A large-scale clinical trial to investigate whether supplementation with the antioxidants vitamin E and selenium can prevent prostate cancer has just about completed enrollment of 32,400 participants, more than two years ahead of schedule. The NCI-sponsored trial - dubbed SELECT, for Selenium and Vitamin E Cancer Prevention Trial - began enrolling patients in August 2001. Achieving the randomization goal was expected to take approximately five years. Instead, it will take approximately 34 months, with randomization set to cease on June 24.

To complete randomization of this many participants in such a short period is rarely seen, said Dr. Charles A. Coltman, Jr., chair of the Southwest Oncology Group (SWOG), which is coordinating the trial. "This accomplishment is a tribute to the men who have volunteered to participate in SELECT at a rate of 1,000 a month and to the researchers and clinical research associates who did a masterful job of recruitment."

Although it is difficult to attribute this achievement to any single factor, Dr. Coltman said, one clearly important component is that all 428 study sites - spread across 50 states, Puerto Rico, and 6 Canadian provinces - are using a Web-based system to conduct nearly every aspect of the trial, including patient registration, randomization, and ordering of supplements.

The impetus for SELECT was the results of secondary analyses from two previous studies. A secondary analysis from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, or ATBC, published in 1998, found that vitamin E supplementation in the form of 50 mg of alpha-tocopherol daily reduced prostate cancer incidence by 32 percent and prostate cancer death by more than 40 percent in Finnish male smokers. In a much smaller trial published in 1996 to examine the impact of selenium on the risk of skin cancer recurrence, a secondary analysis found that 200 micrograms of selenium daily yielded a 63 percent reduction in prostate cancer risk.

Participants in SELECT must be 55 years or older, have a clean digital rectal examination, and a prostate-specific antigen level of less than or equal to 4.0 ng/ml. Black participants can be as young as 50, because they tend to get prostate cancer earlier. In addition, black men in the United States have the highest incidence of prostate cancer in the world. Participants are being randomly assigned to one of four treatment groups: 200 micrograms of selenium daily plus placebo, 400 mg of alpha-tocopherol daily plus placebo, 200 micrograms of selenium and 400 mg of alpha-tocopherol daily, or two placebos daily.

"SELECT is far from over," said Dr. Leslie Ford, associate director for clinical research in the NCI Division of Cancer Prevention. "We appreciate the dedication of the men participating who will continue in the study for several more years in order for us to get the true answers about the benefits and risks of selenium and vitamin E."

Such answers are vitally important. Prostate cancer is one of the most deadly forms of cancer. It is estimated that in 2004 there will be more than 230,000 new cases, and approximately 30,000 men are expected to die from the disease.

Other investigations will be conducted as part of SELECT, including those to determine the effect of selenium and vitamin E on the risk of lung and colon cancer, the genetic underpinnings of prostate cancer risk, and the associations between diet and cancer.

One of the most rewarding aspects of my position as director of the National Cancer Institute (NCI) has been the opportunity to witness the emergence of vital new initiatives and areas of research. In particular, it's been gratifying to see the rapid evolution of research into the needs, problems, and realities of cancer survivors. At NCI, we've made survivorship research a top priority. We are directing and conducting research on an abundance of important topics, including long-term follow-up of childhood cancer survivors, healthy behaviors for all survivors, and unique issues faced by cancer survivors from underserved populations.

The fact that survivorship is such a burgeoning area of research is evidence of the tremendous progress we have made - progress that clearly portends a future in which we can achieve the goal of eliminating the suffering and death due to cancer by 2015. My optimism is well-founded: the number of people who have survived more than five years after being diagnosed with cancer has more than tripled, from 3 million in 1971 to nearly 10 million cancer survivors alive today.

One of the most remarkable cancer survivors is Lance Armstrong. Not only has he won perhaps the most grueling sporting event in the world five times in a row, but he created the Lance Armstrong Foundation, which is playing an important role in addressing survivorship issues. This past weekend, I spoke at the foundation's annual Live to Ride Gala in Austin, Tex. I was honored to be part of this inspirational event, especially because I was onstage when Bill Gimson and Drs. Jim Marks and Nancy Lee accepted one of the foundation's most prestigious awards, the Jeffery C. Garvey Champion of Survivorship Award, on behalf of the Centers for Disease Control and Prevention (CDC).

CDC received this award because of the outstanding work its staff has done on survivorship, including its contributions to A National Action Plan for Cancer Survivorship: Advancing Public Health Strategies, which was just released on April 15. This vitally important plan - developed with the assistance of more than 100 experts in cancer survivorship and public health, including several NCI representatives - establishes an important baseline of identified needs in the area of survivorship and recommends strategies for progress in each area. More information on this action plan is available on the CDC Web site at www.cdc.gov/cancer/survivorship/index.htm.

It is especially rewarding to see CDC honored for its work on survivorship because that is further proof of the importance of NCI's collaborations with our fellow agency. There are many programs and projects on which CDC and NCI are collaborating - too many to mention here - but they include long-standing activities such as joint work on surveillance activities and cancer registries, including the Surveillance, Epidemiology, and End Results (SEER) Program. CDC and NCI also collaborate on the development of the Annual Report to the Nation on the Status of Cancer, which gives policymakers and all Americans a yearly snapshot of the progress we are making in cancer research and care.

Our two agencies also are partnering on a one-of-a-kind resource, the Cancer Control PLANET, a Web-based service that offers communities tools with which they can plan, implement, and evaluate evidence-based comprehensive cancer control programs. And NCI and CDC are working on important infrastructure endeavors. This includes a meeting in June, scheduled to coincide with the second NCI and American Cancer Society biennial Cancer Survivorship Conference (June 16-18), to identify the best approaches for disseminating cancer survivorship research and fostering transdisciplinary collaborations and partnerships that support and enhance cancer survivorship research.

What is evident from these few examples of collaboration between NCI and CDC is the potential for rapid progress that can be created through cooperation and team science. With such collaborations and partnerships, we are building bridges between world-class scientists, bringing together the research and advocacy communities, and creating a momentum that will propel us all the way to 2015.

Dr. Andrew C. von Eschenbach
Director, National Cancer Institute

Proteomics Shows Promise in Colon Polyp Chemoprevention Study

Using proteomics technology, NCI researchers have made a step toward predicting which people with familial adenomatous polyposis (FAP), an inherited condition that often leads to colon cancer, will respond to the COX-2 inhibitor celecoxib. In a study published in the April 15 Cancer Research, Dr. Iqbal U. Ali and colleagues examined protein patterns from serum samples of participants in a chemoprevention clinical trial in which celecoxib reduced the number of colon polyps characteristic of those seen in patients with FAP. The results of the chemoprevention trial, reported in the June 2000 New England Journal of Medicine, led to approval by the Food and Drug Administration of celecoxib as an adjunctive chemopreventive agent for people with FAP.

Not all participants in the 2000 study who took celecoxib, however, experienced polyp reduction. Dr. Ali's laboratory took serum samples from the blood of 55 people who had participated in the celecoxib prevention trial and, using mass spectroscopy, identified specific proteomic markers that differentiated trial participants who did and did not respond to the drug. Although the technique has not been sufficiently tested for use in a clinical setting to identify those with FAP who will respond to celecoxib, Dr. Ali explained, the scientists are refining the technique and plan to evaluate it again in future trials.

Aspirin Use Is Not Associated with Pancreatic Cancer Mortality, Study Reports

Results from a large U.S. cohort of nearly 1 million adults found that aspirin use was not associated with mortality from pancreatic cancer. Dr. Eric Jacobs and colleagues from the American Cancer Society concluded that aspirin use did not have an important effect on pancreatic cancer mortality, even when measured by frequency of use that ranged from no use to more than 30 times a month.

The study, published in the April 7 issue of the Journal of the National Cancer Institute, was based on questionnaires completed by 987,590 U.S. adults from the Cancer Prevention Study II. The participants filled out a baseline report in 1982 that included questions about aspirin use. Participants were followed for mortality through 2000.

The research team also looked at the associated risk factors of cigarette smoking, body mass index, and diabetes. They found no apparent differences from those risks in the cohort of mainly white and middle-aged or elderly participants.

"An important strength of this analysis is its unusually large size, resulting in risk estimates with narrow confidence intervals that excluded a strong association between aspirin use and pancreatic cancer mortality," the study authors wrote. "Our results therefore provide evidence against an important effect of aspirin use on risk of pancreatic cancer."

Five previous studies of aspirin use and pancreatic cancer, including the Nurses' Health Study and the Iowa Women's Health Study, gave conflicting results showing reduced and increased risks.

Study Demonstrates Limitations of Virtual Colonoscopy

Virtual colonoscopy "is not yet ready for widespread clinical application," concludes a study published in the April 14 issue of the Journal of the American Medical Association. The study, by Dr. Peter Cotton and colleagues, was conducted at nine major hospital centers across the United States. Virtual colonoscopy's "techniques and training need to be improved," caution the study's authors. Moreover, "multidisciplinary collaboration will be needed to ensure its efficient application."

Virtual colonoscopy detected only 55 percent of polyps at least 10 millimeters (mm) in diameter and 39 percent of polyps at least 6 mm in diameter. In contrast, using standard colonoscopy, 100 percent and 99 percent of all polyps at least 10 mm and 6 mm in diameter, respectively, were detected.

These results are in stark contrast to the findings of a study published in the New England Journal of Medicine last December, which reported that virtual colonoscopy could be as effective as or more effective than standard colonoscopy - at least in the hands of experts using the latest technology. In that study, Dr. Perry Pickhardt and colleagues reported that virtual colonoscopy detected 92 percent of polyps 10 mm in diameter or greater and 86 percent of polyps 6 mm in diameter or greater.

Dr. Cotton and colleagues state, "Even if the results of [virtual colonoscopy] continue to be good in the hands of experts, it has yet to be proven that this expertise can be taught and disseminated reliably into daily practice."

Trends Indicate Lung Cancer Disparities Between Women and Men

Lung cancer remains the leading cause of cancer death in American women, surpassing breast cancer and all gynecological cancers combined, according to a report published in the April 15 Journal of the American Medical Association. New cases of diagnosed lung cancer in men have been on the decline since the early 1980s, authors Drs. Jyoti D. Patel, Peter B. Bach, and Mark G. Kris reported. For women, however, a 60 percent increase in the number of diagnosed cases occurred between 1990 and 2003. Overall, lung cancer was expected to account for an estimated 25 percent of cancer deaths among women in the United States in 2003.

Although it is still debatable whether women are more susceptible to the carcinogenic effects of tobacco smoke than are men, the authors noted, it is clear "that important differences exist among men and women with lung cancer. Women smokers are more likely than men to develop adenocarcinoma of the lung." Many studies have demonstrated genetic differences between women smokers who develop lung cancer and their male counterparts; such differences include higher mutation rates of p53 and greater numbers of smoking-related DNA adducts in women as compared with men. The researchers also observed that "women who have never smoked are more likely to develop lung cancer than men who have never smoked. Mounting evidence suggests that this could be due, in part, to estrogen signaling."

The authors recommend that the trends highlighted in their report be factored into the design of new and emerging lung cancer studies. And they stressed that "effective tobacco control measures" must be implemented in developing countries where smoking rates among women continue to rise.

As more studies reveal the damage being inflicted by obesity on health in the United States, the role of physical activity in promoting well-being has taken on increased importance. Approximately two-thirds of Americans are considered to be overweight or obese, and obesity significantly increases risk of stroke, high blood pressure, and diabetes.

And a large body of literature also suggests being overweight or obese increases the risk for postmenopausal breast cancer, colon cancer, adenocarcinoma of the esophagus, endometrial cancer, renal cell carcinoma, and several other cancers, explains Dr. Rachel Ballard-Barbash, associate director of the Applied Research Program in NCI's Division of Cancer Control and Population Sciences.

"Increasing regular physical activity and improving diet with careful attention to calorie control are two important health behaviors for controlling overweight and obesity," she says. "As more research is starting to reveal, physical activity may also play an important role in improving cancer risk, quality of life, and possibly prognosis."

Many studies suggest that exercise may offer a survival benefit for those with cancer. In one study, presented at the recent annual meeting of the American Association for Cancer Research, researchers from Brigham and Women's Hospital and Harvard University analyzed data on physical activity from nearly 2,300 women diagnosed with breast cancer from the long-running Nurses' Health Study. The results: the risk of death from breast cancer was reduced by anywhere from 23 to 54 percent, depending on the extent of weekly exercise.

The study's results aren't necessarily unexpected, says Dr. Ballard-Barbash. Studies have shown that women who exercise regularly have lower levels of circulating estrogen, perhaps because they have lower body fat and, for premenopausal women, longer, and therefore fewer, menstrual cycles. "We know that estrogen is a critical factor in the development of breast cancer," she explains. "So, in terms of breast cancer patients, it's not surprising that exercise would improve survival."

The most abundant and strongest evidence linking physical activity with reduced cancer risk exists for colon and breast cancers. With colon cancer, for example, there is ample evidence that individuals who are physically active can reduce their risk by as much as 50 percent. In these studies, however, the greatest reduction in risk was among those who were most active, and the benefit was seen more consistently in men. A more limited number of studies also have reported links between physical activity and a reduced risk of prostate, lung, and endometrial cancers.

The hypotheses on how physical activity may confer a benefit vary by the type of cancer. Physical activity's effect on factors such as insulin resistance, metabolism, and inflammation, among other things, may reduce colon cancer risk. With breast and endometrial cancers, the effect of exercise on sex hormones like estrogen may play an important role.

NCI is funding studies to further clarify the impact of physical activity on cancer risk, as well as whether physical activity may improve the quality of life of cancer patients and survivors. One study, for example, is examining the feasibility and benefits of a home-based moderate exercise program among breast cancer survivors. Another is testing the effectiveness of a nurse-directed walking exercise program to mitigate fatigue and maintain physical functioning during treatment for prostate, breast, or colorectal cancer.

On the prevention side, NCI is funding research such as a study to investigate whether women who engage in moderate or strenuous physical activity have a reduced risk of endometrial and ovarian cancers and if strenuous physical activity reduces this risk more than moderate physical activity.

Dr. Rachel Ballard-Barbash, associate director of the Applied Research Program in the NCI Division of Cancer Control and Population Sciences, is helping lead NCI's new "energy balance" initiative. She has directed her related research efforts at expanding the evidence on the effect of diet, physical activity, and weight on cancer outcomes and at evaluating the factors influencing the adoption of recommended health behaviors in these areas.

Is there enough information on exercise and cancer risk to start applying that information clinically?
Clinical trials have not been done to test what specific types of exercise will reduce cancer risk or improve the prognosis of those with cancer. But there is sufficient evidence to suggest that exercise is likely to be beneficial for cancer. In addition, there is extensive evidence on exercise's benefits for other disease end points, such as heart disease or diabetes. The general health recommendations for regular activity apply to everyone, including people at high risk for cancer or those living with cancer. We can now say that, in addition to the evidence of a benefit for health problems such as high blood pressure and heart disease, there is some evidence that exercise can improve cancer outcomes.

What kind of activity appears to confer the most benefit?
Unlike with some other disease end points, we don't have specific information on what types of exercise are more beneficial for different cancers. For example, we know that aerobic exercise has a proven benefit for reducing heart disease risk. And weight-bearing exercise, particularly strength training, has proven to be very beneficial for osteoporosis. But for cancer, we don't yet have those kinds of specific data. One of NCI's efforts now is to inform the public and health community of the beneficial connection between exercise and cancer outcomes.

There are hypotheses about how exercise may confer a cancer benefit, but are any studies attempting to identify specific mechanisms?
A number of researchers - both basic and clinical - are initiating research to identify mechanisms. For example, in the NCI Center for Cancer Research, the Laboratory of Biosystems and Cancer is conducting research using animal models to delineate the mechanisms and investigate the interaction between exercise and chemoprevention agents. Work is also being done in the extramural community. Dr. Anne McTiernan at Fred Hutchinson Cancer Research Center, for instance, is conducting clinical studies focused on how specific exercise interventions affect mechanisms, such as alterations in estrogen and insulin metabolism, that influence cancer outcomes.

The Early Detection Research Network: Biomarker Reference Laboratories

RFA-CA-05-009
Letter of Intent Receipt Date: July 16, 2004
Application Receipt Date: Aug. 16, 2004

This RFA is a reissue of RFA CA-99-008, which was published in the NIH Guide on March 16, 1999.

NCI's Division of Cancer Prevention invites new and competing renewal cooperative agreement applications to continue the Early Detection Research Network's national Biomarker Reference Laboratories, which have the responsibility for the development, evaluation, and validation of biomarkers for earlier cancer detection and risk assessment. The network has four main components: Biomarker Developmental Laboratories, Biomarker Reference Laboratories, Clinical Epidemiology and Validation Centers, and a Data Management and Coordinating Center.

This RFA will use the NIH Cooperative Agreement (U24) award mechanism.

For more information see http://cri.nci.nih.gov/4abst.cfm?initiativeparfa_id=2000.

Inquiries: Dr. Sudhir Srivastava, srivasts@mail.nih.gov; Dr. Jacob Kagan, kaganj@mail.nih.gov

Name of the Trial
Phase II Randomized Study of Topical Halofuginone Hydrobromide in Patients with HIV-Related Kaposi's Sarcoma (AMC-036). See the protocol summary at http://cancer.gov/clinicaltrials/AMC-036.

Principal Investigators
Dr. Susan E. Krown, Dr. Henry Koon, and Dr. Merrill Egorin, from the AIDS-Associated Malignancies Clinical Trials Consortium (AMC)

Why Is This Trial Important?
Kaposi's sarcoma is the most common cancer in patients infected with HIV, the virus that causes AIDS. Although various methods can be used to treat Kaposi's sarcoma, better and less toxic treatments are needed.

Laboratory studies have shown that halofuginone, an experimental drug, can block the growth and spread of certain cancer cells and can also block the flow of blood to tumors, a process called antiangiogenesis. Unlike other drugs used to treat Kaposi's sarcoma, which must be given by vein or by mouth, halofuginone may be effective when given as a cream or ointment and applied directly to tumors. This could result in fewer side effects."

In animal studies, halofuginone has been found to inhibit collagen production and angiogenesis, even if applied directly to tumors rather than given internally," said Dr. Krown. "With this trial, we are applying halofuginone to skin lesions of Kaposi's sarcoma to see if this treatment approach is effective and safe."

In this trial, people with Kaposi's sarcoma will have some of their skin tumors treated with an ointment containing halofuginone, while other tumors will be treated with an ointment that does not contain the drug. Several of the tumors will be biopsied to see if the halofuginone ointment affects tumors differently than the non-halofuginone ointment. After 12 weeks, if the halofuginone-treated tumors are improved or do not get worse, all of the skin tumors may be treated for another 12 weeks with halofuginone ointment.

Who Can Join This Trial?
This trial seeks to enroll 30 men and women aged 16 and older who have Kaposi's sarcoma confined to the skin, with at least 14 skin lesions, and HIV infection. See the full list of eligibility criteria for this trial at http://cancer.gov/clinicaltrials/AMC-036.

Where Is This Trial Taking Place?
Multiple study sites in the United States are enrolling patients in the trial. See the list of study sites at http://cancer.gov/clinicaltrials/AMC-036.

Who to Contact
See the list of study contacts at http://cancer.gov/clinicaltrials/AMC-036 or call the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The call is toll free and completely confidential. For more information about the NCI AIDS Malignancy Program, visit http://cancer.gov/dctd/aids/.

DCTD Hosts Malignancies and Immunodeficiencies Conference
NCI's Division of Cancer Treatment and Diagnosis will host the 8th International Conference on Malignancies in AIDS and Other Immunodeficiencies: Basic, Epidemiologic and Clinical Research. The conference will be held April 29-30 at the Natcher Conference Center on the NIH campus in Bethesda, Md. It will focus on basic and clinical research on the viral oncology, immunology, genetics, epidemiology, pathogenesis, drug discovery, early diagnosis, and clinical investigation of malignant diseases in AIDS and other immunodeficiency states, including organ transplantation. The meeting will feature invited lectures from more than 25 faculty members from across the country and around the world, as well as oral and poster presentations of submitted abstracts. This conference is for all clinical and laboratory investigators, postdoctoral researchers, students, physicians, health care workers, and others who are involved, interested, or participating in malignancy research in AIDS and other immunodeficiencies and in tumor virology. Online registration is available at http://cancer.gov/dctd/aids/conference. For more information, contact Jaime Kenyon at kenyonj@mail.nih.gov.

2004 Spring Research Festival at Frederick
NCI-Frederick, in partnership with the U.S. Army Medical Research and Materiel Command at Ft. Detrick, in Frederick, Md., will sponsor the eighth annual NCI-Frederick/Ft. Detrick Spring Research Festival. The festival will be held at Ft. Detrick May 12-13. At the festival, resident scientific staff, including students, technical support staff, postdoctoral fellows, and investigators, will present posters describing their research to the joint scientific communities. In addition to scientific poster sessions, the festival will include a health and safety exposition; educational information; and safety, scientific, and commercial exhibits. For more information and guidelines for poster submission, visit http://web.ncifcrf.gov/events/springfest.

Minority Cancer Awareness Week New Data Support the Need to Address Cancer Disparities New data released last week by NCI's Surveillance, Epidemiology and End Results (SEER) program show that several minority groups continue to have higher incidence and death rates for a number of cancers than white Americans. The release of the data marks the National Minority Cancer Awareness Week, a national observance that is now in its 18th year. "It is not acceptable that persons from communities of color tend to have cancer diagnosed at more advanced stages and that once diagnosed they have poorer cancer-specific survival," said NCI Director Dr. Andrew C. von Eschenbach. "The fact that any segment of the population bears a larger cancer burden is something we must strive to eliminate." A sampling of the new SEER data reveals the extent of the cancer burden minority populations now face. African American men, for example, have the highest rates for new cancers and cancer deaths from all cancer sites combined. Among Hispanics, children have lower cancer survival rates than white or Asian American children. Asian Americans and Pacific Islanders have the highest liver cancer death rates. And similar disparities exist for American Indians and Alaska Natives, such as high incidence rates of kidney cancer with lower survival for these women. "National Minority Cancer Awareness Week is about reaching out to minority populations and trying to increase their understanding of the risks that cancer poses, as well as the important steps they can take to reduce that risk and the prevention and treatment services available to them," said Dr. Harold Freeman, director of NCI's Center to Reduce Cancer Health Disparities (CRCHD). NCI staff are personally delivering the awareness message to communities. Dr. Freeman will be featured in an interview running this week on American Urban Radio Networks radio stations across the country. And last Saturday, Dr. Michaele Christian, associate director of NCI's Cancer Therapy Evaluation Program, spoke in South Bend, Ind., about cancer and African Americans at an annual health conference sponsored by a local hospital. NCI and other Health and Human Services agencies have made reducing cancer health disparities a top priority. In addition to the CRCHD's creation in 2001, reducing disparities has been earmarked as one of the seven strategic initiatives launched as part of the NCI 2015 challenge goal to eliminate suffering and death due to cancer. NCI leadership also is reviewing the recommendations presented in a Progress Review Group report released last month on combating cancer disparities (see March 30 NCI Cancer Bulletin 3).