Research ArticleClinical Studies

Liver Function Changes After Technetium-99m-Macroaggregated Albumin Administration and Their Predictive Value Regarding Hepatotoxicity in Patients Undergoing Yttrium-90-Radioembolization

MATTHIAS P. FABRITIUS, FABIAN HARTMANN, RICARDA SEIDENSTICKER, MACIEJ PECH, MACIEJ POWERSKI, SERGIO GROSU, STEFAN MAURUS, ANDREI TODICA, HARUN ILHAN, JAZAN OMARI, ROBERT DAMM, OLIVER GROßER, JOSEFINE ALBERS, JENS RICKE and MAX SEIDENSTICKER
Anticancer Research January 2021, 41 (1) 437-444; DOI: https://doi.org/10.21873/anticanres.14793

Abstract

Background/Aim: Intraarterial Technetium-99m-Macroaggregated Albumin (99mTc-MAA) administration is an established method to predict particle distribution prior to radioembolization. This study aimed to analyse the impact of intraarterial administration of 99mTc-MAA on changes in liver-specific laboratory parameters and to assess whether such changes are associated with post-radioembolization hepatotoxicity. Patients and Methods: A total of 202 patients treated with radioembolization received prior mapping angiography with 99mTc-MAA administration. All patients underwent clinical and laboratory examinations, including liver-specific parameters at certain times before and after mapping angiography/99mTc-MAA administration, as well as before radioembolization and during follow-up. Results: Bilirubin increased temporarily after 99mTc-MAA administration (p<0.001), but was not clinically relevant, and returned close to the initial value before radioembolization. These changes showed no association with subsequent postradioembolic hepatotoxicity or shortened overall survival. Conclusion: 99mTc-MAA administration results in a significant, however, not clinically relevant transient increase in bilirubin levels, which does not provide a predictive value for subsequent radioembolization outcome or postradioembolic hepatotoxicity.

Key Words:

Radioembolization (RE) with Yttrium-90 (90Y) resin microspheres plays an important role in the treatment of primary and chemotherapy-resistant secondary liver malignancies (1-9). A limiting factor for RE treatment is the radiosensitivity of the liver parenchyma, which can lead to a deterioration in liver function and even hepatic failure, typically 4 to 8 weeks after RE (10). This syndrome is known as radioembolization-induced liver disease (REILD) and is characterized by jaundice, development of, or increase in, ascites, hyperbilirubinemia and hypoalbuminemia in the absence of tumor progression or biliary obstruction (11).

Known risk factors for the occurrence of REILD are previous chemotherapy, liver cirrhosis and a high administration of activity per target volume or absorbed dose on healthy liver tissue (1, 10-15). To ensure the highest possible functional reserve of the liver after RE, there are different approaches, such as the sequential radioembolization of the right and left lobe of the liver, the reduction of radiation dose or hepatoprotective concomitant medication (16-18). However, a better risk prediction of the risk of post RE hepatotoxicity would be desirable. Therefore, precise individual therapy planning for each patient is crucial. As part of the treatment evaluation, serum tests of liver function, including the evaluation of bilirubin levels, can estimate the functional liver reserve. Furthermore, patients undergo standard pre-treatment mapping angiography to detect relevant aberrant vessels (which could lead to extratumoral deposition of microspheres) and to simulate Y90 microsphere distribution with diagnostic Technetium-99m-Macroaggregated Albumin (99mTc-MAA). Besides the objective to detect and quantify possible extrahepatic shunting, the ratio of tumor dose to liver dose can be determined more accurately (17, 19-22). In clinical routine at our institute we observed that some patients showed a temporarily increase in liver specific enzymes already after mapping angiography with 99mTc-MAA-administration (ma/99mTc-MAAa), before the actual RE therapy. To our knowledge, it is unclear if such laboratory value changes after preparatory technetium angiography are significant and have a predictive value for the occurrence of post RE hepatotoxicity.

We conducted a retrospective single-centre study to evaluate these observations in more detail. The primary endpoint was to evaluate whether intra-arterial administration of 99mTc-MAA leads to significant changes in liver-specific parameters. In addition, it should be determined, which patients are affected and if there are risk factors. The secondary endpoint was to analyse whether changes in the liver function tests after 99mTc-MAA administration have a predictive value for post radioembolization hepatotoxicity.

Patients and Methods

Study design and population. For this retrospective analysis, we selected all patients who were evaluated for RE treatment by ma/99mTc-MAAa at a single centre in a 4-year period. The study was approved by the local ethics committee. Written informed consent was waived due to the retrospective nature.

We included all patients with available liver function parameters [bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), Glutamate dehydrogenase (GLDH)] at certain time points (see below).

Selection of patients for RE was based on the presence of unresectable HCC, CCC or hepatic metastases and lack of further chemotherapeutic options. Patients had to have liver-predominant disease, preserved liver function and an acceptable performance status [Eastern Cooperative Oncology Group (ECOG) performance status ≤2].

RE evaluation with mapping angiography and 99mTc-MAA. Pretherapeutic angiography was performed via a transfemoral approach as described in detail before (17). Anatomical variants were depicted and aberrant or risk vessels for potential extra-hepatic deposition of 90Y microspheres were coil embolized (23, 24). 150 MBq 99mTc-MAA (TechneScan® LyoMAA, Covidien, Neustadt/Donau, Germany) were injected in the planned catheter positions for later treatment. Technetium-99m emits gamma rays with a photon energy of 140 keV and a half-life of 6 h. It is coupled to Macroaggregated Albumin (10-150 μm). A gamma camera (E.CAM 180, Siemens, Erlangen, Germany) determined the extent of hepatopulmonary shunting and a single-photon emission-computed tomography (SPECT) scan of the upper abdomen was used to evaluate the particle distribution. In case of non-target extrahepatic deposition of 99mTc-MAA, the angiography procedure was repeated, aberrant vessels were coil embolized and injection position re-determined. Patients with unmanageable extrahepatic particle distribution or a lung shunting fraction of more than 20% were excluded from RE treatment. Dose was reduced if shunting volumes were between 10 and 20%.

Radioembolization. RE was performed 2-4 weeks after mapping angiography/99mTc-MAA administration according to a standard algorithm, as described in detail before (17), using 90Y resin microspheres (SIR-Spheres®, Sirtex Medical, Kane Cove, Australia). The activity was calculated by the body surface area (BSA) method. Depending on tumor distribution, 90Y resin microspheres were delivered selectively into the hepatic arteries in a single session (unilobar or bilobar) or in two sessions as sequential treatment of each lobe 4-8 weeks apart (sequential bilobar).

Imaging and volumetry. Routine baseline and follow-up imaging (every 2-4 months) consisted of Gd-EOB-DTPA (Primovist, Bayer Healthcare, Leverkusen, Germany; 0.025 mmol/kg/bodyweight) enhanced magnetic resonance imaging (MRI) of the liver (1.5 Tesla system, Achieva 1.5 T, Philipps, Best, The Netherlands). MRI (hepatobiliary phase T1-weighted imaging, 5 mm slice thickness) was used for tumor and liver measurements using the image processing software Osirix (Antoine Rosset, 2003-2011).

Laboratory parameters and toxicity analysis. All patients underwent in-house standard clinical and laboratory examinations, including liver-related parameters at first presentation 1-4 days before ma/99mTc-MAAa (“baseline”), 1-3 days after ma/99mTc-MAAa (“post-ma/99mTc-MAAa”), 2-4 weeks after ma/99mTc-MAAa before the first RE (“pre-RE”) and during a follow-up visit at 4-8 weeks (“post-RE”) (Figure 1). The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 4.02 (National Cancer Institute, Bethesda, MD, USA) were used for toxicity assessment. REILD was diagnosed according to Sangro et al. by clinical presentation of jaundice and ascites and a total bilirubin increase over 50 μmol/l (10). Furthermore, cases were considered as REILD in this cohort if MRI showed an extensive and large scale reduced Gd-EOB-DTPA uptake after RE, but could not be diagnosed reliably as REILD according to Sangro et al. (e.g. no bilirubin increase over 3 mg/dl or ascites) (25). Factors with potential radio sensitizing or liver toxic properties, such as type and number of chemotherapy lines, presence of liver cirrhosis and the degree of dysfunction according to CHILD Pugh were recorded (26). Therapy-associated influences, such as the activity of 99mTc and 90Y, as well as complications during the therapy procedure were documented.

Figure 1.
Figure 1.

Flowchart of laboratory examinations. All patients underwent standard clinical and laboratory examinations, including liver-specific laboratory parameters at first presentation, 1-4 days before 99mTc-MAA administration (“baseline”), 1-3 days after 99mTc-MAA administration (“post-99mTc-MAA”), 2-4 weeks after 99mTc-MAA before the first RE (“pre-RE”) and during a follow-up visit at 4-8 weeks (“post-RE”). RE: Radioembolization.

Survival. Overall survival (OS) was recorded, defined as the time from the date of ma/99mTC-MAAa until the death of the patient.

Statistical analysis. Statistical analysis was performed with SPSS Statistics 23 (IBM, Armonk, NY, USA). Normal distribution was evaluated using the Kolmogorov-Smirnov test. In case of non-normal distribution, we applied the Wilcoxon signed-rank test to identify significant changes in liver specific laboratory values at two different timepoints. For toxicity and survival analysis variables were dichotomized. Survival was estimated according to the Kaplan–Meier method. Univariate Cox regression analysis was performed to identify potential pre- and post-therapeutic factors influencing OS. Factors found to have an independent impact on survival in the multivariate model were used as stratifying variables in a Kaplan–Meier analysis of survival. The log rank test was used for survival comparison. Logistic regression analysis was used to determine the influence of variables on changes in liver specific laboratory values as well as on the occurrence of hepatotoxicity. Correlation analysis was performed according to Pearson. Metric and ordinal variables are reported as median (interquartile range). Categorical variables are presented as frequency and percentage. p Values below 0.05 were considered as statistically significant.

Results

Patient and treatment characteristics. A total of 202 patients fulfilled the inclusion criteria (124 males; median age 66 years). Median follow up time was 7 months. Detailed patient and treatment characteristics are shown in Table I. Complications during the angiographic procedures are shown in Table II.

View this table:
Table I.

Baseline and treatment characteristics.

View this table:
Table II.

Angiography complications.

Laboratory parameters. Bilirubin increased significantly after ma/99mTC-MAAa, but was still within the normal range (Median=11.4, IQR=7.9-15.4 vs. baseline 8.6, 6.2-13.1 μmol/l; p<0.001), and decreased significantly back to near the initial value at the time before RE, 2-4 weeks after ma/99mTC-MAAa (8.7, 6.0-13.3 μmol/l; p<0.001) (Table III, Figure 2). Those findings were also seen in subgroup analysis depending on tumor entity. AST showed a discrete but significant increase before RE (p=0.017), whereas other changes were not significant. ALT and GLDH showed no significant increase at any time, on the contrary, after ma/99mTC-MAAa there was a significant decrease in ALT compared to the preliminary examination. Due to the significant changes in bilirubin levels in all tumor entities, these were further statistically analyzed with respect to potentially influencing factors via logistic regression. A dichotomization was performed to analyze possible factors influencing an increase in bilirubin by more than 5 μmol/l or 10 μmol/l. The grading of 5 or 10 μmol/l was determined arbitrarily but should be outside the range of normal intraindividual (circadian) variation (27, 28) (Table IV). The following conceivably influencing variables were included in the analysis: Gender, age, complications during ma/99mTC-MAAa, tumor burden, cirrhosis, portal vein thrombosis and previous chemotherapy or interventions such as local and surgical therapies. None of these variables were significantly associated with an increase in bilirubin by more than 5 or 10 μmol/l after 99mTc-MAA. Pearson correlation analysis demonstrated a significant but only slight correlation between complications during ma/99mTC-MAAa and a bilirubin increase of ≥10 μmol/l after 99mTc-MAA administration (r=0.154, p=0.029).

View this table:
Table III.

Course of laboratory parameters.

Figure 2.
Figure 2.

Bilirubin course.

View this table:
Table IV.

Predictors of laboratory changes in bilirubin after 99mTc-MAA.

Hepatotoxicity. The above-named factors, including bilirubin fluctuations after ma/99mTC-MAAa, were tested for a possible influence on postradioembolic hepatotoxicity (after RE) and thus, theoretically might represent predictors for toxicity. Following constellations were evaluated as descriptors of hepatotoxicity via logistic regression: bilirubin after RE ≥ 1.5-fold above the standard value (CTCAE grade 1 or more), bilirubin value after RE graded according to CTCAE grade 3 or 4 and the presence of REILD.

A total of 26 (12.9%) patients had a bilirubin value graded according to CTCAE grade 1 or more after RE. A significant correlation could be demonstrated for the presence of liver cirrhosis (p=0.021), the initial (baseline) CHILD stage (p=0.009), chemotherapy applied before RE (p=0.042) and elevated baseline values of bilirubin (above normal) before the start of therapy (p=0.007).

A total of 6 (3.0%) patients had a bilirubin value graded according to CTCAE grade 3 and 4 after RE. Baseline CHILD stage (p=0.025) and elevated baseline values of bilirubin (p=0.017) showed a significant correlation.

A total of 5 (2.5%) patients showed a REILD according to the criteria of Sangro et al. (10). Another 6 (3.0%) patients showed an extensive and large scale reduced Gd-EOB-DTPA uptake on MRI after RE but could not be diagnosed reliably as REILD according to Sangro et al. (e.g. no bilirubin increase over 3 mg/dl or ascites). These cases were nevertheless considered as REILD (though just lobar). A significant association with the occurrence of REILD after RE was found for the presence of liver cirrhosis (p=0.008), the initial CHILD stage (p=0.002) and an initial tumor volume ≥500 ccm (p=0.012). The increase in bilirubin after ma/99mTC-MAAa did not affect the occurrence of postradioembolic hepatotoxicity.

Survival. Median overall survival (95%CI) from the timepoint of ma/99mTC-MAAa was 7.9 (range=7.0-8.8) months. An increase in bilirubin after ma/99mTC-MAAa did not show a significant effect on survival whereas patients with a bilirubin increase 6-8 weeks after RE by more than 1.5 times the normal value (CTCAE grade 1), showed a significantly lower survival (p<0.001) (Table V). Further, a high tumor burden of ≥25% (p=0.003) and a large tumor volume of ≥500 ccm (p=0.002) were significant factors influencing overall survival.

View this table:
Table V.

Overall survival and influencing factors.

Discussion

The analysis of liver parameters before and after mapping angiography with the administration of 99mTc-MAA demonstrated a significant, though clinically irrelevant, temporary increase in bilirubin levels after ma/99mTC-MAAa, which then returned to the initial value before RE approximately 2 weeks later. Bilirubin is known to exhibit a physiological circadian rhythm with median coefficients of variation of around 20% (27, 28). Due to the significant bilirubin value progression, which applies equally to all tumor entities, it cannot be explained by a merely intraindividual or circadian fluctuation. The other liver-specific laboratory parameters showed no uniform significant changes. Changes in AST before RE in certain tumor entities, although statistically significant, are presumably not clinically relevant due to the inconsistent and only slight increase. It is not possible to clearly differentiate whether the increase in bilirubin levels was caused solely by the administration of 99mTc-MAA or whether it was already caused by the previously performed angiography by manipulation, contrast injection and the associated microemboli of air, small thrombi or complications like coil dislocation. Statistically a slight correlation – but no causal association - between complications during ma/99mTC-MAAa and an increase in bilirubin levels of ≥10 μmol/l after ma/99mTC-MAAa was demonstrated. The subsequent normalization of bilirubin and blood flow (angiographically verified at RE procedure) until RE are also congruent and allow an influence of the initial iatrogenic perfusion changes to appear at least realistic. Consistently the changes in bilirubin after ma/99mTC-MAAa showed no association with subsequent postradioembolic hepatotoxicity and thus, do not represent a sole predictive diagnostic tool for the occurrence of REILD. Further on, it also had no effect on overall survival.

It should be noted that most patients in this study were limited in their liver function due to the underlying diseases or previous therapies (chemotherapy, surgical therapies, interventional therapies). Therefore, ma/99mTC-MAAa does not allow a statement about a possible hepatotoxicity of a healthy liver. Since this is a retrospective study, there is no randomized comparison group. A direct comparison with the results of other studies investigating changes in liver-specific laboratory parameters through ma/99mTC-MAAa is not possible, as to our knowledge, no further publications on this topic are available at the current state. There is also no official statement of the company about a potential hepatotoxicity of the 99mTc-MAA particles TechneScan LyoMAA (TechneScan® LyoMAA, Covidien, Neustadt/Donau, Germany), used at our institute. The size of the particles is similar to the size of the Yttrium-90 spheres with an average diameter of 35 μm. Since these are known to tend to aggregate to larger clots and thus, remain in the tumor bed, an embolizing effect might also be possible for 99mTc-MAA particles. However, the number of 99mTc-MAA particles is significantly smaller, and in contrast to the 90Y spheres, are degraded with a biological half-life of 6 h. Thus, at best, a small temporary embolization can be assumed, but this could be an explanation of the proven increase in bilirubin values with an individual normalisation within a short time period.

Conclusion

Mapping angiography with administration of 99mTc-MAA continues to represent a low-risk evaluation procedure in preparation for RE. The transient increase in bilirubin after ma/99mTC-MAAa did not provide a predictive value for potential hepatotoxicity and is more likely associated with angiography than 99mTc-MAA administration.

Footnotes

  • Authors’ Contributions

    MF: data collection, data analysis, data interpretation, manuscript writing. FH: data collection, data analysis, manuscript editing. RS: data collection, radiologic review, manuscript writing. MP: data collection, radiologic review, data analysis, manuscript editing. MPo: data collection, manuscript writing. SM, SG: data analysis, radiologic review, manuscript editing. AT: data interpretation, manuscript writing. HI: data interpretation, manuscript editing. JO: data collection and analysis. RD: data collection, radiologic review, data analysis, manuscript editing. OG: data collection, radiologic review, data analysis, manuscript editing. JA: data analysis, manuscript writing. JR: data analysis, radiologic review, data interpretation, manuscript editing. MS: study design, data collection, data analysis, data interpretation, manuscript writing.

  • Conflicts of Interest

    The Authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

  • Received November 6, 2020.
  • Revision received November 21, 2020.
  • Accepted November 22, 2020.

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Liver Function Changes After Technetium-99m-Macroaggregated Albumin Administration and Their Predictive Value Regarding Hepatotoxicity in Patients Undergoing Yttrium-90-Radioembolization
MATTHIAS P. FABRITIUS, FABIAN HARTMANN, RICARDA SEIDENSTICKER, MACIEJ PECH, MACIEJ POWERSKI, SERGIO GROSU, STEFAN MAURUS, ANDREI TODICA, HARUN ILHAN, JAZAN OMARI, ROBERT DAMM, OLIVER GROßER, JOSEFINE ALBERS, JENS RICKE, MAX SEIDENSTICKER
Anticancer Research Jan 2021, 41 (1) 437-444; DOI: 10.21873/anticanres.14793
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