Successful hepatocellular carcinoma downstaging with transarterial chemoembolization followed by stereotactic radiotherapy

Treatment Approach

An a priori decision to use TACE followed by SRT to down-stage HCC patients so they could be considered for liver transplantation was made at a multidisciplinary tumor board comprising of transplant surgeons, hepatologists, radiologists, interventional radiologists, nuclear medicine physicians, medical oncologists, and radiation oncologists.

When SRT was planned to follow TACE, conventional TACE with lipiodol and chemotherapy was used. Lipiodol is visible on fluoroscopy and noncontrast computed tomography (CT), which facilitates localization of the target for image-guided radiotherapy. Targeted super-selective TACE was performed initially in all patients. Briefly, a microcatheter was advanced to the tumor-feeding artery or arteries. Nontumor liver tissue was spared as much as possible. A mixture of 50 mg of doxorubicin and lipiodol was delivered until the tumor was saturated. This is followed with 400-μm Embozene microsphere particles (CeloNova BioSciences, San Antonio, TX) to achieve complete stasis. The lipiodol used during embolization typically remains in the tumor for several months when administered as described above (Fig. 1).

If the tumor-lipiodol was not well visualized following TACE, patients underwent CT-guided placement of liver fiducials (Civco Polymark 1 mm × 3 mm fiducials; Civco Medical Solutions; Orange City, IA) to facilitate image registration and tumor targeting at the time of radiation treatment.

SRT for HCC was typically performed using a 3-fraction schedule for a total of 45 Gray (Gy), delivered over 10 calendar days. Clinically accepted practices were followed including custom immobilization, treatment planning, respiratory correction, and image-guided treatment delivery.4 Fixed-field intensity-modulated radiation therapy or dynamic arc plans were used for treatment delivery on a linear accelerator. At least 800 cc of normal liver parenchyma volume was spared to receive less than 15 Gy during SRT. Changes in SRT dosing were made only when 800 cc of uninvolved liver could not be spared, or dose-tolerance limits to adjacent critical organs could not be met.

Case Series

There were 12 patients who were treated with TACE-SRT combination, with a mean follow-up of 29 months (range 6-48; Table 1). These patients (9 male, 3 female) were not initially transplant candidates because their tumors exceeded the Milan criteria. The mean age of the patient group was 58.6 years (range, 42-70 years). The Model for End-Stage Liver Disease (MELD) score ranged from 6 to 14, and no patients had clinically evident hepatic decompensation symptoms. HCC diagnosis was made based on Organ Procurement and Transplant Network criteria: one 5a tumor (6 patients), two 5b tumors (5 patients), one 5b and one 5a tumors (1 patient). In addition to meeting imaging criteria, 4 of the patients had an alpha-fetoprotein level over 100 and the 4 patients had biopsy-proven HCC. The underlying liver disease was hepatitis B (n = 3), hepatitis C (n = 6), alcohol (n = 1), alpha-1-antitrypsin (n = 1), and nonalcoholic steatohepatitis (n = 1). A total of 18 tumors were treated in these 12 patients, sizes ranging from 1.7 to 7.6 cm (mean, 4.2 cm). A single TACE procedure was performed in 7 patients, whereas the remaining 5 patients had 2 TACE procedures performed to completely embolize the HCC before SRT. Though thermal ablation was typically used at our institution to treat HCC < 3 cm, 5 patients in this series had lesions < 3 cm that were too close to major blood vessels or the biliary tree, and hence were treated with SRT. The mean time from diagnosis to first TACE was 7.8 weeks (range, 3-24) and from TACE to SRT was 13 weeks (range, 6-18). The mean biological equivalent dose of radiation delivered using SRT was 255 Gy₃ (range, 180-270 Gy₃). The mean time from SRT to liver transplantation was 7.8 months.

Six patients have undergone liver transplantation. The liver transplant operations were straightforward with 3/6 recipients receiving no blood products (mean red blood cell transfusion, 3.2 units). There were no complications with the hepatic artery reconstruction. Two of the 6 patients developed biliary strictures after transplant, which were managed endoscopically. One patient developed acute cellular rejection within 90 days of transplantation managed with pulse steroid therapy. Explant pathology demonstrated pathological complete response, with no viable tumor detected in the 10 treated HCC sites in the 6 case series patients (100% necrosis). However, there was viable HCC tumor present in 2 patients in areas of the liver that were not treated with either TACE or SRT. In 1 patient, there was evidence of small diameter (<1 cm) multifocal HCC involving both lobes, whereas in another patient, there was a single focus of additional HCC (1.4 cm) away from the treated site, not apparent on the diagnostic imaging. One patient died without evidence of tumor recurrence at 29 weeks following liver transplantation due to medication noncompliance. Five patients are alive and without signs of tumor recurrence at the time of reporting.

Six patients did not undergo transplantation (Table 1). One patient is active on the transplant wait list. One patient died of sepsis 2 months after SRT. Three patients developed new HCC tumors outside the SRT treatment field while on the wait list and were delisted. In each of these 3 patients, the TACE+SRT-treated HCC tumors demonstrated a complete radiographic response based on mRECIST criteria. One patient developed progressive tumor growth at the margin of the SRT treatment field and also was delisted.