To review the effectiveness of various treatments of cirrhotic patients with hepatocellular carcinoma.

The authors searched the MEDLINE database (1981 to 1997) for relevant studies and also consulted with colleagues in the Mount Sinai Liver Transplant Program. The search was restricted to English language publications.

Study designs of evaluations included in the review

Large series, comparative studies and multimethod approaches of various therapies.

Specific interventions included in the review

Resection, liver transplantation with and without adjuvant chemotherapy, and non-surgical methods e.g. percutaneous ethanol injection and transarterial chemoembolization.

Participants included in the review

Cirrhotic patients with hepatocellular carcinoma.

Outcomes assessed in the review

Recurrent disease and survival rates at 1, 3 and 5 years (cumulative survival rates as calculated by life-table estimates or the Kaplan- Meier method, unless they were noted to be actual survival rates (or the proportion of patients surviving at a specific time interval)).

How were decisions on the relevance of primary studies made?

The authors do not state how the papers were selected for the review, or how many of the authors performed the selection.

The authors report that the study design of each included study wasassessed but the method and results of the assessment are not reported.The authors do not state how the papers were assessed for validity, or how many of the authors performed the validity assessment.

The authors do not report who, or how many of the authors, performed the data extraction. Data were extracted for patient population characteristics, tumour stage distribution, treatment, survival, and rate of recurrent disease.

How were the studies combined?

The studies were combined in a narrative review classified into treatment categories.

How were differences between studies investigated?

The authors did not test for homogeneity.

Fourteen studies of resection were included with 3,153 participants (12 case series and 2 studies comparing two treatment strategies.) Eight studies of liver transplantation without adjuvant chemotherapy (with 433 participants) were included (6 case series and 2 studies comparing two treatment strategies). Seven studies of liver transplantation with adjuvant systemic or local chemotherapy (multimethod therapies) (n = 206) were included (7 case series). Fourteen studies of non-surgical methods for disease control were included with 592 participants in 5 of the studies (9 studies did not list the number of participants).

In resection, despite the low perioperative mortality rate seen when careful selection criteria are implemented, long-term survival is limited by recurrent tumour and progression of liver disease. Actuarial survival rates at 1, 3 and 5 years range from 62-90%, 35- 75%, and 17-53% respectively. The recurrence rate ranged from 28-78% from 1-5 years following treatment.

Using non-surgical methods, ethanol injections seem to be advantageous for small hepatocellular carcinomas in patients with poor hepatic reserve in whom surgical resection is risky. The results of systemic chemotherapy with adriamycin and 5-fluorouracil for inoperable hepatocellular carcinoma have been disappointing with response rates of less than 20%. Targeted regional chemotherapy using transcatheter arterial chemoembolization, appears to be more effective, particularly for patients with hypervascular single tumours.

In liver transplantation without adjuvant chemotherapy, results were discouraging. Actuarial survival rates at 1, 3 and 5 years range from 40-90% (8 studies), 21-77% (7 studies), and 21-36% (3 studies) respectively. The recurrence rate ranged from 4-67% (6 studies) from 1-5 years following treatment.

In liver transplantation with adjuvant chemotherapy, results were good. Actuarial survival rates at 1, 3 and 5 years range from 70- 100% (7 studies), 46-85% (4 studies), and 81% (1 study) respectively. The recurrence rate ranged from 1-8% from 1-5 years following treatment.

In summary, the authors state that the efficacy of liver transplantation for hepatocellular carcinoma has been proven mainly in patients with advanced cirrhosis and small lesions. Non-surgical measures are effective for the temporary control of disease spread in patients with unresectable small hepatocellular carcinoma and in a selected group of patients with advanced tumours. In patients with unresectable large tumours, techniques that achieve complete tumour necrosis through a combination of transcatheter arterial chemoembolization and percutaneous ethanol injection may provide better long-term disease-free survival.

The authors have clearly stated their research question. Inclusion, but not exclusion, criteria are given. The literature search is limited. Some details of the search strategy are given but they may have missed studies published outside the United States by focusing the search on only the MEDLINE database and by limiting their search to English language publications.

The data extraction is reported in tables and text and the narrative review was appropriate because of the small number of trials in each grouping and the differences between study characteristics. The quality of the included studies was not assessed and the authors have not reported on how the articles were selected, or how many of the reviewers were involved in the data selection and extraction. The authors have not tested for homogeneity.

The authors have provided a model for treatment strategy which is useful to practitioners. Although the conclusions appear to follow from the results, because of the methodological limitations of the review, the conclusions should be viewed with caution.

Practice: The authors state that in practice the treatment approach to a cirrhotic patient with hepatocellular carcinoma should be designed to achieve the lowest immediate mortality and the longest possible tumour-free survival. Several factors must be considered, including the patient's general status, the severity of liver disease, and the influence of tumour characteristics (such as size, location, and multi-focality) on outcome after resection and transplantation.

Research: The authors state that future studies may clarify the role of approaches combining neo-adjuvant chemotherapy with transplantation for large (stage III) tumours. The authors also state that in addition to developing better methods for managing cirrhotic patients with hepatocellular carcinoma, the prevention and arrest of viral infection and genetic therapies should be studied for their potential value in preventing and treating hepatocellular carcinoma.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.