Treatment of unresectable hepatocellular carcinoma : Results of a randomized controlled trial

Abstract

Most patients with hepatocellular carcinoma present late with unresectable disease and, to date, an effective and safe palliative treatment has not been found. From December 1971, to December 1981, a randomized controlled trial was conducted to evaluate the following treatments against a control group receiving only symptomatic therapy (group I): hepatic dearterialization (group II), hepatic artery ligation and cannulation for infusion of chemotherapeutic agents (group III), hepatic artery ligation and portal vein cannulation for chemotherapeutic agents infusion (group IV), and external irradiation (group V). Response to various treatments was assessed with respect to symptomatic relief and duration of survival. A total of 166 patients with histologically confirmed tumor confined to the liver were studied. All patients had similar preoperative general status and biochemical findings. Patients in group IV had the best symptomatic improvement; 58.6% responded to some degree. Hepatic artery ligation intraportal infusion (group IV) offered significantly longer survival than infusion via the intra-arterial route (group III) (p = 0.023). However, when compared with the control group, the survival times in the 4 treatment groups were not significantly different. Hepatic dearterialization (group H) had the highest 7-day mortality rate, 33.3%. The results of this trial suggested that none of the modalities of treatment studied offered patients with unresectable hepatocellular carcinoma any better survival and symptomatic palliation than did symptomatic treatment alone.

Review article: overview of medical treatments in unresectable hepatocellular carcinoma—an impossible meta‐analysis?

“…Among 53 references identified, 4 –56 23 randomized controlled trials were excluded for the following reasons: modalities were evaluated in fewer than two randomized controlled trials; 4 –14 randomized controlled trials evaluated the same treatment given by different route; 15 , 16 randomized controlled trials included patients with adenocarcinomas or hepatocarcinomas; 17 –20 randomized controlled trials evaluated multiple modalities of treatment; 21 , 22 randomized controlled trials were partially randomized; 23 or randomized controlled trials had no survival data at 1 year 24 –26 . Thirty randomized controlled trials published as full papers or abstracts were included in the present meta‐analysis 27 …”

“…New strategies are emerging using biotechnology such as gene transfer therapy, but further pre‐clinical and clinical developments are warranted before achieving true clinical benefits. Medical treatment of advanced hepatocellular carcinoma has been extensively studied using cytotoxic agents and hormonal therapy administered by systemic and loco‐regional routes 4 –56 . At present, surgical resection and orthotopic liver transplantation remain the only treatment options for resectable hepatocellular carcinoma that are able to produce disease‐free survival 57 –60 .…”

Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival

“…Four studies included 2 72 IV doxorubicin (50) Excluded (1) 73 IV doxorubicin ϩ VM26 ϩ 5-FU (n ϭ 24) Excluded (1) IV m-AMSA ϩ VM26 ϩ 5-FU (n ϭ 24) 53. Lai et al (Cancer, 1988) 74 IV doxorubicin (60) Excluded (2) 76 Oral tegafur/uracil (28) Excluded (2) 81 Arterial dearterialization (33) Excluded (2) arms, [29][30][31][32] and 2 studies included 3 arms. 27,33 Two studies applied a sequential design.…”

“…-73,75,76 immunotherapy [2], 77,79 and tamoxifen [1] 64 ) or because of an insufficient sample size to perform a meta-analytic approach in 12 cases (including arterial chemotherapy [2 studies, 118 patients], 47,52 systemic chemotherapy [2 studies, 154 patients], 74,76 interferon [2 studies, 129 patients], 78,80 antiandrogens [1 study, 244 patients], 65 octreotide [1 study, 58 patients], 66 megestrol [1 study, 45 patients], 67 internal radiation 131 I [1 study, 27 patients], 55 external radiation [1 study, 166 patients],81 and linolenic acid [1 study]) 82. …”

Hepatoma

“…Single agent therapy with 5-fluorouracil (5-FU), dichloromethotrexate, and cis platinum systemically has produced limited responses, (less than lo%), with median survivals comparable to those achieved by placebos [56-621. Responses with combination chemotherapy, including 5-FU, doxorubicin, methyl CCNU, and streptozotocin, were disappointingly low and not better than those achieved with single agents [63-701. In some series, intra-arterial chemotherapy was associated with a higher response rate, perhaps reflecting patient selection in these individual series , no significant prolongation of survival was observed in controlled clinical trials with the use of intra-arterial chemotherapy compared with intravenous drug administration [74]. Similarly, the combination of intra-arterial administration of cystostatics and hepatic artery ligation or hepatic artery ligation with portal vein infusion have shown no survival differences between treated and untreated patients [75]. Chemoembolization using doxorubicin, neocarcinostatin cisplatin, and other chemotherapeutic agents mixed with lipiodol or Gelfoam particles has also been tried [76-831. This therapeutic modality has also been used as a neoadjuvant treatment in Japan [84-861. Although some good responses were reported with the use of this approach, the real assessment of its value will require well-designed prospective randomized studies.…”