National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
July 14, 2009 • Volume 6 / Number 14

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NEWS

Clinician/patient discussions about cost are a key component of high-quality care. Cancer Doctors Urged to Discuss Treatment Costs With Patients

The skyrocketing cost of medical care has been front and center in the current deliberations over how to reform the country’s health care system. A new guidance statement released last week by the American Society of Clinical Oncology (ASCO) tackles one component of the issue head on, urging oncologists to discuss the potential financial costs of care with their patients. These clinician/patient discussions about cost, the guidance statement declares, are “a key component of high-quality care.” Read more > >

COMMENTARY

A Conversation With...Dr. Edith Perez

Dr. Edith Perez is a professor of medicine at the Mayo Clinic in Jacksonville, FL, and the co-principal investigator and North American coordinator for the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) clinical trial, an international phase III clinical trial that aims to define the optimal treatment for early stage HER2-positive breast cancer. Read more > >

IN DEPTH

UPDATES

  • FDA Update

    • Black Box Warnings Added to Two Smoking Cessation Drugs
    • Agency Approves First Maintenance Chemotherapy Agent for NSCLC

    Notes

    • State-of-the-Science Conference on Ductal Carcinoma In Situ Slated for September
    • Chemical Biology Consortium Kick-off Meeting Set for August
    • Manifesto on Childhood Cancer Emerges from Meeting in Senegal
    • New Issue of CCR Connections Released
    • New State Cancer Legislative Database Newsletter and Fact Sheet Now Available

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

Cancer Doctors Urged to Discuss Treatment Costs with Patients

Clinician/patient discussions about cost are a key component of high-quality care. Clinician/patient discussions about cost are a key component of high-quality care.

The skyrocketing cost of medical care has been front and center in the current deliberations over how to reform the country’s health care system. A new guidance statement released last week by the American Society of Clinical Oncology (ASCO) tackles one component of the issue head on, urging oncologists to discuss the potential financial costs of care with their patients. These clinician/patient discussions about cost, the guidance statement declares, are “a key component of high-quality care.”

The economics of cancer care was a focus of the recent ASCO annual meeting in Orlando, where presenters often provided frank assessments of the situation.

“We’re reaching a critical inflection point, if we’re not already past it, with respect to health care costs in this country,” said Dr. Lowell Schnipper of the Beth Israel Deaconess Medical Center, who led the ASCO task force charged with developing the guidance statement, during one of the sessions. The numbers back him up. Spending on health care in the United States was $2.2 trillion in 2007, representing approximately 16 percent of the country’s gross domestic product. Cancer, not surprisingly, is a key driver of health care costs, said Dr. Schnipper, with expenses for cancer care increasing at a clip of about 15 percent annually.

Helping Cancer Patients Find Financial Assistance

Organizations across the country, at the national, state, and local level can help patients with cancer and other serious illnesses find ways to pay for medical expenses. Many of these organizations, including CancerCare and the American Cancer Society, recently established a Web site, www.cancerfac.org, to provide a centralized, streamlined way for patients in need to find financial assistance.

ASCO has also developed a new booklet, Managing the Costs of Cancer Care, which is available on their patient Web site, and NCI maintains a fact sheet on Financial Assistance and Other Resources for People With Cancer.

The new guidance statement, published in the Journal of Clinical Oncology, is intended to help not just oncologists, Dr. Schnipper explained, but also other stakeholders—including patients, insurers, and industry members—better understand how cost can affect care choices and decisions.

Cost is an issue that can no longer be ignored, stressed ASCO task force member Dr. Deborah Schrag of Dana-Farber Cancer Institute.

“We have to accept the fact that cost is part of the conversation,” she said. In other areas of health care, such as dental care, Dr. Schrag continued, discussions about the cost of care are up front, frank, and even expected. “But when it comes to cancer, because it can be fatal, we don’t accept that cost belongs on the same table in quite the same way. Now as oncologists, we are recognizing that we have to put our toes in these cold waters. We can’t avoid it any longer. Wishing the system were different doesn’t make it so.”

Oncologists should acknowledge in discussions with patients that treatments may be very expensive and “should seek to identify any specific cost-related barriers to optimal treatment,” the guidance document recommends. To aid in these discussions, oncologists should be “armed with information that will help them assess and communicate the value of specific cancer treatments,” including trying to quantify “how much benefit might be expected from a particular therapeutic option.”

These aren’t easy conversations to have, acknowledged Dr. Nicholas Robert, who specializes in breast cancer treatment for a large oncology practice in Virginia that is part of the nationwide oncology company U.S. Oncology. “It’s different than the way we have been trained, with an emphasis on making a diagnosis and treatment.”

In the current health care environment, “Everyone will have to do their part, and physicians are responsible for a lot of expenses,” Dr. Robert continued. “We need to play a more active role not only in discussing cost with patients, but also in using resources in an evidence-based fashion and not using treatments of unproven value.”

And, he argued, such discussions make sense from a practical perspective. “One of the proper things to do is to make sure patients can afford” the treatments being prescribed, he stressed. The electronic medical records system used by U.S. Oncology aids in cost discussions, he said, because it has embedded “clinical pathways” that lay out the treatment options for a given cancer type that national guidelines indicate are the most effective. This can help oncologists develop more suitable treatment plans for their patients.

Oncologists aren’t alone in their reticence to bring up cost. “A lot of patients are uncomfortable talking about costs,” said Diane Blum, executive director of CancerCare, a New York-based nonprofit organization that provides support services for cancer patients. In some cases, she said, “patients are scared it will have an influence” on their treatment.

“We’re not saying that physicians should be experts on insurance or even have all the direct conversations [with patients],” stressed Ms. Blum, a patient representative on the ASCO task force. “But it has to be some place in the care protocol. Ideally, the physician would talk about the relative costs and benefits of treatment, but the doctor doesn’t have to be the one to help the patient sort out what a situation will allow them to choose.”

Carmen Phillips

Cancer Research Highlights

Risk of Ovarian Cancer from Hormone Therapy Confirmed

Women who have taken hormone therapy are at a higher risk of developing ovarian cancer than women who have not, according to a nationwide study involving nearly 910,000 women in Denmark. The findings, which confirm and extend the results of previous studies, suggest that the risk of ovarian cancer should be a factor when women consider using hormone therapy to treat postmenopausal symptoms.

Lina Steinrud Mørch of Copenhagen University and her colleagues used detailed information from national registries to detect an increased risk of ovarian cancer among former and current hormone users, compared with non-users. A woman’s risk did not seem to depend on the type of hormones, the duration of use, or the mode of administration. The findings translate into about 1 extra ovarian cancer per approximately 8,300 women taking hormone therapy each year, the researchers reported in the July 15 Journal of the American Medical Association.

Since the Women’s Health Initiative reported in 2002 that combination hormone therapy (estrogen plus progestin) was associated with an increased risk of breast cancer, several studies have linked estrogen-alone therapy to the risk of ovarian cancer. There have also been hints of an increased risk from combination therapy, and these are now confirmed.

“Here we see that combination therapy had essentially the same amount of increased risk as estrogen-alone therapy,” said Dr. Garnet Anderson, an ovarian cancer researcher at the Fred Hutchinson Cancer Research Center. The results, she added, are not likely to alter the current guidelines on hormone therapy, which urge women to use the smallest possible dose for the shortest time period.

Hormone therapy may have caused approximately 140 extra cases of ovarian cancer in Denmark during the study period, or 5 percent of the ovarian cancers. “Even though this share seems low, ovarian cancer remains highly fatal, so accordingly this risk warrants consideration when deciding whether to use hormone therapy,” the authors concluded.

Second Cervical Cancer Vaccine Protects Against Additional HPV Types

A large international trial funded by GlaxoSmithKline Biologicals shows that the Cervarix vaccine is highly effective against infections with human papillomavirus (HPV) types 16 and 18. Final results of the Papilloma Trial Against Cancer In Young Adults (PATRICIA) were published July 8 in The Lancet.

Dr. Jorma Paavonen, of the University of Helsinki in Finland, and his colleagues in the PATRICIA study group followed 18,644 women aged 15 to 25 for a median of 34.9 months after vaccination (17,106 women received the full sequence of three injections). About half of the women were in a blinded control group that received a hepatitis A vaccine conferring no protection against HPV infection.

The Cervarix vaccine reduced the risk of precancerous lesions known as grade II cervical intraepithelial neoplasias (CIN2+) by nearly 93 percent in participants who completed the full sequence. The vaccine also provided a lesser but significant degree of cross-protection against HPV types 31, 33, and 45. This added protection could raise the potential effectiveness of HPV vaccination from about 70 percent to between 81 and 86 percent.

About 62 percent of women in the trial had never been exposed to any of the 14 HPV types associated with cervical cancer. This group “is closest to the population targeted by universal mass HPV vaccination,” said the authors, referring to young girls who are not sexually active. Only one event of CIN2+ was observed in 5,449 of these unexposed study participants.

Although it is important to continue testing for HPV in vaccinated and unvaccinated women, “HPV vaccination has the potential to substantially reduce the incidence of cervical cancer and precancer,” the authors concluded.

Cervarix is licensed in 90 countries and was approved last week by the World Health Organization, which allows United Nations agencies and partners to use the vaccine in developing countries. The vaccine is still under review and awaiting approval by the FDA.

Genome Scans Provide Clues to Brain Cancer Risk

Common genetic variations may increase a person’s risk of developing brain cancer, and it is now possible to identify these potential risk factors. In two genome-wide association studies, researchers have discovered and validated a small number of inherited genetic variants linked to the disease. The causes of brain cancer are not well understood, and the findings, published online in Nature Genetics July 5, could provide clues for investigating the inherited component of disease risk.

In one study, researchers at the University of Texas M.D. Anderson Cancer Center and the Institute of Cancer Research in the United Kingdom scanned the DNA of 1,900 patients with gliomas, the most common brain tumor, and several thousand unaffected individuals. The top “hits” among the patients pointed to five genes, including CDKN2A, which plays a role in activating the tumor-suppressor gene p53. Another gene, TERT, is known to be active in tumors.

Four of the five genes turned up in the second study, led by Dr. Margaret Wrensch of the University of California, San Francisco. In addition, two genes, CDKN2A and CDKN2B, were implicated in the risk of melanoma and basal cell carcinoma, a type of non-melanoma skin cancer. This evidence appeared in separate studies also published by Nature Genetics.

“Some of the genes suspected in brain cancer are crossing over to other types of cancer, and it appears that there may be some common risk genes in cancer,” said coauthor Dr. Melissa Bondy of M.D. Anderson. She noted that the results represent a new beginning. “This is a hard tumor to understand. But we now have the technology to untangle the puzzle that we’ve been trying to work on for so many years.”

Study Aims to Improve Common Protein Discovery Method

A new study has identified several common problems that hinder the accuracy and reproducibility of using mass spectrometry to discover potential protein biomarkers of cancer. With feedback and training for laboratories conducting these analyses, the study authors believe, these issues can be overcome. The study was published in the June 2009 Nature Methods.

Conducted by the international Human Proteome Organization (HUPO), the study involved 27 laboratories that were asked to independently identify test samples spiked with 20 human proteins, each one with at least one specific peptide (a sequence of amino acids that join together to form proteins) of approximately the same mass. Each lab performed a mass spectrometry-based analysis of the samples, using their typical methodology, and reported the results and their raw data to HUPO for a centralized analysis.

Only 7 of the labs correctly identified all 20 proteins, and only 1 identified all of the peptides. However, when the raw data submitted by each lab was reanalyzed by the study leaders, they found that “members of each of the labs, with a few exceptions, had in fact generated mass spectrometry data of very high quality, more than sufficient to identify” all of the proteins and most of the peptides, the study authors wrote. Across the participating labs, several common problems led to the protein misidentifications, the researchers reported, such as discrepancies in searching the protein databases to match peptides to their respective proteins and test sample contamination.

Aside from the database issues, many of the problems encountered by individual labs “could be rapidly found and diagnosed,” explained the study's lead investigator, Dr. John Bergeron. In fact, after providing feedback to the participating labs on the problems discovered by the centralized analysis, all of the labs were then able to correctly identify the 20 proteins.

The study by HUPO “shows that with sufficient experimental care and technical training, currently available mass spectrometry-based methods” could produce accurate results, wrote Dr. Ruedi Aebersold, director of the Institute of Molecular Systems Biology at the University of Zurich in Switzerland, in an accompanying editorial. “It also makes a strong case for making data from proteomic studies accessible for comparison and meta-analyses and for the optimization and testing of software tools.”

Death Rates for Certain Cancers Remain Higher for African Americans

Although breast cancer death rates in the United States have declined substantially during the last 15 years, the trend has been less favorable for African American women, according to a study published online July 7 in the Journal of the National Cancer Institute (JNCI).

Using SEER data, Dr. Idan Menashe and his colleagues from NCI’s Division of Cancer Epidemiology and Genetics (DCEG) calculated ratios of mortality, incidence, hazard of death, and incidence-based mortality for nearly 250,000 women diagnosed with breast cancer from January 1990 through December 2003. They found a statistically significant higher hazard of death in African American women diagnosed with breast cancer compared with Caucasian women, especially during the first few years after breast cancer diagnosis. These results suggest that the widening black-to-white disparity in breast cancer mortality rates in the United States is largely driven by the consistently higher hazard of death among African American women, irrespective of tumor estrogen-receptor (ER) expression at diagnosis. 

The authors noted that various biological and non-biological factors could have caused the differential hazard rate patterns among African Americans and Caucasians within each ER category, including response to innovations in breast cancer treatment and access to these treatments. “Hence, greater emphasis should be placed on identifying the reasons for these increased hazards among black women, especially during the initial years following diagnosis, and on developing new therapeutic approaches to address the disparity,” they wrote.

In a second study in JNCI, Dr. Kathy Albain of Loyola University Medical Center and her colleagues analyzed records from more than 19,000 patients who participated in phase III cancer clinical trials conducted by the Southwest Oncology Group. Their analysis showed that even when African American patients received the same cancer treatment as all other patients, their overall survival rates were lower following treatment for breast, prostate, and ovarian cancers, but were equivalent after treatment for all other major cancers.

These two articles “help bring some focus to [racial disparities in cancer incidence and mortality] and help better define the questions that should be asked,” wrote American Cancer Society Chief Medical Officer Dr. Otis Brawley in an accompanying editorial. “It is only through clearly defining the problem that we can most appropriately address it and develop the interventions that may overcome these disparities.”

Mayo Clinic Streamlines Development Process for Cancer Trial Protocols

By streamlining the development process for clinical trial protocols, the Mayo Clinic Cancer Center reduced by approximately 40 percent the time from the initiation of protocol to submission of the document to an institutional review board (IRB) for approval. Results of the initiative were reported June 29 in the Journal of Clinical Oncology.

Cancer clinical trials with prolonged activation times have been shown to have less success in meeting patient accrual goals. Such failed trials may delay getting potentially beneficial new cancer treatments to patients.

Mayo investigators and protocol development staff used Six Sigma, an improvement process developed and widely used in industry, to analyze where time was spent during protocol development and how process changes could reduce delays. They found that of a total of 199 days required to finalize a trial protocol, 174 days were “non-value-added”—that is, days spent waiting for something to happen (e.g., a revision, a response to a question, a document signature).

By introducing a standard template for all clinical trial processes and making other process changes, such as identifying steps that could be completed concurrently rather than sequentially, the cancer center reduced the “turnaround time” (that is, the time from initiation to IRB submission) from 25 weeks to 10 weeks for internally authored protocols and from 20.6 weeks to 7.8 weeks for externally authored protocols.

The experiment showed that significant progress can be made “in decreasing protocol development [turnaround times] through focused process engineering,” the authors, led by Terre A. McJoynt of the Mayo Clinic Cancer Center Research Office, wrote. “Such improvements can be realized within an extremely short timeframe and with little or no incremental investment in administrative resources.”

The group is now undertaking a second phase of the improvement effort, which will focus on the entire protocol development time from study concept through patient enrollment.

A Conversation With

A Conversation with...Dr. Edith Perez

Dr. Edith Perez Dr. Edith Perez

Dr. Edith Perez is a professor of medicine at the Mayo Clinic in Jacksonville, FL, and the co-principal investigator and North American coordinator for the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) clinical trial, an international phase III clinical trial that aims to define the optimal treatment for early stage HER2-positive breast cancer.

What are the primary goals of the ALTTO study?

Our goal is to optimize adjuvant anti-HER2 therapy in patients with early stage HER2-positive breast cancer. Translational research goals include enhancing our understanding of the biology of HER2-positive disease and identifying molecular markers of sensitivity and/or resistance to trastuzumab and lapatinib.

Why test lapatinib as adjuvant therapy when trastuzumab is already approved in the United States for that purpose?

Lapatinib has been approved in the U.S. and other countries for metastatic HER2-positive breast cancer. ALTTO is the definitive trial to determine whether lapatinib merits not only regulatory approval but also routine use in clinical practice in the adjuvant setting. Adding trastuzumab to standard adjuvant treatments for breast cancer has resulted in dramatically improved disease-free and overall survival in most trials, but it does not always prevent recurrence or cure all patients. We need to work together to determine whether we can improve on what we have accomplished so far in targeting HER2.

What is the role of adjuvant chemotherapy in this study?

Based on improved survival data, chemotherapy is standard for breast cancer patients at high risk of recurrence after surgery. Previous research has shown that the activity of anti-HER2 agents alone is modest and that their benefit is improved when administered with chemotherapy. So at this time, optimization of anti-HER2 adjuvant therapy requires the integration of HER2-targeted agents with other effective treatments such as chemotherapy.

ALTTO currently requires anthracycline therapy prior to enrollment because these agents have clearly demonstrated improved survival in patients with breast cancer, and they were used by more than 10,000 patients in the pivotal adjuvant trastuzumab trials (N9831, B-31, HERA, BCIRG-006, PACS-04, and FinHER). 

In the interest of broadening chemotherapy regimens to include a non-anthracycline option, we are conducting a pilot study to determine the safety of a regimen of non-anthracycline chemotherapy, trastuzumab, and lapatinib (NCCTG-N083E). We anticipate modifying the ALTTO protocol to allow a non-anthracycline pretreatment regimen before the end of this year, if we can document safety.

What data collection challenges have the ALTTO investigators faced?

The study currently requires submission of tumor blocks so that we can conduct subsequent translational studies. This has been a challenge here in North America, and some sites are not offering this important trial to patients because of institutional rules “prohibiting” submission of tumor blocks in the context of clinical trials. We are particularly concerned about this trend, as speeding up incorporation of new agents and bringing about cures for breast cancer patients depends on good science, collaboration, and biological understanding of this disease. We will continue working with investigators, patients, the College of American Pathologists, and NCI to further address this barrier.

In terms of other data issues, our case report forms are comprehensive, but not substantially different from other adjuvant trials. We collect relevant safety and efficacy parameters, and we propose to follow patients for longer than 10 years from enrollment in order to gather short- and long-term data.

Is ALTTO predominantly a European trial?

No, ALTTO is a global trial. We actually began proposing incorporation of adjuvant lapatinib in trials back in 2004, even before we had data from the pivotal trastuzumab studies. This was based on the prediction that trastuzumab would improve adjuvant outcomes, early preclinical data with lapatinib, and our prediction that it would be the most rational next step in adjuvant anti-HER2 trials. We then collaborated with investigators around the world, NCI, and industry to develop a single global study. The idea was, and is, to avoid duplication of efforts and to work together to advance the care of patients with early HER2-positive breast cancer. Because of regulatory issues and the IRB processes in the United States and Canada, the trial was activated first in Europe, but it is now active not only in North America and Europe but also on four other continents (50 countries total), making this a truly global collaboration.

A Closer Look

Cutting Calories to Prevent Cancer

Weight and height are used in computing body mass index, an indicator of risk for developing obesity-associated diseases. Weight and height are used in computing body mass index, an indicator of risk for developing obesity-associated diseases.

A great deal of effort has been spent trying to understand how the food we eat—diets that are high in red meat, vitamins, minerals, or fiber, for example—affects our cancer risk. A similar question, fueled no doubt by the rising rates of obesity around the world, relates to the calorie content of our diet. What happens if we simply take in fewer calories?

To survive and proliferate, all cells, including cancer cells, need energy. Since the early 1900s, researchers could see how this axiom might be used in treating cancer; their experiments showed that calorie reduction inhibited the growth of transplanted tumors in mice.

Today it is the most widely studied and effective strategy for prolonging survival in mammals, said Dr. Stephen Hursting, formerly a deputy director in NCI’s Division of Cancer Prevention and now the chair of the Department of Nutritional Sciences at the University of Texas.

“It is the most potent broadly acting dietary intervention we know of that actually prevents cancer in experimental models,” he said. A study that appeared July 10 in the journal Science, for example, provided some evidence that a diet 30 percent lower than normal may be delaying diseases and extending the lifespan of rhesus monkeys. It was the first study to test this long-term intervention in primates, but whether it works in humans, and in the real world, is a question that hasn’t yet been answered.

Watching What We Eat

Dietary interventions used in animal experiments are sometimes called dietary energy restriction (DER). Ad libitum is a term that describes eating freely as much as one wishes; DER reduces calories usually in the range of 10 to 40 percent below ad libitum.

Even small differences in energy intake have been shown to have an effect in animal studies, noted Dr. Henry J. Thompson, director of the Cancer Prevention Laboratory at Colorado State University. “In fact, as little as a 10 percent reduction from ad libitum correlates with significant health benefits,” he explained.

How DER may be causing these benefits is still unclear—is it a simple gross reduction of calories consumed, could the same effect be seen if more calories are burned with exercise, or is a combination of the two the optimal approach? Researchers have found some clues, which they are now using as the basis for several clinical studies in humans.

Moving Beyond Mice

By slowing the metabolic rate, DER seems to interfere with the production of reactive oxygen species and also interfere with cell growth factors and signals, impeding angiogenesis and bolstering tissue breakdown. And by diverting stored energy from growth and development to basic cellular survival, DNA replication appears to happen less often, with less energy available to drive the transformation of healthy cells into cancer cells.

Underfeeding mice to test these relationships is simple. The calories that animals eat each day can be limited to levels below what they would normally eat, which is usually in the range of 115 calories per week.

It’s much trickier to test DER in humans. Outside of observational studies, most of the clinical research on dietary restriction and cancer prevention has focused on those who are overweight or obese, a population for whom the health risks of staying at their current weight (including cancer) clearly warrant an intervention.

The largest project funded by NCI in this area is the Transdisciplinary Research on Energetics and Cancer (TREC) initiative, a $54 million, 5-year project that began in 2005 to help molecular biologists, nutritionists, clinicians, behavioral scientists, epidemiologists, and others who work in the diet/exercise/cancer arena translate findings from cells into mice and then into clinical studies more efficiently. Many of the TREC projects are studying factors that contribute to obesity, but some are looking more closely at the link between calories in/calories out and cancer.

At the Fred Hutchinson Cancer Research Center, for example, Drs. Cornelia Ulrich and Anne McTiernan, the principal investigator of the Hutchinson TREC Center, are leading a project with overweight or obese post-menopausal women who are put on a restricted-calorie weight loss diet, a moderate-intensity aerobic exercise regimen, or both. The study’s goal is to explore what happens with biomarkers that in mouse studies have been linked to carcinogenesis and DER.

Women in the general U.S. population who are aged 50 to 70 eat approximately 1,700 to 1,800 calories a day, according to a survey by the CDC in which participants recalled what they had eaten from the most recent day or two; in Drs. McTiernan and Ulrich’s study, women assigned to the diet arms of the experiment are restricted to somewhere between 1,200 and 1,500 calories a day, depending on their weight at the start. The goal is to reduce their weight by 10 percent in the first 6 months. Meanwhile, their blood is checked for markers of DNA damage and repair to lymphocytes. Inflammation markers, including interleukin 6, serum amyloid A, and C-reactive protein, are also checked to see how the interventions affect these factors, which have been linked with increased cancer risk and poorer outcomes for cancer patients.

“We want to know whether health benefits for cancer can be achieved if women exercise regularly, even if they do not lose much weight or, alternatively, if weight loss is essential, which is achieved more easily through caloric restriction,” Dr. Ulrich explained. “We can also figure out whether body fat loss or other changes in body composition are critical to reduce risk factors for cancer, or whether an increase in fitness is equally important.”

A previous study with this group has shown that women who are part of the exercise intervention (45 minutes a day of brisk exercise, like walking, 5 days a week) decreased C-reactive protein, one of their markers for inflammation, by 10 percent over the course of a year, while those in the control arm who performed simple stretches showed an increase of 12 percent in this marker. Measurements from the ongoing TREC trial of exercise and caloric restriction will be collected in the next few months, with the results most likely published early in 2010.

More than Simple Subtraction

Most evidence shows that people resist lifestyle changes, even when it is clear that what they are doing may eventually kill them after making them very, very sick. With overweight and obesity, the issue is especially complicated because of contributing socioeconomic and cultural factors.

Dr. Linda Nebeling, who oversees the TREC initiative and is chief of the Health Promotion Research Branch in NCI’s Division of Cancer Control and Population Sciences, says that an important result from the TREC studies will be helping clinicians understand why it is physiologically harder for some people to lose weight through simple diet and exercise than it is for others.

“We used to think that body fat was inert, basically nothing more than a storage tank. But now we know that it is very different,” she explained. “Body fat has hormonal effects, it influences how your body responds to physiologic demands, and even the kinds of fat in our bodies—whether it’s brown or white fat, located within the muscle or wrapped around your abdomen like a blanket—can make a difference.” Learning about the biomarkers associated with cancer risk and obesity, weight loss, dietary energy restriction, and exercise may one day help clinicians tailor their interaction with patients for more effective cancer prevention strategies, Dr. Nebeling said.

Featured Clinical Trial

Combining Immunotoxin and Chemotherapy for Pleural Mesothelioma

Name of the Trial
Phase I Study of SS1(dsFv)-PE38 Immunotoxin in Combination with Pemetrexed Disodium and Cisplatin in Patients with Unresectable Malignant Epithelial Pleural Mesothelioma (NCI-08-C-0026). See the protocol summary.

Dr. Raffit Hassan Dr. Raffit Hassan

Principal Investigator
Dr. Raffit Hassan, NCI Center for Cancer Research

Why This Trial Is Important
Malignant mesothelioma is a rare cancer that affects the tissue lining the chest (pleura) or the abdomen (peritoneum). Based on the appearance of the cancer cells under a microscope, mesothelioma is classified as epithelial, sarcomatoid, or mixed; epithelial mesothelioma is associated with slightly better outcomes than the other types.

Patients with pleural mesothelioma (mesothelioma of the pleura) that cannot be removed by surgery (unresectable or inoperable) are usually treated with combination chemotherapy using the drugs pemetrexed and cisplatin. Although this therapy can delay progression of the disease, the benefits are often short lived and most patients die within 2 years.

Researchers hope an experimental immunotoxin called SS1(dsFv)-PE38 (or SS1P) can improve the outcomes of patients with unresectable mesothelioma. SS1P is a genetically engineered biological agent in which part of a bacterial toxin is linked to an antibody that recognizes the protein mesothelin. Mesothelin is found in abundance on the surface of epithelial mesothelioma cells and cells of several other types of cancer. In laboratory studies, combining SS1P with chemotherapy leads to increased antitumor activity compared with either therapy alone.

In this trial, patients with inoperable epithelial pleural mesothelioma will be given SS1P in combination with pemetrexed and cisplatin. The dose of SS1P will be increased in consecutive groups of 3–6 patients until the maximum tolerated dose is reached. Researchers will also study any side effects of this combination treatment and examine how SS1P is broken down by the body.

“Mesothelin is highly expressed in epithelial malignant mesothelioma, making it a good target for tumor-specific therapy with SS1P,” said Dr. Hassan. “Given the marked synergy between SS1P and chemotherapy in preclinical studies, combining them could potentially result in increased antitumor activity in patients.” 

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.

Community Update

Oncology Nursing
This is the first article in a new series of stories related to oncology nursing. Look for the symbol on the left in an upcoming issue for the next article in the series.

Making a Difference: Nurses Help Cancer Patients Quit Smoking

One of the most cost-effective ways to improve the care of many patients with cancer is to help smokers stop smoking. Quitting increases a patient’s chances of responding to a particular treatment and it can reduce complications as well as the risk of a recurrence—all of which can save precious health care resources.

While the benefits of quitting smoking after a diagnosis of cancer are clear to researchers, many patients and even health care professionals have not heard this message. That is starting to change. A group of nurse scientists is working to increase awareness among cancer nurses through publications, professional meetings, and Web conferences in some states. At the same time, this group is using new research to develop policies that support their efforts.

“We know that quitting is tough and that patients need support. But just because it’s hard doesn’t mean we shouldn’t try to help these patients.” - Dr. Linda Sarna

As the Oncology Nursing Society (ONS) said in a recent statement on global tobacco use, the leadership and active involvement of nurses will be required to address the worldwide epidemic of smoking-related illnesses.

“Nurses are in a perfect position to do this work,” said Dr. Linda Sarna, a professor at the UCLA School of Nursing and a leader in the field. “We’ve found that a certain percentage of patients continue to smoke after a diagnosis of cancer, and that speaks to the challenges of breaking dependence on tobacco.”

With their knowledge of medications and skills in supporting patients, cancer nurses are uniquely able to help. At all stages of cancer care, from prediagnostic screening to hospital stays and outpatient visits, nurses can identify patients who smoke and assess their willingness to quit. Just as important, studies have shown that when cancer nurses deliver smoking cessation treatments to patients, quit rates rise.

The problem has been that many nurses in cancer care are not aware of the benefits of quitting smoking after the diagnosis of cancer, said Dr. Stella Bialous, president of Tobacco Policy International and a consultant for the World Health Organization. “The biggest challenge has been to make nurses realize that they are incredibly powerful in helping patients with cancer quit smoking.”

“Quitting Is Tough”

Although medications are available to help with the withdrawal symptoms, research suggests that many smokers with cancer are not getting the help they need to quit.

In a recent study of 94 patients with potentially curable lung cancer, only half of the patients who smoked received cessation treatments prior to surgery. And only one patient received the recommended treatment (counseling plus medication). The study also found high rates of smoking relapse in those who were able to quit, including those who had quit more than a year prior to surgery.

Even for patients whose cancers are potentially curable by surgery, quitting can be a challenge, the researchers, led by Dr. Mary Cooley of the Dana-Farber Cancer Institute, concluded. Nonetheless, it is essential for patients to quit smoking in order to improve their survival and quality of life, Dr. Cooley stressed.

“We know that quitting is tough and that patients need support,” commented Dr. Sarna. “But just because it’s hard doesn’t mean we shouldn’t try to help these patients. This is what a good nurse has to do. This must be part of good cancer care.” 

Overcoming Barriers

Like millions of Americans, some nurses also smoke, and researchers believe that this has prevented some nurses from participating fully in efforts to reduce patient tobacco use. To address this problem, Dr. Sarna led the creation of a national program called Tobacco Free Nurses, which includes a Web site dedicated to helping nurses and student nurses stop smoking. The program, funded by the Robert Wood Johnson Foundation, has ended, but the Web site continues to offer resources on tobacco control for all nurses.

Misconceptions among nurses have also hampered efforts, most notably the idea that patients who smoke do not want to quit. In fact, studies suggest just the opposite—patients do want to quit and expect to discuss this with their care providers. For this reason, researchers have encouraged nurses to “not be squeamish” about bringing up the subject.

Another barrier has been lack of training. Most nurses, like most health care professionals, are not trained to help patients quit smoking, leaving some nurses to feel as though they don’t know enough to help patients.

“Once nurses get over the misconception that patients don’t want to quit, the next biggest barrier is the lack of training,” said Dr. Bialous. “We need to get nurses feeling comfortable about doing this work, even if it is just a minimum-level intervention followed by referring patients to a nurse or cessation specialist who can do more, or to the toll-free telephone quitline.” A single nurse with expertise on smoking cessation may serve both patients and nurses in hospital settings as a source for referrals, she added.

Finally, the difficulty of discussing tobacco use near the end of a patient’s life may dissuade some nurses from doing so, particularly when patients blame themselves for smoking-related cancers. But researchers are quick to point out that there are serious safety risks here, too, especially for smokers who use oxygen or are sedated.

Stressful Time

“We have to acknowledge that it is a very stressful time when patients are trying to quit smoking, but all health care providers, and nurses in particular, can tell patients that there are now effective drugs to help them get over some of the symptoms and discomfort associated with withdrawal,” said Dr. Mary Ellen Wewers, a nurse scientist at Ohio State University who has pioneered research in the field. “And in the hospital, the nurse is right there at the bedside and can deliver the behavioral counseling that is so effective,” she added.    

Because smokers tend to live in families that smoke, Dr. Wewers stressed the importance of trying to reach out to the family members of patients. When a family member who smokes brings in a patient for treatment, she noted, it can be an opportunity to discuss smoking cessation with the relative as well.

Important questions about how best to reduce smoking among patients with cancer are still unanswered, including which types of cessation treatments patients prefer and why resources such as online and telephone quitlines are not more widely used. These are questions for future studies.

In the meantime, the leaders of this emerging movement believe there is both momentum and unprecedented interest among nurses. They note that presentations on tobacco control at professional nursing meetings have been packed of late, something that few could have imagined a few years ago.

“This is a very exciting time to be an oncology nurse,” said Dr. Bialous. “We are starting to reach a critical mass at the level of policy making. And among nurses at the staff level, there is both a need and eagerness to learn more and do more.”

—Edward R. Winstead

FDA Update

Black Box Warnings Added to Two Smoking Cessation Drugs

The FDA now requires the addition of “black box” warnings to the labels of two popular smoking cessation drugs, varenicline (Chantix) and bupropion (Zyban). The new warnings caution users about the risk of “serious neuropsychiatric symptoms” associated with both drugs, according to a safety alert issued to clinicians by the FDA, including “hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide.”

Varenicline and bupropion are on the list of recommended first-line medications in the U.S. Public Health Service’s clinical practice guidelines, Treating Tobacco Dependence and Use. A meta analysis found that both cessation drugs at least double the likelihood of long-term (more than 5 months) abstinence from smoking compared with placebo.

The addition of a warning label to both drugs stems from a review by FDA officials of reports to the agency’s Adverse Event Reporting System. Although the adverse event reports often included a “temporal relationship” between use of either of these drugs and suicidal thoughts or behavior “in patients with no history of psychiatric disease,” the report also noted that some of these symptoms may have been “confounded by symptoms typically seen in people who have stopped smoking and are experiencing withdrawal from nicotine.”

The alert advised health care professionals to recommend against continued use of these drugs in patients experiencing any of these symptoms or “any changes in behavior that are not typical of nicotine withdrawal,” along with continued monitoring until the symptoms resolve.

“The risk of serious adverse events while taking these products must be weighed against the significant health benefits of quitting smoking,” said Dr. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research. “Smoking is the leading cause of preventable disease, disability, and death in the United States and we know these products are effective aids in helping people quit.”

Agency Approves First Maintenance Chemotherapy Agent for NSCLC

The first-ever “maintenance therapy” for patients with certain subtypes of advanced or metastatic non-small-cell lung cancer (NSCLC) has been approved by the FDA. The drug, pemetrexed (Alimta), is already approved for patients with NSCLC whose disease has progressed after chemotherapy and as a first-line treatment for patients with advanced NSCLC.

The approval is based on results from a phase III clinical trial presented at the recent American Society of Clinical Oncology annual meeting, in which patients with subtypes other than squamous cell NSCLC had an improved median overall survival (15.5 months versus 10.3 months) when they continued to receive pemetrexed following the completion of standard chemotherapy compared with patients who received a placebo.

“This drug represents a new approach in the treatment of advanced non-small-cell lung cancer,” said Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research.

Notes

State-of-the-Science Conference on Ductal Carcinoma In Situ Slated for September

Logo for NIH State-of-the-Science Meeting on Ductal Carcinoma In Situ

On September 22–24, NCI and the NIH Office of Medical Applications of Research will convene a state-of-the-science conference on ductal carcinoma in situ (DCIS) at the Natcher Conference Center on the NIH campus. The conference will address the following key questions:     

  • What are the incidence and prevalence of DCIS and its specific pathologic subtypes, and how are incidence and prevalence influenced by mode of detection, population characteristics, and other risk factors?
  • How does the use of MRI or sentinel lymph node biopsy impact important outcomes in patients diagnosed with DCIS?
  • How do local control and systemic outcomes vary in DCIS based on tumor and patient characteristics?
  • In patients with DCIS, what is the impact of surgery, radiation, and systemic treatment on outcomes?
  • What are the most critical research questions for the diagnosis and management of DCIS?

Invited experts will present information pertinent to these questions, and a systematic literature review will be summarized. Conference attendees will have the opportunity to ask questions and provide statements during open discussion periods. After weighing the scientific evidence, an unbiased, independent panel will prepare and present a consensus statement addressing the key conference questions.

The conference is free and open to the public but advance registration is recommended. Go online to find more information and register.

Chemical Biology Consortium Kick-off Meeting Set for August

Logo for NCI's Chemical Biology Consortium meeting

NCI invites the drug discovery and development communities to the inaugural meeting of the Chemical Biology Consortium (CBC), which will be held August 10 at the Natcher Conference Center on the NIH campus.

The CBC is part of a new, rapidly evolving NCI Experimental Therapeutics (NExT) program, which is opening the oncology drug discovery and development pipeline to researchers in academia, industry, and the government. The CBC will be one entry point into the pipeline and it will interface with other NCI programs that aim to expedite new drugs from the laboratory to the bedside.

The day-long meeting will showcase the 11 newly established CBC centers, chosen by NCI for their world-class screening and chemistry qualifications.

More meeting information and registration are available online.

Manifesto on Childhood Cancer Emerges from Meeting in Senegal

Dakar Manifesto

Representatives from 21 countries met in Dakar, Senegal, on July 1 and 2 to review progress and strengthen measures in the fight against cancer in low- and middle-income countries through the My Child Matters program, created in 2004 by the International Union Against Cancer (UICC).

At the Dakar meeting, experiences were shared by representatives from Bangladesh, Burkina Faso, Cameroon, Côte d’Ivoire, Egypt, France, Honduras, Italy, Kenya, Mali, Morocco, the Netherlands, Paraguay, the Philippines, The Republic of Congo, Senegal, Switzerland, Tanzania, Turkey, Ukraine, and the United States. Dr. Joe Harford, director of NCI's Office of International Affairs and member of the My Child Matters steering committee, represented NCI at the meeting and gave the opening lecture, “The Burden of Cancer in Africa.”

Meeting participants signed the Dakar Manifesto, which calls on all stakeholders and institutions concerned for more participation and action to improve the outcome of childhood cancers around the world.

My Child Matters is one of the largest initiatives dedicated to fighting childhood cancer in low- and middle-income countries. With support from sanofi-aventis, it has supported 33 field projects led by hospitals and nongovernmental organizations in 21 countries on 4 continents to improve cancer care, including providing better information, education, and prevention; improving professional training and ensuring earlier diagnosis; fostering better access to health care, pain management, and palliative care; and increasing understanding of the social aspects of this disease, both for children and their families. By the end of 2008, more than 12,800 children and 6,600 families had been helped by this program, and some 2,850 health care professionals had received training.

New Issue of CCR Connections Released

cover of CCR Connections

NCI’s Center for Cancer Research (CCR) recently released a new issue of its news magazine, CCR Connections. The Web version of volume 3, issue 1 is available online.

In the latest issue, readers will find features on metastatic cancer and Wnt signaling in cancer development and progression, a commentary by former CCR fellow Dr. Aurora Medina-Sanson, and information on recent journal articles and staff awards.

CCR Connections is published semiannually. Send a request for a print or online subscription to tellccr@mail.nih.gov.

New State Cancer Legislative Database Newsletter and Fact Sheet Now Available

cover of State Cancer Legislative Database

NCI’s State Cancer Legislative Database (SCLD) Web site has been updated. A fact sheet on cancer screening and the spring 2009 issue of the SCLD Update have been added to the site. This latest issue of the SCLD Update includes a summary of enacted legislation and adopted resolutions between January and March 2009, as well as a legislative data “byte” highlighting the number of states with measures related to private health insurance coverage for breast cancer treatment services.

The SCLD program contains information synthesized from state-level laws. SCLD does not contain state-level regulations; measures implemented by counties, cities, or other localities; case law; Attorneys General opinions; or data addressing the implementation of state laws—all of which may vary significantly from the laws reported by the SCLD. For more information, go to http://www.scld-nci.net.