres: results from a pilot study. Cancer 113, 2119–2128 (2008).
DEB TACE • 24 patients half of whom had failed resection and/or RFA • 17.5 month median survivalSchiffman, S. C. et al. Precision Hepatic Arterial Irinotecan Therapy in the Treatment ofUnresectable Intrahepatic Cholangiocellular Carcinoma: Optimal Tolerance and ProlongedOverall Survival. Annals of Surgical Oncology 18, 431–438 (2010).
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 yearsMurad, 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
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 andOxaliplatin Failure in Patients With Metastatic Colorectal Cancer. JCO 26, 2311–2319 (2008).
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 monthsFiorentini, G. et al. Intra-Arterial Infusion of Irinotecan-Loaded Drug-Eluting Beads (DEBIRI) VersusIntravenous Therapy (FOLFIRI) for Hepatic Metastases from Colorectal Cancer: Final Results of a Phase IIIStudy. Anticancer Res 32, 1387–1395 (2012).
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 SupportiveCare Versus Best Supportive Care Alone for Chemotherapy Refractory Liver-Dominant ColorectalMetastases. CardioVascular and Interventional Radiology 35, 1066–1073 (2011).
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).
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 renalcell carcinoma: a meta-analysis of case series studies. BJU Int. 110, 510–516 (2012).
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 necrosisRossi, G. et al. Selective Embolization with N-butyl Cyanoacrylate for Metastatic Bone Disease. Journal ofVascular and Interventional Radiology 22, 462–470 (2011).
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