Chapter 4: Chemotherapy and radiotherapy

Abstract

Hepatology ResearchVolume 40, Issue s1 p. 74-95 Free Access Chapter 4: Chemotherapy and radiotherapy First published: 19 May 2010 https://doi.org/10.1111/j.1872-034X.2010.00657.xCitations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat INTRODUCTION UNLIKE CHEMOTHERAPY FOR other malignant tumors, there are relatively few articles on chemotherapy for hepatocellular carcinoma with a high evidence level using designs such as randomized controlled trials (RCT) involving many patients. Various chemotherapy regimens have been reported, but most are phase I/II prospective or retrospective studies without a control group. In articles published up to June 2007, according to our published work searched, no standard chemotherapy for the treatment of advanced hepatocellular carcinoma has been established. Nonetheless, a large-scale, double-blind, RCT demonstrated the efficacy of sorafenib for advanced hepatocellular carcinoma in July 2008; this may well become a standard treatment in the future. In Japan, sorafenib was approved in May 2009. As of 2008, the following anticancer drugs had been approved for hepatocellular carcinoma in the insurance medical examination. Currently, the health-care insurance is not applicable to other anticancer drugs mentioned in the Guidelines: • Alkylating agents (mustards) Cyclophosphamide • Antimetabolites (pyrimidines) Fluorouracil (5-FU), Tegafur–uracil combination drug (UFT), Cytarabine • Antibiotics (anthracyclines) Doxorubicin, Epirubicin, Mitoxantrone • Antibiotics (others) Mitomycin C • Platinum Cisplatin* • Molecular-targeted agents Sorafenib ( *Arterial injection ) SELECTION OF PUBLISHED WORK Using MEDLINE as a database for our search, we identified 855 articles written in English that were published during the period from 1982 to the third week of October 2002, with study designs involving guidelines, systematic review, meta-analysis, RCT, controlled clinical trial (CCT), clinical trial, multicenter study, cohort study, case–control study and case series, using “hepatocellular carcinoma” and “chemotherapy” as key words. We evaluated their abstracts. For the Japanese published work, we evaluated the abstracts of 2103 articles found using the Japana Centra Revuo Medicina as a database with “hepatocellular carcinoma” and “chemotherapy” as key words. In principle, the English-language published work was adopted, and we selected assessments based on the article style, sample size and study design. In addition, treatments including embolization, pre- and postoperative chemotherapy, drugs under development and drugs no longer used were excluded. Ambiguous assessments of antitumor effect were also eliminated. In the revised version, we also evaluated the abstracts of articles corresponding to a search formula specified for clinical questions (CQ) among reports published up to June 2007. SECTION 1. CHEMOTHERAPY CQ31 For which hepatocellular carcinoma patients should chemotherapy be performed? RECOMMENDATION There is no recommendation based on scientific evidence that hepatocellular carcinoma is an indication for chemotherapy. (grade C1) SCIENTIFIC STATEMENT Because no article examining the indications for chemotherapy themselves was found, we reviewed a selection of target patients in articles on studies of chemotherapy for hepatocellular carcinoma. Chemotherapy for hepatocellular carcinoma was provided to patients to whom the existing treatments such as surgery, transcatheter arterial embolization (TAE) and percutaneous therapy was not applicable. Some articles do not clearly mention the stages of hepatocellular carcinoma such that there was a lack of consistency among the reports. In those stating the stages of hepatocellular carcinoma, chemotherapy was given to patients with tumor thrombosis in the major portal vein or the primary branch, bilateral lobe multiple intrahepatic tumors and distant metastasis. In a report evaluating the effect of factors for systemic chemotherapy, there were no responders among patients with performance status 2–3, the presence of ascites, tumor occupying more than 50% of the liver, major portal vein tumor thrombus and a serum bilirubin level of 2.0 mg/dL or higher. Therefore, it was concluded systemic chemotherapy cannot be recommended for patients with highly advanced hepatocellular carcinoma or patients with severely impaired liver function (LF024401 level 4). Hepatic arterial infusion chemotherapy was performed in patients with tumor thrombosis or multiple intrahepatic tumors. With regard to advanced hepatocellular carcinoma with distant metastasis, there are reports on studies giving chemotherapy only to patients with distant metastasis (LF102382 level 4, LF101923 level 4), and there was no scientific evidence that chemotherapy is not indicated for such patients. COMMENTS Because no articles discussed the indications for chemotherapy themselves, no recommendations based on scientific evidence were made. This time, we organized the selection of patients in the articles in relation to the indications for chemotherapy as a reference. The majority of subjects were patients who were not candidates for the existing treatments including hepatectomy, local therapy and embolization, or were difficult to treat using these modalities. The eligibility criteria for the subjects were specified according to drugs to be used: white blood cell count (neutrophil count), platelet count, performance status, renal function (serum creatinine level), liver function (serum bilirubin and aminotransferases) and cardiac function (e.g. past history of myocardial infarction). REFERENCES 1 LF02440 Nagahama H, Okada S, Okusaka T et al. Predictive factors for tumor response to systemic chemotherapy in patients with hepatocellular carcinoma. Jpn J Clin Oncol 1997; 27: 321– 4. CrossrefCASPubMedWeb of Science®Google Scholar 2 LF10238 Ikeda M, Okusaka T, Ueno H, Takezako Y, Morizane C. A phase II trial of continuous infusion of 5-fluorouracil, mitoxantrone, and cisplatin for metastatic hepatocellular carcinoma. Cancer 2005; 103: 756– 62. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 3 LF10192 Park SH, Lee Y, Han SH et al. Systemic chemotherapy with doxorubicin, cisplatin and capecitabine for metastatic hepatocellular carcinoma. BMC Cancer 2006; 6: 3. CrossrefCASPubMedWeb of Science®Google Scholar CQ32 Is hepatic arterial infusion chemotherapy more beneficial than systemic chemotherapy? RECOMMENDATION There is no sufficient scientific evidence that hepatic arterial infusion chemotherapy is more beneficial than systemic chemotherapy. (grade C1) SCIENTIFIC STATEMENT With regard to the accumulation of drugs in hepatocellular carcinoma by hepatic arterial infusion chemotherapy and systemic chemotherapy, a comparison using cisplatin (CDDP) revealed that accumulation of the drug in tumors was higher for hepatic arterial infusion chemotherapy (LF018851 level 4). In an RCT comparing hepatic arterial infusion chemotherapy and systemic chemotherapy with doxorubicin, the antitumor effect (response rate) of the former was superior (60% vs 44.1%, Table 3), but there was no statistically significant difference in survival time between the two groups (LF022152 level 1b). Hepatic arterial infusion chemotherapy using an implantable subcutaneous arterial port was superior in terms of duration of hospitalization, costs and quality of life (QOL) (LF024193 level 2a, LF026534 level 4). Table 3. Administration chemotherapeutic drugs for hepatocellular carcinoma: Response rate and survival time by drug (hepatic arterial infusion, 30 patients or more) Drug No. of patients Response rate (%) Median survival (m) Reference ID Study design EV level Single drug doxorubicin (HAI) 72 60 7.0 LF022151 RCT Level 1b doxorubicin (systemic) 44.1 6.5 CDDP 67 37 10.7 LF018852 Cohort study Level 4 Multiple drug CDDP, 5-FU (low FP) 52 71 ND LF003193 Case-control study Level 2b CDDP, 5-FU (low FP) 48 48 10.2 LF071404 Case-control study Level 4 CDDP, 5-FU (low FP) 37 56.3 32.4 LF100335 Case-control study Level 3 CDDP, 5-FU (low FP) 38 47 6.2 LF101516 Cohort study Level 4 CDDP, 5-FU 41 22 12.0 LF116637 Cohort study Level 4 CDDP, mitomycin C, 5-FU, LV 53 28.3 13.2 LF120768 Cohort study Level 4 IFN, CDDP 68 33 4.4 LF020899 RCT Level 1b CDDP 14 2.6 BSC 1.2 IFN, CDDP, 5-FU, MTX, LV 34 45 ND LF0191610 Cohort study Level 4 IFN, 5-FU 116 52 6.9 LF1024411 Cohort study Level 2b 5-FU, 5-fluorouracil; BSC, best supportive care; CDDP, cisplatin; HAI, hepatic arterial infusion; IFN, interferon; low FP, 5-fluorouracil + cisplatin; LV, leucovorin; MTX, methotrexate; ND, not described; RCT, randomized controlled trial. COMMENTS Hepatic arterial infusion chemotherapy requires a special procedure but can be used to administrate anticancer drugs at high concentrations directly into the hepatocellular carcinoma and maintain the concentrations of these drugs at low systemic levels; thus, the incidence of generalized adverse reactions may be low. There was only one RCT comparing systemic chemotherapy and hepatic arterial infusion chemotherapy as treatment methods for hepatocellular carcinoma, but the data were not sufficient to conclude that arterial infusion chemotherapy would be useful. In addition, we also compared response rates in articles on studies of each type of chemotherapy. While sample size and the selection of subjects varied, response rates for systemic chemotherapy and hepatic arterial infusion chemotherapy were reportedly 0–39% and 14–71%, respectively; the rate thus tended to be higher for hepatic arterial infusion chemotherapy (see Tables 1–3). Based on these response rates, a difference in the response rate in an RCT, and a report on hepatic arterial infusion chemotherapy being superior in terms of the duration of hospitalization, cost and QOL, we have determined that hepatic arterial infusion chemotherapy is more beneficial. Nonetheless, evidence from the RCT is available from only one study. In the study, the sample size in each group is approximately 35 patients, no significant difference in survival is seen, and no conclusion as to the usefulness of hepatic arterial infusion is drawn. For these reasons, the degree of this recommendation was rated grade C1. Table 1. Administration route of chemotherapeutic drugs for hepatocellular carcinoma: Response rate and survival time by drug (systemic administration, single drug, 30 patients or more) Drug No. of patients Response rate (%) Median survival (m) Reference ID Study design EV level doxorubicin 106 3.3 10.6 LF030631 RCT Level 1b placebo 7.5 doxorubicin 35 28 ND LF033112 RCT Level 1b VP-16 18 ND doxorubicin 66 24.5 8.0 LF032383 CCT Level 4 doxorubicin 52 11 4.2 LF032654 Cohort study Level 4 epirubicin 52 9 13.7 LF019575 Case-control study Level 4 mitoxantrone 74 8 3.3 LF031076 CCT Level 4 CDDP 17 3.3 CDDP 42 2.3 ND LF062227 Case series Level 4 topotecan 36 13.9 8.0 LF024168 Cohort study Level 4 gemcitabine 48 2.1 3.2 LF102019 Cohort study Level 4 gemcitabine 30 0 6.9 LF1207410 Cohort study Level 4 pegylated liposomal doxorubicin 40 10 3 LF1025611 Cohort study Level 4 seocalcitol 50 4 2.8 LF1019812 Cohort study Level 4 nolatrexed dehydrochloride 48 2.6 7.4 LF1060813 Cohort study Level 4 octreotide 120 0 4.7 LF1055714 RCT Level 1b placebo 0 5.3 octreotide 71 ND 5.1 LF1108215 RCT Level 1b rofecoxib ND ND octreotide, rofecoxib ND 4.9 octreotide 61 ND 11.4 LF1207916 RCT Lebel 1b placebo ND 6.5 octreotide 70 ND 1.93 LF0189817 RCT Level 1b placebo ND 1.97 octreotide 63 2 8 LF1020618 Cohort study Level 4 CCT, controlled clinical trial; CDDP, cisplatin; ND, not described; RCT, randomized controlled trial; VP-16, etoposide. Table 2. Administration chemotherapeutic drugs for hepatocellular carcinoma: Response rate and survival time by drug (systemic administration, multiple drugs, 30 patients or more) Drug No. of patients Response rate (%) Median survival (m) Reference ID Study design EV level epirubicin, VP-16 36 39 10.0 LF024021 Cohort study Level 4 epirubicin, CDDP, UFT, LV 53 16.9 5.7 LF102602 Cohort study Level 4 doxorubicin, CDDP 42 18.9 7.3 LF102583 Cohort study Level 4 gemcitabine, doxorubicin 50 11.8 4.6 LF071394 Cohort study Level 4 gemcitabine, CDDP 30 20 4.8 LF110145 Cohort study Level 4 gemcitabine, oxaliplatin 34 18 11.5 LF102476 Cohort study Level 4 gemcitabine, oxaliplatin 40 2.5 ND LF120757 Cohort study Level 4 gemcitabine, oxaliplatin, bevacizumab 33 20 9.6 LF106508 Cohort study Level 4 5-FU, mitoxantrone, CDDP 51 27 11.6 LF102389 Cohort study Level 4 5-FU, mitoxantrone, CDDP 63 28.3 4.9 LF1207710 Cohort study Level 4 IFN, CDDP 56 13.3 7.7 LF0251611 CCT Level 3 IFN, doxorubicin, tamoxifen 30 24 6 LF1051112 Cohort study Level 4 IFN, 5-FU 34 14.3 15.5 LF1064013 Cohort study Level 4 IFN, 5-FUDR, doxorubicin 30 7 3.0 LF1062314 Cohort study Level 4 IFN, CDDP, doxorubicin, 5-FU 188 20.9 6.36 LF1075915 RCT Level 1b doxorubicin 10.5 6.83 IFN, CDDP, doxorubicin, 5-FU 149 16.8 30.9 LF0188316 Case-control study Level 3 5-FU, 5-fluorouracil; CCT, controlled clinical trial; CDDP, cisplatin; IFN, interferon; LV, leucovorin; ND, not described; RCT, randomized controlled trial; UFT, tegafur/uracil; VP-16, etoposide. In terms of adverse reactions, hepatic arterial infusion chemotherapy may interfere with liver function and can cause catheter-related complications as compared with systemic chemotherapy; however, there were no articles comparing adverse reactions between these two forms of chemotherapy. As a special procedure, percutaneous hepatic perfusion has been developed, and good results have been reported (LF101305 level 4). REFERENCES 1 LF01885 Court WS, Order SE, Siegel JA et al. Remission and survival following monthly intraarterial cisplatinum in nonresectable hepatoma. Cancer Invest 2002; 20 (5–6): 613– 25. CrossrefCASPubMedWeb of Science®Google Scholar 2 LF02215 Tzoracoleftherakis EE, Spiliotis JD, Kyriakopoulou T, Kakkos SK. Intra-arterial versus systemic chemotherapy for non-operable hepatocellular carcinoma. Hepatogastroenterology 1999; 46: 1122– 5. CASPubMedWeb of Science®Google Scholar 3 LF02419 Sakai Y, Izumi N, Tazawa J et al. Treatment for advanced hepatocellular carcinoma by transarterial chemotherapy using reservoirs or one-shot arterial chemotherapy. J Chemother 1997; 9: 347– 51. CrossrefCASPubMedWeb of Science®Google Scholar 4 LF02653 Iwamiya T, Sawada S, Ohta Y. Repeated arterial infusion chemotherapy for inoperable hepatocellular carcinoma using an implantable drug delivery system. Cancer Chemother Pharmacol 1994; 33 (Suppl): S134– 8. CrossrefPubMedWeb of Science®Google Scholar 5 LF10130 Ku Y, Iwasaki T, Tominaga M et al. Reductive surgery plus percutaneous isolated hepatic perfusion for multiple advanced hepatocellular carcinoma. Ann Surg 2004; 239: 53– 60. CrossrefPubMedWeb of Science®Google Scholar CQ33 Which drugs are effective for chemotherapy? RECOMMENDATION There are no effective drugs, alone or in combination, that can be recommended as chemotherapy for hepatocellular carcinoma based on scientific evidence. (grade C1) SCIENTIFIC STATEMENT Various drugs were used alone or in multiple combinations. Many of the articles are on pilot studies with a small sample size, and drugs assumed to be effective, alone or in combinations, were in an investigational stage. Because of this, we compared response rates in individual articles. The response rates for systemic administration and hepatic arterial infusion of a single drug were 0–28% and 37–60%, respectively. The response rates for systemic administration and hepatic arterial infusion of multiple drugs were 2.5–39% and 22–71%, respectively (see Tables 1–3). COMMENTS There were reports that the response rate was above 50%, but all were non-controlled studies in a small number of patients and were rated evidence level 4; therefore, we determined that there were no drugs, alone or in combination, which could be recommended. With regard to the drugs used, mainly doxorubicin was administrated in the past. Lately, however, 5-FU and CDDP have primarily been employed. In addition, new anticancer drugs such as topotecan, gemcitabine and oxaliplatin were recently studied but showed low efficacy. The majority of reports corresponded to phase II studies with a small sample size. The response rate tended to be higher for multidrug therapy than monotherapy. A combination regimen of low-dose CDDP and 5-FU, and chemotherapy in combination with interferon (IFN) achieved relatively good response rates. Nowadays, therapy including pegylated liposome doxorubicin and octreotide aimed at prolonging survival and improving QOL, instead of increasing the response rate, are being carried out (see Tables 1–3). REFERENCES Table 1 1 LF03063 Lai CL, Wu PC, Chan GC, Lok AS, Lin HJ. Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. A prospective randomized trial. Cancer 1988; 62: 479– 83. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 2 LF03311 Melia WM, Johnson PJ, Williams R. Induction of remission in hepatocellular carcinoma. A comparison of VP 16 with adriamycin. Cancer 1983; 51: 206– 10. Wiley Online LibraryPubMedWeb of Science®Google Scholar 3 LF03238 Colombo M, Tommasini MA, Del Ninno E, Rumi MG, De Fazio C, Dioguardi ML. Hepatocellular carcinoma in Italy: report of a clinical trial with intravenous doxorubicin. Liver 1985; 5: 336– 41. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 4 LF03265 Chlebowski RT, Brzechwa-Adjukiewicz A, Cowden A, Block JB, Tong M, Chan KK. Doxorubicin (75 mg/m2) for hepatocellular carcinoma: clinical and pharmacokinetic results. Cancer Treat Rep 1984; 68: 487– 91. PubMedWeb of Science®Google Scholar 5 LF01957 Pohl J, Zuna I, Stremmel W, Rudi J. Systemic chemotherapy with epirubicin for treatment of advanced or multifocal hepatocellular carcinoma. Chemotherapy 2001; 47: 359– 65. CrossrefCASPubMedWeb of Science®Google Scholar 6 LF03107 Falkson G, Ryan LM, Johnson LA et al. A random phase II study of mitoxantrone and cisplatin in patients with hepatocellular carcinoma. An ECOG study. Cancer 1987; 60 (9): 2141– 5. Wiley Online LibraryPubMedWeb of Science®Google Scholar 7 LF06222 Ravry MJ, Omura GA, Bartolucci AA, Einhorn L, Kramer B, Davila E. Phase II evaluation of cisplatin in advanced hepatocellular carcinoma and cholangiocarcinoma: a Southeastern Cancer Study Group Trial. Cancer Treat Rep 1986; 70: 311– 12. PubMedWeb of Science®Google Scholar 8 LF02416 Wall JG, Benedetti JK, O'Rourke MA, Natale RB, Macdonald JS. Phase II trial to topotecan in hepatocellular carcinoma: a Southwest Oncology Group study. Invest New Drugs 1997; 15: 257– 60. CrossrefCASPubMedWeb of Science®Google Scholar 9 LF10201 Guan Z, Wang Y, Maoleekoonpairoj S et al. Prospective randomised phase II study of gemcitabine at standard or fixed dose rate schedule in unresectable hepatocellular carcinoma. Br J Cancer 2003; 89: 1865– 9. CrossrefCASPubMedWeb of Science®Google Scholar 10 LF12074 Fuchs CS, Clark JW, Ryan DP et al. A phase II trial of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer 2002; 94 (12): 3186– 91. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 11 LF10256 Hong RL, Tseng YL. A phase II and pharmacokinetic study of pegylated liposomal doxorubicin in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 2003; 51: 433– 8. CASPubMedWeb of Science®Google Scholar 12 LF10198 Dalhoff K, Dancey J, Astrup L et al. A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma. Br J Cancer 2003; 89: 252– 7. CrossrefCASPubMedWeb of Science®Google Scholar 13 LF10608 Jhawer M, Rosen L, Dancey J et al. Phase II trial of nolatrexed dihydrochloride [Thymitaq, AG 337] in patients with advanced hepatocellular carcinoma. Invest New Drugs 2007; 25: 85– 94. CrossrefCASPubMedWeb of Science®Google Scholar 14 LF10557 Becker G, Allgaier HP, Olschewski M, Zahringer A, Blum HE. Long-acting octreotide versus placebo for treatment of advanced HCC: a randomized controlled double-blind study. Hepatology 2007; 45 (1): 9– 15. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 15 LF11082 Treiber G, Rocken C, Wex T, Malfertheiner P. Octreotide alone or in combination with rofecoxib as palliative treatment for advanced hepatocellular cancer. Z Gastroenterol 2007; 45: 369– 77. CrossrefCASPubMedWeb of Science®Google Scholar 16 LF12079 Dimitroulopoulos D, Xinopoulos D, Tsamakidis K et al. Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: randomized placebo-controlled trial. World J Gastroenterol 2007; 13: 3164– 70. CrossrefCASPubMedWeb of Science®Google Scholar 17 LF01898 Yuen MF, Poon RT, Lai CL et al. A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology 2002; 36 (3): 687– 91. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 18 LF10206 Cebon J, Findlay M, Hargreaves C et al. Somatostatin receptor expression, tumour response, and quality of life in patients with advanced hepatocellular carcinoma treated with long-acting octreotide. Br J Cancer 2006; 95: 853– 61. CrossrefCASPubMedWeb of Science®Google Scholar Table 2 1 LF02402 Bobbio-Pallavicini E, Porta C, Moroni M et al. Epirubicin and etoposide combination chemotherapy to treat hepatocellular carcinoma patients: a phase II study. Eur J Cancer 1997; 33: 1784– 8. CrossrefCASPubMedWeb of Science®Google Scholar 2 LF10260 Kim SJ, Seo HY, Choi JG et al. Phase II study with a combination of epirubicin, cisplatin, UFT, and leucovorin in advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 2006; 57: 436– 42. CrossrefCASPubMedWeb of Science®Google Scholar 3 LF10258 Lee J, Park JO, Kim WS et al. Phase II study of doxorubicin and cisplatin in patients with metastatic hepatocellular carcinoma. Cancer Chemother Pharmacol 2004; 54: 385– 90. CrossrefCASPubMedWeb of Science®Google Scholar 4 LF07139 Yang TS, Wang CH, Hsieh RK, Chen JS, Fung MC. Gemcitabine and doxorubicin for the treatment of patients with advanced hepatocellular carcinoma: a phase I–II trial. Ann Oncol 2002; 11: 1771– 8. CrossrefWeb of Science®Google Scholar 5 LF11014 Parikh PM, Fuloria J, Babu G et al. A phase II study of gemcitabine and cisplatin in patients with advanced hepatocellular carcinoma. Trop Gastroenterol 2005; 26 (3): 115– 18. CASPubMedGoogle Scholar 6 LF10247 Louafi S, Boige V, Ducreux M et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): results of a phase II study. Cancer 2007; 109: 1384– 90. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 7 LF12075 Li S, Niu Z, Tian H et al. Treatment of advanced hepatocellular carcinoma with gemcitabine plus oxaliplatin. Hepatogastroenterology 2007; 54 (73): 218– 23. CASPubMedWeb of Science®Google Scholar 8 LF10650 Zhu AX, Blaszkowsky LS, Ryan DPK et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006; 24: 1898– 903. CrossrefCASPubMedWeb of Science®Google Scholar 9 LF10238 Ikeda M, Okusaka T, Ueno H, Takezako Y, Morizane C. A phase II trial of continuous infusion of 5-fluorouracil, mitoxantrone, and cisplatin for metastatic hepatocellular carcinoma. Cancer 2005; 103: 756– 62. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 10 LF12077 Yang TS, Chang HK, Chen JS, Lin YC, Liau CT, Chang WC. Chemotherapy using 5-fluorouracil, mitoxantrone, and cisplatin for patients with advanced hepatocellular carcinoma: an analysis of 63 cases. J Gastroenterol 2004; 39: 362– 9. CrossrefCASPubMedWeb of Science®Google Scholar 11 LF02516 Ji SK, Park NH, Choi HM et al. Combined cis-platinum and alpha interferon therapy of advanced hepatocellular carcinoma. Korean J Intern Med 1996; 11: 58– 68. CrossrefCASPubMedWeb of Science®Google Scholar 12 LF10511 Lu YS, Hsu C, Li CC et al. Phase II study of combination doxorubicin, interferon-alpha, and high-dose tamoxifen treatment for advanced hepatocellular carcinoma. Hepatogastroenterology 2004; 51 (57): 815– 19. CASPubMedWeb of Science®Google Scholar 13 LF10640 Patt YZ, Hassan MM, Lozano RD et al. Phase II trial of systemic continuous fluorouracil and subcutaneous recombinant interferon Alfa-2b for treatment of hepatocellular carcinoma. J Clin Oncol 2003; 21: 421– 7. CrossrefCASPubMedWeb of Science®Google Scholar 14 LF10623 Feun LG, O'Brien C, Molina E et al. Recombinant leukocyte interferon, doxorubicin, and 5FUDR in patients with hepatocellular carcinoma – a phase II trial. J Cancer Res Clin Oncol 2003; 129 (1): 17– 20. CASPubMedWeb of Science®Google Scholar 15 LF10759 Yeo W, Mok TS, Zee B et al. A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouraci (l PIAF) combination chemotherapy for unresectable hepatocellular carcinoma. J Natl Cancer Inst 2005; 97: 1532– 8. CrossrefCASPubMedWeb of Science®Google Scholar 16 LF01883 Leung TW, Tang AM, Zee B et al. Factors predicting response and survival in 149 patients with unresectable hepatocellular carcinoma treated by combination cisplatin, interferon-alpha, doxorubicin and 5-fluorouracil chemotherapy. Cancer 2002; 94 (2): 421– 7. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Table 3 1 LF02215 Tzoracoleftherakis EE, Spiliotis JD, Kyriakopoulou T, Kakkos SK. Intra-arterial versus systemic chemotherapy for non-operable hepatocellular carcinoma. Hepatogastroenterology 1999; 46: 1122– 5. CASPubMedWeb of Science®Google Scholar 2 LF01885 Court WS, Order SE, Siegel JA et al. Remission and survival following monthly intraarterial cisplatinum in nonresectable hepatoma. Cancer Invest 2002; 20 (5–6): 613– 25. CrossrefCASPubMedWeb of Science®Google Scholar 3 LF00319 Okuda K, Tanaka M, Shibata J et al. Hepatic arterial infusion chemotherapy with continuous low dose administration of cisplatin and 5-fluorouracil for multiple recurrence of hepatocellular carcinoma after surgical treatment. Oncol Rep 1999; 6: 587– 91. CASPubMedWeb of Science®Google Scholar 4 LF07140 Ando E, Tanaka M, Yamashita F et al. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: analysis of 48 cases. Cancer 2002; 3 (95): 588– 95. Wiley Online LibraryWeb of Science®Google Scholar 5 LF10033 Sumie S, Yamashita F, Ando E et al. Interventional radiology for advanced hepatocellular carcinoma: comparison of hepatic artery infusion chemotherapy and transcatheter arterial lipiodol chemoembolization. AJR Am J Roentgenol 2003; 181 (5): 1327– 34. CrossrefPubMedWeb of Science®Google Scholar 6 LF10151 Tanioka H, Tsuji A, Morita S et al. Combination chemotherapy with continuous 5-fluorouracil and low-dose cisplatin infusion for advanced hepatocellular carcinoma. Anticancer Res 2003; 23 (2C): 1891– 7. CASPubMedWeb of Science®Google Scholar 7 LF11663 Park JY, Ahn SH, Yoon YJ et al. Repetitive short-course hepatic arterial infusion chemotherapy with high-dose 5-fluorouracil and cisplatin in patients with advanced hepatocellular carcinoma. Cancer 2007; 110: 129– 37. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 8 LF12076 Lin CP, Yu HC, Cheng JS et al. Clinical effects of intra-arterial infusion chemotherapy with cisplatin, mitomycin C, leucovorin and 5-flourouracil for unresectable advanced hepatocellular carcinoma. J Chin Med Assoc 2004; 67 (12): 602– 10. PubMedG