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May 19, 2009 • Volume 6 / Number 10

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NEWS

A microscopic view of a typical neuroblastoma with rosette formation An Experimental Treatment Improves Survival for Patients with Neuroblastoma

An experimental treatment significantly improved progression-free survival in patients with neuroblastoma at high risk for recurrence, including many young children, researchers from the Children’s Oncology Group reported last week. Speaking at a press briefing sponsored by the American Society of Clinical Oncology, the trial’s lead investigator, Dr. Alice Yu from the University of California, San Diego, said the finding makes the treatment—an antibody-based immunotherapy—“the new standard of care” for patients with high-risk neuroblastoma. Read more > >

COMMENTARY

Dr. Robert Yarchoan

Guest Director's Update: Marking a Memorable Moment in AIDS Research

By Dr. Robert Yarchoan

NCI has played a critical role in HIV- and AIDS-related research from the day in 1981 when one of the first AIDS patients was admitted to the NCI Metabolism Branch. NCI's advances in AIDS research, in part, resulted from the Institute's long-term commitment to research on the interrelationship between viruses and cancer. Read more > >

IN DEPTH

UPDATES

  • FDA Update

    • Bevacizumab Approved for Recurrent Glioblastoma Brain Cancer

    Notes

    • In Memoriam: NCI's Dr. John Brady
    • Deadline Approaching for DCLG Nominations
    • IOTF Fellowship Program Seeks Applicants
    • Women's Health Hearing and Workshop Series Continues
    • NCI Cancer Bulletin Writer Wins NAGC Award
    • Meet NCI Experts at ASCO

    Cancer.gov Update

    • Smokefree Women Web Site Launched
    • NCI Publications Locator Web Site Improved

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

An Experimental Treatment Improves Survival for Patients with Neuroblastoma

A microscopic view of a typical neuroblastoma with rosette formation A microscopic view of a typical neuroblastoma with rosette formation

An experimental treatment significantly improved progression-free survival in patients with neuroblastoma at high risk for recurrence, including many young children, researchers from the Children’s Oncology Group (COG) reported last week. Speaking at a press briefing sponsored by the American Society of Clinical Oncology (ASCO), the trial’s lead investigator, Dr. Alice Yu from the University of California, San Diego, said the finding makes the treatment—an antibody-based immunotherapy—“the new standard of care” for patients with high-risk neuroblastoma.

Because of the significant early benefit seen in patients given the experimental treatment, randomization in the NCI-sponsored trial was stopped and the trial was altered so that all enrolled patients can receive the immunotherapy. “We are expending an enormous amount of effort to ensure that this treatment can be available to those children with neuroblastoma for whom the immunotherapy has been shown to be effective,” said Dr. John Maris from the Children’s Hospital of Philadelphia and chair of COG’s Neuroblastoma Committee.

Neuroblastoma is the most common cancer diagnosis in the first year of life. The disease arises in children in the developing cells of the sympathetic nervous system, and it often appears as a tumor in the chest or abdomen. Overall, more than 90 percent of those under 1 year of age survive for 5 years, but rates are much lower for patients who have distant disease.

The trial, which will also be presented in 2 weeks at the ASCO annual meeting in Orlando, involved more than 220 patients with certain clinical and biological factors that put them at high risk for recurrence. The trial’s main objective was to determine the role in the treatment of high-risk neuroblastoma of the ch14.18 monoclonal antibody. The antibody stimulates an immune response to the tumor by binding to a glycolipid (a fat molecule attached to a carbohydrate) known as GD2 that sits on the surface of neuroblastoma cells.

All patients in the trial had responded to standard therapy, which includes intensive chemotherapy, surgery, and a stem cell transplant, followed by radiation therapy. Half were then randomized to receive standard treatment with 13-cis-retinoic acid (RA) alone, while the others received RA plus the experimental treatment, consisting of the ch14.18 monoclonal antibody plus an alternating regimen of two immune-stimulating cytokines, GM-CSF and IL-2.

Progression-free survival at 2 years was 66 percent in the immunotherapy arm and 46 percent in the standard treatment arm, and overall survival at 2 years was 86 percent and 75 percent, respectively. Some significant side effects were associated with the immunotherapy, including pain and an accumulation of fluid in the body caused by vascular leakage, but they were “quite manageable and reversible,” Dr. Yu said.

The trial marks several firsts, Dr. Yu noted, including being the first study to definitively demonstrate that a monoclonal antibody-based immunotherapy with cytokines is an effective cancer treatment. NCI’s Cancer Therapy Evaluation Program (CTEP) is sponsoring clinical trials of the ch14.18 monoclonal antibody, and NCI’s Biopharmaceutical Development Program (BDP) at NCI-Frederick is manufacturing the agent. NCI has on hand a supply of ch14.18 that is being used to treat patients in the trial, said Dr. Stephen Creekmore, chief of NCI’s Biological Resources Branch. BDP is continuing to produce the agent, he added, and more will be available in 2010.

NCI is seeking private-sector collaborators for the continued development of ch14.18 through a Cooperative Research and Development Agreement. Based on the trial results, said Dr. Malcolm Smith, CTEP’s associate branch chief for pediatric oncology, several biotechnology companies have expressed interest in further developing the antibody for commercialization.

The COG study will continue as an “open-label” trial so that children with neuroblastoma can receive the effective immunotherapy. NCI will also sponsor a new ch14.18 clinical trial through COG that will allow collection of additional toxicity and safety data to help support an application to the FDA for marketing approval of ch14.18.

The COG study results, Dr. Smith stressed, “are a critical step in a more than 20-year line of research on antibody-based immunotherapy by NCI and NCI-supported researchers to bring a new life-saving treatment to children with aggressive neuroblastoma.”

—Carmen Phillps

Cancer Research Highlights

Ginger Helps Reduce Nausea from Chemotherapy

Ginger helped prevent or reduce chemotherapy-induced nausea when taken with traditional anti-nausea drugs by patients with cancer, researchers have found. The results are from a randomized, double-blind, placebo-controlled clinical trial, the largest study to examine the potential effects of ginger on chemotherapy-related nausea. The study will be presented May 30 at the ASCO annual meeting in Orlando, FL.

“We have found that ginger supplementation is an effective tool against chemotherapy-related nausea,” said lead investigator Dr. Julie Ryan of the University of Rochester Medical Center, who discussed the findings at a press briefing last week. All doses of ginger evaluated in the study significantly reduced nausea compared with placebo, she noted.

The trial, funded by NCI’s Community Clinical Oncology Program, included 644 patients, most of them women, who were receiving chemotherapy for breast, digestive, lung, or other cancers. These patients received a placebo or one of three doses of ginger (0.5 g, 1.0 g, or 1.5 g) for 6 days, including 3 days leading up to the first day of chemotherapy and 2 days after chemotherapy began. They also received traditional anti-nausea medications during the study. Patients rated their nausea four times per day on a scale of 1 to 7.

Each dose of ginger was more effective than the placebo at mitigating nausea. The most effective doses were either 0.5 g or 1.0 g, taken during the first day of chemotherapy. Effectiveness decreased linearly over a 24-hour period. The highest dose may not be as effective, the researchers speculated, because it is more than the maximum absorption dose for biological activity.

Sentinel Lymph Node Biopsy Suitable for Staging Penile Carcinoma

A new study led by the Netherlands Cancer Institute (NKI) and published online May 4 in the Journal of Clinical Oncology confirms that sentinel lymph node biopsy (SLNB) is a valid staging option for men with early stage penile cancer.

Removal of the lymph nodes in the groin (called inguinal lymph node dissection) is often performed in patients who have early stage penile carcinoma and no obvious lymph node metastases to prevent the possible growth of undiscovered metastases. However, this procedure can cause significant long-term side effects and may be unnecessary in 75 to 80 percent of these patients.

Researchers from two institutions performed SLNB on 323 patients using a modified procedure involving ultrasound imaging and other improvements to reduce the rate of false-negative results seen in earlier studies. Lymphatic mapping after surgery to remove the primary tumor was performed 596 times (including both sides of the body in most patients). Seventy-nine groins contained a sentinel lymph node positive for tumor cells; these patients underwent immediate inguinal lymph node dissection. Patients with a negative SLNB did not have further surgery.

After a median follow-up period of 17.9 months, the overall false-negative rate was 7 percent: 6 patients with negative SLNB had an inguinal recurrence of their cancer. The researchers pointed out that no learning curve was seen when the modified procedure was introduced from the first institution to the second; the earlier procedures performed at the second institution were not more likely to produce false-negative results.

Although the authors caution that a longer follow-up time may reveal more false-negative results, they conclude that “with the use of an up-to-date protocol, sentinel node biopsy for penile carcinoma is a suitable procedure to identify patients with clinically node-negative disease who have occult metastasis…The risk of a false-negative procedure should be weighed against the morbidity of an elective inguinal lymph node dissection.”

Three Genes Help Breast Cancer Invade the Brain

Breast cancer can appear in the brain years after a tumor in the breast has been removed. This, researchers say, suggests that breast cancer cells must acquire special abilities in order to metastasize to the brain, possibly through the activation of certain genes. Three genes involved in this process in mice have now been identified by Dr. Joan Massagué of Memorial Sloan-Kettering Cancer Center (MSKCC) and his colleagues, according to a study published online in Nature on May 6.

While the research is in its early stages, the hope is that it could eventually lead to new strategies for preventing and treating brain metastases. These are needed because many women are living longer with breast cancer and, as a result, the incidence of brain metastases in breast cancer is rising.

Two of the genes, COX2 and HBEGF, were found to help breast cancer cells enter into the brain. These genes were previously found to help breast cancer cells invade the lungs. A shared mechanism underlying breast cancer’s spread to the brain and lungs may help explain why some patients develop the disease in both organs, the researchers said.

But additional mediators seem to be required to help cancer cells get across the blood-brain barrier, which prevents harmful substances from reaching the brain. A third gene, ST6GALNAC5, may offer assistance. Though the gene is normally active only in brain tissue, it appears to help breast cancer cells acquire a “coating” that allows them to cross into the brain, the researchers reported.

“The next step is to develop a better understanding of how these three genes allow the tumor cells to get into the brain,” said Dr. Paula D. Bos of MSKCC, the study’s first author. “Other genes are almost certainly involved, and we will use our model to find and evaluate them,” she added.

DEAR1 Gene May Help Drive Early-onset Breast Cancer

In a new study led by researchers at the University of Texas M.D. Anderson Cancer Center, a gene has been identified that regulates the development of the cells that form milk-secreting glands in the breast. The gene, called DEAR1, is mutated or not expressed in many cases of early-onset breast cancer, and it may also serve as a biomarker for identifying patients at high risk of local recurrence.

After using a technique called suppression subtractive hybridization to identify DEAR1 as a gene of interest, the researchers tested cell lines and tissue samples to determine its role in breast cancer. Expression of DEAR1 was absent or reduced in six out of eight breast cancer cell lines examined; in addition, 13 percent of 55 primary breast tumor samples tested contained DEAR1 mutations.

The researchers used gene-transfer techniques to restore DEAR1 expression in a breast cancer cell line. Without DEAR1, over 60 percent of the cultured cells formed large, disorganized structures. With the introduction of DEAR1, more than 80 percent of cells produced small, normal-shaped structures. When the gene was silenced in normal breast cells, they failed to form normal structures and instead showed morphology similar to breast cancer cells.

The researchers screened tissue samples from 158 premenopausal women with breast cancer and found that 56 percent of the tumor samples had completely lost DEAR1 expression, noting that this “correlated with a strong family history of breast cancer in this young cohort.” Loss of DEAR1 expression also correlated significantly with triple-negative breast cancer, which is the most difficult type to treat successfully.

Because DEAR1 expression was also a significant prognostic marker for local recurrence in early-onset tumors, the authors suggested that measurement of DEAR1 expression “could be an important marker to stratify early-onset breast cancer patients for increased vigilance in follow-up and adjuvant therapy.”

Formaldehyde May Cause Some Blood Cancers, but Risk Drops over Time

Follow-up data from an ongoing study of U.S. industrial plant workers exposed to formaldehyde support previous findings of a possible link between formaldehyde exposure and risk of death from cancers of the blood and lymphatic system. The latest report by NCI researchers, which appeared online May 12 in the Journal of the National Cancer Institute, includes data through 2004, extending the previous observation period by 10 years.

Since the 1980s, researchers from NCI’s Division of Cancer Epidemiology and Genetics have studied a cohort of 25,619 people who worked in 10 formaldehyde-using or -producing plants before 1966. The researchers estimated formaldehyde exposure among the workers by a number of methods, including the use of monitoring data and information about individual jobs. Death certificates and the National Death Index were used to record mortality and the cause of death.

Their analysis showed that, overall, those who were exposed to formaldehyde had a risk of death from all causes that was similar to that of the general U.S. population. However, workers with highest peak exposure to formaldehyde had a statistically significant relative risk (RR) of 1.37 for death from blood or lymph cancer compared with those at the lowest level of peak exposure. This represents an excess risk of death from several specific cancers, including Hodgkin lymphoma, multiple myeloma, and myeloid leukemia—the type most often associated with chemical exposure. The observed increase in risk of death from myeloid leukemia was 1.78, and 1.42 for all leukemias. The highest level of increased risk of death from myeloid leukemia in this study occurred early on and has been declining steadily over time. This pattern could be due to chance, but the investigators note that similar risk patterns over time have been seen for agents that are known to cause leukemia relatively soon after exposure.

The relationship was observed only for those who had been exposed to formaldehyde at the highest level of peak exposure relative to members of the cohort who had minimal exposure. There were no significant relationships observed when exposure was classified using average-intensity or cumulative exposure.

ALSO IN THE NEWS

Canary Foundation and NCI Team up to Fund Lung Cancer Research

The nonprofit Canary Foundation and NCI’s Early Detection Research Network (EDRN) recently announced a new funding partnership to find biomarkers to detect early stage lung cancer in people who have never smoked. Researchers at five institutions in the United States will use this new funding initiative to study cell lines, tissue, and blood samples from such people who developed the disease. The EDRN and Canary Foundation are each providing initial funding of $1 million for the initiative. More information, including a list of the funded projects, is available online.

Guest Director's Update

Marking a Memorable Moment in AIDS Research

Dr. Robert Yarchoan

By Dr. Robert Yarchoan
Director, NCI's Office of HIV and AIDS Malignancy

I had the honor recently of joining an illustrious group of scientists and scientific leaders at a symposium to honor Dr. Robert C. Gallo on the 25th anniversary of his reports on the co-discovery of HIV, the proof that it was the cause of AIDS, and the development of the first blood test for HIV. The co-discovery of HIV—work done by Dr. Gallo’s group, then at NCI, and that of Dr. Luc Montagnier, then at the Pasteur Institute in France—was a seminal moment in biomedical research. It provided the tools to stop the spread of AIDS by blood transfusion, and allowed researchers to rapidly develop effective treatments for AIDS, which had emerged as a global health threat only a few years earlier.

NCI has played a critical role in HIV- and AIDS-related research from the day in 1981 when one of the first AIDS patients was admitted to the NCI Metabolism Branch. NCI’s advances in AIDS research, in part, resulted from the Institute’s long-term commitment to research on the interrelationship between viruses and cancer. I was fortunate to be part of a research team, alongside Drs. Samuel Broder and Hiroaki Mitsuya, that helped to develop and clinically test the first therapies—zidovudine (AZT), dideoxycytidine (ddC), and dideoxyinosine (ddI)—that could effectively treat HIV. As Dr. Broder pointed out in his talk at the Gallo symposium, this work took place with astonishing speed: HIV was shown to be the cause of AIDS just 3 years after AIDS was recognized, and AZT received FDA approval as the first AIDS drug less than 3 years later. It is estimated that advances in the treatment of HIV infection have saved more than 3 million person-years of life in the United States alone.

Our success in preventing and treating AIDS, however, has also led to many new challenges. Perhaps foremost among them is the increasing problem of cancer and the expanding array of tumor types in people with AIDS. In fact, cancer is emerging as the most common cause of death in HIV-infected patients, many from tumors that previously had not been strongly associated with AIDS, such as cancers of the head and neck, anus, and lung.

We cannot forget that, despite our success, we still do not have an AIDS vaccine, and AIDS kills nearly 175,000 people a month worldwide. In the developing world, many of these deaths are due to AIDS-related malignancies, especially in Africa, where Kaposi sarcoma was a common tumor even before the AIDS epidemic. So, clearly, we still have much to accomplish. That is part of the reason why NCI Director Dr. John E. Niederhuber formed the NCI Office of HIV and AIDS Malignancy (OHAM), a new venture that he has asked me to lead. OHAM’s role will be to coordinate and provide broad oversight for the HIV and AIDS malignancy research at NCI.

NCI’s AIDS- and HIV-related research programs include research on new preventive and therapeutic vaccines, HIV drug resistance, and HIV-related malignancies, among others. OHAM will focus on strengthening collaboration and broadening the impact of NCI’s HIV- and AIDS-related research. Greater collaboration can help bridge work being done in the laboratory and clinic, creating a plethora of opportunities to conduct important translational research.

Yes, there are still significant challenges to overcome, particularly in developing countries where access to modern AIDS therapies can be very limited and where AIDS-related malignancies have exacted a great toll. As Drs. Gallo and Montagnier exhorted in marking the 25th anniversary of their discovery, these are challenges that the world public health community must jointly address.

For my part, it has been gratifying to use science to end human suffering and to see one’s work lead to such progress in a relatively short period of time. I’m hopeful that we will see even greater progress in the next 25 years, and I’m confident that NCI will continue to play a valuable part in this effort.

Special Report

Decades Later, Seeing the Benefits of Radiation after Prostate Surgery

Many cases of prostate cancer progress so slowly that it can literally take decades to learn whether a treatment works. Just ask Dr. Ian Thompson, who chairs the department of urology at the University of Texas Health Science Center at San Antonio. In 1985, he was a young researcher just starting out when he proposed a study to find out whether the practice of giving radiation therapy to some men after prostate cancer surgery was actually helping and not just causing side effects.

'The field is now convinced that there is a benefit from adjuvant radiation therapy for the right patients.' -Dr. Eric A. Klein

About a third of men with this cancer who elect to have their prostates removed surgically learn, after the operation, that the disease has spread beyond the confines of the prostate. Dr. Thompson and his colleagues wanted to know whether giving additional (adjuvant) radiation, as was being done at the time, could delay a recurrence and prevent metastatic disease.

Two decades later, they have their answer. Men in the trial who received radiation therapy within 12 weeks of surgery delayed a recurrence of the cancer, and this led to longer survival compared with men with did not receive the treatment. Results from the randomized 425-person trial, which was sponsored by the Southwest Oncology Group (SWOG), appeared in the March Journal of Urology.

This evidence is bolstered by similar results from Europe. Last week, German investigators reported in the Journal of Clinical Oncology that adjuvant radiation therapy reduced the risk of prostate cancer progression compared with men who did not have the therapy. Though only the SWOG trial has had enough data to report on survival, the collective results all point in the same direction.

“It took 20 years, but we now know that adjuvant radiation therapy does reduce a man’s risk of developing metastatic cancer and it can improve survival by almost 2 years,” said Dr. Thompson. “In a disease that is as common as prostate cancer, this advance will affect tens or hundreds of thousands of men for many years to come.”

Tremendous international cooperation among investigators and long-term commitments from more than 1,800 participants led to the advance, Dr. Thompson noted. The SWOG trial was a partnership between U.S. and Canadian researchers, while the other trials were led by the German Cancer Society and the European Organization for Research and Treatment of Cancer (EORTC).

A Question of Timing

“The field is now convinced that there is a benefit from adjuvant radiation therapy for the right patients,” said Dr. Eric A. Klein, chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic. But the success of these studies, he noted, has raised a question that may be harder to answer: When is the optimal time to give the radiation?

Specifically, will benefit be the same whether the radiation comes immediately after surgery or later on, only after a man shows signs of a recurrence?

Considering the time and resources that would be involved, a trial that could answer this question seems unlikely, the researchers said. But clues may eventually come from a British and Canadian study called RADICALS that, in part, will compare radiation after surgery with radiation at the time of progression, or salvage radiation therapy.

Some physicians advocate withholding radiation until there is evidence of a recurrence in order to spare men who may not need the treatment. After all, not every candidate for the treatment will develop life-threatening disease, and those who do develop a recurrence can be identified by rising blood levels of the prostate specific antigen, or PSA, a protein marker for prostate cancer.

The choice “is really a matter of philosophy more than anything else,” Dr. Klein said, though he noted that radiation therapy has side effects such as urethral strictures, which can be hard to treat and lead to a condition called bladder outlet obstruction or incontinence.

More side effects were reported in the radiation therapy group in the SWOG trial, but after the first few years both groups reported a similar quality of life. The people who seemed to benefit the most from the radiation therapy were the men at the highest risk of a recurrence, based on the pathology report and other factors.

There is no evidence yet that salvage radiation therapy is associated with an improvement in survival, Dr. Thompson cautioned. And one of his concerns, based on the study results, is that for some men, by the time a recurrence is evident it may be too late to control the cancer.

Nonetheless, among his patients, only some men who are eligible for adjuvant radiation choose the treatment. Men who are feeling better after surgery and want to avoid additional side effects often choose surveillance, he said, while men who, above all else, want to control the cancer opt for radiation. The choice is up to them.

“As physicians, we work for the patient,” said Dr. Thompson. “In the age of evidence-based care, our responsibility is to inform these men about the results of the three clinical trials, and let them decide which approach is the best fit for them.”

—Edward R. Winstead

Spotlight

Comparative Effectiveness Research Stirs Excitement as Well as Debate

'There are 18,000 randomized trials conducted every year and yet we always say we don't have enough good evidence.' -Dr. Steven Pearson

It doesn’t take a randomized clinical trial, the joke goes, to prove that it’s unwise to leap from an airplane without a parachute. However, randomized clinical trials have been vital in helping clinicians make informed choices about patient care, whether in treating advanced colorectal cancer or controlling high blood pressure.

Unfortunately, much of the treatment and medical management provided in the United States—some estimates suggest nearly half of all the care delivered—doesn’t have a large cache of evidence to support its effectiveness, many health services researchers stress. The result, they argue, is uneven, sometimes poor-quality care that varies greatly from region to region and that’s often accompanied by a hefty price tag.

One potential remedy for this dilemma that has been touted by the Institute of Medicine (IOM), among others, is comparative effectiveness research (CER). Interest in, and debate about, CER has exploded recently thanks to $1.1 billion in funding in the recently enacted American Recovery and Reinvestment Act (ARRA), approximately one-third of which went to NIH. (See sidebar.)

A Flurry of Activity on CER

Under ARRA, the $1.1 billion set aside for CER is being split three ways:

  • $300 million for the Agency for Healthcare Research and Quality
  • $400 million for NIH
  • $400 million for other HHS agencies

The NCI challenge grants for CER should be announced in the coming months, according to Dr. Brown. As a requirement of the ARRA bill, the IOM was asked to develop a report with recommendations on the priority areas that HHS should address with its CER funding. The IOM report is due by June 30.

Just last week, in fact, a committee of leaders in cancer research convened by the Friends of Cancer Research released a report calling for a “new paradigm” of CER in the United States, offering cancer care as a case study in how and why it should be done.

In the mean time, NIH institutes report being flooded with applications for funding to support the CER opportunities created by ARRA. And according to Dr. Martin Brown, chief of the Health Services and Economics Branch in NCI’s Division of Cancer Control and Population Sciences, NCI has also issued funding opportunities intended to help create a sturdier infrastructure for CER “that will really help to push the field forward.”

But What Is CER?

CER is typically defined as an evaluation of the impact of different options for treating or managing a given condition in a particular patient group. Because, while clinical trials and other studies can help define appropriate care, many researchers concede that they all have limitations.

“We do a lot of things in medicine for which there are different approaches, and often we don’t know which one is the best,” Dr. Brown said. He cites, for example, managing patients with advanced cancers. “All kinds of treatments and strategies are being undertaken” in these patients, he said, “and we don’t have a good handle on what’s being done.”

Ideally, says Dr. Diana Buist from the Group Health Center for Health Studies in Seattle, comparative effectiveness studies will incorporate data from “real world” settings, because most clinical trials are tightly controlled and have homogenous patient populations, so they are often not representative of the majority of patients being treated in the community.

Under the auspices of the NCI-supported Breast Cancer Surveillance Consortium, Dr. Buist and her colleagues have been conducting comparative effectiveness studies, including clinical trials in community clinics, of imaging for breast cancer screening and diagnosis. “There’s a tremendous amount of variability in clinical practice—at the patient, provider, and facility/clinic levels—that influences outcomes in imaging,” she said. “We’re trying to study how to provide the most effective breast cancer screening in community practices that reduces variability and optimizes screening delivery.”

Unlike most clinical trials, comparative effectiveness studies aren’t necessarily aimed at drawing a clear line of superiority between two interventions, said Dr. Steven Pearson of the Institute for Clinical and Economic Review (ICER) at Massachusetts General Hospital. Instead, these studies often look at a broader picture of effectiveness.

Last year, for example, ICER published a comparative effectiveness study of standard optical colonoscopy and computed tomography colonography (CTC), or “virtual” colonoscopy. The assessment did not focus solely on detection of certain sized polyps, the “efficacy” endpoints used in colonoscopy clinical trials. Rather, it looked at data on factors such as mortality, patient preference, procedure costs, and procedure risks, in addition to polyp detection. The final report graded CTC according to different scenarios: compared against no screening at all and against standard colonoscopy based on different possible reimbursement rates for a CTC procedure.

These more expansive approaches for assessing effectiveness are desperately needed, Dr. Pearson said. “There are 18,000 randomized trials conducted every year and yet we always say we don’t have enough good evidence.”

Not Everybody Is Convinced

Although CER has its proponents, it has also raised concerns in different quarters of the health care system. During a White House-sponsored conference on health care reform last month, for example, Pfizer CEO Jeffrey Kindler questioned whether the results from comparative effectiveness studies would be “automatically linked” to insurance coverage decisions.

To a limited extent, insurers and other payers are using CER to guide coverage decisions, explained Dr. Barbara McNeil, who heads the Department of Health Care Policy at Harvard Medical School and sits on medical coverage advisory boards for Medicare and Blue Cross and Blue Shield. Last year, the Washington State Health Care Authority, for example, relying in part on the ICER study, cited lack of efficacy data and cost among the deciding factors against adding CTC as a covered benefit for state Medicaid patients.

Some oncologists also have misgivings. “We would certainly welcome more data and are always looking for better ways to treat our patients,” said Dr. Patrick Cobb, president of the Community Oncology Alliance and a managing partner of an oncology practice in Montana. But he’s concerned that results from CER could be used to limit treatment choice. “There could be instances where one treatment would be better for a certain patient than another.”

But, countered Dr. Brown, it’s a misconception that CER will lead to “one-size-fits-all” medicine. “There’s nothing inherent in CER that rules out looking at the issue of heterogeneity in many ways,” he said. “And that’s a good reason for NIH to be involved in CER, because the research managers and grantees have informed expertise on those sorts of issues.”

Carmen Phillips

Featured Clinical Trial

Cetuximab and Chemoradiotherapy for Locally Advanced Esophageal Cancer

Name of the Trial
Phase III Randomized Study of Chemoradiotherapy Comprising Paclitaxel, Cisplatin, and Radiotherapy with Versus without Cetuximab in Patients with Locally Advanced Esophageal Cancer (RTOG-0436). See the protocol summary.

Dr. Mohan Suntharalingam Dr. Mohan Suntharalingam

Principal Investigators
Dr. Mohan Suntharalingam, Dr. David Ilson, Dr. Adam P. Dicker, Dr. Lisa Kachnic, Dr. André Konski, Radiation Therapy Oncology Group; Dr. Bapsi Chakravarthy, Eastern Cooperative Oncology Group

Why This Trial Is Important
More than 16,000 Americans were diagnosed with esophageal cancer in 2008, and more than 14,000 died from the disease. Most cases of esophageal cancer are not detected until the disease has spread to nearby lymph nodes or beyond, leading to the very poor survival rate. The incidence of esophageal cancer is increasing in the United States and worldwide.

Most patients with locally advanced esophageal cancer (cancer that has spread to nearby lymph nodes) either are not candidates for surgical treatment or prefer not to undergo surgery. Such patients are often treated with a combination of chemotherapy and radiation therapy (sometimes called chemoradiotherapy). The use of chemoradiotherapy has been shown to prolong the lives of these patients when compared with radiotherapy alone; however, the prospects for long-term patient survival remain poor. Doctors want to know if adding a targeted biologic agent to chemoradiotherapy can help these patients live longer.

In this trial, patients with locally advanced esophageal cancer will all undergo chemoradiotherapy using the drugs cisplatin and paclitaxel, and half of them will be randomly assigned to also receive the biologic agent cetuximab, a monoclonal antibody that targets the epidermal growth factor receptor (EGFR). Combining cetuximab and chemoradiotherapy has produced benefits in patients with head and neck cancer, and a phase II clinical trial of the combination for esophageal and gastric cancer showed a high response rate.

“This study should definitively answer the question of whether adding an EGFR inhibitor to chemoradiotherapy can improve response rate and survival,” said Dr. Suntharalingam. “This is the first national phase III study in esophageal cancer to emerge from NCI’s intergroup task force process, during which experts from around the country agreed that this is the most pressing question to answer in terms of improving outcomes for patients with locally advanced esophageal cancer.”

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

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

FDA Update

Bevacizumab Approved for Recurrent Glioblastoma Brain Cancer

Avastin logo

The FDA has granted accelerated approval of bevacizumab (Avastin) for patients with previously treated glioblastoma multiforme (GBM), a deadly form of brain cancer. Accelerated approval is granted to treatments for life-threatening diseases on the basis of preliminary evidence, with the requirement that additional studies be conducted to confirm a true clinical benefit. Bevacizumab is a monoclonal antibody that inhibits the formation of new blood vessels that tumors need for continued growth.

The approval was based on results from two early phase clinical trials in which a modest portion of patients had partial responses, but no patients had complete responses. The first trial included 85 patients, with approximately 25 percent experiencing a partial response (tumor shrinkage of greater than 50 percent). In the other trial, conducted at NCI, of 56 patients treated with bevacizumab, 20 percent had a partial response. One-year overall survival in the first trial was 38 percent, compared with approximately 25 percent historically seen in patients who had recurrent GBM and received salvage chemotherapy.

In March, the FDA’s Oncologic Drugs Advisory Committee voted unanimously in favor of granting accelerated approval of bevacizumab for this indication. A global, randomized phase III trial of bevacizumab in patients with newly diagnosed GBM will start enrolling patients some time in 2009.

Notes

Dr. John N. Brady Dr. John N. Brady

In Memoriam: NCI's Dr. John Brady

Dr. John N. Brady, chief of the Virus Tumor Biology Section of NCI’s Laboratory of Cellular Oncology, died April 27 of colon cancer at the age of 57.

Dr. Brady joined the Center for Cancer Research (CCR) in 1984. In 1998, he received an NCI Intramural Award for Innovative Research, and in 2002, the NIH Director named him an NIH Senior Biological Research Scientist, a highly competitive appointment reserved for researchers with outstanding achievements. In his lab, he was dedicated to mentoring many undergraduate students and fellows who have since flourished in science.

In 1996, he added teaching to his career, being appointed adjunct professor at the George Washington University Institute for Biomedical Sciences. Dr. Brady also found time to serve as president of the Montgomery County Baseball Association, an organization that promotes youth baseball.

Dr. Brady’s research career began at Kansas State University, where he earned a Ph.D. for work on the molecular structure of polyoma virus under the guidance of Dr. Richard Consigli. During the early stage of his career, he focused on SV40 transcription regulation, working as a staff fellow with Dr. Norman Salzman at the National Institute of Allergy and Infectious Diseases and with Dr. George Khoury at NCI.

“John brought a formidable intellect and commitment to his work here at NCI’s Center for Cancer Research, tackling cell-virus interactions that influence viral gene regulation, viral pathogenesis, and oncogenic transformation,” said CCR Director Dr. Robert Wiltrout. “He published over 200 research papers, served on editorial boards for several virology journals, and was named to the Advisory Board for the International Retrovirology Association.”

Deadline Approaching for DCLG Nominations

NCI is currently identifying individuals to serve on the Director’s Consumer Liaison Group (DCLG). The DCLG is a Federal Advisory Committee of 16 individuals who advise the NCI Director from the viewpoint of the consumer advocate. The Institute will be filling three positions on the board with dates of service beginning July 2009 and running through June 2013. All nomination materials must be received by NCI no later than 6:00 p.m. on May 22.

Further information about the DCLG and complete details about the nomination process can be found online. Previous nominees should be aware that in order to be considered for current vacancies, their updated materials must be re-submitted.

Please direct questions to ncidclgnominations@mail.nih.gov.

IOTF Fellowship Program Seeks Applicants

NCI and the FDA encourage Ph.D.s, M.D.s, and M.D./Ph.D.s or their equivalents to apply for Interagency Oncology Task Force (IOTF) fellowship training opportunities in cancer-related scientific research and research-related regulatory review. By combining training in these two disciplines, this program will help fellows learn to bridge the development and review processes. Fellows will also learn to build awareness of regulatory requirements into the early stages of medical product development and to improve planning throughout both processes.

Visit the IOTF Web site to learn more about the joint fellowship program.

Women's Health Hearing and Workshop Series Continues

NIH’s Office of Research on Women’s Health launched a series of four regional scientific workshops and public hearings to ensure that research on women’s health continues to be on the cutting edge of science and based upon the most advanced techniques and methodologies.

Researchers, advocates, and others from the cancer field are encouraged to attend the next hearing and workshop on May 27–29 in San Francisco, CA: “Moving into the Future: New Dimensions and Strategies for Women’s Health Research at NIH.”

The workshop—hosted by the University of California, San Francisco’s Department of Obstetrics, Gynecology, and Reproductive Sciences—will highlight five topic areas of research in women’s health: stem cell research, HIV/AIDS and women, global health, information technology and health, and women’s health and the environment. A sixth area focused on women in biomedical careers will explore the range of issues and strategies for creative opportunities to support the emergence and development of successful women researchers.

Additional information is available online.

NCI Cancer Bulletin Writer Wins NAGC Award

The National Association of Government Communicators awarded NCI Cancer Bulletin writer Addison Greenwood a 2009 Blue Pencil Award. He received second place in the Writer's Portfolio category for the following collection of articles:

National Association of Government Communicators logo


Duke Forging Research Ties in China
Profiles in Cancer Research: Dr. Chad Mirkin
Cancer Disparities: A Biological and Psychosocial Perspective

Greenwood’s work was selected from several hundred submissions in that category.

Meet NCI Experts at ASCO

Logo for the American Society of Clinical Oncology 2009 Annual Meeting NCI exhibit booth

NCI Director Dr. John E. Niederhuber will discuss the recent federal investment in cancer research and NCI's future goals at the American Society of Clinical Oncology annual meeting's opening session on Saturday, May 30. Learn about NCI's programs and Web sites by visiting booth #3018 in the exhibit hall during the meeting. NCI experts will be available to talk about a wide range of topics. See the schedule below.

Saturday, May 30
9:00 a.m.NCI SPORE and Other Translational Research Programs
 Ivan Ding, Division of Cancer Treatment and Diagnosis
10:00 a.m.The Cancer Biomedical Informatics Grid: Resources to Support Clinical and Translational Research
 William J. Dyer and Dianne Reeves, Center for Biomedical Informatics and Information Technology 
11:00 a.m.NCI-Funded Research Portfolio
 Lisa Krueger, Division of Extramural Activities
1:00 p.m.Ixolaris: A Potent Inhibitor of Tumor Growth
 Charles Rainwater, National Institute of Allergy and Infectious Diseases
 
Sunday, May 31
10:00 a.m.NCI-Funded Research Portfolio
 Lisa Krueger, Division of Extramural Activities
11:00 a.m.The Cancer Biomedical Informatics Grid: Resources to Support Clinical and Translational Research
 William J. Dyer and Dianne Reeves, Center for Biomedical Informatics and Information Technology 
12:00 p.m.NCI Cancer Complementary and Alternative Medicine Program
 Libin Jia, Office of Cancer Complementary and Alternative Medicine
1:00 p.m.Ixolaris: A Potent Inhibitor of Tumor Growth
 Charles Rainwater, National Institute of Allergy and Infectious Diseases
2:00 p.m.NCI Cancer Bulletin
 Carmen Phillips, Office of Communications and Education
3:00 p.m.NCI-Funded Research Portfolio
 Lisa Krueger, Division of Extramural Activities
   
 
Monday, June 1
9:00 a.m.NCI-Funded Research Portfolio
 Lisa Krueger, Division of Extramural Activities
10:00 a.m.Epigenetics and Cancer Control
 Mukesh Verma, Division of Cancer Control and Population Sciences 
11:00 a.m.The Cancer Biomedical Informatics Grid: Resources to Support Clinical and Translational Research
 William J. Dyer and Dianne Reeves, Center for Biomedical Informatics and Information Technology 
12:00 p.m. Specialized Programs of Research Excellence (SPOREs)
 Rajeev K. Agarwal, Division of Cancer Treatment and Diagnosis
2:00 p.m.NCI Cancer Bulletin
 Carmen Phillips, Office of Communications and Education
3:00 p.m.NCI-Funded Research Portfolio
 Lisa Krueger, Division of Extramural Activities

Cancer.gov Update

Smokefree Women Web Site Launched

Screenshot of Smokefree Women Web siteThe popular Smokefree.gov Web site has spun off a new section, Smokefree Women (http://women.smokefree.gov) and a companion Facebook page with information, tools, and discussion forums specifically developed to help female smokers quit. Women who smoke experience the same health hazards as men. But, they also face hazards unique to women, including endangering the life and health of a developing child if they smoke during pregnancy. The new site focuses on helping women integrate smoking cessation into daily life and family matters to help women stay smokefree. It was designed with the knowledge that different women need different resources to quit.

The Web site and Facebook page contain interactive features, as well as tools that users can download to their personal Facebook profiles. For example, the “Talk to an Expert” feature allows users to receive information and advice about quitting smoking through real-time telephone-based or online LiveHelp messaging with an NCI smoking cessation counselor. A step-by-step Quit Guide is also provided, and the “Topics that Interest You” section includes information on smoking and pregnancy, depression, weight management, and relationships.

Smokefree Women was developed by the Tobacco Control Research Branch in NCI’s Division of Cancer Control and Population Sciences, with assistance from the CDC, Health Canada, American Legacy Foundation, The Robert Wood Johnson Foundation, American Cancer Society, and NCI's Office of Communications and Education.

NCI Publications Locator Web Site Improved

NCI recently redesigned and improved its Publications Locator Web site: www.cancer.gov/publications. Publications Locator offers users the ability to view and order NCI publications online. The new Web site is a secure system with advanced features that are easier to use.

Screenshot of NCI Publications Locator Web page

Improvements to the site include:

  • A homepage that offers additional browsing options
  • Links to announcements, featured publications, and new and updated publications
  • Improved search capabilities to locate, select, and order materials
  • More publication information, including last reviewed date, publication format, and page count
  • An expanded Publications Details page that includes audience, language, physical description, and related products
  • Thumbnail images for most publications
  • Advanced ordering capabilities, including a shopping cart and order-progress bar
  • Self-printing options