Elena Bozzi

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.

Doxorubicin-eluting bead-enhanced radiofrequency ablation of hepatocellular carcinoma: a pilot clinical study

BACKGROUND/AIMS Experimental studies have shown synergy between radiofrequency (RF) ablation and adjuvant chemotherapy in animal tumour models. We aimed to assess safety and efficacy of doxorubicin-eluting bead (DEB)-enhanced RF ablation in the treatment of human hepatocellular carcinoma (HCC). METHODS Twenty patients with single HCC ranging 3.3-7.0 cm (mean, 5.0 cm+/-1.4) showing evidence of residual viable tumour after standard RF ablation underwent intraarterial DEB administration (50-125 mg doxorubicin; mean, 60.2 mg+/-21.8). Follow-up period ranged 6-20 months (mean, 12 months+/-5). RESULTS No major complication occurred. No deterioration of liver function was observed. The volume of treatment-induced necrosis--as measured on imaging--increased from 48.1 cm3+/-35.7 after RF ablation to 75.5 cm3+/-52.4 after DEB administration, with an increase of 60.9%+/-39.0. The enhanced effect resulted in confirmed complete response (CR) of the target lesion in 12 (60%) of 20 patients. Incomplete response with persistence of <10% of initial tumour volume was observed in 6 (30%) of 20 patients, and local tumour progression in 2 (10%) of 20. CONCLUSIONS Intraarterial DEB administration substantially enhances the effect of RF ablation. DEB-enhanced RF ablation is safe and results in a high rate of CR in patients refractory to standard RF treatment.

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.

Modified RECIST to assess tumor response after transarterial chemoembolization of hepatocellular carcinoma: CT–pathologic correlation in 178 liver explants

PURPOSE To retrospectively evaluate agreement between modified RECIST (mRECIST) assessed at Computed Tomography (CT) and pathology in a large series of patients with hepatocellular carcinoma (HCC) who were transplanted after transarterial chemoembolization (TACE). MATERIALS AND METHODS IRB approval was obtained. The study included 178 patients (M/F=155/23; mean age 55.8 ± 6.3 years) with HCC who were transplanted after TACE from January 1996 to December 2010 and with at least one CT examination before liver transplantation (LT). Two blinded independent readers retrospectively reviewed CT examinations, to assess tumor response to TACE according to mRECIST. Patients were classified in responders (complete and partial response) and non-responders (stable and progressive disease). On the explanted livers, percentage of tumor necrosis was classified as 100, >50 and <50%. RESULTS The mean interval between latest CT and LT was 57.4 ± 39.8 days. At latest CT examination, the objective response rate was 78.1% (139/178), with 86 cases (48.3%) of complete response (CR). A good intra- (k=0.75 and 0.86) and inter-observer (k=0.81) agreement was obtained. On a per-patient basis, agreement between mRECIST and pathology was obtained in 120 patients (67.4%), with 19 cases (10.7%) of underestimation and 39 cases (21.9%) of overestimation of tumor response at CT. CT sensitivity and specificity in differentiating between responders and non-responders were 93 and 82.9%, respectively. Out of 302 nodules, sensitivity and specificity of CT in detecting complete necrosis were 87.5 and 68.9%, respectively. CONCLUSIONS CT can overestimate tumor response after TACE. Nonetheless, mRECIST assessed at CT after TACE are reproducible and reliable in differentiating responders and non-responders.

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.

HCC Diagnosis with Liver-Specific MRI – Close to Histopathology

Thanks to the sensible and continuous improvements achieved, magnetic resonance imaging (MRI) can nowadays be considered the most accurate modality to image the liver. Moreover, the technique is the only one able to provide at the same time information about intracellular and vascular changes occurring in parenchymas. For these reasons, MRI plays a major role in the surveillance and follow-up of patients with cirrhosis. If a baseline MR study investigates the progressive alteration of lesion architecture, grading, stromal component, as well as intracellular content of fat, glycogen, or metal ions, thus leading to a frequent confident diagnosis of lesion nature, a dynamic study provides additional information about lesion vascular enhancement, which may represent the only clue for the differential diagnosis between premalignant and malignant lesions. In addition, the introduction of hepatobiliary contrast agents has further implemented the diagnostic confidence of the technique, permitting to explore the so-called grey area in which significant histological changes are already present without an evident arterial supply of the nodule. Although in the evaluation of liver pathologies MRI is mainly applied in the study of cirrhosis, the technique also plays a fundamental role in the assessment of other primitive liver malignancies, such as fibrolamellar carcinoma or cholangiocarcinoma. In these cases in particular, MRI is required to pose a differential diagnosis with other liver malignancies (such as metastases), and, once the nature of the neoplasm is assessed, to give an accurate locoregional staging.

Hepatocellular nodules in liver cirrhosis: contrast-enhanced MR

Nowadays, the diagnosis of hepatocellular carcinoma (HCC) is increasingly demanded to imaging techniques. Anyway, imaging cirrhotic patients still remains a challenging issue, since pre-neoplastic hepatocellular lesions, as dysplastic nodules (DNs), may frequently mimic small neoplasms. Differently from other imaging modalities, magnetic resonance (MR) can give an accurate evaluation of both intracellular and vascular changes occurring during the carcinogenetic pathway from dysplasia to full malignancy. Both DNs and HCC may in fact show a large variety of signal intensities, strictly reflecting nodules’ characteristics, such as lesion architecture, grading, stromal components, as well as intracellular contents. In these last years, the introduction of dedicated contrast media has increased MR diagnostic efficacy, permitting to explore both vascular as well as the pathological changes occurring in the biliary and reticuloendothelial systems during the carcinogenetic process. MR performed with tissue specific contrast agents (hepatobiliary and reticulo-endothelial) may thus give an insight on this “gray area”, in whom significant histological changes are already present without an evident nodule arterial supply. This peculiar MR prerogative permits to give predictive information about the evolution trend in a cirrhotic parenchyma and to identify patients at high risk for developing carcinoma who would benefit from well-timed treatments.

Radiological diagnosis of hepatocellular carcinoma

Diagnosis of hepatocellular carcinoma (HCC) still remains a challenging issue. In the setting of liver cirrhosis, international guidelines have set the noninvasive criteria for HCC diagnosis, represented by the detection of contrast hyperenhancement in the arterial phase (wash-in) and hypoenhancement in the portal or delayed phase (wash-out) with dynamic multi-detector computer tomography or magnetic resonance (MR) imaging. Although highly specific, this typical enhancement pattern has relatively low sensitivity, since approximately one-third of HCC nodules are characterized by atypical enhancement patterns. In atypical HCC nodules larger than 1 cm, the majority of international guidelines recommend liver biopsy. However, there is an increasing interest in exploiting new noninvasive diagnostic tools, to increase the sensitivity of radiological diagnosis of HCC. Diffusion-weighted MR imaging and MR hepatobiliary contrast agents may represent useful tools for the detection and characterization of borderline hypovascular lesions by providing functional information such as water molecule motion in diffusion-weighted imaging and residual hepatobiliary function, which can be impaired early during the course of hepatocarcinogenesis. Also, dual-energy computed tomography (CT) represents an interesting new CT technology that could increase detectability and conspicuity of hypervascular lesions, thus possibly improving CT sensitivity in small HCCs. However, more data and further developments are needed to verify the usefulness of these new technologies in the diagnosis of HCC and to translate these recent advances into clinical practice.

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