Surgical treatment of hepatocellular carcinoma: evidence-based outcomes

Abstract

Surgeons may be severely criticized from the perspective of evidence-based medicine because the majority of surgical publications appear not to be convincing. In the top nine surgical journals in 1996, half of the 175 publications refer to pilot studies lacking a control group, 18% to animal experiments, and only 5% to randomized controlled trials (RCT). There are five levels of clinical evidence: level 1 (randomized controlled trial), level 2 (prospective concurrent cohort study), level 3 (retrospective historical cohort study), level 4 (pre-post study), and level 5 (case report). Recently, a Japanese evidence-based guideline for the surgical treatment of hepatocellular carcinoma (HCC) was made by a committee (Chairman, Professor Makuuchi and five members). We searched the literature using the Medline Dialog System with four keywords: HCC, surgery, English papers, in the last 20 years. A total of 915 publications were identified systematically reviewed. At the first selection (in which surgery-dominant papers were selected), 478 papers survived. In the second selection (clearly concluded papers), 181 papers survived. In the final selection (clinically significant papers), 100 papers survived. The evidence level of the 100 surviving papers is shown here: level-1 papers (13%), level-2 papers (11%), level-3 papers (52%), and level-4 papers (24%); therefore, there were 24% prospective papers and 76% retrospective papers. Here, we present a part of the guideline on the five main surgical issues: indication to operation, operative procedure, peri-operative care, prognostic factor, and post-operative adjuvant therapy.

Figures

Figure 1

Selection criteria and proportion of evidence level in surgical treatment of hepatocellular carcinoma. We searched the literature using the Medline Dialog System with four keywords: HCC, surgery, English papers, in the last 20 years. The 915 publications were systematically reviewed by 3 steps. Almost all publications were retrospective (76%), there were only 24 (24%) with a high level evidence.

Figure 2

Algorithm before proceeding to safety hepatectomy for HCC with cirrhotic liver. Makuuchi's criteria include three factors: ascites, total serum bilirubin, and the ICG-R15: indocyanine green 15 min retention rate. This algorithm shows the maximal area for which an operation can be performed safely.

Figure 3

Treatment for HCC with portal vein tumor thrombus. Patient survival can be improved by TACE plus hepatectomy, when the number of primary nodules is not greater than two, the portal trunk is not occluded by tumor thrombus, and the indocyanine green retention rate at 15 min is > 20%. Minagawa et al. Ann Surg. 2001.

Figure 4

The result of repeat hepatic resection. Repeat hepatic resection is a satisfactory result in patients previously having undergone resection of a single HCC at primary resection and in whom recurrence developed after a disease-free interval of one year or more and the recurrent tumor had no portal invasion. Minagawa et al. Ann Surg. 2003.

Figure 5

Anatomical resection in HCC. Overall (A) and disease-free (B) survival in anatomical and non-anatomical resection for single HCC. Both the five-year overall survival and disease-free survival rates in the anatomic resection group were significantly better than those in the non-anatomic resection group. Hasegawa et al. Ann Surg. 2003.

Figure 6

The relation between blood transfusion and recurrence. A close relationship between blood transfusion and recurrence-free survival was shown. Yamamoto et al . surgery 1994.

Figure 7

Prognostic factors in HCC. The eight main prognostic factors (vascular invasion, liver function, the stage of TNM classification, tumor diameter, number of tumor, degree of cirrhosis, Edmondson classification, and pathological type) were identified in twelve major publications. Vascular invasion, pTNM stage, and liver function are the most powerful prognostic factors.

Figure 8

Adoptive immunotherapy in HCC. Autologous lymphocytes activated in vitro with recombinant interleukin-2 and infused five times during the first month. Adoptive immunotherapy reduces recurrence and improves recurrence-free survival after surgery for HCC. Takayama et al. Lancet 2000.

Figure 9

Effects of adjuvant therapy in HCC. Relative risk of recurrence in three RCTs by meta-analysis. The boxes show the relative risk, and the lines indicate 95% CI. A significant relative risk reduction was seen for recurrence (60%, SD 16%). O-E: observed-expected difference by Peto’s method. Takayama et al. Cancer Reviews 2003.