1Department of Radiology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Linkou Medical Center, Taoyuan 333, Taiwan.
2Department of Surgery, Xiamen Chang Gung Hospital, Xiamen 361000, Fujian, China.
3Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Linkou Medical Center, Taoyuan 333, Taiwan.
4Department of Nuring, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
5Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan 333, Taiwan.
*Authors contributed equally to this study.
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Aim: Sorafenib is a multi-tyrosine kinase inhibitor and the standard therapy for advanced hepatocellular carcinoma (HCC). This retrospective study aimed to observe the anti-fibrotic effect of sorafenib in patients with advanced HCC.
Methods: Seventeen patients with advanced HCC were recruited. Shear wave velocity (SWV) using acoustic radiation force impulse elastography and non-invasive serum markers for liver fibrosis, such as the aspartate aminotransferase (AST) to alanine aminotransferase ratio (AAR), the AST to platelet ratio index, the fibrosis-4 index and the Lok index, were recorded at the beginning of sorafenib treatment and 3-6 months after sorafenib treatment in 2014-2015.
Results: Nine (52.9%) patients achieved disease control status and 8 had progressive disease after a mean duration of 11.1 months with sorafenib treatment. The mean SWV decreased from 2.37 m/s at the beginning to 1.90 m/s after sorafenib treatment (P < 0.01). This trend was observed in patients with and without liver cirrhosis (from 2.49 to 2.06 m/s, P = 0.06, and from 2.32 to 1.69 m/s, P < 0.05, respectively). Among the non-invasive serum markers, no statistically significant differences were observed except for the AAR in the cirrhotic group.
Conclusion: Sorafenib has potential antif-ibrotic effects in patients with advanced HCC.
Sorafenib, liver stiffness, attenuation, advanced hepatocellular carcinoma
Liver fibrosis is a wound-healing response and a common consequence of hepatic inflammation/injury caused by a variety of etiologies, such as infection, drugs, metabolic disorders or immune attack. Platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) are important for the sustained activation and proliferation of hepatic stellate cells (HSCs), which are activated and transformed into myofibroblasts during liver injury.[2,3] The treatment of liver fibrosis by curing/controlling underlying liver diseases or interfering with receptor/ligand interactions has been reported in clinical trials or observational studies.
The inhibition of tyrosine kinase receptors for proliferative cytokines, such as PDGF, VEGF and fibroblast growth factors (FGF), could reverse liver fibrosis. The binding of PDGF to PDGF receptor (PDGFR)-b activates Ras and sequentially propagates the stimulatory signal via the phosphorylation of the mitogen-activated protein kinase (MAPK)/extracellular-signal-regulated kinase (ERK) pathway, which regulates protein synthesis, transcription of profibrogenic genes, proliferation, cell cycle control and apoptosis in HSCs. The anti-fibrotic effect of imatinib, which occurs via the targeting of PDGF, has been observed in mouse and rat studies. Sorafenib is a multi-tyrosine kinase inhibitor that targets the receptor tyrosine kinases VEGF receptor (VEGFR) and PDGFR-b and inhibits the activation of Raf/ERK signaling pathways. Sorafenib is the standard therapy for the treatment of advanced hepatocellular carcinoma (HCC).[9,10] Recent studies have shown that sorafenib can induce anti-fibrotic effects by reducing HSC proliferation and enhancing apoptosis.[6,11] Sorafenib also attenuates liver fibrosis and injury through the up-regulation of signal transducer and activator of transcription 3 (STAT3) phosphorylation in hepatocytes or through STAT3 inhibition in HSCs.[12,13]
Liver biopsy has been considered to be a “gold standard” for the assessment of liver fibrosis. However, a number of well-known characteristics, such as the associated risk of morbidity, including the risk of bleeding and perforation, inter-observer variability in the interpretation of biopsies, sampling variability in the context of accurate staging, monetary costs and the turnover time for results, limit the clinical application of liver biopsy. Non-invasive methods that use serum biologic markers or elastography via ultrasound and magnetic resonance imaging-based techniques have emerged recently for the indirect assessment of liver fibrosis. Acoustic radiation force impulse (ARFI) elastography is an ultrasound-based technique for quantifying the mechanical properties of tissue stiffness.[16,17] ARFI has been utilized in comparison with various stages of liver fibrosis and shows good diagnostic accuracy in predicting hepatic fibrosis.[18,19]
We conducted an observational case-series study to assess liver fibrosis/stiffness using ARFI elastography among sorafenib-treated patients with advanced HCC to explore anti-fibrotic effects and the correlation with non-invasive methods.
Patients with HCC were treated for recurrence after resection or advanced HCC as stage C or stage III-IV according to the Barcelona Clinical Liver Cancer staging system or the 7th edition of American Joint Committee on Cancer/Union for International Cancer Control) staging system respectively from May 2014 to July 2015.[20-22] A total of 17 consecutive patients with advanced HCC were recruited retrospectively for this observational study in the clinic of Chang Gung Memorial Hospital (CGMH) fourteen patients had previously undergone surgical resection and tumor recurrence developed in the follow-up period. Sorafenib was administered as salvage treatment. The remaining three patients were unresectable with typical imaging findings. The status of advanced HCC included major portal vein thrombosis (n = 5) and distant metastasis (n = 12, 5 in the lung, 2 in the bone, 2 in the peritoneum, 1 in the bone and peritoneum, 1 in a lymph node and 1 in the adrenal gland). The treatment of HCC was based on clinical practice guidelines,[20,21] and all patients were under the care of the liver cancer team of the Linkou branch of CGMH. The daily oral dosage of sorafenib was administered and adjusted with toxicity evaluation and without drug interruption in the observation period. The dosage was deescalated with toxicity intolerance from 800 mg to 400 mg.
This study was approved by the Institutional Review Board (IRB) of CGMH, Linkou branch (IRB No. 103-1747B). All methods of data collection were performed in accordance with the relevant guidelines and regulations of IRB in CGMH.
The ARFI elastography examinations were performed with an Acuson S2000 ultrasound (Siemens Medical Solutions, Mountain View, California, USA) with ARFI technology equipment, a curvilinear array transducer operating at 4 MHz (4C1) and the virtual touch tissue quantification system every 3 months. With the liver parenchyma free of visible hepatic tumors, blood vessels and bile ducts, as confirmed by conventional ultrasonic images, 10 valid measurements of shear wave velocity (SWV, m/s) were made by a single experienced examiner (Chen YC) with the patients holding their breath for a few seconds. The results of ARFI elastography were expressed as the median of the 10 SWV measurements in the liver parenchyma. The SWV measurements in this study were validated using the ratio of the interquartile range (IQR) to the median value, which is currently used to assess the validity of transient elastography. An IQR/median ratio of less than 0.3 is considered to indicate a homogeneous set of measurements.[23,24]
The non-invasive serologic index values at the beginning of sorafenib treatment and 3 months post-treatment were compared. The aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), the AST to platelet ratio index (APRI), the fibrosis-4 index (FIB-4), and the Lok index for the non-invasive assessment of liver fibrosis were examined at 3 months interval.[25-28] The variables of AST, ALT, international normalized ratio and platelets were recorded at the time of ARFI elastography.
The treatment response of HCC to sorafenib was assessed based on the modified response evaluation criteria in solid tumors every 3-6 months after sorafenib administration and the treatment protocol was continued if the treatment response was disease control, including complete response (CR), partial response (PR), and stable disease (SD). Four types of response are defined as: (1) CR, which indicates the disappearance of any intratumoral arterial enhancement in all target lesions; (2) PR, which indicates a decrease of at least 30% in the sum of the diameters of viable (enhancement in the arterial phase) target lesions, taking as a reference the baseline sum of the diameters of the target lesions; (3) SD, which includes any cases that do not qualify for either PR or progressive disease (PD); and (4) PD, which indicates an increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of viable (enhancing) target lesions recorded since treatment started. All patients have regular assessment every 2 or 3 months as 1 cycle and sorafenib administration was discontinued if the treatment response of PD was identified by liver CT assessment or if the patient’s clinical condition deteriorated. All patients survived in the observation peroid; 1 lost to follow-up in 1 year; and the others were disease free or shifted to second line treatment. We used Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 for adverse events severity evaluation and there was no grade IV adverse event in this study.
Clinical data were evaluated with descriptive statistics. The SWV measurements of the liver parenchyma were expressed as the median for each patient. For the overall values, the values of SWV measurements were expressed as the mean ± standard deviation. A paired t-test was performed for a paired comparison of variables before and 3-6 months after treatment with sorafenib, including SWV measurements and non-invasive serologic indices. A P value < 0.05 was considered to indicate a significant difference. Statistical analysis was performed using the Statistical Package for the Social Sciences (version 19.0, IBM SPSS Statistics, New York, USA).
The baseline clinical characteristics of the 17 patients with advanced HCC are shown in Table 1. The mean age was 59.7 ± 10.2 years, and 14 (82.4%) patients were males. Ten (58.8%) patients had chronic hepatitis B infection, 5 (29.4%) patients had chronic hepatitis C infection and 10 (58.8%) patients had liver cirrhosis. The mean duration of sorafenib treatment was 11.1 months, and the mean survival time was 15.1 months (range: 8.3-19.1 months; 95% confidence interval: 13.3-17.0 months) [Table 1].
Baseline clinical characteristics
|Age, years||59.7 ± 10.2|
|Male, %||14 (82.4)|
|Liver cirrhosis, %||10 (58.8)|
|Albumin, g/dL||4.1 ± 0.4|
|AST, U/L||56.2 ± 37.3|
|ALT, U/L||44.6 ± 24.5|
|Bilirubin, mg/dL||0.8 ± 0.3|
|INR||1.13 ± 0.08|
|Leukocytes, 103/L||6,288.0 ± 2,198.0|
|Hemoglobin, mg/dL||13.5 ± 1.7|
|Platelets, 109/L||171.5 ± 57.2|
|Duration of sorafenib, months||8.5 ± 3.9|
|Survival time, months||11.1 ± 4.0|
The clinical characteristics of the case series are shown in Table 2. Two patients achieved CR, 1 patient achieved PR, 6 patients experienced SD and 8 patients experienced PD after a mean of 2.5 cycles of sorafenib treatment (range 1-4 cycles). The disease control rate, including CR, PR, and SD in the first 2 cycles was 52.9%. A 64-year-old male patient (No. 11) suffered from recurrence of mesentery HCC after the initial surgical resection and achieved a CR after 4 months of sorafenib treatment. A 34-year-old female patient (No. 12) experienced lung metastases 6 weeks after partial hepatectomy. She had a complete pathological response after 9 months of sorafenib treatment. Both patients also had decreased SWV (liver stiffness) during sorafenib treatment, as indicated by ARFI elastography [Table 2]. Of the 9 patients with decreased liver stiffness, all of the reductions of SWV by ARFI elastography were > 10% from baseline, whereas there was no statistical difference in the change in SWV after sorafenib treatment between patients with and without a treatment response (decreased SWV in 5 and 4 patients with and without a treatment response, respectively, P = 1.000).
The clinical characteristics of 17 advanced HCC patients with sorafenib treatment
|No.||Age, years||Gender||Personal history||HBV||HCV||Cirrhosis||Distant metastasis||ARFI elastography, media n, m/s||Dosage (mg)||Staging||Outcome||Treatment cycles||Survival time (months)|
|3||75||Male||Peptic ulcer, chronic lung disease||+||-||Yes||Bone||2.98||1.88||400||IV||PD||2||14.3|
|4||68||Male||DM, HTN||-||-||No||Bone, peritoneum||2.99||1.23||400||IV||PD||2||10.0|
|11||64||Male||Peptic ulcer, HTN||+||-||Yes||Peritoneum||2.65||1.42||600||IV||CR*||3||12.3|
|13||56||Male||Peptic ulcer, HTN||+||-||No||Lymph node||1.29||1.42||600||IV||SD||3||11.6|
|16||69||Male||DM, HTN, chronic lung disease||-||+||Yes||Adrenal gland||2.37||1.71||600||IV||SD||2||8.3|
The paired comparison of SWV, the AAR, the APRI, the FIB-4, and the Lok index between the beginning of sorafenib treatment and the end of treatment with sorafenib is shown in Table 3. The mean SWV was 2.37 ± 0.83 m/s at the beginning of sorafenib treatment, which decreased to 1.90 ± 0.64 m/s 3 months after sorafenib treatment (P < 0.01). However, there were no statistically significant differences in the non-invasive serum markers of AAR (1.39 vs. 1.15, P = 0.05), APRI (1.14 vs. 1.31, P = 0.52), FIB-4 (3.50 vs. 3.65, P = 0.77), and the Lok index (0.63 vs. 0.41, P = 0.30) between the beginning of sorafenib treatment and the end of treatment [Table 3]. The decline of the mean SWV was also significant (2.32 vs. 1.69 m/s, P < 0.05), whereas the differences in the AAR, APRI, FIB-4 and the Lok index were not significant in the 7 patients without cirrhosis. Among the 10 patients with cirrhosis, the mean AAR decreased significantly after sorafenib treatment (1.61 vs. 1.19, P = 0.04). The observed differences in the mean SWV by ARFI elastography, the APRI, the FIB-4 and the Lok index were not statistically significant.
Comparison of SWV, AAR, APRI, FIB-4 and the Lok index at the beginning of sorafenib treatment and 3 to 6 months after sorafenib treatment
|Group||Overall (n = 17)||Cirrhosis (n = 10)||Non-cirrhosis (n = 7)|
|SWV||2.42 ± 0.78||1.91 ± 0.64||< 0.01||2.49 ± 0.76||2.06 ± 0.73||0.06||2.32 ± 0.87||1.69 ± 0.45||< 0.05|
|AAR||1.39 ± 0.64||1.15 ± 0.36||0.05||1.61 ± 0.73||1.19 ± 0.39||0.04||1.10 ± 0.34||1.10 ± 0.36||0.96|
|APRI||1.14 ± 1.05||1.31 ± 0.51||0.52||1.07 ± 1.02||1.48 ± 0.53||0.25||1.24 ± 1.16||1.08 ± 0.39||0.70|
|FIB-4||3.50 ± 2.45||3.65 ± 1.28||0.77||3.89 ± 2.29||4.38 ± 0.86||0.52||2.94 ± 2.74||2.62 ± 1.05||0.69|
|Lok||0.63 ± 1.27||0.41 ± 0.77||0.30||1.16 ± 1.31||0.67 ± 0.65||0.49||-0.13 ± 0.78||0.05 ± 0.83||0.38|
To our knowledge, this investigation is the first study to evaluate the anti-fibrotic effect of sorafenib based on changes in liver parenchymal stiffness using ARFI elastography. The results of the present study showed significantly reduced stiffness of the liver parenchyma based on the SWV after short-term sorafenib treatment (reduction from 2.42 to 1.91 m/s in 3-6 months, P < 0.01), and this trend was observed in both cirrhotic and non-cirrhotic patients [Table 3].
In addition to its clinical application in advanced HCC treatment due to its ability to inhibit tumor-cell proliferation and tumor angiogenesis,[9,10] sorafenib has been demonstrated to have anti-fibrotic effects in vivo and in vitro.[6,11,13] These anti-fibrotic effects have been reported to occur through the inhibition of the Raf/ERK signaling pathway, which reduces HSC proliferation and enhances apoptosis.[6,8,11,13] As observed in the present study, the decline of the mean SWV was suggestive of the attenuation of liver parenchymal stiffness after sorafenib treatment.
Although liver biopsy is a well-known method for assessing liver fibrosis, it is not possible to perform repeated liver biopsy for the assessment of liver fibrosis in patients with advanced HCC because of possible complications and ethical issues. The development of non-invasive methods based on serum markers offers an alternative approach for clinical practice. These markers are classified as direct markers that reflect the pathophysiology of liver fibrogenesis and represent components of the extracellular matrix; indirect markers use routine laboratory data and reflect the consequences of liver damage.[15,25] However, liver biochemistry and platelet counts could change over time in patients with deteriorating advanced HCC, and non-invasive serum markers, such as the AAR, the APRI, the FIB-4 or the Lok index, may be inadequate for assessing liver fibrosis in such patients.
With the advantage of combination with conventional B-mode ultrasound, ARFI technology can be easily used for the evaluation of liver parenchyma free of hepatic tumors, blood vessels and bile ducts, which cannot be achieved by transient elastography (Fibroscan®). Therefore, ARFI elastography may be the better choice among non-invasive methods for evaluating the severity and serial changes of liver fibrosis during sorafenib treatment.
There are some limitations in the present study. First, this study is a case-series study, and the number of patients is small. However, the stiffness of the liver parenchyma was observed to decrease, as indicated by a reduced SWV, after sorafenib treatment. Furthermore, the results of the present study have provided a basis for future prospective large-scale studies that test the anti-fibrotic efficacy of sorafenib in the liver parenchyma. Second, the follow-up duration may be too short to see long-term changes in SWV or the stiffness of the liver parenchyma during sorafenib treatment. Third, no control group was included for comparison. Nevertheless, this study can be viewed as a pilot study to explore the anti-fibrotic effect of sorafenib in patients with advanced HCC.
In conclusion, sorafenib has potential anti-fibrotic effects and efficacy in patients with advanced HCC. Large-scale, long-term, and randomized control studies are needed to confirm the results of this study.
Study design and ARFI evaluation: M.C. Yu, Y.C. Chen
Data collection and manuscript writing: C.F. Hung, D. Liu
Clinical practice for HCC patients as the guideline at this institute: T.H. Wu, C.W. Lee, K.T. Pan, C.T. Wang, H.Y. Chai
This study was supported by the Chang Gung Medical Foundation (CMRPG3D0511-3).
There are no conflicts of interest.
Each patient was informed of the study and gave their consent.
This study was approved by the Institutional Review Board (IRB) of CGMH, Linkou branch (IRB No. 103-1747B).
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