National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
February 8, 2011 • Volume 8 / Number 3

NEWS

Bevacizumab binds to the protein VEGF and blocks signals from tumors that would recruit new blood vessels.When Combined with Chemo, Bevacizumab Is Associated with Increased Risk of Death

Cancer patients who receive the targeted therapy bevacizumab (Avastin) in combination with chemotherapy are at increased risk of serious side effects that may lead to death, according to a meta-analysis of 16 clinical trials that was conducted by researchers at Stony Brook University School of Medicine in New York. The risk of fatal adverse events varied by the type of chemotherapy agents used with bevacizumab, lead author Dr. Vishal Ranpura and his colleagues reported. Read more > >

SCIENCE SNAPSHOTS

A 3D in vitro assay that mimics the formation of vasculature in vivo. (Image courtesy of Dr. Enrique Zudaire)What is this? Click on the image to find out.
A photo of single nucleotide polymorphism (SNP) genotyping arrays assembled for reagent loading on the liquid handling robot. SNPs, the most common type of change in DNA (molecules inside cells that carry genetic information), occur when a single nucleotide (building block of DNA) is replaced with another. These changes may cause cancer or other diseases, and may affect how a person reacts to bacteria, viruses, drugs, and other substances.
  

IN DEPTH

UPDATES

  • FDA Updates

    • Another Radioactive Tracer Approved for Bone Scans
    • Rituximab Approved as Maintenance Therapy for Follicular Lymphoma
    • FDA Investigates Breast Implants and a Rare Lymphoma
  • Notes

    • DCTD Appoints New Chief to Monitor Clinical Trials
    • NCAB Holds First Meeting of 2011
    • Experts Discuss National Cancer Communications Plan
    • Funding Encourages Research Collaborations in China and U.S.
    • Directory of Surveillance Data for Obesity Research Available
    • What You Need to Know About Booklets Updated

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

When Combined with Chemo, Bevacizumab Is Associated with Increased Risk of Death

Bevacizumab binds to the protein VEGF and blocks signals from tumors that would recruit new blood vessels. Tumors release the protein VEGF (pictured above next to the tumor in gray) as a signal to recruit the growth of nearby blood vessels, so that they can establish their own nutrient supply. Bevacizumab (pictured above as green and purple Y-shaped molecules) binds VEGF, blocking signals that can help sustain tumor survival and growth. (Image courtesy of Genentech)

Cancer patients who receive the targeted therapy bevacizumab (Avastin) in combination with chemotherapy are at increased risk of serious side effects that may lead to death, according to a meta-analysis of 16 clinical trials that was conducted by researchers at Stony Brook University School of Medicine in New York. The results were published February 2 in JAMA.

The risk of fatal adverse events varied by the type of chemotherapy agents used with bevacizumab, lead author Dr. Vishal Ranpura and his colleagues reported. There were also suggestions that the risk might vary by tumor type and bevacizumab dose, but the study did not have the statistical power to provide a definitive answer in either case. 

More than 10,200 patients were enrolled in the randomized trials included in the analysis. Overall, fatal events were relatively rare, occurring in 2.5 percent of trial participants who received bevacizumab, compared with 1.7 percent of patients who did not—an approximately 50 percent increase in risk. However, the increased risk was more than threefold higher in patients who received bevacizumab in combination with platinum or taxane chemotherapy agents, such as carboplatin and paclitaxel, respectively.

The most common fatal event, accounting for nearly one-quarter of the total, was hemorrhage. Neutropenia, a decrease in a specific type of white blood cell that can put patients at increased risk of infections, was next, followed by perforations of the gastrointestinal tract, blockages of the pulmonary arteries, and cerebrovascular events such as stroke.

The benefits of bevacizumab can outweigh the risks of its use in a proportion of patients, explained Dr. Shenhong Wu, the study’s senior author, but the finding should prompt closer scrutiny of how bevacizumab is used. Oncologists, he said, “should have a healthy respect for the toxicity of this drug and the possibility that it can cause fatal events.”

The finding of an increased risk of serious events in patients treated with bevacizumab “is generally consistent with what’s known about the drug,” said Dr. Helen Chen of NCI’s Division of Cancer Treatment and Diagnosis. “What is clear [about bevacizumab] at this point is that the patients’ susceptibility to serious adverse side effects from bevacizumab can have a lot to do with the tumor setting and comorbidity.” Certain tumor types can predispose patients to an increased risk of certain events, she continued, such as bleeding in patients with advanced lung cancer.

Dr. Cary Presant of the Wilshire Oncology Medical Group, who is also a clinical professor of medicine at the USC Keck School of Medicine, believes that the study’s finding will likely affect clinical practice. “I do believe…that [bevacizumab] usage will go down,” he said. “This obligates every physician who wants to use [bevacizumab] to have a conversation with their patients about fatal events, and it will lead to less use of this drug in cases where the beneficial effects are more marginal.”

The strongest evidence of benefit with bevacizumab still seems to be in treating patients with metastatic colorectal cancer, Dr. Presant continued. “But some patients with lung [or] breast cancer might be inclined to choose not to receive it because the benefits are not as great.”

An antiangiogenic agent that binds to vascular endothelial growth factor (VEGF), bevacizumab was the first FDA-approved drug designed to target the blood supply that feeds tumors. In addition to being approved for the treatment of colorectal cancer, the monoclonal antibody is approved to treat lung cancer, kidney cancer, and glioblastoma. (See the table below on specific indications.)

Bevacizumab is also approved to treat metastatic, HER2-negative breast cancer. In December 2010, however, the FDA announced it was beginning the process of withdrawing that approval for breast cancer based on results from several post-market clinical trials that failed to show an improvement in overall survival and which, the agency stated, did not “provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients.” Genentech, which manufactures bevacizumab, has asked for a public hearing on the FDA’s withdrawal decision.

In an accompanying JAMA editorial, Dr. Daniel Hayes of the University of Michigan Comprehensive Cancer Center noted that treatment with bevacizumab can run as high as $100,000 a year, yet there is still substantial uncertainty around appropriate use of the drug in cancer care.

“Why, despite the impressively solid preclinical data and the promising early clinical results, has bevacizumab not been more successful in improving overall survival?” he wrote. Improvements in median overall survival were seen in only three of the pivotal trials on which the FDA based its approvals. In two of the trials, survival increased by less than 3 months.

“Careful review of response rates to bevacizumab suggest that bevacizumab works well, but only in selected patients,” Dr. Hayes wrote further. Despite being broadly tested in numerous clinical trials, he continued, “few insights are available about specific subgroups of patients who may benefit.”

In a statement responding to the JAMA study, Genentech noted that “the majority of our clinical studies include collection of blood, tumor tissue, and DNA for biomarker analysis as part of a comprehensive biomarker program.” To date, although some studies have reported a correlation between certain markers and outcomes of bevacizumab-based therapy, no markers have undergone the rigorous validation studies needed for use in the clinic, Dr. Chen stressed.

Genentech has proposed a phase III clinical trial of bevacizumab in HER2-negative breast cancer that would have a biomarker component. Based on a retrospective analysis of a previous trial, the company explained in a document filed with the FDA, the new trial would assess whether plasma levels of the protein VEGF-A are indicative “of a more substantial benefit” with bevacizumab.

Carmen Phillips

Bevacizumab and Its Indications

IndicationTreatmentTrial results on which the FDA based its approval
Metastatic colorectal cancer, first-lineIn combination with IFL (irinotecan, fluorouracil, leucovorin)

Improved median overall survival (OS) by 4.7 months; also improved progression-free survival (PFS)

Metastatic colorectal cancer, second-lineIn combination with FOLFOX4 (folinic acid [leucovorin], fluorouracil, oxaliplatin)Improved OS by 2.2 months; also improved PFS
Unresectable locally advanced, recurrent, or metastatic non-small cell lung cancer (non-squamous histology), first-lineIn combination with carboplatin and paclitaxelImproved OS by 2.0 months
Metastatic kidney cancer, post-nephrectomyIn combination with interferon-alfaImproved PFS
Progressive glioblastoma, second-lineSingle agentObjective response rate
Metastatic breast cancer, no prior chemotherapy*In combination with paclitaxelImproved PFS

* The FDA is in the process of removing the indication for breast cancer

Cancer Research Highlights

Starting Hormone Therapy at Menopause Increases Breast Cancer Risk

Women who start taking menopausal hormone therapy around the time of menopause have a higher risk of breast cancer than women who begin taking hormones a few years later. The finding, from the Million Women Study (MWS)—a large observational study in the United Kingdom—adds to a growing body of evidence that the use of combined hormone therapy (estrogen plus progestin) to treat menopausal symptoms increases the risk of breast cancer and deaths from the disease. The results appeared in the Journal of the National Cancer Institute on January 28.

The pattern of increased breast cancer risk “was seen across different types of hormonal therapy, among women [in the MWS] who used hormonal therapy for either short or long durations, and also in lean and in overweight and obese women,” Dr. Valerie Beral of Oxford University and her colleagues wrote. Their findings support results from the Women’s Health Initiative (WHI), a randomized clinical trial that, in 2002, first reported evidence linking combined hormone use to breast cancer.

“The new findings underscore the idea that there’s really no safe window of time for women to take combined hormone therapy,” said Dr. Leslie Ford of NCI’s Division of Cancer Prevention and the Institute’s WHI liaison. After the initial WHI results were announced, she noted, some people had argued that hormones may be safer when started at the time of menopause. “The new findings refute that argument,” she added.

WHI and MWS investigators have both reported that breast cancer incidence rates declined rapidly once women stopped taking combined hormone therapy. “It is important for women to know that if they stop using hormones, the risk of breast cancer very quickly returns to where it was before hormone therapy began,” Dr. Ford said.

There has been a discrepancy between the WHI and MSW results to date as to whether estrogen-only therapy raises breast cancer risk in postmenopausal women. WHI reports have found little risk associated with this treatment, whereas the MWS investigators have observed a statistically significant increased risk.

Additional follow-up from the WHI estrogen-only intervention trial should help clarify this issue in the coming years, noted Drs. Rowan T. Chlebowski of Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center and Garnet L. Anderson of the Fred Hutchinson Cancer Research Center in an accompanying editorial.

Vaccine Reduces HPV Infections in Young Men

An international randomized clinical trial has shown that the vaccine Gardasil, which arms the immune system against four strains of the human papillomavirus (HPV), can reduce the incidence of anogenital HPV infections in young men 16 to 26 years of age at the time of vaccination. The results were published in the New England Journal of Medicine on February 3.

Gardasil was first approved by the FDA in 2006 for females 9 to 26 years of age to prevent cervical, vulvar, and vaginal cancers, as well as genital warts. Two of the four strains targeted by the vaccine—HPV-6 and HPV-11—cause most cases of genital warts, and the other two strains—HPV-16 and HPV-18—cause about 70 percent of all cervical cancers. In addition, HPV-16 and HPV-18 have been linked to cancers of the anus, penis, and oropharynx. In 2009, the FDA extended approval of the vaccine for the prevention of genital warts in young men based on the results of the current trial.

The trial, designed by Merck Pharmaceuticals, enrolled 4,065 young men from 18 countries; 2,032 of the participants were randomly assigned to receive the three-dose vaccine over a 6-month period, and 2,033 received a series of placebo injections over the same period of time. Dr. Anna R. Giuliano of the H. Lee Moffitt Cancer Center and Research Institute and her colleagues measured HPV infection status at the time participants joined the study and again periodically for up to 3 years after enrollment. The men also underwent regular physical examinations to identify genital skin lesions associated with HPV.

The researchers performed analyses in two overlapping groups of men. The intention-to-treat cohort included men who all received at least one dose of vaccine or placebo, regardless of HPV status at enrollment. The per-protocol cohort included only men who received all three doses and tested negative for all four HPV types targeted by the vaccine throughout the vaccination phase of the study, and thus excluded men who developed infections before the vaccination was complete. Gardasil is designed to prevent HPV infections and does not appear to increase the rate of clearance of established infections; thus, the estimates of effectiveness will be higher in the per-protocol cohort than in the intention-to-treat cohort.
                  
In the intention-to-treat cohort, the vaccine prevented 65.5 percent of skin lesions, mostly genital warts, associated with two of the four targeted HPV types; in the per-protocol population containing men with no evidence of previous exposure to the viruses, the vaccine prevented 83.8 percent of lesions.

The rate of persistent HPV infection with any of the four types anywhere in the body that lasted at least 6 months was reduced by 47.8 percent in the intention-to-treat cohort and by 85.6 percent in the per-protocol cohort. For HPV types 16 and 18—the two that can eventually cause cancer in a small proportion of infected individuals—persistent infection was reduced by 79 percent and 96 percent, respectively, in the per-protocol cohort, though these data are based on very small numbers of people. Much longer follow up and additional studies will be needed to determine whether the vaccine prevents the development of HPV-related cancers in men, explained the authors.

On December 22, 2010, the FDA approved Gardasil for both men and women ages 9 through 26 to prevent anal cancer and associated precancerous lesions. This approval was based on results in the subset of men in the current trial who have sex with other men. Dr. Giuliano and her colleagues found a 78 percent reduction in anal intraepithelial neoplasia grades 1, 2, and 3 related to HPV-16 and HPV-18 infection. Approximately 90 percent of anal cancers have been linked to HPV infection.

Adoptive Cell Transfer Targets New Cancer Antigen for Immunotherapy

Results from a phase II trial suggest that an immunotherapy strategy called adoptive cell transfer (ACT) may be effective for patients with metastatic cancers, including melanoma and a tumor of the soft tissues of joints known as synovial cell sarcoma. The study, published January 31 in the Journal of Clinical Oncology, is part of an effort by researchers from NCI’s Center for Cancer Research to engineer a patient’s own white blood cells to recognize and attack his or her specific cancer.

For the treatment, Dr. Steven Rosenberg and his colleagues genetically modified the receptors on the patient’s own T cells to bind to an antigen called NY-ESO-1, which is expressed in 80 percent of synovial cell sarcomas and 15 to 30 percent of metastatic melanoma, breast, prostate, lung, and ovarian cancers. The antigen is not commonly present in normal tissues except in the testis.

From each patient who had tumors that heavily expressed the NY-ESO-1 antigen, T cells were removed. The extracted T cells were then genetically altered using a retrovirus that delivered the genetic code for building NY-ESO-1 receptors into the cells. The modified T cells were then grown in the laboratory and infused back into the patients. To prepare for the infusion of their altered T cells, the patients received chemotherapy to eliminate any other immune cells in their blood.

All 17 patients enrolled in the trial had progressive metastatic disease. The six patients with synovial cell sarcoma had been treated with multiple chemotherapies, and the 11 melanoma patients had been previously treated with interleukin-2. After ACT, five of the melanoma patients had measurable responses, and two of them had complete responses (disappearance of all signs of cancer) that were sustained at 20 and 22 months, respectively. Among the three remaining melanoma responders, one had a partial response (shrinkage of tumor size) that persisted 9 months after initial treatment. Four of the synovial cell sarcoma patients had objective partial responses, with one patient’s response lasting 18 months.

Patients in the trial experienced no toxic effects beyond those that are common with stem-cell transplantation and interleukin-2 treatment, which include neutropenia and thrombocytopenia, and the toxicities were less severe than in other trials in which ACT was used against different tumor antigens, the authors wrote.

The study “represents the first successful immunotherapy for patients with synovial cell sarcoma,” they concluded, noting that the small number of patients in the trial limits the interpretation of their results. However, the strategy against NY-ESO-1 should be explored further, they continued, because the antigen is expressed by common cancers and, thus, the treatment may be extended to many tumor types.

Mouse Studies Point to Prognostic Test for Prostate Cancer

Some mice, like some men, develop prostate cancer that never spreads beyond the prostate, and researchers have used these mice to learn why only some tumors metastasize and become fatal. By studying genetically engineered mice, the researchers identified four genes that drive the progression of prostate tumors. The corresponding genes in humans also appear to influence the spread of prostate cancer and could become prognostic markers for identifying potentially lethal tumors in patients, the researchers reported online in Nature on February 2.

New tests are needed to distinguish lethal prostate tumors from those that would never cause harm in a man’s lifetime. But, given the enormous intratumoral heterogeneity of human prostate cancers, Dr. Ronald DePinho of the Belfer Institute for Applied Cancer Science at Dana-Farber Cancer Institute and his colleagues decided to look for prognostic markers in genetically engineered mice, which are more amenable to genetic analysis. Using unbiased approaches, the investigators discovered that a mouse gene called Smad4 constrains the spread of tumor cells.

Additional experiments and lines of evidence, including functional studies and cross-species comparisons of genes, implicated four genes, including Smad4, in the progression of prostate cancer in mice. The researchers concluded that the process is governed largely by the inactivation of the genes Smad4 and Pten and activation of two other genes, cyclinD1 and Spp1.

They next assessed the prognostic value of the corresponding genes in human prostate cancer, using the protein products of the genes as markers. When added to standard clinical parameters such as the Gleason score, the researchers found these markers improved predictions of death from metastatic prostate cancer among men who participated in the Physicians’ Health Study and in a second study.

“We used the mouse models to filter out the intractable genomic complexity that presents itself in early-stage human cancers,” said Dr. DePinho. “And this allowed us to identify a collection of markers that are functionally relevant to the biology of invasion.” A company has licensed the four markers for further development, he added.

Protein May Help Predict Cancer Recurrence and Metastasis

An altered form of a protein called CPE-delta N that is found in several cancer types may be used to predict cancer recurrence and metastasis with high sensitivity, reported an international team of researchers online February 1 in the Journal of Clinical Investigation.

The researchers, led by Drs. Terence Lee of the University of Hong Kong and Saravana Murthy of the National Institute of Child Health and Human Development, found that highly metastatic liver cancer cell lines had elevated levels of messenger RNA (mRNA) for CPE-delta N compared with liver cancer cells that were unlikely to spread. When the scientists blocked CPE-delta N expression in the metastatic cells using small interfering RNA (siRNA) technology, both cell growth and invasiveness were inhibited. Similar results were obtained with breast, colon, and head and neck cancer cell lines.

The researchers also found that CPE-delta N-expressing liver tumors implanted in mice grew as much as 16-times larger than control tumors containing siRNA that blocked CPE-delta N, and that the tumors without the siRNA block spread in the liver and to the lungs.

The researchers then evaluated whether CPE-delta N could be used as a biomarker to predict recurrence (including metastasis) in patients with hepatocellular carcinoma, a type of liver cancer. Using data from 99 patients, the researchers found that 75.8 percent of those whose disease did not return had CPE-delta N mRNA levels in their liver tumors that were no more than twice the level found in normal tissues. In contrast, 92.3 percent of patients whose tumors recurred had liver tumors with CPE-delta N mRNA levels greater than twice the level found in normal tissues. These findings translate to a sensitivity—the likelihood of the biomarker correctly predicting whether disease will recur—of 92.3 percent

A confirmatory study in 80 additional patients showed similar results. Importantly, explained the authors, CPE-delta N was able to predict risk of recurrence independent of tumor stage, a parameter that is commonly used to help predict risk of recurrence in the clinic.

The researchers then tested the predictive power of CPE-delta N in 14 patients with pheochromocytoma or paraganglioma, rare neuroendocrine tumors. They found that highly elevated copy numbers of CPE-delta N mRNA predicted recurrence with 100 percent accuracy in those patients.

“What’s unique about this paper is the fact that the marker works in two unrelated cancers,” said Dr. Stephen Hewitt, staff scientist in NCI’s Center for Cancer Research and a co-author on the paper. “Many biomarkers do not generalize into multiple tumor types.” If confirmed, CPE-delta N could be used to guide clinical care for some patients, such as sparing a patient whose tumor has already spread unnecessary surgery, he explained.

Spotlight

Coming Home to Roost: The Self-Seeding Hypothesis of Tumor Growth

An illustration of the self-seeding concept of cancer growth and metastasis In the self-seeding concept of cancer growth and metastasis, a mobile tumor cell can take one of five different pathways in the body. (Reprinted by permission from Macmillan Publishers Ltd: Norton L and Massagué J. Is cancer a disease of self-seeding? Nature Medicine, 12(8); 2006: 875-878. Copyright 2006.) [Enlarge]

The spread of cancer cells from their original location to other sites in the body, known as metastasis, has long been thought of as a one-way journey. But some researchers also believe that metastatic cancer cells can fuel primary tumor growth, with potentially important implications for the timing and nature of cancer treatment.

The concept of tumor self-metastasis, or tumor “self-seeding,” originated at Memorial Sloan-Kettering Cancer Center, based on a series of studies led by Drs. Joan Massagué, head of the Metastasis Research Center, and Larry Norton, deputy physician-in-chief of the center’s breast cancer programs.

In studies of mice, Dr. Massagué observed that breast tumors expressing genes associated with metastasis were growing faster than tumors that didn’t express these genes, even though the genes had no apparent role in increased cell division or decreased cell death. “Moreover, the fraction of dividing cells was not higher in fast-growing tumors versus tumors that are slower growing,” explained Dr. Norton.

These results did not fit in with the standard theories of tumor growth. In 2006, the two researchers proposed that cells that break free from a tumor and colonize distant tissues may also return home via the circulatory system to the welcoming microenvironment in which they first developed.

“We started discussing the possibility that maybe some tumors are growing faster not because the cells were dividing faster or because there was a higher percentage of dividing cells—because none of those things seemed to be true—but because the tumor mass itself was a recipient of metastatic cells,” said Dr. Norton. “Twenty masses growing at rate x are going to be growing 20 times faster than one mass growing at rate x.”

Proof of Concept

The two researchers tested their hypothesis in a mouse model of cancer and published their results in 2009 in Cell. For one experiment, they chose a non-metastatic breast cancer cell line and an isolated set of daughter cells from that line that had gained the ability over time to metastasize to the lungs.

When the researchers implanted the parent cells in one mammary gland and the metastatic daughter cells in the opposite gland to serve as “donor tumors,” the daughter cells migrated to the lungs and to the tumors that were being formed by the parent cells in the opposite gland, accounting for 5 to 30 percent of the eventual size of the parent tumors. Parent tumors seeded by daughter cells grew faster than parent tumors that were implanted alone without daughter cells in the opposite gland.

The researchers observed this same seeding behavior with daughter cells that metastasize to the bones and brain, and with colon cancer and melanoma cell lines, but they did not see the effect when they transplanted daughter cells that were not metastatic.

In a set of follow-up experiments performed in the laboratory, the researchers showed that cells from primary tumors can attract circulating metastatic tumor cells, and they identified several proteins that likely encourage this migration. They also found that the returning metastatic cells promoted primary tumor growth by releasing proteins that change the tumor’s microenvironment, including blood vessels and immune cells, explained Dr. Massagué in an e-mail.

Their hypothesis began to get support from other researchers who were testing it in their own laboratories. “Since publishing this work, we get about an e-mail a week from someone who has repeated our experiment with a tumor line they’re working with, and who has found that their tumor line self-seeds,” recounted Dr. Norton.

Room to Grow

Systems biologists at the Center of Cancer Systems Biology at Tufts University School of Medicine in Boston have provided a clearer picture of how self-seeding could fuel rapid primary tumor growth.

In 2009, Dr. Philip Hahnfeldt and his colleagues published the results of computer modeling studies designed to look at the intersection of two biological phenomena found in tumors. One of these phenomena is that a small population of cancer cells may act like stem cells; they may have the ability to reproduce an infinite number of times, creating more cells like themselves with the capability for endless proliferation but also producing daughter cancer cells that eventually lose the ability to divide.

The second phenomenon is that tumor growth is limited by the space available for expansion. Normal, healthy cells have an amount of space between them that is not available in a tumor. Cancer cells grow tightly together in a dense mass until all available space has been occupied, at which point cell division stops. But at the edges of the tumor, where the normal tissues are less dense, cancer cells continue to multiply and push outward, expanding the tumor’s size.

“This gives value to the idea that tumor growth is helped by metastatic movement,” explained Dr. Hahnfeldt, “where tumor cells get away from the main mass through migration and then…the resulting space [is filled],” creating many smaller masses growing together at a faster rate. Thus, the growth of a primary tumor may be more dependent on metastatic cells populating areas adjacent to the tumor than on the outward growth and invasion of the primary tumor itself.

Their models showed an important—and counterintuitive—relationship between cell migration, cell death, and tumor growth. When the progeny of a cancer stem cell in the model did not migrate or die spontaneously, tumor growth stagnated at around 110 cells. In contrast, a combination of high death rate among the non-stem cell progeny and a high cell migration rate produced the largest tumors in the shortest amount of time, to almost 100,000 cells in just over 3 years.

Clinical Implications of Self-Seeding

This theoretical phenomenon—accelerated tumor growth jump-started by a high rate of tumor cell death—has potential implications for the clinical treatment of cancer. Traditional cytotoxic chemotherapy drugs kill large numbers of rapidly dividing cancer cells, but may not affect cancer stem cells in every tumor type.

“Our model suggests that discouraging migration might provide an alternative means of cancer suppression. Importantly, the results suggest that antimitotic treatments alone, despite killing cancer cells, may actually promote tumor progression if eradication of cancer stem cells cannot be achieved,” wrote Dr. Hahnfeldt and his colleagues in their 2009 paper.

Currently, no anticancer drugs exist that specifically interfere with the process of metastasis, though researchers are actively working on understanding the genetic changes that drive a cancer cell’s ability to break away from a tumor and survive in the blood stream, in the hopes of making metastasis a valid therapeutic target.

And, although the concept of cancer stem cells remains under debate, if self-seeding can be confirmed in cancer patients, what is learned could influence the timing and nature of cancer treatment.

“Some of the things that we do to a tumor—are they inhibiting the process of seeding or are they augmenting the process of seeding?” asked Dr. Norton. “That’s something we don’t know the answer to yet, but it is something we need to seriously consider.” In some cases, removing a primary tumor without first attempting to kill circulating tumor cells may actually encourage distant metastases, as those cells lose their preferred “home” and lodge elsewhere in the body, he explained.

Dr. Massagué’s laboratory is working to understand the molecular basis of self-seeding, which may supply future targets for anticancer drugs. Dr. Norton is also interested in exploring immunotherapeutic approaches to encourage cells within the primary tumor to attack returning self-seeds, a so-called “poison sponge” effect.

Dr. Hahnfeldt is also expanding his modeling work with a grant from NCI’s Integrative Cancer Biology Program (ICBP), overseen by the Division of Cancer Biology. That research will look at how the immune system influences the way cancer cells interact with each other.

“Systems biology has focused a lot on the cancer cell itself, on the genetic changes that occur within that cell. And because cancer is a genetic disease, we’re interested in the changes that occur within a normal cell that cause it to take on these cancer characteristics and become malignant,” said Dr. Dan Gallahan, director of the ICBP. “But it’s also true that population dynamics or cell interactions are equally important. We now know that these dynamics, along with the microenvironment and the immune system, are critical to tumor development.”

The self-seeding of a tumor with its own metastatic cells, Dr. Gallahan continued, may represent a crucial step in this development.

Sharon Reynolds

Featured Clinical Trial

Study of a Statin to Prevent Polyps after Colon Cancer Resection

Name of the Trial
Phase III Randomized Study of Adjuvant Rosuvastatin in Patients with Resected Stage I or II Colon Cancer (NSABP-P-5). See the protocol summary.

Dr. Bruce M. Boman Dr. Bruce M. Boman

Principal Investigator
Dr. Bruce M. Boman (Protocol Chair), National Surgical Adjuvant Breast and Bowel Project (NSABP)

Why This Trial Is Important
Millions of Americans take drugs called statins to lower their cholesterol levels and protect against heart attacks. Statins may also protect against some types of cancer, including colorectal cancer. However, this is somewhat controversial. “While some retrospective observational studies suggest that statins prevent colorectal cancer, others do not. Moreover, most of these studies were short term and were not designed to look at tumor development; so the jury is still out on the efficacy of statins," said Dr. Boman. “What is needed is a properly designed, long-term, prospective study that evaluates tumor development, and that’s why the randomized, placebo-controlled, double-blind NSABP-P-5 study was developed.” To determine the effectiveness of statins as a form of chemoprevention against colorectal cancer, NSABP researchers are testing statins in people who are at high risk of developing colorectal tumors, specifically those who have already been treated for early-stage colon cancer.

Although surgical resection alone is successful in curing most patients with early-stage colon cancer, as many as 50 percent will develop a new colon or rectal tumor (mainly adenomatous polyps) within 3 years of surgery. Adenomatous polyps are not cancerous, but they have the potential to become cancer if not removed. Some patients will even develop a second primary cancer (known as a metachronous cancer) in the colon or rectum after removal of their first, or primary, cancer. Doctors are eager to find new ways to prevent the formation of adenomatous polyps and colorectal cancers in these patients and in the general population.

Patients diagnosed with stage I or II colon cancer are eligible for this trial after they have undergone surgical treatment (resection) to remove their primary tumor. Patients may also have received post-surgical (adjuvant) therapy. Study participants will be stratified (categorized) according to whether or not they have a family history of colorectal cancer, whether they regularly take aspirin and at what dose (none, 81 mg, or 325 mg), and whether they received prior adjuvant therapy. They will then be randomly assigned to take either rosuvastatin (Crestor) or a placebo pill daily for 5 years. Participants will have physical exams every 6 months during the 5-year study period and will undergo complete colonoscopies within 180 days before randomization, and at 1, 3, and 5 years afterward. Doctors will follow the participants for the development of adenomatous polyps, the incidence of metachronous colorectal cancers, and the recurrence of their primary colon cancer.

“We’re also very interested in aspirin because we know that it has some benefit in preventing colorectal polyps and cancer. So, this study is designed to accept people who currently take aspirin as long as they agree to continue their aspirin over the course of the study,” Dr. Boman added. 

Like statins, aspirin is widely used to protect the heart. The long-term use of aspirin has been shown to provide protection against the development of colorectal polyps and cancer. Since statins and aspirin are often used together, researchers are interested in exploring their ability, when combined, to prevent colorectal polyps and cancer. A recent case-control study examined the effects of a daily statin and low-dose aspirin, individually and together, on the development of colorectal tumors. The researchers found that using both drugs together reduced colorectal cancer risk more than the use of either drug alone. Consequently, one of the secondary endpoints in the NSABP-P-5 trial is to see if the combination of rosuvastatin and aspirin has either additive or synergistic effects.

For More Information
See the lists of entry criteria and trial contact information or call 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.

Community Update

Oncology Nursing
This is the fifth article in a series of stories related to oncology nursing. You can read more articles in the series here.

Translating Clinical Care for Callers to NCI’s Cancer Information Service

Most oncology nurses are on the front lines of cancer care, interacting with and helping patients on a daily basis. But what if that front line is a few steps removed from the face-to-face contact of the clinic?  That’s exactly the situation for the oncology nurses of NCI’s Cancer Information Service (CIS), a resource which handles approximately 100,000 calls, e-mails, and live chat sessions annually.

More than 70 information specialists, who are trained and monitored by experienced oncology nurses, tackle these requests for help and information, often engaging in lengthy discussions about treatment options with someone who has just been diagnosed with cancer, or with the spouse of a cancer patient who’s having a hard time taking care of their loved one and needs some help or guidance on what to do or where to turn.

Before they can begin direct engagement with callers, the information specialists undergo 6 weeks of intense training on everything from the basics of cancer diagnosis and therapy to proven treatments for nausea and pain. These specialists, in many respects, “are the voices of NCI,” said Randy Jacobs, an oncology nurse educator with the CIS.

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Video produced and edited by Sarah Curry.

Jacobs’ charge is to help ensure that those voices are “empathetic, knowledgeable, and responsive,” she explained. As an oncology nurse, Jacobs understands the kind of impact a one-on-one interaction with patients and caregivers can have.

“My background in oncology and as a bedside nurse really helps to bring some of the clinical aspects of cancer care to the information specialists, who often don’t have that intimate level of knowledge,” she explained.

In her role with the CIS, Jacobs is heavily involved in nearly all aspects of the information specialists’ training, including how to develop a rapport with patients, providing education about specific cancers, and continuing education programs.

“We can help the information specialists understand the complexity of cancer and the patient experience,” said Judy Petersen, an oncology nurse who recently joined the CIS as an educator. “In this call-center environment, that’s where an oncology nurse is particularly helpful, because we can really put into context what patients and their families are going through.”

A Nurse’s Touch

An important part of their job, Jacobs explained, is helping the information specialists determine what each caller actually wants, without being able to rely on the telling physical cues that face-to-face interactions with patients can provide.

“Sometimes callers don’t want to share too much information, but other times they want to tell you everything,” she said. “They may be going through a very emotional time, they may be crying, or they may break down during the call. So the information specialists have to balance how much cancer knowledge the callers have, where they are coming from, what’s their state of mind, and try to give them the information they’re really looking for.”

And if, during a call, the expertise of an oncology nurse is needed, the information specialists can turn to the nurse educators for help. “A specialist will come to me and say, ‘Can you help me with this person who has stage III colorectal cancer and really wants to know more about the side effects of chemotherapy?’” Jacobs explained. “We can get very specific and provide the information the caller needs in real time.”

Nurse educators also play an important role by making callers aware of clinical trials, said Deborah Pearson, an oncology nurse who worked as a clinical and research nurse at the NIH Clinical Center for 9 years and now plays a dual role with both the CIS and NCI’s Public Inquiry Office. “These nurses are using their real world experience; information from NCI, including the wealth of information on Cancer.gov; and the patients’ situations to help the information specialists direct appropriate patients to clinical trials for which they may be eligible,” she said.

Keeping Up with the Research

One aspect of their positions that can be challenging at times, Jacobs and Petersen agreed, is keeping up with the constantly evolving nature of oncology care, changing care patterns and paradigms based on clinical trials, and other high-impact research.

“That’s one of the challenges of not being in a clinical setting,” Petersen said, “maintaining that awareness of how research outcomes are being translated into clinical practice.” That requires a lot of journal reading, attending conferences, and paying attention to reliable sources of clinical cancer news.

Overall, Petersen said, the CIS culture is ideal for an oncology nurse who, like herself, first entered the profession because of the relationships with patients and the opportunity to have such a profound impact on people’s lives.

“Everybody here is so open to learning and transferring that knowledge accurately and empathetically to our callers,” she said. “They all have a strong, genuine interest in helping people.”

Carmen Phillips

Further reading: NCI’s Cancer Information Service: Providing Information and Assistance Nationwide

FDA Update

Another Radioactive Tracer Approved for Bone Scans

As a first step toward solving the ongoing shortage of a drug used in bone scans, called Technetium-99m (Tc-99m), NCI has won Food and Drug Administration (FDA) approval for a radioactive positron emission tomography (PET) tracer called Sodium Fluoride F18. This drug was originally approved in 1972 but was withdrawn in 1975, when a less-expensive alternative became available. This new approval covers a different dose and strength.

Radioactive tracers are used for bone scans with PET to diagnose skeletal metastases from primary cancers elsewhere in the body. Bone metastases are a serious issue for many types of cancer, particularly for patients with breast and prostate cancers.

One reason NCI submitted a New Drug Application (NDA) for Sodium Fluoride F18 was to make it possible for manufacturers to develop cheaper generic versions of the drug. The manufacturing of generic drugs could not begin until the NDA had been approved.

“We put together the NDA, and now that the drug has been approved, academic and commercial sites can file an abbreviated new drug application for generic versions,” said Dr. Paula M. Jacobs, acting associate director of NCI’s Division of Cancer Treatment and Diagnosis.

FDA approval is also important for reimbursement, noted Dr. Jacobs. The Centers for Medicare & Medicaid Services released a statement this week that it would reimburse for Sodium Fluoride F18 when patients are enrolled in a registry, and this could lead private insurers to do so, as well.

Until now, the only approved radioactive tracer has been Tc-99m. Over the last 5 years, there have been widespread shortages of that drug, which is a decay product of molybdenum-99 (Mo-99). The shortages, which are expected to continue for several more years, have been caused by problems with the few aging nuclear reactors that manufacture Mo-99, according to information from NCI’s Cancer Imaging Program.

A shortage of Mo-99 that lasts more than a week or two leads to immediate market shortages and can prevent clinicians from obtaining medical scans that use this agent. In 2007, more than 2.5 million patients underwent bone scans. Although not all of these scans used Tc-99m, millions of patients each year undergo scans involving radioactive tracers, noted Dr. Jacobs.

“The new approval will certainly help with the supply of these drugs going forward, and it will facilitate reimbursement,” she said.

See a history and rationale behind NCI’s filing of a New Drug Application for Sodium Fluoride F18.

Rituximab Approved as Maintenance Therapy for Follicular Lymphoma

On January 28, the FDA approved rituximab (Rituxan) as a maintenance therapy for patients with follicular lymphoma who responded to initial treatment with rituximab in combination with chemotherapy. The approval is the drug’s sixth cancer indication since it was initially approved in 1997 as a second-line treatment for non-Hodgkin lymphoma (NHL). In addition to several NHL indications, rituximab is also approved for the treatment of chronic lymphocytic leukemia.

The FDA granted the new indication based on the international phase III PRIMA trial, which involved 1,200 patients. Those in the trial who responded to initial treatment with rituximab and chemotherapy, and who continued to receive rituximab every 2 months for the next 2 years, had a 46 percent improvement in progression-free survival compared with patients who did not receive the maintenance therapy. After 2 years, 82 percent of patients in the maintenance therapy arm compared with 66 percent of patients in the control arm were still alive with no progression of their disease.

The PRIMA trial results were presented last year at the American Society of Clinical Oncology’s annual meeting.

FDA Investigates Breast Implants and a Rare Lymphoma

The FDA is investigating a possible association between breast implants and a very rare form of cancer called anaplastic large cell lymphoma, or ALCL. Based on a review of the scientific literature and discussions with experts, the agency said that women with breast implants may have a very low but increased risk of developing ALCL compared with women who do not have breast implants. The announcement came in a January 26 news release.

At this time, there is not enough information available to determine whether the implants might be a cause of ALCL, and the FDA is not recommending breast implant removal in patients without symptoms or other abnormalities. Nevertheless, the FDA said it would work with breast implant manufacturers to update their product labeling materials for patients and health care professionals in the coming months.

To date, FDA scientists have learned of approximately 60 cases of ALCL in women with breast implants worldwide, though they said the actual number of cases could be difficult to determine. (An estimated 5 to 10 million women have breast implants.) The agency is working with the American Society of Plastic Surgeons and other experts to establish a registry of breast implant patients, which researchers could use to study the possible association.

“We need more data and are asking that health care professionals tell us about any confirmed cases they identify,” said Dr. William Maisel, chief scientist and deputy director for science in FDA’s Center for Devices and Radiological Health, in a statement.

ALCL is diagnosed in about 1 out of 500,000 women in the United States each year and appears in different parts of the body, including the lymph nodes and skin. ALCL located in breast tissue is found in only about 3 out of every 100 million women nationwide without breast implants.

“Health care providers should be aware ALCL in women with breast implants is a very rare condition,” said the authors of an FDA white paper on the subject. Currently, it is not possible to identify a type of implant (silicone versus saline) or a reason for implant (reconstruction versus aesthetic augmentation) associated with a smaller or greater risk, the authors added.

Some researchers have suggested that breast implant-associated ALCL may represent a new clinical entity with less-aggressive (indolent) behavior. However, in view of the small number of cases and the short median duration of follow-up, the FDA said it is premature to draw conclusions regarding the prognosis of ALCL in women with breast implants.

For more information see the FDA’s Questions and Answers about Anaplastic Large Cell Lymphoma (ALCL) and a Consumer Update.

The NCI Fact Sheet on breast implants is here.

Notes

DCTD Appoints New Chief to Monitor Clinical Trials

Gary Smith Gary Smith

Gary Smith was named the new chief of NCI's Clinical Trials Monitoring Branch (CTMB) in the Cancer Therapy Evaluation Program (CTEP) of the institute's Division of Cancer Treatment and Diagnosis (DCTD). Smith has been overseeing the branch in an acting capacity since the untimely death of the previous branch chief, Joan Mauer, last October.

Smith began his career as a medical technologist in the Hematology Service at the NIH Clinical Center and began working as a clinical trials monitoring specialist for CTEP in 1988. He became associate chief of CTMB in 2008. He earned a master's degree in general administration, with a concentration in health care administration, from the University of Maryland. He holds a bachelor's degree in medical technology from the University of Maryland School of Medicine.

National Cancer Advisory Board Holds First Meeting of 2011

The National Cancer Advisory Board held its first meeting of 2011 on February 8. In addition to the Director's Report delivered by Dr. Harold Varmus, the agenda included an update from the President's Cancer Panel; a report on new legislation related to cancer; a presentation on the inclusion of women and minorities in clinical research; a session on conflicts of interest in working with industry; an update on the status of recommendations from the Institute of Medicine that are being implemented for clinical trials; and an overview of The Nation's Investment in Cancer Research for FY 2012.

An archived videocast of the meeting will be available in a few days.

Experts Discuss National Cancer Communications Plan

The American Cancer Society (ACS), the Centers for Disease Control and Prevention (CDC), and NCI will host a free live videocast of "Cancer Communication: State of the Science and Practice," on February 14 and 15. This first-ever joint ACS-CDC-NCI meeting on cancer communication will serve as the foundation upon which the three organizations will construct a national cancer control action plan.

A variety of cancer communication experts will discuss how to empower communities in cancer control, extend the reach and effectiveness of public health, engage consumers through networking and information technologies, and empower patients through clinical systems. On the second day, officials from the three organizations will provide their perspectives on next steps and priorities for the national cancer communication blueprint.

Members of the public are invited to take part in this unique dialogue. Go to www.CancerCommunicationConference.com to view the agenda before the meeting and return to the site on February 14 and 15 to watch the live videocast. There is no need to preregister. To join the conference on Twitter, follow @CancerComm2011—be sure to use the conference hash tag #cacomm2011 in your tweets. 

China and NIH Supplement Funding to Encourage Research Collaborations

NIH and the National Natural Science Foundation of China (NSFC) recently published corresponding funding announcements to encourage and support research cooperation between U.S. and Chinese scientists studying cancer, allergy, immunology, and infectious diseases, including HIV/AIDS and its comorbidities. NIH released an announcement for administrative supplements for U.S. collaborating investigators, and NSFC published an announcement for new 1-year projects from Chinese collaborating investigators. This initiative is part of a U.S.-China Program for Biomedical Research Cooperation that was recently established by NIH and NSFC.

U.S. and Chinese collaborating investigators will work together to develop corresponding applications to NIH and NSFC. Applications will be reviewed in parallel by both agencies using similar selection factors, and funding decisions will be made by both agencies according to research priorities of both countries. NIH has pledged to support up to $3 million in FY 2011 under this program, while NSFC has indicated that approximately 300,000 renminbi (Chinese currency) will be available per project to support Chinese collaborators.

Additional information and application instructions are available online.

Directory of Surveillance Data for Obesity Research Available

The National Collaborative on Childhood Obesity Research (NCCOR)—a joint project between the CDC, Robert Wood Johnson Foundation, NIH, and the U.S. Department of Agriculture—has released a Catalogue of Surveillance Systems containing local, state, and national data to help researchers study childhood obesity.

The catalogue is available online, provides access to 75 systems in the United States that contain data gathered in the last 10 years, and is designed to be updated with additional data systems that are identified as relevant in the future.

What You Need to Know About Cancer Booklets Updated

Three booklets in NCI's What You Need to Know (WYNTK) series have been updated:

WYNTK booklets are designed for patients who have been recently diagnosed with cancer and want to learn more about the disease. They are written in simple language and describe possible risks, symptoms, diagnosis, and treatment for different cancer types, and they also list questions that patients may want to ask their doctor. Booklets are posted online in html or PDF formats, and they can also be ordered in print.