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Battling Inoperable Liver Cancer
August 26, 2010   
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A group of doctors in Warsaw are testing a pioneering method to treat patients with “incurable” liver cancer. Thanks to precisely targeted radiation therapy, the doctors say they have been able to achieve the impossible—extend the lives of patients who have failed to respond to any other treatment methods known to contemporary medicine.

This innovative therapy was developed more than 18 months ago by doctors at the Radiology and Imaging Diagnostics Unit of the Ministry of Internal Affairs and Administration’s Central Research Hospital in Warsaw.

The hospital is managed by Prof. Jerzy Walecki, and the research team involved in the project is led by Dr. Jarosław Ćwikła, a nuclear medicine specialist. The group also includes Dr. Mirosław Nowicki, an interventional radiologist, Dr. Artur Sankowski, an imaging assessment radiologist, as well as several other doctors who prepare patients for the therapy, treat them and provide post-treatment care. The project is being developed in association with several other cancer and surgery clinics across the country.

The project involves the use of radioactive isotopes for treating patients with advanced inoperable primary or metastatic liver cancer. At first, the doctors only used the [90Y] yttrium isotope, but now—with the consent of the hospital’s bioethics board—they also apply [188Re] rhenium. The rhenium therapy method is their own research project financed by the Ministry of Science and Higher Education and the Association of Patients and Supporters of Patients with Neuroendocrine Tumors.

Radioisotope therapy

“Our field is treating cancer with radioisotopes,” says Ćwikła. “This involves diseases that are either forms of primary advanced liver cancer or other popular tumors that have metastasized to the liver, such as cancer of the large intestine, breast cancer or neuroendocrine tumors, which do not respond to other treatment methods.”

Specifically, the method used by the researchers is called radioembolization. The idea is to supply radioactive material via blood vessels (the hepatic artery) directly to the vessels supplying the tumor, to expose the tumor to radiation and destroy it without harming healthy tissue. The aim of this therapy is not so much curing the patient—because this is usually impossible due to the advanced state of the disease—as reducing the tumor’s mass in an attempt to extend the patient’s life and make it more comfortable, Ćwikła says. In some cases the tumor can shrink so much that it can be removed surgically or chemically, which could in fact be tantamount to a cure, according to Ćwikła.

Hepatocellular carcinoma

Hepatocellular carcinoma, or liver cancer, is a disease that most often ends in death. It can develop over a long time without causing any symptoms, which is dangerous in that the patient’s chances of survival depend on how early the disease is diagnosed. Early symptoms, meanwhile, like minor pain in the abdomen, flatulence and loss of appetite, are easy to confuse with less serious diseases. Once a patient has intense pain, fever, jaundice or ascites, the disease is usually very advanced and has spread, which makes it harder to treat.

Liver cancer is the fifth most frequent cancer in the world, and third in terms of death rate. The average survival rate from diagnosis is six months. If the disease is restricted to one lobe, just 10 percent of patients survive five years.

Treatment consists primarily of surgical procedures (excision of the whole tumor), a liver transplant or thermal ablation, and in more advanced states—chemoembolization or chemotherapy. In many cases, however, the disease is too advanced for any of these methods to be effective. These are the kind of patients who are treated by Ćwikła’s team.


“When other kinds of treatment end and the patient cannot be helped, surgery proves impossible, chemotherapy doesn’t work or has stopped working, the tumor cannot be removed by thermal ablation and the patient has exhausted all the standard methods, that’s where we step in,” says Ćwikła. “We try to help with a nonstandard method.”

The procedure is called radioembolization. It involves the occlusion of blood vessels with various materials, most often resin or glass spheres.

“Apart from commercial [90Y] yttrium-labeled substances, we use [188Re] rhenium-labeled human serum albumin microspheres,” says Ćwikła. These microspheres are specially prepared first and coated with the radioactive isotope. The radioembolic material is then introduced into the vessel which supplies the tumor; in most cases this is the hepatic artery or a branch of the hepatic artery.

To be accurate and safe, the procedure has to be carried out by an experienced interventional radiologist with excellent intuition and precision in identifying the visceral vessels in the abdominal cavity. The tumor has to be exposed to radiation selectively, only in the area where the microspheres are deposited. Embolization anchors the spheres in the target site in the liver—the tumor.

This technique uses extremely large doses of radiation, from a few dozen to several hundred grays (Gy). To compare, a single exposition of the whole body to radiation exceeding 5 Gy usually leads to death within 14 days, while a single dose of traditional radiotherapy ranges from 1.5 to 2.5 Gy.

The doctors can use such high doses only because these are precisely targeted and do not affect any healthy tissue. Radioembolization allows patients to avoid external radiation sources which, if they were to reach the tumor with the same kind of energy, would be lethal for the body as a whole.

The element that destroys the tumor and makes the patient respond to the treatment are fast electrons radiated from the nucleus of the [188Re] isotope as a result of its decay. Irradiation of the cancer cells starts a whole cascade of events ultimately leading to the cancer’s eradication, for example by inducing programmed cell death (apoptosis) or at least halting the cancer cells’ further development.

Rhenium makes the difference

Specialist medical centers around the world have provided similar therapy for over 10 years, using commercially made yttrium-labeled resin (SIR-Spheres, Sirtex Medical) or glass (TheraSpheres, MDS Nordion) microspheres.

“Data from research reports confirm the effectiveness of this kind of therapy,” says Ćwikła. “At present, two large, multiple-center clinical trials are under way that aim to provide further proof. One of them involves patients with colorectal cancer that has metastasized to the liver, the other is treating advanced hepatocellular carcinoma. We intend to join both projects soon.”

The Polish scientists have decided to use the [188Re] rhenium isotope instead of yttrium isotopes. Why? The [90Y] yttrium isotope in the commercially made preparations used elsewhere in the world is expensive, according to Ćwikła. “The cost per unit is zl.38,000-zl.42,000, to which you have to add the cost of the procedure itself, so a single treatment costs from zl.55,000 to zl.60,000,” he says. “The procedure needs to be performed just once—with the response to the treatment usually spanning a year or more—so even despite the high cost it is still more economical than chemotherapy, which costs up to zl.100,000 per month and requires constant administration as long as the disease progresses.”

According to Ćwikła, the use of yttrium leads to difficulties with imaging, while this is an essential part of the treatment—accurately determining the location of the isotope in the organs 24 hours after the procedure. This is necessary to establish where the medication is, whether it has reached the site it was supposed to or not, Ćwikła says.

“The blood flow in a liver with tumors is extremely complex, which is why it is always necessary to assess where and in what amount the isotope is located,” says Ćwikła. “It is only after imaging has been performed that it becomes clear that some sites have the ideal accumulation of the medication, meaning that a response to the treatment is highly likely, while in other areas it has not collected at all—then the treatment is ineffective. It is of key importance to monitor what goes on inside the patient’s body. If the medication has not accumulated in the right place, the procedure has to be repeated.”

Thanks to the nature of its radiation, rhenium enables doctors to determine where the medication is located with greater accuracy. Rhenium is simpler to use in imaging, but also simpler to obtain. The preparations with yttrium have to be ordered from manufacturers in Australia or Canada. Deliveries take place once a week. In the case of rhenium, Polish-made equipment is available that can produce the required amount of the isotope at any time. The cost of treatment per unit is half that in the case of yttrium, no more than about zl.30,000, according to Ćwikła.

The equipment for making rhenium 188 is also a Polish invention. It is a tungsten/rhenium [88W/188Re] generator developed at the Polatom Institute of Atomic Energy in ¦wierk near Warsaw.

Yet another advantage of rhenium 188 is that the microspheres coated with it, unlike in the case of resin or glass microspheres with yttrium, are completely natural, made from human albumin, Ćwikła says.

Work on radioembolization involving rhenium began at the Warsaw hospital a year ago; the method started being used routinely six months ago. First, due to the complexity of the therapeutic process, the doctors from the hospital’s radiology unit gathered experience in radioembolization by using commercial yttrium-labeled preparations. They went through an intensive training course at the Clinic of Radiology and Nuclear Medicine in Magdeburg, Germany. Today the Warsaw hospital is one of two medical centers in Poland that have a certificate for performing radioembolization using [90Y] SIR-Spheres.

Treatment program

Before being admitted to the treatment program, patients sent to the Warsaw hospital from cancer treatment centers all over Poland have to undergo numerous tests. The doctors determine how advanced the disease is and what the possibilities are for carrying out the procedure. The patients have to meet certain criteria—clinical, imaging-related, and physiological. Another important criterion is the lack of any hepatopulmonary leakage and the physical viability of administering the radioembolic material. The issue is whether there is any danger that the medication might leak from the liver to the lungs, which could cause toxic, post-radiation pneumonia, and whether the blood vessels are sufficiently patent and have no unique anatomical features precluding the procedure.

Once a patient is admitted, the doctors start the procedure, which involves two stages. In the first, preparatory, stage, they perform an angiography, which is like an ordinary diagnostic procedure, to assess the tumor vasculature and plug some of the visceral blood vessels—for example, the gastric artery, the gastroduodenal artery, or the cystic artery. This is a non-invasive procedure in which a catheter is introduced through the femoral artery and special guides help locate the vasculature of the liver and other visceral structures. These vessels have to be closed when the radioisotope is being introduced so that the radioactive material does not go any farther—to the gall bladder, duodenum or pancreas—and irradiate healthy tissue, which would be dangerous for the patient.

The second stage takes place a few weeks after the preparatory procedure. The radiologist introduces the radioisotope into the left or right hepatic artery, depending on which side the tumor is. This takes 45 minutes to two hours. After a whole day has passed, the doctors perform an imaging procedure to see if the medication has collected in the tumor. If everything is fine, the patient can go home the next day and, depending on how they feel, return to their usual activities. This is a safe technique benefiting patients, well tolerated and significantly improving the quality of life for patients with chronic progressive cancer.

So far, the hospital’s Radiology and Imaging Diagnostics Unit has carried out a dozen or so procedures using [188Re] rhenium and a comparable number with [90Y] yttrium. The preliminary results are being analyzed and a scientific publication is in preparation.

Julia Pawłowska

Jarosław B. Ćwikła, M.D., specializes in nuclear medicine and radiology. He heads the Nuclear Medicine Laboratory at the Ministry of Internal Affairs and Administration’s Central Research Hospital in Warsaw. He is also chairman of the Association of Patients and Supporters of Patients with Neuroendocrine Tumors.

He has published more than 40 research papers in both Polish and international periodicals. In addition to isotope radiotherapy and radioembolization, his work involves diagnosis of neuroendocrine tumors, improving the quality of life for patients with such tumors, and the use of radioisotope methods for treating cancer and arthritis.
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