Luc Defreyne

Phase III Trial Comparing Protracted Intravenous Fluorouracil Infusion Alone or With Yttrium-90 Resin Microspheres Radioembolization for Liver-Limited Metastatic Colorectal Cancer Refractory to Standard Chemotherapy

PURPOSE Liver dissemination is a major cause of mortality among patients with advanced colorectal cancer. Hepatic intra-arterial injection of the beta-emitting isotope yttrium-90 ((90)Y) bound to resin microspheres (radioembolization) delivers therapeutic radiation doses to liver metastases with minimal damage to adjacent tissues. PATIENTS AND METHODS We conducted a prospective, multicenter, randomized phase III trial in patients with unresectable, chemotherapy-refractory liver-limited metastatic CRC (mCRC) comparing arm A (fluorouracil [FU] protracted intravenous infusion 300 mg/m(2) days 1 through 14 every 3 weeks) and arm B (radioembolization plus intravenous FU 225 mg/m(2) days 1 through 14 then 300 mg/m(2) days 1 through 14 every 3 weeks) until hepatic progression. The primary end point was time to liver progression (TTLP). Cross-over to radioembolization was permitted after progression in arm A. RESULTS Forty-six patients were randomly assigned and 44 were eligible for analysis (arm A, n = 23; arm B, n = 21). Median follow-up was 24.8 months. Median TTLP was 2.1 and 5.5 months in arms A and B, respectively (hazard ratio [HR] = 0.38; 95% CI, 0.20 to 0.72; P = .003). Median time to tumor progression (TTP) was 2.1 and 4.5 months, respectively (HR = 0.51; 95% CI, 0.28 to 0.94; P = .03). Grade 3 or 4 toxicities were recorded in six patients after FU monotherapy and in one patient after radioembolization plus FU treatment (P = .10). Twenty-five of 44 patients received further treatment after progression, including 10 patients in arm A who received radioembolization. Median overall survival was 7.3 and 10.0 months in arms A and B, respectively (HR = 0.92; 95% CI, 0.47 to 1.78; P = .80). CONCLUSION Radioembolization with (90)Y-resin microspheres plus FU is well tolerated and significantly improves TTLP and TTP compared with FU alone. This procedure is a valid therapeutic option for chemotherapy-refractory liver-limited mCRC.

Aneurysm Study of Pipeline in an Observational Registry (ASPIRe)

Background and Objective: Few prospective studies exist evaluating the safety and efficacy of the Pipeline Embolization Device (PED) in the treatment of intracranial aneurysms. The Aneurysm Study of Pipeline In an observational Registry (ASPIRe) study prospectively analyzed rates of complete aneurysm occlusion and neurologic adverse events following PED treatment of intracranial aneurysms. Materials and Methods: We performed a multicenter study prospectively evaluating patients with unruptured intracranial aneurysms treated with PED. Primary outcomes included (1) spontaneous rupture of the Pipeline-treated aneurysm; (2) spontaneous nonaneurysmal intracranial hemorrhage (ICH); (3) acute ischemic stroke; (4) parent artery stenosis, and (5) permanent cranial neuropathy. Secondary endpoints were (1) treatment success and (2) morbidity and mortality at the 6-month follow-up. Vascular imaging was evaluated at an independent core laboratory. Results: One hundred and ninety-one patients with 207 treated aneurysms were included in this registry. The mean aneurysm size was 14.5 ± 6.9 mm, and the median imaging follow-up was 7.8 months. Twenty-four aneurysms (11.6%) were small, 162 (78.3%) were large and 21 (10.1%) were giant. The median clinical follow-up time was 6.2 months. The neurological morbidity rate was 6.8% (13/191), and the neurological mortality rate was 1.6% (3/191). The combined neurological morbidity/mortality rate was 6.8% (13/191). The most common adverse events were ischemic stroke (4.7%, 9/191) and spontaneous ICH (3.7%, 7/191). The complete occlusion rate at the last follow-up was 74.8% (77/103). Conclusions: Our prospective postmarket study confirms that PED treatment of aneurysms in a heterogeneous patient population is safe with low rates of neurological morbidity and mortality. Patients with angiographic follow-up had complete occlusion rates of 75% at 8 months.

Transarterial embolization with ONYX for treatment of intracranial non-cavernous dural arteriovenous fistula with or without cortical venous reflux

Background and purpose To report our experience with transarterial ONYX embolization of intracranial non-cavernous dural arteriovenous fistulas (DAVFs) with or without cortical venous reflux. Materials and methods Retrospective analysis of transarterial ONYX embolization in 20 patients with 21 DAVFs, presenting with intracranial hemorrhage (n=7), pulsatile bruit (n=7), vertigo (n=3), non-pulsatile bruit (n=1), headache (n=1) and epilepsy (n=1). Risk grading of DAVFs was Borden type I (n=6), type II (n=4) and type III (n=11). Results 18 of 21 (85.7%) DAVFs were angiographically occluded immediately after embolization, with ONYX embolization only, in either one (n=12) or two sessions (n=2); with a combination of ONYX and glue or transvenous coiling in a single session (n=2) or in two sessions (n=1); or after previous transvenous coiling/glue embolization (n=1). At the 6 (4–14) month control digital subtraction angiography (DSA), available in 14 of 18 occluded DAVFs, one patient showed a small residual fistula (17/21 or 81% occluded). Mid-term DSA was not available because of early death (n=2) or patients were awaiting the examination (n=2). In three cases, treatment was incomplete. Of six Borden type I DAVFs, four were cured and two partially occluded with resolution of symptoms. In two DAVFs, neurosurgical access to the feeding artery allowed distal microcatheterization and successful embolization. Conclusion Transarterial ONYX embolization offers an effective and safe treatment for all non-cavernous DAVFs, whether with or without cortical venous reflux.

Arterialization of the portal vein in pediatric liver transplantation - A Report of two cases.

Abstract Portal vein arterialization (PVA) is an acquired concept in shunt surgery for portal hypertension. This technique, recently described as both a temporary and permanent procedure in adult liver transplantation, is reported by the authors in two cases of pediatric transplantation. The indication was low portal blood flow after reperfusion with poor graft function due to persistence of spontaneous retroperitoneal venous shunts. In both cases described, PVA allowed for satisfactory macroscopic liver reperfusion. The increase in portal blood flow from 150 to 500 ml/min in the second patient enabled the liver to be reperfused correctly and led to successful transplantation. The graft function in both cases improved in the 1st postoperative week, but thrombosis of the PVA occurred in the 1st patient 2 months after transplantation. Signs of hepatic hyperarterialization occurred in the second patient and this necessitated a dearterialization of the portal vein 2 weeks later. Although the benefit of this procedure appears to be beyond doubt in the immediate postoperative period, we have no data on long‐term arterialization. We do think that PVA can be performed in pediatric liver transplantation, but it may need to be done only in special, individual situations when no valid alternative can be proposed, such as in the absence of a mesenteric vein and/or the presence of spontaneous retroperitoneal venous shunts.

Transarterial RAdioembolization versus ChemoEmbolization for the treatment of hepatocellular carcinoma (TRACE): study protocol for a randomized controlled trial

BackgroundHepatocellular carcinoma is a primary malignant tumor of the liver that accounts for an important health problem worldwide. Only 10 to 15% of hepatocellular carcinoma patients are suitable candidates for treatment with curative intent, such as hepatic resection and liver transplantation. A majority of patients have locally advanced, liver restricted disease (Barcelona Clinic Liver Cancer (BCLC) staging system intermediate stage). Transarterial loco regional treatment modalities offer palliative treatment options for these patients; transarterial chemoembolization (TACE) is the current standard treatment. During TACE, a catheter is advanced into the branches of the hepatic artery supplying the tumor, and a combination of embolic material and chemotherapeutics is delivered through the catheter directly into the tumor. Yttrium-90 radioembolization (90Y-RE) involves the transarterial administration of minimally embolic microspheres loaded with Yttrium-90, a β-emitting isotope, delivering selective internal radiation to the tumor. 90Y-RE is increasingly used in clinical practice for treatment of intermediate stage hepatocellular carcinoma, but its efficacy has never been prospectively compared to that of the standard treatment (TACE). In this study, we describe the protocol of a multicenter randomized controlled trial aimed at comparing the effectiveness of TACE and 90Y-RE for treatment of patients with unresectable (BCLC intermediate stage) hepatocellular carcinoma.Methods/designIn this pragmatic randomized controlled trial, 140 patients with unresectable (BCLC intermediate stage) hepatocellular carcinoma, with Eastern Cooperative Oncology Group performance status 0 to 1 and Child-Pugh A to B will be randomly assigned to either 90Y-RE or TACE with drug eluting beads. Patients assigned to 90Y-RE will first receive a diagnostic angiography, followed by the actual transarterial treatment, which can be divided into two sessions in case of bilobar disease. Patients assigned to TACE will receive a maximum of three consecutive transarterial treatment sessions. Patients will undergo structural follow-up for a timeframe of two years post treatment. Post procedural magnetic resonance imaging (MRI) will be performed at one and three months post trial entry and at three-monthly intervals thereafter for two years to assess tumor response. Primary outcome will be time to progression. Secondary outcomes will be overall survival, tumor response according to the modified RECIST criteria, toxicities/adverse events, treatment related effect on total liver function, quality of life, treatment-related costs and cost-effectiveness.Trial registrationNCT01381211

99mTc-labelled macroaggregated albumin (MAA) scintigraphy for planning treatment with 90Y microspheres

Purpose90Y microspheres are used for intra-arterial treatment of liver tumours. In the patient preparation, a hepatic angiogram is performed and all arteries that could transport microspheres from the targeted liver vasculature to extrahepatic organs are blocked. 99mTc-labelled macroaggregated albumin (MAA) is injected intra-arterially to simulate the treatment and whole-body scintigraphy and single photon emission computed tomography (SPECT) of the abdomen are performed.MethodsVarious aspects of lung shunt fraction (LSF) estimation were studied: interobserver and intrapatient variability, influence of scan quality and underlying disease. Secondly, the interobserver variability in reading the MAA SPECT of the abdomen was investigated. We reviewed 90 whole-body scans and 20 SPECT scans performed at our institution. Readers were blinded to each other’s findings. Scoring the scan quality was based on the visualization of tracer degradation.ResultsThe mean difference in LSF between the readers was 1%. In 1 of 23 patients who underwent repeated MAA injections a marked change in LSF was observed. No significant differences in LSF were recorded for primary versus secondary liver tumours. There was a correlation between scan quality and LSF, suggesting that low scan quality leads to overestimation of the LSF. Concordant results in ruling out the presence of extrahepatic tracer deposition were reached in 17 of 20 scans (85%).ConclusionInterobserver and intrapatient variability in LSF calculation was limited. LSF was clearly dependent on scan quality. The underlying disease had no significant impact on the LSF. Interobserver variability for reading the MAA SPECT scans was acceptable.

Cirsoid renal arteriovenous malformation treated by endovascular embolization with n-butyl 2-cyanoacrylate.

Abstract. The authors report a rare case of renal arteriovenous malformation (rAVM) which was diagnosed by arteriography years after onset of intermittent haematuria. The rAVM of the cirsoid type was superselectively catheterized and embolized in toto with n-butyl 2-cyanoacrylate. Diagnostic imaging modalities and the technique of embolization are discussed.

Modified intra-arterial calcium stimulation with venous sampling test for preoperative localization of insulinomas

Abstract.Background: To determine the accuracy and safety of a modified intra-arterial calcium stimulation with the venous sampling test (ASVS) for preoperative localization of insulinomas. Modification included stimulation with a fixed low dose of calcium gluconate, additional stimulation in the distal splenic artery, and no insulin sampling in the left hepatic vein. Methods: In 10 patients showing biochemical evidence of organic hyperinsulinemia, 0.45 mmol of Ca2+ was injected into the gastroduodenal, superior mesenteric, proper hepatic, proximal, and distal splenic arteries during angiography. Insulin levels were measured in samples taken from the right hepatic vein before and 30, 60, 90, 120, 180, and 300 s after Ca2+ injection. Results: Insulin gradients with an increase of more than fourfold indicated direct tumor supply, two- to fourfold correlated with collateral supply, and less than twofold correlated with normal tissue vascularization. ASVS localized all the adenomas of the pancreatic head (n = 3) and body (n = 2) and two of four adenomas of the tail correctly, as confirmed by surgery. Two adenomas of the proximal pancreatic tail were erroneously localized to the body segment, but the fault was rectified by angiography. In one patient with a negative ASVS and without exploration, the diagnosis of an insulinoma was revised. Conclusion: ASVS with a fixed low dose of calcium gluconate is a highly accurate and safe method for preoperative localization of insulinomas. Sampling in the left hepatic vein can be routinely omitted. Additional stimulation in the distal splenic artery seems helpful in surgical decision making, but additional experience is needed.

Spontaneous thrombosis of a pseudoaneurysm complicating pancreatitis

Patients with a visceral aneurysm are at high risk for acute transpapillary, intra-, or retroperitoneal hemorrhage, necessitating either surgical or endovascular therapy. We report an instance of spontaneous thrombosis of a pseudoaneurysm complicating pancreatitis before endovascular treatment could be performed. Causality and the literature of spontaneous thrombosis in pseudoaneurysms are discussed.

The anti-tumoral activity of neoadjuvant intra-arterial 131I-lipiodol treatment for hepatocellular carcinoma: a pilot study.

BACKGROUND The high recurrence rate after curative resection has stimulated the development of adjuvant treatment modalities, such as local embolization. This study was set up to investigate the anti-tumoral potential of neo-adjuvant 131I-lipiodol administration before liver transplantation. METHODS In this preliminary, prospective study we treated 10 consecutive HCC patients by intra-arterial injection of 131I-lipiodol into the hepatic artery followed by liver transplantation within 1-9 months (mean 3.4). After hepatic catheterization, 1332-2146 MBq (mean 1887 MBq) or 36-58 mCi (mean 51 mCi) was instilled as selective as possible, depending on the distribution of the tumors: non-selectively in the hepatic artery propria (n = 4), selectively in the right and/or left hepatic artery (n = 3) or super-selectively in segmental arteries (n = 3). RESULTS Anti-tumoral activity was regarded as obvious with 1) a strong decrease of alfa-fetoprotein (AFP), comparing the highest recorded value before and after 131I-lipiodol and/or 2) a downstaging in TNM classification on the posttherapy MRI as compared to the pre-therapy MRI and/or 3) tumors with > 50% necrosis on histo-pathology of the explanted liver, without previous chemoembolization. Either of these criteria were met by 5/10 (50%) of patients. A 4) downstaging in pTNM classification on histopathology compared to the TNM classification of the MRI and/or a 5) tumor necrosis of only 10-50% were regarded as possibly tumor-related but were not accepted as a single criteria of anti-tumoral activity. This was seen in 3/10 (30%) of patients. Clinical side-effects of the 131I-lipiodol therapy were generally mild with a temperature rise in two cases, nausea without vomiting in another two and upper back pain in one patient. In one patient progressive liver failure developed one week after 131I-lipiodol therapy necessitating premature liver transplantation after 4 weeks. CONCLUSION With the use of stringent anti-tumoral criteria, this study shows evidence of an anti-tumoral effect in 50% of patients. Our data support the evaluation on larger patient numbers to confirm the promising anti-tumoral activity of 131I-lipiodol in HCC patients candidated for liver transplantation.