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C L I N I C A L I N V E S T I G A T I O N Bland Embolization in Patients with Unresectable HepatocellularCarcinoma Using Precise, Tightly Size-Calibrated,Anti-Inflammatory Microparticles: First Clinical Experienceand One-Year Follow-Up Guido Bonomo • Vittorio Pedicini • Lorenzo Monfardini •Paolo Della Vigna • Dario Poretti • Gianluigi Orgera •Franco Orsi Received: 30 April 2009 / Accepted: 2 November 2009Ó Springer Science+Business Media, LLC and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2009 The purpose of this study is to report on the outcome after TAE with Embozene microspheres are ve- feasibility, local response, and 1-year clinical outcome of ryly encouraging, however, further studies, a larger patient bland transarterial embolization (TAE) with 40- and 100- population, and a longer follow-up are mandatory to assess lm Embozene microspheres in patients affected by unre- sectable hepatocellular carcinoma (HCC). Up to January2009, 53 patients underwent superselective TAE for a total Hepatocellular carcinoma Á Embolization Á of 74 lesions. Diagnosis of HCC was based on multide- tector computed tomography (MDCT), a-fetoprotein, andbiopsy. MDCT was performed 24 after treatment andrepeated at 1 month, 3 months, and then every 6 months.
Local efficacy was defined according to RECIST criteria.
Technical success was always achieved. Local results at Hepatocellular carcinoma (HCC) is the most common form 1-month, 3- to 6-month, and 6- to 12-month follow-up of primary liver malignant cancer worldwide [1], it is the were 62%, 37%, and 16%, respectively, for stable disease sixth most common cancer and the third most common and 35%, 56%, and 51%, respectively, for partial response.
cause of cancer-related death globally [2], and its incidence Complete response (no evidence of lesion) has been in the United States and Western Europe has been observed only at late follow-up (three lesions; 7%). To increasing [3, 4]. In 80% of patients, HCC is a complica- date, 20 of 53 patients have had at least 1 year of follow- tion of cirrhosis, and it is the leading cause of death in up, with an overall survival rate of 96%. Hepatic pro- cirrhotic patients in Europe [5]. Despite many efforts to gressive disease (i.e., new nodules) was observed in 14 of screen for HCC, only 20–30% of patients present with 20 patients due to underlying liver disease. Minor com- early-stage disease amenable to curative treatments, plications were observed in four patients. A major com- including surgical resection and liver transplantation [5, 6], plication occurred in one patient, who died unexpectedly and most patients are only suitable for locoregional thera- 24 h after TAE due to pulmonary embolism of necrotic pies or palliative care. Radiofrequency ablation (RFA) for pathologic tissue and passage of particles through a dis- treatment of HCC can be indicated as a stand-alone rupted hepatic vein. Local results as well as 1-year clinical approach for patients considered not to be candidates forresection. Although criteria for RFA have not been widelydefined, most patients are selected on the basis of lesion G. Bonomo (&) Á L. Monfardini Á P. Della Vigna Á G. Orgera Á size (\5 cm), number of lesions (B3 lesions), and degree of underlying hepatic impairment [7]. Intra-arterial treat- Unit of Interventional Radiology, European Instituteof Oncology, Via Ripamonti 435, 2041 Milan, Italy ments such as transarterial chemoembolization (TACE) and transarterial embolization (TAE) are considered palli-ative therapy for multifocal HCC which is not suitable for surgical resection or percutaneous ablation therapies.
Radiology, Istituto Clinico Humanitas, Via Manzoni 56,20089 Rozzano, Milan, Italy However, the efficacy of intra-arterial treatment in patients G. Bonomo et al.: Bland Embolization in Patients with HCC affected by HCC is not well defined [8–10]. Several alternative treatments have been proposed, but recently only chemoembolization has been shown to improve sur-vival compared with the best supportive care in meta- analyses of randomized trials [11, 12]. However, it is unclear whether embolization alone gives the same sur- vival advantage [5], whether specific patient characteristics affect outcome, or whether any particular technique for performing transarterial therapy is better than others.
The aim of this study was to assess the feasibility and local response in patients affected by unresectable HCC, treated with TAE using precise, small, narrowly calibrated microparticles (40 and 100 lm) targeting the adequate No evidence of disease 3 (*6%)Death due to other/unknown 1 (*2%) vascular anatomy and possible anatomical variations.
Between October 2007 and January 2009, 66 HCC patients Angiography of the main hepatic arterial branches was with underlying hepatic cirrhosis were evaluated for TAE.
performed to identify feeding vessels of the lesions; then All patients were unsuitable for surgical resection or per- superselective catheterization of feeding vessels was cutaneous therapies. Exclusion criteria included patients obtained with the coaxial technique using microcatheters older than 85 years and patients with advanced liver disease (Renegade High Flow; Boston Scientific, Natick, MA, (Child-Pugh class C), active gastrointestinal bleeding, USA) to perform subsegmental embolizations.
encephalopathy, refractory ascites and portal branch Just before commencement of embolization, 1 ml of 5% occlusion, and documented pulmonary shunting. Thirteen levobupovacaine was injected via the microcatheter to patients were excluded according to these criteria. Fifty- obtain local parenchymal analgesia for procedural and three of 66 patients were selected for TAE and the diagnosis early postembolization pain control. Embolization was of HCC was based on radiological findings (multidetector performed using small, precise and tightly calibrated mi- computed tomography [MDCT scan]), a-fetoprotein level, croparticles 40 ± 10 and/or 100 ± 25 lm in diameter.
and biopsy according to the Barcelona criteria [13]. A total This new spherical embolic agent is designed with a of 74 target lesions were embolized using a superselective hydrogel core and an anti-inflammatory, bacterial-resistant, technique (see Table 1). A specific informed consent was obtained from every patient included in this Institutional Advanced Microspheres; CeloNova BioSciences, Newnan, Guideline for Hepatic Local Therapies by a multidisci- GA, USA). Transcatheter injection of 40-lm microspheres plinary task force composed of surgeons, oncologists, was carried out until blood flow was stopped or a total pathologists, radiation therapists, and interventional radi- amount of 4 ml was injected. If residual enhancement and/ ologists. Once included, all patients underwent upper or patency of feeding arteries was still detected, 100-lm abdomen MDCT no more than 7 days before treatment in microparticles were then employed. The procedure was order to assess the number, location, and dimension of considered completed only when vascular shutdown and no lesions to be treated and to establish a pretreatment baseline feeding vessels to the target tumor were detected at final for comparison during follow-up. Scans of the liver were angiography. Embolization was repeated if there was evi- acquired in the cranium-caudal direction, and a quadruple- dence of viable tumor on follow-up imaging, including phase enhancement protocol was used (unenhanced phase, previously embolized vessels and/or collateral new vessels early arterial phase, late arterial phase, portal venous phase). Pretreatment MDCT images were analyzed to When it was not possible to identify the vessels feeding evaluate the anatomy of liver arteries and to detect, when the lesion with angiography, ultrasound (US) liver evalu- possible, the feeding vessels to the tumor.
ation was performed during injection of CO2 microbubbles Femoral or left subclavian arterial percutaneous access via the arterial microcatheter; CO2 microbubbles were was obtained after subcutaneous injection of local anes- prepared by vigorously mixing 10 ml of CO2, 10 ml of thesia (Mepivacaine, 100/200 mg) at the site of vessel normal saline, and 5 ml of heparinized patient’s own blood puncture. Then selective angiography of the celiac trunk [14, 15]. By positioning the microcatheter tip into different and superior mesenteric artery was performed to assess the arterial branches feeding the tumor, it was possible to G. Bonomo et al.: Bland Embolization in Patients with HCC detect the corresponding supplied parenchyma as an intense hyperechoic confined area and precisely embolizeonly the pathologic arteries.
From October 2007 to January 2009, 53 selected patients After a major complication occurred (reported under underwent bland arterial embolization for unresectable Results) all patients included in this study were screened HCC. Seventy-four target lesions (size range, 12–122 mm) for lung shunting immediately before embolization.
were embolized using Embozene microspheres (40 ± 10 Whole-body perfusion scintigraphy was performed by and/or 100 ± 25 lm) for a total of 76 procedures (range, injecting 99Tc-labeled albumin macroaggregates (MAA), 1–5). Technical success was achieved in all procedures.
via the main hepatic artery, according to the technique Median follow-up for all 53 patients was 6 months (range, reported in the literature [16–18].
1–19 months). Two of 53 patients died: 1 died within 24 h If lung shunting was detected within the range of 1–10 after intervention, and 1 patient died from progressive liver %, embolization was carried out using 100-lm micropar- ticles alone. Lung shunting of more than 10% was inter- To date, 20 of 53 patients have had at least 1 year of preted as an exclusion criterion for treating patients with follow-up, with an overall survival rate of 96%. The 1-year microparticles. Antibiotic prophylaxis after treatment was follow-up results for these 20 patients are as follows: 3 carried out with ciprofloxacin. Pre- and posttreatment with complete response (CR), 5 with partial responses laboratory values were drawn for monitoring liver and (PR), 3 with stable disease (SD), and 9 with progressive disease (PD). Hepatic progressive disease (i.e., new nod- Twenty-four hours after treatment, upper abdomen ules) was observed in 14 of 20 patients due to underlying MDCT was performed to assess the early local result after embolization. Once discharged, patients were evaluated both The local outcome of 74 treated lesions at 1-month clinically and with MDCT on a regular basis at 30 days, follow-up, as reported in Table 2, shows an SD rate of 62% 3 months, and then every 6 months after treatment.
(46 lesions) versus a PR rate of 35% (26 lesions). At the The early efficacy of the treatment was defined by next follow-up there was an inversion of this tendency, assessing the amount of tumor devascularization at 24-h with an increase in PR from 35 to 56% at 3–6 months and MDCT. Complete embolization was defined as the absence to 51% at 6–12 months versus a reduction in SD rate from of any contrast enhancement in any enhanced phases.
62% to 37% and 16%, respectively. A CR (no evidence of Persistent viable (= enhanced) tumor demonstrated at lesion) (Fig. 1) has been observed only at late follow-up MDCT was an indication for scheduling a new TAE ses- (three lesions; 7%). Five complications occurred in 53 sion. Local results of embolization were assessed according According to SIR criteria, ‘‘minor’’ complications were Complications were considered as those due to the observed in four patients. In two patients, pancreatitis treatment, which occurred after TAE. Complications were occurred the day after treatment. Symptoms were con- classified according to the Society of Interventional Radi- firmed with laboratory amylases and by MDCT scan in ology (SIR) Standards of Practice into ‘‘minor,’’ if they which irregular hypodensity of the head of the pancreas required no therapy or nominal therapy, and ‘‘major,’’ if was observed. Pancreatitis occurred due to accidental they required treatment, had permanent adverse outcomes, reflux of microparticles into pancreatic feeding arteries.
These patients were treated conservatively and were dis-charged 3 days after the scheduled date.
In one patient, temporary respiratory insufficiency was observed due to diaphragmatic artery embolization. In thiscase a portion of the treated lesion was fed by the right Table 2 Local results according to RECIST criteria diaphragmatic artery, and during TAE distal branches of the vessel were embolized. Symptoms disappeared a fewhours after treatment. Additionally, one patient experi- enced temporary abdominal ascites the day after treatment One major complication occurred in a patient who died within 24 h after TAE. This 74-year-old patient had a history of breast cancer, colorectal cancer, and heart infarction due to chemotherapy. The patient had undergoneliver surgery for HCC 2 years earlier (S2–S3 resection), SD stable disease; PR partial response; CR complete response; PDprogressive disease with early recurrence within S4, between the right and the G. Bonomo et al.: Bland Embolization in Patients with HCC Fig. 1 A, B MDCT shows a huge HCC mass relapsed 2 months after left hepatic lobectomy, arterial and portal phase. C, D MDCT shows acomplete response (RECIST criteria) 22 months after TAE median hepatic vein. Postmortem examination showed the failed to demonstrate a significant difference in survival presence of a large necrotic portion of the lesion and the between the two treatments [29]. In most of the published presence of necrotic emboli in the right pulmonary artery.
studies on TAE for HCC, embolization has been performed Microspheres were observed in arterial and portal liver using gelatin sponge, an older embolic agent that induces vessels, and in both lungs. Pathologists suggested that ischemia temporarily by occluding only the proximal ves- massive tumor necrosis and tumor wall rupture invading sels. Gelatin sponge was also employed in a group of the hepatic vein occurred a few hours after TAE, with patients treated with TAE in the randomized clinical trial passage of both necrotic tissue and microspheres into the reported by Llovet [30]. Ischemia resulting from emboli- zation might be the main factor inducing a reduction in Two of the patients who underwent liver perfusion tumor size after TAE as well as TACE. Conversely, scintigraphy showed 3% and 5% pulmonary shunting, hypoxia, as it is a potent simulator of angiogenesis, might respectively. These two cases were treated by upsizing inadvertently promote tumor growth [31–35] if emboliza- microparticles to 100 lm, to avoid the risk of pulmonary tion is not complete. Kobayashi et al. [36] showed an increased serum concentration of vascular endothelialgrowth factor (VEGF) in patients who underwent TACE,suggesting a direct link among the degree of embolization, tumor hypoxia, and the stimulation of new blood vesselgrowth. Moreover, it has been suggested that TACE may There is no standard therapy for patients with HCC unsuit- facilitate the hematogenous dissemination of malignant able for resection. Cirrhotic patients with HCC not suitable cells in systemic circulation by disrupting cell-cell adhe- for surgical therapy have a poor prognosis influenced by both sion and by damaging the endothelium [37]. Although hepatic reserve function and tumor staging [20, 21]. TAE TACE is considered to be an effective treatment for HCC, and TACE are the most frequently used treatments, with an one of the factors potentially affecting local results is the improvement of survival rate in selected patients with well- hypothetical neoangiogenic reaction due to ischemia. A preserved liver function [22]. Six randomized trials on recent study [38] has evaluated the changes in blood levels arterial embolizations, with or without chemotherapy, have of two angiogenesis factors, VEGF and b-FGF (basic shown a strong anti-tumoral effect [23–27].
fibroblast growth factor), and one parameter of invasive- There is no clear evidence that TACE is better than ness, uPA (urokinase-type plasminogen activator) in TAE. Theoretically, TACE, combining the pharmaceutical patients treated with TACE. It was concluded that when an effect with hypoxia, should be more effective than TAE untreated portion of tumor is missed, TACE may induce a [28]. Marelli et al, in a PubMed study on cohorts and significant neoangiogenic reaction, as suggested by an randomized trials (n = 175) testing transarterial therapies, increase in VEGF and b-FGF after treatment, which may performed a meta-analysis showing that TAE appeared to affect patient survival. Overall, VEGF emerges as the most be as effective as TACE [29] in achieving the same sur- reliable prognostic parameter and could be measured to vival improvement. Three randomized trial studies have G. Bonomo et al.: Bland Embolization in Patients with HCC Survivin is another important regulator of mitosis and microspheres, for liver embolization of HCC, and there is programmed cell death and it could be used as a thera- no consensus on the most effective embolic agent for liver peutic target in early HCC [39]. Its concentration only treatment. To our knowledge, this is the first publication on increases with anticancer drug concentrations during the use of Embozene microspheres for liver embolization.
hypoxia, emphasizing that the association between anti- In a large TAE series [46] in which small (50-lm) cancer drugs and hypoxia (as in TACE) could have an polyvinyl alcohol particles were used at the beginning, and opposite effect when devascularization of the tumor is then, when available, spherical trisacryl gelatin embolic incomplete because of the stimulation of neoangiogenic microparticles (40–120 lm) were employed, the authors and antiapoptotic factors in the viable tumor tissue.
demonstrated the efficacy of TAE for treating patients with An embolic agent of standardized, precisely, and tightly unresectable HCC. Based on their results, they emphasized calibrated small particle size that can be delivered into that in the literature different drugs for TACE are usually smaller peripheral arteries, and may cause permanent focused on more than the specific technique used for ischemia, should theoretically be more effective than embolization (selectivity, embolics, catheters, end point for temporary or heterogeneously sized embolic agents [40– embolization, etc.): there are still no evidence-based data 43]. To be most effective, embolization with particles demonstrating that the addition of chemo agents may add a should result in terminal vessel occlusion and blood flow survival benefit versus bland embolization alone.
obstruction, maximizing permanent ischemia. It is well In our series an overall survival rate of 96% was known that proximal vessel occlusion may result in observed at 1-year follow-up, which is well comparable recruitment of intraparenchymal collateral flow, reconsti- with the survival rates of 84% at 1-year follow-up reported tuting the distal vasculature to the tumor.
by Brown et al. [46]. Embozene microspheres, 40 and Geschwind et al., on histopathologic analysis, observed 100 lm, were chosen for bland liver embolization because that only 100- to 300-lm microparticles were detected of their well-calibrated small size and proven anti-inflam- within the liver tumor in 70% of animals studied. Con- matory reaction compared to other embolic agents. Anti- versely, no microparticles sized 300–500 lm were detected inflammation was well demonstrated [47, 48] when various within the tumor in any embolized animals [44]. Based on embolic agents of different sizes were compared in an this background, very small, precisely and narrowly cali- animal model to assess specific inflammatory and foreign- brated microparticles are needed to obtain occlusion of the body reactions after liver embolization. Fewer giant cells distal intratumoral vessels, if the goal is maximizing vas- were observed around Embozene microsphere particles cular shutdown of the tumor and achieving permanent than around particles of corresponding size [47]. This anoxia (no oxygen at all) rather than hypoxia of tumor observation can be attributed to the nanothin Polyzene-F coating, which reduces the inflammatory reaction after Regarding target vessels, microparticles for emboliza- embolization, with a lower stimulation of vascular growth tion should be as small as possible to flow within the deeper portion of the tissue and fill up the vascular space Devascularization with a progressive reduction in and then the more peripheral space [45]. Moreover, dimension of the treated lesions, with a durable 51% PR embolic particles should be tightly size-calibrated with a and 16% SD rate at medium- to long-term follow-up (6– small-diameter bandwidth. If the size range is broad, larger 12 months) and a CR in 7% of lesions, was achieved in this particles within the same vial may occlude microvessels study. Retreatments were necessary in lesions where there more peripherally and prevent deeper penetration of were more feeding vessels than detected and consequently smaller particles during administration. Embozene Color- treated at the first session, and their existence was revealed Advanced Microspheres, due to their engineered technol- at the first MDCT follow-up after first embolization.
ogy, are precise and tightly size-calibrated, with a range Hepatic lesions, as well known, are usually fed by many of ± 10 lm for 40 lm and a range of ± 25 lm for different vessels, and not all the feeders are detected and 100 lm. This should guarantee a more homogeneous dis- embolized in the same session. This will lead to tumor tribution of particles deep inside the tumor bed. The deep persistence and regrowth. When this happens, other ses- penetration within the tumor obtained with the use of 40- sions are needed to treat the whole lesion. In this situation lm particles perhaps explains the long-lasting local results the lack of efficacy is not related to the material employed after superselective embolization in our series. Most of the for embolization, but is due only to the missed identifica- lesions that had complete devascularization immediately tion of feeders to the tumor during the procedure. Fol- after treatment continued to show no enhancement at lowing the preference of our oncologists, the RECIST criteria were chosen to assess local results, by evaluating There are currently few studies on clinical applications only variation in size of treated lesions, with no reference of new embolic agents, such as resin and gelatin to the enhancement at instrumental follow-up: lesions that G. Bonomo et al.: Bland Embolization in Patients with HCC Fig. 2 A, B Hypervascular 42.5-mm HCC nodule at pre-TAE arterial and portal phase MDCT. C, D Twelve-month MDCT follow-up shows anunenhanced 15-mm nodule considered to be a partial response by the RECIST criteria or a complete response by the EASL amendment were completely devascularized at MDCT, after TAE with The main limitation of this study was the absence of relative shrinkage, were considered response PR (Fig. 2).
patient stratification according to tumor and/or liver stage The objective response rate remained high in this study at of disease, even though our aim was mainly focused on 6- to 12-month follow-up, with only 26% PD. A CR to the feasibility and local tumor response, instead of clinical treatment, with no evidence of disease, was seen only at the late follow-up, and up to now no recurrence of disease hasbeen detected in these patients. Moreover, good diseasecontrol was achieved even in patients with multifocal dis- ease, where multisession treatment was necessary to em-bolize all the lesions. Multisession treatment planning for Bland embolization appears to be an effective therapeutic multifocal disease may reduce treatment toxicity (i.e., po- option for treating unresectable HCC. As reported, the use of 40- and 100-lm Embozene microspheres resulted in enhance patient compliance. Minor complications were promising local disease control during a median follow-up observed in 8% of treated patients, for which no specific of 12 months. The clinical outcome of the patients was also good, but patients must be carefully selected to reduce As previously reported, the use of new small embolic major complications such as pulmonary embolism. As for agents is associated with rarely observed major complica- other intra-arterial liver therapies, nuclear medicine exams tions related to TACE/TAE [49, 50]. The risk of pulmonary may reduce the risks of pulmonary embolism in patients embolism after liver embolization is related to the presence with hepatic-lung shunting. Larger patient populations and of pulmonary shunting. In this study, one fatal complica- longer follow-ups are needed to determine long-term effi- tion was due to dramatic tumor necrosis induced by 40- and cacy and clinical outcome and, thus, understand the dif- 100-lm microspheres, with passage of necrotic tissue and ferences in long-term survivors treated with different-sized microspheres to the lungs via the hepatic vein, which was close to and invading the treated tumor. After this fatalevent, 99Tc-labeled MAA perfusion scintigraphy wasstarted in all patients considered for bland TAE, to rule outthe presence of pulmonary shunting. This is identical to what has been described for radioembolization. In twocases, pulmonary shunting was detected and evaluated in 1. Alba E, Valls C, Dominguez J et al (2008) Trancatheter arterial 3% and 5% of patients, respectively. Treatments were chemoembolization in patients with hepatocellular carcinoma on performed by upsizing Embozene microspheres from 40 to the waiting list for orthotopic liver transplantation. AJR190(5):1341–1348 100 lm, and in both patients no respiratory symptoms were 2. Parkin DM, Bray F, Ferlay J et al (2002) Global cancer statistics G. Bonomo et al.: Bland Embolization in Patients with HCC 3. El-Serag HB, Mason AC (1999) Rising incidence of hepatocellular 23. Lin DY, Lee TY, Liaw YF et al (1988) Hepatic arterial embo- carcinoma in the United States. N Engl J Med 340(10):745–750 lization in patients with unresectable hepatocellular carcinoma: a 4. El-Serag HB, Davial JA, Petersen NJ et al (2003) The continuing randomized controlled trial. Gastroenterology 94(2):453–456 increase in the incidence of hepatocellular carcinoma in the 24. Pelletier G, Roche A, Ink O et al (1990) A randomized trial of United States: an update. Ann Intern Med 139(10):817–823 hepatic arterial chemoembolization in patient with unresectable 5. Llovet JM, Real MI, Montana X et al (2002) Arterial embolisa- hepatocellular carcinoma. J Hepatol 11(2):181–184 tion or chemoembolization versus symptomatic treatment in 25. Madden MV, Krige JE, Bailey S et al (1993) Randomised trial of patients with unresectable hepatocellular carcinoma: a random- targeted chemotherapy with lipiodol and 5-epidoxorubicin com- ised controlled trial. Lancet 359(9319):1734–1739 pared with symptomatic treatment for hepatoma. Gut 34(11): 6. Schwartz M, Roayaie S, Konstadoulakis M (2007) Strategies for the management of hepatocellular carcinoma. Nat Clin Pract 26. Bruix J, Llovet JM, Castells A et al (1998) Transarterial embo- lization versus symptomatic treatment in patients with advanced 7. Clark HP, Carson WF, Kavanagh PV et al (2005) Staging and HCC: results of randomized controlled trial in a single institution.
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