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Question. Dr. Broder, I understand that there is a new treatment for ovarian cancer and the clinical trial is underway using the natural product derived from the bark of the yew tree. Unfortunately, it takes 20,000 pounds of bark to produce 1 to 2 pounds of the drug and the yew tree is an important habitat for the spotted owl in the Northwest. What can you tell us about efforts to produce this drug synthetically, in the laboratory, therefore avoiding destruction of the yew tree?
Answer. The development of taxol is a crucial priority. Numerous approaches are being pursued actively to develop alternative sources of taxol in order to decrease and eventually eliminate the need to harvest bark. The structure of the molecule is very complex and, although many chemists are pursuing total synthesis, it may not be possible to devise a commercially useful synthesis from scratch. Since taxol is found not only in the bark of the Pacific Yew but in the needles of that and other species of taxus, the major effort at present is focused on locating adequate sources of wild and cultivated species in the U.S. and worldwide, and developing the process technology for utilizing needle clippings, a renewable resource. Other approaches being pursued for more long-range application include plant tissue culture, propagation of high yielding specimens, genetic manipulation, and semi-synthesis, the production of taxol from naturally occurring precursors and analogs. Significant relief from dependence on bark should be accomplished in two to three years.
Question. How did we uncover the medicinal properties of the bark of the yew tree?
Answer. The activity of taxol, a product derived from the bark of the Pacific Yew, was first detected in the NCI experimental rodent tumor screens in the 1960s as part of our natural products discovery and development program. The production of taxol is linked to serious environmental issues. Development was very slow because of the extreme difficulty in obtaining the drug and the rather limited activity observed originally. Interest was stimulated greatly by the increased activity observed in other models in the late 1970s and the demonstration of its unique mechanism of action. Clinical studies were initiated in 1983.
CANCER MORTALITY AMONG NON-WHITES
Question. NCI's Atlas study states that mortality from two types of cancer, Non-Hodgkin's Lymphoma and Leukemia, is higher in Midwestern farming states, suggesting a possible link between the use of certain agricultural herbicides and these cancers. What specific research has NCI conducted to date in order to study the possible cancer-causing effects of exposure to and use of these herbicides and pesticides?
Answer. Since the late 1970s, the NCI has conducted a series of increasingly sophisticated epidemiologic studies to evaluate cancer risks from pesticide exposure. Early correlation studies that linked mortality rates at the county level with agricultural
activities were followed by death certificate investigations that noted elevated risks of lymphatic and hematopoietic cancer among farmers in Nebraska and Wisconsin. Case-control interview studies in Kansas and Nebraska that obtain information on pesticide use directly from study subjects, uncovered associations between nonHodgkin's lymphoma (NHL) and use of the herbicide, Dichlorophenoxyacetic acid (2,4-D). The risk of NHL was three to six times greater among farmers who used this herbicide twenty or more times per year than among subjects who did not use the chemical. NCI has made a special effort to study the risks associated with the use of 2,4-D. Efforts of the NCI have been instrumental in encouraging the adoption of some very effective methods of lowering the exposure of agricultural workers to this chemical. . By utilizing these recommendations, the risks associated with 2,4-D and specifically, the risk of non-Hodgkins lymphoma, can be significantly minimized. NCI has undertaken extensive information dissemination activities on this topic. One example is the use of compact disk read-only-memory (CD-ROM) computers which enable NCI to distribute the latest information rapidly.
Some lymphatic and hematopoietic cancers have also been associated with insecticide use. In Nebraska, NHL was elevated among farmers who reported using organophosphate insecticides. The Nebraska study also included cases of Hodgkin's disease, multiple myeloma, and chronic lymphatic leukemia. Analyses are underway of risks for these cancers from pesticide exposure among men and women.
In a study in Iowa and Minnesota, the risk of leukemia among farmers was associated with use of several insecticides, particularly those used on animals. A large study of members of the American Federation of Grain Millers found elevated mortality from NHL, leukemia, and pancreatic cancer among those employed in the flour industry, a segment of the grain industry where fumigants are more heavily used.
Other investigations of pesticide-exposed populations have noted excesses for soft-tissue sarcoma and cancer of the lung. The risk of soft-tissue sarcoma was elevated among farmers reporting the use of insecticides on animals. Licensed nonagricultural applicators from Florida had an increased risk of lung cancer that rose to nearly three-fold among those licensed for twenty or more years.
Several studies are planned or underway to further investigate cancer risks associated with pesticide exposure: Information on employees of a national lawn care company has been assembled to evaluate mortality from exposure to insecticides and herbicides. A cohort of Noxious Weed Department employees in Kansas is being studied because of their heavy use of herbicides. A methodologic study on current and past use of pesticides is being conducted in Iowa to improve exposure assessment procedures in epidemiologic studies of farmers. An NCI review of cancer risks among farmers from around the world noted rather consistent excesses of leukemia, NHL, multiple myeloma and cancers of the lip, melanoma of the skin, brain, stomach, soft-tissue sarcoma, and prostate. Case-control interview studies of cancers of the stomach and brain are planned in Nebraska among men and women to
identify agricultural factors that might account for the elevated rates observed among farmers.
Question. One of the most alarming trends documented in the NCI report concerns the increased number of deaths among non-white males from prostate cancer in the Southern region of the U.S. What future in-depth research is planned to identify the causes of these specific increased cancer mortality rates and to determine the risk factors associated with them?
Answer. Cancer of the prostate remains the most common cancer among men, the incidence having surpassed that for lung cancer in recent years. There is indirect evidence that the increasing incidence for this cancer may be due to increased detection of clinically asymptomatic cases associated with increasing rates of transurethral resection of the prostate (TURP). The incidence rate for black men in 1984-88 (134.0 per 100,000) continues to exceed that for white men (92.2 per 100,000) by fifty percent.
of great concern is the 13 percent increase in prostate cancer mortality for men of all races during the period 1973-1988, an increase affecting men primarily over 65 years of age. The 1984-88 prostate cancer death rate among black men (47.0 per 100,000) is more than twice the rate for white men (22.2 per 100,000). During the 16-year period between 1973 and 1988, the incidence of prostate cancer among white men increased by 60 percent and mortality among white men increased by 12 percent. In contrast, the increase in incidence for black males during this same interval was 35 percent with an increase in mortality of 20 percent. Data on stage of cancer at diagnosis indicate that black men present with more advanced disease at diagnosis and have lower survival, even when adjusted for stage.
The SEER (Surveillance Epidemiology and End Results) Program has a small pilot study underway to assess the availability and utility of data in medical records for investigating the role of TURPs on diagnosis and early detection of prostate cancer. This feasibility study is designed to review medical and SEER records from past years to determine whether changes in surgical or diagnostic procedures may explain the apparent increase in prostate cancer incidence over time.
Additionally, the NCI is formulating the development of a new research initiative on prostatic carcinoma that will focus on this rising problem within the non-white population. For example, in the Black population, research is being planned to identify and remedy key factors that contribute to avoidable prostate cancer mortality. These factors include geographic areas, occupation, tobacco, diet-nutrition, lifestyle, endogenous hormones, etc. Also, attention will be placed on barriers such as cultural and behavioral nuances that are unique to the Black population as well as barriers within the health care delivery system. This research will develop and test innovative prostate cancer interventions in Black populations as well as support investigations into the unexplained differences in prostate cancer biology and diagnosis in black and white males.
The NCI is also about to launch a large, randomized study to see if screening for prostate cancer in men aged 60-74 years is effective in decreasing mortality from prostate cancer. This is part of a large trial designed to test the efficacy of screening for prostate, lung, and colorectal cancers in men; and ovarian, lung and colorectal cancers in women. Investigators will pay careful attention to ensure that the study population is balanced with regard to inclusion of members of minority groups. The screening tests to be used to detect prostate cancer are rectal examination and a blood test for prostate specific antigen. As part of that study, there are plans to elucidate some of the causes of proståte cancer. Epidemiologic information which may uncover risk factors will be collected on each study subject. This will include information on smoking habits, life style, and diet. Of note, a recent study has suggested that cigarette smoking is a risk factor for prostate cancer. There is controversy over whether dietary factors play a role in prostate cancer. We plan to expand upon these observations and explore other possibilities in a prospective manner as part of our study.
Studies continue to examine the descriptive characteristics of prostate cancer in the United States, with emphasis on geographic patterns, time trends, and racial/ethnic disparities. In the new nonwhite atlas, a landmark finding is the recent emergence of high-rate areas for prostate cancer among black men in the South Atlantic states.
In a collaborative multicenter case-control study of prostate cancer in Atlanta, Detroit, and several communities in New Jersey, a variety of risk factors are being investigated, with special emphasis on the determinants of the higher rates in blacks than whites. Analyses are underway of interview data on lifestyle, diet, medical, and occupational history. Laboratory assays will be carried out on blood specimens to clarify the influence of dietary and hormonal factors. The role of diet is also being evaluated in the follow-up study of men in the first National Health and Nutrition Examination Survey (NHANES), which was recently extended through 1988 to permit further prospective investigation of the cohort. Initial analyses found serum vitamin A to be protective, with subjects in the lowest quartile having 2.2 times the risk of prostate cancer than those in the highest quartile.
In collaboration with the University of Minnesota, dietary and other information are being analyzed in relation to prostate cancer risk in a Lutheran Brotherhood cohort of nearly 18,000 males who responded to a questionnaire in 1966-1967. Recent analyses of the cohort suggest that cigarette smoking and smokeless tobacco may be risk factors for prostate cancer. A role for smoking in prostate cancer risk is suggested also by recent findings from the Dorn cohort study, using data from a 26-year extended follow-up of 250,000 U.S. veterans.
Extramural grants support a number of epidemiologic studies of prostate cancer. The role of nutrition is being explored in several of these, with emphasis on clarifying the role of dietary fat and micronutrients. In a multicenter case-control study being coordinated at Stanford University, risk factors for prostate
cancer are being evaluated among blacks, whites, and Asians in Los Angeles, San Francisco, Hawaii, Vancouver, and Toronto. A second grant at Stanford is focusing on the influence of physical activity and diet in cancer of the prostate. A grant activity at the Kuakini Medical Center is assessing prediagnostic serum hormone levels, diet, and body mass in the origins of prostate cancer among migrant Japanese in Hawaii. At the University of Southern California, grant-supported activities are examining the role of androgenic hormones in prostate cancer, with data suggesting that excess risk among blacks may be due to higher levels of certain testosterone metabolites.
This past year, the NCI epidemiology group organized a session on the etiology of prostate cancer which was part of a workshop held under the auspices of the Organ Systems Program. Special attention was given to factors that may account for the excess risk among black men, and plans for future research were developed. Another workshop, which involved intramural and extramural scientists, was held on the subject of cancer . epidemiology in minority groups. As a result, a Request for Applications (RFA) was issued to encourage research in this area, including multidisciplinary studies on the etiology of prostate cancer.
CANCER-RELATED INTERNATIONAL ACTIVITIES
Question. Dr. Broder, last year, this Committee included language in the Committee Report expressing our interest in international collaboration in cancer research. Could you please summarize for me the efforts you currently have underway to promote international scientific exchange, particularly in the areas of research training, joint research projects and prevention.
Answer. The National Cancer Institute places high priority on international collaboration. Cross-national research provides unique opportunities to advance the frontiers of cancer research. , This commitment to international cooperation will continue, as NCI pursues promising new areas for collaborative investigations with foreign scientists and institutions and increases its efforts to disseminate cancer information worldwide.
The unique opportunities provided by international collaboration are determined either by the special knowledge, skill, or ability of an individual foreign scientist or by the availability of special populations or nutritional or environmental exposure to carcinogenic agents in a foreign country. Such is the case of the high incidence of esophageal cancer in Linxian Province in China; the high incidence of stomach cancer in China, Chile, Costa Rica, Italy, and Hungary; the high incidence of pediatric AIDS in Romanian orphanages; the Chernobyl, disaster; and the enormous levels of polycyclic aromatic hydrocarbons and other contaminants found in the air, soil, and water in Silesia in Poland.