National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
May 4, 2010 • Volume 7 / Number 9

Page Options

  • Print This Document
  • Email This Document

NEWS

An illustration of antigen-presenting cells that process and present antigens from vaccines, which leads to T-cell activation.FDA Approves First Therapeutic Cancer Vaccine

The field of cancer immunotherapy received an important boost last week with the FDA’s approval of the first therapeutic cancer vaccine, sipuleucel-T (Provenge). The vaccine was approved for use in some men with metastatic prostate cancer based on the results of a phase III randomized trial called IMPACT that demonstrated a more than 4-month median improvement in overall survival compared with a placebo vaccine. However, because of the way in which the vaccine is produced, its availability will be very limited for at least the next 12 months. Read more > >

COMMENTARY

Dr. Maureen R. JohnsonGuest Director's Update: NCCCP—Building a Community-based Research Platform and Enhancing Cancer Care

In 2007, NCI funded 16 community cancer centers at hospitals around the country in a pilot program called the NCI Community Cancer Centers Program (NCCCP). This program is a unique public-private partnership designed to support cancer research and to study ways to enhance access and increase the quality of cancer care at community hospitals. The participating sites form a network to serve as a community-based platform to support basic, clinical, and population-based research spanning the cancer care continuum—from screening, prevention, diagnosis, and treatment to survivorship and end-of-life care—with a particular focus on addressing health care disparities across the continuum. Read more > >

  

A MESSAGE TO READERS

Special Issue on Clinical Trial Recruitment

Don’t miss our May 18 special issue, which will highlight important factors that affect clinical trial recruitment, as well as resources and ongoing programs that address obstacles to recruitment for specific population groups.

NCI Cancer Bulletin special issues are some of the most popular among our readers. Past special issues have focused on cancer research training, personalized drug development, and cancer imaging.

IN DEPTH

UPDATES

  • FDA Update

    • FDA Reviewing Potential Risks of Commonly Used Prostate Cancer Drugs
  • Legislative Update

    • NIH Director Testifies Before House Appropriations Subcommittee
  • Cancer.gov Update

    • Online Tool Provides NCI Funding Trends
  • Notes

    • NCI-Frederick Hosts Annual Spring Research Festival This Week
    • Tribute to Celebrate Dr. Ruth Kirschstein’s Contributions to Science and NIH
    • Second Telephone Workshop for Cancer Survivors on May 18

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

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

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

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

Featured Article

FDA Approves First Therapeutic Cancer Vaccine

An illustration of antigen-presenting cells that process and present antigens from vaccines, which leads to T-cell activation. Antigen-presenting cells, such as dendritic cells found under the skin, process and present antigens from vaccines, which leads to T-cell activation. [Enlarge]

The field of cancer immunotherapy received an important boost last week with the FDA’s approval of the first therapeutic cancer vaccine, sipuleucel-T (Provenge). The vaccine was approved for use in some men with metastatic prostate cancer based on the results of a phase III randomized trial called IMPACT that demonstrated a more than 4-month median improvement in overall survival compared with a placebo vaccine. However, because of the way in which the vaccine is produced, its availability will be very limited for at least the next 12 months.

Approval of the vaccine by the FDA is important on several levels, said Dr. Philip Kantoff, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute and the IMPACT trial’s principal investigator. “This represents the first proof of principle that immunotherapy works and can work in cancer in general,” he said. “I’m hopeful that investigators will look at this as an opportunity to build upon these findings and improve upon them with other treatment strategies.”

From a clinical perspective, Dr. Kantoff continued, many men with advanced prostate cancer whose tumors are no longer responding to hormonal therapy—often called hormone-resistant or castration-resistant cancer—now have a new, relatively nontoxic treatment option. The only other approved treatment for such patients is the chemotherapy drug docetaxel (Taxotere), which, on average, improves overall survival by 2.4 months. The vaccine offers “meaningful benefits for patients,” Dr. Kantoff said. “It’s not a cure for cancer, of course, but it does provide a significant clinical benefit.”

The FDA requested IMPACT, which enrolled more than 500 men with metastatic, castration-resistant prostate cancer who were asymptomatic or mildly symptomatic, to support approval of sipuleucel-T. Overall survival was the primary endpoint. According to the most updated trial results, presented in March at the American Society of Clinical Oncology Genitourinary Cancers Symposium, sipuleucel-T improved median 3-year survival by nearly 40 percent compared with placebo (32.1 percent versus 23 percent), with a median improvement in overall survival of 4.1 months (25.8 months versus 21.7 months). These results have yet to be published in a peer-reviewed journal.

Another Vaccine, a Different Approach

NCI researchers Dr. Gulley and Dr. Jeffrey Schlom have led the development of another prostate cancer vaccine called Prostvac that will be tested in an international phase III clinical trial expected to launch in late 2010. Prostvac was given a fast-track designation by the FDA last week, a move intended to expedite its development and regulatory review.

In two separate phase II randomized clinical trials, Prostvac, much like sipuleucel-T, improved overall survival but not progression-free survival. In the most recent trial, also led by Dr. Kantoff and which included men with metastatic, castration-resistant prostate cancer who were mildly symptomatic, the therapeutic vaccine improved median overall survival by 8.5 months compared with a placebo vaccine.

Unlike sipuleucel-T, Prostvac, which is being commercialized by the German company Bavarian Nordic as part of a collaborative research and development agreement with NCI, is a more traditional “off-the-shelf” treatment, explained Dr. Gulley, who will be the principal investigator on the much larger phase III trial.

Prostvac uses two viruses as delivery vehicles, or vectors, as well as other molecules known to stimulate the immune system. Each viral vector encodes prostate-specific antigen (PSA), which is commonly found on prostate cancer cells. So the vaccine is actually two different viral vectors combined with co-stimulating molecules: The first, vaccinia-PSA-TRICOM, is given once, via injection, to prime the immune system for an anticancer response, and the second, fowlpox-PSA-TRICOM, is delivered (also via injection) several times for repetitive immune boosting.

The approval validates the concept of an active treatment approach such as immunotherapy, which is intended to train the immune system to attack cancer cells and potentially get a response “that can last for months or even years down the road,” said Dr. James Gulley of NCI’s Center for Cancer Research, who has led several clinical trials of a different therapeutic vaccine for prostate cancer. (See the sidebar.)

Despite the approval and several decades of research, Dr. Gulley acknowledged that immunotherapy is still an emerging field. “We’re just now learning how to develop potent-enough vaccines, what patient populations they are most appropriate for, and how to augment them by adding other therapies,” he said.

A Different Paradigm

The FDA’s decision marks the end of a somewhat tumultuous 15-year journey for sipuleucel-T and the company that developed it, Seattle-based Dendreon.

In 2007, the FDA declined to approve the vaccine based on results from two smaller randomized phase III trials in which the immune-stimulating treatment also demonstrated a modest improvement in overall survival, but did not meet the primary endpoint of improved survival without tumor growth, typically called progression-free survival. In that earlier decision, the FDA went against a recommendation for approval from its Cellular, Tissue, and Gene Therapies Advisory Committee, sparking criticism from several quarters, including many in the prostate cancer advocacy community.

Failure to approve the vaccine at that time gets to the heart of the difference between immunotherapy and other cancer treatments, explained Dr. Charles Drake, an immunotherapy researcher and co-director of the Prostate Cancer Multi-Disciplinary Clinic at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center.

The available data on immunotherapy, he said, “suggest that it establishes a new balance” in patients. With the vaccine’s assistance, “the immune system restricts the growth of the tumor. Some tumor cells might be dying, but generally the tumor has to fight harder to grow, and the immune system is more able to fight back to keep it in check,” he explained.

Unlike some other therapeutic cancer vaccines under development, sipuleucel-T is customized to each patient. In the days prior to treatment, patients undergo a procedure called leukapheresis to isolate antigen-presenting cells (APCs) from their blood. These APCs include dendritic cells and macrophages, among other cells, that can “present” markers, or antigens, on their surfaces that are recognized by other immune cells, thereby sparking an immune response.

The APCs are sent to a Dendreon facility where they are cultured with a proprietary manufactured protein. The end result is a vaccine with hundreds of millions of “activated” APCs loaded with an antigen commonly found on most prostate cancer cells, called prostatic acid phosphatase (PAP). The vaccine is returned to the patient’s treating physician and infused into the patient, with the intent of spurring powerful immune system cells, T cells, to neutralize tumor cells that express PAP. Patients receive three treatments over the course of 4 to 6 weeks, with each round requiring the same manufacturing process.

Early Challenges

Initially, the vaccine’s manufacturing requirements will limit its impact on patients, Dendreon officials acknowledged. Currently, the company has only one licensed manufacturing facility in New Jersey, which is operating at 25 percent capacity. Two other manufacturing facilities, one in Georgia and the other in California, are expected to be completed and receive approval from the FDA to manufacture the vaccine by mid-2011, meaning that for the next 12 months “the demand will exceed the supply,” said Dendreon CEO Dr. Mitch Gold during a telephone briefing.

For the next year, the treatment will be available to approximately 2,000 patients at 50 oncology and urology clinics that were approved sites for the sipuleucel-T clinical trials, company officials explained. The three-course treatment will cost $93,000, which the company expects will be covered by private insurers and Medicare.

There is also the question of how to optimally use the vaccine. In the IMPACT trial, Dr. Drake explained, there was no pre-designated point to define disease progression that warranted additional therapy—namely docetaxel—after completion of sipuleucel-T treatment. In some cases, docetaxel wasn’t given until patients became highly symptomatic, he said, while in others it was given shortly after the vaccine treatment was completed.

“This agent is not like traditional chemotherapy in terms of its side effects or in terms of causing obvious tumor shrinkage or declines in [prostate-specific antigen],” Dr. Drake said. “So when do you move onto the next step, chemotherapy or a clinical trial? We honestly don’t know the answer to that yet.”

Sipuleucel-T is being tested in several other clinical trials, including a phase III study called PROTECT, that involves men with early-stage, nonmetastatic prostate cancer. Earlier-stage disease is likely the optimal setting for immunotherapy, researchers in the field believe.

“Having something approved allows us to start those trials,” Dr. Drake stressed. “It allows us to use vaccines in combination with other therapies. Because we know from animal models that immunotherapy can be at least additive and sometimes synergistic with other therapies, this [approval] gives us legs to go earlier and with combinations.”

Carmen Phillips

Cancer Research Highlights

Breast Tissues May Express Biomarkers Linked to DCIS Recurrence

Biomarkers found in the breast tissue of women with ductal carcinoma in situ (DCIS) may predict subsequent risk of DCIS recurrence and invasive breast cancer, according to a report online April 28 in the Journal of the National Cancer Institute. “Interestingly, the combinations that predicted subsequent [invasive breast cancer] were different from those that predicted DCIS,” wrote Dr. D. Craig Allred from the Washington University School of Medicine in St. Louis in an accompanying editorial.

Using SEER data, researchers from the University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center identified 1,162 women who had originally been treated by lumpectomy alone for DCIS between 1983 and 1994 at 63 hospitals in the Bay area. After an average of 7.5 years, 838 had no recurrence, while 170 had developed invasive breast cancer and 154 had their DCIS recur. Tissue samples preserved from their original lumpectomies were tested for a number of histopathologic characteristics and molecular markers that have since been associated with breast cancer.

The researchers found that 28 percent of the women expressed three key markers: p16, Ki67, and COX-2. The 8-year risk for invasive breast cancer in these women was 19.6 percent, compared with 4.1 percent when those markers were negative.

The factors associated with greater risk of DCIS recurrence were positive or uncertain surgical margins and two different sets of markers: 1) p16 positive, Ki67 positive, and COX-2 negative, or 2) estrogen receptor negative, Ki67 positive, and human epidermal growth factor receptor-2 positive. In addition to these marker combinations, consistent with other studies, the 15–20 percent of women whose DCIS lesions were detected by palpation had a higher risk of invasive breast cancer than did those whose lesions were detected by mammography.

“The mode of detection and the biomarkers p16, COX-2, and Ki67 may be used to help stratify a woman’s risk of subsequent invasive cancer and to help her decide whether she should undergo adjuvant therapies,” wrote lead author Dr. Karla Kerlikowske and colleagues.

A number of limitations to this study, however, were noted by the authors and Dr. Allred, including the fact that the treatment regimen received by women who were included in the study—lumpectomy alone—would be uncommon in current medical practice.

Circulating Tumor Cells Detected in Patients with Localized Cancers

Researchers from Massachusetts General Hospital (MGH) have isolated tumor cells circulating in the blood of patients with localized prostate cancer as well as from patients with advanced disease. The researchers were then able to characterize genetic changes in these circulating tumor cells (CTCs), which they stressed was an important step toward potentially using CTCs to guide the selection of therapies and improve patient care. The findings appeared in the March 31 Science Translational Medicine.

The discovery of CTCs in men with localized disease was unexpected, but this may simply have been because until now the technology had not been sensitive enough to capture the cells in patients with early-stage disease, noted one of the lead authors, Dr. Sunitha Nagrath of MGH and Harvard Medical School.

She presented the study’s findings at the recent American Association for Cancer Research annual meeting in Washington, DC. At the same meeting, researchers from Ohio State University presented a poster about a new way to detect CTCs in patients with breast cancer. They also found the cells in women with localized disease.
 
“We develop our notions about the nature of CTCs based on the existing technologies, but advances in technology can change these assumptions,” said Dr. Nagrath. “What we have found until now is only the tip of the iceberg. We believe these cells have tremendous potential not only for diagnostic purposes and early detection, but also to noninvasively monitor patients and the effectiveness of treatments over time, enabling targeted therapeutic treatments in the new era of personalized medicine.”

Although the MGH technology, a microfluidic device called a CTC chip, is not ready for clinical use, the researchers are enrolling 200 patients with various stages of prostate cancer in a clinical trial. The trial will evaluate the prognostic and predictive value of monitoring these rare cells as a kind of “liquid biopsy” in patients.

Of particular interest will be whether CTCs can help solve one of the major problems in managing prostate cancer—the inability to distinguish patients with early-stage disease who need aggressive treatments from those who do not.

Costs and Use of Diagnostic Imaging Rise among Medicare Patients

The use of diagnostic imaging in older cancer patients has increased rapidly, and the expense of these procedures has grown at a rate faster than the overall rate of increase in cancer care costs, according to researchers at the Duke Clinical Research Institute. Their report appeared in the April 28 Journal of the American Medical Association.

Most patients with cancer are enrolled in Medicare. The study used claims from a 5 percent sample of Medicare beneficiaries to identify 100,954 cancer patients between 1999 and 2006 and measured imaging use for a period of up to 2 years after diagnosis. The researchers selected a sample of patients with major cancers for which diagnostic imaging is commonly used––breast, lung, colon, prostate, leukemia, and lymphoma. Together these cancers account for about 57 percent of all cancer costs paid by Medicare.

They found that the number of positron emission tomography (PET) scans per Medicare beneficiary increased each year of the study by 35.9 to 53.6 percent. Meanwhile, the costs of PET and five other imaging technologies increased by 5.1 to 10.3 percent annually, compared with increases in overall cancer care costs of 1.8 to 4.6 percent each year.

The researchers pointed out that growth in the use of PET during the study period coincided with expanding FDA approvals of its use for multiple cancer types. To a lesser extent, use of the other advanced imaging modalities for cancer care also increased each year: bone mineral density scans (6.3–20.0 percent), echocardiograms (5.0–7.8 percent), magnetic resonance imaging (4.4–11.5 percent), computerized tomography scans (4.5–7.6 percent), and ultrasound (0.7–7.4 percent). Conventional x-rays are still the most commonly used imaging modality, but their use during the study period either stayed the same or decreased in each group of cancer patients.

Lead author Michaela A. Dinan and colleagues wrote, “It is unclear whether the rapid increase in the use of advanced imaging is a result of the novelty of the technologies, better outcomes, or a shift to new revenue sources.” They noted that the health reform legislation passed by Congress in March 2010 aims to reduce reimbursement for imaging tests, and that the consequences of this effort will likely become an area of increasing study in the years ahead.

Also in the Journals: Updated Guidelines on Hormone-receptor Testing for Breast Cancer

Up to 20 percent of the results from hormone-receptor tests of breast tumors could be inaccurate due to differences in the way the tests are conducted and how the results are interpreted. New guidelines developed jointly by the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) aim to mitigate the rate of false-negative and false-positive results by outlining specific algorithms for conducting and criteria for interpreting these tests.

The guidelines—an update from those last released in 2007—were published early online April 19 in the Journal of Clinical Oncology. ASCO and CAP will promote their use with educational opportunities in print, online, and at society meetings for the benefit of clinicians, patients, third-party payers, and regulatory agencies; through partnerships with other clinical organizations; and with a certificate program that CAP is developing for pathologists and laboratories to encourage quality control.

Guest Director's Update

NCCCP: Building a Community-based Research Platform and Enhancing Cancer Care

Dr. Maureen R. Johnson Dr. Maureen R. Johnson

In 2007, NCI funded 16 community cancer centers at hospitals around the country in a pilot program called the NCI Community Cancer Centers Program (NCCCP). This program is a unique public-private partnership designed to support cancer research and to study ways to enhance access and increase the quality of cancer care at community hospitals. The participating sites form a network to serve as a community-based platform to support basic, clinical, and population-based research spanning the cancer care continuum—from screening, prevention, diagnosis, and treatment to survivorship and end-of-life care—with a particular focus on addressing health care disparities across the continuum.

To build this research platform, sites are enhancing their clinical trials infrastructure to support early-phase clinical trials and a broader range of trials, changing procedures to collect high-quality biospecimens following NCI’s Best Practices for Biospecimens Resources, implementing electronic health records (EHRs), and adopting tools from NCI’s cancer Biomedical Informatics Grid (caBIG), an extensive information technology network that supports cancer research.  

To enhance quality cancer care in local communities, sites are studying ways to reduce cancer health care disparities by expanding outreach, screening, and care across the cancer care continuum. They are designing and evaluating specific projects to meet focused needs for unique populations within their communities. Sites are also studying ways to promote evidence-based and coordinated care and ways to extend supportive care after treatment through enhanced cancer survivorship and palliative care programs at community hospitals. These activities have already resulted in unique NCCCP research collaborations with programs and organizations such as the NCI-designated cancer centers, The Cancer Genome Atlas program, the American Society of Clinical Oncology, and the American College of Surgeons’ Commission on Cancer.

Using this community-based research platform, the long-term goals of the NCCCP are to support research to: reduce cancer health care disparities, improve the quality of cancer care, enhance cancer survivorship and palliative care programs, encourage cancer advocacy, and support the investigation of new drugs through clinical trials. In addition, they will continue to expand their information technology capabilities through adoption of oncology-enhanced EHRs and caBIG tools and increase high-quality biospecimen collection to support research for personalized medicine

Based on the progress made in the pilot program, NCI used $80 million from the American Recovery and Reinvestment Act (ARRA) to expand the number of participating hospitals, as well as the breadth of activities at the current sites. The original network of 16 community cancer centers in 14 states has grown to 30 hospitals in 22 states.

Expansion of the NCCCP is supporting a number of critical NCI priorities in the area of translational research. For example, some sites are collaborating with investigators from NCI’s Early Drug Development Program to conduct early-phase clinical trials. Several partnerships with NCI’s Community Networks Program investigators were established to increase cancer screening for racial and ethnic minorities and other underserved populations. Sites are conducting a study to evaluate the impact of multidisciplinary care on the processes and outcomes of cancer care, and are participating in a research project that is under way in settings across the United States and internationally to evaluate the Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), a reporting system for clinical trial patients to self-report adverse events. Additional projects are under way to study ways to help survivors transition to living with cancer after treatment and promote smoking cessation among cancer survivors and their family members.

The NCCCP has accomplished many of the pilot goals, and the original 16 sites are currently summarizing their experience and lessons learned to be shared with the broader community. Results of the formal evaluation will be available in the coming year, allowing further refinement so the program can continue to study the best ways to enhance cancer care in the community setting and expand a community-based cancer center network to support research across the cancer continuum.

Dr. Maureen R. Johnson
Project Officer, NCI Community Cancer Centers Program
Office of the NCI Director

Special Report

Sigmoidoscopy Markedly Reduces Colorectal Cancer Incidence, Mortality

A sigmoidoscopy is an examination of the lower colon using a thin, tube-like instrument inserted through the rectum to look for precancerous or cancer lesions. Approximately 41,000 participants in a U.K. study had a one-time examination of the lower colon using a sigmoidoscope, a thin, tube-like instrument inserted through the rectum to look for precancerous or cancerous lesions. The device also has a tool to remove potentially precancerous polyps. [Enlarge]

A single sigmoidoscopy procedure between ages 55 and 64 can be an effective screening method for reducing the incidence of and mortality from colon cancer, according to long-term results from a study involving more than 170,000 participants in the United Kingdom, the largest randomized clinical trial of its kind published to date. Published online April 27 in The Lancet, the trial results are the first to demonstrate that sigmoidoscopy can reduce both incidence and mortality from the disease.

In several earlier randomized trials, regular screening with fecal occult blood testing produced a modest improvement in cancer incidence and mortality. But these new trial results, said lead investigator Dr. Wendy Atkin of Imperial College London, show that a single sigmoidoscopy in patients of this age group “gives a very big effect,” reducing overall colorectal cancer incidence and mortality by 31 percent and 43 percent, respectively.

To be part of the study, participants had to return a questionnaire, which was sent to nearly 370,000 people, asking if they would be likely to accept an invitation to undergo a screening procedure. From the group that responded they would accept an invitation, approximately two-thirds (about 130,000 people) were randomly assigned to the control group, meaning that they did not receive an actual invitation for screening, and the rest (about 57,000 people) were invited to be screened. Of this latter group, 71 percent, or about 41,000 people, underwent a sigmoidoscopy.

Small polyps were removed when found in participants who underwent the procedure. Participants with polyps that met certain high-risk criteria, such as those classified as adenomas, were referred for a colonoscopy. The results published last week cover a median of 11 years of participant follow-up, which was done via a centralized database operated by the United Kingdom’s National Health Service.

When the analysis was limited to just the lower part of the colon (or distal colon), colorectal cancer incidence was reduced by approximately 50 percent for those who underwent screening compared with those in the control group; no mortality figures for cancers from just this part of colon were reported, however.

Incidence of cancers in this area of the colon after patients underwent the screening procedure “was very low, and so far there seems to be little attenuation of the protective effect of the screening test,” the study authors wrote. As time passes, Dr. Atkin said, the expectation is that the impact on incidence and mortality will grow.

“The good news is that this size of benefit is large for any cancer screening test, certainly compared with mammography for breast cancer or assay of prostate-specific antigen for prostate cancer,” wrote Dr. David Ransohoff from the Departments of Medicine and Epidemiology at the University of North Carolina at Chapel Hill, in a commentary that accompanied the study results in The Lancet. But the reductions don’t measure up, he continued, to those “popularly quoted for colonoscopy but on the basis of nonrandomized data.”

The trial did not compare sigmoidoscopy with colonoscopy, which is commonly used in the United States but not in the United Kingdom. While a colonoscopy can be used to view the entire length of the colon, the flexible sigmoidoscope reaches only the lower quarter to half of the colon, explained Dr. Theodore R. Levin, a gastroenterologist and researcher at the Kaiser Permanente Northern California Division of Research.

That fact is not necessarily a downfall of the study, he noted, because the available evidence suggests that 60 to 70 percent of colorectal cancers arise in the area of the colon that can be reached with a sigmoidoscope. The trial design was “novel and innovative,” Dr. Levin continued, because it looked for the “most efficient way to have the maximum impact.”

Is More Better?

There is a question of whether “more frequent endoscopy might lead to still greater reductions in colorectal cancer,” Dr. Ransohoff wrote. The NCI-led Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial may help answer this question, he said. PLCO involves two sigmoidoscopy procedures, one at study entry and another 5 years later, and has more aggressive requirements for referring patients to colonoscopy.

Whether the magnitude of the benefit is enough to justify more frequent screening is an important issue, Dr. Levin said. “Because the more intensely you screen, the more risk you expose people to.”

In the United States, just getting people over age 50 (the age at which most groups recommend screening begin) to undergo any screening procedure for colorectal cancer, remains a significant clinical challenge. Estimates put the screening rate for this group at about 55 percent. In February, an expert panel participating in a state-of-the-science conference on colorectal cancer identified strategies for improving colorectal cancer screening rates in the United States. Screening rates have improved, due mostly to increased use of colonoscopy. But because of accessibility and staffing issues, the panel acknowledged, there are limits to how much can be achieved with colonoscopy alone.

It is also unclear whether colonoscopy should be the preferred method for screening. Recent studies, Dr. Ransohoff explained, have called into question whether screening with colonoscopy reduces incidence or mortality risk from cancers in the upper part of the colon. Current guidelines on colorectal cancer screening, meanwhile, are mixed. In its most recent recommendations, for example, the U.S. Preventive Services Task Force did not single out any screening method, which can also include fecal occult blood testing or barium enema, as superior to another. But both the U.S. Multi-Society Task Force on Colorectal Cancer and American Cancer Society’s guidelines favor colonoscopy over the other available methods.

In addition to PLCO, two large, randomized trials of colorectal cancer screening with sigmoidoscopy are ongoing, both of them in Europe. A trial comparing sigmoidoscopy head-to-head with colonoscopy would be extremely difficult to pull off, Dr. Levin noted. Because of the efficacy of sigmoidoscopy, huge numbers of participants would be required to demonstrate a statistically significant difference between the two.

Carmen Phillips

A Closer Look

When Allogeneic Stem Cell Transplants Fail

Reader Suggested

The field of hematopoietic stem-cell transplantation (HSCT) has come a long way since the first successful procedure was performed on a patient with severe combined immunodeficiency syndrome in 1968.

In patients with cancers of the blood, such as leukemia and lymphoma, HSCT was initially used to allow for higher doses of chemotherapy and radiation therapy during treatment; today, oncologists also use it to take advantage of a phenomenon known as the graft-versus-leukemia/lymphoma (GVL) effect, in which the new immune cells produced by a matched donor (allogeneic) transplant can recognize cancer cells as a threat to the body and destroy them, reducing the rate of disease relapse.

An NCI clinical trial is under way to examine the ability of an antitumor vaccine to increase the efficacy of donor lymphocyte infusion. The vaccine is designed to trigger an immune response against a protein called WT1, which is produced by many blood cancers but not by normal cells. Six clinical trials are part of a new program at NCI focusing on the problem of relapse after allogeneic hematopoietic stem cell transplantation. One of these trials, featured in this issue of the NCI Cancer Bulletin, will examine the ability of an antitumor vaccine to increase the efficacy of donor lymphocyte infusion. The vaccine is designed to trigger an immune response against a protein called WT1, which is produced by many blood cancers but not by normal cells. [Enlarge]

At the same time, reduced-intensity conditioning regimens that don’t completely destroy a person’s bone marrow are being used more commonly before allogeneic transplantation, making the procedure itself safer—cutting the risk of treatment-related death—and extending the benefit of the GVL effect to older patients who could not undergo more intensive conditioning regimens.

Unfortunately, despite the GVL effect, the number one cause of death following HSCT is relapse, with more than a third of patients eventually dying from recurrent disease. And the risk of relapse after reduced-intensity regimens is up to double that seen with higher-dose conditioning, reducing the survival benefit gained from the lower risk of death during treatment.

When patients do relapse after HSCT, the only standard treatment available to them is a procedure known as donor lymphocyte infusion (DLI), in which additional immune cells from the donor are re-infused in hopes of triggering additional GVL activity. But this option is effective only in a minority of patients, mostly those with chronic myelogenous leukemia.

For these reasons, several new initiatives are under way to bring together leaders in the transplantation and oncology communities for a more organized approach to address the problem of relapse after HSCT.

Creating a Road Map for the Field

NCI-sponsored International Workshop Focused on Relapse

More than 250 participants came to the workshop in Bethesda, MD, including transplantation experts but also scientists working in tumor immunology, tumor biology, and non-immunotherapeutic approaches to treating hematologic cancers. The focus areas included:

  • The biology underlying recurrence of malignant disease following allogeneic HSCT: factors related to the graft-versus-leukemia effect
  • The biology underlying recurrence of malignant disease following allogeneic HSCT: factors unrelated to the graft-versus-leukemia effect
  • The epidemiology and natural history of relapse
  • Strategies and therapies used in the prevention of relapse
  • Methods and strategies for monitoring relapse following allogeneic HSCT
  • Treatment of disease relapse following allogeneic HSCT

Each of the six focus groups from the workshop will publish a review article in the journal Biology of Blood and Marrow Transplantation in 2010. The articles will outline the current state of the science, ongoing research, and areas where additional focus and collaborative research efforts are most needed.

Two of the six articles, on the biology of the graft-versus-leukemia effect and the epidemiology and natural history of relapse, were published online in February and April, respectively.

NCI sponsored the First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in November 2009.

“We wanted to bring the transplant community together, but also bring in fresh ideas,” explained Dr. Michael Bishop of NCI’s Center for Cancer Research (CCR), who served as co-chair of the workshop along with Dr. Sergio Giralt from the University of Texas M. D. Anderson Cancer Center.

The workshop covered six major areas of focus, and the proceedings from those discussions will be published throughout 2010. (See the sidebar.) “We wanted to create a reference manual for everyone who is doing transplantation—where we are in terms of the science, and where we need to be,” said Dr. Giralt.

The workshop is only one part of a larger NCI effort to tackle the problem of relapse after transplant in a more organized, systematic fashion, said Dr. Alan Wayne, clinical director of the Pediatric Oncology Branch in CCR.

“Researchers have been developing clinical trials focused on this problem for many years, but for the most part these trials have been driven by individual investigators in the context of relatively specific research questions,” he explained. “It became clear to us that we didn’t really have an organized program that crossed branches of NCI and other institutes at NIH.”

Under the leadership of Dr. Bishop, Dr. Wayne, and Dr. Nancy Hardy from CCR, a new program that aims for cross-institutional organization now includes a tumor board where doctors can present cases to a group and discuss recommendations for care, including treatment in clinical trials, and a special clinic for patients who have relapsed after allogeneic HSCT.

The team is also writing a dedicated protocol to study the natural history, biology, and treatment of patients with relapse after allogeneic HSCT across age groups and institutes. “This will serve as a mechanism to recruit, study, and treat these patients in a more systematic, organized way,” said Dr. Wayne.

The program currently has six new clinical trials in progress, including one trial examining the ability of a vaccine to enhance the efficacy of DLI after relapse, and more planned for the near future.

“Less than five percent of patients with relapsed, progressive disease after allogeneic transplantation are currently treated on institutional review board-approved clinical trials,” said Dr. Bishop. “This is an area that needs significant research focus to systematically address what remains the primary cause of death after transplant.”

Sharon Reynolds

Featured Clinical Trial

Vaccine Therapy for Patients with Recurrent Blood Cancers

Name of the Trial
A Pilot Trial of WT1 Peptide-Loaded Allogeneic Dendritic Cell Vaccine and Donor Lymphocyte Infusion for WT1-Expressing Hematologic Malignancies (NCI-08-C-0051). See the protocol summary.

Dr. Alan S. Wayne Dr. Alan S. Wayne

Principal Investigator
Dr. Alan S. Wayne, NCI Center for Cancer Research

Why This Trial Is Important
Many patients, including children, with hematologic malignancies—leukemias, lymphomas, and other blood or bone marrow diseases—are treated with allogeneic hematopoietic stem cell transplantation (HSCT). In allogeneic HSCT, blood stem cells from a genetically similar donor are infused into a patient’s bloodstream after he or she has been treated with preparatory chemotherapy or radiation therapy. Although allogeneic HSCT is often initially successful in treating hematologic malignancies, residual disease sometimes remains, and many patients see their cancer return (recurrent cancer).

The success of allogeneic HSCT depends not only on the infused stem cells but also on the accompanying immune cells, such as T lymphocytes and natural killer cells, that are present in the infused material. These T lymphocytes can recognize cancer cells as being foreign and produce a beneficial graft-versus-tumor/leukemia (GVL) effect. Consequently, researchers are studying ways to safely enhance the GVL effect to protect against relapse, treat persistent disease, and improve disease-free survival after allogeneic HSCT. One approach being investigated is to infuse patients with additional donor T lymphocytes. The use of anticancer vaccines to generate more specific anticancer immune responses is also being studied.

One method of anticancer vaccine preparation is to isolate white blood cells called mononuclear cells and mature them in the laboratory into immune cells called dendritic cells, and then expose the dendritic cells to protein molecules that are found primarily in cancer cells. The dendritic cells will take up the molecules (known as tumor antigens), process them, and display them on the cell surface, where they will be “visible” to other immune cells. Then, the dendritic cells are injected into the patient, where they will hopefully stimulate an immune response that selectively targets and kills cells that have the target molecules.

In this phase I/II trial, patients will be treated with donor T-lymphocyte infusions and a dendritic cell vaccine that is designed to trigger an immune response against cells producing a protein called Wilms tumor 1 (WT1). WT1 is produced by cells of many hematologic malignancies. Vaccines targeting this protein have shown promise in animal and some human studies.

Patients will be treated with the WT1 vaccine every 2 weeks for a total of 6 doses. They will receive donor lymphocyte infusions every 4 weeks for a total of 3 infusions. The researchers will assess the safety of the treatments and determine whether they cause any side effects. Immune system responses and anticancer effects will also be measured.

“Patients with hematologic malignancies who relapse after transplantation will commonly get infusions of lymphocytes if their original donor is willing and available to donate again,” said Dr. Wayne. “By adding a vaccine, we are trying to provide a ‘one-two punch’ and generate a more potent and specific anticancer immune response.”

For More Information
See the lists of entry criteria and trial contact information or call the NCI's Clinical Trials Referral Office at 1-888-NCI-1937. 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

FDA Reviewing Potential Risks of Commonly Used Prostate Cancer Drugs

The FDA advised health care professionals yesterday to be aware of potential health risks that may be associated with gonadotropin-releasing hormone (GnRH) agonists, drugs commonly used to treat prostate cancer. The agency based the announcement on its ongoing review of GnRH agonists, which, in several studies, have been associated with a small increased risk for diabetes, heart attack, stroke, and sudden death. Last year, for instance, a retrospective study conducted in Sweden found a small increased risk of fatal and nonfatal heart attacks, as well as other cardiac problems, such as arrhythmias and heart failure, in men with prostate cancer treated with GnRH agonists.

GnRH agonists work by blocking the production of testosterone, a hormone that, like estrogen in some women with breast cancer, can fuel tumor growth. In addition to weighing the risks and benefits of treatment with these drugs, the FDA also advised that patients undergoing treatment with GnRH agonists be monitored for the development of diabetes and cardiovascular disease. The ongoing review has not established whether these drugs can cause these conditions, the agency stressed. But the FDA believes “it is important to tell patients and health care professionals that there may be an increased risk of serious side effects,” said Dr. Robert Justice from the FDA Center for Drug Evaluation and Research.

The GnRH agonists currently on the market include Eligard, Lupron, Synarel, Trelstar, Vantas, Viadur, and Zoladex, as well as several generic options.

Legislative Update

NIH Director Testifies Before House Appropriations Subcommittee

NIH Director Dr. Francis Collins and several institute directors testified at an April 28 hearing on the fiscal year (FY) 2011 NIH budget before the House Appropriations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies. The President’s FY 2011 budget request for NIH is $32.2 billion, an increase of $1.0 billion, or 3.2 percent above the FY 2010 level. This includes a proposed FY 2011 budget for NCI of $5.26 billion, an increase of $163 million, or 3.2 percent above the FY 2010 NCI budget.

Dr. Collins provided an overview of recent NIH discoveries and advances, including opportunities made possible through the American Recovery and Reinvestment Act (ARRA), as well as research priorities to be supported by funding appropriated to NIH for FY 2011. In describing the post-ARRA funding situation, Dr. Collins pointed out that, although the President’s budget does include a funding increase for NIH, the increase is not likely to exceed inflationary increases in research costs, so success rates for grants will likely be lower in FY 2011 than in recent years.

Dr. Collins also focused on NIH’s goal of transforming discovery into health, stating that “Science is not a 100-yard dash. It is a marathon run by a relay team that includes researchers, patients, industry experts, lawmakers, and the public.” He identified five potential areas of opportunities: taking greater advantage of high-throughput technologies, accelerating translational science, helping to reinvent health care, focusing more on global health, and reinvigorating the biomedical research community.

Whereas Dr. Collins’ testimony highlighted research efforts across NIH, he also responded to a number of questions specific to cancer research from members of the subcommittee. He discussed examples of critical progress, including The Cancer Genome Atlas, as well as challenges to address in the coming fiscal year. Specific topics of interest to the subcommittee included pancreatic cancer, childhood cancers, breast cancer screening, and the implementation of recommendations from the Institute of Medicine’s report on the cancer clinical trials system.

More information on the hearing, including Chairman David Obey’s (D-WI) opening statement and Dr. Collins’ testimony for the record, can be found on the subcommittee Web site.

For more information about this and other NCI congressional activity, visit the NCI Office of Government and Congressional Relations Web site.

Cancer.gov Update

Online Tool Provides NCI Funding Trends

Screenshot of Interactive Budget Analysis Tool web page

NCI recently released a new Interactive Budget Analysis Tool based on NCI Annual Fact Book data. The online tool presents Fact Book information and statistics graphically and allows users to tailor the results to their interests. Users can explore the NCI budget using the following four funding categories:

  • Funding by mechanism provides NCI budget information broken down by the types of grants, contracts, or programs funded.
  • Funding by state provides information on the amount of NCI funding received by institutions and organizations within individual states and territories.
  • Funding by cancer type provides estimated funding levels for frequently requested areas of cancer research.
  • Funding by institution provides a list of institutions and organizations, within individual states, that received more than $15 million of grants and/or contract support from NCI in a given fiscal year.

The Interactive Budget Analysis Tool currently covers fiscal years 1999 through 2008. The tool will be updated to include 2009 data in the coming weeks.

Notes

NCI-Frederick Hosts Annual Spring Research Festival This Week

Spring Research Festival logo

NCI at Frederick and Fort Detrick will host the 14th Annual Spring Research Festival, May 5 and 6, at Fort Detrick in Frederick, MD. Festival events include health education and community services exhibits, poster presentations, and a commercial science and technology exposition.

The festival is a collaborative effort between NCI-Frederick, the National Biodefense Analysis and Countermeasures Center, the U.S. Department of Agriculture Foreign Disease-Weed Science Research Unit, the CDC, the U.S. Army Medical Research Institute of Infectious Diseases, the Navy Medical Biological Defense Research Lab, and the National Institute of Allergy and Infectious Diseases Integrated Research Facility. The event provides a forum for civilian, military, and contractor scientists employed by these agencies to share information across scientific disciplines and to acquaint those in the NCI-Frederick and Fort Detrick communities with the research, discoveries, and challenges that lie ahead for these agencies.

Tribute to Celebrate Dr. Ruth Kirschstein’s Contributions to Science and NIH

Dr. Ruth L. Kirschstein Dr. Ruth L. Kirschstein

On May 17, NIH staff and other colleagues will gather to celebrate the life and accomplishments of Dr. Ruth Kirschstein. The day of celebration and science, which begins at 9:00 a.m., will conclude with a poster session and reception from 5:30 p.m. to 7:30 p.m. All events will be at the Natcher Conference Center, and the presentations will be webcast.

Over more than 5 decades at NIH, Dr. Kirschstein made stellar contributions to biomedical research, including her early work on the development of a safety test for the polio vaccine and her later efforts to organize the NIH response to the AIDS epidemic. Dr. Kirschstein was the first woman to direct an institute on campus, and she twice served as acting NIH director.

In addition to commemorations on May 17, several recipients of the Ruth L. Kirschstein National Research Award will talk about their research and reflect on the inspirations of their work. The speakers will include Dr. Laurie Boyer of the Massachusetts Institute of Technology, Dr. Howard Chang of Stanford University, Dr. Francis Lee of Weill Cornell Medical College, Dr. Alfredo Quiñones-Hinojosa of the Johns Hopkins University, Dr. Gonzalo Torres of the University of Pittsburgh, Dr. Dorothy Sipkins of the University of Chicago, Dr. Anna Penn of Stanford University, Dr. Sara Cherry of the University of Pennsylvania, and Dr. Julie Pfeiffer of the University of Texas Southwestern Medical Center.

“Ruth Kirschstein was a pioneer,” said NCI Director Dr. John E. Niederhuber. “She was also an extraordinary leader and a dedicated scientist. Above all, I believe she was the embodiment of one of the principles I hold most dear—that it is an unparalleled honor to devote one’s career to the service of others.”

Second Telephone Workshop for Cancer Survivors on May 18

The second of four telephone workshops in NCI’s annual “Living With, Through, and Beyond Cancer” series will be held May 18 from 1:30 to 2:30 p.m. EDT. Part II of the series is titled “Communicating with Your Health Care Team After Treatment: Making the Most of Your Visit.”

The free series offers cancer survivors, their families, friends, and health care professionals practical information to help them cope with concerns and issues that arise after treatment ends. The workshops are presented by CancerCare, in collaboration with NCI, LIVESTRONG, the Intercultural Cancer Council, Living Beyond Breast Cancer, and the National Coalition for Cancer Survivorship.

Speakers for the May 18 workshop include Dr. Neeraj K. Arora of NCI’s Division of Cancer Control and Population Sciences, Dr. Sheldon Greenfield of the University of California at Irvine, and Dr. Thomas J. Smith of Virginia Commonwealth University’s Massey Cancer Center.

Part III, “Survivorship and Workplace Transitions,” will take place on June 22. And Part IV, “Survivors Too: Communicating With and Among Family, Friends, and Loved Ones,” will take place on July 13.

These workshops are free; no phone charges apply. To register, visit the CancerCare Web site.

If you missed part I of the series, “Trouble Sleeping? Sleep Better to Feel Better: Tips You Can Use,” a recording is available online via podcast.