Introduction: Until today, an optimal palliative treatment regimen has not been defined for patients with advanced hepatocellular carcinoma. Since the novel cytidine analog gemcitabine has shown strong antitumor effects in vitro in a human hepatoma cell line and its therapeutic potential seems well established in several different tumors including gastrointestinal adenocarcinomas, the present phase II trial using a dose-intensified biweekly administration schedule was initiated. Patients and Methods: 17 patients with histologically confirmed unresectable advanced or metastatic hepatoma were treated with gemcitabine 2,200 mg/m2 given as a 30-min intravenous infusion on days 1 and 15. Treatment courses were repeated every 4 weeks. Results: All patients were evaluable for response and toxicity assessment. No objective response was achieved, stable disease occurred in 8 patients (47%), and 9 progressed while on chemotherapy. The median time to progression was 4 months (range 1.5–14 months), and the median survival time was 8.5 months (range 2.5–16.0+ months). Treatment was well tolerated with mild or moderate leukopenia, thrombocytopenia and anemia representing the most common side effects. Gastrointestinal and other subjective toxicities were infrequent and also generally mild. Conclusions: In view of the disappointing treatment results, gemcitabine using this particular dose regimen should not be considered for further investigation in patients with advanced hepatocellular carcinoma.

Keywords:
Gemcitabine, Chemotherapy, Hepatocellular carcinoma
1.
El-Serag HB, Mason AC: Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999;340:745–750.
2.
Venook AP: Treatment of hepatocellular carcinoma: Too many options? J Clin Oncol 1994;12:1323–1334.
3.
Schafer DF, Sorrell MF: Hepatocellular carcinoma. Lancet 1999;353:1253–1257.
4.
Minemura M, Tanimura H, Tabor E: Overexpression of multidrug resistance genes MDR1 and cMOAT in human hepatocellular carcinoma and hepatoblastoma cell lines. Int J Oncol 1999;15:559–563.
5.
Thomas A, Steward WP: Gemcitabine – A major advance? Ann Oncol 1998;9:1265–1267.
6.
Graziadei I, Kelly T, Schirmer M, et al: Antitumor effect of the nucleoside analogs 2-chlorodeoxyadenosine and 2′2′-difluorodeoxycytidine on human hepatoma HepG2. J Hepatol 1998;28:504–509.
7.
Yang T, Lin Y, Chen J, Wang H, Wang C: Phase II study of gemcitabine in patients with advanced hepatocellular carcinoma. Cancer 2000;89:750–756.
8.
Csoka K, Liliemark J, Larrson R, Nygren P: Evaluation of the cytotoxic activity of gemcitabine in primary cultures of tumor cells from patients with hematologic or solid tumors. Semin Oncol 1995;22(suppl 11):47–53.
9.
Godefridus JP, Plunkett W: Gemcitabine: Status of preclinical studies and perspectives for future clinical applications of this novel nucleoside analog. Semin Oncol 1995;22(suppl 11): 1–3.
10.
Von Hoff DD: Activity of gemcitabine in a human tumor cloning assay as a basis for clinical trials with gemcitabine. San Antonio Drug Development Team. Invest New Drugs 1996;14:265–270.
11.
Kreil A, Bauer J, Scheithauer W: In vitro Evaluierung potentiell effektiver Gemcitabinekombinationstherapien beim exokrinen Pankreaskarzinom. Acta Med Austriaca 1999;26:93–100.
12.
Kassem B, Miketic LM, Landrenau RJ, Ferson PF, Keenan R, Yousem A: Phase I study of gemcitabine given weekly as short infusion (abstract). Proc Am Soc Clin Oncol 1995;14:383.
13.
Fossella FV, Lippman SM, Shin DM, Tarassoff P, Calayag-Jung M, Perez-Soler R: Maximum-tolerated dose defined for single agent gemcitabine: A phase I dose-escalation study in chemotherapy-naive patients with advanced non-small-cell lung cancer. J Clin Oncol 1997;15:310–316.
14.
Ulrich-Pur H, Kornek GV, Raderer M, Haider K, Kwasny W, Depisch D, Greul R, Schneeweiss B, Krauss G, Funovics J, Scheithauer W: A phase II trial of biweekly high dose gemcitabine for patients with metastatic pancreatic adenocarcinoma. Cancer 2000;88:2505–1511.
15.
Valencak J, Kornek GV, Raderer M, Ulrich-Pur H, Krauss G, Greul R, Piedlich J, Pfeffel F, Haider K, Kwasny W, Schneeweiss B, Scheithauer W: Gemcitabine for the treatment of advanced biliary tract carcinomas: Evaluation of two different dose regimens. Onkologie 1999;22:498–501.
16.
Miller AB, Hoogstraten B, Staquet M: Reporting results of cancer treatment. Cancer 1981;147:207–214.
17.
Gehan EA: The determination of the number of patients required in a follow-up trial of a new chemotherapeutic agent. J Chronic Dis 1961;13:346–353.
18.
Rogatko A, Litwin S: Phase II studies: Which is worse, false positive or false negative? J Natl Cancer Inst 1996;88:62.
19.
Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 1958;53:458–481.
20.
Storniolo AM, Allerheiligen SRB, Pearce HL: Preclinical, pharmacologic, and phase I studies of gemcitabine. Semin Oncol 1997;24(suppl 7):S7-2–S7-7.
21.
Cascinu S, Frontini L, Labianca R, Catalano V, Barni S, Graiff C, Picone G, Farinati F, Zonato S, Pessi MA, Curti C, Catalano G: A combination of a fixed dose rate infusion of gemcitabine associated to a bolus 5-fluorouracil in advanced pancreatic cancer, a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Ann Oncol 2000;11:1309–1311.
© 2001 S. Karger AG, Basel
2001
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