讀書匯報(bào)讀書匯報(bào)Mu LuwenMu Luwen2016-04-272016-04-27Intermediate stage (Barcelona clinic liver cancer stage B) HCC Asymptomatic Non-invasive Multinodular Unresectable tumors Adequate preservation of liver function Background & Aims Transarterial chemoembolization with doxorubicin-eluting beads (DC Bead; DEB-TACE) is effective in patients with Barcelona clinic liver cancer stage B hepatocellular carcinoma (HCC). The multikinase inhibitor sorafenib enhances overall survival (OS) and time-to-tumor progression (TTP) in patients with advanced HCC. This exploratory phase II trial tested the efficacy and safety of DEB-TACE plus sorafenib in patients with intermediate stage HCC.Why choose DEB-TACE？ TACE procedures can vary substantially, with regards to both the chemotherapeutic agent and embolization method, making these procedures quite heterogeneous. No consensus has been reached concerning the number of TACE administrations or the time between administrations. DEB-TACE reduce peak concentrations and total systemic exposure to doxorubicin, and ensure high concentrations in the tumor and adequate arterial occlusion. These beads show sustained, continuous release of doxorubicin for 14 days, with a significantly lower systemic plasma concentration of doxorubicin compared with intraarterial injection. DEB-TACE reduced the rates of systemic adverse events (AE) and liver toxicity compared with conventional TACE with Lipiodol and doxorubicin.Patients were included if: Age 18 years, with a life expectancy 12 weeks; BCLC stage B HCC with measurable lesions on CT or MRI; Child-Pugh class A and compensated liver function; ECOG performance status of 0; Bone marrow function (hemoglobin 9.0 g/dl; absolute neutrophil count (ANC) 1500/mm3; platelet count P60 109/L); Liver function (bilirubin 3 mg/dl; ALT and AST5 times the upper limit of normal (ULN); no ascites; alkaline phosphatase 4 times upper limit of normal (ULN); PT-INR 2.3 or PT 6 seconds above control) kidney function (serum creatinine 1.5 times ULN; amylase and lipase 3 times ULN).Patients were excluded if： diffuse HCC; vascular invasion (including segmental portal obstruction); extrahepatic tumor spread; advanced liver disease, as shown by Child-Pugh class B or C liver function, gastrointestinal bleeding, encephalopathy, or ascites; contraindications for embolization, including known hepatofugal blood flow or portosystemic shunt. if the target lesion had previously undergone local treatment, including resection, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), or TACE; if they had received local therapy within 4 weeks of a baseline scan; had prior transarterial embolization or TACE; were previously treated with a kinase inhibitor; had received anthracyclines or radiotherapy for HCC. Study protocol Patients were randomized 1:1 to DEB-TACE (300500 lm beads; 150 mg doxorubicin) plus sorafenib (400 mg twice daily, continuously) or matching placebo. Patients were stratified by geographic region (Americas, Europe, Asia Pacific) and by serum alpha-fetoprotein (AFP) concentration (2; platelet count 60109/L. Kudo M, Matsui O, Izumi N, et al. Transarterial chemoembolization failure/refractoriness: JSH-LCSGJ criteria 2014 update. Oncology. 2014. 87 Suppl 1: 22-31.Trial profileEnrolled 307 patients at 85 centers in 13 countries.Results of the SPACE trialTTPTime to MVI/EHSOSTime to unTACEable progression (TTUP)Overall response rate (ORR) Disease control rate (DCR)SafetyTime-to-progression (TTP)Time to macrovascular invasion/extrahepatic spread (MVI/EHS)Time to unTACEable progression (TTUP) The leading cause in the sorafenib arm was deterioration of Child-Pugh status (68/110 or 61.8% of patients). In the placebo arm it was failure to achieve an objective response (50/96 or 52.1%) followed by deterioration of Child-Pugh status (41/96 or 42.7%).Overall survival (OS) The median OS not reached in either group after a median follow-up of 270 days (52 events) and 272 days (49 events), respectively.Safety Four deaths in the sorafenib arm (two due to hepatobiliary/liver dysfunction and one each to constitutional (unspecified) and syndromeother (unspecified) One death in the placebo arm (due to perforation of the duodenum)Safety Summary The combination of sorafenib plus DEB-TACE was feasible, with manageable toxicities, in patients with intermediate stage HCC and good liver function. The combination did not provide meaningful clinical benefit compared with DEB-TACE alone. The regional differences highlight that the amount of combined treatment received may have been a critical determinant of the clinical outcomes. Discordance between investigator and central radiologic review and the criteria for additional TACE also may have impacted outcomes. Whether DEB-TACE is the optimal backbone for combination with sorafenib is still unresolved.ThinkingTACE and Sorafenib: A Good Marriage? The multidisciplinary approach to treating HCC. TACE causes increased hypoxia leading to an upregulation in hypoxia inducible factor-1 (HIF-1), which in turn upregulates vascular endothelial growth factor (VEGF), platelet-derived growth factor receptor, and increases tumor angiogenesis. The use of an antiangiogenic therapy in combination with TAE is supported in a preclinical model to cause a reduction in tumor volume and vessel density, as well as a prolongation in survival compared with TAE alone.Li X, Feng GS, Zheng CS, et al: Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 10:2878-2882, 2004Wang B, Xu H, Gao ZQ, et al: Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol 49:523-529, 2008Jiang H, Meng Q, Tan H, et al: Antiangiogenic therapy enhances the efficacy of transcatheter arterial embolization for hepatocellular carcinomas. Int J Cancer 121:416-424, 2007 The dose modification and treatment discontinuation More than one-third of patients in the sorafenib group received only one round of TACE, with the major reasons for TACE discontinuations in the sorafenib arm being worsening of liver function and decrease of platelet count to 60,000/mm3. Such strict criteria did not take into account transient changes in liver function or platelet count and indeed at least 30% deemed ineligible for additional TACE per protocol did receive further TACE outside the study. The conservative TACE continuation rules in the SPACE trial may have contributed to the low response rate and shorter TTUP. The high biological heterogeneity across HCC Certain clinical or biological subsets of patients might be more likely to respond to sorafenib, and an unselected adjuvant population could obscure a signal of efficacy within a subset. However, without established predictive biomarkers of sorafenib response in advanced disease, a biomarker-enriched adjuvant population cannot be defined. The timing of antiangiogenic therapy with sorafenib The first is a sequential model where the TACE is completed and then followed by the antiangiogenic therapy. A second model is that of an interrupted approach where antiangiogenic therapy is given throughout and is only temporarily interrupted around the time of the embolization. A third model is that of continuous administration of antiangiogrenic therapy throughout the embolization period. Strebel BM, Dufour JF: Combined approach to hepatocellular carcinoma: A new treatment concept for nonresectable disease. Expert Rev Anticancer Ther 8:1743-1749, 2008 The first two models address the risk of bleeding from continuing sorafenib at the time of an invasive vascular procedure like TACE or DEB-TACE. The third continuous administration approach, as yet untested clinically, aims at inhibiting the surge of VEGF after embolization that rises to approximately 160% of the baseline level on day 1, and falls back to 130% and 120% on days 2 and 3, respectively. The optimal clinical approach will depend on the balance between safety and efficacy. Li X, Feng GS, Zheng CS, et al: Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 10:2878-2882, 2004 The best way to assess outcome (embolization + sorefenib) RECIST criteria the EASL guidelines modified RECIST assessment Await a prospective validation The definition of efficacy The optimal end point controversy will remain unanswered at least for now. The SPACE study has time to tumor progression as the primary end point and defines failure of therapy as an inability to achieve objective response after more than two TACE procedures in the treated tumor nodule.In conclusion There remains no established role for sorafenib as adjuvant therapy for patients with hepatocellular carcinoma after liver-directed therapy. We should reassess the optimum starting dose of sorafenib to avoid these liabilities of delay and discontinuation for future trials and patients, across disease stages.THANK YOU!Sun Yat-sen University Cancer Center