FY 1998 Questions and Answers provided For The Record for the FY 1998 House Appropriations Subcommittee.
These responses, developed by NCI program and OD staff, are to the questions submitted by Subcommittee members following the NCI Director’s testimony before the Subcommittee. The dialogue among the Subcommittee members and Dr. Klausner during the appropriation hearing is available in hard copy through the NCI Financial Management Branch.

Table of Contents

Mr. Porter: What is the status of your intramural program at Frederick?

Dr. Klausner: The research conducted at the Frederick Cancer Research Development Center has experienced major changes over the last year and a half. This is due to several reasons. First, two of the major research divisions using Frederick have hired new division directors, and under their leadership, programs have been altered and research emphasis have been modified to focus on state-of-the-art needs. Secondly, FCRDC programs have undergone rigorous scientific reviews by the NCI Board of Scientific Counselors (BSC) and as a result of these reviews many reallocations of resources have been recommended and implemented.

The Division of Clinical Science has closed the Clinical Research Branch (CRB) in Frederick and transferred the clinical staff and patient protocols to the NIH campus in Bethesda. All patients enrolled in these protocols are now being seen at the NIH Clinical Center or the NCI Medical Oncology Branch located at the National Naval Medical Center (NNMC) in Bethesda. The research portion of this branch will be relocated back to the Bethesda campus once space constraints are resolved. This type of change permits the NCI to fully utilize the resources at the Bethesda campus while allowing the Frederick operation to be primarily utilized for new initiatives and basic laboratory support.

The reallocation of laboratory space and resources resulting from BSC reviews permits new initiatives to be implemented. The Division of Basic Sciences will be establishing a new multi-disciplinary program on human immunodeficiency virus (HIV) drug resistance.

This program will coordinate exciting, cutting edge programs at FCRDC in a) structural biology of HIV proteins, b) molecular modeling, and c) chemical synthesis. Principal investigators with expertise in informatics and biochemistry will be sought as well. The considerable expertise of FCRDC scientists in computational analysis and structural biology will also be coordinated with clinical researchers in NIH Bethesda laboratories to develop novel strategies and therapeutics for the treatment of HIV-infected individuals and to develop new knowledge on how pathogens like HIV develop resistance to existing drugs.

The overall research effort at the FCRDC has significantly improved as a result of these types of organizational changes and will permit the Institute to move more efficiently toward its new research goals.

Mr. Porter: Do you intend to move additional portions of the program back to the Bethesda campus?

Dr. Klausner: As stated previously, the NCI has closed down the CRB and transferred patients and protocols to NCI programs at the Clinical Center and NNMC, with relocation of the research lab to follow. The National Cancer Institutes Board of Scientific Counselors has not recommended further relocation of any additional Frederick intramural laboratories to the Bethesda campus. Should future program initiatives warrant it, FCRDC operations could be considered in order to implement these new initiatives.

Mr. Porter: Do you intend to broaden the mission of Frederick to include other NIH Institutes?

Dr. Klausner: Currently, it is not the intention of the National Cancer Institute to recommend other institute relocations involving direct research operations to FCRDC. However, the National Cancer Institute is establishing state-of-the-art core support services which will be available for NCI intramural laboratories and then extended to other NIH institutes in the future.

Mr. Porter: Provide FY '96-98 totals for intramural research, including the research conducted under the Frederick contract.

Dr. Klausner: The following figures represent NCI's FY1996 actual intramural spending, including the intramural amount spent on the Frederick contract, and the FY1997 and 1998 projections:
FY1996 actual spending $427 million
FY1997 projected spending $424 million
FY1998 projected spending $433 million

Mr. Porter: Your Institute has experienced a fairly significant FTE drop since FY '93. In which parts of your program did decreases occur?

Dr. Klausner: This approximate 15% reduction in FTEs has impacted on most of the activities -- scientific and administrative -- of the NCI; our intramural research efforts, cancer control initiatives and the management of scientific programs of the institute. Difficult decisions have been made for all operations and we have been looking at ways to streamline our operations and improve the quality of service. Aiding us for the intramural research program was the initiation of a review of the NCI intramural operations by an Ad Hoc Working Group of the National Cancer Advisory Board. Their recommendations were presented to me and many have been implemented already. The NCI recognizes its responsibilities to function as efficiently as possible and to make difficult decisions about redirecting funds to reflect priorities and opportunities. In that context, eight programs, eight branches, and eighteen sections have been abolished. In addition, six administrative branches have been merged into two organizational components with improved efficiency and service to the research programs. One area of business operations change over the past several years has been in the field of Information Management. In that arena and as a streamlining and FTE savings initiative we have consolidated our support services from the seven divisions and eight offices into a single management structure.

Mr. Porter: What share of your construction request is intended for extramural facilities and what portion is designated for the Frederick center?

Dr. Klausner: The NCI 1998 budget request includes $2.6 million for construction funding. Of this amount, almost 60% will be used to fund grants from the extramural community and the remainder will be will be used for repairs and maintenance at the Frederick Cancer Research and Development Center.

Mr. Porter: In what percentage of cases is radiation used to treat cancer?

Dr. Klausner: Radiation is one of the most frequently used and successful curative modalities in oncology, and its use continues to expand. It is often used as definitive treatment in a number of diseases -- Hodgkin's disease, early stage non-Hodgkin's lymphoma, gliomas, cervical, lung, head and neck, bladder, anal, prostate, retinoblastoma, and others; for organ preservation following local excision -- breast, soft tissue sarcoma, rectal cancer; to improve local/regional control after radical excision -- breast, rectal, lung, head and neck; and for palliation.

Seventy to eighty percent of cancer patients will be eligible for radiation therapy at some time during their disease. According to the American College of Radiology, fifty percent of all cancer patients actually receive radiation therapy during the course of their disease. The discrepancy is due to multiple factors such as: lack of access, failure to refer patients for treatment, lack of understanding of role of the RT, lack of awareness by the patient, patients' insurance does not cover or limits the patients' access to treatment.

Mr. Porter: How much funding does NCI devote to radiation research?

Dr. Klausner: The NCI spent about $142 million on radiation research in FY 1996 and our current projections are to maintain approximately that level of support over each of the next two years.

Mr. Porter: What is the Institute doing to encourage the generation of meritorious proposals in the area of radiation research?

Dr. Klausner: The NCI has made presentations at radiation oncology meetings. These have included talks on the process of applying for research grants. The NCI staff attended major scientific meetings which have included lectures encouraging applications for funding of meritorious ideas. During this year the NCI has conducted a workshop on Radiation Molecular Biology which addressed the problems of translating discoveries in the laboratory into benefits for cancer patients treated with radiation therapy. In addition, the NCI will be conducting a future workshop on Treatment Planning which will determine the directions radiation oncology should go in development and research in radiation dose distributions in the treatment volume. Also, a workshop on Radiation Oncology and Tumor Imaging will be held to find frontiers of cancer imaging research as related to diagnosis, treatment and follow-up of cancer patients treated with radiation therapy. Finally, a workshop on Brachytherapy will be held to establish research needs and quality assurance guidelines in the use of radioactive materials in the treatment of patients with cancer.

The Radiation Therapy Oncology Group (RTOG) is a group of physicians, physicists, and statisticians committed to clinical radiation oncology research. This group is funded by NCI. The NCI works with the Radiation Therapy Oncology Group to support and fund clinical research protocols. The RTOG continues to generate meritorious proposals in the area of clinical radiation research on cancer patients. These protocols provide important information on the best methods for improving the survival and quality of life of cancer patients needing radiation therapy.

Mr. Porter: What is NCI doing to enhance its research portfolio in the area of tobacco use and children?

Dr. Klausner: Efforts to control tobacco use and tobacco-related morbidity and mortality in the United States have met with reasonable success, at least through the early 1990s. In the 33 years since the publication of the first Surgeon General's Report on Tobacco and Health, adult smoking rates in the U.S. have been reduced by nearly 34%, with reductions among males accounting for much of this success. Other indices of success, such as changing attitudes toward tobacco use in public places, widespread perception of tobacco use as a health hazard, and increasing numbers of laws restricting tobacco use have also been positive.

Controlling tobacco use among U.S. youth, however, has not been as successful. Although there was considerable success in reducing adolescent tobacco use in the late 1970s and early 1980s, tobacco use among high school seniors - for whom data with the longest time trends are available - have remained essentially stable for more than a decade, with just under 20% of seniors reporting daily smoking. Furthermore, high school dropouts smoke at an alarmingly high rate. One study in Minnesota found that 77% of both male and female 16-year old dropouts smoked on a daily basis; a similar study in Ontario, Canada, found a nearly 68% smoking rate among high school dropouts.

When the high school senior tobacco use prevalence rates are considered in tandem with the dropout smoking rates, the smoking prevalence rate among U.S. adolescents nearly equals that among adults, i.e. about 25%. Smokeless tobacco use - chewing tobacco - among youth, especially among males, also continues to rise. If these trends continue, the prospect for further reductions in national tobacco use prevalence rates - and accompanying tobacco-related disease rates and economic costs - is unlikely to change substantially in the foreseeable future. Nevertheless, a great deal has been learned about tobacco use by children and youth - as demonstrated by several recent reviews of this issue - but there is also a great need to learn more and, especially, to apply broadly and systematically what has already been learned.

In January, 1997, the NCI issued a Request for Applications (RFA) entitled "Prevention and Cessation of Tobacco Use among Children and Youth in the U.S." The stated purpose of this RFA is to support "innovative research which has clear implications for the immediate and significant reduction of tobacco use by children and youth in the United States." This RFA represents the largest and most targeted effort ever undertaken by the NCI and the NIH to reduce tobacco use and its attendant disease burden among our youth. The NCI has budgeted up to $32 million for this initiative between FY1997 and FY2001.

While there is little doubt that it is the combination of effort from many channels, public awareness and commitment, policy change, and research, as demonstrated through the NCI's and American Cancer Society's ASSIST (American Stop Smoking Intervention Study) program, that will likely have the greatest effect on reducing tobacco use among children and youth, this new research initiative can make an enormous contribution to reducing tobacco use among children. Among the questions to be addressed by this initiative are the following:

• What are the characteristics - pharmacological, physiological, and psychological - of nicotine dependence in its early stages and, especially, during the transition between experimental and dependent use? Are there differences in individual susceptibility to nicotine dependence among youth? What is the relationship between the characteristics of different tobacco products and early nicotine dependence? Are there pharmacological treatments from which nicotine dependent children and youth will benefit? What are the characteristics of successful nicotine dependence cessation programs for youth under age 18? How can these programs be adopted on a large scale?
• What are the factors influencing the decline in, or relative lack of involvement in, tobacco use among particular ethnic, social, religious, or racial groups in the U.S., e.g. African-American youth? How can these factors be applied to the larger population of U.S. youth? Conversely, is there need for prevention programs aimed at youth subpopulations at high risk for tobacco use? Can such programs be successfully developed, evaluated, and adopted on a large scale?
• What are the factors that influence youths' responses to advertising, promotional, and warning messages aimed at discouraging tobacco use? What are factors the influence youth's responses to advertising and promotional messages aimed at encouraging tobacco use? What are the ethnic, gender, and social class differences which influence these responses? What are the characteristics of failed and successful advertising campaigns aimed at discouraging tobacco use by children and youth?
• How do tobacco price increases, especially through higher taxes, affect youth tobacco use in comparison to the effect of prices increases on adult tobacco use, i.e. are youth more, less, or equally price-sensitive to tobacco prices than adults?
• What is the optimal age, and circumstances, at which programs aimed at discouraging tobacco use by children and youth should begin? Is it better to focus on tobacco use alone in these programs or to include other youth-relevant health issues such as diet and exercise? What is the role of the family in discouraging tobacco use among children and youth? What is the role of the health care community, ranging from practitioners - e.g. nurses, pediatricians, dentists, OB-GYNs, family physicians, - professional organizations, and health-care delivery and reimbursement systems?
• What is the optimal way to disseminate and implement successful youth and children tobacco prevention/cessation programs on a large scale?

The results derived from the NCI's new research initiative on children's tobacco use will complement our ongoing research activities in this area. This research includes the ASSIST project and a wide array of investigator-initiated research focusing on such diverse and important issues as the role of school health education in the reduction of youth tobacco use; differences in tobacco use incidence among white, African-American, and Hispanic youth; the role of health care professionals in advising children about tobacco use; youth spit tobacco prevention and cessation; use of multimedia systems for tobacco use prevention among children; and many others.

Mr. Porter: How is the "Five a Day" program, which encourages people to eat five servings of fruits or vegetables each day, working?

Dr. Klausner: The 5 A Day for Better Health Program is a national public/private partnership nutrition education program which approaches Americans with a simple, positive message--to eat 5 or more servings of fruits and vegetables every day. The 5 A Day objective mirrors the Healthy People 2000 nutrition objective of increasing fruit and vegetable consumption. The NCI takes the lead in the Program by serving as the credible health source, maintaining scientific integrity, funding research in nutritional behavior change, and organizing and providing technical support to the 55 state and territorial health departments in the 5 A Day infrastructure. The produce industry organized the nonprofit Produce for Better Health Foundation (PBH) to work with the NCI on this endeavor.

The 1991 5 A Day Baseline Survey revealed that awareness of the recommended number of daily servings was low and overall consumption lagged well below recommended amounts. Only 8% of the survey subjects were aware of the need to consume 5 or more servings of fruits and vegetables a day, and over 77% of the U.S. population were not eating the minimum daily amount of fruits and vegetables recommended. From the baseline survey, the median daily intake of fruits and vegetables was about 3.4 servings. As a result of the combined efforts of the NCI, the 5 A Day coordinators at the state level, and the industry partners, the program continues to have a positive effect on the awareness, knowledge and behavior of the American public.

I will attempt to give you a brief overview of the first five years of the program. In 1993, nine four-year grants were awarded to develop and test strategies to help Americans increase fruit and vegetable consumption. Preliminary data show that all nine projects achieved a significant increase in fruit and vegetable intake among populations in specific channels, e.g. worksites, schools, etc. These projects end in the spring of 1997. Additionally, in collaboration with the CDC, the NCI has funded 14 small 5 A Day grants to state health departments to evaluate existing 5 A Day interventions at the community level. Organizationally, the NCI has licensed and provides technical support for 55 of the 56 state and territorial health departments, as well as the health promotion programs of the uniformed services and the Indian Health Service, to conduct 5 A Day interventions at the community level. The Produce for Better Health Foundation has licensed over 1000 industry partners, representing approximately 35,000 supermarkets. Well over 80% of all states have 5 A Day health promotion coalitions, representing over 1600 organizations nationwide. The 5 A Day Program has a formal relationship with the CDC and with the American Dietetics Association to collaborate and disseminate the 5 A Day message. Eleven other countries are implementing similar programs to increase fruit and vegetable consumption, and are using the U.S. 5 A Day Program as a model. I'm pleased to report that consumer awareness of the need to consume 5 or more servings of fruits and vegetables daily has risen from 8% in 1991 to 38% in 1996. Additionally, the most recent (1994) USDA nationwide food consumption survey reveals that average adult consumption of fruits and vegetables has increased ½ serving. However, children and adolescent intake has remained the same at about 3 servings per day.

In the future, the NCI plans to continue set aside funding for 5 A Day nutrition and behavior change research, particularly research projects focused on children, in addition to conducting policy and evaluation research on public/private partnerships focused on improving American diets. Other efforts will include technology transfer research designed to transfer the scientific knowledge gained from our behavior change research to the community level programs, and dedicated funding for state health department 5 A Day demonstration projects at the community level.

Mr. Bonilla: I am proud to say that in my hometown of San Antonio has one of only 28 "comprehensive" cancer centers in the country. The San Antonio Cancer Institute (SACI) is a partnership between the University of Texas Health Science Center and the Cancer Therapy and Research Center. NCI recognized SACI as a comprehensive center last spring.

It is my understanding that for years, the San Antonio group has been among the few authorized by NCI to conduct Phase I clinical trials. These are first time trials of promising anti-cancer agents in humans. Please comment on the effectiveness of the San Antonio program.

Dr. Klausner: Cancer centers vary substantially in the scientific focus of the research which they conduct. This is determined by a number of factors, not the least of which are the areas of interest and expertise of the scientists which they employ. The University of Texas at San Antonio (UTSA) has an extremely successful and productive new drug development program. UTSA has been one of a small number of institutions funded by NCI to do Phase I trials with its IND agents. They have been funded for this purpose since 1985. At that time the NCI funded approximately 8 institutions for this purpose. Currently, 17 Cancer Centers conduct these trials.

Mr. Bonilla: Will NCI award additional comprehensive cancer centers?

Dr. Klausner: The NCI has just completed a major evaluation of the Cancer Centers Program using of panel of experts in all areas of cancer research and in outreach and education. The implementation of the panel's recommendations has resulted in substantive changes in the guidelines for cancer centers that should result in an increase in the number of NCI-designated Comprehensive Cancer Centers throughout the nation. We have replaced a cumbersome two-stage peer review system with a simpler one-stage system, for the first time allowing new cancer centers to be evaluated for the comprehensive designation, and are working on novel ways to enhance and sustain high quality outreach and education activities in the communities and regions that cancer centers serve. All of these changes should provide additional incentives for more centers to become comprehensive cancer centers. Within the next 3 to 5 years we could easily see ten additional cancer centers successfully receive the comprehensive designation, raising the total from the current 26 -- out of 55 -- to approximately 36 -- out of 55 or, hopefully, more.

Mr. Bonilla: Dr. Klausner, in the past the Committee has expressed its support for the National Cancer Advisory Board's 1994 report entitled "Cancer at the Crossroads" which concluded that the National Cancer Program suffered from a lack of coordination of cancer fighting efforts in the public, private and voluntary sectors. As a result the Committee has recommended that NCI take the lead in coordinating the nation's cancer prevention and control programs with the CDC and other Federal agencies to reestablish coordination of the National Cancer Program. Could you update us on your progress in this area?

Dr. Klausner: As I'm sure you know, the NCI was asked following last year's testimony to prepare a comprehensive report addressing the NCI's coordination activities. That report has been forwarded and should be available to you shortly. However, I would be pleased to provide a summary of its contents here.

The reduction in cancer death rates that has occurred since about 1990 is but one very tangible result of the Nation's commitment to cancer research. In addition to improvements in mortality rates for many malignancies, the National Cancer Program (NCP) has achieved important improvements in the quality of life for America's 10 million cancer survivors through less disfiguring and less damaging surgical procedures, better pain control, and more effective medication for the side effects of cancer therapy. Progress against cancer should also be measured in the growth of knowledge about the group of diseases that collectively bear that name. It is upon this knowledge base that the progress of the next century will rest.

This progress will be enhanced by the coordination of the many activities that comprise the NCP, and it is in this coordination that the NCI has and will continue to take the lead. NCI recognizes and stimulates research opportunities through its infrastructure of discovery that leads to understanding of the etiology and biology of cancer and thus provides the means to control and prevent it. NCI facilitates exchange of information, seeks to ensure that overlap and duplication are avoided, and supports the many areas of expertise needed to overcome cancer. NCI's activities in leading the NCP often involve interactions with entities outside of the NCI -- individuals, groups, organizations, and other components of the Federal government. The brief report mentioned above will outline the types of NCI efforts related to coordination of the NCP and provide selected, significant examples of these activities to underscore the progress made in the area of coordination.

Mr. Bonilla: For the record, I would like NCI to submit a copy of their general counsel's response to the Inspector General's inquiry. I believe the document was printed on January 15, 1997 and is entitled, "Inspector General inquiry concerning local lobbying: ASSIST Program."

Dr. Klausner: The NCI response to the Inspector General's inquiry has not yet been finalized. When it is completed and submitted to the IG, a copy will be forwarded to you and to the Committee.

Mr. Bonilla: Has the ASSIST program been extended for another year?

Dr. Klausner: Yes. The ASSIST contractors were recently notified that their contracts would be extended at full funding through September 30, 1999.

Mr. Bonilla: The IG has indicated that one of the difficulties in completing an audit is due to the fact that it is difficult to distinguish between federal and non-federal money once it leaves HHS. What safeguards have been put in place to ensure that federally and non-federal funds are not commingled?

Dr. Klausner: The NCI has been extremely careful to monitor the use of federal funds in the ASSIST program. Redundant monitoring mechanisms are used to assess activities before and after they are completed. NCI receives annually from each contractor a description of all proposed ASSIST activities. These proposed activities are reviewed for adherence to scientific principles and all applicable laws and regulations. In addition, prior approval by NCI is required for each subcontract. Detailed reports of all completed activities and expenditures are required quarterly. Site visits by NCI staff are used to confirm the written reports.

Mr. Bonilla: What procedures does NCI follow to ensure funding is not commingled?

Dr. Klausner: As discussed above, NCI requires detailed reports of all use of federal funds. In addition, the ASSIST contractors have received detailed instruction in allowable uses of federal funds. This instruction included written materials and in-person training. When activities are proposed that are judged to be unallowable, NCI staff inform the contractors and do not approve expenditures of funds for those activities.

Mr. Bonilla: Has NCI ever indicated to the ASSIST contractors what actions would be considered lobbying and which actions are permissible?

Dr. Klausner: The NCI has provided detailed information to the ASSIST contractors regarding permissible use of federal funds. This information was provided prior to the beginning of the intervention phase. The contractors have been reminded of the relevant laws on a regular basis.

Mr. Bonilla: Is one of the goals of the ASSIST program to increase and strengthen public support for certain policy changes?

Dr. Klausner: Yes. Increasing support for public and private policies that are known to reduce tobacco use, especially among children, is a goal of ASSIST. Just like policies that require children to be vaccinated in order to attend public schools, the Department has recognized that public policies are critical to improving the health of the public. In another area of cancer prevention, the NCI has worked to make women aware of the importance of mammograms and the need for mammography quality assurance laws. We are very aware that federal funds can not be used for certain activities related to public policies. We have made sure that ASSIST contractors are in compliance with all regulations related to this issue. Reducing smoking among children is a major priority of the Department, so the NCI has taken extra care to be sure that the ASSIST project is in full compliance with the law.

Mr. Dickey: A major emphasis of the NCI is cancer prevention, including the identification of avoidable risk factors. I have seen a paper called, "Induced abortion as an independent risk factor for breast cancer: a comprehensive review and meta-analysis" published last October in the Journal of Epidemiology and Community Health. The authors say they found 23 studies that looked at abortion and breast cancer and found that , overall, there seems to be a 30% increased breast cancer risk due to having an abortion. What is the National Cancer Institute doing to explore the possible link between abortion and breast cancer?

Dr. Klausner: Recent studies with stronger study design have yielded different results than the analysis to which you refer. Because the issue is so important, the NCI continues to explore all leads from epidemiology, clinical and laboratory studies. The Institute has several on-going and planned case-control and cohort studies that collect reproductive history, including induced and spontaneous abortions. Examples of these studies include the ongoing Long Island Breast Cancer Study, the Agricultural Health Study, and the planned study on Breast Cancer Gene-Environment Interaction.

Mr. Dickey: I understand that the recent Danish study has several flaws which could invalidate its conclusion. For example, the study includes all Danish women born from April 1, 1935 through March 31, 1978. However, the study does not take into account tens of thousands of legal abortions performed on women before 1973. So if the Danish study classified a lot of women who had abortions as not having had abortions, and then said that the thousands of women who developed breast cancer had no history of abortion, wouldn't you agree that this misclassification might have affected the study's conclusion?

Dr. Klausner: All epidemiology studies have limitations, and that is why a variety of study designs have been used to explore the complicated issue of abortion and breast cancer. In the Danish study recently published in the New England Journal of Medicine, the lack of data on abortions before 1973 would primarily affect the oldest women in that study, whose reproductive years could have included unrecorded abortions. If the lack of risk observed in the older women was the result of such misclassification, then we would have expected to have seen an effect in women who were born later, if they are followed sufficiently long. However, the investigators reported no effect in those women either. In those women, there was no measurable increased risk of breast cancer associated with previous abortion.

It is important to note that unbiased classification of abortion history is a great strength of the Danish study. This is the only large study that documented which women underwent an abortion and then measured subsequent risk of breast cancer in women who had an abortion compared to those that did not. This study design is the best way to eliminate the well-known possibility of inaccurate recall of past events and exposures in retrospective studies -- so called "recall bias". People affected by life threatening diseases tend to recall and report past risk exposures more accurately than would healthy control subjects. On balance, therefore, the Danish study yields stronger evidence than the meta-analysis of retrospective studies reported last October in the Journal of Epidemiology and Community Health.

Mr. Dickey: Other problems with the Danish study have been pointed out to me. The study data base was completed as of December 31, 1992. So Danish women who were born between 1968 and 1978 would be between the ages of 14 and 24 at the end of the study. Aren't virtually all women who develop breast cancer older than this age group?

Dr. Klausner: Although the Danish study included some young women who, as you accurately point out, are at low risk of breast cancer, the study included women over a broad range of ages, 14 to 57 years old. Since the study was very large and included more than 10,000 women who developed breast cancer and more than 370,000 women who had undergone abortions the investigators were able to make a statistically secure statement: they found no overall risk of breast cancer associated with abortion. The large data set and range of ages of the women in the study also permitted the investigators to look for any associations between abortion and breast cancer in women of various ages. The investigators did not find any effect on their conclusion of the age at which a woman had an abortion or of the age attained in the study. That is, there was no measurable link between abortion and breast cancer for any age at abortion or any age attained during the study follow-up period.

Mr. Dickey: It is very disturbing to me that Dr. Patricia Hartge at the NCI wrote an editorial in the New England Journal of Medicine, in the same issue in which the Danish study was published, saying, "In short, a woman need not worry about the risk of breast cancer when facing the difficult decision of whether to terminate a pregnancy." As a scientist, can you tell me that, after reading the meta-analysis by Dr. Joel Brind and others which found an increased risk of breast cancer due to having an abortion, and after hearing these questions raised about the Danish study-can you tell me that abortion poses no increased risk of breast cancer to women?

Dr. Klausner: In the meta-analysis to which you refer, studies as early as 1957 were included. Many older studies have well-documented methodologic flaws. This meta-analysis did not take into account the strength of study design. Perhaps even more importantly, even the methodologically strongest studies included in the meta-analysis were prone to the potentially serious problem of recall bias mentioned earlier.

A large body of epidemiologic data, critical reviews and editorials have all commented on this bias. To be precise, the extent of recall bias, which varies somewhat from study to study, has been widely recognized as the greatest problem in the ability of retrospective studies which rely on personal recall to assess reliably any possible association between breast cancer and abortion. The use of meta-analysis, which simply combines data from many individual studies, does not eliminate problems inherent in a study, but rather may propagate or even compound the errors. Statistically combining studies with systematic methodologic flaws and biases will still give biased results, magnified to the level of statistical significance. In medicine and in public health, one cannot simply count up the number of studies that support one hypothesis or another to determine which hypothesis is correct. As studies of better design are reported, their results should be given more weight.

With respect to the editorial by Dr. Hartge, she was expressing her view as an individual epidemiologist with extensive experience in retrospective cancer case-control interview studies, prospective record-based studies, epidemiologic methodology, and meta-analysis. She judged that the data accuracy, design, and analysis of the Danish registry linkage study provided important new evidence to help resolve the controversy among epidemiologists over this issue. She concluded that the Danish study added to the existing body of evidence critical information in that data collected without recall bias showed no overall effect on breast cancer risk in women who had abortions.

In her editorial, Dr. Hartge noted that there remain unresolved biologic questions in this area that need further study. Such issues are certainly of importance to the understanding of breast cancer. The Danish study points to late abortions as an area that needs further research. The NCI will continue to support research into all areas likely to increase our understanding of breast cancer etiology. As I mentioned earlier, several studies dealing with abortion as a risk factor are underway. However, at present, the best epidemiologic evidence does not indicate that increased risk of breast cancer is posed by abortion.

Ms. Northup: You mentioned environmental factors which can alter the risk of cancer -- one that was noted was diet. It was my understanding that studies relating to diet have been inconclusive when it comes to cancer. What has NCI done in this regard, and where are we on evidence that diet changes may be helpful to preventing cancer?

Dr. Klausner: Most of the current evidence relating diet and dietary components to cancer has been obtained from epidemiological (observational) studies and animal experiments. Results of such studies suggest that high levels of calories and fat in the diet is associated with an increased risk of a number of cancers and that high consumption of fruits and vegetables, dietary fiber, and some vitamins and minerals is associated with a reduced risk of a variety of cancers. These findings serve as the basis for general dietary guidance for the public. However, because of the inherent limitations of epidemiological and animal studies, the evidence they provide must be considered suggestive rather than conclusive regarding the potential role for diet and dietary components in the prevention of cancer. Controlled clinical trials are needed to establish the benefit of specific dietary patterns and/or components in cancer prevention. A number of such intervention trials of the effects of low-fat and/or high-fiber diets are ongoing.

One is a study to determine whether a low fat, high fiber, high fruit and vegetable dietary pattern will decrease the recurrence rate of large bowel adenomatous polyps. This is a multi-center randomized controlled trial involving 2,000 men and women.

A prospective, multi-site, randomized clinical trial has been initiated to test whether dietary fat reduction as an adjuvant breast cancer intervention will reduce disease recurrence and increase survival for postmenopausal women with localized breast cancer. This study will enter a total of 2,000 postmenopausal women over 50 years of age who have a dietary fat intake of greater than 25 percent of calories at baseline assessment.

A randomized controlled clinical trial of the Women's Health Initiative is enrolling approximately 63,000 postmenopausal women aged 50 to 79 years of age. This trial, which is supported by the NIH, has three intervention components; one will evaluate the effect of a low-fat dietary pattern on the prevention of breast and colon cancer and coronary heart disease.

Trials of individual dietary components have also been conducted and some have been completed.

The Physicians' Health Study, the Alpha-Tocopherol, Beta-Carotene (ATBC) Lung Cancer Prevention Study, the Carotenoid and Retinoid Efficacy Trial) found that beta-carotene was not effective in decreasing the incidence of lung cancer, whether administered alone or in combination with vitamin A or vitamin E.

An intervention trial in Linxian, China, showed that a supplement of selenium, vitamin E, and beta-carotene resulted in a decrease in stomach cancer mortality. In another study, selenium supplementation failed to reduce the incidence of skin cancer, but did reduce the incidence of prostate cancer.

Vitamin E supplementation in the ATBC Study resulted in a significantly lower incidence of prostate cancer in male smokers. The ongoing Women's Health Study is examining the effects of vitamin E supplementation on cancer incidence in women.

The NCI is also supporting human metabolic studies designed to improve understanding of the mechanisms of action by which components of plant foods and dietary fats may modulate cancer risk. Results of such studies will be useful in guiding plans for additional dietary intervention trials and in helping to refine dietary guidance for the public.

Ms. Northup: In your testimony you mentioned the ability to more precisely determine the risk associated with specific alteration in specific genes. Could you go into greater detail about the work which is being done in this area and what types of cancer this research may address?

Dr. Klausner: We have developed an entire program of studies to investigate the risk of cancers associated with specific alterations of genes. The ability to define and understand whether variations in genes within the human population will allow us to better predict sensitivity to specific causes of cancer is one of our great challenges. There are two broad categories of genes being evaluated: those that confer high risk of cancer but are relatively rare in the population, and those that confer much lower risk but are much more frequent. Studies of alterations in these two types of genes are being conducted for almost every type of cancer.

Examples of the high-risk relatively rare genes are BRCA1 and BRCA2. In families with multiple members with breast and ovarian cancer, it is estimated that those family members who have alterations in these genes are at a very high risk of developing both breast and ovarian cancer. It is not known, however, whether alterations in the genes confer the same magnitude of risk in the general population, and it is difficult to test for alterations throughout these large genes. Knowing the cancer risks associated with specific alterations is essential for adequate genetic counseling. Among the Ashkenazi Jewish population, two specific alterations in BRCA1 and one alteration in BRCA2 have been found at a total frequency of about 2%. The technical feasibility of only looking for three specific alterations and the frequency of 2% in a defined group make it possible to try to assess the risk of breast and ovarian cancer associated with these specific changes. We have recently conducted a large study of these three specific alterations in the Jewish population in the metropolitan Washington area. We are still finalizing the results of these studies, and hope to have the manuscripts published this summer.

Examples of genes in which common variations may influence cancer risk are ones involved in clearing out the toxins from cigarette smoking. One of these genes, GSTM1, has a variation present in about half of the general population. In heavy smokers, this variation has been found to confer about a 2-fold increased risk of lung cancer. In a similar fashion, a common variation in another gene, ADH₃, has been associated with a 5-fold increased risk of oral cancer among people who are heavy alcohol drinkers. Although the risks of cancers seen with these common variations is much lower than with genes like BRCA1 or BRCA2, the effect in the general population may contribute to a greater percentage of cancers.

Ms. Northup: It is intriguing the role that genetics play in cancer. Please describe the funding you plan to give to the Cancer Genetics Network and how many centers of excellence will be involved in preparing protocols for individuals at genetic risk.

Dr. Klausner: Capitalizing on advances in the area of hereditary cancer predisposition requires scientific resources and study populations that are currently unavailable to most human genetics programs. The purpose of the Cancer Genetics Network is to support the formation of a multicenter, interdisciplinary cooperative which will serve as an infrastructure for collaborative research investigations into the genetic basis of human cancer susceptibility, explore mechanisms for integrating this information into medical practice, and identify means to address the psychosocial, ethical and legal issues associated with human cancer genetics.

The Cancer Genetics Network will also facilitate the exchange of human cancer genetics information and resources within the larger cancer genetics community. The Network will develop mechanisms to broaden access to genetic services and educational materials by both the public and health care professionals. It will establish a clearinghouse of human cancer genetics resources and develop means to extend access to and connections between cancer genetics researchers, providers of genetic services, and the general public.

Thus, the Network will be a hybrid between the traditional models of Cancer Centers -- with recognized scientific excellence -- and the cooperative clinical trials groups -- with efficient multiline recruitment. Through this research infrastructure, potential study populations are preassembled through multiple participating centers and linked to a collective scientific expertise in cancer genetics. It is envisioned that groups participating in the Cancer Genetics Network consortium will have access to resources, information, and expertise that are beyond the scope of any single institution or organization.

Initially, a maximum of eight Network participating centers will be funded. If this pilot is successful, additional funds will be sought to expand the number of participating Network centers. In addition, an Informatics and Information Technology Group will be supported to serve as a resource in helping to meet the information management needs and requirements of the Network. This Group will help develop and maintain an internet-based data management system, which will expand and enhance the heterogeneous computer capabilities of the individual participating centers. Data security and confidentiality will be of primary importance in the design and implementation of this information system. Individual participating centers must demonstrate competency in electronic management of data that will become part of the larger Network repository.

The Network will provide funds for the development of pilot studies in all aspects of cancer genetics research, including the psychosocial, ethical, and legal impact of genetic testing, and will seek to foster collaborative research among Network centers and between Network and other researchers to encourage optimal utilization of this national resource.

Ms. Northup: What ethical considerations do you intend to accompany genetic risk testing development?

Dr. Klausner: There are a number of complicated scientific and ethical issues in genetic testing for cancer susceptibility. Questions related to rights to privacy and protection from discrimination on the basis of genetic testing must be addressed. But these are not simple questions. Do family members who may share genes have a right to know the results of another family member's test? The uncertainty involved in the scientific issues has a profound bearing on theses ethical issues, so I would like to focus on the scientific issues.

My remarks pertain to genetic testing for the relatively rare genetic variations that confer substantial risk. The common variations in genes that are associated with smaller risks in combination with specific exposures like cigarette smoking have completely different implications for genetic testing, because they frequently have little medical implications for disease risk without the relevant exposure. With respect to the genetic alterations associated with high risk in selected families, it should be pointed out that almost all of the current risk estimates are derived from the rate of cancer in families selected because many members have cancer. These families are essential for finding cancer susceptibility genes, but the risk in these families is very likely different than the risk associated with exactly the same alteration in other people. Before reasonable genetic counseling about risk associated with a specific alteration can be done, the risk has to be evaluated in an unselected group that is more like the general population, as we have done in the study in the Washington metropolitan area of the specific changes in BRCA1 and BRCA2 genes in the Jewish population. These large efforts are very expensive and time consuming, since many people need to be studied to identify a very few with alterations in a specific gene. Investigators all over the world are planning and conducting the large, long-term investigations in the general population which will give us the needed information to adequately assess risk of cancer associated with these alterations.

Another major scientific issue relates to most of the genes we have currently identified. For these genes, we need to evaluate whether we can change risks associated with a specific genetic alteration by modifying other risk factors. The development of cancer is a complex process that occurs over many years, and perhaps can be arrested at several points. For instance, since oral contraceptive use has been shown to lower the risk of ovarian cancer, investigators are trying to establish if their use can decrease the risk of this cancer type associated with alterations in BRCA1. In a different example, we think the risk of melanoma in members of melanoma-prone families can be reduced by protecting them from sun exposure. These types of interactions with other risk factors may well modulate the risk associated with specific genetic alterations.

These levels of scientific uncertainty have implications for genetic testing. Individuals need to know about the levels of uncertainty prior to deciding whether or not to have genetic testing. At this time, the best way to educate people about genetic testing and to deliver test results are unclear. Both education and risk notification are being systematically evaluated in a number of research studies funded by the NCI and the National Human Genome Research Institute (NHGRI) at NIH. In addition, we do not yet fully understand the risks and possible benefits of genetic testing, which will differ depending on the specific test and type of cancer. Ensuring the privacy of genetic test results is also a major ethical issue because of the potential for discrimination in employment, insurance, or other areas. Finally, there is the dilemma of how to proceed once the results of the testing are known. We are working on developing reliable screening tests for early diagnosis and preventive interventions for many of the cancers for which we have identified susceptibility genes. We also need to establish whether the cancers occurring in people with a genetic susceptibility respond to various treatments in the same way as other cancers.

It is clear that the ethical, legal and social implications of genetic testing for cancer are profound and cannot and should not be separated from the conduct of genetic research. In this respect, the work of other NIH funded groups, such as the NCI Cooperative Family Registries for Breast and Colon Cancer Studies and the NHGRI Cancer Genetics Studies Consortium in establishing guidelines for informed consent and counseling procedures and in exploring the psychosocial impact and adverse outcomes associated with genetic testing, provide a starting point for consideration of these critical issues within the Cancer Genetics Network.

Ms. Northup: In regard to infectious causes of cancer, could you please provide the time line for testing of the multivalent vaccine against cancer that you referred to in your testimony (related to human papilloma virus).

Dr. Klausner: Several commercial groups around the world are pursuing different time lines for testing vaccines against human papillomavirus infection. With regard to NCI's effort, we are expecting to spend about three years on the Phase I and Phase II trials needed to establish the safety and optimal dose of the vaccine components. On a parallel track, we are busy organizing the full-scale Phase III population trial, which will determine the usefulness of the vaccine. Once the proper dose is known, we will be able to start the full-scale Phase III trial without delay. The Phase III trial will require the long-term follow-up of thousands of women randomized according to whether or not they receive the vaccine. We expect to be able to draw the first conclusions from the Phase III trial about 3-4 years after we begin, although genital malignancies take much longer to develop. Initially, we will be able to look for reductions in the rate of new infection and cancer precursor states, not just a reduction in the rarer cancers which will take years longer to prove definitively. In summary, if the safety and dosage experiments proceed without significant problems, we should have some important answers about the vaccine in about 6 years, but it will take about a decade to determine its longer-term effectiveness.

Ms. Northup: In addition, is this vaccine addressing a certain population which is susceptible to this virus, and who are these individuals?

Dr. Klausner: The rates of infection with genital papillomaviruses are so high that it appears that nearly all women are susceptible. The virus is spread primarily by sexual intercourse with an infected partner. Poorer populations tend to have higher prevalence rates of infection, but this association with income level has been weakening over the past few decades. The same viral types are found everywhere in the world among women with cervical cancer, indicating that no population is particularly immune or susceptible. It is worth noting that most women are able to spontaneously clear the viral infection. Men also get the same infections, but almost never develop cancer as a consequence. In summary, all sexually active people seem to be at risk of infection, since we have not yet found anyone who is naturally immune.

Ms. Northup: In working on imaging research, are you working with other agencies such as the Food and Drug Administration to develop new innovations? I imagine the FDA hears a lot from the field during its certification program, especially in regard to mammography.

Dr. Klausner: Since early 1990, NCI established collaborative efforts with FDA in all stages of technology innovation and transfer: concept development, technology evaluation, and implementation.

The joint NCI/FDA efforts in the development of new ideas for innovations are reflected in the active and extensive FDA participation in numerous conferences and workshops held by the NCI in diagnostic imaging and devoted to the identification and support of new promising areas of science and technologies in diagnostic imaging. In particular, NCI staff has been closely working with FDA on the development and testing of novel breast imaging technologies, such as digital x-ray mammography and Magnetic Resonance Imaging of the breast. Since May 1993, NCI has joined efforts with the FDA to facilitate transfer of defense and space technologies to digital mammography. Since July 1994, NCI has joined efforts with the DHHS Office on Women's Health and the FDA to establish a Joint Working Group with the CIA for transfer of intelligence technologies to breast imaging.

In March 1996, encouraged by this experience, NCI joined efforts with the DHHS Office on Women's Health to formalize these collaborations by establishing a Federal Multi-Agency Consortium of Imaging Technologies to Improve Women's Health. The goal of the Consortium is to foster identification, evaluation and transfer of intelligence, space, defense, energy and other relevant technologies to advance the state-of-the-art in medical imaging critical for women's health. Under the leadership of this Consortium, many Federal agencies have been brought together to join efforts, expertise, and resources in the area of imaging technologies. In addition to the Office on Women's Health, FDA, and NCI, this Consortium includes such organizations as the Department of Defense, CIA, NASA, DOE, NSF, and the Department of Commerce.

Ms. Northup: Who will be involved in the consortium to evaluate innovations?

Dr. Klausner: The NCI is planning to issue a Request for Applications for the establishment of a multicenter clinical trials consortium expert in the evaluation of imaging innovations. The devices or pharmaceuticals that will be tested by the consortium will be products of development in industry, government or academia. We expect that the consortium will include both academic health centers and community sites with the requisite technical expertise and patient volume. Responsibility for the governance of the consortium will be in the hands of the principal investigators, and the research will be investigator-initiated.

Ms. Northup: re you working with businesses such as Kodak and professional groups as well in this endeavor?

Dr. Klausner: The NCI will act as a partner in this effort and will have responsibility for protocol review and general oversight. It is expected that many private companies involved in imaging research and development will wish to partner with this consortium for clinical trials of novel devices. The NCI has had extensive discussions with industry representatives from many companies about the desirability of a clinical trials consortium of this type, and there seems to be a great deal of interest in industry.

Ms. Northup: In mammography imaging you mentioned the ability to reduce the number of false positives. What percentage of false positives are due to the quality of imaging versus human error in interpreting mammography?

Dr. Klausner: There are no data to directly address the question of what percentage of false positives are due to the quality of imaging versus human error in interpreting mammography. False positives may be largely due to the fact that the radiographic signs of some early breast cancers are indistinguishable from some benign abnormalities. In fact, the question is likely to be less one of quality of imaging versus human error but rather more the inherent conservatism of medical practitioners who do not want to miss a cancer if it is present. Improvements in image quality have resulted in a reduction of false positive mammograms in the last few years. The characteristics of the population being screened -- such as family history, estrogen use, menopausal status, and breast density, etc.-- are considered important in determining false positive rates. Additionally, published studies have shown modest variation in false positive rates among radiologists in the first few years of interpreting mammograms. However, after the initial period these differences in false positive rates disappear and false positive rates drop to a fairly constant and low rate. This finding is commonly interpreted as indicating that early in practice radiologists are more conservative, and as they gain experience with interpretation and learn of subsequent diagnoses they become more comfortable in interpreting the mammogram as normal without additional work-up -- i.e. their false positive rate declines. Ongoing research at NCI may provide more information to address this question in the future.

We do know, however, that human error is known to account for about 40% of false NEGATIVE mammograms, which themselves occur in about 15% of breast cancers. Since October 1, 1994, all facilities performing mammography must be certified by FDA as meeting quality standards, in accordance with the Mammography Quality Standards Act (MQSA). Today, 10,000 facilities are certified.

Ms. Northup: Please go into more detail on how you are working with the Department of Defense and the Department of Veterans Affairs to ensure that patients have access to clinical trials.

Dr. Klausner: In March 1996, the National Cancer Institute (NCI) and the Department of Defense (DoD) signed an agreement that authorized TRICARE/CHAMPUS to cover beneficiary participation in NCI-sponsored clinical trials. Under the terms of this three year demonstration project, TRICARE/CHAMPUS now provides coverage for participation in Phase II or III, NCI-sponsored, treatment clinical trials.

This agreement marks the first public commitment to provide coverage for NCI-sponsored clinical trials by a single payer organization. TRICARE/CHAMPUS beneficiary participation in this demonstration project extends clinical trials opportunities beyond the military treatment facility (MTF) system into private practices, community hospitals and comprehensive cancer centers.

In support of the NCI/DoD agreement, PDQ, the NCI's computerized cancer and clinical trials database, has been expanded to list all clinical trials included under this agreement. PDQ now has a search field for "sponsorship" where all NCI-sponsored treatment studies can be located under one subheading providing the most comprehensive listing of NCI peer-reviewed studies.

To assist physicians seeking an appropriate clinical trial for a patient, the NCI offers clinical trials case management support for physicians. Based on the physician's request, NCI staff can conduct a nationwide search for NCI-sponsored trials that meet the criteria set forth by the NCI/DoD demonstration project. To date, a number of TRICARE/CHAMPUS beneficiaries have participated in the demonstration project as a result of this service.

Promotion of the NCI/DoD agreement is currently underway. Key civilian and military audiences have been targeted for promotional mailings including: the Surgeon Generals of three of the armed services, TRICARE/CHAMPUS managed care medical directors, military oncologists, civilian oncologists, and CHAMPUS beneficiary groups. Following these general mailings, more specific promotional activities will be undertaken with these audiences.

The most recent clinical trials partnership was signed in October 1996 and began implementation in January 1997. This partnership resulted in an agreement between the NCI and the Department of Veterans Affairs (VA) to provide eligible veterans participation in the full range of NCI-sponsored studies. Under terms of the three year demonstration project, eligible veterans will have access to all phases of NCI-sponsored clinical trials in diagnosis, treatment and prevention.

Most of the eligible veterans that will be participating in this demonstration project will be treated within the VA's primary-care delivery system as VA facilities conduct many NCI-sponsored trials on site as affiliates of NCI cooperative groups and as participants in the NCI's early clinical trials program. Support structures for this agreement will be similar to the structures already in place for the NCI/DoD agreement and implementation plans are currently underway. The PDQ database will expand its current listing of prevention trials and will begin to list diagnostic clinical trials.

Ms. Northup: In regard to all clinical trials, what type of outreach is NCI doing to ensure that physicians are aware of clinical trials in cases where a patient might be appropriately referred?

Dr. Klausner: The NCI uses multiple resources to educate physicians and patients about clinical trials including state-of-the-art electronic technology, print media, and partnerships with health professional organizations and patient advocacy groups. PDQ, the NCI's comprehensive, computerized cancer information and clinical trials database represents the most comprehensive source of information on clinical trials. Physicians can access PDQ directly through the NCI's web site, online through commercial and non-profit vendors, by joining the NCI's member service (Information Associates Program), or indirectly, by utilizing NCI's toll-free PDQ physician search service (1-800-345-3300). Information is also accessible to patients via the NCI home page on the World Wide Web.

Another source of information for physicians, patients and health professionals is the NCI's Cancer Information Service- a national network of regional offices which, through its toll-free telephone service (1-800-4-CANCER), provides up-to-date information on cancer and clinical trials.

The NCI has developed an extensive inventory of educational materials for health professionals, patients and the public. Among these materials are a health professional newsletter highlighting cancer clinical research activities and high priority clinical trials- distributed to approximately 3,500 individuals --including health professionals and organizations -- and a clinical trials information booklet specifically designed for patients which physicians may provide to patients as part of their treatment discussions.

Recognizing that sustained media coverage over a period of years is essential to raising awareness of clinical trials, the NCI regularly disseminates press materials on new clinical trials-related issues to many major and local media outlets.

The NCI has developed partnerships with many professional organizations including the American College of Physicians (ACP) and the American Association of Family Physicians (AAFP) to disseminate NCI clinical trials information to their members. Presentations at professional organization meetings such as American Society of Clinical Oncologists (ASCO) and ACP also heighten physician awareness of cancer clinical trials and research.

Because patients frequently seek out their own information about clinical trials , the NCI has developed partnerships with many patient advocacy groups. One such partnership between the NCI and the National Alliance of Breast Cancer Organizations (NABCO) has resulted in the creation of easy-to-read summaries of all of the breast cancer clinical trials currently listed in PDQ. These summaries are available on both the NCI and NABCO web sites and can be easily downloaded for review with physicians. Eventually, all of the NCI clinical trials summaries on PDQ will be available on the NCI's web site in a similar format for patients.

Ms. Northup: You mentioned 12 new cancer drugs approved by the FDA for use in cancer. Are these drugs a result of NCI research or research done in the private sector?

Dr. Klausner: The National Cancer Institute collaborated directly in the clinical development of 6 of the twelve approved drugs in that we held INDs (Investigational New Drug Applications) and sponsored cancer clinical trials which contributed to the evaluation and determination of efficacy of the agents. In one case, the pivotal study used as the basis for approval was conducted by a NCI funded Cooperative Group, Southwest Oncology Group. In two other cases, NCI was substantially involved in preclinical development of the drug, for example, with topotecan, a soluble active analog of camptothecin, NCI was critically involved in initial preclinical work. In fact, discovery of topotecan occurred through the NCI-funded National Cooperative Drug Discovery Group Program. It was developed subsequently by the corporate partner in that program (Smith, Kline, and Beecham). With gliadel, NCI was critically involved in funding initial studies of gliadel through its National Cooperative Drug Discovery Group Program.

Ms. Northup: Do you measure the outcomes of NCI research in relation to drug approval by the FDA, or how do you measure NCI outcomes?

Dr. Klausner: NCI sponsors research covering virtually the entire spectrum of biomedical and biobehavioral science relevant to cancer. The approval of cancer drugs by FDA is, therefore, only one measure of success and it is relevant only to a restricted segment of NCI programs. For example, the success of NCI's large investment investigator-initiated basic research would be more appropriately measured by the new scientific insights produced by the research. Certainly some of these insights might eventually translate into the discovery of new drugs that gain FDA approval, but other might have practical significance in other, equally important ways: for example, the identification of a new carcinogen, a new cancer-control research would generally not result in new FDA approvals but might result in the improved strategies for cancer-avoiding behavior, such as smoking cessation. Ultimately the success of NCI research will be best measured by reductions in the national morbidity and mortality from cancer, as has already occurred dramatically for many pediatric and some adult malignancies.

Ms. Northup: What is the status of the Cancer Genome Anatomy Project and how many federal agencies and personnel (FTE) are involved in this project?

Dr. Klausner: The two primary components of the Cancer Genome Anatomy Project (CGAP) are to establish an index of all genes that are regulated during tumor formation and progression and to support the development and dissemination of new technologies that will allow high through analysis of gene and protein expression as well as mutation detection. With respect to the tumor gene index the program is coordinated through the NCI intramural program with significant collaborative contributions from the National Center for Biotechnology Information (NCBI) and the Department of Energy. The NCI and NCBI currently have three and two FTEs assigned to CGAP, respectively. In addition, cDNA libraries are being prepared at Columbia University and two private companies, and DNA sequence analysis is being performed at Washington University. It is expected that additional collaborators will participate in the project during this fiscal year.

The technology development goals of CGAP are primarily being addressed through extramural initiatives although advances from the NCI intramural program are also expected. Already two Requests for Applications (RFAs) and one Program Announcement (PA) have been issued to stimulate technology development and facilitate the interface of new technologies with clinical cancer research.

Ms. Northup: What level of funding do you propose for this effort?

Dr. Klausner: In the NCI Budget Proposal for FY 1997/98 several extraordinary opportunities for investment were identified. Because of the enormity of the opportunity and the need to act promptly, the NCI has provided seed funding to initiate CGAP with FY 1997 funds. The current total funding for CGAP, excluding funds for the intramural FTEs, is approximately $21 million for FY 1997 and full implementation during FY1998 would require an additional investment of about $15 million included in the President's Budget Request.

Ms. Northup: When did the blue ribbon panel come out with its recommendations on guidelines regarding NCI, what are the recommendations, and what are you doing to address these suggestions?

Dr. Klausner: The Cancer Centers Program Review Group, a blue ribbon panel of experts asked to evaluate the NCI Cancer Centers Program and make recommendations that will prepare us for the next decade of cancer research, submitted its Report in October 1996 after a year of deliberation. The report clearly recognized that NCI Cancer Centers were particularly well-positioned to be the leaders of the future in translational cancer research; that is, the bidirectional process of discovery in moving laboratory findings into patient and population research settings and the reverse. There were three general themes to the Review Group's recommendations if centers were to function in this capacity more effectively: (1) the time spent by cancer centers satisfying the rigid record keeping requirements of the NCI had to be reduced significantly if centers were to have more time to do innovative research; (2) there needed to be increased flexibility in the use of cancer center funds to ensure that the most exciting new research opportunities could be pursued without delay; (3) the peer review system had to be modified in order to attract reviewers who are the most knowledgeable about cancer centers and have experience in taking advantage of research opportunities that have had an impact on preventing and curing cancer. The report was reviewed by the National Cancer Advisory Board and the Board of Scientific Advisors at their November meetings. In response to the Review Group's recommendations, the NCI has completely revamped it's cancer center guidelines and will implement a completely new approach to cancer centers starting in June 1997.

Mr. Stokes: According to your opening statement, "Sometime around 1990, we appeared to have reached the peak in the mortality rate, and for the past 5 years, overall age-adjusted mortality rates have fallen." To what extent did this encouraging finding hold true for African Americans, and for other minorities that disproportionately suffer from cancer?

Dr. Klausner: The decline in overall cancer mortality was seen for both white Americans and black Americans. While the rates for Americans of races other than white or black did not decline, their overall cancer mortality rate (107 per 100,000) was less than half that for black Americans (222 per 100,000) and approximately one-third less than that for white Americans (167 per 100,000).

Mr. Stokes: As you have indicated, African Americans experience a 20 to 30 percent excess rate of cancer death compared to white Americans. Specifically, how is the FY 1997 appropriation being used to address this problem, and how will the FY 1998 budget request allow you to build on that effort?

Dr. Klausner: The NCI remains committed to reducing the burden of cancer in all segments of the population. Toward this end an internal Special Actions Committee was formed at the request of the NCI Director to review NCI's activities and program mechanisms to ensure that the cancer problems of minorities, the undeserved, and persons age 65 and over were being adequately addressed. The Special Actions Committee issued its report and recommendations in May 1996. The report was intended to identify the specific efforts to deal with the cancer problems among these populations and to indicate opportunities for further action. Issues addressed by the Special Action Committee include the definition of minority and special population activities, monitoring of minority training, organization of NCI programmatic data on minority/special population activities, leadership and coordination of minority and special population activities, input of NCI staff into management of minority and special population activities, and identification of research opportunities.

As a tangible outcome of this analysis, the Office of Special Populations was established within the Office of the Director, NCI in June 1996. The Office of Special Populations will serve as a focal point to provide leadership and coordination on research related to minorities and special populations. The office will coordinate NCI programs addressing scientific questions pertinent to these populations. Important elements of this office are the evaluation of current NCI programs and planning new initiatives. Through its evaluation function the office will determine what questions are important to special populations, what questions are being addressed through NCI's programs and portfolio of grants, and what research questions should be raised. Established epidemiologic data bases and current research findings will be used to define scientific questions pertinent to special populations. The office will develop concepts for new programs that need to be implemented by the scientific divisions of the NCI. An advisory committee of NCI staff will help define these questions. The expertise of individuals from the community will also be called upon.

The mortality data cited is derived from data developed by the NCI Surveillance, Epidemiology and End Results Program. NCI has expanded its surveillance efforts in tracking cancer rates for minorities. The institute has sponsored a number of patterns-of-care studies looking at the differences in cancer care among regions and among racial groups in the U.S. The NCI Black-White study reviewed differences in cancer biology, treatment, and outcomes in Blacks and Whites with bladder, uterus, breast, and colon cancer in several regions of the U.S. Several outreach initiatives have been established including the National Black Leadership Initiative on Cancer, the Hispanic Leadership Initiative on Cancer, and the Appalachian Leadership Initiative on Cancer providing grants to non-government agencies to provide information concerning cancer prevention, early detection, and treatment to some special populations. For NCI treatment clinical trials, minority representation among the individuals enrolled reflects their representation among individuals with the disease under study. The NCI has also sponsored a national conference, concerning the accrual and retention of minorities in clinical trials. Additional regional conferences on this topic will be held in the coming year utilizing NCI support.

Mr. Stokes: In your professional judgement, what must we do to effectively address this continuing health disparity?

Dr. Klausner: There is a definite association between poverty and cancer. Cancer mortality rates are the highest among the poor. To some extent, statistics from the NCI Surveillance, Epidemiology, and End Results Program about the high mortality of minorities relate to poverty, since minorities are over-represented among the poor. While it is our responsibility to study and describe the causes or etiology of cancer and the causes of cancer mortality, many of the solutions to the cancer problem are ultimately beyond the NCI.

It is also important to remember that cancer is not the only disease that disproportionately affects minorities. Indeed, heart disease, obesity, hypertension and other diseases disproportionately affect minority cancer patients. These diseases often complicate or even prevent desired treatments and increase the chances of mortality which will be attributed to cancer. The cancer disparity cannot be fully addressed until we address co-morbid disease. NCI programs such as 5-A-Day for Health, designed to encourage an increase in the consumption of fruits and vegetables and decrease the amount of fat in the diet may also decrease rates of cancer, diabetes, and heart disease.

Mr. Stokes: You mentioned that today over 10 million Americans are cancer survivors. What is the racial and ethnic percentage distribution of these survivors?

Dr. Klausner: Of cancer survivors approximately 91% are white and 7% are black. The U.S. population is approximately 83% white and 12.5% black. Whites are over-represented among cancer survivors because of differences between the races in cancer incidence rates, survival rates for cancer, and overall mortality rates.

Mr. Stokes: As we look back over the 25 years of the National Cancer Act, what do you consider to have been the most significant advances that have brought us to where we are today, -- to be able to say that mortality rates have fallen?

Dr. Klausner: The past quarter century has seen remarkable advances against cancer, many coming as a direct or indirect result of passage of the National Cancer Act in 1971. Among them, as you mentioned, are the drop in several cancer mortality rates. There have also been significant developments made in the technologies available in the field of cancer research. The last twenty-five years has seen an explosion in cancer genetics which has helped lead to important progress in treatment - including several promising drugs, detection and diagnosis and prevention. A number of significant epidemiological studies have also been released. Advances have been made in information technology that have strengthened our information dissemination programs. The following is a list of some of our most important advances in carrying out the National Cancer Program in the past twenty-five years.

Cancer Mortality Rates(from analysis available by January 1997)

• Overall cancer death rates fell 2.6 percent from 1991 to 1995
• Lung cancer death rates for men fell 6.7 percent from 1991 to 1995
• Death rate for colorectal cancer dropped 18.6 percent from 1973 to 1993, and 5.4 percent between 1991 and 1995
• Death rate for breast cancer fell 2.9 percent from 1973 to 1993, and 6.3 percent between 1991 and 1995
• Testicular cancer death rate dropped 65.7 percent from 1973 to 1993
• Hodgkin's disease death rate fell 58.4 percent from 1973 to 1993
• Death rate for cancers in children -- up to age 14 -- fell 44.4 percent from 1973 to 1993; leukemia, the most common childhood cancer, decreased 52.9 percent in that period

Technologies

• Recombinant DNA techniques developed for cloning genes, mid-1970s
• Hybridoma technology developed for production of monoclonal antibodies, 1975
• Southern blot technique developed to identify DNA fragments, 1975
• Methods developed to sequence DNA fragments, 1975 to 1976
• Restriction fragment length polymorphism (RFLP) technique used in cancer, 1983
• Polymerase chain reaction technique (PCR) developed, mid-1980s
• Severe combined immunodeficiency (SCID) mice developed, mid-1980s
• Techniques developed to manipulate the genetic makeup of laboratory animals, facilitating the study of the effects specific genes and gene alterations on tumor development, 1980s
• Fluorescence in situ hybridization (FISH) technique developed, about 1990

Cancer Genetics

• First of some 50 now-known human proto-oncogenes discovered (src), 1976
• Most frequently mutated gene in human cancer, p53, discovered, 1979
• First of some 20 now-known tumor suppressor genes cloned (RB1), 1986
• First human gene therapy for cancer (melanoma), 1991
• First of the hereditary nonpolyposis colon cancer genes cloned (hMSH2), 1993
• Isolation of VHL gene, associated with familial and non-familial kidney cancer as well as other tumors, 1993
• RET gene, linked to thyroid and adrenal cancers and to multiple endocrine neoplasia, cloned, 1993
• Inherited breast cancer genes cloned (BRCA1 and BRCA2), 1994 and 1995
• CDK4 gene, associated with melanoma, identified, 1996.
• Cloning of gene, called patched or PTC, linked with an inherited basal cell carcinoma of the skin, 1996

Epidemiology

• Surveillance, Epidemiology, and End Results (SEER) Program established, 1973
• Statistical methods developed to control simultaneously for several factors in the analysis of studies and to quantify cancer risks, 1970s and 1980s
• Studies in human populations link cancer risk to infectious agents, such as human papillomavirus (cervical cancer) and Hepatitis B (liver cancer), 1970s and 1980s
• Studies link cancer risks to hormonal drugs, such as diethylstilbestrol (DES) taken during pregnancy and hormonal replacement therapy, 1970s and 1980s
• Studies clarify the patterns of cancer risk following exposure to ionizing radiation, 1970s and 1980s
• Studies associate risk of certain cancers with dietary and nutritional factors, such as low intake of fruits and vegetables, obesity, and sedentary lifestyle, 1980s
• Biochemical and genetic assays integrated into epidemiologic studies (molecular epidemiology), 1980s
• Precursors, such as specific moles as precursors to melanoma, linked to several forms of cancer, late 1970s and early 1980s
• Statistical genetic techniques developed to define modes of inheritance, localize genes, and evaluate gene-environment interactions in cancer risk, 1970s through 1990s

• Several common genetic variants linked to the risk of lung and other cancers, 1990s

Treatment

• Limb-sparing surgeries developed for sarcomas of the extremities, late 1970s
• Development or intensive multi-drug treatments, followed by long-term oral chemotherapy, bring dramatic improvements in survival rates for childhood leukemia, 1970s.
• Bone marrow transplants proven to effect long-term survival and cures in certain leukemias and lymphomas, 1970s
• Development of the highly curative regimen, cisplatin, vinblastine, and bleomycin (PVB) for testicular cancer, 1970s
• Interleukin-2 discovered, 1976
• First human testing of a biological therapy (alpha interferon), 1978
• Total mastectomy replaced radical mastectomy for breast cancer, 1979
• Continuous pain medication infusion pumps developed, early 1980s
• First effective anti-nausea drugs developed to alleviate side effects of chemotherapy, early 1980s
• First human cancer vaccine developed (Hepatitis B virus vaccine for liver cancer), 1981
• Lumpectomy plus radiation found equivalent to mastectomy for breast cancer, 1985
• Modified prostatectomy designed to preserve potency and urinary continence introduced, 1986
• Adjuvant chemotherapy proven to increase disease-free survival in early breast cancer, 1988
• Adjuvant chemotherapy found to increase survival in colon cancer, 1989
• Larynx-sparing surgery for laryngeal cancer developed, 1990s
• Adjuvant radiation and chemotherapy found to improve survival in rectal cancer, 1991
• Combination chemotherapies proven effective, first for Hodgkin's disease and later for a variety of cancers

Anticancer Drugs (year of FDA approval)

• Doxorubicin (1974)
• Cisplatin (1978)
• Tamoxifen (1978)
• Levamisole (1990)
• Paclitaxel (1992)
• Topotecan (1996)

Prevention

• Flexible sigmoidoscopy and colonoscopy developed to help detect and remove precancerous growths, 1980s
• Dietary guidelines to reduce cancer developed, 1984
• First chemoprevention trial to show efficacy (vitamin A analogue against mouth and throat tumors), 1990
• ASSIST, largest tobacco prevention and control project in United States, launched, 1991
• National Cancer Institute-sponsored studies in China show importance of nutrition in preventing cancer, 1991
• Prevalence of adult cigarette smoking dropped from 37 percent in 1971 to 24 percent in 1993

Detection and Diagnosis

• Computed tomography introduced to the United States, 1973
• Positron emission tomography (PET) developed, mid 1970s
• Magnetic resonance imaging (MRI) introduced, early 1980s
• The Bethesda System conference developed system for standardized reporting of Pap smear results, 1988
• Transition from film-based radiology to digital computer-assisted medical imaging, 1990s
• Molecular diagnostics developed, using immunological, chromosomal, DNA, and protein markers, 1990s
• Mammography Quality Standards Act passed, 1992

Cancer Concepts

• Established that proto-oncogenes play important roles in normal cellular control, 1970s
• Cytochrome P450 enzyme system shown to activate many carcinogens, 1970s
• Genes identified that are involved in deactivating the metabolism of carcinogenesis, 1970s
• Metastatic cells shown to arise from pre-existing subpopulations in primary tumors, 1978
• Metastatic cells shown to arise from a unique subpopulation of cells within the primary tumor, 1978
• Discovery of multiple steps by which cancer cells metastasize and invade other tissues and organs, 1970s-1980s
• Development of laboratory animals with specific genetic makeups to serve as models of human cancers, 1980s
• First tumor suppressor genes identified and shown to be critical in control of cell growth, 1980s
• Apoptosis shown to be a critical mechanism in tumor suppression, tied to specific genes, 1990s
• Carcinogenesis linked to discrete events in the cycle of cell division and replication, 1990s
• Multistep nature of carcinogenesis documented and correlated with genetic changes, 1990s
• Understanding of how angiogenesis -- the growth of new blood vessels -- supports tumor growth and spread, offering a potential target for treatment, 1990s

Information Transfer

• CANCERLINE, a national database of published cancer research, established, 1974
• Cancer Information Service (1-800-4-CANCER) opened, 1976
• First national cancer patient education program (I Can Cope) founded, 1977
• First major DNA sequence databases established in United States (GenBank) and Germany, 1982
• PDQ (Physician Data Query) database established, 1984
• Human Gene Mapping database established, 1989

Cancer Specialists

• Certification in medical oncology (6,550 certified to date) first offered, 1973
• Certification in gynecologic oncology (559 now certified) first offered, 1973
• Society for Surgical Oncology (1,600 members now) established from earlier group, 1975
• Oncology Nursing Society (24,000 members now) established, 1975
• Certification in radiation oncology (3,130 new certified) first offered, 1989
• Number of medical oncologists certified annually grew from 351 in 1973 to 597 in 1995
• Membership in the American Society of Clinical Oncology, established in 1964, grew to about 10,500 in 1996

Mr. Stokes: As researchers examine cancer's risk factors some are more tangible than others, how is the impact of stress on disease assessed?

Dr. Klausner: Research on the role stress may play in either developing or ameliorating the effects of cancer is usually grouped within the broad field of psychoneuroimmunology, which is the study of the role social and psychological factors may play in the alteration of human neurological and immunological systems. Research on the role of stress in cancer may be divided into two parts, i.e. whether controlling stress plays any part in preventing cancers from developing and whether controlling stress can ameliorate the effects of any cancers once they have been diagnosed.

Mr. Stokes: Do we know what role stress plays in cancer?

Dr. Klausner: The complex relationship between physical and psychological health is not well understood. As you might imagine well-controlled studies comparing individuals with a high level of stress with those with lower stress are difficult to design and conduct. Reduction of stress is likely to be beneficial in terms of certain quality of life issues, but there is little evidence that stress plays a role in cancer. Some studies have focused on hormone levels and the immune system, but these involve complex networks whose activities are affected by a number of factors. It has not been shown that stress-induced changes in the immune system is relevant to cancer formation or progression. One NCI-sponsored study suggested that there is no important association between breast cancer and stressful life events such as the death of a loved one or divorce. The NCI is continuing to support additional work in the field of psyconeuroimmunology.

Mr. Stokes: I understand that scientists have identified the locus for the first prostate cancer susceptibility gene. Can you tell us what this means in terms of furthering advances in the treatment, prevention and early detection of the disease?

Dr. Klausner: The identification of a region of chromosome 1 that contains candidate genes for prostate cancer susceptibility immediately suggests that the potential exists for identification of individuals at high risk for this disease. These individuals may then undergo intensive surveillance and be enrolled in chemoprevention trials. Moreover, the protein products of these susceptibility genes may provide a handle on the molecular mechanisms leading to prostate cancer and may lead us to targets for therapeutic intervention.

Mr. Stokes: How critical are clinical trials to furthering advances in the treatment, prevention, and early diagnoses of cancer?

Dr. Klausner: A clinical trial is an experiment that attempts to answer a medical question, most often about the effect of a therapeutic intervention on the outcome of a disease, or of an intervention to prevent the development of the disease. Clinical trials are absolutely essential to furthering advances in the treatment, prevention, and early diagnoses of cancer. While interventions, such as new medical treatments or diagnostic techniques, may appear to be promising based on scientific rationale, evidence obtained in animals, or anecdotal usage in patients, clinical trials are critical to reliably establish their benefit and define their toxicities. The need to reach accurate conclusions about the benefit of toxic and expensive interventions is self-evident and requires systematic use of clinical trials. Nonexperimental approaches, in which reasoning rather than observation is used to reach conclusions, or flawed experimental research, in which the intervention is inconsistent or uncontrolled, can severely restrict progress toward the cure of cancer by erroneously supporting the value of what are actually useless or harmful interventions.

Mr. Stokes: What is the extent of the participation of women and minorities in NCI trials?

Dr. Klausner: The NCI has at any one time almost 3 million subjects enrolled in clinical studies concerning the detection, diagnosis, treatment, prevention or control of cancer. These subjects, which are predominately healthy individuals, are composed of 71% women and 45% minorities. NCI has vigorously pursued on its own and with its grantees recruitment of women and minorities in all studies, and conducts many trials specifically targeted at gender-specific cancers of high prevalence and impact. NCI has been extremely successful in ensuring representation in trials with therapeutic intent and with population-based data collections. For NCI treatment clinical trials, minority representation among the individuals enrolled in the trial reflects their representation among individuals with the disease under study. For treatment clinical trials approximately 183,000 individuals are participating, of which nearly 88,000 are women and about 95,000 are men. The NCI has also sponsored a national conference, the topic of which was the accrual and retention of minorities in clinical trials. Additional regional conferences on this topic will be held in the coming year utilizing NCI support.

NCI's internal assessment of the fulfillment of meeting the inclusion requirement has assured compliance with the NIH Revitalization Act of 1993: Women and Minorities as Subjects in Clinical Research. A grant application that fails to meet the standard for inclusion receives an unacceptable gender or minority code, which results in an administrative bar-to-funding. This bar may be removed upon receipt of additional information. Program staff has some flexibility to work with an applicant and resolve problems the may prevent award of highly meritorious projects.

On February 26, 1997, based upon the review of the data presented to the National Cancer Advisory Board (NCAB), the NCAB concurred with the NCI's compliance in implementing the NIH Guidelines on the inclusion of women and minorities in clinical studies.

Mr. Stokes: How much is included in the FY 1998 budget request for clinical trials, and how does this compare with FY 1997 and FY 1996?

Dr. Klausner: In the FY1998 budget request, $412,618,000 is included for both treatment and prevention clinical trials. This represents an $8.6 million increase, or 2.1%, over FY 1997 and an increase of $18.8 million, or 4.8%, over the FY 1996 amount.

Mr. Stokes: Over the 25 years of the National Cancer Act, what clinical trials have given the nation the biggest payoff and explain why?

Dr. Klausner: It should be noted that over this period, clinical trials numbering in the tens of thousands have been conducted. Collectively, they have significantly improved the prognosis for patients with many types of tumors. I will highlight only a tiny fraction of these trials. A series of trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) established that lumpectomy (breast-sparing surgery) with breast irradiation results in overall survival comparable to that achieved with mastectomy for women with early invasive breast cancer confined to the breast and axillary lymph nodes and for women with non-invasive (ductal in-situ) breast cancer. These trials demonstrated that women with breast cancer can choose to avoid mutilating surgery without fear of reducing their life expectancy.

A trial by the NSABP has demonstrated that tamoxifen administered daily for five years is an effective and well tolerated adjuvant hormonal therapy in pre- and postmenopausal women with breast cancer who have negative axillary lymph nodes and whose tumor is positive for the estrogen receptor. This seminal trial demonstrated a near 20% reduction in the risk of death from breast cancer, or an absolute improvement in survival of nearly 5%, compared to a placebo. Tamoxifen was also shown to reduce the risk of new contralateral breast cancers; a finding that laid the foundation for the NSABP's Breast Cancer Prevention Trial (BCPT) in which tamoxifen is used as a preventive agent. Based in large part on the results of this trial, tamoxifen has become a mainstay of therapy for women with hormone sensitive tumors and has prolonged the lives of many women world-wide.

A series of breast cancer adjuvant trials conducted within the Clinical Trials Cooperative Group Program established that combination chemotherapy results in a 20-30% reduction in the risk of death compared to pre- and post-menopausal women receiving surgery alone and compared to surgery and tamoxifen therapy alone in postmenopausal women. These trials established that chemotherapy is effective in pre- and postmenopausal women as well as in women with positive axillary lymph nodes and in certain subsets of women with negative axillary lymph nodes. These Cooperative Group trials have made a major contribution to the overview analysis of world-wide chemotherapy trials in breast cancer. This overview analysis has demonstrated that chemotherapy results in a near 10% absolute improvement in survival which translates to the prolongation of about 10,000 American lives annually considering that over 100,000 women are candidates for chemotherapy every year in the U.S.

Hodgkin's disease represents one of the major successes of contemporary oncology. The MOPP combination chemotherapy regimen developed at the NCI was able to achieve complete remissions in two-thirds of patients with advanced disease, half of whom were cured. Unfortunately, this regimen had a number of serious associated toxicities, including secondary acute leukemia and infertility. In an attempt to improve on the results with MOPP, several combination regimens were developed which included the anthracycline drug, adriamycin, while eliminating the drugs in MOPP implicated in the secondary leukemias. In a randomized trial involving almost 400 patients, three anthracycline-based regimens were compared to MOPP. More than 80% of patients treated with the newer regimens achieved a complete remission, and two thirds of these remained free of disease. Overall survival was also better with each of the newer programs compared with MOPP. Of critical importance is the fact that these newer regimens are also associated with a significantly lower risk of secondary leukemia and infertility compared with MOPP

A series of colorectal cancer adjuvant studies conducted within the Clinical Trials Cooperative Groups established a 33% reduction in risk of death in patients receiving adjuvant chemotherapy compared to those receiving surgery alone. For stage III colon cancer alone, there are about 25,000 cases diagnosed each year in this country, so that the results translate to potentially 4,000 additional lives saved among these patients. As the results appear to apply in roughly equal proportions to stage II colon and to rectal cancers as well, the overall benefit is even greater.

A series of trials conducted by the Gynecologic Oncology Group have established the optimal combination of surgery and chemotherapy for women with ovarian cancer. These trials have shown that women who undergo effective surgical staging and cytoreductive ("debulking") surgery live longer than those who have less extensive surgical procedures. In addition, these trials have helped identify the best chemotherapy regimen to use after initial surgery. The best chemotherapy regimen currently available is a combination of platinum and paclitaxel (taxol). Paclitaxel was originally identified and developed by the NCI as an anticancer drug. Thanks to these trials, the treatment of choice, which combines effective surgery and chemotherapy, has prolonged the lives of many women with ovarian cancer.

A trial of limited surgical resection versus removal of the entire lobe of the lung for early stage lung cancers demonstrated that limited resection was associated with a 75% increase in overall deaths, a 30% increase in overall deaths, and a 50% increase in deaths with cancer as compared to patients treated with the more extensive surgery. This was important in maintaining lobectomy as the surgical approach of choice in early stage lung cancer, and prevented the adoption of a less successful surgical approach which would have led to thousands of needless deaths.

Nasopharyngeal cancer is a malignancy of the part of the throat which sits just above the soft palate. An NCI-sponsored intergroup trial has demonstrated that combined modality treatment -- chemotherapy plus radiotherapy -- is superior to standard radiotherapy alone in patients with advanced nasophayrygeal cancer in terms of both progression-free and overall survival, thus establishing combined modality therapy as the treatment of choice. The impact of this trial result has world-wide application. While this type of cancer occurs most frequently in China and Southeast Asia, North Africa, the Middle East, and among Eskimos, the incidence of nasopharyngeal cancer in the United States may increase with immigration from these other areas. Chinese-Americans have the highest statistical risk for nasopharyngeal cancer in the U.S. -- six times higher than that of any other ethnic group.

Over the past 25 years, bone marrow transplantation (BMT) has emerged as an important therapeutic advance in the treatment of diseases such as the acute and chronic leukemias. Prior to this therapy, chronic myelogenous leukemia was an incurable disorder. If transplanted within a year of diagnosis, as many as 60% of patients in the chronic phase of the disease can now be cured. Whereas combination chemotherapy can cure 20-30% of patients with acute myeloid leukemia (AML), and 40% of adult patients with acute lymphoblastic leukemia (ALL), there is no satisfactory treatment upon disease recurrence; however, BMT can cure about 25% of such patients. Similarly, there is no cure for patients with myelodysplastic syndromes, yet 40% of select patients are cured with BMT. Other diseases in which BMT is showing promise include multiple myeloma, chronic lymphocytic leukemia, and the non-Hodgkin's lymphomas. The major problem with BMT has been the high rate of treatment-related mortality, ranging from 20-50% of patients, depending on age, disease, and other factors. However, continued research is focusing on reducing the complications of this treatment, which should increase the number of patients cured by BMT.

Acute promyelocytic leukemia (APL) accounts for 15% of adult patients with acute myeloid leukemia. This disease is characterized by a specific chromosome abnormality, severe bleeding, and with most patients dying from the disease despite aggressive chemotherapy. In 1988, Chinese investigators published a paper suggesting that all-trans-retinoic acid, administered orally, could reduce the hemorrhagic complications of the disease and was able to induce complete remissions in more than 80% of patients. Subsequently, a small trial from France confirmed these observations. The NCI coordinated a North American trial in 401 pediatric and adult patients with APL. Although response rates were the same whether or not ATRA was included, the estimated disease-free survival was 54% with chemotherapy alone compared with 92% with ATRA. Subsequent follow-up also noted a survival advantage to the incorporation of ATRA. This study led to approval of ATRA by the FDA. Importantly, these clinical observations opened a whole new area of research into the biology and genetics of leukemia and the function of retinoids.

A sequence of clinical trials carried out through the NCI clinical trials network in the 1970s demonstrated remarkable but temporary antitumor activity for several individual chemotherapeutic agents in advanced (metastatic) testicular germ cell cancers, and then that combining these in the PVB regimen (cisplatin, vinblastine and bleomycin) was curative in most patients with testicular cancer. The following generation of NCI-sponsored trials established that substitution of etoposide for vinblastine reduced the toxicities while maintaining the efficacy, and that bleomycin could not be eliminated from the regimen. Currently, about 90 percent of all patients with testicular cancer are cured while approximately 80 percent of patients with advanced disease are cured. Clinical studies are continuing to maintain the high cure rates and decrease the side effect resulting in an improved quality of life.

The most important contributions of the pediatric Cooperative Groups to the treatment of children with acute lymphoblastic leukemia (ALL) have come not from single trials, but from series of trials conducted over the past 25 years which have resulted in successive incremental increases in survival rates. For example, children with ALL treated on Children's Cancer Group treatment protocols in the years from 1968-72 had event-free survival (EFS) rates of only 10-20%. Event-free survival rates improved to approximately 60% by the mid-1970s and to approximately 70% by the mid-1980s. With current therapy, EFS rates approach 80%, which is a dramatic improvement in outcome from that possible 25 years ago. The most important improvements in treatment identified in these Cooperative Group studies have included: (I) the importance of effect central nervous system treatment and the ability to prevent central nervous system recurrences without the use of cranial radiation for many children; (ii) the benefit for "delayed intensification" therapy following achievement of remission; and (iii) the benefit for the use of "intermediate-dose" methotrexate.

As in childhood ALL, outcome for children in the United States with Wilms' tumor has improved over the past 25 years as a result of clinical trials conducted by the NCI-supported National Wilms' Tumor Study Group. The major conclusions of these studies are that: (I) the two drug combination of vincristine and dactinomycin gives better results than either agent used alone; (ii) routine, post-operative radiation therapy is not necessary for most children with localized tumors that are resected; and (iii) a three-drug combination plus radiation therapy is curative for most children with localized, but not fully resectable tumors. With current therapy, the vast majority of children with Wilms' tumor -- greater than 90% -- are long-term survivors.

Osteosarcoma and Ewing's sarcoma are the two primary types of bone cancers that occur in children and adolescents, and the NCI-supported pediatric Cooperative Groups have made important contributions in both. Pediatric Oncology Group investigators conducted a randomized controlled trial to determine whether intensive multi-agent adjuvant chemotherapy improves relapse-free survival in patients with nonmetastatic high-grade osteosarcoma of the extremity. After undergoing definitive surgery, patients were randomly assigned to adjuvant chemotherapy or to observation without adjuvant treatment. The 2-year RFS rate was 17% for those not receiving adjuvant therapy and 66% in the adjuvant-chemotherapy group (P < 0.001). This trial clearly documented the benefit of adjuvant chemotherapy following complete surgical resection and established a standard of treatment for osteosarcoma.

The Children's Cancer Group and the Pediatric Oncology Group collaborated in a study for Ewing's sarcoma to evaluate the role of the ifosfamide + etoposide combination. The impetus for this clinical trial was reports from phase II studies in the 1980s showing that the ifosfamide + etoposide combination had significant activity for Ewing's sarcoma and for other pediatric solid tumors. The study clearly demonstrated that the addition of the ifosfamide + etoposide combination to standard therapy improved outcome, with the 3-year survival rate increasing from 56% to 80%. As a result of this clinical trial, the ifosfamide-based regimen of this trial has become the standard therapy for children with Ewing's sarcoma.

Mr. Stokes: How many clinical trials are currently being funded and how much of the budget is invested in clinical trials?

Dr. Klausner: For this year the NCI is projecting to spend $403 million to support therapeutic and prevention clinical trials. Within the clinical trials site on the NCI's Web site (CancerNet) over 1,500 NCI clinical trials are listed with a description of each trial. Approximately, two-thirds are NCI sponsored. Besides studying new anticancer drugs, clinical trials study new combinations of drugs already used in cancer treatment, new ways of giving treatment, and how changes in lifestyle can help cancer patients or prevent cancer from occurring including studies of the psychological impact of the disease and ways to improve the patient's comfort and quality of life -- including pain control. Other clinical trials compare the best known standard therapy with a newer therapy to see if one produces more cures and causes fewer side effects than the other.

Mr. Stokes: How does this compare with the number and funding level in the FY 1998 budget request?

Dr. Klausner: The request for next year includes $412 million, an increase of approximately $9 million over FY 1997. I would expect that the number of trials would increase slightly above the current level.

Mr. Stokes: How well are we doing with regard to rapidly disseminating clinical trial results?

Dr. Klausner: The NCI has a variety of procedures in place to inform the public, patients and health professionals about results obtained from cancer clinical trials. One method of informing the public is through the national media, using television, radio, or print materials such as newspapers or magazines. When new scientific information is available, an investigator who is familiar with the study or the NCI Director may be identified as a spokesperson who makes an announcement to the national media at a press conference. In addition, a press release is written containing scientifically accurate information about the results of the clinical trial. Those who typically disseminate this information through the national media are able to directly phone staff at NCI's Office of Cancer Communication (OCC) to confirm the trial results. In addition, staff members of the OCC may write news releases or articles to be placed in appropriate scientific journals or magazines. They also provide a list of Questions and Answers to help media personnel to understand the results of the clinical trial. In addition, a newsletter, UPDATE, is written by OCC specifically to focus on issues related to cancer clinical trials and is sent bi-annually to approximately 3,500 health professionals and related organizations.

Another important means of disseminating this information is through NCI's Cancer Information Service (CIS), a national network using two complementary program components, the 1-800-4-CANCER telephone service and the regional outreach program. The CIS meets the information needs of patients, the public, and health professionals. Specially trained staff provide the latest scientific information about the results of the clinical trial in understandable language. OCC provides each of the nineteen regional CIS offices with the appropriate information concerning the results of the clinical trials, including information on the study prior to any national announcement. In this way the results are disseminated to those who phone in for information as well as to regional partners identified in each region.

OCC also has lines of communication, such as newsletters or electronic methods, with staff at cancer treatment institutions and organizations, including advocacy groups, and NCI-designated comprehensive, clinical and consortium cancer centers. OCC also disseminates clinical trials results to sister DHHS agencies.

Use of electronic methods to disseminate results of clinical trials has become a popular means of informing the public and health professionals about the most up-to-date cancer information. Specific up-to-date information is available through CancerFAX® (301-402-5874) and CancerNet^TM . CancerNet^TM can be accessed using E-mail at the following address: cancernet@icicc.nci.nih.gov or via the Internet through the World Wide Web: http://cancernet.nci.nih.gov and Gopher: gopher://gopher.nih.gov servers.

The NCI also uses the PDQ as a resource to educate physicians and patients about clinical trials. PDQ is NCI's comprehensive cancer database which includes a registry of summaries of trials that are open or approved for patient accrual, including protocols for cancer treatment, supportive care, screening and prevention. In addition, you can reference more than 8,000 summaries of protocols that have been completed or are no longer accepting patients. All protocols supported by the NCI are listed in PDQ. Clinical trials not sponsored by the NCI, including foreign protocols, are included in PDQ after review and approval by the PDQ Voluntary Protocol Review Board.

Mr. Stokes: Please provide for the record a list of clinical trials that are underway and of those that are ready for implementation in FY 1998?

Dr. Klausner: As a part of the NCI's efforts to rapidly disseminate the latest information on cancer research, the NCI developed the PDQ as a comprehensive, computerized cancer information database. A wide variety of cancer information is available from PDQ including details on over 1,500 ongoing clinical trials is now available through the World Wide Web (WWW). PDQ contains an extensive register of clinical trial protocols, with information from studies around the world, full-text information statements describing the latest advances in cancer treatment, supportive care, screening, and prevention, as well as information about selected anti-cancer drugs currently under clinical evaluation, and directories of over 23,000 physicians and over 11,000 organizations active in cancer treatment and care. Most information statements appear in two versions, a technical version for the health professional and a lay version that is in English and Spanish. The database is updated monthly by editorial boards of oncology experts.

CancerNet, the World Wide Web site of the NCI's International Cancer Information Center (ICIC), provides health professionals and the public access to PDQ cancer information. Individuals can search for specific trials by a variety of criteria including cancer type, geographic region, and sponsorship -- including NCI sponsorship. Studies conducted at the NIH Clinical Center can be identified as well. The clinical trials information in CancerNet is updated each month to reflect the frequent changes in the details of these trials. For example, when trials are closed to patient accrual they are removed, the design of a trial may be modified through an amendment process resulting in a revision of the description of the trial, and the specific institutions and investigators participating in a specific trial may change. Up-to-date listings and detailed information about cancer clinical trials are now available to members of the public as well as health care professionals on the CancerNet. It is preferable that anyone interested in information about cancer clinical trials get it directly from the CancerNet web site directly since a printed listing of the trials included in CancerNet would soon be out of date.

To access CancerNet one can point a Internet browser to ICIC's Web site by entering the following Internet address: http://cancernet.nci.nih.gov in the place where the browser calls for a location or address. To use CancerNet to search for clinical trials, once you have reached the CancerNet homepage, click on "Patients and the Public"; then click on "Clinical Trial Information"; next, click on "PDQ --- Comprehensive, International Clinical Trial Information"; next, click on "Search PDQ for Comprehensive, International Clinical Trials Information". You will then see the PDQ Clinical Trial Search Form. Complete the form, and click on "Search"; the results of your search will be returned momentarily. Click on the title of each clinical trial to view the full PDQ protocol summary.

In addition, the NCI homepage, accessible through http://www.nci.nih.gov, contains significant other information relevant to the operation of the National Cancer Institute.

The following list represents NCI sponsored trials that are ready to be implemented in FY 1998:

1. A Phase I pilot study of Recombinant IL-2 in children and adolescents with Human Immunodeficiency Virus Infection

2. A Phase I and Pharmacologic study of a Three Drug Combination of Chemotherapy Drugs (Idarubicin, ARA-C and Etoposide) in conjunction with the Multi-drug Resistance Modulator PSC-833 in patients with refractory acute leukemia.

3. A Phase I and Pharmacological study of Penclomedine (NSC#338720, IND#43409) administered daily by mouth for five consecutive days in patients with Advanced Solid Tumor Malignancies

4. A Phase I Clinical and Pharmacologic Evaluation of Phenylbutyrate in patients with Refractory Solid Tumors Study of Continuous Exposure Oral Phenylbutyrate on a three times daily schedule

5. A Phase I Clinical and Pharmacologic Trial of Irinotecan Hcl (Irinotecan, Cpt-11) by Chronic Low-dose Daily Injections in patients with Advanced Solid Tumor Malignancies

6. A Phase I Pilot Study of 5-azacytidine in HIV Patients with Relapsed and /or Refractory EBV-associated Malignancies

7. A Phase I Pilot Study of Paclitaxel/Cyclophosphamide and High Dose Melphalan/Etoposide with Autologous Progenitor Cell Transplantation for the Treatment of Metastatic and High Risk Breast Cancer

8. A Phase I Pilot/dose-finding Study of the Toxicity, Anti-kaposi's Sarcoma (KS) Activity, and Immunologic Activity of Interleukin-12 administered to patients with AIDS-associated KS

9. A Phase I Study of a Human Papillomavirus E7 Lipopeptide Vaccine for the Treatment of Recurrent or Persistent Cervical Cancer

10. A Phase I Study of active Immunotherapy with Carcinoembryonic Antigen Peptide (CAP-1)-pulsed, Autologous Human Cultured Dendritic Cells in patients with Metastatic Malignancies Expressing Carcinoembryonic Antigen

11. A Phase I Study of Continuous Infusion Immunotoxin IGG-RFB4-SMPT-DGA in Refractory Cd22-positive B-cell Lymphoma

12. A Phase I Study of Depsipeptide in Patients with Advanced Cancer

13. A Phase I Study of Irinotecan (Cpt-11) Administered as a Prolonged Infusion in Adult Patients with Solid Tumors

14. A Phase I Study of Levamisole in Children and Adolescents with Advanced Human Immunodeficiency Virus Infection

15. A Phase I Study of Perillyl Alcohol in Patients with Refractory Malignancies (NSC #641066)

16. A Phase I Study of Prolonged Low Dose Topotecan Infusion Combined with Taxol

17. A Phase I Study of Pyrazoloacridine given as a weekly 24 Hour Continuous Intravenous Infusion in Adult Cancer Patients

18. A Phase I Study of Recombinant Vaccinia Virus that expresses Prostate Specific Antigen in Adult Patients with Adenocarcinoma of the Prostate

19. A Phase I Study of the Combination of CAI and Paclitaxel in Adult Patients with Refractory Cancers or Lymphoma

20. A Phase I Study: FdDA Therapy in Children Infected with HIV

21. A Phase I Translational Study of Chronobiologic Timing of Intravenous IuDr(NSC#39661) in the Treatment of Advanced Malignancies

22. A Phase I Trial of a Recombinant Vaccinia-CEA (180-kd) Vaccine delivered by Intradermal Needle Injection Versus Subcutaneous Jet Injection in Patients with Metastatic CEA-expressing Adenocarcinoma

23. A Phase I Trial of Perillyl Alcohol (NSC 641066) administered on a Two Weeks On, Two Weeks Off Schedule

24. A Phase Ib Study to Evaluate the Safety and Tolerance of Repetitive Daily Intravenous Doses of RSR13 Administered to patients receiving Cranial Radiation Therapy for Glioblastoma Multiforme

25. A Phase Ib Vaccine Study of Recombinant ras Protein combined with Adjuvant Qs-21 in patients with Adenocarcinomas Expressing an Activated ras Oncoprotein

26. Phase I and Pharmacokinetic Trial of Phenylacetate given as a 28-day Continuous Infusion in Pediatric Patients with Refractory Malignancy

27. Phase I and Pharmacokinetic Trial of Phenylbutyrate given as a Continuous Infusion in Pediatric Patients with Refractory Malignancy

28. Phase I and Pharmacologic Study of Sequences of Pyrazoloacridine (NSC 366140; Pd115934) and Cisplatin Without and With Granulocyte-colony Stimulating Factor (R-METHG-CSF) in Patients with Advanced Cancer

29. Phase I Cancer Vaccine Studies

30. Phase I Clinical and Pharmacokinetic Study of Diethylhomospermine (Dehspm) Administered by Subcutaneous Injection

31. Phase I Clinical and Pharmacokinetic Study of Oral 9-aminocamptothecin (Nsc-603071) on a 5 Days Every 2 Week Schedule

32. Phase I Evaluation of a Protracted Daily Bolus Schedule of 9-amino-20(s)-camptothecin [Colloidal Dispersion Formulation] in patients with Advanced Solid Tumors

33. Phase I Evaluation of Krn5500 (NSC-650426)

34. Phase I Protocol for the Administration of 2'-beta-fluoro-2',3'-dideoxyadenosine (F-DDA) to Patients with HIV-associated Diseases

35. Phase I Study of a Human Papillomavirus E7 Peptide Vaccine with Incomplete Freund's Adjuvant for the Treatment of Cervical/Vulvar Squamous Intraepithelial Neoplasia

36. Phase I Study of Adoptive Cellular Therapy of Solid Tumor Malignancies with Tumor-draining Lymph Node Cells Activated and Expanded in Vitro with Bryostatin 1, Inonomycin, and Interleukin-2

37. Phase I Study of ANTI-TAC(FV)-PE38 (LMB-2), a Recombinant Single-chain Immunotoxin for Treatment of TAC-expressing Malignancies

38. Phase I Study of IL-6, GM-CSF and CBDCA in Patients with Recurrent Ovarian Cancer

39. Phase I Study of SMS 201-995 PA LAR (NSC 685403) with/without Tamoxifen in Patients with Osteosarcoma

40. Phase I Study of Taxotere in Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction

41. Phase I Study to Determine the Safety and Pharmacokinetics of Farnesyltransferase Inhibitor, R115777, in Advanced Cancer

42. Phase I Study to Evaluate the Safety and Immunogenicity of HIV-1 Immunogen in Children with HIV-1 Infection

43. Phase I Trial in Patients with Metastatic Melanoma of Immunization with a Recombinant Adenovirus Encoding the gp100 Melanoma Antigen

44. Phase I Trial in Patients with Metastatic Melanoma of Immunization with a Recombinant Fowlpox Virus Encoding the gp100 Melanoma Antigen

45. Phase I Trial in Patients with Metastatic Melanoma of Immunization with a Recombinant Fowlpox Virus Encoding the Mart-1 Melanoma Antigen

46. Phase I Trial in Patients with Metastatic Melanoma of Immunization with a Recombinant Vaccinia Virus Encoding the gp100 Melanoma Antigen

47. Phase I Trial of 9-Cis Retinoic Acid (Alrt1057,NSC #659772) and Interferon-alpha-2b in Patients with AIDS-Associated Kaposi's Sarcoma

48. Phase I Trial of Adriamycin Combination with Suramin for the Treatment of Patients with Advanced Androgen-independent Prostatic Carcinoma

49. Phase I Trial of Combined Treatment with Ch14.18 and R24 Monoclonal Antibodies and Interleukin-2 For Patients with GD2+/GD3+tumors

50. Phase I Trial of Irinotecan and Tomudex in Combination on an Every Three Week Schedule

51. Phase I Trial of Rhizoxin (NSC 332598) Administered as a 72 Hour Continuous Intravenous Infusion Every 21 Days

52. Phase I Trial of Tomudex and 5-iodo-2'-deoxyuridine (IdUrd) in Patients with Advanced Cancer

53. Phase I, Open Label, Multicenter Dose Escalation Study of Gliadel in Patients with Recurrent Malignant Glioma

54. Phase I-II Study of Fluorouracil in Combination with Phenylbutyrate in Advanced Colorectal Cancer

55. Phase I/II Trial of Estramustine and Vinblastine Plus 3-d Conformal Radiation Therapy in Patients with Poor Prognosis Non-metastatic Prostate Cancer

56. A Phase I Pilot Study 5-azacytidine given as a 7-day Continuous Infusion Patients with Relapsed and/or Refractory EBV-Associated Malignancies

57. A Phase I Treatment of Patients with Advanced Epithelial Ovarian Cancer using Anti-CD3 Stimulated Peripheral Blood Lymphocytes Transduced with a Gene Encoding a Chimeric T Cell Receptor Reactive with Folate Binding Protein

58. A Phase I Study: vaccination of Follicular Lymphomas with Tumor-derived Immunoglobulin Idiotype Combined with Qs-21 Adjuvant

59. A Phase I Trial and Pharmacokinetic Study of the Sequential Administration of Carmustine (BCNU) and Temozolomide in Patients with CNS or Systemic Tumors Refractory to Standard Therapy

60. A Phase II Pilot Study of the Recombinant Vaccinia-CEA (70 Kd) Vaccine in Patients with Low Tumor Burden Adenocarcinoma of the Colon/rectum

61. A Phase II Randomized Study of Epoch II Versus Epoch II and Immunotherapy in Lymphomas

62. A Phase II Study of 9-aminocamptothecin in Patients with Refractory Breast Cancer

63. A Phase II Study of Chemoimmunotherapy in Patients with Mullerian Carcinoma Utilizing Intravenous Paclitaxel and Cisplatin Followed by Intraperitoneal rIL-2 Expanded TIL and a Low Dose Schedule of rIL-2.

64. A Phase II Study of CI-958 (NSC #635371) in Refractory or Recurrent Ovarian Cancer

65. A Phase II Study of Intravenous Phenylacetate in Metastatic, Hormone Refractory Prostate Cancer

66. A Phase II Study of Oral CAI in Patients with Androgen-independent Prostate Cancer

67. A Phase II Study of Suramin in Patients with Platinum-resistant Epithelial Ovarian Cancer

68. A Phase II Study: Familial Renal Carcinoma

69. A Phase II Trial of Bryostatin-1 in Low Grade Non-Hodgkins Lymphoma

70. A Phase II Trial of CI-980 in Patients with Stage D2, Hormone Refractory Prostate Cancer

71. A Phase II Trial of Phenylacetic Acid for Recurrent Malignant Glioma and Primitive Neuroectodermal Tumors: a Clinical and Pharmacokinetics Study of the North American Brain Tumor Consortium

72. A Phase II Study of Combined Modality Therapy for Good Prognosis Patients with Extensive-stage Small Cell Lung Cancer: Efficacy of Alternating Chemotherapy with Etoposide/cisplatin and an In-Vitro Best Regimen

73. A Phase II Study: CWRU 1296: Biochemical and Pharmacokinetic Predictors of Colon Cancer Response to a Topoisomerase I Directed Treatment with Irinotecan

74. A Phase II Study: Evaluation of CI-958 (NSC #635371) in Patients with Hormone Refractory Metastastic Prostate Carcinoma

75. A Phase II Study: Interleukin-12 and Epoch Chemotherapy in Untreated and Interleukin-12 in Previously Treated AIDS-related Lymphoma

76. Phase I/II Clinical and Pharmacologic Study of 9-amino-20(s)-camptothecin (9-AC) Administered as a 72 Hour Infusion in Adults with Recurrent or Progressive Malignant Glioma

77. Phase II Clinical Evaluation of Bryostatin 1 in Patients with Relapsed Multiple Myeloma

78. Phase II Clinical Evaluation of Bryostatin 1 in Patients with Relapsed Non-Hodgkin's Lymphoma and CLL

79. Phase II Evaluation of CI-980 in Untreated Extensive Stage Small Cell Lung Cancer

80. Phase II Study of All-trans Retinoic Acid and Subcutaneous Cytosine Arabinoside in Unfavorable Myelodysplastics

81. Phase II Study of Chemotherapy of Non-Hodgkin's Lymphoma arising in the CNS or Eye

82. Phase II/I Clinical and Pharmacologic Study of Pre-irradiation 9-amino-20(s)-camptothecin (9-AC) Administered as a 72 Hour Infusion in Adults with Newly Diagnosed Glioblastoma Multiforme

83. A Phase II Study: Pilot Study for the Evaluation of Rhgm-CSF Before Induction Chemotherapy in Hairy Cell Leukemia

84. A Phase II Study: Treatment of Patients with Metastatic Melanoma Using Peripheral Blood Lymphocytes Sensitized in Vitro, to the Gp209-2m Immunodominant Peptide

85. A Phase II Study: Treatment of TAC-expressing Cutaneous T-cell Lymphoma (CTCL) and Adult T-cell Leukemia (ATl) with Anti-TAC-h, a Humanized Antibody that Binds to the IL-2 Receptor

86. A Phase II Study: Use of Safety-modified Retroviruses to Introduce Chemotherapy Resistance Sequences Into Normal Hematopoietic Cells for Chemoprotection during the Therapy of Breast Cancer.

87. A Phase III Cell Kinetic Examination of Tumors in Patients Entering The Trial: Conventional Fractionation vs Continuous Hyperfractionated Accelerated Radiotherapy (w/wo Mitomycin C) in Advanced Head and Neck Cancer

88. A Phase III Current Practice Study of Antibiotic Treatment of Gastric Malt Lymphoma

89. A Phase III Study Comparing Cisplatin, Dacarbazine, Carmustine and Tamoxifen with Dacarbazine Alone in Patients with Advanced Melanoma

90. A Phase III Study: Prostate Cancer Intervention Versus Observation Trial (PIVOT): a Randomized Trial Comparing Radical Prostatectomy Versus Palliative Expectant Management for the Treatment of Clinically Localized Prostate Cancer

91. A Phase III Study: Randomized Multi-institutional Phase III Trial of Bep and High Dose Chemotherapy Versus Bep Alone in previously Untreated Patients with Poor and Intermediate Risk Germ Cell Tumors

92. A Bioavailability and Bioequivalence Study of Three Oral Formulations of Tretinoin Capsules (Ro 01-5488/109;/108; C 160449-01) and an Oral Solution in Healthy Volunteers

93. A Feasibility Study of Budr Labelling of Human Breast Cancer DNA in Vivo: Determination of Proliferation Fraction and Cell Viability in Individual Tumors

94. A Pilot Trial of Sequential Chemotherapy with Antimetabolite Induction, High-dose Alkylating Agent Consolidation with Peripheral Blood Progenitor Cell Support, and Intensification with Paclitaxel and Doxorubicin for Patients with High-Risk Breast Cancer.

95. A Study of the late Cardiac Effects of Two Different Adjuvant Chemotherapy Regimens in Women with Node Negative Breast Cancer Treated on SWOG-8897

96. A Study of The Prognostic Value of Flow Cytometric Data in Primary Colorectal Carcinoma

97. A Trial to Evaluate the Worth of Tumor Biomarkers Obtained by FNA or Core Biopsy in Predicting Response to Preoperative Chemotherapy & Long-term Outcome in Patients with Operable Breast Cancer who are Participating in NSABP Protocol B-27

98. Coagulation Studies in Acute Promyelocytic Leukemia

99. Colorectal Cancer Screening in First Degree Relatives of Colorectal Cancer Patients

100. Effect of Stem Cell Factor Presentation on AML Blasts

101. Estimation of Potential Doubling Time (TPDT) in Vivo by Iodo-deoxy-uridine

102. Fractionated Mixed Proton: Photon Radiation Therapy for Malignant Gliomas: Analysis of Local Control, Morbidity, and Patterns of Failure

103. Functional and Biomechanical Assessment of Selected Limbsparing Patients with Endoprosthesis

104. Gastrointestinal Tumor Repository Protocol

105. Human Immunodeficiency Virus and Cervical Cancer in Zambia

106. In Vitro Assay of Hematologic Tumors from Human Bone Marrow Samples

107. In Vivo Administered Iododeoxyuridine (IdUrd) as a Tool to Measure Tumor Cell Kinetics and Drug Distribution in Breast Cancer Tissue in Patients

108. Intracellular Rbc Thiopurine Pharmacokinetics in All Patients Receiving Oral 6mp vs Oral 6tg: Companion Study to CCG 1952

109. Laparoscopic Retroperitoneal Lymph Node Sampling Followed by Immediate Laparotomy in Women with Cancers of the Cervix

110. Local Excision Alone for Selected Patients with DCIS of the Breast

111. Minimal Residual Disease in Relapsed Acute Lymphocytic Leukemia: a Companion Study for CCG 1941

112. Molecular Biology of Pediatric Brain Tumors

113. Monitoring First Dose Recombinant Human Granulocyte-Macrophage Colony Stimulating Factor Toxicity

114. Positron Emission Tomography (PET) of Tumor Glucose Metabolism as an Indication of Tumor Response to Radiation Therapy

115. Prognostic Factors in Chemotherapy-treated Patients with Non-small Cell Lung Cancer

116. Prognostic Significance of Ki-67 Proliferative Index Utilizing the Mib-1 Antibody in Low Grade Gliomas in Young Children

117. Proliferative Potential of Primary Human Brain Tumors with Particular Reference to Intracranial Meningiomas and Pituitary Adenomas

118. Self-care Outcomes in Adolescents with Cancer

119. The Role of Salvage Prostatectomy for Radiation Failure in Prostate Carcinoma: a Phase II Trial

120. Validating PET Scan Measurements of Glucose Utilization in Human Extremity Sarcomas

Mr. Stokes: What is the extent of the infectious causes of cancer in the United States?

Dr. Klausner: The major types of virus-associated cancers in the United States are cervix (human papillomavirus), liver (hepatitis B and C viruses), Kaposi's sarcoma (human immunodeficiency virus and human herpesvirus 8), and lymphomas (Epstein Barr virus and human immunodeficiency virus). Stomach cancer also is common in the United States, and is strongly related to bacterial infection with Helicobacter pylori.

Two other cancers are clearly caused by viruses, anal cancer (human papillomavirus) and nasopharyngeal cancer (Epstein Barr virus), but these are uncommon in the United States.

The following table summarizes the number of cases of these cancer types in the United States during 1995 and the proportion attributed to an infectious cause:

Mr. Stokes: What is the possibility of developing a vaccine against these types of cancers?

Dr. Klausner: A safe, highly effective vaccine is on the market against hepatitis B virus (HBV), which is a major cause of liver cancer worldwide. Although HBV is not a major cause of liver cancer in the United States, HBV vaccination will also reduce acute, life-threatening hepatitis and cirrhosis. Vaccines against human papillomavirus and Helicobacter pylori appear feasible and development of prototype vaccines against these agents is underway. Progress in developing a human immunodeficiency virus (HIV) vaccine has been slow. However, in addition to steady advances in understanding the nature of an effective immune response to HIV, the past year saw a breakthrough in the discovery of HIV "co-receptors" that are likely targets for a vaccine. Hepatitis C virus (HCV), which is unrelated to HBV but also contributes to liver cancer in the United States, presents serious obstacles to vaccine development, including no clearly defined, effective immune response to natural infection and great molecular diversity in the infecting strains. Vaccines against Epstein Barr virus and human herpesvirus 8 are possible, but as with HIV and HCV, there is no prototype of an effective vaccine against this class of viruses.

Mr. Stokes: In your opening statement, you state that "the success of early detection depends upon awareness, access and availability of tests that are sensitive and specific. All of the increase in breast cancer incidence that we saw through the 1980s [now leveled off] was the result of an increased detection of early disease and now 65 percent of breast cancer is found as localized disease compared to less than 40 percent twenty years ago with a 5-year survival rate of 92 percent." With this type of evidence in hand, what was the rationale for the recent determination with respect to regular mammograms in women in the 40 to 49 year old age group?

Dr. Klausner: Stage shift, that is finding localized cancer versus late stage cancer is a necessary but not sufficient condition for reductions in mortality. A decrease in late stage incidence is a critical factor relating to reductions in mortality. The National Cancer Advisory Board, the chartered body responsible for advice to, and oversight of, the NCI is currently deliberating on this and other facts. It is anticipated that they will complete these deliberations in the next few weeks.

Mr. Stokes: How does this mesh with the recent decision of the consensus panel?

Dr. Klausner: The National Institutes of Health Consensus Development Conference panel examined all relevant studies on the subject of screening mammography in women ages 40-49. Studies in this analysis also included indicators of sensitivity and specificity. Several published studies have shown a statistically significant reduction in mortality for women who have mammography beginning some time in their forties, while other studies have not. The panel analyzed nearly 150 published research papers and more than 300 research abstracts over a period of two months, and listened to more than 30 oral presentations at the Consensus Conference. In its initial draft statement, the panel concluded that the available data do not warrant a single recommendation for mammography for all women in their forties. This draft statement and the data presented at the consensus development conference are being considered by the National Cancer Advisory Board in its deliberations regarding mammography.

Mr. Stokes: What major improvements have been made in mammography and other breast cancer screening technologies over the past few years, and how does this compare with what is currently being used by the majority of health care providers?

Dr. Klausner: There continue to be incremental -- but measurable --improvements in conventional (film-based) mammographic systems that are available in the market place. These improvements are based on physical and chemical progress in silver-halide (film) technology.

Significant technological improvements in high-definition diagnostic and Doppler ultrasound now allow this modality to go beyond its traditional role of making the solid vs. cyst determination. One company claims that their high-definition ultrasound can work adjunctively with mammography to incrementally improve the benign vs. cancer determination, and this claim was supported by a clinical study and recently approved by the FDA.

Computer-assisted "back-up" or "second-read" image processing and display tools for mammography continue to make incremental improvements in performance. It was recently announced that new image analysis software may be capable of maintaining high sensitivity while reducing the false-cues per image from the neighborhood of two to less than one per image in mammographic screening.

Mr. Stokes: Is there anything new on the shelf that is ready to go, and if so, how far away are we from having that technology widely used?

Dr. Klausner: It appears from public discussions that several manufacturers of digital mammographic systems are close to seeking Food and Drug Administration approval to market these systems. Digital mammography generates images directly on a computer rather than on traditional X-ray film. There, the images can be digitally enhanced perhaps allowing radiologists to detect smaller lesions. Another attraction of digital mammography is its use in telemedicine. Digital images can be readily transmitted from community clinics and remote areas to academic centers for expert radiologic consultation. This feature is of particular value to women in isolated or underserved areas by providing access to experts nationwide who can assist in the interpretation of their mammograms.

To optimize our efforts in breast cancer, NCI has established a Progress Review Group, to assess research opportunities in breast cancer, including those related to imaging, and to place the current activities of the NCI in the context of these opportunities. The Breast Cancer Progress Review Group along with the Prostate Cancer Progress Review Group represent the first uses of this mechanism. The Breast Cancer Progress Review Group will work with NCI staff in conducting an in-depth evaluation of the current state-of-knowledge regarding this area, survey the literature and related fields of science, and recommend to the NCI, through the National Cancer Advisory Board and the Board of Scientific Advisors, how the Institute can optimally respond to and stimulate research opportunities related to breast cancer including the improvement in detection technologies. This exercise will help set the NCI's research agenda in breast cancer by identifying and prioritizing those scientific opportunities that are most likely to expand our knowledge base and that will ultimately reduce the burden of this cancer. An important feature of the Progress Review Group is its linking of planning at NCI with a comprehensive program analysis and with all of the institute's program implementation mechanisms.

This year the NCI will be investing over $40 million in studies related to imaging in breast cancer. This includes improvements to X-ray based mammography, but also includes Several other technologies with potential for breast cancer detection that do not involve the use of radiation. These include magnetic resonance, both magnetic resonance imaging and something called magnetic resonance spectroscopy, to look at the characteristics of any possible lesions. There are other techniques as well, such Positron Emission Tomography--the PET scan, ultrasound, microwave, and photon migration. There is a proliferation of ideas that are beginning to be tested.

The NCI has created a new think tank to advise us on new opportunities in detection technologies. We are also proposing for the first time to have a standing group for clinical trials of diagnostic imaging procedures. I believe that the real break through in detection will come as we have more molecular diagnostics whose meaning we understand. Here, I think that the Cancer Genome Anatomy Project will yield tremendous return on our investment. As we identify the molecular characteristics of breast cancer cells that define their behavior, we will be able to develop increasingly "smart" diagnostics that may enable us to distinguish those breast cancers that are more aggressive from those that are less aggressive.

I have stated before and will restate for the record that it is very important to develop new means for early detection of breast cancer. However, while early detection improves prognosis, it does not guarantee a cure. We much not lose sight of the need for improvements, not only in detection, but also in therapies.

Mr. Stokes: Given that the data used to make determinations about the use of mammography is taken from trials conducted in other countries, have we compared follow-up treatment in those countries to the clinical and psycho-social care provided in the United States?

Dr. Klausner: The conduct of the randomized mammography screening trials around the world spanned the three decades of the 1960's, 1970's, and the 1980's. Over this period, the practice of follow-up treatments such as adjuvant chemotherapy and hormone therapy after initial surgery changed substantially. For example, the only trial performed in the United States, the HIP study, was conducted in the 1960's, well before the proof of benefit of adjuvant therapy had been tested and put into common use. Likewise, at the recent National Institutes of Health Consensus Development Conference, the Swedish investigators reported that very few women diagnosed with breast cancer received adjuvant therapy in their trial. In contrast, adjuvant therapy for women with breast cancer which had spread to regional lymph nodes was standard practice in Canada during the period in which the Canadian National Breast Screening Study (NBSS) was conducted. In this regard, Canadian practice was more similar to that of the United States than was Swedish practice. In the NBSS, investigators examined the medical records of women who died of breast cancer. They found that adjuvant therapy, surgery, and radiotherapy had been given appropriately to both women in the screened group as well as control women. This may have contributed to the relatively good survival rates in both arms of the NBSS trial. None of the screening trials directly addressed psycho-social issues after diagnosis of breast cancer.

The HIP study was the only study to include substantial numbers of African-American women (about 18%) of study participants). In that study, the overall effectiveness of screening was about the same for African-Americans as for the white majority. While not direct proof, this offers some evidence that similar outcomes are achievable in both racial/ethnic groups.

Finally, it is clear that the follow-up of mammograms differs from country to country. In Sweden, the ratio of breast biopsies to cancers found is generally lower than in the United States. This suggests that there is room to improve upon the biopsy:cancer ratio in our country so that fewer surgical biopsies would be needed to diagnose the same number of cancers. The efforts of the American College of Radiology to give specialty training to mammographers and of the Food and Drug Administration Mammography Quality Standards Act (MQSA) are likely to improve this aspect of quality control in breast cancer screening in our country.

Mr. Stokes: here has been an appallingly low accrual of African American women to clinical trials, particularly randomized clinical trials. What do you plan to do differently to recruit African American women to the mammography screening trial and what message will you send to African American women that is different from what the message given to white women.

Dr. Klausner: Actually, the NCI has a very good history of racially and ethnically proportional representation on randomized clinical treatment trials. Indeed in certain diseases such as breast and prostate cancer we disproportionately over accrued Blacks to cancer treatment trials. The Institute published its accrual figures in the Journal of the National Cancer Institute in June of 1996. Among women enrolling on breast cancer treatment trials 10% of participants were African American while only 8.4% of breast cancer patients in the U.S. are African American and 3.2% of participants were Hispanic compared to 3.3% of breast cancer patients in the U.S. who are Hispanic.

The Institute has had difficulty enrolling minority women into many prevention and screening studies. The institutions that provide us with proportional representation on treatment trials are the same institutions that are unable to accrue minorities to prevention trials. The Division of Cancer Prevention and Control and the newly formed NCI Office of Special Populations have published on and continue to study the dynamics of accrual to clinical trials. A key theme among participants in prevention trials is they tend to be highly educated and of higher than average socioeconomic status.

For NCI treatment clinical trials, minority representation among the individuals enrolled in the trial reflects their representation among individuals with the disease under study. For treatment clinical trials approximately 183,000 individuals are participating, of which nearly 88,000 are women and 95,000 are men. The NCI has also sponsored a national conference, the topic of which was the accrual and retention of minorities in clinical trials. Additional regional conferences on this topic will be held in the coming year utilizing NCI support.

One major NCI research effort that has been successful in recruiting minority women is the Breast Cancer Screening Consortium. It is evaluating community-based mammography screening. Two sites have significant percentages of black or Hispanic women in their study samples: Los Angeles with 27% black and 37% Hispanic women and North Carolina with 15% black women.

The NCI Office of Special Populations is convening meetings of persons interested in breast cancer in special populations -- both advocates, medical and public health professionals. These experts are being asked to help shape the message we should send to minority women about the importance of participating in these non-therapeutic studies as well as help determine how to convey that message.

Mr. Stokes: Last year alone, more than 314 thousand new cases of prostate cancer were projected to be diagnosed, and 41 thousand deaths from the disease. African American males have the highest rate of prostate cancer than any other segment of the world's population. What progress do you have to report with regard to the institutes' prostate cancer initiative in general, and also as it relates to African American males?

Dr. Klausner: NCI research efforts concerning prostate cancer, and this specific population, are and have been vigorous and varied encompassing development of new treatments, epidemiology and prevention research, the study of practice patterns, and basic science studies to understand the disease at a molecular level. A Prostate Cancer Progress Review Group is being established. It along with the Breast Cancer Progress Review Group represent the first use of this mechanism. The Prostate Cancer Progress Review Group will assess research opportunities in prostate cancer and the activities of the NCI in the context of these opportunities. The Prostate Cancer Progress Review Group will work with NCI staff in conducting an in-depth evaluation of the current state-of-knowledge regarding this area, survey the literature and related fields of science, and recommend to the NCI, through the National Cancer Advisory Board and the Board of Scientific Advisors, how the Institute can optimally respond to and stimulate research opportunities related to prostate cancer. This exercise will help set the NCI's research agenda in prostate cancer by identifying and prioritizing those scientific opportunities that are most likely to expand our knowledge base and that will ultimately reduce the burden of this cancer. An important feature of the Progress Review Group is its linking of planning functions at NCI with a comprehensive program analysis and with all of the institute's program implementation mechanisms.

NCI has recently established the Urologic Oncology Branch within the Division of Clinical Sciences. One of the major areas of emphasis of this branch will be prostate cancer. In addition, NCI has established a new fellowship program in urologic oncology that will also have as a major focus NCI's commitment to reduce the burden of prostate cancer in all segments of our society.

The NCI recently conducted a large interview-based study of prostate cancer in African Americans and whites. Analysis of the results have not thus far revealed any specific factor that could explain the racial differences in risk. However, further studies are underway, including an extensive evaluation of the role of different components of the diet. In addition, since a number of molecular alterations have been reported recently in prostate tumors, stored tumor specimens from these study subjects are being obtained to look for tumor-stage and race differences in these molecular markers, and the potential relation of the markers to possible risk factors. The molecular events associated with the initiation and progression of prostate cancer are poorly understood, and NCI researchers continue to initiate research aimed at learning more about these changes.

The NCI has issued a Request for Applications which was co-funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Environmental Health Sciences (NIEHS) in order to stimulate innovative molecular epidemiologic research into the origins of prostate cancer. Eleven epidemiologic studies were funded or co-funded by NCI in September 1995 for three years. Eight of the 11 studies include an assessment of risk factors among African American men.

A consortium of investigators is being formed to collaborate on interdisciplinary studies following the recent discovery localizing the prostate cancer susceptibility gene on chromosome 1. Leads from this effort may help to clarify genetic and gene-environment interactions responsible for black-white difference in risk. NCI plans to support physical mapping of a region of chromosome 8 thought to contain a gene involved in prostate cancer, and to isolate and screen candidate tumor suppressor genes on this chromosome.

Researchers continue to evaluate anti-cancer agents that appear to inhibit tumor growth though novel mechanisms. One agent which has shown clinical promise is suramin. In the mid-1980's, suramin was tested as an antiviral agent in patients with AIDS because of its ability to inhibit reverse transcriptase in vitro. During this trial, it was noted that some AIDS-associated malignancies, e.g., Kaposi's sarcoma and high-grade B-cell lymphomas, regressed under suramin therapy. Suramin has since been tested as a treatment for a variety of human solid tumors. The greatest potential benefit of suramin appears to be in the treatment of patients with advanced prostate cancer. Other agents currently being evaluated clinically are high-dose tamoxifen, thalidomide, and CAI in patients with hormone-refractory prostate cancer.

NCI clinical studies in prostate cancer have significant African-American participation. A recent NCI study shows that 14.7% of men enrolled onto NCI sponsored prostate cancer treatment trials are Black while 10.3% of Americans diagnosed with prostate cancer are Black. Serum and tissue samples from NCI sponsored treatment, prevention and screening trials are being used to study racial differences. To date NCI sponsored studies have shown that increased length of the trinucleotide CAG repeat on the androgen receptor gene seem to correlate with decreased prostate cancer risk. NCI sponsored studies have also shown that blacks have shorter CAG repeats than whites. This may be a biologic reason explaining, in part, why blacks have a higher incidence and mortality from prostate cancer.

NCI is planning to study CAG repeat differences among black and white men in the Prostate Cancer Prevention Trial. The major goal of the trial is to determine if a drug finasteride can prevent prostate cancer. By following these men over the next decade the hypothesis that shortened CAG repeat length confers greater risk of prostate cancer may be validated. These studies, though preliminary, are the first to link a specific germline genomic polymorphism and prostate cancer risk. The ability to stratify men according to prostate cancer risk by a relatively simple genomic test could potentially alter current approaches to prostate cancer screening and/or prevention efforts.

An NCI funded researcher is studying the enzyme 5-alpha reductase in a special population in the Dominican Republic. There is a suggestion that individuals with lower 5-alpha reductase activity have a lower risk of prostate cancer. It is known that individuals who genetically lack 5-alpha reductase do not develop prostate cancer. There is also some evidence of a racial variation in 5 alpha reductase activity. Some studies suggest that blacks have a higher average 5-alpha reductase activity than whites. Working in collaboration with Howard University, NCI scientists will analyze a large number of stored prostate samples from African American patients with prostate cancer. This will compare those results to tissue available from non-African American patients, looking at a series of molecular endpoints. Samples from patients currently being treated at Howard University and NCI will also be obtained for analysis.

The NCI has begun the Cancer Genome Anatomy Project (CGAP). The first two goals of CGAP are designed to build an infrastructure of resources, information, and technologies that will provide a platform for the establishment of an index of all genes that are expressed in tumors and support development of new technologies that will allow high throughput analysis of gene and protein expression as well as mutation detection. An early component of CGAP is the preparation to tumor sample for generation of cDNA libraries. During the first year of CGAP libraries will be produced from tissues derived from prostate tumors -- as well as from breast, colon, lung, and ovarian tumors -- and from corresponding non-tumor tissue samples. This project is aimed at accelerating our ability to develop new markers for prostate cancer and to provide accurate and predictive diagnostic tests. Prostate cancer is not one disease, and the CGAP is intended to identify the molecular characteristics that distinguish one prostate cancer from another in ways that will guide future approaches to the design and choice of effective interventions.

Mr. Stokes: here are we with regard to reaching some consensus on treatment and early detection?

Dr. Klausner: The value of any screening test used in a healthy population is dependent upon the incidence of the disease, the mortality associated with that incidence as well as on the performance characteristics, shortcomings, and risks of the screening procedure. More than fifteen organizations in the U.S., Canada, and Europe have expressed concern that the benefits prostate cancer screening is unproven and only three organizations have recommended routine screening of the population using the currently available procedures. Screening for prostate cancer is widespread only in the U.S. The studies to determine definitively if prostate cancer screening saves lives such as the NCI-sponsored Prostate, Lung, Colon, and Ovarian Cancer Screening Trial will take still a number of years to complete. Since the results of these essential trials are not yet available, the data on which the three organizations have recommended screening is very soft. A true consensus about the efficacy screening and treatment can only reached after completion of well-designed clinical trials. There is clear consensus in support of these trials.

The efficacy of radical prostatectomy as a treatment of low stage disease also continues to be a question. It is being addressed by the Prostate Cancer Intervention Versus Observation Trial. This high priority NCI study is being run in a number medical centers across the country. The NCI and its cooperative groups are also a discussing a trial comparing radiation therapy and observation for men with low stage disease. Because men in these trials have to be followed for some time, the answers will not be available for five to ten years. There is less controversy in the treatment of advanced disease, current studies are focusing on whether hormonal therapy is better early in the course of disease versus later in the course of disease. The NCI is committed to providing men with accurate, up-to-date information regarding the pros and cons of prostate screening so that individuals can make an informed decision in conjunction with their physician.

NCI research efforts concerning prostate cancer are and have been vigorous and varied encompassing development of new treatments, epidemiology and prevention research, the study of practice patterns, and basic science studies to understand the disease at a molecular level. A Prostate Cancer Progress Review Group is being established. It along with the Breast Cancer Progress Review Group represent the first use of this mechanism. The Prostate Cancer Progress Review Group will assess research opportunities in prostate cancer and the activities of the NCI in the context of these opportunities. The Prostate Cancer Progress Review Group will work with NCI staff in conducting an in-depth evaluation of the current state-of-knowledge regarding this area, survey the literature and related fields of science, and recommend to the NCI, through the National Cancer Advisory Board and the Board of Scientific Advisors, how the Institute can optimally respond to and stimulate research opportunities related to prostate cancer. This exercise will help set the NCI's research agenda in prostate cancer by identifying and prioritizing those scientific opportunities that are most likely to expand our knowledge base and that will ultimately reduce the burden of this cancer. An important feature of the Progress Review Group is its linking of planning at NCI with a comprehensive program analysis and with all of the institute's program implementation mechanisms.

In addition, NCI has recently established the Urologic Oncology Branch within the Division of Clinical Sciences. One of the major areas of emphasis of this branch will be prostate cancer. In addition, NCI has established a new fellowship program in urologic oncology that will also have as a major focus NCI's commitment to reduce the burden of prostate cancer in all segments of our society.

Mr. Stokes: With respect to African Americans, what is the institute doing to ascertain why this segment of the population is more prone to prostate cancer, and why the mortality rate from the disease is exceedingly high?

Dr. Klausner: Of the studies described above several are specifically aimed at defining the etiology of prostate cancer and may help explain why Blacks have a higher mortality. Among them are ongoing projects such as: the case control interview study which is intensively looking at diet and prostate cancer; the search for a prostate cancer gene; and studies of hormonal differences such as the 5 alpha reductase study in the Dominican Republic. There are new projects such as the study of CAG repeat length and the Cancer Genome Anatomy Project which is likely to prompt other studies that may answer the question "Why do Blacks have a greater incidence and mortality from prostate cancer?"

The study that compares prostate cancer tissues taken from Black and White patients may lead us to better understanding of the differences in biologic behavior, if differences do exist. Staff from the NCI and the Department of Defense have collaborated in a study of treatment data from an equal access system (the DoD) and shown that equal treatment yields equal outcome within stage. This finding suggests that all NCI efforts to improve prevention, diagnosis and treatment of this disease benefit all patients equally. However, NCI staff analyzing SEER Program data have shown that there are tremendously differing patterns of care among black and white Americans with prostate cancer.

Mr. Stokes: That major community-based programs focusing on prevention, detection, diagnosis, and treatment are underway, and what is planned for FY 1998?

Dr. Klausner: The Prostate Cancer Prevention Trial (PCPT) began in 1993. This trial is assessing whether hormonal manipulation with finasteride will prevent prostate cancer. It involves more than 18,000 men from more 220 medical centers in the U.S. Two-thirds of these sites are community medical centers involved in either the NCI Community Clinical Oncology Program or the NCI Community Group Outreach Program.

Other studies with significant community involvement are the Prostate Intervention Versus Observation Trial (PIVOT) and the Prostate, Lung, Colon and Ovarian Cancer Screening (PLCO). PIVOT is an NCI high priority trial to determine if radical prostatectomy is effective and is currently being run in nearly one hundred medical centers across the country. The PLCO study is designed to answer the question "Does prostate cancer screening save lives?" and is being run in ten centers around the country.

The nature of the disease is such that the PCPT, PIVOT, and PLCO, which all began more than three years ago, are not likely to give us definitive answers for several years, perhaps early in the next century. This does not mean that we are not learning important information now.

The NCI Office of Cancer Communications has developed a productive working relationship with the "Us Too", a prostate cancer support group. Over the next year there are plans to develop objective information for men considering screening and for men considering prostate cancer treatment options. The NCI funded National Black Leadership Initiative on Cancer is also planning a major community effort aimed at explaining the significant questions concerning prostate cancer and prostate cancer screening in 1998. Our goal is that men will have the information to make informed decisions with their physicians.

Mr. Stokes: What major activities are underway to further the understanding of cancer genetics and molecular biology?

Dr. Klausner: Recent discoveries have enhanced our understanding of how tumors develop. We now know that cancer is a disease caused by mutations in key target genes that give selective advantage to the growth of a tumor cell. The accumulated mutation allows the cells to grow out of control. The most direct and ultimately the most effective approach to preventing, detecting, diagnosing, and treating cancer is to learn the properties of responsible genes. Genes those dysfunction accounts for cancer are being rapidly identified. These genes ultimately determine the behavior and the relentless growth of cancer cells. Although our knowledge about these genes is growing daily, it is still incomplete, and many cancer genes remain to be found. Ideas abound on ways to use the new information for cancer prevention, diagnosis, prognosis, detection, and treatment. In short, the whole field of cancer research has been revolutionized and energized by this recent and continuing genetic revolution.

The research programs of the NCI take place in three settings: the laboratory, the clinic, and the community. In the laboratory, research is pursued on the biology of cancer, the fundamental properties of cancer-causing agents and processes, and the body's defense against and response to cancer. In the clinic, patient-oriented research is carried out concerning prevention, detection, diagnosis, treatment, and rehabilitation. In the community, research is carried out on the causes, risks, predispositions, incidence, and behavioral aspects of cancer. Each of these settings has been profoundly affected by the genetics revolution. In FY1996, the NCI expended over $1.06 billion in support of over 3,600 separate research projects. Many of these projects are aimed at understanding genetic factors related to cancer predisposition, genes involved in tumorogenesis, genes involved in the fatal consequences of oncogenesis, as well as gene-gene and gene environment interactions.

In addition, several new and highly interesting projects have been identified by the NCI as principle targets for expansion in this area. The NCI has begun its ambitious Cancer Genome Anatomy Project (CGAP) to convert emerging biological knowledge into clinical tools. The growing understanding of the roles of specific genes in the development and behavior of cancer offers an unprecedented set of opportunities to fundamentally alter our approach to cancer. NCI has identified a new set of initiatives to produce a new generation of knowledge and technology to read the molecular fingerprint of cancer cells to aid in early detection, diagnosis, prevention and treatment of cancer. These programs are intended to provide us with the tools to unravel the critical interactions of genes with diet, hormones and the environment that have eluded us for so long.

The first two goals of CGAP are designed to build an infrastructure of resources, information, and technologies that will provide a platform for the establishment of an index of all genes that are expressed in tumors and support development of new technologies that will allow high throughput analysis of gene and protein expression as well as mutation detection. An early component of CGAP is the preparation of tumor samples for generation of cDNA libraries. During the first year of CGAP, libraries will be produced from tissue derived from tumors--breast, colon, lung, ovarian, and prostate tumors-- and from corresponding non-tumor tissue samples. This project is aimed at accelerating our ability to develop new markers for cancer and to provide accurate and predictive diagnostic tests. Cancer is not one disease--even cancers that share site and appearance differ from one another at the molecular level. The CGAP is intended to identify the molecular characteristics that distinguish one cancer from another in ways that will guide future approaches to the design and choice of effective interventions.

Another major new initiative of the NCI is the Cancer Genetics Network. The recent discovery of specific genes that are predictive of predisposition to cancer will only benefit people if we rapidly move to provide interested individuals with an expanded opportunity to seek information, counseling and testing at centers of excellence. In addition, we must establish the best surveillance and interventions to reduce the chances that individuals at risk will develop cancer. This will require additional clinical research. The Cancer Genetics Network will address these issues by establishing a network of centers of excellence in human cancer genetics to enhance our ability to answer the many pressing questions that these new discoveries raise.

While recent advances in the understanding of the genetic basis of tumor development represents an extraordinary opportunity for investment in cancer research, the need is critical for an integration of basic, clinical, and epidemiologic research in this area. The aim must be not only to identify and characterize genes which modify inherited predisposition to cancer, but also to assess the efficacy of risk-reduction strategies. The NCI intends to facilitate the construction of the Cancer Genetics Network as a dynamic informatics and research infrastructure linking institutions that test individuals for hereditary cancer susceptibility and provide counseling and intervention to these individuals.

Mr. Stokes: What investment opportunities are built into the FY 1998 budget request to further work in this area?

Dr. Klausner: The area of Cancer Genetics was identified as an area of extraordinary investment opportunities and it is a field that we are moving rapidly. The NCI deems that, furthering the study of cancer genetics and molecular biology, will greatly enhance our ability to understand and control cancer.

We desire to identify and characterize every major human gene responsible for inherited predisposition to cancer and, with this knowledge, transform medical practice. The discovery that the development of cancer is driven by mutations in our genes, the identification of certain genes that predispose individuals to cancer, and recent advances in our understanding of human genetics and molecular biology make this a compelling area of research.

Since each cancer is ultimately defined by its particular pattern of altered gene activity, these patterns will define what each cancer is and how many different cancers there are. By defining these molecular patterns, we will be able to distinguish each cancer from its normal counterpart. Advances in our ability to detect, diagnose, and treat each cancer will most likely be found in these differences.

Therefore, the NCI seeks to establish a comprehensive genetics initiative. This will give us insight into cancer at its most fundamental levels. This will allow us to identify high-risk individuals and develop new interventions, both preventive and therapeutic, for people with, or at high risk for, cancer.

Mr. Stokes: As I am sure you would agree, the cancer research field is broader than the NCI. Would you bring the committee up-to-date with respect to collaborative efforts that the institute have underway with other agencies?

Dr. Klausner: As I'm sure you know, the NCI was asked following last year's testimony to prepare a comprehensive report addressing the NCI's coordination activities. That report has been forwarded and should be available to you shortly. However, I would be pleased to provide a summary of its contents here.

The reduction in cancer death rates that has occurred since about 1990 is but one very tangible result of the Nation's commitment to cancer research. In addition to improvements in mortality rates for many malignancies, the National Cancer Program (NCP) has achieved important improvements in the quality of life for America's 10 million cancer survivors through less disfiguring and less damaging surgical procedures, better pain control, and more effective medication for the side effects of cancer therapy. Progress against cancer should also be measured in the growth of knowledge about the group of diseases that collectively bear that name. It is upon this knowledge base that the progress of the next century will rest.

This progress will be enhanced by the coordination of the many activities that comprise the NCP, and it is in this coordination that the NCI has and will continue to take the lead. NCI recognizes and stimulates research opportunities through its infrastructure of discovery that leads to understanding of the etiology and biology of cancer and thus provides the means to control and prevent it. NCI facilitates exchange of information, seeks to ensure that overlap and duplication are avoided, and supports the many areas of expertise needed to overcome cancer. NCI's activities in leading the NCP often involve interactions with entities outside of the NCI -- individuals, groups, organizations, and other components of the Federal government. The brief report mentioned above will outline the types of NCI efforts related to coordination of the NCP and provide selected, significant examples of these activities to underscore the progress made in the area of coordination.

Mr. Stokes: Why are these efforts critical to the fight against cancer?

Dr. Klausner: These efforts are necessary to expedite the nation's fight against cancer. While NCI is the primary Federal agency whose mission is cancer research, we have extensive collaborations. The key is to communicate all our efforts to avoid overlap and duplication between the NCI and the larger community of cancer researchers, cancer care providers, cancer patients, and cancer survivors. I believe we have a very effective process and good working relationships with our many collaborators. Many research questions deal with issues that are also related to the mission of other ICDs within the NIH or other entities within the Federal government. This includes numerous collaborations with other Federal entities in the form of Working Groups, Task Forces and collaborations on areas of mutual interest.

Mr. Stokes: What major studies are underway to determine and evaluate the benefits of combinations of therapy including combination chemotherapy with radiation?

Dr. Klausner: Malignant tumors consist of cells that are capable of invading the surrounding tissues and establishing metastatic deposits at distant sites in the body. The major modalities for treating malignancies include surgery, radiation therapy, and chemotherapy. Surgery and radiation therapy are effective for treating localized disease, and chemotherapy is primarily effective for treating metastatic deposits of malignant cells as well as enhancing the effects of radiation therapy for localized malignancy. Metastatic deposits of malignant cells may be undetectable, either by physical exam, imaging techniques, or biomarkers, and the capacity to cure a patient may be limited by the presence of these viable micrometastates outside of the local treatment field.

Clinical trials vary in their accrual size and scope. Dependent on the questions to be addressed the study population within the trial will range significantly. All of the NCI sponsored clinical trials are included within the comprehensive, computerized cancer information database found on the NCI Web site. Over 1,500 clinical trials are identified, many of which utilize combination therapies -radiation, surgery, and chemotherapy. About 30% of NCI-sponsored trials involve radiation therapy or radiosensitization.

There are a number of currently active major randomized clinical trials in malignancies in which both locoregional disease and distant metastases are major determinants of morbidity and mortality. These malignancies include those of the central nervous system, gastrointestinal tract, gynecological organs, head and neck, lung, and prostate. The objectives of some of these studies are to determine if combined modality therapy with both chemotherapy and radiotherapy gives superior outcome in terms of local and regional control, palliation of symptoms, and overall survival, compared to single modality therapy with either radiotherapy or chemotherapy. Objectives of other studies are to define the proper sequencing of these two modalities - e.g., given sequentially, or concurrently -, the role of altered fraction and dose schedules of the radiotherapy, and to identify whether radiosensitizers lead to enhanced tumor control and survival.

Active major trials in central nervous system malignancies include a pediatric trial comparing standard with dose-intensified chemotherapy with or without radiotherapy to the brain; a pediatric trial comparing radiotherapy to the brain and spinal cord with one of two sequential chemotherapy regimens; a trial comparing sequential chemotherapy + radiotherapy with concurrent chemotherapy + radiotherapy; a trial comparing radiotherapy + chemotherapy with and without a radiation sensitizing drug; and a trial comparing single or double agent chemotherapy with either standard or altered fraction radiotherapy.

An ongoing major trial in gastrointestinal malignancy is comparing chemotherapy with either high or conventional dose radiotherapy in cancer of the esophagus. There are trials in gynocological malignancies of the cervix, which include a trial comparing standard radiotherapy with 3 different regimens of chemotherapy; a trial comparing radiation therapy + surgery with or without chemotherapy; a trial comparing radiation therapy with or without concurrent chemotherapy; and a trial in vulvar cancer, a six-arm study of surgery followed by either observation or radiotherapy alone to those with negative lymph nodes, or to more extensive radiotherapy with or without chemotherapy to those with evidence of tumor in their lymph nodes.

Ongoing major trials in head and neck include a three-arm study comparing radiotherapy alone vs radiotherapy + chemotherapy vs altered fractionation radiotherapy + chemotherapy; a trial comparing 3 different methods of organ preservation for cancer of the vocal cords, and a trial comparing radiotherapy with or without chemotherapy to patients after they have been surgically resected, but are at high risk for recurrent tumor.

Active major trials in lung include trials in locally advanced non-small cell lung cancer: a trial comparing chemotherapy with either standard or altered fractionation radiotherapy; a trial comparing chemotherapy and radiotherapy either given in sequence or given concurrently. One active trial in prostate cancer compares hormonal therapy with or without radiotherapy.

Mr. Stokes: What is there that is new to report with regard to the molecular characteristics of cancer?

Dr. Klausner: Technologic advances are making it possible to characterize the molecular alterations present in tumors more rapidly and more completely. For instance, refinements in the technique of Comparative Genomic Hybridization (CGH) have resulted in the ability to analyze archival tumor specimens so that studies requiring many years of patient follow-up can be performed on specimens collected 10-20 years ago. CGH is a technique that allows direct, simultaneous visualization of changes in the number of copies of DNA sequences across all chromosomes. Researchers have now applied this technique to identify regions of chromosomal amplification and deletion in prostate cancer that are associated with metastasis. These regions are being studied further by techniques that have greater resolution to identify the specific genes that are involved.

Genomic scanning technologies have recently identified mutations in a gene important in the induction of cell death in colon tumors with genomic instability. The initiation and progression of cancer in individuals with genomic instability syndromes, such as hereditary nonpolyposis colon cancer (HNPCC), results from secondary mutations in genes important in regulation of the cell cycle. Ongoing studies will determine whether inactivation of pathways leading to cell death plays a role in cancer initiation in these high risk patients.

The NCI recently launched the Cancer Genome Anatomy Project (CGAP) to identify all the genes expressed in tumors and to make nucleic acid sequence data and reagents available to the research community. Identification of molecular alterations in tumor cells will provide insight into the biological processes underlying cancer. As part of this project, the institute is making a major investment in the development of new technologies to speed the process of gene discovery and characterization. The long term goals of this project are to assure translation of the knowledge and technologies to improve the care of cancer patients.

Mr. Stokes: How does this knowledge help further advance cancer treatment, early detection, and prevention?

Dr. Klausner: Knowledge of specific alterations that play a role in cancer initiation and progression may identify markers that facilitate earlier detection of disease. Particular alterations may aid in the choice of specific therapies tailored to the individual patient. For example, patients with tumors that demonstrate genomic instability may benefit from therapies designed to induce cell death through an unaltered pathway. Other alterations may be used to determine, at the time of diagnosis, whether a tumor is likely to be aggressive or indolent and help the physician and patient decide on the management of the disease. This is of significant importance in early stage breast cancer and in organ-confined prostate cancer. Evaluation of the clinical importance of molecular alterations found through the CGAP will require considerable further research, but we are very confident that significant benefit will accrue from this initiative.

Mr. Stokes: With regard to the relationship between diet and cancer, what major research initiatives and/or research projects are underway to study the relationship between diet and cancer in African American women?

Dr. Klausner: Diet plays a significant role in cancer risk, and the NCI supports a number of studies aimed at clarifying the role of diet in cancer. Several of these studies have particular relevance to dietary factors and cancer incidence in minority populations. In a prospective study, an NCI grantee at Boston University has enrolled approximately 65,000 African American women to investigate the relation of obesity and other factors, including cigarette smoking, physical activity, alcohol use, diet, exogenous estrogen use and reproductive factors to the incidence of various cancers. In another study, an NCI grantee at the University of Hawaii has enrolled 35,000 African American men and women in a prospective multi-ethnic study to investigate cancer risk associated with dietary and other factors. Since dietary and nutritional factors are thought to be associated with a significant proportion of cancer, whenever feasible, NCI epidemiologic studies are designed to collect information to elucidate the etiologic role of these factors, especially as they may influence the ethnic and racial patterns of cancer incidence.

In addition, the NCI has two major initiatives that involve studies of dietary change among African Americans. The first initiative is the "Dietary Change Program for African Americans," which encourages investigator-initiated grant applications for research to develop and evaluate the effectiveness of culturally sensitive intervention strategies to assist African Americans in adopting eating patterns consistent with the NCI Dietary Guidelines. Twenty applications have been received in response to an ongoing Program Announcement; two studies were favorably reviewed and funded during FY 96 and an additional two studies are expected to be supported during FY 97. The second major NCI initiative aimed at cancer prevention through dietary change among African Americans is included as part of the 5 A Day for Better Health program. Two of the research projects supported through the 5 A Day program are targeting dietary change among African Americans. Total support for these two studies is approximately $4 million.

Mr. Stokes: What specifically is the institute doing to strengthen its research, research training, and outreach efforts which focus on breast, lung, and colorectal cancers particularly with regard to their impact on minority populations?

Dr. Klausner: The NCI remains committed to reducing the burden of cancer in all segments of the population. Toward this end an internal Special Action Committee was formed at my request to review NCI's activities and program mechanisms to ensure that the cancer problems of minorities, the underserved, and persons age 65 and over were being adequately addressed. The Special Action Committee issued its Report and Recommendations in May 1996. The report was intended to identify the specific efforts to deal with the cancer problems among these populations and to indicate opportunities for further action. Issues addressed by the Special Action Committee included the definition of minority and special population activities, monitoring of minority training, organization of NCI programmatic data on minority/special population activities, leadership and coordination of minority and special population activities, input of NCI staff into management of minority and special population activities, and identification of research opportunities.

As a tangible outcome of this analysis, I established in June, 1996 the Office of Special Populations within the Office of the Director. The Office of Special Populations will advise and guide the Director and serve as a focal point to provide leadership and coordination on research related to minorities and special populations. The office will coordinate NCI programs addressing scientific questions pertinent to these populations. Important elements of this office are the evaluation of current NCI programs and planning new initiatives. Through its evaluation function the office is determining what questions are important to special populations, what questions are being addressed through NCI's programs and portfolio of grants, and what research questions should be raised. Established epidemiologic data bases and current research findings will be used to define scientific questions pertinent to special populations. The office will develop concepts for new programs that need to be implemented by the scientific divisions of the NCI. An advisory committee of NCI staff will help define these questions. The expertise of individuals from the community will also be called upon.

NCI has expanded its surveillance efforts in tracking cancer rates for minorities. The institute has sponsored a number of patterns-of-care studies looking at the differences in cancer care among regions and among racial groups in the U.S. The NCI Black-White study reviewed differences in cancer biology, treatment, and outcomes in Blacks and Whites with bladder, uterus, breast, and colon cancer in several regions of the U.S. Several outreach initiatives have been established including the National Black Leadership Initiative on Cancer, the Hispanic Leadership Initiative on Cancer, and the Appalachian Leadership Initiative on Cancer providing grants to non-government agencies to provide information concerning cancer prevention, early detection, and treatment to some special populations. For NCI treatment clinical trials, minority representation among the individuals enrolled in the trial reflects their representation among individuals with the disease under study. The NCI has also sponsored a national conference, the topic of which was the accrual and retention of minorities in clinical trials. Additional regional conferences on this topic will be held in the coming year utilizing NCI support.

The National Office of Samoan Affairs and the University of California at Irvine have entered a cooperative agreement with the NCI to conduct a phase I study to develop and validate needs assessment instruments to measure the effectiveness of cancer control methods among American Samoans. Findings from the review of cancer incidence data have provided valuable insights about the cancer control needs of this minority population. The most common cancers among American Samoans -- breast, lung, and cervix among women and lung in men-- are diseases for which primary or secondary preventative measures are available. Findings from the cancer incidence data also suggests that American Samoans receive diagnosis of cancer of all sites at later stages of the disease than does the general population.

A request for grant applications was issued in 1995 to improve the geographic, rural, and minority representation within the Breast Cancer Surveillance Consortium. An additional major NCI research effort evaluating community-based mammography screening is the Breast Cancer Screening Consortium. Two sites have significant percentages of black or Hispanic women in their study samples: Los Angeles -- 27% black and 37% Hispanic -- and North Carolina -- 15% black. In April, 1996, data on cancer incidence and mortality by specific racial/ethnic group were published in Racial/Ethnic Patterns of Cancer in the United States, 1988-1992. The groups represented are Alaska Natives, American Indians, Blacks, Chinese, Filipinos, Hawaiians, Japanese, Koreans, Vietnamese, Whites, Hispanics, White Hispanics, and White non-Hispanics. Efforts have been made to link routinely collected cancer incidence data to other data sources containing additional information on access to health care, health care costs, treatment and diagnosis. These data provide important clues in understanding differences in cancer rates and ultimately provide a blueprint for research and intervention. In response to the recent changes in prostate cancer incidence rates, the NCI has initiated a Surveillance, Epidemiology and End Results (SEER) special study involving 3,500 men in six SEER areas. An over sampling of African American and Hispanic men was built into this study.

Mr. Stokes: As you know, compared to the general population, African American and other minority populations have a disproportionately higher risk of developing cancer. Can you update the subcommittee with respect to the NCI's environmental justice research activities?

Dr. Klausner: NCI continues to conduct studies into environmental determinants of cancer in minority and low income communities. An example of one such initiative is the proposed Triana, Alabama study of DDT exposure and breast cancer risk among African American women. A DDT production plant was discovered to have discharged large quantities of the pesticide into tributaries of the Tennessee River for several decades, and local residents who consumed fish from the river accumulated body burdens of the chemical. Given this exposure and the availability of previously collected information and blood samples, NCI has proposed to investigate the relation between tissue levels of DDT and risk of breast cancer in this predominately African-American population.

As part of its efforts to identify and evaluate cancer hazards in the workplace, the NCI intramural research program has developed the Computerized Occupational Referent Population System (CORPS) database. This database now includes sufficient number of minority entries to permit cancer risks to be analyzed by racial and occupational group. Other efforts are attempting to identify environmental -- including lifestyle -- factors that may be related to the higher rates of multiple myeloma and cancers of prostate, esophagus and pancreas among African-American men. In addition, studies are underway to investigate racial disparities in rates of breast cancer among African American and Asian women, and cervical cancer among Hispanic women.

NCI's intramural program along with NIEHS and the Environmental Protection Agency (EPA) are collaborating on a large, comprehensive evaluation of the health risks associated with agricultural exposures. Special efforts are being made to enroll minority study participants so as to allow an assessment of risk factors that may be unique to this population. The collaboration of the three agencies will permit a comprehensive evaluation of a variety of environmental exposures -- for example, pesticides, solvents, dusts, and animal viruses -- and their relation to health outcomes -- such as cancer, neurologic disease, and reproductive effects. In the extramural program, NCI is supporting a wide variety of epidemiologic studies aimed at clarifying the racial variation in cancer environmental risks among minority groups.

The NCI is continuing to collaborate with the National Institute of Aging on a series of research projects to investigate the effects of advanced age on the diagnosis and treatment of cancer in the elderly. A study is underway to assess the availability and quality of data in medical records regarding co-morbid conditions and functional limitations at initial diagnosis of cancer among the elderly. This study involves over 7,000 patients diagnosed with cancer of the colon, prostate, breast, ovary, cervix, bladder, and stomach in six SEER catchment areas.

The National Office of Samoan Affairs and the University of California at Irvine have entered a cooperative agreement with the NCI to conduct a phase I study to develop and validate needs assessment instruments to measure the effectiveness of cancer control methods among American Samoans. Findings from the review of cancer incidence data have provided valuable insights about the cancer control needs of this minority population. The most common cancers among American Samoans -- breast, lung, and cervix among women and lung in men -- are diseases for which primary or secondary preventative measures are available. Findings from the cancer incidence data also suggests that American Samoans receive diagnosis of cancer of all sites at later stages of the disease than does the general population.

Several grants from the NCI are investigating the role of environmental exposures in ethnic populations. These include a case-control study of women in the New York metropolitan area is evaluating the association of exposures to pesticides and polychlorinated biphenyls and breast cancer risk. The study population will consist of approximately 67% African-American or Hispanic women.

Another study is evaluating numerous potential biomarkers of lung cancer susceptibility in African-American, Mexican-American, and Caucasian men and women. Analysis will include ethnic comparisons by lung cancer cell-type, epidemiologic data, demographic characteristics, environmental exposures, and biomarker interactions.

There is a case-control study of American Indian women is assessing risk factors of cervical dysplasia including human papillomavirus (HPV) infections, dietary history, sexual behavior, lifestyle factors, and past sexually transmitted diseases. The data obtained will allow comparison with an ongoing, similar study in New Mexico Hispanic and non-Hispanic white women.

An epidemiologic study is investigating the synergistic relationship between HPV and diet, cigarette smoking and race in the development of cervical intraepithelial neoplasia (CIN). The study population is being recruited from a South Carolina health department family planning clinic and will be comprised of approximately 60% African-American.

Mr. Stokes: With regard to environmental justice, what major progress do you have to report to the committee with respect to collaborative research efforts that are underway between NCI and NIEHS?

Dr. Klausner: The NCI spends over $350 million a year on environmental carcinogenesis research. As part of this effort, the NCI collaborates with the NIEHS on several environmental justice research activities.

The Northeast/Mid-Atlantic Breast Cancer Study made up of six ongoing projects is being supported by the NCI and the National Institute of Environmental Health Sciences (NIEHS) to investigate environmental exposures and breast cancer risk in the Northeast and mid-Atlantic regions of the United States. Women, including minority women, who are participating in this effort reside in New Hampshire, Connecticut, Delaware, Massachusetts, Maryland, New Jersey, New York, Rhode Island, Vermont, and the District of Columbia. A major objective of the project is to assess the effects of organochlorine pesticides, polychlorinated biphenyls (PCBs), and electromagnetic field radiation, as well as known breast cancer risk factors such as reproductive and family history. The identification of breast cancer cases and controls, collection of questionnaire information, and laboratory analyses of biological specimens are nearing completion. Analyses of the data will be done for each study site, as well as to compare the different geographical regions.

In another effort, the NCI and NIEHS are coordinating a series of studies to investigate the contribution of environmental agents to the relatively high rate of breast cancer reported on Long Island. Among the agents that will be evaluated are DDT and chlordane pesticides, PCBs from electrical insulators, electromagnetic fields, and polycyclic aromatic hydrocarbons from car exhaust, cigarette smoke and other sources. Pioneering approaches are planned in assessing the impact of these environmental exposures on the risk of breast cancer.

Another major collaboration between NCI and NIEHS is the Agricultural Health Study, a large prospective cohort study of predominantly farm families. NCI is providing the majority of funding for this effort, and is the lead group for conducting the study and assessing cancer endpoints. NIEHS will evaluate a variety of non-neoplastic outcomes in relation to agricultural exposures.

Mr. Stokes: What initiatives are planned for FY 1998?

Dr. Klausner: The ongoing initiatives are slated to continue through FY1998. The outcome of these efforts will help to determine the future direction of new research.

Mr. Stokes: How much is included in the budget request for this activity, and how does it compare with the current funding level?

Dr. Klausner: NCI funding for these collaborative projects will be approximately $6.5 million in Fiscal Year 1997. The 1998 budget request for these projects would continue funding at about that same level.

Mr. Stokes: As the director of the National Cancer Institute, in your professional judgement, what specific activities and what level of funds are needed to effectively address environmental justice as it relates to activities under the purview of your institute?

Dr. Klausner: NCI will continue to support initiatives that address the Departmental strategy on environmental justice, particularly those with an emphasis on the goal of focusing attention on the human health and environmental conditions in minority and low-income communities. Epidemiologic studies will continue to be pursued to assess specific environmental and occupational hazards as they relate to undeserved populations.

Of particular concern is the finding that there is a 30% excess of certain cancers in the African-American population. These cancer sites include esophagus, multiple myeloma, stomach, larynx, pancreas and oral cavity for both sexes; lung and prostate in men; and uterine cervix in women. Some of these differences are related to higher exposure levels, such as higher tobacco use patterns in African-American men and greater rates of human papillomavirus infection in African-American women. Future research opportunities include increasing efforts to mitigate these risk factors through outreach activities, which should impact positively on racial differences in cancer rates. Additional studies include efforts to identify biologic markers of risk, such as for specific hazardous exposures, profiles of genetic susceptibilities, and gene-environment interactions. Expansion of research in these areas should culminate in a better understanding of the environmental and genetic determinants of cancer, resulting in applications to reduce the disproportionate burden of cancer in African-Americans and other minority groups.

Mr. Stokes: The Cancer mortality by race and gender chart indicates a significant decline in cancer among black men as compared to the rest of the population. Can you elaborate on this. Which cancers accounted for this decline?

Dr. Klausner: The overall cancer mortality rate declined for black males between 1990 and 1994. For black males, there were statistically significant declines in mortality for the following cancers: oral cavity and pharynx, lung and bronchus, and urinary bladder. There were also apparent declines for the following cancers: esophagus, stomach colon/rectum, melanomas, kidney, brain, thyroid, Hodgkin's disease, multiple myeloma and leukemia. For these cancers, the decline for African-American men have not reached statistical significance.

Mr. Stokes: What role did prevention, access to health care services, and early detection play? Please elaborate on your response to this question for the record?

Dr. Klausner: The decline in the overall mortality rate is probably due to a combination of factors, including behavioral changes, screening, advancements in therapy and possibly a decrease in risk factor exposures. It is therefore difficult to make a precise attribution to any one factor or set of factors.

The NCI recognizes that all of the issues that you include in your question are factors that have an impact on the course and outcome of cancer. The NCI has numerous programs that encompass one or more of these issues.

Mr. Stokes: Last year's Senate report that accompanied the FY 1997 appropriations bill included language calling for the Institute of Medicine to conduct a review of the status of NIH research on cancer among minorities and the medically underserved. What is the status of that study and when is it expected to be completed?

Dr. Klausner: NIH recently received the Institute of Medicine's proposal to conduct the review of research on cancer among minorities and the medically underserved. We expect the study to be completed in early summer of 1998.

Mr. Stokes: All the leading newspapers, television, and science journals just recently reported on the Scottish scientists' cloning of adult sheep. These articles expressed excitement with regard to opportunities for advances in medical treatments and concern with regard to misuse of the technology and the possibility of human cloning. This is another area where we must now be certain to assess and address the ethical, legal, and social issues of research on the front end. As a leading researcher and as the director of the National Cancer Institute, what is your professional opinion of this technology and what are your most serious concerns?

Dr. Klausner: The President has made clear the administration's position on human cloning. No federal funds may be used for such research, and the President has requested a voluntary ban on such research in the United States even if federal funding is not employed. The President has asked the National Bioethics Advisory Commission to examine the issues raised by the successful cloning of an adult mammal. I believe this to be the appropriate body to discuss the issues and to make recommendations.

I agree with Dr. Varmus in his testimony before the committee that there may be advantages that can come form research on cloning in non-human species. One concern is that the cloning of Dolly will result in a rush to regulate all cloning that might preclude the legitimate benefits of cloning research that does not involve humans.

Mr. Stokes: With regard to cancer, what are the most significant benefits that cloning would yield for your major areas of research?

Dr. Klausner: Perhaps the most significant benefit from non-human cloning research will be an increase in the understanding of how genes are turned on and turned off. All cells of an individual contains the same genetic material. The distinction between liver cells and brain cells lies in which of the genes that both contain are on or off. In the case of the cloning of Dolly, the nucleus from a differentiated adult tissue was reprogrammed to allow the expression of genes that were not on in the cell from which Dolly was derived. Just as the difference between liver cells and brain cells is in the genes that are on and off, so too the difference between a normal liver cell and a liver cancer cell is related to differential gene expression. Which genes are expressed in a given tumor that are not expressed in normal cells? How do these changes in gene expression come about during carcinogenesis or during normal development? These questions are the kinds of questions that CGAP is intended to address. While We know something about their answers, there is certainly more to learn. Animal cloning experiments may help shed light on these processes.

Animal cloning may also be instrumental in the production of better animal models for human diseases including cancer. NCI has a Preclinical Models Working Group one of the aims of which is to address the inadequacies of current animal models for research in cancer. With models that more accurately reflect human cancer, we would be better able to test prevention, detection, and therapy innovations than is possible today.

It is also possible that animal cloning research would enable the more efficient production of therapeutic human proteins. It may be able to produce organs in animals that would be suitable for transplantation into humans. One procedure that is not uncommon in cancer treatment is bone marrow transplantation. Animal cloning could lead to the ability to produce bone marrow cells that would not be rejected by human recipients.

Mr. Stokes: What steps have you taken to apply internet technology to the way NCI interfaces with the public in the dissemination of cancer information?

Dr. Klausner: NCI has made a tremendous effort to take advantage of network technology as a vehicle for providing information about NCI and NCI sponsored research, and NCI clinical trials to the public. The public can access a wealth of information about NCI through four primary vehicles; the NCI Homepage, CancerNet, and PDQ (Physicians Data Query), and the Cancer Information System (CIS).

Data ranging from basic information about NCI, to information about specific studies can be found using the NCI Homepage. It is organized topically to assist users. Sections for intramural and extramural research are included as well as technology transfer, administrative information, public information such as the NCI fact book, and the Frederick Cancer Research and Development Center. A hot link is provided to quickly connect users to the CancerNet. Most of the administrative branches within NCI have created home pages here as well.

The CancerNet is targeted to three separate audiences; Patients and the Public, Health Professionals, and Basic Researchers. The Patients and the Public section provides general information about cancer including treatment, detection, prevention, genetics, support and advocacy groups, clinical trials and provides a kid's homepage and information about the 1-800-4CANCER program. The Health Professionals section provides the latest treatment information, information about active clinical trials, cancer statistics, and provides a "hot news" digest. Finally, the Basic Research module includes information on the NCI Cooperative Breast Cancer Tissue Resource Database, the NCI AIDS Malignancy Bank Database, the NCI Cooperative Human Tissue Network, the NCI Cooperative Family Registry for Breast Cancer Studies and the NCI-NAPBC Breast Cancer Specimen and Data System.

CancerNet provides information both in English and Spanish and is intended to provide a wide range of accurate, credible cancer information. All information located on CancerNet has been reviewed by oncology experts and is based on the results of current research.

PDQ was developed by the National Cancer Institute (NCI) with the help of cancer experts from across the Nation. It contains information statements on state-of-the-art cancer treatment, cancer screening and prevention, supportive care for cancer patients, and investigational and newly approved anticancer drugs. PDQ state-of-the-art treatment statements contain a description of prognosis (probable outcome), cellular classification, staging (extent of disease), and treatments for all major cancers and some related conditions. State-of-the-art treatments are the best therapies currently available for a specific type and stage (extent) of cancer. PDQ does not recommend one treatment over another, but lists treatment options so that the doctor can select the one that is best suited for a patient. Because advances in treatment are being made all the time, PDQ statements are reviewed monthly by doctors and other experts on PDQ Editorial Boards and are updated as needed.

The Cancer Information Service provides accurate, up-to-date information on cancer to patients and their families, health professionals, and the general public. The CIS has two main features: a telephone service that responds to more than 600,000 callers a year, and an outreach service that proactively takes cancer information to under served and minority populations that do not often use the telephone to gather information. CIS information is also available through the NCI's CancerFax and CancerNet services, and in the News Section of the PDQ database. Individuals who have access to the Internet may access the document on CancerNet, through an electronic mail (E-mail) service or via the National Institutes of Health gopher. To get the CancerNet contents list from the E-mail service, send an E-mail message that says "help" in the body of the message to cancernet@icicc.nci.nih.gov. To get the document from CancerNet via the NIH gopher, point your gopher client to gopher.nih.gov and look for CancerNet under "Health and Clinical Information." To get the document from NCI's PDQ database, access PDQ News on the National Library of Medicine's MEDLARS system or consult a medical librarian for assistance.

The CIS outreach service reached about 19 million people last year. Through both the telephone and outreach services, CIS provides information on the latest cancer treatments and how to manage their side effects, studies that test new treatments, tips on how to detect cancer early, tips on how to reduce cancer risk, and community services for patients and their families. The CIS operates regionally in 19 offices, but is reached with a single phone number, 1-800-4-CANCER. Its telephone counselors take calls in both English and Spanish. CIS also provides access to the hearing impaired. Hallmarks of the CIS are the rigorous and continuing training programs for its counselors, and its sophisticated quality control program.

We continuously try to identify useful new information to include in these systems, and new avenues of reaching the public using network technology as it continues to develop.

The addresses for the sites mentioned are:

NCI Homepage - www.nci.nih.gov

CancerNet - wwwicic.nci.nih.gov

PDQ -http://cancernet.nci.nih.gov

CIS - By Phone - 1-800-4CANCER

Mr. Stokes: Can you give us an update on what the NCI is doing in the area of behavioral research? I am particularly interested in the smoking and behavioral arena.

Dr. Klausner: A significant part of NCI's research in the area of smoking and behavior is the ASSIST (American Stop Smoking Intervention Study) program, begun October 1, 1991 with a two-year planning phase during which the states defined the structure, direction and course of action for the implementation period. During Phase II, (October 1, 1993 - September 30, 1999) the states will implement their comprehensive smoking control plans.

States have developed 220 tobacco control coalitions with about 3,000 members, comprising an unprecedented infrastructure to improve public health. It is estimated that more than 90 million Americans will be directly affected by ASSIST and nearly 1.2 million premature smoking-related deaths will be prevented. ASSIST is designed to prevent 2 million children from becoming addicted to tobacco products. ASSIST will reach vulnerable populations who are targeted by the tobacco industry, including ethnically diverse groups, blue collar workers and families, and the underprivileged.

In addition to ASSIST, the NCI is addressing behavioral issues in cancer prevention and control, and especially tobacco use, through a number of other initiatives. These include:

• Prevention and Cessation of Tobacco Use among Children and Youth in the U.S. - this Request for Applications, announced in January, 1997, represents the NCI's largest research commitment to reducing youth tobacco use in the U.S. Through this initiative, the Institute has committed $32 million over the next five years to support at least 16 studies to develop the most innovative, cost-effective, and durable methods of addressing the problem of tobacco use among children and youth in this country.
• Priorities in Behavioral Research in Cancer Prevention and Control - this Program Announcement, published in March 1997, articulates the NCI's goals for behavioral research in cancer prevention and control. This initiative calls for research in such areas as tobacco use, risk communication, preventive services and health care delivery, outcomes of genetic testing, enhancement of quality of life among cancer patients, and promotion of healthy diets and physical activity.
• Skin Cancer Prevention Program - this initiative, begun in 1994, is supporting four intervention trials which are investigating the most effective approaches to educating both children and adults who are at high risk for skin cancer, especially through schools, day care programs, and primary care practices.
• 5 A Day for Better Health Community Intervention Research Program - this initiative, begun in 1994, is supporting nine intervention trials investigating how best to increase community-wide consumption of fruits and vegetables.
• Pharmaco-Behavioral Treatment of Nicotine Dependence - this initiative, begun in September, 1996, is supporting seven intervention trials to develop the most effective adjuvant behavioral therapies to support the pharmacological treatment of nicotine dependence.
• Investigator-Initiated Behavioral Research - the Investigator-Initiated Research Program remains the NCI's most visible and active initiative focusing on behavioral research in cancer prevention and control. More than one hundred studies are currently investigating a wide variety of approaches to such behavior-related issues as reducing tobacco use, changing diets, increasing adherence to screening advice, post-treatment rehabilitation, and amelioration of cancer pain.

Mrs. Lowey: I understand that you are working to create a science information portfolio which when completed would allow scientists and interested lay persons to find out what type of cancer research grants are currently being funded. Can you say more about this project as it applies to breast cancer?

Dr. Klausner: The NCI supports scientific investigations into breast cancer as one of its highest priorities. During this year, 184,000 new cases of breast cancer will be diagnosed and 44,000 women are expected to die of the disease. Given the magnitude of this disease, NCI recognizes its obligation to supply or coordinate the dissemination of current information concerning NCI funded research grants and other NCI breast cancer related research and activities. Although there is a new Science Information System (SIS) in the developmental stage, other mechanisms to obtain information on grants and other activities funded by the NCI are currently operational.

The SIS is being designed as a Web-accessible, computer based virtual repository of information about the science that NCI supports, and its programs and activities. Many of the information sources -- reports of workshops, progress review groups, summaries of research activities -- will provide information on the state of the science for a particular area of cancer research. For example, concerning breast cancer research, SIS might be used to identify the major areas of breast cancer research currently being addressed, or what clinical trials NCI currently sponsors in breast cancer and the status of each. It could be used to identify what workshops related to breast cancer have taken place in the past three years, what recommendations came out of those workshops, and determine whether other workshops on breast cancer are planned for this year. It could help identify which NCI investigators and laboratories are involved in research relevant to breast cancer, what are they doing, and what their results have been to date.

Initially, the SIS will attempt to meet the needs of NCI scientific managers. However, over time it will be enhanced and expanded to provide useful interfaces for the larger community of cancer researchers, clinicians, and the general public.

SIS will not create many new information sources; rather, the SIS will link to and retrieve information from sources of data that already exist. Under SIS, the user will be able to access data from such diverse sources as grants and contract databases, reports from working groups and progress review groups, program analyses, and tools that enable the user to locate people, resources, and expertise--all through a single interface.

The NCI maintains a number of current information retrieval systems. The Computer Retrieval of Information on Scientific Projects (CRISP) system is an existing major biomedical database containing information on research ventures supported by the National Institutes of Health (NIH). Most of this research falls within the broad category of extramural projects: grants, contracts, and cooperative agreements conducted primarily by investigators at universities, hospitals, and other research institutions. CRISP also contains information on NIH intramural research programs.

The CRISP database is updated weekly and is currently available on the Internet as a gopher-based system. To enhance search and retrieval capabilities of the database, there is also a plan to publish CRISP on the World Wide Web (WWW). Retrieval of scientific information for each project in CRISP is made available by the project title, principal investigator's abstract, and the term descriptors assigned by the Division of Research Grants, NIH.

In addition, NCI maintains internal databases indexed to provide information about special categories of research and specific anatomic sites. These databases include administrative information and principal investigator abstracts. There are plans to develop a subset of the data for access and limited searching over the World Wide Web.

Additionally, the NCI supports a comprehensive research program focused on breast cancer research. The portfolio includes research on risk factors, tumor biology, screening, diagnostics, therapeutics, novel clinical approaches, prevention and control, and quality-of-life issues. To better monitor and optimize all these efforts in breast cancer, NCI has established a Progress Review Group (PRG). The mission of the PRG is to identify research opportunities in breast cancer and assess the activities of the NCI in the context of these opportunities. It, along with a Prostate Cancer PRG, represents the first use of this mechanism. The Breast Cancer PRG will work with NCI staff to assess the current state of knowledge regarding this area and recommend how the Institute can optimally respond to and stimulate research opportunities in breast cancer. This approach will help set the NCI's research agenda in breast cancer by identifying and prioritizing those scientific opportunities that are most likely to expand our knowledge base and that will ultimately reduce the burden of this cancer. Information resulting from the PRG will be made accessible through the Scientific Information System.

Mrs. Lowey: When would you hope to have it completed?

Dr. Klausner: The full development of the SIS will require several years. Feasibility testing for parts of the system is being conducted in the current year. Depending upon the success of the prototypes, one or more years of operational implementation may follow.

Mrs. Lowey: Is progress affected by cuts in your administrative budget?

Dr. Klausner: We are committed to improving our collection and categorizing of scientific information and sufficient funds will be available to implement this effort.

Mrs. Lowey: The major risk factors for breast cancer point to a potentially significant role of estrogen in the development of breast cancer. In fact, one researcher is experimenting with artificially lowering estrogen levels as a means of preventing breast cancer. What research are you funding in this area, particularly with regard to the prevention of the disease?

Dr. Klausner: NCI is currently supporting several projects, clinical trials as well as laboratory-based studies, which are assessing the effectiveness of strategies to reduce estrogen exposure in breast cancer prevention. The best known of these initiatives, the Breast Cancer Prevention Trial (BCPT) was implemented in 1992 by the National Surgical Adjuvant Breast and Bowel Project (NSABP). The study is testing the ability of tamoxifen, an agent with anti-estrogen properties used in post-surgical treatment of early-stage breast cancer, to prevent the first-time development of breast cancer in women at increased risk for developing the disease. Approximately 13,000 women at increased risk for breast cancer due to age, family history, and personal history, such as age at first birth, age at menarche, and previous breast biopsies, are being randomized to receive 20 mg of tamoxifen per day or a placebo for an initial period of five years. The study is being implemented in about 300 nucleus and sub-centers across the country and in Canada. As of Fall 1996, over 12,300 participants have been enrolled and randomized to either tamoxifen or placebo. The women who have volunteered for the BCPT typically have a 4 to 5 times higher chance of developing breast cancer than women in the general population.

While the study focuses on decreasing incidence of breast cancer as the major endpoint, cardiovascular effects, alterations in bone/mineral metabolism, occurrence of second primary cancers, and impact on quality of life will also be assessed. The effect of tamoxifen as it relates to the molecular genetics of breast cancer development as well as endometrial and ocular changes in women receiving tamoxifen are being studied. Information from these studies will guide the future routine care of women receiving tamoxifen in both treatment and prevention settings. The trial includes a program to defray costs for economically disadvantaged participants.

Several laboratory studies of the effect of modulators of estrogen production on breast and proliferation and breast cancer metastasis are also in progress. In one study, a naturally occurring component - indole-3-carbinol - of cruciferous vegetables such as broccoli and cauliflower is being evaluated for its ability to enhance the rate of estrogen metabolism and/or decrease the sensitivity of breast cells to estrogen. Another study is focused on exploiting the ability of the vitamin A metabolite, retinoic acid, to reduce the ability of estrogen or other substances to promote proliferation of breast cancer cells. Other studies involve the use of vitamin E-related chemicals and fatty acids to neutralize or reverse estrogen's effect on normal breast cells and breast tumor cells. It is anticipated that laboratory studies such as these will provide researchers with a new generation of potential breast cancer preventive agents based on reducing or modulating estrogen effects.

Ms. DeLauro: In FY 1997, NIH will spend only $41 million out of a $12.7 budget on ovarian cancer research. Over the past few years, increases in ovarian cancer research funding have been extremely incremental. How much does NCI plan to spend this year on ovarian cancer research?

Dr. Klausner: I have made a special effort to develop a Scientific Information System that will be responsive to the needs of the institute in at least two areas-- to identify areas and descriptions of what the NCI is supporting as well as areas that need to be addressed. It will take some time to complete this process which is, in fact, an experiment. Through that process, we hope to more clearly delineate funding. NCI represents the dominant share of the NIH ovarian cancer funding, currently projected to be $39 million in FY 1997 and $41 million for FY 1998.

Ms. DeLauro: What types of initiatives does this include?

Dr. Klausner: We have placed ovarian cancer as one of the first things to look for in the Cancer Genome Anatomy Project (CGAP). Libraries of genes from ovarian cancer cells have been started, so we can search for tags or molecules in systematic way. We are optimistic that this will provide us with better detection as well as better intervention. The National Cancer Institute has an active program in basic and applied ovarian cancer research including studies of the genetics of inherited ovarian cancer. The NCI has implemented or continued activities related to the recommendations of the NIH consensus conferences on ovarian and cervical cancer.

Major screening studies are underway for ovarian cancer as part of the PLCO (Prostate, Lung, Colorectal, and Ovarian) trial. The PLCO trial is designed to determine whether particular screening modalities will reduce the number of deaths through early detection and treatment. This trial is very large involving 148,000 participants. For ovarian cancer, women will have an annual ovarian palpation, transvaginal ultrasound, and blood test for the molecular tumor marker CA-125. Four geographically diverse clinical centers - Birmingham, Alabama; Pittsburgh, Pennsylvania; Oklahoma City, Oklahoma; and Seattle, Washington - will enroll a total of 7,200 women in this study.

NCI currently sponsors nine ongoing clinical trials for ovarian germ cell tumors and sixty ovarian epithelial cancers trials. Through the Gynecologic Oncology Group and NCI-designated cancer centers, the NCI continues to support critical research into the treatment of ovarian cancer. In addition, the NCI is working to strengthen gynecologic oncology services and research at the NIH Clinical Center.

Ms. DeLauro: Will the research be done primarily through the extramural or intramural program?

Dr. Klausner: NCI's effort in ovarian cancer is primarily through the extramural scientific community through investigator initiated research grants. Over 90% of our funding in this area is conducted by scientists located throughout the nation at universities and academic institutions. This proportion within the extramural program is similar to that of other areas and to the overall distribution of effort between the extramural and intramural research program.

Ms. DeLauro: Dr. Klausner, I believe in the current clinical center there is one lab for gynecologic cancer research. Are you proposing that additional lab space in the new Mark O. Hatfield Clinical Canter be designated for gynecologic cancer research?

Dr. Klausner: There are actually four laboratories -- and one section -- performing active research in issues pertaining to gynecologic oncology. Work on growth factors in ovarian cancer growth as well as the development of vaccines against the human papilloma virus which is responsible for the majority of cervical cancer is one area of investigation. Another is the role of oncogenes in ovarian cancer growth, especially the role of nuclear proto oncogenes such as fos and jun. A number of clinical trials extending observations that DNA repair genes are associated with potential drug resistance in ovarian cancers are being conducted. Seminal work on alkylator therapy has led to the formulation of triple alkylator treatment in advanced ovarian cancer that is now standard in the field. A new chemotherapeutic agent CAI that appears to have efficacy in ovarian cancers has been developed.

Thus, the NCI work on gynecologic cancers is broad and intense. An NCI investigator has developed a new method of producing HPV vaccines that may revolutionize the field. Based on viral protein production in insect cells in culture, this effort has been able to reassemble the viral coat without the viral genetic material. This material acts as a superb vaccine in animal studies. Human trials are anticipated.

The NCI intends to continue to strengthen its program in gynecological cancers. These efforts will be accomplished within the clinical center space currently designated for the NCI.

Ms. DeLauro: What kinds of strides has NCI made to include woman in clinical trials?

Dr. Klausner: The NCI has at any one time almost 3 million subjects enrolled in clinical studies concerning the detection, diagnosis, treatment, prevention or control of cancer. These subjects, which are predominately healthy individuals, are composed of 71% women and 45% minorities. NCI has vigorously pursued on its own and with its grantees recruitment of women and minorities in all studies, and conducts many trials specifically targeted at gender-specific cancers of high prevalence and impact. NCI has been extremely successful in ensuring representation in trials with therapeutic intent and with population-based data collections. For NCI treatment clinical trials, minority representation among the individuals enrolled in the trial reflects their representation among individuals with the disease under study. For treatment clinical trials approximately 183,000 individuals are participating, of which nearly 88,000 are women and about 95,000 are men. The NCI has also sponsored a national conference, the topic of which was the accrual and retention of minorities in clinical trials. Additional regional conferences on this topic will be held in the coming year utilizing NCI support.

Ms. DeLauro: How is the inclusion of women in clinical trials addressed in your FY 98 budget request?

Dr. Klausner: NCI's internal assessment of the fulfillment of meeting the inclusion requirement has assured compliance with the NIH Revitalization Act of 1993: Women and Minorities as Subjects in Clinical Research. A grant application that fails to meet the standard for inclusion receives an unacceptable gender or minority code, which results in an administrative bar-to-funding. This bar may be removed upon receipt of additional information. Program staff has some flexibility to work with an applicant and resolve problems the may prevent award of highly meritorious projects.

On February 26, 1997, based upon the review of the data presented to the National Cancer Advisory Board (NCAB), the NCAB concurred with the NCI's compliance in implementing the NIH Guidelines on the inclusion of women and minorities in clinical studies.

Ms. DeLauro: I noticed that NCI convenes a variety of panels and advisory boards which aid the complex decision-making that goes into determining the next steps for biomedical research in the cancer field. Yet, given the recent controversy surrounding the panel on mammography, how effective are these panels in helping to assess NCI's priorities?

Dr. Klausner: I believe the NCI's advisory panels to be critical to the success and progress of the nation's cancer research investment. Our advisors represent the nation's leading experts in the varied disciplines of cancer research. The National Cancer Advisory Board, for example, has played a central role in the reformulation of the NCI Bypass Budget and in defining topics to be considered as priority opportunities for extraordinary investments. The NCI's Board of Scientific Advisors has initiated a series of reviews of major extramural program areas such as Cancer Centers, Clinical Trials and Cancer Prevention and Control to ensure the structure of the NCI is poised to take advantage of priorities as they emerge in the future, as well as to ensure sound management of current resources.

I would note that the Development Conference on Mammography Consensus was convened by the NIH Office of Medical Applications of Research (OMAR) and that this panel is not one of our chartered advisory groups. The Consensus Conference process serves a useful purpose. The mammography conference led to the presentation of data that had not previously been presented. It brought together scientists in the field of mammography and led to a spirited discussion of the issues. The data presented at the conference and the panel's draft report is being used by our official advisory body-- The National Cancer Advisory Board (NCAB) in their chartered role of advising and overseeing the NCI. The NCAB is in the process of developing its recommendation to the NCI regarding mammography.

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