Downstaging of bilobar hepatocellular carcinoma after radioembolization with 90Y microspheres as a bridge to liver transplantation

Rev Esp Med Nucl Imagen Mol. 2017;36(5):329–332

Clinical note

Downstaging of bilobar hepatocellular carcinoma after radioembolization with 90 Y microspheres as a bridge to liver transplantation夽 ˜ b, L. Reguera-Berenguer a,∗ , J. Orcajo-Rincón a , A. Rotger-Regí a , A.M. Matilla-Pena c a a M. Echenagusia-Boyra , R. Pérez-Pascual , A. Marí-Hualde , J.C. Alonso-Farto a a

Servicio de Medicina Nuclear, Hospital General Universitario Gregorio Mara˜ nón, Madrid, Spain Sección de Hepatología, Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Mara˜ nón, Madrid, Spain c Sección de Radiología Intervencionista, Servicio de Radiodiagnóstico, Hospital General Universitario Gregorio Mara˜ nón, Madrid, Spain b

a r t i c l e

i n f o

Article history: Received 27 September 2016 Accepted 23 December 2016 Keywords: Hepatocellular carcinoma Intra-arterial therapy Radioembolization 90 Y microspheres Downstaging Liver transplantation

a b s t r a c t Hepatic radioembolization with 90 Y is an increasingly widely used locoregional therapy in the treatment of hepatocellular carcinoma. Its potential benefit has recently been described as a downstaging treatment, achieving a decreased tumour burden and allowing patients to be rescued for more radical treatments, such as liver transplantation. The case presented refers to a patient diagnosed with multifocal bilobar hepatocellular carcinoma, Barcelona Clinic Liver Cancer (BCLC) intermediate stage, in whom treatment with 90 Y achieved a satisfactory radiological response with a very significant reduction of tumour burden, allowing a rescue treatment with liver transplantation. ˜ S.L.U. and SEMNIM. All rights reserved. © 2017 Elsevier Espana,

Downstaging de carcinoma hepatocelular bilobar tras radioembolización con microesferas de 90 Y como puente al trasplante hepático r e s u m e n Palabras clave: Carcinoma hepatocelular Terapia intraarterial Radioembolización con 90 Y Microesferas de 90 Y Downstaging Trasplante hepático

La radioembolización hepática con 90 Y es una terapia locorregional cada vez más ampliamente empleada en el tratamiento del carcinoma hepatocelular. Recientemente, se ha descrito su potencial beneficio como tratamiento de downstaging, logrando una disminución de la carga tumoral que permite rescatar a los pacientes para tratamientos más radicales como el trasplante hepático. Presentamos el caso de un paciente con el diagnóstico de carcinoma hepatocelular estadio intermedio de la Barcelona Clinic Liver Cancer (BCLC), multicéntrico y bilobar, en quien el tratamiento de radioembolización con 90 Y consiguió una adecuada respuesta radiológica, reduciéndose de forma muy significativa la carga tumoral, permitiendo su rescate con trasplante hepático. ˜ S.L.U. y SEMNIM. Todos los derechos reservados. © 2017 Elsevier Espana,

Introduction Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and the sixth most common tumour in the world. Besides, it is the third leading cause of death related to cancer.1 It is an aggressive tumour, which appears in the majority of cases in the setting of a chronic liver disease, such as cirrhosis of the liver. The only current treatments, available, which are potentially

夽 Please cite this article as: Reguera-Berenguer L, Orcajo-Rincón J, Rotger-Regí A, ˜ AM, Echenagusia-Boyra M, Pérez-Pascual R, et al. Downstaging de carMatilla-Pena cinoma hepatocelular bilobar tras radioembolización con microesferas de 90 Y como puente al trasplante hepático. Rev Esp Med Nucl Imagen Mol. 2017;36:329–332. ∗ Corresponding author. E-mail address: [email protected] (L. Reguera-Berenguer). ˜ S.L.U. and SEMNIM. All rights reserved. 2253-8089/© 2017 Elsevier Espana,

curative, are radiofrequency ablation (RFA), surgical resection and hepatic transplantation (HT),2,3 but due to frequent late diagnosis, comorbidity, the usually impaired liver function and the limited availability of donors, between 50% and 70% of the HCC cases diagnosed are not candidates to curative treatment.4 HT is restricted, according to the Milan criteria, to a single node of up to 5 cm or up to 3 nodules with a maximum diameter of 3 cm.5 For stage A HCCs that exceed these criteria, intra-arterial therapies may be used to reduce tumour burden and, therefore, downstage, making these patients potential candidates for liver transplantation.4 In this context, locoregional therapies have been developed, including hepatic radioembolization (RE) with yttrium 90 (90 Y) or selective hepatic radiation therapy (SIRT).2 SIRT is a form of selective brachytherapy based on the injection of 90 Y-labeled glass or resin microspheres by catheterization of the common hepatic artery or its branches.6 These ␤-radiation emitting particles, ranging in size from 20 to 60 ␮, are deposited in the

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Fig. 1. Image of enhanced CT (a), 18 F-FDG PET/CT (b) and post-RE 90 Y-PET/CT (c). Images (a) and (b) show a nodular hypervascular and hypermetabolic (SUVmax 6.02) lesion of approximately 20 mm, compatible with HCC in segment III. Image (c) shows selective deposit of the microspheres on the lesion after 90 Y treatment.

tumour microvasculature and, due to preferentially arterial blood supply of tumours compared to healthy liver parenchyma, which is nourished mainly through the portal vein, it is possible to administer a high dose of radiation to the tumour bed with a minimum exposure of healthy liver parenchyma.7 In daily clinical practice, SIRT is used in advanced HCC not candidate for curative treatments, however, some groups propose the use of RE with the intention of reducing tumor burden and, consecutively, their stage to T2 (downstaging) as a bridge treatment for liver transplantation. Clinical case A 51-year-old male with a history of compensated liver cirrhosis, secondary to hepatitis C virus (HCV) and hereditary hemochromatosis, was diagnosed in July 2014 of multicentric hepatocellular carcinoma (BCLC Stage B), which presented as 8 hypervascular nodules from 5 to 23 mm, with radiological criteria of HCC, the largest of which was located in segment VII, with ␣-fetoprotein of 9.8 ␮g/L. PET/CT with 18 F-FDG showed hypermetabolism foci in relation to neoplastic activity in the larger lesions (Fig. 1). It was a patient not candidate for curative treatment with RFA, surgery or HT given the bilobar multicentric affectation, and was also a bad candidate to TACE given the size of the nodules and the difficulty of performing a selective treatment. Therefore, SIRT to both lobes was decided. In the pretreatment arteriography, the gastroduodenal artery, the right gastric and a segment IV branch were occluded to prevent backflow of particles to gastric and intestinal territories. After injection of a dose of 4 mCi (185 MBq) of macroaggregated albumin labeled with 99m -technetium (99m Tc-MAA), scintigraphic planar imaging and SPECT imaging were acquired, obtaining a hepatopulmonary shunt (HPS) of 4.8% (not significant), and absence of extrahepatic migration that would contraindicate the treatment. RE was performed in two times with a gap of eight weeks between treatments. We administered intraarterially, 1.18 GBq ® resin microspheres labeled with 90 Y (SIR-Spheres ) to the left hepatic lobe and 0.55 GBq to the right lobe with a previous 99m Tc-MAA planning study, where no contraindications as extrahepatic deposits or significant HPS were observed.90 Y PET/CT scan was performed in the first 24 h after administration of the microspheres showing selective deposit of microspheres in larger lesions, and less evident, in smaller lesions. No uptake was observed in extrahepatic structures. When monitoring treatment response with thoraco-abdominopelvic CT every three months, a favorable radiological evolution of

the HCC foci maintained over time was observed. At 3 months scan, a smaller size of 3 of the 8 nodules and disappearance of the rest was observed. In the control performed at 9 months, a favourable evolution was maintained, showing two nodules that did not show contrast uptake in the different phases of the study and persistence of hypervascular nodules in segments III and IV. A decrease to stage A was then demonstrated for almost two years (Fig. 2). Because of the favourable biological evolution and the low tumour burden, a multidisciplinary tumour board considered it as a suitable downstaging and the patient was accepted for HT, which was carried out presenting an immediate complicated postoperative phase, that required the removal of the graft and re-transplantation because of a poor initial function. At present, 9 months after transplantation, the patient continues in complete clinical, radiological and analytical remission, with current ␣FP values lower than 0.1 ␮g/L. The anatomopathological study of the explants confirmed the presence of multiple nodules, three of them with neoplastic proliferation accompanied by necrosis areas of 40–80%, with no neoplastic vascular invasion signs. In addition, areas of parenchymal fibrosis were observed in relation to embolization material, the remaining lesions detected in the macroscopic study corresponded to regeneration nodules, with no signs of malignancy (Fig. 3). Discussion 90 Y-RE

is today a very attractive locoregional type of therapy in the treatment of HCC, achieving an adequate safety profile in intermediate or advanced stages, even in patients with complete portal vein thrombosis (DVT).3 The inclusion criteria are a preserved liver function, HPS less than 20% and exclusion of extrahepatic disease spread. Several recently published studies have demonstrated the efficacy of SIRT in bridging liver transplantation, Lewandowski et al.8 obtained an efficacy of 58% in a series of patients with RE-treated HCC T3, greater than that obtained with TACE (31%). For M. ˜ Inarrairaegui et al.,4 the real impact of downstaging is the increase in survival being 75% at 3 years, comparable to the survival of patients with early stages of the disease. Riaz et al.,9,10 in a study of 38 nodules in 35 patients, observed complete necrosis in 61% of lesions, being the better response in lesions smaller than 3 cm, showing a 89% necrosis, while lesions >5 cm did not exceed 33%. The patient of this study initially presented a TNM of T4aN0M0 by the presence of 4 or more nodules, of any size, Child–Pugh A, BLCL B. The efficacy of treatment with SIRT was based on the complete radiological response of most of the smaller lesions with stability

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Fig. 2. CT in arterial phase. Evolution of segment VII lesion. In image (a) it is identified as a hypervascular lesion that becomes avascular at 9 and 15 months post-RE scans (b and c, respectively).

Fig. 3. Histological image of the same field at different magnifications, where there are mainly areas of ductular proliferation (thick red arrow) associated with fibrosis in ® relation to embolization material (resin microspheres, SIR-Spheres ) inside the capillaries (thick white) and preserved hepatic parenchyma (hepatocytes) (black fine arrow).

of the other 2 lesions, achieving a downstaging to stage A and, thus, allowing liver transplantation. In the histopathological analysis of the explant, three of the persistent lesions had necrosis areas of 40 and 80%, probably slightly less than would be expected according to the data obtained in the literature, in which necrosis is described above 80% since they were lesions smaller than 3 cm. This could be justified by the different levels of radiosensitivity of the lesions, their vascularization or the irregular distribution of the microspheres among the different lesions. In this sense, Lee et al.8,11 observed that complete responses varied between 35 and 70% of the published series. Kulik et al. achieved a decrease in the effective stage in 56% of their patients, undergoing liver transplantation in 23% of them. Even in patients with unresectable HCC and transpulmonary portosystemic shunt (TIPS) pending transplantation, Donahue et al. claim that RE is safe and effective. Regarding AFP levels, Mazzaferro et al.,3 describe a mean AFP decrease of 20% after RE. However, these authors mostly included patients with DVT, where this variation was even more evident, observing a 48% decrease after therapy. On the other hand, Riaz et al.9 described that in 67% of their patients with complete histological necrosis a decrease of 50% with respect to basal AFP was observed. In the present clinical case, an adequate hepatic function with bilirubin (Br) of 1 mg/dL and normal coagulation were present at diagnosis, values that persisted within the range of normality after the radioembolic treatment in relation to the minimum expected SIRT toxicity, as Mazzaferro et al.

In conclusion, and in agreement with the current clinical practices in the more specialized centers, we consider that liver radioembolization should not be applied solely with palliative intention, as it is able to provide greater benefit if it is incorporated in the therapeutic algorithms of HCC in earlier stages.

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