Research Areas and Partnering Nations Featured in this Portfolio

Introduction

Understanding the Causes and Mechanisms of Cancer

Accelerating Progress in Cancer Prevention

Improving Early Detection and Diagnosis

Developing Effective and Efficient Treatments

Understanding the Factors that Influence Cancer Outcomes

Improving the Quality of Cancer Care

Improving the Quality of Life for Cancer Patients, Survivors, and Their Families

Improving Cancer Communications

Scientist Exchanges and Training Programs

Building the Capacity and Infrastructure for Cancer Research and Care

Director's Message

The National Cancer Institute (NCI) plays an important role in promoting global health and contributing to the economy and security of nations around the world. As this portfolio demonstrates, NCI's international activities are both broad and deep. However, the activities described here are only a small sample of the Institute's efforts.

NCI is committed to playing an even greater role in international cancer control in the future. That is evidenced by our involvement in emerging international collaborations, most notably the World Health Organization's (WHO) global cancer prevention and control resolution.

During the 2005 World Health Assembly, WHO passed Resolution WHA58.22, a first-of-its-kind resolution calling for improved cancer prevention measures, improved early detection and treatment, and more palliative care in all WHO Member State countries.

NCI scientists have joined some of the world's leading cancer control researchers in providing WHO with scientific expertise to develop and implement this global strategy. Mark Clanton, M.D., M.P.H., Deputy Director, NCI, and Deputy Director for Cancer Care and Delivery Systems, serves as the Institute's representative to the WHO Director-General's Cancer Advisory Committee and WHO's Cancer Technical Working Group.

Dr. Clanton is also the NCI lead for another important project with the International Atomic Energy Agency (IAEA) as part of a program called the Program of Action for Cancer Therapy, or PACT. IAEA has provided radiation therapy machines in low-resource settings for the last decade, giving support to treatment centers in developing countries so they can deliver appropriate radiation therapy to patients. IAEA is now greatly expanding these cancer control activities through the launch of the PACT Alliance - an alliance of cancer organizations from across the globe to help develop and implement cancer control programs in developing countries.

NCI will help support a pilot of this expanded PACT program, including bringing together a team of experts in cancer control from the United States to assist in its development and implementation. It is an inspiration to witness the effort put forth by scientists and health care providers around the world to improve the health of all humans, regardless of race, gender, age, or religion. I am proud - as I believe the entire U.S. cancer community should be - of NCI's continued commitment to reducing the global cancer burden.

John E. Niederhuber, M.D.
Director, National Cancer Institute

Addressing the Global Challenge of Cancer
The global burden of cancer is large and growing larger. Each year, more than 11 million people are diagnosed with cancer worldwide. By the year 2020, this number is expected to increase to 16 million. In addition, cancer causes more than 8 million deaths each year -- or approximately 13 percent of all deaths worldwide.

In many developed countries, including the United States, cancer accounts for more than 20 percent of all deaths. In less developed countries, overall cancer rates are generally lower and cancer accounts for a lower percentage of deaths. However, it is within developing countries that cancer is projected to increase most rapidly over the next few decades. Unless current trends change, cancer in developing countries is expected to represent 70 percent of the global cancer burden by the year 2030, a statistic driven by demographic shifts toward more elderly populations and the movement toward more Western lifestyles, most notably increased per capita tobacco consumption and higher fat-lower fiber diets.

In the National Cancer Act of 1971, the National Cancer Institute (NCI) was charged to: "Collect, analyze, and disseminate all data useful in the prevention, diagnosis, and treatment of cancer…[and to] disseminate insofar as feasible the results of cancer research undertaken in any country for the use of any person involved in cancer research in any country." In addition, the Institute was directed to: "Support research in the cancer field outside the United States by highly qualified foreign nationals…; support collaborative research involving American and foreign participants; and support the training of American scientists abroad and foreign scientists in the United States."

Clearly, it was the intent of the U.S. Congress that NCI should not only address the challenge of cancer among American citizens but also among the citizens of all nations. This challenge is daunting indeed, but it is one from which we cannot shrink.

Expanded Research Opportunities
A global perspective offers a myriad of research opportunities that a U.S.-only research focus would not afford. For example, international studies enable us to investigate "rare" cancers -- such as certain inherited, familial types of kidney cancer, melanoma, and other cancers -- by providing access to much larger populations of patients than can be found within the confines of our national borders. A global perspective also opens to us the diversity of environments occupied by humans, providing unique opportunities to explore relationships between genes and specific environmental exposures, including infectious agents that may be associated with cancer.

Furthermore, international programs give us access to resources found only in other countries. These resources allow for consistency in diagnosis and tumor classification.

Shared Knowledge and Capacity Building
NCI also recognizes the importance of investing in developing countries, especially with respect to improving research and health care infrastructure. No nation exists in a vacuum and cancer does not recognize international borders. NCI is committed to sharing our expertise to foster cancer research and build research and health care infrastructure around the world. Just as American researchers benefit from a broader perspective by engaging in research outside U.S. borders, international researchers make significant contributions to NCI's overall mission while acquiring knowledge, skills, and abilities to enhance the research environment in their home countries.

The mission to train both American and foreign scientists to battle cancer is one that NCI takes seriously. When we cooperate internationally to address a shared health burden, knowledge is expanded, solutions are discovered more efficiently, and the health of all people is improved.

NCI's Office of International Affairs
Monitoring NCI's international activities, many of which are managed within the Institute's intramural and extramural divisions, is the responsibility of the Office of International Affairs (OIA). OIA also directs a range of activities that are intended to catalyze research advances through individual and group training and through fostering interactions between cancer researchers in the United States and abroad. These latter activities include initiating, developing, and implementing bilateral and multilateral agreements to share information and expertise with other nations and groups of nations. One excellent example of this type of OIA activity is the Middle East Cancer Consortium (MECC), which is described in Building the Capacity and Infrastructure for Cancer Research and Care ¹.

OIA also coordinates NCI's involvement in the global clinical trials enterprise. This key role for OIA is demonstrated by the work of NCI's Liaison Office in Brussels, Belgium (see The NCI Liaison Office in Europe ²).

NCI's International Portfolio
This report provides an overview and brief descriptions of NCI's international cancer control and research programs, as well as the Institute's efforts to share scientific knowledge, build and support cancer research infrastructure in other nations, and improve the delivery of cancer information and care to people around the globe. You will find compelling reports that demonstrate NCI's efforts towards addressing the global challenge of cancer. However, keep in mind that the efforts and activities presented here are just a sample of the work being done by NCI scientists, our grantees, and our international partners.

Cancer is invariably caused by changes in the function of genes that regulate vital cellular processes, such as growth and proliferation and programmed cell death (apoptosis). These changes may be caused by mutations in the DNA sequence of a person's genes or by epigenetic events, in which gene expression is altered without the occurrence of DNA mutations.

NCI and its partners worldwide are striving to identify the genetic, epigenetic, and environmental factors that contribute to the development of cancer. We are also seeking to understand how genes and the environment interact to influence the cancer process. In this effort, we are developing innovative technologies and harnessing the power of bioinformatics.

Environmental Carcinogens

Identifying and characterizing the environmental causes of cancer are crucial if we are to develop effective strategies for cancer prevention and control. Two major NCI-supported efforts in this area are the International Agency for Research on Cancer's (IARC) Program on the Evaluation of Carcinogenic Risks to Humans (see below) and the Institute's long-standing partnership with Chinese health authorities to investigate the effects of occupational exposure to benzene, which is described in Benzene and Cancer: East Meets West.

Other NCI-supported international activities that focus on environmental risk factors for cancer include the following:

A collaboration involving NCI's Chernobyl Research Unit and investigators in Ukraine and Belarus to study the long-term health consequences of the Chernobyl nuclear accident
NCI's Chernobyl Research Unit (CRU) is participating in three epidemiologic studies related to the 1986 accident at the Chernobyl nuclear facility in Ukraine: 1) a study of leukemia, lymphoma, and other blood diseases among Ukrainian clean-up workers; 2) a study of thyroid cancer and other thyroid diseases among Ukrainians who were exposed as children to radiation from the Chernobyl reactor; and 3) a study of thyroid cancer and thyroid diseases among Belarusians who were exposed as children to radiation from Chernobyl. The Chernobyl facility is located about 12 kilometers south of the Ukraine-Belarus border.

The thyroid studies involve biannual thyroid gland examinations of approximately 12,000 to 13,000 individuals in each country who were exposed to radiation from the accident when they were 0 to 18 years of age and who had thyroid radiation dose measurements made in the weeks following the accident.

This program has relevance to international concerns about nuclear terrorism because the Chernobyl exposures are similar to those expected from a "dirty bomb" attack.

A U.S.-Mexico binational study of the relationship between arsenic exposure and gastrointestinal cancer
Arsenic exposure is an established risk factor for kidney, bladder, lung, and skin cancers, but the relationship between arsenic, its metabolites, and gastrointestinal cancer has received only limited attention. In this study, researchers are investigating the role of arsenic in the development of gastrointestinal cancer in two geographic areas of Sonora, Mexico that have different levels of arsenic in their drinking water supplies. Researchers from the University of Arizona, the University of Sonora, and the Technological Institute of Sonora - who are experienced in arsenic research, exposure assessment, and cancer research - are conducting the study.

A project at the University of Alberta, Canada to develop innovative, cost-effective, and reliable technology for quantifying DNA damage caused by environmental exposures, including low-level exposures
Historically, attempts to link environmental exposures to cancer have frequently relied on population surveys, which provide indirect information in the form of responses to questionnaires or personal interviews. The inherent errors associated with these kinds of assessments have long hindered the identification and quantification of important exposures. Rather than relying on these traditional methods of dose estimation and extrapolation from high-dose exposures in rodent models, researchers at the University of Alberta are developing new technology to provide sufficiently sensitive DNA damage measurements that would permit more realistic assessments of environmental risk. The technology would also be useful for measuring the DNA damage induced by anticancer agents and for studying DNA repair, which is an essential cellular defense mechanism against DNA damage and cancer development.

Genes, Infectious Agents, and Gene-Environment Interactions

Although our understanding of the causes and mechanisms of cancer initiation and progression has expanded rapidly, much remains to be learned. We now recognize that a person's susceptibility to cancer can be governed by the interaction of genetic and environmental factors. If we are to continue making progress in the prevention and treatment of cancer, it is clear we must increase our understanding of the interplay between susceptibility genes and the environment. To achieve our goal of eliminating the suffering and death due to cancer, broad collaboration of persons, organizations, and nations in this effort is crucial.

A prime example of such collaboration is the InterLymph Consortium, more formally known as the International Consortium of Investigators Working on Non-Hodgkin's Lymphoma Epidemiologic Studies. This consortium is described in InterLymph Leads Global Research in Non-Hodgkin Lymphoma. Other examples include the following:

The International Head and Neck Cancer Epidemiology (INHANCE) Consortium to address the global challenge of head and neck cancer incidence and mortality
In the year 2000, an estimated half-million cases of head and neck cancer were diagnosed worldwide and 300,000 people died of the disease. Most of these cancers can be attributed to tobacco and alcohol use, but other risk factors that may play a role include viral infection, occupational exposures, radiation exposure, dietary factors, and genetic susceptibility. In 2004, NCI and the World Health Organization (WHO) joined forces to establish the INHANCE Consortium, which is comprised of research groups that are conducting large molecular epidemiology studies of head and neck cancer. These studies should increase our understanding of the causes and mechanisms of head and neck cancer worldwide. The consortium is managed by IARC and includes investigators from the United States, France, the Czech Republic, Slovakia, Romania, Hungary, Poland, Russia, Spain, Costa Rica, Italy, Switzerland, Brazil, Argentina, Germany, the United Kingdom, Norway, Greece, Estonia, and Croatia.

A collaboration of NCI scientists and research groups in China to study the interaction of infection with Epstein-Barr virus (EBV) or hepatitis B virus (HBV) and host genetic factors in cancer development
NCI scientists and researchers from China's Institute for Viral Disease Control and Prevention, Beijing and the Wuzhou Red Cross Hospital, Guangxi Province are attempting to characterize genes associated with susceptibility or resistance to the development of nasopharyngeal carcinoma (NPC). The population in Guangxi Province has a high incidence of NPC. This population offers a unique model of this human malignancy for understanding a multistep carcinogenic process that involves a virus (EBV), environmental carcinogens (dietary and other causes), and genetic factors.

Similarly, NCI scientists have joined forces with the Department of Infectious Diseases at Peking University First Hospital, Beijing to study how outcomes of HBV exposure and infection are influenced by host genetic factors in the Chinese population. In China, more than 120 million individuals are infected with HBV. Among persons persistently infected with this virus, 10 to 30 percent will develop cirrhosis and liver cancer.

A study at the University of Cape Town, South Africa to investigate the role of the NDRG1 gene in squamous cell esophageal carcinoma
In South Africa, squamous cell esophageal cancer occurs with high frequency, causing the majority of cancer-related deaths among black males. Better understanding of the molecular events leading to the development of this cancer will allow earlier diagnosis, the development of better therapeutic strategies, and enhanced prevention of metastasis. Reduced expression of NDRG1 (N-Myc Downstream Regulated Gene 1) - which has been implicated in cell differentiation, cell proliferation, and cancer cell metastasis - has been found in poorly differentiated esophageal tumors.

A study at the Hospital General de Grand Yoff in Senegal of the epidemiology of prostate cancer among African men
Despite the knowledge that prostate cancer occurs with high frequency in men of African descent in the Americas, little information is available regarding the epidemiology of prostate cancer in native African men, even though prostate cancer seems to be prevalent in that population as well. The objective of this study is to examine the role of genes that regulate the physiological disposition of testosterone in the development of prostate cancer and to evaluate whether these genes explain, in part, ethnic differences in prostate cancer rates. An understanding of the complex interplay of genetic variability at multiple loci and of environmental agents may improve our understanding of ethnic differences in prostate cancer development and risk prediction.

Two studies conducted by IARC of the genetics of tobacco and alcohol-related cancers Even though lung and upper aerodigestive tract (UADT) cancers are predominantly
caused by tobacco and alcohol use, only a minority of heavy smokers and heavy drinkers will develop these cancers. A possible explanation for this phenomenon is that individuals vary widely in their metabolism of carcinogenic products, internal dose levels of these products and/or their metabolites, DNA repair capacity, and cell-cycle control mechanisms due to genetic factors. In separate investigations, the researchers will study the role of 45 genes that may be involved in the susceptibility to lung and UADT cancers.

A study of breast and prostate cancer risk in relation to genetic polymorphisms and gene-environment interactions that affect hormone metabolism
The goal of this study is to identify single-nucleotide polymorphisms (SNPs) and haplotypes in steroid hormone metabolizing genes, genes in the insulin-like growth factor (IGF) pathway, and genes that encode related receptor proteins. SNPs are DNA sequence variations that arise from single nucleotide (A, T, C, or G) changes. Haplotypes are sets of genes that are linked closely enough to be inherited as a unit.

Woman smoking

In the study, the investigators will have access to prospectively gathered plasma samples, genetic material, anthropometric measurements, and extensive questionnaire data on diet, physical activity, exogenous hormone use, smoking, and other lifestyle factors from over 790,000 men and women worldwide. The biological samples and other data are from the following large prospective cohorts: the American Cancer Society's Cancer Prevention Study II; Harvard University's Harvard Cohort Studies; IARC's European Prospective Investigation into Cancer and Nutrition (EPIC) Study; the University of Hawaii and the University of Southern California's Multiethnic Cohort Study; and two NCI intramural cohorts (the Prostate, Lung, Colon, and Ovarian Cancer Screening Study and the Alpha-Tocopherol, Beta-Carotene Prevention Trial).

The ultimate goal of this study is to provide the foundation for reducing the public health burden of breast and prostate cancers.

A study at the Queensland Institute of Medical Research in Australia of the molecular genetics and genetic epidemiology of cutaneous melanoma and its risk factors
Over the past few decades, the incidence of cutaneous melanoma has increased dramatically in light-skinned populations worldwide. The Australian state of Queensland has the highest incidence of cutaneous melanoma in the world, with lifetime incidences of 1 in 13 males and 1 in 16 females. Although these rates are almost five times greater than those in the United States, the shapes of the age-specific incidence curves are almost the same in the two populations, suggesting similar causal factors.

In this study, the researchers will extend several earlier large-scale investigations into the molecular genetics and genetic epidemiology of melanoma and its risk factors (in particular, nevus density and pigmentation). They will analyze DNA specimens obtained from 6,248 individuals. These analyses will include DNA sequencing and singlenucleotide polymorphism (SNP) analyses of genes in the cell-cycle control and pigmentation pathways. The researchers will look for associations of melanoma risk variables with SNPs and environmental risk factors. They will also investigate whether melanoma in childhood or adolescence can be explained solely by the same risk factors that operate in adults or whether affected children or adolescents carry rare alleles in cell cycle or pigmentation genes.

InterLymph Leads Global Research in Non-Hodgkin Lymphoma The InterLymph Consortium - more formally known as the International Consortium of Investigators Working on Non-Hodgkin Lymphoma Epidemiologic Studies - is an open scientific forum for epidemiologic research that was formed in 2001. The Consortium is comprised of international investigators who have completed or have ongoing case-control studies of non-Hodgkin lymphoma and who discuss and undertake research projects that pool data across studies or otherwise conduct collaborative research. The ultimate goal of InterLymph is to speed progress toward understanding the etiology of non-Hodgkin lymphomas. Support for the logistical needs of InterLymph is provided by NCI, the International Agency for Research on Cancer (IARC), and the United Kingdom's Leukaemia Research Fund. Some InterLymph investigators also receive grant support for research projects from NCI. Investigators from the United States, Europe, Canada, Australia, the Middle East, and Asia have participated in the Consortium. Eight InterLymph working groups develop ideas for coordinated research in the areas of diet and behavior, family studies, genotyping, immunology, infections, occupation, pathology, and sunlight. Recently reported studies investigated the relationships between cigarette smoking, alcohol consumption, and common genetic variants in immune system and inflammatory response genes and the risk of non-Hodgkin lymphoma.1,2,3 Interlymph 5th Annual Meeting Washington, D.C. March 30-April 1, 2006 1 Morton L, Hartge P, Holford T, Holly E, Chiu B, Vineis P, Stagnaro E, Willett E, Franceschi S, La Vecchia C, Hughes A, Cozen W, Davis S, Severson R, Bernstein L, Mayne S, Dee F, Cerhan J, Zheng T. Cigarette smoking and risk of non-Hodgkin lymphoma: a pooled analysis from the International Lymphoma Epidemiology Consortium (InterLymph). Cancer Epidemiology, Biomarkers & Prevention, April 2005; 14(4):925-933. 2 Morton L, Zheng T, Holford T, Holly E, Chiu B, Costantini A, Stagnaro E, Willett E, Dal Maso L, Serraino D, Chang E, Cozen W, Davis S, Severson R, Bernstein L, Mayne S, Dee F, Cerhan J, Hartge P; InterLymph Consortium. Alcohol consumption and risk of non-Hodgkin lymphoma: a pooled analysis. Lancet Oncology, July 2005; 6(7):469-476. 3 Rothman N, Skibola C, Wang S, Morgan G, Lan Q, Smith M, Spinelli J, Willett E, De Sanjose S, Cocco P, Berndt S, Brennan P, Brooks-Wilson A, Wacholder S, Becker N, Hartge P, Zheng T, Roman E, Holly E, Boffetta P, Armstrong B, Cozen W, Linet M, Bosch F, Ennas M, Holford T, Gallagher R, Rollinson S, Bracci P, Cerhan J, Whitby D, Moore P, Leaderer B, Lai A, Spink C, Davis S, Bosch R, Scarpa A, Zhang Y, Severson R, Yeager M, Chanock S, Nieters A. Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncology, January 2006; 7(1):27-38.

The International Familial Chronic Lymphocytic Leukemia (CLL) Consortium to identify inherited susceptibility genes
CLL is the most common form of leukemia among adults in the Western world. No specific environmental risk factors have been established for CLL, but epidemiologic and family studies indicate that 8 to 10 percent of CLL cases involve inherited susceptibility to the disease. Because it was recognized that no single institution could recruit a sufficient number of CLL families to achieve the goal of identifying a susceptibility gene(s), the International Familial CLL Consortium was established in 2002. Enrolling new CLL families and coordinating research efforts among the participating centers are core tasks of the consortium. Countries participating in the consortium include the United States, the United Kingdom, France, and Italy.

The Australian Breast Cancer Family Registry and the Australasian Colorectal Cancer Family Registry to identify genetic and environmental risk factors for breast and colorectal cancer
These large cancer family registries are resources for population-based, case-control family studies conducted by the Centre for Molecular, Environmental, Genetic and Analytic Epidemiology at the University of Melbourne's School of Population Health.

The Australian Breast Cancer Family Registry is also part of the Cooperative Family Registry for Breast Cancer Studies (CFRBCS), which is an international collaboration involving six registries that was initiated by NCI in 1995 to provide the scientific community with a resource for interdisciplinary and translational breast cancer research. CFRBCS resources include a repository of biological specimens from a racially and ethnically diverse set of families that have a history of breast cancer and a large, computerized database containing both genetic and environmental risk information.

Similarly, the Australasian Colorectal Cancer Family Registry is part of the Cooperative Family Registry for Colorectal Cancer Studies (CFRCCS), which is another international collaboration initiated by NCI in 1998. The six CFRCCS registries perform several tasks, including the assembly and maintenance of comprehensive lists of families with histories of colorectal cancer, the collection of detailed information about possible factors involved in the cancer process, and the storage of blood samples and tumor biopsy specimens from family members for research purposes. The data and samples collected by the participating registries are available to researchers worldwide.

The Ontario Familial Breast Cancer Registry and the Ontario Familial Colorectal Cancer Registry to identify genetic and environmental risk factors for breast and colorectal cancer
These registries collect and store personal and family health information from residents of Ontario, Canada, who have a family history of breast or colorectal cancer and who are willing to participate in research studies. The registries provide an infrastructure for current and future research on breast and colorectal cancer genetics and new preventive and therapeutic strategies to combat these diseases. The Ontario registries are partner registries in the Cooperative Family Registry for Breast Cancer Studies and the Cooperative Family Registry for Colorectal Cancer Studies (see The International Familial Chronic Lymphocytic Leukemia (CLL) Consortium to identify inherited susceptibility genes).

A collaboration of NCI scientists and research groups in Canada, the United Kingdom, and Ireland to understand the molecular etiology of kidney cancers
The study of kidney cancers associated with rare genetic disorders is limited by the infrequent occurrence of the individual diseases and the small numbers of patients available for study in any one nation. Therefore, international collaboration is essential.

One such collaboration between NCI scientists and investigators at the University of Manitoba in Winnipeg, Canada and the University of Birmingham in the United Kingdom led to the successful cloning of the Birt Hogg Dube (BHD) gene, which is associated with a rare hereditary syndrome characterized, in part, by a high predisposition to malignant kidney tumors that are often bilateral and multifocal.

Ongoing efforts include the identification of additional patients with familial kidney cancers of undetermined etiology worldwide to increase our ability to identify major genes that contribute to the development of kidney tumors.

A study at the Karolinska Institute in Stockholm, Sweden of the influence of human papilloma virus (HPV) viral load on the progression of localized cervical carcinoma to invasive cervical cancer
Although HPV infection is an established cause of cervical cancer, it is not known whether viral load influences the progression from localized cervical carcinoma in situ (CIS) to invasive cancer and/or interacts with host genetic factors. Since clinical intervention precludes direct observation of this progression, unconventional approaches are required. The investigators are attempting to: 1) quantify the absolute and relative risks for CIS and invasive cancer as a function of time since the detection of HPV and high viral load of HPV strain 16 (HPV-16); 2) assess whether a persistent HPV-16 high viral load is a determinant of CIS and invasive cancer development; 3) assess whether a specific histocompatibility antigen genotype is associated with risks for CIS and invasive cancer and if the association is mediated via a higher viral load and/or persistence of HPV infection; and 4) assess whether infection with the bacterium Chlamydia trachomatis is associated with risks for CIS and invasive cancer. The researchers will take advantage of Sweden's extensive documentation in computerized registries of its population-based Pap smear screening program, its ascertainment of all incident cases of cervical CIS and invasive cancer, and archived Pap smears and tissue specimens.

Molecular Diagnosis of Burkitt's Lymphoma	Epstein-Barr Virus (EBV)

A U.S.-Brazil binational study of Epstein-Barr virus (EBV)-associated lymphoma, particularly Burkitt lymphoma, in Brazil
EBV is ubiquitous worldwide, with more than 80 percent of people over the age of 30 having been infected. Once EBV infection has occurred, it persists for the lifetime of the individual. EBV infection is strongly associated with the development of several cancers, including Hodgkin disease and Burkitt lymphoma (BL). Three variants of BL have been identified: endemic, sporadic, and human immunodeficiency virus-1 (HIV-1)-associated. However, the molecular differences between these variants have not been well characterized. BL is also commonly identified in patients with acquired immunodeficiency syndrome (AIDS), with the EBV association being more common in developing countries.

In this study, scientists from the University of Miami; the University of North Carolina, Chapel Hill; the Federal University of Bahia in Salvador, Brazil; and the Brazilian Pediatric Non-Hodgkin Lymphoma Treatment Group are molecularly characterizing primary EBV-positive BLs using virus-specific microarrays. Other goals of the study are to identify the mechanism by which the common antiretroviral drug azidothymidine (AZT) induces apoptosis (cell suicide) in EBV-positive BL and to use the data to develop novel therapies.

The study is supported by independent grants and by supplemental funding from the NCI-sponsored AIDS-Associated Malignancies Clinical Trials Consortium.

One way to eliminate the suffering and death due to cancer is to develop ways to prevent the disease. Toward this end, NCI and its international collaborators are seeking to identify medical, behavioral, and environmental approaches to cancer prevention that can be translated effectively to public health settings. Basic biomedical research relevant to the prevention of cancer is one avenue of investigation. Exploring strategies to modify behaviors that can increase a person's risk of cancer - such as poor diet, physical inactivity, excessive sun exposure, and tobacco use - is a second. How to mitigate the influence of environmental risk factors, including occupational exposures and infectious agents, is yet another.

The following summaries highlight some of NCI's international activities in the area of cancer prevention.

The World Health Organization's Tobacco Free Initiative to reduce the global burden of disease and death caused by tobacco
In 1996, the Director-General of the World Health Organization (WHO) was called upon to initiate development of a Framework Convention on Tobacco Control (FCTC). The resulting international convention - the first global health treaty negotiated under the auspices of WHO - was adopted unanimously by the World Health Assembly in 2003 and entered into force in 2005. Thus far, 126 nations have ratified, accepted, approved, formally confirmed, and acceded to the treaty.

The WHO's Tobacco Free Initiative (TFI) was established in this context, with the objective of reducing the global burden of disease and death caused by tobacco. Under the TFI, the WHO created a scientific advisory committee, called the Scientific Advisory Committee on Tobacco Product Regulation (SACTob), to provide scientifically sound recommendations regarding the most effective and evidence-based means to achieve a coordinated regulatory framework for tobacco products. In 2003, SACTob became a formal study group, called the Study Group for Tobacco Regulation (TobReg). TobReg provides a formal mechanism for reporting to WHO's Executive Board in order to draw the attention of member nations to WHO's efforts in tobacco regulation. NCI scientists have worked with SACTob/TobReg since 2002 on the development of numerous recommendations aimed at improving public health and scientific research related to the effects of tobacco use.

In addition, NCI participated in the TFI effort in 2004 to create an International Network for Tobacco Testing and Research for Regulation (INTTARR) to address research issues related to the development of a global capacity for tobacco product testing and research. INTTARR, which has since been renamed the Tobacco Laboratory Network (TobLabNet), is a global network of government, university, and independent laboratories across the world to advance research on tobacco product testing. Testing and measuring tobacco products at the national or regional level are essential to monitoring compliance by tobacco manufacturers of their obligations under the FCTC to test and disclose the contents and emissions of their products. Regulators must also have the capacity to test and measure tobacco products in order to propose tobacco product content and emissions regulations in the future. Furthermore, a capacity for testing and research is one of the factors needed to ensure manufacturers package and label their products in a manner that does not mislead consumers about the health risks of tobacco.

Finally, NCI contributes to a multi-agency collaboration, which includes five other institutes of the National Institutes of Health (NIH), the NIH's Fogarty International Center, and the TFI, that funds research on tobacco use and related illness in developing countries.

A study at the University of London using international tobacco industry documents to analyze industry influence on tobacco control policies
The tobacco industry has exerted substantial influence on tobacco policies throughout the world, and it is important to understand this influence as we strive to reduce tobaccorelated disease.

NCI-supported investigators at the University of London's School of Hygiene and Tropical Medicine are analyzing efforts made by the tobacco industry to influence tobacco control policies in selected countries, regions, and around the world. These investigators are using industry documents housed at the Guildford Depository in the United Kingdom to compile country profiles of tobacco industry activities in 14 countries.

The Guilford Depository was established as a consequence of litigation brought against several tobacco companies by the State of Minnesota and Minnesota Blue Cross Blue Shield. The parties settled in 1998, with the agreement of the Minnesota Consent Judgment, in which the British American Tobacco Company agreed to provide public access to the internal documents it produced during the discovery process. The documents were to be made available at the Guildford Depository for a period of 10 years, which expires in February 2009.

Analysis of the country profiles is offering valuable insights into how the tobacco industry may have influenced tobacco-related, public policy-making, and scientific research efforts in the countries being studied. This information is also enabling investigators to examine the connections between globalization, the tobacco industry, and policy influence, and to develop recommendations about how to create more effective tobacco-control strategies and policies to prevent and reduce tobacco use.

Two NCI Transdisciplinary Tobacco Use Research Center (TTURC) projects to examine tobacco prevention programs in international populations
In 1999, NCI, the National Institute on Drug Abuse, and the Robert Wood Johnson Foundation, created the TTURCs to facilitate a transdisciplinary approach to the full spectrum of basic and applied research on tobacco use. The goal of research projects conducted through the TTURCs is to help reduce the burden of tobacco-related diseases. In 2004, the National Institute of Alcohol Abuse and Alcoholism joined as a funding partner, and two TTURCs are currently investigating tobacco use in international populations.

The Roswell Park Cancer Institute's TTURC will expand the ongoing International Tobacco Control Policy Evaluation Survey (ITCPES), which is a longitudinal study of smokers in the United States, Canada, the United Kingdom, and Australia. The expanded study will include smokers in Ireland, Thailand, and Malaysia. This expansion will allow researchers to assess whether tobacco control and prevention policies that are effective in developed countries are equally effective in developing nations. The researchers will also conduct follow-up surveys of the 8,300 smokers from the four countries that initially participated in the ITCPES to evaluate whether comprehensive tobacco control policies being implemented in these countries are effective in reducing tobacco use. The results of this TTURC project can provide insights into how and why specific policies influence tobacco-related behaviors.

A pilot study to assess variations in plasma phytoestrogen levels in Europe
People can be exposed to two types of phytoestrogens through their diet, isoflavones and lignans. Isoflavones are found in soy and soy products, and lignans are found in whole grains, fruits, and vegetables. Some evidence suggests that these agents may protect against hormone-dependent cancers; however, human studies to date have yielded only inconclusive results. Large-scale, prospective studies are needed to fully evaluate whether dietary phytoestrogens are effective in preventing cancer. Such studies, however, are expensive and difficult to undertake.

NCI is supporting a pilot study, using a subgroup of participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) project, to determine whether a large-scale prospective study of phytoestrogens is justified. The EPIC project - the largest study of diet and health ever undertaken - has registered more than 500,000 men and women aged 35 to 69 years from 10 different European countries. The pilot study will examine variations in plasma phytoestrogen levels in 1,600 randomly selected EPIC participants from 17 different regions across Europe. In particular, plasma levels of the isoflavones genistein, daidzein, glycetin, and equol and the lignans enterolactone and enterodiol will be measured. The influence of age, gender, geographic region, and habitual diet on the plasma levels of these phytoestrogens will also be determined.

A collaboration with Karolinska Institute in Sweden to examine ovarian cancer risk using markers of hormone exposure during pregnancy
Factors associated with reproduction likely play an important role in the development of ovarian cancer. During pregnancy, the placenta produces large amounts of the female sex hormones estrogen and progesterone. A number of factors, including gestational age of the developing fetus, affect the levels of these hormones during pregnancy. Although research has shown that increasing parity (number of births) reduces a woman's risk of ovarian cancer, no study to date has examined the associations between indictors of hormonal exposures during pregnancy and subsequent ovarian cancer risk.

NCI is collaborating with the Karolinska Institute to conduct a large cohort study aimed at exploring these associations. Investigators are using information gathered on more than 1.2 million women who delivered their first infant between 1973 and 2000 and who were included in the nationwide Swedish Medical Birth Register. Researchers will: 1) study ovarian cancer risk using markers of hormone exposures during pregnancy, including birth weight, gestational age, single or multiple birth, pregnancy-induced hypertensive diseases, and placental weight; 2) examine whether the protective effects of increasing parity and a high age at first birth are influenced by markers of hormone exposures during pregnancy; and 3) assess the importance of other factors on ovarian cancer risk.

The investigators plan to gather information about maternal characteristics, pregnancy complications, placental weight, and birth characteristics for all births associated with the women in the cohort. In addition, information about gynecologic surgeries, vital status, and ovarian cancer incidence for these women will be collected from population-based registries.

Ovarian cancer accounts for approximately 4 percent of all cancers among women worldwide and has the highest mortality of all cancers of the female reproductive system. Use of the Swedish research registries in this study allows a large, cost-effective study to be conducted where information has been prospectively collected about markers of hormone exposure during pregnancy.

A study conducted by IARC of etiologic mechanisms relating "over-nutrition" to the development of colon cancer

Unhealthy, High-fat, High-carbohydrate

Living a Western lifestyle, which is characterized by a low level of physical activity and an energy-dense diet rich in easily digestible (refined) carbohydrates and fats, is associated with an increased risk of colon cancer. Etiologic models to explain this association have focused mostly on the effects of diet in exposing the colonic mucosa to mutagenic or tumor-promoting compounds. The results of this study should allow formulation of more precise nutritional guidelines for the effective prevention of colon cancer.

Two multinational clinical trials to evaluate the effectiveness of celecoxib in preventing colorectal cancer
Several NCI-sponsored clinical trials are currently testing the effectiveness of celecoxib (Celebrex®) in preventing a variety of cancers. Celecoxib, used to treat osteoarthritis and adult rheumatoid arthritis, reduces inflammation by blocking the activity of the cyclooxygenase- 2, or COX-2, enzyme. The COX-2 enzyme is activated only during inflammation, and evidence suggests that elevated levels of COX-2 may contribute to the development of a variety of cancers, including esophageal, stomach, colon, pancreas, liver, breast, lung, bladder, cervical, and head and neck cancers.

NCI and Pfizer, Inc., jointly sponsored the Adenoma Prevention with Celecoxib (APC) Trial to investigate whether celecoxib could reduce the occurrence of new colorectal adenomas (precancerous polyps) in people who already had such a polyp removed. More than 90 centers - located in the United States, the United Kingdom, Australia, and Canada - and more than 2,000 men and women age 30 years or older participated in this trial. From November 1999 to March 2002, study participants were randomly assigned to take either 200 mg of celecoxib twice a day, 400 mg of celecoxib twice a day, or a placebo twice a day for 3 years. Initial results of the trial were reported in April 2006 and showed that those taking celecoxib had 33 to 45 percent fewer new adenomas and 57 to 66 percent fewer high-risk adenomas than those taking the placebo. When adenomas recurred in the participants taking celecoxib, the growths were fewer and smaller than those in the participants who took the placebo.

In December 2004, use of celecoxib in the APC Trial was suspended because an analysis by an independent data safety and monitoring board showed that participants taking the drug had a 2.5-times greater risk of fatal and major non-fatal cardiovascular events (cardiovascular death, heart attack, stroke, or heart failure) than those on placebo. In February 2005, the APC investigators published a full analysis of the cardiovascular events, reporting that celecoxib use for an average of almost three years was associated with a dose-related increased risk of serious events.

In view of the increased risk of serious cardiovascular events found in the APC trial, NCI notified all principal investigators of its sponsored trials involving COX-2 inhibitors and asked them to inform their institutional review boards, data safety and monitoring boards, and trial participants about this new information. NCI also required that the informed consent forms for the trials be revised to reflect the new information. Trial participants were asked to sign new consent forms with updated information about the risks and benefits of the trials.

A Phase II trial comparing the effectiveness of celecoxib, taken alone or in combination with eflornithine, in preventing colorectal cancer in patients with familial adenomatous polyposis (FAP) is currently underway in the United States and the United Kingdom. FAP is an inherited disorder that is characterized by the development of numerous polyps in the colon and rectum. People diagnosed with FAP are at increased risk of colon cancer. Although most FAP patients undergo colectomy (surgical removal of all or part of the colon), researchers are interested in developing drugs that may offer an additional measure of protection to individuals with this condition. In the trial, 120 patients between the ages of 18 and 65 who have been diagnosed with FAP will be randomly assigned to receive celecoxib alone or celecoxib plus eflornithine. Eflornithine, also known as alpha-difluoromethylornithine, is an inhibitor of the enzyme ornithine decarboxylase (ODC). Inhibitors of ODC have been shown to suppress tumor formation in experimental models of bladder, breast, colon, and skin carcinogenesis.

A trial in China to investigate the chemoprevention of esophageal tumors
Esophageal squamous cell carcinoma (ESCC) is the third most common cancer of the digestive tract and the seventh leading cause of cancer-related deaths worldwide. The incidence of this cancer varies greatly according to geographic location. It is more common in Northern China, Iran, and the southern regions of the former Soviet Republic and is less common in Japan, Europe, and Canada. Patients with ESCC are often diagnosed when the cancer is advanced. However, clinicians have noted that premalignant lesions can precede the onset of ESCC, and these lesions may represent a potential target for prevention efforts.

NCI-funded scientists recently completed a randomized, placebo-controlled chemoprevention trial among people in Lixian, China, who had mild or moderate premalignant disease and were, therefore, considered to be at high-risk for ESCC. The study participants were randomly assigned to receive selenomethionine alone, celecoxib alone, a combination of selenomethionine and celecoxib, or a placebo over a period of 10 months. A total of 360 individuals were randomized to the four groups; 238 individuals were included in the final analysis. The results of the trial were reported in 2005.

Overall, there was a trend toward increased regression and decreased progression of premalignant lesions in selenomethionine-treated subjects in comparison with those not treated with selenomethionine, but the results were not statistically significant. In unplanned analyses, treatment with selenomethionine favorably affected a change in dysplasia grade among the 115 subjects who had mild premalignant disease at baseline but not among the 123 subjects who had moderate premalignant disease at baseline. Treatment with celecoxib had no effect on disease regression or progression. This is the first report of a potential chemoprevention agent for ESCC.

A prototype of an international version of NCI's Cancer Control PLANET Web portal to provide an organizing framework for international cancer control planning efforts
In 2003, NCI, the Centers for Disease Control and Prevention, and the Substance Abuse and Mental Health Services Administration, jointly developed and launched a Web portal called Cancer Control PLANET (Plan, Link, Act, Network with Evidence-based Tools). This Web portal serves as a doorway to new evidence-based tools - developed through a public-private effort involving these federal agencies and the American Cancer Society - that can help communities better understand and address their cancer burden. Cancer Control PLANET is organized around five steps that U.S. communities can take to develop a comprehensive cancer control plan.

A prototype of an international version of the Cancer Control PLANET Web portal will be demonstrated at the 2006 International Cancer Control Conference, in conjunction with the UICC World Cancer Congress in Washington, D.C. Full implementation of the International Cancer Control PLANET Web portal is anticipated in 2007, with ongoing NCI involvement in updating international data for the portal in future years.

For nearly all cancers, treatment options and survival are related to the stage of disease at diagnosis. The prognosis is generally better and treatment usually more successful if the disease is detected and diagnosed early while still localized. Unfortunately, many cancers have no symptoms at early stages and are not detected until the disease is advanced. Methods to detect and diagnose cancer include imaging procedures and laboratory tests. Laboratory tests may identify cancer cells (e.g., urine cytology for bladder cancer), specific biomarkers (e.g., the KIT receptor protein for gastrointestinal stromal tumors), or, more recently, distinctive gene-expression microarray patterns (e.g., the Lymphochip for diagnosing different types of lymphoma; see The Leukemia and Lymphoma Molecular Profiling Project).

NCI actively invests in biomarker development programs and in research toward the development of advanced technologies for cancer detection and diagnosis. Some of these efforts are conducted in international laboratories and medical institutions.

One NCI-supported effort in this area is the Early Detection Research Network (EDRN) to identify early cancer biomarkers (described below). Other NCI-supported efforts that involve international collaborators and seek to improve methods for the early detection and diagnosis of cancer are described here.

DNA microarray technology is a powerful new research tool that allows scientists to assess the level of expression of a large subset of the 100,000 human genes in a cell or tissue. This technology can quickly produce a snapshot of the genes that are active in a tumor cell, critical information in narrowing the precise molecular causes of a cancer.

A collaboration of NCI and international researchers to construct tissue microarrays using human tissue specimens from Spain and Canada
NCI established the Program for the Assessment of Clinical Cancer Tests (PACCT) to ensure that promising cancer biomarkers are appropriately evaluated for clinical usefulness. A critical barrier to advancing cancer diagnostics is the lack of reference tissues for evaluating promising biomarkers. NCI identified two valuable collections of tissue specimens at the Institut Municipal d'Investigació Mèdica (IMIM) in Barcelona, Spain and the British Columbia Cancer Agency (BCCA) in Canada. The IMIM specimens are from bladder cancer patients diagnosed in five areas of Spain, and the BCCA specimens are from Canadian ovarian cancer patients. Although the BCCA microarrays are still under construction, the IMIM arrays are currently available. The IMIM microarrays are statistically designed to address major research questions in bladder cancer.

A collaboration with researchers at the University of Tokyo to develop a new optical imaging system to detect cancers at an early stage
The University of Tokyo is home to one of the world's premier fluorescence imaging laboratories, and NCI scientists are working with Japanese researchers to develop new activatable imaging probes for discovering cancers at an early stage. Activatable optical probes produce a signal and become detectable only after they reach their target. This new method can detect very small cancer nodules with very high sensitivity compared to current imaging methods, and it may also provide improved specificity over current methods.

A collaboration with Princess Margaret Hospital in Toronto, Canada to improve a magnetic resonance imaging-guided prostate biopsy system
Magnetic resonance imaging is emerging as the most effective diagnostic imaging tool for visualizing the anatomy and pathology of the prostate. NCI scientists are working with researchers at the Princess Margaret Hospital in Toronto to improve a magnetic resonance imaging-guided prostate biopsy system and to design the next generation of these devices. In addition, NCI is examining targeted biopsy specimens of prostate tissue to identify the next generation of molecular targets for diagnosis and therapy.

Images of Blood Leukocytes from an AIDS Patient Producing HIV

An international repository of HIV-infected human materials to serve as a resource for researchers around the globe
To encourage research on acquired immunodeficiency syndrome (AIDS) and cancer, NCI established the AIDS and Cancer Specimen Resource (ACSR). This international resource for tissue and biological samples serves researchers working in the fields of AIDS, cancer, virology, immunology, pathology, epidemiology, tumor biology, and assay development, as well as others. The ACSR is a repository of human immunodeficiency virus-1 (HIV-1)-infected materials from a wide spectrum of HIV-related or associated diseases and from appropriate HIV-negative controls. Special sets of specimens include serial samples from patients undergoing treatment in clinical trials. More than 100,000 individual specimens are contained in the repository, including samples from Africa, Brazil, Russia, and Thailand.

The Leukemia and Lymphoma Molecular Profiling Project (LLMPP), a collaboration of researchers in the United States, Canada, and Europe
NCI investigators are working with researchers at the University of Nebraska Medical Center in Omaha to define the gene expression profiles of all types of human lymphoid malignancies. The project is supported by an international collaboration involving investigators from the Southwest Oncology Group; the British Columbia Cancer Agency in Vancouver, Canada; the Norwegian Radium Hospital in Oslo, Norway; the University of Würzburg in Würzburg, Germany; the University of Barcelona in Barcelona, Spain; and St. Bartholomew's Hospital in London, England.

The LLMPP uses "Lymphochip" cDNA (complementary DNA) microarrays, which are enriched in genes that are expressed in and/or function in lymphocytes. Lymphochip microarrays allow measurement of the RNA expression levels of the represented genes. Gene expression profiles developed as a result of this project may someday be used for disease classification (diagnosis), prognosis, and therapy selection. Already, results from the LLMPP indicate that these profiles can improve diagnostic accuracy and provide prognostic information.

The LLMPP is initiating a multicenter clinical trial to evaluate a lymphoma diagnostic chip, called LymphDX, which was designed by the company Affymetrix in collaboration with NCI researchers using LLMPP data. The study will demonstrate the feasibility of disseminating the LymphDX microarray technology to all of the participating sites and will also evaluate the diagnostic utility of the LymphDX chip in a prospective study.

The American-Russian Cancer Alliance, a consortium of American and Russian institutes engaged in cancer research and education
The American-Russian Cancer Alliance (ARCA), established in 2001, is a consortium of American and Russian cancer research institutes that conducts scientific research and medical education conferences both in the United States and Russia. The participating institutes include the University of Maryland Greenebaum Cancer Center in Baltimore, Maryland; the Fox Chase Cancer Center in Philadelphia, Pennsylvania; and the Kurchatov Institute and the N.N. Blokhin Cancer Research Center in Moscow, Russia. The Fox Chase Cancer Center is an NCI-designated Comprehensive Cancer Center, while the Kurchatov Institute is Russia's premier nuclear research center. Among ARCA's programs is a groundbreaking effort funded by the United States to use Russia's expertise and nuclear facilities to produce radioisotopes for diagnostic and therapeutic applications in oncology.

In one project, scientists at the Fox Chase Cancer Center have been developing agents for positron emission tomography (PET) detection and staging of cancer using iodine-124 from the Kurchatov Institute. In another study, University of Maryland researchers are investigating novel ways to use isotopes to destroy blood vessels that feed malignant tumors. Their initial research focused on actinium-225, but now they are working with another isotope, polonium-210. In a third project, Fox Chase Cancer Center investigators are studying the use of bismuth-213 for the radiotherapy of solid tumors.

NCI provides support for the infrastructure of ARCA through a supplement to the Cancer Center Core Grant awarded to the Fox Chase Cancer Center. The Institute is also providing funding for a tobacco research grant involving Fox Chase and the N.N. Blokhin Cancer Research Center through the Fogarty International Center's International Tobacco and Health Research and Capacity Building Program. In March 2006, NCI supported a major conference in Moscow that was organized by three ARCA partners (the Fox Chase Cancer Center, the University of Maryland Greenebaum Cancer Center, and the N.N. Blokhin Cancer Research Center) and entitled "Prevention and Treatment of Tobacco-Related Cancers." Approximately 200 Russians attended this conference, including a representative of the Russian legislature, as well as the U.S. Ambassador to the Russian Federation. Several NCI scientists were invited speakers. In Autumn 2006, NCI will host a workshop, involving ARCA partners, in Bethesda, Maryland, on the use of isotopes in cancer diagnosis and treatment.

In conjunction with ARCA, NCI's Office of International Affairs (OIA) is sponsoring a 1-year (2006-2007) training visit of a Russian scientist from Lomonosov Moscow State University to the University of Maryland School of Medicine's Division of Nuclear Medicine. In 2005, OIA sponsored shorter training visits of three Russian scientists to the same institution. In February 2005, NCI sponsored a visit of three representatives from the N.N. Blokhin Cancer Research Center to various cancer research centers and governmental and non-governmental organizations in the United States, including NCI. The purpose of the visit was to observe "best practices" in cancer communications to be adapted in Russia. Also in 2005, NCI sponsored six Russians to participate in the Institute's Summer Curriculum in Cancer Prevention and Control which is described in NCI's Summer Course on the Principles and Practice of Cancer Prevention and Control ³.

An international conference cosponsored by NCI and the European Organization for Research and Treatment of Cancer (EORTC) to share data on cancer molecular markers
In 2004, the third EORTC-NCI International meeting to discuss cancer molecular markers drew more than 200 participants from Europe, Asia, Africa, and the United States. NCI staff members were involved in planning the meeting and participated as session chairs and speakers. During the meeting, staff from the NCI and the U.S. Food and Drug Administration and members of the EORTC developed and presented a 1-day tutorial for industry on pathways for development of clinical laboratory tests using cancer molecular markers. The next international EORTC-NCI meeting on cancer markers is scheduled to be held in September 2006.

NCI's Early Detection Research Network In 2000, NCI formed the Early Detection Research Network (EDRN), a consortium of government, academic, and private-sector institutions focused on developing, evaluating, and validating biomarkers for early cancer detection and risk assessment. Today, the more than 300 researchers and 40 institutions that make up the EDRN are at the forefront of technology-driven research on the use of biomarkers for the early detection of cancer. NCI is funding many laboratories that develop biomarkers, including several overseas. One example is the laboratory of Dr. Zvi Livneh at the Weizmann Institute of Science in Rehovot, Israel. This laboratory is investigating whether detecting lower-than-normal activity of DNA repair enzymes in blood cells can be used as a biomarker for lung cancer risk in smokers. Another example is the laboratory of Dr. Bruce Robinson of the University of Western Australia in Perth, Australia. This laboratory has identified a novel protein that shows promise as a biomarker for mesothelioma. Work performed in Dr. Robinson's laboratory is part of a multicenter study that will evaluate and validate several biomarkers for this deadly disease. Once biomarkers are identified, they must be validated and undergo testing in large clinical trials with human participants. Ultimately, the lab tests that result from EDRN research will be added to the clinician's toolbox to aid in cancer prevention and in early therapeutic intervention. The Web site for the EDRN is located at http://edrn.nci.nih.gov/. Dr. Zvi Livneh Dr. Bruce Robinson

Approximately one third of all cancers are avoidable through lifestyle changes. These changes include: stopping smoking, maintaining a healthy weight, being physically active, eating a moderate-fat diet with enough fruits and vegetables, avoiding too much alcohol, and protecting the skin from harmful sun exposure. Enough information is also available to permit the early detection and effective treatment of another one third of cancer cases. Some of the most commonly occurring cancer types are curable with existing treatments. Nonetheless, millions of cancer cases worldwide cannot currently be prevented or cured. Therefore, we must continue to develop new and effective treatments.

Developing new therapies for cancer is central to much of the research supported by NCI. By partnering with research institutions and investigators around the world, we should be able to accelerate the pace of development of new drugs and other treatments and shorten the time required to recruit patients into and complete clinical trials.

In Europe, NCI created a liaison office to coordinate many of its research and treatment programs conducted with European collaborators (see article on the NCI Liaison Office). More examples of global NCI-supported programs and efforts to develop new, effective, and efficient treatments for cancer are described in this section.

A German clinical trial of radioimmunotherapy for non-Hodgkin lymphoma (NHL)
NCI is assisting international research institutions with clinical trial investigations of targeted radiation therapy - also known as radioimmunotherapy - by supplying overseas scientists with the necessary reagents and expertise pertaining to their use. One clinical trial that is currently being conducted at the German Cancer Research Center in Heidelberg, Germany is evaluating a monoclonal antibody conjugated to the radioisotope bismuth-213 for the treatment of NHL. The monoclonal antibody targets a protein antigen called CD20, which is found on NHL cells. The German researchers obtained the reagents they needed for this trial from NCI through a Material Transfer Agreement with the Institute.

Cooperative agreements with Canadian researchers conducting clinical trials
The NCI supports research projects at several Canadian universities, cancer centers, and hospitals, as well as clinical trials run by Canadian cooperative groups. One group that receives NCI support is the Princess Margaret Hospital Phase II Consortium. This consortium is the only non-U.S.-based trial group funded by NCI to carry out Phase II studies of new anticancer drugs. In addition, the National Cancer Institute of Canada is a participant in the NCI Clinical Trials Cooperative Group Program. Individual Canadian institutions are also members of other NCI-supported cooperative groups, including the American College of Surgeons Oncology Group, the Cancer and Leukemia Group B, the Children's Oncology Group, the Eastern Cooperative Oncology Group, the Gynecologic Oncology Group, the National Surgical Adjuvant Breast and Bowel Project, the North Central Cancer Treatment Group, the Radiation Therapy Oncology Group, and the Southwest Oncology Group. More than 90 percent of the investigational drugs shipped internationally by NCI's Cancer Therapy Evaluation Program (CTEP) currently go to Canadian investigators (see related article on CTEP).

An international lymphadenectomy trial to study a less invasive method of identifying microscopic metastasis of melanoma to lymph nodes
Routine, complete lymphadenectomy - the surgical removal of regional lymph nodes - for patients with clinically localized primary melanoma remains controversial because most patients will have tumor-free nodes. A minimally-invasive procedure called intraoperative lymphatic mapping and biopsy of the sentinel lymph node is a promising alternative. Examination of the sentinel lymph node - defined as the regional node most likely to contain cancer cells spreading from the primary tumor - can identify patients with occult (microscopic) metastasis. These patients should undergo complete lymphadenectomy, while other patients do not require further nodal assessment.

The Multicenter Selective Lymphadenectomy Trial (MSLT-I), headed by investigators from the John Wayne Cancer Institute in Santa Monica, California, is comparing two treatments for early melanoma: 1) wide excision plus sentinel node biopsy (SNB), followed immediately by complete lymphadenectomy if the sentinel node contains cancer; and 2) wide excision, followed by complete lymphadenectomy only for clinical evidence of nodal metastasis during postoperative observation.

MSLT-I, the largest randomized surgical trial for melanoma, enrolled 338 patients from North America, 630 from Europe, and 1,033 from Australia. International enrollment allowed rapid accrual. Interim results, which were reported in 2005, showed that SNB performed by doctors with adequate training and experience can identify occult nodal metastases with 95 to 97 percent accuracy. The interim data also indicate that SNB significantly lengthens the disease-free survival of all patients and prolongs the overall survival of patients with occult nodal metastases.

Because these findings strongly support early lymphadenectomy for occult nodal metastasis, MSLT-I data are changing the standard of care. A follow-up study, MSLT-II, is now open to patient accrual and will enroll at least 1,925 patients in another international collaboration of melanoma centers.

An international clinical trial to test the drug letrozole for lowering risk of breast cancer recurrence

Scanning Electron Microscope Picture of a Breast Cancer Cell

An international clinical trial led by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG), with support from the Canadian Cancer Society (CCS), and in partnership with NCI and Novartis Pharmaceuticals, showed that the estrogen-suppressing drug letrozole (Femara®) reduced the risk of breast cancer recurrence and the incidence of new breast cancer in the opposite breast by 42 percent compared to placebo in women whose tumors were hormone receptor-positive.

Previous studies had shown that 5 years of treatment with the drug tamoxifen after surgery, radiation therapy, and chemotherapy for early-stage breast cancer could reduce the risk of recurrence by almost half in women whose tumors were estrogen receptorpositive. Some of these studies also showed, however, that no additional benefit is obtained by continuing tamoxifen treatment beyond 5 years. Because more than 50 percent of the women who experience a recurrence of their cancer do so more than 5 years after diagnosis, additional treatment options are necessary. This trial showed that a 5-year course of letrozole, when given after 5 years of tamoxifen therapy, significantly reduced the risk of local recurrence and metastasis (distant recurrence).

In addition to patients recruited through the NCIC CTG and NCI, European participants were enrolled in the letrozole study by the European Organization for Research and Treatment of Cancer (EORTC) and the International Breast Cancer Study Group (IBCSG). Participants in the trial were enrolled through hospitals, cancer centers, and institutes throughout Canada, the United States, England, Belgium, Ireland, Italy, Poland, Portugal, and Switzerland. The trial's participants will continue to be followed for 10 to 15 years.

NCI's Developmental Therapeutics Program acquires plants and marine organisms from tropical and subtropical countries

NCI Frederick Cancer Research and Development Facility Prepares Samples of Natural Substances for Chemical Analysis

Between 1986 and 2004, NCI's Developmental Therapeutics Program (DTP) acquired plants and continues to collect marine organisms to screen for potential anticancer compounds through collection agreements with over 25 tropical and subtropical countries. More than 50,000 plant specimens were collected in Africa and Madagascar, Central and South America, and Southeast Asia. More than 13,000 specimens of marine invertebrates and marine algae have been collected to date, initially from the Indo-Pacific region, and, since 2002, from areas worldwide.

In undertaking these collections, NCI committed itself to the conservation of biological diversity, as well as to policies of fair and equitable collaboration and compensation in interacting with the source countries participating in the collection programs. Agreements based on the NCI Letter of Collection (LOC) or Memoranda of Understanding (MOUs) have been signed with relevant government organizations in many of the source countries. The first such agreement was signed with Madagascar in 1990, 3 years before an international conference in Rio de Janeiro, Brazil, that led to the signing of the Convention on Biodiversity (CBD). In addition, the NCI model agreements have formed the basis for many international accords not involving the Institute or the United States and are still used as a basis for discussion by many organizations wishing to conduct biodiscovery programs.

More information about DTP's international outreach initiatives is found in NCI's Developmental Therapeutics Program.

Three Strains of Mice Used in Experiments

A study of bortezomib and immunotherapy in preclinical mouse tumor models
NCI is collaborating with investigators at the Peter McCollum Cancer Centre in Melbourne, Australia and Juntendo University in Tokyo, Japan to explore combination treatment of a number of mouse tumor types with bortezomib (Velcade®) and an agonist antibody against the Apo2L/TRAIL "death receptor." As part of the collaboration, the Australian and Japanese investigators have supplied NCI with a quantity of the purified antibody and with lymphocyte - tumor hybrid cells called "hybridomas" that produce it.

The Apo2L/TRAIL receptor is one of several members of the tumor necrosis factor superfamily of receptors that are able to induce apoptosis (programmed cell death) when activated. This receptor has received considerable attention lately because of the finding that many cancer cell types are sensitive to Apo2L/TRAIL-induced apoptosis, whereas most normal cells are not.

Bortezomib works by blocking the action of structures inside cells called "proteasomes," which are large enzyme complexes that degrade abnormal or misfolded proteins and proteins that are normally targeted for destruction. Some proteins are normally targeted for orderly destruction to maintain cellular growth control. Research has shown that proteasome inhibition can induce apoptosis and that cancer cells are more sensitive to this effect of bortezomib than normal cells.

The antibody against the Apo2L/TRAIL receptor alone has shown some efficacy against tumor cells, but preliminary experiments have indicated that bortezomib enhances its activity. This combination treatment will hopefully allow a reduction of tumor burden in the absence of the major immunosuppression that can occur during traditional chemotherapy or radiation therapy. The investigators' aims are to promote local tumor destruction and, hopefully, to improve the natural immune response against the tumor cells.

An NCI-supported International Center for Studies of Traditional Chinese Medicine (ICTCM) for cancer treatment
Following a successful pilot study, NCI is supporting a cooperative agreement to develop an ICTCM that partners the University of Texas M. D. Anderson Cancer Center with the Cancer Hospital, Fudan University in Shanghai, China. Researchers affiliated with the center will investigate the benefits of some traditional Chinese medicine (TCM) treatments for cancer patients.

During the 2-year pilot study, which began in 2003, the ICTCM investigated three categories of TCM: 1) herbal and natural treatments that target the disease and related symptoms; 2) acupuncture for some side effects of cancer treatment; and 3) the biobehavioral effects of qigong, a self-healing art that combines movement and meditation, and other mind/body interventions. This work is being advanced further under a new 4-year cooperative agreement.

While the NCI has supported research in individual topics related to TCM, such as acupuncture, these are the first NCI grants to support the development of an international partnership to study multiple aspects of TCM.

Dr. Yosef Yarden

An NCI MERIT Award for Israeli researcher into new strategies for targeted therapies
NCI has named Dr. Yosef Yarden of the Weizmann Institute of Science in Rehovot, Israel as a MERIT Award recipient for his project titled "Next Generation Strategies to Intercept ErbB Signaling." The MERIT Awards were established to provide experienced investigators with long-term, stable support to foster their continued creativity.

Dr. Yarden is investigating the epidermal growth factor receptor (EGFR/ErbB) family of proteins with the goal of designing therapies that inhibit their oncogenic properties. He has been involved in many crucial developments in this field, including isolating EGFR/ErbB-1, identifying several proteins that bind to EGFR/ErbB-1, and understanding the role of another member of the EGFR family (HER2/ErbB-2) in cell signaling and tumor development.

In his MERIT-funded research, Dr. Yarden will focus on developing therapies that target ErbB. This work will be carried out through development of: 1) novel molecules that bind EGFR/ErbB receptors; 2) engineered soluble portions of these receptors; and 3) inhibitors of EGFR/ErbB receptor activation that promote receptor degradation. Immunotherapy strategies will also be explored.

An International Working Group of the AIDS Malignancy Consortium to pursue clinical trials for AIDS-associated malignancies in developing nations
The AIDS Malignancy Consortium (AMC) is an NCI-supported clinical trials group founded in 1995 to support innovative trials for AIDS-associated malignancies, including non-Hodgkin lymphoma, primary central nervous system lymphoma, Kaposi sarcoma, and cervical cancer. The International Working Group of the AMC - one of five AMC working groups - is focused on developing partnerships with international investigators to pursue non-myelosuppressive, hypothesis-driven clinical trials for AIDS-associated malignancies that are suitable for evaluation in resource-poor settings.

In one such clinical trial, researchers with the East Africa-Case Western Reserve University Research Collaboration confirmed that dose-modification of oral chemotherapy in the management of AIDS-related non-Hodgkin lymphoma results in less toxicity and does not compromise efficacy. Future AMC clinical trials will include international sites in areas most affected by the global AIDS pandemic, such as Uganda, Zambia, Kenya, Tanzania, and Brazil.

NCI is dedicated to improving cancer-related outcomes and reducing the impact and burden of cancer on patients, their families, and society. The Institute seeks to identify, measure, and understand factors that influence the quality and effectiveness of cancer-related programs and care both in the United States and abroad. These factors may be biological, behavioral, sociocultural, environmental, or economic in nature. Cancer-related outcomes can be measured in terms of: intervention efficacy; survival; health-related quality of life; satisfaction with care; performance of the health care system; and the economic burden on individuals, families, or society at large.

For clinicians and patients, cancer outcomes research can provide evidence about the benefits, risks, and results of interventions, which can then be used to make more informed decisions. For health care managers and purchasers, cancer outcomes research can identify potentially effective strategies that can be implemented to improve the quality and value of cancer-related care.

The following are examples of NCI research with international partners into possible factors that can influence cancer-related outcomes. Of special note is the NCI's involvement with the International Breast Cancer Screening Network (IBSN), which is described below.

An NCI-supported microsimulation model to evaluate colorectal cancer (MISCANCOLON) screening programs and policies, which was developed by researchers at the Erasmus University, The Netherlands
It is difficult to directly assess the impact of cancer-related interventions on a population level. Mathematical modeling, however, may be an appropriate method for performing such assessments. Researchers at the Erasmus University Medical Center, Department of Public Health (Rotterdam, The Netherlands) have developed a microsimulation model, called MISCAN-COLON, to evaluate the population benefit and expenditures for interventions to reduce the burden of colorectal cancer.

Using MISCAN-COLON, a large number of individual life histories can be simulated in each of which several colorectal lesions can emerge. Screening for colorectal cancer can then be simulated, which will alter some of the life histories. Multiple factors can be specified in the MISCAN-COLON model, including: demographic, epidemiologic, and economic information; the characteristics of screening; and other information, such as risk factors, treatment practice, and behavioral aspects. Various assumptions about the natural history of colorectal cancer and screening and about surveillance strategies can also be incorporated in the model. MISCAN-COLON produces a detailed output of colorectal cancer incidence, prevalence, and mortality, as well as the results and effects of screening. It can be used to test hypotheses against empirical data. The model can also be used for evaluating screening policies and for choosing between competing policies by comparing their simulated costs and effectiveness outcomes.

The Erasmus University Department of Public Health and NCI are working with researchers in Europe, Canada, and the United States to conduct additional validation studies of MISCAN-COLON and to use the model for program and policy evaluation. In 2004, MISCAN-COLON was used to evaluate the colorectal cancer screening coverage policy of the U.S. Center for Medicare and Medicaid Services.

Erasmus University is also a partner in an NCI-funded Cancer Intervention and Surveillance Modeling Network (CISNET) grant on colorectal cancer, and MISCANCOLON was used in the CISNET evaluation of the U.S. Department of Health and Human Services' Healthy People 2010 goals.

A Center for International Blood and Marrow Transplant Research (CIBMTR) to foster research on patient outcomes from transplant treatments for cancer
The CIBMTR is a research program funded by a grant from NCI that collects detailed data on blood and bone marrow transplant patients from more than 450 transplant centers in 48 countries. Formed in 2004, the center helps researchers share patient data and conduct scientific studies on transplant treatments for cancer. The CIBMTR collects data on about 65 percent of the allogeneic hematopoietic cell transplants (HCTs) done in North and South America, about 35 percent of the allogeneic transplants done elsewhere, and about 60 percent of autologous HCTs done in North and South America. The center's database contains information on more than 100,000 blood and marrow transplants.

The ability to perform retrospective analyses on worldwide transplant data has led to a number of important conclusions regarding transplant patient outcomes, including the following:

Chronic graft-versus-host disease (and its treatment) increases the risk of developing squamous cell carcinoma of the skin and of mucosal surfaces, and bone marrow transplant patients should be screened for this c