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December 14, 2010 • Volume 7 / Number 24

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Surgeon General Dr. Regina M. Benjamin discusses the report at the National Press Club. (Photo courtesy of Christopher Smith)New Surgeon General’s Report Outlines How Tobacco Smoke Causes Disease

The U.S. Surgeon General, Dr. Regina M. Benjamin, released a report last week describing in detail how tobacco smoke causes disease and death. A compendium of basic research, the 700-page report demonstrates that any exposure to tobacco smoke, either direct or secondhand, causes immediate damage to cells in the body and can lead to disease and death. Read more > >


A Conversation with Dr. James H. Doroshow about NCI’s Clinical Trials Cooperative Group Program

Dr. James H. DoroshowThe director of NCI’s Division of Cancer Treatment and Diagnosis addresses the Institute of Medicine’s recommendations to improve NCI’s Clinical Trials Cooperative Group Program by consolidating the existing adult groups into a smaller number of groups that would function in a more closely integrated manner. Read more > >



NCI Cancer Bulletin Publication Break

The next issue of the NCI Cancer Bulletin will be published on January 11, when we resume our usual biweekly schedule. If you are not yet a subscriber, please submit your e-mail address in the toolbox above to begin your free subscription.



  • FDA Update

    • FDA Advisory Committee Votes against Two Drugs for Prostate Cancer Prevention
  • Update

    • NCI Recovery Act Web Site Highlights Research on Genomic Mutations in Childhood Cancers Article contains video
  • Notes

    • Final NCAB Meeting of 2010 Held Last Week
    • NCI Director Announces New Senior Staff Member

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.

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Featured Article

New Surgeon General’s Report Outlines How Tobacco Smoke Causes Disease

Surgeon General Dr. Regina M. Benjamin discusses the report at the National Press Club. (Photo courtesy of Christopher Smith) Surgeon General Dr. Regina M. Benjamin discusses the report at the National Press Club. (Photo courtesy of Christopher Smith)

The U.S. Surgeon General, Dr. Regina M. Benjamin, released a report last week describing in detail how tobacco smoke causes disease and death. A compendium of basic research, the 700-page report demonstrates that any exposure to tobacco smoke, either direct or secondhand, causes immediate damage to cells in the body and can lead to disease and death.

“This report makes it clear there is no such thing as a safe cigarette,” said Secretary of Health and Human Services Kathleen Sebelius at a press briefing on December 9. Even brief exposure to secondhand smoke can damage blood vessels and lead to heart problems, including a heart attack. As a nation, she added, “every additional cigarette smoked is making us less healthy.”

The report, How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease, is the 30th in the series of Surgeon General’s reports on tobacco. The series began with a landmark 1964 report that provided the most rigorous review of the evidence at that time on the hazards of smoking. Subsequent reports focused primarily on which diseases are caused by smoking.

The current report is the first to focus primarily on how smoking-related damage occurs, detailing how nearly every organ in the body is harmed by tobacco smoke, often through similar molecular mechanisms, such as inducing inflammation and oxidative stress.

“It’s important that every American understands what smoking does to their bodies,” Dr. Benjamin said at the briefing. Explaining to the public the science behind the harms of smoking, she continued, could aid efforts to reduce tobacco use. Smokers need to know the biological basis of what happens to their bodies, so that they don’t give up trying to quit, she said, adding that most smokers require multiple quit attempts.

Dr. Benjamin’s mother was a smoker who died of cancer, and her uncle needed help breathing due to emphysema caused by smoking, she recounted. It is never too late to quit, she stressed, and the sooner the better. “Quitting smoking gives your body a chance to heal from the damage caused by cigarettes,” she said.

When a person smokes or inhales secondhand smoke, he or she takes in a complex mixture of more than 7,000 chemicals and compounds, including at least 69 that are known to cause cancer. Every exposure to these cancer-causing chemicals can damage DNA in a way that may lead to cancer. Other chemicals in tobacco smoke can lead to heart disease and chronic lung conditions, such as emphysema.

A graphic illustrating the health consequence of smoking and exposure to secondhand smoke. The health consequences causally linked to smoking and exposure to secondhand smoke (Image from U.S. Department of Health and Human Services 2004, 2006) [Enlarge]

“When you document the damage that smoking does to every organ in the body, the evidence against tobacco becomes overwhelming—it’s pretty scary stuff,” said Dr. David Sidransky, director of the Head and Neck Cancer Research Division at Johns Hopkins University and the report’s lead scientific editor.

“It is the harms that we don’t tend to think about, such as early heart attacks, that are really scary,” he added. The report includes evidence linking sudden infant death syndrome to secondhand smoke exposure. Reproductive effects are also cited, including an increased risk of low birth weight in babies born to mothers who smoke, which increases the risk of infant death.

Research on the biology of addiction is also featured in the report. “These studies show how incredibly complex the biology—and molecular biology—of addiction is,” said Dr. Sidransky. “The only safe answer is to never smoke because you don’t know if, from the perspective of molecular biology, you’re going to become hooked.”

Written for scientists, the report has been summarized in an illustrated booklet using plain language, which Dr. Benjamin said will be translated into Spanish. A one-page summary of the report, including tips for clinicians to help their patients quit, is also available.  

Dr. Benjamin called on clinicians to talk with their patients who smoke about the changes that occur at the cellular and DNA level. “We should give the patients the information and let them make decisions based on the information,” she added.

Studies show that most smokers want to quit and that cessation programs and services can help, explained Assistant Secretary for Health Dr. Howard K. Koh. The national tobacco quitline, 1-800-QUIT-NOW, is one such service. Comprehensive state tobacco control programs and state and local laws that protect the public from exposure to secondhand smoke have also had a significant effect. California has the longest running comprehensive state program, as well as strong smoke-free laws, and rates of lung cancer are declining faster there than in other states, Dr. Benjamin noted.

Even so, smoking remains the leading preventable cause of premature death in the United States and results in more than 440,000 deaths each year. The new report is part of an effort to “renew the national momentum for ending the epidemic,” said Dr. Koh.

The report’s findings are expected to reach a global audience. “Surgeon General’s reports are the scientific basis for tobacco-control efforts in the U.S. and around the world,” said Dr. Cathy Backinger of NCI’s Tobacco Control Research Branch. “This report emphasizes that the best way to reduce your risk for cancer is not to smoke or be exposed to secondhand smoke from others.”

Since the first Surgeon General’s report on tobacco was published in 1964, scientists have continued to develop a deeper understanding of how tobacco smoke causes disease, said Dr. Jonathan Samet of the University of Southern California’s Department of Preventive Medicine and the Norris Comprehensive Cancer Center, who was a contributing editor of the latest report.

Although this information does not change the core message about tobacco, he noted, the findings have implications for trying to better understand, for example, the biology of addiction and whether there are people who are predisposed to addiction. This could lead to more targeted approaches for preventing tobacco-related diseases. “Stay tuned,” he said.

—Edward R. Winstead

Cancer Research Highlights

Study Estimates More than 600,000 Deaths Worldwide Caused by Secondhand Smoke

Secondhand tobacco smoke is estimated to have caused more than 600,000 deaths and the loss of more than 10 million disability-adjusted life years (DALYs) worldwide in 2004, according to the first analysis of its kind. Women and children were more likely than men to be exposed to secondhand smoke and to suffer morbidity and mortality from this exposure. The findings were published online November 25 in The Lancet.

Researchers led by Dr. Mattias Öberg of the Karolinska Institute in Stockholm, Sweden, used data for their analysis from the Global Youth Tobacco Survey and 19 additional surveys published between 1980 and 2007. They used models to estimate the burden of disease from secondhand smoke exposure for countries without direct survey data. The research team used the comparative risk assessment method, which is based on the proportion of people exposed to a pollutant and the known relative risk of disease related to that exposure.

The authors estimate that, worldwide, 40 percent of children, 35 percent of female nonsmokers, and 33 percent of male nonsmokers are exposed to secondhand smoke. In 2004, secondhand smoke caused 379,000 deaths from ischemic heart disease, 165,000 deaths from lower-respiratory infections, 36,900 deaths from asthma, and 21,400 deaths from lung cancer. Forty-seven percent of these deaths occurred among women and 28 percent occurred among children.

“Two-thirds of these deaths [among children] occur in Africa and south Asia…. The combination of infectious diseases and tobacco seems to be [deadly] for children in these regions,” wrote the authors. “Prompt attention is needed to dispel the myth that developing countries can wait to deal with tobacco-related disease until they have dealt with infectious diseases.

“The provisions of the WHO Framework Convention on Tobacco Control should be enforced immediately to create complete smoke-free environments in all indoor workplaces, public places, and on public transport,” the authors recommended.

“This landmark study documents the global magnitude of the problem of secondhand smoke exposure and its devastating consequences,” said Dr. Cathy Backinger, chief of NCI’s Tobacco Control Research Branch. “These findings should encourage a sense of urgency for ensuring that nonsmokers are protected from secondhand smoke exposure—a completely preventable health hazard.”

Zoledronic Acid Does Not Improve Disease-Free Survival in Breast Cancer

The addition of zoledronic acid, a bisphosphonate, to standard adjuvant therapy for women with stage II or III breast cancer does not extend disease-free survival (DFS), according to results from the phase III AZURE trial presented December 9 at the San Antonio Breast Cancer Symposium (SABCS). The findings run counter to those from an earlier trial, ABCSG-12, which showed improved DFS in premenopausal women with early-stage breast cancer who received zoledronic acid in addition to hormone therapy.

It is important to note, said Dr. Robert Coleman, the AZURE trial’s principal investigator, that the patient populations in the two trials were very different. AZURE enrolled both premenopausal and postmenopausal women; ABCSG-12 enrolled only premenopausal women who, as part of the trial, received the drug goserelin to induce early menopause.

The AZURE investigators enrolled 3,360 women at 174 treatment centers in the United Kingdom. The women were randomly assigned to receive either standard adjuvant treatment—chemotherapy, hormone therapy, or both, chosen by their treating physician—or to standard adjuvant treatment plus 5 years of zoledronic acid.

After almost 5 years of follow-up, no difference in DFS or overall survival (OS) was observed between the groups. However, in a preplanned subset analysis, women who had been menopausal for at least 5 years had significantly increased DFS and OS with the addition of zoledronic acid to standard treatment. Premenopausal women experienced no benefit from the addition of the bisphosphonate in the subset analysis. The updated results from ABCSG-12 presented at SABCS continued to show a statistically significant improvement in DFS and a trend toward improved OS in women who received zoledronic acid.

“Our results are strikingly different from those observed in ABCSG-12, and we need to understand why. I don’t believe one is right and one is wrong. I think we need to understand the biology as to why we’re seeing these different outcomes,” said Dr. Coleman. “Our hypothesis would be that adjuvant bisphosphonate efficacy is dependent on a low estrogen or inhibited concentration within the bone microenvironment,” he continued.

“Based on these data, I believe the routine adjuvant use of zoledronic acid to prevent recurrence is not indicated,” said Dr. Sharon Giordano from the University of Texas M. D. Anderson Cancer Center at the press conference. “The difference in outcome by menopausal status is very intriguing but not definitive.” She continued, “the AZURE trial will not be the final word on this topic.” Ongoing large trials testing bisphosphonates for the adjuvant treatment of breast cancer include NSABP B-34, the Gain trial, the NATAN trial, and SWOG-S0307.

Regular Sunscreen Use May Reduce Invasive Melanoma Risk

Regular sunscreen use may reduce the risk of developing melanoma, according to results of a randomized controlled trial that were reported December 6 in the Journal of Clinical Oncology. The trial is the first prospective, randomized study to investigate the link between sunscreen use and melanoma, the most deadly type of skin cancer.

Researchers led by Dr. Adèle Green of the Queensland Institute of Medical Research examined the incidence of melanoma among 1,621 white adults in a township in Queensland, Australia. They divided the study participants, age 20 to 69, into two groups. From 1992 to 1996, the participants in one group were given an unlimited supply of a broad-spectrum sunscreen with a sun protection factor (SPF) of 16 and were asked to apply it every morning to their head, neck, arms, and hands, and reapply it after heavy sweating, bathing, or long sun exposure. The control group continued using sunscreen of any SPF at their usual discretionary frequency, which for some included no use.

Dr. Green and her colleagues followed the study participants for 10 additional years and tracked all cases of primary melanoma newly diagnosed between 1993 and 2006. They found 11 new cases of melanoma in the daily sunscreen group compared with 22 cases in the discretionary sunscreen group, a 50 percent reduction. Invasive melanoma was reduced by 73 percent in the daily sunscreen group compared with the control group (3 versus 11 cases).

The authors noted that their results are of borderline statistical significance and suggested that their findings for invasive melanoma in particular “should be interpreted cautiously.” Nevertheless, they concluded, “among adults age 25 to 75 years, regular application of SPF 15+ sunscreen in a 5-year period appeared to reduce the incidence of new primary melanomas for up to 10 years.”

In an accompanying editorial, Drs. Phyllis Gimotty and Karen Glanz of the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania School of Medicine wrote: “To our knowledge, the trial’s findings are the first to provide strong evidence for a reduction in the incidence of invasive melanoma after regular application of broad-spectrum sunscreen in adults…. It is unlikely that another trial of comparable scope and rigor will be conducted in the foreseeable future.”

Furthermore, they wrote, although “the question of its efficacy with respect to melanoma prevention should no longer deter scientists or clinicians from recommending sunscreen use,” effective skin cancer prevention should also include avoiding exposure to ultraviolet rays, using clothing to shield skin from the sun, and performing regular skin self examinations.

“This study provides important evidence regarding the role of sunscreen use as part of a range of sun-protective behaviors that effectively reduce risk of melanoma,” commented Dr. Margaret Tucker of NCI’s Division of Cancer Epidemiology and Genetics.

Hormone Therapy for Low-Risk Prostate Cancer Declines When Medicare Reimbursements Are Reduced

Reducing physician reimbursements for androgen suppression therapy (AST) led to a 40 percent drop in prescriptions for men with low-risk prostate cancer, while AST use among men with metastatic disease remained stable, according to findings published online December 3 in the Journal of the National Cancer Institute.

AST with a gonadotropin-releasing hormone (GnRH) agonist or surgical removal of the testicles (orchiectomy) is standard therapy for metastatic prostate cancer. So far, no study has shown a benefit for men with local-regional disease, yet use of AST for prostate cancer increased more than threefold in the 1990s “irrespective of whether the treatment was considered clinically indicated or not,” wrote Dr. Sean Elliot of the University of Minnesota and his colleagues. The 2003 Medicare Modernization Act reduced reimbursements of AST by 64 percent between 2004 and 2005.

The researchers used the SEER-Medicare Linked Database to analyze data from more than 72,000 men over the age of 66 who were diagnosed with prostate cancer between 1992 and 2005. They found that AST use among men with low-risk prostate cancer peaked at 10.2 percent in 2003 and then fell to 7.1 percent in 2004 and 6.4 percent in 2005, a statistically significant decrease. AST use among men with metastatic disease remained constant at 60 percent even after the payment change, the authors said.

Increased risks of diabetes, cardiovascular disease, bone fractures, and colorectal disease have been associated with the use of GnRH agonists, “highlighting the importance of targeting these drugs to patients who are likely to benefit and avoiding them for patients who will not,” wrote Dr. Nancy Keating of Brigham and Women’s Hospital and Harvard Medical School in an accompanying editorial. This study demonstrates “that the decreased reimbursement for GnRH agonists was associated with a substantial decrease in their use for an indication that very likely reflected overuse,” she wrote.

Study Shows Strong Link between Obesity and Mortality

The largest study of its kind has confirmed a strong association between overweight and obesity and an increased risk of death. The study also identified a range of body-mass index (BMI) at which mortality risk is lowest, confirming earlier studies indicating that people who are in the normal weight range have a significantly lower risk of dying from a host of causes compared with those who are overweight. The findings were published December 2 in the New England Journal of Medicine.

Obesity and overweight continue to be major health problems in the United States. Approximately two-thirds of the adult U.S. population are overweight or obese, meaning that they have a BMI of 25 or higher.

Researchers from NCI and other NIH institutes, as well as from other U.S. and foreign health agencies and universities, pooled data on 1.46 million people from 19 long-term prospective cohort studies. The participants in these cohort studies were white and from more industrialized countries, limiting the extent to which the findings can be extrapolated to other populations, the researchers explained. The analysis focused on participants who had never smoked and did not have cardiovascular disease or cancer at study entry, eliminating “potentially strong confounders” of mortality risk that have affected some earlier studies, explained the study’s lead author, Dr. Amy Berrington de Gonzalez of NCI’s Division of Cancer Epidemiology and Genetics.

Overall, the lowest mortality risk was seen for those with a BMI between 20 and 24.9. Above that level, every 5-unit increase in BMI increased the risk of death by 31 percent. The risk of death was substantially elevated in the severely obese, those with a BMI of 40 or higher. Women who fell into this category had a 2.5-fold higher risk of death compared with women in the lowest risk BMI range. The risk relationship was similar for men.

Across the BMI levels that correspond with overweight and obesity, the relationship between BMI and mortality was strongest for participants who were younger than 50 at study entry, Dr. Berrington de Gonzalez added.

Although the cancer-specific mortality risk was smaller than the mortality risk associated with cardiovascular disease, the study only assessed overall cancer risk, she said. “Based on previous studies, we know that the relationship between obesity and cancer varies by cancer type,” she continued. So, while obesity is strongly associated with an increased risk of postmenopausal breast cancer and renal cancer, for example, it is not associated with some other cancers. As a result, when cancer is considered as a single disease, the overall association is weaker, Dr. Berrington de Gonzalez said.

New Subtype of Acute Myeloid Leukemia Identified

By profiling epigenetic changes in the genomes of patients with acute myeloid leukemia (AML), researchers have identified a biologically distinct subtype of the disease that could be amenable to new forms of molecularly targeted therapy. Epigenetic changes, such as DNA methylation, include chemical modifications to DNA that alter the activity of genes without changing their coding sequence. In this study, patients whose tumors had mutations in the genes IDH1 or IDH2 showed widespread DNA methylation changes, including changes to key genes associated with leukemias, the researchers reported online in Cancer Cell on December 2.

The research team, co-led by Dr. Ari Melnick of the Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College, were surprised by the results because IDH1 and IDH2 are involved in cell metabolism and have not been linked previously to epigenetic changes. But once these genes are mutated, the researchers found, they encode abnormal proteins that produce an aberrant metabolite that, in turn, increases DNA methylation. This increased methylation causes genes to function abnormally and causes hematopoietic cells to develop leukemic features.

To make the discovery, the researchers compared gene activity and DNA methylation patterns in tumors from 750 patients with AML. They also sequenced selected genes, including IDH1 and IDH2, which have been implicated in AML and in glioma, a form of brain cancer. The gene-expression patterns of patients with IDH1 or IDH2 mutations were not distinct from those of other AML patients, but clear differences were seen in the epigenetic profiles.

In additional experiments, the researchers found that the abnormal metabolite produced by the mutant IDH1 and IDH2 proteins disrupts the functions of a factor called TET2 that can otherwise reduce DNA methylation. They also showed that some AML patients have genetic mutations that inactivate the TET2 gene, and this causes the same abnormal patterns of DNA methylation as IDH1 and IDH2 mutations.

“This study marks the first time that genes involved in energy balance and abnormalities in cancer epigenetic programming have been linked,” said Dr. Melnick, who led the work with Drs. Craig Thompson and Ross Levine of Memorial Sloan-Kettering Cancer Center. The study further suggests that a gene can acquire an entirely new function when it is mutated. “In these kinds of studies, it is important to expect the unexpected,” Dr. Melnick added.

Screening Compliance, Stage of Cancers Detected Vary by Demographic

New national population-based data on screening, prevalence, and incidence of three cancer types show that about a third of breast cancers and half of colorectal and cervical cancers were diagnosed at a late stage, which means that timely and effective screening might have detected them earlier at a more treatable stage. The findings were reported by the CDC in the November 26 MMWR Surveillance Summaries.

Cancer incidence and prevalence trends were collected from state cancer registries according to sex, age, and race/ethnicity from 2004 to 2006, the latest data available, and then compared with 2008 self-reported data in the Behavioral Risk Factor Surveillance System, reflecting national rates of compliance with screening procedures recommended by the U.S. Preventive Services Task Force.

More than 82.1 percent of women age 50 to 74 received the recommended screening for breast cancer, and 87.6 percent of women age 21 to 64 were screened for cervical cancer as recommended. “Screening rates seem to have plateaued for cervical and breast cancer screening but are increasing steadily for colorectal cancer screening,” wrote the researchers.

Overall, 61.9 percent of men age 50 to 75 received colorectal screening as recommended, but the rates were lower for younger men (52.6 percent for men age 50 to 59), American Indians/Alaskan Natives (53.0 percent), Asian-Pacific Islanders (50.7 percent), and Hispanic men (46.5 percent). Similar trends were found for women, although the drop off in rates for those groups was not quite as large. Although black women and men had screening rates nearly as high as their white counterparts, they also had colorectal cancer incidence rates higher than all other groups.

Patterns of cancer incidence and prevalence for all three cancers varied geographically, and the CDC researchers suggested that state cancer control planners look at national and state data to explore whether these patterns might reflect demographic variables, ineffective screening, or poor follow-up of abnormal screening results. They noted that “social and economic disparities, lack of awareness of the need for screening, lack of physician recommendation, and lack of insurance coverage are major factors in the underuse of cancer screening.”

NCI has initiated a request for applications (RFA), called PROSPR, to evaluate the screening process in community practice and provide further insights into factors associated with late-stage cancers. The RFA will fund 9 to 12 research sites and a statistical coordinating center over 5 years.

A Conversation With

A Conversation with Dr. James Doroshow about NCI’s Clinical Trials Cooperative Group Program

Dr. James H. Doroshow Dr. James H. Doroshow

At NCI’s request, the Institute of Medicine (IOM) conducted a review of the NCI Clinical Trials Cooperative Group Program. The IOM was asked to gather independent, expert perspectives on the state of cancer clinical trials in the United States. In April 2010, the IOM issued its report, A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program, which recommended that the program be restructured and its funding increased to overcome shortcomings due to inefficient, cumbersome, underfunded, and overly complex systems. The authors of the report also commended the changes NCI has made to the Cooperative Groups in recent years, including changes to the Cancer Trials Support Unit (CTSU), enhancements to the Central Institutional Review Board (CIRB), and implementation of disease-specific steering committees. The authors concluded, however, that the system requires a major transformation that can only be accomplished by consolidating the existing adult groups into a smaller number of groups that would function in a more closely integrated manner. In this short interview, Dr. James H. Doroshow, director of NCI’s Division of Cancer Treatment and Diagnosis, addresses that recommendation.

Why does the Cooperative Group Program need reinvigorating?

The practice of oncology has evolved significantly with the development of research focused on the molecular and chemical bases of malignant transformation, including assessments of specific processes related to cancer cells, genetic changes, and drug and hormonal responses and resistance. The evolution in our understanding of cancer also requires an evolution in the design and conduct of clinical trials.

Screenshot of Transforming the NCI Clinical Trials EnterpriseFor more information about NCI's Clinical Trials Cooperative Group Program and the IOM recommendations, or to send a comment, click on the image above.

Consistent with the IOM recommendations, we at NCI have concluded that a smaller number of large Cooperative Groups that have broad membership and the ability to function as a coordinated network will be better able to run the complex clinical trials that today’s science demands. And we are now discussing with the leaders of the Cooperative Groups how to implement the consolidation recommended by the IOM.

NCI supports 10 U.S.-based Cooperative Groups—nine adult groups and one pediatric group. In line with the IOM’s recommendations, we are working with the leaders of these groups to consolidate the program to a maximum of four adult groups and one pediatric group. The pediatric group resulted from the previous merger of four pediatric clinical trials groups and will probably remain in its current form.

We expect that merging the existing nine adult groups into no more than four multidisease adult groups will fulfill the need for complex, multidisciplinary cancer trials; achieve more sophisticated capabilities across the board; and facilitate highly integrated group structures. Discussions on how best to consolidate the groups continue. In these discussions, the unique needs of subspecialties (such as radiation therapy, surgery, and imaging) and their unique capabilities in cancer prevention, screening, and diagnosis must be considered.

What long-term results are expected from the consolidation?

Modern clinical trials typically use sophisticated genetic profiling of tumors, and for these types of studies, it is necessary to screen large numbers of patients to find subsets that have tumors that demonstrate changes in specific genetic pathways. These types of trials also require systems for collecting and distributing specimens, sequencing DNA, performing molecular stratification, and correlating genomic data. Needless to say, these circumstances increase the complexity of the trials, and multidisease, multimodality groups with adequate resources are best suited to manage such complex trials. In addition, a few large Cooperative Groups will be better able to train investigators and adopt new clinical discoveries.

Our current Cooperative Group structure, with several small groups, makes it difficult to complete clinical trials in which patients are stratified on the basis of molecular tumor characteristics. In the future, these smaller groups would be less competitive given the relatively small size of their infrastructures and staffs. In view of the changing nature of clinical trials, some of the Cooperative Groups have already begun to consolidate their data management operations independently and are beginning to discuss integration of their scientific programs.

Consolidating the number of adult groups will reduce redundancy and improve the effectiveness and efficiency of trials. These changes will also help streamline and better harmonize operations centers, data management centers, and tumor banks. Fewer group disease committees should also foster a more collaborative approach to selecting the most important trials to perform.

NCI remains committed to completing all of the Cooperative Group trials that are currently active. Once the consolidation is completed, we anticipate that this improved, nationwide system of more efficient clinical trials will provide the most rapid and effective transfer of new treatments and cancer control discoveries to patients.

Strategies to Ease the Transition

Consolidation of the adult groups is expected to foster competition for the best trial ideas while encouraging collaboration among researchers. In anticipation of potential investigator concerns about consolidation, NCI has identified several strategies that may ease the transition to fewer groups:

  • Permit multiple principal investigators on a single trial, as is allowed by NIH grants
  • Incentivize the transition with additional resources
  • Allow ongoing trials to continue with a distributed data management and operations system until they are completed
  • Combine (rather than disband) the various groups’ overlapping disease committees to include all current participants

NCI is working with the Cooperative Groups and critical stakeholders, including current Cooperative Group principal investigators, professional groups, and patient advocates, to develop consensus. NCI staff will provide opportunities for presentations at Group meetings, one-on-one meetings, and feedback online at:

Special Report

Trial Suggests New Treatment Option for Hodgkin Lymphoma

An illustration showing the mechanism of action of brentuximab vedotin, an antibody-drug conjugate The antibody-drug conjugate (ADC) brentuximab vedotin works by binding to CD30 proteins on the surface of Hodgkin lymphoma cells. The ADC then forms a complex with CD30 and enters the cell. Inside the cell, the ADC’s chemotherapy component is released and kills the cancer cell. [Enlarge]

Intermediate results from a phase II clinical trial indicate that an investigational agent called brentuximab vedotin may be an effective alternative for some patients with Hodgkin lymphoma who have few viable treatment options. The results are promising enough that the drug’s manufacturer, Seattle Genetics, will submit the agent to the Food and Drug Administration (FDA) for approval in early 2011. The trial results were presented last week at the American Society of Hematology (ASH) annual meeting in Orlando, FL.

In the 102-patient clinical trial, 75 percent of patients saw their tumors shrink to at least half their original size (an objective response), and one-third of patients had complete tumor regressions (a complete response). Overall, the estimated 1-year survival rate was 88 percent.

The antitumor effect is particularly impressive, according to trial investigator Dr. Robert Chen of City of Hope Comprehensive Cancer Center, because most of the patients in the trial were high risk: they had never achieved a complete response to standard first- and second-line therapies such as chemotherapy or hematopoietic stem cell transplantation. Brentuximab is “very active for a single-agent therapy in this setting,” Dr. Chen said during a press briefing.

Hodgkin lymphoma most often occurs in younger patients, and the median age of trial participants was 31. The prognosis is generally poor for patients whose disease doesn’t respond to therapy or returns after an autologous hematopoietic stem cell transplant, explained Dr. Ginna Laport of Stanford University Medical Center, during the briefing. “There is usually not much to offer them,” she said. So the results with brentuximab represent “a big breakthrough for this [patient] population.”

Although other therapies can be somewhat effective in such patients, if the FDA does approve brentuximab, it should fill an important clinical niche, said Dr. Wyndham Wilson, head of the Lymphoma Therapeutics Section in NCI’s Center for Cancer Research (CCR). “Certainly as a salvage regimen, it may become the first drug to turn to in the post-transplant setting,” he said.

Patients in the trial received brentuximab—also known as SGN-35—once every 3 weeks during a 30-minute infusion for as many as 16 cycles of therapy. Side effects were limited, mostly low-grade nausea, fatigue, and peripheral neuropathy. About 10 percent of patients had to halt treatment because of peripheral neuropathy, which often consists of intense tingling, burning, or pain in the extremities. But, in most patients, the symptoms could be managed and many could resume treatment, Dr. Chen said.

The Technology behind the Results

Brentuximab is an antibody-drug conjugate (ADC) in which an antibody directed against the protein CD30 is chemically linked to a potent chemotherapy drug called MMAE. The CD30 protein frequently is found on the surface of cancer cells in Hodgkin lymphoma but is present on less than 1 percent of healthy cells.

Also in the News: Panobinostat Shows Promise for Hodgkin Lymphoma

Brentuximab is not the only investigational agent that has shown promise for the treatment of relapsed/refractory Hodgkin lymphoma. Results from a 129-patient phase II trial of the drug panobinostat, part of a class of drugs known as HDAC inhibitors, showed strong antitumor activity in this same patient population, including 30 objective responses and five complete responses.

Those results were also presented at the ASH meeting. The most problematic side effect was a dangerous drop in blood platelets, reported the trial’s lead investigator, Dr. Anna Sureda of the Hospital of the Holy Cross and Saint Paul in Barcelona. However, this could be reversed by temporarily withholding treatment or modifying the dose.

Unlike some other antibodies currently approved for treating cancer, the antibody component of brentuximab does not have any anticancer effect in Hodgkin lymphoma, explained the trial’s lead investigator, Dr. Anas Younes of the University of Texas M. D. Anderson Cancer Center. Rather, Dr. Chen explained, “the antibody allows for selective delivery of the chemotherapy agent directly into Hodgkin lymphoma cells.”

The chemical that tethers the antibody to the chemotherapy drug is also extremely important, explained Dr. Helen Chen of the Cancer Therapy Evaluation Program in NCI’s Division of Cancer Treatment and Diagnosis. “The first critical requirement is that the linker has to be very stable in the blood,” she said. “You don’t want it to release the drug before getting to the cell.”

The linker also determines whether the conjugate only kills cancer cells to which it has attached through the antibody component, or whether the drug component can be released back out of the cell to kill surrounding cancer cells (but also, potentially, healthy cells), a so-called bystander effect, Dr. Helen Chen noted. Brentuximab is designed to have a bystander effect.

In addition to the design and selection of the linker, she continued, the safety and efficacy of ADCs also depend on the chosen antibody target and the “cytotoxic payload” to which the antibody is attached.

One of the first ADCs to receive FDA approval was gemtuzumab (Mylotarg) for the treatment of acute myeloid leukemia. Gemtuzumab is composed of a CD33-targeted antibody linked to the chemotherapy drug ozogamicin. But gemtuzumab was withdrawn earlier this year after a post-approval clinical trial required by the FDA found that, in combination with chemotherapy, it was no more effective than chemotherapy alone and was associated with serious liver complications and a greater risk of death. Gemtuzumab, Dr. Helen Chen noted, used an older generation linker and a different class of chemotherapy drug than brentuximab, in addition to targeting a different cell-surface antigen, all of which may have contributed to its failure in the confirmatory trial.

A number of ADCs are under investigation. Trastuzumab-DM1, for example, an ADC that couples the HER2-targeted antibody trastuzumab (Herceptin) with the chemotherapy drug DM1, is being tested in multiple breast cancer clinical trials. And at NCI, Dr. Ira Pastan’s lab in CCR has developed numerous ADCs that link an antibody to a bacterial toxin, including a conjugate called HA22, which has shown promise in patients with hairy cell leukemia and is now being developed by MedImmune.

Already Thinking Ahead

Dr. Philip Bierman of the University of Nebraska Medical Center called the results exciting. “There’s no question that this is an advance, and there’s no question that this is a drug that will get used,” he said. What these results mean for the future is of even more intense interest among oncologists, he continued.

“I think people are even more enthusiastic about possibly using this drug in the upfront setting,” he said, in combination with a four-drug chemotherapy regimen called ABVD that is the standard first-line therapy for Hodgkin lymphoma. The ABVD regimen has been used since the 1970s and leads to complete remissions in approximately 70 to 80 percent of patients. “So, this could become the new rituximab,” Dr. Bierman said, referring to the CD30-targeted monoclonal antibody used to treat non-Hodgkin lymphoma. (Rituximab initially showed efficacy as a third-line treatment but eventually became a first-line treatment in combination with chemotherapy.) A phase I trial of brentuximab in combination with ABVD is already under way.

“The goal in Hodgkin lymphoma is to cure,” Dr. Wilson stressed. So, testing brentuximab with chemotherapy as an initial therapy makes perfect sense, he continued, “to see if you can improve the cure rate.”

Also presented at the ASH meeting were the results from a smaller phase II clinical trial of brentuximab against a subtype of non-Hodgkin lymphoma called anaplastic large cell lymphoma. The findings were similar, with 87 percent of patients—all of whom had relapsed/refractory disease—achieving an objective response and 57 percent achieving a complete response. Seattle Genetics will also apply for FDA approval of brentuximab for use in this patient population.

Carmen Phillips

Featured Clinical Trial

Targeting Tumor Metabolism in Papillary Kidney Cancers

Name of the Trial
Phase II Study of Bevacizumab and Erlotinib in Subjects with Advanced Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) or Sporadic Papillary Renal Cell Cancer (NCI-10-C-0114). See the protocol summary.

Dr. Ramaprasad Srinivasan Dr. Ramaprasad Srinivasan

Principal Investigator
Dr. Ramaprasad Srinivasan, NCI Center for Cancer Research

Why This Trial Is Important
Papillary renal cell cancer is an aggressive type of kidney cancer that accounts for approximately 15 percent of kidney cancer cases in the United States. Most cases of papillary kidney cancer develop in the absence of inherited gene mutations (sporadic cases), whereas some result from inherited disorders associated with the mutation of specific genes. One of these disorders is hereditary leiomyomatosis and renal cell cancer (HLRCC). Patients with HLRCC often develop benign tumors called leiomyomas in the skin and the uterus, as well as a very aggressive type of papillary kidney cancer that spreads (metastasizes) quickly even when the primary tumors are small.  

Inherited mutations in a gene called FH have been associated with HLRCC. This gene produces a protein called fumarate hydratase (FH). FH protein deficiency resulting from mutation of the FH gene can lead to the inappropriate activation of molecular pathways that involve another protein called hypoxia-inducible factor α (HIFα). These pathways are activated normally when the supply of oxygen available to cells is inadequate, a condition known as hypoxia. Under normal conditions, cells use oxygen to generate most of the energy they need to survive, but, when oxygen is scarce, they may resort to an alternative way to produce energy, such as an oxygen-free metabolic process called glycolysis. HIFα increases the activity of enzymes involved in glycolysis as part of the cellular response to hypoxia. Researchers at NCI and elsewhere have demonstrated that HLRCC tumors rely almost exclusively on glycolysis for energy. This discovery may provide a means for targeting the metabolism of HLRCC.

NCI researchers want to know if inhibiting components of the HIFα pathway will help shrink malignant kidney tumors in patients with HLRCC. The drug erlotinib (Tarceva) suppresses tumor growth pathways that become overactive due to excess HIFα, and it may also interfere with the uptake of glucose and glycolysis by blocking proteins important to these processes. In addition, the biological agent bevacizumab (Avastin) targets a protein called VEGF that cancer cells use to spur the growth of new blood vessels (tumor angiogenesis). Tumors need an adequate blood supply to get the glucose and other nutrients they need for continued growth. Therefore, the researchers hope that targeting both the tumor blood supply and glycolysis will lead to the starvation of these tumors and result in tumor shrinkage or prolonged inhibition of tumor growth.

In this trial, patients with HLRCC or sporadic papillary renal cancer that has spread beyond the kidneys will be treated with erlotinib and bevacizumab. Patients will take erlotinib pills daily and receive bevacizumab intravenously once every 2 weeks. After 8 weeks of treatment (two 28-day treatment cycles), and every 8 weeks thereafter while they are in the study, the patients will be assessed at the NIH Clinical Center for response to treatment.

“Papillary kidney cancers are very difficult to treat and usually don’t respond to therapies used for other kidney cancers,” said Dr. Srinivasan. “We have seen in both the lab and the clinic that tumors associated with HLRCC are addicted to glucose and completely dependent on glycolysis for growth, so with this study we are targeting that metabolic basis for the cancer. And we are taking that approach and applying it to patients with noninherited [sporadic] papillary kidney cancer to see if they will respond to this novel therapy, as we hope patients with HLRCC will.”

For More Information
See the lists of eligibility 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

Community Update

Statistical Strength in Numbers: International Clinical Trials for Rare Cancers

Altogether, rare cancers account for about one-third of all cancer cases. Researchers believe this proportion will likely grow as molecular characterization reveals that even common cancers have rare subtypes, strengthening the public health rationale for finding safe and effective therapies for these tumors. For some rare cancers, however, the only practical way to carry out a meaningful clinical trial is for investigators around the world to work together, because no single country has access to a sufficient number of patients with a given tumor type.

By bringing patients together, international trials can accrue faster, and they offer lower collective administrative costs, shared infrastructure, centralized resources, and use of existing networks.

—Dr. Jack Welch

“International trials for rare cancers offer many advantages over separate trials done in different countries or regions,” explained Dr. Jack Welch of the Clinical Investigations Branch in NCI’s Cancer Therapy Evaluation Program (CTEP). “By bringing patients together, international trials can accrue faster, and they offer lower collective administrative costs, shared infrastructure, centralized resources, and use of existing networks.”

On December 10, NCI and the American Society of Clinical Oncology (ASCO) convened a meeting of international stakeholders to explore ways to collaborate across borders on clinical trials for rare cancers. Nearly 100 representatives from 75 institutions participated in the day-long meeting, which was supported by CTEP, NIH’s Office of Rare Diseases Research (ORDR), NCI’s Office of Advocacy Relations (OAR), and ASCO. In addition to representatives from NIH, the FDA, the HHS Office for Human Research Protections, and NCI’s Clinical Trials Cooperative Group Program, attendees included investigators from Canada, France, Italy, Japan, Korea, the United Kingdom, the European Organisation for Research and Treatment of Cancer, and representatives of patient advocacy organizations and the pharmaceutical industry.

Building on previous meetings that examined international collaboration in clinical trials and how to design trials for rare cancers, this meeting focused on circumstances that make it impractical to perform a phase II or phase III trial solely in North America. Participants heard presentations on research on rare cancers in the international setting, leveraging patient advocacy for rare cancer trials, human subject and data privacy considerations, and other regulatory and administrative barriers. They also attended breakout sessions that explored five previously identified priority research areas: rare pediatric cancers, adult brain cancers, sarcoma, cholangiocarcinoma, and rare gynecologic malignancies.

“The potential rewards of international trials are great, in terms of generating results that will help doctors and patients make informed decisions about treatment options for rare cancers,” said Dr. Welch. “But, there are significant challenges to overcome.” Among the barriers discussed by meeting participants were varying regulatory requirements, duplicative layers of study review, intellectual property concerns of pharmaceutical companies, restrictive agreements between academic investigators and pharmaceutical concerns, lack of recognition for team science, and the need to harmonize administrative operations between clinical trial organizations performing these studies.

“Many of these challenges, however, can be overcome with early planning, frequent communication, and flexibility,” stressed Dr. Ted Trimble, also of CTEP’s Clinical Investigations Branch.

When it comes to conducting small-population trials, there are some important gaps that need to be addressed, explained Dr. Samir Khleif, head of the Cancer Vaccine Section in NCI’s Center for Cancer Research. “We need to explore new statistical models that might allow a higher error rate in one area, in order to accomplish the study with fewer patients,” he said.

At the meeting, participants learned how patient advocacy groups can help recruit participants for trials and serve as conduits of information between researchers and patient communities. Some charities and foundations sponsor research activities, and some even support research infrastructure.

International collaboration is as much art as it is science, explained NCI’s Dr. Jorge Gomez in a recent editorial on health diplomacy in the NCI Cancer Bulletin. Dr. Gomez pointed out that successful collaborations must also strengthen relationships among countries, increase research capacity for all collaborators, and serve as a model for others to follow. Although working across international borders poses some challenges, he noted, planning, communication, and collaboration is the key to overcoming those challenges.

“This meeting brought together a catalytic group spanning various domains that can continue to plan and communicate with the goal of getting new trials under way in the next 3 to 5 years,” said Dr. Welch. “A series of teleconferences and face-to-face meetings will be convened to explore available resources and prioritize next steps.”

—Karen Eddleman and Shannon P. Hatch

FDA Update

FDA Advisory Committee Votes against Two Drugs for Prostate Cancer Prevention

An advisory committee to the Food and Drug Administration (FDA) has recommended against agency approval of two drugs for the prevention of prostate cancer. On December 1, the agency’s Oncologic Drugs Advisory Committee heard presentations about two large clinical trials, REDUCE and the NCI-supported PCPT, which found regular use of the drugs dutasteride (Avodart) and finasteride (Proscar), respectively, decreased the risk of prostate cancer in men undergoing regular prostate-specific antigen (PSA) screening and/or prostate biopsies. Both drugs are already FDA approved for the treatment of benign prostatic hyperplasia.

Based on the REDUCE results published in April, dutasteride’s manufacturer, GlaxoSmithKline, submitted a supplemental New Drug Application (NDA) to the FDA to market the drug for the reduction of prostate cancer risk. Although a similar NDA has not been submitted for finasteride, the committee was asked to vote on whether each drug had a favorable risk/benefit ratio for prostate cancer prevention in healthy men. In the case of finasteride, the claim was for prevention in men age 55 or older with a PSA of 3 ng/ml or less, and with dutasteride, the claim was for use in men with an elevated PSA but a previous biopsy that was negative for prostate cancer.

Much of the debate focused on the clinical significance of the cancers prevented by these drugs, as well as the concern that these agents may increase the risk of high-grade cancer, both of which were highlighted in a briefing document prepared by FDA staff. Dr. Ian Thompson of the University of Texas Health Science Center at San Antonio and the PCPT’s principal investigator presented follow-up analyses that suggested a substantial proportion of cancers prevented by finasteride are, in fact, clinically significant and the observed increase in high-grade disease was due, at least in part, to enhanced detection. Finasteride and dutasteride both shrink the prostate, making it easier to detect high-grade cancers with a needle biopsy.

The vote against finasteride was unanimous, while the vote against dutasteride was nearly unanimous. Although the FDA is not bound by the committee’s recommendations, in most cases the agency’s approval decisions are in line with advisory committee votes. Update

NCI Recovery Act Web Site Highlights Research on Genomic Mutations in Childhood Cancers

Opening image from 'Targeting Neuroblastoma' videoNCI TARGET researchers are working to keep 5-year-old Hayley's neuroblastoma in remission through genetic targeting. Recovery Act funds are making it possible. Click on the image above to watch her story.

The NCI Recovery Act Web site has added a new article and video that highlight NCI’s Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Through this initiative, researchers aim to identify genetic markers that will lead to new and more effective therapies for childhood cancers.

Supplemental funding through the Recovery Act has expanded the TARGET initiative to include more pediatric cancer types, as well as sustained research on neuroblastoma, a solid tumor that arises in immature nerve cells. The goal of the neuroblastoma project is to find alterations in the neuroblastoma genome that are important to the development of the high-risk form of the disease and, more importantly, which forms of the disease can potentially be treated with targeted therapies.


Final NCAB Meeting of 2010 Held Last Week

The National Cancer Advisory Board (NCAB) held its final meeting of 2010 in Bethesda, MD, on December 7. NCI Director Dr. Harold Varmus provided an update on the status of NCI’s budget and announced plans to add several new members to his senior staff. (See the related note below.)

Dr. James H. Doroshow, director of NCI’s Division of Cancer Treatment and Diagnosis, gave a presentation on the Operational Efficiency Working Group, which is addressing recommendations from the Institute of Medicine on transforming NCI's Clinical Trials Cooperative Group Program. (See the Conversation with Dr. Doroshow in this issue.)

In addition, researchers from NCI’s Center for Cancer Research highlighted progress in prostate cancer imaging, including molecular imaging and image-guided biopsies. (See Testing a “Smarter” Biopsy for Prostate Cancer from the October 19 issue.)

NCAB members also heard a status report from the Division of Cancer Epidemiology and Genetics, including the future of genome-wide association studies, the burden of cancer in immunosuppressed people in the United States, and medical radiation exposure.

The full agenda and videocast of the entire meeting are available online.

NCI Director Announces New Senior Staff Member

Rick Borchelt Rick Borchelt

During his Director’s Report to the National Cancer Advisory Board, Dr. Harold Varmus announced the appointment of a new addition to his senior staff. 

Rick Borchelt will join the Office of the Director as a special assistant for public affairs. Borchelt most recently served as executive communications director for the Pew-funded Genetics and Public Policy Center at Johns Hopkins University and as communications director of the U.S. Department of Agriculture’s Research, Education, and Economics Mission Area.  An award-winning science writer, Borchelt has directed media relations for the National Academy of Sciences, acted as press secretary for the U.S. House of Representatives Science Committee, and was special assistant for public affairs in the Executive Office of The President during the Clinton administration.

Borchelt also held senior communications positions at the Department of Energy’s Office of Science and the Whitehead Institute for Biomedical Research at MIT. He spent time abroad in Nairobi, Kenya, as executive speechwriter to the United Nations Under Secretary General and Executive Director of the United Nations Environment Programme. A former reports editor for the journal Science Communication, Borchelt also is a past president of the D.C. Science Writers Association.