ObjectiveTo determine the long-term results of liver transplantation for hepatocellular carcinoma (HCC) measuring 5 cm or larger treated in a multimodality adjuvant protocol. Summary Background DataTransplant has been established as a viable treatment of HCC measuring less than 5 cm, but the results for larger tumors have been disappointing. Several studies have shown promising preliminary results when combining transplant with preoperative transarterial chemoembolization and/or perioperative systemic chemotherapy in the treatment of advanced HCC that is not amenable to resection. However, follow-up in the studies has been limited and the number of patients has been small. MethodsBeginning in October 1991, all patients with unresectable HCC measuring 5 cm or larger, as measured by computed tomography, were considered for enrollment in the authors' multimodality protocol. Entry criteria required that all patients be free of extrahepatic disease based on computed tomography scans of the chest and abdomen and bone scan and have a patent main portal vein and major hepatic veins on duplex ultrasonography. Patients received subselective arterial chemoembolization with mitomycin C, doxorubicin, and cisplatin at the time of diagnosis, repeated as necessary based on tumor response. Patients received a single systemic intraoperative dose of doxorubicin (10 mg/m 2 ) before revascularization of the new liver and systemic doxorubicin (50 mg/m 2 ) every 3 weeks as tolerated, for a total of six cycles, beginning on the sixth postoperative week. ResultsEighty patients were enrolled; 37 were eventually excluded, due mainly to disease progression while on the waiting list, and 43 underwent liver transplant. Mean pathologic tumor diameter was 5.8 Ϯ 2.7 cm. Median follow-up of surviving transplanted patients was 55.1 Ϯ 24.9 months. There were two (4.7%) perioperative deaths. Median overall survival was significantly longer in transplanted patients (49.9 Ϯ 10.42 months) than in those who were excluded (6.83 Ϯ 1.34 months). Overall and recurrence-free survival rates in transplanted patients at 5 years were 44% and 48%, respectively. A tumor size larger than 7 cm and the presence of vascular invasion correlated significantly with recurrence. Recurrencefree survival at 5 years was significantly higher for the 32 patients with tumors measuring 5 to 7 cm (55%) than the 12 patients with tumors larger than 7 cm (34%). ConclusionsA significant proportion of patients with HCC measuring 5 cm or larger can achieve long-term survival after liver transplantation in the context of multimodal adjuvant therapy. Patients with tumors measuring 5 to 7 cm have significantly longer recurrence-free survival compared with those with larger tumors.

These results demonstrate that cooption of host vasculature is an early event in tumor formation, and that persistence of this effect is related to the degree of blockade of VEGF activity.

Vascular endothelial growth factor (VEGF) is a critical promoter of blood vessel growth during embryonic development and tumorigenesis. To date, studies of VEGF antagonists have primarily focused on halting progression in models of minimal residual cancer. Consistent with this focus, recent clinical trials suggest that blockade of VEGF may impede cancer progression, presumably by preventing neoangiogenesis. However, VEGF is also a key mediator of endothelial-vascular mural cell interactions, a role that may contribute to the integrity of mature vessels in advanced tumors. Here, we report that high-affinity blockade of VEGF, using the recently described VEGF-Trap, abolishes mature, preexisting vasculature in established xenografts. Eradication of vasculature is followed by marked tumor regression, including regression of lung micrometastases. Thus, the contribution of relatively low levels of VEGF to vessel integrity may be critical to maintenance of even very small tumor masses. Potent blockade of VEGF may provide a new therapeutic option for patients with bulky, metastatic cancers.