blocking transformation of normal cells into cancerous cells and tumor development. The accompanying chart illustrates the inter-relationships of these approaches to form the total Program. Each component of the Plan has been developed in much greater detail as definitive plans available for implementation and program surveillance. It should be noted that the implementation of some of the control measures proposed in the latter steps of the plan would likely be performed by agencies other than the NCI. However, through the generation of information resulting from the National Cancer Institute research efforts, essential information would be supplied to other agencies concerned with control activities. Thus, the outputs of the Program would be information forming the basis for improved means for preventing cancers in man by: (1) eliminating or reducing exposures to chemical agents of serious potential cancer-causing hazards; and (2) blocking or interfering in the living organism with one or more steps in the process leading to the formation of cancers.

Implementing Plans and Magnitude of the Planned Program

The first of the four approaches requires an extensive effort in epidemiologic studies relating exposure to environmental chemicals with cancer incidence in exposed populations. In addition to the customary type of epidemiologic' aspects of the studies, monitoring of the environment and of specimens from individuals for concentrations of selected chemicals at different points in time will be needed to permit correlation of requisite data.

The second approach calls for a large increase of efforts to evaluate the potential carcinogenic activity of selected chemical substances in the environment through bioassay studies. Minimum standards for bioassay of a chemical compound require lifetime study of at least two animal species, using both sexes, two or three dose levels of the subject compound, two different routes of administration of the compound, and adequate control groups. Since it would not be possible to screen all compounds, selection of those entering the carcinogenesis screens would be based on criteria judged to be most significant for the more important types of cancers in man.

The third approach in the plan concerns the need for development and standardization of biological models for carcinogenesis studies. This will require a coordinated research program to: (1) develop and standardize animal bioassay systems; (2) develop standards of pathology for the evaluation of carcinogenic effects in animal systems; and (3) correlate chemical and toxicological data in the selection and screening of chemical substances. Plans for expanding these activities provide for a more integrated and concentrated effort to improve existing screening systems and develop more predictive systems. At this point in the "state of the art", this commitment to improve and define bioassay systems requires an effort comparable to that devoted to routine testing. Because of the expense and slowness of present methods of testing and screening for carcinogenicity in whole animal experiments, shorter, less expensive assays will be sought. Leads currently available involving transformation of cells growing in flasks (tissue cultures) when exposed to cancer-causing chemicals suggest the possibility of using such an in vitro system as a screen. It should be noted, however, that the results of such tests will need to be compared to those from whole animal studies.

The fourth approach involves studies utilizing new leads, developed through various scientific disciplines, as points of attack on the process of transformation from the normal to cancerous state, and the development of tumors. In general, these points of attack include blockage of agents from penetrating the body or cells; changing the way certain chemical compounds are altered after they enter the body or the way the body processes work in detoxifying or otherwise modifying certain chemicals; counteracting the effects of chemicals by the administration of drugs or other chemicals; modifying cell surfaces, e.g., through immunological means, which may prevent cancerous cell transformation or successful growth into a tumor even if some cells have been transformed.

Plans also call for expanded efforts in biometry to evaluate the statistical significance of animal studies and their relation to cancer incidence in man. Furthermore, because it is essential to integrate the large amount of various kinds of information at different levels of complexity in man and in animals and to insure appropriate feedback of information in program operations, the plan outlines more extensive means for specifying, handling, coordinating, and utilizing the extensive data that will be accrued.

The magnitude of the Program outlined in this plan could cost well over $20 million to $100 million annually at full operation, assuming adequate matching staff and facilities. This magnitude of program was selected as reasonable in view of the large size and complexities of the problems; the significance, farreaching implications and extensive ramifications of the subject; and the current "state of the art" and capabilities.

About half the cost of the Program is assessed to the efforts aimed at prevention of cancers by eliminating or reducing exposures to chemical agents of potential hazard (development of improved model bioassay systems, testing, screening, developing control measures for reducing hazards, etc.). Expansion of carcinogenesis testing and screening will involve commercial firms as well as academic organizations, and, to insure the requisite coordination, the mechanism of funding for this part of the Program would be primarily contracts.

The other halt of the cost of the Program is assessed to: (1) efforts aimed at blocking the steps involved within the living organism in the process of tumor development; and (2) epidemiologic and biometric efforts (identification of population groups at risk to cancers, statistical developments and processing, evaluation of results in human population groups, etc.). Both grants and contracts would be used as the main mechanism of funding for these efforts, with increases in staff added to manage the program and provide a modest expansion of in-house research.

A program of the magnitude outlined in this plan would not move forward rapidly in the first year of implementation, but would need phasing because of present deficiencies. Modification of current administrative procedures and practices would be necessary if operations of this magnitude are to be conducted. Given the required dollars, facilities and personnel (including staff positions), there are three manpower areas where shortages would likely make it difficult to attain the $20 million level sooner than three to five years. These are: (1) a supply of competent pathologists willing to participate by examining the large numbers of tissues which would be required in the operation of the program; (2) epidemiologists who are willing to undertake the long-term and difficult studies required in human populations as part of the program; and (3) research program managers competent and willing to make commitments to the management of the complex, long-term program elements outlined in the plan. It is anticipated, given sufficient funds, that schools of veterinary medicine might be a valuable source of the kind of skills and knowledge required in pathology for operating the program at a greatly expanded level. As regards the second shortage area, it is anticipated that some physicians and scientists interested in carcinogenesis, particularly those who have had some training in occupational medicine, can supplement the supply of those trained in epidemiology, who can conduct the studies called for in the plan. With an expanded program and drawing on previous experiences of managing complex biomedical research programs such as the Special Virus Cancer Program and the Cancer Chemotherapy Program, new research program managers can be trained on the job to meet the tasks demanded by the plan, given sufficient staff positions. After the initial period, selected training efforts could provide the manpower needed to attain projected levels. With some recent changes in the Etiology Area of the Institute, there now exists an organizational nucleus that could be developed to conduct research at different levels reflected in this plan.

CHEMICAL CARCINOGENESIS AND PREVENTION OF CANCERS (Summary of Program Plans)

PROGRESS IN TREATMENT OF ACUTE LEUKEMIC CHILDREN

Dr. BAKER. In addition to the virus area, I would like to mention some progress in the area of drug treatment of cancers.

In the area of acute leukemia of childhood, we have some concrete progress to discuss in terms of actual remissions. This is, of course, a term applied to the disappearance of signs and symptoms of disease. Prior to the advent of drug therapy back in the 1950's, a child with acute leukemia was usually dead on an average of about 3 months from the time of diagnosis. By 1960, a 2-year survival of these patients had been obtained in 9 percent of the patients. By 1965, it had run to about 42 percent of the patients reaching 2 years.

Now I am pleased to report that 75 percent of children with acute lymphocytic leukemia are alive and free of disease after 2 years.

Also, we have identified nearly 200 children now who are free of of evidence disease for 5 or more years. This was unheard of a few years ago.

The idea of giving new, untried drugs to far-advanced patients with cancer was an important part of the research in the past. In the past, since we had no good treatment for leukemia patients, these patients, of course, were receiving drugs that had not been established. Now, because of successes in the treatment of leukemic children, we can no longer ethically try out new drugs in these patients. We must use other kinds of patients where we have no drugs to help them, such as advanced lung-cancer patients.

This too, then, indicates progress since it is no longer ethical to try new drugs on leukemic children because we would be depriving them of the drug treatment which can now produce remissions in over 90 percent of these patients in the best centers routinely.

COST REDUCTION

Lastly, I think it is important to note that we have reduced the actual cost for treatment of leukemic children. We have made two studies that came out quite close. Seven years ago it was $10,000 per child per year for treatment of acute leukemia. This has been cut in half, primarily in terms of the length of hospital stay, which has fallen on an average from 77 days to 15 days now. So this reduction in cost of health care, through research and development, we think, is another concrete sign of progress.

In general, we are making these successes in the rapidly growing tumors. These are the leukemias, the lymphomas, Wilm's tumor (a kidney tumor of childhood), and in a few other types of cancers. With the more common forms of cancer such as those of large bowel, lung, breast, etc., we have good palliation in some cases, but I regret to report that we still do not have the successes in these slow-growing tumors that we have had in the rapidly growing ones.

The main thrust of chemotherapy in the future is to apply the research development in these rapidly growing tumors to the slowgrowing ones.

Senator MAGNUSON. What types of cancer seem to be in the virus category?

Dr. BAKER. We have three groups of tumors where the evidence is strong in associating viruses with them.

As I am sure you know, we still have not proved in man that any single cancer is caused by a virus, although we have established this in animals. One group includes leukemias, sarcomas of bone, muscle, cartilage and connection tissues, and Wilm's tumor (a children's kidney tumor). A second group includes lymphomas, cervical cancer, cancer of the penis, cancer in the back part of the throat or nose cavity, and chronic myeloid leukemia. Another group concerns leads in breast cancer, large-bowel, neuroplastomas, and possibly lung cancer.

All these show associations with virus, and we are in different stages of development on the amount of evidence on how tightly we can pinpoint the likelihood of virus causation.

ADVANCEMENT IN BURKITT'S LYMPHOMA RESEARCH

The one type of cancer that we are furthest along on is called Burkitt's lymphoma, a solid tumor of the lymph glands and certain other tissues common in certain parts of Africa.

Here the association of antibodies against this virus leads us to feel we are close to pinning down the viral causation of this particular form of cancer.

Senator MAGNUSON. Are the viruses contagious?

Dr. BAKER. We have no evidence in man that they are contagious. Under certain conditions in the laboratory we can certainly transmit viruses from one animal to another. In fact, in laboratory experiments, in only 3 weeks after virus inoculation we can produce animals with leukemia. We can also infect human cells growing in tissue culture with a number of cancer-causing viruses and produce changes that appear to be associated with cancer transformation.

In some animal systems, such as Marek's disease in chickens, there is evidence that the virus can spread among chicken flocks. We have no evidence that this disease is transmissible to man, and we have no evidence showing it is contagious in the ordinary sense.

Senator MAGNUSON. As I understand it, you don't have any known case as yet where that type of cancer has been communicated from a person who has it to another person who might be living in the same household.

Dr. BAKER. That is correct. We have no clear evidence of this kind

of passage.

Senator MAGNUSON. Now we always get a lot of communications and people talk to us about different things that NIH ought to be doing. Somebody on the outside has had some success, sometimes allegedly and sometimes not, with different approaches and the like. But we like to be inquisitive and inquire about them.

Senator MAGNUSON. In the justification material for the NCI there is an interesting statement that is not again referred to. It says on page 40 "Recently two new viruses have been associated with breast cancer and lung tumors." The breast cancer reference is explained later, but the lung tumor virus is not. What can you tell us about this? Dr. BAKER. One piece of preliminary information was reported by investigators at the University of Oklahoma who suggest a possible linkage of a "C" type virus particle with human alveolar lung