INSTITUTE OF PHYSICS - USP/SÃO CARLOSThe dentist Cristina and doctor Cestari carrying out an application with a laser beam at the Amaral Carvalho Hospital in JaúINSTITUTE OF PHYSICS - USP/SÃO CARLOS
Apprehension. Perhaps this word sums up in a bland form the reaction of people when they receive the diagnosis that they have some type of cancer, a problem that hits close to 350,000 Brazilians every year. When they get the news, these people, among the many questions, have doubt about the form of treatment. Surgery, radiotherapy and chemotherapy are the three consecrated alternatives that save many lives. What many patients and doctors are not yet aware of is that there is a new type of treatment – Photo Dynamic Therapy or PDT – which is quickly gaining ground, in a promising advance in the cure or improvement in the quality of life of the patients with cancer, without leaving permanent damage.
In Brazil, the new technique, which uses a laser beam of special characteristicsas the main therapeutic measure, is being pushed forward by the Research Center into Optics and Photonics, one of the ten Research, Innovation and Diffusion Centers (Cepids) established during the year 2000 by FAPESP. A group of almost thirty people composed of researchers, doctors, biomedics and technicians, have developed the equipment, perfected the technique and are now carrying out clinical tests to finalize the protocol that is going to guide the Brazilian doctors in this specialty. Approved in 1998 by the Food and Drugs Administration (FDA), the agency that controls food, medicines and therapeutic techniques on humans in the United States, the PDT is already in operation in eighteen countries.
“We’ve already attended to 230 patients and treated more than 1,000 tumors, because each patient can have many lesions”, says the group coordinator, professor Vanderlei Salvador Bagnato, of the Physics Institute (IF) in São Carlos, of the University of São Paulo (USP). One of the main advantages for patients who receive the PDT is the elimination of the disagreeable effects of chemotherapy, which brings on nausea, vomiting and skin burns. Also it avoids surgeries that often mutilate and shrink the volume of skin and muscles.
“The PDT promotes the regeneration of skin tissue, doesn’t leave scars, as well as not provoking a hollowing at the treated location nor does it bring on a loss of cartilage”, enumerates the medical doctor Guilherme Cestari Filho, the coordinator of the clinical trials at the Amaral Carvalho Hospital in the town of Jaú, a reference center in oncology that gives preferential treatment to national health system (SUS in the Portuguese acronym) patients, and where a large number of the first applications of PDT took place in Brazil.
Cure and reduction
In the first survey presented by the research group, of the 63 patients with skin cancer, 79% had their tumors eliminated. With the same type of problem in the mouth, of the 10 patients 40% had a complete cure. “The complete cure depends a lot on the stage of the illness, at the beginning the chances are very good for the total elimination of the lesions”, explains the dentist Cristina Kurachi, who carried out the applications on patients at the Amaral Carvalho Hospital and finalized her doctorate thesis at the IF with her theme being the use of the laser in the diagnosis of mouth cancer. “Even in the cases where the elimination of the tumor was incomplete, we always observed a reduction of 50% in the lesion”, says Bagnato.
The light beam for the PDT has a more consecrated application on cancers of the skin and the mouth called carcinomas non-melanoma, or that is to say, those that do not bring on metastasis, reproducing themselves in other regions of the body. Happily, the melanoma represents only 4% of skin cancers. The non-melanoma is the type of cancer most frequent in the Brazilian population according to the National Cancer Institute, an organ of the Ministry of Health. Of the almost 350,000 cases of cancer per year in Brazil, 17%, or a little more than 50,000, are of skin carcinomas. The main reason for this “epidemic” is the excessive sun exposure by the population. The PDT has also been approved for tumors of carcinoma type that grow in other parts of the body such as the esophagus, stomach, urinary bladder, larynx and pharynx.
Within the offered perspective, the PDT technique is gaining ground and new research fronts under a wide range of studies that use the laser as a primary tool, in one of the arms of the Cepid in Optics and Photonics, the IF of São Carlos of USP – the other is the Physics Institute of the State University of Campinas (Unicamp). One of the practical effects of this work is that the IF of São Carlos is ready to pass on the developed technology in the production of laser equipment to a company in the city, the Fotonmed company, formed in a large part by ex-students from the institute. The objective of this technological transfer is to make the equipment cheaper and more efficient, increasing the possibility of it being purchased by a wide number of hospitals and clinics across the country.
As well as spreading the treatment of cancer by using the photodynamic therapy in a pioneering manner in Latin America, Bagnato is also preparing a cancer diagnostics system by way of light. “With a laser tool, possibly portable in the near future, it will be possible for the doctor or dentist, without the necessity of the traditional biopsies, to check in seconds during a surgery or in a simple consultation, if, for example, a spot is or is not a cancer”, explains Bagnato. “The basis of the – called optical biopsies are already in existence, and we here in Brazil – thanks to an interdisciplinary group formed at the Cepid – are on equal footing or even more advanced than the rest of the world”, compares Bagnato in an enthusiastic manner. “Our goal is to understand and promote important innovations in this technique.”
Bagnato’s interdisciplinary team involves five institutions that are working on laser applications and are carrying out clinical tests. They are the Physics Institute and the Chemistry Institute of USP in São Carlos, the Amaral Carvalho Hospital, the Clinical Hospital of the Medical School and the Pharmaceutical Sciences College of USP, both in the town of Ribeirão Preto. “The center permits the development of partnerships to incorporate the PDT into medicine”, assures Bagnato, who received special authorization from USP to also accumulate the function of scientific director of the Amaral Carvalho Hospital.
Without anesthesia
In practice, the application of the PDT technique varies from a few minutes to a few hours, depending on the case and the extension of the lesions. “We had a patient who had thirty seven tumors on his head”, recalls Cestari. “All of the lesions were cured with the patient receiving the laser beam during a single day. Without the PDT he would have had to have been submitted to various surgeries, possible mutilating ones, as well as receiving a general anesthesia”, explains the doctor. With the PDT it is possible to also attend to elderly patients or those with problems that impede surgery, not recommended to take an anesthesia or have clinical complications such as, for example, diabetes.
Vanderlei Bagnato keeps the data in his computer and appends to the Cepid studies that he runs, several cured cases with patients photos, before and after the treatment applications. Those who see the photos – impressive to a layman – easily realize the improvement and the benefits that the treatment brings to patients often hopeless ones under other treatments. In some cases, with chronic and advanced tumors, the treatment serves merely as a palliative. “We attempt to improve the patient’s quality of life. We had the case of the forty-one-year old man who had had a tumor on his head since he was seventeen and after we managed to diminish the area, he then returned to work”, says Cristina.
There is no shortage of accumulated experiences also at the Medical School of Ribeirão Preto. The clinical studies coordinator at that unit, Cacilda da Silva Souza, tells that a patient from the interior of the state of Minas Gerais, had a skin tumor of 17cm in diameter for more than fifteen years. “After a PDT application, the tumor decreased by some 80% and in the second application it was eliminated 100%”. Satisfied with the results, she recalls the initial difficulties for the development of the first studies using the PDT technique in Ribeirão Preto during 1997. “We had no money to purchase the equipment – the laser sources are expensive instruments and there was no interaction with other research groups to set up the equipment here. The go ahead for the project happened through our interaction with the Cepid. There, we were able to get resources both for the equipment and the photosensitizing drugs which are imported from the United States, Russia and Germany”, related Cacilda.
The photosensitizing drugs, of which professor Cacilda spoke, are the key to understanding how the laser eliminates, or as doctor Bagnato prefers, “kill” the tumor cells. Most of these drugs are synthesized beginning with a component of blood, named porphyrin, a red blood cell pigment, consequently turning it only slightly toxic to the organism. These drugs are injected into the blood stream of the patient and run all the way through the body, concentrating themselves in the cancerous cells by up to twenty times more than in the healthy cells. In order for the desired concentration to be established, it is necessary to inject the drug before the treatment, at least twenty four hours before.
Reaction with oxygen
When this photosensitive drug is concentrated in the tumors, it is illuminated by a specific color laser beam to the frequency equivalent to 630 nanometers, a chemical chain reaction begins which leads the cancerous cell to its death. “The drug absorbs the energy from the laser and reacts with oxygen, which turns it highly reactive to the membranes of the tumor cells”, explains Bagnato. The depth that the laser beam penetrates into the skin is 1 centimeter. In deeper lesions various applications on the same location are made, in order to obtain the elimination of the tumor. With this technique, the tumor dries up, forms a scab just like any other wound, which falls off after a few days.
The only side effect of the treatment is the increase in light sensitivity of the patient’s skin. Consequently, if the patient stays in the sun for a period of up to thirty days after the treatment, he could suffer burns or skin irritations. In an attempt to diminish this effect, the researchers at Ribeirão Preto are testing new photo sensitive drugs used in a topical form, applied directly on the tumor. “They have an effect on the location and are more indicated for surface tumors”, says Cacilda. The researchers at Ribeirão Preto and São Carlos are also developing experimental models – laboratory animals – in order to test the new drugs that are coming on the market.
“What we are developing is research that could better define the dose of light and medicines, the area to be covered by the laser, thus generating medical and scientific knowledge, as well as training professionals to spread out this new technique”, says Bagnato. “For example, establishing a plan for the illumination according to the tumor’s geometry, is still missing. This means that a lot about this technique is not established” Bagnato says that in the future it will be possible to eliminate brain cancer using PDT. “Due to the high selectivity of the cells proportioned by the laser, it will be possible to open up the patient’s skull, kill the tumor and close the skull without any damage, as it is already happening in some international centers.”
New approach
Today, if a hospital or clinic purchased the cancer treating laser equipment, it would have to spend around, at least, US$ 100,000. With this high laser cost on mind, whose light source is imported, Bagnato’s team has already patented equipment based on the technology Light Emitting Diodes (Led) that emits light of the same frequency of the PDT laser. “The problem with the LED is that it emits scattering light and not concentrated like a laser”, he explains. “We’re still in a very experimental phase and if we manage to make this new apparatus practical, we could lower the cost from US$ 100,000 to less than US$ 3,000 the price of a piece of equipment used in skin cancer.”
The Bagnato team is also testing an advanced system of cancer diagnosis through a laser. Bringing together laser emissions of various colors and the development of a specific piece of software, the researchers are setting up a system that is going to produce a quick tumor diagnosis. With a metallic bar with a blue light at the tip, which reminds one of a magic wand belonging to a children’s story fairy queen, Bagnato explained how the diagnosis technique works.
“When we throw monochromatic light – that can be blue or green – over the skin, we provoke a phenomenon called fluorescence which bounces back light in other frequencies.” Based on this information the computer determines the malignity or not of the lesion. Also in this area there is a competitive race throughout the world by researchers and companies to systematize the diagnosis and to develop software and specific equipment. In this project the team can count upon the physicist Luís Marcassa, of the IF of São Carlos, a specialist on the interaction of light with materials.
With the clinical experience and technology acquired, as well as various published scientific articles in specialist magazines, the Cepid on Optics and Photonics has gained its credentials and was one of the organizers of the first International Workshop on Photodynamic Therapy held during February in Rio de Janeiro. Seventy participants took part with representatives – the majority medical doctors – from the United States, Russia, Germany, Chile, France and Portugal.
Production center
With a total annual budget of R$ 3.4 million (divided half and half between São Carlos and Campinas), the Center of Optics and Photonics is accumulating a series of studies and developments that have resulted in eight new products. Among them is an atomic clock produced in São Carlos, the first to be built in Brazil. “We’re thinking about making equipment that attends to the necessities and to the limitations of an emerging country with few resources to invest in expensive equipment”, analyzes Bagnato. Recently the group also developed an oxygraph, a device capable of measuring with precision cellular respiration.
Besides the more than one hundred and twenty scientific papers published internationally and the eight registered patents, only during the first year of its existence, added to the work at USP and at Unicamp, the center has had a wide social impact with the production of forty five didactic videos that are in use in the country’s universities and in primary and secondary schools. With these and with seminars such as the “Optics Week” as well as special programs carried out at Unicamp throughout the year, teachers receive additional information on the field of optics and Photonics.
Through all of this, the center has more and more gained credibility, and is looked upon as the hub of basic and applied technological research that deals with a wide spectrum of action. Their actions assist in the understanding of optical phenomena, train researchers, fill in the technological needs in the area of photonics, such as optical fibers in telecommunications, and cover primary and secondary teachers with information. Now the center is truly preparing innovative weapons in the fight against and diagnosis of cancer, the second highest killer illness in the country.
The project
Laser in Medicine and Dentistry; Modality Research, Innovation and Diffusion Center (Cepid) – Center of Optics and Photonics; Coordinator
Vanderlei Salvador Bagnato – USP Physics Institute of São Carlos; Investment R$ 60,000 per year
