In Japan there have been multiple cases of non-cirrhotic HCV patients who went on to develop liver cancer even when sustained response was achieved. But as reported this has only rarely been documented outside of Asia.
FAQ: The Link Between Hepatitis C and Liver Cancer
By Paul Hansen, M.D, director, Providence Liver Cancer Clinic, Providence Cancer Center; and Ken Flora, M.D., gastroenterologist/hepatologist with The Oregon Clinic and consulting physician to Providence Liver Cancer Clinic
No — in fact, most don’t. Only people who develop cirrhosis as a complication of hepatitis C have a higher risk of developing liver cancer. About 20 percent of people with hepatitis C develop cirrhosis — advanced liver scarring caused by decades of inflammation. Of those who do develop cirrhosis, about 20 percent eventually develop liver cancer. So overall, among all people with hepatitis C, the chance of developing liver cancer at some point in your life is about 4 percent.
Hepatitis C inflames the liver, and over the course of many years, this inflammation can lead to scarring. Most people with hepatitis C never experience significant scarring or complications, but about 20 percent develop cirrhosis, which is advanced scarring throughout the liver.
Because hepatitis C is a slowly progressive virus, it can take 30 or 40 years for cirrhosis to develop. Meanwhile, the liver is resilient — when damage occurs, the liver goes to work to regenerate itself. We believe that cancer occurs during this ongoing cycle of injury and regeneration. The more cells the liver regenerates, the higher the chances that a mutation will occur in one of those cells, and it’s these mutations that can lead to hepatocellular cancer.
The Liver
The Liver Function
What is a Liver Tumor?
Tumors are abnormal masses of tissue that form when cells begin to reproduce at an increased rate. The liver can grow both noncancerous (benign) and cancerous (malignant) tumors. Malignant tumors of the liver fall into two broad categories, those that start in the liver (primary tumors) and those that spread to the liver from other sites (secondary or metastatic tumors).
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Common Cancer In HCV Is Hepatocellular Carcinoma
*Start In The Liver (Primary Tumors)
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The most common primary tumor of the liver is hepatocellular carcinoma, also known as hepatoma. This tumor typically occurs in patients with cirrhosis from chronic hepatitis or long-term alcohol use.
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Metastatic Tumors
Metastatic tumors to the liver can originate from many different types of cancer. Many of these tumors are treated with systemic chemotherapy, although there are cases where resection of the tumor or other liver-directed therapy can be curative. Two of the most common metastatic liver tumors that can be treated with liver-directed therapy include colorectal and neuroendocrine neoplasms.
What Causes Liver Cancer?
Cancer develops when healthy liver cells become abnormal and grow too quickly. The abnormal cells form a mass called a tumor. When a tumor has the ability to spread to other parts of the body, it is called malignant. Another word for a malignant tumor is cancer. The exact cause of liver cancer is not known. Risk factors for primary liver cancer (hepatocellular carcinoma) include:
Viral hepatitis B and C
Alcohol
Cirrhosis
Exposure to toxins
Intake of anabolic steroids
Non-alcoholic cirrhosis (fatty liver)
In many patients, liver tumors result from the spread (metastasis) of another cancer to the liver through the bloodstream. This spread of metastatic disease represents the most common form of cancer in the liver in the United States. Most commonly, cancer occurring in the colon, rectum, breast, or kidney may spread to the liver.
What are the Symptoms of Liver Cancer?
Many patients do not experience symptoms; the cancer is discovered during routine follow-up tests for a previous cancer outside of the liver, or during diagnostic testing for the presence of cirrhosis or viral hepatitis B or C. Symptoms of liver cancer may include:
Fever: Fever is always a possible sign of infection. Fever, without infection, is occasionally associated with liver cancer.
Jaundice: Jaundice shows up as yellow skin and eyes, dark urine, and light colored stool. Jaundice occurs when a substance called bilirubin builds up in the blood. Bilirubin is made in the liver to help with fat metabolism and then travels down the bile duct just before emptying into the duodenum, a section of the small intestine. If a large amount of the liver is replaced by tumor, or if bile duct obstruction occurs, bilirubin builds up in the blood. This buildup causes a person to become noticeably yellow, or jaundiced. The other signs of jaundice are a change in stool color (stools become white) and a change in urine color. Itching can occur when bilirubin builds up in the blood. Obstructed (blocked) bile ducts can increase the risk of infection, including sepsis (infection in the blood).
Indigestion, lack of appetite, nausea, and weight loss:
Abdominal or leg swelling: Abdominal fluid (ascites) can build up in the setting of chronic (long-standing) liver disease. It may be accompanied by swelling of the legs. Abdominal and leg swelling can also be caused by other illnesses such as heart or kidney disease. Liver cancers can be associated with ascites (abdominal fluid). This fluid can be removed temporarily with a needle (paracentesis) or sometimes can be controlled with diuretics (fluid pills).
Types of Non-cancerous Liver Tumors
Noncancerous (benign) tumors are quite common and are usually without symptoms. Often they are not diagnosed until an ultrasound, CT scan, or MRI is performed. There are several types of benign tumors, including:
Hemangioma: This type of benign tumor is the most common tumor found in the liver. They are a mass of abnormal blood vessels. Up to five percent of adults have small liver hemangiomas that cause no symptoms. Treatment is usually not required. Sometimes infants with large liver hemangiomas require surgery to prevent clotting and heart failure.
Focal Nodular Hyperplasia: Are benign tumors that occur primarily in women of age 20-30 years old. They are the second most common tumors of the liver after hemangiomas. They usually present as a single mass and have no malignant potential. Treatment is usually performed for patients because of symptoms or size.
Hepatocellular Adenoma: This benign tumor occurs most often in women of childbearing age. Most of these tumors remain undetected. Sometimes an adenoma will rupture and bleed into the abdominal cavity, requiring surgery. Rarely does an adenoma turn cancerous.
These are the tests which are used most frequently to evaluate liver cancer:
Blood tests: Some tumors produce measurable amounts of chemicals known as tumor markers in the blood. Blood tests to determine the presence of these markers can be used to help diagnose or monitor the disease process. Other tests measure the functions of the liver and other organs.
CEA: CEA is a marker that has been found to be elevated in some patients with colorectal cancer. Not all patients have elevation in the CEA, and thus this test is only useful in patients with known elevation.
AFP: alpha-feto protein is a marker used in patients with hepatocellular cancer. Not all hepatocellular cancers have an elevated AFP. This marker is only useful in patients with elevated AFP.
CA19-9: is a marker that has been shown to be helpful in the diagnosis and follow up in some patients with cholangiocarcinoma.
X-rays: Many different types of x-rays can been used in the diagnosis and management of patients with liver cancer.
Ultrasound (US): This test uses sound waves to form a picture that can be seen on a small television screen. The picture can show organs in the abdomen and possibly the presence of a tumor. Ultrasound is commonly performed by placing a probe on the surface of the abdomen.
Computed tomography (CT) scan: This test gives detailed pictures of the body and can show how far the cancer has spread. The CT scan is the primary test used to determine the number and size of tumors in the liver and whether the tumor can be surgically removed.
Magnetic resonance imaging (MRI): This test is obtained when further details of the liver and tumor anatomy are required. Through the use of a magnetic field, precise images of the liver can be obtained.
Paracentesis: With this procedure, a needle is placed into the abdominal cavity (but not into the liver) to remove excess abdominal fluid (ascites). This fluid can be tested for cancer cells or infection. Sometimes the fluid is removed in large quantities (for example, 3 to 5 quarts) in order to provide symptomatic relief.
Laparoscopy: This test is done in the operating room under general anesthesia. The surgeon guides a small camera through a half-inch incision in the abdomen. The organs in the abdomen can then be examined directly. This test is done to find out if the liver tumor has spread to other parts of the liver or other organs or structures inside the abdomen.
The treatment of hepatocellular carcinoma (HCC) is quite challenging and requires a multi-disciplinary approach. A recent review of patients with HCC indicated that, of the population at risk for HCC, 23.9% were due to hepatitis C virus (HCV), approximately 10% were due to hepatitis B virus (HBV), and approximately 41% related to daily alcohol consumption, while in 25% no clear cause could can be identified. At least 50%-60% of all HCC patients seen have associated liver cirrhosis which can be clinically diagnosed.
The presence of liver cirrhosis presents a major challenge to the treatment of hepatocellular carcinoma. Associated low platelets (thrombocytopenia), low white blood cell count (neutropenia), fluid in the patients abdomen (ascites), elevated bilirubin all must be considered when treatment is being planned. Patients who have severe confusion (encephalopathy and liver failure) are more likely to die from liver failure rather than from HCC. Thus, treatment of hepatocellular carcinoma has to take into consideration the residual functioning liver reserve.
Small HCC liver lesions may be managed by interventions such as resection, radio frequency - or cryo-ablation, alcohol ablation, or even orthotopic liver transplantation (OLT). Obviously, such interventions are limited by the size, the number, the location of tumors and the underlying liver reserve. Most importantly, none of these interventions will deal with micrometastatic disease or additional primary lesions present in the liver or outside the liver.
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November 2010
COLUMBIA, Md., Nov. 11, 2010 /PRNewswire-FirstCall/ — Celsion Corporation a leading oncology drug development company, today announced that the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) has issued a positive opinion on the application for Orphan Drug Designation for ThermoDox®, a proprietary heat-activated liposomal encapsulation of doxorubicin, for the treatment of hepatocellular carcinoma (HCC), commonly referred to as primary liver cancer. A positive opinion by the COMP immediately precedes official designation of ThermoDox® as an orphan drug by the EMA.
ThermoDox® is currently being evaluated under a Special Protocol Assessment with the FDA in a 600 patient pivotal Phase III trial (the HEAT study) in patients with non-resectable primary liver cancer at 76 clinical sites in 11 different countries.
Orphan designation for a medicinal product by the EMA provides for scientific advice and regulatory assistance from the EMA during the product development phase, direct access to centralized marketing authorization, and certain financial incentives. The designation also provides 10 years of marketing exclusivity subsequent to product approval. Orphan drugs are eligible for full reduction of fees associated with pre-authorization inspections, as well as full reduction of marketing application fees and annual fees for qualifying companies.
“We are very pleased to receive a positive opinion from the Committee for Orphan Medicinal Products, which immediately precedes final Orphan Drug designation from the EMA, for ThermoDox®,” stated Mr. Michael H. Tardugno, Celsion’s President and Chief Executive Officer. ”This positive opinion on our application for orphan designation status is an acknowledgement of the significant unmet medical need to develop a new treatment for patients with primary liver cancer, a life threatening disorder for which today there is no effective chemotherapeutic standard of care. Centralized approval provides for rapid commercialization across the European Union. We look forward to continuing our positive interactions with the EMA, the FDA and other regulatory agencies around the world to make ThermoDox® available to patients as soon as possible.”
Regulatory agencies around the world, as well as the liver cancer medical community, have all recognized the potential of ThermoDox® for the treatment of this unmet medical need as evidenced by the following:
Orphan Drug designation for ThermoDox® by the FDA and a positive opinion by the COMP for similar designation in Europe;
The HEAT study has been granted a Fast Track Designation by the FDA; and
The National Cancer Institute’s recent designation of the HEAT study as a Priority Clinical Trial at its recent Clinical Trial Planning Meeting for HCC.
About Primary Liver Cancer
Primary liver cancer is one of the most deadly forms of cancer and ranks as the fifth most common solid tumor cancer. The incidence of primary liver cancer is approximately 20,000 cases per year in the United States, approximately 40,000 cases per year in Europe and is rapidly growing worldwide at approximately 750,000 cases per year, due to the high prevalence of Hepatitis B and C in developing countries. The standard first line treatment for liver cancer is surgical resection of the tumor; however 80% to 90% of patients are ineligible for surgery. Radio frequency ablation (RFA) has increasing become the standard of care for non-resectable liver tumors, but the treatment becomes less effective for larger tumors. There are few non-surgical therapeutic treatment options available as radiation therapy and chemotherapy are largely ineffective in the treatment of primary liver cancer.
About ThermoDox® and the Phase III HEAT Study
ThermoDox® is a proprietary heat-activated liposomal encapsulation of doxorubicin, an approved and frequently used oncology drug for the treatment of a wide range of cancers. In the HEAT study, ThermoDox® is administered intravenously in combination with RFA. Localized mild hyperthermia (39.5-42 degrees Celsius) created by the RFA releases the entrapped doxorubicin from the liposome. This delivery technology enables high concentrations of doxorubicin to be deposited preferentially in a targeted tumor.
For primary liver cancer, ThermoDox® is being evaluated in a 600 patient global Phase III study at 76 clinical sites under an FDA Special Protocol Assessment. The study is designed to evaluate the efficacy of ThermoDox® in combination with RFA when compared to patients who receive RFA alone as the control. The primary endpoint for the study is progression-free survival (PFS) with a secondary confirmatory endpoint of overall survival. A pre-planned, unblinded interim efficacy analysis will be performed by the independent Data Monitoring Committee when enrollment in the trial is complete and 190 PFS events are realized in the study population. Additional information on the Company’s ThermoDox® clinical studies may be found at http://www.clinicaltrials.gov/
About Celsion
Celsion is a leading oncology company dedicated to the development and commercialization of innovative cancer drugs including tumor-targeting treatments using focused heat energy in combination with heat-activated drug delivery systems. Celsion has research, license, or commercialization agreements with leading institutions such as the National Institutes of Health, Duke University Medical Center, University of Hong Kong, Cleveland Clinic, and the North Shore Long Island Jewish Health System. For more information on Celsion, visit our website: http://www.celsion.com/ .
Celsion wishes to inform readers that forward-looking statements in this release are made pursuant to the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. Readers are cautioned that such forward-looking statements involve risks and uncertainties including, without limitation, unforeseen changes in the course of research and development activities and in clinical trials by others; possible acquisitions of other technologies, assets or businesses; possible actions by customers, suppliers, competitors, regulatory authorities; and other risks detailed from time to time in the Company’s periodic reports filed with the Securities and Exchange Commission.
Source
Zeroing in on Liver Cancer Treatment
Selecting the best treatment for liver cancer depends on the physician being able to precisely identify the type, location, size and borders of the tumor or tumors. By matching that information to a variety of treatment possibilities and considering the benefits and limitations of each, the physician can select the best course of action. Key to this decision is the patient's condition and anticipated ability to tolerate the treatment.
Surgical removal of liver cancer tumors is considered to be the most effective treatment for liver cancer. Unfortunately, about 70% of patients cannot have this surgery due the size or location of the tumors or other health factors. Other local treatments (those targeted specifically at the tumors) are less effective or have higher risks. Systemic treatments such as biologic therapy, hormonal therapy or chemotherapy are less precise in their attack; as a result, these therapies may have effects on the patient ranging from major discomfort to damage of healthy tissue.
For situations in which surgical removal of tumors is not possible, there is a new option that can increase the physician's ability to target the lesion more precisely, focusing the effect on the cancerous or unwanted tissues and minimizing the destruction of healthy tissues. The advent of this new procedure, called radiofrequency ablation (RFA), promises to increase the options for eradicating lesions while reducing the risks and side effects associated with other options or procedures.
Two technologies come together in RFA. With CT or ultrasound imaging, the physician can precisely identify the lesions. High frequency radio waves, produced by alternating current, are then used to apply heat to destroy the lesion cells with great accuracy. It is this combined technological precision that allows the physician to more accurately target the lesion, and at the same time, reduce collateral damage to healthy tissue.
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. The RFA procedure is performed in the radiology or operating room, either percutaneously (through the skin), laparoscopically (through a scope) or with an open incision. In either case, the patient experiences minimal discomfort and most can go home the same day. After the patient is sedated and given a local anesthetic, the physician uses CT or ultrasound to visually guide a needle into the lesion. An array of wires, guided through the needle, spread out into the lesion in a starburst form to infiltrate the lesion. Some of these wires contain a tiny thermometer by which the temperature of the surrounding tissue can be measured. These wires are attached to a generator that produces alternating current in the controllable range of radio waves. Radiofrequency ablation provides patients with liver cancer new hope. The minimal risks and side effects are welcome relief from the apprehension patients face with many other options. The prospect of a minimally invasive procedure combined with greater accuracy in targeting and destroying cancer cells, presents a more promising outlook for patients with liver cancer.
Source
By Kristina Fiore, Staff Writer, MedPage TodayPublished: March 17, 2010Reviewed by Zalman S. Agus, MD; Emeritus Professor University of Pennsylvania School of Medicine andDorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
SIR: Microspheres Promising in Liver Cancer
Other treatments can cause additional liver toxicity, which could further strain an organ that is already diseased, the researchers said.
Intra-arterial Yttrium-90 microspheres, on the other hand, can deliver higher doses of radiation directly into the tumor, without exposing healthy tissue.
"It's like seed implant but with higher doses and very highly localized," Salem said.
The microspheres are injected via a catheter from the groin into the liver artery that supplies blood to the tumor.
A total of 291 patients were treated with the microspheres as part of a single-center, prospective, longitudinal cohort study conducted between December 2003 and December 2008.
The researchers viewed 1,250 scans to assess response and time-to-progression.
They found that the overall time-to-progression was 7.9 months (95% CI 6 to 10.3), a finding that Salem called "promising."
He also said that the group wanted to focus on which patients would receive the most benefit from the therapy, so they looked at progression based on staging.
They found that those with Child-Pugh A disease benefited the most, no matter whether they had portal vein thrombosis.
Their survival was 17.2, compared with 7.7 months for those with type B (P=0.002).
If Child-Pugh B patients had portal vein thrombosis, their survival was even shorter, at 5.6 months (95% CI 4.5 to 6.7). Some 43% of the patients in the study had portal vein thrombosis.
Survival also differed by Barcelona Clinic Liver Cancer staging: 26.9 months for stage A versus 17.2 months for stage B (P<0.001).
"Identifying which patients really benefit and which are not the best candidates for this therapy -- trying to triage based on benefit -- was something we worked really hard on," Salem said, adding that the elderly also seemed to benefit.
He also noted that in many cases, patients tumors had downstaged to the point of transplant or resection. A total of 58% of those followed long-term saw their tumors downstaged from T3 to T.2.
"We're able to shrink patients' tumors to potential transplant or cure," Salem said. "The concept of converting incurable disease to potentially curable is appealing."
Most common side effect was fatigue (57%), pain (23%), and nausea or vomiting (20%).
Response rates were 42% or 57%, depending on scaling, and 30-day mortality was 3%.
"It appears to be very well tolerated, and so many have converted to cures," said SIR president Brian F. Stainken, MD, who was not involved in the study. "Those who don't [convert to cure] have their lifespan extended. That's remarkable."
Kieran J. Murphy, MD, of the University of Toronto, who was likewise not involved in the study, said the key is to "preserve the patient."
"You want to protect them from unnecessary radiation and Y-90 does that beautifully," he said.
Salem said the data can be used to design future Y-90 trials and to describe Y-90 as a potential treatment option for patients with hepatocellular carcinoma.
Amazing liver surgery
Professor Alan Hemming from the University of California, San Diego, is one of the few surgeons in the US who has treated otherwise unresectable liver cancer by temporarily removing the patient's entire liver for reconstruction.
Coming Soon *This blog will post a reminder with a link when the transcript is ready to view
Broadcast On Monday Nov 15th.............................
The transcript of this program will be available by late afternoon on the Tuesday following Monday's broadcast.
When Monday is a public holiday in NSW, the transcript will not appear until late Wednesday..
Mon 8.30am
repeated Tuesday 12.30am
Presented by Norman Swan
In This Program
08:32: Amazing liver surgery
http://www.abc.net.au/rn/healthreport/stories/2010/3064982.htm
Liver Disease Treatment - UCSD Medical Center
From 2009
Professor Alan Hemming from the University of California, San Diego
Discusses Liver Treatment At UCSD..
*Touches On Out Of Body Liver Surgery
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