SANDRA JAVERAThis month two Brazilians sign the main article in the world’s most influential journal in the oncology area: the CA – A Cancer Journal for Clinicians, published by the American Cancer Society and the benchmark in oncological therapy for surgeons and clinicians. In the text, written at the invitation of the periodical’s editors, surgeons Angelita Habr-Gama and Rodrigo Oliva Perez analyze some 200 recent works on the therapy of tumors of the rectum and conclude that it is no longer possible to think about a single strategy for treating all cases. The advance of image examinations, which make it easier to monitor the evolution of the tumor, and the promising results of the combined use of radiotherapy and chemotherapy, allow us to imagine, according to the authors, less aggressive treatment for some of the cases than the one that is adopted as the standard in a substantial part of the world: the definitive elimination of the end portion of the intestine, which then requires the use of an external bag for collecting the feces.
The invitation to prepare this review represented for the Brazilian group the recognition that Angelita was right when, some two decades ago, she defended a daring idea. Based on her clinical experience she proposed that in very strictly selected cases cancer of the rectum should be treated initially with radiotherapy and chemotherapy and that its evolution should be closely monitored, instead of the patient being sent straight for radical surgery. Since 1991 the group coordinated by Angelita has already treated approximately 700 patients with rectal cancer, who were cared for at the Angelita & Joaquim Gama Institute in the Clinicas Hospital of the University of São Paulo (USP) and in the Oswaldo Cruz German Hospital. In a little over a quarter of the times (more precisely 28%), therapy with medication and radiation led to the complete regression of the tumor.
The combination of radiotherapy and chemotherapy is usually the first alternative for combating various types of cancer. However, it was always regarded with reservation in the case of tumors of the rectum, which appear at the end of the intestine, close to the anus and every year affect some 10,000 Brazilians. The main argument of surgeons in favor of the procedure that eliminates the rectum and the tissue around it was the difficulty in knowing with certainty if the tumor that had been eliminated from the walls of the intestine persisting in the adjoining tissue. “There was a fear that we were burying the tumor,” says Perez, who since 1995 has been a member of Angelita’s team.
SANDRA JAVERAShe decided to test the use of radiation and medication as an initial strategy to fight cancer of the rectum, inspired by the pioneering work of a North American surgeon. At the beginning of the 1970s, Norman Nigro, from Wayne State University began to adopt this combination to try to reduce the size of another type of tumor, that of the anus, before extracting them surgically. The idea of applying radiotherapy and chemotherapy to the tumors that developed at the end of the rectum, the procedure used by Norman, was not trivial. Although they are close, the anus and rectum have an embryonic origin that is different and are affected by different tumors from a histological point of view.
In Angelita´s view it is worth running a certain degree of risk in order to avoid cutting out the rectum and to try to improve the patient’s quality of life. “I was fortunate enough to be trained by a group of surgeons who always did everything possible to preserve organs,” says the surgeon, the first woman to do an internship in general surgery at the Clinicas Hospital of the Medical School of the University of São Paulo (USP) in 1958. At the beginning, not even the Brazilian medical team imagined that the radiotherapy and chemotherapy sessions would manage to entirely eliminate the cancer, but this started to become obvious when they found that in some of the cases there were no longer any traces of the tumor cells.
“I felt sorry about the times we removed the rectum and no longer found any signs of the tumor,” says Angelita. At the time in USP’s Medical School there was an interchange with researchers from Pittsburgh, who suggested that the Brazilian group should start a comparative random study of the two strategies, in which patients are selected by a draw to become part of one group or another. “I was against it and this harmed us from the scientific point of view,” says Angelita. “I didn’t agree with removing the rectum and definitive colostomy [installation of the bag for collecting feces] in cases in which it might be unnecessary.”
It was not easy to convince foreigners that there might be an alternative to radical surgery. When she presented her first results in 1997, at an international congress of colon and rectum surgery in Philadelphia in the United States, Angelita heard the coordinator of the debate say: “Cancer of the rectum is something serious. This work is not worth discussing.” Until then, the association of chemotherapy and radiotherapy was only adopted after extracting the tumor to reduce the risk of it reappearing, which occurred in up to 40% of the cases after the operation. But the results were unsatisfactory. “It’s different treating whole and well-oxygenated tissue from that which has undergone the process of scarring and fibrosis after surgery,” explains Perez.
SANDRA JAVERASince they identified the first cases of full regression of the tumor, Angelita and her team have been working to improve the therapy and try to reduce even more the need for surgical intervention. Some years ago she, Joaquim Gama-Rodrigues, her husband and a digestive tract surgeon, Perez and a multidisciplinary team of radiotherapists and clinical oncologists doubled the number of chemotherapy sessions and increased the radiation dose by 7%. There were six cycles of treatment with medication (the person receives intravenous doses of 5-fluorouracil on three consecutive days, which makes the cells more sensitive to the effects of the radiation) accompanied in the first six weeks by daily sessions of radiotherapy, with a total dose of 5,400 gray.
The result improved. The strategy was efficient in 65% of the cases. According to the article published in 2009 in the journal Diseases of the Colon and Rectum, it eliminated the tumor from 19 of the 28 patients who concluded the treatment – these people were still cancer-free a year later.
Despite the advance, there is no general agreement on the widespread adoption of this treatment strategy. Dr. Rob Glynne-Jones, from the Mount Vernon Cancer Treatment Centre in England, believes that more evidence is necessary regarding the fact that the use of radiotherapy and chemotherapy before surgery for treating cancer of the rectum is in fact effective. In a study published in 2008 in the journal Diseases of the Colon and Rectum, he and other researchers evaluated some 240 Phase 1,2 and 3 clinical trials done in different countries and concluded that the information available did not yet allow this strategy to be supported in all cases. “In our view [the evidence] is not robust enough to place at risk the well-being of a young patient, although it might be justified for treating tumors in initial stages in older patients who have co-morbidities [other illnesses],” wrote Glynne-Jones and his collaborators.
More recently Brazilian researchers saw that the success rate of 65% might in fact be a little more modest than they had observed. By means of an image examination, called positron emission tomography, the group monitored the evolution of a tumor in 91 people who completed the combined radiation and medication therapy. In all cases the activity of the tumor tissue reduced to almost a third of the initial activity in the sixth week after conclusion of the treatment. But unlike what was expected it did not always reduce continuously: in half the cases the metabolism of the tumor increased, albeit slightly. “This is an indication that not everyone responds as well as we hope,” says Perez, the first author of the article that describes the data to be published shortly in the International Journal of Radiation Oncology. “We believe that the combined therapy can be more effective and sustained for some than for others,” he says.
In these cases the treatment may have eliminated the more sensitive cells and left the more resistant. “We don’t yet know if they’re reproducing, but they seem to have recovered their metabolic activity,” says Perez. In this situation positron emission tomography could help the doctors identify those for whom the treatment is not going to work and send them for surgery earlier.
Angelita’s group is working with geneticist Anamaria Camargo, from the Ludwig Institute of Cancer Research, to produce molecular tests to guide the therapy. After diagnosis of the disease and before treatment one of the tests tries to identify the people who would benefit most from the use of chemotherapy and radiation. Over the last few months the researchers have sequenced the genes expressed in the tumor cells from 27 samples taken from the tumor bank of the Oswaldo Cruz Hospital and of the Angelita & Joaquim Gama Institute. Of the 18,000 genes analyzed some 50 cases allow those who would respond well to treatment with radiotherapy and chemotherapy and can be spared surgery, to be distinguished from those who should be sent directly to have rectal resection. “These genes are a type of molecular signature of the tumor, which allows us to predict in which cases the treatment may work,” explains Anamaria.
Another examination that the group is trying to develop is a market for detecting residual tumor cells and helping discover if the therapy is working. The idea is to see if the tumor cells persist in the blood stream after treatment with medication and radiation. This is an individualized test in which, from the biopsy of the tumor, genetic alterations of the cancer are identified that are typical of each person. “It’s a pretty sensitive method, which would allow small tumors to be detected that are too small to be identified by clinical assessment and screening exams,” says the geneticist, who is also trying to discover what is altered in the functioning of tumor cells that is resistant to the therapy. “We want to reach the point where it’ll be possible to know beforehand if the patient will respond well or not to radiotherapy and chemotherapy before starting the treatment,” plans Perez.
1. Genetic heterogeneity in rectal tumors – identification of tumor sub-populations resistant to neoadjuvant treatment with radiotherapy and chemotherapy (nº 2011/51130-6); Modality Young Researcher; Coordinator Rodrigo Oliva Perez – Medical School/USP; Investment R$ 362,043.70 (FAPESP)
2. Neoadjuvant treatment in rectal cancer: identification of a genic signature capable of predicting response to treatment and the development of personalized biomarkers for assessing minimal residual disease (nº 2011/50684-8); Modality Regular Research Funding; Coordinator Anamaria Aranha Camargo – Ludwig Cancer Research Institute; Investment R$ 317,922.39 (FAPESP)
KOSINSKI, L. et al. Shifting concepts in rectal cancer management: a review of contemporary primary rectal cancer treatment strategies. CA – A Cancer Journal for Clinicians. In Press.