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© 2000 American Society for Clinical Oncology Feasibility and Toxicity of Chemoembolization for Children With Liver TumorsFrom the Departments of Pediatrics and Radiology, University of Southern California School of Medicine, and Division of Hematology/Oncology, University of California Los Angeles, Los Angeles, CA. Address reprint requests to Marcio H. Malogolowkin, MD, University of California Los Angeles School of Medicine, Department of Pediatrics, Division of Hematology/Oncology, University of California Los Angeles Medical Center, 10833 Le Conte Ave, Los Angeles, CA 90024-1752; email mmalogol{at}ucla.edu
PURPOSE: To determine the feasibility, toxicity, and efficacy of hepatic arterial chemoembolization (HACE) in pediatric patients with refractory primary malignancies of the liver. PATIENTS AND METHODS: Six patients with hepatoblastoma (HB), three with hepatocellular carcinoma (HCC), and two with undifferentiated sarcoma of the liver were treated with HACE every 2 to 4 weeks until their tumors became surgically resectable or they showed signs of disease progression. All but one newly diagnosed patient with HCC had previously received systemic chemotherapy. RESULTS: All patients with HB and HCC responded to HACE, as measured by imaging studies and alpha-fetoprotein levels. Surgical resection (complete or microscopic residual disease) was feasible in five of 11 patients, and three patients remain alive with no evidence of disease. Elevated liver transaminase and bilirubin levels were seen after each one of the 46 courses of HACE. Other toxicities included fever, pain, nausea, vomiting, and transient coagulopathy. CONCLUSION: HACE is feasible, well tolerated, and effective in inducing surgical resectability of primary hepatic tumors in children.
THE PROGNOSIS FOR children with hepatic malignancies has significantly improved over the past decade. The overall survival rate is approximately 63% in patients with hepatoblastoma (HB) and 25% in patients with hepatocellular carcinoma (HCC).1 However, the majority of children who survive are those whose tumors are amenable to surgery either at the time of diagnosis or after induction chemotherapy.2,3 When complete surgical resection is impossible, because of the involvement of both lobes of the liver or extension of the tumor into the porta hepatis, children rarely survive for more than 12 months.2,4 The efficacy of preoperative chemotherapy in decreasing the size of the tumor in children with primary hepatic malignancies to allow surgical resectability has recently been demonstrated.1,2,5 Despite the improvement in the treatment of children with liver tumors, the outcome for patients with unresectable tumor after chemotherapy and for those with recurrent disease continues to be dismal. Therefore, there is a need for new therapeutic methods and alternative treatments that will improve the survival rates of these patients. This report describes the results of a study designed to determine the feasibility, toxicity, and efficacy of hepatic arterial chemoembolization (HACE) in pediatric patients with refractory primary malignancies of the liver.
Beginning in March 1991, patients with biopsy-proven unresectable and/or recurrent liver tumors or with newly diagnosed nonmetastatic unresectable HCC were entered onto a study of HACE. Entry criteria included age less than 21 years at time of original diagnosis, performance status  2 (Karnofsky score, 70 to 90), life expectancy of  2 months, full recovery from the toxic effects of prior therapy, absolute neutrophil count (ANC) 1,000/mm3, platelet count 100,000/mm3, normal serum creatinine level for age, adequate liver function, and a normal coagulation profile. All patients underwent computed tomography (CT) scanning or magnetic resonance imaging of the liver within 2 weeks of study entry. Complete blood and platelet counts, liver function tests, and measures of creatinine, amylase, coagulation profile, and alpha-fetoprotein (AFP) levels when applicable were obtained within 1 week before treatment. Written informed consent was obtained from all patients or their legal guardians. Patients were admitted to the hospital the day before the procedure to receive intravenous prophylactic metronidazole, ceftazidime, and piperacillin. Under aseptic conditions, the femoral artery was catheterized using a Seldinger technique. A 4-French catheter was introduced percutaneously into the femoral artery. Under fluoroscopy, the catheter was manipulated into the celiac axis, and arteriography was performed to delineate the anatomy, identify accessory arteries, and confirm the patency of the portal vein. Through this catheter, a microcatheter was introduced and directed to the artery supplying the tumor. The chemoembolization suspension was then injected until near complete stasis of the blood flow had occurred. The chemoembolization suspension consisted of a mixture with a total volume of 8.75 mL, containing Angiostat collagen (a bovine collagen material that causes temporary occlusion; Regional Therapeutics, Inc, Pacific Palisades, CA), nonionic radiopaque contrast media, cisplatin (100 mg), and doxorubicin (30 mg). Mitomycin (30 mg) was also used in three patients. The total volume of the suspension to be administered in any session in order to achieve stasis varied in each session; however, the total volume injected was not to exceed 8.75 mL and treatment was to be limited to no more than 70% of total liver volume. After treatment, patients were hydrated and continued receiving antibiotics for at least 48 hours. Postprocedure pain was managed with parenteral analgesics as needed, and nausea and vomiting were treated with antiemetics. A complete blood count, a platelet count, and liver function tests (AST, ALT, alkaline phosphatase, and total bilirubin) were performed and creatinine, amylase, and disseminated intravascular coagulation panels obtained daily while the patients were in the hospital. Subsequent treatments were generally carried out at 2- to 4-week intervals. Patients who initially had a favorable response to chemoembolization continued to receive treatment until the tumor became surgically resectable or until they showed signs of disease progression. After surgical resection, those patients with microscopic residual disease were eligible to receive two more cycles of chemoembolization as consolidation therapy. Responses were judged by CT scanning or magnetic resonance imaging according to the following definitions: complete response (CR), the complete disappearance of all known disease and normalization of AFP levels for at least 4 weeks; partial response (PR), a reduction of at least 50% in the sum of the products of the perpendicular diameters of measurable lesions and a reduction of more than 50% in AFP levels for at least 4 weeks; stable disease, a decrease of less than 50% or an increase of less than 25% in the sum of the products of the perpendicular diameters of measurable lesions, or when CT changes of reduced density are consistent with tumor necrosis and a decrease of less than 50% in AFP levels; and progressive disease (PD), a 25% or greater increase in the sum of the products of the perpendicular diameters of the measurable lesions or the appearance of new lesions and/or an increase in AFP levels. Patients were removed from study if they showed signs of PD. All scans were reviewed and tumor response to treatment determined by one of the investigators (P.S.). Toxicity was scored according to the Children’s Cancer Group toxicity grading system. Blood samples for cisplatin and doxorubicin levels were obtained at completion of the suspension injection, ie, at 1 hour and 24 hours after injection of the chemoembolization solution. The plasma concentrations of cisplatin were determined by atomic absorption spectrometry and those of doxorubicin by and high-performance liquid chromatography.6
Eleven patients between the ages of 18 months and 14 years were entered onto the study. All patients, except for one patient with HCC, were younger than 7 years of age (average age, 4.2 years). Six patients had progressive or recurrent unresectable HB, two patients had unresectable HCC, and two patients had progressive unresectable undifferentiated sarcoma of the liver. One patient, with liver cirrhosis and an unresectable HCC, was treated with HACE at diagnosis. None of the HCC tumors were of the fibrolamellar subtype. All patients, except the latter one, had received previous systemic chemotherapy including cisplatin and doxorubicin. Before study entry, patients had received an average of five cycles of systemic chemotherapy (range, two to nine cycles). Forty-six courses of HACE were given to 11 patients, with an average of five courses per patient (range, one to nine courses). An average of three courses (range, two to five courses) of HACE was given before surgical resection of the tumor. The average volume of the chemoembolization suspension infused in each HACE treatment was 3.2 mL (range, 1.7 to 8.75 mL). During all HACE courses, except for the first one given to the newly diagnosed patient with HCC (8.75 mL was given), near complete stasis of the blood flow occurred. Table 1 shows the patient characteristics, the response to HACE, surgical resectability after HACE, and final outcome of the patients.
All six patients with HB had a PR to HACE treatment as measured by imaging studies and AFP levels. One of these patients achieved complete surgical resection after four courses of HACE but had recurrent disease in the previously uninvolved hepatic lobe 6 months later. This patient received two more courses of HACE followed by orthotopic liver transplantation (OLT). However, he developed lung metastasis in the immediate posttransplant period and died of PD. Two other patients underwent surgical resection with microscopic residual disease. One of these patients received two more cycles of systemic chemotherapy and is alive with no evidence of disease for more than 33 months. The second patient developed increasing AFP levels a few months after tumor resection and had an OLT after systemic chemotherapy and is alive with no evidence of disease for more than 31 months. The remaining three patients continued to have unresectable tumors despite the initial response to HACE and eventually developed metastatic lung disease after three, six, and nine courses of HACE. Two of the three patients with HCC entered onto the study had been previously treated with systemic chemotherapy and had persistent unresectable disease. Both patients had a PR to HACE with a decrease in tumor size, as measured by imaging studies. One patient achieved a surgical CR after four courses of HACE (Fig 1) and is alive without evidence of disease at more than 73 months after study entry. The other patient continued to have an unresectable tumor and eventually died of PD. The newly diagnosed patient with unresectable HCC was an ex-primie male with bronchopulmonary dysplasia and liver cirrhosis secondary to prolonged total parenteral nutrition during the neonatal period. He achieved a PR after five courses of HACE. He went on to have a surgical resection of the tumor with microscopic residual disease, followed by two more courses of HACE to the area of residual disease. He remained alive with no radiographic evidence of disease for 42 months before his death as a result of progressive liver failure secondary to progressive cirrhosis. No autopsy was obtained due to parental refusal.
The two patients with undifferentiated sarcoma of the liver had signs of PD after one course of HACE. These two patients had received prior systemic chemotherapy with no tumor response. Both patients died of PD within 6 months after study entry. Table 2 shows the toxicity associated with the 46 courses of HACE. All HACE courses were associated with transient mild to moderate elevation (three to five times normal) of bilirubin, AST, ALT, and alkaline phosphatase levels. Fever was reported after 68% (31 of 46) of the HACE treatments, nausea and vomiting in 63% (29 of 46), transient coagulopathy (low platelets, prolonged prothrombin time/partial thromboplastin time) in 63% (29 of 46), and pain in 47% (22 of 46). These symptoms tended to diminish in frequency and intensity with subsequent HACE treatments. Fever, nausea, and vomiting frequently resolved within 2 to 3 days of the procedure and was controlled with hydration and antiemetics. Pain was frequently managed with morphine during the first 24 hours after the procedure. The only significant complication associated with the procedure occurred after the first HACE treatment to the patient with newly diagnosed HCC. This patient had the total volume of the HACE suspension (8.75 mL) injected without achieving stasis, whereas the average volume infused during the other 45 courses of HACE was 3.2 mL before stasis was achieved. This patient developed tumor lysis syndrome and disseminated intravascular coagulation within 24 hours after the procedure. He also developed myelosuppression and mucositis during this course of treatment and CNS hemorrhage secondary to thrombocytopenia, which resolved without sequelae.
The plasma concentrations of cisplatin and doxorubicin were determined after nine courses of HACE in five patients. No detectable levels of these drugs were observed in any of the samples collected at the end of the solution injection, ie, at 1 hour and 24 hours after completion of the HACE treatment.
Preoperative chemotherapy has increased the number of children with HB amenable to complete surgical resection and consequently has improved the overall survival of these children.1-3,5 However, survival of children whose HB is surgically unresectable at diagnosis or after chemotherapy remains dismal.1,2-5,7 Furthermore, chemotherapy has not been equally effective in childhood HCC, and the prognosis for these patients remains extremely poor. These results indicate the need for investigation of new therapeutic alternatives, which would improve hitherto unsatisfactory results. OLT has been used as a means of achieving aggressive surgical control of primary hepatic tumors. Overall survival for patients undergoing OLT for all types of hepatic malignancies ranges from 20% to 40%, with a tumor recurrence rate of approximately 50%.8-10 Although OLT is being indicated in a larger number of patients, the number of liver donors remains limited. Furthermore, the immunosuppression required after OLT is associated with detrimental effects as well as an increased risk of tumor recurrence.11 A combination of permanent or transient interruption of the hepatic arterial flow and intra-arterial chemotherapy infusion has been used as palliative treatment for hepatic tumor.12-15 Chemoembolization refers to the intra-arterial co-administration of chemotherapeutic and vascular occlusive agents to treat malignant disease. Intra-arterial injection of anticancer agents increases the local concentration of drugs and reduces systemic side effects, while the intra-arterial embolization causes ischemic necrosis of the tumor.16 Chemoembolization of the liver has been studied in the adult population using a variety of embolic materials and drugs.17-19 Venook et al20 treated 31 patients with unresectable HCC with a mixture of Gelfoam (Pharmacia & Upjohn, Bridgewater, NJ) and three drugs (doxorubicin, mitomycin, and cisplatin). Of 26 assessable patients, 11 showed a greater than 50% tumor reduction on CT scan, with no toxic deaths. Shibata et al21 treated 71 patients with cisplatin suspended in lipiodol. A PR (> 50% tumor reduction) was seen in 33 patients (46.5%), and a minor response (> 25% and < 50% tumor reduction) was seen in 20 patients (28.2%). This method has also been shown to be effective in children.22-24 The present study demonstrates that chemoembolization is feasible in children with primary hepatic tumors and that it can induce a significant reduction in tumor size, making these tumors amenable to surgical resection. All six patients with progressive or recurrent HB and the three patients with HCC had a response to HACE, as demonstrated by a decrease in tumor size and AFP levels; however, the two patients with undifferentiated sarcoma of the liver showed no response to therapy. Although, complete resection or resection with microscopic residual disease was feasible in five of 11 patients, only three patients remain alive with no evidence of disease. However, because these patients were previously heavily exposed to systemic chemotherapy, our result suggests that chemoembolization should be used before tumor progression as adjuvant therapy in an attempt to induce tumor resectability. Overall, repetitive courses of chemoembolization were well tolerated. Transient elevation of AST, ALT, alkaline phosphatase, and bilirubin levels, coagulopathy, fever, nausea, vomiting, and pain were well tolerated with supportive measures alone. The only significant toxicity resulted from the unexpected lysis of the tumor after the first treatment to the newly diagnosed patient with HCC. This patient showed signs of tumor lysis and disseminated intravascular coagulation within 24 hours after chemoembolization and was the only one to develop systemic toxicity, ie, myelosuppression and mucositis. We believe that this was due to the highly vascular nature of his tumor and possibly due to the fact that the tumor was not previously exposed to systemic chemotherapy. Since stasis was never achieved, the patient received a systemic dose of 100 mg of cisplatin and 30 mg of doxorubicin, which represents an approximately 40% higher dose than the standard systemic dose of cisplatin (100 mg/m2) and doxorubicin (30 mg/m2) for his calculated surface area. The higher total chemotherapy dose and the fact that no stasis was achieved may account for the fact that this was the only course associated with systemic toxicity. This event prompted us to limit the total volume of the chemoembolization suspension given during each HACE treatment so that it would not exceed cisplatin 100 mg/m2 and doxorubicin 30 mg/m2 per HACE course. Recently reported results of a randomized trial of lipiodol chemoembolization and conservative treatment for patients with unresectable HCC showed that chemoembolization did not significantly improve survival despite the fact that it induced a clearly better intrahepatic tumor control.25 The study postulates that repetitive courses of chemoembolization may have exacerbated the underlying cirrhotic damage, because most deaths in the chemoembolization arm were related to cirrhosis (liver failure, gastrointestinal hemorrhage, and peritonitis). Most pediatric hepatic tumors are not associated with cirrhotic changes, which may explain why the only patient who developed progressive liver failure was the child with HCC and cirrhosis at time of study entry. Recent studies, however, have demonstrated the efficacy and safety of transcatheter hepatic arterial chemoembolization (TACE) for the treatment of HCC26,27 and hepatic metastasis of colorectal carcinomas.28 Rose et al26 showed that patients with unresectable HCCs treated with TACE had a longer overall survival time when compared with those patients who received supportive care alone (9.2 months v < 3 months, respectively). Other studies have demonstrated that TACE can provide a chance for tumor resection for those patients with HCC whose tumors were initially judged to be unresectable,29-31 and that TACE is efficacious as a strategy to minimize the risk of tumor progression before OLT for patients with HCC.32 Also, treatment with a combination of TACE and percutaneous ethanol injection has significantly improved the survival rate of patients with inoperable HCC.33-35 The lack of detectable plasma levels of cisplatin and doxorubicin in this study may have been a result of the timing of our sample collection. Raoul et al36 demonstrated detectable plasma levels of doxorubicin after intra-arterial chemoembolization; however, they dropped to undetectable concentrations within the first hour. In conclusion, the use of chemoembolization for children with primary hepatic liver tumors is feasible and associated with tolerable toxicity. HACE is an attractive therapeutic alternative for children who continue to have unresectable tumors after systemic chemotherapy and for children with nonmetastatic HCC.
Supported by a grant from the Cancer Research Foundation of America, Alexandria, VA.
1. Ortega JA, Krailo MD, Haas JE, et al: Effective treatment of unresectable or metastatic hepatoblastoma with cisplatin and continuous infusion doxorubicin chemotherapy: A report from the Childrens Cancer Study Group. J Clin Oncol 9:2167-2176, 1991[Abstract] 2. Weinblatt ME, Siegel SE, Siegel MM, et al: Preoperative chemotherapy for unresectable primary hepatic malignancies in children. Cancer 50:1061-1064, 1982[Medline] 3. Exelby PR, Filler RM, Grosfeld JL: Liver tumors in children in the particular reference to hepatoblastoma and hepatocellular carcinoma: American Academy of Pediatrics surgical section survey–1974. J Pediatr Surg 10:329-337, 1975[Medline] 4. Clatworthy HW, Schiller M, Grosfeld JL: Primary liver tumors in infancy and childhood. Arch Surg 93:355-359, 1974 5. Quinn JJ, Altman AJ, Robinson HT, et al: Adriamycin and cisplatin for hepatoblastoma. Cancer 56:1926-1929, 1985[Medline] 6. Israel M, Pregg WJ, Wilkinson PM: Liquid chromatography analysis of Adriamycin and metabolites in biologic fluids. J Liquid Chromatogr 1:799-809, 1978 7. Ninane J, Perilongo G, Stalens JP, et al: Effectiveness and toxicity of cisplatin and doxorubicin (PLADO) in childhood hepatoblastoma and hepatocellular carcinoma: A SIOP pilot study. Med Pediatr Oncol 19:199-203, 1991[Medline] 8. O’Grady JG, Polson RJ, Rolles K, et al: Liver transplantation for malignant disease. Ann Surg 207:373-379, 1988[Medline] 9. Ringe B, Weittekind C, Bechstein WO, et al: The role of liver transplantation in hepatobiliary malignancy. Ann Surg 209:88-98, 1989[Medline] 10. Koneru B, Cassavilla A, Bowman J, et al: Liver transplantation for malignant tumors. Gastroenterol Clin North Am 17:177-193, 1988[Medline] 11. Whitington PF, Balistreri WF: Liver transplantation in pediatrics: Indications, contraindications, and pretransplant management. J Pediatr 118:169-177, 1991[Medline] 12. Fortner JG, Mulcare RJ, Solis A, et al: Treatment of primary and secondary liver cancer by hepatic artery ligation and infusion chemotherapy. Ann Surg 178:162-165, 1973[Medline] 13. Koudhal G, Funding J: Hepatic artery ligation in primary and secondary hepatic cancer. Chir Scand 138:289-294, 1972 14. Oberfield RA, McCaffrey JA, Polio J, et al: Prolonged and continuous percutaneous intra-arterial hepatic infusion chemotherapy in advanced metastatic liver adenocarcinoma from colorectal primary. Cancer 44:414-423, 1979[Medline] 15. Patt YZ, Mavligit GM, Chuang VP, et al: Percutaneous hepatic arterial infusion (HAI) of mitomycin-C and floxuridine (FUDR): An effective treatment for metastatic colorectal carcinoma in the liver. Cancer 46:261-265, 1980[Medline]
16.
Daniels JR, Sternlicht M, Daniels AM: Collagen chemoembolization: Pharmacokinetics and tissue tolerance of cis-diamminedichloroplatinum (II) in porcine liver and rabbit kidney. Cancer Res 48:2446-2450, 1988 17. Yoshioka T, Hashida M, Muranashi S, et al: Specific delivery of mitomycin C to the liver, spleen and lung: Nano- and microspherical carriers of gelatin. Int J Pharm (Amst) 81:131-141, 1981 18. Lorelius LE, Benedetto AR, Blumhardt R, et al: Enhanced drug retention in VX2 tumors by use of degradable starch microspheres. Radiol 19:212-215, 1984
19.
Ensminger WD, Gyves JW, Stetson P, et al: Phase I study of hepatic arterial degradable starch microspheres and mitomycin. Cancer Res 45:4464-4467, 1985 20. Venook AP, Stagg RJ, Lewis BJ, et al: Chemoembolization for hepatocellular carcinoma. J Clin Oncol 8:1108-1114, 1990[Abstract] 21. Shibata J, Fujiyama S, Sato T, et al: Hepatic arterial injection chemotherapy with cisplatin suspended in an oily lymphographic agent for hepatocellular carcinoma. Cancer 64:1586-1594, 1989[Medline] 22. Ogita S, Tokiwa K, Taniguchi H, et al: Intraarterial chemotherapy with lipid contrast medium for hepatic malignancies in infants. Cancer 60:2886-2890, 1987[Medline] 23. Sue K, Ikeda K, Nakagawara A, et al: Intrahepatic arterial injections of cisplatin-phosphatidylcholine-lipiodol suspension in two unresectable hepatoblastoma cases. Med Pediatr Oncol 17:496-500, 1989[Medline] 24. Nakagawa N, Cornelius A, Kao SC, et al: Transcatheter oily chemoembolization for unresectable malignant liver tumors in children. J Vasc Interv Radiol 4:353-358, 1993[Medline]
25.
Group d’Etude et de Traitement du Carcinome Hepatocellulaire: A comparison of lipiodol chemoembolization and conservative treatment for unresectable hepatocellular carcinoma. N Engl J Med 332:1256-1261, 1995 26. Rose DM, Chapman WC, Brockenbrough AT, et al: Transcatheter arterial chemoembolization as primary treatment for hepatocellular carcinoma. Am J Surg 177:405-410, 1999[Medline] 27. Gattoni F, Cornalba G, Brambilla G, et al: Survival of 184 patients with hepatocellular carcinoma in cirrhotic liver treated with chemoembolization: A multicentric study. Radiol Med 95:362-368, 1998 28. Tellez C, Benson AB, Lyster MT, et al: Phase II trial of chemoembolization for the treatment of metastatic colorectal carcinoma to the liver and review of the literature. Cancer 82:1250-1259, 1998[Medline] 29. Taschieri AM, Elli M, Cristaldi M, et al: Hepatocarcinoma: Considerations on surgical treatment in a personal series of 23 patients. Hepatogastroenterology 46:2500-2503, 1999[Medline] 30. Raoul JL: Is chemoembolization of value in inoperable primary hepatocellular carcinoma. HPB Surg 10:406-408, 1998[Medline] 31. Fan J, Tang ZY, Yu YQ, et al: Improved survival with resection after transcatheter arterial embolization (TACE) for unresectable hepatocellular carcinoma. Dig Surg 15 (6):674-678, 1998[Medline] 32. Harnois DM, Steers J, Andrews JC, et al: Preoperative hepatic artery chemoembolization followed by orthotopic liver transplantation for hepatocellular carcinoma. Liver Transpl Surg 5:192-199, 1999[Medline] 33. Allagaier HP, Deibert P, Olschewski M, et al: Survival benefit of patients with inoperable hepatocellular carcinoma treated by combination of transarterial chemoembolization and percutaneous ethanol injection: A single-center analysis including 132 patients. Int J Cancer 79:601-605, 1998[Medline] 34. Palma LD: Diagnostic imaging and interventional therapy of hepatocellular carcinoma. Br J Radiol 71:808-818, 1998[Abstract] 35. Troisi R, Defreyne L, Hesse UJ, et al: Multimodal treatment for hepatocellular carcinoma on cirrhosis: The role of chemoembolization and alcoholization before liver transplantation. Clin Transplant 12:313-319, 1998[Medline] 36. Raoul JL, Heresbach D, Bretagne JF, et al: Chemoembolization of hepatocellular carcinomas: A study of the biodistribution and pharmacokinetics of doxorubicin. Cancer 70:585-590, 1992[Medline] Submitted December 2, 1998; accepted November 15, 1999.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
