Selective intraarterial radionuclide therapy with Yttrium-90 (Y-90) microspheres for unresectable primary and metastatic liver tumors

The clinical and follow-up data of 124 patients who were referred to our department for SIRT between June 2006 and October 2010 were evaluated retrospectively. SIRT has been applied to 78 patients who were suitable for treatment. Of the remaining 46 out of 124 patients, the treatment could not have been performed because of the main contraindications of SIRT such as bilirubin levels>2 mg/dl or 5 fold elevation of AST and ALT levels or albumin levels< 3 mg/dl or bulky tumor>70% of liver tissue. All the patients had unresectable liver metastasis of different malignancies (35/78 colorectal, 25/78 hepatocellular, 7/78 gastric, 4/78 breast, 1/78 malign melanoma, 1/78 pancreas, 1/78 renal cell, 1/78 esophagus and 3/78 neuroendocrine tumor patients). All the patients had received chemotherapy for the treatment of primary tumors. Furthermore, all of them had taken chemotherapy for liver metastases and they had been accepted as refractory to chemotherapy. Partial hepatectomy, chemoembolization and radiofrequency ablation treatment had been performed in 2, 2 and 6 patients respectively. The treatment was repeated at least one more time in 5 patients to the same or other lobes.

All the patients underwent liver function tests and dynamic liner MRI as well as basal F18-FDG PET/CT examination before the treatment. The first control F18-FDG PET/CT scan was undergone by all patients 6 weeks after treatment for the evaluation of treatment response.

The patients were divided into two groups according to the disease stage; those with only liver metastases (H) and those with metastases in other organs (EH).

In all patients, widely accepted parameters regarding liver reserve, bone marrow reserve (granulocytes > 1500/μL, platelets > 60000/μL), and hepatic vascularity were used as inclusion and exclusion criteria. Liver reserve was evaluated using bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) levels in blood. A bilirubin level < 2 mg/dl and AST/ALT/ALP levels less than 5 times the normal upper limit were required for radioembolization. 10 patients did not receive the therapy according to these criteria. Patients with ascites, portal hypertension, portal venous thrombosis or an expected survival < 3 months were excluded as well as the patients with contraindications for angiography and selective visceral catheterization. To evaluate vascular tree, a therapy-planning angiogram was performed. With this angiogram, branches of hepatic artery to the gastrointestinal tract were coiled to prevent Y-90 reflux to the stomach, i.e. to gastro-duodenal artery and right gastric artery. At the end of this planning angiogram, a 150 MBq dose of ^99mTc-labelled macroaggregated albumin (MAA) was administered through the catheter in an attempt to detect arteriovenous shunts from the hepatic arterial system to the pulmonary system or gastrointestinal tract. After this procedure, gamma imaging was obtained and regions of interest were drawn around the liver and lungs in anterior planar images, and the pulmonary shunt was calculated using the following equation: pulmonary shunt fraction = ROI _{lung counts}/(ROI _{lung counts} + ROI _{liver counts}. Patients with a pulmonary shunt less than 20% were eligible for therapy. 2 patients were excluded because of the pulmonary shunt higher than 20%. In 78 patients who were suitable for therapy, the Y-90 dose was adjusted according to the following body surface area method: activity (GBq) = (BSA - 0.2) + tumor volume/total liver volume. The Y-90 resin microspheres (Sirtex Medical, Australia) were injected through the hepatic artery catheter under intermittent fluoroscopic visualization. Within 1 to 24 hours after microsphere infusion, Bremsstrahlung images were obtained to confirm that the Y-90 was deposited only in the liver. All patients were hospitalized overnight and medications like analgesics, antiemetic, and H₂ antagonist were administered, if necessary. All patients were closely monitored until acute or late toxicities were resolved.

PET/CT images were acquired with GE Discovery ST PET/CT scanner. During imaging patients were required to have at least 6 hours fasting and checked if their blood glucose levels were under 150 mg/dl. Oral contrast agents were applied to all patients. Images were obtained while patients were lying in a supine position from vertex to proximal femur. Whole body F18-FDG PET/CT imaging was performed approximately 1 hour after an intravenous injection of 8-10 mCi FDG. During the waiting period patients rested in a quiet room without receiving muscle relaxant. PET images were acquired for 4 minutes per bed position. Emission PET images were reconstructed with non-contrast CT. A CT image was obtained from the patient's integrated F18-FDG PET/CT with the use of a standardized protocol involving 140 kV, 70 mA, a tube rotation time of 0.5 s per rotation, a pitch of 6 and a section thickness of 5 mm. Patients were allowed to breathe normally during procedure. Attenuation-correction was done by PET/CT fusion images on three planes (trans-axial, coronal and sagittal) and were reviewed on Xeleris Workstation (GE Medical System). F18-FDG PET/CT images were evaluated visually and semi-quantitatively by two experienced nuclear medicine specialists. The number, location and SUV values of liver lesions were recorded.

Metabolic treatment response evaluated by PET/CT in the 6^th week after treatment. FDG-PET/CT was repeated in per six weeks periods. The response criterion had been described as at least 20% decrease of SUV value. Also in patients with neuroendocrine tumor serial Ga-68 PET/CT was used for evaluation of response. Patients were divided into 2 groups according to their treatment response (R = responder, NR = non-responder).

According to R, NR, H and EH groups, overall survival analysis was performed using Kaplan-Meier method and comparison was done using the log rank (Mantel-Cox) test. SPSS version 15.0 was used for statistical analysis. Statistical significance was as accepted p < 0.05.

78 patients (49 M; 29 F; mean age: 62.4 ± 2.3 years) received intraarterial radionuclide therapy with Y-90 microspheres for liver metastasis or primary HCC between June 2006 and October 2010. Although 25 patients had primary HCC diagnosis, the remainder had unresectable multiple liver metastases of different cancers (35 colorectal, 7 gastric, 4 breast, 1 pancreas, 1 renal cell, 1 esophagus cancer, 3 neuroendocrine tumor and 1 malignant melanoma).

68 patients received treatment for the right lobe, seven patients received treatment for the left lobe and 3 patients for both lobes. The mean treatment dose was estimated at 1.62 GBq (range: 1-1.8 GBq). In all patients, the leakage to the lungs was less than 20%. Therefore, neither reduction in the estimated dose nor discontinuation of the treatment was required.

The technical success of the intraarterial delivery of Y-90 microspheres was 100% and none of the patients experienced complications due to angiographic intervention. All patients experienced post-radioembolization syndrome characterized by mild abdominal pain, nausea, and sub-febrile fever. A combination of a non-opioid analgesic, an antiemetic and a H₂ receptor blocker was given to patients not tolerating these symptoms. Symptoms decreased in intensity within one week and completely disappeared within 15 days. No difference has been found in complication rates between the two lobes. Bremsstrahlung imaging done 24 hours after treatment did not show any activity outside the liver. All patients were hospitalized for one night as a preventive measure and prolonged hospitalization was not required by any of the patients.

In the evaluation of treatment response; 43 (55%) patients were responder (R) (Figure 1, 2, 3) and 35 (45%) patients were non-responder (NR) in the sixth week F18-FDG PET/CT. Mean pretreatment SUVmax value of R group was 11.6 and NR group was 10.7. While only 11 (31%) out of 35 NR patients had H disease, 30 (69%) out of 43 R patients had H disease (p < 0.05) (Table 1).

The mean overall survival time of R group was calculated as 25.63 ± 1.52 months and NR group's 20.45 ± 2.11 (p = 0.04) (Table 2, 3). The mean overall survival time of H group was computed as 25.66 ± 1.52 months and EH group's 20.76 ± 1.97 (p = 0.09) (Table 4, 5). The survival curves of the whole patient group, the colorectal group and the HCC group, according to the treatment response and disease stage were demonstrated in Figure 4, 5 and 6, respectively.