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CASE REPORT
Ahead of print publication  

Hepatic necrosis following yttrium-90 radioembolization for hepatocellular carcinoma in a patient with a recent history of external radiotherapy


1 Department of Interventional Radiology, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, China
2 Department of Radiology, Mayo Clinic, Jacksonville, FL, USA

Date of Submission11-Jan-2019
Date of Decision15-Apr-2019
Date of Acceptance20-May-2019
Date of Web Publication28-Jan-2020

Correspondence Address:
Weiping Wang,
Department of Radiology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224
USA
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_27_19

 > Abstract 


Hepatobiliary complications from yttrium-90 (90Y) radioembolization have been described previously but are often clinically inconsequential. This report describes the case of a patient in whom a large area of hepatic necrosis occurred after the patient underwent both stereotactic body radiotherapy and glass-based90Y radioembolization for the management of hepatocellular carcinoma. This case suggests that90Y microspheres can cause severe local hepatic injury when administered after external radiotherapy.

Keywords: Complication, radioembolization, radiotherapy, yttrium-90



How to cite this URL:
Jia Z, Wang W. Hepatic necrosis following yttrium-90 radioembolization for hepatocellular carcinoma in a patient with a recent history of external radiotherapy. J Can Res Ther [Epub ahead of print] [cited 2020 Apr 2]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=276987




 > Introduction Top


The management of unresectable hepatocellular carcinoma (HCC) remains a clinical challenge.[1] Yttrium-90 (90 Y) radioembolization is a form of intra-arterial brachytherapy that has been widely used in the treatment of advanced HCC.[2] External radiotherapy has been used in patients with lesions in locations that are unfavorable for other local treatments. The use of both90 Y radioembolization and external radiotherapy is uncommon, and so the potential radiation-induced hepatobiliary complications from such a combination are largely unknown.[3] Here, we describe the case of a patient in whom a large area of hepatic necrosis occurred after the patient underwent both stereotactic body radiotherapy (SBRT) and glass-based90 Y radioembolization for HCC.


 > Case Report Top


A 52-year-old woman with no history of liver disease presented to her physician with symptoms of nausea and vomiting. Subsequent evaluation with abdominal magnetic resonance imaging (MRI) revealed a well-circumscribed liver mass approximately 4.6 cm in diameter [Figure 1]a. A biopsy of the mass revealed the presence of HCC. The patient underwent exploratory laparotomy and en bloc resection of segments VII and VIII, along with partial resection of the inferior vena cava and right hepatic vein. Histological examination confirmed the diagnosis of HCC without significant evidence of cirrhosis or chronic liver disease. The patient recovered uneventfully. However, 8 months later, a surveillance MR scan of the abdomen revealed two new hepatic lesions: a 1-cm lesion at the periphery of segment III [Figure 1]b and a 3-cm lesion at the dome adjacent to the diaphragm [Figure 1]c. Because of the anatomic challenges involved in treating these lesions with local treatments, the decision was made to treat the segment III lesion with cryoablation [Figure 1]d and to treat the dome lesion with SBRT (total dose, 48 Gy in four fractions) [Figure 1]e, [Figure 1]f, [Figure 1]g. SBRT rather than thermoablation was chosen to treat the dome lesion because of concerns about the risk of diaphragmatic or lung injury and because of the potential for pain after the procedure. Unfortunately, a follow-up MR scan performed 4 months after locoregional therapy demonstrated multiple new focal lesions involving both hepatic lobes (at least 11 lesions, approximately 1 cm each). In addition, there was an incidental finding of an area of clear demarcation of signal transition zone at the dome in the area treated with SBRT; this likely represented postradiation injury and possible parenchymal edema [Figure 2]a. Treatment with90 Y microspheres and oral sorafenib was suggested as the most appropriate option for further management.
Figure 1: (a) Initial magnetic resonance delay contrast enhancement scan (T1) of the liver showing a low-attenuation mass in segment VII near the junction of the inferior vena cava and right hepatic vein. This mass was identified as hepatocellular carcinoma on both biopsy and surgery. (b and c) Magnetic resonance imaging scan obtained 8 months after surgery showed two new hepatic lesions, one at the periphery of segment III (b, T1, contrast enhancement scan, arrowhead) and one at the dome (c, T2-weighted imaging, arrowhead). (d) The segment III lesion was treated with computed tomography-guided cryoablation (white arrowhead) with a balloon for organ protection (black arrowhead). (e and f) The right lobe lesion at the dome was treated with stereotactic body radiotherapy. The region of interest and dose of target areas in radiotherapy are shown. (g) The dose–volume histogram of stereotactic body radiotherapy

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Figure 2: (a) Magnetic resonance imaging scan (T2-weighted imaging) obtained 4 months after stereotactic body radiotherapy showed slightly increased signal on T2-weighted image at the dome with a clear demarcation (arrowheads) in the area that had been treated with stereotactic body radiotherapy; these results were compatible with liver parenchyma edema. (b) Hepatic angiography during90Y therapy showed vascular congestion (arrowhead) in the area that had been treated with stereotactic body radiotherapy. (c) A routine contrast-enhanced computed tomography scan performed 1 month after radioembolization demonstrated multiple irregularly shaped low-attenuation lesions at the dome (arrowheads) in the area that had been treated with stereotactic body radiotherapy and90Y. (d) At 55 days after90Y treatment, a repeat contrast-enhanced computed tomography scan of the abdomen demonstrated a new low-attenuation lesion in the right lobe (arrowhead). (e) Magnetic resonance imaging (T2-weighted imaging) confirmed the presence of the new low-attenuation lesion and suggested that the lesion was liquid in nature (arrowhead). (f) The new low-attenuation lesion was drained via a 10 Fr pigtail catheter, which was seen to communicate with multiple cavities at the dome (white arrowhead) and common bile duct on sinogram

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Radioembolization planning angiography revealed conventional anatomy but vascular congestion and sluggish flow at the dome of the liver in the area treated with SBRT [Figure 2]b; this was consistent with the findings seen on MRI. A split dose of90 Y glass microspheres was planned, and a low desired dose was calculated to account for the bilobar administration and previous external radiation. The administered activity in the right lobe was 3.07 GBq (82.9 mCi) for a dose to perfused liver of 100.4 Gy. The administered activity in the left lobe was 1.32 GBq (35.6 mCi) for a dose to perfused liver of 85 Gy.

A routine contrast-enhanced computed tomography (CT) scan obtained 1 month after radioembolization revealed multiple irregularly shaped low-attenuation lesions at the dome in the area treated with SBRT and90 Y [Figure 2]c. At 55 days after90 Y treatment, a repeat contrast-enhanced CT scan demonstrated a new low-attenuation lesion in the right lobe [Figure 2]d, in addition to the irregularly shaped low-attenuation lesions at the dome. MRI confirmed the presence of this new low-attenuation lesion, and MR results suggested that this lesion was liquid in nature [Figure 2]e.

Because the patient's symptoms were worsening, she agreed to have a percutaneous drain placed, and a 10 Fr pigtail catheter was inserted into the new low-attenuation lesion [Figure 2]f. When the catheter was injected, the contrast material was seen in the low-attenuation lesions at the dome via multiple connections from the cavity [Figure 2]f. A total of 30 mL of necrotic material was aspirated during the procedure, but the cultures of this material were negative. After drain placement, the output gradually transitioned to pure bile, with a daily output of approximately 80–120 mL. The biloma cavity eventually resolved over the next 5 weeks of external drainage, and the drain was converted to an internal/external biliary drain. The catheter was capped to internal drainage with the intention of possibly removing the catheter if clinical stability was documented. Unfortunately, the patient's overall condition continued to deteriorate as the disease progressed, and she died 6 months after90 Y treatment.


 > Discussion Top


SBRT is an advanced radiotherapeutic technology that delivers a high dose of external radiation to the targeted tumor while reducing the volume of healthy tissue in the irradiated field. This procedure has emerged as a definitive treatment for HCC and as a bridge to liver transplant in patients with early-stage, inoperable HCC.[4] A consensus panel at the 7th Asia-Pacific Primary Liver Cancer Expert Meeting recommended SBRT as a first-line treatment for inoperable HCC confined to the liver.[5]

90 Y radioembolization is also considered a locoregional liver-directed therapy. In the setting of multiple or diffuse lesions, selective delivery of radioactive particles may not be possible, and lobar or whole-liver treatment may be preferred. This lobar or whole-liver treatment can expose the entire lobe or liver to radiation; however, radiation-induced hepatobiliary complications are rare when the current guidelines for dosimetry are followed.[6]

Despite being a rare occurrence, hepatobiliary injuries have been recognized as a potential complication of radiation therapy. Such injuries may include hepatic necrosis, ischemic cholangitis, bile duct strictures, biliary necrosis, and bilomas.[7] In general, SBRT at a dose of 40 Gy in five fractions is considered safe in terms of hepatobiliary complications.[8] In a study of patients treated with a median SBRT dose of 85.5 Gy (range, 37.5–151.2 Gy), 18.8% of patients experienced hepatobiliary injuries.[9] Severe hepatobiliary injuries induced by90 Y radioembolization are uncommon, and injuries requiring intervention occur in only approximately 1.8% of treated patients.[7]

The risk of combined90 Y radioembolization and external beam radiation therapy was assessed in a previous study.[10] In this study, most cases of liver toxicity manifested as abnormal laboratory tests except for two cases of fatal liver failure. The investigators suggested that liver toxicity after90 Y radioembolization depends on fractional liver exposure to external beam radiation therapy and cumulative dose level, with a fractional liver exposure of ≥30 Gy considered the strongest predictor of toxicity.[10] The dose of SBRT administered to our patient was 48 Gy in four fractions, which was believed to be safe for a single-lesion treatment despite the appearance of radiological changes on follow-up MRI and conventional hepatic arteriogram. Typically, external radiation-induced liver disease occurs 4–8 weeks after treatment.[10]

The decision to use both SBRT and radioembolization in the current case was based on the patient's condition and the disease process. Because of the patient's history of treatment with SBRT, the90 Y dose to the right lobe was reduced to 100.4 Gy. The cumulative radiation dose to the right lobe from SBRT and90 Y microspheres was 148.4 Gy, which is considered safe under the current guidelines.[6] Unfortunately, liver necrosis occurred in the area that was exposed to both external and internal radiation from SBRT and90 Y. There are several possible explanations for the occurrence of this radiation-induced hepatobiliary injury in our patient such as (1) superimposed external and internal radiation in the treated area; (2) preferential distribution of90 Y microspheres to the SBRT area; (3) high radiation activity with90 Y glass particles (fifty times more radiation activity per particle than with resin particles), which tend to deliver more radiation dose to the hyperperfused area before vascular beds are occluded; (4)90 Y microsphere embolization leading to tissue ischemia; and (5) continuous cellular and microvascular injuries from SBRT leading to progressive microvasculitis and eventually to tissue hypoxia.[11]


 > Conclusion Top


A history of previous external radiotherapy to the liver may be a risk factor for radiation-induced hepatobiliary complications of90 Y therapy. Routine dosimetry may not allow for correct calculation of a safe dose due to the inhomogeneous perfusion induced by SBRT.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgments

We thank Megan Griffiths, scientific writer, Cleveland, Ohio, USA, for her help with revising the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Hernandez-Alejandro R, Levstik MA, Linehan DC. Hepatectomy for early hepatocellular carcinoma: Not if, but when and how? JAMA Surg 2017;152:e165042.  Back to cited text no. 1
    
2.
Titano J, Voutsinas N, Kim E. The role of radioembolization in bridging and downstaging hepatocellular carcinoma to curative therapy. Semin Nucl Med 2019;49:189-96.  Back to cited text no. 2
    
3.
Bujold A, Dawson LA. Stereotactic radiation therapy and selective internal radiation therapy for hepatocellular carcinoma. Cancer Radiother 2011;15:54-63.  Back to cited text no. 3
    
4.
Moore A, Cohen-Naftaly M, Tobar A, Kundel Y, Benjaminov O, Braun M, et al. Stereotactic body radiation therapy (SBRT) for definitive treatment and as a bridge to liver transplantation in early stage inoperable hepatocellular carcinoma. Radiat Oncol 2017;12:163.  Back to cited text no. 4
    
5.
Zeng ZC, Seong J, Yoon SM, Cheng JC, Lam KO, Lee AS, et al. Consensus on stereotactic body radiation therapy for small-sized hepatocellular carcinoma at the 7th Asia-Pacific primary liver cancer expert meeting. Liver Cancer 2017;6:264-74.  Back to cited text no. 5
    
6.
Murthy R, Nunez R, Szklaruk J, Erwin W, Madoff DC, Gupta S, et al. Yttrium-90 microsphere therapy for hepatic malignancy: Devices, indications, technical considerations, and potential complications. Radiographics 2005;25 Suppl 1:S41-55.  Back to cited text no. 6
    
7.
Atassi B, Bangash AK, Lewandowski RJ, Ibrahim S, Kulik L, Mulcahy MF, et al. Biliary sequelae following radioembolization with yttrium-90 microspheres. J Vasc Interv Radiol 2008;19:691-7.  Back to cited text no. 7
    
8.
Eriguchi T, Takeda A, Sanuki N, Oku Y, Aoki Y, Shigematsu N, et al. Acceptable toxicity after stereotactic body radiation therapy for liver tumors adjacent to the central biliary system. Int J Radiat Oncol Biol Phys 2013;85:1006-11.  Back to cited text no. 8
    
9.
Osmundson EC, Wu Y, Luxton G, Bazan JG, Koong AC, Chang DT. Predictors of toxicity associated with stereotactic body radiation therapy to the central hepatobiliary tract. Int J Radiat Oncol Biol Phys 2015;91:986-94.  Back to cited text no. 9
    
10.
Lam MG, Abdelmaksoud MH, Chang DT, Eclov NC, Chung MP, Koong AC, et al. Safety of 90Y radioembolization in patients who have undergone previous external beam radiation therapy. Int J Radiat Oncol Biol Phys 2013;87:323-9.  Back to cited text no. 10
    
11.
Cherqui D, Palazzo L, Piedbois P, Charlotte F, Duvoux C, Duron JJ, et al. Common bile duct stricture as a late complication of upper abdominal radiotherapy. J Hepatol 1994;20:693-7.  Back to cited text no. 11
    


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