Drug therapy: Sorafenib
Authors: Richard S. Finn
Journal: Hepatology (2010)

A 72-year-old active male patient with cirrhosis secondary to nonalcoholic steatohepatitis is evaluated for liver masses. He has no stigmata of end-stage liver disease such as ascites, icterus, or hepatic encephalopathy on physical examination. Laboratory values include a hemoglobin of 12 g/dL with a mean corpuscular volume of 98, white cell count of 3.9 thousand, platelet count of 76,000, total bilirubin of 1.2 mg/dL, albumin of 3.5 g/dL, international normalized ratio of 1.2, and serum creatinine of 1.3 mg/dL. The alpha-fetoprotein is 620 ng/mL. The computed tomographic scan of the abdomen shows two masses in the right lobe of the liver and three in the left lobe, all with arterial enhancement. The largest mass is 4 cm in diameter and appears to invade the portal vein; the liver appears cirrhotic but there is no ascites. HCC, hepatocellular carcinoma; MELD, Model for End-Stage Liver Disease; PEI, percutaneous ethanol injection; RFA, radiofrequency ablation; TACE, transarterial chemoembolization; VEGFR, vascular endothelial growth factor receptor. The above case highlights an increasing problem in medical practice. Hepatocellular carcinoma (HCC) is the third leading cause of cancer death world-wide and ranks as the fifth most common cancer diagnosis globally.1 In the United States, we have known for several years now that HCC is an increasing problem that is not expected to decrease anytime soon.2 Interestingly, unlike most malignancies, the majority of patients that develop HCC have an underlying risk factor for the disease. Overwhelmingly, viral hepatitis is the leading factor associated with the development of HCC and its association with hepatitis B or hepatitis C is largely driven by the geographic incidence of these two entities.3 In addition, other risk factors associated with the development of liver disease and cirrhosis carry a significant risk for the development of HCC including alcohol liver disease, aflatoxin exposure and metabolic liver disease from nonalcoholic steatohepatitis (NASH) and hemochromatosis among others.3 Again, in contrast to most other malignancies, because of its integral association with liver disease, the assessment of patients with HCC for treatment (i.e., "staging") must not only take into account the tumor burden ("anatomical staging") but also the patients underlying liver function ("physiological staging"). Several staging systems have been put forward without a consensus.4-6 The commonly accepted International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) Tumor Node Metastasis (or TNM) used in other solid tumors is of limited value in HCC as it does not take into account the competing risk of liver dysfunction which certainly plays a role in outcomes and treatment decisions. Most recently, the Barcelona Clinic Liver Cancer Staging (BCLCS) system has been adopted in many prospective studies in HCC for patient selection and provides a reasonable framework for clinical decision-making (Fig. 1).7 Barcelona Clinic Liver Cancer (BCLC) Staging System. Adapted from Llovet et al.7 Potentially curative treatments for HCC require surgical expertise; however, both hepatic resection and orthotopic liver transplantation require careful patient selection. Both modalities are limited in their practical implementation by the fact that most patients present with an advanced tumor burden.3 Whereas no definite size criteria for liver resection has been recognized, contraindications include radiographic evidence of vascular involvement or extrahepatic spread of the tumor because of the association with an unjustifiable high rate of recurrent tumor.3 The presence of portal hypertension (e.g., presence of esophageal varices, splenomegaly or diminished platelet count) is also a relative contraindication to liver resection as it signifies advanced liver disease, limited hepatic reserve and places the patient at a high risk for postoperative hepatic decompensation and death. Similarly, an assessment of tumor burden is required in determining the appropriateness of a patient for liver transplant. The relative shortage of donor liver grafts available has made the allocation of organs to patients with HCC somewhat of a challenge. The so called Milan criteria for receiving a higher priority for liver transplantation requires patients to have a single tumor <5 cm in diameter, or 3 or fewer tumors, with the largest <3 cm in diameter.8 Currently, in the United States, only patients with HCC who fall within the Milan criteria are assigned a higher Model for End-Stage Liver Disease (MELD) score to facilitate their early transplantation. They are initially assigned a MELD score of 22 (corresponding to a 10% risk of dropping out in 3 months). Additional MELD points are allocated every 3 months corresponding to an additional 10% risk of drop-out. Some centers have accepted the University of California, San Francisco (UCSF) criteria for transplantation that allows for 1 tumor up to 6.5 cm or up to three lesions, none greater than 4.5 cm with a total tumor diameter <8 cm.9, 10 Both Milan and UCSF exclude patients with evidence of vascular invasion on imaging or biopsy. Patients with unresectable HCC form a heterogeneous group. For unresectable tumors, but confined to the liver and without vascular invasion, locally ablative approaches provide reasonable options to control the disease, and in select cases extend survival.11, 12 For patients within Milan criteria who are also acceptable transplant candidates, locally ablative techniques including percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), and transarterial chemoembolization (TACE) are often used to control the disease and keep them within Milan criteria prior to transplant.13, 14 There is a trend to superior results with RFA over PEI.15, 16 The specific modality used is often based on institutional preference but there are also anatomical considerations. For example, exophytic lesions, subcapsular lesions, or lesions near intrahepatic vessels lend themselves less accessible to RFA, and TACE may be preferred. In addition, the failure rate for PEI and RFA is higher with increase in the size of the lesions (>3 cm).15, 16 Multifocal disease often lends itself to TACE, but in some institutions RFA is still performed. In addition, poor liver function is a contraindication to locally ablative treatment as well. For patients with a definite contraindication to transplant but with tumor confined to the liver, locally ablative treatment is the backbone of management. These patients will generally fall into BCLC Stage B. Again, as mentioned above, the decision to treat these patients with a percutaneous, transarterial, or combination approach is largely dependent on institutional practice and specific imaging results. Most data would favor use of TACE for these patients.13 Historically, most studies have excluded patients with vascular invasion for locally ablative therapy. In addition, new modalities are being looked at for this population including adjuncts to RFA17 and radioembolization with yttrium-90 microspheres.18 Only recently has there been a proven effective therapy for patients with advanced HCC. Again, in the context of BCLC, these are patients with stage C disease. These patients are clearly identified by having extrahepatic metastatic disease and/or portal vein invasion. In addition, patients with large, multifocal disease confined to the liver and symptomatic often fall into this category. Many patients that are not cured with surgery will require some systemic treatment if they live long enough and do not succumb to complications of cirrhosis. A recurrent theme in assessing all patients with HCC for treatment is underlying liver function, often assessed in relation to the Child-Pugh score. Again, in patients with advanced disease this is an important issue for consideration because for patients with decompensated cirrhosis, survival is not dictated by their cancer as much as by their cirrhosis.19 Sorafenib is the first systemic agent to show a survival advantage when used to treat patients with advanced HCC. In reality, the most convincing data for the management of patients regardless of stage now exists for this group where two large placebo controlled, randomized studies showed a survival benefit for sorafenib.20, 21 Sorafenib is an oral, small molecule tyrosine kinase inhibitor of several intracellular proteins suspected to be important in tumor progression, including the platelet derived growth factor receptor-β (PDGFR), raf kinase, and the vascular endothelial growth factor receptors (VEGFR) including VEGFR-1, VEGFR-2, and VEGFR-3.22 The proposed mechanism of action of sorafenib is shown in Fig. 2. This includes potential inhibition of growth promoting signals within the tumor cell itself, as well as inhibition of the tumor vasculature by its ability to block the VEGFR on endothelial cells. Preclinical models have demonstrated the ability of Sorafenib to do both, but the actual effects in human tissue have not been assessed.22 Proposed mechanism of action of the multikinase inhibitor sorafenib. Adapted from Wilhelm et al.22 (© Molecular Cancer Therapeutics. Reprinted by permission of Molecular Cancer Therapeutics and by the author.) As mentioned, two large randomized studies, one conducted in Europe and North America, and a second in Asia, have proven a benefit for sorafenib in BCLC Stage C liver cancer. Importantly, both studies required well-compensated liver disease (Child-Pugh A) at study entry. Although this was imperative to demonstrate the anticancer activity of sorafenib, it has left unanswered the true benefit of sorafenib in patients with less compensated cirrhosis. The Europe-North American study, SHARP, enrolled over six hundred patients and randomized them between placebo and sorafenib 400 mg orally twice a day.20 Patients were stratified for region, performance status and the presence or absence of macroscopic vascular invasion (portal vein or branches). Patients underwent imaging every 6 weeks to assess radiographic time-to-tumor progression (TTP). Patients were also assessed for symptomatic endpoints based on a questionnaire. The primary endpoints to the study were overall survival (OS) and the time to symptomatic progression. This study was the first to demonstrate a significant improvement in overall survival with a median OS of 10.7 months in the sorafenib group and 7.9 months in the placebo group (hazard ratio = 0.69; 95% confidence interval = 0.55-0.87; P < 0.001). There was no significant difference in the time to symptomatic progression. The median TTP which was 2.8 months in the placebo group increased to 5.5 months in the sorafenib group (P < 0.001). Interestingly, this benefit was not driven by an increase in tumor shrinkage on imaging using standard clinical trial criteria, suggesting the benefit was largely driven by inducing stable disease and slowing progression. Common and predictable toxicities in this population included hand-foot skin reaction, anorexia, and diarrhea. These are highlighted in Table 1. Of note, there was no significant difference in changes in liver dysfunction or bleeding events between the two groups. 76% of patients in the sorafenib group received more than 80% of the planned daily dose. Importantly, the control group in this study clearly defined the natural history of patients with untreated BCLC Stage C HCC and Child A cirrhosis. The tandem study to SHARP, performed in Asia, evaluated the role of sorafenib in a predominantly hepatitis B population.21 The dosage of sorafenib was the same and again only patients with Child A cirrhosis were selected. Similar to the SHARP study, sorafenib improved OS (6.5 months for patients treated with sorafenib, compared with 4.2 months in the placebo group (hazard ratio = 0.68; 95% confidence interval = 5.56-7.56; P = 0.014) and median TTP was 2.8 months in the sorafenib treated group compared to 1.4 months in the placebo group (P = 0.0005). Although the magnitude of benefit was the same in both studies as represented by the hazard ratios of 0.69 and 0.68, respectively, both control and treated groups in the Asian study had a lower survival than the corresponding arms in the SHARP study. One explanation for this it the fact that more of the patients in the Asian study had BCLC C stage than in SHARP, which included a population of BCLC stage B patients. Again, the toxicities seen in the Asian study were similar to the SHARP study though there was an increased incidence of any grade hand-foot skin reaction, 45% in Asia versus 21% in SHARP. Based on the data above, sorafenib has become the standard of care for patients with advanced HCC. The median improvement of 3 months in survival and 30% reduction on the risk of death is a significant first step in the management of this group of patients. In the context of other approved agents in oncology, this benefit is a significant first-step for patients. For example, the gemcitabine (Gemzar, Eli Lilly, Indianapolis, IN) for metastatic pancreatic cancer increased survival from 4.41 months to 5.65 months (P = 0.0025),23 and in another example, the addition of bevacizumab (Avastin, Genentech, South San Francisco, CA) to chemotherapy for advanced colon cancer improved median survival from 15.6 months to 20.3 months with a hazard ratio of 0.66.24 Now that sorafenib has been shown to improve survival in advanced HCC, studies evaluating the agent in patients with earlier stage disease are ongoing, and may provide even greater gains. Nevertheless, this is an important advance for patients with HCC and will likely lead to further approvals based on combinations of new agents with sorafenib and additional new single agents to use in the front-line setting and after progression on sorafenib and beyond.25 In clinical practice, the decision to initiate sorafenib is guided by a patient's tumor burden, liver disease, and ability to carry out daily activities/performance status (PS). For patients with Child A cirrhosis and good PS, studies have proven a benefit of 400 mg orally twice a day. Baseline hematologic and chemistry parameters should be drawn, as well as an alfa-fetoprotein (AFP) when relevant. Although AFP as an endpoint was not well studied in the sorafenib trials, it may provide additional insight into the clinical activity in any one patient.26 The success in keeping patients on therapy requires proactive management of side effects by the treating physician. Patients should be assessed within 7-10 days of starting drug for adverse events. Careful questioning regarding changes in general activity, oral intake, skin changes, nausea, vomiting and stool changes are important as these are the most common toxicities. In addition, careful examination of the skin is required with particular attention to areas exposed to repetitive trauma such as the hands and feet as these are areas where skin toxicity is most noticeable and symptomatic. During this first follow-up repeat hematology and chemistries are drawn including a phosphorus level as hypophosphatemia has been associated with sorafenib. In addition, a transient rise in total bilirubin can occur after initiation of sorafenib though this often returns to baseline quickly. If a patient is tolerating the drug well, then the same dose can be continued with a follow-up at 2 week intervals until the patient has proven to be stable on the drug. For patients experiencing toxicities consideration to either dose reduce or hold the drug should be made depending on the severity. Reintroduction of the drug can occur once toxicities have approached baseline. Consideration can be given to reintroduce the drug at the same level with close follow-up or, if toxicity was significant, dose reduction by one level. Dose modifications in response to adverse events are shown in Table 2 and is meant to serve as a guideline for clinicians but need to be personalized for any given patient and toxicity. For patients with concomitant medical problems or more symptomatic disease, some clinicians may choose to start at a reduced dose, such as 400 mg daily and titrate to the 400 mg twice daily dose, as tolerated. Regardless, the fact that sorafenib is given orally, unlike many traditional anticancer agents given parenterally, does not diminish the need for patient education, for close follow-up, and experience in prescribing and managing adverse events. One of the most common questions encountered in clinical oncology is, "Doctor, how long do I need to take this drug?" In the management of some tumors, there is a predefined treatment period, however, in the case of advanced HCC, the answer is really "indefinitely". Clearly we are not "curing" patients with advanced HCC, but the use of sorafenib is not palliative either, it is initiated with the intent to extend survival. However, this needs to balanced by the side effects as well as documented efficacy. The former issue needs to be determined on a patient by patient basis and open discussion regarding goals of care. Most drug toxicity can be managed with appropriate use of urea based creams and topical emollients, antiemetics, and antidiarrhea medication.27, 28 Efficacy should be documented with imaging. Computed tomography or magnetic resonance imaging of the chest, abdomen, and pelvis to include areas of active disease should be performed at regular intervals. A bone scan should be considered for patients with known bone metastasis as well. In general oncologic practice, these evaluations are performed after every 2 cycles (1 cycle = 4 weeks, so every 8 weeks). As discussed, sorafenib generally does not induce shrinkage of tumors so tumors that are relatively stable in size would be considered "responding". In addition, vascular changes have been described with sorafenib which also are evidence of treatment effect.29 More recently, changes in enhancement have been incorporated into assessing response to molecular therapeutics in the management of HCC.7 If sorafenib does not cause tumor shrinkage, outside of unmanageable toxicity, the question of when to stop the drug becomes important. Typically the appearance of a new lesion would suggest clear progression. Alternatively, small interval growth may reflect differences in imaging technique and suggest continuing sorafenib with follow-up until serial imaging documents some significant growth in the tumor. Changes in AFP alone are not considered appropriate for initiating a change in management. Currently, there is no agent (in the second-line setting) that has proven efficacy when there is tumor progression on sorafenib, but there are ongoing studies of new agents for this group. It is imperative that patients be referred for clinical trials in this area of unmet medical need if we are to continue to build on the initial efficacy of sorafenib.25 There is still is a great deal to learn before integrating sorafenib into the broader medical practice. For one, the registrational studies with sorafenib have focused on patients with Child-Pugh A cirrhosis. Small series have evaluated sorafenib safety and efficacy in patients with Child-Pugh B cirrhosis, and have generally found the drug tolerable in this patient population. Efficacy is hard to assess as these are single-arm studies without a control arm.29, 30 One could rationalize that because sorafenib has proven anticancer activity in Child-Pugh A patients it would have the same activity in patients with less compensated liver disease so in the absence of a clinical trial, patients in stable condition and adequate performance status could be offered treatment with close monitoring. The unknown variable being, that even if their cancer was controlled with sorafenib, will it impact their overall survival given the extent of liver dysfunction. In general, Child-Pugh B patients treated with sorafenib do not live as long as patients with Child-Pugh A, but that could very well reflect the natural history of their liver disease rather than a difference in anticancer activity of sorafenib. This is magnified for patients with Child-Pugh C liver disease as well in which treatment is unlike to be of any benefit. The answer as to how, if at all, to use sorafenib in other clinical stages remains to be answered. Randomized studies aiming at assessing sorafenib after curative resection or RFA (STORM study, NCT00692770) or in combination with TACE (SPACE study, MCT00855218) are ongoing. These randomized studies are aimed at improving survival with sorafenib in the adjuvant setting. To date, there has been no significant safety signal for its use in these settings. The role of sorafenib in liver transplantation needs to be addressed as well in the context of clinical studies. In this case, one could envision use prior to transplant (neoadjuvant setting) in an attempt to control tumor burden and keep patients within Milan criteria and thus on the transplant list. As discussed, sorafenib does not typically induce tumor shrinkage, but for patients with long wait times, its use may provide them a way of not exceeding Milan criteria and remaining on the list. Conceivably, this would be used in conjunction with locally ablative therapies. Theoretical concerns in this case include potential complications at the time of transplant. The exact timing of liver transplant is typically not known, which means a patient could be taking the drug a few hours prior to transplantation. Although the half-life of sorafenib is relatively short, any lingering effects on the vasculature are not known and safety of the graft must be ensured. In another scenario, after transplant, pathologic review of the explanted liver often differs from the noninvasive assessment done pre-operatively. In cases of vascular invasion or unexpected large tumor burden that puts patient at increased risk of relapse, consideration could be given to initiating sorafenib in the posttransplant (adjuvant) setting in hopes of preventing or delaying recurrence. Ongoing studies are initially evaluating the safety and feasibility of sorafenib in this setting (NCT00997022). Clearly, there is a high risk for drug-drug interactions in this scenario, though case-reports have suggested that sorafenib is tolerated and has efficacy in patients treated for HCC recurrence after transplant.31 Finally, HCC is a heterogeneous disease at the molecular level.32, 33 Rather than approaching all HCCs as "one disease" ongoing work is aimed at understanding which patients receive a greater benefit than others. Ultimately, this may identify a predictive marker based on serum or tumor measurements that will allow us to identify which patients will benefit from sorafenib and allow us to individualize treatment decisions. The patient presented in the case above is the ideal candidate to receive systemic treatment. He has well-compensated liver disease as indicated by the lack of physical signs and symptoms of liver disease and the preserved laboratory values. There is evidence of portal hypertension with moderate thrombocytopenia but no evidence of significant bleeding or iron deficiency given the relatively normal hemoglobin and mean corpuscular volume. The patient dose not require a biopsy to confirm the diagnosis given the clinical scenario of a hypervascular tumor in the setting of cirrhosis and an elevated AFP.34 The patient is beyond transplant criteria given evidence of portal vein invasion. However, even without the portal vein thrombus, the patient's tumor volume precludes transplant size criteria. Similarly, the portal vein thrombus would preclude any survival advantage from locally ablative therapies such as RFA and TACE. This patient appears to be asymptomatic and would be staged as BCLC Stage C. As we have reviewed, there is strong clinical evidence to support the use of sorafenib in this setting to extend survival. Although this patient is very similar to those enrolled in the SHARP study and could be started at 400 mg orally twice daily, many experienced clinicians start at a dose of 200 mg orally twice a day to minimize early toxicity and increase the dose to 400 mg orally twice a day after 1 month of therapy if the patient is tolerating the drug well. Such an approach may be associated with better long term patient tolerance of the drug and improved outcomes. Alternatively, the patient could be referred for one of the many clinical trials aimed at building on sorafenib's success in improving survival for patients with advanced HCC. Note: Sorafenib is marketed by Onyx/Bayer Pharmaceuticals as Nexavar. The medication is available only in a 200 mg strength. The Wholesale Acquisition Cost (WAC) in the United States for a 30-day supply of Nexavar 400 mg twice daily is $6,660.95.