Metastatic Hepatocellular Carcinoma Patients Research Articles

Prognostic Factors in Patients with Advanced Hepatocellular Carcinoma Treated with Sorafenib: A Retrospective Comparison with Previously Known Prognostic Models

Background: Sorafenib, a multitargeted tyrosine kinase inhibitor, is now the treatment of choice for systemic therapy of patients with advanced hepatocellular carcinoma (HCC). Herein, we present the clinical characteristics and outcomes of patients with advanced HCC who were treated with sorafenib. Methods: Data of 201 sorafenib-treated, metastatic HCC patients were collected from a single institution tumor registry. The primary and secondary endpoints were overall survival (OS) and failure-free survival (FFS). Results: Chronic hepatitis B was the predominant cause of HCC (84%). Of 162 evaluable patients, 4 partial responses were recorded. With a median follow-up of 15.7 months, the median FFS and OS were 2.5 months (95% CI 2.3–2.7) and 5.3 months (95% CI 4.4–6.3), respectively. In multivariate analysis, the prognostic factors associated with FFS were the presence of ascites, portal venous thrombosis, serum α-fetoprotein ≧400 ng/ml, albumin, bilirubin, tumor size and number, and performance status. Likewise, the presence of ascites, portal venous thrombosis, tumor size and number, performance status and baseline levels of α-fetoprotein, albumin and bilirubin were significantly related with OS. After adjusting for performance status, the Cancer of the Liver Italian Program scoring system and Okuda stages can better predict the hazard of failure or death than the Child-Pugh classification. Conclusions: Our results suggest that Cancer of the Liver Italian Program scores or Okuda stages, along with performance status, can be useful in stratifying patients with advanced HCC treated with sorafenib.

MAGE-3 and MAGE-4 genes as possible markers for early detection of metastases in hepatitis C virus Egyptian patients complicated by hepatocellular carcinoma

The dissemination of hepatocellular carcinoma (HCC) cells into the circulation plays a critical role in post-operative recurrence and metastasis. Early detection of metastatic tumor cells is critical to identify HCC patients at high risk of relapse. MAGE-3 and -4 genes were evaluated by reverse transcription polymerase chain reaction for the possibility of using them as new markers for early detection of metastases in 160 chronic HCV Egyptian patients, 115 of them were complicated with HCC. The expressions of MAGE-3 and MAGE-4 mRNA in peripheral blood of patients with metastatic HCC were 36 and 52%, respectively. While the expressions of MAGE-3 and MAGE-4 mRNA in peripheral blood of patients with localized HCC were 12.5 and 15%, respectively. Moreover, at least one type of mRNA was found in the peripheral blood of 68% of the metastatic HCC patients and in 20% of the localized HCC patients. While neither the controls nor the cirrhotic patients show expression of MAGE-4 mRNA in their peripheral blood. MAGE-3 and MAGE-4 may be a promising diagnostic tool for monitoring the prognosis of HCC patients and early detection of occult hematogenous metastasis of HCC.

Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib: A comparison with previously known prognostic models.

323 Background: Sorafenib, a multiple-targeted tyrosine kinase inhibitor, is now the treatment of choice for systemic therapy of patients with advanced hepatocellular carcinoma (HCC). Herein we present the clinical characteristics and outcomes of patients with advanced HCC who were treated with sorafenib. Methods: Data of 201 sorafenib-treated, metastatic HCC patients were collected from a single institution tumor registry. The primary and secondary endpoints were overall survival (OS) and failure-free survival (FFS). Results: Chronic hepatitis B was the predominant cause of HCC (84%).Of 162 evaluable patients, four partial responses were recorded. With a median follow-up of 15.7 months, the median FFS and OS were 2.5 months (95% confidence interval [CI], 2.3-2.7 months) and 5.3 months (95% CI, 4.4-6.3 months), respectively. In multivariate analysis, the prognostic factors associated with FFS were the presence of ascites, portal venous thrombosis, serum alpha- fetoprotein (AFP) ≥400 ng/mL, albumin, bilirubin, tumor size and number, and performance status. Likewise, the presence of ascites, portal venous thrombosis, tumor size and number, performance status, and baseline levels of AFP, albumin and bilirubin were significantly related with OS. After adjusting for performance status, the Cancer of the Liver Italian Program (CLIP) scoring system and Okuda stages can better predict the hazard of failure or death than Child-Pugh classification. Conclusions: Our results suggest that CLIP scores or Okuda stages, along with performance status, can be useful in stratifying patients with advanced HCC treated with sorafenib. No significant financial relationships to disclose.

Studying circulation times of liver cancer cells by in vivo flow cytometry

Hepatocellular carcinoma (HCC) may metastasize to lung kidney and many other organs. The survival rate is almost zero for metastatic HCC patients. Molecular mechanisms of HCC metastasis need to be understood better and new therapies must be developed. A recently developed "in vivo flow cytometer" combined with real-time confocal fluorescence imaging are used to assess spreading and the circulation kinetics of liver tumor cells. The in vivo flow cytometer has the capability to detect and quantify continuously the number and flow characteristics of fluorescently labeled cells in vivo in real time without extracting blood sample. We have measured the depletion kinetics of two related human HCC cell lines high-metastatic HCCLM3 cells and low-metastatic HepG2 cells which were from the same origin and obtained by repetitive screenings in mice. >60% HCCLM3 cells are depleted within the first hour. Interestingly the low-metastatic HepG2 cells possess noticeably slower depletion kinetics. In comparison <40% HepG2 cells are depleted within the first hour. The differences in depletion kinetics might provide insights into early metastasis processes.

Clinical outcome of 251 patients with extrahepatic metastasis at initial diagnosis of hepatocellular carcinoma: Does transarterial chemoembolization improve survival in these patients?

The therapeutic efficacy of transarterial chemoembolization (TACE) has not been evaluated in hepatocellular carcinoma (HCC) patients with extrahepatic metastasis. We investigated the efficacy of TACE with/without systemic chemotherapy (s-chemo) in these patients. We performed a survival analysis of consecutive HCC patients with extrahepatic metastasis, diagnosed at initial presentation according to treatment modality after stratification, using the Child-Pugh classification and intrahepatic HCC T stage, retrospectively. Between 2005 and 2007, 251 patients were newly diagnosed with HCC involving extrahepatic metastasis at our institution. Among those, 226 were classified as Child-Pugh A-B and the other 25, Child-Pugh C. Within the Child-Pugh A-B group, repeated TACE or transarterial chemoinfusion (TACI) was performed with/without s-chemo in 171 patients. Eight of 226 received s-chemo alone, and 47, conservative management (CM) alone. The median survival time of patients treated with TACE/TACI with s-chemo, TACE/TACI alone, and CM was 10, 5, and 2.9 months in patients classified as Child-Pugh A and T3-stage HCC (TACE/TACI with s-chemo vs CM, P=0.0354; TACE/TACI alone vs CM, P=0.0553) and 7.1, 2.6, and 1.6 months in Child-Pugh B and T3-stage patients, respectively (TACE/TACI with s-chemo vs CM, P=0.0097; TACE/TACI alone vs CM, P<0.0001). Individual treatment with TACE/TACI or sorafenib showed independent prognostic significance in the multivariate analysis. Repeated TACE could show significant survival benefits in metastatic HCC patients with conserved liver function and intrahepatic HCC T3 stage. The survival data of our study could be used as a historical control for TACE monotherapy in future clinical trials evaluating combination treatments containing TACE in these patients.

Circulation times of hepatocellular carcinoma cells by in vivo flow cytometry

Hepatocellular carcinoma (HCC) may metastasize to many organs. The survival rate is almost zero for metastatic HCC patients. Molecular mechanisms of HCC metastasis need to be understood better and new therapies must be developed. We have developed the

Detection of circulating tumor cells (CTCs) in patients with hepatocellular carcinoma (HCC)

15037 Background: Allard et al. (2004) has established the accuracy, sensitivity, reliability and linearity of circulating tumor cells (CTCs) detection using the CellSearch System. 57% prostate cancers, 37% breast cancers, 37% ovarian cancers, 30% colorectal cancers, and 20% lung cancers specimens had &gt;= 2 CTCs per 7.5 mL of blood. Only 0.3% healthy non-malignant disease subjects had &gt;= 2 CTCs per 7.5 mL of blood. Cristofanilli et al.(2004,2005) have shown that CTCs at baseline and first follow-up were a significant prognostic factor for survival in metastatic breast cancer patients. However, HCC data on CTCs are not available. Methods: 20 locally advance or metastatic HCC patients who had not received prior treatment had been recruited after informed consent and 7.5 mL of blood were collected using the CellSave Preservative tubes (Veridex LLC, Raritan, NJ) that prevents CTCs degradation. The CellSearch system (Veridex LLC) similar to the previous studies was used to analyze the specimen. The CellSearch system consists the CellPrep system, the CellSearch Epithelial Cell Kit, and the CellSpotter Analyzer. All the procedures and interpretation of results followed closely with the quality control procedure of Veridex LLC including accreditation of trained laboratory personnel. Results: 13/20 (65%) had locally advanced disease and the rest had metastatic HCC. All patients had multiple lesions. 9/20 (45%) patients had detectable CTCs, 7/20 (35%) had &gt;= 2 CTCs, and about 5/20 (20%) had 5 or more CTCs. For locally advanced HCC 4/13 (31%) patients had &gt;= 2 CTCs per 7.5 mL of blood. For HCC patients with metastatic diseases 3/7 (43%) patients had &gt;= 2 CTCs per 7.5 mL of blood. Conclusions: HCC patients with locally advance or metastatic disease had detectable CTCs in 7.5 mL of blood. We expected that the performance of CTCs in HCC is similar to that of breast cancer. Future study of using CTCs as prognostic factor at baseline and during treatment for HCC is being planned. No significant financial relationships to disclose.

Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment

Hepatocellular carcinoma (HCC) is an aggressive malignancy mainly due to metastases or postsurgical recurrence. We postulate that metastases are influenced by the liver microenvironment. Here, we show that a unique inflammation/immune response-related signature is associated with noncancerous hepatic tissues from metastatic HCC patients. This signature is principally different from that of the tumor. A global Th1/Th2-like cytokine shift in the venous metastasis-associated liver microenvironment coincides with elevated expression of macrophage colony-stimulating factor (CSF1). Moreover, a refined 17 gene signature was validated as a superior predictor of HCC venous metastases in an independent cohort, when compared to other clinical prognostic parameters. We suggest that a predominant humoral cytokine profile occurs in the metastatic liver milieu and that a shift toward anti-inflammatory/immune-suppressive responses may promote HCC metastases.

Thalidomide for Treating Metastatic Hepatocellular Carcinoma: A Pilot Study

BackgroundThalidomide has been reported to have antitumor activity for treating metastatic hepatocellular carcinoma (HCC). We evaluated the safety and efficacy of using thalidomide for treating selected patients with unresectable or metastatic HCC, and their disease was refractory to systemic chemotherapy.MethodsEight patients with measurable and metastatic HCC that had progressed with prior systemic chemotherapy and who desired further active therapy were enrolled in this study. Thalidomide was given orally at bedtime and it was started at 200 mg/day with no further dose escalation. The response was measured at 2-month intervals.ResultsThe median age was 44 years (range: 34-52 years) and all the patients had received doxorubicin-based systemic chemotherapy prior to their enrollment. Each patient received thalidomide for a median of 152 days (range: 5-422 days). One partial response was observed (12.5%, 95% CI; 0-42%) along with 4 cases of stable diseases. The most commonly encountered toxicity was somnolence; grade 3 somnolence was noted for one patient, which led to treatment discontinuation. Skin rash was observed in one responding patient.ConclusionsThe results indicate that thalidomide may feasibly offer disease stabilization to metastatic HCC patients. Further dose escalation of thalidomide, or its combination with other chemotherapeutic agents, may be of interest and this should be investigated for treating patients with metastatic HCC.

Prognosis of patients with metastatic hepatocellular carcinoma (HCC)

4127 Background: There has been no study regarding the long-term survival of a large number of metastatic HCC patients. The current study was conducted to clarify their prognostic factor. Methods: We surveyed 196 consecutive patients with metastatic HCC admitted to our hospital. We divided patients into subgroups according to their backgrounds, and compared survival times to determine favorable prognostic factors. We also analyzed relationship between the cause of death and site of metastasis. Results: The top 4 sites of the first metastasis were the lung in 78 patients, the bone in 69, an abdominal lymph node in 42, and the adrenal gland in 22. The first additional treatment after metastasis was observation in 58, surgery in 35, systemic chemotherapy in 14, transcatheter arterial chemoembolization in 41, and radiotherapy in 48. The median survival time and 1-, 3-, and 5-year survival rates were 4.5 months, and 31.1%, 9.7%, and 3.8%, respectively. Good performance status, good hepatic reserve, low alpha-fetoprotein, no bone metastasis, and low T factor were shown to be favorable significantly in survival time. Although 84% of the patients died of hepatic cause, patients with lung and bone metastasis tended to die due to lung metastasis and cachexia, respectively. Conclusion: The prognosis of metastatic HCC patients was generally poor, however, there were long survivors among them. Their prognosis corresponded well to intrahepatic factors, i.e., primary cancer status and hepatic reserve. No significant financial relationships to disclose.

A decade's studies on metastasis of hepatocellular carcinoma.

Metastasis remains one of the major challenges before hepatocellular carcinoma (HCC) is finally conquered. This paper summarized a decade's studies on HCC metastasis at the Liver Cancer Institute of Fudan University. We have established a stepwise metastatic human HCC model system, which included a metastatic HCC model in nude mice (LCI-D20), a HCC cell line with high metastatic potential (MHCC97), a relatively low metastatic potential cell clone (MHCC97L) and several stepwise high metastatic potential cell clones (MHCC97H, HCCLM3, and HCCLM6) from their parent MHCC97 cell. Endeavors have been made for searching human HCC metastasis-related chromosomes/proteins/genes. Monogene-based studies revealed that HCC invasion/metastasis was similar to that of other solid tumors, and the biological characteristics of small HCC were only slightly better than that of large HCC. Using comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), genotyping, cDNA microarray, and 2-dimensional gel electrophoresis, we obtained some interesting results. In particular, in collaboration with the National Institute of Health (NIH) in the United States, we generated a molecular signature that can classify metastatic HCC patients, identified osteopontin as a lead gene in the signature, and found that genes favoring metastasis progression were initiated in the primary tumors. We also found that chromosome 8p deletion, particularly in the region of 8p23, was associated with HCC metastasis. Cytokeratin 19 was identified as one of the proteins, which was found in MHCC97H, but not in MHCC97L cells. Experimental interventions using the high metastatic nude mice model have provided clues for the prevention of HCC metastasis. Translation from workbench to bedside demonstrated that serum VEGF, microvessel density, and p53 scoring may be of value for the prediction of postoperative metastatic recurrence. Interferon alpha proved effective for the prevention of recurrence both experimentally and clinically. In conclusion, HCC metastasis that probably initiated in the primary tumor is a multigene-involved, multistep, and changing process. The further elucidation of the mechanism underlying HCC metastasis will provide a more solid basis for the prediction and prevention of the metastatic recurrence of HCC.