Bone metastases from hepatocellular carcinoma:clinical features and prognostic factors

Yang Lu, Jin-Gen Hu, Xiang-Jin Lin and Xi-Gong Li

Hangzhou, China

Bone metastases from hepatocellular carcinoma:clinical features and prognostic factors

Yang Lu, Jin-Gen Hu, Xiang-Jin Lin and Xi-Gong Li

Hangzhou, China

BACKGROUND: Bone metastases (BMs) from hepatocellular carcinoma (HCC) is an increasingly common disease in Asia. We assessed the clinical features, prognostic factors, and differences in outcomes related to BMs among patients with different treatments for HCC.

METHODS: Forty-three consecutive patients who were diagnosed with BMs from HCC between January 2010 and December 2014 were retrospectively enrolled.e clinical features were identified, the impacts of prognostic factors on survival were statistically analyzed, and clinical data were compared.RESULTS:e median patient age was 54 years; 38 patients were male and 5 female.e most common site for BMs was the trunk (69.3%). BMs with extension to the sotissue were found in 14 patients (32.5%). Most (90.7%) of the lesions were mixed osteolytic and osteoblastic, and most (69.8%) patients presented with multiple BMs.e median survival aer BMs diagnosis was 11 months. In multivariate analyses, survival aer BM diagnosis was correlated with Karnofsky performance status (P=0.008) and the Child-Pugh classification(P＜0.001); BM-free survival was correlated with progression beyond the University of California San Francisco criteria(P＜0.001) and treatment of primary tumors (P＜0.001). BMs with extension to sotissue were less common in liver transplantation patients. During metastasis, the control of intrahepatic tumors was improved in liver transplantation and hepatectomy patients, compared to conservatively treated patients.

(Hepatobiliary Pancreat Dis Int 2017;16:499-505)

hepatocellular carcinoma;

bone metastases;

survival;

prognostic factors

Introduction

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer worldwide and the third leading cause of cancer-related death. HCC has a heterogeneous geographical distribution, with most cases (＞80%) occurring in eastern Asia and sub-Saharan Africa.[1]Bone metastases (BMs) from HCC are highly vascularized lesions and cause severe deterioration of the patients' quality of life.e reported incidence of BM from HCC was relatively low before the 20th century.However, bone is now the second major site and accounts for approximately 25% of extrahepatic metastases from HCC.[2-4]is increase is due to the advances of bone imaging technique and the prolonged survival of HCC patients.[5-8]Hepatectomy, radiofrequency ablation, transhepatic arterial chemotherapy and embolization, and tyrosine kinase inhibitors such as sorafenib are effective treatment modalities for HCC.[9]Liver transplantation(LT) has also been established as a promising treatment for malignant liver diseases.[10-12]However, whether these treatments contribute towards the survival of patients with BMs from HCC, and whether they are related to the condition of patients during metastasis, remain unclear.In this study, the clinical features and prognostic factors were investigated in patients with BMs from HCC, and the clinical data were compared among patients with different treatments for intrahepatic tumors.

Methods

Study design

We reviewed the data of 43 consecutive patients diagnosed with BMs from HCC in the First Affiliated Hospital, Zhejiang University School of Medicine betweenJanuary 2010 and December 2014. Sixteen patients underwent LT as treatment for HCC and subsequently developed BMs.e final follow-up date was June 30, 2015,and the median follow-up time was 11 months. None of the patients were enrolled in any clinical trials or experimental protocols.e Institutional Research Ethics Committee approved this retrospective observational study.

All patients diagnosed with BMs from HCC were provided with histological confirmation of the disease via bone biopsy or surgical pathology.99mTc bone scintigraphy was used to locate all possible sites of BM.Magnetic resonance imaging (MRI) or computed tomography (CT) was performed to either confirm or provide detailed information on symptomatic sites.[13]Additional pretreatment evaluation included assessment of the patient's medical history, as well as a physical examination,complete blood routine, serum chemistries, blood gas analysis, alpha-fetoprotein (AFP) level, γ-glutamyl transpeptidase (γ-GT) level, chest X-ray, and abdominal and cardiac ultrasonography.

Statistical analysis

Clinical features were assessed based on descriptive statistics.e impact of prognostic factors on survival was analyzed by the Kaplan-Meier method and tested using the log-rank test. Median survivals were also calculated. Variables were entered using the Backward-Wald method in a Cox regression analysis (the level of statistical significance was set at aPvalue ＜0.05).e features of BMs in patients given different treatments were compared using Fisher's exact test (atP＜0.017). All analyses and calculations were performed using the SPSS statistical soware (version 17.0; SPSS Inc., Chicago, IL, USA).

Results

Clinical features

Of the 43 patients, 38 were male and 5 female, with a median age of 54 years (range 26-83). For the first BM-related event, 28 patients had pain (65.1%), 5 had dysneuria(11.6%), and 4 had a continuous rise in AFP levels (9.3%).Eight patients experienced no clinical symptoms, and their BMs were discovered by follow-up imaging studies of the HCC (18.6%). Five patients were diagnosed with BMs immediately aer HCC diagnosis (11.6%), and 38 developed BMs later on (88.4%).irty patients had multiple BMs (69.8%), 39 presented with mixed osteolytic and osteoblastic lesions (90.7%), 4 presented with purely osteolytic lesions (9.3%), and no patient had a purely osteoblastic lesion. BMs with extension to the sotissue were discovered in 14 patients (32.6%). Of the 101 BM sites, 69.3% were located on the trunk.e lumbar vertebrae (35.3%) were the most common responsible site, followed by the thoracic vertebrae (29.4%) (Table 1).

Table 1.BM sites in the 43 HCC patients (n, %)

All 43 patients were prescribed zoledronic acid.Twenty-two patients underwent palliative EBRT, 3 had curettage, 9 had curettage following EBRT, and 6 underwent wide resection following EBRT.e 1-year survivals for patients with EBRT, curettage, and wide resection were 40.9%, 50.0%, and 33.3%, respectively. Intraosseous recurrence occurred in one patient who had a wide resection.

Outcomes

Seven patients survived until the end offollow-up.Five of them had undergone LT and two had a hepatectomy for the treatment of the primary tumors, and their intrahepatic tumors remained under control since then.Five of these patients were treated with EBRT for BMs and two were treated with curettage. Causes of death included liver failure, tumor progression, or both in 33 patients (91.7%), pulmonary infection in 2 patients (5.6%),and stroke in 1 patient (2.8%).

Table 2.Univariate analysis of predictors in 43 patients

Fig. 1.Survival curves of different surgical modalities for BM.The survival after BM diagnosis was not significantly different(P=0.989).

Fig. 2.Survival curves of different treatments for intrahepatic tumors.e treatment of the primary tumors significantly influenced the BM-free survival (P=0.002).

BM-free survival

Table 3.Comparison offactors among patients who underwent different treatments

Comparison of patients with different treatments for intrahepatic tumors

Discussion

Due to an increased understanding of the interactions between metastatic tumor cells and the bone marrow microenvironment,[29]bone-targeted therapies such as zoledronic acid and denosumab have been used for the prevention of skeletal morbidities associated with malignant bone diseases, particularly in advanced-stage solid tumors arising from the breast, prostate, and multiple myeloma.[30-32]However, the efficiency of these treatments in patients with BMs from HCC has only been reported by several authors.[23,33]Sorafenib may improve patients' survival and affect bone metastasization,[34]but due to financial reasons, only two patients in the present study were treated with it and the treatment time was no longer than 3 months. We hope to recruit more patients treated with sorafenib and provide more clinical data in the future.

Hematogenous spread through the pulmonary circulation or vertebral venous plexus is the paramount approach for the metastasization of HCC to bone.[36,37]Our work demonstrates that larger intrahepatic tumors (＞5 cm in diameter) are a strong predictor for faster metastasization to bone. Furthermore, patients with multiple intrahepatic tumors had a poorer survival aer the diagnosis of BMs.e UCSF criteria and Hangzhou criteria are efficient methods for predicting survival in patients treated with LT,[15]factors that also predicted BM-free survival in this study. In fact, the death of patients with BMs from HCC is mainly due to liver failure or tumor progression.[38]erefore, follow-up examination and treatment of intrahepatic tumors should be thoroughly implemented.

For patients with resectable HCC, surgery is the only proven potentially curative therapy.[9,39]Our work shows that the surgical removal of intrahepatic tumors helps to limit tumor metastasis. With the extensive use of LT in China, the number of LT patients with BMs is increasing in clinical practice. LT patients generally receive immunosuppressants, which will accelerate the recurrence or metastasization of tumors.[40,41]Previous studies have revealed that the presence of BMs is a contraindication for LT as well as an independent unfavorable prognostic factor for LT patients.[42,43]However, in this study, we found that LT patients had a longer BM-free survival and fol-lowed a trend for increased survival aer BM diagnosis,which means that LT is a favorable prognostic factor for BMs from HCC. We compared patients who underwent different treatments for HCC and found that LT patients had better intrahepatic tumor control and that fewer LT patients experienced extension to sotissue. We believe that the smaller tumor burden aer LT may have contributed towards this. Overall, the characteristics of HCC and the treatment of primary tumors were related to the speed of bone metastasization and the patient's prognosis.

A limitation of this study was the small sample size and retrospective nature. Analyses of data on patients with different first BM-related events may introduce bias into the calculated survival intervals because there is a time lapse in diagnosis for patients who present to the hospital due to clinical symptoms compared to those whose BMs are discovered by periodic examination.Meanwhile, the retrospective nature makes it difficult to control the homogeneity of the extent of disease between patients undergoing different treatments.

In conclusion, the independent prognostic factors of survival aer BM diagnosis were the KPS and Child-Pugh classification. HCC patients who went on to develop BMs may also benefit from LT or hepatectomy. A future study with a larger sample size, or a laboratory study into sotissue masses, should be conducted to better prove or illustrate the findings of this study and to explore potential therapeutic targets.

Acknowledgements:We thank Division of Hepatobiliary Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine for providing clinical data of primary tumors. We also thank Dr. Hong-Xun Zhou from University of Western Australia for advice on this article.

Contributors:LXJ proposed the study. LY and HJG performed research and wrote the first dra. LY and HJG collected and analyzed the data. All authors contributed to the design and interpretation of the study to further dras. LY and HJG contributed equally to this study. LXJ is the guarantor.

Funding:e study was supported by grants from Zhejiang Provincial Clinical Scientific Research Foundation of China(2013ZYC-A17), Ministry of Health of China (WKJ-ZJ-12) and Health Bureau of Zhejiang Province (2013KYB098).

Ethical approval:is study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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December 21, 2015

Accepted after revision September 30, 2016

Author Affiliations: Department of Orthopedics, First Affiliated Hospital,Zhejiang University School of Medicine, Hangzhou 310003, China (Lu Y,Hu JG, Lin XJ and Li XG)

Xiang-Jin Lin, MD, Department of Orthopedics,First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Tel/Fax: +86-571-87236848; Email: doclinxj@zju.edu.cn)© 2017, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(16)60173-X

Published online January 25, 2017.