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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 7  |  Page : 1556-1562

Liver computed tomographic perfusion for monitoring the early therapeutic response to sorafenib in advanced hepatocellular carcinoma patients


1 Department of Radiology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
2 Department of Radiology, Zhongshan Hospital of Fudan University; Department of Medical Imaging, Shanghai Medical College, Fudan University; Shanghai Institute of Medical Imaging, Shanghai 200032, China
3 Department of Liver Surgery, Zhongshan Hospital of Fudan University, Shanghai 200032, China
4 Department of Pathology, Zhongshan Hospital of Fudan University, Shanghai 200032, China

Date of Web Publication19-Dec-2018

Correspondence Address:
Dong Wu
Department of Radiology, Zhongshan Hospital of Fudan University, 180 Fenglin Rd, Xuhui District, Shanghai 200032
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_979_17

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 > Abstract 


Background: Sorafenib is the only approved treatment for advanced hepatocellular carcinoma (HCC). However, it is a diagnostic challenge to monitor its early treatment effects on HCC.
Purpose: The purpose of this study is to investigate the effects of sorafenib on HCC with liver computed tomography perfusion (CTP) and investigate its efficacy in assessing the early therapeutic response of sorafenib for advanced HCC.
Materials and Methods: A total of 23 HCC patients were included in this study. Sorafenib was continuously administered orally at a dose of 400 mg twice daily. CTP was performed before and after 2 weeks of sorafenib treatment, and the changes of perfusion parameters were obtained with a 320-detector row CT scanner including hepatic artery flow (HAF), portal vein flow (PVF), and perfusion index. The modified response evaluation criteria in solid tumor (mRECIST) assessment were performed after two and 4 months of treatment.
Results: According to the result of mRECIST, three patients (13%) showed partial response, eight patients (34.7%) showed stable disease (SD) and 12 patients (52.2%) showed progressive disease (PD) after 2 months of treatment, whereas 10 patients (43.5%) showed SD and 13 (56.5%) showed PD after 4 months of treatment. The group that responded to sorafenib showed a significantly decreased HAF value after 2 months compared to that of baseline, whereas nonresponder group showed a significant increase in HAF. The patients with PD showed significantly higher HAF compared to that of SD patients.
Conclusions: CTP might be applied to evaluate therapeutic effects of sorafenib in advanced HCC, where HAF could potentially serve as imaging biomarkers for monitoring early therapeutic effects after treatment.

Keywords: Computed tomography perfusion, hepatic artery flow, hepatocellular carcinoma, sorafenib


How to cite this article:
Shen X, Wu D, Tang M, Sun H, Ji Y, Huang C, Zeng M. Liver computed tomographic perfusion for monitoring the early therapeutic response to sorafenib in advanced hepatocellular carcinoma patients. J Can Res Ther 2018;14:1556-62

How to cite this URL:
Shen X, Wu D, Tang M, Sun H, Ji Y, Huang C, Zeng M. Liver computed tomographic perfusion for monitoring the early therapeutic response to sorafenib in advanced hepatocellular carcinoma patients. J Can Res Ther [serial online] 2018 [cited 2019 Jan 24];14:1556-62. Available from: http://www.cancerjournal.net/text.asp?2018/14/7/1556/247737




 > Introduction Top


Hepatocellular carcinoma (HCC) is one of the most common primary cancers worldwide, which has been a leading cause of cancer-related mortality.[1],[2],[3],[4],[5] The incidences of HCC are increasing in both the Europe and United States, and only 30%–40% of patients have been amenable to potentially curative treatments.[6] For patients with advanced HCC, current treatment options were very limited.[6],[7] Sorafenib is the only approved treatment for advanced HCC to date.[2],[8],[9] Sorafenib is an oral multikinase inhibitor with anti-angiogenic effects that target the tyrosine kinase Vascular Endothelial Growth Factor Receptor (VEGFR)-2 and-3 and Raf/MAPK/ERK signaling pathway.[6]

Anti-angiogenic response induces necrosis and vascular changes, which do not automatically lead to a variation in tumor size. Thus, sorafenib treatment has reduced the accuracy of radiological markers of tumor size-based response tools, such as the response evaluation criteria in solid tumor (RECIST).[10] Similarly, it is also difficult for the modified RECIST (mRECIST) to evaluate the irregularly shaped HCC.[11] Therefore, it is urgent to combine current morphological analysis with novel diagnostic tools, for detecting early treatment response in tumor microvascularization and predicting treatment response.

Early identification of those patients who could benefit from sorafenib therapy is necessary because sorafenib is costly with moderate side effects. Hence, it is important to select the optimal treatment candidate, as well as monitor the treatment response.[12] Emerging studies demonstrated that quantitative assessment of angiogenesis with noninvasive perfusion measurements is more sensitive indicator than tumor size (RECIST).[12],[13],[14] In the measurements restricted to tumor size, more profound changes in tumor vascularity may be neglected, which may otherwise make an impact on assessing treatment outcome. Computed tomography perfusion (CTP) imaging of liver could take serial images after a contrast bolus injection, thus providing functional information on the microcirculation of normal parenchyma and focal liver lesions.[15],[16] The previous studies showed that liver CTP was a promising technique for assessing the efficacy of various anticancer treatments.[17],[18] In longitudinal follow-up, Kaufmann et al. demonstrated the prognostic value of CTP in HCC treatment with sorafenib and compared it with mRECIST.[12] Decreased intralesional blood flow (BF) and hepatic perfusion index after 2 months of sorafenib treatment predicted disease stabilization after 4 months. Tamandl et al. showed that treatment response and long-term disease control could be predicted by the early response evaluation with CTP 1 day after transarterial chemoembolization for HCC.[19] Dynamic contrast-enhanced CT with perfusion imaging showed diagnostic value in the quantitative assessment of tumor response to sorafenib in HCC patients.[11],[17] However, the role of CTP in response assessment has only been evaluated in studies with small sample sizes, yielding controversial results.[12],[13],[20] In addition, different parameters were involved, and these parameters were acquired at different time points after treatment. Therefore, it is important to establish evaluation criteria of CTP.

Here, based on above findings, we investigated whether CTP could be applied to assess early therapeutic response to sorafenib in advanced HCC. Our data demonstrated that one of the perfusion parameters, hepatic artery flow (HAF) was decreased in the sorafenib-responder group, whereas nonresponder group showed a significantly increased HAF.


 > Materials and Methods Top


Study population

This retrospective study was approved by the Ethics Committee of Zhongshan hospital affiliated to the Fudan University. From March 2014 to May 2016, 238 patients with suspected liver tumor were enrolled and examined by CTP. Among these patients, 133 were not validated as malignant liver tumor and excluded from the study. The other 105 patients were diagnosed as liver tumor with CT. This candidate patients were graded into different stages according to Barcelona Clinic Liver Cancer classification: Seven patients were confirmed at a very early stage (Stage 0), with a single lesion <2 cm; 20 patients were at an early stage (Stage A), with a single lesion or nodule <3 cm; 39 patients were at an intermediate stage (Stage B) with multinodular tumors. Of remaining 39 patients, 33 were diagnosed at the advance stage (Stage C), and six patients were postoperative recurrence, which were divided into two groups according to whether with portal invasion (Stage N1, M1). When this criterion was met, they were suggested to continuously take sorafenib orally at a dose of 400 mg, twice daily. Among 26 patients treated with sorafenib, three patients withdrew from treatment due to side effects, 12 patients developed progressive disease (PD), three patients achieved a partial response, and eight patients achieved stable disease (SD), with a disease control rate of 47.8%, determined by mRECIST. The enrolling procedure was exhibited [Figure 1]. Regular clinical features (sex, age, and origin of liver diseases, etc.,) were listed [Table 1] to show that no difference existed between sorafenib-resistant group and efficient group.
Figure 1: Enrollment of the study patients

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Table 1: Patient's main characteristics

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Computed tomography perfusion scanning

CTP was performed on an average of 4.4 days (ranged 1–10 days) before treatment and after 2 weeks of treatment, with a 320-slice multidetector CT scanner (Aquilion ONE vision; Toshiba Medical Systems Corporation, Otawara, Japan). The noncontrast helical CT of the liver before and after sorafenib treatment was initially performed as a baseline study. Then, a 320-slice liver perfusion CT acquisition was performed using a dynamic volume scan mode with 16-cm z-axis coverage, without no table movement as the description of our previous study.[16] Approximately 0.5 ml/kg of nonionic iodinated contrast medium was intravenously injected, followed by 30 mL of saline solution using a power injector at a rate of 8 mL/s through an 18G cannula placed in an antecubital vein.[16] The CTP acquisition protocol was simultaneously initiated following contrast injection, and the first volume acquisition was performed after 8 s. Patients were instructed to breathe regularly and gently throughout the examination. In addition, the restraining bands were placed around the abdomen to limit respiration movement. There two three phases in the total scan duration of 74 s: the first 11 volumes were acquired every 2.0 s, followed by 7 volumes every 3.0 s, and 5 volumes every 5.0 s. Each patient was exposed to the X-ray for 6.9 s. All volumes were acquired with the following parameters: 100 mA, 100 kVp, and 0.3 s rotation speed. Each volume was reconstructed at a 0.5 mm thickness with 0.5 mm spacing, providing a total of 7360 (23 volumes × 320 images) images.[16] The CT analysis was performed by Prof. Dong Wu. The reproducibility has been assessed before the study.

Computed tomography perfusion analysis

CTP images were transferred to an image processing workstation to performed CTP analysis as the demonstration of our previous study.[16] Briefly, before analysis, deformation registration was carried out on the workstation to consider the volume mismatch between the volumes. The entire registration process takes about 15 min for a single examination. Body perfusion software V4.74 was applied to perform CTP analysis, which applied the dual-input maximum slope analysis method.[21],[22] To generate time-density curves, the regions of interest (ROI) were placed on the abdominal aorta at the level of celiac axis, main portal vein, liver, and spleen. Then, functional maps were automatically generated, and each pixel value of portal vein flow (PVF) (mL/100 ml/min), HAF (mL/100 ml/min), and PI (expressed as a percentage) was represented with a color scale.

The perfusion maps were then viewed in 5 mm slice thickness. The values of HAF, PVF, and PI were measured in both tumor tissues and adjacent normal liver tissues for each patient, by two radiologists with >16 years of experience in abdominal imaging. A tissue time-enhancement curve as well as colored functional maps of HAF, PVF, and PI was automatically derived for selected ROIs. HAF, PVF, and PI of tumor tissues and adjacent normal liver tissue were automatically calculated by above software.

Statistical analysis

Advanced HCC patients were divided into four subgroups according to responses to sorafenib, which were the complete response, PR, SD, and PD. Quantitative data were expressed as mean ± standard deviation if normally distributed or as median and interquartile range if the distribution was skewed (determined with a test of normality). For comparing the CTP parameters between the groups, the independent samples t-test was applied for normally distributed data (which were presented as means [SDs]), and the univariate paired Wilcoxon signed-rank test was used for data with a skewed distribution (presented as medians and interquartile ranges). The Fisher exact test or Pearson Chi-square test was applied for categorical data, and the independent samples t-test was applied for continuous data. Statistical analyses were performed with Statistical Package for the Social Sciences 13.0 software (Statistical Product and Service Solutions, Chicago, USA). P < 0.05 was considered statistically significant.


 > Results Top


Clinical features

The clinical features of all 23 patients (sorafenib responder group and nonresponder group) were listed [Table 1]. The mean age of patients in responder group (4 males and 1 female) was 54 years old (ranged 51–60) and that of the resistant group (9 males and 3 females) was 56 (ranged 44–69). The enrolling procedure was exhibited [Figure 1]. All patients tolerated the CTP examination without adverse effects. Nearly all of them have an origin of hepatitis B (10/11 in the responder group and 11/12 in the nonresponder group) before HCC was developed, and majority of them had a hepatitis B history between 10 and 30 years. There was no significant difference between the two groups in following general and clinical characteristics: age, gender, etiology of the liver disease, history of hepatitis, and hepatitis B virus markers (P > 0.05).

Comparison of perfusion computed tomography parameters between hepatocellular carcinoma lesions and adjacent normal tissues before treatment

For all these enrolled patients, the perfusion parameters of the tumor zone and adjacent normal tissues were compared. The HAF and PI were significantly higher in HCC than that of in normal liver parenchyma (P = 0.0027 and P = 0.0093, respectively. Wilcoxon signed-rank test), whereas PVF was significantly lower in HCC than that of in normal liver parenchyma tissues (P = 0.0045. Wilcoxon-signed rank test) [Table 2].
Table 2: Comparison of perfusion parameters between HCC lesions and adjacent normal tissues before treatment (n=23)

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Comparison of perfusion parameters in hepatocellular carcinoma lesions before and after treatment in the responder group

Among patients in responder group (n = 11), the descriptive analysis of perfusion parameters measured in HCC lesions before treatment was showed as follows [Table 3]: HAF 131.1 ± 18.2, PVF 123.2 ± 19.7, PI 52.2 ± 14.8. The corresponding values after treatment were as follows: HAF 108.8 ± 13.6, PVF 126.9 ± 18.7, and PI 58.3 ± 10.8. The quantitative values of HAF were significantly lower (P < 0.05) after treatment, compared to that of before treatment in the responder group [Table 3] and [Figure 2]. Other perfusion measurements (PVF and PI) did not show significant differences between before and after treatment in the responder group [Table 3] and [Figure 2].
Table 3: Comparison of perfusion parameters in HCC lesions before and after treatment in the responder group (n=11, 3 partial response and 8 stable disease)

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Figure 2: (a) Time-activity curves determined from regions of interests placed on the abdominal aorta at the level of celiac axis, the main portal vein, the liver, and the spleen. The peak value of the artery was 386 Hounsfield units, and the time to peak was 10 s. The peak value of the portal vein was 108 Hounsfield units, and the time to peak was 32 s. The peak value of the spleen was 107 Hounsfield units, and the time to peak was 17 s. (b) The perfusion parameters of a 50-year-old man at baseline and 2 weeks treated with sorafenib 400 mg/d. All hepatic artery flow, portal vein flow, and PI values were not improved. (c) The perfusion parameters of a 55-year-old male at baseline and 2 weeks treated with sorafenib 400 mg/d, hepatic artery flow was significantly downgraded although other indicators were also improved, they were not very noticeable

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Comparison of perfusion parameters in hepatocellular carcinoma lesions before and after treatment in the nonresponder group

Among patients in nonresponder group (n = 12), the descriptive analysis of perfusion parameters measured in HCC lesions before treatment was showed as follows [Table 4]: HAF 127.9 ± 22.5, PVF 123.8 ± 18.3, and PI 55.4 ± 12.7. The corresponding values after treatment were as follows: HAF 148.5 ± 21.4, PVF 119.3 ± 16.5, PI 57.2 ± 14.6. The quantitative values of HAF were significantly higher (P < 0.05) after treatment, compared to that of before treatment in the nonresponder group [Table 4] and [Figure 2]. Other perfusion measurements (PVF and PI) did not show significant differences between before and after treatment in the nonresponder group [Table 4] and [Figure 2].
Table 4: Comparison of perfusion parameters in HCC lesions before and after treatment in the non-responder group (n=12, progressive disease)

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Comparison of perfusion parameters in patients with stable disease and progressive disease after treatment for 4 months

After 4 months of treatment, 10 patients (43.5%) showed SD and 13 (56.5%) showed PD. Among 10 SD patients, the descriptive analysis of perfusion parameters measured in HCC lesions was showed as follows [Table 5]: HAF 113.59 ± 18.3, PVF 120.3 ± 11.7, PI 53.8 ± 14.2. The corresponding values of 13 PD patients were as follows: HAF 153.1 ± 16.7, PVF 118.7 ± 14.6, and PI 55.0 ± 15.6. The quantitative values of PD patients were significantly higher (P < 0.05) than that of SD patients [Table 5]. Other perfusion measurements (PVF and PI) did not show a significant difference before and after treatment in the nonresponder group [Table 5].
Table 5: Comparison of perfusion parameters in patients with SD and in patients with PD after treatment for 4 months (n=23)

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 > Discussion Top


The major finding of this study was that the CTP parameter HAF may be applied to predict the early therapeutic response to sorafenib in patients with advanced HCC. Our data demonstrated although the HAF, PI, and PVF parameters were significantly different between tumor tissues and adjacent normal liver tissues, only HAF variations exhibited a potential in monitoring the early therapeutic effect of sorafenib in advanced HCC patients. The group that responded to sorafenib showed a significantly decreased HAF values after 2 months compared to baseline, whereas nonresponder group showed a significant increase of HAF. Moreover, the patients with PD showed a significant increase in HAF compared to that of patients with SD.

As previously demonstrated that sorafenib is the only standard treatment available for advanced HCC.[23] However, marked treatment effect of sorafenib (significant shrinkage of tumor size and good clinical outcome, etc.) may not be easily observed in the early treatment stage. Therefore, a precise evaluation of early therapeutic response to sorafenib has been vital to determine whether sorafenib treatment was effective and should be continued. The previous studies attempted to identify effective biomarkers to assess the early effects of sorafenib in advanced HCC patients.[24],[25]

Modified RECIST (mRECIST) has been so far the gold standard for HCC evaluation. However, this criterion just can assess the morphology of cancer, did not reflect tumor cell activity, tumor hemodynamic changes, especially the internal microenvironment changes of tumors. Therefore, he needs of predicting the progression of HCC could not be fully met. CTP has been widely applied in the clinical examination of human diseases, including cardiovascular diseases, stroke, and cancers.[26],[27] CTP scanning realizes quantitative assessment of the BF changes of the microenvironment. Given perfusion imaging could detect regional alterations of BF within organs, it was sufficiently reasonable to discover novel parameters in CT data. The HAF level has been a widely agreed index for assessing hepatic pathological changes and malignancy,[28] which was also considered as a potential ideal guideline to distinguish between precarcinoma and early HCC nodules.[29]

HAF was previously suggested as an ideal reference index for assessing the severity of fibrotic changes [30] and HCC condition evaluation, which had the highest areas under the ROC curves.[29] It also helped to identify metastatic sites in liver.[31] Theoretically, enhanced HAF indicated increased arterial blood supply (and highly possibly accompanied by reduced portal vein blood supply) due to intrahepatic lesions. Those patients with highest levels of HAF were almost sorafenib resistant ones in late treatment. A possible mechanism may be that higher HAF indicated more difficulties for the arrival of drug in the lesion and thus leading to weaker response. In line, the decreased HAF also indicated a repair of the liver function in HCC.[32] The special significance of this study was that, compared to all kinds of molecular markers, the HAF parameter could potentially serve as an early predictor for sorafenib response, besides of a reflection of the malignancy. This study highlighted the possible application of quantitative data to evaluate the therapeutic outcomes. Moreover, the HAF value might help the mRECIST criterion to be further developed and more predictive.

The limitations of the current study lied in the following aspects: (i) The sample size was small. It was necessary to verify the accuracy of the correlation of HAF with sorafenib response., (ii) our software only allowed the use of ROIs drawn in a single image plane (in which the tumor diameter was maximal); it was not possible to use the volumes of interest for analyzing the perfusion parameters, which may be a more robust approach.[33],[34],[35] (iii) Variations in the degree of the disease conditions among the study participants may also have made some effects on the results. Hence, further research with larger sample sizes would be required to validate the study results.

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.

Acknowledgement

This work was supported by the Shanghai municipal health and Family Planning Commission (201540142).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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