TACE and Sorafenib: A Good Marriage?

Hepatocellular carcinoma (HCC) has always been a cancer with more questions than answers. This reflects the complexity of a disease that is actually two problems in one: the cancer itself and, in general, underlying cirrhosis of the liver. When one adds in the differing medical and philosophical approaches of the multidisciplinary specialists who manage patients with HCC, it becomes clear why the treatment algorithms remain a subject of debate. In the systemic therapy arena, doxorubicin is the most studied drug, with no less than three decades of continued experimentation. An initial phase II study that lacked a true definition of response reported a “response rate” of 79%. Thereafter many subsequent trials failed to replicate this activity. Ultimately, the true value of doxorubicin was probably best defined as the control arm of a randomized phase III trial comparing it to a combination of cisplatin, interferon, doxorubicin, and fluorouracil (PIAF). Despite an improvement in response (10% for doxorubicin versus 21% for PIAF), the study failed to show an improvement in survival (6.8 months for doxorubicin v 8.6 months for PIAF, P .83). After three decades, sorafenib broke through the 6-month median survival ceiling, with selected HCC patients surviving a median of 10.7 months and with sorafenib proving superior to placebo in two randomized phase III trials. This median survival figure was reproduced recently in the control arm of a sorafenib (10.2 months) versus sunitinib (7.9 months) randomized phase II trial. These various studies all selected patients with well-preserved liver function as one means of normalizing cancer survival compared with death from liver failure. This modest advance has encouraged investigators to aim for survival of patients with advanced HCC beyond the 1-year mark; the current strategy is to maximize the antiangiogenic effect of therapies like sorafenib. The combination of erlotinib plus bevacizumab has shown a median survival of 15.7 months and is now being tested as part of a randomized phase II study evaluating erlotinib plus bevacizumab versus sorafenib. A combination of doxorubicin plus sorafenib yielded an improvement in survival to 13.7 months and is currently being evaluated in a randomized phase III trial evaluating sorafenib plus doxorubicin versus sorafenib, Cancer and Leukemia Group B (CALGB) 80802. Local therapeutic approaches have become particularly popular based on two clinical trials reporting a survival advantage for transarterial chemoembolization (TACE) versus symptomatic treatment in select patients. Llovet et al found a 1 and 2 years survival probability of 82% and 63% for chemoembolisation, and 63% and 27% for control (chemoembolization versus control P .009), while Lo et al showed a similar actuarial survival that is significantly better in the chemoembolization group (1 year, 57%; 2 years, 31%; 3 years, 26%) compared with the control group (1 year, 32%; 2 years, 11%; 3 years, 3%; P .002). Other trials have either been negative or less compelling. A recent, and frequently cited, randomized controlled study comparing TACE, bland trans-arterial embolization (TAE), and supportive care demonstrated a survival advantage to TACE over supportive care. A meta-analysis of randomized controlled trials between 1980 and 2000 that included 2,466 patients concluded that TACE significantly reduces overall 2-year mortality, but that TACE was not more effective than TAE., but two less recent meta-analyses reported no survival advantage for different forms of local therapies including TACE. As the debate between proponents of systemic or local therapy continues, the possibility of combining the two approaches in patients with locally advanced HCC became a reality. In the article accompanying this editorial, Pawlik et al report the use of a combination of drug-eluting beads trans-arterial chemoembolization (DEB-TACE) and sorafenib in 35 patients with locally advanced unresectable hepatocellular carcinoma of whom 64% were Barcelona Clinic liver cancer (BCLC) C category of patients that are usually treated with systemic therapy. Patients received a median number of two DEB-TACE cycles (range, 1 to 5 cycles). Sorafenib was started one week before DEB-TACE with a median of 71 days of therapy (range, 4 to 620 days). Seventeen percent of all reported toxicities were grade 3 and 4, which is modest in this patient population. The study also reported disease control of 92% by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Using the European Association for the Study of the Liver (EASL) guidelines, the objective response rate was 58% and the disease control rate 100%. Thus, similar to the previously reported phase I study by Defour et al, their recommendation was that the combination be further studied. Indeed, Eastern Cooperative Oncology Group (ECOG) 1208 and Sorafenib or Placebo in Combination with Transarterial Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma (SPACE) are two such studies evaluating the combination of sorafenib and varied forms of embolization therapy in unresectable HCC. Efforts in the adjuvant, neoadjuvant, and bridging to liver transplant are currently underway in clinical trials worldwide. The study by Pawlik et al not only demonstrates the value of the multidisciplinary approach to treating HCC but also recognizes the importance of tumor biology by attempting to compensate for the increase in angiogenesis induced by embolization. TACE causes increased hypoxia leading to an upregulation in hypoxia inducible JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 29 NUMBER 30 OCTOBER 2