New study finds advanced liver cancer patients live longer by taking anti-cancer drug sorafenib

24 july 2008--Researchers at Mount Sinai School of Medicine in New York have found that sorafenib (Nexavar) helps patients with advanced liver cancer live about 44 percent longer compared with patients who did not receive the anti-cancer drug. The findings, published in the July 23rd, 2008 issue of the New England Journal of Medicine, is a significant advance in the management of liver cancer, which is the third cause of cancer death globally, often resulting in death within a year of diagnosis.
"This is the first time that we've had an effective systemic treatment for liver cancer," said Josep Llovet, MD, Director of Research in Liver Cancer at Mount Sinai School of Medicine in New York, and a Professor at the Barcelona Clinic Liver Cancer (BCLC) Group in Barcelona, Spain and lead author of the study. "Our findings demonstrated survival advantages that are both statistically significant and clinically meaningful."
Sorafenib, a tablet that is taken orally, is approved in the United States for treating a form of advanced kidney cancer, and is currently being evaluated in patients with other cancers. Some 40 percent of liver cancers (and up to 80 percent in Asia and sub-Saharan Africa) are diagnosed at an advanced stage. Therapy for advanced liver cancer may include surgery (if possible), radiation therapy and/or regional chemotherapy (delivered directly into the liver). However, no systemic treatment—anti-cancer medication that enters the bloodstream, either as an oral or intravenous medicine—has proven effective to date for advanced liver cancer.
Dr. Llovet and his associates examined overall survival and the time it took for cancer to grow among patients with previously untreated liver cancer who were randomly assigned to receive either 400 mg of sorafenib twice daily (299 patients) or a placebo (303 patients).
Patients who received sorafenib lived a median of 10.7 months compared with 7.9 months for those who received a placebo. Time to cancer progression was also significantly longer in the treatment group: 5.5 vs. 2.8 months. Due to the positive findings, the study was terminated early.
The incidence of adverse side effects was similar between the two groups (52 percent in the sorafenib group and 54 percent for placebo). The most common moderate to serious side effects were diarrhea (11 percent vs. 2 percent), skin reactions in the hands and feet (8 percent vs. 1 percent), fatigue (10 percent vs. 15 percent) and bleeding (6 percent vs. 9 percent).

Sorafenib (Nexavar) Okayed for Inoperable Liver Cancer


ROCKVILLE, Md., Nov. 20 -- The FDA has given sorafenib (Nexavar) an indication for unresectable hepatocellular carcinoma on the basis of a three-month survival edge and improved time to progression.
The drug, an oral kinase inhibitor, was previously approved two years ago for advanced renal cell carcinoma.
The significant improvements in survival and time to progression that led to approval were demonstrated by an international, multicenter, randomized, double-blind, and placebo-controlled trial, the agency said.
"This is an important new treatment option for patients who are fighting this very difficult form of cancer," said Robert Justice, M.D., director of FDA's division of oncology drug products.
"The group of patients with inoperable hepatocellular carcinoma who received Nexavar survived 2.8 months longer than the group of patients who didn't receive the drug," Dr. Justice said.
That trial, involving 602 volunteers, was stopped early following a planned interim analysis, which showed a statistically significant survival advantage for sorafenib -- a median of 10.7 versus 7.9 months. The hazard ratio was 0.69, with a 95% confidence interval from 0.55 to 0.87, which was significant at P=0.00058.
The trial also showed time to progression was significantly improved in the sorafenib arm -- a median of 5.5 months versus 2.8. The hazard ratio was 0.58, with a 95% confidence interval from 0.45 to 0.74, which was significant at P=0.000007.
The most common drug-related adverse reactions -- seen in more than 20% of volunteers -- were fatigue, weight loss, rash or desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea, and abdominal pain.

Nexavar Approved for Liver Cancer

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MONDAY, Nov. 19 (HealthDay News) -- The Bayer anticancer drug Nexavar (sorafenib) has been approved by the U.S. Food and Drug Administration to treat the most common form of liver cancer that can't be surgically removed, medically called unresectable hepatocellular carcinoma (HCC), the drug maker said Monday.
In 2005, Nexavar was approved to treat advanced kidney cancer. It's among a newer class of drugs called kinase inhibitors, which target enzymes that spur tumor cell growth.
HCC is responsible for about 90 percent of malignant liver tumors, Bayer said in a statement. Liver cancer is the world's sixth most common form of cancer, with roughly 600,000 cases diagnosed globally each year, including 19,000 annually in the United States.
In clinical testing, Nexavar improved overall survival by 44 percent among people with HCC. Median overall survival was 10.7 months among those treated with the drug, versus 7.9 months among those who took a placebo, Bayer said.
More information
The FDA has more information about this drug.

AACR-NCI-EORTC: Sunitinib Shows Early Promise in Liver Cancer

SAN FRANCISCO, Oct. 26 -- Sunitinib (Sutent) appears to be effective in advanced hepatocellular cancer, according to a small study.A preliminary analysis showed antitumor activity, including an average 39% decrease in tumor blood vessel permeability after two weeks of sunitinib therapy, Andrew X. Zhu, M.D., Ph.D., of Massachusetts General Hospital Cancer Center and Harvard, and colleagues, reported here at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.
Although it is too early to say whether the findings are relevant to inhibition of the tumor itself, Dr. Zhu called them "very, very encouraging."
"We know that hepatocellular carcinoma is very vascular," Dr. Zhu said. "We have actually postulated that antiangiogenesis may be a very important strategy to inhibit the cancer growth in this type of malignancy."
Hepatocellular cancer has been associated in previous studies with increased levels of angiogenic factors, which sunitinib is designed to block.
Sunitinib is FDA approved only for treatment of advanced renal cell carcinoma and gastrointestinal stromal tumor, and a similar receptor tyrosine kinase inhibitor, sorafenib (Nexavar), is under review by the FDA for treatment of hepatocellular carcinoma after demonstrating improved survival in clinical trials.
So, the researchers evaluated efficacy, toxicity, and angiogenic parameter changes with sunitinib among 31 patients with unresectable or metastatic measurable hepatocellular carcinoma who had undergone no more than one prior chemotherapy regimen and had adequate organ function.
Participants in the phase II study received sunitinib at 37.5 mg a day for four weeks followed by a standard six-week cycle regimen. They were evaluated with dynamic contrast-enhanced MRI and multiplex protein array.
After an average follow-up of 15 months from enrollment, the average progression-free survival was four months. This is "in the same neighborhood" as the 4.5-month median progression-free survival seen in the trial of sorafenib for hepatocellular carcinoma, Dr. Zhu said.
Cancer stabilized in 10 patients for at least three months, and one patient had a partial response.
There were also preliminary signs of antiangiogenic activity in the subset of patients who were evaluated for these endpoints.
Vascular endothelial growth factor (VEGF) levels had increased in 14 of 18 patients on day 15. Levels of placental growth factor (PIGF) increased in all 18 patients.
However, the basic fibroblast growth factors were decreased in 11 patients on day 15. VEGFR2 was also decreased in 14 of 15 patients. Viable circulating progenitor cells evaluated by flow cytometry in fresh whole blood samples were also decreased (P<0.01), which "may affect angiogenesis more profoundly," Dr. Zhu said.
"The key for us is determining whether any of the changes are relevant to the antiangiogenesis pathway," he said.
The treatment was generally well tolerated, he added, with less than 20% of patients experiencing grade 3 toxicity in any category. These included 16% leukopenia, 16% lymphopenia, 10% fatigue, 19% elevated aspartate transaminase (AST), 6% elevated alanine transaminase (ALT), 6% skin rash, 6% hand-foot syndrome, and 6% thrombocytopenia.
The only grade 4 toxicity was thrombocytopenia in 6% of patients.
"Sunitinib administered in the current dose schedule can be safely given with close monitoring in the majority of hepatocellular carcinoma patients," the researchers said.
"Sunitinib clearly is modifying the disease in this specific patient population," Dr. Zhu concluded. But, he noted, "whether this drug will eventually prove to be effective in hepatocellular carcinoma clearly requires rigorous testing in future large studies."
The study was funded by Pfizer, manufacturer of sunitinib. Dr. Zhu reported no relevant conflicts of interest. Primary source: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
Source reference: Zhu AX, et al "Efficacy, safety, and changes in angiogenic markers following sunitinib monotherapy in patients with advanced hepatocellular carcinoma: Experience from a phase II study" AACR-NCI-EORTC meeting 2007; Abstract PR7.

Glycan Test May Aid Diagnosis of Liver Cancer

GHENT, Belgium, Aug. 9 -- Noninvasive serum N-glycan profiling might unmask undiagnosed hepatocellular carcinoma in HBV-infected patients with cirrhosis, investigators here said.
Analysis of two different N-glycans found that one was elevated in patients with hepatocellular carcinoma and the other was elevated in patients with cirrhosis, Cuiying Chen, Ph.D., of Ghent University, and colleagues reported in the August issue of Hepatology.
The log ratio of the two peaks distinguished between patients with liver cancer, cirrhosis or fibrosis, and healthy controls, they said.
About 60% to 80% of liver cancers are preceded by cirrhosis, so screening cirrhosis patients for early-stage carcinoma could reduce mortality, the authors noted.
Imaging techniques used to diagnose hepatocellular carcinoma cannot distinguish between it and benign hepatic lesions. Serum α-fetoprotein (AFP) is widely used in the diagnosis, but the sensitivity and specificity of the test vary greatly.
Because serum N-linked glycoproteins are synthesized by the liver and B-lymphocytes, changes in serum total N-glycans could reflect changes in liver or B-lymphocyte physiology, the authors hypothesized.
Altered N-linked sugar chains occur in various types of tumors, providing a rationale to evaluate serum N-glycan fingerprinting as a means to diagnose cancer in patients with cirrhosis induced by hepatitis-B infection, they said.
So they examined the diagnostic potential of N-glycan profiling in 440 HBV-infected patients from four hospitals in China. The study population comprised 143 patients with liver fibrosis, 80 patients with cirrhosis alone, and 147 patients with cirrhosis and hepatocellular carcinoma. Liver cancer was diagnosed by various means, including biopsy, autopsy, surgical specimens, imaging studies, and AFP measurement.
The investigators examined the N-glycan profile by means of DNA sequencer-assisted fluorophore-assisted carbohydrate electrophoresis (DSA-FACE). Blood samples from 130 healthy volunteers served as a control. Each peak in the profile from the patients was quantified and compared against the peaks of the control group.
To be able to detect cancer against a cirrhosis background, "we focused on identifying glycan structures whose abundance would not increase in patients with cirrhosis but would be elevated in [cancer] patients," the authors stated.
They found that one peak (NA3Fb, peak 9) was significantly elevated in patients with carcinoma (P<0.0001). A second peak (NA2FB, peak 7) was significantly lower in cancer patients than in patients with cirrhosis (P<0.0001).
Moreover, they said, the log ratio (peak 9/peak 7) was significantly elevated in patients with cancer compared with cirrhosis patients, fibrosis patients, and controls (P<0.0001).
By means of receiver operating characteristic curve analysis, Dr. Chen and colleagues determined that the log ratio (peak 9/peak 7), which they have named the GlycoHCCTest, could distinguish hepatocelllular cancer patients from those with cirrhosis with 81% accuracy.
The accuracy of the test compared favorably with the 78% diagnostic accuracy of AFP, they noted. Moreover, a cutoff value of -0.34 identified liver cancer with 88% specificity and 57% sensitivity, similar to the values associated with AFP at a cutoff of 100 ng/ml. The test generated a constant value in the patients with fibrosis, regardless of stage, indicating specificity for cancer.
The concentration of the two glycans and the log ratio (peak 9/peak 7) predicted tumor stage.
Dr. Chen and colleagues subsequently defined their test as the ratio of the two glycans. According to information provided by the Flanders Interuniversity Institute of Biotechnology (a research institute affiliated with Ghent and three other Belgian universities), the N-glycan profile test detects about 50% of hepatocellular carcinomas that are missed by AFP. Using the tests in tandem results in diagnostic accuracy exceeding that of either test alone.
The investigators reported no potential conflicts. The study was supported by Ghent University, the Flanders-China Bilateral Project, and a Marie Curie Excellence Grant. Primary source: HepatologySource reference: Liu XE et al. "N-glycomic changes in hepatocellular carcinoma patients with liver cirrhosis induced by hepatitis B virus." Hepatology 2007;46:epub.

Scientists develop new test for liver cancer

Wed Aug 8, 1:01 PM ET
A simple blood test can detect early stage liver cancer and more accurately diagnose a disease that is a major killer in Asia and Africa, researchers said on Wednesday.
Current tests include biopsies, imaging and the so-called AFP test in which doctors can detect malignant tumors based on the concentration of particular substances -- called markers -- in the blood.
But those methods are not as sensitive as the new test that can also indicate whether a tumor is in the early or latter stages and offers patients a better chance at survival, said Chitty Chen, a researcher at the Flanders Institute for Biotechnology and Ghent University in Belgium, who led the study.
"When you have liver cancer you do not have symptoms in the early stages," Chen said in a telephone interview. "Once you have symptoms your liver dysfunctions and it is often too late for treatment."
Liver cancer kills nearly 700,000 people each year, mainly in Africa and Asia which have a high prevalence of hepatitis infections that cause the disease.
In the study, published in the journal Hepatology, the researchers developed a simple blood test to detect changes in sugars attached to proteins that occur in liver cancer, Chen said.
The researchers, who included scientists from Beijing and Shanghai Universities in China, also showed they could determine the size of the tumor based on the amount of two particular sugar groups that appeared in the proteins, she said.
When used in conjunction with the AFP test, the new method was more accurate and represents a more powerful tool to better detect liver cancer and save lives by getting patients earlier treatment, she added.
"If you use them together, you increase the effectiveness of the test," Chen said. "The best is to use them together."

Analysis Validates Reduced Risk of Liver Cancer by Coffee Drinking

MILAN, Italy, Aug. 2 -- The oft-reported inverse relationship between coffee and liver cancer is real, but the reasons for it remain unclear, researchers here said.
A meta-analysis of 10 studies with quantitative estimates of coffee drinking found a 41% reduction of liver cancer risk among coffee drinkers compared with rates for non-drinkers, Francesca Bravi, Sc.D., of the Instituto di Ricerche Farmacologiche Mario Negri, and colleagues, reported in the August issue of Hepatology.
Several studies have reported a potentially favorable effect of coffee on liver enzymes, cirrhosis, and hepatocellular carcinoma, while others have shown decreasing risk with the number of cups a day consumed, the researchers wrote.
To get an overall quantitative estimate of the association, the researchers undertook a meta-analysis of studies including 2,260 patients with hepatocellular carcinoma in six case-control studies in southern Europe, where coffee is a favorite drink, and Japan (1,551 cases), where coffee drinking is less frequent. There were also four cohort studies in Japan (709 cases).
Interestingly, the definition of high coffee consumption included drinking three or more cups a day in Europe but only one or more in Japan, yet reduced risks were similar in both regions
The overall relative risk for coffee drinkers versus non-drinkers was 0.59 (95% confidence interval 0.49-0.72), the meta-analysis found.
The RR in case-control studies for coffee drinkers versus non-drinkers was 0.54 (CI 0.38-0.76), and for cohort studies 0.64 (CI 0.56-0.74).
Analyzed by actual consumption, the increase of one cup of coffee a day amounted to a decreased overall risk of 23% (RR 0.77, CI 0.72-0.82), the researchers reported.
Analyzed by case-control and cohort studies, the RR from case- control studies for an increase of one cup of coffee per day was 0.77 (CI 0.72-0.83) and for cohort studies, the RR was 0.75 (CI 0.65-0.85).
The overall relative risk for low or moderate coffee drinkers was 0.70 (CI 0.57-0.85). For high-quantity drinkers (three or more cups a day in Europe), the RR was 0.45 (CI 0.38-0.53).
The consistency of an inverse relation between coffee drinking and the risk of liver carcinoma across the two study designs and various geographic areas weighs against a major role of bias or confounding, the researchers said.
However, they added, the inverse relationship observed may in fact be spurious and may be due to the fact that patients with a broad spectrum of digestive-tract diseases, liver disorders, and cirrhosis may reduce their coffee consumption, even though it is not routinely recommended.
The researchers noted that animal models and cell-culture systems have indicated that some coffee compounds including diterpenes, cafestol, and kahweol, may act as blocking agents by modulating enzymes involved in carcinogenic detoxification.
Other components of coffee, including caffeine and antioxidant substances in coffee beans, have been shown to have favorable effects on liver enzymes.
The beneficial effect of coffee on liver cancer may also result from its inverse relationship with cirrhosis, although a clinical history of cirrhosis did not totally account for this, the researchers added. Nevertheless, they said, there seems to be a continuum for the favorable effect of coffee on liver enzymes, cirrhosis, and hepatocellular carcinoma.
Discussing the study's limitations, the researchers wrote that it is difficult to derive a causal inference on the basis of observational studies alone. The patients with digestive disorders may have reduced their coffee consumption, and, in addition, the assessment of coffee drinking was based on patients' self-reports.
However, allowance for other confounding factors, such as hepatitis B and C, cirrhosis, social class, alcohol use, and smoking, suggests that such factors did not influence the results, the researchers said.
No financial conflicts were reported. The study was supported by the Italian Association for Cancer Research, the Italian League Against Cancer, and the Italian Ministry of Research. Dr. Bravi is a Fellow of the Rosario Samanin Fund.Additional source: HepatologySource reference: Bravi F, et al "Coffee Drinking and Hepatocellular Carcinoma Risk: A Meta-Analysis" Hepatology 2007; 46: 430-435.

Study: Liver cancer breakthrough found

For the first time, doctors say they have found a pill that improves survival for people with liver cancer, a notoriously hard to treat disease diagnosed in more than half a million people globally each year.
The results in a multinational study of 602 patients with advanced liver cancer are impressive and likely will change the way patients are treated, cancer specialists including the study authors say.
Patients got either two tablets daily of a drug called sorafenib or dummy pills in the study, which started in March 2005. Some patients are still alive, although on average, sorafenib patients survived 10.7 months versus almost 8 months for those on dummy pills.
That type of survival advantage "has never happened" with liver cancer "and is a major breakthrough in the management of the disease," said Dr. Josep Llovet, the lead author.
"That may not sound like a lot of time," but for liver cancer, "this is actually a quite impressive gain," said Dr. Nancy Davidson of Johns Hopkins' Bloomberg School of Public Health. "It is the first effective systemic treatment for liver cancer, which is such a huge problem internationally."
Sorafenib attacks cancer with a targeted double-barreled approach. It zeros in on malignant cells themselves and cuts off the blood supply feeding the tumor. It is believed to work on tumors within the liver and those that have spread elsewhere.
In the study, tumors didn't shrink or disappear but in many cases they also didn't grow.
"You are not curing the disease but you are delaying the progression of the disease significantly and strikingly," said Llovet, of Mount Sinai School of Medicine in New York and Hospital Clinic of Barcelona, Spain.
The study was halted early, in February, because of the good results, and patients on dummy pills were switched to sorafenib.
"This is a very good step forward in this disease," said Dr. Emily Chan of Vanderbilt-Ingram Cancer Center in Nashville, Tenn.
Results were prepared for release Monday in Chicago at the American Society of Clinical Oncology's annual meeting.
The drug, sold under the brand name Nexavar, is approved in the United States and dozens of other countries to treat advanced kidney cancer. It is marketed by Bayer Pharmaceuticals Corp. and Onyx Pharmaceuticals Inc., which funded the liver cancer study. They hope to receive approval for liver cancer use from U.S. and foreign regulators.
Llovet has done consulting for the sponsors.
Liver cancer is diagnosed in about 19,000 Americans annually but is much more common elsewhere and is the fifth most common cancer globally. Risk factors include chronic liver infections and some forms of hepatitis. The disease is common in China and countries without widespread use of the hepatitis B vaccine, which is routinely given to U.S. infants.
Liver cancer doesn't respond well to conventional chemotherapy and is often diagnosed too late for surgery to be an option. Many patients die within a year of diagnosis.
Robert Throckmorton, a 73-year-old attorney in Orange County, Calif., said his doctor told him "You better get your affairs in order" after he was diagnosed with inoperable liver cancer last August.
But then the doctor offered sorafenib off-label, and Throckmorton readily agreed. He did not take part in the study.
After nine months on the drug, Throckmorton said his cancer shows no sign of progression and he has no significant side effects. He said he walks three miles six days a week to stay active and feels fine.
Instead of thinking about wills and funerals, Throckmorton is looking forward to get-togethers with his eight children and 18 grandchildren, and even a possible church trip to Uruguay with his wife.
"I have good energy," Throckmorton said. "We are optimistic."