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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 1  |  Page : 42-47

Noncirrhotic portal hypertension: An under-reported late adverse event of SIRT in metastatic colorectal cancer patients


1 Department of Medical Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain
2 Department of Vascular Radiology, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain
3 Department of Nuclear Medicine, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain
4 Department of Gastroenterology, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain
5 Department of Pathology, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain

Date of Web Publication13-Mar-2019

Correspondence Address:
Dr. Lourdes Gutierrez
Department of Medical Oncology, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid
Spain
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1398_16

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 > Abstract 


Introduction: Selective internal radiation therapy (SIRT) is increasingly used in different scenarios. Although portal hypertension (PHT) has been described as a nonclinically relevant finding after SIRT, its real incidence could have been neglected due to the nature of the diseases for which SIRT is indicated.
Case Reports: Here we report three cases with clinically relevant late PHT after treatments including SIRT and oxaliplatin among others.
Discussion: The sequential use of oxaliplatin and SIRT in patients with colorectal cancer metastases could have additive effects on the liver.

Keywords: Late toxicity, liver metastases, portal hypertension, regenerative nodular hyperplasia, SIRT


How to cite this article:
Gutierrez L, Méndez S, Mitjavila M, Llop E, Salas C, Ruiz-Casado A. Noncirrhotic portal hypertension: An under-reported late adverse event of SIRT in metastatic colorectal cancer patients. J Can Res Ther 2019;15:42-7

How to cite this URL:
Gutierrez L, Méndez S, Mitjavila M, Llop E, Salas C, Ruiz-Casado A. Noncirrhotic portal hypertension: An under-reported late adverse event of SIRT in metastatic colorectal cancer patients. J Can Res Ther [serial online] 2019 [cited 2019 Aug 26];15:42-7. Available from: http://www.cancerjournal.net/text.asp?2019/15/1/42/243483




 > Introduction Top


Selective internal radiation therapy (SIRT) using 90yttrium-radiolabeled microspheres can be a treatment modality for patients with unresectable liver tumors and it is being increasingly used for the treatment of colorectal metastases to the liver. In colon cancer, 90yttrium therapy is recommended for chemorefractory patients with liver-only or liver-predominant disease and in patients who do not wish or have a contraindication to have systemic chemotherapy. The use of 90Y therapy in conjunction with standard first-line or second-line chemotherapy requires more rigorous data and is only recommended in a clinical trial setting. SIRT can prolong the time to progression of hepatic metastases in pretreated patients,[1] but more evidence is required on progression-free survival (PFS), overall survival, and quality of life. The use of 90Y is not recommended in patients with extensive extrahepatic disease or extensive bilobar hepatic involvement. Similarly, patients with poor performance status (Eastern Cooperative Oncology Group performance status [ECOG PS] >2) or poor liver function are not suitable for 90Y therapy.

Abdominal pain, fatigue, and hyperbilirubinemia are the most common acute and subacute Grade 2 adverse events.[2],[3] Radioembolization-induced liver disease (REILD) has been defined as jaundice and ascites appearing 1–2 months after SIRT in the absence of tumor progression or bile duct occlusion.[4] Its incidence in the most recent series is reported to be <1%.[2] Portal hypertension (PHT) has not yet been recognized as an adverse event[5] despite having been communicated by some authors[6] as a nonclinically relevant finding. Late liver toxicities related to SIRT have not been reported to the best of our knowledge.

Here, we report three clinical cases with signs, symptoms, and radiological images of clinically relevant late PHT after SIRT with resin microspheres labeled with 90Y SIR-Spheres (Sirtex Medical Europe, Bonn, Germany). An exemption from approval was obtained from the local ethics committee.


 > Case Reports Top


Patient 1

A 64-year-old male with a social history of mild drinking was diagnosed in April 2012 with a sigmoid cancer with synchronous liver metastases. Resection of primary tumor was performed at the time of diagnosis. The tumor was staged as pT3N0 (out of 23 lymph nodes) well-differentiated, RAS-native adenocarcinoma, with no vascular or lymphatic invasion. It was initially considered as potentially resectable at the multidisciplinary team meeting (MTM). After four cycles of FOLFOX6, no morphological response was seen and a second line with FOLFIRI-cetuximab was started. Surgery was finally rejected and the patient was treated with radiofrequency, showing an early progression after the procedure. After 8 months of treatment according to AVEX (Capecitabine-Avastin®), a unique bilobar liver selective intra-arterial radiotherapy with a reduced dose (1.45 GBq) of yttrium-90 (SIR-Spheres®) was proposed. Two months after the procedure, chemotherapy with AVEX was resumed. After two cycles, the treatment was stopped because of hyperbilirubinemia (bilirubin 6). At that point, radiological signs of PHT which were not present before became evident. The patient had ascites and splenomegaly (enlarged spleen, 16 cm), without esophageal varices. Bilirubin returned to normal values with supportive treatment. Ten months after the SIRT procedure, a monotherapy with panitumumab was started after documenting liver progression and a local relapse. Nine months later, the positron emission tomography–computed tomography (PET-CT) confirmed a pathologically increased locoregional uptake and liver extension. He did not have any new episodes of liver failure or hydropic decompensation. Measurement of the hepatic venous pressure gradient was proposed to better define the liver disease which led to the decompensation after the SIRT procedure. An increased hepatic venous pressure gradient compatible with intrahepatic presinusoidal PHT was documented, and no evidence of cirrhosis could be found in the healthy liver.

The biopsy described liver nodule regenerative and the absence of fibrosis, moderate steatohepatitis, and presence of microspheres in the portal space [Figure 1]. Diagnosis is often difficult in needle-biopsy specimens, and nodularity may be more defined in reticulin preparations [Figure 2]. FOLFOX6 was reintroduced, and after three cycles, a disease progression was documented. A new episode of decompensation occurred. The cytology was negative and palliative care was initiated. The patient died in October 2016.
Figure 1: Patient 1 – Microspheres were visible in the portal area (arrow)

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Figure 2: Patient 1 – Reticulin stain shows a regenerative micronodule in the absence of fibrosis

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Patient 2

A 48-year-old woman was diagnosed with nonresectable synchronous liver metastases from left colon cancer. Biopsy revealed an invasive adenocarcinoma (native NRAS/KRAS with preserved expression of MMR genes: MLH1, MSH2, MSH6, and PMS2). She denied any previous use of alcohol and she had not any relevant comorbidity. Evaluation for evidence of viral infection was negative. A gastroscopy was done as part of the workup which was normal. She had an ECOG PS 1 and the following liver function tests: bilirubin – 1.9 mg/dl (0.3–1.1), alanine transaminase – 188 U/l (6–40), aspartate transaminase – 211 U/l (6–40), lactate dehydrogenase – 2593 U/L (230–460), alkaline phosphatase (FA) –723 U/L (35–104), carcinoembryonic antigen (CEA) – 4576 ng/ml (0–3), and cancer antigen – Ca 19.9 2229 U/ml (0–40).

She started chemotherapy according to mFOLFOX6-bevacizumab in September 2013 with an immediate normalization of bilirubin. A partial response was achieved after eight cycles. A splenomegaly was also documented without any significant thrombocytopenia. After 14 cycles, a unique bilobar liver selective intra-arterial radiotherapy with yttrium-90 (SIR-Spheres) was performed in February 2014. She received prophylaxis with corticosteroids, proton-pump inhibitors, and ursodeoxycholic acid. No complications were initially reported except Grade 1 abdominal pain and Grade 2 emesis. Oxaliplatin was withdrawn due to nonreversible neuropathy, but she continued on biweekly 5FU-Avastin® with progressive decrease of CEA (May 14, CEA – 95 and CA 19.9 95). Eight months after SIRT, the patient showed significant anemia (Hb – 7.6 g/dl), and gastroscopy revealed a bleeding duodenal ulcer with negative biopsy (spheres were not found in the biopsy) and Grade 3 esophageal varices with no signs of bleeding [Figure 3]. The CT scan showed stable disease, but other indirect signs of PHT were present, namely, ileocecoapendicular, perirectal, periuterine, periesophageal, and left gastric vein varices with a minimal quantity of liquid [Figure 4] and [Figure 5]. She started prophylactic treatment with propranolol. Liver and lung progression was verified 9 months after SIRT. A second-line therapy with panitumumab every 2 weeks was proposed to avoid any additional liver toxicity or risk of bleeding with a very good radiological and biological response. In July 15, pulmonary progression was documented and the third line with FOLFIRI-aflibercept was started. The patient did not have ascites or any other complications related to PHT. After six cycles, the disease progressed and she started TAS-102. The patient finally died 32 months until diagnosis, 25 months after SIRT, because of liver failure (total bilirubin – 22.2 mg/dl). Bile obstruction could not be seen at any moment.
Figure 3: Patient 2 – Images of gastroscopy with Grade 3 esophageal varices

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Figure 4: Patient 2 – Computed tomography scan liver after selective internal radiation therapy where it is possible appreciate calcifications secondary to treatment

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Figure 5: Patient 2 – Coronal computed tomography images with ileocecoapendicular, perirectal, periuterine, periesophageal, and left gastric vein varices

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Patient 3

A 74-year-old male, ex-smoker of <10 cigarettes a day, with an anomalous venous drainage of pulmonary veins with left-side-right short circuit, benign prostate hypertrophy, and in situ bladder carcinoma treated with transurethral resection and Bacillus Calmette Guerin therapy (BCG) in 1996. The patient denied alcohol abuse. He was incidentally diagnosed with cT3cN1cM1a wild-type RAS adenocarcinoma. A PET/CT scan was consistent with the CT and confirmed eight liver metastases. Laboratory investigations showed CEA (57.7 ng/mL; normal <3) and Ca 19.9 182 U/mL (normal <40). Liver function tests were normal.

After discussing the case in MTM, it was considered as resectable and he underwent neoadjuvant chemotherapy with mFOLFOX6, and after four cycles, a partial response was documented. An atypical resection of the right liver (segments, i.e., VI, VII, and VIII) and a metastasectomy in Segment III were done. After two more cycles of treatment, resection of the primary tumor was performed obtaining a high-grade adenocarcinoma, ypT4a ypN1b pM1a (Stage IVa; R0), with lymphovascular and perineural infiltration. Adjuvant treatment was proposed to complete a total of 12 cycles, but before administering the 10th mFOLFOX6 cycle, a new 12 mm liver nodule on Segment IVb was discovered on routine CT which was treated with radiofrequency. After the 11th cycle, oxaliplatin was withdrawn because of pulmonary fibrosis.

Five months later, a new liver relapse was identified. The CT scan showed three lesions, and the CEA marker rose to 22.4 ng/ml. The patient rejected systemic therapy, and after discussion at MTM, a treatment with SIRT was proposed. The patient underwent the procedure with SIR-Spheres® (1.58 GBq) targeting bilobar lesions (November 20, 2014) with one procedure. He received corticosteroids and proton-bump inhibitors. Two months later (January 15), there was a clear tumoral marker response (CEA – 5.3 ng/ml). The CT scan performed 3 months post-SIRT and showed a partial response. Six months after SIRT, the patient reported an increase of the abdominal perimeter which responded to diuretics. Radiologically, new venous collaterals were described in the territory of the left gastric, periesophageal veins and appearance of moderate ascites. The hepatic lesions were controlled, with progression in number and size of pulmonary nodules and CEA of 5 ng/ml. Six months after the SIRT procedure, the patient had hypoalbuminemia – 3.3 g/dl (normal >3.5 g/dl) and hyperbilirubinemia – 2 mg/dl (normal <1.1) and he developed an episode of hepatic encephalopathy. Bile obstruction could not be seen at any moment. He died 33 months after diagnosis and 15 months after the SIRT procedure because of liver failure. Total bilirubin was 20.90 mg/dl.


 > Discussion Top


SIRT is a minimally invasive procedure that delivers glass or resin microspheres impregnated with 90yttrium, a β-emitting radioisotope, into small arterioles supplying the tumor. 90Yttrium has a short half-life of 64 h and tissue penetration of 2.5 mm; thus, when administration is selective into the vessel(s) supplying a tumor, damage to nontumoral liver is minimized.[6]

Several studies have identified a possible connection between the use of oxaliplatin and the development of hepatotoxicity.[7] Approximately half of the patients receiving preoperative chemotherapy with oxaliplatin develop some degree of hepatic sinusoidal dilation and microscopic hemorrhage related to damage to the hepatic sinusoidal endothelial cell barrier. Among those with sinusoidal injury, 48% ultimately develop a more advanced form of sinusoidal injury noted by perisinusoidal fibrosis. Regenerative nodular hyperplasia (RNH) is considered the end stage of vascular lesions induced by chemotherapy and may occur in 15% of patients treated with chemotherapy. It occurs most frequently in patients receiving oxaliplatin,[8] and a few cases of PHT associated with oxaliplatin have been reported.[9] RNH may have deleterious long-term consequences related to the development of PHT. The natural history of RNH remains unknown, but because it is a noncirrhotic liver disease without fibrosis, RNH can theoretically regress.[10] Recently, different authors have suggested a protective effect of bevacizumab on the development of vascular toxicity.[11]

Sangro et al.[4] described an uncommon but potentially life-threatening form of hepatic sinusoidal obstruction syndrome secondary to SIRT with an increased susceptibility of younger patients. REILD is characterized by jaundice and ascites in the absence of tumor progression or bile duct obstruction developing 4–8 weeks after treatment, with pathological changes consistent with sinusoidal obstruction that may resemble veno-occlusive disease. REILD could be a broader syndrome and appearance at later stages does not seem to be rare.[12]

Late hepatotoxicity could be more frequent and more clinically relevant than it has been described when SIRT is used in early phases of metastatic colorectal cancer. Three otherwise healthy patients with synchronous liver-only colorectal cancer metastasis, who had previously been treated with oxaliplatin and treated with SIRT in the first-to-fourth line, developed late PHT [Table 1]. Two cases were extensively studied with transjugular liver biopsy and hepatic venous pressure gradient. In both cases, an increased hepatic venous pressure gradient was documented with no evidence of cirrhosis in the healthy liver. Pathological findings suggest nodular regenerative hyperplasia [Figure 1] in one case with sufficient nontumorous liver tissue. Hepatic failure was the final cause of death in two patients with demonstrated high figures of bilirubin (>20 mg/dl) with no bile duct obstruction, precluding the use of any chemotherapy. These hepatic failures occurred at the late stages of the disease with long survivals after SIRT. Therefore, we are not concluding that the hepatic sinusoidal injury necessarily increases the mortality though this possibility cannot be excluded. Chemotherapy, particularly oxaliplatin, may have worked synergistically with yttrium-90 to induce these changes. We acknowledge that exposure to capecitabine could be a trigger in Case 1. Capecitabine is a classical contraindication for SIR-Spheres®.[5] However, two posterior clinical trials showed that its use was safe.[13]
Table 1: Patient characteristics

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PHT is not considered an expected adverse event with SIRT according to the package insert of SIR-Spheres® or TheraSphere®. Only one case of clinically significant PHT has been reported to the best of our knowledge.[14] In that case, a severe PHT was confirmed during a surgical procedure. The young patient had also received oxaliplatin before liver local therapy. Other authors have confirmed the presence of nonclinically significant PHT in some SIRT-treated cases.[1] The recently published report on a Phase III trial failing to demonstrate an improvement in PFS with SIRT arises some other questions about the safety of the combined treatment (chemotherapy plus SIRT).[15] Ascites and thrombocytopenia were significantly more frequent in the SIRT arm (P = 0.005 and <0.001, respectively). Five patients had SIRT-related hepatotoxicity, namely, radiation hepatitis and hepatic failure. One hepatic failure occurred >2 years after SIRT. This latter case presented with PHT (splenomegaly and thrombocytopenia).

The use of oxaliplatin and SIRT could have additive effects regarding liver toxicity. Chemotherapy, particularly oxaliplatin, may have primed the liver parenchyma to develop veno-occlusive disease by injuring sinusoidal endothelial cells. SIRT could have triggered the clinical consequences of PHT which are not often seen when patients are treated only with oxaliplatin. The imbalance of liver toxicities between the two arms of SIRFLOX supports a definitive role of SIRT in the development of late PHT. Late PHT could be the end stage of RNH REILD/oxaliplatin related. Surgery would also be expected to increase the risk of PHT. We propose that clinically significant PHT is an under-reported late adverse event related to SIRT and probably aggravated by the use of chemotherapy. The reasons why this adverse event has not been properly described could be related to the fact that initially, this procedure was done in people with a short-life expectancy; the late appearance could suggest to the treating physicians, a situation related to cancer progression. It is very well-known identification of new toxicities during the postmarketing surveillance of drugs, and this will also happen with medical devices.

We propose to consider some strategies such as reducing the dose of 90Y in some cases, splitting the procedure, or increasing the time between chemotherapy and SIRT to avoid this event. We recommend variceal surveillance for those patients who develop signs of PHT such as splenomegaly with >50% increase or radiographic evidence of varices. We still think that caution should be taken when treating patients with SIRT in the first and second line and also after surgery. The recent publication of a combined analysis of three randomised phase 3 trials, confirms the lack of benefit of SIRT in first line in terms of survival with an increase in serious liver toxicities.[16] The EPOCH trial will clarify the indication of SIRT in second line.

Acknowledgment

The authors would like to thank Janice Hicks for her writing assistance.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Hendlisz A, Van den Eynde M, Peeters M, Maleux G, Lambert B, Vannoote J, et al. 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. J Clin Oncol 2010;28:3687-94.  Back to cited text no. 1
    
2.
Kennedy AS, Ball D, Cohen SJ, Cohn M, Coldwell DM, Drooz A, et al. Multicenter evaluation of the safety and efficacy of radioembolization in patients with unresectable colorectal liver metastases selected as candidates for (90)Y resin microspheres. J Gastrointest Oncol 2015;6:134-42.  Back to cited text no. 2
    
3.
Hickey R, Lewandowski RJ, Prudhomme T, Ehrenwald E, Baigorri B, Critchfield J, et al. 90Y radioembolization of colorectal hepatic metastases using glass microspheres: Safety and survival outcomes from a 531-patient multicenter study. J Nucl Med 2016;57:665-71.  Back to cited text no. 3
    
4.
Sangro B, Gil-Alzugaray B, Rodriguez J, Sola I, Martinez-Cuesta A, Viudez A, et al. Liver disease induced by radioembolization of liver tumors: Description and possible risk factors. Cancer 2008;112:1538-46.  Back to cited text no. 4
    
5.
Package Insert for SIR-spheres® Y-90 Resin Microspheres in English. Available from: http://www.sirtex.com/us/clinicians/package-insert/. [Last accessed on 2016 Nov 13].  Back to cited text no. 5
    
6.
Jakobs TF, Saleem S, Atassi B, Reda E, Lewandowski RJ, Yaghmai V, et al. Fibrosis, portal hypertension, and hepatic volume changes induced by intra-arterial radiotherapy with 90yttrium microspheres. Dig Dis Sci 2008;53:2556-63.  Back to cited text no. 6
    
7.
Rubbia-Brandt L, Audard V, Sartoretti P, Roth AD, Brezault C, Le Charpentier M, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 2004;15:460-6.  Back to cited text no. 7
    
8.
Overman MJ, Maru DM, Charnsangavej C, Loyer EM, Wang H, Pathak P, et al. Oxaliplatin-mediated increase in spleen size as a biomarker for the development of hepatic sinusoidal injury. J Clin Oncol 2010;28:2549-55.  Back to cited text no. 8
    
9.
Slade JH, Alattar ML, Fogelman DR, Overman MJ, Agarwal A, Maru DM, et al. Portal hypertension associated with oxaliplatin administration: Clinical manifestations of hepatic sinusoidal injury. Clin Colorectal Cancer 2009;8:225-30.  Back to cited text no. 9
    
10.
Brouquet A, Benoist S, Julie C, Penna C, Beauchet A, Rougier P, et al. Risk factors for chemotherapy-associated liver injuries: A multivariate analysis of a group of 146 patients with colorectal metastases. Surgery 2009;145:362-71.  Back to cited text no. 10
    
11.
Ribero D, Wang H, Donadon M, Zorzi D, Thomas MB, Eng C, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer 2007;110:2761-7.  Back to cited text no. 11
    
12.
Riaz A, Lewandowski RJ, Kulik LM, Mulcahy MF, Sato KT, Ryu RK, et al. Complications following radioembolization with yttrium-90 microspheres: A comprehensive literature review. J Vasc Interv Radiol 2009;20:1121-30.  Back to cited text no. 12
    
13.
Cohen SJ, Konski AA, Putnam S, Ball DS, Meyer JE, Yu JQ, et al. Phase I study of capecitabine combined with radioembolization using yttrium-90 resin microspheres (SIR-spheres) in patients with advanced cancer. Br J Cancer 2014;111:265-71.  Back to cited text no. 13
    
14.
Ayav A, Habib N, Jiao LR. Portal hypertension secondary to 90Yttrium microspheres: An unknown complication. J Clin Oncol 2005;23:8275-6.  Back to cited text no. 14
    
15.
van Hazel GA, Heinemann V, Sharma NK, Findlay MP, Ricke J, Peeters M, et al. SIRFLOX: Randomized phase III trial comparing first-line mFOLFOX6 (Plus or minus bevacizumab) versus mFOLFOX6 (Plus or minus bevacizumab) plus selective internal radiation therapy in patients with metastatic colorectal cancer. J Clin Oncol 2016;34:1723-31.  Back to cited text no. 15
    
16.
Wasan HS, Gibbs P, Sharma NK, Taieb J, Heinemann V, Ricke J, et al. First-line selective internal radiotherapy plus chemotherapy versus chemotherapy alone in patients with liver metastases from colorectal cancer (FOXFIRE, SIRFLOX and FOXFIRE-global): A combined analysis of three multicentre randomised, phase 3 trials. Lancet Oncol 2017; 18:1159-71.  Back to cited text no. 16
    


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