Xiaobin et al. BMC Cancer 2012, 12:340 http://www.biomedcentral.com/1471-2407/12/340 Background Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and has been ranked the second leading cancer killer in China since the 1990s [1]. Chronic hepatitis B virus (HBV) infection is the most common etiology in China [2]. Curative resection remains the best choice of HCC therapeutic strategies to date, but local tumor recurrence and remote metastasis unfortunately occur in many patients who have undergone surgery. Although there have been great advances in the diagnosis and treatment of HCC, the long-term prognosis is still unsatisfactory due to a high incidence of tumor recurrence, ranging from 50% to 60% [3-6]. The reason for this high recur- rence rate is not entirely clear. Locoregional tumor re- currence with concomitant hepatic decompensation is the main cause of death. It is suggested that further strategies may be needed for the prevention and treat- ment of early and late recurrence [7]. The Pringle maneuver is a classical surgical technique widely used during hepatectomy since its advent in 1908 [8]. During hepatic resection, severe bleeding represents a major life-threatening risk [9,10]. The Pringle maneu- ver (continuous or intermittent clamping of the hepatic artery and portal vein) is routinely used to reduce intrao- perative bleeding [11,12]. It seems inevitable that man- euver causes ischemia-reperfusion (I/R) injury, resulting in complex metabolic [13,14], immunological [15], and microvascular [16-18] changes, which together might contribute to hepatocellular damage and dysfunction [13,19]. Over the past century, the effects of the Pringle maneuver have been widely discussed [8,20-32]. From the reported data, we know that the technique can sig- nificantly reduce blood loss during hepatectomy, mean- while damaging the liver remnant through the I/R injury. Interestingly, the effects of the Pringle maneuver on the prognosis of oncology patients and on the behav- ior of tumor cells have not been specifically discussed. It remains unknown whether tumor recurrence and metas- tasis can be influenced by this surgical stress. However, this possibility has been raised by the results of recent animal studies [33,34]. It has been shown that surgical stress, such as I/R injury, might cause delayed damage to the residual liver (“soil”), and may also affect the behavior of the tumor cells (“seeds”) by activating cell invasion and migration signal pathways, thus accel- erating tumor recurrence. I/R injury tends to disrupt normal liver tissues and create an environment that may promote tumor recurrence. Hepatic resection will also induce tumor cells to become more aggressive by pro- moting the production of cytokines by nonparenchymal liver cells [35]. From the results of these studies, it can easily be concluded that I/R injury to the liver remnant may be a significant factor promoting tumor recurrence Page 2 of 8 and metastasis in experimental animal models. Ani- mal models may introduce potentially important con- cepts related to the mechanisms involved in tumor recurrence associated with surgical stress, specifically hepatic I/R injury. Furthermore, the promotion of liver metastasis by hepatic I/R injury during liver re- section has been reported in colon cancer patients [36,37], and minimization of I/R injury can attenuate metastasis of colorectal cancer to the liver [38-40]. Liver transplant recipients with HCC who receive living-donor grafts experience a higher recurrence rate [41,42] due to the more severe acute-phase injury to the liver graft. For primary liver cancer patient undergoing hepatect- omy, the effects of I/R injury on tumor recurrence need to be determined. Because use of the Pringle maneuver during hepatic resection will lead to I/R injury to the liver remnant, we can rationally deduce that it may harm liver function, make the tumor cells more aggressive, and increase the likelihood of recurrence. If this is found to be true in humans, routine use of the Pringle maneu- ver should be re-evaluated. It is unfortunate that there are currently no reported data or randomized controlled studies examining this issue. Our hypothesis We hypothesize that the high incidence of tumor recur- rence and the poor long-term prognosis of patients with HCC might be partly due to the I/R injury resulting from use of the Pringle maneuver during hepatectomy. If possible, this procedure should be avoided or revised when performing a hepatectomy on cancer patients [43]. In a clinical setting, many factors such as blood loss, blood transfusion, liver function, and HBV load affect the prognosis of cancer patients. These factors may each have different, and sometimes even opposing, effects on laboratory test results. However, evaluation of the effects of the Pringle maneuver remains an important and ur- gent issue in liver surgery, which may lead to a signifi- cant change to our current knowledge. We therefore designed a multicenter, prospective, randomized trial to test our hypothesis. Methods Aims of the study This trial aims to assess the long-term effects of the Pringle maneuver on the rate of tumor recurrence after curative resection of HCC. The effects on disease-free survival, overall survival, operative morbidity and mor- tality, duration of operation, blood loss, transfusion requirements, hospital stay, intensive care unit stay, and blood test results with prognostic relevance, will be examined. The trial will test whether hepatic resection