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Cancer, divided hopes

Advances in medical research save many lives, but the disease is still a challenge for science

miguel boyayanIn rural Brazil in the 1930, a newly-born child had an average life expectancy of less than 40 years, and almost half the deaths were caused by infectious/parasitic diseases. Of each 37 deaths, only one was due to cancer. In the urban Brazil of the 21st century, seven decades later, babies show a life expectancy of 70 years, and less than 5% of the deaths are debited to the account of the infectious/parasitic illnesses.

One in eight deaths is caused by malignant tumors. Today, cancer has beaten all the causes of death, except cardiovascular problems, basically heart attacks and strokes, which, since the 1960s, have been leading the death statistics. In 2002, about 400,000 new cases of cancer were recorded, and almost 130,000 Brazilians died because of the disease. Four out of every five fatal victims were over 50 years old, with a slight predominance of victims amongst men.

Deaths from cancer accounted for 13.2% of all the deaths in the country, almost half of the percentage reached by the fatal victims of problems in the circulatory system. According to the National Cancer Institute (Inca), an organ of the Ministry of Health headquartered in Rio de Janeiro, a little over 2 million Brazilians died of the disease between 1979 and 2002. In this period, the adjusted mortality rates of the eight principal types of cancer in the country – lung, stomach, breast, prostate, colorectal, esophageal, leukemias, and cervical – remained unchanged or increased in the majority of cases (see graphs on page 51). Significant falls, in both sexes, only occurred with the death rates referring to stomach cancer, a tendency also seen in other countries. “Breast cancer, lung cancer in women, and prostate cancer are on the increase”, says Gulnar Mendonça, Inca?s coordinator for Prevention and Surveillance.

The increase in the number of deaths does not mean that every kind of cancer remains incurable, as many people still believe. In the A.C. Camargo Cancer Hospital, in São Paulo, one of the Brazilian referral centers for the treatment of the disease, for example, two thirds of the 5,000 or so patients attended to every year are cured. This is without taking into account age, sex, type of tumor, or stage of the disease that these people showed at the moment they started the treatment. Similar rates can be found in the main oncological centers in Brazil and abroad.

In the United States, where there are many statistics, half of cancer victims would overcome the disease 30 years ago. Today, the average rate comes to 63%. For some, this has been scant progress, compared with the reductions in the order of 60% in the number of deaths from heart attacks and strokes in the same period. For others, it was an advance not to be despised.

One obstacle in the fight against cancer continues in effect: the process of metastasis, the dissemination of the abnormal cells from the tumor to other parts of the body, beyond the original place where they appeared. “Metastases are a watershed”, says Ricardo Brentani, the president of the Cancer Hospital and director of the São Paulo branch of the Ludwig Cancer Research Institute. Against them, the therapeutic resources are still limited, and the prognostics for the patients, restricted.

Cancer is an epidemic practically all over the world, where it curtails the existence of 6 million individuals, causing 12 % of deaths. In Japan and Australia, cancer now accounts for the majority of deaths. In the United States, deaths from cardiovascular problems still come at the top of the list, although their share of victims has been falling. The death rate from cancer, in turn, is either stable or growing. The years of survival have increased for patients with tumors diagnosed and treated in the initial stages, but the outlook for those cases in which the disease has proved to have been disseminated has practically not changed.

The prospects for patients with metastases of lung, breast, prostate, and colorectal cancers – the ones that kill most in the United States – are almost the same today as three decades ago. The best prognosis is for patients with prostate cancer at an advanced stage: a little more than 30% keep themselves alive for over five years. In the country that is Mecca for science, it is possible that cancer will shortly become the main killer of its population.

The same may happen in a large part of the globe. The incidence of cancer is growing for several reasons, some of them, paradoxically, directly linked to the improvement in the conditions of health and hygiene of large slices of the world population and to the progress of science. People today live much longer than in the past. “The older and more developed a country is, the larger the number of deaths from cancer”, comments statistician Marceli de Oliveira Santos, from Inca’s coordination of Surveillance and Prevention.

In the last few decades, medical research has built up a tremendous knowledge about this vast and diversified group of clinical conditions, originating from the uncontrolled growth of cells in some part of the body, which is given the generic name of cancer. Such advances, added to greater information about the disease amongst laymen, have helped in the early diagnosis of several kinds of cancer. All this means that more cases and deaths attributed to cancer feature in the statistics. These are, so to speak, the “good” causes, the progresses of humanity, which, unfortunately, favor the incidence of cancer.

Now come the intrinsically bad reasons. Modern man’s lifestyle exposes him to risk factors that bring a predisposition to cancer, like smoking (the most dangerous of them all), overexposure to the sun, drinking too much, and having prolonged contact with potentially carcinogenic chemical products or viruses. There is also the genetic question. “About 15% of the causes of cancer are hereditary”, Brentani says. And to worsen things even more, a question arises that causes a certain discomfort and polemics amongst researchers and oncologists: in the last three decades, the really significant advances for treating cancer have been slower and more localized than all the talent, time, and money invested in studies and clinical tests about the disease would lead one to suppose.

“For the more common types of cancer, which kill a lot, like lung and breast cancer, our progress has been practically zero. We are still treating the patients basically in the same way as we did decades ago”, explains biochemist Andrew Simpson, from the Ludwig Institute in New York, who lived for several years in Brazil, where he headed up projects for genetic sequencing. “There have been, though, significant advances in the treatment of pediatric cancers, in adolescents, of Hodgkin’s lymphomas, leukemias, and of some rare forms of tumor.” In some of these conditions, the cure rate – here understood as a survival of at least five years without the return of the tumor – exceeds 90%.

The skeptics will say that, in the last few decades, few novelties of weight have joined the classic anticancer therapeutic arsenal. Indeed, even today, the use, combined or not, of surgery, radiotherapy, and chemotherapy – the first procedure tries to extirpate the tumor cells from the organism, which the other two hope to kill them – forms the underlying foundation on which rests almost the totality of treatments against the most varied types of cancer.

To be sure, no silver bullet has appeared, capable of putting an end to the majority of tumors, but one cannot forget that even these three approaches have been perfected, so as to be more effective and less aggressive. The adoption of transplants of peripheral stem cells of blood and of bone marrow has, for example, made it possible to employ higher doses of chemo – or radiotherapy against some grave cases of cancer. “Before this, treatment used to be more empirical”, explains oncologist Gilberto Schwartsmann, from the School of Medicine of the Federal University of Rio Grande do Sul (UFRGS). “Today, we can adopt more sophisticated approaches.”

New families of treatments have also appeared, which little by little are gaining ground as alternative or complementary therapies. This is the case of immunotherapy, which, by giving monoclonal antibodies or vaccines to the patients, tries to reinforce the defense system of the organism itself, and thus to minimize the side effects of the more traditional approaches, or even to combat the tumors directly. There are monoclonal antibodies like Herceptin, from the laboratories of Roche, which is being used against some aggressive types of breast cancer.

In São Paulo Hospital and Clinics, a gene vaccine developed in Brazil, with modified DNA, is being tested on patients with head and neck tumors at a very advanced stage, against which the traditional resources of oncology have brought no result. Other bets of science against cancer are the antiangiogenesis drugs. These compounds have the objective of cutting off the source of the nutrients that, through the blood vessels, supply the tumors.

This kind of drug has worked well in rats, but its performance in humans is, for the while, disappointing. Understanding the biological mechanisms that make cancer reappear even after the use of high doses of chemotherapy is one of the objectives most pursued by science. Recent works, such as those by Michael Clarke, from the University of Michigan, suggest that tumor stem cells, which are slow-growing and difficult to kill, may be responsible for the reappearance of some forms of cancer and for part of the failures of this form of treatment.

In a not very optimistic view of the situation of the disease in its country, the American magazine Fortune, a publication specialized in news of the economy and business, dedicated its cover of March 22 to the theme “Why we’re losing the war on cancer (and how to win it)”. Amongst the culprits for this distressing situation, the magazine reserves a prominent place for the scientific research carried out in the United States. According to Fortune, a series of mistakes or incompetences have made cancer research pedal, pedal, and pedal, and almost not leave the spot.

The list is really a long one: science has been good so far for generating in-depth knowledge about cancer, but not solutions; the research groups work in an isolated manner, without collaboration, and sometimes study extremely specific aspects of the disease; few people are studying the process of metastasis, which, in the last instance, is responsible for the death of the patients; rats are a very bad animal model for studying cancer, inducing scientists to precipitated or wrong conclusions; the candidates for new drugs are tested on patients at a terminal stage, when no other treatment is working any more, in a kind of experiment fated not to produce good results.

Fortune estimates that US$ 200 billion has been channeled into cancer research in the United States since 1971 until today. In the light of this figure and of the modest results in terms of new treatments, the magazine suggests that the return on the investment for the American taxpayer has not been one of the best.In Brazil, there are no estimates about the size of the budgets allocated for cancer research. The total amount, whatever it is, is certainly a drop in the ocean compared with the billions of dollars invested internationally.

A major part of Brazilian research in oncology is centered on Rio de Janeiro, around projects run or supported by Inca, and in São Paulo, where FAPESP is supporting some heavyweight enterprises. One of these is the Clinical Cancer Genome, which started two years ago. This is a venture that analyzes the behavior of 20,000 human genes in healthy tissues and in nine different types of tumors. Its US$ 1 million budget comes in equal parts from FAPESP and the Ludwig Institute.

“The idea is to produce data that can generate tools for improving the diagnosis or treatment of tumors, and to see how activating genes alters such parameters as survival and propensity for metastases in the patients”, explains Marco Antonio Zago, from the Ribeirão Preto School of Medicine of the University of São Paulo (USP), who is the coordinator of the program.

Test of risk
The Clinical Genome, incidentally, is what unfolded from another joint program between FAPESP and the Ludwig Institute, the Human Cancer Genome, which ended recently. The Human Cancer Genome produced 823,000 ESTs (expressed sequence tags) derived from human tissues, both healthy and with cancer. Each EST is a fragment of a gene activated in a given tissue. The quantity of ESTs produced by the Brazilian researchers is equivalent to 40% of all the expressed sequences extracted from human tissues and deposited in public databases.

This feat deserves a double recognition, for having been achieved with the use of an alternative – and Brazilian – methodology for finding pieces of active genes, the Orestes technique.Besides being a referral center for the treatment of the disease, the A.C. Camargo Cancer Hospital also does cutting-edge science in the oncological area, almost always jointly with the Ludwig Institute.

On February 15 this year, the American magazine Cancer Research highlighted a work done by researchers from the two institutions. The team of biochemist Luiz Fernando Lima Reis, linked both to the hospital and to the institute, saw that the occurrence of a kind of benign lesion in the stomach, intestinal metaplasia, can be a factor that predisposes towards the occurrence of cancer of the stomach.

Not that all the lesions of this kind are going to turn into cancer, but some with a certain molecular signature (with a given pattern of working of some genes), seem to be a prediction of the formation of malignant tumors. “If our results are confirmed in later studies, we may perhaps be able to create a test to point out the population with greater risks of developing stomach cancer”, explains Lima Reis. A major part of the scientific works of the Cancer Hospital is funded by FAPESP’s Research, Innovation and Diffusion Center (Cepid) program.

One of the most interesting ramifications of the researches at Inca are the studies in pharmacogenomics. In this kind of scientific effort, the researchers are looking for mutations in genes, in the DNA of Brazilians, that may be related to a better or worse response to treatments against cancer. Another line of pharmacogenomics is the study of the prevalence of genetic alterations that favor the habit of not smoking or of smoking less.

It is known, for example, that certain mutations in the CYP2A6 gene may make quitting cigarettes easier. “From our own budget, we have invested R$ 4 million in scientific studies and works”, explains Guilherme Kurtz, the general coordinator of Inca’s research sector. “But the amount does not include external funding, from development agencies, which also finance our works.” Outside the Rio-São Paulo axis, cutting-edge results about cancer are also being produced by the Federal University of Paraná (UFPR), above all in the area of leukemias and bone marrow transplants, and by UFRGS.

In spite of all this news coming merely from cancer research in a peripheral country like Brazil (just imagine what they must be doing right now in the laboratories of the United States and Europe), does it still make sense to talk about a “defeat by cancer”, as Fortune says? Could it be an exaggeration? Or pessimism? Perhaps. Nobody who deals with patients or does research agrees openly with this verdict, but the majority of scientists and physicians interviewed for this article admit that the advances in the fight against the disease are taking place at a slower pace than was hoped for. “I do not believe that we are losing the fight against cancer”, explains the head of Inca’s clinical research sector. “The truth is that we are making progress much more slowly than we would wish.”

There is also consensus that science has difficulties in transforming the knowledge generated in the laboratory about the biological mechanisms of cancer into new practices, tests, and treatments that can actually be useful for the patients. “There is a lot of research on cancer, but a focus is missing”, Zago comments. There is a lack of what the jargon of science calls translational research, the research that transforms the discovery of the academic world into a tool for medical use. This is one of the goals of the Clinical Cancer Genome.

Can changing the way of doing research speed up the quest for really effective treatments against cancer? In theory, yes. But it is not easy to bring this revolution about. There are almost insurmountable practical difficulties. The critics of the current model for generating knowledge on the disease say that rodents are not capable of reproducing all the complexity of a human cancer. Sometimes, a tumor only appears in a person after prolonged exposure, of years, to a carcinogenic factor, like cigarettes. How can one reproduce this situation in an animal that lives only two years? “OK, the rat is a bad model. But what I am going to study then?”, asks Brentani.

“It is up to the researcher to know the limitations of the model and to pose questions that this model can answer effectively.” Without the assistance of rats, it would be practically impossible to do research in biological areas. Another obstacle, this time of a moral nature, is the process of testing new drugs against cancer on human beings. Some way has to be found that does not offend ethics and allows greater flexibility for carrying out experiments on patients at the initial stages of the disease, when the chances of a cure are greater. The problem is that nobody knows how and if this can be done. “Every doctor is morally obliged to give his patient the best treatment available”, Lima Reis comments.

If there is a recently created drug that delights physicians and scientists, and is always cited as a proof that modern anti-cancer research does indeed bring practical results, then this drug is Glivec, manufactured by the multinational Novartis. The drug was especially designed to neutralize the molecular cause, or the genetic defect, that causes chronic myeloid leukemia (CML), a kind of cancer of the blood and bone marrow that accounts for 14% of the leukemias in adults and from 3% to 5% in children.

In 2001, its use against this form of leukemia, the conventional therapy for which consists of a bone marrow transplant and, in some case, doses of chemotherapy, was approved by the American agency that regulates the use of medicines, the FDA. This has meant that some patients are managing to control the disease today without having to undergo a transplant. The snag is that the patient has to take the drug for the whole of his life – Glivec neutralizes the molecular defect that leads to CML, but does not suppress it.

“The results from this drug are really good, but it is still too soon for us to know whether the benefits are going to be maintained in the long term”, Zago ponders. In 2002, Glivec gave another proof of its efficiency: its use was approved in treating metastases of a rare kind of gastrointestinal tumor, known by the acronym Gist. In 80% of the cases, the medicine works.

Should science meet with success in designing compounds like Glivec to combat other types of tumors, above all the more common ones, the arsenal of treatments against cancer will really expand and become more efficient in the future. But, for the time being, this is still a promise. It will not be easy to produce a series of Glivecs for wider use, since few kinds of cancer derive from a single genetic defect, such as happens with chronic myeloid leukemia. In general, a succession of mutations, not to mention environmental factors, are involved in the genesis of many tumors.

For Andrew Simpson, from the Ludwig Institute, in New York, the scientists, above all those in the United States, who dictate fashion and the course of science, need to learn to work in a group and to establish clear and practical objectives for their studies into cancer. “The excess of competitiveness of the research groups in the United States is good for generating discoveries, but it is not sufficient for generating an impact in the clinical area”, says Simpson. “There has to be a coordinated effort in search of a common objective. More or less as Nasa did when it decided to make it viable for man to go to the Moon. Brazilians know how to work in a team, as they proved in the Human Cancer Genome project and in sequencing the genome of the Xylella fastidiosa bacterium. I think that Brazil can have an impact on cancer research.”