HEPATIC ARTERIAL CHEMOEMBOLIZATION   IN THE TREATMENT OF LIVER TUMORS

COMMENTS?

 

 
Michael Cohn, M.D.

INTRODUCTION

Primary and secondary hepatic malignancies remain one of the leading causes of cancer deaths worldwide. Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. Especially prominent in Asia, Africa, and Greece, it has an annual incidence of 30 in every 100,000 males [1]. In the Western Hemisphere HCC, although not uncommon, is less prevalent and usually associated with pre-existing liver disease (i.e. alcoholic cirrhosis). The liver is the organ most commonly involved by metastatic disease. Although hepatic resection is the treatment of choice and is the only treatment that is potentially curative, only 10 - 15% of patients have disease that meets the criteria for surgical resection for reasons such as large tumor volume, tumor location, and poor baseline liver function [2,3].

In the past, prior to the development of percutaneous treatment, main therapeutic regimens for hepatic malignancies included systemic chemotherapy with clinical response rates being poor and systemic toxicity common [4].Markowitz, in 1953, first established that liver metastases can be palliated by surgical ligation of the common hepatic artery [5]. This is well tolerated because malignant hepatic tumors derive nearly 100% of their blood supply from the hepatic artery and the liver parenchyma is predominantly supplied by the portal vein. Transarterial chemoembolization (TACE), a technique described by Kato and colleagues in 1981 [6], is the infusion of chemotherapeutic agents and embolic particles directly into the tumor vascular supply with the dual aim of prolonging contact time of the drug with the tumor as well as provoking tumor ischemia. Superselective sequential hepatic artery chemoembolization permits selective targeting of drugs and embolization of tumor blood supply, while preserving normal liver tissue flow by portal venous flow. TACE has been used extensively in Asia and Europe for treatment of unresectable HCC (hepatocellular carcinoma.). More recently, this method has been applied to metastatic disease to the liver such as metastatic colon cancer. Colon metastases have a high incidence of liver involvement and since the liver is the only site of metastatic involvement in many patients this disease process has been shown to have favorable results with TACE. Neuroendocrine and other hypervascular metastases (i.e. carcinoid) have also has shown favorable results with TACE due to their increased vascularity [7]. TACE is a viable treatment modality for unresectable hepatic malignancies.

Intraarterial infusion of chemotherapeutic agents and embolic particles deliver a higher concentration of agent to a limited anatomic area. It has been shown that renal concentration of platinum in rabbits after infusion of cisplatin with a 5 x 75 micron embolic agents directly into the kidney, showed a 220:1 ratio between levels of the chemotherapeutic agent in the targeted kidney compared to the contralateral one [8]. The combination of intraarterial infusion of chemotherapeutic agent and arterial embolization of the vascular supply to the neoplasm, not only has the direct effect of tumor ischemia, the emboli prolong the transit time through the tumor vascular bed prolonging contact time between the agent and neoplastic cells [9]. Anoxia also increases tumor permeability thus increasing drug concentration within the tumor. Systemic toxic effects are decreased by metabolism of the chemotherapeutic agent on its first passage through the infused organ [9].

PROCEDURE

Pretreatment evaluation for TACE should consists of a complete medical history, physical, laboratory studies for hepatic (liver function tests), renal (creatinine), and hematologic function (prothrombin time (PT), partial thromboplastin time (PTT)). Measurements of appropriate tumor markers (i.e. AFP, CEA) should also be obtained, as they will be followed through out the treatment process. Radiologic assessment of the size and number of hepatic tumors should be obtained usually with a contrast enhanced CT with a tissue diagnosis obtained prior to the procedure.

Hepatic encephalopathy and jaundice are absolute contraindications to embolization. An obstructed biliary system (presence of dilated intrahepatic bile ducts) with or without an elevated bilirubin places the patient at risk for infarction of the obstructed liver segment [10]. Other relative contraindications for this procedure include active infections, thrombosed portal vein or hepatic artery, intractable ascites serious comorbid conditions and extensive extrahepatic metastatic disease. A subgroup of patients has been identified who are at high risk of acute hepatic failure following TACE. These are patients who have greater than 50% of the liver volume replaced by tumor, LDH (lactate dehydrogenase) greater than 425 IU/L, AST (aspartate amino transferase also (SGOT)) greater than 100 IU/L, and total bilirubin greater than or equal to 2 mg, dl [11].

Patients fast overnight and are admitted to the hospital the morning of the procedure. They receive a Foley catheter, hydration, prophylactic antibiotics and antiemetics prior to the procedure. Patients with carcinoid syndrome should continue to receive octreotide at their usual dosage. Initially a diagnostic visceral arteriogram is obtained under conscious sedation to evaluate the arterial hepatic anatomy and confirm portal vein patency. Variation in hepatic vascular anatomy is carefully identified to prevent bowel embolization. The chemoembolic mixture is infused until nearly complete stasis of blood flow is obtained to the treated portion of the liver. One hundred fifty mg of cisplatin, 50-mg doxorubicin, and 10 mg of mitomycin dissolved in 10 ml of radiographic contrast material and emulsified with iodized oil and polyvinyl alcohol particles used. Intraarterial lidocaine is given during the procedure to alleviate pain.

After the procedure, hydration, IV antibiotics, and antiemetics are continued. Narcotics and acetaminophen are liberally supplied for pain and fever. When oral intake is adequate and parental narcotics are no longer required for pain control the patient is discharged usually within 3 days. Oral antibiotics are continued for 5 days. Two to four treatments are usually required to treat the entire liver. Patients should be followed with repeat imaging and tumor markers [10]. Repeat treatment is often performed in 4 to 6 weeks focusing on untreated areas. A good clinical response, lowering serum tumor markers, and a decreasing tumor size or tumor necrosis characterize favorable response to the procedure.

Eighty to 90% of patients suffer a postembolization syndrome, characterized by right upper quadrant abdominal pain, fever (less than 39 degrees C), nausea, anorexia and vomiting. The severity is very variable and can last from a few hours to several days but then resolves spontaneously [10,12]. There has also been shown to be a transient rise in liver function tests after the procedure soon returning to normal. Major complication following TACE are rare (3 - 4%) and may include hepatic insufficiency or infarction, hepatic abscesses, cholecystitis, or gut embolization. Rare complications (< 1 %) may include renal insufficiency and anemia requiring transfusions.

Patient selection is important and can help avoid significant complications following TACE. This is especially true for patients with underlying hepatic disease. In-patients with a relatively preserved hepatic function, TACE are well tolerated and the adverse effects after TACE can be anticipated and well managed medically.

RESULTS

The largest TACE studies to date have shown survival rates to be superior to those of systemic chemotherapy. Hepatocellular carcinoma is the most frequent tumor worldwide. In western population hepatocellular carcinoma median survival is 3 to 6 months, with close to 100% mortality at 1-year [10]. Surgical removal of tumor is frequently not possible due to hepatic vascular involvement, multicentric hepatic growth, or poor hepatic reserve in-patients with cirrhosis. Systemic chemotherapeutic response rates generally do not exceed 20%. Even when tumor is amenable to primary surgical excision recurrence rates are high and overall survival rates are poor [13]. Deng-YN Lin et al showed that TACE was superior to 5-FU, in terms of survival rate, in the treatment of unresectable HCC. Patients with multiple chemoembolizations had a 1-year survival of 42.4%, 2-year survival rate of 25.4% compared to the group receiving systemic chemotherapy with a 1 and 2 year survival rate of 12.8% and 12.8% respectively. Yamada et. al. also found 1 and 2 year survival rates receiving TACE as high as 44% and 29% respectively [14]. Among a combined series of 800 patients with unresectable HCC treated with TACE in Asia, Europe, and USA, response rates as measured by decreased tumor volume and decreased serum alpha-fetoprotein levels were 60% to 83% [15-21]. Cumulative probability of survival ranged from 54% to 88% at 1 year, 33% to 64% at 2 years, and 18% to 51% at 3 years [10].

Approximately 150,000 new cases of colorectal carcinoma are diagnosed annually, of these 15 - 25% present with metastatic liver disease at the time of diagnosis. Another 25% develop metastases later in the course of their disease [10]. The median survival after the diagnosis of hepatic colonic metastases ranges from 5-6.5 months [10]. Systemic chemotherapy with 5-flourouuracil (5-fu) produces usual response rates of up to 20% and can have significant systemic toxicity [22]. Soulen reported 20 patients treated with TACE using cisplatin, doxorubicin, mitomycin, iodized oil, and polyvinyl alcohol particles had a biological response rate of 100%, and a mean decrease in CEA levels of 74%. Actuarial survival at 1 year from first diagnosis and first chemoembolization are 100% and 67% respectively [10]. Lang et. al. performed TACE on 46 patients with colorectal liver metastases. Ethiodized oil and doxorubicin was infused. Complete disappearance in lesions was obtained in 17%. The treatment resulted in a mean survival of 23 months, with 7 patients surviving over 2 years [23]. The largest studies to date have found a 3-year survival rate 12 - 23% for colon metastases compared to a 3 year survival rate of 5% with systemic chemotherapeutic infusion [24-26].

Embolization has also been shown to be very effective in palliation of hypervascular tumors (i.e. neuroendocrine tumors). Theresa reported a 100% symptomatic response and 42% morphological response rate in 22 patients after chemoembolization. Mean duration of symptomatic relief was 209 months. Survival was 81 months from diagnosis, 47 months from liver metastases, and 24 months from first chemoembolization [27]. Stokes et al treated 20 patients and achieved a 100% symptomatic response; hormone levels decreased 90%, and mean tumor size decreased 84% [28]. Studies have shown a 3 year survival rate of 33% for neuroendocrine metastases [29] compared to 20% for neuroendocrine metastases on systemic chemotherapy) [30].

CONCLUSION

The use of TACE to treat unresectable liver malignancies is by no means a new treatment and is becoming more and more prevalent around the world. TACE combines tumor arterial embolization with simultaneous infusion of concentrated chemotherapeutic drugs having the theoretic advantage of causing tumor ischemia, increased drug levels as well as prolonged drug time interaction within the tumor and the added benefit of decreased systemic toxicity. Worldwide experience has proven chemoembolization to be the treatment of choice for unresectable hepatoma and also proven to be effective in the treatment of neuroendocrine and hypervascular metastases. The use of TACE in the treatment of colorectal and other metastatic disease to the liver with studies still ongoing are showing promise as a safe palliative procedure with decreased side effects and favorable outcomes when compared to other treatment modalities now available.

REFERENCES

1. Farmer DG, Rosove MH, Shaked A, Busuttil RW: Current Treatment Modalities For Hepatocellular Carcinoma. ANN Surg 219:236-247, 1994.

2. Scheele J, Stangi R, Altendorf-Hofman A: Hepatic Metastases From Colorecctal Carcinoma: Impact Of Surgical Resection On The Natural History. BR J Surg 1990;77(11):1241-6

3. Cady B, Mcdermott WV: Major Hepatic Resection From Metachronous Metastases From Colon Cancer. Ann Surg1985;201:204-9

4. Falkson G, Machitype JM, Moertel CG, et al: Primary Liver Cancer:An Eastern Cooperative Oncology Group Trial. Cancer 54:970-977, 1984.

5. Markowitz J: The Hepatic Artery. Surg Gynecol Obstet 95:644-646, 1952.

6. Kato T, Nemoto R, Mori H, et al: Arterial Chemoembolization With Microencapsulated Anticancer Drug. JAMA 245:1123-1127,1981.

7. Drougas JG, Anthony LB, Blair TK, et al: Hepatic Artery Chemoembolizationfor Management Of Patients With Advanced Metastatic Carcinoid Tumors. AM J Surg 175:408-12, 1998.

8. Sternlicht M, Sales SF, Daniela JR: Renal Cisplatin Embolization With Angiostat, Gelfoam, And Ethiodol In The Rabbit:Renal Platinum Distributions. Radiology 170:1073-1075, 1989;

9. Wallace SC, Carrasco CH, Charnsangevej C, et al: Hepatic Artery Infusion And Chemoembolization In The Management Of Liver Metastases. Cardiovasc intervent Radiol 13:153-60, 1990.

10. Soulen MC: Chemoembolization Of Hepatic Malignancies. Oncology 8(4):77-89, 1994.

11. Charnsangavej C: Chemoembolization Of Liver Tumors. Sem Invest Radiol 10:150-160, 1993.

12. Trinchet JC, Ganne-Carrie N, Beaugrand M: Intra-Arterial Chemoembolization In Patients With Hepatocellular Carcinoma. Hepatogastroenterology 45:1242-1247, 1998.

13. Lehnert T, Otto G, Herfarth C: Therapeutic Modalities And Prognostic Factors For Primary And Secondary Liver Tumors. World J Surg 19:252-263, 1995.

14. Yamada R, Sato M, Kawabata M, et al: Hepatic Artery Embolization In 120 Patients With Unresectable Hepatoma. Radiology 148:397-401, 1983.

15. Nakamura H, Hashimoto T, Oi H, et al: Transcatheter Oily Chemoembolization Of Hepatocellular Carcinoma. Radiology 170:783-786, 1989.

16. Onishi K, Tsuchiya S, Nakayama T, et al: Arterial Chemoembolization Of Hepatocellular Carcinoma With Mitomycin C Microcapsules. Radiology 152:51-55, 1984.

17. Nakao N, Miura K, Takahashi H, et al: Hepatocellular Carcinoma:Combined Hepatic Arterial And Portal Venous Embolization. Radiology 161:303-307, 1986.

18. Van Beers B, Roche A, Cauquil P, et al: Transcatheter Arterial Chemotherapy Using Doxorubicine, Iodized Oil And Gelfoam Embolization In Hepatocellular Carcinoma. Acta Radiol 30:415-418, 1989.

19. Venook AP, Stagg RJ, Lewis BJ, et al: Chemoembolization For Hepatocellular Carcinoma. J Clin Oncol 8:1108-1114, 1990.

20. Nakao N, Kamino K, Miura K, et al: Recurrant Hepatocellular Carcinoma After Partial Hepatectomy: Value Of Treatment With Transcatheter Arterial Chemoembolization. AJR 156:1177-1179, 1991.

21. Stokes KR, Stuart K, Jenkins RL, et al: Chemoembolization With Adriamycin/Ethiodol In Hepatocellular Carcinoma. J Vasc Intervent Radiol 3:17,1992.

22. Kemeny N, Schneider A: Regional Treatment Of Hepatic Metastases And Hepatocellular Carcinoma. Curr Problems,Cancer 13(2):210-27, 1989.

23. Lang Ek, Brown Cl: Colorectal Metastases To The Liver: Selective Chemoembolization. Radiology 189:417-22, 1993. 24. Bavisotto L, Patel N, Althaus S, et al: Hepatic Transcatheter Arterial Chemoembolization Alternating With Systemic Protracted Continuous Infusion 5-FU For GI Malignancies Metastases To The Liver: A Phase II Trial Of The Puget Sound Oncology Consortium. Clin Cancer Res 5:95-109, 1999.

25. Tuite C, Soulen M, Baum R, et al: Hepatic Metastases From Colorectal Carcinoma Treated With CAM/Ethiodol/PVA Chemoembolization: Evaluation Of Survival, Biologic And Morphologic Response. (abstract 137) SCVIR 24th annual Scientific Meeting, Orlando, FL, 1999.

26. Stangl R, Altendorf-Hoffman A, Charnley RM, et al: Factors Influencing The Natural History Of Colorectal Liver Metastases. Lancet 343:140501410, 1994.

27. Therrase E, Breittmayer S, Roche A, et al: Transcatheter Chemoembolization Of Progressive Carcinoid Liver Metastases. Radiology 189:541-546, 1993.

28. Stokes KR, Stuart K, Clouse ME: Hepatic Chemoembolization For Metastatic Endocrine Tumors. J Vasc Intervent Radiol 4:341-345, 1993.

29. Drougas JG, Anthony LB, Blair TK, et al: Hepatic Artery Chemoembolization For Management Of Patients With Advanced Metastatic Carcinoid Tumors. AM J Surg 175:408-412, 1998.

30. Zeiteis J, Naunheim K, Kaplan E, et al: Carcinoid Tumors: A 37-Year Experience. Arch Surg 117:732-737, 1982.