National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
March 10, 2009 • Volume 6 / Number 5

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BREAKING NEWS

Funding Ban Lifted on Human Stem Cell Research

Yesterday, President Barack Obama signed a Presidential Executive Order removing federal funding barriers to scientific research involving human embryonic stem cells. For background on stem cells and their potential impact on scientific research, please visit NIH’s stem cell information page.

NEWS

Ex vivo reconstructed skin model of melanoma. This skin sample contains melanoma cells without SOX9, which have formed invasive tumors. (Image courtesy of Drs. Thierry Passeron and Vincent Hearing.)

Potential New Target for Melanoma Treatment Identified

Melanoma skin cancers are notoriously resistant to chemotherapy and radiation therapy, and most patients have few treatment options once the cancer has spread to other parts of the body. Researchers have now identified a protein called SOX9 that both inhibits the proliferation of melanoma cells and makes them sensitive to the chemotherapy drug retinoic acid. These findings, published March 9 in the Journal of Clinical Investigation, suggest that SOX9 may be a promising new target for melanoma therapies. Read more > >

COMMENTARY

Dr. Robert Croyle

Guest Director's Update: Collaborative Initiative Will Tackle Obesity among Youth

By Dr. Robert Croyle

Convincing evidence has been found associating excess body fat and colorectal, pancreatic, esophageal, endometrial, postmenopausal breast, kidney, and thyroid cancers, as well as associating excess abdominal fat and colorectal cancer.

This is why NCI has signed on to be part of an ambitious new initiative that we believe can help improve the health of families in communities across the country. Dubbed the National Collaborative on Childhood Obesity Research (NCCOR), other partners in the initiative include four NIH institutes, divisions and offices in the CDC, and the Robert Wood Johnson Foundation. Read more > >

A MESSAGE TO READERS

More Information about the Recovery Act and Challenge Grants

NCI has created a Web site—http://www.cancer.gov/
recovery—in recognition of the cancer community’s interest in the American Recovery and Reinvestment Act of 2009. The site includes an overview of the legislation and will be updated regularly with NCI’s implementation plans and related announcements, including links to detailed information about the NIH Challenge Grants in Health and Science Research and recently posted funding opportunities. Updated information on NCI’s Recovery Act efforts will also be made available on HHS’ Recovery Web site. Your suggestions about NCI’s participation in meeting the Recovery Act goals are important, and we welcome your comments and suggestions.

IN DEPTH

UPDATES

  • Notes

    • New NCI Fellowship Honors Dr. Alan Rabson
    • NCI Lecture Series Features Dr. Michael Jung
    • Call for U.S.-Japan Workshop Proposals
    • BSA Meeting Held
    • First Lady of Senegal Visits NCI
    • New Orleans Community Clinical Programs Honored

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

Potential New Target for Melanoma Treatment Identified

An ex vivo reconstructed skin model of melanoma. The skin sample on the top contains melanoma cells without SOX9, which have formed invasive tumors. The skin sample on the bottom contains the same type of melanoma cells transfected with SOX9, which have not formed tumors. Both pictures were taken 10 days after cell transfer. (Images courtesy of Drs. Thierry Passeron and Vincent Hearing.) An ex vivo reconstructed skin model of melanoma. The skin sample on the top contains melanoma cells without SOX9, which have formed invasive tumors. The skin sample on the bottom contains the same type of melanoma cells transfected with SOX9, which have not formed tumors. Both pictures were taken 10 days after cell transfer. (Images courtesy of Drs. Thierry Passeron and Vincent Hearing.)

Melanoma, a type of cancer that usually begins in the melanocytes (the pigment cells) of the skin, is notoriously resistant to chemotherapy and radiation therapy, leaving few treatment options once the cancer has metastasized.

Researchers from the Laboratory of Cell Biology in NCI’s Center for Cancer Research have identified a protein called SOX9 that both inhibits melanoma cell proliferation and restores the sensitivity of melanoma cells to the chemotherapy drug retinoic acid. The research team believes that these results, published March 9 in the Journal of Clinical Investigation, highlight SOX9 as a promising new target for melanoma therapies, and work is already underway to identify SOX9-directed agents to bring to early human trials.

The researchers had previously examined how SOX9 affects melanocytes’ response to ultraviolet B exposure and found that the protein plays a role in increasing skin pigmentation. “We put two and two together and figured that if SOX9 helps regulate the pigmentation and growth of normal melanocytes, maybe we should look at melanoma cells and see whether or not the SOX9 function was decreased, and if so, whether we could increase it and slow the cells’ growth,” said senior author Dr. Vincent Hearing.

The researchers compared SOX9 expression in normal human skin cells, nevi (moles, some of which can develop into melanoma), primary melanoma samples, and samples from metastatic tumors. While SOX9 was found in all of the normal skin samples, the protein was weakly expressed or missing in most of the nevi, in more than 90 percent of the primary tumors, and in all of the metastatic tumors.

When the researchers used gene transfer to restore SOX9 expression to melanoma cells grown in culture, the protein caused cell cycle arrest—the cancerous cells stopped dividing. In an ex vivo model of skin tissue with melanoma, in which normal melanocytes were replaced with cancerous cells, the introduction of SOX9 into the melanoma cells prevented them from forming tumors. Melanoma cells without SOX9 were able to form invasive tumors in the same skin model. Similar results were found when melanoma cells were injected under the skin of mice (subcutaneously)—untreated melanoma cells formed large tumors in the mice, while melanoma cells transfected with SOX9 grew poorly or not at all.

The researchers then looked for a way to restore SOX9 function in melanoma cells without gene transfer, which is currently an extremely difficult technique to use as a cancer treatment. They found that treating melanoma cells with a substance found naturally in the body called prostaglandin D2 (PGD2) increased the expression of SOX9 in the cells.

Treatment with either PGD2 or PGD2 plus retinoic acid inhibited the proliferation of melanoma cells by 50 percent and 75 percent, respectively. A drug called BW245C, which has been tested in humans for diagnostic purposes, is known to increase PGD2 levels in the body. When BW245C and retinoic acid were administered to mice with subcutaneous melanomas, “the combination…induced marked and significant decreases in tumor size” compared to tumors in mice that did not receive the drugs, explained the authors.

Dr. Thierry Passeron, lead author of the study and a dermatologist and researcher at the University Hospital of Nice, France, is currently exploring the use of other compounds—most of which are already used in humans—that may upregulate SOX9 expression. “We want to find the optimal combination to decrease proliferation and potentiate the effect of retinoic acid derivatives,” he explained. Dr. Passeron hopes to begin phase I clinical trials of a chosen combination beginning in 2011.

—Sharon Reynolds

Cancer Research Highlights

Survival Benefit from Brain Cancer Regimen Persists over Time

Patients with brain cancer who received a combination of temozolomide (Temodar) and radiotherapy lived longer than those who received radiotherapy alone, and evidence of a benefit was seen in some patients for up to 5 years, according to updated results from a large clinical trial published online March 9 in The Lancet Oncology. The researchers cautioned, however, that most patients who were successfully treated with the combination therapy eventually had a recurrence and died.

In 2004, European and Canadian researchers first reported a survival benefit for patients in the EORTC-NCIC trial who received the combination therapy compared with patients who received radiation alone. Though the improvement was modest (several months), it was the first treatment advance in decades for the deadly disease. Consequently the regimen of temozolomide plus radiation became a standard treatment for glioblastoma.

The newly updated results show that at 3 years, 16 percent of patients in the temozolomide group were alive compared with only 4 percent in the radiation-alone group. At 4 years, 12 percent were alive after treatment with temozolomide compared with 3 percent for radiation therapy alone, and at 5 years, 9.8 percent were alive versus 1.9 percent, respectively.

Improvements in survival were seen in patients from all prognostic subgroups, including older patients and those whose tumors could not be removed by surgery. Among patients with more favorable prognoses, 41 percent were alive at 2 years and 28 percent at 5 years. The strongest predictor for a benefit from temozolomide was the inactivation of a gene called MGMT.

New treatments for the disease are needed, and several trials are investigating the addition of other treatments to temozolomide and radiotherapy, the researchers noted. “Until better treatments are available, radiotherapy with concomitant and adjuvant chemotherapy is the current standard of care,” they wrote.

Study Suggests Low, Moderate Alcohol Use Increases Cancer Risk

According to a new study by British researchers, low to moderate alcohol consumption among women increases their risk for numerous cancers but also appears to reduce the risk of some other cancers. The study was published online February 24 in the Journal of the National Cancer Institute.

For those cancers associated with an increased risk—breast cancer, for example, a finding that is consistent with other studies—it made no difference what type of alcohol was most frequently consumed or whether women had received hormone replacement therapy, the researchers found. However, for cancers of the upper aerodigestive tract (oral cavity, esophagus, larynx, and pharynx) the increased risk associated with alcohol intake was seen only in women who were also current smokers. The incidence of rectal and liver cancers also increased with alcohol use, while thyroid cancer, renal cell carcinoma, and non-Hodgkin lymphoma decreased.

“Although the magnitude of the excess abso­lute risk associated with one additional drink per day may appear small for some cancer sites, the high prevalence of moderate alco­hol drinking among women in many populations means that the proportion of cancers attributable to alcohol is an important public health issue,” lead author Dr. Naomi Allen from the University of Oxford and her colleagues concluded.

Their analysis involved data from nearly 1.3 million participants in the Million Women Study, which included women in the United Kingdom recruited from national breast cancer screening clinics between 1996 and 2001. Women in the study who reported drinking had an average of one drink per day, and approximately 25 percent of participants were nondrinkers.

What is not known at this point, explained Dr. Arthur Schatzkin, chief of the Nutritional Epidemiology Branch in NCI’s Division of Cancer Epidemiology and Genetics, is whether for certain women there is a trade-off in possible benefits of alcohol consumption, such as a decreased risk of cardiovascular disease, as numerous epidemiologic studies have suggested. However, it’s clear, he said, that for certain cancers, particularly of the breast, “alcohol consumption, even at moderate levels, is a modifiable risk factor.”

NCI is planning to use data from the NIH-AARP Diet and Health Study to investigate overall disease risks and benefits from low to moderate alcohol consumption, Dr. Schatzkin noted.

Chemoradiotherapy for Hodgkin Lymphoma Raises Mesothelioma Risk

The primary risk factor for malignant mesothelioma is exposure to asbestos. However, new results published online February 20 in Blood add to the evidence that radiotherapy, especially to the chest, also increases the risk. This study of long-term Hodgkin lymphoma (HL) survivors found that the risk was greatest in radiation patients who had also received chemotherapy.

A group of 2,567 patients treated for HL in the Netherlands between 1965 and 1995 were followed for a median of 18.1 years. While only eight men and five women developed mesothelioma, this rate was 25.7 times that found in the general population. Risk in women was dramatically greater (85 times the general population rate) than in men (18 times the general population rate).

The researchers also analyzed the risk according to the type of treatment the patients originally received for HL. Mesothelioma developed in only 1 of the 730 who received radiation alone (a 5.8 fold increase over the general population), and in none of the 232 patients who received chemotherapy alone. The remaining 12 patients received both treatments, and their chances of getting the disease were 44.8 times that of the general population. In all cases but one, the mesothelioma tumors developed in the field that had been irradiated during HL treatment.

Only seven of the patients had a documented history of asbestos exposure. Historically in the Netherlands, only about one in seven malignant mesothelioma patients have no history of exposure. Thus, said Dr. Marie L. De Bruin of the Netherlands Cancer Institute, “the diagnosis mesothelioma should be kept in mind whenever new symptoms arise in patients who had previous irradiation.”

Links between Genes and Smoking Confirmed

Early evidence that genes may influence a person’s use of tobacco came years ago from studies of twins. More recently, genome-wide association studies (GWAS) have explored links between genes and aspects of smoking behavior, such as the age of initiation and the amount of cigarettes smoked per day.

Building on this work, researchers have now tested associations between genes and seven key events across the spectrum of smoking behavior, from initiation through the development of dependency and health outcomes. DNA from 4,600 individuals, including 2,600 smokers, was analyzed using genome-wide and candidate gene approaches. For the candidate genes, several hundred previously identified genes suspected of playing a role were specifically evaluated.

The results confirm previous reports implicating nicotine receptor genes and genes involved in the dopamine system in the brain. In particular, a gene called MAOA, which helps break down dopamine, was strongly associated with the number of cigarettes smoked per day.

No specific chromosome regions achieved the genome-wide threshold of statistical significance, but the study provides a list of priority genes for further investigation. Reporting their findings online in PLoS One on February 27, Dr. Neil Caporaso of NCI’s Division of Cancer Epidemiology and Genetics and his colleagues said that the lack of genome-wide significant results suggests that common variants individually have at most a modest influence on smoking behavior.

“This was the first such study to look at a variety of smoking behaviors,” said Dr. Caporaso. “By identifying genes involved in smoking, we hope to develop more effective prevention and treatment strategies.” Two drugs used to help smokers quit, bupropion and varenicline, are likely to interact with targets related to genes that are associated with smoking behavior, he noted.

Guest Director's Update

Collaborative Initiative Will Tackle Obesity among Youth

Dr. Robert Croyle

By Dr. Robert T. Croyle
Director, NCI Division of Cancer Control and Population Sciences

“We’re fighting a losing battle,” a pediatrician in Watsonville, CA, recently told the Santa Cruz Sentinel. Her blunt statement reflects a startling reality: Nearly 1 in 3 children aged 8 and younger in the city are obese. Another 23 percent are overweight. The majority of the children in Watsonville—which, ironically, is in the heart of one of the most prolific vegetable and fruit growing regions of California—are Hispanic.

Situations like this one are sad and, unfortunately, not uncommon. Nationally, about 1 in 5 Mexican American boys and girls aged 12 to 19 are obese. Among African American girls in the same age group, more than 1 in 4 are obese.

Today, 12 million children and adolescents in the United States are obese and another 11 million are overweight. And studies have demonstrated that these kids have a strong likelihood of maintaining that weight status as adults. That translates into a huge population that is at significantly elevated risk for adverse health outcomes in the short and long terms, including asthma, diabetes, heart disease, and, as a number of studies have now shown, cancer.

Convincing evidence has been found associating excess body fat and colorectal, pancreatic, esophageal, endometrial, postmenopausal breast, kidney, and thyroid cancers, as well as associating excess abdominal fat and colorectal cancer.

This is why NCI has signed on to be part of an ambitious new initiative that we believe can help improve the health of the families and communities in places like Watsonville. It is called the National Collaborative on Childhood Obesity Research (NCCOR), and its other partners in the initiative include four NIH institutes, divisions and offices in the CDC, and the Robert Wood Johnson Foundation.

I don’t use the term “ambitious” lightly. At its core, NCCOR is intended to reverse the significant increases in adolescent and teen obesity over the last 3 decades (see graphic), and to witness results in years, not decades. And NCCOR is not designed to be a one-trick pony. Because, although there will be an emphasis on communities and populations where the obesity crisis is most severe, NCCOR is intended to be a long-term effort to create sustainable, population-wide change.

A bar graph showing the prevalence of obesity among U.S. children and adolescents aged 2-19 years. (Graph courtesy of the CDC.) Prevalence of obesity among U.S. children and adolescents aged 2-19 years (Graph courtesy of the CDC.)

One of the key tactics the NCCOR initiative will employ is to identify and help implement strategies that studies have shown are effective and that can be replicated across broad populations. Special emphasis will be put on those interventions that can influence multiple aspects of the “energy imbalance” that leads to obesity, simultaneously influencing what and how people eat and their activity levels. Such interventions often don’t just focus on the individual, but—much like the idea of developing new anticancer therapies that target the tumor “microenvironment”—alter local environments, whether that’s at school, in the home, or in the types of programs and services offered by local and state agencies.

One such example is the Trial of Activity for Adolescent Girls (TAAG), a national study funded by the National Heart, Lung, and Blood Institute aimed at improving physical activity. The rationale behind TAAG is strong: Physical activity levels have dropped precipitously among adolescents and teens, particularly teen girls. TAAG is designed to develop and test school- and community-based interventions that get girls more involved in gym class, organized sports, or recreational play, for example.

In addition to identifying and implementing successful strategies for combating obesity, the NCCOR initiative will help develop the capacity for greater obesity-related research and surveillance, and also establish more effective means of translating that research into practice and evaluating our efforts.

Achieving these goals will not be easy. But it’s something we can no longer afford to ignore. This holds true from a public health perspective, but also from an economic one, with direct obesity-related costs annually accounting for more than $100 billion in health care spending.

Sharing this recognition that childhood obesity must be addressed swiftly and comprehensively, the Alliance for a Healthier Generation, a joint initiative of the American Heart Association and the William J. Clinton Foundation, has announced the formation of the Alliance Healthcare Initiative, a collaborative effort with national medical associations, leading insurers, and employers. NCCOR’s research goals complement this new initiative, which focuses on health care coverage for and delivery to children and families for the prevention, assessment, and treatment of childhood obesity.

Clearly, continuing on the current course with regard to the obesity epidemic and the factors that influence it is no longer an option. The costs in terms of physical and economic well being are too high. By taking bold action now, we have the opportunity to improve the health and wellness of millions of Americans.

Special Report

One Person's Genes Offer Clues to Pancreatic Cancer

One way to discover susceptibility genes for an inherited disease is to analyze DNA from large families with many affected members. But this strategy unfortunately does not work with inherited forms of pancreatic cancer because the disease is so deadly that there are very few large families with adequate numbers of samples.

Genome sequencing may offer a solution. Researchers at the Johns Hopkins Kimmel Cancer Center have shown for the first time that sequencing the genes in both the normal and the cancer cells of a single patient can reveal genes that are altered in both types of cells. Some of these changes, when they occur in the same gene in both the normal and the cancer cells, can help identify susceptibility genes.

The team tested this strategy in a man with an inherited form of pancreatic cancer and discovered a gene that in some families appears to cause familial pancreatic cancer.

Among some 20,600 sequenced genes, three had inactivating mutations in both copies of the gene. The researchers focused on a gene called PALB2, because the mutations resulted in a truncated protein and because the gene has been linked to cancer previously. Further analysis showed that PALB2 was mutated in 3 more patients with familial pancreatic cancer out of 96 patients tested.

A New Strategy

Reporting their findings online in Science on March 5, the researchers said PALB2 mutations may be important in about 3 percent of familial pancreatic cancers. They stressed that the work may have implications beyond this disease.

“This strategy offers a new way to find hereditary susceptibility genes, and it applies to other cancers as well as to other hereditary diseases,” said senior author Dr. Alison Klein, who directs the National Familial Pancreas Tumor Registry at Johns Hopkins.

The process involves sifting through thousands of normal genetic variations and apparently harmless DNA changes to discover, in this case, a prime suspect. PALB2 has been implicated in Fanconi anemia and breast cancer, and the gene also interacts with the breast cancer susceptibility gene BRCA2, which normally helps repair damaged DNA. The loss of this gene in cancer is certainly plausible, the researchers said.

“This gene is part of a very important pathway in cancer, and it immediately made sense to us as a candidate,” said coauthor Dr. Michael Goggins, professor of pathology, medicine, and oncology at Johns Hopkins. As further circumstantial evidence, mutations in the gene’s partner, BRCA2, occur in some familial pancreatic cancers, he noted.

Brute Force

The results support the view that when both copies of a gene are lost or damaged, cancer may result, especially if the gene normally repairs DNA, thereby suppressing tumors. According to this theory, a person may inherit a mutated copy of a DNA-repair gene and then acquire mutations in the second copy later in life.

Given this scenario, the “brute force” sequencing approach used in this study is potentially a “very fast and productive method for finding these genes,” said coauthor Dr. James Eshleman, associate professor of pathology and oncology at Johns Hopkins. Pending funding, his group plans to sequence eight more patients with familial pancreatic cancer, further extending work that began with a genome analysis of pancreatic tumors reported last year.

“The scientific logic behind the study is sound and based on paradigms that have stood the test of time,” commented Dr. Steven Gallinger, an investigator at the University of Toronto. “This is definitely a breakthrough. And like all breakthroughs it needs to be validated, but then we can move on and find other genes.”

The hope is that understanding the genetics of a small number of familial cases will lead to insights into more common forms of the disease, as has happened with colorectal and other cancers, added Dr. Gallinger, who was not involved in the research.

Preventing Pancreatic Cancer

Familial pancreatic cancer is likely to involve many genes, and “this study points a way around the problems associated with traditional genetic analysis in pancreatic cancer,” said Dr. Teresa Brentnall of the University of Washington School of Medicine, who was not an author of the study.

Dr. Brentnall is cautiously optimistic that in the future PALB2 could be part of a panel used to evaluate patients with familial pancreatic cancer. There are no effective ways to detect early signs of pancreatic cancer, which is the fourth most deadly cancer, though it is not among the 10 most common.

A test for predisposing mutations could help identify people at high risk of the disease who could be monitored for precancerous changes. “If we can identify high-risk families, then we can enroll them in screening programs and potentially prevent them from ever getting pancreatic cancer,” said Dr. Goggins.

A clinical test for PALB2 mutations is not yet available but appears likely. It would need to be a sequencing-based test in order to capture a broad spectrum of mutations. Larger studies will also be needed to further assess the frequency of these mutations and to determine how often people with these mutations progress to cancer.

New Questions

As is often the case, the findings raise interesting questions that can now be explored. One is whether there are identifiable subtypes of familial pancreatic cancer with distinct clinical features (e.g., BRCA2 mutations versus PALB2 mutations), noted Dr. Gloria Petersen of the Mayo Clinic, who leads a consortium of research institutions that studies and supports patients with familial pancreatic cancer.

“This study is very exciting because it demonstrates for the first time that sequencing the protein-coding genes of a single patient can lead to the discovery of novel susceptibility genes,” said Dr. Petersen. “We hope that this approach will soon be within reach of researchers who are doing the genomic analyses of pancreatic cancers, and our groups can start to mine the data,” she added.

The cost to determine the sequence of all genes in an individual for this project was approximately $150,000. The costs of sequencing have declined significantly in recent years and are expected to continue dropping in the future.

—Edward R. Winstead

Spotlight

Tracking Heart CT Scans and Radiation Dose

A cardiac computed tomography angiogram. (Copyright © 2009 Massachusetts Medical Society. All rights reserved.) A cardiac computed tomography angiogram. (Copyright © 2009 Massachusetts Medical Society. All rights reserved.)

On a nearly daily basis, most people are exposed to small amounts of so-called background radiation from naturally and not-so-naturally occurring sources. For many people, though, medical procedures are a significant source of radiation exposure, and this has raised concerns among some physicians about whether procedures intended to help patients may eventually cause long-term harm by increasing their cancer risk.

One increasingly common source is computed tomography, or CT, which delivers a dose of radiation nearly 600 times that of a typical x-ray. According to one analysis, approximately 50 percent of the collective medical radiation exposure in 2006 was attributable to CT scans. For that reason, CT has come under intense scrutiny.

A new study by German researchers, dubbed PROTECTION-1, provides a clearer picture of the real-world use of CT scans to perform the increasingly popular diagnostic cardiovascular procedure CT angiography. The procedure is a noninvasive alternative to standard coronary angiography, which also requires radiation, but typically a lower dose. Both procedures are used to investigate cardiac symptoms such as chest pain and identify underlying problems like dangerous arterial plaque buildup.

In PROTECTION-1, which involved 50 facilities and nearly 2,000 patients, there was a sixfold difference between the facility that reported the highest median radiation dose with CT angiography and the lowest median dose. Published in the February 4 Journal of the American Medical Association (JAMA), the study also offered some encouraging news: Many facilities are taking steps to reduce the radiation doses delivered during CT angiography procedures. One tactic, called electrocardiographically controlled tube current modulation (ECTCM), for example, was used in nearly three-quarters of procedures, the researchers found, reducing radiation doses by approximately 25 percent.

Quantifying Risk

One attempt to help quantify the risk associated with CT angiography came in a July 2007 study, co-authored by Dr. Einstein, that used a computer model to estimate the cancer risk of CT angiography in different patient populations with and without dose-reducing strategies. Younger patients, women in particular, were found to be at the highest cancer risk, while dose-reducing strategies were found to significantly decrease cancer risk.

Even so, in a related commentary in JAMA, Dr. Andrew J. Einstein, from the departments of radiology and cardiology at Columbia University, called the dose differential seen in the observational study “striking.” The study, he continued, demonstrates that cardiac CT angiography “is still a potentially high-dose procedure, and like all procedures involving the use of ionizing radiation, a patient-specific benefit-risk analysis should always be performed to justify the imaging study.”

Risk versus Benefit: A Difficult Measure

Perhaps the chief concern with CT scans is their ballooning use in susceptible populations, especially children and young adults, following a car accident, for example, or to investigate reports of persistent headaches or stomach pain. Because of the growth in its popularity, CT angiography is increasingly under the microscope.

Two days prior to the PROTECTION-1 publication, the American Heart Association issued a science advisory that recommended against the routine use of CT angiography in “asymptomatic patients at low risk of ischemic heart disease,” arguing that any benefit does not outweigh the small cancer risk associated with the procedure.

This recommendation is appropriate for asymptomatic, low-risk patients, Dr. John McB. Hodgson, chair of the cardiology department at Geisinger Health System in Pennsylvania noted, adding that the decision to perform a CT scan has to be individualized.

“Scanning an asymptomatic 60-year-old, where the likelihood [of underlying cardiovascular disease] is higher, might make sense in some situations,” Dr. Hodgson said. “You have to contrast that with scanning a healthy 20-year-old. You would certainly have to have much greater justification in younger people who are asymptomatic.”

It can be very difficult to quantify the risks or benefits of some procedures with precision, explained Dr. Amy Berrington de Gonzalez, from NCI’s Division of Cancer Epidemiology and Genetics. “If the exam is clinically justifiable, then the benefits should outweigh the risks,” she said. In the case of CT angiography, she noted, there have been reports of physicians using the procedure as a screening test. “And in those circumstances it is less certain that the benefits will exceed the risks.”

Teach Them and They Will Lower

CT angiography has grown in popularity, explained Dr. Hodgson, due in large part to the advent of 64-slice CT scanners, which can scan the heart more quickly, making the procedure more accurate and easier to conduct. In fact, according to a recent market research report, the number of 64-slice CT scanners in U.S. cardiology practices has more than doubled over the last 2 years.

Coupled with CT angiography’s expanded use, Dr. Hodgson stressed, are newer, more effective dose-reduction strategies and a concerted effort by cardiac and radiation medicine organizations and the device manufacturers to educate medical personnel about the importance of avoiding unnecessary cancer risks by consistently implementing these strategies.

“Along with the [CT] manufacturers, we are doing whatever we can to reduce the radiation dose patients receive,” Dr. Hodgson said. “Are we going to get rid of all of it? No. But remember, we’re trying to diagnose the number one cause of death in the country. You have to weigh the risks and benefits.”

The available data indicate that education and quality improvement programs can have a significant impact on the radiation doses used in CT angiography procedures. In Michigan, for example, a quality improvement program led by the Advanced Cardiovascular Imaging Consortium showed that in less than a year, the average radiation dose used at the 15 participating centers decreased by nearly 50 percent without diminishing the quality of the resultant images.

—Carmen Phillips

A Closer Look

Researchers Urge Caution, Greater Scrutiny of Colon-related CAM Treatments

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With a general push toward cleaner, more “natural” lifestyles, many Americans are turning to complementary and alternative medicine (CAM) to try to improve the health of their large intestines.

March is National Colorectal Cancer Awareness Month. According to NCI’s Physicians Data Query (PDQ) summary:

  • Age, obesity, lack of exercise, smoking, and alcohol may increase the risk of colorectal cancer.
  • Hormone replacement therapy and polyp removal may decrease the risk of colorectal cancer.
  • The effect of non-steroidal anti-inflammatory drugs, vitamins, diet, and cholesterol-lowering drugs on colorectal cancer risk is still unclear.

More information from NCI about colon and rectal cancer, including clinical trials to test new ways of diagnosing, treating, and preventing the disease, is available online.

Given our position in the food chain, the thinking goes, our colons may be a target for toxic elements in the environment, from pollutants in the air and water to artificial colors and preservatives in our foods.

Anecdotes favoring the use of colon-CAM regimens are widespread, but is there sufficient scientific evidence to support a belief that they can prevent cancer? The answer is no, but the existence of these trends warrants closer inspection into why such beliefs persist.

A “Hygienic” Approach?

One such practice that is increasing in popularity is colonic hydrotherapy, commonly referred to as a “colonic.” It involves inserting a special nozzle into the rectum, where warm filtered water is gently flushed through the large intestine, drained back out into a waste receptacle, and then repeated with fresh solution. The procedure lasts about an hour and consumes up to 20 gallons of liquid, removing all fecal material in the process.

Dr. Kamau Kokayi, an integrative medicine practitioner and medical director of the Integrative Healing Center & Spa, said of all the holistic therapies offered at his clinic, colonics are the most popular. His office in Manhattan, NY, performs approximately 2,000 of them a year. “If the main pipeline in our body is clogged with sludge and isn’t moving properly, it creates a state of autotoxicity,” he explained. “This procedure is actually useful in cleaning up the body.”

Approximately half of the people who come in for this procedure mention a concern about reducing their risk for colon cancer, said Barbara Chivvis, a registered nurse who works with Dr. Kokayi. Some of the people who come for colonics have already gone through cancer treatment, she said, and are hoping the procedure will help to clean out toxic residues leftover by chemotherapy or radiation.

Both Ms. Chivvis and Dr. Kokayi admit that there is no published scientific evidence of a cancer-preventive effect for the treatment that they feel certain is helping people.

Plausible or Placebo?

Anatomy of the lower digestive system, showing the colon and other organs. (© 2009 Terese Winslow) Anatomy of the lower digestive system, showing the colon and other organs (© 2009 Terese Winslow) [Enlarge]

Dr. Brooks Cash, chief of gastroenterology at the National Naval Medical Center in Bethesda, MD, acknowledged, “People will absolutely feel different after they have a colonic. They will feel lighter or cleaned out, whatever that means. But there is no evidence that our intestines clog like old metal pipes. Stool isn’t adherent like spackle. It’s constantly being pushed along for evacuation.”

He added, “In terms of deriving a health benefit, the fact that there are no supporting data for colonics, despite this practice going on for hundreds of years, should give people pause.”

Most articles published in scientific journals on colonics are cases where people used liquids other than water for the flush—coffee or peroxide solutions, for example—and suffered serious injuries afterward. Other dangerous side effects include electrolyte imbalance, bacterial infections, fluid overload, and bowel perforation.

Because of the weight of negative evidence and the lack of research providing positive evidence, the American Cancer Society issued a statement in 2007 to discourage people from believing claims that colonics are effective treatments for cancer or any other disease.

Dr. Jeffrey White, who directs NCI’s Office of Cancer Complementary and Alternative Medicine, said that a randomized, prospective clinical trial examining the health effects of colonics in the future could come from the cancer research community, the medical community, or even the “alternative” health care community—as long as they can provide potential funding agencies in the government or private sector with some preliminary data suggesting how the treatment might work (specific effects on bacterial populations in the gut, for example) and indicating how the procedure affects the development or progression of premalignant colon polyps. But no such data have been gathered yet.

“Clinical research would also help determine what types of patients are most likely to benefit from a CAM therapy such as this, and identify the characteristics of those patients who are unlikely to benefit,” Dr. White said.

Bringing in Bacterial Reinforcement

Another CAM trend that is becoming more mainstream, and that is the focus of early clinical investigation, is the use of probiotics and prebiotics. Probiotics are live microorganisms (mostly bacteria) that are available commercially as supplements or in food products such as yogurt and kefir, a fermented version of yogurt. According to the National Center for Complementary and Alternative Medicine, American spending on probiotic supplements nearly tripled between 1994 and 2003.

Prebiotics are related supplements; a food source for bacteria living in our gut. The goal with both of these is to increase the population of “helpful” bacteria that may improve digestion and create a healthier environment for the surrounding tissues. The probiotic trend also relates to colonics, in that people sometimes take these supplements after the procedure to replace bacteria that get lost in the flush.

There is a growing body of published research investigating how probiotics and/or prebiotics might work to prevent cancer.

For example, a randomized, prospective, 12-week trial was conducted in which 80 patients who had been treated for colon cancer or suspicious polyps ate a combination of a prebiotic long-chain sugar derived from chicory root, known as inulin, and the bacterial strains Bifidobacterium lactis and Lactobacillus rhamnosus. The regimen resulted in some changes in their colon biomarkers for cell survival, including the levels of interleukin-2 and interferon gamma, cytokines that the immune system uses to fight infection. The responses were different for cancer patients, however, than for those who had a history of polyps.

To examine this more closely, NCI is currently sponsoring a phase II clinical trial to test the effect of inulin on the risk for precancerous lesions called aberrant crypt foci, comparing it with a combination of the cholesterol-lowering drug atorvastatin (Lipitor) and non-steroidal anti-inflammatory drug sulindac.

Dr. Asad Umar, chief of the Gastrointestinal and Other Cancers Research Group in NCI’s Division of Cancer Prevention, noted that these trials are not designed to investigate cancer incidence and, at best, can only point toward the direction in which research may be continued in the future.

Other preclinical animal studies have shown that some short-chain fatty acids produced by bacteria during the process of fermentation in the gut can stimulate an immune response in the surrounding mucosal tissue. Dr. Umar noted, however, that human and animal gut bacteria are very different. “If the initial study for biomarker modulation is positive, any extension of these findings would have to be answered in randomized clinical trials,” he said.

He emphasized that the best thing people can do to mediate their risk for colon cancer is still to follow screening guidelines, which help clinicians to identify precursors or early stages of the disease, when it is more easily and successfully treated.

Dr. Umar said that he finds the trend of colonic hydrotherapy alarming. Those who are concerned, he said, about long-term exposure of their gut to “toxic” elements in fecal matter during the course of digestion, should know that studies such as the Polyp Prevention Trial have not been able to show that low-fat, high-fiber diets including fruits and vegetables can reduce the risk of colon polyps.

“It’s true that the environment is a factor in many cancers,” he said, “but family history is still one of the strongest predictors.”

Brittany Moya del Pino

Featured Clinical Trial

Study of the Natural History of Neurofibromatosis Type 1

Name of the Trial

Study of Natural History and Longitudinal Assessment of Pediatric and Adult Patients with Neurofibromatosis Type 1 and Their Healthy Siblings (NCI-08-C-0079).  See the protocol summary.

Dr. Brigitte Widemann Dr. Brigitte Widemann

Principal Investigator

Dr. Brigitte Widemann, NCI Center for Cancer Research 

Why This Trial Is Important

Neurofibromatosis type 1 (NF1) is a genetic condition caused by mutations in the NF1 gene. It is characterized by multiple skin changes, including brown spots on the skin, freckling in the groin and underarms, and the formation of benign tumors called neurofibromas. People with NF1 are prone to developing a number of tumors, including benign plexiform neurofibromas that grow along peripheral nerves and cancerous tumors called malignant peripheral nerve sheath tumors. In addition, NF1 can cause changes in every organ system, including the bones, heart, and endocrine system.

NF1 generally becomes evident in childhood, but the development of NF1 symptoms varies greatly from person to person, and not much is known about how it progresses as patients grow older or about the biological changes that coincide with the physical manifestation of symptoms.

To expand our understanding of NF1, researchers are conducting a long-term study of children and adults with the condition and their healthy siblings. They hope that by studying patients and siblings over time they can learn how the disease progresses and how to better detect and treat its symptoms.

“This study will allow us to follow patients over long periods of time to gain a much better understanding of the natural history of NF1, develop better endpoints for future clinical trials, and determine whether treatments for some manifestations of the disease affect the development of other manifestations,” Dr. Widemann said.

Patients in this study will undergo detailed clinical evaluations and genotyping to help identify the genetic mutation that causes NF1 in individual patients. About half of NF1 patients inherit a mutant NF1 gene from their parents, whereas the rest develop the disorder from spontaneous mutations in the NF1 gene.

“The development of symptoms can be highly variable among family members with NF1,” added Dr. Widemann. “Unlike previous NF1 studies we have conducted, in this study we will monitor both the tumor and non-tumor manifestations of the disease to gain a better understanding of how these symptoms progress and relate to each other.”

For More Information

See the list of entry criteria and trial contact information or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll free and confidential.

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

Notes

New NCI Fellowship Honors Dr. Alan Rabson

Dr. Alan Rabson Dr. Alan Rabson

The U.S. House Appropriations Committee has directed NCI to establish a fellowship honoring Dr. Alan S. Rabson, deputy director of NCI, in recognition of his 53 years of service to NIH. The directive to establish the “Alan S. Rabson Award” was part of the explanatory statement accompanying the FY2009 Omnibus Appropriations Act (H.R. 1105) passed by the U.S. House of Representatives on February 25. The statement acknowledges Dr. Rabson’s work as a pathologist, researcher, administrator, and clinical advisor, and highlights his numerous discoveries in virology and authorship of more than 100 scientific journal articles. In particular, the statement recognizes Dr. Rabson’s life-long dedication to helping cancer patients and their families cope with their diagnoses. The statement also honors the service of Dr. Rabson’s wife, Dr. Ruth L. Kirschstein, who served as the acting director of NIH and director of several institutes. NCI plans to implement this directive in the near future.

NCI Lecture Series Features Dr. Michael Jung

Dr. Michael Jung Dr. Michael Jung

NCI’s Center for Cancer Research (CCR) continues its “Eminent Lecture Series,” with presentations by nationally recognized scientists working on cutting-edge research designed to stimulate a scientific exchange of ideas. 

Dr. Michael Jung, professor in the Department of Chemistry and Biochemistry at the University of California, Los Angeles, will present the next lecture on March 23 at 3:00 p.m. in Lipsett Amphitheater on the NIH campus in Bethesda. The title of Dr. Jung’s talk is “Rational Drug Design for the Treatment of Hormone Refractory Prostate Cancer.” Dr. Jung is an authority on synthetic organic and medicinal chemistry and has more than 25 patents. His lab developed an antagonist of the androgen receptor, which is in phase I and II clinical trials for the treatment of hormone refractory prostate cancer. The lecture series is free and open to the public.

Call for U.S.-Japan Workshop Proposals

NCI and the Japan Society for the Promotion of Science (JSPS) are soliciting proposals for a workshop supporting advances in cancer research and clinical care. The workshop is held annually in the U.S. or Japan, and its theme alternates between basic, clinical, and epidemiological and behavioral science. Proposals are now being accepted for the 2009–2010 workshop, which will focus on epidemiology and behavioral sciences. Participation is limited to 20 people each from the U.S. and Japan, with the possibility for a small number of third country participants. The submission deadline is April 30, and the selection process should be completed by July 2009. More information and proposal submission forms are available from NCI’s Office of International Affairs.

BSA Meeting Held

NCI’s Board of Scientific Advisors (BSA) met March 2–3 on the NIH campus in Bethesda, MD. The public portions of the meeting can be viewed at http://videocast.nih.gov/PastEvents.asp.

First Lady of Senegal Visits NCI

First Lady of Senegal, Viviane Wade, and Dr. Joe Harford First Lady of Senegal, Viviane Wade, and Dr. Joe Harford

The First Lady of Senegal, Mrs. Viviane Wade, visited NCI on January 16. Since the election of her husband, President Abdoulaye Wade, in 2002, Mrs. Wade has dedicated herself to the health and well-being of the people of Senegal. She is the president of Association Education Santé, a nongovernmental agency focusing on the needs of impoverished communities, especially those of children, in remote areas of Senegal. Mrs. Wade has also organized and participated in symposia in Africa on economic empowerment and education for women, public health issues (e.g., HIV/AIDS, malaria, malnutrition, and sickle cell anemia), and agriculture.

During her visit, Mrs. Wade toured the NIH Clinical Center, led by Dr. Lee Helman of NCI’s Center for Cancer Research, and heard presentations by representatives from NIH’s Fogarty International Center (FIC) and various NCI staff. These presentations focused on the burden of cancer in Africa, an overview of FIC and NCI, cancer control planning and screening, and affordable cervical cancer screening in Senegal. Speakers included Dr. James Herrington, director of FIC’s Division of International Relations; Dr. Joe Harford, director of NCI’s Office of International Affairs (OIA); Dr. Makeda Williams of OIA; Dr. Deidre Lawrence, Cynthia Vinson, and Dr. Stephen Taplin of NCI’s Division of Cancer Control and Population Sciences; and Dr. Mark Schiffman of NCI’s Division of Cancer Epidemiology and Genetics. Potential collaborations with NCI on cancer screening and prevention in Senegal were discussed, as Mrs. Wade’s priorities include improving clinical care, education, and health outcomes in Senegal.

New Orleans Community Clinical Programs Honored

The NCI’s Community Clinical Oncology Program honored its two Louisiana CCOPs with the Harry Hynes Award for excellence in community clinical research on March 2. The Oschner Community Clinical Oncology Program and the Minority-based CCOP at Louisiana State University’s Stanley S. Scott Cancer Center (SSSCC) were recognized for their efforts after Hurricane Katrina on behalf of patients with cancer and for their cancer prevention and control efforts. Dr. Carl G. Kardinal, the retired principal investigator of the Oschner CCOP, and Drs. Augusto Ochoa and John Estrada from SSSCC were also included in the awards.

The CCOP program established the Harry Hynes Award in 2001 to recognize and acknowledge outstanding commitment by community investigators to clinical research. The award was named for Dr. Harry Hynes, the principal investigator of the Wichita Community Clinical Oncology Program, for his tremendous dedication and commitment to bringing clinical trials to the community setting.