Although there are many cancers that have defied the promise of new therapies, hepatocellular carcinoma (HCC) has long been perceived as a particularly challenging disease, a third rail of drug development: touch it and your drug is dead. This presumably represents the usual duality of problems and competing causes of death for patients with HCC—a lethal, invasive cancer and compromised hepatic function from the underlying liver disease that spawns the cancer. HCC presents other obstacles as well. Response rate, the conventional go/no-go decision maker from phase II trials, is an unreliable surrogate for HCC because of the inelasticity of the cirrhotic liver and the failure of tumor death to lead to lesion shrinkage, even when substantial tumor necrosis occurs. HCC also poses the challenge of intrinsic resistance to chemotherapy drugs as a result of increased expression of multidrug resistance transporters and active intracellular metabolism. Impaired liver function brings into question the proper dosing of medications (compared with phase I studies in patients with normal organ function) and complicates the interpretation of toxicities. Furthermore, given the wide range of primary ablative and embolization techniques used for unresectable HCC, it is typically only the far advanced patient with HCC who is referred for systemic therapy. For all of these reasons, no systemic treatment until now has been demonstrated to confer a survival advantage for patients with HCC in a randomized clinical trial. This has changed with the report and now publication of the Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol (SHARP), a study comparing sorafenib with placebo in patients with HCC. The multikinase inhibitor sorafenib is a bi-aryl urea that targets the serine-threonine kinase Raf-1 and has antiangiogenic activity. Preclinical studies show that Raf-1 kinase signaling along with prolific tumor angiogenesis together play an important role in the evolution of HCC, lending a molecular rationale for the use of sorafenib in this malignancy. In the phase I setting, sorafenib demonstrated an acceptable safety profile as well as the observation of a partial response in a patient with HCC. The phase II trial of sorafenib in advanced HCC, published by Abou-Alfa et al in 2006, demonstrated minimal toxicity but also little in the way of conventional Response Evaluation Criteria in Solid Tumors (RECIST) responses. Many tumors seemed to have necrosis, however, including some with apparent size increase by conventional imaging. Survival parameters were comparable to those of the best published combinations of systemic chemotherapy in advanced HCC. What followed was the international, multicenter, randomized, double-blind, placebo-controlled, phase III SHARP trial. The SHARP trial enrolled 602 patients with advanced HCC and preserved liver function. The population comprised approximately 30% of patients with hepatitis C virus (HCV) infection, 20% with hepatitis B virus (HBV) infection, and 25% with alcoholic liver disease. Nearly all patients had Child-Pugh class A (CPA) cirrhosis, with Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned to receive sorafenib at a starting dose of 400 mg twice daily versus placebo. The primary end points were overall survival (OS) and time to symptomatic progression, and patients could remain on treatment until they experienced disease progression both radiographically and symptomatically. At the second planned interim analysis, OS was significantly longer in the sorafenib group compared with placebo, with OS of 10.7 months versus 7.9 months, respectively, and hazard ratio for sorafenib of 0.69 (P .001). There was no difference in time to symptomatic progression, though time to radiologic progression was significantly longer in the sorafenib group. Only nine RECIST responses were seen in the entire patient population. Disease control rate (a composite of complete response, partial response, and stable disease) was significantly higher in the sorafenib group (43% v 32%; P .002). This study offers the first hope for life prolongation for the more than 600,000 patients who die each year from HCC worldwide. Approximately 80% of these cases occur in developing countries with limited resources. Reminiscent of the HIV epidemic, the potential difference in availability of sorafenib for patients with advanced HCC again offers a harsh reminder of the disparities in health care between the first and third worlds. Leaving aside the challenges of access to drug, however, the question remains unanswered whether sorafenib will prove an efficacious and appropriate therapy for the majority of patients with HCC. With the first hope of an active therapy in a grim disease, there is a natural tendency toward expansiveness—the hype. Returning to the basics, one must remember to ask “Do the data from this trial apply to the patient in my office?” There are several key differences between the patients in the SHARP trial and the majority of patients with advanced HCC. Foremost among these differences is the relative proportion of viral hepatitides. In the SHARP study, HCV was the cause of liver disease in approximately 30% of patients, and HBV in approximately 20%. In contrast, more than 70% of patients with HCC in the United States JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 26 NUMBER 36 DECEMBER 2