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Radioactive seeds against cancer

Ipen masters the technology for manufacturing capsules containing iodine-125 for the treatment of prostate tumors

Patients suffering from prostate cancer will shortly have access facilitated to a therapy that brings about a rate of cure of up to 88%. At the moment, this treatment depends on importing the drug, and is therefore little used in the country, due to its high cost. The treatment uses radioactive capsules or seeds of iodine-125 implanted by special needles in the patient’s prostate. The mastery of the technology for producing these seeds was achieved by a team of researchers from the Nuclear and Energy Research Institute – IPEN. Now, they will be produced at the institute, located in the university city in São Paulo, and they should begin to go on sale in mid-2004. The Brazilian seeds will cost 40% less than the foreign ones, imported at prices of between US$ 35.00 and US$ 40.00 each. Brazil will thus become the third country in the world, after England and the United States, to have the technology to make this kind of radioactive seed.

“With the reduction in the prices of the seeds, more people will be able to make use of the treatment”, concludes Constância Pagano Gonçalves da Silva, the manager of Ipen’s Radiopharmacy Center and the coordinator of the project financed by FAPESP, in the amount of R$ 750,000, which provides for a prototype to be concluded and a laboratory to be set up to produce the capsules. According to this researcher, the price of the seeds will be lower, because the labor force in Brazil is cheaper.

As the treatment involves the implantation of between 80 to 120 seeds, the cost with the imported product can come to US$ 4,800, not counting any doctors’ fees and hospital charges. With the seeds from the Ipen, this cost can fall to R$ 8,000. According to physicist Maria Elisa Chuery Martins Rostelato, head of Ipen’s Radioactive Sources Production Laboratory, the monthly demand for these seeds is from 2,000 to 3,000 units, which forecasts an annual market of US$ 840,000. For the time being, this treatment is still not covered by the Single Health System (SUS-the public health system in Brazil).

The importance of these radioactive sources lies in the fact that prostate cancer is the one with the second highest incidence amongst Brazilian men, behindonly nonmelanoma skin cancer. According to estimates by the National Cancer Institute (Inca), this year will be 25,000 new cases of the disease and about 8,000 deaths. The conventional treatment is surgery to remove the prostate, or external radiation therapy [RJS37] with a linear particle accelerator. Radiation therapy with iodine seeds is part of a treatment called brachytherapy, characterized by a radioactive source very close to or in contact with the organ to be treated. Patients with prostate cancer are also treated with hormones, which have the function of reducing the size of the prostate, or of awaiting the best moment for a curative treatment with brachytherapy.

The implantation of iodine-125 seeds is a relatively recent kind of treatment, suitable for tumors at an early stage. The first experiment was carried out in Denmark, in 1983, and, two years later, in the United States. The treatment consists of implanting the seeds inside the prostate, to destroy the sick cells. As the material used in the manufacture of the seeds is biocompatible, they do not need to be removed, and the implant is permanent.

The iodine-125 seeds have almost microscopic dimensions and are smaller than a grain of rice. They are made up of a cylindrical capsule of titanium, 0.8 millimeters in outside diameter and 4.5 mm in length. Titanium was chosen, because it has a low level of rejection and it has a sufficiently thin wall to allow radiation to pass through. Inside the capsule, there is a silver wire 0.5 mm in diameter, with iodine-125 deposited on its surface. The typical activity (the quantity of radiation emitted by the nucleus of the isotope) of the seeds is 0.5 mCi (millicuries) of iodine-125. With this dosage, the action of the seed is limited to the prostate and hits, with a lesser intensity than with external radiation therapy, healthy organs like the bladder, the rectum and the urethra. “Saving healthy tissues is another great advantage of brachytherapy”, Elisa explains.

The action of the seed is very concentrated, because the radiation emitted by the iodine-125 covers only five millimeters of human tissue. “It acts inside the patient for ten months, but the major part of its activity takes place in the first two months”, Elisa says. This period corresponds to iodine-125’s half-life (58 days). Half-life is the time that a radioactive material takes to reduce its activity by half. It only ceases to be radioactive after ten half-lives. Therefore, the full radioactivity of iodine-125 disappears after 580 days, or almost 20 months.

Detailed application
The implantation of radioactive seeds is a quick and safe procedure. With the help of special needles, and guided by the direct view from transrectal ultrasound equipment, the doctor introduces the seeds inside the patient’s prostate through the perineum (the region between the root of the penis and the anus). The application is done in just one session. Before this, though, detailed planning is carried out. The specialist studies the prostate, with detailed ultrasound images, which identify its size, shape and outline, and inform the exact position of the urethra and the pelvic bones. These images are sent to a computer that, with the help of software, calculates the quantity of seeds needed for the treatment and the exact place where each seed should be implanted.

Ipen’s initiative was well received by doctors specialized in the treatment of prostate tumors. “It is a leading edge technology, with the advantage of having a far lower cost”, explains radiotherapist Rodrigo Hanriot, responsible for the Brachytherapy Sector at the Albert Einstein Hospital, in São Paulo. “Thanks to Ipen, access to the treatment is going to be expanded.” The project for developing the seed in Brazil arose, incidentally, from requests from the doctors. “Doctors complained about the high cost of the imported capsules”, recalls Elisa, from Ipen. On that occasion, in mid-1998, only two companies, Amersham, from the UK, and North American Scientific, in the US, made the product, and there was no literature available on the seeds.

“I had to cut a capsule in half to know how it was made up”, says the researcher. Less than two years later, in April 2000, Ipen’s prototype was ready. “But because of the lack of funds, our research made slow progress, and today some ten companies have mastered the technology”, Elisa says. The finance granted by FAPESP at the beginning of this year is proving vital for the research to be concluded. “We still need to carry out dosimetry studies, which is to assess the dose of radiation along the seed”, says the researcher. The money will also be used in building Sources for Radiotherapy Production Laboratory, which will have airtight stainless steel chambers for the handling of the seeds.

The capsules developed at Ipen have a few differences from the seeds made abroad by Amersham, the ones most used in Brazil. “We use other chemical reactions to deposit the radioactive iodine on the silver wire”, says Elisa. In addition, the process for welding the capsule is done with microplasm – a process that uses electric arcs, special electrodes and flows of inert gas between the solder and the object to be welded – contrary to the seeds from our competitors, which are sealed by laser”, she explains. “Thanks to these differences, we have a new product and we will not have to pay royalties to any foreign company, and we will even have a patent”.

Less invasive
Brachytherapy of the prostate has increasingly won the trust of the doctors, since it is a technique with a high cure rate, and less invasive than surgery to remove the prostate, though it needs a local anesthetic and sedation. Not to mention that the recuperation of the patient is quicker, since he only has to stay in hospital for a day and a half, and can go back to his normal activities in 48 hours. Radical prostatectomy (the complete removal of the prostate gland), in turn, requires five days in hospital and from weeks to months of recuperation, while the traditional external radiation therapy takes up a period of nearly seven weeks of out-patient treatment.

The great advantage of therapy with seeds of iodine-125 is that the collateral effects are far blander, compared with radical prostatectomy. While from 60% to 90% (depending of the extent of the surgery and factors like diabetes and arteriosclerosis) of the patents submitted to this surgery show problems related to sexual impotence, only 30% of the men who do brachytherapy suffer from this disorder.

Another use for the radioactive seeds of iodine-125 is in the treatment of ophthalmic cancer. Since 1997, they have been used in Brazil in the treatment of ophthalmic tumors, malignant and benign, with a rate of cure of up to 95%, with sight being preserved in 70% of the cases. In the conventional treatment, the eyeball is removed.

Iridium wires
Ipen produces a series of radiotherapies and radiopharmaceuticals, and some of them, like the seeds of iodine-125, were also developed in the institute’s laboratories. For example, the researchers developed wires of iridium-192, for the treatment of some types of cancer (neck, breast and soft tissues). The institute buys inactive iridium wires from the French company, and irradiates them in its own reactor, to produce the iridium-192. Thanks to a device designed by the researchers from the laboratory of the Radiation Technologies Center, the wires are irradiated uniformly throughout their length. t the end of the process, the radioactivity has to be the same at each point of the wire, with a variation of no more than 5% upwards or downwards.

Unlike the capsules of iodene-125, the implant of iridium wires is not permanent. The patient stays in hospital, in a special room, for three to four days. Afterwards, the wires are taken out and the patient is sent home. This product has been marketed by Ipen since 1997, and amongst its customers are the Albert Einstein and Syrian-Lebanese Hospitals in São Paulo, and the Radium Institute, in Campinas. The wire, 50cm long, costs about R$ 1,100. “We sell around 18 wires a year. The number is still limited, because there are still few hospitals using this technology”, explains Elisa, who is also in charge of the development of this product. With the use of the seeds produced by the Ipen, this situation may be turned around and the distribution of these materials expanded.

The project
Development of the Technique for Producing Iodine-125 Seeds for use in Brachytherapy (nº 01/04768-3); Modality Regular research project – benefit line; Coordinator Constância Pagano Gonçalves da Silva – Ipen; Investment RS$ 474,083.14 and US$ 169,623.25