At the Abramson Cancer Center and Penn Medicine, a team of specialists is exploring the use of radiotherapy for liver cancer. A leading cause of cancer deaths worldwide, hepatocellular carcinoma (HCC) is expected to increase in prevalence in the United States secondary to the aging cohort of patients with chronic hepatitis C infection and the rising incidence of cirrhosis from nonalcoholic steatohepatitis related to obesity.
Cholangiocarcinoma, a tumor originating in bile ducts, is also increasing in incidence. The latest SEER database analysis reports that ~16% of patients with primary liver cancer–most of which is HCC–survive five years. The majority of patients with cholangiocarcinoma die within 6 – 12 months of diagnosis.
Proton Therapy for HCC and Intrahepatic CholangiocarcinomaLiver transplantation offers a potentially curative treatment for many patients with HCC, but is not an option for patients with multiple, large or metastatic hepatic lesions or intrahepatic cholangiocarcinoma. The efficacy of standard cancer treatments for HCC, including chemotherapy and radiation, is poor. Studies now suggest that proton therapy may offer improved local control and survival rates for these patients.
Proton dose distributions can be designed that conform more closely to the tumor volume with a marked reduction in radiation exposure to the non involved liver. This allowes delivery of higher doses to tumors within the liver, an organ extremely sensitive to the effects of radiation.
The Abramson Cancer Center and Penn Medicine are participating in a multi-center phase II clinical study investigating the use of proton therapy in patients with unresectable primary hepatoma (hepatocellular carcinoma) or intrahepatic cholangiocarcinoma.
Phase II study of proton beam irradiation of unresectable primary liver tumors [ClinicalTrials.gov Identifier: NCT00976898]
Objectives: The primary objective of this study is to demonstrate 2 yr LC of >80% with proton beam irradiation for unresectable hepatocellular cancer. This will be benchmarked against 2yr LC of 55%. Secondary objectives include a determination of the safety and tolerance of this treatment program, an evaluation of tumor response, patterns of failure and five-year overall survival, among other goals.
Methods: Patients will receive proton beam irradiation in 15 fractions over 3 weeks. Acute toxicity evaluations will occur weekly during study treatment, and at 3 month follow up. Thereafter, evaluation for tumor response will be conducted using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and for acute and late toxicity per Common Terminology Criteria for Adverse Events (CTCAE ) v. 3.0.
The primary investigator for this trial at Penn is Edgar Ben-Josef. Please contact Kristi Varillo at 215.615.3273 for more information.
Proton/IMRT Case StudyRG, a 46 y.o. man, presented in 2009 with a large hepatic mass involving the entire left lobe as well as portions of segment 8. There was an additional 1.3 cm right hepatic tumor in segment 6, most likely multifocal HCC. He had an FNA and core needle biopsy confirming HCC. At that time his AFP was 70,000.
RG had excellent responses to multiple chemoembolizations (6 total) and one radio embolization with Y-90 TheraSpheres®. In 4/12, however, an enlarged 2 cm pericardiac lymph node was noted, supplied by the right internal mammary artery. RG was treated with chemoembolization via the left hepatic artery and bland embolization via the right internal mammary artery, but his AFP continued to rise and imaging suggested progression of disease.
An MRI in 11/12 showed an enlarging right pericardiophrenic lymph node and a 6.2 x 7.1 cm tumor in the left lobe with multiple scattered foci of peripheral enhancement. RG was then referred for radiation therapy and received 55 Gy in 25 fractions, using a combination of protons and IMRT (Figures 1&2). His treatment was completed in 1/13.
RG had a very good clinical and radiographic response. An MRI in 7/13 demonstrated a decrease in size of the left lobe lesion (to 5.5 x 6.4 cm), as well as the size of the pericardiac lymph node. His AFP decreased from 375 to 1.2. He had no clinical toxicity and no change in liver enzymes.
TACE and SBRT for Patients Awaiting Liver TransplantationSpecialists at the Abramson Cancer Center and Penn Medicine have initiated a prospective randomized trial assessing the use of a powerful new technology, stereotactic body radiation therapy (SBRT), in combination with transarterial chemoembolization (TACE) versus TACE alone as a therapeutic bridge to transplantation.
SBRT delivers highly focused radiotherapy to tumors in five or fewer fractions. Because the distribution of dose conforms so well to the target, very high doses (biologically more effective) can be delivered at any one session. SBRT also excells at limiting dose to normal tissue, and has been shown to be an effective therapy for liver metastases; with a short follow up of 2 years its efficacy rivals that of resection.
The Abramson trial will combine this technology with TACE in patients awaiting OLT. Theoretically, SBRT complements TACE by more easily targeting residual tumor cells at the periphery of a lesion and delivering higher doses to tumors partially shrunken by chemoembolization.
A pilot trial of transarterial chemoembolization with or without stereotactic body radiation therapy for hepatocellular carcinoma patients awaiting liver transplantation [ClinicalTrials.gov Identifier: NCT01918683]
Objectives: This study examines the efficacy of TACE with or without SBRT as a bridge to transplantation in patients with HCC awaiting OLT. The primary objective of the study is to determine whether adding SBRT to TACE improves local tumor control and rate of complete necrosis in patients with HCC.
Methods: Patients will be randomized into two arms: (A) TACE alone (i.e. control group) or (B) TACE combined with SBRT (i.e. experimental group). After initial TACE, patients will be followed with contrast enhanced MRI or CT scans at 1 month post-TACE and then every 3 months until OLT.
In Arm A, additional TACE of a previously treated lesion will be performed for (1) >50% viable tumor following initial TACE (i.e. less than a partial response by EASL criteria to initial TACE) (2) disease progression defined as >25% increase in amount of enhancing tissue in target lesion(s) and/or new enhancement in previously treated lesions warranting further locoregional therapy, or (3) as needed to maintain the patient within criteria for OLT. Patients with stable disease by imaging criteria otherwise will not undergo additional TACE.
In Arm B, SBRT will be performed after initial TACE. SBRT will only be performed on lesions previously treated by TACE (i.e. no HCC will receive SBRT only as a bridging therapy), and may occur as early as one month following TACE. Following SBRT, further treatment of a previously treated lesion with additional TACE will be performed for (1) disease progression or (2) to maintain patient within criteria for OLT. Patients with stable disease (SD) by imaging criteria otherwise will not undergo additional TACE of previously treated lesions.
Patients may undergo liver transplantation at anytime during the study period according to organ availability as governed by OPTN guidelines and the treating physicians in the Department of Transplant Surgery.
The primary investigator for this study at Penn is Edgar Ben-Josef, MD. Please contact Sally McNulty at 215.662.7720 for more information.
Faculty TeamThe Abramson Cancer Center of the University of Pennsylvania supports eleven Research Programs that bring together investigators from 41 departments and eight University schools with a shared interest in specific types of cancer or scientific themes. Many programs span multiple research disciplines (e.g., fundamental and translational).
Clinical Research Team for Proton Therapy and TACE/SBRT Clinical Trials
Interventional RadiologyMichael Soulen, MD
Professor of Radiology
Gregory Nadolski, MD
Medical OncologyNevena Damjanov, MD
Associate Professor of Clinical Medicine
PathologyEmma Furth, MD
Professor of Pathology and Laboratory Medicine
RadiologyMark A. Rosen, MD, PhD
Associate Professor of Radiology
Radiation OncologyEdgar Ben-Josef, MD
Vice-Chair for Translational Research
Professor of Radiation Oncology
John P. Plastaras, MD
Assistant Professor of Radiation Oncology
Transplant and Hepatobiliary SurgeryAbraham Shaked, MD, PhD
Eldridge L. Eliason Professor of Surgery
Kim Olthoff, MD
Donald Guthrie Professor in Surgery
Gastroenterology/HepatologyMaarouf Hoteit, MD
Assistant Professor of Clinical Medicine
Center for Clinical Epidemiology and BiostatisticsRosemarie Mick, MS
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