British Journal of Radiology (2005) 78, 433-436
© 2005 British Institute of Radiology
doi: 10.1259/bjr/62169440
Hepatic transit time: indicator of the therapeutic response to radiofrequency ablation of liver tumours
X Zhou, MD1,2,
D Strobel, MD1,
J Haensler, MD1 and
T Bernatik, MD1
1 Department of Ultrasound, Department of Medicine I, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, D-91054 Erlangen, Germany and 2 Ultrasound Department, Union Hospital, Hua Zhong University of Science and Technology (HUST), Wuhan, P. R. China
Correspondence: PD Dr. med. Thomas Bernatik
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Abstract
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The aim of this study was to evaluate changes of hepatic transit time (HTT) in patients treated by radiofrequency ablation (RFA). Five consecutive patients (2 females, 3 males; mean age 66 years) referred for treatment of liver neoplasm with percutaneous application of RFA were included in this study. The HTT of contrast agent (Sonovue®; Bracco International B.V., Amsterdam, The Netherlands) was measured in patients with liver metastases on the basis of time intensity curve (TIC®) before and after RFA, respectively. Changes of HTT before vs after RFA were compared with therapeutic response based on three-phase dynamic CT or MRI. Before RFA HTT in all 5 patients was less than 10 s (mean 6.2±1.5 s). After RFA HTT in patients with complete therapeutic response was 11.3±1.2 s, whereas two patients with incomplete treatment showed unchanged HTT below 10 s (mean 6.3±1.8 s). Successful RFA leads to a normalization in HTT. HTT using ultrasound contrast agent appears to provide a new and alternative approach in assessing the therapeutic effect of RFA in liver metastases.
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Introduction
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Although the radiofrequency ablation (RFA) technique has been greatly improved, incomplete therapy or tumour recurrence still remains a problem [1]. Tumour recurrence rates vary depending on tumour size and remain high for tumours with a diameter above 4 cm [1]. Thus, post-procedural assessment is important for control of tumour ablation. A novel, simple and easy method using microbubble ultrasound contrast agents to measure the so-called hepatic transit time (HTT) was developed [2–4]. It has been shown that HTT is significantly shortened in patients with liver metastases [2–4]. A shortened HTT might be a potential marker to identify patients with residual or recurrent metastases after RFA. We have evaluated the changes of HTT in a series of patients treated with RFA, to test the hypothesis that HTT will lengthen with successful treatment.
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Patients and methods
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Five consecutive patients (2 females, 3 males; mean age 66 years) with liver metastases who were referred for percutaneous RFA using perfusable radiofrequency electrode needles (Berchtold, Tuttlingen, Germany) were included in the study. All treated lesions (Table 1
) were histologically proven by ultrasound-guided biopsy. All treatments were approved by the ethical committee of Erlangen-Nuremberg University. Written informed consent was obtained from all patients at enrolment. Ultrasound examinations were performed by one experienced ultrasound specialist using Sonoline Elegra Advanced with 3.5C4H ultrasound probe (Siemens Medical Systems Inc., Issaquah, Washington) equipped with phase inversion harmonic imaging (ensemble contrast imaging, ECI®) and time intensity curve (TIC®) software.
Method of the hepatic transit time (HTT) measurement
All patients included in the study underwent HTT measurement of the US contrast agent (Sonovue®; Bracco International B.V., Amsterdam, The Netherlands) before and after RFA. The ultrasound investigator was blinded for the CT or MRI results. The hepatic artery and a branch of the hepatic vein were visualized simultaneously in an intercostal section. The patient was asked to either hold his/her breath or, if this was not possible, to take small breaths with half-filled lungs. After activation of the ECI mode with a medium mechanical index (MI: 0.5) and adaptation image quality, 4.8 ml Sonovue® was administered intravenously as a bolus followed by 10 ml of 0.9% saline solution. We have not used low MI (
0.1) as commonly used for characterization of liver tumours. For measuring arrival of contrast media in the liver vein higher MI is needed to get a sufficient contrast. We have not used high MI (
1.0) as commonly used for Levovist on detection of liver metastases to prevent bubble destruction. Because MI of 0.5 still leads to some bubble destruction we had to use twice the standard dose of Sonovue® (4.8 ml). The entire image sequence from the entry of the ultrasound contrast agent into the hepatic artery up to its visualization in the hepatic vein was acquired (TIC® software). After rewinding the sequence to the first image (in a cine loop), two "regions of interest" (ROI) were placed over the hepatic artery and hepatic vein. The sizes of the ROI were adapted to vessel diameter. After activation of automatic movement correction, the smooth time–intensity curve of the brightness (intensity) alterations in the ROI were automatically calculated by means of the aforementioned TIC software (Figure 1). Thus, an increase in brightness provides a graphic representation of the arrival of ultrasound contrast agent in the intrahepatic artery or, respectively, in the vein. The difference between the arrival times of the ultrasound contrast agent (defined as 10% rise above baseline) presents the real HTT.
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Figure 1. Hepatic transit time calculated using the time intensity curve (TIC) software in a patient with liver metastasis before radiofrequency ablation. Left curve: arrival of contrast agent in the hepatic artery; right curve: arrival of contrast agent in the hepatic vein.
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Follow-up
CT or MRI results for evaluation of the therapeutic response was considered as gold standard in this study. Complete response was defined as absence of any liver metastases and complete necrosis of the treated lesion. Incomplete response was defined as either incomplete necrosis of the treated lesion or presence of further liver metastases elsewhere. At the time of follow up (Table 1
) the HTT was repeated to see any changes compared with pre-treatment values.
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Results
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A total of 5 patients (2 females, 3 males; mean age 66 years) were enrolled in the study. Complete response was achieved in 3 of 5 patients (Figure 2). The other two patients, although showing successful local treatment, had to be classified as incomplete because both were found to have extra small metastases demonstrated by contrast-enhanced ultrasound imaging and CT and not visualized by conventional ultrasound.
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Figure 2. 57-year-old man with liver metastases of hypernephroma. Before radiofrequency ablation (RFA) treatment, hepatic transit time (HTT) was 6 s. 1 month after RFA HTT increased up to 12 s while contrast-enhanced ultrasound and MRI show complete ablation. (a) Conventional ultrasound before RFA showing one liver nodule (arrow), diameter 2.4 cm. (b) MRI T1 weighted image showing the same tumour (arrow). (c) Contrast-enhanced ultrasound after RFA showing complete necrosis. (d) Contrast-enhanced MRI T1 weighted image showing the same area after RFA.
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Table 1 and Figure 3 show the analysis of HTT. Before RFA, the mean HTT was 6.2±1.5 s (mean±standard deviation (SD)) ranging from 4 s to 8 s. After RFA, HTT in three patients with proven complete response was 11.3±1.2 s (mean±SD) ranging from 10 s to 12 s [delay rate 
ge;100%, delay rate=(HTT after RFA–HTT before RFA)/HTT before RFA]. On the other hand, the mean HTT of the other two patients with incomplete treatment was 6.3±1.8 s (mean±SD). The HTT of the complete response patients increased significantly compared with unchanged HTT in incompletely treated patients (p<0.05 using a Fisher-test). There was no change in the shape of the TIC curve (rate of rise) for hepatic vein arrival after RFA.
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Discussion
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As RFA is becoming an increasingly accepted local treatment method for malignant liver tumours, the evaluation of the therapeutic response is extremely important for correctly deciding whether further treatment is necessary. Preferably, as most RFA are guided by ultrasound, application of ultrasound for evaluation of the therapeutic response is most suitable. Blomley et al [2] first suggested that the transit time of a contrast agent from injection to its arrival in the hepatic vein could be a simple marker for diagnosis of metastatic spread to the liver, as it was shown to be shortened in seven patients with liver metastases. Bernatik et al [3, 4] improved the method by measuring transit time from the hepatic artery to the hepatic vein directly and showing that this HTT is a reliable indicator of the presence of metastatic liver disease [4]. In our study, findings showed no difference between patients before and after RFA with incomplete treatment. However for the three patients with complete therapeutic response, HTT demonstrated significant differences before and after RFA. The HTT was significantly changed with delay rate ge;100% and value ge;10 s after complete RFA. Normal cut-off point of 10 s for HTT corresponded well with previous report, where no patient with proven liver metastases showed HTT of more than 10 s [4].
HTT may be a sensitive and practical indicator for assessing effectiveness of RFA. Achieving normalization of the HTT, might indicate the therapy being complete. On the other hand in patients with complete necrosis after RFA but still abnormal HTT one should look more thoroughly for so far undetected liver metastases. Thus, measurement of HTT combined with a contrast enhanced ultrasound of the liver parenchyma may increase the detection sensitivity for metastasis by drawing attention to patients with abnormal HTT.
This pilot study suggests that CT, MRI or contrast-enhanced ultrasound together with HTT may be a promising protocol for therapeutic assessment following liver ablation, and larger numbers are needed in future studies to evaluate the potential of the technique.
Received for publication May 14, 2004.
Revision received November 2, 2004.
Accepted for publication December 16, 2004.
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References
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- Solbiati L, Livraghi T, Goldberg SN, et al. Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: long-term results in 117 patients. Radiology 2001;221:159–66.[Abstract/Free Full Text]
- Blomley MJ, Albrecht T, Cosgrove DO, et al. Liver vascular transit time analyzed with dynamic hepatic venography with bolus injections of the US contrast agent: early experience in seven patients with metastases. Radiology 1998;209:862–6.[Abstract/Free Full Text]
- Bernatik T, Becker D, Neureiter D, et al. Hepatic transit time of an echo enhancer: an indicator of metastatic spread to the liver. Eur J Gastroenterol Hepatol 2004;16:313–7.[CrossRef][Medline]
- Bernatik T, Strobel D, Haensler J, Hahn EG, Becker D. Hepatic transit time of an ultrasound echo enhancer indicating the presence of liver metastases – first clinical results. Ultraschall Med 2002;23:91–5.[CrossRef][Medline]
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Abstract
Introduction
patients showing complete response after RFA, 
patients with incomplete response).