The following table indicates level of support by these major program areas:

Adoption of the proposed plan for reorganization of the National Cancer Institute transferred a number of units from intramural research into field studies to form the new etiology area. This area is charged with responsibility for the major share of the Institute's programmed research on cancer causation and prevention, including the special virus leukemia program. It will emphasize investigations that extend from the study of defined human and animal populations, to studies under laboratory conditions of the fundamental aspects of growth and metabolism in living systems. Scientists will be responsible not only for their individual research, but also for provision of strong central leadership in the conceptualization, design, and implementation of an imaginative and integrated attack upon these problems, in collaboration with other investigators in this country and abroad.

Central to the etiology area's approach is the concept of an interaction of multiple factors contributed by man as a host and his environment. The demography programs are designed to analyze defined populations having unusual risks to specific cancers or known exposure to high risk environments, in order to reveal statistically significant cause-and-effect associations and disassociations leading to the discovery of etiologic factors and agents. The experimentally oriented units of the etiology area select and combine, under carefully controlled conditions, those host and environmental factors which appear to be significant in cancer etiology. From this point, they proceed to verify or deny such significance by success or failure in producing cancer in animals. It may then be seen that the synthetic approach on one hand and the analytic approach on the other are purposely united in the etiology area to complement one another Program plans in 1966 and 1967

Demography.-A prerequisite to an analytical approach to cancer etiology in both human and animal populations is a thorough description and documentation of the natural history of the disease. For this purpose, the biometry and epidemiology branches will continue to pursue studies to characterize the occurrence and behavior of cancers by specific sites in human populations, both in the United States and abroad, and the effects of migration on these cancer patterns.

Cancers of domestic animal populations are also being characterized for the purposes of identifying animal species especially useful for cancer experimentation and for studies of the relationship of animal to human cancer patterns, i.e., spread of diseases among species.

These branches will continue to be responsible for the conceptualization and development of unique mathematical and statistical approaches to biological problems, such as those pertaining to clinical testing of anticancer agents. The seminar on congenital malformations, conducted at the United States-Japan cooperative science program meetings, in November 1965, did much to focus attention upon the association of childhood cancers with development of abnormalities of a noncancerous nature. An outgrowth of this collaboration may be field studies established to determine the relationship between the ingestion of aflatoxins and the occurrence of grastic cancer in populations. Environmental factors will be studies in uranium miners, in steelworkers, in radiology technicians, in factory workers exposed to mustard gas (Japan), and in miners of metal ores, in an attempt to determine the role of occupation in the induction of cancer.

Recent developments have focused attention upon the opportunities for advancement of our understanding of cancer biology by the study of multiple

cancers occurring in single individuals. It is highly probable that concentrated examination of persons developing more than one cancer will help to isolate and identify factors in cancer induction. This approach requires the most skillful application of pathology and epidemiology. The etiology area has established an epidemiologic pathology unit and has recruited an eminent pathologist with superior training in epidemiology to lead its research along these lines.

In 1967, the biometry branch proposes to prepare for the scientific community a series of reviews of the current state of knowledge with respect to cancer patterns by specific organ sites, and an extension of the cancer registry principle to more fully characterize special disease categories such as lymphoma and leukemia.

The epidemiology branch proposes to augment its above-described programs by the establishment of a registry of births and deaths for all of the U.S. population dying of cancer under the age of 15 years, from 1960 onward, and also, field studies designed to ascertain the relationship of primary liver cancer among native African populations and the ingestion of aflatoxins.

Carcinogenesis.-Studies conducted by the carcinogenesis studies branch may be divided into those experiments that elucidate the basic biology of matter, and experiments designed to demonstrate the role of environmental and host-factor cancer induction. In the latter group, the emphasis will continue to be upon determination of the carcinogenicity of a wide range of environmental agents in several species of animals of known and contrasting susceptibilities to cancer. This work is twofold in purpose: (1) the identification of hazardous materials and items in the environment; and (2) the study of the mechanisms of action of these agents.

Those environmental agents which have indicated a potential for cancer induction and are the subject of study within the carcinogenesis program include tobacco and tobacco products, a broad spectrum of chemotherapeutic agents and other pharmaceuticals, and toxins elaborated by fungi called mycotoxins that contaminate a spectrum of crops stored for human consumption.

The large collaborative research program being conducted by the National Cancer Institute and the Atomic Energy Commission, at the Oak Ridge National Laboratory, to define the roles of multiple physical, chemical, and biological factors in cancer induction has gathered momentum and soon will be fully operational in all areas planned for activation.

In recognition of its responsibility to fulfill a cohesive role in cancer research, the Institute will continue to provide to the research and educational communities of alerting service keyed to the rapidly expanding carcinogenesis literature of the world. At its recent meetings, the National Advisory Cancer Council underscored the value of carcinogenesis abstracts to the scientific community in diverse regions of the United States.

In 1967, these activities will be augmented to include studies of the carcinogenicity of asbestos, polyurethane-foam dusts, and the ever-increasing meeromolecular and polymeric agents to which an increasing segment of the general population is being exposed. Further studies of the significance of mycotoxins for man will also be undertaken to attempt to determine the relevance of experimental information obtained from animals.

In addition to $200,000 made available through the reprograming of funds previously used to support activities in Ghana, an increase to two positions and $324,000 is requested to support the expansion of this program.

Viral oncology. The three branches within the viral oncology area are staffed with specialists in the scientific disciplines specifically needed to conduct comprehensive basic research on all of the aspects of the virus-cancer relationship. and to manage the related programs of developmental and applied research that are essential to the achievement of the goals of the National Cancer Institute with respect to viral oncology.

The National Cancer Institute's activities in viral oncology may be divided into several major programs, including the special virus leukemia program, the pro gram of experimental work on “fluid" tumors, and the program to devise and develop physical and other resources to facilitate expanded efforts in viral oncology. The special virus-leukemia program is conceptually based on the assumption that viruses are causally associated with cancer in man. This assumption is based upon experience with laboratory and domestic animals in which the causal asso ciation has been established. The purpose in establishing this program has been to accelerate the progress of research directed to clarifying the viral role in human cancer causation, using leukemia as the model system. Ultimately, if viral agents

can be identified and shown to be causative, it may be possible to develop and produce effective vaccines and other modes of treatment to prevent or cure leukemia and other virus-induced cancers.

Various segments of the special virus-leukemia program are seeking simultaneously to expand the fund of knowledge pertaining to the viral role in animal cancers, to devise and establish improved methods of handling dangerous or potentially dangerous biological materials for the safety of the research community, to pursue vigorously the characterization and replication of viruses derived from cases of human leukemia and lymphoma, and to lay bear much of the fundamental biology of viruses in the induction of cancer. In the past year, significant progress has been made in each of these areas, although perhaps the most striking has been the detection and isolation of viruses derived from cases of human leukemia but not known to bear any relationship to any other viruses obtained from human material.

Special efforts are being made this year to produce, concentrate, and purify enough of the viruses recently derived from human leukemia material to conduct animal experiments in leukemogenesis, ultimately leading to the development and testing of vaccines from these viruses.

In 1967, efforts will be made to acquire fresh material from different types of human leukemia and lymphoma and to begin development of a computer storage and retrieval system for data obtained on these patients.

A special report has been prepared to provide a comprehensive description of the total virus-leukemia program and detailed progress to date.

In other programs concerned with viral oncology, scientists will continue studies on the interactions of cancer viruses which induce solid tumors (e.g., sarcomas and carcinomas) in living animals. Intensive studies are planned on a new virus which appears to cause solid cancers (sarcomas) in mice. Collaborative studies with scientists of other disciplines (electron microscopy, physical chemistry, tissue culture virology, immunology, radioisotope technology, pathology) will attempt to completely characterize this new virus and elucidate the mechanism by which it transforms normal cells to cancer cells. Of particular importance are many studies on factors and conditions which enable cancer viruses of one species to infest and/or cause cancer in animals of different species. Since humans cannot be used for testing candidate human agents, proof of cancer inducing ability must depend on studies in lower animals. In this regard approximately 600 newborn primates of 9 different species will be inoculated wth human cancer materials suspected to contain specific viruses.

In addition to participating in the special virus-leukemia program the electron microscopy staff will continue their basic studies on the ultrastructure of viruses as well as on normal and cancer cells. It is the accumulated results of such studies that have made possible the recognition of cancer viruses on the basis of morphological appearance, and their distinction from normal cellular subcellular particles which play a role in normal cell activity.

The responsibilities of the National Cancer Institute to the community of researchers concerned with viral oncology continue to be met through a logistical services program that provides special materials such as tissue culture cell lines, purified viruses, virus-defined laboratory animals, and normal and malignant human tissues. These materials in many instances would otherwise be unavailable to the research community at large.

New plans for 1967 include the initiation of programs to study the action of DNA viruses in the induction of "solid" tumors. These viruses, producing tumors in solid tissues as opposed to circulating tissues (blood and lymph), require studies analogous to those in the study to RNA viruses in the induction of leukemia. Preparatory to establishing a major effort in this area, the National Cancer Institute must develop a cadre of trained personnel upon which to build a program of major dimensions in this area. Preliminary plans for this, a collaborative research program, were discussed at a recent meeting of the National Cancer Institute's scientists with the Nation's most eminent researchers concerned with the role of DNA viruses in tumor induction. It is expected that ultimately the plan will provide for the coordinated application of the most elegant laboratory techniques and seroepidemiologic methods to insure significant progress in this area. Initiation of this effort will be made possible through the reprograming of six positions and $103,000 previously used to support activities in Ghana.

An additional $71.000 is requested for mandatory items, including annualization of the general schedule pay increases, the commissioned officers' pay increase and the social security tax increase.

During 1966, the National Cancer Institute undertook an intensive review of the accomplishment of the chemotherapy program during its first decade. The staff reexamined its problems and developed a detailed program plan for future direction and reorganization. The staff concluded from this review that three major principles had emerged from the program to date. The analysis strikingly reaffirmed the need to focus intensively on the therapy of specific diseases— especially the leukemias, lymphomas and breast cancer. Secondly, the cure of

cancer by means of drugs or radiation in experimental models and in a few clinical cancers, was best interpreted by the hypotheses of Dr. Howard Skipper of the Southern Research Institute and Dr. Emil Frei, formerly of NCI and now with M. D. Anderson Hospital. In this hypothesis, cure of widespread cancer can occur when drugs (or radiation) are given in tumoricidal doses geared to the number of tumer cells in the body and their rate of multiplication. Thirdly. a full examination of the data of animal tumor screens in predicting useful drugs for clinical cancer, revealed new correlations, permitting considerable simplification of the screen. Since the budget for chemotherapy had been reduced by $2 million for 1966, many of the contracts that did not directly contribute to the three principles mentioned above, or to their corollaries, were reduced or phased out. The net result is a more intensive and focused program of chemotherapy capitalizing on the information acquired during the program operations since 1955.

A considerable effort during 1966 was devoted to studies of the circumstances by which it is possible to eliminate tumor cells completely from animals and patients. Special models in leukemias and solid tumors of mice have made it possible to calculate the lethal number of cancer cells at about 1 billion. The more potent drugs can be shown to destroy 99.9999 percent of these cells. Cure did not result however until all cells were killed. Fortunately, a slight increase in drug dosage enormously increased the percent of cells killed, and new pharmacological studies have shown how to increase this dosage without serious effect on the animal.

The acute leukemia task force has extend these findings to patients with leukemia, with marked increase in benefits. Application of both the more intensive therapy and new dosage schedules results in 80 percent of patients surviving 2 years or longer after the diagnosis of acute lymphocytic leukemia. The previous studies completed only 2 years ago showed only a 10 percent 2 year survival. Widespread liberal use of platelet transfusions has been one of the factors permitting more intensive treatment. Use of "life islands" and similar protected environments now being extended by the task force should protect the patients against infections, safely allowing even more vigorous therapy.

A thorough examination of 10 years of screening data has shown that the activities of the 30 agents known to have effect against clinical cancer can be uncovered by the use of two animal tumors used in sequence.

This clarification has permitted a redesign of the primary screen. The other animal tumors previously used are being eliminated or reserved for purposes other than primary screening. The reduction of the budget by $2 million in 1966 has been absorbed by this sharp simplification of screening. It has also been found in this NCI analysis that all the known clinically active drugs (with two minor exceptions) have effects in three groups of clinical tumors-the leukemias, the lymphomas and breast cancer. It has been decided therefore, as an extension of these economies and simplification, to make the major early trials of promis

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ing new agents in these three disease groupings. The cooperative groups (funded through grants but provided services through Cancer Chemotherapy National Service Center interested in these diseases have been drawn closer to this narrowed drug development program. While the primary clinical work with new agents is concentrated on the three disease areas, the resources of these eight groups will permit later clinical studies in all the common tumors. The acute leukemia task force continues its vigorous leadership in the development of new chemotherapeutic principles. The lymphoma task force and the chronic leukemia task force have extended their activities and coordinated them with the new program. Research in breast cancer is being reviewed with the recently established breast cancer task force.

Pharmacological study of antitumor drugs has begun to play a major role in the most efficient use of known antitumor drugs. This will become even more essential with the increase in intensive treatment required for the destruction of all tumor cells. New studies have been started, relating concentration of drugs at the target site, to their tumoricidal capacity. The same techniques are needed for predicting their toxic effects on normal cells. Study of the clinical correlates of pharmacology have been underway in new ventures in several of the cooperative groups. In addition, renovation of the 15,000 square feet of laboratory space at the Baltimore Public Health Service Hospital will permit sizable increases in clinical pharmacology.

The question remains as to the kinds and number of agents to put into the screen. Since there are no broadly established relations between chemical structure and antitumor effects of drugs, empirical searching its required-and the broader the search, the greater the possibility of finding an active chemical. In the past year, the following have been screened; synthetics, antibiotics, plant natural products, and endocrine materials. Clinically active drugs are found in all four categories. The size of the empirical search should be as large as one can afford.

PROGRAM PLANS IN 1967

The kinetic model, relating percent of tumor cell kill by drugs to the nature and circumstances of drug administration, will be intensively pursued in leukemias and solid tumors in animals and in patients. While this model is now worked out largely on the basis of drug dosage, the growing pharmacologic resources will be used to redefine tumor cell kill and drug toxicity in terms of concentrations of the drug reaching the cells through the blood. The need to increase drug dosage slightly will be extended in patients by the research on patient support.

Platelets have been essential to intensive chemotherapy. Only a few institutions have platelets available, despite increased grant support for this purpose. This limitation exists because platelets must be used within a few hours of collection. Research on freezing and prolonged storage of platelets will be fostered in an attempt to remove this limitation. Similar and more severe limitations of chemotherapy exist because the effect of drugs on the patient increases the likelihood of fatal infections. If the present investigations of protected environments should show the way to more general usefulness, this limitation may also be modified.

Particular attention is being paid to the rapid collection of data on screening, pharmacology and clinical trial, and their interpretation to the end that drugs may move safely and yet with great speed to clinical trial as soon as the animal data give strongly positive signals. Improvement and extension of data retrieval and analysis is planned.

Recent clinical data on Hodgkin's disease shows that approximately 50 percent of very early disease can be cured by tumoricidal doses of irradiation to all involved areas. On the other hand, application of cell-kill hypotheses to late Hodgkin's has shown marked improvement in the drug control of advanced Hodgkin's. Efforts will be made to use the best of both X-ray and drugs in appropriate patients to improve on the 50-percent cure of early disease and to attempt total tumor cell kill and care of late disease.

The work of the breast cancer task force will be extended to include studies on the viral etiology, early diagnosis and combination surgery and intensive chemotherapy of breast cancer.

1 Leukemia Group A; Leukemia Group B; Eastern Solid Tumor Group; Southeast Group; Southwest Group; Central Surgical Group; Western Group; and CCRF and Boston PHS.