COMMENTARY

Dr. Otis Brawley

The Benefits and Harms of Cancer Screening

by Dr. Otis Brawley

In the United States, we are bombarded with information on cancer screening. Radio advertisements try to lure people to clinics by touting the benefits of lung cancer screening. Some cancer advocacy groups encourage prostate or breast cancer screening. And the media emphasizes the benefits of screening. But many people do not understand the complexity of cancer screening. Read more >>

Dr. Virginia Moyer

A Conversation with Dr. Virginia Moyer, Chair of the U.S. Preventive Services Task Force

The United States Preventive Services Task Force (USPSTF) generates evidence-based recommendations about clinical preventive services, including cancer screening. The chair of the USPSTF spoke with the NCI Cancer Bulletin about the task force's mandate, challenges, and lessons learned.

FEATURES

MULTIMEDIA

NEWSSUPPLEMENT TO THE SPECIAL ISSUE

UPDATESSUPPLEMENT TO THE SPECIAL ISSUE

  • HHS Update

    • Launch of New Online Resource: BeTobaccoFree.gov
  • CDC Update

    • New Statistics on Breast Cancer Incidence and Mortality Show Disparities, Opportunities
  • Notes

    • NCI's Steven Rosenberg Awarded Keio Medical Science Prize
    • NCI Advisory Committee on Clinical Trials Will Meet Friday
    • AccrualNet Website Gets New Look

A MESSAGE TO READERS

NCI Cancer Bulletin Special Issues

This issue of the NCI Cancer Bulletin focuses on the science behind cancer screening. Other recent special issues have covered diverse research topics, including oncology nursing, obesity and cancer research, and adolescent and young adult cancers.

To read other special issues, please visit the special issues archive.


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

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Guest Commentary by Dr. Otis Brawley

The Benefits and Harms of Cancer Screening

Dr. Otis Brawley
Dr. Otis Brawley

In the United States, we are bombarded with information on cancer screening. Radio advertisements try to lure people to clinics by touting the benefits of lung cancer screening. Some cancer advocacy groups encourage prostate or breast cancer screening. And the media emphasizes the benefits of screening. But many people do not understand the complexity of cancer screening. Nor do they know that most expert organizations recommend that patients be aware of the potential risks and benefits of a screening test.

Screening is looking for cancer in an asymptomatic individual only because he or she is the age or gender of people at risk for the disease.

While the wise use of screening tests can save lives, and screening is one important element in the 20 percent decline in the cancer death rate over the last 20 years, screening is complicated.

As a screening expert, I worry that many people view these issues too simplistically. Cancer screening should be practiced with some caution. In assessing the science behind common screening tests, most expert panels have advised that the patient be told about the potential risks and benefits associated with a screening test, as well as the diagnostic tests and treatments associated with a positive result.

Patients should understand that no screening test is 100 percent accurate. Any test will miss some cancers. For example, high-quality mammography misses at least 20 percent of tumors, and prostate cancer screening misses at least half of all prostate cancers. Screening can also cause anxiety. And, in rare cases, screening can lead to treatment and diagnostic interventions that can even cause an early death.

In some cases, screening can find an early cancer, yet still lead to unnecessary treatment and all of the side effects associated with the treatment. These cancers are overdiagnosed. They fulfill all the criteria for cancer and look like cancer under a microscope, but if left alone they will not progress and kill. Some studies suggest that about one-third of screen-detected localized breast cancers and up to 70 percent of localized prostate cancers are overdiagnosed. A number of other cancers, especially cancers of the thyroid and lung, are also overdiagnosed.

Because of overdiagnosis, greater survival time after diagnosis or larger proportions of patients alive 5 years after diagnosis are not necessarily evidence of benefit from screening. This is because some patients might have been overdiagnosed, and some patients may have been diagnosed earlier but not lived longer. (See “Crunching the Numbers:What Cancer Screening Statistics Really Tell Us.”)

Nevertheless, screening is an important part of the effort to reduce the number of lives lost to cancer. And, as this special issue of the NCI Cancer Bulletin highlights, a tremendous amount of research focused on improving the effectiveness and efficiency of cancer screening is under way.

Many investigators, for example, are developing the next generation of screening tests for a host of cancers. This is painstaking research that requires patience and perseverance, but the progress to date is encouraging.

Other researchers are trying to solve one of the most persistent and pernicious problems in cancer care—and our health care system as a whole: disparities. Any gynecologic oncologist will tell you that Pap and HPV testing can prevent cervical cancer. But they will also tell you that they are treating too many women—in many cases, African American women or those without health insurance—with late-stage cervical cancer who were inadequately screened or never screened at all. An innovative program, called PROSPR, is aimed at reversing that trend by improving the entire cancer screening process, with a particular focus on underserved populations.

Another effort, called CISNET, is using sophisticated computer modeling to find how best to extrapolate the results of cancer screening studies, including large randomized trials, to the general population. This work includes a deeper analysis of the results of the National Lung Screening Trial, a study that focused on people at high risk for lung cancer based on their smoking history.

This special issue of the NCI Cancer Bulletin also includes several discussions with noted screening experts about interpreting cancer screening statistics and how we think and talk about screening, especially during conversations between patients and physicians.

The breadth of the research being done to improve how we screen for cancer is extremely encouraging. Although progress may not always come as quickly as we might like, given the expertise and dedication of investigators working in this area, the future holds great promise.

Dr. Otis W. Brawley
Chief Medical and Scientific Officer, American Cancer Society
Professor of Hematology, Medical Oncology, Medicine, and Epidemiology, Emory University

A Conversation With

A Conversation with Dr. Virginia Moyer, Chair of the U.S. Preventive Services Task Force

Dr. Virginia Moyer
Dr. Virginia Moyer

The United States Preventive Services Task Force (USPSTF) generates evidence-based recommendations about preventive health services, including cancer screening. Mandated by Congress, the task force consists of 16 volunteer experts from the fields of preventive medicine and primary care. Dr. Virginia Moyer, chair of the USPSTF and professor of pediatrics at Baylor College of Medicine, spoke with the NCI Cancer Bulletin about the task force’s mandate, challenges, and lessons learned.

Why was the USPSTF formed in 1984?

The task force was created in response to a perception that physicians in primary care didn’t really focus much on prevention. So, the idea was to look at what works in prevention and encourage primary care physicians to do those things.

Not everything you might do that sounds like prevention actually works, so the goal was to get effective prevention into practice.

How does the task force come up with its recommendations?

Once we’ve decided that we’re going to address a topic—say, a particular cancer screening test—then we lay out a logic model that asks: if you screen, what harms might come from screening, and what benefits might come from screening? Screening leads to detection and treatment, so what benefits come from treatment, and what harms come from treatment?

We very carefully look at all the available research. And then, using an explicit system to grade the evidence, we determine how sure we are that there is a net benefit and how big that potential net benefit is. Using that model, we come up with a recommendation.

The process is clear and explicit, and anyone is welcome to look at our process.

Are the task force members’ opinions independent, or do the members represent their institutions or other organizations?

We’re all volunteers, so we do not represent our organizations. We all have day jobs, but, for example, I don’t go to the task force meetings and say, “I’m representing Baylor College of Medicine.” I’m representing my own expertise.

So we are independent. We are also not federal employees, though the task force is federally supported. The USPSTF is congressionally mandated, and the Agency for Healthcare Research and Quality provides logistical support.

When is screening beneficial?

The only time screening for cancer works is when a test can distinguish people with and without a type of cancer for which we have treatment that works, but not all that well.

If treatment works fantastically well, you don’t need to screen. Testicular cancer is an example; such a high proportion of men do well regardless of stage at diagnosis that screening cannot affect outcome.

Screening is also pointless when no treatment works. With pancreatic cancer, for example, we simply don’t seem to be able to come up with a treatment that works, so there’s no point in screening yet.

But the ones in the middle are the ones where screening has the potential to be beneficial: where treatment does work, but seems to work better if you catch the cancer earlier.

The better treatment gets, the less useful screening is. In breast cancer, for example, what’s happened is that mammography was much more clearly beneficial when treatment wasn’t quite as good. And the apparent benefit of mammography is decreasing, because treatment is getting better.

So there’s this sort of “sweet spot” for cancer screening that sits somewhere in between incredibly treatable and incredibly untreatable. And that’s where we have to have studies, and we have to keep doing studies, because cancer treatment is changing.

Does the task force consider cost when grading a screening test?

We do not do formal cost-effectiveness analyses. We do think about the resource implications of a recommendation, because those are important in any medical decision. For example, our depression screening recommendation says that you should screen when treatment is available. There’s really no point in screening if treatment resources aren’t available.

The one thing we don’t do is look for ways to cut costs—that is explicitly not something we do.

What has been the task force’s biggest challenge in devising cancer screening recommendations?

I think the biggest challenge is that the general public does not understand that cancer is not a linear disease. You don’t start with one cancer cell that, if it isn’t stopped, will inevitably grow and then kill you. That simply is not how cancer works. If cancer worked that way, you would never overdiagnose people because, if you found a cancer, it would be destined to progress. And if you had treatment available that worked better earlier in the course of the disease, screening would always work.

But that’s not how cancer is. It’s a highly varied disease, even within a single cancer type. For example, even within breast cancer, there are some cells that look like cancer under a microscope but never progress and probably regress. Other cells that look exactly the same under the microscope progress very rapidly and don’t seem to be stoppable no matter what you do.

So given that we have that much variability, you can pretty much predict that screening isn’t going to be perfect. What we’re trying to determine is, how good is screening? Is it good enough that its benefits outweigh its harms? Because there are always harms, sometimes real physical harms.

The toughest experience was the 2009 mammography screening recommendation, but the challenge was not really the science. The challenge was communicating with the public.

What did you learn from that experience?

What we learned from the breast cancer screening recommendation experience is that we need to do a far better job of making sure people understand who we are and how we get to our decisions. Since then, we’ve opened up pieces of our process for public comment, which has been incredibly helpful.

So, now, our research plans go out for public comment. We call everybody we can think of who might be interested; we call every advocacy group; we call all of our partners—federal agencies, physician organizations, and other kinds of provider organizations. We want to make sure we’re asking the right questions.

Once we’ve voted on a recommendation and it’s in draft form, the draft goes out for public comment as well. The chance that someone will bring information to light that we didn’t know about is pretty small at that point, but we quickly find out what we have communicated badly and how we can improve our communication.

As painful as the mammography controversy was, it has turned out to be something that probably helped us move years ahead in terms of the openness of our process.

— Interviewed by Sharon Reynolds

A Closer Look

Crunching Numbers: What Cancer Screening Statistics Really Tell Us

This article was first published in the May 1, 2012, issue of the NCI Cancer Bulletin.

Over the past several years, the conversation about cancer screening has started to change within the medical community. Be it breast, prostate, or ovarian cancer, the trend is to recommend less routine screening, not more. These recommendations are based on an emerging—if counterintuitive—understanding that more screening does not necessarily translate into fewer cancer deaths and that some screening may actually do more harm than good.

Much of the confusion surrounding the benefits of screening comes from interpreting the statistics that are often used to describe the results of screening studies. An improvement in survival—how long a person lives after a cancer diagnosis—among people who have undergone a cancer screening test is often taken to imply that the test saves lives. 

But survival cannot be used accurately for this purpose because of several sources of bias.

Sources of Bias

Graphic illustrating lead-time bias (Image from O. Wegwarth et al., Ann Intern Med, March 6, 2012:156)A graphic illustrating lead-time bias. Click to enlarge the image and to read the full caption. (Image from O. Wegwarth et al., Ann Intern Med, March 6, 2012:156)

Lead-time bias occurs when screening finds a cancer earlier than that cancer would have been diagnosed because of symptoms, but the earlier diagnosis does nothing to change the course of the disease. (See the graphic on the right for further explanation.)

Lead-time bias is inherent in any analysis comparing survival after detection. It makes 5-year survival after screen detection—and, by extension, earlier cancer diagnosis—an inherently inaccurate measure of whether screening saves lives. Unfortunately, the perception of longer life after detection can be very powerful for doctors, noted Dr. Donald Berry, professor of biostatistics at the University of Texas MD Anderson Cancer Center.

"I had a brilliant oncologist say to me, 'Don, you have to understand: 20 years ago, before mammography, I'd see a patient with breast cancer, and 5 years later she was dead. Now, I see breast cancer patients, and 15 years later they're still coming back, they haven't recurred; it's obvious that screening has done wonders,'" he recounted. "And I had to say no—that biases could completely explain the difference between the two [groups of patients]."

Another confounding phenomenon in screening studies is length-biased sampling (or "length bias"). Length bias refers to the fact that screening is more likely to pick up slower-growing, less aggressive cancers, which can exist in the body longer than fast-growing cancers before symptoms develop.

Graphic illustrating overdiagnosis bias (Image from O. Wegwarth et al., Ann Intern Med, March 6, 2012:156)A graphic illustrating overdiagnosis bias. Click to enlarge the image and to read the full caption. (Image from O. Wegwarth et al., Ann Intern Med, March 6, 2012:156)

Dr. Berry likens screening to reaching into a bag of potato chips—you're more likely to pick a larger chip because it's easier for your hand to find, he explained. Similarly, with a screening test "you're going to pick up the slower-growing cancers disproportionately, because the preclinical period when they can be detected by screeningthe so-called sojourn timeis longer."

The extreme example of length bias is overdiagnosis, where a slow-growing cancer found by screening never would have caused harm or required treatment during a patient's lifetime. Because of overdiagnosis, the number of cancers found at an earlier stage is also an inaccurate measure of whether a screening test can save lives. (See the graphic on the left for further explanation.)

The effects of overdiagnosis are usually not as extreme in real life as in the worst-case scenario shown in the graphic; many cancers detected by screening tests do need to be treated. But some do not. For example, recent studies have estimated that 15 to 25 percent of screen-detected breast cancers and 20 to 70 percent of screen-detected prostate cancers are overdiagnosed.

How to Measure Lives Saved

Because of these biases, the only reliable way to know if a screening test saves lives is through a randomized trial that shows a reduction in cancer deaths in people assigned to screening compared with people assigned to a control (usual care) group. In the NCI-sponsored randomized National Lung Screening Trial (NLST), for example, screening with low-dose spiral CT scans reduced lung cancer deaths by 20 percent relative to chest x-rays in heavy smokers. (Previous studies had shown that screening with chest x-rays does not reduce lung cancer mortality.)

However, improvements in mortality caused by screening often look small—and they are small—because the chance of a person dying from a given cancer is, fortunately, also small. "If the chance of dying from a cancer is small to begin with, there isn't that much risk to reduce. So the effect of even a good screening test has to be small in absolute terms," said Dr. Lisa Schwartz, professor of medicine at the Dartmouth Institute for Health Policy and Clinical Practice and co-director of the Veterans Affairs Outcomes Group in White River Junction, VT.

For example, in the case of NLST, a 20 percent decrease in the relative risk of dying of lung cancer translated to an approximately 0.4 percentage point reduction in lung cancer mortality (from 1.7 percent in the chest x-ray group to 1.3 percent in the CT scan group) after about 6.5 years of follow-up, explained Dr. Barry Kramer, director of NCI's Division of Cancer Prevention.

A recent study published March 6 in the Annals of Internal Medicine by Dr. Schwartz and her colleagues showed how these relatively small—but real—reductions in mortality from screening can confuse even experienced doctors when pitted against large—but potentially misleading—improvements in survival.

Tricky Even for Experienced Doctors

To test community physicians' understanding of screening statistics, Dr. Schwartz, Dr. Steven Woloshin (also of Dartmouth and co-director of the Veterans Affairs Outcomes Group), and their collaborators from the Max Planck Institute for Human Development in Germany developed an online questionnaire based on two hypothetical screening tests. They then administered the questionnaire to 412 doctors specializing in family medicine, internal medicine, or general medicine who had been recruited from the Harris Interactive Physician Panel.

The effects of the two hypothetical tests were described to the participants in two different ways: in terms of 5-year survival and in terms of mortality reduction. The participants also received additional information about the tests, such as the number of cancers detected and the proportion of cancer cases detected at an early stage.

The results of the survey showed widespread misunderstanding. Almost as many doctors (76 percent of those surveyed) believed—incorrectly—that an improvement in 5-year survival shows that a test saves lives as believed—correctly—that mortality data provides that evidence (81 percent of those surveyed).

Recent Screening Recommendation Changes

About half of the doctors erroneously thought that simply finding more cases of cancer in a group of people who underwent screening compared with an unscreened group showed that the test saved lives. (In fact, a screening test can only save lives if it advances the time of diagnosis and earlier treatment is more effective than later treatment.) And 68 percent of doctors surveyed said they were even more likely to recommend the test if evidence showed that it detected more cancers at an early stage.

Doctors were three times more likely to say they would recommend the test supported by irrelevant survival data than the test supported by relevant mortality data.

In short, "the majority of primary care physicians did not know which screening statistics provide reliable evidence on whether screening works," Dr. Schwartz and her colleagues wrote. "They were more likely to recommend a screening test supported by irrelevant evidence…than one supported by the relevant evidence: reduction in cancer mortality with screening."

Teaching the Testers

"In some ways these results weren't surprising, because I don't think [these statistics] are part of the standard medical school curriculum," said Dr. Schwartz.

"When we were in medical school and in residency, this wasn't part of the training," Dr. Woloshin agreed. 

"We should be teaching residents and medical students how to correctly interpret these statistics and how to see through exaggeration," added Dr. Schwartz.

Some schools have begun to do this. The University of North Carolina (UNC) School of Medicine has introduced a course called the Science of Testing, explained Dr. Russell Harris, professor of medicine at UNC. The course includes modules on 5-year survival and mortality outcomes.

The UNC team also recently received a research grant to form a Research Center for Excellence in Clinical Preventive Services from the Agency for Healthcare Research and Quality. "Part of our mandate is to talk not only to medical students but also to community physicians, to help them begin to understand the pros and cons of screening," said Dr. Harris.

Drs. Schwartz and Woloshin also think that better training for reporters, advocates, and anyone who disseminates the results of screening studies is essential. "A lot of people see those [news] stories and messages, so people writing them need to understand," said Dr. Woloshin.

Patients also need to know the right questions to ask their doctors. "Always ask for the right numbers," he recommended. "You see these ads with numbers like '5-year survival changes from 10 percent to 90 percent if you're screened.' But what you always want to ask is: 'What's my chance of dying [from the disease] if I'm screened or if I'm not screened?'"

Sharon Reynolds

With Ocean of Data

Using an Ocean of Data, Researchers Model Real-Life Benefits of Cancer Screening

Randomized clinical trials are widely acknowledged as the best way to determine whether a cancer screening test saves lives. But even when trial results indicate that a particular screening method has a clear benefit, the findings may not be easily translated into recommendations for the public. The results of a screening trial may apply only to certain people, and the findings can change as the study period lengthens—all of which means that the results may not apply to the general population.

A graphic illustrating the idea of a wave of data
CISNET runs enormous amounts of data through computer models to identify the best way to implement screening for different types of cancer.

For example, the National Lung Screening Trial (NLST) showed that screening of current or former heavy smokers with three annual low-dose spiral CT scans can reduce their risk of dying from lung cancer. But NLST enrolled only people aged 55 to 74 who had smoked for 30 pack years and had quit less than 15 years previously.

“Would a similar screening regimen also benefit younger or older smokers? Would lighter smokers benefit equally? And when should they start and stop screening?” asked Dr. Eric “Rocky” Feuer, scientific coordinator of NCI’s Cancer Intervention and Surveillance Modeling Network (CISNET). Patients and doctors alike will almost certainly ask these questions.

CISNET’s five research teams use modeling to try to answer these types of questions for several different cancer types. Using the results of screening trials, the teams are trying to estimate the true benefit of screening in the general population and to identify the optimal way to implement screening within the health care system.

The teams’ extremely complex computer programs, which for some cancer types (such as breast and colorectal) have been used and constantly refined for over a decade, incorporate a wide variety of information. This information includes not only trial data but observational data, epidemiologic data, and information on the natural history of each cancer type.

One of CISNET’s original mandates was to tease out the role that screening has played in the observed decline in deaths from some cancer types over the last few decades. In a landmark 2005 paper in the New England Journal of Medicine, CISNET researchers determined that screening mammography likely accounted for half of the 24 percent decrease in breast cancer mortality that was observed between 1989 and 2000.

From there, the teams moved to providing data that inform screening guidelines, said Dr. Feuer. In 2008, the United States Preventive Services Task Force (USPSTF) used a CISNET modeling study as part of the evidence behind the update of its screening recommendations for colorectal cancer. In 2009 a similar modeling study was used to update the USPSTF mammography screening recommendations. Now, CISNET teams are trying to help resolve some of the questions emerging from screening trials in lung, prostate, and esophageal cancer.

Matching the Population Experience

A major goal of the CISNET lung cancer team is to “integrate the NLST results into general practice,” said Dr. Pamela McMahon of Massachusetts General Hospital, the principal investigator of the lung cancer team, which also includes researchers from five other universities. “We have to extrapolate from the limited scenario of the NLST, because that [trial] doesn’t match the population experience.” (See "After Landmark Study, Exploring Questions about Lung Cancer Screening.")

“We’re looking at every permutation you can think of: ages to start screening, ages to stop screening, how many pack years [smoked], how many years since quitting, how frequently to do the screens,” said Dr. McMahon.

The team is aided by access to data on every single patient enrolled in NLST as well as every patient in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), also funded by NCI.

Once the results are complete, the researchers hope to use them to create an interactive projection tool that will let policy makers see how implementations of different lung cancer screening programs in their community would alter lung cancer mortality, similar to the mortality projection tool produced by the CISNET colorectal cancer team.

Two Enormous Trials, Two Different Results

The three research groups in the CISNET prostate cancer team are tackling an equally ambitious, although entirely different problem. Two large randomized clinical trials of prostate cancer screening—one in the United States and one in Europe—have generated long-term data on how screening may affect prostate cancer mortality. And the two trials had different results.

In the European Randomized Study of Screening for Prostate Cancer (ERSPC), men who were screened for prostate cancer were less likely to die from prostate cancer than men who were not screened. That was not the case in the PLCO trial, which found that men who were screened did not have a lower risk of dying from prostate cancer than unscreened men. The trials were conducted very differently, and each had limitations, including a large number of unscheduled screenings (referred to as “contamination”) in the control group of the PLCO trial and a lack of standardized cancer treatment in ERSPC.

“So the question that we’re trying to answer is whether there is a range of screening benefits that is consistent with the results of both trials,” said Dr. Ruth Etzioni of the Fred Hutchinson Cancer Research Center, principal investigator of the CISNET prostate team. Researchers from both trials have allowed the CISNET team access to all of their data, down to the level of each individual patient, to resolve whether screening reduces prostate cancer deaths.

The CISNET team has spent years modeling the natural history of prostate cancer. “We can’t see when a person’s cancer begins…but we can see how disease is diagnosed in the population, at what ages people get diagnosed, and at what stages they get diagnosed. All of that informs us about what’s happening at a somewhat-below-the-surface level,” explained Dr. Etzioni.

The prostate modeling groups will use their knowledge of the natural history of prostate cancer and overall health and life histories of men in the United States “to ‘replicate’ what happened in ERSPC and PLCO on top of those life histories and disease histories,” Dr. Etzioni elaborated. “And when we replicate the two trials we’ll see if there is a range of true benefit, where we get something reasonably close to what was observed in both trials.”

The team is also beginning to look at how immediate versus delayed treatment may change the benefit/harm ratio of prostate cancer screening and at how the prevention of endpoints other than mortality—such as metastatic disease—may also alter that ratio. (See "Benefits and Harms of Prostate Cancer Screening.")

Modeling Targeted Screening

For the first 10 years of the program, CISNET focused on four of the most common cancers in the United States: breast, prostate, lung, and colorectal. In 2010, it added a less common cancer—esophageal—which presents a different set of issues: determining how to screen for a cancer in a subpopulation of people with well-known risk factors for the disease.

“Esophageal cancer is not common enough to do population-based screening, but [doctors do] targeted screening based on individual risk,” explained Dr. Chin Hur of Massachusetts General Hospital, principal investigator of the esophageal cancer team.

[Modeling] is better than someone just taking a best guess. It’s a systematic approach, with intense peer review and multiple modeling groups, that tries to distill the evidence that is out there.

—Dr. Chin Hur

“We chose a less common cancer [to include in CISNET] because the effort that we go through to find a relatively few esophageal cancers is incredibly inefficient,” commented Dr. Feuer. Although gastroesophageal reflux disease and a related condition called Barrett esophagus are known risk factors for esophageal cancer, relatively few people with either problem will develop the disease.

But doctors do not yet know how to identify which people with these conditions are most likely to develop esophageal cancer and may, therefore, benefit from targeted screening. “There’s huge potential to do things better,” said Dr. Feuer. The goal for the CISNET team is “to come up with cost-effective strategies to diminish the morbidity and mortality from esophageal cancer,” added Dr. Hur.

The esophageal team is developing three models using existing clinical trial data and is collaborating with modelers working at the molecular level of cancer. This so-called “multiscale modeling” will let the team build a more accurate representation of the natural history of esophageal cancer into their models. Once the models have been finalized, the researchers will use them to virtually “re-run” and analyze trials not only of endoscopic monitoring and radiofrequency ablation in people with Barrett esophagus but also other emerging strategies for preventing the progression of esophageal cancer.

Although endoscopic screening and radiofrequency ablation of Barrett esophagus have been tested in many smaller clinical studies, these trials have nowhere near the numbers of patients—or, therefore, the statistical power or general applicability—that large screening trials for breast, prostate, lung, and colorectal cancer have.

This poses a paradox for the modelers and for the esophageal cancer research community in general: “Where there is less clinical trial data available, there’s more uncertainty about the projections. At the same time, there is less data around to inform both clinical decision making and policy, so our results are more important. So, although there’s more uncertainty about [modeling], there’s also more need for it,” summarized Dr. Hur.

“We need to be very open and transparent about the limitations, explore those fully, and be careful about the conclusions of our analyses,” he said. “But [modeling] is better than someone just taking a best guess. It’s a systematic approach, with intense peer review and multiple modeling groups, that tries to distill the evidence that is out there.”

Sharon Reynolds

After Landmark Study

After Landmark Study, Exploring Questions about Lung Cancer Screening

Two years ago, NCI released initial results from the National Lung Screening Trial (NLST), which showed, for the first time, that a screening test could potentially reduce the number of deaths from lung cancer among current or former heavy smokers. 

A low-dose helical CT scanner
NLST used low-dose helical CT scanners like this one to screen for lung cancer.

The lung cancer screening study, which enrolled more than 53,000 current or former heavy smokers, found that a 20 percent relative reduction in deaths from lung cancer occurred among participants screened with low-dose helical computed tomography (helical CT) compared with those screened with standard chest x-rays. (This means about a 0.3 to 0.4 percent absolute reduction in deaths at about 6.5 years.)

The release of the NLST findings caused “a huge resurgence in interest in lung cancer screening and a great excitement about the possibility of using it to prevent deaths from the disease,” noted Dr. David A. Lynch, pulmonary radiologist at the National Jewish Health hospital in Denver.

But despite the enthusiasm about the results, some researchers caution that more research is needed before lung cancer screening with helical CT is widely used. Since the results were released in November 2010, only a handful of U.S. clinicians and medical centers have adopted the screening method and the patient selection and evaluation criteria used in NLST. Additional studies are under way to better understand just how the NLST results should be interpreted and applied in everyday practice.

Cautious Pace of Adoption

Despite the benefits of lung cancer screening with low-dose CT scans, the NLST findings came with some caveats.

“A critical issue is to whom lung cancer screening should be offered,” commented Dr. Christine Berg, NCI project officer for NLST. The NLST researchers can generalize the results only to the population that participated in the trial: current or former smokers (defined as having quit within 15 years of joining the trial) aged 55 through 74 who smoked the equivalent of at least a pack a day for 30 years.

But, Dr. Berg added, “NCI is involved with a number of research studies to better define high-risk groups that could benefit from lung cancer screening. It is also critically important to define groups that are at very low risk, such as never smokers, even if they’ve been exposed to secondhand smoke. They remain at such a low risk for lung cancer that the harm-benefit ratio is not in favor of screening.”

We were impressed with the results of the NLST….[but] there were still lots of questions about how to do screening and whether we could achieve that same result in a real-world setting.

—Dr. Linda Kinsinger

Those potential harms of lung cancer screening are another concern that needs to be addressed. Nearly 25 percent of all CT scans in NLST showed false-positive results, meaning that on follow-up 1 in 4 observed abnormalities turned out not to be cancer. In addition to suffering unnecessary anxiety, these patients underwent some kind of additional diagnostic procedure, some of which carry risks. The high false-positive rate raises questions about how to follow up when a nodule is found.

“In my medical center’s practice, we find the main thing that physicians need help with is nodule management,” when abnormalities are detected on the CT scan, said Dr. Lynch. “That remains their biggest concern: what to do about those findings?” he added.

National Jewish Health hospital responded by developing a multidisciplinary approach that “automates tracking of lung nodules and ensures that follow up is performed,” he said. Comprehensive lung cancer screening initiatives at other institutions should include such support, as well as effective smoking cessation programs, Dr. Lynch recommended.

Another barrier to wider use of screening for lung cancer so far has been lack of insurance coverage, noted Dr. Paul Kvale, pulmonologist at Henry Ford Hospital in Detroit. “Until now, most insurance carriers have not agreed to cover low-dose CT scans for their subscribers for purely screening purposes.”

Guidelines and Recommendations Expected Soon

Dr. Kvale believes this lack of coverage will change in the next year or so if medical societies and government agencies recommend the adoption of lung cancer screening, citing NLST findings. He is working on such guidelines with the American College of Chest Physicians (ACCP) that he hopes will be published in early 2013.

Lung cancer screening recommendations are also expected soon from the U.S. Preventive Services Task Force (USPSTF). NCI’s Cancer Intervention and Surveillance Modeling Network (CISNET) is working to provide modeling analysis of NLST findings, as well as of the findings from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), to inform the USPSTF recommendations, reported CISNET Principal Investigator Dr. Pamela McMahon.

“We’re working on basically triangulating between the NLST results—which had a CT arm and a chest x-ray arm—and the PLCO results, which had a chest x-ray arm and a no-screening arm, and also many lighter smokers, nonsmokers, and even never smokers,” Dr. McMahon explained.

Dr. Berg believes the CISNET analysis will provide important information and guidance on optimal methods for lung cancer screening “in terms of screening intervals, how long to continue screening, when to start screening,” and impact of smoking history, all aimed at balancing the harms and benefits of screening for high-risk individuals.

Testing Lung Cancer Screening in the Real World

In anticipation of the USPSTF recommendations, the U.S. Veterans Health Administration’s (VHA) National Center for Health Promotion and Disease Prevention is planning to conduct a lung cancer screening pilot program, based on the NLST findings, at six to eight VHA medical centers starting early next year.

“The goal of the pilot will be to gather information that will inform how this procedure would work in the VHA system,” explained Dr. Linda Kinsinger, chief consultant for preventive medicine at VHA. “We were impressed with the results of the NLST—a 20 percent reduction in lung cancer mortality is a finding that we didn’t feel could be ignored,” she added. “On the other hand, we also felt that there were still lots of questions about how to do screening and whether we could achieve that same result in a real-world setting compared with a research setting.

“We’re not ready to strongly endorse lung cancer screening to our patients just yet,” Dr. Kinsinger continued. “Rather, during the pilot program, we plan to give people the right information, let them make their choices, and see how that works within our system.”  

Bill Robinson

Further reading: “Low-Dose CT Shows Clear Mortality Benefit for Lung Cancer Screening in Heavy Smokers

See also: “Patient and Physician Guide: National Lung Screening Trial” (pdf)

Building a Better

Building a Better Cancer Screening Process

The cancer screening process is complex, and failures can occur at any step—from testing and diagnosis to referral for treatment. And although the reasons the process sometimes fails are not always clear, a better understanding of screening approaches could lead to significant improvements overall.  

Woman having a mammogram
PROSPR investigators are asking whether women are getting the appropriate type of breast cancer screening.

Some answers could emerge in the next few years from a project known as PROSPR (Population-Based Research Optimizing Screening through Personalized Regimens). This NCI-sponsored research initiative is designed to improve the cancer screening process for all who are eligible for particular screening tests, including underserved populations.

“It is important to understand which steps in the process may fail, because these failures are the kinds of things that lead to disparities in cancer screening,” said PROSPR investigator Dr. Jennifer Haas of Brigham and Women’s Hospital in Boston.

The researchers will focus on developing better ways to implement screening in community settings. At seven sites in the United States, investigators will study screening for the three cancers for which the evidence of potential benefits of screening is strongest—breast, cervical, and colorectal.

“We do a lot of cancer screening in the United States, and there is an accumulating body of evidence that says we don’t do screening as well as we should,” said Dr. Carrie Klabunde of NCI’s Division of Cancer Control and Population Sciences (DCCPS), a leader of the project.

Dr. Douglas Corley, a PROSPR investigator from the Kaiser Foundation Research Institute, added, “This project will look at the whole pathway of cancer screening to get a global understanding of how people go through this process and to identify where the problems are.”

Screening Vulnerable Populations

One of the main study sites for colorectal cancer screening is Dallas. Researchers there will follow more than 30,000 uninsured or underinsured residents served by a dozen health clinics for up to 5 years. The clinics provide primary health care, including cancer screening, regardless of a person’s ability to pay or immigration status.

“In several years, we’ll have a lot of knowledge about the best way to do screening in a large, vulnerable, low-insurance population,” predicted Dr. Celette Skinner of the University of Texas Southwestern Medical Center. “We will share this with other safety-net health care systems.”

In a study that is already under way, participants are using touchscreen computers to help them assess their own risks of developing colorectal cancer. Based on the user’s responses to questions about health and family history, a computer program recommends, for example, that a person be screened with a stool-based test or go straight to a colonoscopy.

“We’re trying, on the one hand, to prevent the underuse of screening and, on the other hand, to prevent the overuse of screening,” said Dr. Skinner. An example of overuse would be when someone who has had a colonoscopy that found no precancerous polyps and does not need to be screened again for a decade continues to get a colonoscopy every few years.

What Influences Screening Outcomes?

PROSPR researchers in California are studying a different aspect of colonoscopy screening: factors that influence outcomes. This is possible thanks to a database of health-related information on 6 million California residents who are insured through Kaiser Permanente.

“We have access to detailed information on these patients, such as which medications they were taking when they were screened,” noted Dr. Corley.

His team will look at factors that may influence outcomes from cancer screening, including race, sex, ethnicity, and the person’s overall health. The  instructions a person received before screening and what time of day the person was screened will also be considered.

“The strength of PROSPR is that we can see the contributions of each step in the screening process,” explained Dr. Corley. “This will help us get the best bang for the buck in terms of trying to increase the effectiveness of cancer screening.”

All PROSPR investigators are contributing their results to a central repository, which will be a resource for the field.

Matching Screening Tools to Cancers

Meanwhile, researchers in Philadelphia are looking into whether women are getting the appropriate type of breast cancer screening. This PROSPR site serves a population that is 40 percent African American.

The strength of PROSPR is that we can see the contributions of each step in the screening process.

—Dr. Douglas Corley

“We’ve made some progress toward reducing breast cancer mortality, but we’re not close to being all the way there,” said co-leader Dr. Katrina Armstrong of the University of Pennsylvania Abramson Cancer Center. “And among African American women, it’s not clear that the tools we have for early detection are working the way they should be.”

The researchers are comparing the rates of false-positives associated with different types of digital mammography in the population they serve. Black women are more likely than white women to develop triple-negative breast cancer, which is difficult to treat, and some types of mammography may detect this form of the disease better than others, according to Dr. Armstrong.

“The million-dollar question is: Can we figure out how the screening modalities work for different subtypes of breast cancer?” she said.

This information, if available, could be used to improve the detection of breast cancer among all women and reduce false-positive rates.

Another PROSPR breast screening project will test an intervention designed to improve discussions of cancer risk between patients and doctors. Previous studies have suggested that white women who are not at high risk of breast cancer tend to overestimate their risk of the disease, whereas black women, who may be at high risk, tend to underestimate their risk.

The new project will test an intervention designed to foster more accurate self-assessments of risk. Dr. Haas and her colleagues will deliver information about the risk of breast cancer to some participants in a small randomized clinical trial before they see their doctors.

“If you don’t believe you are at risk for breast cancer, then you are probably not going to get recommended screening,” said Dr. Haas. “We hope that this intervention will move both groups toward the center and reduce the disparities in self-perceived risk.”

Realistic Screening Environments

Screening in the community is different from the carefully controlled randomized clinical trials in which new screening tests are usually evaluated. In such trials, participants are invited, guided, and supported throughout the process. But this support may not be present in the community.

“Just because a screening test works in an experimental setting doesn’t mean that it will also work when tried in the community setting,” noted Dr. Pamela Marcus of DCCPS, who is the NCI scientific coordinator for PROSPR. For example, if a screened person gets a positive test result but does not have health insurance, “that person may fall through the cracks of the system.”

This project will show us “what’s working and what is not working in cancer screening,” Dr. Marcus added. “Then we can address these issues and improve the process.”

Edward R. Winstead

All That Glitters

All That Glitters: A Glimpse into the Future of Cancer Screening

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A magneto-sensor chip used to detect protein biomarkers (Photo courtesy of Dr. Sanjiv Gambhir, Stanford University)
This magneto-nanosensor chip may someday be used for cancer screening tests that rely on panels of protein biomarkers. Photo courtesy of Dr. Sanjiv Gambhir, Stanford University.

Ask experts to predict the future of cancer screening, and you’ll get a range of answers. But all would agree that we need better ways to detect cancers early in the course of disease, and these new tools should improve on the benefits of screening while limiting the harms.

“There have been some improvements in triaging patients with new molecular approaches, but with the possible exception of spiral CT screening for lung cancer, we haven’t had any major breakthroughs in early detection” for more than two decades, noted Dr. David Sidransky, director of head and neck cancer research at the Johns Hopkins University School of Medicine.

The dearth of such advances is not for lack of trying. Developing new screening approaches and rigorously establishing their validity is challenging, however, and there are many potential stumbling blocks along the way.

“The bar for ‘proof’ that a particular screening strategy is clinically effective is very high,” noted Dr. Mark Greene, chief of the Clinical Genetics Branch in NCI’s Division of Cancer Epidemiology and Genetics (DCEG). “A screening test must be shown to reduce the death rate from the disease for which screening is being done.”

Much of the search for new screening tests focuses on biomarkers—proteins, DNA, RNA, or other molecules that can signal the presence of cancer and be detected noninvasively in blood, urine, or other readily obtained patient samples or tissues. Researchers are also developing new imaging methods that could be used for early detection, either alone or in concert with biomarkers.

Whatever the approach, “screening is moving away from detecting an advanced consequence of cancer, which is the formation of a mass [or tumor], toward detecting the very earliest changes in the cancer process,” said Dr. Larry Norton, deputy physician-in-chief for breast cancer programs at Memorial Sloan-Kettering Cancer Center.

Dr. Norton chairs the external consulting team for the Early Detection Research Network (EDRN), an initiative of NCI’s Division of Cancer Prevention that supports efforts to discover and validate new cancer biomarkers and technologies.

“Molecular detection of cancer is possible only through evidence-based strategies and implementation,” commented Dr. Sudhir Srivastava, who directs the EDRN. “It takes a village to meet the challenges of early-detection research.”

The Post-PSA Era

In the case of some cancers, researchers are developing new screening tests because the value of existing tests for those cancers has been called into question, perhaps most notably in the case of prostate specific antigen (PSA) testing for prostate cancer. (See "Benefits and Harms of PSA Screening for Prostate Cancer.")

“The idea that one biomarker such as PSA is going to be useful for all settings has evolved. We now believe that we’ll need panels of biomarkers,” said Dr. Mark Rubin, a professor of pathology at Weill Cornell Medical College. To identify those biomarkers, researchers are using methods such as microarrays and whole-genome sequencing, which rapidly yield a wealth of information, to profile changes that occur in cancer.

Using such an approach, Dr. Rubin, Dr. Arul Chinnaiyan of the University of Michigan, and their colleagues discovered the fusion gene TMPRSS2-ERG, which is found in about half of all prostate cancers. “That fusion gene is seen only in cancer, and, in particular, only in prostate cancer,” said Dr. Rubin, whose team has developed a test to assess the levels of this fusion gene in urine samples. “Our approach now is to try to explain the other 50 percent of prostate cancers with other cancer-specific molecular events” that could eventually form a screening test based on a panel of genetic markers.

For example, Dr. Rubin co-led a recent study that identified a gene called SPOP that is mutated in about 10 percent of prostate cancers. “We can add that gene mutation to the gene fusion to improve on the test,” he explained. “This is the sort of approach we think will be useful for prostate cancer, as well as other cancers in the future.”

Applying Lessons Learned

To avoid unnecessary biopsies or treatment of prostate and other screen-detected cancers, researchers are trying to find biomarkers that better identify which cancers are likely to progress, noted Dr. Joshua LaBaer, director of the Center for Personalized Diagnostics at the Biodesign Institute at Arizona State University and co-chair of EDRN’s steering committee. Whereas some cancers detected by screening will progress and metastasize, others may never cause illness during a person's lifetime.

“What we’ve learned from PSA is that if we’re going to come up with new screening tools, we also have to develop tools that give us a better idea of disease prognosis,” said Dr. James Brooks, a professor of urology at Stanford University.

Dr. Brooks and Dr. Sanjiv Gambhir, chair of the department of radiology at Stanford, lead a project to deploy new technologies that could form the basis for the next generation of prostate cancer screening tests.

To pave the way for tests that rely on panels of blood-based diagnostic or prognostic protein biomarkers, they are starting to test the performance of a magneto-nanosensor chip technology developed at Stanford. The sensor, which detects proteins tagged with magnetic particles, can measure the levels of up to 64 different proteins simultaneously, in very small sample volumes.

The Stanford team also hopes to adapt an imaging technology being studied in Dr. Gambhir’s lab to improve the accuracy of prostate cancer detection by transrectal ultrasound. The method uses gas “microbubbles” that are encased in a lipid shell to which specific antibodies are attached as a contrast material for ultrasound imaging. The antibodies target a receptor for vascular endothelial growth factor, which is a protein found in newly formed tumor blood vessels. The patented antibody-labeled microbubbles are awaiting Food and Drug Administration approval for human testing.

The Stanford team’s long-term goal is to combine their blood-based biomarker and imaging methods to improve early detection and prognostic assessment of prostate cancer and eventually other cancers. Combining molecular biomarkers and imaging for cancer screening “is a very powerful approach,” commented Dr. Sidransky. “We used to believe in the power of a marker to do everything,” he added. “We now know that’s not true.”

A Sense of Urgency

Researchers have long sought an effective screening strategy for ovarian cancer, and numerous candidate biomarkers for the disease have fallen short of expectations.

“Ovarian cancer is the paradigm for why we need early detection,” said Dr. Michael Birrer, a professor of medicine at Harvard Medical School. The disease can be cured by surgery if discovered early. But “75 percent of tumors are detected at the advanced stage, and those patients are hard to cure,” said Dr. Birrer.

Dr. Birrer and Dr. Steven Skates, an associate professor of medicine at Harvard, are leading a two-pronged effort to discover new biomarker candidates that may ultimately lead to a blood test for the early detection of ovarian cancer.

The first strategy will use extensive proteomic profiling of fluids from benign and malignant tissues, such as ovarian cysts, “to find candidate biomarkers that are systematically different between the two,” Dr. Skates explained.

We used to believe in the power of a marker to do everything. We now know that’s not true.

—Dr. David Sidransky

The second strategy involves genomic analyses to identify genes that are expressed differently in ovarian cancer tissue samples than they are in normal tissues that may give rise to ovarian cancer, and then bioinformatic analyses to look for genes whose protein products are also likely to be secreted into the bloodstream.

Using either the proteomic or genomic approach, or a combination of both, the researchers hope to come up with a short list of candidate biomarkers for further testing and refinement. “We may be lucky to find that some of those candidates are actually early-detection biomarkers that can be measured in blood,” Dr. Skates said.

Those biomarkers could form the basis of a blood test to screen postmenopausal women, and other women at increased risk of ovarian cancer, at regular intervals. For women who test positive on the blood test, a follow-up test, such as transvaginal ultrasound or newer imaging methods, might be used as part of an overall screening approach in the future, Drs. Birrer and Skates suggested.

Gazing into the Crystal Ball

No one can predict with certainty which types of tests will be most effective for screening for particular cancers. However, “if you want to prognosticate the future of cancer screening, my guess is that nucleotide [RNA or DNA]-based tests are going to be the most promising, at least in the short term,” Dr. Brooks said. “The power of nucleic acids is that you can amplify them to an extraordinary degree, which you can’t do with proteins,” Dr. LaBaer added.

Future DNA-based screening tests might detect methylation or other epigenetic modifications of DNA that occur specifically in cancer. “For example, we published a paper last year showing widespread and reproducible changes in DNA methylation in prostate cancer,” Dr. Brooks said.

And future screening tests may detect biomarkers in patient samples other than blood or urine. “One area where I think you’re going to see a change is in…tumors that affect the gastrointestinal tract” or other parts of the digestive system, Dr. LaBaer predicted. “You can look in stool for aberrant nucleic acids [from cells shed by tumors].” Researchers are also investigating sputum-based tests to detect lung cancer early.

“A possibility for the future is that we may stop thinking about cancers in terms of organ sites and may think more in terms of disrupted pathways or molecular variants of cancer,” Dr. LaBaer continued. In that case, “the biomarker people are going to have to work closely with the imaging people to very quickly turn a biomarker discovery into identifying where the tumor is.”

“We’re rapidly changing our concept of what cancer is,” noted Dr. Norton. “You can’t separate screening from understanding biology, from therapy, from prevention. The biggest challenge is weaving it all together [into] the big picture.”

Furthermore, he added, “we may find out that early detection is not helpful in certain situations, and that’s also important. We may not want to screen for certain cancers if we find out that prevention may be a better place to put our resources.”

“Mortality rates for some cancers have remained constant for the past 40 years, and in some of these cancers, new therapies have extended life for a few years but are not increasing the cure rates,” Dr. Skates noted. “Improved early detection for these cancers could shift that number so that more people are cured…. The payoff could be so big.”

Elia Ben-Ari

Further Reading: “Ovarian Cancer Study Raises Questions about Developing Markers for Early Detection

Selected Resources: Cancer Screening

Selected Resources: Cancer Screening

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General

Bladder and Other Urothelial Cancers Screening

Breast Cancer Screening

Cervical Cancer Screening

Colorectal Cancer Screening

Endometrial Cancer Screening

Esophageal Cancer Screening

Stomach (Gastric) Cancer Screening

Liver (Hepatocellular) Cancer Screening

Lung Cancer Screening

Neuroblastoma Screening

Oral Cancer Screening

Ovarian Cancer Screening

Pancreatic Cancer Screening

Prostate Cancer Screening

Skin Cancer Screening

Testicular Cancer Screening

A Conversation With

Inside NCI: Dr. Barry Kramer on Cancer Screening

This video first appeared in the NCI Cancer Bulletin on January 11, 2011.

The director of NCI’s Division of Cancer Prevention and editor-in-chief of NCI's Physician Data Query Screening and Prevention Editorial Board talks about the types of effective cancer screening tests available and the risks that are sometimes associated with cancer screening.

To read Dr. Kramer's recent article on cancer screening campaigns, co-authored with Drs. Steven Woloshin, Lisa Schwartz, and William Black, see “Cancer Screening Campaigns—Getting Past Uninformative Persuasion.”

You must have flash installed and enabled to view the video.


Video produced and edited by Daniel Marmorstein and Sarah Curry

Questions to Ask Your Doctor

Questions to Ask Your Doctor about Cancer Screening

Drs. Lisa Schwartz and Steven Woloshin of the Dartmouth Institute for Health Policy discuss the benefits and harms of cancer screening and highlight popular misconceptions about cancer screening statistics.

They also spoke to the NCI Cancer Bulletin about these topics for the article "Crunching Numbers: What Cancer Screening Statistics Really Tell Us."

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Type: (MP3) | Time 6:09 | Size: 7.3 MB | Read Transcript

Info

Infographic: Benefits and Harms of PSA Screening for Prostate Cancer

As more has been learned about the benefits and harms of prostate-specific antigen (PSA) screening, organizations have begun to recommend against routine screening. Screening is a personal decision that, according to most experts, a man should make in consultation with his doctor, after he has been informed in detail about the potential benefits and harms.

The infographic below depicts the benefits and harms of PSA screening for prostate cancer. The estimates appeared in the U.S. Preventive Services Task Force Recommendation Statement, published July 17 in the Annals of Internal Medicine. The estimates were based on 13- and 11-year follow-up data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer. According to the two trials, the best evidence of possible benefit of PSA screening is in men aged 55 to 69.

Graphic showing the number of men who would experience benefits and harms if 1,000 men aged 55 to 69 were screened every 1 to 4 years for 10 years with a PSA test

Cancer Research Highlights

Decades of Data Point to Overdiagnosis from Breast Cancer Screening

Since breast cancer screening came into widespread use in the United States in the 1970s, more than 1 million women may have been diagnosed with cancers that never would have caused them harm or required treatment, a new study suggests. These women may have been exposed unnecessarily to the adverse effects of treatment, the authors reported in the November 22 New England Journal of Medicine.

The detection of cancers that do not grow or grow so slowly that they would never cause illness is known as overdiagnosis. Previous studies have shown that screening mammography, which looks for breast cancer in the absence of symptoms, can lead to overdiagnosis.

Overdiagnosis may account for nearly one-third of newly diagnosed breast cancers among women aged 40 and older in the United States, the authors of the new study estimated. In 2008, for example, more than 70,000 women may have received an unnecessary diagnosis, they noted.

"This is a significant public health concern," said co-author Dr. Archie Bleyer of St. Charles Health System in Bend, OR. "Women need to be aware of the potential benefits of screening, as well as the downsides—including being diagnosed with cancers that [are not life-threatening]."

To look for evidence of overdiagnosis, Dr. Bleyer and Dr. H. Gilbert Welch of Dartmouth Medical School in Hanover, NH, used NCI's Surveillance, Epidemiology, and End Results (SEER) database to analyze trends in breast cancer incidence between 1976 and 2008.

The authors reasoned that if screening leads to the earlier detection of cancers that are destined to become lethal, detecting more breast cancers at an earlier stage—when they tend to be curable—should lead to a corresponding drop in late-stage cancers. But the SEER data did not show this to be true: The rise in early-stage breast cancers over three decades (an absolute increase of 122 cases per 100,000 women) was not matched by an equivalent drop in late-stage cancers. Instead, there was an absolute decrease of 8 cases per 100,000 women. This imbalance, the authors concluded, must be due to overdiagnosis.

This estimate of overdiagnosis is generally consistent with estimates from other countries. A recent Norwegian study found that as many as 1 in 4 invasive breast cancers diagnosed in that country through its population-based mammography screening program never would have caused harm.

Nonetheless, comparing studies can be a challenge because of differences in study design. For instance, Drs. Bleyer and Welch counted noninvasive tumors known as ductal carcinomas in situ among the early-stage breast cancers, whereas the Norwegian researchers did not.

A limitation of the current study was the fact that the authors had to infer overdiagnosis from incidence statistics in the population, because overdiagnosis cannot be directly observed at the individual patient level.

The study does not clarify whether an individual woman should be screened for breast cancer, the authors acknowledged. But they noted that the potential harms of unnecessary diagnoses are clear: emotional stress and anxiety, surgery, radiation therapy, hormonal therapy, chemotherapy, or, as is often the case, a combination of these treatments—all for abnormalities that would not have caused illness.

“Women need to understand that screening has positive and negative consequences,” said Dr. Stephen Taplin of NCI’s Division of Cancer Control and Population Sciences, who has studied screening for 25 years but was not involved in this study. “But they also need to know that a decision about screening is not a forever choice. A woman can choose to be screened later, or not at all.” 

He added, “This is one of many studies that is expanding the discussion about screening. It demonstrates that women need to make decisions based on their circumstances, not just based on recommendations.”

After Negative Colonoscopy, Rescreening with Other Tests May Be Effective

According to a new modeling study, people who have a colonoscopy that finds no precancerous polyps (a negative colonoscopy) at age 50 can be rescreened beginning at age 60 with one of three alternative methods rather than having colonoscopies every 10 years, without affecting their life expectancy. Rescreening with one of the alternative methods—highly sensitive fecal occult blood testing (HSFOBT), fecal immunochemical testing (FIT), or computed tomographic colonography (CTC or "virtual colonoscopy")—would also cause fewer complications and cost less.

These results, from the NCI-funded Cancer Intervention and Surveillance Modeling Network (CISNET) team from the University of Minnesota School of Public Health and their colleagues, were published November 6 in the Annals of Internal Medicine.

Most current guidelines recommend rescreening with colonoscopy 10 years after an initial negative colonoscopy. However, these recommendations are not based on results from randomized trials. "There are ongoing trials of colonoscopy, but none of them have reported results yet," said lead author Dr. Amy Knudsen.

The researchers used a model called SimCRC, which was used to inform the 2008 update of the United States Preventive Services Task Force guidelines on colorectal cancer screening. Dr. Knudsen and her colleagues used the model to simulate five different rescreening strategies: no further screening, colonoscopy every 10 years, HSFOBT every year, FIT every year, or CTC every 5 years.

Two adherence scenarios were evaluated: one in which people received the tests as scheduled (perfect adherence) and one that mimicked real-life adherence, as recorded in several published studies (imperfect adherence).

The results were the same in both scenarios: all four rescreening methods reduced the number of deaths from colorectal cancer compared with no rescreening, and the difference among the four methods was small. For example, the imperfect-adherence scenario yielded between 6.1 and 6.7 deaths per 1,000 persons for all four screening methods. (See the table.)

Rescreening with colonoscopy not only produced the highest rates of perforation (tears in the colon) and other complications, but it was the most expensive strategy. Rescreening with one of the other three screening methods produced lifetime savings of up to $495 per person, compared with imperfect adherence with colonoscopy. (See the table.) At a population level, these savings could add up to nearly $3 billion for HSFOBT or FIT, and $0.6 billion for CTC, over the lifetimes of the estimated 6.5 million people who had negative colonoscopy results in 2008.

"Models can be helpful to inform [population] guidelines overall. On an individual level, decisions should be made in consultation with one's doctor," concluded Dr. Knudsen.

Screening Methods Compared (Imperfect Adherence)
Screening Method

Deaths per 1,000 People

Estimated Lifetime Savings Per Person, Compared with Colonoscopy

Colonoscopy

6.4

n/a

Fecal immunochemical testing

6.4

$450

Computed tomographic colonography

6.1

$91

Highly sensitive fecal occult blood test

6.7

$495

This study was funded by the National Institutes of Health (RC1CA147256 and grants U01CA088204, U01CA152959.)

Longer Delays in Breast Cancer Treatment May Affect Survival

Delays between a breast cancer diagnosis and treatment increase the risk of death for women with late-stage cancers, according to a study published November 19 in the Journal of Clinical Oncology (JCO). A second study appearing in the same issue of JCO found that the median wait time between diagnosis and treatment has grown longer. According to the authors, findings from the studies may provide data that can be used to develop quality measures for breast cancer care.
 
The first study looked at the length of time between a breast cancer diagnosis and the start of treatment among women who were enrolled in the North Carolina Medicaid system. Dr. John M. McLaughlin and his colleagues found that women with late-stage breast cancer who waited more than 60 days between diagnosis and treatment had a 66 percent greater risk of death from any cause and an 85 percent greater risk of death from breast cancer than women who began treatment within 60 days.

By contrast, treatment delays of more than 60 days in patients with early-stage breast cancer were not associated with survival differences.

The findings "suggest that interventions should target late-stage patients to increase the timeliness of receiving breast cancer treatments and that clinicians should structure their practice settings to promptly triage and initiate treatment for patients diagnosed at late stage," the authors wrote.

The second study looked at patients with nonmetastatic breast cancer from the SEER-Medicare Linked Database and found that the median wait between the first physician visit and first surgery rose from 21 days in 1992 to 32 days in 2005. Dr. Richard Bleicher of the Fox Chase Cancer Center in Philadelphia and his colleagues found that times to surgery were longest among black and Hispanic patients, patients in the northeast, and patients in large metropolitan areas. The researchers also found that more complex surgeries—for example, a simultaneous mastectomy and reconstruction—were associated with longer wait times.

Imaging, biopsies, and clinician visits all made statistically significant contributions to surgery delays. "More episodes of care may cause delay but may allow for better assessment of treatment alternatives," the authors explained.

"One challenge in caring for patients is not just to give quality care but to give timely care," Dr. Bleicher said. "My hope is that this study provides physicians—and patients—a point of reference for time to surgery that we've never really had before."

These studies were funded in part by the National Institutes of Health (1R01CA121317 and N01-PC-35136).

Fusion Gene Linked to Rare Form of Childhood Leukemia

Researchers have identified a fusion gene that may drive some rare and difficult-to-treat cancers in children called acute megakaryoblastic leukemias (AMKL). The investigators have also developed a test that can detect this genetic change in children at the time of diagnosis, which will help doctors identify candidates for future clinical trials of much-needed new therapies.

The findings, published November 13 in Cancer Cell, are from the Pediatric Cancer Genome Project. Led by St. Jude Children's Research Hospital in Memphis and Washington University in St. Louis, the project is analyzing the normal and cancer genomes of hundreds of children and adolescents with a variety of cancers.

This particular study focused on AMKL that develops in children without Down syndrome, an aggressive form of the disease whose biology is poorly understood. (Children with Down syndrome who develop AMKL have excellent prognoses.)

The researchers initially found the fusion gene in 7 of the first 14 patients whose RNA they analyzed, which was an unexpectedly high frequency. After finding the fusion gene in a substantial fraction of another, larger group of patients, the researchers estimated that 27 percent of children with AMKL have the fusion gene.

When the investigators looked at survival statistics, the results were striking. At St. Jude, only 34 percent of children with the fusion gene were alive 5 years after diagnosis, compared with nearly 89 percent of those who lacked the fusion gene. AMKL in children without Down syndrome "is very rare, but the outcomes are very poor," noted Dr. Tanja Gruber of St. Jude, the study's first author.

The fusion gene codes for a chimeric protein that includes part of CBFA2T3, a protein that helps immature blood cells continue to divide (proliferate), and GLIS2, a transcription factor that is expressed in the kidneys and that had not been associated previously with cancer. Studies in mice suggested that the fusion protein helps immature blood cells proliferate for longer than normal cells.

In further experiments, the authors traced this effect to a signaling pathway known as BMP, which was much more active in cells with the fusion gene than in cells without it. The fusion protein is likely to affect other signaling pathways as well, the researchers said.

No drugs are currently available to block the effects of the fusion protein. But a diagnostic test based on a laboratory technique called PCR will enable clinical trials to begin as promising treatments emerge, Dr. Gruber noted. For now, the fusion gene could be a marker of poor prognosis.

The researchers also found that patients with the fusion gene had, on average, seven other genetic changes, whereas patients without the fusion had 17 other genetic changes. "This tells us that while you do need additional mutations beyond the fusion gene to cause the disease, you need very few of them," said Dr. Gruber. Which of these lesions are important in the disease still needs to be determined in future studies, she added.

This work was supported in part by the National Institutes of Health (P30 CA021765).

Further reading: Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment (PDQ)

Alternative Type of Brachytherapy Proves Effective in Mice

An injectable genetically engineered peptide polymer may one day offer an alternative to conventional brachytherapy, a commonly used radiation therapy technique, according to the results of a new study in mice. The treatment could eliminate some of the difficulties associated with brachytherapy, the researchers believe, and could be used to treat more cancer types than brachytherapy. The study results were published November 15 in Cancer Research.

Using mouse models of two different cancer types, the researchers showed that their alternative brachytherapy approach—directly injecting tumors with a biodegradable elastin-like polypeptide (ELP) that is "labeled" with radioactive iodine—effectively shrank tumors and, in many cases, eliminated them completely.

In conventional brachytherapy, radioactive seeds are implanted in tumors and later removed. This type of internal radiation therapy is used frequently to treat localized prostate cancer and, to a lesser extent, to treat breast cancer. The seeds must be implanted and removed surgically, however. Another disadvantage is that implanted seeds can travel to other, healthy tissues, explained the study's lead investigator, Dr. Wenge Liu of Duke University, and his colleagues.

By contrast, ELPs are liquid at room temperature and can be injected into tumors. Once inside tumors, they assemble into small seeds, or depots. In the study, the researchers tested ELP formulations that varied in their amino acid composition, size, and concentration to determine which one developed the most stable depots and was retained longest in the tumor before breaking down.

The researchers identified the ELP that had demonstrated the best tumor retention, and they tested three variations in mouse models of prostate and head and neck cancers. After only a single administration, the most effective variation shrank tumors in all of the mice regardless of tumor type. It also completely eliminated tumors in two-thirds of the mice with head-and-neck tumors and all of the mice with prostate tumors.

A potential advantage of the ELP is that it eventually breaks down into nontoxic forms that are naturally excreted by the body, Dr. Liu and his colleagues wrote. They reported no clinical signs of side effects in the treated mice, and additional examinations showed that the radioactive iodine was concentrated at the tumor site, with very little accumulation in healthy tissues.

In addition to treating several types of localized tumors, an ELP has other potential uses, the researchers wrote, including shrinking (debulking) tumors considered to be inoperable so that they can be removed surgically.

The researchers are continuing to refine the approach, Dr. Liu said in an e-mail message, including investigating whether the radioactive iodine dose can be lowered without sacrificing efficacy and working to improve delivery of the ELP "to solid tumors located deep in the body, such as in the esophagus, bronchus, stomach, and colon or abdominal cavity."

This research was supported in part by the National Institutes of Health (5R01CA138784-03).

HHS Update

Launch of New Online Resource: BeTobaccoFree.gov

BeTobaccoFree.gov tile

The Department of Health and Human Services (HHS) has created a new resource to educate people about the harmful effects of tobacco use. The new website, BeTobaccoFree.gov, brings together information on tobacco products, the health hazards of tobacco use, quitting smoking, and more from across HHS, including NCI.

The content is accessible on multiple platforms, including smartphones and tablets. The site also features “Say It—Share It,” a social media dashboard that provides updates from HHS tobacco-related social media accounts, including Facebook, Twitter, YouTube, and Tumblr.

Further reading: NCI Fact Sheet: Harms of Smoking and Health Benefits of Quitting

CDC Update

New Statistics on Breast Cancer Incidence and Mortality Show Disparities, Opportunities

Currently, black women in the United States have higher rates of death from breast cancer than white women, even though fewer black women are diagnosed with the disease. The latest evidence on these disparities comes from a study in the November 16 Morbidity and Mortality Weekly Report (MMWR).

Dr. Lisa Richardson of the Centers for Disease Control and Prevention (CDC) and her colleagues analyzed statistics on breast cancer incidence, stage at diagnosis, and mortality for U.S. women. They used United States Cancer Statistics (USCS) data from 2005 to 2009. Among other results, the authors found that 27 deaths occurred for every 100 black women diagnosed with breast cancer, whereas 18 deaths occurred for every 100 white women diagnosed.

"This study provides further description of disparities in breast cancer between white and black women and discusses factors that contribute to the differences," said co-author Dr. Kathy Cronin of NCI's Division of Cancer Control and Population Sciences (DCCPS). Another contribution of the study, she noted, are national maps that visually represent the ratio of incidence and mortality for white women and black women across states.

The authors offered some suggestions for reducing the disparity at the individual level and at the health care-system level. At the individual level, the authors noted, timely follow-up care after an abnormal screening exam and access to state-of-the-art treatments are critical to improving survival among black women. At the health care-system level, their recommendations included expanding the use of information technology and patient navigation.

Although biological differences in tumors explain some of the disparities, Dr. Cronin noted, there are "considerable opportunities to reduce the gaps throughout the continuum of care—from early detection and follow up of abnormal results through access to and compliance with high-quality treatment."

Further reading: "Building a Better Cancer Screening Process"

Notes

NCI's Steven Rosenberg Awarded Keio Medical Science Prize

Dr. Steven Rosenberg
Dr. Steven Rosenberg

Dr. Steven Rosenberg, chief of surgery at NCI’s Center for Cancer Research, has won a 2012 Keio Medical Science Prize for his development of immunotherapies for patients with cancer. Japan’s Keio University awards the prize each year to recognize research achievements in the fields of medicine and life science.

Dr. Rosenberg was the first to show that stimulating the immune system with interleukin-2, a protein that helps regulate immune responses, could cause durable tumor shrinkage in patients with metastatic melanoma and kidney cancer. Dr. Rosenberg and his colleagues have identified and characterized dozens of tumor antigens—molecules on cells that can generate immune responses—that have been widely used in the development and study of cancer vaccines.

Dr. Rosenberg also led efforts to improve the effectiveness of immunotherapies by pioneering a technique called adoptive cell transfer, which has led to durable, complete cancer remissions in a number of patients with metastatic cancer. His recent work using genetically engineered T cells was the first to successfully treat patients with advanced metastatic melanomas, sarcomas, and lymphomas that did not respond to standard therapies.

Further reading: “A Transfer of Power: Harnessing Patients’ Immune Cells to Treat Their Cancer;” “Complex Immune-Based Cancer Treatment Shows Signs of Progress;” and “Genetically Engineered Immunotherapy for Advanced Cancer

NCI Advisory Committee on Clinical Trials Will Meet Friday

The Clinical Trials and Translational Research Advisory Committee (CTAC) will meet later this week on November 30 on the NIH main campus in Bethesda, MD.

The meeting will highlight the NCI Cancer Clinical Investigator Team Leadership Award program, the Pancreatic Cancer Working Group, an update on efforts to transform the NCI clinical trials enterprise, and changes to NCI’s community oncology trials programs.

The agenda is available online, and the meeting is open to the public. Those who cannot attend in person can watch the videocast

AccrualNet Website Gets New Look

Accrual Net website

NCI recently redesigned the AccrualNet website, a centralized resource for clinical trial professionals that features information on trial recruitment, strategies, and tools. The new design makes it easier to access the site’s resources, including training tools for new staff, sample letter templates, and best practices for communicating with patients.

AccrualNet seeks to help clinical trial professionals connect with others across the country and around the world. Registered users can now create their own “Community of Practice,” where invited members can interact and learn from each other about common issues related to clinical trial accrual. To learn more about Communities of Practice and how to use AccrualNet, watch the video tutorial.

New features include

  • A growing repository of more than 700 resources aligned with each phase of the clinical trial accrual lifecycle;
  • An updated space to connect with clinical trial colleagues and ask questions, share experiences, solve challenges, and celebrate success;
  • Updated professional education resources to help train new team members; and
  • Patient education materials.