Cutting-edge treatments for hepatocellular carcinoma, including contrast-enhanced ultrasound, combined CRT/TACE, sorafenib, & LCCRT for patients with PVT.
The International Liver Cancer Association (ILCA) takes a multidisciplinary approach to furthering the understanding and management of hepatocellular carcinoma (HCC). September 5-7, 2008, researchers from more than 40 countries attended the ILCA’s Second Annual Conference in Chicago, Illinois, to discuss the most recent findings on diagnosis and treatment of HCC.
The ILCA conference features cutting-edge symposia, and this year’s conference included a series of lectures highlighting innovative approaches to treating HCC; as well as general sessions, where the world’s leading clinical experts and researchers discussed recent discoveries about the pathology and molecular pathogenesis of HCC and presented the latest developments in surgical and medical treatments, clinical trials, and targeted therapies. The following summaries offer highlights of key presentations from the ILCA Second Annual Conference.
CEUS May Offer Early Evidence of Anti-Angiogenesis
Hui-Chuan Sun and colleagues at the Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China, evaluated whether contrast-enhanced ultrasonography (CEUS) use could identify a correlation between microvessel density (MVD) of HCC and tumor perfusion parameters in human patients. Then, using an animal model, they tested whether CEUS could monitor changes in angiogenesis induced by anti-angiogenesis treatment. The tumor perfusion parameters that CEUS detected include peak intensity, increased peak intensity, increased signal intensity, area under curve, and blood-flow index. These parameters are associated with MVD.
In the animal model experiment, researchers administered a vascular EGFR inhibitor to suppress the motility of human umbilical vein endothelial cells; this significantly delayed tumor growth. Investigators noted that changes in tumor perfusion parameters were detectable 3 days earlier than changes in tumor size. This study has important clinical ramifications, indicating that it may be possible to use CEUS to monitor tumor perfusion and identify changes in tumor size, providing earlier biological evidence on the efficacy of anti-angiogenesis treatment. Researchers believe further study is warranted.
Researchers Establish Radius of Effect for Doxorubicin-loaded Drug-eluting Beads
Researchers have been conducting clinical investigations on using doxorubicin-loaded drug-eluting beads (DEBs) in the management of HCC prior to liver transplantation. The rationale behind using DEBs to deliver doxorubicin is to decrease systemic concentration of the drug while delivering high doses locally.
A study by Julien Namur, Pharmacy University, Reims, France, and colleagues evaluated explanted livers with HCC from patients who underwent chemoembolization with doxorubicin DEBs prior to transplantation. They sought to determine concentration of doxorubicin in the tissue according to time of explanation.
Doxorubicin was mapped and quantified around 162 different DEBs ranging from 100 to 300 micro-meters with a mean dose of 98.3 mg ± 24.4 mg (75-150 mg). Pathology analysis detected the drug in liver tissue surrounding the DEBs for all times of explantation. Investigators concluded that cytostatic levels of doxorubicin are detectable in a radius of tissue around the DEBs that spans several hundred micrometers. The concentration of doxorubicin in the tissue decreased exponentially in relation to the sample’s distance from the DEB and over time, from day 1 to day 30. This work makes it possible to correlate drug profiles with tissue and cellular damage. It could also facilitate more accurate monitoring of a patient’s therapy progress when DEBs are used.
Sorafenib Monotherapy Demonstrates Favorable Efficacy
Joong-Won Park and colleagues at the National Cancer Center, Goyang, South Korea, performed a retrospective study to evaluate the efficacy and safety of sorafenib (Nexavar) in Korean patients with HCC. Many were from areas where chronic infection with hepatitis B virus is endemic. The review included 48 patients with grade 3 or 4 unresectable or metastatic HCC primarily related to hepatitis B (45.8%), hepatitis C (6.3%), or both (2.1%); an ECOG performance status from 0 to 2; and Child-Pugh class A-B. Vascular invasion and extrahepatic spread were observed in 48% and 63% of patients, respectively. All patients had been treated with a starting dose of sorafenib 400 mg twice daily, and tumor response was evaluated by an independent radiologist and a hepatologist.
Two patients (4.2%) achieved a partial response, and 18 (37.5%) achieved stable disease, yielding a disease control rate (DCR) of 41.7%. The DCR was significantly greater in patients without vascular invasion ( = .045). At a median follow-up of 13 weeks, the median time to progression was 7.7 weeks. The most common grade 3 and 4 adverse events included hand-foot skin reaction (8.3%), diarrhea (8.3%), and skin rash (6.3%). Investigators concluded that, for the retrospective series of Korean patients analyzed, monotherapy with sorafenib demonstrated favorable efficacy with modest improvement in survival outcome.
Patients with Portal Vein Thrombosis Benefit from LCCRT
Patients with advanced HCC and portal vein thrombosis have a poor prognosis and little hope for survival. Kwang-Hyub Han and colleagues at the Yonsei University College of Medicine, Seoul, South Korea, evaluated the survival benefit and therapeutic efficacy of localized concurrent chemoradiation therapy (LCCRT) with 3-dimensional radiotherapy. They performed a prospective trial of LCCRT following relapsed intra-arterial therapy in 80 patients (72 men, 8 women) with advanced HCC and portal vein thrombosis with preserved hepatic function. Patients received LCCRT 45 Gy over 5 weeks with conventional fractionation; on the first and fifth weeks of treatment, patients also received hepatic arterial infusion chemotherapy (HAIC) with fluorouracil. A month after LCCRT, patients underwent HAIC with fluorouracil and cisplatin every 4 weeks.
One month after undergoing LCCRT, investigators observed an objective response of intention-to-treat analysis in 34 of 80 patients (42.5%). The 3-year rate of overall survival was 34.5%. Median survival time was 17.5 months for patients who received LCCRT, which is a significant improvement over the 8.0-month survival time for patients who did not receive LCCRT from the start of treatment. Responders after LCCRT treatment showed significantly better survival than nonresponders ( = .005). Due to the substantial response rate, as well as the improved median survival time in responders, the study’s authors suggest that LCCRT after repeated intra-arterial chemotherapy might constitute an encouraging new approach for treating HCC in patients who have concurrent portal vein thrombosis.
Combined CRT and TACE Provides Local Control for HCC
Philippe Merle and colleagues from the Centre Hospitalier Lyon Sud, Lyon, France, presented interim results of an ongoing open pilot study to determine whether high-dose conformal radiotherapy (CRT) combined with transcatheter arterial chemoembolization (TACE) would achieve good rates of local control for large HCC nodules. In total, 15 patients received treatment and 14 were assessed for objective tumor response (the primary end point). Of these 14 patients, 9 demonstrated complete response (CR), 4 had partial response (PR), and 1 patient’s lesion was progressing. At 15 ± 11.5 months follow-up, none of the CR patients showed signs of relapse in the targeted tumor nodule. At a mean of 12.6 ± 5.5 months, however, 5 CR patients had developed distant metastasis or recurrent HCC in the liver. All 14 CR patients were alive as of September 2008.
At follow-up, none of the 4 patients with PR showed progression in the targeted nodule, but 1 had developed liver recurrence and pulmonary metastasis at 6 months; 2 PR patients died—1 at 5 months and the other at 15 months. The authors reported a cumulative 86% rate of overall survival for all 14 patients, with acceptable hepatic tolerance and no grade 4 clinical toxicity.
Investigators concluded that, based on preliminary data, treatment consisting of combined CRT and TACE appeared to provide excellent local control for patients with a single, large (>5 cm) HCC nodule that was not suitable for resection.