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January 10, 2012 • Volume 9 / Number 1

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NEWS

Bevacizumab May Benefit Some Women with Ovarian Cancer

Illustration of a targeted drug binding to a cancer cell's growth factor receptors.The targeted drug bevacizumab (Avastin) extends the amount of time women with advanced ovarian cancer live without their disease progressing, according to findings from two phase III clinical trials. The results were published December 29 in the New England Journal of Medicine.

In both trials, women initially received a combination of bevacizumab and standard chemotherapy, followed by bevacizumab alone for a defined period. Not enough time has passed in either trial to determine whether the approach extends lives (improves overall survival), although data from both trials suggest a possible small survival increase. Read more > >

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IN DEPTH

UPDATES

  • Legislative Update

    • Most States Fall Short of Requirements for Insurance Coverage of Cancer Clinical Trials
  • Notes

    • Glycoscience, Disease, and Clinical Practice Symposium Will Be Held January 24
    • Cyber-Seminar to Address the Delivery of Patient-Centered Cancer Care
    • Genomics in Medicine Series Features Two Lectures on Cancer

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

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Featured Article

Bevacizumab May Benefit Some Women with Ovarian Cancer

Illustration of a targeted drug binding to a cancer cell's growth factor receptors.Bevacizumab (blue) is thought to work by binding to the vascular endothelial growth factor (orange) and keeping it away from receptors (purple) on the surface of cells. This disrupts the signaling that promotes the formation of new blood vessels to tumors.

The targeted drug bevacizumab (Avastin) extends the amount of time women with advanced ovarian cancer live without their disease progressing, according to findings from two phase III clinical trials. The results were published December 29 in the New England Journal of Medicine.

In both trials, women initially received a combination of bevacizumab and standard chemotherapy, followed by bevacizumab alone for a defined period. Not enough time has passed in either trial to determine whether the approach extends lives (improves overall survival), although data from both trials suggest a possible small survival increase.

Bevacizumab is thought to work by blocking the formation of blood vessels (angiogenesis) that feed tumors. Common side effects, including severe hypertension, were more frequent in patients who received bevacizumab but were generally manageable with medications, trial investigators reported. More dangerous side effects, such as gastrointestinal perforations, were also more frequent in those receiving bevacizumab, although such complications were relatively rare. Deaths that were likely to be related to treatment were also rare, but they were more frequent in women treated with bevacizumab.

Progress over the past two decades in developing effective therapies for the initial treatment of women with advanced ovarian cancer has been limited. These trials suggest that bevacizumab could change that, at least for some women, explained Dr. Ronald Alvarez, director of the Division of Gynecologic Oncology at the University of Alabama at Birmingham.

"I think these two studies have shown that bevacizumab has some promising efficacy [in women with ovarian cancer]," Dr. Alvarez said. Whether the drug is more valuable as an initial treatment or after the disease has returned is still unclear, he continued. "But clearly bevacizumab has activity in ovarian cancer."

Similar Trials, Important Differences

Although similar, the two trials—one conducted primarily in the United States and the other in Europe—had important differences, including different enrollment criteria and different doses of bevacizumab used.

The larger trial—co-sponsored by NCI and Genentech, which manufactures bevacizumab, and led by the Gynecologic Oncology Group (GOG)—enrolled nearly 1,900 patients newly diagnosed with advanced ovarian cancer. The trial had three arms: a control arm and two experimental arms. In the control arm, initial treatment with standard chemotherapy (carboplatin plus paclitaxel) was followed by placebo. In one experimental arm, initial treatment consisted of chemotherapy plus bevacizumab, followed by placebo. The other experimental arm consisted of the same chemotherapy and an extended bevacizumab treatment.

Patients in the trial, called GOG-0218, who received bevacizumab for the extended period (a maximum of 10 months) had the longest progression-free survival, a median of approximately 14 months—nearly 4 months longer than the median time for women treated with chemotherapy alone and 3 months longer than the median time for women who received the shorter course of bevacizumab. (See Table 1.) Quality-of-life scores were similar among the trial's three treatment groups.

Table 1. Findings from the GOG-0218 Trial

TreatmentProgression-Free Survival
Chemotherapy plus placebo, followed by placebo10.3 months
Chemotherapy plus bevacizumab (15 mg/kg), followed by placebo11.2 months
Chemotherapy plus bevacizumab (15 mg/kg), followed by bevacizumab14.1 months

A lower dose of bevacizumab was used in the other trial, called ICON7, which was funded in part by Genentech's parent company, Roche. The more than 1,500 patients in the trial were randomly assigned to receive either standard chemotherapy or chemotherapy plus bevacizumab, followed by bevacizumab alone for a maximum of 7 months. Most women in ICON7 had advanced ovarian cancer, except for the approximately 30 percent who had earlier-stage disease but, based on several factors, were considered to be at high risk of their cancer returning after surgery.

Among all patients in ICON7, treatment with bevacizumab was associated with a median improvement in progression-free survival of less than 2 months. But in a subset of women considered at high risk of progression, there were more substantial differences in progression-free survival, as well as overall survival. (See Table 2.) This was an unplanned subset analysis, however, and such analyses are considered to be less reliable than analyses that are specified before a study's launch.

Table 2. Findings from the ICON7 Trial

TreatmentProgression-Free Survival
Chemotherapy plus placebo, followed by placebo17.3 months
Chemotherapy plus bevacizumab (7.5 mg/kg), followed by bevacizumab19 months
*Chemotherapy plus placebo, followed by placebo (high-risk patients)10.5 months (28.8 months overall survival)
*Chemotherapy plus bevacizumab (7.5 mg/kg), followed by bevacizumab (high-risk patients)15.9 months (36.6 months overall survival)

* Unplanned subset analysis

Impact on Practice

A number of important uncertainties remain about using bevacizumab to treat ovarian cancer, several researchers said. Among the most critical, said Dr. Deborah Armstrong of the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, is the lack of clinical or biological markers that indicate which patients are most likely to benefit from the drug or are at increased risk for serious adverse events.

Without a marker that identifies those most likely to benefit, she said, "you're just treating everybody, and the subgroup that gets the benefit gets diluted out."

Bevacizumab is currently approved by the FDA to be used as a single agent to treat glioblastoma, in combination with interferon alpha to treat kidney cancer, and in combination with chemotherapy for colorectal and lung cancer. Last fall, the FDA withdrew the drug's accelerated approval for the treatment of metastatic breast cancer based on several trials that showed that it failed to extend women's lives and was associated with potentially serious side effects.

Genentech had previously stated the company was unlikely to pursue FDA approval for bevacizumab in women with ovarian cancer based on the GOG-0218 and ICON7 results. According to a spokesperson, however, a final decision will be made after a full assessment of the trial data, including the overall survival findings.

FDA approval is likely to heavily influence the extent to which bevacizumab is used in the clinic to treat women newly diagnosed with ovarian cancer, Dr. Alvarez explained, since most insurers typically won't pay for the drug without such approval. At up to $100,000 for a year of treatment, few patients can afford to pay for it themselves. (In the European Union, the drug was recently approved as a first-line treatment for women with advanced ovarian cancer.)

Even so, bevacizumab has for many years been used outside clinical trials in women with ovarian cancer, often after their disease has returned following surgery and chemotherapy, noted Dr. Robert Burger of the Fox Chase Cancer Center, the lead investigator of the GOG-0218 trial.

Based on the available data, Dr. Burger said, he believes the drug is a good option for the initial treatment of patients who, following standard surgery, are found to have either stage III disease in which the tumor could not be removed completely, or stage IV disease. However, based on the latest data from the OCEANS trial of women with recurrent ovarian cancer, he continued, the drug "probably should be continued at least until progression in those appearing to benefit and having no unacceptable side effects."

Outside of clinical trials, Dr. Armstrong said, she typically uses bevacizumab only in women whose cancer has recurred, and then only by itself, not in combination with chemotherapy. As an initial treatment, she believes there are still too many unknowns.

"[Bevacizumab] doesn't improve survival. In that situation, should it be embraced as a standard of care?" she asked. Factors including the drug's cost and potentially serious side effects require serious consideration. "I think those are things we have to look at," she said.

Numerous clinical trials are testing bevacizumab with different therapies and at various schedules to treat ovarian cancer. Many other promising agents are being investigated in phase III trials as well, Dr. Burger noted, including drugs such as AMG386, BIBF 1120, pazopanib, and cediranib, which target angiogenesis in different ways than bevacizumab.

Carmen Phillips

Cancer Research Highlights

Use of Robotics May Not Reduce Side Effects of Prostate Cancer Surgery

Older men who have their prostates removed to treat cancer have a high risk of developing incontinence and sexual problems within a year, regardless of whether their surgeons use robotic technology in the operating room, a new survey suggests. The results appeared online January 3 in the Journal of Clinical Oncology.

More than four out of five prostatectomies are done with the use of robotic technology to remove the organ laparoscopically. Some researchers have noted that the widespread adoption of this technology has occurred in the absence of evidence demonstrating that the robotic approach has clear benefits for patients over traditional surgery.

To explore this question further, Dr. Michael Barry of Massachusetts General Hospital and his colleagues sent surveys to a random sample of 800 men, drawn from Medicare claims files, who had undergone radical prostatectomy for prostate cancer. They received responses from 685 men; nearly twice as many respondents reported having robotic-assisted surgery as having a traditional open radical prostatectomy.

Both groups of patients reported high rates of incontinence and sexual dysfunction, indicating that the robotic technology did not appear to reduce these complications.

“The very rapid dissemination of robotic surgeries for radical prostatectomy seems to have come with an assumption that there may be fewer side effects because of the increased precision offered by the technology,” said Dr. Barry. But the new results, which are consistent with those of an earlier study, challenge that assumption. In fact, the study showed a slight increase in incontinence among men who had robotic surgery, although the difference was not statistically significant.

One limitation of the study was that the authors did not have baseline information about continence and sexual function for the men prior to the prostatectomy. Prospective studies and studies of younger men will be needed to assess the risks and benefits, as well as the cost effectiveness, of robotic surgery for prostate cancer compared with traditional surgery, the authors noted.

Despite the study’s limitations, the results are “sobering,” given the high rates of problems associated with both procedures, the authors of an accompanying editorial concluded. They noted that the outcomes for any type of procedure “are based not only on the technology but also on the skill and experience of the provider and the hospital system.”

Dr. Barry agreed. “Each man should know that the type of surgery he chooses is not as important as the experience that his surgeon has with that particular procedure,” he said. “And just because the surgery is robotic does not mean that it is safer or better than another technique.”

Chemotherapy Associated with Microscopic Changes in the Brain

A new study adds to an emerging body of evidence suggesting that subtle physical changes in the brain may underlie the constellation of symptoms dubbed “chemobrain”—cognitive changes associated with cancer or cancer treatment that are most often experienced as difficulties with concentration, memory, multitasking, and planning.

Using an advanced imaging technique, European researchers found evidence that changes in cognitive functioning in women with breast cancer who were treated with chemotherapy are associated with physical alterations in the fibers that connect neurons in the brain. The study appeared online December 19 in the Journal of Clinical Oncology.

The researchers used a type of magnetic resonance imaging (MRI) known as diffusion tensor MRI (DT-MRI) to detect changes in the brain’s white matter, which regulates communication among different brain regions. Previous studies have shown that damage to white matter can lead to changes in cognitive performance.   

Three groups of premenopausal women, whose median age was 43, participated in the study: 34 women with early-stage breast cancer who were scheduled to receive chemotherapy; 16 women with early-stage breast cancer who were not scheduled to receive chemotherapy; and 19 healthy, cancer-free control subjects.

Before receiving any chemotherapy, and again 3 to 5 months after completing their treatment, the chemotherapy-treated patients underwent whole-brain DT-MRI imaging and a series of neuropsychological and cognitive tests to measure abilities such as concentration, memory, and capacity to plan. The patients who were not exposed to chemotherapy and the healthy control subjects underwent the same assessment at matched intervals. The three groups showed no difference in performance on the pretreatment tests.

In the follow-up tests, however, women in the chemotherapy-treated group performed worse on the neuropsychological tests and reported more cognitive problems than women in both control groups. This poorer performance correlated with findings on the DT-MRI imaging tests that indicated microscopic alterations to the white matter in the brains of the chemotherapy-treated women.

“These results suggest that microstructural [white matter] changes in patients exposed to chemotherapy may underlie their cognitive dysfunction,” wrote the study authors, who were led by Dr. Stefan Sunaert of University Hospital in Leuven, Belgium.

“Patient complaints of persistent cognitive difficulties after cancer treatment ends must not be dismissed,” wrote Dr. Patricia Ganz of the University of California, Los Angeles, in an accompanying editorial. But “fears of developing cognitive difficulties should not deter the use of potentially beneficial chemotherapy,” she cautioned.

Dr. Ganz added: “We can no longer deny the existence of this long-term effect of cancer treatment; we must work to tailor future treatments to minimize this adverse outcome.”

Further reading: “Delving Into Possible Mechanisms for Chemobrain” and “Brain Scans Show Structural Effects of Chemotherapy

Drug Shows Promise against Hard-to-Treat Chronic Lymphocytic Leukemia

Navitoclax, an experimental drug that inhibits a group of proteins that promote cell survival, has shown encouraging results in a phase I trial in patients with difficult-to-treat chronic lymphocytic leukemia (CLL). The drug targets several related proteins in the BCL2 family, which are present in many types of tumor cells and which block the natural tendency of abnormal cells to undergo programmed cell death, or apoptosis.

Among 26 patients who received navitoclax after their cancer had relapsed or stopped responding to other treatments, nine experienced a partial response and seven maintained stable disease for more than 6 months, an international research team reported December 19 in the Journal of Clinical Oncology. And of 21 patients with lymphocytosis (an increase in the number of lymphocytes in the blood) at the start of the trial, 19 had a reduction in lymphocyte count of at least 50 percent. The main dose-limiting toxicity was thrombocytopenia.

This study “provides the first convincing clinical validation of BCL2 as a useful therapeutic target in CLL,” wrote the authors, Dr. Andrew W. Roberts of the Royal Melbourne Hospital in Australia and his colleagues.

The response to navitoclax was “impressive” considering that the drug was given as a single agent to patients who had received multiple prior therapies, Dr. Peter Hillmen of St. James’s Institute of Oncology in the United Kingdom commented in an accompanying editorial.

The strategy of inhibiting anti-apoptotic BCL2 family members “seems likely to herald the beginning of a revolution in the treatment of CLL,” Dr. Hillmen continued. He added that navitoclax is one of several investigational agents now in clinical development that target different aspects of CLL biology. The next steps, he went on, are to determine how to combine these new agents most effectively. “The logical combination of these agents promises to dramatically alter the treatment of CLL and may eventually lead to therapy that is both more effective and less toxic,” he wrote. 

Previous phase I studies have demonstrated the safety and preliminary efficacy of navitoclax in patients with difficult-to-treat lymphomas and small-cell lung cancer, wrote Dr. Loren D. Walensky of the Dana-Farber Cancer Institute in an accompanying article describing the biological pathway of navitoclax in CLL. The drug now “advances to phase II testing as a single agent and in combination to combat cancer chemoresistance, he noted.

A Closer Look

Studies Raise Concerns about Partial-Breast Radiation Therapy

The trend in surgery for early-stage breast cancer over the last 30 years can be summed up in one word: less. Breast-conserving surgery (BCS) plus radiation therapy has supplanted removal of the breast (mastectomy) as the standard of care. More recently, sentinel-lymph node biopsy has largely replaced the more invasive axillary lymph node dissection as the method for determining a tumor's spread and guiding adjuvant therapy.

In the last decade, researchers have begun to focus on whether "less" can also apply to radiation therapy. Studies have consistently shown the benefit of radiation therapy after BCS. But although the therapy is effective, traditional radiation to the whole breast requires up to 7 weeks of treatment, for 5 days each week. This schedule can approach the impossible for many women, such as those in rural areas who live far from a treatment center, those who continue to work during treatment, those who lack reliable transportation, and many others.

The majority of women are still getting whole-breast irradiation, but in the community there's no question that partial-breast irradiation is catching on.

—Dr. Thomas Julian

If the time required for radiation therapy could be shortened, many women could benefit. Recent randomized studies have shown that delivering whole-breast radiation therapy over 3 weeks (hypofractionation) is as safe and effective for some women as delivering it over 6 to 7 weeks. Another approach being studied is accelerated partial-breast irradiation (APBI), in which radiation is given only to the area immediately surrounding the tumor site instead of to the whole breast over a short period of time (a week or less). Both hypofractionation and APBI use larger doses of radiation per individual treatment session (fraction) than traditional whole breast irradiation.

"The majority of women are still getting whole-breast irradiation, but in the community there's no question that partial-breast irradiation is catching on," said Dr. Thomas Julian, associate director of medical affairs for the National Surgical Adjuvant Breast and Bowel Project (NSABP).

Like most treatments, APBI has advantages and disadvantages. In addition to the advantage of a woman being able to complete radiation therapy in a week or less, APBI may reduce radiation exposure to other organs near the breast, such as the lungs and heart. But on the downside, long-term data on the safety and effectiveness of APBI have not yet emerged from the large randomized trials currently under way.

Too Much, Too Soon?

Recently, concerns have been raised that the use of one type of APBI, breast brachytherapy, may be outpacing the available evidence on the technique's safety and efficacy. In breast brachytherapy, small radioactive seeds are temporarily implanted in the cavity left after surgery to deliver highly localized radiation over a period of several days.

After the Food and Drug Administration (FDA) cleared a device called the MammoSite® balloon catheter for breast brachytherapy in 2002, the use of breast brachytherapy started to rise. Unlike anticancer drugs, which must be approved by the FDA, devices used to facilitate treatment can be cleared without proof of their efficacy compared with standard care, though they must meet basic safety requirements. Medicare approved reimbursement of MammoSite treatment in 2004, after which use of breast brachytherapy rose further.

Several new studies have tracked the increases in the use of breast brachytherapy. A study published in January 2011 with data from almost 7,000 Medicare beneficiaries with supplemental insurance reported an increase in breast brachytherapy from less than 1 percent of patients in 2001 to 10 percent in 2006.

Another study, published last August, that analyzed data from more than 120,000 patients in the Surveillance, Epidemiology, and End Results (SEER) database found that its use rose from less than 1 percent in 2000 to 6.8 percent of patients in 2007.

Last month at the 2011 San Antonio Breast Cancer Symposium (SABCS), research presented by Dr. Benjamin Smith and his colleagues from the University of Texas M. D. Anderson Cancer Center suggested that this rise in the use of brachytherapy may have a measurable downside.

The researchers reviewed Medicare claims for women older than 66 who were diagnosed with invasive breast cancer between 2000 and 2007. All 130,535 women included in the study had BCS followed by either APBI or whole-breast irradiation. In 2000, less than 1 percent of women underwent APBI, whereas in 2007, 13 percent had this form of radiation therapy.

The researchers used subsequent mastectomy as a surrogate for breast cancer recurrence. Within 5 years of follow-up, 4 percent of women who had undergone APBI required a subsequent mastectomy, compared with 2 percent of those who had had whole-breast irradiation. Women who had undergone APBI also had a higher risk of both immediate and late side effects from treatment, including post-operative complications, infections, rib fractures, and breast pain.

"Our results suggest a higher risk of mastectomy in patients treated with brachytherapy. The most intuitive explanation for that is that some patients who are treated with brachytherapy had residual tumor cells in the breast…outside the confines of the target volume for brachytherapy," said Dr. Smith at a press conference at SABCS.

Our results suggest a higher risk of mastectomy in patients treated with brachytherapy. The most intuitive explanation for that is that some patients who are treated with brachytherapy had residual tumor cells in the breast.

—Dr. Benjamin Smith

During the press conference, Dr. Smith noted several limitations of the study. He stressed that in addition to being observational, the study had limited follow-up time and did not control for hormone therapy use, although it did control for chemotherapy use. He also pointed out that the data "do not apply to all partial-breast irradiation techniques," which can include external-beam radiation techniques as well as intraoperative radiation therapy.

But what concerns Dr. Smith is that "our data indicated that APBI using brachytherapy was both less effective and had a worse side-effect profile—that [combination] starts to change how you think about a therapy," he said in a follow-up conversation.

"I think that the doubling of the mastectomy rates is a big deal, [even though] it's retrospective data," said Dr. Bhadrasain Vikram, chief of the Clinical Radiation Oncology Branch of the Radiation Research Program in NCI's Division of Cancer Treatment and Diagnosis. If doctors could predict which women need radiation therapy to prevent recurrence, and they measured the rate of subsequent mastectomies among those women, the difference would be higher than 2 percent, explained Dr. Vikram. (Since doctors cannot predict which women need radiation therapy to prevent recurrence, it is part of standard care for all women after BCS.)

Waiting on the Evidence

Without evidence from randomized trials to guide whether breast brachytherapy can be used safely in some women, doctors have had to rely on their own experiences and results from some smaller, single-institution studies. In 2009, Dr. Smith and other members of the American Society for Radiation Oncology (ASTRO) released an opinion-based consensus statement that attempted to identify women who can be safely treated with APBI (including, but not limited to, brachytherapy) outside a randomized clinical trial.

The statement also defined two other groups: a "cautionary" group, "for whom caution and concern should be applied when considering APBI outside of a clinical trial," and an "unsuitable" group, for whom APBI outside a clinical trial is not warranted.

Whether these guidelines will affect the use of breast brachytherapy remains to be seen. In a paper published January 4 in the Journal of the National Cancer Institute, researchers from Brigham and Women's Hospital in Boston analyzed data from the SEER database and found that two-thirds of patients treated with breast brachytherapy between 2000 and 2007 would have been classified as part of the cautionary or unsuitable groups as defined in the ASTRO guidelines.

"There's no question that hard outcome data [for partial-breast irradiation] from clinical trials is needed," said Dr. Julian. A large, NCI-sponsored randomized trial, NSABP B-39/RTOG-0414, that is comparing whole-breast irradiation with accelerated partial-breast irradiation for women with early-stage breast cancer should provide such data.

The trial will not look at breast brachytherapy alone; participating physicians have the option of using one of two different brachytherapy systems or using 3-D conformal radiation therapy, an external-beam technique, to deliver APBI. Interestingly, with the trial nearing completion of patient accrual, only one-quarter of participants in the APBI arm have received brachtherapy so far, reported Dr. Julian. The majority received APBI with external-beam radiation therapy equipment.

"External-beam radiation is the easiest approach for radiation oncologists to use because they have the equipment already in place," explained Dr. Julian. Academic centers, such as the ones participating in the trial, also have less of a financial incentive to put in brachytherapy catheters, he added.

But with the large number of participants planned for enrollment in the trial, the researchers hope "that we will have the ability to draw conclusions about the safety and efficacy" of APBI using brachytherapy as well as APBI using external-beam radiation, Dr. Julian concluded.

"We would certainly like to see people waiting for the trial data before broad implementation, but there is more than 10 years of partial-breast irradiation experience that shows that in low-risk women the recurrence outcomes are fairly good, comparable to what happens in low-risk patients who were treated with whole breast radiation. However, for higher-risk women, the data are just not available," he concluded.

Some doctors feel more strongly that the available evidence does not support the risk of using an unproven technique outside a clinical trial. "If you are looking for hard evidence, for now you should consider breast brachytherapy with caution," opined Dr. Vikram—especially, he added, because randomized trials have already shown excellent early results for hypofractionation and intraoperative partial-breast irradiation, where radiation therapy is completed during surgery. These may be safer options for a woman looking to avoid 7 weeks of whole-breast radiation, he said.

The wait for long-term brachytherapy data will be a long one. Although the treatment phase of NSABP B-39/RTOG-0414 is coming to a close, and several other large APBI trials under way in Canada and Europe are also nearing completion, it may be as long as a decade before mature results are available.

Because advances in hormone therapy and chemotherapy have greatly extended the average time to breast cancer recurrence, "anything you start reporting at 2 or 3 years of follow-up is really not enough time," said Dr. Julian. "You have to look beyond that, at the 5- and 10-year event rates, to see what is actually happening."

Sharon Reynolds

Featured Clinical Trial

Making Decisions about Cancer Prevention Medications for Breast Cancer

Name of the Trial
Study of Factors Influencing Decision Making about Chemoprevention Agents in Women at Increased Risk for Breast Cancer (NSABP-DMP-1). See the protocol summary.

Dr. Christine HolmbergDr. Christine Holmberg

Principal Investigators
Dr. Christine Holmberg and Dr. Angela Fagerlin, National Surgical Adjuvant Breast and Bowel Project

Why This Trial Is Important
Breast cancer is the second most common cancer among women in the United States, with more than 200,000 new cases diagnosed each year. Some risk factors for developing breast cancer include age, race, prior breast cancer or breast carcinoma in situ, number of first-degree relatives with the disease, age at onset of menstruation, whether a woman has given birth and at what age, and a history of breast biopsies.  

With a risk assessment tool, such as the Gail model, these factors can be used to determine whether a woman is at higher than average risk of developing breast cancer. The Gail model calculates the probability that a woman will develop the disease over the next 5 years and over her lifetime. Women with a 5-year risk of 1.7 percent or higher are considered to be at increased risk and are eligible to take the drug tamoxifen to reduce that risk.

Tamoxifen and a similar-acting drug called raloxifene (Evista) are selective estrogen receptor modulators, or SERMs. These drugs block estrogen's ability to stimulate the growth of breast cancer cells. Large chemoprevention studies have shown that tamoxifen and raloxifene substantially reduce the risk of breast cancer in women at increased risk of this disease.

By some estimates, more than 10 million American women qualify to use a SERM for breast cancer prevention based on their level of risk. Despite proven benefits, however, most women at increased risk of breast cancer either choose not to take these medications or simply do not come to a decision, even after discussing the drugs' risks and benefits with a health care provider and perceiving a personal high risk of disease. Cancer prevention researchers are eager to understand how women make choices about whether to take these drugs for cancer prevention.

In this study, women age 35 or older who discuss the use of a SERM for breast cancer prevention with a health care provider will be asked to complete a questionnaire about their discussion and whether they have come to a decision about using a SERM for risk reduction. Women who indicate that they have made a decision will be asked to complete a second questionnaire about their decision-making process. The second questionnaire will be mailed to women who have not indicated that they have made a decision within 6 months of completing the first questionnaire.

"We want to know how people actually make decisions—what's important for their decision-making," said Dr. Holmberg. "[Researchers and health care providers] are focusing on numbers all the time, but increasingly we know that numbers are not the deciding factor. We need to be sure that we present numbers appropriately, but we also need to understand what other factors play a role in decision-making" about breast cancer chemoprevention.

"We are interested in the decision-making process, so we are fine with any woman who decides she is not going to take a SERM," she explained. "We just want to know, how did you make your decision?

"Our ultimate goals for this study are to use the information we collect to guide us in making better decision aids, and finding out what people's needs are for chemoprevention drugs so that we know what type of drugs we need to focus our efforts on," Dr. Holmberg concluded.

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/featured.

Community Update

CommunicationsThis article is part of a series of stories related to cancer communications. You can read more articles in the series here.

Physician Data Query Offers Authoritative Information for Cancer Patients and Professionals

Screenshot of PDQ Page

"Wikipedia, Twitter, and blogs, oh my!" That could well be the lament of newly diagnosed cancer patients, their families, and caregivers as they anxiously enter the cancer "information superhighway" for the first time.

"For a lot of new patients, stepping into the world of cancer is like going to a foreign country where they don't know the language," said medical librarian Naomi Miller, manager of Consumer Health Information at the National Library of Medicine (NLM). "After a patient gets over the initial shock of receiving a diagnosis of cancer, the next thing they want to know is: What is the outlook, and what are the treatments I need?"

For the past 30 years, patients, their physicians, and other health professionals have relied on NCI's Physician Data Query (PDQ®), a comprehensive and authoritative resource for up-to-date, evidence-based cancer information. PDQ's cancer information summaries, available on NCI's website, address prognoses and treatments for many adult and pediatric cancers, as well as supportive and palliative care, screening, prevention, genetics, and complementary and alternative medicine. Most summaries come in two versions—one tailored for health professionals and the other for patients.

"What makes the PDQ cancer information summaries unique is the fact that they are…evidence-based and are maintained by PDQ editorial board members who are experts in their fields," noted Dr. Margaret Beckwith, acting chief of NCI's International Cancer Research Databank Branch (ICRDB), which oversees and maintains the PDQ database. "The summaries are revised and updated in a very timely manner as new information comes in." All of the PDQ treatment summaries, and many of the other summaries, are also available in Spanish.

Created by Congressional Mandate

The PDQ database resulted from congressional mandates that NCI "continue and expand programs to provide physicians and the public with state-of-the-art information on the treatment of particular forms of cancers, and to identify those clinical trials that might benefit patients while advancing knowledge of cancer treatment." 

In the early 1980s, NCI assembled an expert editorial board to develop treatment information summaries. That initial board has since expanded to six separate PDQ editorial boards, each of which includes 15 to 30 academicians, clinicians, nurses, and other specialists, Dr. Beckwith explained. 

Dr. A. Kim Ritchey, chief of Pediatric Hematology/Oncology at the Children's Hospital of Pittsburgh, joined the PDQ Pediatric Treatment Editorial Board in 1997 and became the board's editor-in-chief in 2000. "Being on a PDQ editorial board is a public service whereby we keep health professionals and patients informed about the best current understanding of treatment for cancer," he said. "We feel very dedicated to ensuring that the treatment summaries we produce are both accurate and timely."

PDQ® Summaries Now on PubMed Health

NCI and the National Library of Medicine have joined forces to make PDQ's cancer information summaries for health professionals and patients available through PubMed Health, an online resource that specializes in reviews of research on the effectiveness of interventions in clinical care. The health professional summaries are available in the Clinical Guides section of PubMed Health, and the patient summaries are available in the For Consumers section.

The PDQ editorial boards review the peer-reviewed biomedical literature monthly to keep the cancer information summaries up to date. At the heart of this process, ICRDB and contract staff regularly search the NLM PubMed database for research studies of greatest relevance to each PDQ editorial board. "[The editorial boards] provide the expertise to judge whether a published report on a clinical trial is of high enough quality to be added to a cancer treatment summary," Dr. Ritchey explained.

Online and Beyond

The PDQ database predated the Internet revolution. Since then, scientists and information researchers have studied and compared PDQ's cancer information summaries with the often bewildering array of online resources that now offer information about cancer, including Wikipedia.

For example, a study published last fall in the Journal of Oncology Practice compared cancer information on Wikipedia with that in PDQ's patient summaries. The researchers concluded, "although the wiki resource had similar accuracy and depth as the professionally edited [PDQ] database, it was significantly less readable."

NLM librarian Miller commented, "There is a place for 'crowd-sourced' information like Wikipedia. However, PDQ is the best place to start a search for cancer information because it's authoritative and updated frequently."

ICRDB acting chief Dr. Beckwith noted that the PDQ patient summaries now contain additional background information not found in the health professional versions, as well as numerous medical illustrations to help visually convey concepts such as anatomy, tests and procedures, and disease staging for various cancers. In the near future, the patient summaries will be offered in formats designed for mobile devices, she said.

"We're also reformatting all of the health professional summaries," Dr. Beckwith added. "We're trying to make them more accessible in a web environment by adding more tables, figures, and bulleted information, by breaking up the text, and by adding more links to related information." Eventually, NCI plans to make all of the PDQ summaries available for e-book readers, such as Kindle and Nook, she added.

Bill Robinson

Legislative Update

Most States Fall Short of Requirements for Insurance Coverage of Cancer Clinical Trials

U.S. map showing states that have passed legislation or instituted special agreements requiring health plans to pay for clinical trial participants' medical costs.The states shaded in blue have passed legislation or instituted special agreements requiring health plans to pay the cost of routine medical care for clinical trial participants.

Clinical trials are the primary vehicle for advancing the treatment, detection, and prevention of cancer. Participation is low, however, with only about 3 percent of adult patients taking part in clinical trials. Many different factors have been identified that contribute to this low participation rate. But for some patients, lack of insurance coverage for care provided in a clinical trial is a barrier to trial enrollment.

The Patient Protection and Affordable Care Act (PPACA), enacted by Congress in March 2010, requires health insurers to provide coverage for routine patient care costs for patients taking part in federally funded or approved cancer clinical trials or in trials conducted under, or exempt from, FDA investigational new drug applications. Routine patient care costs include doctor visits, hospital stays, clinical laboratory tests, and x-rays that would normally be covered under the individual's plan, but not the drug, device, or intervention being studied. These requirements apply to health plans and coverage sold after 2013.

Although many states have enacted laws that mandate some coverage for care provided in cancer clinical trials, a study published online December 27 in the Journal of Clinical Oncology concluded that most states do not meet the PPACA requirements and will need to make changes to comply with the federal law by 2014.

Researchers surveyed existing laws and agreements in all 50 states and the District of Columbia concerning coverage of patient care costs in cancer clinical trials. They found that 30 have coverage mandates for cancer clinical trials and six more have voluntary agreements with health insurers. 

In 17 states and the District of Columbia, existing mandates or agreements meet the PPACA's requirements. Of the 33 states that do not meet the PPACA's requirements, 15 have no existing laws or agreements in place regarding coverage of patient care costs in cancer clinical trials, and the remainder provide for coverage that falls short of the PPACA's requirements. The most common deficiencies are lack of coverage for phase I trials and for trials not focused on cancer treatment, such as prevention studies.

The researchers also note that the new federal requirements do not apply to "grandfathered" health plans, defined as any plan or coverage in which an individual was enrolled on or before March 23, 2010, when the PPACA was enacted.

"Given that initially the vast majority of group health plans and health insurance coverage will be grandfathered, it may be some time before most Americans benefit from the clinical trials coverage requirement," wrote Dr. Al B. Benson III of Northwestern University and his colleagues.

Further reading: "Insurance Coverage Expanding for Cancer Clinical Trials" and "States That Require Health Plans to Cover Patient Care Costs in Clinical Trials"

Notes

Glycoscience, Disease, and Clinical Practice Symposium Will Be Held January 24

Alliance of Glycobiologists logo

The NCI-funded Alliance of Glycobiologists for Detection of Cancer and Cancer Risk will host a symposium on January 24, entitled "Interfacing Glycoscience with Disease and Clinical Practice." The symposium will take place at the Natcher Conference Center on the NIH main campus in Bethesda, MD, from 8:30 a.m. to 4:30 p.m.

The symposium will highlight key developments in our understanding of how sugars are used to make complex structures critical for many life functions and provide examples of how these developments are informing areas such as disease treatment and prevention. Presentations will emphasize the many ways glycans and their binding proteins influence fundamental biological processes and how these discoveries are advancing medicine.

Speakers include:

  • Dr. John Magnani, GlycoMimetics, Inc.
  • Dr. Ira Pastan, NCI
  • Dr. Robert Sackstein, Harvard Medical School
  • Dr. Carole Bewley, National Institute of Diabetes and Digestive and Kidney Diseases
  • Dr. Ronald Schnaar, Johns Hopkins University
  • Dr. Robert Haltiwanger, SUNY Stony Brook
  • Dr. Richard Cummings, Emory University
  • Dr. Michael Pierce, University of Georgia
  • Dr. David Walt, Tufts University

The agenda is online, and advanced registration is not required. Questions regarding the symposium may be directed to Dr. Karl Krueger at 301-594-1044 or via e-mail at NCIGlycomicsAlliance@mail.nih.gov.

Sign language interpreters will be provided. Individuals with disabilities who need reasonable accommodation to participate in this meeting should contact Annalisa Gnoleba at 301-594-7635 or gnolebaad@mail.nih.gov.

Cyber-Seminar to Address the Delivery of Patient-Centered Cancer Care

Connie Bura and Dr. Teresa PonnConnie Bura and Dr. Teresa Ponn

The January 24 Research-to-Reality (R2R) cyber-seminar will focus on new accreditation standards recently released by the American College of Surgeons' Commission on Cancer (CoC).

These standards aim to ensure that key elements of quality cancer care are provided to every person treated in a CoC-accredited facility. They also challenge cancer programs to address patient-centered needs and to measure the quality of the care they provide against national standards.

Connie Bura, administrative director of Cancer Programs at the CoC, and Dr. Teresa Ponn, of the New Hampshire Comprehensive Cancer Control Collaboration, will outline the evidence for and details of the new patient-centered standards and include strategies to link the patient-centered standards and their implementation at the community level with the objectives of comprehensive cancer control plans.

For more information and to register for this event, visit the R2R website, where you can watch presentations and join discussions. All R2R cyber-seminars are archived on the website approximately 1 week after the presentation.

Genomics in Medicine Series Features Two Lectures on Cancer

Last month, the National Human Genome Research Institute (NHGRI); Suburban Hospital in Bethesda, MD; and the Johns Hopkins University School of Medicine jointly launched a lecture series to improve participants' understanding of the intersection of genomics and medicine.

Last week, Dr. Lawrence Brody of NHGRI delivered a lecture on how knowledge of breast cancer genetics has influenced risk assessment and screening. A video archive will soon be available on NHGRI's YouTube channel

The next lecture, on February 3, will feature Dr. Stanley Lipkowitz of NCI's Laboratory of Cellular and Molecular Biology speaking on how genomic characterization of breast cancer is used in diagnosis and treatment.

For more information on upcoming speakers, visit the series' webpage. Lectures take place at 8:00 a.m. on the first Friday of each month at the Suburban Hospital Auditorium, 8600 Old Georgetown Road, Bethesda, MD.

Special Report

Long-Term Trial Results Show No Mortality Benefit from Annual Prostate Cancer Screening

An older male patient speaks with a physician.Doctors and policy makers seek to understand which, if any, men may benefit from routine prostate cancer screening.

New data from the Prostate, Lung, Colorectal and Ovarian (PLCO) randomized screening trial show that, after 13 years of follow up, men who underwent annual prostate cancer screening with prostate-specific antigen (PSA) testing and digital rectal examination (DRE) had a 12 percent higher incidence of prostate cancer than men in the control group but the same rate of death from the disease. No evidence of a mortality benefit was seen in subgroups defined by age, the presence of other illnesses, or pre-trial PSA testing. The results were published January 6 in the Journal of the National Cancer Institute.

When the PLCO researchers published their initial prostate screening results in 2009, which also revealed no prostate cancer mortality or overall mortality benefit from annual screening, critics countered that participants had not been followed long enough to detect a difference in prostate cancer mortality, if one existed.

“The natural history of prostate cancer is so long that 10 to 15 years of follow up is usually the window we look for” when determining the effectiveness of a screening intervention, explained first author Dr. Gerald Andriole, who is chief urologic surgeon at the Siteman Cancer Center at Barnes-Jewish Hospital in St. Louis and the Washington University School of Medicine.

The persistent increase in incidence of prostate cancer in the screening arm of the study may indicate that regular screening can lead to overdiagnosis—finding tumors that never would have caused symptoms or death. “Even if there was just a tiny mortality benefit [from prostate cancer screening], overdiagnosis wouldn’t be so bad if we didn’t hurt people. But we do hurt people by finding a lot of trivial cancers that are most often overtreated,” explained Dr. Andriole.

The PLCO began in 1993 and enrolled men through mid-2001. More than 38,000 men were randomly assigned to annual screening for 6 years (including DRE for the first 4 years and PSA testing for all 6), and the same number of men were assigned to usual care.

Because prostate cancer screening is so common, more than half of the participants in the control arm underwent at least one prostate cancer screening test outside the trial. This contamination made it more difficult to determine whether annual testing affected mortality. However, “the level of screening in the intervention arm was substantially greater than that in the control arm throughout the trial screening period,” wrote the authors.

“Every time we screened [in the intervention arm] we got a bump of excess cases,” said Dr. Philip Prorok, a lead NCI investigator on the study. “What we can’t say for sure is whether we would have seen more of an effect on mortality had there been absolutely no screening in the control arm.”

Another recent large trial, called the European Randomized Study of Screening for Prostate Cancer, did report a mortality benefit for prostate cancer screening. Although that trial had less contamination in the control arm, it had other limitations that could bias the results, such as differences in the treatments given to men in the screening and control arms.

To help reconcile the differing results from these two trials—the largest trials to date of organized prostate cancer screening—an effort is under way by the NCI-funded Cancer Intervention and Surveillance Modeling Network (CISNET) to use mathematical modeling to tease out how differences in the trial designs and populations may have contributed to the disparate trial results, explained Dr. Paul Pinsky, an NCI investigator on the PLCO trial and consultant to the CISNET project.

“Even though the results seem to be disparate, because one [trial] found a [statistically] significant protective effect [on prostate cancer mortality] and one didn’t, it could be because of the ways the trials were designed and carried out,” he said. The CISNET study began last year and is examining data from the two trials.

Men and their health providers agree that a more definitive answer is needed as doctors and policy makers seek to understand which, if any, men may benefit from routine prostate cancer screening. In October 2011, the United States Preventive Services Task Force released new draft guidelines for prostate cancer screening for public comment. The new draft guidelines, which are based in part on PLCO findings, recommend against routine PSA testing in men who do not have prostate cancer symptoms.

Some doctors think the new recommendations go too far in not accounting for the informed decisions of individual men. “If prostate cancer constitutes a continuum of disease and its overdiagnosis and overtreatment are mainly limited to low-grade disease, then instead of completely eliminating the potential benefits of screening along with the risks, why not consider managing low-risk patients differently?” asked Drs. Jeri Kim and John W. Davis of the University of Texas M. D. Anderson Cancer Center in a commentary published last month in JAMA.

Practice appears to be moving in this direction, with a greater emphasis on active surveillance instead of immediate treatment for some men who have prostate cancer that is thought to be at low risk of progressing. A big advance, explained Dr. Andriole, would be the ability to predict, even before a biopsy, whether a man with an elevated PSA level is likely to have an aggressive versus a nonaggressive cancer.

“There’s a lot of effort now being put into this, and not just for prostate cancer, but for a lot of other cancer types as well,” added Dr. Prorok. “If we diagnose someone with symptoms, or you find something on a screening test, can we eventually find a way to determine for which individuals the cancers are in fact aggressive and need more aggressive treatment, versus some that need less aggressive treatment or don’t need any treatment at all?”

Researchers are looking for biomarkers, including genes and proteins, that may give clues to a cancer’s aggressiveness. “If we could selectively change our criteria for biopsy such that only men who are at high risk for aggressive cancer get biopsied, we might be able to substantially shift the overall risk/benefit [ratio] of screening,” said Dr. Andriole.

Sharon Reynolds