National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
July 27, 2010 • Volume 7 / Number 15

NEWS

FDA logoFDA Advisory Committee Recommends against Bevacizumab for Metastatic Breast Cancer

On July 20, the Oncologic Drugs Advisory Committee (ODAC) of the FDA’s Center for Drug Evaluation and Research voted 12 to 1 to recommend against the use of bevacizumab (Avastin) in combination with chemotherapy for the first-line treatment of metastatic breast cancer. The FDA granted accelerated approval for bevacizumab in March 2008 for this indication, but it was contingent on additional positive results from ongoing clinical trials.

At last week’s meeting, committee members reviewed mature results from those trials, and the trials failed to confirm the data that led to the accelerated approval. Read more > >

A MESSAGE TO READERS

Sun Safety Featured on Cancer.gov

Skin cancer is the most common form of cancer in the United States, with more than 1 million cases diagnosed each year. This month, the NCI Web site highlights the importance of protecting yourself from the sun and other sources of ultraviolet light. Read more about skin cancer resources and research online.

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IN DEPTH

UPDATES

  • Notes

    • Plan to Attend NCI’s Clinical Proteomic Technologies for Cancer Meeting
    • Register Now for caBIG Annual Meeting in September
    • Join Leaders in the Field of Cancer and Inflammation at September Conference

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

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Featured Article

FDA Advisory Committee Recommends against Bevacizumab for Metastatic Breast Cancer

FDA logo

On July 20, the Oncologic Drugs Advisory Committee (ODAC) of the FDA’s Center for Drug Evaluation and Research voted 12 to 1 to recommend against the use of bevacizumab (Avastin) in combination with chemotherapy for the first-line treatment of metastatic breast cancer. The FDA granted accelerated approval for bevacizumab in February 2008 for this indication, but it was contingent on additional positive results from ongoing clinical trials.

At last week’s meeting, committee members reviewed mature results from those trials, and the trials failed to confirm the data that led to the accelerated approval. Women in the initial trial, called E2100, received either paclitaxel (Taxol) alone or paclitaxel plus bevacizumab for locally recurrent or metastatic breast cancer. The women in E2100 who received the bevacizumab combination experienced a median improvement in progression-free survival (PFS)—time without tumor growth—of 5.5 months compared with those who received paclitaxel alone.

The FDA’s decision to grant accelerated approval went against the recommendations of ODAC, which voted five to four against approval in December 2007. The FDA is not required to follow the recommendations of its advisory committees, although it does so more often than not. The results of E2100 had not shown an increase in overall survival and PFS remains a contentious surrogate endpoint in oncology clinical trials.

“FDA believes that, in accepting PFS as a regulatory endpoint, a close examination of the magnitude of improvement in PFS must be closely evaluated in a risk-benefit analysis,” said Dr. Richard Pazdur, director of the FDA’s Office of Oncology Drug Products, in his opening remarks at last week’s meeting. “Because treatment with Avastin is associated with considerable toxicity, the magnitude of PFS improvement—especially if not supported by an improvement in overall survival—should be substantial, clinically meaningful, and be able to be replicated in additional trials.”

The additional trials performed by Genentech, the manufacturer of bevacizumab, called AVADO and RIBBON1, together enrolled almost 2,500 women. The women in AVADO were randomly assigned to receive chemotherapy with docetaxel (Taxotere) plus placebo or docetaxel plus bevacizumab. In contrast with the E2100 trial, the women in the bevacizumab arm of AVADO showed a median improvement in PFS of less than a month.

In RIBBON1, patients were assigned at the discretion of their physicians to receive chemotherapy with a taxane, an anthracycline, or capecitabine (Xeloda). Within those three groups, the researchers randomly assigned women to receive additional bevacizumab or a placebo. The improvement in PFS with the addition of bevacizumab was larger than in AVADO but still substantially smaller than that seen in E2100: 1.2 months for women in the taxane and anthracycline groups and 2.9 months for women in the capecitabine group.

In both trials, women in the bevacizumab groups had an increased risk of death. In an analysis of the trial data, prepared by the FDA, 0.8 percent of the women in AVADO and 1.2 percent of the women in RIBBON1 who received bevacizumab died from side effects thought to be related to the drug.

Given bevacizumab’s side effects and the lack of an overall survival benefit, “we need to consider what value [PFS] has to a woman with metastatic breast cancer,” said Dr. Mikkael Sekeres, associate professor of medicine at the Cleveland Clinic Taussig Cancer Institute and an ODAC member.

“Since PFS is the endpoint being studied,” said Dr. Wyndham Wilson, the ODAC chair, “what we are here to judge is whether or not there is a clinically meaningful—from a patient’s point of view—[difference in] quality of life between the patients who received Avastin and those who didn’t.”

The committee found any such difference impossible to ascertain, since the trials had not collected patient-reported quality-of-life data that could show an improvement in symptoms or psychological state in tandem with PFS. The AVADO trial collected a set of quality-of-life data, but only to show that the addition of bevacizumab did not decrease patients’ quality of life.

Sponsors of future trials evaluating PFS should take this issue to heart, stated Dr. Pazdur. “Sponsors really need to pay very close attention to [measuring quality of life], build it carefully into their protocols, and approach it with the same degree of caution and resources…as one would with a primary endpoint,” he said.

The committee’s decision to recommend removing metastatic breast cancer as an indication for bevacizumab does not mean that the FDA regrets awarding the accelerated approval, said Dr. Pazdur. “We do not look at this as a mistake,” he concluded. “There is a risk…in approving these drugs, and this [process today] is management of that risk.”

—Sharon Reynolds

Cancer Research Highlights

PSA Screening Leads to Aggressive Treatment, Even in Older Men at Low Risk

A new study confirms previous research showing that screening for prostate cancer with the prostate-specific antigen (PSA) test has led to overtreatment of many prostate cancers, including aggressive treatments in older men considered to be at low risk for progression of the disease. The results appeared in the July 26 Archives of Internal Medicine.

The researchers found that 77 percent of men with a serum PSA level of 4.0 nanograms per milliliter (ng/mL)—the level at which a prostate biopsy is often recommended—or lower underwent either complete removal of their prostate, known as a radical prostatectomy, or radiation therapy. This treatment occurred even though more than half of these men were considered to be at low risk of disease progression based on commonly used factors, such as the Gleason score and the extent of local tumor spread.

Despite evidence that suggests older men are less likely to have a survival benefit from surgery or radiation compared with more conservative treatments, age was not a barrier to low-risk men receiving aggressive treatment. Nearly 69 percent of men age 65 to 74 and approximately 40 percent of men 75 and older underwent either surgery or radiation.

“Our study demonstrates that Gleason score, PSA level, and risk stratification does not appear to substantially influence the decision to have attempted curative therapy,” wrote lead investigator Dr. Yu-Hsuan Shao of the Cancer Institute of New Jersey and colleagues.

To conduct the study, the researchers used data from NCI’s SEER registry to identify nearly 124,000 men who were newly diagnosed with prostate cancer between 2004 and 2006. Of these men, 14 percent had PSA levels of 4.0 ng/mL or lower. Rates of radical prostatectomy and radiation were actually higher among men whose PSA levels were at or below 4.0 ng/mL than among men whose PSA levels were between 10.1 and 20.0 ng/mL.

“It has been documented that men who receive any treatment have increased risk of treatment-related adverse effects,” Dr. Shao and colleagues wrote. “Therefore, it is critical that patients be counseled about treatment-associated adverse effects and benefits when they are deciding about therapy.”

In an accompanying editorial, Drs. Richard Hoffman of the University of New Mexico and Steven Zeliadt of the University of Washington advocated for greater use of so-called active surveillance. This approach “balances the desire to avoid treatment complications against the equally strong desire not to ignore a cancer—while at the same time minimizing the risk of overtreatment,” they explained.

See also: “PSA Screening and Cancer Mortality: Swedish Study Adds to the Debate

Chemotherapy Regimen Benefits Men with Metastatic Penile Cancer

Men with cancer of the penis that had spread to nearby lymph nodes have benefited from three chemotherapy drugs given prior to surgery, known as neoadjuvant therapy, according to results published online July 19 in the Journal of Clinical Oncology. The nonrandomized phase II study, one of the first such prospective trials of its kind, included 30 men with stage III or stage IV penile squamous cell carcinoma and affected regional lymph nodes, but without distant metastases.

Half of the patients had either a partial or complete response, and 36.7 percent remained free of recurrence at the last clinical assessment. The vast majority of patients were able to tolerate the chemotherapy at full doses and on schedule, and 76.7 percent received all four planned courses. Based on these results, the researchers are recommending that the chemotherapy regimen, which included paclitaxel, ifosfamide, and cisplatin, becomes the new standard treatment for this disease.

The chemotherapy regimen was selected because it has helped some patients with squamous cell carcinoma of the head and neck. Men with penile cancer have a low probability of surviving with lymphadenectomy alone, and a multimodal approach to treatment is desirable for such patients, the researchers said.

“This is a rare disease for which there is no standard of care in stages III and IV,” said lead investigator Dr. Lance Pagliaro of the University of Texas M. D. Anderson Cancer Center. “There has been an urgent need in the field for a well-designed prospective trial to establish a standard chemotherapy regimen. We view this study as a starting point for moving forward in this disease.”

Other chemotherapy drugs currently being tested in this disease can now be evaluated against this regimen, he noted. As a next step, his group and others have been developing trials that will include targeted therapies, such as epidermal growth factor receptor inhibitors.

Hormone Therapy Increases Breast Cancer Risk for Women with Dense Breasts

Women who have dense breasts according to a system radiologists use to score mammograms, the Breast Imaging Reporting and Data System (BIRADS), are at an increased risk of developing breast cancer compared with women whose breasts are of average density. And hormone therapy (HT) after menopause, in particular estrogen plus progestin, also increases the risk of breast cancer. Now a report from the NCI-funded Breast Cancer Surveillance Consortium (BCSC) shows that the combination of these two factors increases breast cancer risk by up to twofold. The study appeared online July 19 in the Journal of Clinical Oncology.

The BCSC team, led by Dr. Karla Kerlikowske of the University of California, San Francisco, examined data from seven registries that represent more than 580,000 women and nearly 1,350,000 screening mammograms. The women were age 30 or older, had normal body-mass indices, and completed questionnaires to report menopausal status, surgical histories, and their use of HT.

The association between breast density and cancer risk was strongest for premenopausal women and women using HT after menopause. In the study, premenopausal women with low or average breast density had a 5-year cancer risk ranging from 0.3 to 1.5 percent, compared with a range of 0.9 to 3.1 percent for women with dense or very-dense breasts. The researchers found that postmenopausal women with low or average breast density who used HT had 5-year risks ranging from 0.3 to 2.5 percent, whereas women with dense or very-dense breasts had a risk ranging from 1.1 to 4.4 percent. (Risk was slightly higher for those who used estrogen plus progestin versus estrogen alone.) However, whether they used HT or not, the risk of breast cancer was low for postmenopausal women who had low breast density.

How HT and breast density act together to increase cancer risk—whether the hormones slow the natural changes in the breast that occur with aging, for example, or whether they spur cell growth in cancer-prone cell types—remains unknown, noted the authors. But, in the meantime, “Postmenopausal women with high breast density may want to consider the added risk of breast cancer when deciding on whether to start or stop [HT], especially estrogen plus progestin,” they wrote.

Brain Cancer Incidence Trends Do Not Support Link to Cell Phones

A new analysis by NCI researchers has turned up no evidence to support a link between cell phone use and brain cancer in the United States. The analysis was carried out in view of concerns about a possible link between widespread use of cell phones and brain cancer risk. With more than 279 million U.S. wireless subscribers today, the researchers reasoned that it should be possible to detect an increase in brain cancer rates over time if, in fact, cell phone use does contribute to risk of this particular cancer. The caveat would be that no effect would be expected if the induction period for brain tumors is very long or increased risk is limited to long-term users.

Dr. Peter Inskip and his colleagues in NCI’s Division of Cancer Epidemiology and Genetics used NCI’s SEER database to examine brain cancer incidence trends between 1992 and 2006. In almost all age groups and in both men and women, the trends for brain cancer during these years were, if anything, slightly downward.

The one exception was a statistically significant increasing trend among females in their twenties, but not males. This increase, however, was driven by cancers in the frontal lobe of the brain, which is not where the researchers would have expected to see an effect from cell phones. Studies have shown that other parts of the brain are more highly exposed to the radiofrequency radiation from cell phones.

The U.S. findings are consistent with a recent study of brain cancer incidence trends in four European countries. That study found no change in rates from 1998 to 2003, the period when possible associations between mobile phone use and cancer risk would likely be apparent assuming an induction period of 5 to 10 years.

See also: Study Finds No Overall Increased Brain Tumor Risk from Cell Phones

For more information, see: NCI’s Cell Phones and Cancer Risk Fact Sheet

Expert Panel Reports on Knowledge Gaps for 20 Suspected Carcinogens

In a monograph released July 15, a coalition of leading health organizations called for more research into the possible cancer-causing effects of exposure to 20 chemical agents. Some of the named agents are commonly found in the environment, whereas others are more often limited to occupational exposures. A summary paper in Environmental Health Perspectives provides an overview of the technical report.

The monograph, titled Identification of research needs to resolve the carcinogenicity of high-priority IARC carcinogens, summarizes available evidence and provides specific guidance on the appropriate studies needed to definitively classify these agents. Several overarching issues were identified that pertain to multiple agents, including recognizing that carcinogenic agents can act through multiple pathways and mechanisms of toxicity.

“This report highlights the importance of conducting research in occupational settings to identify human carcinogens,” said Dr. Debra Silverman, a co-author of the report and chief of the Occupational and Environmental Epidemiology Branch in NCI’s Division of Cancer Epidemiology and Genetics. “Findings from such occupational studies often allow experts to extrapolate the possible effects of low-level exposure to these agents in the general environment.”

“There is significant concern among the public about substances or exposures in the environment that may cause cancer, and there are some common occupational agents and exposure circumstances where evidence of carcinogenicity is substantial but not yet conclusive for humans,” added the report’s lead author, Dr. Elizabeth Ward, from the American Cancer Society (ACS).

The project originated as part of the National Institute for Occupational Safety and Health’s National Occupational Research Agenda to enhance occupational cancer research, and it involves collaboration with NCI, the International Agency for Research on Cancer (IARC), the ACS, and the National Institute of Environmental Health Sciences.

Special Report

The Evolving Science of Cancer Stem Cells

A diagram showing stem cells and progenitor cells Stem cells can both self-replicate, as well as produce progenitors that differentiate into other, more mature cell types, such as endothelial cells. Similarly, a cancer stem cell is thought to self-replicate and produce progenitors that generate all of the cell types that make up a tumor. Click to Enlarge.

The theory of the cancer stem cell (CSC) has generated as much excitement and optimism as perhaps any area of cancer research over the last decade. Biologically, the theory goes, these cells are distinct from the other cells that form the bulk of a tumor in that they can self-perpetuate and produce progenitor cells, the way that traditional stem cells do. The progenitors’ job is then to repopulate tumor cells eradicated by treatments such as chemotherapy or radiation.

But for all the attention and fanfare CSC research has received, the findings reported to date are far from clear-cut, investigators acknowledge. For example, most of the studies that have identified human CSCs have used mouse xenograft assays and cells from only a small number of human tumor samples, making it difficult to draw firm conclusions. In addition, other researchers haven’t always been able to replicate initially reported findings. (See the sidebar: “Tools of the CSC Trade: Markers and Xenografts.”) And while these tumor-initiating cells, as they are also called, have been described as being a rare class, several studies have found that the number of cells that can form tumors in these mouse experiments is actually quite large, suggesting that perhaps CSCs aren’t such a privileged breed.

In other words, the idea of just what cancer stem cells are, and their role in different cancers, appears to be changing.

“The [stem cell] model has not been adequately tested in most cancers,” said Dr. Sean Morrison, who directs the Center for Stem Cell Biology at the University of Michigan. “I think that there are some cancers that do clearly follow a cancer stem cell model…But it will be more complicated than what’s been presented so far.”

An Evolving Idea

Unlike the random or “stochastic” model dominant in cancer research, which holds that nearly any cancer cell has the potential to form a tumor, the cancer stem cell model is one of a hierarchical organization, with the pluripotent cancer stem cell sitting ready and able to amass all of the components of the original tumor.

It’s also thought, with some experimental evidence to support it, that CSC pluripotency allows these cells to adapt and to resist chemotherapy, radiation therapy, and even current molecularly targeted therapies. If true, then these treatments may not harm the most lethal tumor cells, those that can lead to a recurrence with the production of a new set of progenitors.

Despite numerous studies published in the last 16 years that identified CSCs for different cancers—including colon, brain, pancreatic, and breast cancer—the consensus among researchers seems to be that the evidence is strongest for the first cancer in which a population of tumor-initiating cells was discovered, acute myeloid leukemia (AML), as well as for other blood cancers.

“The reason why it’s so much stronger for hematologic malignancies is because hematopoiesis research goes back 40 or 50 years and it’s very stem cell-based,” said Dr. Jean Wang, a stem cell researcher at the University of Toronto. “Whereas in solid tumors, there’s less of a foundation for identifying the normal cellular hierarchies and for [cell-surface] markers that identify different populations of cells like stem cells and progenitors.”

Even so, Dr. Wang believes the existence of CSCs is pretty well demonstrated for breast and brain cancers. But, she cautioned, “I don’t know if it applies to all cancers. In a lot [of cancers] it does seem to apply. But most of the markers we have right now are still very rough.”

Despite the evidence for CSC-like cells in a growing number of cancers, the theory clearly has its skeptics, who point to problems such as shortcomings in the mouse xenograft assay and the variable specificity of the cell-surface markers used to demarcate a CSC from a non-CSC.

“I still feel that it’s a concept yet to be proven,” said Dr. Barbara Vonderhaar, who, along with colleagues in NCI’s Center for Cancer Research, recently published a study identifying a population of CSC-like cells in estrogen receptor-negative breast cancer. “It’s certainly a good idea, but it’s only a hypothesis at this point. We still don’t have definitive proof that cancer stem cells exist.”

The CSC concept is “a work in transition,” said Dr. William Matsui, from the Johns Hopkins School of Medicine, whose lab studies the role of stem cells in hematologic cancers. “To me, as a clinical person, the ideal model is one where you can find something that is going to work in humans. We’re far from that.”

Case Study: Melanoma

One of the most well-known studies in the CSC literature came from Dr. Morrison’s lab in 2008. Earlier studies had suggested that, consistent with the CSC model, there was only a rare population of cells from human melanoma tumors that, when injected into mice with compromised immune systems (called NOD/SCID mice), could form new tumors.

But in a study published in Nature, Dr. Morrison’s team tweaked the common experimental approach: they used mice with immune systems that were even more impaired than NOD/SCID mice and waited longer to assess tumor growth. The result: approximately one in four randomly selected single cells taken from a human melanoma sample could form a tumor.

The results “made clear that estimates of the frequency of tumorigenic cells are far more assay-dependent than we realized,” Dr. Morrison said. In addition to factors such as the status of the mouse’s immune system in the experiments, he continued, “there are probably other variables that have a much bigger influence that we still haven’t discovered.”  (In AML, it’s worth noting, use of more immunocompromised mice does not significantly increase the number of cells that can form tumors.)

Researchers from Stanford University earlier this month reported in Nature that they had found a marker, CD271, that identified a somewhat unique population of cells that could produce melanoma in highly immunocompromised mice; anywhere from 2.5 percent to 41 percent of cells in their human tumor samples expressed the marker. In additional experiments using similar mice on which human skin was engrafted, only tumor cells with the marker could produce tumors and metastases in the mice. (In his lab, Dr. Morrison noted, the same marker did not differentiate tumor-forming from nontumor-forming cells.)

The fact that a fairly large percentage of the cells from the nine human melanoma tumors used in the study could initiate a tumor reflects a number of things, wrote lead author Dr. Andrew Boiko and colleagues in the Nature paper. Among them, an evolutionary type process selects for the survival of tumor cells that fail to normally differentiate during tumor development.

That might mean that a cancer stem cell isn’t necessarily part of the original tumor, but due to various factors or influences—such as interactions with the immune system or hypoxia—certain tumor cells, maybe many of them, can activate a stem cell-like “program.”

“I’m a firm believer that the microenvironment, the stem cell ‘niche,’ is every bit as important as the cell itself,” Dr. Vonderhaar said. “I don’t know if just any cell can become [a CSC], but there is a hierarchy of cells, and some may be able to function in a stem cell-like manner, and others may not.”

The CSC field itself, Dr. Matsui noted, needs to move more quickly beyond just determining whether these cells can grow tumors on their own, “and ask what other properties they might have that contribute to clinical outcomes.” Those might include their role in problems such as drug resistance or metastasis.

Some of the controversy surrounding CSCs “is a good thing,” Dr. Matsui said, “because it forces us to be more rigorous in our work. The more rigor we can get in the research, the more clinically applicable all of the ideas are going to be.”

Carmen Phillips

Tools of the CSC Trade: Markers and Xenografts

Although there are several experiments that can be used to identify potential CSCs, a functional in vivo experiment with immunocompromised mice has been the “gold standard” assay, Dr. Wang said.

Many of the markers used to identify CSCs came from “studying normal systems,” Dr. Matsui explained. In brain tumors, for instance, early research focused on the cell-surface protein CD133, which had been identified as a marker for normal neural stem cells. In addition to brain cancer, CD133 has been used to identify potential CSCs in colon cancer, whereas CD44 has been used to identify breast cancer stem cells, and aldehyde dehydrogenase (ALDH), in combination with other markers, has been used to identify CSCs for breast, prostate, and pancreatic cancer.

Once researchers have identified a marker or multiple markers of interest, they take a human tumor sample and separate them from one another based on the presence or absence of those markers.

The cells are injected into the mice at varying sites to see if the mice that received the potentially tumorigenic cells—those with the proposed stem cell marker(s)—develop tumors, while those that received the nontumorigenic cells do not. If the initial experiment shows the expected tumor development, additional “passages” of the proposed CSCs—this time, fractionated out from the mouse tumors—are done in other mice to more firmly establish the marker-bound cells’ tumor-forming capacity.

Other animal-model assays are also being used, including mice that are genetically engineered to develop certain tumors and a zebrafish model.

Spotlight

When Brain Cancer Returns, Test May Aid Decisions about Surgery

Dr. John Park operates on a patient with recurrent glioblastoma at the NIH Clinical Center. Dr. John Park (left) operates on a patient with recurrent glioblastoma at the NIH Clinical Center.

Neurosurgeons who regularly operate on patients with malignant brain tumors learn to identify which patients are good candidates for additional surgeries when the disease recurs, as it usually does. And while there is no substitute for a surgeon’s experience, a new test could help select patients who may benefit from surgery to treat recurrent glioblastoma multiforme (GBM), the most common brain tumor in adults.

The test uses readily available preoperative clinical information to quantify the likelihood of survival after surgery. Predictions are based on a scale of three factors associated with prognosis—how well a patient performs day-to-day tasks, the volume of a tumor, and whether the tumor is in or near critical regions of the brain.

“We think the scale could help patients and families decide whether to have surgery,” said Dr. John Park of the National Institute of Neurological Disorders and Stroke, who led the team that developed the scale. In a retrospective study of 34 patients with recurrent GBM, those who scored lowest on the scale lived longer than those with higher scores, a statistically significant finding that was validated in a second population of patients.

In addition to aiding decisions about surgery, the scale may be helpful for stratifying patients during enrollment in clinical trials, the researchers said online July 19 in the Journal of Clinical Oncology.

“This study is a significant contribution to the scientific literature,” said Dr. John Yu, director of the Brain Tumor Center at Cedars-Sinai Medical Center, who was not involved in the research. “Those of us who do a lot of these surgeries have an intuitive sense of how patients will do. Dr. Park took what we intuitively know and formalized it into a simple scale for determining whether a patient is a viable candidate for surgery.”

Seeing a Benefit

The test, called the NIH Recurrent GBM Scale, gives patients a total score of 0 to 3 points. After surgery, patients with 0 points had relatively good survival (10.8 months), while those with 1 to 2 points had intermediate survival (about 4.4 months) and those with 3 points had poor survival (1 month).

For the group that fared the best, the median overall survival was 24.9 months, including the time from diagnosis to additional surgeries. The median overall survival for all patients with GBM is approximately 14 months. “The results of this study suggest that a lot of patients do benefit from additional surgery,” despite the risks, said Dr. Park.

The study was not designed to assess the role of postoperative therapies such as radiation and chemotherapy in the survival of patients, noted Dr. Yu. But he acknowledged that, for many patients, the available treatments are not effective. “We need novel therapies for this disease,” he said.

Dr. Park agreed with this point and said that patients with good prognostic scores should be encouraged to have surgery and then to join an appropriate clinical trial of an experimental treatment.

In the validation component of the study, the researchers applied the scale to 109 patients treated at Brigham and Women’s Hospital. As with the NIH patients, there were statistically significant differences in the postoperative median survival between groups with the lowest and highest scores.

Sparing Patients

“The value of this scale is that it gives you a good sense of which patients should not be sent to surgery, because their survival is likely to be so short that they would not see a benefit,” said Dr. Howard Fine, chief of the Neuro-Oncology Branch in NCI's Center for Cancer Research and a senior author of the study. “If we could save patients from surgery who ultimately would not benefit from it, then we’ve done a service.”

Developing genetic and other kinds of molecular markers for assessing the prognosis of patients is an active area of research in the field. “As our knowledge of the genetics involved in tumors increases, we’ll have to add clinical information from the patient with genetic parameters to refine prognostication,” said Dr. Yu. “But the decision to do surgery may be influenced more by clinical parameters.”

Furthermore, it’s not yet clear whether the results from this study will be applicable to surgeons in smaller community hospitals who do very few such surgeries each year, noted Dr. Yu. The study should therefore be validated in the community setting as well as additional large medical centers, he said.

Looking Ahead

As new therapies are introduced, the scale may need to be updated or revised. In the future, Dr. Fine explained, new treatments could make surgery worthwhile for patients who are currently in the worst-prognosis group and who, based on today’s treatment options, would be unlikely to realize a benefit from surgery.

“This is a very important study relative to the care of gliomas now,” he continued. “Here at the NIH, we’re generally geared toward the future and new treatments, but the power of this study is that it should help us improve the care of patients today.”

—Edward R. Winstead

Also in the Journals: Brain Cancer May Diminish Patient’s Ability to Consent for Research Studies

Brain cancer causes cognitive impairments that may affect a patient’s capacity for consenting to participate in research such as clinical trials, new findings suggest. In the study, published online July 19 in the Journal of Clinical Oncology, a substantial portion of patients with malignant gliomas had a diminished capacity to consent for research studies. Patients, for example, generally performed worse than the control group on tests designed to measure cognitive abilities such as appreciation, reasoning, and understanding. “This study highlights the importance of careful attention to consent issues when enrolling patients with malignant gliomas in clinical trials and other research studies,” researchers from the University of Alabama, Birmingham, concluded.

A Closer Look

Using e-Health Tools to Improve Quality of Life for Cancer Patients

Communications
This is the fourth article in a series of stories related to cancer communications. Look for the symbol on the left in an upcoming issue for the next article in the series.

A cancer diagnosis can quickly rob individuals of normalcy. The news often also leaves people confused about how and where to get the information and support they need. To address these difficult issues, researchers at the University of Wisconsin-Madison have developed electronic communications tools to help provide this information and improve the quality of life of patients with cancer and others suffering from serious illnesses.

CHESS started out as a DOS-based system run from a local computer, and now it's on smartphones.

—Dr. David Gustafson

The work has been under way for more than 3 decades at the university’s Center for Health Systems Research and Analysis (CHSRA), an NCI Center of Excellence in Cancer Communication Research (CECCR). The CHRSA’s flagship communications program, called the Comprehensive Health Enhancement Support System (CHESS), has grown in parallel with the rise of the Internet and online advancements.

“CHESS started out as a DOS-based system run from a local computer, and now it’s on smartphones,” said Dr. David Gustafson, principal investigator of the CHSRA. “The Internet has influenced CHESS in an enormous number of ways. Things like online discussion groups were not nearly as effective before the Internet, and they are now the heart of key parts of CHESS.”

Fundamentally, CHESS is a type of consumer health informatics system designed to provide patients with expert information, decision aids, and emotional support. In its current form, it contains information services, such as a library of cancer articles and a resource directory; communications services, such as moderated discussion groups and the ability to speak with online experts; and decision services, which help patients weigh treatment options against their personal values. Recent upgrades have added a clinician report feature, which updates doctors on the health status information a patient enters into CHESS.

Randomized trials and population-based studies have shown that CHESS can improve quality of life in diverse groups of participants, such as women with breast cancer (including those in underserved populations and the elderly), people with HIV, and people battling substance abuse. CHESS has also been shown to improve the doctor–patient relationship. The system’s efficacy has been widely accepted, to the point where CHESS is being used as a control arm for trials of new communications interventions.

One advantage CHESS has over the Internet is that it’s a self-contained system, Dr. Gustafson explained. “When patients go onto the Internet, they get so much conflicting information,” he said. “In one trial, we even found that anxiety increased for some patients who were given access to the Internet.” In that study, women in the group using CHESS improved their quality of life, social support, and health information competence, whereas these measures did not improve in women who had Internet access alone.

Testing CHESS in the Real World

So far, the studies of CHESS have been performed under idealized conditions, where researchers often provided participants with computers and detailed coaching on how to use the system. But such a resource-intensive strategy would be difficult to implement in a normal clinical setting. To test whether CHESS remains effective in the real world, Dr. Timothy Baker, professor of medicine at the University of Wisconsin-Madison, is currently leading a randomized trial of CHESS in collaboration with Kaiser Permanente Northwest in Oregon and Washington.

“We’re trying to understand what proportion of women will use CHESS if a health care system offers it as part of their usual care, given the normal constraints and barriers that the women will face,” explained Dr. Baker.

The researchers are in the process of recruiting 600 women newly diagnosed with breast cancer into the study. Participants will be randomly assigned either to CHESS or to a control group that will have access to several electronic health resources in use at Kaiser Permanente. So far, about 35 percent of the women approached have agreed to participate in the study.

The women have access to CHESS or the control resources for a year after enrollment and will complete follow-up questionnaires at points up to 8 months afterward. The researchers plan to measure changes in quality of life using the Health Utilities Index, a tool used to classify health status. They will also look at the impact on the care process, such as whether women who receive CHESS call their health care providers less or more than women in the control group and whether patients and doctors rate their encounters more favorably if the patients received CHESS.

“We’re measuring a lot of real world outcomes, such as health care utilization, that are of great relevance to health care systems,” said Dr. Baker. Having such information, he continued, will allow hospital administrators and physicians “to make informed decisions about whether to offer more intensive e-health resources as part of standard care.”

Sharon Reynolds

Mobile Access, Mobile CHESS

Access to the Internet is increasingly mobile, as smartphones and other wireless communications devices grow in popularity and availability. Dr. Deborah Mayer, associate professor in the School of Nursing at the University of North Carolina, is interested in bringing CHESS to these on-the-go platforms to help colon cancer survivors increase their physical activity after treatment and improve their quality of life.

“There are a lot of mobile health applications out there, but our mobile CHESS (Survivorship CHESS) system is really tailored to the colon cancer survivor,” explained Dr. Mayer. “It presents information about issues that might be unique to them, like if they had chemotherapy and have peripheral neuropathy in their feet. Or, if they’re still having problems with their bowels, it talks about how someone in that situation might be able to successfully increase their physical activity,” she continued. The system also features colon cancer survivors telling their stories about how they managed their transition when treatment ended and how they became more physically active.

Dr. Mayer and her colleagues are recruiting 294 patients who have completed treatment for colon cancer into the trial at three different sites (the University of Wisconsin-Madison, the University of North Carolina at Chapel Hill, and the University of Texas M. D. Anderson Cancer Center). The researchers will randomly assign participants to either CHESS or no intervention for 6 months, and the patients will be followed for an additional 3 months to track whether their physical activity levels continue to change after the intervention.

The Survivorship CHESS system includes interactive feedback, such as a tool that allows participants to set and track their exercise goals week by week. Survivorship CHESS also features a buddy system that lets participants chat with other survivors in the study, and information about colon cancer survivorship that would be of interest to participants, including interactive evidence-based recommendations on cancer surveillance. “We’re integrating the survivorship care plan into this system,” said Dr. Mayer. “If this really works for patients, we could negotiate and make it usable on a BlackBerry or an iPhone or any number of mobile application platforms—it could really be scalable for access to other survivors.”

Profiles in Cancer Research

Dr. Carol Fabian

Director, Breast Cancer Prevention Center
University of Kansas Medical Center

Dr. Carol Fabian Dr. Carol Fabian

At the University of Kansas Medical Center in Kansas City, less than a 15-minute drive from her childhood home, Dr. Carol Fabian leads a team of researchers who are trying to understand how to prevent breast cancer. What is most notable about their work is that they are focusing on markers in tissue and genes as guideposts—a strategy now used to develop many targeted cancer treatments.

At the start of her career in the mid-1970s, Dr. Fabian began working with Dr. Barth Hoogstraten, who was head of oncology at the University of Kansas Medical School and chair of the Southwest Oncology Group (SWOG); there she shared in the excitement over tamoxifen, an investigational drug originally developed as a fertility agent. By the mid-1980s, tamoxifen was proving to be so effective in treating breast cancer, she recalled, that “many of us began to ask whether we could predict who was at highest short-term risk for breast cancer, so we could pick an optimal time to apply prevention therapy.”

Breast cancer treatment in the 1970s entailed surgery and radiation for local disease, but cancer recurred in about 40 percent of women. The discovery that women who responded to antihormonal therapies had tumors that were predominately estrogen receptor-positive ushered in the era of targeted therapy for breast cancer. “Before the discovery of estrogen receptors, we knew that estrogen increased breast cancer growth,” Dr. Fabian said, “but we did not widely appreciate exactly how.”

Birth of a Translational Researcher

With the early success of combination chemotherapy for Hodgkin disease, non-Hodgkin lymphoma, testicular cancer, and breast cancer, Dr. Fabian remembers how she and her colleagues “thought we could cure almost anything by applying the right drugs at the right time.”

  

She was drawn to Dr. Marc Lippman’s idea that, if women with hormone receptor-positive disease had tumors that depended on estrogen to grow, then providing them with estrogen for a short period of time might induce a growth spurt that would make the cancer cells more susceptible to chemotherapy. She realized that this approach would require knowing how much estrogen would trigger the cells to begin to divide and then how long one would have to wait before administering chemotherapy.

After first testing various doses of estrogen, she got her first R01 grant and performed serial biopsies—with fine needle aspirations of tumors—to determine if and when the cells began to divide more rapidly. “I really got hooked on translational medicine with that grant,” Dr. Fabian said.

By the mid-1980s, Dr. Fabian had been treating women with breast cancer for nearly a decade. “Survival rates were increasing and recurrence was less frequent, but too many women were still dying from breast cancer,” she recalled. She and other researchers were beginning to realize that, no matter how early they detected a woman’s cancer or how aggressive the treatment, some women were going to see their cancer recur. “We really needed to take stock and ask if there might be a better way,” she said.

“The idea of cancer prevention is to prevent the disease altogether or block it before it grows beyond the precancerous stage,” Dr. Fabian continued. By the late 1980s, tamoxifen had become the most widely used drug in breast oncology, and oncologists understood that the drug interfered with estrogen receptor signaling. Most side effects were moderate and women were able to take it over long periods of time. But, when it became apparent that women taking adjuvant therapy were getting fewer cancers in the opposite breast, the idea of primary prevention therapy for high risk women had arrived. Soon after came the landmark P-1 clinical trial, launched in 1992 by the National Surgical Adjuvant Breast and Bowel Project, to test long-term use of tamoxifen as a preventive agent.

Necessity is the Driving Force

“Despite the fact that tamoxifen reduces the risk of breast cancer by 50 percent, less than 5 percent of risk-eligible women agree to take it,” Dr. Fabian said. “While there were some rare but more serious side effects, commonly the patients I was seeing were concerned about the hot flashes and mood changes that threatened their quality of life.” The lesson for prevention researchers, she continued, is that “we need to pay attention to the personal beliefs and perceptions that can affect uptake and adherence, not just whether a drug gives us better results.” Adherence, as well as efficacy, drives prevention.

“I knew that for chemoprevention to have a chance, we would have to be able to predict with greater accuracy which women were likely to get breast cancer over the next 5 to 10 years,” Dr. Fabian recalled. She tackled this problem by following women classified broadly as high risk (for example, young women with a family history of close relatives with breast cancer) and looked for atypical cells and molecular markers in their breast tissue. “If we could predict which women were more likely to get cancer in the next 5 years, they would be most likely to have the best benefit-to-side-effect ratio with preventive therapy,” she said.

The practical problem, however, was getting women to submit to an invasive breast biopsy without any assurance that it would find an early cancer or reveal their future risk. The solution was to minimize their discomfort and, with funding from local philanthropic organizations and institutional support, Dr. Fabian developed and refined a technique called random periareolar fine needle aspiration (RPFNA). (Watch the “In Their Own Words” video slide show above.)

“The women we enrolled were fully aware that I didn’t have any idea what any of this meant and that we were going to follow them for 5 to 10 years to see who developed cancer,” said Dr. Fabian. “Most breast tissue was known to be stroma or fat, and when we first started the prospective cohort project in 1989, pathologists strongly believed you should put a needle into a breast only when you can aim at a specific lesion. So, at the time, they saw this as a really ridiculous exercise.”

However, after following the first 480 women for an average of 4 years, it was clear that women who exhibited cells with atypical characteristics were at very high short-term risk of developing either ductal carcinoma in situ or invasive breast cancer. What began in her clinic in Kansas City has become widely used to test new interventions in phase I and II prevention trials and to help locate biomarkers in benign breast tissue that correlate with cancer risk. “RPFNA as a tool has facilitated risk stratification and prevention therapy research,” she explained.

Reflecting on her career, Dr. Fabian recommends that young translational and clinical researchers “get a broad-based multidisciplinary education, focus early on an area that can be your lifetime passion, and get hands-on training in the techniques necessary to successfully complete your research.”

Addison Greenwood

Featured Clinical Trial

Electroacupuncture for Radiation-induced Chronic Dry Mouth

Name of the Trial
Randomized Pilot Study of Electroacupuncture for Chronic Radiation-induced Xerostomia in Patients with Head and Neck Cancer (MAYO-MCS285).  See the protocol summary.

Dr. Michele Haylard Dr. Michele Haylard

Principal Investigator
Dr. Michele Yvette Halyard, Mayo Clinic Scottsdale

Why This Trial Is Important
Head and neck cancers are often treated with external-beam radiation therapy. Although this treatment can be effective in controlling head and neck tumors, it may cause side effects that can compromise a patient’s quality of life. Chronic dry mouth, also called xerostomia, is common among patients treated with radiation to the head and neck. This condition results from damage to the glands that produce saliva. Chronic dry mouth can have a major impact on quality of life by causing pain and discomfort, affecting the ability to sleep, altering taste, and/or increasing the likelihood of dental problems. 

Some drugs are available for xerostomia induced by radiation therapy, but many patients experience only a partial improvement or no benefit at all.  The drug amifostine can help protect the salivary glands of some head and neck cancer patients from radiation damage, but this drug cannot be used in all patients. 

Some studies have suggested that acupuncture can help relieve the sensation of mouth dryness in cancer patients who have undergone head and neck radiation therapy. Based on these studies and other evidence, researchers at the Mayo Clinic in Scottsdale, AZ, are investigating the ability of a procedure called electroacupuncture to help improve the production of saliva and the quality of life of patients with chronic dry mouth. Electroacupuncture involves stimulating traditional acupuncture points on the skin using small electrodes instead of needles inserted into the skin.

In this clinical trial, head and neck cancer patients with chronic dry mouth who completed radiation therapy at least 6 months before joining the trial and who received no benefit from treatment with the drug pilocarpine (Salagen) will be randomly assigned to undergo electroacupuncture using a machine called a LISS stimulator, or a sham procedure using a similar-looking machine that does not produce electrical stimulation. Treatment will last for 4 weeks (20-minute sessions 5 days a week for the first 2 weeks, and then 3 days a week for the last 2 weeks) and will be administered at the Mayo Clinic in Scottsdale. Saliva flow, the patients’ subjective sensation of mouth dryness, and quality of life will be assessed during the first 3 weeks of treatment and then again 1, 3, and 6 months following treatment.

“Depending on the radiation techniques used and the location of the tumor, up to 90 percent of head and neck cancer patients receiving radiation therapy will experience chronic dry mouth,” said Dr. Halyard. “Electroacupuncture is a non-needle approach that uses electrical stimulation of the acupuncture points thought to control salivation. The hypothesis is that this stimulation will alter the energy flow of the acupuncture points and result in an increase in saliva production.

“To date, we have enrolled 24 of 30 patients for the study, so we have 6 slots left,” Dr. Halyard continued. “I would be happy to discuss the study with any patients who think they might be interested and who can commit a month to treatment in Scottsdale, as well as return for the three post-treatment assessments.” (See contact information link.)

For More Information

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

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

Notes

Plan to Attend NCI’s Clinical Proteomic Technologies for Cancer Meeting

CPTC 2010 Annual Meeting banner

NCI’s Clinical Proteomic Technologies for Cancer (CPTC) will host its fourth annual meeting on September 8–9 at the Bethesda North Marriott Hotel & Conference Center. This year’s event, “Establishing the Standards in Clinical Proteomics,” will highlight key areas in which CPTC has made significant achievements, including an optimized proteomics pipeline, FDA regulatory science, international open data access policies, and highly characterized affinity reagents.

Session themes include:

  • CPTC: Facing Clinical Application
  • Advances in Proteomic Technologies
  • Bioinformatics Resources and Tools for the Proteomics Community
  • Platforms for Protein Discovery and Post-translational Modification Studies
  • Targeted Quantitative Proteomics
  • Reagents/Standards Development

CPTC has achieved tremendous progress since its inception because of its dedication to the highest quality of research and open standards by its investigators, as well as a deep commitment to team science. Visit the CPTC Web site to register or learn more about the annual meeting and list of confirmed presenters.

Register Now for caBIG Annual Meeting in September

caBIG Annual Meeting banner

The 2010 cancer Biomedical Informatics Grid (caBIG) annual meeting, “Building a Collaborative Biomedical Network,” will take place September 13–15 at the Marriott Wardman Park Hotel in Washington, DC.

caBIG is an information network led by NCI’s Center for Biomedical Informatics and Information Technology that enables cancer researchers, physicians, and patients to share data and knowledge. The components of caBIG are widely applicable beyond cancer as well. The caBIG mission is to develop a collaborative information network that accelerates the discovery of new approaches for the detection, diagnosis, treatment, and prevention of cancer, ultimately improving patient outcomes.

Registration and abstract submissions are now being accepted. Admission is free and open to the public. Registration, however, is required and available online.

Join Leaders in the Field of Cancer and Inflammation at September Conference

NCI’s Center for Cancer Research will host a 2-day national symposium titled “Immunity, Inflammation & Cancer” on September 23–24, in the Masur and Lipsett Auditoriums on the NIH main campus. This NCI-sponsored conference will host international leaders in the field of cancer and inflammation and provide a forum for discussion and debate on the current state of understanding in this field. The conference is intended for researchers interested in the latest developments in the role of inflammation in the development and progression of cancer.

Sessions will include:

  • Cancer immunity and immunosurveillance
  • Cancer and inflammation
  • The microbiome’s role in immunity, tissue homeostasis, and cancer
  • The tumor microenvironment

Registration is free, but seating is limited. Find more information and register online by August 20.