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afforded from investigating those peculiarities of locale or habit which predispose geographic or ethnic groups toward cancer.
On the basis of several studies indictment of a number of compounds present in the environment as agents that cause or contribute to the initiation of cancer in man has been made. Such compounds are tar, some petroleum products, radioactive materials, certain metallic materials, e. g., chromates, obtained in metal-smelting processes, certain aniline dye intermediates and other products or byproducts of industrial activity and modern civilization. From such findings it has been possible to prevent exposure to these materials by the industrial worker handling these agents; it is clear that numerous cancers have, therefore, been avoided, and such preventive methods will continue to pay inestimable dividends in terms of human suffering, loss of life, and dollars.
Current studies continue the search for such agents in the adulterants or condiments added to food, in materials used as herbal or synthetic medicines, in plastics and other widely used synthetic chemical materials, in the byproducts of industry discharged into the air we breathe (smog) and in the numerous chemicals to which workers may be exposed during manufacture or handling. In addition to the above-mentioned compounds numerous other cancer-producing chemical agents have been prepared synthetically. Such synthesis programs are valuable in three ways: (1) They provide convenient tools to aid the laboratory investigator in the production, in a controlled and quantitative fashion, of cancer tissue; (2) although no common factor has yet been found among the diverse types of cancer-producing agents, to account for the cancerigenic activity, the possibility still exists that some subtle common factor can be discovered (perhaps giving clues to what is affected in the living cell which brings about the transformation to cancer); and (3) many of the agents synthesized are unusual compounds not known to occur naturally or to be found in industry, but our knowledge of natural products and the industrial use of new synthetic chemicals is expanding so rapidly that what was an esoteric compound yesterday may become an important and common industrial material tomorrow. Also important in the production of cancer are the different forms of radiation: X-rays, the high-speed particles produced by radioactive materials and the modern apparatus employed in atomic energy research, and ultraviolet light. A great amount of work done in this field has enabled better understanding of the relationships between radiation exposure time and exposure levels and the production of cancer by radiation. From such studies it has become evident what precautions must be taken by the patient receiving radiation, either for diagnosis or treatment, the doctor, those in certain laboratories, industrial plants, mining operations, military operations, etc. Subsequent investigations must be directed toward giving us greater understanding of how radiation produces tumors and must tell us what are the long-term effects of lower dosages of radiation.
Some cancer-producing agents (e. g., X-rays and a chemical 3,4-benzpyrene) induce a variety of tumor types in a number of different animal species; others (e. g., the agent causing the disease in poultry, fowl leukosis, and the agent demonstrated in the milk of mice that affects the incidence of breast cancer in the offspring) induce cancer ordinarily in a single species. Many of these agents also produce different effects in the two sexes and in different strains of the same animal species. These findings indicate the importance of the constitution of the species concerned and emphasize the heritable factors that influence the reaction to an agent which produces cancer. That is to say, in addition to the many agents discussed above which can lead to the production of cancer (extrinsic factors), there are numerous factors in the laboratory animal and in man which can affect both the initiation of cancer and the course of development of the established cancer (intrinsic factors).
Controlled experiments have shown that susceptibility and resistance to cancer are to some degree heritable. But susceptibility and resistance are relative terms, and an overwhelming stimulus may overcome natural resistance. Conversely, an inherent or constitutional predisposition to cancer may find an adequate inciting stimulus in a quantity of noxious agents that would not elicit cancer in others of the same species. The importance of the heredity influence in production of experimental cancer has been demonstrated by developing many genera tions of inbred strains of animals. This inbreeding provides an invaluable tool for cancer research, especially in the investigation of the relationship between cancer and heredity, but the translation of the results obtained in this type of experimentation into clinical terms is extremely difficult since human heredity is the result of the opposite of inbreeding. Nevertheless, even in studies in
humans the effects of heredity can be detected. It becomes imperative, therefore, that the investigations which are attempting to define hereditary influences in terms of physiologic or biochemical functions be continued and correlated with the probability of developing cancer and other diseased states. This is a gargantuan task, but a start has been made in this direction.
The hormonal secretions of the body constitute another important group of intrinsic factors about which much has been learned. Quantitative studies of the effects of some of the hormones on the initiation of cancer have given a fair picture of the operating factors present, and a beginning has been made in attempts to understand the interrelaionships of different hormones acting together. Much remains to be done in this area, but the work has already provided information leading to hormonal treatment, so valuable in certain types of cancer, such as prostatic cancer.
For many years it has been known that cell-free (filtered) extracts of certain tumors could produce a few specific types of cancer when injected into the same species of animal from which the tumor tissues was taken. Such extracts are believed to contain viruses (the same kind of agent that produces certain infectious diseases, such as infantile paralysis, chicken leukosis, smallpox, influenza, the common cold, etc.). Some cancer-research workers believe that all cancers are caused by viruses that lurk in the body tissues in an inactive form and are activated by the extrinsic factors discussed above. Most cancer investigators believe only a few cancers are caused by viruses. Recently, some experiments have been reported which indicate that leukemia can be produced in mice by injection of cell-free filtrates into the young mice. If these observations can be corroborated, their implications are exceedingly important for new research, especially in that important type of cancer, leukemia.
The nature of cancer and its relation to the host
In most respects cancer may be considered to be not a single disease, but several. A varied picture occurs in the clinical nature of the disease in the patient and in the body site attacked. In addition, the behavior of cancer tissue varies widely in these important respects: (1) Progressive growth of the tumor; (2) transplantability; (3) nature deviation in structure from the normal; (4) invasiveness into the surrounding tissue; (5) the setting up of distant, new sites of growth (metastases); (6) the production of a wasting away in the host (cachexia); (7) occurrence of a superimposed infection; (8) production of hemorrhage in the area of the tumor. Tumors also vary in their deviation from the normal as regards function. It has been shown that some tumors retain their function so well that in tissues which produce a physiologically active secretion the added mass and consequently greater amount of secretion may cause striking changes in the functioning of the body. Other tumors lose completely some of the functions present in the normal tissue from which the tumor
A measurable function in a given tumor may be lost completely while the structural characteristics are changed but slightly. Conversely, a function may be retained even though the structural picture shows great deviation from the normal. These phenomena are probably a reflection of our crudeness of technique. A number of studies in progress are directed toward increasing our understanding of the relationships between structures and function. Much additional work is in order, and it is to be expected that as these relationships become better known improvements in therapy and diagnosis will result. There is great need for diagnostic tests more sensitive than those based only on the picture of tissues as viewed through the microscope.
The bulk of our knowledge about the chemical mechanisms taking place in cancer tissues has been obtained within the past decade. By means of an extensive study of the chemical properties of tumor tissue it has been shown that in many respects tumors tend to resemble one another more than normal tissues tend to resemble each other. The extremes of function in tumor tissue fall well within the extremes found in normal tissues. In certain chemical functions cancer tissue has been shown to be deficient-e. g., the ability to oxidize certain chemical raw materials. In other functions cancer tissue exhibits remarkable activity-e. g., the ability to manufacture protein as the tumor mass grows. The last 10 years have seen remarkable advances in the study of the complex structure of protein and its formation in the living organism and in cancer tissue. Such investigations involve key problems in cancer research, and these studies must continue to be vigorously pursued.
Certain important relations between a tumor and its host have been established. It was long suspected that tumor tissue elaborates some material which has an effect on the body. For example, as a tumor grows to a certain size the activity of a chemical component of the liver (an organic catalyst or enzyme, called catalase) is reduced. When the tumor is removed the activity increases. A material has been obtained from tumor tissue which, when injected, can also produce a like change in the liver. Studies are underway, both on the nature of the material obtained from tumor tissue and on the mechanisms underlying the reduction of the activity in the liver.
Another important area of investigation is the problem of nitrogen metabolism in the tumor-bearing subject. Nitrogen is an essential constituent of tissues, especially in protein. It has been shown that nitrogen moves into the tumor tissue at the expense of nitrogen in the body tissues, even though large amounts of nitrogen are given to the patient as a well-balanced diet. Much additional work needs to be done to follow up some of these important leads. Such experiments are necessary if we are to learn more about the striking wasting away (cachexia) so impressive to all who have seen the advanced cancer patient. Such experiments must be extended if we are to obtain rational leads to be followed in the search for a means of treating this dread disease. Treatment and palliation of cancer
Since no real cure is as yet available for all cancers physicians have defined the results of their treatment in the practical and understandable terms of years free from clinical evidence of the disease. In general, the majority of recurrences of cancer before the patient dies from some other cause come during the first five posttreatment years. It has become customary, therefore, to speak of "5-year cures" and to make comparisons of one form of treatment with another form on the basis of results expressed in terms of 5-year cures. Any evaluation of a form of treatment in the patient therefore takes several years to carry out, and it must be remembered that patience must be exercised in awaiting results of a new form of therapy.
Surgery and radiation have been and still are the only effective techniques available for curative therapy. They are curative only when the tumor cells have remained localized to areas from which they can all be removed by surgery or destroyed by radiation. For disseminated cancer, with cancer cells spread no one knows how widely, surgery and radiation with other adjuncts of good medical care can still be of considerable palliative value in prolonging life with reasonable comfort afforded. There is no sound basis for the attitude that there is nothing more that can be done. This is the attitude which leads patients and their families to squander their substance and hope in the vain patronage of quack remedies.
Both surgery and radiation have become more effective in recent years for cancer therapy because other scientific and medical advances have permitted. them to be used more extensively and adequately. Infections, hemorrhage, shock, anemia, and other blood deficiencies, faulty nutrition and metabolic disorders were a few of the secondary problems that limited the amount of surgery or radiation that could be used in cancer treatment and the length of survival of the patient after treatment. A number of accomplishments in several fields of investigation have allowed greatly improved management of these problems before, during, and after treatment and the surgeon and roentgenologist are now able successfully to extend both his curative and his palliative surgery to tumors that were previously "inoperable." The operative mortality rate has gone down, the 5-year surgical-cure rate for some types of cancer is improving, and many patients with disseminated cancer are living much more comfortable lives up to the time of their inevitable deaths.
Two important techniques in radiation therapy have been introduced to mitigate against some of those factors that limit the administration of an adequate tumor dose. Both are attempts to apply greater radiation to the tumor without injuring the surrounding normal tissue. One technique involves a carefully calculated placement of the patient in such a position that he may be rotated during exposure to the radiation beam so that the tumor is at the center of rotation in line with the radiation beam. Thus, a maximum amount of radiation is given to the tumor and a minimum amount delivered to the skin and intervening tissues in any one area. Evaluation of this method in comparison with other methods of treatment is in progress, but it is too early as yet to be able to say if this procedure offers any improvement over other methods or if the more complicated and somewhat more expensive equipment can be justified.
The second technique relatively recently introduced into radiation therapy is the employment of very high or supervoltage radiation. With a high-voltage therapy (up to a million electron volts) there is less scatter of radiation into the surrounding normal tissues and greater depths of penetration of an effective radiation dose than can be obtained with lower voltages. Investigations are currently in progress to evaluate supervoltage radiation therapy (produced by instruments capable of delivering up to 70 million electron volts and with differing qualities of radiation). At least 10 years more of good clinical evaluation studies must be made before the true value of the giant radiation instruments as compared to other methods can be ascertained.
Radiation is no panacea. Many cancers regress under the bombardment, but others are radiation resistant and grow unchecked. Some may even be stimulated to more vigorous growth.
In some cases this weapon saves many and prolongs the lives of others, but it has sharp limitations and does not in itself provide an answer to the cancer problem.
Experiments designed to increase our understanding of the biological effects. of radiation are in progress in laboratory animals. In addition to the impor
tance for cancer research, such studies are, of course, needed because of the development of atomic-energy weapons. Especially important to both areas are studies on radiation sickness (nausea, vomiting, diarrhea, fatigue, and weakness, plus, in severe cases, anemia, hemorrhage, and superimposed infection resulting from large doses of radiation). It has recently been found that shielding of the spleen or bone marrow or the prompt administration of nonirradiated spleen or bone-marrow material to an individual exposed to a normally fatal dose of radiation can prevent or counteract many of the usual consequences of such exposure. These findings give new leads to possible effective means of protection against large amounts of radiation. Much remains to be learned in this area.
Along with the prevention of cancer one of the main goals of cancer research is the discovery of a drug-i. e., a chemotherapeutic method-which will destroy the tumor tissue without injuring the other tissues in the cancer patient. If such a discovery were available, it would be the ideal therapy, for not only could localized cancer be treated without the mutilating effects of surgery and radiation but disseminated cancer could also be effectively treated. A single such drug for all cancers presupposes that tumor cells contain a component common to all types of cancer cells which distinguishes them from normal cells. No such component has been demonstrated as yet, and, although many do not believe such a component exists, certain similarities (e. g., biochemical) suggest, at least, the possibility of such a common factor. At any rate, since no demonstration has as yet been brought forward, the research worker in chemotherapy is seeking agents which will (1) modify the systemic toxicity produced by cancer; (2) alter the relationship between the systemic environment of the cancer cell and the cell itself; (3) interfere with the blood supply of the tumor; (4) stimulate defenses of tissues adjacent to tumors against invasion; and (5) differentially damage functional and metabolic processes in normal and cancer cells.
A wide variety of observations in a number of basic disciplines, e. g., organic chemistry, pharmacology, experimental pathology, biochemistry, physiology, etc., have provided the leads which have been the basis of testing well over 10,000 compounds against animal tumors. The laboratory worker, as well as the clinician, is faced with the problem of selecting agents which will inhibit or destroy tumor cells but which will not exert simultaneously unacceptably high toxic effects against normal cells and organs. Evidence that a compound meets one or another of the criteria of effectiveness in any screening program precipitates a chain reaction of chemical syntheses in attempts to make series of similar and related compounds, some of which will show an increase in anticancer activity, or a decrease in toxicity for the host, or both. Much additional work needs to be done to improve the criteria for anticancer activity. We need to know much more about the basic mechanisms operating in the living organism if we are to shift our approach from what has been mostly empirical to one more rational. Furthermore, while a number of valuable leads for treatment in the patient have come from the studies in animals, a number of examples are known which show that a compound may be rather potently active in the experimental animal and yet show no activity when tested in the cancer patient.
In spite of difficulties such as those mentioned above a number of compounds have been made available which, in certain types of tumors, have given benefit for the cancer patient. The sex hormones, both estrogens and androgens, have met with a limited degree of acceptance in the management of breast and pros
tatic cancer. Cortisone and ACTH appear to be of benefit in modifying the course of certain leukemias and related cancer (lymphomas). Urethan has enjoyed a measure of success in certain leukemias and myelomas. Nitrogen mustard has been of benefit in treating some of the leukemias and lymphomas, particularly Hodgkin's disease. The folic acid antagonists, in the hands of some clinicians, appear to have been of distinct value in the management of acute leukemia. Currently the purines and pyrimidines and their related compounds have shown promise in the treatment of leukemia.
On the basis of the numerous factors given above, a number of cancer investigators believe the time is now ripe for an expansion of a chemotherapy program for cancer, especially leukemia, particularly in terms of increasing numbers of compounds synthesized and of an enlarged program of testing for anticancer activity in the patient. Many believe a coordinated program of research can be insttiuted in this area of investigation, achieved by deliberate participation of selected scientists experienced in the intricacies of scientific exploration in a limited area who pool their specialized knowledge and skill for the common good. Various therapeutic programs in malaria, syphilis and antibiotics have succeeded from this type of program. Success requires that sufficient progress shall have already been made in the birth of ideas when the study is undertaken to form a frame of reference or a point of departure for future work, for if such ideas are not available, all the meetings for the purpose of coordinating the research, all the activity as team research, will be of little value. It is always more difficult to discover the elements of a subject than to develop the subject. Once a sufficient number of basic ideas have accumulated, however, cooperative techniques can be employed to bring about full development of the subject.
APPLICATIONS OF CANCER KNOWLEDGE
Progress in the control of cancer depends not only upon continued laboratory and epidemiological research, but also upon application of the products of research as rapidly as practicable to the problem of discovering and treating individual cases. Responsibility for promoting such application through the development of case-finding techniques and programs of professional and law education rests upon both Government and voluntary groups.
The key to succesful medical management of cancer is finding and treating the disease early. Therefore, the watchwords, particularly for the medical profession but also for the lay public, are "early suspicion, accurate diagnosis, and effective treatment." The two general objectives are: First, to find ways to shorten the dangerous time intervals between the onset of the disease and diagnosis, and between diagnosis and the start of treatment; and second, to improve the level of cancer diagnosis and management.
Developments in therapy of cancer by surgery, irradiation, and chemical compounds have been reviewed earlier in this statement. The possibilities of prevention through knowledge of the nature of cancern-causing agent and influences have also been discussed. An extremely important area, however, is that of specialized and general public education for better cancer control, and the provision of facilities by means of which the most advanced techniques for discovering and treating cancer can be used to best advantage.
As with any disease, case finding is extremely important in the control of cancer. Because of the importance of early diagnosis to successful management of cancer, every effort must be made to find individual cases in the earliest stage, if possible even before ordinary symptoms appear. This gives added importance to frequent medical examinations with reliance upon all available aids to diagnosis.
Advances which have been made in the diagnosis of cancer of specific sites have made it necessary to abandon many basic concepts in order to make possible the detection of early cancer. For example, it is recognized today that abnormal vaginal bleeding as a direct result of uterine cancer means, in the majority of case that a gross lesion with possible ulceration is present, and that this is not an early cancer in the present sense of the term. By examining cells from the vaginal tract, a microscopic lesion of the uterine cervix, referred to as "carcinoma-in-situ," can be detected. Some authorities believe that all cervical cancers begin in this symptomless manner and after a time grow and become a truly invasive cancer. If this can be substantiated it will mean that this lesion is cervical cancer at its early stage and is curable in practically 100 percent of cases.