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NCI's spending in the developing world
During its 2006 fiscal year, NCI's international spending, including intramural research and training, was approximately $80 million. This included support and lab supplies for visiting scientists.

In a typical year, NCI has about 80 foreign grants and 10 contracts to such countries as Australia, Belgium, Canada, China, Denmark, Finland, France, Germany, India, Israel, Italy, Jamaica, Netherlands, Russia, Senegal, South Africa, Spain, Sweden, Switzerland and the United Kingdom. During the 2006 fiscal year, NCI, foreign grants totaled $24.5 million, and foreign contracts totaled an additional $3.7 million. Over half (57 percent) of international grants in 2006 went to research into the causes of cancer. Eighteen percent of funding dollars went into treatment research. Research into the biology of cancer accounted for 15 percent of funding; six percent was for detection and diagnosis, and the other four percent went into cancer control efforts (2 percent) and manpower development (2 percent).

Additionally, in 2006 there were 376 domestic grants and six domestic contracts with foreign components, including 134 in non-high-income countries. (See the Photos/Stills section for a graphic of NCI funding by country income levels, as well as a graphic of the division of funds described above.)

Basic Research
Working with international researchers, NCI participates in several research projects studying the environmental and genetic factors that contribute to the development of cancer. As an example, the NCI's Chernobyl Research Unit is working with researchers in Ukraine and Belarus to research leukemia, lymphoma and other blood diseases among Ukrainian clean-up workers, and thyroid cancers and other thyroid-related disease among Ukrainians and Belarusians exposed to radiation as children during the Chernobyl nuclear accident in 1986.

Cancer Prevention
As part of its Tobacco Free Initiative (TFI), the World Health Organization (WHO) established a scientific advisory committee on tobacco product regulation. NCI scientists have been working with this group since 2002, developing recommendations to improve public health and scientific research on the effects of tobacco use.

NCI has also worked with WHO's TFI to create an International Network for Tobacco Testing and Research for Regulation to address research issues related to global capacity building for tobacco product testing and research. In addition, NCI, as part of a multi-agency collaboration with five other institutes of the National Institutes of Health, the NIH Fogarty International Center and the WHO's TFI, funds research on tobacco use and related illnesses in the developing world.

Cancer Detection and Diagnosis
NCI researchers are working with scientists at the University of Tokyo, which hosts one of the world's premier fluorescence imaging laboratories, to develop a new optical imaging system to detect smaller cancers with a higher sensitivity compared to current methods. NCI scientists are also working with researchers from Princess Margaret Hospital in Toronto to improve magnetic resonance imaging-guided (MRI-guided) prostate biopsy techniques, which improve the ability to visualize the anatomy and pathology of the prostate.

In the field of AIDS-related malignancies, NCI established the AIDS and Cancer Specimen Resource, a repository of tissue and biological samples available to researchers working in the fields of AIDS, cancer, virology and others, to encourage research on AIDS and cancer. The repository contains over 100,000 specimens, including samples from Africa, Brazil, Russia and Thailand.

Cancer Treatment
The NCI supports the International Center for Studies of Traditional Chinese Medicine, a partnership between the University of Texas M.D. Anderson Cancer Center in Houston, and the Cancer Hospital of Fudan University in Shanghai, China, to study the benefits of some traditional Chinese medicine treatments for cancer patients.

In addition, the NCI has a liaison office in Brussels, Belgium, which coordinates several of the Institute's research and treatment programs in Europe. The goal of the NCI liaison office is to facilitate the interchange of information, ideas and research between NCI and its European partners. The office works with universities, research institutions and other organizations through a mixture of informal partnerships and formal agreements with international organizations, such as the European Organization for Research and Treatment of Cancer, Cancer Research U.K., the Southern Europe New Drugs Organization, the European Drug Development Network and the International Network for Cancer Treatment and Research.

Quality of Care
The National Cancer Institute has been involved in a number of workshops and training programs to improve the quality of care in various nations. In collaboration with the International Network for Cancer Treatment and research, NCI co-sponsored a series of workshops for health care providers in developing countries about the latest tools and techniques in the treatment of cancer and symptom relief. These conferences have been held in China, the United Arab Emirates, Jordan, the Palestinian Authority, Egypt and Iraq.

In addition, in April 2006, NCI sponsored a conference on traditional Chinese medicine which brought together researchers from China and the National Cancer Institute, as well as a conference on palliative care in the Middle East.

Training of Scientists
Yearly, approximately 1,000 visitors (including post-doctoral trainees) from more than 74 countries contribute to intramural research projects being conducted at NCI's Center for Cancer Research through the NIH Visiting Program. Formal researcher exchange programs also exist through the U.S.-Japan Cooperative Cancer Research program and the Ireland-Northern Ireland-NCI Cancer Consortium. The NCI Office of Nursing Affairs has also hosted nurses from Ireland and Jordan to provide mentoring on core oncology nursing training, cancer genetics and clinical trials. Each summer, NCI's Division of Cancer Prevention hosts a course on the Principles and Practice of Cancer Prevention and Control which draws a number of international attendees. In the past, scientists and health professionals from countries such as China, Ghana, India, Lithuania, Russia and Turkey have attended this course.

In addition, the NCI Office of International Affairs hosts a Scientist Exchange program in which NCI partially funds training of scientists from developing countries in non-NCI laboratories in the United States and other developed countries.

Building Capacity and Infrastructure
The All-Ireland NCI Cancer Consortium, also known as the "Ireland-Northern Ireland-NCI Cancer Consortium" was established to facilitate collaboration between the governments and cancer research communities of the United States, Ireland and Northern Ireland in order to improve the infrastructure for cancer research and cancer care on the island of Ireland, and to develop joint research programs and educational exchange programs.

The consortium has several working groups, the most active of which has been the prevention working group, which has participated in several workshops in Ireland related to tobacco control and obesity, and is working to build an Ireland-wide community of prevention-oriented scientists and caregivers.

Cancer communications have also been improved through TELESYNERGY®, a global medical consultation workstation developed by the National Institutes of Health. (See BenchMarks Volume 3 Issue 6 for more information about TELESYNERGY®). The TELESYNERGY® system combines cameras, microscopes, audio equipment and other devices to enable clinicians and scientists from multiple locations to collaborate. The full version of the TELESYNERGY® system is being used in five hospitals on the island and smaller versions have been installed in five other sites. The TELESYNERGY® system links researchers with scientists and clinicians in the United States and in Amman, Jordan.

The King Hussein Cancer Center (KHCC) in Jordan forged a cooperative agreement with NCI to enhance medical sciences and improve care in the Middle East region. Major achievements of this cooperation include the launch of the TELESYNERGY® system.

Jordan is also part of the Middle East Cancer Consortium (MECC), a coalition between the United States and the Ministries of Health in Cyprus, Egypt, Israel, Jordan, the Palestinian Authority and Turkey. Their principal initiative, the Cancer Registry Project, supports the development of population-based cancer registries in all of the member countries. The first report on cancer incidence, which includes date from Cyprus, Egypt, Israel and Jordan, was released in 2006 and is available on the NCI website.

In Africa, the NCI, in cooperation with other parts of the National Institutes of Health, provides awards to establish and maintain several Centers for AIDS Research (CFARs) including one at Case Western Reserve University which conducts research on prevention, detection and treatment of HIV, AIDS and AIDS-related malignancies, such as cancer, with Makere University in Kampala, Uganda. NCI also supported the 6th International Conference on the Burden of Cancer in Africa which was held in October 2007 in Cape Town, South Africa.

The NCI also provides capacity building assistance through an expansion of its Comprehensive Cancer Control Leadership Institutes (CCLI). As a collaboration between the NCI's Cancer Information Service, the American Cancer Society, the U.S. Centers for Disease Control and Prevention, and the Intercultural Cancer Council, the CCLIs provide an opportunity for highly-skilled, influential individuals to support cancer control implementation efforts in their local areas. After a successful run in the United States, the program has spread to Peru, Mexico, Brazil and Uruguay.

The NCI Office of International Affairs, lead by Joseph Harford, Ph.D., coordinates the Institute's international activities. The office collaborates and works with international agencies, as well as coordinating international cancer research and overseeing international scientist exchange programs. The OIA is also very involved in sponsorship of international workshops, and dissemination of cancer information.

For more information about the international activities of the National Cancer Institute, please visit http://oia.cancer.gov.

Benchmarks: What makes international clinical trials unique?

Dr. Richard Love: It is important is to recognize how little we know about applying our current therapeutic approaches in cancer -- particularly systemic therapies that have been mostly derived from studies of upper middle class Caucasian, American or northern European populations -- to populations with different genetic backgrounds and major differences in culture and health systems.

What often happens is that our therapies are applied abroad with expectations that they will have similar efficacies and toxicities. What then occurs, because of [unexpected] toxicities or economic issues, is that the specific therapeutic regimens get changed from those that were previously tested and proven efficacious with certain levels of toxicity in populations. One has to then wonder whether, in these circumstances, such altered regimens are effective at all, or at a minimum, effective to the previously demonstrated degree.

Particularly with systemic treatments, but also with surgical and radiotherapeutic interventions, the morbidity and mortality associated with our Western therapies in different populations, other cultural settings, and often resource-limited health system settings, must be expected to differ.

Benchmarks: Could you give us an example of a treatment that may not work as effectively in another country as it works here?

Dr. Richard Love: Let's take a systemic therapy in breast cancer, for example. There are emerging data indicating that, in patients, metabolism of tamoxifen, the mostly widely used hormonal therapy in breast cancer, is critical in taking the drug from status as a pro-drug [an inactive drug] to status as an active drug. Tamoxifen is usually metabolized to a major metabolite [called] endoxifen, and it is endoxifen that has the therapeutic effect -- and interestingly, the bothersome side-effect of hot flashes. There are limited, but compelling, data to the effect that if individuals are non-metabolizers because of a genetic polymorphism that prevents them from metabolizing this drug, they do not get the therapeutic benefits of the drug. There is some suggestion that instead of the frequency of non-metabolism polymorphisms that we see in Western populations -- maybe six percent -- in Asian populations we see non-metabolizing polymorphisms in 40 to 50 percent of women. This raises the possibility that tamoxifen treatment for breast cancer in Asian populations may be ineffective in that particular percentage of patients.

Benchmarks: Cancer is often seen as a problem of Western countries, and many people think that cancer isn't a problem in developing countries. What would you say to that?

Dr. Richard Love: Well, it's certainly true that the major health challenges in many low and middle income countries are with communicable diseases, but increasingly these are being successfully dealt with as a consequence of much-to-be lauded efforts by Bill Gates and Warren Buffet and Bill Clinton with respect to AIDS, tuberculosis and malaria, and Jimmy Carter with respect to "orphan" communicable diseases, and general public health improvements, particularly water purification. As this happens and populations age, more people survive to adulthood and as a consequence we are seeing a greater burden of adults with major malignancies in developing countries, since most common malignancies increase in incidence with age.

The other major factor, of course, is tobacco use. Because of the high and increasing prevalence of tobacco use in many low and middle income countries, as the adult population increases, these countries are seeing an increase in case burdens of very difficult to treat tobacco-caused malignancies.

Benchmarks: What are the most common challenges related to cancer in the developing world?

Dr. Richard Love: First and foremost, addressing the public health issues of tobacco, immunization, and palliative care. Next, application of therapies that are genuinely effective in the specific settings is a big challenge. This is currently where the majority of financial resources for cancer is spent in low and middle income countries. In this context, I think greater educational efforts need to be made with researchers and clinicians, to get them thinking more often about research or at least formative evaluation, when considering cancer treatments in their different populations. We also need to directly and indirectly deal with what has been called the "affordability gap," that is the gap between the cost [of drugs] as they are sold in low and middle income countries and the ability of the potential consumers there to pay. What happens is that pharmaceuticals are usually extremely expensive and in fact it ends up that only those with very significant financial resources tend to get treated. There are major global ethical and justice issues with the application of our currently available technologies in low and middle income countries. One gets the impression of widespread application of therapeutic modalities internationally, such as we apply them in this country, but when you get to low and middle income countries you find out that, yes, practitioners are treating people in ways we are familiar with, but the vast majority of patients are being left behind by cancer medical science. We have a long way to go to make good on the promise of the Declaration of Human Rights (1948) that the fruits of medical science should be enjoyed by all human beings.

Benchmarks: Could you tell us a little about recruitment issues that must be addressed in international clinical trials?

Dr. Richard Love: Over 15 years I've had experience conducting clinical trials and recruiting people for clinical trials in low and middle income countries where we have had to tackle issues in three domains. First, you have to tackle biomedical/clinical issues with doctors. For example, we are [currently] conducting a clinical trial treating women with advanced breast cancer in Bangladesh. There are issues of getting the doctors there to appreciate the treatment state-of-the-art, issues of getting surgical pathology services up to speed, and being able to assure that the treatment we want to study can in fact be safely given.

Second, there are psychosocial-culture issues. In Bangladesh there is very little education about breast cancer and so we have to somehow provide that education as part of what we are doing for our clinical trial. To address this, we have contracted with a cultural development organization that does performance art. The organization's talented artists are preparing a 20-25 minute musical-dance-song presentation about how to successfully address breast cancer problems. The presentation will be culturally sensitive, and one that the Imams [Islamic religious leaders] are involved with and which they will hopefully approve. We are going to put this on for village audiences in Bangladesh within the context of a trial and see what happens. We have to make sure people get the messages that we think they ought to get and that they make take the behavioral steps we hope will be helpful for them.

Third, there are health system issues. Again in Bangladesh there are about one to two working physicians per about 100,000 people, so we have to do something to create some sort of health system fix to take care of women if we are going to actually have clinical trial participants. What we did was create a breast problem walk-in clinic in the context of a rural information technology education office. These were offices that an NGO [non-government organization] in Bangladesh operated, where they had five to 10 computers and were offering classes for rural populations about the internet and computers. On the days when they held classes for women, we created, off in a corner, a breast problem clinic with a woman physician and a local community women's health worker who was well respected. In the clinic, these staffers would ask women if they had any breast problems they wanted to talk about. Culturally, this is a situation where women often don't have permission to deal with such problems on their own initiative and so our staff could begin to address such delicate problems quietly with women who had an excuse otherwise to be present in the building.

For the past week I have been in Morocco, where we are gearing up for a clinical trial, and in the meetings we had with investigators trying to make arrangements for this trial, it became clear that cultural and health system issues are ones that we are going to have to get into if we are going to conduct this trial successfully. We can't just focus on the treatment issues that the trial is about. As a practical matter, when you do a clinical trial with some intervention you want to evaluate, you have to follow people up. You cannot do that unless you can contact them or somehow get them back. There are major cultural barriers preventing women from either coming back to the treating institution or to finding out what's happened to them.

Benchmarks: Is there any benefit to Americans when their tax dollars are used for cancer research in developing countries?

Dr. Richard Love: There are enormous benefits of many kinds. First, apropos of the subject I was discussing before about the differences in drug metabolism in populations with different genetic background, we can learn more rapidly about efficacy and toxicities of treatments of all kinds by studying them in populations where there are major differences in levels of these parameters in large percentages of the population. Obviously, also these genetic differences are important not only in the native populations in a foreign country but very likely also in immigrant populations from these countries to the United States.

There are unique circumstances in other countries that allow us to answer questions that we would like to answer but cannot do so efficiently in the United States, because of the spread of patients across the country, limited participation in clinical trials, and the expensive and large regulatory bureaucracy attendant on working on clinical trials in this country. All these things constitute significant barriers; one can tackle some of these issues at considerably less expense in foreign countries. For example, for clinical trial participation in cooperative groups in this country, it's reasonable to talk about clinical case management costs of at least $5,000 per case. Well, even with adding expenses for ancillary studies, in the Philippines, we can get people into clinical trials, manage them, and get all kinds of other data and tissue samples for about 18 percent of that cost.

Additionally, of course there are geopolitical benefits of Americans in medicine working constructively with people in foreign countries at a time when the feelings about this country among citizens of other countries are significantly negative.

Then there are reasons why we should be interested in doing cancer research abroad out of pure selfishness. For example, we are working on inflammatory breast cancer in Morocco. Inflammatory breast cancer accounts for only one to two percent of breast cancers in this country, but it occurs more frequently in young, African American, and Hispanic women, it is increasing in frequency, and it continues to be significantly lethal. Of particular interest is that it may be a breast stem cell disease. For reasons unknown, the frequency of inflammatory breast cancer is somewhere around eight to 10 percent in countries of the Maghreb, that is the western Middle East which includes Morocco, Algeria and Tunisia. So here is a circumstance where we can study this entity more efficiently abroad. If we can understand the biology of inflammatory breast cancer, get a better idea of what causes it, and how to manage it, then we may get windows on really bad breast cancer in this country. I argue that we should be studying inflammatory breast cancer in the Maghreb because if we are concerned about breast cancer then we ought to be concerned about the worst breast cancer and its biology, and we ought to go where the worst of breast cancer is more frequent so we can study it efficiently.

Dr. Richard Love: We are far too simplistic in thinking about medicine. Often, people tend to focus on the biology and less on application of biology to people -- we fail to see real people outcomes. Sometimes we aren't very sensitive, if not pejorative, when we talk about people with cancer in developing countries.

We often see descriptions of women who have neglected breast cancer, or at least that's how it's described. Other times we are given portraits of women who have unique ideas about what caused their breast cancers and these presentations lead us to believe that the women, if they aren't delusional, are at a minimum badly educated about health and biology. From my time in the field and from spending time with clinical psychologists, I find these stories not very insightful. They are repeatedly offered, followed by simplistic suggestions for educational approaches to change presumed unwise behaviors.

Let me consider each of these stories further. First, this matter of women who have a serious breast problem that doesn't get taken care of. This is often the case in Bangladesh -- we estimate that seven out of 10 women who develop breast cancer there die of this without any medical intervention at all. We sat down with groups of rural poor Bangladeshi women and asked them about such situations. We found that they make incredibly difficult decisions with considerable insight and thought. Here's what they said, in essence, summarizing multiple comments in one story:

"I began developing this breast problem -- a lump, and it didn't go away and it was getting bigger and harder. Then it began to hurt, and then later it began to bleed, and to smell. Later I began getting pains in my bones. From the beginning and all the way along as this was happening I knew it was bad. We don't have very much money in our family, and what happened along the way was after a while, every day, I had to make a decision about whether what little bit of money we had was going to go towards my getting on the bus and trying to go the hospital where they would demand some more money for me to get something done about this problem, or I was going to make sure that my children had something to eat so they could go to school and study without their stomachs hurting, and that my children had paper and pencils for school. Everything I know, everything I have heard, says that education is important, and the only way that my children are going to have a better chance than I've had, is if they go to school and that they are able to think in school because they are not hungry. I love my children."

Obviously we found this very revealing and upsetting. Think about this kind of decision-making, day in and day out. I don't know about your lives, but I have been very lucky, and I've never had to make any decisions like these. In sum, when you see the neglected breast problem story the way it is often portrayed, you wouldn't know of these possible explanations. Being poor places unbelievable decision burdens on people. The situation is as the Nobel Prize winner Amartya Sen has described it in studying behavior in disasters: under extreme duress poor people make astonishingly rational decisions.

A second example: women in low income countries with different ideas about what caused their breast cancers. We all have what the clinical psychologists call personal representations of illness and health. We have a constellation of events and information in our heads that leads us to a picture of where we are with health, what has caused our problems, and what is going on with us. Assuming that we are not schizophrenic and delusional, these representations of illness are usually mostly grounded in commonly known facts. My take on the poor women with unusual ideas about the causes of their breast cancers is the following: I bet if you talked to them, you would learn of some very cogent reasons and demonstrable facts that led to their representations of breast cancer. It isn't so simple that you could just show them some American literature and that would get them up to speed about our Western scientific picture of breast cancer causation.

My point is that we tend to view things through a privileged, and certainly Western, model of medicine, biology, culture, and health systems, but that's not the way things are in the rest of the world. There are other models. I think if we are going to be helpful and true scientists, then we need to approach things with considerably more respect for the possibilities of extraordinary differences in biology, and certainly huge differences in culture and health systems. In studying cancer in other populations, we can learn things that are very relevant for us. How do we view sickness? What is sickness? By studying people in other countries we can better understand for ourselves what sickness is, and certainly understanding health systems in other countries can help us understand and maybe improve our own health system. It is about these complexities that I think we need to better share with our colleagues who write about cancer.