National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
June 29, 2010 • Volume 7 / Number 13

NEWS

Illustration of a DNA strandGenome Studies Start to Unravel Prostate Cancer’s Complexity

Researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) have completed the largest genomic analysis of prostate tumors to date. The results, based on clinical and genomic information collected from 218 patients, provide an overview of the common genetic changes in the disease and point to new directions for research, including a way to potentially differentiate aggressive tumors from those that are not life threatening. The researchers have made the data available to the community through a public Web site, and a summary of the results appeared online last week in Cancer Cell.  Read more > >

COMMENTARY

Dr. Julia H. RowlandGuest Director's Update: Cancer Survivorship Research Conference— Recovery and Beyond

I was pleasantly surprised and very gratified that this year’s Fifth Biennial Cancer Survivorship Research Conference, held June 17–19 in Washington, DC, was our biggest meeting yet. Despite a weak economy and many competing scientific meetings, more than 550 researchers, patient advocates, cancer care specialists, public health officials, and others attended from 44 states, the District, Guam, and a number of foreign countries. This is testament to the rapid growth and evolution within the field of cancer survivorship, both in the rigor of scientific inquiry being pursued and the numbers of those engaged in research and care that addresses the long-term needs of cancer survivors.  Read more > >

  

IN DEPTH

UPDATES

  • FDA Update

    • Leukemia Drug Pulled from U.S. Market
    • New Treatment Approved for Advanced Prostate Cancer that Resists Docetaxel
    • Nilotinib Approved to Treat Rare Form of Chronic Myeloid Leukemia
  • HHS Update

    • ODPHP Releases Health Literacy Guide
  • Cancer.gov Update

    • DCB Launches Updated Web Site
  • Notes

    • Fourth Telephone Workshop for Cancer Survivors Slated for July 13
    • NCI Program Will Aid Development and Validation of Trial Assays
    • Budget, Clinical Trials, and Training Highlighted at NCAB Meeting
    • NCI Scientists Awarded 2010 Federal Laboratory Consortium Awards
    • PARADE Magazine Spotlights Cancer in America
    • NCI and Chinese Academy of Medical Sciences Host caBIG Workshop

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

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

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

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

Featured Article

Genome Studies Start to Unravel Prostate Cancer’s Complexity

Illustration of a DNA strand

Researchers at Memorial Sloan-Kettering Cancer Center (MSKCC) have completed the largest genomic analysis of prostate tumors to date. The results, based on clinical and genomic information collected from 218 patients, provide an overview of the common genetic changes in the disease and point to new directions for research, including a way to potentially differentiate aggressive tumors from those that are not life threatening. The researchers have made the data available to the community through a public Web site, and a summary of the results appeared online last week in Cancer Cell.

“We now have a much better picture of the common genetic alterations in prostate cancer,” said lead investigator Dr. Charles Sawyers. Although more samples need to be analyzed, he continued, the results could provide a roadmap for designing future clinical trials in this disease. “When it comes to developing and testing targeted cancer drugs, you need to be able to subclassify patients, and you can’t do this intelligently until you know what the alterations are.”

This would change how doctors talk to patients about the disease and the need for adjuvant therapy or not, which is why this finding is so exciting.

—Dr. Jonathan Simons

Genome studies have yielded insights into glioblastoma and cancers of the lung, colon, pancreas, and breast, but prostate cancer has been a challenge. Prostate tumors are relatively small, and expert pathologists are needed to obtain adequate samples of tumor tissue. With a large prostate cancer program and skilled pathologists, MSKCC was able to overcome these challenges.

“Dr. Sawyers and his colleagues have made an extraordinarily important contribution to the field of prostate cancer research,” said NCI Deputy Director Dr. Anna Barker. “Certain tumors are going to be difficult to collect and analyze, but this study—which used high-quality samples and multidimensional data—now gives the community new opportunities to understand the disease.”

The researchers sequenced 157 genes that were known to be associated with prostate and other cancers. Mutations in these genes were rare. But when the researchers included additional information, such as DNA copy-number changes (gains and losses of DNA), they identified several genetic pathways, including the PI3K pathway, that were altered in nearly all metastatic tumors and many primary tumors.

“Just as we’ve seen in brain tumors, when you combine all these different sources of information, there is a uniform consistency of pathways that are altered in the disease,” said co-author Dr. Peter Scardino, chairman of the Department of Surgery at MSKCC. “We found many more abnormalities in localized prostate cancer than we expected.”

The researchers also identified a gene called NCOA2 that appears to play an important role in about 11 percent of prostate tumors. The protein encoded by this gene may drive prostate cancer by amplifying signals from the androgen-receptor pathway; this pathway plays a critical role in early- and late-stage prostate cancer.

Potential Biomarker

The analysis also revealed a striking association between changes in DNA copy number and the risk of recurrence after surgery, and this association could not be explained entirely by Gleason score. “This was one of the most exciting findings from the study,” said Dr. Scardino. “It offers the possibility of a biomarker that could be used to characterize the aggressiveness of prostate cancer, which is something we greatly need.”

Doctors currently do not have a way to distinguish between prostate cancers that require aggressive treatment and those that will cause no harm if left alone. Consequently, many men receive treatment unnecessarily. Genomic tests can provide prognostic information in breast cancer, for example, but none yet exists in this disease.

The new findings, if confirmed, represent a prototype for developing these kinds of prognostic tests for prostate cancer, said Dr. Jonathan Simons, CEO and president of the Prostate Cancer Foundation. “This would change how doctors talk to patients about the disease and the need for adjuvant therapy or not, which is why this finding is so exciting,” he added.

Dr. Scardino runs the Specialized Program of Research Excellence (SPORE) in prostate cancer at MSKCC, and his group has launched follow-up studies. The current work was done using frozen tumor specimens collected during prostatectomies. The researchers will now see whether copy-number changes are informative using paraffin-embedded tissues. If the answer is yes, they will test cells obtained from a needle biopsy.

The genome analysis also revealed that some patients whose tumors include a fusion of the genes TMPRSS2 and ERG are also missing part of chromosome 3. This fusion gene occurs in about half of all prostate cancers, and researchers have suspected that other genes also play a role in these cases. 

“This deletion on chromosome 3 appears to be very strongly associated with the fusion,” said Dr. Sawyers. “The next steps are to see which genes in the region that is deleted are involved in the disease. We have a clear path forward.”

The TMPRSS2-ERG fusion was discovered in 2005 by University of Michigan researchers supported by NCI’s Early Detection Research Network. At the time, fusions were thought to be limited to cancers of the blood, but it is now known that these alterations are present in common cancers as well. About two dozen have been identified in prostate cancer.

New Class of Gene Fusions

Earlier this month, the Michigan group, led by Dr. Arul Chinnaiyan, reported a new class of prostate cancer gene fusions derived from the RAF pathway. One of these fusions involves the gene BRAF, which plays a role in melanoma. Drugs targeting BRAF are in clinical trials, and it appears, based on experiments in cells, that these drugs may be active in up to 2 percent of patients with prostate cancer, the researchers reported.

“The clinical promise of this discovery is that patients who have these RAF gene fusions may be candidates for drugs that target these changes,” said Dr. Chinnaiyan. “Some of the newer inhibitors, in particular, might be useful in treating this molecular subtype of prostate cancer as well as some other cancers.”

In the future, every man whose prostate cancer is biopsied is going to have his DNA read for gene fusions, just as women have their breast cancers tested for overexpression of the HER2 protein to determine whether they should receive trastuzumab (Herceptin), predicted Dr. Simons. “To cure every man of advanced prostate cancer, we’ll need at least 24 strategies,” he continued. “Now that we know what we’re facing, we can make research plans and do the work.”

Two prostate cancer genome sequences have been presented at scientific meetings and will likely be published later this year, Dr. Simons said. “It’s a complicated disease, but key properties of the disease are going from being in total darkness to full clarity. And that’s what is so amazing.”

For Dr. Barker, a founder of The Cancer Genome Atlas (TCGA) project with colleagues from the National Human Genome Research Institute, the MSKCC study is both exciting and gratifying. Dr. Sawyers and his colleagues essentially followed the TCGA approach by profiling high-quality tumor samples and integrating clinical and multiple kinds of genomic information into their analysis. As with TCGA, they made the results public so that investigators in the community can now mine the information for new insights.

The hope from the beginning of TCGA has been that the approach would be adopted by investigators performing cancer genomics studies in the community, said Dr. Barker. And now that this study has been completed, TCGA investigators will use the data when they launch an even larger study of prostate tumors in the future.

“This study gives us a much better starting point for prostate cancer than we’ve ever had before,” Dr. Barker said. “It’s a great day for cancer research, and an even better day for patients.”  

—Edward R. Winstead

Cancer Research Highlights

Gefitinib Improves Progression-free Survival for Metastatic Lung Cancers with EGFR Mutations

Patients newly diagnosed with metastatic non-small cell lung cancer (NSCLC) who received gefitinib (Iressa) had significantly higher response rates and longer progression-free survival compared with patients who received carboplatin plus paclitaxel (73.7 percent versus 30.7 percent and 10.8 months versus 5.4 months, respectively), according to results of a phase III trial conducted in Japan. The results were published in the June 24 New England Journal of Medicine.

All patients enrolled in the study had epidermal growth factor receptor (EGFR) mutations that were sensitive to the tyrosine kinase inhibitor (TKI) gefitinib. The patients did not have the resistant EGFR mutation T790M, and they had not been previously treated with chemotherapy.

The researchers, led by Dr. Makoto Maemondo of the Miyagi Cancer Center in Miyagi, Japan, believe that this study establishes the clinical benefit of an EGFR tyrosine kinase inhibitor as first-line therapy in patients with NSCLC and sensitive EGFR mutations.“If gefitinib is administered as second-line or third-line treatment,” he and his colleagues wrote, “patients may miss the opportunity to receive treatment because of rapidly progressive disease during or after first-line treatment.”

The trial was stopped early in 2009 after a planned interim analysis of the first 200 patients revealed a 70 percent reduction in disease progression or death in patients receiving gefitinib. Ultimately, 230 patients from 43 institutions in Japan were enrolled and analyzed. At 1 year, 42.1 percent of patients receiving gefitinib had not progressed, compared with 3.2 percent of those receiving chemotherapy; after 2 years, all chemotherapy patients had progressed, while 8.4 percent of those receiving gefitinib still had not. Women had significantly longer progression-free survival than men.

Patients who completed their first-line therapy or whose disease progressed while receiving chemotherapy were allowed to cross over and receive gefitinib, and 106 out of 112 did so. Fifty-nine percent of these patients responded to second-line therapy with gefitinib. This crossover, the researchers wrote, may have affected the overall survival difference between the two study arms, which was not statistically significant.

Gefitinib fell out of favor in the United States after a 2005 clinical trial indicated the drug had little benefit in unselected patients, and the drug currently has a very restricted label in this country, where erlotinib (Tarceva) is the approved second-line EGFR TKI of choice. Both gefitinib and erlotinib work in a similar way, and patients with sensitive EGFR mutations are also very responsive to erlotinib treatment.

Study Finds Poor Physician Adherence to Cervical Cancer Screening Guidelines

A survey of more than 1,200 primary care physicians indicates that many are not following clinical practice guidelines on recommended screening intervals for cervical cancer, both with regard to traditional Pap testing as well as a newer screening method, a DNA test for the human papillomavirus (HPV). The FDA has approved HPV DNA testing for use in conjunction with Pap testing, a process called co-testing, for women age 30 and older.

At the time the survey was conducted, guidelines from the American Cancer Society and those from the American Congress of Obstetricians and Gynecologists advised extending the interval between screenings to 3 years for low-risk women over the age of 30 after three consecutive normal Pap tests or a single normal co-test (a normal Pap test plus a negative HPV DNA test). Guidelines from the U.S. Preventive Services Task Force also are consistent with a longer interval between screening tests.

In the survey, based on a hypothetical clinical vignette of a 35-year-old, low-risk woman with three prior normal Pap tests, only 32 percent of respondents reported that they would comply with guideline recommendations, researchers from the CDC and NCI reported in the June 14 Archives of Internal Medicine. Even fewer respondents, 19 percent, would comply when, during a single visit, the low-risk woman had a normal co-test result. Approximately 60 percent of those surveyed—which included general internal medicine physicians, family practice doctors, and obstetrician-gynecologists—said they would still recommend that the woman undergo annual Pap screening.

Although the Pap test is the most commonly used cervical cancer screening method, a number of studies have shown that the DNA test for HPV—the cause of the vast majority of cervical cancer cases—is more sensitive than the Pap test in detecting high-grade precancerous lesions, spurring discussions about the optimal approach to cervical cancer screening in the United States.

This new study, however, suggests that guidelines for extending screening intervals have not influenced current clinical practice, wrote Dr. Mona Saraiya of the CDC’s Division of Cancer Prevention and Control and her colleagues. “When offered the choice for HPV testing,” they wrote, “many physicians deferred to the same pattern they used for Pap testing,” annual screening with both tests or no recommendation for HPV testing.

“These practice patterns are not likely to lead to much improvement in cervical cancer outcomes, but may result in unnecessary follow-up testing, increased risk of colposcopy-associated morbidities, and distress for patients,” said Dr. Robin Yabroff, a study co-author from NCI’s Division of Cancer Control and Population Sciences.

“New HPV infections are extremely common but overwhelmingly benign; they almost always go away by themselves,” said Dr. Mark Schiffman of NCI’s Division of Cancer Epidemiology and Genetics. “Only persistent infections are a risk factor for cancer. If you screen for HPV too often, you will detect new infections rather than persistent infections, and this poses the risk of overtreatment.”

Targeted Drug Tested in Children with Recurrent Medulloblastoma

A small phase I clinical trial testing an experimental drug that blocks the hedgehog signaling pathway has found that the drug appears safe in children with recurrent medulloblastoma, the most common malignant pediatric brain tumor. In addition, two patients whose tumors showed hedgehog pathway activation received the targeted therapy, GDC-0449, for prolonged periods, indicating to researchers that these patients likely benefited from the drug. Based on the results, presented at the annual meeting of the American Society of Clinical Oncology, the Pediatric Brain Tumor Consortium (PBTC) is planning a phase II study to verify the drug’s efficacy in children with this disease.

The hedgehog signaling pathway is important in early embryonic development and in the maintenance of adult tissues, but abnormal activation of the pathway may contribute to cancer. Approximately 20 percent of medulloblastomas are thought to involve inappropriate hedgehog signaling.

In the study, 12 of 13 children with recurrent or drug-resistant medulloblastoma tolerated the drug and did not experience the bone or dental problems observed in mice in preclinical studies. Of the two patients in the trial with confirmed activation of the hedgehog pathway in their tumors, one patient progressed after 6 months on the therapy, and the other remained on the trial without disease progression for at least 391 days, said lead investigator Dr. Amar Gajjar, representing the PBTC, which conducted the study.

The patients, all of who were between the ages of 4 and 21, received one of two different doses of the drug daily for a minimum of 28 days and continued on treatment for as long as their disease did not progress. In addition to determining the safety and proper dose of this experimental drug in children, the researchers also conducted research on pathologic and genomic methods for better identifying tumors that involve activation of the hedgehog pathway.

Although approximately 3 of 4 children diagnosed with medulloblastoma will become long-term survivors, cure is uncommon for children whose tumors recur. New, less-toxic therapies are needed for this cancer, which affects approximately 500 children in the United States each year, noted Dr. Malcolm Smith of NCI’s Cancer Therapy Evaluation Program. GDC-0449 is a high priority for further evaluation in patients with medulloblastoma, Dr. Smith added, especially in those whose tumors show hedgehog pathway activation.

See also: In Cancer, Hitting a Target Called Hedgehog

Vitamin D Concentrations in Blood Not Linked to Risk of Less Common Cancers

A large prospective study has found that levels of vitamin D circulating in the bloodstream are not associated with subsequent risk of developing seven rare cancers, including endometrial, esophageal, stomach, ovarian, pancreatic, and kidney cancers and non-Hodgkin lymphoma. Although each of these cancers is individually uncommon, they collectively account for about a quarter of all deaths from cancer in the United States. The results were reported in a series of studies published online in the American Journal of Epidemiology on June 18.

“These cancer sites were chosen because there was a paucity of previous epidemiological studies, though basic research and biological evidence had suggested vitamin D may play a role in altering risk for these cancers,” said Dr. Demetrius Albanes of NCI’s Division of Cancer Epidemiology and Genetics. “Because these cancers are relatively rare, no one study could address risk; by pooling data from 10 studies, we had greater power to rigorously test the vitamin D hypothesis for these cancer outcomes.” 

The researchers, part of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers, measured blood concentrations of 25-hydroxy vitamin D, which is the primary form of this vitamin circulating in the bloodstream. Lower cancer risk was not observed in persons with high vitamin D blood concentrations compared with normal concentrations for any of these cancers. At the other end of the spectrum, higher cancer risk was not seen in participants with low vitamin D concentrations. However, researchers did observe an increased risk of pancreatic cancer for a small number of patients (2.3 percent) with very high blood concentrations of vitamin D (100 nmol/L or greater). “This finding needs to be followed up in further studies,” said Dr. Albanes.

Dr. Kathy J. Helzlsouer of the Prevention and Research Center at Mercy Medical Center in Baltimore, MD, who served as the chair of the project’s steering committee, wrote in the overview of the importance of optimum concentrations of vitamin D, particularly for bone health. A message of the study, she suggested, was “all things in moderation. You don’t want vitamin D levels that are too low, and you don’t want levels that are too high.”

“These studies offer compelling evidence against the hypothesis that circulating levels of vitamin D are relevant to risk of these cancers,” wrote Dr. Tim Byers of the University of Colorado Cancer Center, Aurora, in an accompanying editorial. This new information is important, he continued, because a review by the International Agency for Research on Cancer had decided that evidence was previously insufficient to draw conclusions about these cancer sites.

Cancer Survivors More Likely Than Peers to Forgo Medical Care Due to Cost

Approximately 12 million adults in the United States have a history of cancer, and this number will likely grow as the population ages. In a study led by Dr. Kathryn Weaver of Wake Forest University School of Medicine, researchers found that cancer survivors under the age of 65 were up to two times more likely to forgo or delay medical services because of cost concerns than adults without a history of cancer. These results were published online June 14 in Cancer.

The researchers used data collected between 2003 and 2006 from 6,602 cancer survivors and 104,364 adults without a history of cancer who participated in the National Health Interview Survey (NHIS); participants who only reported having nonmelanoma skin cancer were excluded. The survey collected information on age, sex, race and ethnicity, cancer site, insurance coverage, and other medical conditions besides cancer. During the interviews, the surveyors asked whether, at any time in the past 12 months, participants forwent or delayed medical care because of the cost, including prescription medications, mental healthcare, or dental care.

Overall, the prevalence of forgoing one or more medical services because of cost was 17.6 percent among cancer survivors; 7.8 percent reported forgoing medical care, 10.7 percent reported delaying medical care, 9.9 percent reported forgoing prescription medication, 11.3 percent reported forgoing dental care, and 2.7 percent reported forgoing mental health care. When the data were stratified by age, survivors 65 or older were not significantly more likely to forgo or delay care due to cost than their peers, unlike those younger than 65. Dr. Weaver believes that more uniform health insurance coverage through Medicare in those older than 65, as well as differences in the need for medical services by age, likely explain this pattern.

Extrapolating these numbers to the general population, the researchers estimated that more than 2 million cancer survivors in the United States did not get one or more medical services during the period studied, due to cost concerns. “Lack of access to medical care among cancer survivors is a significant public health concern given the importance of regular medical care for cancer survivors and their growing number,” stated the authors. More research is required, they concluded, to understand whether the medical services not received are cancer related or related to other medical conditions.

Also in the Journals: Cancer Affects Many Parents Living with Children Younger Than 18

An estimated 1.58 million U.S. cancer survivors reside with one or more children under the age of 18, according to an analysis published online June 28 in Cancer. The estimate is based on data from 13,385 adults with a history of cancer who participated in the National Health Interview Survey (NHIS) between 2000 and 2007. Dr. Kathryn Weaver, formerly of NCI’s Office of Cancer Survivorship, and her colleagues noted that 18.3 percent of recently diagnosed survivors (within the past 2 years) and 14.0 percent of all survivors were living with children younger than 18. Most of these cancer survivors are female (78.9 percent), married (69.8 percent), and under 50 years of age (85.8 percent).

The authors urged further research to assess the needs and resource referrals for this large population of families. “We hope that by documenting the significant number of families affected,” they wrote, “greater attention will be given to the identification of these potentially at-risk groups.”

Guest Director's Update

Cancer Survivorship Research Conference: Recovery and Beyond

Dr. Julia H. Rowland Dr. Julia H. Rowland

I was pleasantly surprised and very gratified that this year’s Fifth Biennial Cancer Survivorship Research Conference, held June 17–19 in Washington, DC, was our biggest meeting yet. Despite a weak economy and many competing scientific meetings, more than 550 researchers, patient advocates, cancer care specialists, public health officials, and others attended from 44 states, the District of Columbia, Guam, and a number of foreign countries. This is testament to the rapid growth and evolution within the field of cancer survivorship, both in the rigor of scientific inquiry being pursued and the numbers of those engaged in research and care that addresses the long-term needs of cancer survivors.

Reflecting increased awareness of the potential public health impact of cancer survivorship, the CDC joined with NCI, the American Cancer Society, and the Lance Armstrong Foundation as a co-sponsor of this year’s conference. All of us share the hope and belief that this national survivorship conference will act as a catalyst for future research and for promoting clinical care that helps cancer survivors and caregivers move beyond recovery. The forum certainly offered an opportunity to highlight cutting-edge survivorship science, meet and network with cancer survivorship investigators from multiple disciplines, and interact with survivors whose personal experiences were often reflected in—and may potentially be affected in the future by—this emerging field of research.

Among the major themes at this year’s conference was the growing attention being paid to issues of energy balance, especially the role of physical activity and weight in cancer survivors’ health-related outcomes. Emerging evidence shows that physical activity and weight loss may favorably affect not only quality of life and symptom management, but also recurrence and survival. There is also a shift in thinking around the need to develop and offer effective cancer rehabilitation programs for survivors, something that our European colleagues have embraced but has yet to become mainstream practice in the United States. While there have been cardiac rehabilitation programs in this country for many years, the growing field of exercise research among cancer survivors points toward incorporating more structured physical activity into cancer treatment and survivorship care. (See “Guidelines Urge Exercise for Cancer Patients, Survivors” in this issue.)

Experts at the meeting addressed the increasing challenge of identifying the best model of care for cancer patients to facilitate their transition from active treatment to recovery. Such a program should provide survivors with the knowledge necessary for understanding what to expect after treatment ends, including how to manage persistent problems, decrease the risk for late effects, optimize their health, and communicate effectively with their diverse health care providers to coordinate future care.

Finally, conference attendees were energized by remarks from Dr. Carolyn Clancy, director of the Agency for Healthcare Research and Quality, about the new national focus on comparative effectiveness studies and financing. She challenged us to consider how we are going to best research and disseminate the kind of care that is shown to be safe, timely, effective, efficient, equitable, and patient-centered to our growing population of cancer survivors. In the end, finding the answers to these key questions may be one of our best strategies for reducing the national burden of cancer.

Dr. Julia H. Rowland
Director, NCI Office of Cancer Survivorship

Spotlight

Guidelines Urge Exercise for Cancer Patients, Survivors

A cancer survivor exercising on a treadmill

A panel of 13 researchers with expertise in cancer, fitness, obesity, and exercise training is spreading what they believe to be one of the most important messages for cancer patients and survivors: Avoid inactivity.

The panel was convened last year by the American College of Sports Medicine (ACSM) to develop guidelines on exercise and physical activity in patients who are undergoing active treatment for cancer or who have completed treatment.

In addition to promoting the benefits of exercise and physical activity in this group, the panel had another goal in formulating the guidelines, said lead author Dr. Kathryn Schmitz of the University of Pennsylvania’s Abramson Cancer Center. “Our hope is that there will be more conversations about the need for formalized exercise programs for patients during and right after treatment—programs that will be the cancer equivalent to cardiac rehab,” she said.

The benefits of exercise are well documented in a number of cancers, Dr. Schmitz continued, namely in areas such as fatigue and physical functioning, both of which directly influence quality of life. While survival is the ultimate outcome measure, with an estimated 12 million cancer survivors and growing in the United States, the importance of improving quality of life has grown exponentially.

The evidence linking physical activity with improved quality of life in those undergoing active treatment and those who have completed it “is incredibly strong,” said Dr. Rachel Ballard-Barbash of NCI’s Division of Cancer Control and Population Sciences.

The most robust evidence is for people who have completed active cancer treatment, noted Dr. Kerry Courneya from the University of Alberta, who has led a number of clinical trials of physical activity in cancer patients. But, he continued, because of differences in study design and other factors, it’s difficult to compare findings involving patients under active treatment with findings involving patients who have completed treatment.

Overall, said Dr. Courneya during an education session on exercise and cancer at the recent ASCO annual meeting, “We’re finding that patients can do a lot more than we originally thought they could do, even when they’re on chemotherapy or radiation therapy.”

And that’s critical, stressed Dr. Ballard-Barbash. “Even a modest amount of exercise, like brief walks, is beneficial, and we see gains versus doing nothing at all.”

Adapt, but Be Realistic

Patients with different cancer types receive different treatments. So the new ACSM guidelines identify considerations that patients/survivors and the fitness professionals working with them should take into account.

In men who have undergone androgen deprivation therapy for prostate cancer, for example, trainers need to be aware of fracture risk and adjust the exercises accordingly. And many women with breast cancer will have had surgery “that can really debilitate the shoulder,” said McAllister, so the guidelines encourage the use of exercises to stabilize and strengthen the surrounding muscles.

Dr. Schmitz noted that although the benefits of exercise are clear, “sometimes people are just too sick to exercise,” particularly during active treatment. Dr. Ballard-Barbash concurred. “If a patient is finding it difficult to tolerate exercise,” she said, “he or she may need to decrease activity for a while, or wait a few days before starting again.”

Developing the Guidelines

The guidelines, published in the July 2010 Medicine & Science in Sports & Exercise, follow the 2008 release of HHS’ Physical Activity Guidelines for Americans. But the panel suggested adaptations for exercise in people with different cancer types based on factors such as common adverse effects of treatment, for example, increased risk of bone fractures and cardiac side effects. (See the sidebar.)

Specific recommendations—including the objectives and goals of a prescription for exercise training—and contraindications for exercise are, however, available only for patients with breast, prostate, colon, gynecologic, and hematologic cancers, since they are the cancers for which the panel felt there was sufficient evidence for such recommendations.

Two of the primary goals of exercise highlighted in the guidelines are improved body image and body composition. In the case of the former, many cancer patients undergo extensive surgery or receive treatments that can alter their physical appearance and radically alter feelings about things such as sexual attractiveness, said Dr. Schmitz. “There’s good evidence in the literature that physical activity can improve body image, and that may be one mechanism through which exercise can improve quality of life,” she explained.

Body composition changes are common in many cancer patients, but the reasons can vary by cancer site. Some cancers, such as gastrointestinal and head and neck cancers, are typically associated with body wasting (loss of weight and muscle mass), so much so that it can be difficult for some patients to get up out of a chair. In this group, exercises that help build lean muscle are important.

But in breast cancer, where the bulk of the studies on physical activity have been performed, the systemic treatments patients often receive can lead to significant weight gain. In those patients, exercise “that is more useful for controlling body weight and losing fat, getting back to a healthy BMI,” will be more important, Dr. Schmitz said.

The guidelines also make note of the suggestive evidence—but by no means definitive evidence—in breast and colorectal cancer that regular exercise after treatment improves progression-free and overall survival. As the data continue to emerge in this area, a prescription for exercise could be “an adjunct to curative care,” said Dr. Schmitz.

But Dr. Courneya acknowledged that the jury is still out on survival, calling the data “exciting” but “still experimental.”

Putting Exercise into Action

There are numerous issues to address before physical activity becomes proactively integrated into treatment or survivorship plans, including insurance coverage of exercise training; educating oncologists, other clinicians, and patients about the benefits of exercise; and expanding the ranks of fitness professionals who understand the issues and needs faced by cancer patients and survivors.

From her perspective, said Marilyn McAllister, a trainer from Boise, ID, who often works with breast cancer survivors in her own studio and at a local hospital, the environment around exercise and cancer is improving, but more progress needs to be made. In her experience, physicians often are “too swamped” dealing with day-to-day patient care issues to learn about or discuss exercise with their patients. “And patients, when they first start treatment, are just overwhelmed with information, so handing them a piece of paper with information about yoga or strength training isn’t very helpful.”

Several initiatives are under way to expand the supply of fitness professionals with cancer-specific training. ACSM and the American Cancer Society (ACS) have a certification program for trainers who want to work with cancer patients and survivors, and Dr. Schmitz helped ACSM develop a new, six-session cancer exercise trainer certification Webinar. In addition, the Lance Armstrong Foundation has partnered with the YMCA to help train fitness staff at YMCAs across the country to work with and meet the needs of cancer survivors.

Helping any of her clients improve their fitness is gratifying, said McAllister, an ACSM/ACS-certified cancer trainer, but working with cancer patients and survivors offers some unique rewards. “Everybody benefits from exercise, but it can be so dramatic in cancer patients,” she said. “It doesn’t take much training to produce big results in their lives.”

—Carmen Phillips

A Closer Look

Four Breast Cancer Trials with Clinical Implications

Reader Suggested

At the recent American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Dr. William Wood of Emory University discussed four NCI-supported clinical trials in breast cancer, each with clinically important results. He said that he could not remember a series of four consecutive reports at ASCO “with as clear conclusions that were consequential for practice” as these.  

The first trial found that a commonly used test to identify rare cells in the sentinel lymph nodes or bone marrow of patients with breast cancer may not provide useful information for patients and physicians. The test, a method for staining cells called immunohistochemistry (IHC), can detect small numbers of cells, or micrometastases, that would not typically be picked up by a pathologist’s examination of a tissue specimen on a slide.

These are practice-changing results. And it’s also interesting to see scientific hypotheses proven, even if it’s only the null hypothesis.

—Dr. William Wood

The researchers hypothesized that IHC could help identify patients at risk of recurrence and determine which ones might need systemic chemotherapy, but the results suggested otherwise. “We had thought that finding micrometastases using immunohistochemistry would portend a worse prognosis, but we did not find that,” said co-investigator Dr. A. Marilyn Leitch, of the University of Texas Southwestern Medical Center at Dallas.

This prospective multicenter trial included more than 5,000 women with early-stage, clinically node-negative (without palpable metastases in the lymph nodes under the arm) breast cancer who had undergone lumpectomy. The women also underwent sentinel lymph node biopsies and bone marrow aspiration to determine whether micrometastases were present.

“In general, as a result of this study, these special stains should probably no longer be done in women with newly diagnosed breast cancer,” said Dr. Eric Winer of Harvard Medical School, who moderated a press briefing. The findings should have an impact on care because IHC is routinely done at many medical centers, he noted.

Regarding the bone marrow test, there was a suggestion of worse outcome in women who were found to have tumor cells in the bone marrow as detected by IHC. But this approach requires further investigation, said Dr. Winer. “I don’t think any of us would recommend that a woman with newly diagnosed breast cancer undergo a bone marrow examination as part of her routine evaluation,” he added.

Improving Quality of Life

Another study in the session was NSABP B-32, a large randomized phase III trial that compared sentinel lymph node biopsy with axillary dissection in clinically node-negative women with breast cancer. The study concluded that, in these women, axillary lymph node dissection did not add a benefit to sentinel node biopsy alone.

“When the sentinel node is negative, sentinel node surgery alone with no further axillary dissection is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes,” said Dr. David N. Krag of the Vermont Cancer Center, who presented the findings. “This is clear evidence of a study that adds benefit to a woman’s quality of life and is also cost-saving.”

Dr. Wood praised the trial’s design and focus on surgical quality control, and he agreed with its conclusion, calling the evidence “definitive.”

In a related trial, researchers found that removing additional axillary lymph nodes to look for more breast cancer cells in women with limited disease that had spread to the sentinel node did not improve survival. These findings are important because many physicians routinely opt for axillary node dissection in women with metastases in the sentinel lymph node, the researchers said.

Axillary lymph node removal has been the standard approach for women with micro- and macrometastases in the sentinel node, explained lead author Dr. Armando Giuliano, director of the John Wayne Cancer Institute Breast Center in Santa Monica, CA. The results are not definitive, noted Dr. Winer, because the study did not meet its goal in accrual.

But the findings suggest that there may not be a benefit to removing more lymph nodes than the sentinel node in such cases, and that many women can avoid the risk of additional side effects associated with more extensive lymph node removal, Dr. Giuliano said. Axillary lymph node dissection will still be needed in some cases, but these findings show it may be necessary for far fewer women, he added.

Helping Older Patients

A fourth trial found that some older women can forgo radiation after surgery for breast cancer. Women 70 years of age or older with early-stage breast cancer did not benefit from the addition of radiation therapy to breast-conserving surgery and tamoxifen, according to the results from a phase III randomized trial. (See the full NCI Cancer Bulletin article.)

“These clinical trials, which were made possible only through government funding, will spare many women the side effects of unneeded treatment without compromising their survival,” said Dr. Jo Anne Zujewski, head of Breast Cancer Therapeutics in NCI’s Division of Cancer Treatment and Diagnosis. “They will also help save health care dollars.”

 Dr. Wood concluded his discussion of the four reports by saying: “These are practice-changing results. And it’s also interesting to see scientific hypotheses proven, even if it’s only the null hypothesis.”

—Edward R. Winstead

Featured Clinical Trial

Inhibiting Angiogenesis in Metastatic Castration-resistant Prostate Cancer

Name of the Trial
A Phase 2 Trial of Bevacizumab, Lenalidomide, Docetaxel, and Prednisone (ART-P) for Treatment of Metastatic Castrate-resistant Prostate Cancer (NCI-09-C-0195). See the protocol summary.

Dr. William Dahut Dr. William Dahut

Principal Investigator
Dr. William Dahut, NCI Center for Cancer Research

Why This Trial Is Important
Men with advanced prostate cancer often receive treatment to block the production of androgens, which are male sex hormones that may help prostate tumors grow. However, prostate cancers that initially respond to antiandrogen therapy eventually develop the ability to grow without androgens. Such cancers are often referred to as hormone refractory, androgen independent, or castration resistant. Metastatic castration-resistant prostate cancer (mCRPC) is usually treated with the chemotherapy drug docetaxel and the steroid prednisone.

The development of new blood vessels, or angiogenesis, is thought to be an important factor in prostate cancer progression. In an effort to extend the survival of men with mCRPC, doctors are exploring the possibility of combining agents that target angiogenesis with docetaxel and prednisone. The monoclonal antibody bevacizumab (Avastin) is an angiogenesis inhibitor that has been studied in numerous types of cancer, including prostate cancer. In a previous clinical trial, the combination of bevacizumab and docetaxel was active and well tolerated in patients with mCRPC. A recent study by NCI researchers showed that adding another antiangiogenic drug, thalidomide, to this combination, along with prednisone, improved survival well beyond what is typically seen in these patients. This improvement, however, came with increased side effects, including fatigue, neuropathy, and suppression of bone marrow function. In an attempt to maintain the activity of this combination while reducing its associated side effects, the NCI research team is replacing thalidomide with a structurally similar drug, lenalidomide (Revlimid).

In this trial, patients with mCRPC who have received no treatment for metastatic disease will be treated with docetaxel, prednisone, bevacizumab, and lenalidomide. The researchers want to find out whether lenalidomide can be safely added to the other drugs and determine the extent to which the patients’ prostate cancers responds to the combined treatment.

“We’ve shown that targeting tumor angiogenesis through two different mechanisms—using bevacizumab and thalidomide—in addition to docetaxel chemotherapy helps patients live longer than one would expect using standard chemotherapy alone,” said Dr. Dahut. “Now we want to see if we can safely replace thalidomide with lenalidomide, which is usually well-tolerated in patients with solid tumors, and still produce the kind of results we’ve seen with thalidomide.

“Ultimately, if the regimen proves safe and effective, we hope that it will offer a life-extending treatment option to men with metastatic castration-resistant prostate cancer,” he added.

For More Information
See the lists of eligibility criteria and trial contact information or call the NCI Clinical Trials Referral Office at 1-888-NCI-1937. The call is toll free and confidential.

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

FDA Update

Leukemia Drug Pulled from U.S. Market

At the FDA’s request, Pfizer Inc. voluntarily withdrew the drug gemtuzumab ozogamicin (Mylotarg) from the U.S. market on June 21. The monoclonal antibody was approved in 2000 to treat patients age 60 and older with recurrent acute myeloblastic leukemia (AML) who were not considered candidates for other chemotherapy. Results from a phase III clinical trial begun in 2004 now show an increased risk of death in patients who received gemtuzumab ozogamicin compared with patients who received standard chemotherapy. The drug has also been associated with veno-occlusive disease, a potentially fatal condition in which small veins in the liver become blocked.

“Mylotarg was granted an accelerated approval to allow patient access to what was believed to be a promising new treatment for a devastating form of cancer,” said Dr. Richard Pazdur, director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. “However, a confirmatory clinical trial and years of postmarketing experience with the product have not shown evidence of clinical benefit in patients with AML.”

New Treatment Approved for Advanced Prostate Cancer that Resists Docetaxel

The FDA has approved a new drug, cabazitaxel (Jevtana), for patients with advanced, hormone-refractory prostate cancer that has progressed during or after treatment with docetaxel (Taxotere). The drug is approved for use in combination with prednisone, a steroid that is often used in this setting. The approval on June 18 was granted under the FDA’s priority review program, which shortens the agency’s analysis to 6 months for drugs that may offer major advances in treatment or provide a treatment when no adequate therapy exists; in fact, this review was accomplished in 11 weeks, said the FDA’s Dr. Richard Pazdur.

The approval was based on the results of the international TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer) trial, which were presented earlier this year at ASCO’s Genitourinary Cancers Symposium. The study compared cabazitaxel head-to-head with mitoxantrone (both used in combination with prednisone) and showed about a 30-percent reduction in the risk of death.

Nilotinib Approved to Treat Rare Form of Chronic Myeloid Leukemia

The FDA has approved the drug nilotinib (Tasigna) to treat newly diagnosed patients with a rare blood cancer, Philadelphia chromosome-positive, chronic-phase chronic myeloid leukemia. Nilotinib was originally approved in 2007 to treat patients whose disease had progressed or who could not tolerate other therapies, such as imatinib.

“It is important for companies to continue developing oncology drugs for earlier stages of [a] disease once they have demonstrated clinical effectiveness in resistant forms of [the] cancer…an approach [that] has the potential to increase the availability of an effective treatment to more patients,” said Dr. Richard Pazdur of the FDA.

The agency took less than 6 months to make this decision under their accelerated approval program, evaluating the safety and effectiveness of nilotinib in a trial using a surrogate endpoint to predict clinical benefit, in this case the number of CML cancer cells in the blood stream. After 1 year of treatment, 44 percent of patients who received nilotinib experienced this “major molecular response” compared with 22 percent of those who received imatinib.

HHS Update

ODPHP Releases Health Literacy Guide

The Department of Health and Human Services’ Office of Disease Prevention and Health Promotion has published Health Literacy Online, a research-based how-to guide for creating health Web sites and Web content for the millions of Americans with limited literacy skills and limited experience using the Web. The strategies in this guide complement accepted principles of good Web design and have the potential to improve the online experience for all users, regardless of their literacy skills.

The guide is written for Web designers, Web content specialists, and other public health communications professionals and includes six chapters on how to:

  • Deliver online health information that is actionable and engaging
  • Create a health Web site that’s easy to use, particularly for people with limited literacy skills and limited experience using the Web
  • Evaluate and improve a health Web site with user-centered design

Cancer.gov Update

DCB Launches Updated Web Site

Screenshot of DCB Web site

NCI’s Division of Cancer Biology (DCB) recently released its newly redesigned and updated Web site. DCB supports and coordinates research projects in basic cancer biology at universities and other research institutions across the United States and abroad.

The site features enhanced resources, including live searches of grant funding opportunities supported by DCB and across NCI, access to information regarding DCB’s current funded research, and guidance on valuable research resources available to investigators from the Division and NCI. Overviews of major scientific programs managed by DCB, including the Mouse Models of Human Cancers Consortium, the Integrative Cancer Biology Program, and the Tumor Microenvironment Network are included on the site as well. Specific scientific topics managed by DCB and the staff contacts for these areas and general questions also are available.

The Web site was redesigned with researchers in basic cancer biology in mind, but the improved layout and access to DCB initiatives, personnel, and grant opportunities, as well as information about DCB’s mission, make it a valuable site for anyone interested in NCI’s efforts in basic cancer biology.

Notes

Fourth Telephone Workshop for Cancer Survivors Slated for July 13

The final telephone workshop in NCI’s annual “Living With, Through, and Beyond Cancer” series will be held July 13 from 1:30 to 2:30 p.m. EDT. Part IV of the series is titled “Survivors Too: Communicating With and Among Family, Friends and Loved Ones.”

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

Speakers for the July 13 workshop include Suzanne Martz-Dones of Montefiore Medical Center, Dr. Laurel Northouse of the University of Michigan Comprehensive Cancer Center, and Dr. Frances Lewis of the University of Washington.

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

If you missed parts I, II, or III of the series, recordings are available online via podcast.

NCI Program Will Aid Development and Validation of Trial Assays

NCI’s Division of Cancer Treatment and Diagnosis has established a new program called the Clinical Assay Development Program (CADP) to aid the development and validation of clinical assays used in clinical trials. These assays are often integral components of phase III and large phase II clinical trials. NCI has issued a request for proposals (RFP) to identify laboratories that can help in the development of these assays.

The laboratories that enroll in this program must have expertise in one or more of the following technologies: immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), in situ hybridization, quantitative reverse transcription-polymerase chain reaction (RT-PCR), quantitative PCR, and DNA sequencing. Additional technologies may be required in the future.

Using reference sets of specimens, the labs that will comprise the clinical assay development network will assess reproducibility, robustness, inter- and intra-laboratory variability, and other relevant measures of assay performance and utility.

NCI’s Program for the Assessment of Clinical Cancer Tests (PACCT) has contributed significantly to progress in the field of biomarker development and clinical application. More information is available about this program and how to access the RFP, which closes on July 23.

Budget, Clinical Trials, and Training Highlighted at NCAB Meeting

The National Cancer Advisory Board’s (NCAB) second meeting of 2010 was held in Bethesda, MD, on June 22–23. NCI Director Dr. John Niederhuber provided an update on the NCI budget, including plans for the fourth quarter of FY2010.

NCAB members also discussed the recent Institute of Medicine report on the National Cancer Clinical Trials System and heard presentations on the NCI Operational Efficiency Working Group and NCI’s training programs.

The agenda and a videocast of the meeting are now available.

NCI Scientists Awarded 2010 Federal Laboratory Consortium Awards

Three NCI technologies and the inventors were awarded the Federal Laboratory Consortium for Technology Transfer’s (FLC) 2010 Technology of the Year Award on April 29. This award recognizes those who have done an outstanding job in transferring technology developed in a Federal laboratory to partners in the private sector, and is awarded to only a few of the hundreds of Federal laboratories, research centers, and facilities represented by the FLC.

Dr. Donald Court and Nina Costantino of the Gene Regulation and Chromosome Biology Laboratory in NCI’s Center for Cancer Research were recognized for their work in the development of a recombination-mediated genetic engineering, or recombineering, technology. The technology has revolutionized genetic engineering techniques, including modifying genes used for cloning and generating knockout mice where an existing gene is replaced or disrupted in order to study what the gene normally does. Over 1,100 nonprofit researchers have received the technology thus far and it has been licensed to 18 commercial entities.

Dr. Jeffrey Schlom, chief of CCR's Laboratory of Tumor Immunology and Biology, was recognized for his work on a new therapeutic prostate cancer vaccine, PROSTVAC. The vaccine induces a specific, targeted immune response that attacks prostate cancer cells. Numerous clinical trials have shown that the vaccine has a good safety profile and may be an effective option for the treatment of advanced prostate cancer. The vaccine is being developed through a Cooperative Research and Development Agreement and license partnership with BN ImmunoTherapeutics.

Drs. Frederic Kaye, Adi Gazdar, John Minna, and Bruce Johnson, formerly of CCR’s Genetics Branch, were recognized for their contributions toward the development of a cell line bank of approximately 439 human tumors. The cell lines contain a mutation that makes them sensitive to the presence of growth-inhibiting drugs and are valuable research tools for identifying compounds with therapeutic potential against cancer. These cell lines have been the subject of more licenses than any other biological material at NCI and can be used by scientists to screen thousands of compounds for anticancer activity.

Finally, as noted earlier this year, CCR Director Dr. Robert H. Wiltrout was named FLC’s Lab Director of the Year and received the award at the FLC national meeting on April 29.

PARADE Magazine Spotlights Cancer in America

The cover of the June 20 PARADE magazine

On June 20, PARADE magazine devoted its weekly edition to a special report on cancer. Among those contributing to the periodical was NIH Director, Dr. Francis Collins. His article, entitled “The Cancer You Can Beat,” highlights scientific progress against colorectal cancer.

PARADE is a staple in over 500 newspapers across the United States, reaching about 32 million Americans each Sunday.

NCI and Chinese Academy of Medical Sciences Host caBIG Workshop

On June 22, NCI held an educational workshop showcasing efforts to share biomedical data among institutions in the United States and China featuring NCI’s cancer Biomedical Informatics Grid (caBIG). The NCI Center for Bioinformatics and NCI’s Office of China Cancer Programs (OCCP) led the workshop planning for the Institute. The workshop took place in Beijing and was hosted by the Chinese Academy of Medical Sciences (CAMS).

Dr. Kenneth Buetow, director of NCI’s Center for Biomedical Informatics and Information Technology (CBIIT), delivered a welcome address by video message. John Speakman, associate director of Clinical Products and Programs for CBIIT, and Sorena Nadaf, director of Translational Informatics at UCSF Helen Diller Family Comprehensive Cancer Center, discussed how caBIG tools are used to manage clinical trial and biospecimen data.

In addition to an introduction to caBIG, attendees learned about national data sharing efforts in China led by CAMS, joint initiatives planned between Peking Union Medical College and UCSF, and a collaborative clinical research study between Duke University and Peking University that is using caBIG tools to support data exchange and analysis. Participants also discussed opportunities for implementing new U.S.–China cooperation using caBIG tools in scientific areas, including cancer epidemiology and biobanking. Dr. Julie Schneider, OCCP Program Director, noted, “Developing technical platforms through initiatives such as caBIG to encourage a culture of biomedical data sharing is critical to advancing research partnerships between scientists working in the United States, China, and around the world.”