M. Bertini

Conventional versus Doxorubicin-eluting Bead Transarterial Chemoembolization for Hepatocellular Carcinoma

PURPOSE To compare short- and long-term clinical outcomes after conventional transarterial chemoembolization and drug-eluting bead (DEB) transarterial chemoembolization in hepatocellular carcinoma (HCC). MATERIALS AND METHODS Patients with unresectable HCC unsuitable for ablative therapies were randomly assigned to undergo conventional or DEB chemoembolization. The primary endpoints of the study were safety, toxicity, and tumor response at 1 month. Secondary endpoints were number of repeated chemoembolization cycles, time to recurrence and local recurrence, time to radiologic progression, and survival. RESULTS In total, 67 patients (mean age, 70 y ± 7.7) were evaluated. Mean follow-up was 816 days ± 361. Two periprocedural major complications occurred (2.9%) that were treated by medical therapy without the need for other interventions. A significant increase in alanine aminotransferase levels 24 hours after treatment was reported, which was significantly greater after conventional chemoembolization (n = 34) than after DEB chemoembolization (n = 33; preprocedure, 60 IU ± 44 vs 74 IU ± 62, respectively; at 24 h, 216 IU ± 201 vs 101 IU ± 89, respectively; P = 0.007). No other differences were observed in liver toxicity between groups. At 1 month, complete and partial tumor response rates were 70.6% and 29.4%, respectively, in the conventional chemoembolization group and 51.5% and 48.5%, respectively, in the DEB chemoembolization group. No differences were observed between groups in time to recurrence and local recurrence, radiologic progression, and survival. CONCLUSIONS Conventional chemoembolization and DEB chemoembolization have a limited impact on liver function on short- and long-term follow-up and are associated with favorable clinical outcomes.

Transarterial chemoembolization in very early and early-stage hepatocellular carcinoma patients excluded from curative treatment: A prospective cohort study

AIM To assess clinical outcome of transarterial chemoembolization (TACE) in a series of patients with early-stage hepatocellular carcinoma (HCC), within Milan criteria, but clinically unfit for liver transplantation (OLT). METHODS From January 2006 to May 2009, 67 patients (43 males, mean age 70 ± 7.6 years) with very early or early-stage unresectable HCC, within Milan selection criteria but clinically unfit for OLT, underwent TACE. The primary endpoint of the study was overall survival. Secondary endpoints were: safety, liver toxicity, 1-month tumour response according to the amended RECIST criteria, time to local and distant intrahepatic tumour recurrence and time to radiological progression. RESULTS Two major periprocedural complications occurred (3%), consisting of liver failure. Periprocedural mortality rate was 1.5% (1 patient). A significant increase in ALT and bilirubin levels 24h after treatment was reported, with progressive decrease at discharge. At 1-month follow-up, complete and partial tumour response rates were 67.2% and 29.8%, respectively, with two cases of progressive disease. Mean follow-up was 37.3 ± 15 months. The 1-, 2-, and 3-year overall survival rates were 90.9%, 86.1%, and 80.5%, respectively. Median expected time to local tumour recurrence and intrahepatic tumour recurrence were 7.9 and 13.8 months, respectively. Radiological disease progression was observed in 12 patients (17.9%) with a mean expected time of 26.5 months. CONCLUSION In patients with early-stage HCC, clinically excluded from OLT and unfit for surgery or percutaneous ablation, TACE is a safe and effective option, with favourable long-term survival.

Complete response for advanced liver cancer during sorafenib therapy: Case Report

BackgroundHepatocellular carcinoma (HCC) is the fifth most common neoplasia in the world. In the past, treatment of advanced HCC with conventional antineoplastic drugs did not result in satisfactory outcomes: recently, in this patient population the oral multikinase inhibitor sorafenib has been able to induce a statistically significant improvement of overall survival. Similarly to other anti-angiogenic drugs employed in other tumour types, also sorafenib seldom induces the dimensional tumour shrinking usually observed with conventional cytotoxic drugs: data gathered from studies carried out with sorafenib and other competitors under development do not report any complete response in HCV-induced HCC.Case presentationAn 84-year old man with a long-lasting history of chronic HCV hepatitis was referred to our Institution for an ultrasonography investigation of a focal hepatic lesion. To better characterize the liver disease and clearly define the diagnosis of the focal hepatic lesion, the patient was hospitalized in our department. Laboratory and instrumental investigations confirmed the clinical picture of HCV-related liver cirrhosis and identified a hepatic lesion of about 6 cm featuring infiltrating HCC with thrombosis of the portal trunk. Due to the advanced stage of the disease, therapy with sorafenib 400 mg bid was started. Right from one month after the treatment was started, a reduction of alpha-fetoprotein level was observed which, by the third month, turned down within the normal limits. In addition the CT scan showed 50% reduction of the neoplastic lesion along with canalization of the portal trunk. At the sixth month the normalization of the alpha-fetoprotein level at the lower limit of normality was confirmed and the MRI showed complete disappearance of the neoplasia. In addition a reduction of a metallo-proteinase serum level was obserdved. At the twelfth month a further MRI confirmed complete response had been maintained. At present the patient is in a follow-up program to evaluate the duration of the complete response.ConclusionsThis case is worth mentioning since, to the best of our knowledge, it represents the first evidence of complete response to sorafenib in an elderly patient with advanced HCV-related HCC.

Long-term results of sorafenib in advanced-stage hepatocellular carcinoma: what can we learn from routine clinical practice?

Background and aims: Prospective randomized trials have proven that sorafenib is a valid treatment option for patients with advanced-stage hepatocellular carcinoma (HCC). The aim of the present study is to evaluate the effectiveness and safety of sorafenib in patients encountered in routine clinical practice. Methods: From September 2008 to March 2011, 42 cirrhotic patients (30 male; 12 female; mean age: 70.2 ± 7.6 years; range: 56–85 years) with HCC of Barcelona Clinic Liver Cancer stage B (n = 5) or C (n = 37; mean size: 66.6 ± 42.3 mm; mean number per patient: 3.3 ± 2.8) were treated with sorafenib at either a standard dose of 800 mg/day (n = 29; 69.1%) or at 400 mg/day with subsequent dose escalation (ramp-up strategy; n = 13, 30.9%). Baseline clinical parameters were comparable. Clinical data and side effects, laboratory analyses (in particular, serum α-fetoprotein) and radiological data (tumor response according to amended RECIST criteria) were assessed every 3 months. Survival was calculated by Kaplan–Meier analysis. Results: Mean follow-up was 12.2 ± 9 months (range: 1–32 months). Median overall survival was 26.1 months with overall 6- and 12-month survival rates of 92.1 and 85%, respectively. Median time to radiological progression was 8 months. The progression-free rate was 64.3%. Fatigue, skin disorders and diarrhea were the most frequent grade 3–4 side effects. Treatment discontinuation occurred in 25 patients. The starting dose for the last 13 enrolled patients was 400 mg/day; in the absence of toxicity this dosage was gradually increased to 800 mg/day after 3 weeks (‘ramp-up strategy’). No grade 3/4 adverse events were observed in the ramp-up group. Conclusion: Sorafenib is a valid treatment option for advanced-stage HCC. Starting at a lower dosage may allow prolonged compliance to treatment and might be considered according to patient tolerance.

Assessment of response to sorafenib in advanced hepatocellular carcinoma using perfusion computed tomography: Results of a pilot study

AIMS This prospective pilot study investigated the feasibility of perfusion computed tomography parameters as surrogate markers of angiogenesis and early response following sorafenib administration in patients with advanced hepatocellular carcinoma. METHODS Ten patients were evaluated with perfusion computed tomography before starting sorafenib and after 3 months. Blood flow, blood volume, mean transit time, hepatic arterial fraction, and permeability surface-product were compared in tumour lesions and in hepatic parenchyma at baseline and at follow-up. Correlation between these parameters and changes in alpha-fetoprotein levels was calculated. RESULTS At baseline, blood volume, blood flow, hepatic arterial fraction and permeability surface values were higher in lesions compared to those in hepatic parenchyma, while mean transit time was lower (p<0.05). After sorafenib treatment, only mean transit time was significantly increased versus baseline (p<0.05). At follow-up, plasma alpha-fetoprotein levels decreased in all patients. At follow-up, an inverse correlation was observed between baseline mean transit time and changes in alpha-fetoprotein (r=-0.6685, p=0.0125), as well as a correlation between baseline blood flow and alpha-fetoprotein (r=0.6476, p=0.0167). CONCLUSION This pilot study suggests that after sorafenib treatment an increase in mean transit time observed in tumour lesions is inversely correlated with alpha-fetoprotein reductions after therapy. Mean transit time may represent a possible marker of response irrespectively of alpha-fetoprotein values.

Transarterial radioembolization for hepatocellular carcinoma: An update and perspectives

In the last decade trans-arterial radioembolization has given promising results in the treatment of patients with intermediate or advanced stage hepatocellular carcinoma (HCC), both in terms of disease control and tolerability profile. This technique consists of the selective intra-arterial administration of microspheres loaded with a radioactive compound (usually Yttrium(90)), and exerts its therapeutic effect through the radiation carried by these microspheres. A careful and meticulous selection of patients is crucial before performing the radioembolization to correctly perform the procedure and reduce the incidence of complications. Radioembolization is a technically complex and expensive technique, which has only recently entered clinical practice and is supported by scant results from phase III clinical trials. Nevertheless, it may represent a valid alternative to transarterial chemoembolization (TACE) in the treatment of intermediate-stage HCC patients, as shown by a comparative retrospective assessment that reported a longer time to progression, but not of overall survival, and a more favorable safety profile for radioembolization. In addition, this treatment has reported a higher percentage of tumor shrinkage, if compared to TACE, for pre-transplant downsizing and it represents a promising therapeutic option in patients with large extent of disease and insufficient residual liver volume who are not immediately eligible for surgery. Radioembolization might also be a suitable companion to sorafenib in advanced HCC or it can be used as a potential alternative to this treatment in patients who are not responding or do not tolerate sorafenib.

Assessment of clinical and radiological response to sorafenib in hepatocellular carcinoma patients.

Sorafenib is an effective anti-angiogenic treatment for hepatocellular carcinoma (HCC). The assessment of tumor progression in patients treated with sorafenib is crucial to help identify potentially-resistant patients, avoiding unnecessary toxicities. Traditional methods to assess tumor progression are based on variations in tumor size and provide unreliable results in patients treated with sorafenib. New methods to assess tumor progression such as the modified Response Evaluation Criteria in Solid Tumors or European Association for the Study of Liver criteria are based on imaging to measure the vascularization and tumor volume (viable or necrotic). These however fail especially when the tumor response results in irregular development of necrotic tissue. Newer assessment techniques focus on the evaluation of tumor volume, density or perfusion. Perfusion computed tomography and Dynamic Contrast-Enhanced-UltraSound can measure the vascularization of HCC lesions and help predict tumor response to anti-angiogenic therapies. Mean Transit Time is a possible predictive biomarker to measure tumor response. Volumetric techniques are reliable, reproducible and time-efficient and can help measure minimal changes in viable tumor or necrotic tissue, allowing the prompt identification of non-responders. Volume ratio may be a reproducible biomarker for tumor response. Larger trials are needed to confirm the use of these techniques in the prediction of response to sorafenib.

Partial Response and Cardiovascular Recovery after Sorafenib Dose Reduction in a Multinodular HCC Patient

In the past, heart failure has been a major adverse event induced by some conventional chemotherapeutic agents [1]. The introduction of the new agents targeting angiogenesis, if on one hand has offered new therapeutic strategies to orphan drug tumors, has on the other hand also enhanced the risk of heart muscle injuries on account of their inhibition of vascular endothelial growth factor (VEGF) and plateletderived grow factor (PDGF) which are fundamental factors for heart cell survival [2]. Several reports have recently raised the concern of potential cardiotoxicity of sunitinib [3]. The multikinase inhibitor sorafenib is the first targeted agent able to extend survival after many trials on the medical treatment of advanced stages of renal cell carcinoma [4] and hepatocellular carcinoma (HCC) [5, 6]. Even if in clinical trials the reduction of ejection fraction (left ventricular failure, LVEF) rarely turned out related to sorafenib [3–6], a monitoring of cardiac adverse events is advocated with more approved antiangiogenic inhibitors [7, 8], and regulatory recommendations have suggested sorafenib discontinuation in case of onset of signs of cardiotoxicity [9, 10]. Few data have been reported regarding the possibility to restart the drug after interruption due to cardiotoxicity [11] and no information is available regarding the efficacy of the drug after a dose reduction. Here we report the case of an HCC patient who restarted sorafenib after a significant drop of LVEF. The lower dose employed at the restart drove to tumor reduction with cardiac heart failure (CHF) recovery.

Treatment Response After Unusual Low Dose Sorafenib: Diagnosis with Perfusion CT and Follow-up in a Patient with Recurrent Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide causing approximately 662,000 deaths per year (http://www.who.int/mediacentre/factsheets/fs297/en/) [1], with an incidence that is rising more rapidly compared with other cancers [2]. The spread of HCC depends on its ability to recruit blood vessels by forming new vessels. This makes HCC a highly vascularized tumor that can be targeted by angiogenesis inhibitors [3]. The introduction of systemic agents targeting HCC was a major advance in the treatment of this disease after many years of failure of classical chemotherapy. Sorafenib is an oral multikinase inhibitor targeting both cellular surface receptor tyrosine kinase receptors and intracellular Raf serine/threonine kinases, which are involved in tumor angiogenesis and cell proliferation, respectively. Sorafenib is the first drug that has demonstrated a statistically significant survival benefit in patients with advanced HCC. Two pivotal studies performed in Western and Asian populations [4, 5], and recently, data available from a large prospective post-marketing study (GIDEON study) have further confirmed the efficacy and the safety profile of this drug [6]. Sorafenib therapy is generally associated to certain adverse events (AEs), such as the hand foot skin reaction (HFSR), is the one of the most frequent AEs observed in clinical practice and in clinical trials [4, 6]. Unfortunately, clinical experience and literature data state that AEs associated with sorafenib can reduce a patients quality of life, leading to drug interruption or discontinuation [7]. The dosing schedule of sorafenib is the subject of much debate as to whether a “ramp-up” strategy should be used [8–10] or a reduced dose-tailored therapy [11, 12] should be employed to improve tolerability and quality of life. The radiological evaluation of tumor response in patients with HCC is an important requirement which arose initially with locoregional therapies [13] and then reinforced with the introduction of angiogenic therapies. In actual fact, tumor necrosis induced by antiangiogenic therapies may not always be associated with a reduction in tumor size. In this situation, standard Response Evaluation Criteria in Solid Tumor (RECIST) criteria are inappropriate to identify responders [14]. To overcome this limitation, the European Association for the Study of the Liver (EASL) guidelines recommended that assessment of tumor response should incorporate the reduction in viable tumor burden [15]. Quantitative CT perfusion analysis (perfusion CT, pCT) is a radiological technique that provides information on the J Gastrointest Canc (2012) 43 (Suppl 1):S234–S238 DOI 10.1007/s12029-012-9403-4

Adherence to EASL-EORTC clinical guidelines for the management of hepatocellular carcinoma in field practice: Results from the ITALICA database

Introduction: Data on adherence to joint guidelines for the management of hepatocellular carcinoma (HCC) published in 2012 by the European Association for the Study of the Liver (EASL) and the European Organization for Research and Treatment of Cancer (EORTC) are lacking. Aim: We retrospectively evaluated the adherence to EASLEORTC guidelines in field-practice, using data from HCC patients registered in the Nation-wide Italian database ITA.LI.CA. and diagnosed from 2012. Methods: The ITA.LI.CA. database contains data of 5428 HCC patients treated at 18 Italian Centers. Patients were stratified according to Child-Pugh (CP) and and the Barcelona Clinic Liver Cancer (BCLC) classifications. We investigated the adherence to surveillance, diagnosis, and first-line treatment recommendations. Results: In ITALICA, 600 patients were diagnosed of HCC since 2012 (466 males; mean± SD age 67.4±10.9 years; 277(46.2%) CP-A and 163(27.2%) CP-B; 44(8%) BCLC-0, 193(35.1%) BCLC-A, 93(16.9%) BCLC-B, 172(31.3%) BCLC-C, 48(8.7%) BCLC-D). Overall, 317(55.2%) were diagnosed during a surveillance program. Of them, 231(57.9%) were cirrhotic (median surveillance duration: 6 months). Four-hundred-ninety-six (85.3%, 449 cirrhotic) patients were diagnosed applying a radiological, 80(13.7%) a histological, and6(1%) a cytological criterion. Five (9.7%) patients in BCLC stage 0 with CPA, and single nodules underwent tumour resection; 3(1.4%) patients in BCLC-A received liver transplantation, and 83(43.1%) received radiofrequency ablation or Percutaneous Ethanol Injection. Intermediate HCC-stage patients (BCLC-B) receiving TACE were 45(47.9%), and advanced-stage patients (BCLC-C) receiving sorafenib were 38(21.9%). Palliative care was provided to terminal stage patients (BCLC-D) in 31(64.3%) cases. Conclusions: Theoverall adherence in a “real-world” practice to EASL-EORTC guidelines was low, particularly in patients with early stageHCC. Difficulties inpatients staging and the high prevalence of older patients with relevant co-morbidities may partially explain these findings. Strategies to help improve adherence to international guidelines for HCC in field-practice and new scoring criteria are required.