Plasma Biomarkers Refine Risk Stratification in Liver Cancer

SAN FRANCISCO – A simple blood test may improve on systems conventionally used to estimate prognosis in patients with hepatocellular carcinoma, new data suggest.

In a study of nearly 300 patients mainly with advanced hepatocellular carcinoma (HCC), baseline plasma levels of insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) significantly refined the risk stratification seen with the Barcelona Clinic Liver Cancer system, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

As a whole, patients with stage C disease had a median overall survival of 11 months. But when levels of both growth factors were also considered, the population split into four groups having widely differing overall survival, ranging from 3 to 14 months.

"Baseline assessment of both markers – IGF-1 and VEGF – significantly improved the prediction of survival and prognostic stratification of HCC patients," reported lead investigator Dr. Ahmed O. Kaseb. "If the results of forthcoming, large collaborative studies confirm our results, this approach will really be beneficial in stratification of patients in clinical trials, ... guiding therapy decisions, and ultimately improving HCC outcome."

Patients with advanced HCC usually have two pathologic processes going on, he observed. "Really, the hallmark of this disease in the majority of patients is the presence of angiogenesis-driven tumor in addition to liver that is affected by underlying liver condition, specifically cirrhosis."

As both processes affect survival, there is marked heterogeneity among patients whose cancer is of similar stage. "So the challenge that prompted our study was the heterogeneity of patients with advanced HCC," he said.

Systems currently used to stratify the HCC population are limited because they do not capture this heterogeneity well, often fail to incorporate liver reserve, and require biopsies in patients having coagulopathy and thrombocytopenia.

"Therefore, integration of noninvasive biomarkers that would reflect [both] the tumor and the liver condition is really needed," commented Dr. Kaseb, a gastrointestinal oncologist at the University of Texas M.D. Anderson Cancer Center in Houston.

The investigators focused on VEGF, because it is a main mediator of angiogenesis, and IGF-1, because it is synthesized primarily in the liver and circulating levels are lower in chronic liver disease. Hence, high levels of the former might be associated with a more advanced tumor, and low levels of the latter might be associated with more severe cirrhosis.

The 288 patients with HCC studied were participants in an ongoing case-control study at the center that began in 2001 and is the largest in this patient population in the United States. Plasma samples were prospectively collected.

The investigators assessed the impact of adding growth factor levels to the Barcelona Clinic Liver Cancer (BCLC) system and the Cancer of the Liver Italian Program (CLIP) system, the two HCC risk stratification systems most commonly used in Western countries.

About 62% of the patients were aged 60 years or older, and 69% were men. Most had cirrhosis (60%) and a Child-Pugh class of A (72%).

The BCLC staging system stratified the patients into groups having significantly different median overall survival (P less than .0001). It classified two-thirds as having stage C disease, the group that is usually the focus of clinical trials, Dr. Kaseb noted.

This group had a median overall survival of 11 months. But their heterogeneity became apparent when they were stratified according to levels of both IGF-1 (up to 26 pg/mL vs. greater than 26 pg/mL) and VEGF (up to 450 vs. greater than 450 pg/mL).

Median overall survival was 14 months for patients with high levels of both growth factors, 12 months for patients with high IGF-1 and low VEGF levels, 6 months for patients with low levels of both growth factors, and 3 months for patients with low IGF-1 and high VEGF levels (P less than .0006).

Adding the two growth factors to the BCLC system improved on its predictive ability: The concordance index was 0.65 with the system alone vs. 0.68 with system plus growth factors.

In a multivariate analysis with the factors used in the CLIP system, levels of both growth factors independently predicted the risk of death. However, they did not significantly improve on the risk stratification seen with this system.

"I hope I was able to make a strong case for the important role of these two biomarkers in HCC, which will be a step forward toward personalizing therapy for HCC, which is really a cornerstone in improving HCC outcome," concluded Dr. Kaseb.

He reported being a consultant and adviser to Bayer/Onyx, which manufactures sorafenib (Nexavar), currently approved by the Food and Drug Administration for the treatment of unresectable HCC.

SAN FRANCISCO – A simple blood test may improve on systems conventionally used to estimate prognosis in patients with hepatocellular carcinoma, new data suggest.

In a study of nearly 300 patients mainly with advanced hepatocellular carcinoma (HCC), baseline plasma levels of insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) significantly refined the risk stratification seen with the Barcelona Clinic Liver Cancer system, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

As a whole, patients with stage C disease had a median overall survival of 11 months. But when levels of both growth factors were also considered, the population split into four groups having widely differing overall survival, ranging from 3 to 14 months.

"Baseline assessment of both markers – IGF-1 and VEGF – significantly improved the prediction of survival and prognostic stratification of HCC patients," reported lead investigator Dr. Ahmed O. Kaseb. "If the results of forthcoming, large collaborative studies confirm our results, this approach will really be beneficial in stratification of patients in clinical trials, ... guiding therapy decisions, and ultimately improving HCC outcome."

Patients with advanced HCC usually have two pathologic processes going on, he observed. "Really, the hallmark of this disease in the majority of patients is the presence of angiogenesis-driven tumor in addition to liver that is affected by underlying liver condition, specifically cirrhosis."

As both processes affect survival, there is marked heterogeneity among patients whose cancer is of similar stage. "So the challenge that prompted our study was the heterogeneity of patients with advanced HCC," he said.

Systems currently used to stratify the HCC population are limited because they do not capture this heterogeneity well, often fail to incorporate liver reserve, and require biopsies in patients having coagulopathy and thrombocytopenia.

"Therefore, integration of noninvasive biomarkers that would reflect [both] the tumor and the liver condition is really needed," commented Dr. Kaseb, a gastrointestinal oncologist at the University of Texas M.D. Anderson Cancer Center in Houston.

The investigators focused on VEGF, because it is a main mediator of angiogenesis, and IGF-1, because it is synthesized primarily in the liver and circulating levels are lower in chronic liver disease. Hence, high levels of the former might be associated with a more advanced tumor, and low levels of the latter might be associated with more severe cirrhosis.

The 288 patients with HCC studied were participants in an ongoing case-control study at the center that began in 2001 and is the largest in this patient population in the United States. Plasma samples were prospectively collected.

The investigators assessed the impact of adding growth factor levels to the Barcelona Clinic Liver Cancer (BCLC) system and the Cancer of the Liver Italian Program (CLIP) system, the two HCC risk stratification systems most commonly used in Western countries.

About 62% of the patients were aged 60 years or older, and 69% were men. Most had cirrhosis (60%) and a Child-Pugh class of A (72%).

The BCLC staging system stratified the patients into groups having significantly different median overall survival (P less than .0001). It classified two-thirds as having stage C disease, the group that is usually the focus of clinical trials, Dr. Kaseb noted.

This group had a median overall survival of 11 months. But their heterogeneity became apparent when they were stratified according to levels of both IGF-1 (up to 26 pg/mL vs. greater than 26 pg/mL) and VEGF (up to 450 vs. greater than 450 pg/mL).

Median overall survival was 14 months for patients with high levels of both growth factors, 12 months for patients with high IGF-1 and low VEGF levels, 6 months for patients with low levels of both growth factors, and 3 months for patients with low IGF-1 and high VEGF levels (P less than .0006).

Adding the two growth factors to the BCLC system improved on its predictive ability: The concordance index was 0.65 with the system alone vs. 0.68 with system plus growth factors.

In a multivariate analysis with the factors used in the CLIP system, levels of both growth factors independently predicted the risk of death. However, they did not significantly improve on the risk stratification seen with this system.

"I hope I was able to make a strong case for the important role of these two biomarkers in HCC, which will be a step forward toward personalizing therapy for HCC, which is really a cornerstone in improving HCC outcome," concluded Dr. Kaseb.

He reported being a consultant and adviser to Bayer/Onyx, which manufactures sorafenib (Nexavar), currently approved by the Food and Drug Administration for the treatment of unresectable HCC.

SAN FRANCISCO – A simple blood test may improve on systems conventionally used to estimate prognosis in patients with hepatocellular carcinoma, new data suggest.

In a study of nearly 300 patients mainly with advanced hepatocellular carcinoma (HCC), baseline plasma levels of insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) significantly refined the risk stratification seen with the Barcelona Clinic Liver Cancer system, researchers reported at a meeting on gastrointestinal cancers sponsored by the American Society of Clinical Oncology.

As a whole, patients with stage C disease had a median overall survival of 11 months. But when levels of both growth factors were also considered, the population split into four groups having widely differing overall survival, ranging from 3 to 14 months.

"Baseline assessment of both markers – IGF-1 and VEGF – significantly improved the prediction of survival and prognostic stratification of HCC patients," reported lead investigator Dr. Ahmed O. Kaseb. "If the results of forthcoming, large collaborative studies confirm our results, this approach will really be beneficial in stratification of patients in clinical trials, ... guiding therapy decisions, and ultimately improving HCC outcome."

Patients with advanced HCC usually have two pathologic processes going on, he observed. "Really, the hallmark of this disease in the majority of patients is the presence of angiogenesis-driven tumor in addition to liver that is affected by underlying liver condition, specifically cirrhosis."

As both processes affect survival, there is marked heterogeneity among patients whose cancer is of similar stage. "So the challenge that prompted our study was the heterogeneity of patients with advanced HCC," he said.

Systems currently used to stratify the HCC population are limited because they do not capture this heterogeneity well, often fail to incorporate liver reserve, and require biopsies in patients having coagulopathy and thrombocytopenia.

"Therefore, integration of noninvasive biomarkers that would reflect [both] the tumor and the liver condition is really needed," commented Dr. Kaseb, a gastrointestinal oncologist at the University of Texas M.D. Anderson Cancer Center in Houston.

The investigators focused on VEGF, because it is a main mediator of angiogenesis, and IGF-1, because it is synthesized primarily in the liver and circulating levels are lower in chronic liver disease. Hence, high levels of the former might be associated with a more advanced tumor, and low levels of the latter might be associated with more severe cirrhosis.

The 288 patients with HCC studied were participants in an ongoing case-control study at the center that began in 2001 and is the largest in this patient population in the United States. Plasma samples were prospectively collected.

The investigators assessed the impact of adding growth factor levels to the Barcelona Clinic Liver Cancer (BCLC) system and the Cancer of the Liver Italian Program (CLIP) system, the two HCC risk stratification systems most commonly used in Western countries.

About 62% of the patients were aged 60 years or older, and 69% were men. Most had cirrhosis (60%) and a Child-Pugh class of A (72%).

The BCLC staging system stratified the patients into groups having significantly different median overall survival (P less than .0001). It classified two-thirds as having stage C disease, the group that is usually the focus of clinical trials, Dr. Kaseb noted.

This group had a median overall survival of 11 months. But their heterogeneity became apparent when they were stratified according to levels of both IGF-1 (up to 26 pg/mL vs. greater than 26 pg/mL) and VEGF (up to 450 vs. greater than 450 pg/mL).

Median overall survival was 14 months for patients with high levels of both growth factors, 12 months for patients with high IGF-1 and low VEGF levels, 6 months for patients with low levels of both growth factors, and 3 months for patients with low IGF-1 and high VEGF levels (P less than .0006).

Adding the two growth factors to the BCLC system improved on its predictive ability: The concordance index was 0.65 with the system alone vs. 0.68 with system plus growth factors.

In a multivariate analysis with the factors used in the CLIP system, levels of both growth factors independently predicted the risk of death. However, they did not significantly improve on the risk stratification seen with this system.

"I hope I was able to make a strong case for the important role of these two biomarkers in HCC, which will be a step forward toward personalizing therapy for HCC, which is really a cornerstone in improving HCC outcome," concluded Dr. Kaseb.

He reported being a consultant and adviser to Bayer/Onyx, which manufactures sorafenib (Nexavar), currently approved by the Food and Drug Administration for the treatment of unresectable HCC.