National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
October 30, 2012 • Volume 9 / Number 21

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NEWS

Study Urges Caution on Source of Unrelated Donor Stem Cell Transplants

Transplant recipient Teresa Hurtado-Diaz and her donor Lydia Gonzalez (Courtesy of the National Marrow Donor Program) The first randomized trial comparing bone marrow and peripheral blood stem cells (PBSCs) as sources for hematopoietic stem cell transplants from unrelated donors suggests that caution may be needed when using PBSCs from unrelated donors to treat leukemia or related blood disorders. The results were published October 18 in the New England Journal of Medicine. Read more > >

COMMENTARY

Dr. Edward Trimble

Building Momentum: NCI's Center for Global Health

Dr. Ted Trimble, director of NCI's Center for Global Health, discusses how the new center will work to reduce the global burden of cancer. video icon

Dr. Loehrer and young orphan

A Conversation with Dr. Patrick Loehrer about Improving Cancer Care in Kenya

The director of the Indiana University Melvin and Bren Simon Cancer Center describes a collaborative effort to establish a cancer program and treatment center at the Moi University School of Medicine in Eldoret, Kenya.

IN DEPTH

UPDATES

  • Notes

    • In Memoriam: Dr. E. Donnall Thomas
    • Board of Scientific Advisors to Meet November 5
    • Cyber-Seminar: Adapting and Using Evidence-Based Programs with Community Partners

A MESSAGE TO READERS

Cancer Resources for Those Affected by Hurricane Sandy

Information is available to help cancer patients, physicians, and researchers who are in areas affected by recent storms.


Selected articles from past issues of the NCI Cancer Bulletin are available in Spanish.

The NCI Cancer Bulletin is produced by the National Cancer Institute (NCI), which was established in 1937. Through basic, clinical, and population-based biomedical research and training, NCI conducts and supports research that will lead to a future in which we can identify the environmental and genetic causes of cancer, prevent cancer before it starts, identify cancers that do develop at the earliest stage, eliminate cancers through innovative treatment interventions, and biologically control those cancers that we cannot eliminate so they become manageable, chronic diseases.

For more information about cancer, call 1-800-4-CANCER or visit http://www.cancer.gov.

NCI Cancer Bulletin staff can be reached at ncicancerbulletin@mail.nih.gov.

Featured Article

Study Urges Caution on Source of Unrelated Donor Stem Cell Transplants

Transplant recipient Teresa Hurtado-Diaz and her donor Lydia Gonzalez (Courtesy of the National Marrow Donor Program)Transplant recipient Teresa Hurtado-Diaz (left) of Windsor, CA, and her donor Lydia Gonzalez (right) of Beeville, TX. (Courtesy of the National Marrow Donor Program)

The first randomized trial comparing bone marrow and peripheral blood stem cells (PBSCs) as sources for hematopoietic stem cell transplants from unrelated donors suggests that caution may be needed when using PBSCs from unrelated donors to treat leukemia or related blood disorders. The results were published October 18 in the New England Journal of Medicine.

Use of PBSCs from related and unrelated donors has skyrocketed in the last decade, largely due to the preference of transplant doctors, explained Dr. Dennis Confer, chief medical officer of the National Marrow Donor Program and the study's senior author.

Currently, about three-quarters of all transplants from unrelated donors use PBSCs, as opposed to bone marrow. PBSC transplants engraft more rapidly than bone marrow but come with a potential downside: they contain large numbers of T cells, a type of immune cell that can trigger graft-versus-host disease (GVHD). In this condition, donor immune cells attack tissues and organs in the recipient's body.

In clinical trials comparing outcomes in patients transplanted with PBSCs or bone marrow from related donors, the incidence of GVHD was sometimes higher with PBSCs than with bone marrow but not enough to deter their use. But the incidence of GVHD is higher with transplants from unrelated donors than with those from related donors, and until now no large trial had directly compared the safety and effectiveness of the two stem-cell sources from unrelated donors.

"We had multiple trials [of bone marrow versus PBSCs] in the related-donor setting that were randomized, international, had large numbers [of patients], and had very conclusive results, and we made the jump to the unrelated setting without having any of that knowledge," explained Dr. Stephanie Lee, a transplant doctor and GVHD researcher at Fred Hutchinson Cancer Research Center and a co-author of the study. "It wasn't a huge leap, but we didn't have any randomized trial data about the risks and benefits of one source versus another in that particular setting."

Tradeoffs between Graft Sources

The researchers, led by Dr. Claudio Anasetti of the H. Lee Moffitt Cancer Center, enrolled 551 patients in the randomized trial. All had high-risk leukemia or a chronic myeloid disorder and an unrelated stem cell donor. The patients were randomly assigned to receive either PBSCs or bone marrow stem cells. Ninety percent of the patients received a transplant of the graft source to which they were randomly assigned. The primary endpoint of the trial was overall survival at 2 years.

Instead of being the default choice for most unrelated-donor transplants, mobilized peripheral blood stem cells should be used in only the minority of patients for whom the benefits outweigh the risks.

—Dr. Frederick R. Appelbaum

Two years after transplantation, 51 percent of the patients who received peripheral blood stem cells were alive, compared with 46 percent of patients who received bone marrow stem cells. This difference was not statistically significant, meaning that it could not be ruled out as being caused by chance alone. Rates of relapse also did not differ between the two groups.

Additional analyses, however, showed that other outcomes did differ. Fewer patients who received peripheral blood stem cells experienced graft failure, in which the donor cells die and fail to form new blood cells for the patient, than those who received bone marrow (3 percent versus 9 percent). Eleven patients who received bone marrow died from graft failure, compared with none of those who received PBSCs.

However, substantially more patients who received peripheral blood stem cells developed chronic GVHD within 2 years after transplant than those who received bone marrow (53 percent versus 41 percent). Thirty patients who received peripheral blood stem cells died of chronic GVHD versus 14 who received bone marrow.

Of the patients alive after 2 years, more of those who received peripheral blood stem cells needed to take drugs to suppress the immune system due to GVHD than those who received bone marrow (57 percent versus 37 percent).

Causes of Death over Two Years of Follow-Up*

 Peripheral Blood Stem CellsBone Marrow
%No. of Patients  %  No. of Patients
Disease relapse  48695073
Graft failurenonenone811
Acute GVHD**17241420
Chronic GVHD21301014
Other causes10141014

*290 out of the 513 patients who received their randomly assigned transplants died during the first 2 years after treatment
**GVHD occurring in the first few months after transplant

"It is…possible that increased mortality from chronic GVHD among recipients of peripheral blood stem cells from unrelated donors offsets the benefits associated with the more rapid and robust engraftment that occurs with peripheral blood stem cells, as compared with bone marrow," wrote the authors.

Different Risk Factors, Different Sources

The researchers suggest that specific characteristics of individual patients may guide the use of one stem cell source over another. For example, patients at high risk of graft failure may benefit from PBSCs, and bone marrow would likely be recommended for other patients, especially those whose immune systems are already suppressed due to prior chemotherapy and who consequently have a lower risk of graft rejection.

As prophylaxis and treatment for GVHD improve, peripheral blood stem cells will likely remain favored over bone marrow.

—Dr. Richard Little

"[These] results provide data that should change current practice. Instead of being the default choice for most unrelated-donor transplants, mobilized peripheral blood stem cells should be used in only the minority of patients for whom the benefits outweigh the risks," wrote Dr. Frederick R. Appelbaum of the Fred Hutchinson Cancer Research Center in an accompanying editorial.

Dr. Richard Little, an investigator with NCI's Cancer Therapy Evaluation Program, agreed, with one caveat: "As prophylaxis and treatment for GVHD improve, peripheral blood stem cells will likely remain favored over bone marrow," he said.

GVHD treatment and prevention is not the only "moving target" in transplantation research, added Dr. Lee. People are also experimenting with different sources of donor cells and with reduced-intensity conditioning regimens, which do not completely kill the host's immune system before transplant, she explained. "Transplant [research] is moving so quickly, it's kind of hard to come up with a result that's then applicable for many, many years afterwards."

And, although the researchers expressed concern that donor preference is helping to drive the choice of stem-cell source, Dr. Confer doesn't see that as a major deciding factor. "The donors are very altruistic, and they're very interested in helping the patients they're matched with. If the transplant doctor asks for bone marrow or peripheral blood stem cells, the vast majority of donors will do whatever that doctor thinks is best for the patient," he concluded.

Sharon Reynolds

This research was supported in part by a grant from the National Institutes of Health (U10HL069294).

National Marrow Donor Program

The first hematopoietic stem cell transplantation from an unrelated donor to treat leukemia was performed in 1979. Since then, rapid improvements in the technique and burgeoning databases of people willing to donate life-saving stem cells to strangers have led to thousands of transplants from unrelated donors being performed each year in the United States alone.

The National Marrow Donor Program, a nonprofit organization in the United States, operates the world's largest database of cord blood donors and potential marrow donors and has facilitated more than 50,000 transplants over the last 25 years. But more volunteers are always needed.

Currently, the registry has a particular need for younger donors (ages 18 to 44) and donors from underrepresented racial groups, such as African Americans, Asians, and Native Americans.

More information on how to be a stem-cell donor can be found online .

Cancer Research Highlights

Study Looks at Terminal Cancer Patients' Expectations of Chemotherapy

A majority of patients who opt to receive chemotherapy to treat newly diagnosed metastatic lung or colorectal cancer believe chemotherapy might cure their cancer, according to a recent survey. The survey results suggest that optimistic assumptions about the benefits of chemotherapy may hamper patients’ abilities to make informed treatment decisions that align with their preferences, said the researchers who led the study. The findings were published October 25 in the New England Journal of Medicine.

Dr. Jane Weeks of the Dana-Farber Cancer Institute and her colleagues interviewed 1,193 patients tracked by the prospective, observational Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) study, 4 to 7 months after diagnosis. All of the patients had been diagnosed with stage IV lung or colorectal cancer and had chosen to receive chemotherapy. A surrogate was interviewed when a patient was too ill to participate. The survey asked patients how likely it was that chemotherapy would cure their disease, extend life, or relieve symptoms. The researchers also collected data on patients’ physical functioning, communication with their physicians, and social and demographic factors.

The majority of patients did not appear to understand that chemotherapy was very unlikely to cure their cancer (81 percent of those with colorectal cancer and 69 percent of those with lung cancer). Black, Hispanic, and Asian/Pacific Islander patients were more likely than white patients to believe that chemotherapy would cure them. Nevertheless, most patients believed that chemotherapy was more likely to extend their life than cure them.

Educational level, functional status, and the patient’s role in treatment decision making were not associated with inaccurate expectations about chemotherapy.

In an accompanying editorial, Drs. Thomas J. Smith of the Johns Hopkins Sidney Kimmel Cancer Center and Dan L. Longo of the National Institute on Aging wrote, “if patients actually have unrealistic expectations of a cure from a therapy that is administered with palliative intent, we have a serious problem of miscommunication that we need to address.”

This research was supported by grants from the National Institutes of Health (U01 CA093344, U01 CA093332, U01CA093324, U01 CA093348, U01 CA093329, U01 CA093339, and U01 CA093326).

Imatinib May Help Treat Aggressive Lymphoma

Based on the results of a new study, researchers are developing a clinical trial to test imatinib (Gleevec) in patients with anaplastic large cell lymphoma (ALCL), an aggressive type of non-Hodgkin lymphoma that primarily affects children and young adults.

The researchers found that a protein called PDGFRB is important to the development of a common form of ALCL. PDGFRB, a growth factor receptor protein, is a target of imatinib. Imatinib had anticancer effects in both a mouse model of ALCL and a patient with the disease, Dr. Lukas Kenner of the Medical University of Vienna in Austria and his colleagues reported October 14 in Nature Medicine.

The authors decided to investigate the effect of imatinib after finding a link between PDGFRB and a genetic abnormality that is found in many patients with ALCL. Previous work had shown that this genetic change—a translocation that leads to the production of an abnormal fusion protein called NPM-ALK—stimulates the production of two proteins, transcription factors called JUN and JUNB.

In the new study, experiments in mice revealed that these proteins promote lymphoma development by increasing the levels of PDGFRB.

Because imatinib inhibits PDGFRB, the authors tested the effect of the drug in mice with the NPM-ALK change and found that it improved their survival. They also found that imatinib given together with the ALK inhibitor crizotinib (Xalkori) greatly reduced the growth of NPM-ALK-positive lymphoma cells in mice.

To test the treatment strategy in people, they identified a terminally ill patient with NPM-ALK-positive ALCL who had no other treatment options and agreed to try imatinib. The patient began to improve within 10 days of starting the therapy and has been free of the disease for 22 months, the authors reported.

The observation that inhibiting both ALK and PDGFRB “reduces lymphoma growth and alleviates relapse rates” led the authors to suggest that the findings might be relevant to lymphomas with PDGFRB but without the NPM-ALK protein. “Our findings suggest that imatinib is a potential therapeutic option for patients with crizotinib-resistant lymphomas.”

A planned clinical trial will be based on the expression of PDGFRB in tumors.

Researchers Identify Possible Biomarker for Early-Stage Lung Cancer

A protein that can be detected in blood samples may one day serve as a biomarker for early-stage lung cancer, according to new study results. The findings, published October 16 in the Proceedings of the National Academy of Sciences, suggest that measuring the levels of a variant form of the protein Ciz1 may help detect lung cancer early and noninvasively in high-risk individuals.

“We have struggled to find cancer biomarkers that are disease-specific, and this may be a step in the right direction,” said Dr. Sudhir Srivastava, chief of NCI’s Cancer Biomarkers Research Group. He called the study “promising” but noted that the results will need further validation.

Researchers led by Dr. Dawn Coverley of the University of York in the United Kingdom found that the “b-variant” form of Ciz1 was present in 34 of 35 lung tumors but not in adjacent tissue. Additional experiments showed that an antibody specific for this Ciz1 variant could detect the protein in small samples of blood from individuals with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

In two independent sets of blood samples—from 170 and 160 patients, respectively—the researchers showed that variant Ciz1 levels above a certain threshold correctly identified 95 to 98 percent of lung cancer patients, with an overall specificity of 71 to 75 percent. Using the second set of samples, they showed that the level of variant Ciz1 could discriminate between patients with stage I NSCLC and age-matched heavy smokers without diagnosed cancer, individuals with benign lung nodules, and patients with inflammatory lung disease.

Although the high rate of false-positive test results seen with variant Ciz1 is a concern, the authors noted that a blood test for the Ciz1 variant might ultimately be shown to be useful when combined with low-dose helical computed tomography, also called spiral CT, for lung cancer screening. In that context, the test could confirm the presence of lung cancer in patients who have suspicious spiral CT results, reducing the need for invasive procedures to confirm a lung cancer diagnosis. And, if used before spiral CT, “the test could reduce the number of people who undergo imaging…[because] the false-negative rate is very low,” Dr. Coverley wrote in an e-mail message.

To assess variant Ciz1 levels, the researchers used a laboratory method known as Western blot analysis. However, this approach could not be routinely applied in a clinical context, the researchers acknowledged, so “a more streamlined method” for testing would need to be developed.

Supported in part by NCI Early Detection Research Network Grant U01CA086137.

In Mice, Combining Cancer Vaccine and Low-Dose Antiangiogenesis Drug Shows Promise against Breast Cancer

A combination of a therapeutic cancer vaccine and low doses of a drug that blocks tumor blood vessel growth (an angiogenesis inhibitor) may be an effective treatment for breast cancer, according to a study in mice.

In two different mouse models of breast cancer, the combination treatment shrank tumors more than either treatment alone, and in one model it also improved survival.

Dr. Rakesh Jain and his colleagues from Massachusetts General Hospital and Harvard Medical School published the findings October 8 in the Proceedings of the National Academy of Sciences.

Evidence from both human and animal studies has suggested that lower doses of angiogenesis inhibitors can “normalize” tumor blood vessels, making them less leaky and more functional—an effect that could improve the delivery of other therapies. And several recent studies suggest that abnormal tumor vasculature “fosters an immunosuppressive [tumor] microenvironment” that may help tumors evade detection or attack by the immune system, the researchers wrote. If so, they continued, normalizing the vasculature could improve vaccine efficacy.

They tested low and high doses of the angiogenesis inhibitor DC101 alone or in combination with a therapeutic vaccine in different mouse models of breast cancer. Based on previous research, they explained, “the schedule of combination treatment…was designed to synchronize vascular normalization and T-cell activation [by the vaccine].”

The researchers also looked for clues that could explain why the combination of the vaccine and low-dose angiogenesis inhibitor was more effective. Compared with blood vessels in mice that received higher doses of DC101 and the vaccine, they found that those in mice treated with lower doses of DC101 and the vaccine were more stable and more evenly distributed throughout the tumor. This appeared to increase the infiltration of immune cells into the tumor following vaccination and to encourage a stronger immune response to the tumor.

According to Dr. James Gulley of NCI’s Center for Cancer Research (CCR), the study findings are consistent with recent research conducted by Dr. Benedetto Farsaci in CCR’s Laboratory of Tumor Immunology and Biology involving a therapeutic cancer vaccine in combination with sunitinib (Sutent).

Clinical trials to test a therapeutic vaccine with low doses of an angiogenesis inhibitor in women with breast cancer are in the early planning stages, Dr. Jain said.

Supported in part by the National Institutes of Health (R01-CA115767, R01-CA126642 , R01-CA096915, R21-CA139168, and R01-CA159258).

Guest Commentary by Dr. Edward Trimble

Building Momentum: NCI's Center for Global Health

Global Health icon
Dr. Edward Trimble Dr. Edward Trimble

“There were two oncologists for 30 million people in Uganda and four oncologists for 87 million in Ethiopia.”

That’s how Dr. Kenneth Miller, an oncologist from Maryland, described what he encountered during several volunteer trips to these countries to help treat patients and train a new generation of oncology care professionals.

For those of us who live in the United States and other developed countries, these statistics are shocking. Our conversations about cancer often focus on new therapies that can target a tumor’s underlying molecular drivers or advances in survivorship that are allowing those affected by cancer to live longer, healthier lives—not on whether there is a trained oncologist available to treat a patient’s disease.

With cancer incidence and death rates climbing rapidly in the developing world—by 2030, it is estimated that of the more than 20 million global cancer deaths, nearly two-thirds will occur in these countries—this is serious cause for concern.

Soon after arriving at NCI, Director Dr. Harold Varmus announced that improving global cancer health was among his top priorities, and he formed NCI’s Center for Global Health (CGH) to better coordinate and expand the institute’s global research activities.

Despite tight budgets, Dr. Varmus and I agree that the opportunity and the obligation to address the global burden of cancer have never been greater. Our efforts can build on the strong foundation created by the success in combating infectious diseases like malaria and AIDS.

Since CGH was formed, a number of important activities have taken place, including a stakeholder meeting in March that included approximately 150 participants. That was followed by a strategic planning process to define CGH’s mission, vision, and, most important, its priorities.

The priorities, which reflect consistent themes from feedback NCI has received, include

  • Supporting research that can have the largest impact on the global burden of cancer
  • Leveraging partnerships to optimize NCI’s investments
  • Monitoring research efforts to help spur the translation of  results into practice and policy
  • Catalyzing training, information dissemination, capacity building, and cancer control

To be certain, there is no shortage of cancer-related problems that require further research. For example, the east coast of Africa, from South Africa to Somalia, has a strikingly high incidence of esophageal cancer, while Chile has the highest rate of gallbladder cancer of any country in the world. NCI can work with researchers in those countries to better understand why those cancers are so prevalent there by collaborating on epidemiologic and molecular biology studies and developing clinical trials to test new prevention and treatment interventions.

Conducting and supporting cancer control and treatment research outside of the United States is nothing new to NCI. The institute has longstanding programs and research collaborations in places such as the Middle East, China, and, more recently, Latin America. Through CGH, we will build on these efforts.

One of the things we have heard repeatedly, for example, is the need to develop global cancer research career tracks at universities in the United States. And we’re working across NCI to develop proposals for a variety of research projects that can influence care beyond our borders, including expanding clinical trials run by NCI-funded cooperative groups to include more sites outside the United States. As we learn more about the molecular biology of different cancers, we have realized that we need to cast a global net to accrue patients to important scientific studies quickly.

Given tight budgets, leveraging existing partnerships and establishing new ones will be essential to expanding our global research efforts. We will work with U.S. Department of Health and Human Services agencies, like other NIH institutes and the Centers for Disease Control and Prevention, the U.S. President’s Emergency Plan for AIDS Relief, the U.S. Agency for International Development, organizations such as the American Society of Clinical Oncology and the Union for International Cancer Control, and universities in the United States and abroad.

As Dr. Miller’s observation about Uganda and Ethiopia demonstrates, there is a desperate need in many countries to build both human and physical capacity. Noted economist Dr. Jeffrey Sachs of Columbia University stressed at the CGH stakeholders meeting that hundreds of millions of people in developing countries are still “not covered even by a rudimentary primary health system.”

Simply put, our collective task is large. Education and training are needed to boost the numbers of oncology professionals, and infrastructure and systems for screening and treatment must be established. Several U.S. cancer centers are already doing excellent work in this area, and through CGH we hope to build on their successes. (See “A Conversation with Dr. Patrick Loehrer” in this issue.)

One way in which we can do that is to take advantage of tremendous advances in information technology, which have the potential to revolutionize cancer control and care in many low-income countries. For example, smartphones and other technologies could be used to enhance access to pathology resources to help diagnose diseases and guide treatment, as well as to monitor patients who live long distances from a treatment center.

By its very nature, global health research is complicated. It requires partners on the ground; cooperation with national and local governments; and training of clinicians, nurses, data managers, and others involved in day-to-day research activities. No two countries’ health or research systems are alike. To be successful, we will need to be creative, nimble, and flexible.

Much work remains to be done to improve cancer care around the world, and we believe this is the right time to expand NCI’s efforts in the global health arena. What we learn in the process will not only ease the cancer burden in developing countries but also enhance our understanding of this complex array of diseases, ultimately benefiting people around the globe, including right here at home.

Dr. Ted Trimble
Director
NCI Center for Global Health

 

A Conversation With

A Conversation with Dr. Patrick Loehrer about Improving Cancer Care in Kenya

Dr. Loehrer and young orphanDr. Loehrer and young orphan at the clinic. Indiana University is helping to set up and train staff for a cancer center in Eldoret, Kenya.

A number of U.S. cancer centers have programs and initiatives to help improve cancer control and care in developing countries. For more than 20 years, the Indiana University (IU) School of Medicine, in collaboration with the Moi University School of Medicine in Eldoret in western Kenya, has led an initiative called AMPATH (Academic Model for Providing Access to Healthcare) to improve access to and the quality of health care in Kenya.

Leaders from Indiana University’s Melvin and Bren Simon Cancer Center have built upon those efforts and are establishing a cancer program and treatment center at Moi. Dr. Patrick Loehrer, director of the Simon Cancer Center, talked with the NCI Cancer Bulletin about the effort and the center’s future plans in Kenya.

How did this effort begin and where do things stand?

Global Health icon

The model for what we’ve done is the work under AMPATH to stem the tide of the HIV epidemic in Kenya. As progress has been made in that area, other chronic diseases have emerged as priorities. Of these, cancer is one of the leading causes of concern. So we’ve been trying to build a cancer program there for the last 8 years.

Initially, we needed to build a platform for training, build the workforce, and provide the essential tools to treat patients. We received a grant from the Frank Levinson Family Foundation, which provided initial funding to treat patients with chemotherapy, and we have received generous help from the Walther Cancer Foundation, the Indiana Hemophilia and Thrombosis Center, Celgene, Lilly, and Pfizer to expand the workforce, as well as to help cover the cost of treatment for those who can’t afford it.

Over the last 2 years, we’ve been focused on building an outpatient facility capable of housing a radiation program and infusion therapy. We have received generous support from IU, its Department of Radiation Oncology, and others to initiate this process and now have an architect on the ground [in Eldoret]. We plan to build a chronic care facility, with much of the first floor used for providing chemotherapy and radiation treatments. We hope to have help from the International Atomic Energy Agency to secure a cobalt unit [for radiation therapy]. 

Additionally, we have partnered with the University of Toronto, Brown University, Vrije University (Amsterdam), and the University of Massachusetts, which have been very helpful in education and training, particularly with gynecology-oncology and medical and pediatric oncology.

What is access to cancer care like in that region of Kenya?

Patient receiving chemotherapy at the cancer clinic in Eldoret, Kenya.Patient receiving chemotherapy at the cancer clinic in Eldoret, Kenya.

By some estimates there are 20 million people in western Kenya. Before we arrived, there were no formally trained medical oncologists, with radiation therapy only available in Nairobi, 4.5 hours away. When we first started in Eldoret, there were two internists—neither of whom was formally trained in oncology—taking care of cancer patients. They would use whatever chemotherapy drugs they could find to treat patients. Often there was uncertainty about patients’ diagnoses and inadequate supplies, which made for some very poor outcomes.

We now have a Kenyan care team led by Dr. Naftali Busakhala, director of oncology at [the Moi Teaching and Referral Hospital (MTRH)], and Drs. Festus Njuguna and Evangeline Njiru. Three years ago, Dr. Matthew Strother joined the faculty at Indiana University, and he spent the first 2 years on the ground in Eldoret with his wife and four children. He really helped to build the program and provide structure.

In January of this year, another fellow joined the IU faculty in Eldoret, Dr. Chite Aswira. Dr. Asirwa was born and raised in Kenya but completed his Internal Medicine residency and Hematology-Oncology fellowship at IU. He’s arguably one of the best trained oncologists in the country, and he is now back in his hometown, leading the program with Dr. Busakhala. He is also joined by one of our new Pediatric Oncology staff, Jodi Skiles, who spends 6 months a year at the AMPATH-Oncology Program. 

The IU and Toronto Obstetrics-Gynecology programs have similarly invested in full-time faculty at MTRH, which has lead to a remarkable growth in capacity for treatment and screening for gynecologic malignancies through their Kenyan partners.

Are you starting to see progress?

We’re up to 9,000 patient visits a year now in Medical Oncology clinics. Three years ago, virtually no women in that part of the country were screened for cervical cancer. Now we’re screening over 8,000 women annually for cervical cancer, and between 8,000 and 9,000 women for breast cancer. We also have a palliative care team that sees 6,000 patients a year.

We see a much wider variety of patients now than we originally did. Because of the HIV/AIDS epidemic, people with Kaposi sarcoma still make up a substantial proportion of the patients we treat. But we also see many women with cervical cancer, which is the number-one cause of cancer death among women in Kenya, as well as breast cancer, lymphoma, and head and neck cancer…. Many of the cancers we see are viral-induced malignancies, so vaccines could have a huge impact.

Transportation is a serious issue in Kenya, so AMPATH has a number of satellite sites. There are more than 50 outreach clinics in rural Kenya, and the cancer program uses about four of them. Eldoret is the third-largest city in Kenya. Because we’ve been providing medical care for needy patients, some patients have been coming up from Nairobi to get care, so our reputation is growing around the country.

So this is clearly a long-term commitment?

It’s been an extraordinary journey, but there’s a lot of work still to be done. We’re working with the Kenyan government to expand insurance coverage for cancer treatment. And the Kenyan Minister of Public Health sent us a memo recently saying that the government is very proud of the program and asking us to submit a budget [that would detail the cost of] running the cancer care program for a year.

What we are trying to build is a sustainable program, not just a research project. Still, we recognize that research is the academic glue that keeps this multi-institutional alliance together. AMPATH’s mantra is to “lead with care,” so our primary goal is to build a generation of Kenyan physician-scientists and health care workers who can adequately care for cancer patients and address the issues unique to sub-Saharan Africa. All the while, remembering that this is a Kenya-led program of which we are privileged to be a part.

Interviewed by Carmen Phillips

A Closer Look

Tackling the Complexity of Genes and Environments in Cancer

DNA sculpture by Miroslaw Stuzik (Photo by Tomasz Gasoir) DNA sculpture by Miroslaw Stuzik (Photo by Tomasz Gasoir)

With few exceptions, cancer and other common diseases are thought to be a result of genetic and nongenetic risk factors that may interact with one another. But studying these joint effects has been a challenge, largely because researchers lack the tools to identify and measure nongenetic risk factors, such as exposures to substances in the environment.

Nonetheless, many researchers believe that studying the interplay between genes and environmental exposures will be critical for understanding the biology of cancer and for preventing and treating the disease. This was the conclusion of a recent scientific meeting on gene-environment interactions hosted by the National Institutes of Health, to take one example.

“It’s tremendously important to understand the interplay between genes and environments,” said Dr. Muin Khoury, who directs the Office of Public Health Genomics at the Centers for Disease Control and Prevention (CDC). “If you can identify subgroups of individuals who are more susceptible to an environmental exposure than others, then you could develop targeted prevention strategies.”

Gene-environment interactions are worth studying for many reasons, added Dr. Duncan Thomas of the University of Southern California Norris Comprehensive Cancer Center, who has written about emerging approaches in the field. Investigating interactions can reveal important biological pathways in cancers and possibly point to new treatment strategies. “In principle, it should be possible to design a drug that exploits a gene-environment interaction,” said Dr. Thomas.

Better Evidence Needed

But at the moment many researchers are calling for more reliable data on interactions.

“Many gene-environment interactions in cancer have been proposed, but few interactions have rigorous support in the scientific literature,” said Dr. John Ioannidis, a professor of epidemiology at the Stanford School of Medicine. “This just means that there has been no systematic approach in the field until now.”

Large Studies, Reliable Data

Concerns about false positives in studies of gene-environment interactions are reminiscent of the early days of genome-wide association studies before the advent of very large, rigorous genome-wide association studies, noted Dr. Ioannidis.

“We need to move to an evaluation of gene-environment interaction on a massive scale,” he said. “And we need accurate reporting and careful grading of the evidence to overcome the ambiguity in the field.”

Dr. Khoury agreed. “To make progress, we need accurate information on longitudinal exposures and genomic data from large-scale epidemiology studies,” he said. “And that information is hard to come by.”

The concept of gene-environment interactions is not new, but there has been a resurgence of interest in them. One reason could be the wealth of new information on genetic risk factors. As several new studies suggest, this knowledge can be leveraged to gain insights into environmental risk factors and possible interactions.

“We believe these interactions could explain a lot of differences between groups in the risk of disease from environmental exposures,” said Dr. Deborah Winn, deputy director of NCI’s Division of Cancer Control and Population Sciences (DCCPS). “There may be people in specific populations who are susceptible. And by looking only at genes or at exposures, you are not going to explain as much as an interaction would.”

A traditional view of gene-environment interactions suggests that people with gene A may be susceptible to disease B after being exposed to something in the environment. But new statistical tools are needed to assess many “environmental” factors, including factors within the human body such as inflammation.

The development of these statistical tools is really in its infancy, noted Dr. Clarice Weinberg of the National Institute of Environmental Health Sciences, who stressed the importance of understanding the biological mechanisms that underlie interactions.

“If two risk factors are known to be related to cancer, then it becomes interesting to learn how they work jointly,” said Dr. Weinberg. “But, fundamentally, in order to advance public health we need to understand the biology and what these factors do.”

Searching for Interactions

The “true biology” of most cancers is going to be much more complicated than a single gene and a single environmental exposure, said Dr. Khoury, who is also affiliated with DCCPS, so “we need creative ways of looking at multiple gene-environment interactions.”

One strategy is illustrated by a new study of well-done meat consumption and the risk of colorectal polyps, which can be precursors for cancer. Meats cooked at high temperatures form chemicals that can damage DNA. Whether exposure to these chemicals poses a risk to people is unclear, but the new findings support the idea that some people, because of their genetic makeup, may be more at risk from these chemicals than others.

In the study, red meat appeared to be a stronger risk factor for colorectal polyps among people who carried certain genetic variants than among people who did not carry these variants, researchers at Vanderbilt-Ingram Cancer Center reported in the American Journal of Clinical Nutrition. But Dr. Wei Zheng, the study’s senior investigator, cautioned that the results need to be confirmed.

“This study is just not large enough to say clearly there is something going on and that people who carry more of these risk variants would benefit from changing their behavior any more or less than those with fewer risk variants,” commented Dr. Peter Kraft of the Harvard School of Public Health, who was not involved in the research.

Chemical mutagens in meats have been suspected of playing a role in colorectal cancer for years. What’s new about this study is that the authors developed a genetic “score” for each participant. The score was based on 16 genetic variants that have been linked to metabolizing heterocyclic amines (HCAs), which are chemical mutagens found in well-done meat.

To look for interactions, the study authors analyzed each participant’s genetic score along with information about the participant’s diet and history of colorectal polyps. “The study is a good example of the research that has been done over the past two decades on enzymes involved in metabolizing heterocyclic amines in red meat,” said Dr. Zheng.

Genes, Sodas, and Obesity

Another recent study used a genetic score to explore the effects of consuming sugar-sweetened beverages on the risk of obesity. For each participant, the researchers calculated a genetic predisposition score based on 32 DNA variants that researchers have linked to body-mass index.

Participants with certain genetic variants appeared to be more susceptible to the adverse effects of sugar-sweetened beverages on obesity, Dr. Qibin Qi of the Harvard School of Public Health and his colleagues reported in the New England Journal of Medicine.

We believe these interactions could explain a lot of differences between groups in the risk of disease from environmental exposures.

—Dr. Deborah Winn

This is “a clear example of gene-environment interaction,” Dr. Sonia Caprio of the Yale School of Medicine wrote in an accompanying editorial. She pointed out that the interaction was apparent only when multiple variants were used to calculate the genetic score.

“Putting multiple genetic variants together in these kinds of scores is both interesting and useful,” said Dr. Kraft. “It’s not a new idea to look for gene-environment interaction, but a decade ago we didn’t know what these gene variants were doing.”

Both studies emphasize the need for “better biomarkers that can assess environmental exposures,” added Dr. Thomas, who has studied chemical mutagens in meat but was not involved in either study. The tools don’t yet exist for accurately measuring most exposures either outside or inside the human body.

Tracking Exposures

The meat study also shows just how complicated interactions can be. Heterocyclic amines form when meat is cooked at high temperatures, but the chemicals are initially inert. It is only after HCAs are metabolized in the body that they become potentially harmful to DNA. At the same time, the body has proteins that detoxify these chemicals, rendering them harmless.

As Dr. Zheng and his colleagues reported, genetic variants associated with the metabolization and detoxification of HCAs may help determine a person’s internal exposure to these chemicals. “The body has ways of getting rid of the effects of these toxic exposures, and some of us are better at doing that than others,” explained Dr. Weinberg.

Similarly, some people's bodies are better at repairing damaged DNA than others, and this may be a piece of the HCA puzzle. As another recent study of HCAs and colorectal cancer concluded, researchers may need to evaluate a number of genetic pathways to gain insights into interactions.

“Our findings show that we need to look at multiple pathways—such as those involved in cell signaling and DNA repair—in addition to the HCA metabolizing pathways,” said Dr. Rashmi Sinha of NCI’s Division of Cancer Epidemiology and Genetics (DCEG), who led that study.

Along with expanding the number of pathways tested, future studies should also try to include data on exposures that take place over many years, if not a lifetime, several researchers said.

Environmental exposures tend to change over time, and little is known about which exposures matter most. Is it the average exposure over 10 years, or the peak exposure, or just the last 2 years? For most diseases, no one knows. Many researchers believe, however, that certain times in life, such as fetal development or adolescence, may be critical for some exposures.

“It gets complicated,” said Dr. Kraft. “These issues are solvable, but it’s going to take very large studies to solve them. The more complicated the data, the larger the study needs to be.”

Edward R. Winstead

Featured Clinical Trial

Safety of Stem Cell Transplants for HIV-Positive Cancer Patients

Name of the Trial
Allogeneic Hematopoietic Cell Transplant for Hematological Cancers and Myelodysplastic Syndromes in HIV-Infected Individuals (BMT-CTN-0903). See the protocol summary.

Drs. Joseph Alvarnas and Richard Ambinder Drs. Joseph Alvarnas and Richard Ambinder

Principal Investigators
Dr. Joseph Alvarnas and Dr. Richard Ambinder, Blood and Marrow Transplant Clinical Trials Network

Why This Trial Is Important
The transplantation of hematopoietic, or blood-forming, stem cells from a healthy donor, a procedure known as allogeneic stem cell transplantation, is one of the few treatments that may provide a cure for patients with some blood cancers (leukemias and lymphomas) and myelodysplastic syndromes (MDS).

People infected with HIV tend to develop the types of cancers that can be treated with allogeneic stem cell transplantation. Historically, they were not considered for this potentially curative therapy because HIV would threaten the immune cells produced by the transplanted stem cells and because HIV infection itself was considered a fatal condition. In recent years, however, HIV-targeted treatment with highly active antiretroviral therapy (HAART) has dramatically improved the lives and health of HIV-infected patients. In fact, HAART has improved the outlook for HIV patients so much that doctors are now investigating whether some HIV-infected cancer patients can be treated with allogeneic stem cell transplantation.

Allogeneic Hematopoietic Stem Cell Transplantation

In allogeneic transplantation, the patient first undergoes a conditioning regimen to wipe out or dramatically reduce the number of cancer cells in the body; conditioning also destroys or severely reduces the number of blood-forming stem cells in the bone marrow. Next, hematopoietic stem cells from a tissue-matched donor are infused into the patient's bloodstream, with the goal of repopulating the bone marrow and restoring its ability to produce blood cells, including red blood cells, platelets, and immune system cells. Although conditioning and allogeneic transplantation can successfully eradicate cancer in the recipient, the treatment is grueling, and treatment-related deaths do occur.

"Improved access to this potentially curative therapy may be possible for individuduals with HIV infection if the results of this clinical trial show the treatment can be safely performed," said Dr. Richard Little, head of Adult Hematologic Cancer Therapeutics for NCI's Division of Cancer Treatment and Diagnosis

In this clinical trial, HIV-positive patients receiving HAART who have a blood cancer or an MDS that may respond to the procedure will be treated with allogeneic stem cell transplantation. These cancers include acute myeloid or acute lymphoblastic leukemia in first or second remission, Hodgkin lymphoma or non-Hodgkin lymphoma beyond first remission that has responded at least partially to the most recent therapy, or an advanced MDS. The safety and feasibility of allogeneic transplantation in this patient population will be assessed using the primary endpoint of 100-day non-relapse mortality, that is, the number of patients who have died of causes other than relapse at 100 days after transplantation.

"In the past, HIV infection was on its own a fatal illness, so it didn't really make sense to subject patients to a very intensive therapy like stem cell transplantation when there was another illness that was imminently life threatening," said Dr. Ambinder. "Clearly, with effective antiretroviral therapy, that has dramatically changed. HIV infection is no longer immediately life threatening and may be more akin to other chronic conditions like diabetes; it requires some special attention but it shouldn't preclude people from having otherwise lifesaving treatment."

As part of this study, an effort will be made to try to identify stem cell donors who have a particular genetic mutation known as the delta 32 mutation in a gene called CCR5. The CCR5 protein is found on immune cells and is often exploited by HIV to infect the cells. In the delta 32 mutation, part of the CCR5 gene is deleted, and, in people with the deletion in both alleles of the gene (that is, a homozygous deletion), the mutation may confer innate resistance to HIV infection.

If a large number of matched donors can be identified for a given patient in this trial, the investigators will conduct further analysis to determine the CCR5 mutation status of those donors in hopes of finding one whose cells may be HIV resistant. "However, these donors are rare, so people considering this trial should do so because they have a cancer that requires treatment with allogeneic transplantation. There may be an added benefit, if such a donor can be found, that the progeny of the donated stem cells are more resistant to HIV, but this is not a trial to treat HIV infection," Dr. Ambinder explained.

For More Information
See the lists of eligibility criteria and trial contact information or call the NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). The toll-free call is confidential.

An archive of "Featured Clinical Trial" columns is available at http://www.cancer.gov/clinicaltrials/featured.

Notes

In Memoriam: Dr. E. Donnall Thomas

Dr. E. Donnall Thomas (Photo by Susie Fitzhugh) Dr. E. Donnall Thomas (Photo by Susie Fitzhugh)

Dr. E. Donnall Thomas, who received the 1990 Nobel Prize in Medicine for perfecting bone marrow transplantation, died October 20 in Seattle at the age of 92. The procedure is widely credited with saving the lives of many thousands of people with leukemia and other blood diseases.

When Dr. Thomas began his research in the 1950s, people with leukemia and other blood cancers had little hope of survival. Dr. Thomas; his wife and research partner, Dottie; and a small team of fellow researchers studied transplantation despite skepticism among many prominent physicians of the day.

In leukemia, blood stem cells that reside in the bone marrow turn cancerous. Chemotherapy treatments available in the 1950s could kill the cancerous cells but left patients without healthy stem cells to make new blood cells and rarely led to remission. Doctors could introduce new bone marrow from a donor, but in many cases the patient's body would reject the foreign marrow or the donor cells would attack the patient's own organs, a condition known as graft-versus-host disease.

In 1956, hoping to avoid such complications, Dr. Thomas conducted the first bone marrow transplant in a leukemia patient using donor cells from the patient's identical twin. And in September 1957, he published his seminal paper on bone marrow transplantation in the New England Journal of Medicine.

A major breakthrough came when Dr. Thomas showed that comprehensive human leukocyte antigen matching could make transplants viable for many more people, including those who are not closely related. He also found ways to counteract the graft-versus-host reaction and render bone marrow transplants safer.

Today, bone marrow transplants are standard treatment for leukemia. The procedure is also used to treat lymphoma, multiple myeloma, a number of autoimmune diseases, aplastic anemia, and myelofibrosis.

Dr. Thomas received his bachelor's and master's degrees in chemistry from the University of Texas at Austin. After graduating from the Harvard School of Medicine in 1946, he served for 2 years in the U.S. Army. In 1963, Dr. Thomas moved to Seattle to become the first chief of the oncology division at the University of Washington School of Medicine. In 1974, he became the first director of medical oncology at the Fred Hutchinson Cancer Research Center. He stepped down as director of the clinical research division in 1990 and retired in 2002.

Further reading:

Board of Scientific Advisors to Meet November 5

The NCI Board of Scientific Advisors will meet November 5 in Bethesda, MD. The board provides scientific advice on program policy, progress, and future directions for NCI's extramural research programs and concept review of extramural program initiatives.

In addition to a report from NCI Director Dr. Harold Varmus, attendees will hear presentations on the Frederick National Laboratory for Cancer Research, the Provocative Questions project, and The Cancer Genome Atlas. The meeting will also address proposed NCI organizational changes, NCI's Early Experimental Therapeutics Network, the Cooperative Human Tissue Network, and the Adult Brain Tumor Consortium.

The meeting is open to the public, and the full agenda is available online. The meeting will also be videocast.

Cyber-Seminar: Adapting and Using Evidence-Based Programs with Community Partners

Research to Reality banner

The November 13 NCI Research to Reality (R2R) cyber-seminar will highlight three R2R Mentorship Program projects that are working with community partners to adapt and implement evidence-based interventions.

Kiameesha Evans, program director at the Cancer Institute of New Jersey, is adapting a diet and nutrition program to include physical activity and is piloting the intervention with several faith-based organizations. Venice Haynes, program coordinator at the Morehouse School of Medicine, has partnered with a local foundation to adapt a cervical cancer awareness program for African American faith-based communities in Atlanta. Finally, Charlene Mitchell, an infection prevention practitioner at St. Luke's Medical Center in Idaho, adapted a sun-safety program for use at rural Idaho public pools.

Evans, Haynes, and Mitchell will share overviews of their projects, outcomes, and lessons learned about partnership, adaptation, and implementation relevant to other communities and researchers interested in these types of cancer control interventions.

To learn more about the R2R Mentorship Program, the projects, and to read the mentees' stories, visit the program's website.

For more information and to register, visit the R2R website, where you can join discussions. All R2R cyber-seminars are archived on the website about 1 week after the presentation. For more information on the cyber-seminar series, please e-mail ResearchtoReality@mail.nih.gov.