NCI has recognized this disparity and has instituted an extensive program of initiatives, touching on all aspects of cancer to address this problem from epidemiology and surveillance studies to identify the differences, to basic research on understanding the differences, to treatment studies, to cancer prevention and control and outreach activities. NCI is committed to reducing the differential in experience as it works to reduce the overall levels of morbidity and mortality from cancer.

Turning to women's health, breast cancer is the most frequent cancer among women, responsible for 175,000 new cancers each year and 44,500 deaths. The next four cancers among females (ranked according to incidence) are colorectal cancer (78,500 cases, 30,500 deaths), lung cancer (60,000 cases, and the leading cause of cancer deaths with 51,000 deaths per year), uterine cancer (33,000 cases, 5,500 deaths), and ovarian cancer (at 20,700 cases and 12,500 deaths annually). Cervical cancer accounts for 13,000 cases and 4,500 deaths annually and ranks tenth among all cancers detected in women. Together, breast, uterine, cervical and ovarian cancers account for 44 percent of the 555,000 cases recorded annually among women. Progress among these cancers has been impressive, particularly among younger women as shown in the following table:

Women under 50 show decreases in each of these major cancers specific to females. (Although breast cancer does occur among males less than one-half of one percent of all breast cancer occurs among males.)

All these figures show that, yes, we are making progress against cancer, but we also face great challenges. As the population ages and increases the burden of cancer may well increase because the highest rates of cancer are among the elderly. These figures show that we have made progress and we expect this progress portends the advances we will see as today's younger population ages and as more prevention, diagnostic, and treatment advances reach the point where technology transfer is feasible.

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OVARIAN CANCER

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. 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.

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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.