National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
August 7, 2012 • Volume 9 / Number 16

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NEWS

Using New Approach, Scientists Find Evidence for Cancer Stem Cells

Breast cancer tissue from a woman who had a BRCA1 mutation, with breast cancer stem cells in red and estrogen receptors in brown. (Courtesy of University of Michigan Comprehensive Cancer Center) With the help of genetic tools, researchers have identified subsets of cells that appear to drive the growth of tumors in mice. The findings, from three independent studies, provide new support for the cancer stem cell hypothesis—the idea that some tumors are sustained by self-renewing cells that give rise to all types of tumor cells. Two of the studies appeared August 1 in Nature, and the third was published on the same day in Science. Read more > >

COMMENTARY

Dr. Walter Willett

A Conversation with Dr. Walter Willett about Diet and Cancer

The chair of the department of nutrition at the Harvard School of Public Health talks about how research has changed views of diet and cancer over the last 40 years. 

A MESSAGE TO READERS

NCI Cancer Bulletin Publication Break

The NCI Cancer Bulletin will not be published on August 21. Our next issue will be released on September 4, when we resume our usual biweekly publication schedule. If you are not yet a subscriber, please submit your e-mail address in the toolbox at the top right-hand corner to begin your free subscription.

IN DEPTH

UPDATES

  • FDA Update

    • New Drug Approved for Metastatic Colorectal Cancer
    • Everolimus Approved for Treating Some Breast Cancers
    • Carfilzomib Approved for Advanced Multiple Myeloma
  • CDC Update

    • Drop in Cigarette Smoking Offset by Rise in Use of Other Forms of Smoked Tobacco
  • Cancer.gov Update

    • New Research Tool Estimates Risk of Radiation-Related Cancers
  • Notes

    • Fraumeni Steps Down as Director of NCI's Division of Cancer Epidemiology and Genetics
    • NCI Releases New Guidelines for National Clinical Trials Network
    • Procedures for Collecting Human Biospecimens Released


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

Using New Approach, Scientists Find Evidence for Cancer Stem Cells

Breast cancer tissue from a woman who had a BRCA1 mutation, with breast cancer stem cells in red and estrogen receptors in brown. (Courtesy of University of Michigan Comprehensive Cancer Center)Breast cancer tissue with a BRCA1 mutation, showing stem cells in red and estrogen receptor in brown. A cluster of expanded stem cells on left shows decreased estrogen receptor expression compared with normal lobules on right. (Courtesy of University of Michigan Comprehensive Cancer Center)

With the help of genetic tools, researchers have identified subsets of cells that appear to drive the growth of tumors in mice. The findings, from three independent studies, provide new support for the cancer stem cell hypothesis—the idea that some tumors are sustained by self-renewing cells that give rise to all types of tumor cells. Two of the studies appeared August 1 in Nature, and the third was published on the same day in Science.

Each research group used the genetic tools to "label" tumor cells and track their ancestry in a different mouse model. The results of each study suggested that at least some tumors contain certain populations of cells that drive the growth and survival of the tumor. These would be the cancer stem cells, also known as tumor-initiating cells.

"The three studies provide nice additional support for the cancer stem cell hypothesis," said Dr. Max Wicha, director of the University of Michigan Comprehensive Cancer Center and a cancer stem cell researcher who was not involved in the three studies. "They are technically challenging and very well done." 

Resisting Chemotherapy

The authors of one of the Nature reports identified a population of brain tumor cells that appeared to allow brain tumors to grow back after treatment with the drug temozolomide. The drug initially depleted proliferating cancer cells, slowing tumor growth. But it did not harm a population of less active cells—the cancer stem cells. As a result, the tumors recurred.

"We think this is a clear and rigorous demonstration that the cancer stem cell hypothesis is alive and well in at least one solid tumor," said lead researcher Dr. Luis F. Parada of the University of Texas Southwestern Medical Center in Dallas. "Time will show how frequently this type of tumor mechanism holds true for other solid tumors."

A second study in Nature identified distinct populations of cancer cells in a mouse model used to investigate the development of skin tumors. Consistent with the cancer stem cell hypothesis, a relatively small population of long-lived tumor cells ultimately gave rise, during tumor growth, to progeny cells that made up a substantial part of the tumor.

"The new method of tracking the fates of tumor cells in situ has demonstrated the existence of cancer stem cells that fuel the growth of tumors in vivo," lead investigator Dr. Cedric Blanpain of the Université libre de Bruxelles wrote in an e-mail message.

The third study, in Science, found evidence of cancer stem cells in precancerous intestinal lesions in mice. Although all three studies point to the existence of cancer stem cells, the relevance of the mouse findings to human cancers is not yet known.

Moving the Field Forward

First discovered in leukemia, cancer stem cells have since been reported in solid tumors such as brain, breast, and colon cancers. Evidence for their existence has come primarily from experiments in which only a small proportion of human tumor cells are able to proliferate extensively and to form new tumors when transplanted into mice.

But factors other than cancer stem cells could explain the formation of new tumors from only certain transplanted cells, researchers have argued. Whether tumors form in mice may depend on how the transplantation was done and the type of mouse model used in the experiment.

There are too many variables to be able to draw firm conclusions about cancer stem cells from these transplantation experiments, noted Dr. Parada. The emergence of genetic tools used to tag tumor cells offered a chance to study potential cancer stem cells in their natural environments.

"The new studies put to rest the idea that you see cancer stem cells only if you perturb the human tumor and transplant it into an animal," said Dr. Wicha. "[These new findings] will move the field forward."

The results also suggest that the same pathways used in normal tissue development may be active in tumor development. "The cellular hierarchy found in early tumor progression is a corruption of the cellular hierarchy found in normal tissue," Dr. Blanpain noted.

Clinical Implications

The concept of cancer stem cells has potential implications for treatment. If these cells exist in human tumors, they would need to be eradicated to achieve long-term survival. The new studies suggest that "to cure a cancer you have to be able to identify and target the cancer stem cells," said Dr. Parada.

Several dozen clinical trials are already testing approaches to target cells with stem-cell-like properties in patients, according to Dr. Wicha. Yet, even with the new findings, cancer stem cells are likely to remain controversial. As Dr. Wicha noted, however, this is not necessarily a problem.

"Controversy is healthy, and questions about cancer stem cells are good for science," he said, adding, "There will always be controversies in the field."

The study led by Dr. Parada was funded in part by the National Institutes of Health (R01 CA131313).

Edward R. Winstead

Further reading: "The Evolving Science of Cancer Stem Cells" and "Tweaking and Testing Cancer Stem Cell Models"

Cancer Research Highlights

Trial Suggests New Treatment Option for Some Women with Metastatic Breast Cancer

Results from a phase III clinical trial suggest that, for some women with metastatic breast cancer, combining two drugs that work in different ways to disrupt estrogen's ability to fuel cancer growth may delay disease progression and death. The results were published August 2 in the New England Journal of Medicine.

Several breast cancer specialists cautioned, however, that the trial results are not enough to change clinical practice and need to be confirmed.

In the trial, women with metastatic breast cancer treated with the aromatase inhibitor anastrozole (Arimidex) and the antiestrogen fulvestrant (Faslodex) had better progression-free and overall survival than women who were treated with anastrozole alone. Both drugs are already approved to treat metastatic breast cancer.

About 700 women took part in the NCI-funded trial, which was led by SWOG, formerly the Southwest Oncology Group. All of the women in the trial were postmenopausal, had hormone receptor-positive metastatic breast cancer, and had not been previously treated for metastatic cancer. Women in the combination group were given the standard dose of fulvestrant (500 mg) the first time they received it, followed by a lower dose (250 mg) for the remaining treatments. About 40 percent of the women in the anastrozole-only arm began to receive low-dose fulvestrant after their disease began to progress.

Median progression-free survival—the trial's primary endpoint—was 15.0 months in women who received both drugs and 13.5 months in women who received only anastrozole. Overall survival was 47.7 months in the combination therapy arm and 41.3 months in the anastrozole-only arm.

In general, toxic effects were relatively mild and did not differ greatly between the two groups. Nevertheless, 42 patients who received anastrozole alone, and 51 who received both drugs, experienced severe toxic effects, including musculoskeletal pain, flu-like symptoms, and difficulty breathing.

But the results are convincing, said lead investigator Dr. Rita Mehta of the University of California, Irvine, in an interview. "Fulvestrant and anastrozole should be standard for women who would qualify for the study," she said.

But Dr. Jung-Min Lee, of NCI's Medical Oncology Branch, stressed that overall survival was a secondary endpoint of the study and said that several questions need to be answered before the combination therapy is used in clinical practice. "We first have to define the population who might benefit most from the combination therapy," Dr. Lee said. "And we need more data to confirm the overall survival benefit."

The results also conflict with those from a similar international trial, called FACT, which found no difference in overall survival between women who received anastrozole and fulvestrant and women who received anastrozole alone. The trials had several major differences that likely explain the discrepant findings, Dr. Mehta said.

The FACT trial was smaller, she explained, included more women who had received prior tamoxifen (70 percent versus 40 percent), enrolled patients who had completed chemotherapy for earlier-stage disease within the previous 12 months, and was restricted to patients who had suffered a relapse. These differences in the study populations likely "enriched [the trial] for patients with relatively endocrine-resistant disease," she said.

This research was supported by grants from the National Institutes of Health (CA32102, CA38926, CA35431, CA35281, CA20319, CA04919, CA67575, CA58861, CA37981, CA46368, CA86780, CA46282, CA63848, CA12644, CA27057, CA95860, CA35119, CA46441, CA11083, CA45450, CA35178, CA13612, CA58882, CA45377, CA45807, CA58723, C14028, CA128567, CA22433, CA52654, CA45560, CA35261, CA073590, CA45808, CA35192, CA42777, CA16385, CA35176, CA63845, CA35128, CA35090, CA63844, CA76447, CA58416, CA63850, CA76462, CA35262, CA77202, and CCSRI155469).

U.S. Prostate Cancer Incidence Falls after Change in Screening Recommendations

Soon after an independent task force recommended against routine screening of men aged 75 and older for prostate cancer with the prostate-specific antigen (PSA) test, the incidence of early-stage prostate tumors in that population declined, a new analysis shows. The findings suggest that the revised recommendations led to a reduction in prostate cancer screening rates in older men.

The U.S. Preventive Services Task Force (USPSTF) conducted a systematic review of the medical literature and issued the recommendations in August 2008.

"There's a lot of skepticism that these types of recommendations will have an impact on practice patterns, but at least in this case it looks like there has been some [impact]," said study author Dr. David Howard of Emory University in an interview posted online.

For his analysis, published July 23 in Archives of Internal Medicine, Dr. Howard used data from more than 254,000 men with prostate cancer from NCI's Surveillance, Epidemiology, and End Results registry.

He hypothesized that if screening rates in men aged 75 and older fell, the incidence of early-stage prostate tumors, which are detected primarily by PSA-based screening, would also fall relative to the incidence of late-stage tumors and of early-stage tumors in younger men. "And that's exactly what I found," he said in the online interview.

Between 2007 and 2009, the incidence rate for early- and late-stage prostate tumors fell 25.4 percent and 14.3 percent, respectively, among men aged 75 and older. By contrast, the incidence rate for early-stage tumors dropped 15.2 percent among men aged 65 to 74, and 11 percent among men aged 30 to 64, over the same period.

Dr. Howard's conclusions differ from those of an earlier report that found that self-reported PSA screening rates in men aged 75 and older did not change between 2005 and 2010. Several factors may explain the discrepancy. For instance, "patients do not [always] accurately report receipt of PSA testing," he explained via e-mail, noting that physicians who stopped screening older men may not have discussed this decision with their patients.

Over time, a clearer picture should emerge of physicians' responses to revised screening recommendations. "Dr. Howard's data are interesting and relevant," commented Dr. Scott Eggener of the University of Chicago, senior author of the earlier study. "As with all self-reported or population-based data, it's important to replicate using multiple sources."

In a study that is still under review for publication, Dr. Howard also examined PSA testing rates directly using Medicare claims, which he noted are more reliable than patient self reports. He expects the findings from that study to be published soon.

Further reading: "U.S. Preventive Services Task Force Advises against PSA Screening"

Single HPV Test Predicts the Risk of Cervical Cancer for 18 Years

In a group of more than 20,000 women, the human papillomavirus (HPV) DNA test more accurately predicted the risk of developing cervical cancer over an 18-year follow-up period than the Pap test. Although both tests could identify women who were most likely to develop high-grade precancerous cervical lesions or squamous cervical cancers within 2 years of testing, only the HPV test result predicted the risk for women up to 18 years later.

Dr. Philip Castle of the American Society for Clinical Pathology and his colleagues reported their findings July 30 in the Journal of Clinical Oncology.

The authors, including researchers from NCI's Division of Cancer Epidemiology and Genetics (DCEG), used data from a study initiated by NCI and Kaiser Permanente of women who, in 1989 and 1990, underwent routine Pap testing in Portland, OR. Samples collected at the start of this study were used for Pap and HPV testing.  

Recently reported research from this group also showed that HPV testing could predict risk for 18 years, but those results were based on HPV tests that are used only in research settings. These new results are based on the type of HPV tests that are used in current clinical practice.

The researchers found that the HPV test more accurately stratified women by their risk of developing cervical cancer than the Pap test. Over the 18-year follow-up period, 199 women were diagnosed with cervical intraepithelial neoplasias grade 3 or cervical cancer (CIN 3+); more of these cases developed in those with a positive HPV test (112 women) than in women who had an abnormal Pap test (65 women). Conversely, fewer cases of CIN 3+ developed over the follow-up period in women with a negative HPV test at the start of the study than in women with a normal Pap test taken at the same time (87 women versus 134 women).

Current screening guidelines recommend that most women aged 30 to 65 be tested for high-risk HPV types in conjunction with a Pap test every 5 years.

DCEG's Dr. Sholom Wacholder, senior author on the study, said that data from the study showed that, for women aged 30 or older, the 3- and 5-year risks for precancer or cancer after a negative HPV test and negative Pap test were very low, consistent with the guidelines.

Risk of Developing Precancer or Cancer 
after Negative HPV and Pap Tests in Women Older than 30

  CIN 2+ CIN 3+
3-year risk0.23 percent0.08 percent
5-year risk0.36 percent0.16 percent

Recent reports have suggested that some doctors worry that if they offer HPV and Pap co-testing every 5 years in accordance with the new guidelines, women might go several more years between screenings.

"HPV testing is a powerful predictor of cervical cancer risk.  This work provides evidence to support extended screening intervals after negative HPV and Pap tests," said Dr. Wacholder. "The very low risk over 10 years in women with a single negative HPV test provides a reassuringly large margin of safety."

This research was supported in part by NCI's Intramural Research Program.

Discovery of Fused Genes in Brain Cancer Points to Possible Treatments

Researchers have found that a small percentage of glioblastoma brain tumors, one of the most lethal forms of cancer, harbors mutations in which portions of two genes are spliced together. The researchers also showed that although the aberrant proteins produced by these fusion genes can transform normal cells into cancer cells, the actions of these fusion genes can be blocked by two experimental drugs being tested for other cancers.

Their findings, published July 26 in Science, raise the possibility that a small subset of people with glioblastoma could be treated with drugs that specifically target the fusion proteins produced by the newly identified fusion genes.

A team led by Drs. Antonio Iavarone, Raul Rabadan, and Anna Lasorella of Columbia University Medical Center found that about 3 percent of the glioblastoma tumors they examined contain FGFR-TACC fusion genes. The fusion activates a tyrosine kinase enzyme whose altered activity has been found to promote tumor growth and survival in several cancer types.

The FGFR-TACC fusion proteins "have a potent pro-tumorigenic effect," Dr. Iavarone said. "That means that when we introduce this fusion [protein] into the brain, we can transform the normal brain cells into cancer cells," he explained. When the researchers put FGFR-TACC into brain cells of healthy mice, 7 of 8 mice died of malignant brain tumors that resembled human glioblastoma.

Additional experiments showed that the FGFR-TACC fusion protein disrupts the process that apportions chromosomes between two daughter cells during cell division. This results in a condition known as aneuploidy, in which cells have an abnormal number of chromosomes. Aneuploidy is a hallmark of cancer, Dr. Iavarone noted.

Finally, the researchers showed that compounds that block the kinase activity of the fusion protein can correct aneuploidy and stop the growth of glioma cells containing FGFR-TACC. These compounds also slowed tumor growth and prolonged survival of mice with malignant brain tumors caused by FGFR-TACC. Two of the compounds, AZD4547 and BGJ398, are being tested in early-stage clinical trials for other cancers, including lung cancer.

Based on these results, "we believe that there is a strong rationale to do a clinical trial where we would target tumors that harbor these gene fusions with these drugs," Dr. Iavarone said. He and his colleagues in the United States and Europe have formed a cooperative research group and begun talks with the drug manufacturers in hopes of moving forward with such a trial.

Further reading: "Common Cancers May Involve Fused Genes"

This research was supported by grants from the National Institutes of Health (R01CA101644, R01CA131126, R01CA085628, R01CA127643, U54 CA121852-05,1R01LM010140-01, R01NS061776).

A Conversation With

A Conversation with Dr. Walter Willett about Diet and Cancer

Dr. Walter WillettDr. Walter Willett

Dr. Walter Willett, chair of the department of nutrition at the Harvard School of Public Health, recently delivered a lecture titled "Diet & Cancer: The Fourth Paradigm" on the NIH campus in Bethesda, MD. An archived videocast of the lecture, sponsored by NCI's Cancer Prevention Fellowship Program, is available online. During his visit, Dr. Willett spoke with the NCI Cancer Bulletin.

How have views on diet and cancer evolved over the last 40 years?

When I started in this area in the 1960s, the thinking revolved around carcinogens in food. These were chemicals produced by high temperatures, such as with barbecuing, that had been shown to cause DNA mutations in animal models and test systems. In fact, this topic has not been totally resolved, but if carcinogens in food were a major problem for humans, we probably would have seen more evidence than we have. This was the first paradigm.

What were the second and third paradigms?

The second paradigm was the idea that fat in the diet is a major cause of cancer. There was never any strong evidence for this idea, but it was repeated so often that it became dogma in the 1980s and 1990s. For conditions such as heart disease and diabetes, the type of fat in the diet is quite important. But the hypothesis that the percentage of calories from fat in the diet is an important determinant of cancer risk, at least during midlife and later, is not supported by the data.

The third paradigm was that fruits and vegetables dramatically reduce risks of cancer. But, as the prospective data came in, the results just did not support this idea either. That's not to say there's no benefit from fruits and vegetables, but [the benefit is] probably very small and limited to certain foods and certain cancers. Overall, we just don't see a relationship.

That brings us to the fourth paradigm.

The fourth paradigm is that a major cause of cancer is excessive adiposity [obesity]. This paradigm, also referred to as positive energy balance, is here to stay, because the evidence is overwhelming from all types of studies. These findings have coalesced from research over the last 10 to 15 years, but the evidence to support this idea actually goes back to animal studies in the 1930s. In a sense, it was right there in front of us all the time.

Can you put the role of obesity and cancer risk in context?

On a population level, the number of cases of cancer attributable to people being overweight and obese is about equal to the number attributable to current smoking. This is in part because smoking is going down and obesity is going up; in terms of importance within a population, they are in the same ballpark. However, on an individual basis, the cancer risk due to smoking remains substantially higher than that due to obesity.

Are you looking for clues to obesity and cancer in younger people?

Yes, this is one of the new frontiers in cancer research. Until now, we've been looking at a pretty narrow period of life—essentially around the time people are getting cancer. But we have lots of epidemiologic hints that many factors operate earlier in life and maybe even across generations.

What are you learning?

For the first time, we are getting a pretty good look at the diets of adolescents and cancer incidence. In the Nurses' Health Study 3, we have retrospectively collected details about high school diets from participants, who were 25 to 42 years old at the time of enrollment. They weren't so far beyond their high school diets, so we have some data that is recalled pretty well.

In addition, we collected data from their mothers about their mothers' experiences with the pregnancy resulting in our participant and the participant's infant feeding patterns and diet and activity before age 5. We're just starting to get follow-up from that information. This approach can piece together the lifespan, which I think will be necessary for a thorough look at diet and cancer.

If money weren't a factor, what kind of study would you launch?

The most critical missing elements in the research right now are the dimensions of time—the time when we start the studies, and the length of follow up. The ideal study would start during pregnancy (perhaps even before) and would collect data about maternal diets and then continue to collect data and follow participants—in other words, a birth cohort.

Are these studies under way?

There have been some attempts in this country to develop a birth cohort that was big enough to look at cancer, but the studies sank under the weight of huge budgets. On the other hand, there are more than 300,000 participants in birth cohorts in Scandinavian countries. The next generations of scientists will be the ones to analyze the results in terms of cancer. I've been involved in this work and am hoping to see some of the results myself.  

—Interviewed by Edward R. Winstead

Further reading: "Energy Balance: Weight and Obesity, Physical Activity, Diet" and "Fact Sheets: Diet and Nutrition"

Featured Clinical Trial

Genetically Engineered Immunotherapy for Advanced Cancer

Name of the Trial
Phase I/II Study of Metastatic Cancer Using Lymphodepleting Conditioning Followed by Infusion of Anti-Mesothelin Gene Engineered Lymphocytes (NCI-12-C-0111). See the protocol summary.

Dr. Steven Rosenberg Dr. Steven Rosenberg

Principal Investigator
Dr. Steven Rosenberg, NCI Center for Cancer Research

Why This Trial Is Important
NCI researchers have been at the forefront of efforts to develop a type of immunotherapy called adoptive cell transfer (ACT). This kind of therapy involves collecting immune system cells from a patient, growing them in the laboratory to many times their original number, and then infusing the cells into the patient to fight his or her cancer. To ensure the survival and optimal functioning of the infused cells, the number of immune cells in the patient's body must be substantially reduced before the cell infusion. This type of preparatory treatment is called lymphodepletion or conditioning.

In one type of ACT, doctors obtain T lymphocytes from the patient's blood and then genetically engineer the cells to recognize and bind to a protein, or antigen, found on the surface of the patient's cancer cells, which will help activate the immune system against these cells. The genetically modified lymphocytes are then multiplied in the laboratory and infused into the patient, where, if the treatment works, they will kill cells that express the targeted antigen.

One potential antigen target is mesothelin, a protein found on normal cells (mesothelial cells) that make up the membranes that line the lungs, heart, and abdominal organs, as well as some other parts of the body. The amounts of this protein are often increased in malignant tumors, including almost all mesotheliomas and pancreatic adenocarcinomas and some types of lung, ovarian, esophageal, and head and neck cancers, making it an attractive target for immunotherapy.

Led by Dr. Steven Rosenberg, researchers in NCI's Center for Cancer Research are exploring the potential of genetically engineering peripheral blood T lymphocytes to recognize and attack cancer cells that express mesothelin.

In this phase I/II clinical trial, doctors will collect T lymphocytes from the blood of patients with metastatic or unresectable cancer that expresses mesothelin and has not responded to previous systemic therapy and genetically engineer these T lymphocytes to recognize mesothelin. The genetically modified cells will then be grown in culture to expand the number of cells, which will be infused into the patients after they have undergone lymphodepleting conditioning. The patients will also receive low-dose aldesleukin, which is a cytokine that will help keep the infused cells alive.

In the phase I part of this trial, groups of patients, called cohorts, will be treated with differing doses of infused lymphocytes to establish a maximum tolerated dose. The phase II part of the trial will involve treating patients with mesothelioma or other mesothelin-expressing cancers at the maximum tolerated dose. All patients will undergo treatment at the NIH Clinical Center in Bethesda, MD, where doctors will assess the safety and effectiveness of this therapy.

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.

Further reading: "Complex Immune-Based Cancer Treatment Shows Signs of Progress"

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

Community Update

Bringing Science to Cancer Survivors: Workshop Series Reaches a Milestone

Survivorship series icon

The Cancer Survivorship Series, "Living With, Through, and Beyond Cancer," recently concluded its 10th year, with record numbers of attendees participating in the teleconferences. For the past decade, the free workshop series has offered cancer survivors, their friends and families, and health care professionals practical information to help them cope with concerns and issues that arise after treatment ends.

More than 10,000 people participated in this year's series of four workshops, reported workshop co-moderator Dr. Carolyn Messner, director of Education and Training at CancerCare. Each hour-long session drew more than 3,000 callers.

Conceptual image of medical information by telephone

"I love listening to the calls," wrote one survivor in a workshop evaluation. "I feel as though the expert presenters—and the other survivors asking them questions—are speaking directly to me about issues that affect my life."

Another participant, who took part in a previous year's workshop on fatigue and methods for addressing sleep problems, commented, "I finally tried some of those mind-body techniques and they worked! They help me sleep better!"

NCI, along with the Lance Armstrong Foundation (now LIVESTRONG), originally joined CancerCare in establishing the survivorship series because "it allows us to feature some more cutting-edge science on a platform that has enormous reach," explained Dr. Julia Rowland, director of NCI's Office of Cancer Survivorship. "What it does brilliantly is not only features the science but also allows the scientific community to interpret their findings for a lay audience and thereby make them much more accessible to the public."

The teleconference workshops have drawn participants from more than two dozen countries. "I think the global reach of this program is really impressive and reflects the growing demand for this type of information around the world," Dr. Rowland continued.

The current planning committee is drawn from the three founding organizations, as well as from the other partner organizations: the American Cancer Society, the Intercultural Cancer Council, Living Beyond Breast Cancer, and the National Coalition for Cancer Survivorship.

Each workshop kicks off with a 30-minute presentation, starting with the perspective of a cancer survivor or caregiver, Dr. Messner said. For example, in this year's workshop on "Recapturing Joy and Finding Meaning," Dr. Keith Bellizzi, a 15-year cancer survivor who is also a researcher in survivorship studies at the University of Connecticut, contributed the survivor's perspective. "I shared my experience with cancer and discussed how understanding the meaning of the cancer experience was an important part of the healing process for me," he said.  

The survivor perspective is followed by brief presentations by two content experts who provide the latest evidence-based findings related to the workshop topic.

Discussions sparked by questions from workshop participants make up the remainder of each session. "We can't take everyone's questions, but we do take a fair number," Dr. Messner said. "We don't prescreen the questions, which is another thing that is really exciting about the program. We have to be prepared and think ahead of time what questions might be coming in and how we want to handle them."

For the rare questions that cannot be answered quickly by one of the workshop experts, callers are referred to the toll-free number for CancerCare (1-800-813-4673) or to the NCI Cancer Information Service (1-800-4-CANCER).

Suggestions and evaluations provided by attendees help guide the topics chosen for the next year's workshops, Dr. Messner noted. A few years ago, the series added a workshop to allow one workshop each year to be devoted to issues faced by caregivers. 

Topics and speakers for the 2013 Cancer Survivorship Series will be announced in December.

Bill Robinson

FDA Update

New Drug Approved for Metastatic Colorectal Cancer

The Food and Drug Administration approved ziv-aflibercept (Zaltrap) for use in combination with the FOLFIRI (leucovorin, fluorouracil, and irinotecan) chemotherapy regimen to treat some adults with colorectal cancer.

The drug is an angiogenesis inhibitor, which means it may prevent the development of tumor blood vessels. It is intended for patients with metastatic colorectal cancer whose tumors are resistant to or have progressed after an oxaliplatin-containing chemotherapy regimen.

“This approval demonstrates the benefits of adding a biological agent, Zaltrap, to a commonly used chemotherapy drug regimen, FOLFIRI,” said Dr. Richard Pazdur of the FDA’s Center for Drug Evaluation and Research in an August 3 news release. “An improvement in median survival time was noted with the addition of Zaltrap to FOLFIRI, accompanied by an improvement in response rate and a delay in tumor progression and growth.”

Ziv-aflibercept was evaluated in a randomized clinical trial of 1,226 patients with metastatic colorectal cancer whose cancers had progressed while they were receiving oxaliplatin-based combination chemotherapy. Participants who had relapsed within 6 months of completing oxaliplatin-based chemotherapy after surgery were also eligible, as were patients who had been treated with bevacizumab. Participants received treatment until their cancer progressed or side effects became unacceptable.

Half of the patients in the trial, called the VELOUR study, were randomly assigned to receive the ziv-aflibercept plus FOLFIRI combination, and the other half to receive FOLFIRI plus placebo. The study was designed to evaluate whether ziv-aflibercept improved overall survival. Patients who received ziv-aflibercept lived an average of 13.5 months, compared with an average of 12 months for those receiving the placebo.

Patients who received aflibercept also had better tumor responses: Tumors shrank in 20 percent of patients in the ziv-aflibercept group versus 11 percent of those in the placebo group.

Ziv-aflibercept also improved progression-free survival. Patients receiving the ziv-aflibercept combination lived without their cancer progressing for an average of 6.9 months, versus 4.7 months for those receiving the placebo.

Ziv-aflibercept was approved with a boxed warning that the drug can cause severe and sometimes fatal bleeding, including gastrointestinal bleeding, and holes in the gastrointestinal tract. The warning also states that the drug can compromise wound healing.

The most common side effects observed in patients receiving ziv-aflibercept plus FOLFIRI were decreased white blood cell count, diarrhea, mouth ulcers, fatigue, high blood pressure, increased amount of protein in the urine, weight loss, decreased appetite, abdominal pain, and headache.

Everolimus Approved for Treating Some Breast Cancers

The Food and Drug Administration (FDA) has approved the drug everolimus (Afinitor) in combination with exemestane (Aromasin) to treat certain postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer.

The treatment is intended for women whose disease has progressed after treatment with letrozole (Femara) or anastrozole (Arimidex), according to a July 20 FDA news release.

Everolimus is also approved for treating some patients with advanced renal cell carcinoma, progressive advanced pancreatic neuroendocrine tumors, or the benign brain tumor called subependymal giant cell astrocytoma.

The new approval was based on a clinical trial that showed a 4.6-month improvement in median time to disease progression or death in women who received everolimus and exemestane compared with women who received exemestane and a placebo.

Everolimus prevents cell proliferation and the formation of tumor blood vessels by inhibiting the mammalian target of rapamycin (mTOR) signaling pathway.

The most common side effects in patients receiving everolimus for breast cancer were mouth ulcers, infections, rash, fatigue, diarrhea, and decreased appetite. The FDA cautioned that patients who are aged 65 and older should be monitored closely because they are more likely to have more serious side effects than younger patients.

Carfilzomib Approved for Advanced Multiple Myeloma

The Food and Drug Administration (FDA) has approved carfilzomib (Kyprolis) to treat patients with multiple myeloma whose disease has progressed after at least two prior therapies, including bortezomib (Velcade) and an agent that modulates the immune system such as thalidomide.

Carfilzomib binds to and inhibits enzymes called proteasomes, which degrade cellular proteins. Inhibiting this process leads to cell death and blocks tumor growth.

The July 20 approval was based on the response rate observed in a single-arm study of 266 patients with multiple myeloma who had received at least two prior therapies. One patient taking carfilzomib had all signs of cancer disappear (complete response) and 60 others saw their tumors shrink (partial response), resulting in an overall response rate of 22.9 percent. The median length of time patients responded to carfilzomib was 7.8 months.

Common side effects (observed in more than 30 percent of patients) included fatigue, nausea, anemia, lower-than-normal numbers of red blood cells or platelets, shortness of breath, diarrhea, and fever. Serious adverse reactions were reported in 45 percent of patients. The most common of these were pneumonia, acute kidney failure, fever, and congestive heart failure. The risk of peripheral neuropathy is less with carfilzomib than with similar drugs already on the market, such as bortezomib.

Carfilzomib was approved through the FDA’s accelerated approval program, which allows the agency to approve a drug based on clinical data demonstrating a drug’s effect on a surrogate endpoint, such as response rate, that is likely to predict its benefit to patients. The manufacturer, Onyx Pharmaceuticals, must submit additional data that confirm the drug’s clinical benefit.

CDC Update

Drop in Cigarette Smoking Offset by Rise in Use of Other Forms of Smoked Tobacco

Consumption of all smoked tobacco products in the United States fell by more than one-quarter between 2000 and 2011. But the drop in cigarette smoking was partly offset by a rise in consumption of other smoked tobacco products. These findings appeared August 3 in Morbidity and Mortality Weekly Report.

Researchers from the Centers for Disease Control and Prevention (CDC) analyzed data from the U.S. Department of the Treasury's Alcohol and Tobacco Tax and Trade Bureau to calculate consumption of cigarettes, loose tobacco, and cigars. Although cigarette smoking declined by 32.8 percent from 2000 to 2011, the use of certain other smoked tobacco products more than doubled during that time. The largest increases were in pipe tobacco (482 percent) and large cigars (233 percent).

Last year alone, total consumption of non-cigarette smoked tobacco products rose more than 17 percent. That jump offset much of the decline in cigarette smoking. As a result, total smoked tobacco consumption fell a mere 0.8 percent in 2011, compared with 3.8 percent in 2010. 

U.S. Consumption of Cigarettes and Other Combustible Tobacco Products, 2001–2011

Graph showing consumption of cigarettes and other combustible tobacco products in the United States during 2001-2011

The CDC report cited two explanations for the increases in consumption of non-cigarette smoked tobacco products. Such products are taxed at substantially lower rates, making them a cheaper alternative to manufactured cigarettes.

In addition, the products are subject to fewer manufacturing and marketing restrictions than cigarettes. For example, the Food and Drug Administration prohibits the use of flavoring or misleading descriptors such as "light" or "low tar" in cigarettes, but cigars and loose tobacco are not subject to these restrictions.

"The availability of low-priced and less-regulated alternative products to smokers who might have otherwise quit smoking has diminished the public health impact that excise tax increases and uniform regulation might otherwise have had on preventing youth initiation, reducing consumption, and prompting quit attempts," the CDC authors wrote.

"The smoke from non-cigarette combustibles contains the same toxic and cancer-causing chemicals as cigarette smoke," added Dr. Yvonne Hunt of NCI's Tobacco Control Research Branch. "The increase in consumption of these tobacco products is concerning. There is no safe level of exposure to tobacco smoke in any form." 

Cancer.gov Update

New Research Tool Estimates Risk of Radiation-Related Cancers

NCI has released the first online radiation risk assessment tool, RadRAT, for use by researchers. The tool can be used for estimating an individual’s lifetime risk of radiation-related cancers. A description of the tool and how it was developed appeared July 19 in the Journal of Radiological Protection.

RadRAT uses risk models based largely on those for low-dose radiation exposures developed by the National Academy of Sciences’ Biological Effects of Ionizing Radiation (BEIR VII) committee.

The BEIR VII models estimate risk for 11 cancers: stomach, colon, liver, lung, breast, uterus, ovary, prostate, bladder, thyroid, and leukemia. RadRAT estimates risk for these cancers and seven more: oral, esophagus, gallbladder, pancreas, rectum, kidney, and brain/central nervous system. The risk estimates for the seven additional cancers are based on data from Japanese atomic bomb survivors.

The tool is most appropriate for research related to radiation doses of less than 1 gray (Gy; a unit of estimated absorbed dose of ionizing radiation) and for individuals with life-expectancy and cancer rates similar to those in the U.S. population, according to Dr. Amy Berrington de Gonzalez of NCI’s Division of Cancer Epidemiology and Genetics, who led the team that developed RadRAT.

“This is a valuable tool for researchers, as it can provide risk estimates with uncertainty intervals for complex exposure histories from sources such as CT scans and dental x-rays to environmental radiation and nuclear accidents,” said Dr. Berrington de Gonzalez. “It covers any external low-dose radiation exposure.” 

Notes

Fraumeni Steps Down as Director of NCI's Division of Cancer Epidemiology and Genetics

Dr. Joseph F. Fraumeni, Jr. Dr. Joseph F. Fraumeni, Jr.

Dr. Joseph F. Fraumeni, Jr., the founding director of NCI's Division of Cancer Epidemiology and Genetics (DCEG), stepped down from the position last month, after marking 50 years at NCI. He will remain at NCI as a senior investigator and advisor.

Dr. Fraumeni received his undergraduate degree from Harvard College, an M.D. from Duke University, and an M.Sc. in epidemiology from the Harvard School of Public Health. After completing a medical residency at Johns Hopkins Hospital and the Memorial Sloan-Kettering Cancer Center, he joined NCI in 1962 as a commissioned officer in the U.S. Public Health Service.

Through his years of leadership at NCI, Dr. Fraumeni developed an epidemiologic and interdisciplinary research program to identify the environmental and genetic determinants of cancer and the means of cancer prevention. Among his many research accomplishments was the discovery with Dr. Frederick P. Li of a familial constellation of multiple cancers, now known as Li-Fraumeni syndrome, which led to collaborative studies that uncovered inherited mutations in the p53 tumor suppressor gene

Another seminal contribution was his creation of maps depicting geographic variation in cancer mortality at the county level. This allowed Dr. Fraumeni and his colleagues to develop a way to identify several environmental and lifestyle exposures driving the distinctive patterns of certain malignancies. 

While building the intramural research and fellowship programs in epidemiology at NCI, Dr. Fraumeni emphasized collaborative research that incorporates new and emerging molecular technologies into population and family-based studies. These studies are helping to dissect the genetic and environmental components of cancer, along with their effects on the origins and progression of cancer.  

Dr. Fraumeni has authored more than 850 scientific publications, including the textbook Cancer Epidemiology and Prevention, co-edited by Dr. David Schottenfeld. Dr. Fraumeni has received numerous honors, including membership in the National Academy of Sciences, the Institute of Medicine, the Association of American Physicians, and the American Academy of Arts and Sciences.

Dr. Margaret A. Tucker, director of the Human Genetics Program in DCEG, is serving as acting director until a permanent director is selected.

NCI Releases New Guidelines for National Clinical Trials Network

In a continuing effort to improve the efficacy and efficiency of NCI's clinical trials program, the institute has released new guidelines for its restructured National Clinical Trials Network (NCTN). The guidelines are intended to encourage a consistently excellent clinical trials program executed by an integrated network of groups that conduct treatment and imaging trials across a broad range of diseases and diverse patient populations. (Read more about the NCTN here.)

The guidelines describe the NCTN program and its policies and procedures, including the terms and conditions of awards; the application format and peer review processes for new funding applications; and the application format for noncompeting continuation applications.

To help investigators understand the new guidelines, NCI is holding several Q&A sessions in August. For information on registering for a session, go online.

  • For Operations Center, Statistics/Data Management Center, Integrated Translational Science Center, and Canadian Collaborating Clinical Trials Funding Opportunity Announcements (FOA):
    Friday, August 10, 1:00–2:30 p.m. ET
    Friday, August 17, 1:00–2:30 p.m. ET
  • For Network Lead Academic Participating Site FOA:
    Friday, August 10, 3:00–4:30 p.m. ET
    Friday, August 17, 3:00–4:30 p.m. ET
  • For Network Radiotherapy and Imaging Core Services Centers FOA:
    Thursday, August 9, 3:00–4:00 p.m. ET
    Thursday, August 16, 3:00–4:00 p.m. ET

Procedures for Collecting Human Biospecimens Released

Preparing biospecimens for molecular analyte extraction Preparing biospecimens for molecular analyte extraction

NCI's Office of Biorepositories and Biospecimen Research's (OBBR) cancer Human Biobank (caHUB) program has released a collection of standard operating procedures (SOPs) that guide the successful collection of postmortem normal human biospecimens for the NIH Genotype-Tissue Expression (GTEx) project. 

Successful collection of normal human biospecimens from organ and tissue donors requires complex operations and stringent quality assurance and control processes. For this reason, caHUB has created SOPs to govern the following areas:

  • Ethical and regulatory procedures
  • Biospecimen collecting and tracking
  • Data collection, validation, and management
  • Logistics management
  • Pathology review

Although these SOPs apply specifically to GTEx, they can serve as a model for other scientists wishing to collect high-quality biospecimens for experimental purposes from postmortem donors. 

For questions or comments about these SOPs, please contact: nciobbr@mail.nih.gov