Università degli Studi di Pisa
Facoltà di Medicina e Chirurgia
Corso di Laurea in Medicina e Chirurgia
Tesi di specializzazione
BENIGN PERITUMORAL ENHANCEMENT AFTER DRUG-ELUTING BEADS TACE OF HCC
Candidato Relatore
Abstract
Purpose: To evaluate incidence and clinical significance of peritumoral contrast
enhancement found at CT one month after drug-eluting beads transarterial chemoembolization (DEB-TACE) of hepatocellular carcinoma (HCC).
Materials and Materials: Data were collected of all consecutive naïve HCC
patients treated with DEB-TACE between February 2008 and September 2013 with reported complete radiological response at one-month follow-up according to modified Response Evaluation Criteria for Solid Tumors (mRECIST).
Patients with <90 days post-TACE follow-up were excluded. One-month CT examinations were retrospectively reviewed to assess the presence of a
peritumoral rim of contrast enhancement, with the following features: 1-2 mm in size, concentric, symmetric, homogeneously hyper-attenuating in the arterial phase and hyper- or iso-attenuating in the portal venous and equilibrium phases. On follow-up, local tumor recurrence was recorded. Time to local progression was calculated with Kaplan-Meier method and curves were compared with log-rank test.
Results: The final study population consisted of 114 patients (M/F: 89/25; mean
age 63.9 ± 10.8 years) with 129 HCC lesions (mean diameter 27.1 ± 12.5 mm). At 1-month CT follow-up, a peri-tumoral rim of enhancement was identified in 49 lesions (38%). Compared to nodules without rim of enhancement, they resulted to be significantly larger (mean diameter 31.3±12.6 mm versus
Local tumor recurrence occurred 60 lesions (46.5%), of which 22 (36.7%) with peritumoral rim of enhancement. Median time to local recurrence in the entire series was 673 days (95% CI, 402-807), with no significant difference (P=.37) comparing lesions with peritumoral rim enhancement (median 618 days, 95% CI 268-807) to lesions without rim of enhancement (median 673 days, 95% CI 378-1299).
Conclusion: As described after percutaneous ablation, a peritumoral symmetric
rim of enhancement can be visualized after DEB-TACE in more than one third of treated lesions with complete radiological response. This rim does not imply tumor persistence and does not increase the risk of local tumor recurrence.
Introduction
Hepatocellular carcinoma (HCC) is the sixth most common cancer and third leading cause of cancer-related death worldwide. Major risk factors include infection with hepatitis B or C viruses and alcohol-related cirrhosis. Non-alcoholic steatohepatitis has recently emerged as a relevant risk factor [1].
Patients diagnosed at an early stage are amenable to treatments with a curative intent, such as liver transplantation, surgical resection and percutaneous
ablation, achieving up to 70% 5-year survival rates [2-4]. However, it is estimated that only about 30-40% of HCC patients are diagnosed at a stage in which curative treatments may be indicated [5]. In unresectable patients,
transarterial chemoembolization (TACE) represents a valid treatment option to control tumour progression and improve long-term survival [6-8]. Today, TACE represents the most frequently used loco-regional therapy for HCC patients [9]. Although there is no agreement on the most appropriate TACE regimen [10], traditionally TACE consists in the intra-arterial administration of a mixture of iodized oil and chemotherapeutic agents (typically doxorubicin, cisplatin and/ or mitomycin C), followed by embolization of the feeding arteries using either absorbable or permanent embolic agents.
In the last decade, drug-eluting beads (DEB) have been introduced in clinical practice, with the attempt to prolong intra-tumoral drug release and decrease systemic toxicity [11-13]. Numerous clinical studies have confirmed the safety profile of DEB-TACE [14-18], although the advantages in terms of tumour
response and patients’ survival remain controversial [18-22]. Nonetheless, DEB-TACE has offered the advantages of a more standardized treatment protocol and of a simplified radiological tumour response assessment at computed
tomography (CT) follow-up, by avoiding the hard beam artefacts related of the iodized oil retention following Lipiodol-TACE.
Radiological tumour response of HCC should be assessed by modified criteria, such as EASL (European Association for the Study of the Liver) criteria [23] or modified RECIST (Response Evaluation Criteria for Solid Tumors,
mRECIST)[24], that take into account the tumour necrosis induced by the loco-regional treatments by measuring only the residual viable portion (recognized by the uptake in the arterial phase of the dynamic imaging). Several studies have validated these criteria in terms of prognostic impact [25-27] and association to pathological necrosis [28].
However, these criteria do not take into account some findings that could be encountered after some specific loco-regional treatments. Therefore, an effort has been made to provide some helpful hints in interpreting tumor response after ablation, TACE or Y90-radioembolization [22-32].
At early follow-up after DEB-TACE, some specific findings can be
encountered, such intratumoral gas collections [31] and biliary injuries [33]. Also, although not previously described, a peritumoral rim of contrast
question of local tumour persistence. Purpose of this retrospective, single-centre study, was to evaluate the one-month follow-up incidence and the long-term clinical significance of this specific finding in a series of HCC patients treated with DEB-TACE.
Materials and Methods
The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by our Institutional Review Board.
We retrospectively searched our database collecting all consecutive naïve HCC patients treated with DEB-TACE between February 2008 and September 2013, with reported complete radiological response at one-month CT follow-up according to mRECIST [24]. Patients lost to imaging follow-up <90 days after TACE were excluded from the analysis.
Drug-eluting beads TACE
All patients were scheduled for TACE after multidisciplinary team discussion. Written informed consent was obtained from all patients before the procedure. All procedures were performed under local analgesia and antiemetic drugs. Digital Subtraction Angiography of hepatic and mesenteric arteries was obtained with a 5-French catheter immediately before TACE, to map vascular liver
anatomy and to identify tumour feeders.
After selective catheterization of the hepatic segmental or subsegmental arteries supplying the lesions, using 2.7–2.8 French microcatheter, 2–6 ml of 100–300 µm drug-eluting beads (DC Beads; Biocompatibles UK, Farnham, Surrey, UK) loaded with doxorubicin (50 mg doxorubicin per vial; mean administered dose 56.6 ± 17.1 mg, range 30-150 mg) were slowly injected. The beads were mixed with a volume of non-ionic contrast medium prior to delivery, using a ratio of
approximately 1:3. Injection was continued until full saturation of the tumour feeding arteries.
CT acquisition and image analysis
After TACE, CT was scheduled at 1 month and every 3 months thereafter. CT protocol included an unenhanced scan followed by a triphasic (late arterial, venous and equilibrium phases) acquisition with mm slice thickness and 2.5-mm interval. Scan delay was calculated by automatic bolus triggering after intravenous injection of iodized contrast medium (110–120 mL, range of iodine concentration 320–400 mg/mL) at a flow rate of 4 mL/s, followed by 40 mL saline flush at the same flow rate.
One-month CT images were retrospectively reviewed by two abdominal
radiologists in consensus (5 and 15 years of experience, respectively) to identify the presence of a peri-tumoral rim of contrast enhancement with the following features: 1-2 mm in size, concentric, symmetric, homogeneously
hyper-attenuating in the arterial phase and hyper- or iso-hyper-attenuating in the portal venous and equilibrium phases [29].
Preprocedural dynamic CT or MR images were also reviewed, to measure the maximum axial diameter of target lesions and to record the presence of a pseudo-capsule, defined as a thin peripheral rim of persistent contrast enhancement in portal venous and delayed phases [34].
Finally, on follow-up local tumour recurrence was recorded.
Data were analysed via descriptive statistics (median, mean and standard deviation, SD) and compared by Pearson’s Chi-square for categorical data and one-way Anova test for continuous data. Time to local progression was
calculated with Kaplan-Meier method and compared with log-rank test.
Statistical analysis was performed with SAS software (SAS Institute, Cary, NC); a P value of less than 0.05 was considered statistically significant.
Results
The final study population consisted of 114 patients (M/F: 89/25; mean age 63.9 ± 10.8 years, age range 38-83 years) with 129 HCC lesions (mean maximum axial diameter, 27.1±12.5 mm, range 10-65 mm) (Figure 1). At pre-procedural CT, a pseudo-capsule was identified in 57 (44.2%) target nodules.
At 1-month CT follow-up, a peri-tumoral rim of enhancement was identified in 49 lesions (38%) (Figure 2); the rim appeared hyperattenuating in portal venous and delayed phases in 29/49 (59.2%) cases, while in the remaining cases
appeared isodense compared to the surrounding liver parenchyma.
Compared to nodules without rim of enhancement, the lesions with peripheral rim of arterial enhancement were significantly larger (mean diameter 31.3±12.6 mm versus 24.5±11.7 mm, P=.0024) and showed more frequently a
pre-procedural pseudo-capsule (P=.0007).
On follow-up, local tumour recurrence was identified in 60 lesions (46.5%), of which 22 (36.7%) with peritumoral rim of enhancement at one month. Median time to local recurrence in the entire series was 673 days (95% CI, 402-807), with no significant difference (P=.37) comparing lesions with peritumoral rim enhancement (median 618 days, 95% CI 268-807) to lesions without rim of enhancement (median 673 days, 95% CI 378-1299) (Figure 3). Among the variables included in the analysis, only pre-procedural lesion size resulted to be significantly associated to local recurrence, with 12-month recurrence rate of
21.4% in lesions < 20mm (median time not reached) and 42.6% in lesions ≥ 20mm (median time to local recurrence, 444 days)(P=.02; Figure 4).
Discussion
DEB-TACE has become an increasingly used treatment modality for HCC lesions excluded from curative treatments. Besides its safety profile [18] and the more standardized treatment protocol compared to Lipiodol-TACE, DEB-TACE has the advantage of a more confident evaluation of tumor response at CT
follow-up [35].
HCC response to loco-regional treatment should be assessed by either EASL criteria [23] or mRECIST [24] that have been extensively validated [25-28]. However, EASL criteria and mRECIST do not precisely describe some specific findings that can be identified after each loco-regional treatment.
In 2005, a panel of expert described some specific benign findings after percutaneous ablation [29]. Among these, a peritumoral area of arterial enhancement has been well described and defined as “benign periablational enhancement”. This is characterized by a thin (1-2mm) rim of concentric,
symmetric and uniform arterial enhancement, with smooth inner margins and no wash-out in the portal and delayed phases of acquisition. It represents a response to thermal injury and it usually solves within 6 months.
Accordingly, some benign specific findings have been described after DEB-TACE. Bisseret et al. reported on the incidence of intratumoral gas after TACE, that can be observed in up 13% of treated patients, more frequently after DEB-TACE, and is rarely associated to abscess formation [31].
Our study describes another relatively frequent finding after DEB-TACE, represented by a peritumoral rim of arterial enhancement, similar to the above mentioned “benign periablational enhancement”. In our series almost 40% of the treated nodules displayed this rim at one-month CT follow-up. Interestingly, this finding was significantly associated with a pre-existing pseudo-capsule in
relatively larger tumours. In the absence of histological demonstration, we might postulate that this rim represents the pre-existing pseudo-capsule that becomes more evident when the tumour is completely necrotic and thus homogeneously hypoattenuating. In fact, as for the HCC pseudo-capsule, this rim typically appeared hyper- or iso-attenuating to the surrounding liver parenchyma in the portal venous and delayed phases of acquisition [34].
A peritumoral rim of arterial enhancement may be misinterpreted as local tumour persistence, leading to redundant loco-regional treatments or follow-up examinations. Our results show comparable local tumour recurrence rates in nodules with or without rim of arterial enhancement. Thus, this finding should not be regarded as a potential source of tumour recurrence and should not required additional follow-up examinations or treatments.
In conclusion, the present study shows that a peritumoral symmetric and concentric rim of arterial enhancement can be visualized after DEB-TACE in more than one third of treated lesions achieving complete radiological response at one month. This rim does not imply tumour persistence and does not increase
References
1) Nordenstedt H, White DL, El-Serag HB. The changing pattern of epidemiology in
hepatocellular carcinoma. Dig Liver Dis 2010; 42(Suppl 3): S206-214.
2) Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996; 334: 693-699.
3) Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update. Hepatology
2011;53(3):1020-2.
4) European Association For The Study Of The Liver; European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012;56:908-943.
5) Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis 2010; 30: 61-74.
6) Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan ST, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology 2002; 35:1164–1171. 7) Llovet JM, Real MI, Montana X, Planas R, Coll S, Aponte J, Ayuso C, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in
patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002; 359:1734–1739.
8) Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003;37(2):429-42.
9) Bargellini I, Florio F, Golfieri R, Grosso M, Lauretti DL, Cioni R. Trends in Utilization of Transarterial Treatments for Hepatocellular Carcinoma: Results of a Survey by the Italian Society of Interventional Radiology. Cardiovasc
Intervent Radiol 2014;37:438-444
10) Marelli L, Stigliano R, Triantos C, et al. Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies. Cardiovasc Intervent Radiol 2007;30:6-25.
11) Lewis AL, Gonzalez MV, Lloyd AW, et al. DC Bead: in vitro
characterization of a drug-delivery device for transarterial chemoembolization. J Vasc Interv Radiol 2006;17:335-342
12) Hong K, Khwaja A, Liapi E, et al. New intra-arterial drug delivery system for the treatment of liver cancer: preclinical assessment in a rabbit model of liver cancer. Clin Cancer Res 2006;12(8):2563-2567
13) Lewis AL, Taylor RR, Hall B, Gonzalez MV, Willis SL, Stratford PW. Pharmacokinetic and Safety Study of Doxorubicin-eluting Beads in a Porcine
1343
14) Varela M, Real MI, Brunet M, et al. Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmakokinetics. J Hepatol 2007;46:407-481.
15) Poon RT, Tso WK, Pang RW et al. A phase I/II trial of chemoembolization for Hepatocellular Carcinoma Using a Novel Intra-Arterial Drug Eluting Bead. Clin Gastroenterol Hepatol 2007;5(9):1100-1108.
16) Malagari K, Pomoni M, Moschouris H, et al. Chemoembolization with doxorubicin-eluting beads for unresectable hepatocellular carcinoma: five-year survival analysis. Cardiovasc Intervent Radiol 2012;35(5):1119-28.
17) Burrel M, Reig M, Forner A, et al. Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design. J Hepatol 2012;56(6):1330-5.
18) Lammer J, Malagari K, Vogl T, et al; PRECISION V Investigators.
Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol 2010;33(1):41-52
19) Song MJ, Chun HJ, Song do S, et al. Comparative study between
doxorubicin-eluting beads and conventional transarterial chemoembolization for treatment of hepatocellular carcinoma. J Hepatol 2012;57(6):1244-1250.
Comparison of conventional transarterial chemoembolization (TACE) and
chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC). J Surg Oncol 2010;101(6):476-480.
21) Sacco R, Bargellini I, Bertini M, et al. Conventional versus doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma. J Vasc Interv Radiol 2011;22(11):1545-52.
22) Golfieri R, Giampalma E, Renzulli M, et al; PRECISION ITALIA STUDY GROUP. Randomised controlled trial of doxorubicin-eluting beads vs
conventional chemoembolisation for hepatocellular carcinoma. Br J Cancer 2014;111(2):255-264.
23) Bruix J, Sherman M, Llovet JM, et al. Clinical management of
hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001;35:421-430. 24) Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30: 52-60.
25) Gillmore R, Stuart S, Kirkwood A, et al. EASL and mRECIST responses are independent prognostic factors for survival in hepatocellular cancer patients treated with transarterial embolization. J Hepatol 2011;55:1309-1316.
26) Shim JH, Lee HC, Kim SO, et al. Which response criteria best help predict survival of patients with hepatocellular carcinoma following
27) Malagari K, Pomoni M, Moschouris H, et al. Chemoembolization with doxorubicin-eluting beads for unresectable hepatocellular carcinoma: five-year survival analysis. Cardiovasc Intervent Radiol 2012;35(5):1119-1128.
28) Bargellini I, Bozzi E, Campani D, et al. Modified RECIST to assess tumor response after transarterial chemoembolization of hepatocellular carcinoma: CT-pathologic correlation in 178 liver explants. Eur J Radiol 2013;82(5):e212-218. 29) Goldberg SN, Grassi CJ, Cardella JF, et al; Society of Interventional
Radiology Technology Assessment Committee; International Working Group on Image-Guided Tumor Ablation. Image-guided tumor ablation: standardization of terminology and reporting criteria. Radiology 2005;235:728-739
30) Kudo M, Kubo S, Takayasu K, et al.; Liver Cancer Study Group of Japan (Committee for Response Evaluation Criteria in Cancer of the Liver, Liver Cancer Study Group of Japan). Response Evaluation Criteria in Cancer of the Liver (RECICL) proposed by the Liver Cancer Study Group of Japan (2009 Revised Version). Hepatol Res 2010;40:686-692.
31) Bisseret D, Ronot M, Abdel-Rehim M, et al. Intratumoral gas in
hepatocellular carcinoma following transarterial chemoembolization: associated factors and clinical impact. J Vasc Interv Radiol 2013;24:1623-1631.
32) Ibrahim SM, Nikolaidis P, Miller FH, et al. Radiologic findings following Y90 radioembolization for primary liver malignancies. Abdom Imaging
33) Guiu B, Deschamps F, Aho S, et al. Liver/biliary injuries following
chemoembolisation of endocrine tumours and hepatocellular carcinoma: lipiodol vs. drug-eluting beads. J Hepatol 2012;56(3):609-617.
34) Grazioli L, Olivetti L, Fugazzola C, et al. The pseudocapsule in hepatocellular carcinoma: correlation between dynamic MR imaging and pathology. Eur Radiol 1999;9:62-67.
35) Lencioni R, de Baere T, Burrel M, et al. Transcatheter treatment of hepatocellular carcinoma with Doxorubicin-loaded DC Bead (DEBDOX): technical recommendations. Cardiovasc Intervent Radiol 2012;35:980–985.
Figures
Figure 2: HCC treated with DEB-TACE
Preprocedural CT (A, arterial phase; B, delayed phase) demonstrates two adjacent HCC lesions in segments IV and II with hyperattenuating
pseudocapsule in the delayed phase. One month after DEB-TACE (C,
unenhanced acquisition; D, arterial phase; E, portal venous phase; F; delayed phase), demonstrates complete response with a thin rim of peritumoral arterial enhancement that appears hyperattenuating in portal venous and delayed phases. At one-year follow-up (G, unenhanced acquisition; H, arterial phase; I, portal venous phase; L; delayed phase), complete response is confirmed with
Figure 3: Time to local recurrence according to presence of rim of enhancement (Kaplan-Meier analysis)
Median time to local recurrence was 618 days (95% CI 268-807) for lesions with peritumoral rim of enhancement and 673 days (95% CI 378-1299) for lesions without rim of enhancement (P=.37).
Figure 4: Time to local recurrence according to tumour size (Kaplan-Meier analysis)
The 12-month local tumour recurrence rate was 21.4% in lesions < 20mm (median time not reached) and 42.6% in lesions ≥ 20mm (median time, 444 days)(P=.02).
