National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
May 1, 2012 • Volume 9 / Number 9

NEWS

Illustration of a woman's abdomen showing the bladder

Chemoradiation May Help Some Patients with Bladder Cancer Avoid Radical Surgery

Researchers in the United Kingdom have found that adding chemotherapy to radiation therapy as a treatment for bladder cancer may reduce the risk of a recurrence more than radiation alone, without causing a substantial increase in side effects.

The combined treatment approach—known as chemoradiation—was tested in 360 patients with muscle-invasive bladder cancer, a potentially deadly form of the disease. Results from the randomized phase III study appeared in the April 19 New England Journal of Medicine. Read more > >

A MESSAGE TO READERS

How Does NCI Fund Grant Applications?

In the 2011 fiscal year, NCI received 4,477 applications for R01 research grants, of which 652 (or approximately 15 percent) received funding. R01 grants are the most common type of NIH research grant. View charts and a table summarizing the overall funding patterns for R01 and R21 grants in various categories of investigators online.

IN DEPTH

UPDATES

  • FDA Update

    • FDA Approves New Drug for Advanced Soft Tissue Sarcoma
  • Cancer.gov Update

    • NCI Report Features Cancer Statistics through 2009 Article contains video
  • Notes

    • Cyber-Seminar Will Explore How to Sustain Community Public Health Programs
    • NCI Experts Contribute to HBO's "The Weight of the Nation" Documentary
    • Free Workshop for Cancer Survivors: Recapturing Joy and Finding Meaning

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

Chemoradiation May Help Some Patients with Bladder Cancer Avoid Radical Surgery

Illustration of a woman’s abdomen showing the bladderNew findings suggest that chemotherapy makes radiation therapy more effective for treating some bladder cancers.

Researchers in the United Kingdom have found that adding chemotherapy to radiation therapy as a treatment for bladder cancer may reduce the risk of a recurrence more than radiation alone, without causing a substantial increase in side effects.

The combined treatment approach—known as chemoradiation—was tested in 360 patients with muscle-invasive bladder cancer, a potentially deadly form of the disease. Results from the randomized phase III study appeared April 19 in the New England Journal of Medicine.

“The success of this trial could mean that fewer patients need to have their bladders removed,” study co-leader Dr. Nick James, of the University of Birmingham, wrote in an e-mail message. “This approach also provides a viable treatment alternative for frailer patients who are too weak for surgery.”

The authors of an accompanying editorial agreed, calling the trial a “landmark” study.

“These data are really quite compelling,” said one of the editorialists, Dr. William Shipley of Massachusetts General Hospital and Harvard Medical School. Chemoradiation, he continued, can now be regarded as one of several treatment options for patients with muscle-invasive bladder cancer and their physicians to consider.

Preserving the Bladder

In the study, 182 participants were randomly assigned to receive chemotherapy with fluorouracil and mitomycin C in addition to radiation therapy; the other 178 received radiation therapy alone. All participants had muscle-invasive bladder cancer.

Thirty-three percent of the patients who received chemoradiation experienced a relapse in the bladder or in the surrounding tissues within 2 years, compared with 46 percent of those who had radiation therapy alone. The results also showed that, after a median follow-up of about 70 months, the addition of chemotherapy cut the relative risk of invasive disease recurrence by almost half.

A medical illustration showing the cross section of a bladder with seven stages of bladder cancer, from non-muscle-invasive cancer to muscle-invasive cancer.Most bladder cancers begin in cells that make up the inner lining of the bladder. In some cases, cancer cells invade the bladder wall and other surrounding tissues. This illustration shows seven stages of bladder cancer, from non-muscle-invasive cancer to muscle-invasive cancer.

There was not a statistically significant difference in overall survival between the chemoradiation and radiation-only groups. More patients in the radiation-only group than in the chemoradiation group had their bladders surgically removed (cystectomy) following a recurrence, and the researchers noted that this increased rate of surgery could make it difficult to determine whether the combination treatment improves survival.

Although the trial did not directly compare chemoradiation with surgical removal of the bladder, the findings add to evidence that a considerable proportion of patients with muscle-invasive bladder cancer can avoid radical surgery for the disease, noted Dr. Bhadrasain Vikram, chief of the Clinical Radiation Oncology Branch of NCI’s Radiation Research Program.

“These trials are hard to do because of the relative rarity of muscle-invasive bladder cancer and—especially in the United States—the conviction of many urologists that removal of the bladder is the preferred treatment whenever possible,” Dr. Vikram added. (Non-muscle-invasive bladder cancers are not life threatening, and minor surgery during cystoscopy is often effective.)

Similar Results Seen in Anal Cancer

The rationale behind testing chemoradiation for bladder cancer was that the chemotherapy would make the radiation therapy more effective, as has been demonstrated in some other cancers. Indeed, the new results mirror the experience of patients with anal cancer, who have been able to avoid the trauma of having the anus removed surgically, noted Dr. Shipley.

When chemotherapy is used to treat bladder cancer in the United States, doctors have traditionally used cisplatin-based combinations rather than fluorouracil and mitomycin C. It will be up to individual physicians to decide which drug to use in a chemoradiation regimen, the editorialists noted.

Regardless of which drugs are used, surgery will remain a critical option for patients treated with an organ-preservation strategy. Patients who have a recurrence after receiving chemoradiation need additional treatment such as surgery; not all patients are candidates for surgery, however.

“Although chemoradiation presents an option for patients who are ineligible for surgery, the current study does not specifically address this patient population,” said Dr. Matthew Milowsky, co-director of the urologic oncology program at UNC Lineberger Comprehensive Cancer Center in Chapel Hill, NC. “This approach is not for all patients, and it is important to appropriately select patients for bladder preservation therapy,” he added.

Matching Patients to Therapies

Future studies will assess potential tumor markers that could help identify candidates for the procedure at the time of diagnosis. One potential marker is a protein called MRE11, which is involved in the cellular response to radiation-induced DNA damage, Dr. Shipley noted.

In the meantime, the new results could increase interest in strategies that aim to preserve the bladder. “Removing the bladder is a major operation with implications for the rest of the patient’s life,” said study co-leader Dr. Robert Huddart, from the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, in a statement.

In the United States, bladder preservation is underutilized, noted Dr. Howard Sandler, chair of Radiation Oncology at Cedars-Sinai Medical Center. The vast majority of patients who are eligible for surgery get surgery, he said, in part because there are few good studies comparing radiation-based approaches with surgery.

“The take-home message of this study is that patients with muscle-invasive bladder cancer should have a discussion with their physicians about the role of bladder preservation using chemotherapy and radiation therapy,” said Dr. Sandler.

Edward R. Winstead

Cancer Research Highlights

Type of Surgery Affects Long-Term Survival in Early-Stage Kidney Cancer

Older patients with early-stage kidney cancer lived longer if only the tumor, and not the entire kidney, was removed, according to a new study. Cancer-specific survival, however, was similar regardless of whether patients had a partial nephrectomy or a radical nephrectomy. The findings were published April 18 in JAMA.

Dr. David Miller of the University of Michigan Comprehensive Cancer Center and his colleagues used NCI’s SEER-Medicare Linked Database to analyze data from approximately 7,100 Medicare beneficiaries who had surgical treatment for kidney tumors that were 4 cm or smaller (stage T1a) between 1992 and 2007.

The authors used a statistical model to adjust for differences between the two treatment groups. This analysis showed that patients who had a partial nephrectomy had a 46 percent lower risk of death from any cause. Based on the model, the research team estimated that one death was averted during 8 years of follow-up for every seven patients treated with partial nephrectomy instead of radical nephrectomy.

Radical nephrectomy can substantially increase the risk of developing chronic kidney disease, studies have shown. The survival difference seen in the JAMA study and others, explained Dr. Miller, may be due to a greater frequency of long-term complications from chronic kidney disease, including cardiovascular adverse events, among patients who received radical surgery. He cautioned, however, that further research is needed to demonstrate whether complications are, in fact, the cause of the survival difference.

Although clinical guidelines now recommend partial nephrectomy for most patients with early-stage kidney cancer, the procedure has not been widely adopted. In this study, only 27 percent of the patients had undergone a partial nephrectomy. Choosing which type of surgery to have, Dr. Miller acknowledged, can involve a trade-off because partial nephrectomy is more technically challenging than radical nephrectomy and can be associated with more short-term complications.

Active surveillance—forgoing immediate treatment after diagnosis and closely monitoring the tumor—is another option for some patients. And minimally invasive robotic surgery is also increasingly being used to perform partial nephrectomy, added Dr. Miller. “From my view, the robotic platform has made partial nephrectomy a much more technically accessible procedure.”

Survival Differences Persist Between Black and White Children with Cancer

Despite substantial improvements in childhood cancer survival over the past several decades, racial disparities in survival rates persist—and, in fact, have worsened for some cancer types—according to a study published online April 30 in the Journal of Clinical Oncology.

The study, by researchers from St. Jude Children’s Research Hospital, showed that over two different study periods, black children diagnosed with cancer in the United States were less likely to survive 5 years after diagnosis than white children. But when the researchers analyzed survival rates for children treated at St. Jude specifically, there was no survival difference between black and white patients. St. Jude accepts and treats all patients regardless of ability to pay and absorbs all costs not covered by third-party insurers.

To conduct the study, the research team analyzed data from NCI’s Surveillance, Epidemiology, and End Results (SEER) database and from St. Jude’s own patient registry. The researchers looked at data for two periods: 1992 to 2000 and 2001 to 2007. The analysis included only black and white patients.

Although survival rates improved substantially for several cancers from the earlier to the later study period, the SEER data analysis “showed significantly inferior outcomes for black patients in the vast majority of disease categories,” the researchers reported. The survival disparity narrowed over time for acute lymphoblastic leukemia and Hodgkin lymphoma but expanded for acute myeloid leukemia and neuroblastoma. At St. Jude, survival rates also improved between the two time periods for most types of cancer but were similar in blacks and whites.

Although information on participants' socioeconomic status was not available, when the researchers looked at insurance coverage as a proxy for socioeconomic status, black patients were far more likely to have public insurance and far less likely to have private insurance.

The study’s lead investigator, Dr. Ching-Hon Pui, chair of St. Jude Department of Oncology, said he was “disappointed” to see that survival disparities between black and white patients in the United States had not narrowed but was encouraged by the results at St. Jude showing that this disparity can be overcome.

Lack of access to team-oriented care with strong medical and psychosocial support is clearly a driving factor behind the continued disparities, Dr. Pui added. He cited, for example, lower rates of adherence to treatments among underprivileged patients. “It takes a lot of time and effort to explain to parents or guardians how to take the medicine and to make sure that patients actually get their medicine,” he said. “[At St. Jude] we have a team of nurse practitioners, nurses, social workers, and doctors of pharmacy to help with those sorts of things.”

For more information about cancer disparities research, visit NCI’s Center to Reduce Cancer Health Disparities.

Hispanics Have Lower Death Rates for Common Lung Cancer

A large population-based analysis of U.S. patients diagnosed with non-small cell lung cancer (NSCLC) indicates that Hispanic white patients have better overall survival than non-Hispanic whites and blacks, according to a report published online April 23 in Cancer. The researchers also found that Hispanic whites had higher rates than non-Hispanic whites of a subtype of NSCLC that has a more favorable prognosis than other subtypes of the disease.

Dr. Brian Lally and his colleagues at the University of Miami analyzed data from more than 172,000 patients in NCI’s Surveillance, Epidemiology, and End Results (SEER) database who were diagnosed with NSCLC between 1988 and 2007. Among the clinical variables that could account for the differences in survival, the investigators found that the NSCLC subtypes associated with better survival, particularly the bronchioalveolar carcinoma subtype, were more common in Hispanic whites.

The authors noted that previous studies have indicated that Hispanic white patients have better survival than non-Hispanic white and black patients for several diseases, including cardiovascular disease, breast cancer, and prostate cancer. “This finding was previously termed the ‘Hispanic paradox,’ because [Hispanic whites] in the United States tend to have fewer resources and less access to care than [non-Hispanic whites] and also tend to have a poverty rate similar to that of blacks,” the authors noted.

“The results of our analysis suggest that different molecular phenotypes of NSCLC may be the product of an interaction between genetic and environmental factors that could be related to ethnicity,” the researchers said. Further studies into these factors are needed, they concluded.

Women at High Risk for Breast Cancer May Benefit from Starting Mammography at Age 40

For women with twice the average risk of developing breast cancer, the benefits and harms of beginning biennial (every-other-year) screening mammography at age 40 are similar to those for average-risk women aged 50 to 74 screened biennially, according to a new modeling study. These results, published May 1 in the Annals of Internal Medicine, may provide important information to move toward individualized, risk-based screening, the study authors wrote.

A companion paper published in the same issue of Annals identified women aged 40 to 49 with a first-degree relative with breast cancer or with extremely dense breasts (Breast Imaging Reporting and Data System category 4 breast density) as having double the average risk of breast cancer.

To determine which women younger than 50 might benefit from mammography at a level similar to those aged 50 to 74, Nicolien van Ravesteyn of Erasmus Medical Center in the Netherlands and her colleagues used four breast cancer models developed by the NCI-funded Cancer Intervention and Surveillance Modeling Network (CISNET). These models allowed the authors to estimate the benefits and harms associated with mammography screening for women in their 40s under a variety of different assumptions about a woman’s risk of developing breast cancer. The models also incorporated additional data on film and digital mammography use in community practices from the Breast Cancer Surveillance Consortium.

Among younger women, screening mammography prevents fewer deaths because their risk of breast cancer is lower to begin with, explained the authors. Thus, for most younger women, the harms of screening mammography may outweigh the benefits.

According to the models, for women with twice the average risk of developing breast cancer, “the balance of benefits and harms…of starting biennial screening at age 40 years approximates that of biennial screening for average-risk women starting at age 50 years,” wrote the authors. In the models, annual screening added little benefit, and the risk of false-positive results was higher with digital mammography than with film mammography.

“Decisions related to screening women in their 40s on a personal or public policy level are complex, and these results add to the body of knowledge available to inform these decisions,” said Dr. Kathy Cronin of NCI’s Surveillance Research Program and scientific coordinator of the CISNET breast cancer group. “The results do not directly answer the question of which women should be screened in their 40s, but rather highlight the importance of including individual risk in the discussion between women and their physicians.”

Combination Targeted Therapy for Liver Cancer Shows Promise in Mice

New findings show that a combination of two drugs that act on the same target by different mechanisms is more potent than either drug alone in shrinking tumors and reversing altered gene expression in a mouse model of liver cancer. On the basis of these unexpected findings, published online April 25 in Science Translational Medicine, researchers have initiated an early-phase clinical trial of the drug combination in patients with liver cancer and other solid tumors.

The two drugs—everolimus, which is already approved for the treatment of a number of cancers, and an experimental drug being tested in clinical trials known as BEZ235—inhibit mTOR, a protein that controls cell growth, proliferation, and autophagy. The mTOR signaling pathway is overly active in many human cancers, including 40 to 50 percent of liver cancers. Everolimus and other related mTOR inhibitors, called rapamycins, are being tested in patients with liver cancer in clinical trials.

However, the rapamycins now in clinical use do not completely block the effects of mTOR signaling in cells, explained Dr. Sara Kozma of the University of Cincinnati, who led the new study. She and her colleagues originally set out to determine whether BEZ235 was more effective than the rapamycins. To their surprise, they found that the two drugs had synergistic effects when used together at low doses.

Further experiments showed that the two-drug combination increased autophagy, a process thought to suppress liver tumors, compared with a placebo or either drug alone. More studies are needed to explore how increased autophagy could contribute to tumor regression, Dr. Kozma commented.

“The fact that we could find synergy of BEZ235 with a drug that is already approved for clinical use may facilitate [BEZ235’s] introduction into the clinic,” Dr. Kozma said. Furthermore, she noted, adverse side effects would be reduced if lower doses of the two-drug combination prove effective in treating human cancers.

Also in the Journals: New Diet and Exercise Guidelines for Cancer Survivors

Cancer survivors should eat a healthy diet, get adequate physical activity, and maintain a healthy weight, according to new guidelines from the American Cancer Society (ACS). The guidelines were published April 26 in CA: A Cancer Journal for Clinicians.

The guidelines make recommendations for diet and exercise for various stages of cancer survivorship and review scientific findings on nutrition and physical activity for several common cancers. In general, a diet low in saturated fat and high in fruits, vegetables, whole grains, and protein is recommended, as is 150 minutes per week of moderate exercise or 75 minutes per week of vigorous exercise. The guidelines also include a section with frequently asked questions about alcohol, antioxidants, fat, dietary supplements, and other topics.

Further reading: “The Right Balance: Helping Cancer Survivors Achieve a Healthy Weight

Spotlight

This is the first article in a two-part series on an immune-boosting therapy for cancer called adoptive cell transfer (ACT). Part one focuses on a form of ACT that uses tumor-infiltrating lymphocytes to treat advanced melanoma.

In the May 15 NCI Cancer Bulletin, the second article will describe a form of ACT that uses genetically engineered T cells and is being investigated for the treatment of a variety of cancers. It will also explore the challenges of moving ACT from small clinical trials to everyday use in the clinic.

A Transfer of Power: Harnessing Patients' Immune Cells to Treat Their Cancer

Before and after pictures of a patient with advanced melanoma who underwent treatment with tumor-infiltrating lymphocytes.Before and after pictures of a patient with advanced melanoma who underwent treatment with tumor-infiltrating lymphocytes. Within 2 weeks of treatment, the large tumor had disappeared.

"These patients are probably cured" is not something most oncologists get to say about their patients with advanced cancer. Yet that's exactly how NCI's Dr. Steven Rosenberg describes a number of patients with advanced melanoma treated in three small clinical trials he has led at the NIH Clinical Center.

The patients in these trials—most of whom had tumors throughout their body (metastatic disease) and had nearly exhausted other treatment options—underwent a procedure known as adoptive cell transfer (ACT).

ACT involves removing some of a patient's own immune-system cells, growing billions of them in the laboratory, and infusing the cultured cells into the patient. The idea is to provide an invading force of immune cells that can attack tumors in a way that the immune system was incapable of doing on its own.

"The results in melanoma have been impressive," said Dr. Rosenberg, who, along with his colleagues in the Surgery Branch of NCI's Center for Cancer Research, has done pioneering work on ACT for more than a decade.

Based in large part on the Surgery Branch's success, a small but growing group of researchers at medical centers in the United States and abroad have launched their own programs to study ACT for melanoma and, increasingly, other cancers.

To date, only a few hundred patients have been treated with some form of ACT, but with the promising results reported thus far the treatment is gaining more attention and raising hopes among researchers in the field that it can one day be available to many more patients.

When TILs Attack

The ACT approach used in the three NCI trials entails collecting lymphocytes from patients' tumor samples, known as tumor-infiltrating lymphocytes (TILs), performing tests to identify the cells with the greatest antitumor activity, and then growing those particular cells in the laboratory over a period of weeks.

In this one-time-only treatment, the newly grown lymphocytes, composed primarily of T cells, are infused into the patient along with a cytokine (an immune-stimulating agent) called interleukin-2 (IL-2).

At high enough doses, IL-2 on its own can be a highly effective, even curative, treatment for a small proportion of patients with melanoma and advanced kidney cancer, explained Surgery Branch senior investigator Dr. James Yang. (IL-2 is approved by the Food and Drug Administration for both indications.) But it is difficult to administer and can have significant side effects, which have severely limited its use in clinical practice.

Before receiving the expanded TIL cells, patients also undergo lymphodepletion that consists of a round of chemotherapy and, in one of the treatment's current forms, whole-body radiation. The lymphodepletion "prepares patients to receive the infused lymphocytes without impediments," such as other immune cells that can thwart the incoming T-cell flood, Dr. Yang said.

The results to date are impressive. Of the 93 patients treated in the three trials, 20 have seen their tumors disappear completely (complete response); 19 of those 20 have remained tumor-free for longer than 5 years. (Most of these patients' tumors had not responded to other immunotherapy treatments.) Overall, tumors shrank substantially in 52 patients.

The idea [behind adoptive cell transfer] is to provide an invading force of immune cells that can attack tumors in a way that the immune system was incapable of doing on its own.

Several of the complete responses have extended beyond 8 years. "In my view, that's good evidence that we can probably cure some patients with metastatic melanoma," Dr. Rosenberg said. "And I don't use the term 'cure' lightly."

At the University of Texas MD Anderson Cancer Center, Dr. Patrick Hwu, who trained in NCI's Surgery Branch, has seen similar results in a small clinical trial of patients with metastatic melanoma. Half of the 50 patients treated at MD Anderson have had partial or complete tumor responses, he reported.

TIL therapy "is clearly one of the best treatments for metastatic melanoma," said Dr. Hwu. The use of TIL and other forms of ACT beyond NCI was an important step for the field, he stressed. "We had to prove it could be done at other centers."

As part of that process, researchers at established immunotherapy programs such as those at NCI and MD Anderson consult with their colleagues at other centers that are in the process of or hoping to set up their own programs. Dr. Hwu and his colleagues, for example, worked with researchers at the Moffitt Cancer Center in Florida to establish its immunotherapy program.

TIL therapy has moved overseas as well. Dr. Jacob Schachter leads a TIL therapy program at the Sheba Medical Center in Israel that is seeing similar results in patients with metastatic melanoma. Of the 51 patients treated to date, 6 have had complete responses, 15 have had partial responses, and a number of others have stable disease.

"Seventy percent of the clinical responders are still alive 2 years after treatment," he said.

Making Improvements

As promising as this treatment approach is, there are hurdles to overcome. Like other cancer therapies, TIL therapy has side effects. In addition to toxicities associated with IL-2 and the lymphodepletion regimen, the infusion of billions of T cells can trigger massive immune responses that can cause serious, potentially fatal, problems for patients. And for some patients, an army of T cells can't be grown.

Dr. Schachter's group is attempting to address the latter problem by focusing their efforts on "young" TILs, meaning that the lymphocytes removed from patients' tumors are grown for a shorter period in the laboratory and are not selected for expansion based on whether they exhibit antitumor activity in lab tests.

These "young" TILs, which Surgery Branch researchers are also investigating, "are relatively easy to grow compared to the 'selected TILs,'" Dr. Schachter explained, which has allowed the researchers to successfully formulate treatments for more patients.

Surgery Branch researchers have launched a trial of TILs that are genetically engineered to secrete the cytokine interleukin-12 when the TILs lock onto their molecular target on cancer cells. Some promising results have been seen in the first few patients to receive the treatment.

Dr. Hwu and his colleagues at MD Anderson are combining TIL therapy with other immunotherapies, such as dendritic cell vaccines and ipilimumab (Yervoy). They are also engineering TILs to express receptors to molecules known as chemokines that help guide them to cancer cells.

A major focus of his program's work, Dr. Hwu said, is to standardize the entire process. "We still can't grow TIL cells successfully for every patient," he said. "So we're constantly looking for ways to make the end product better and to grow cells for a higher percentage of patients."

There are clearly challenges to making TIL therapy more broadly available, Dr. Rosenberg acknowledged. But with further research, support, and experience, they can be overcome, he believes.

"If you have a deadly disease like melanoma and a treatment that can induce durable complete regressions of disease," he said, "people are going to want the treatment."

Carmen Phillips

From the Lab to the Clinic and Back

The TIL therapy regimen used by NCI's Surgery Branch serves as the foundation for the ACT treatments being studied at other centers around the world and has been refined based on laboratory and mouse model studies led by Surgery Branch researchers.

For example, mouse model studies led by Dr. Nicholas Restifo showed that more intense lymphodepletion with a radiation regimen made the treatment more effective, a finding that led to similar changes in the TIL regimen used in the NCI-led human trials. Of the three trials, the one that used the highest dose of radiation had the highest complete response rate: 10 of 25 patients, 9 of whose responses have persisted for at least 5 years.

Dr. Rick Morgan led the laboratory and mouse model studies of TILs engineered to express IL-12—an important advance because, although IL-12 can potently kill tumors in mice, it is highly toxic and potentially fatal when administered systemically in humans.

The iterative nature of the process is a cornerstone of the Surgery Branch's work. "I think that's the really unique feature of the NIH Clinical Center and the NIH intramural program," said Dr. Yang. "We can sit together at lunch, talk about results we're seeing in the clinic and how they apply to our lab studies. [We talk about] what's happening with our lab studies and how they should influence our approach in the clinic. It's as quick and productive as anything I've ever been involved in."

A Closer Look

Crunching Numbers: What Cancer Screening Statistics Really Tell Us

Reader Suggested

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

Also in the Journals: Prostate Cancer Screening Rates in Elderly Men Unchanged Despite 2008 Recommendations

Rates of self-reported prostate-specific antigen (PSA) screening for prostate cancer in men aged 75 or older did not change between 2005 and 2010, despite recommendations against routine prostate cancer screening in men of this age group issued by the U.S. Preventive Services Task Force (USPSTF) in 2008. The findings, based on data from the Cancer Control supplements of the 2005 and 2010 U.S. National Health Interview Survey (NHIS), were reported in the April 25 issue of JAMA.

Dr. Scott Eggener of the University of Chicago and his colleagues found that in 2005, 43 percent of 1,552 men aged 75 or older reported having PSA-based screening, whereas in 2010, 44 percent of 1,205 men in the same age group reported being screened.

“The discrepancy between the USPSTF recommendation and subsequent practice patterns may reflect lack of guideline awareness, financial incentives, or patient or physician confidence in PSA screening,” the study authors wrote. Dr. Eggener said he would have expected to see changes in practice patterns by 2010, “particularly since the 2008 recommendations were so widely covered in the mainstream press.”

Last October, the USPSTF issued a draft recommendation against routine PSA-based cancer screening in healthy asymptomatic men of any age. “Clinical practice patterns [following the release of those recommendations] should be monitored,” the study authors concluded.

Featured Clinical Trial

Surgical and Radiation Therapies for High-Risk Early Lung Cancer

Name of the Trial
Phase III Randomized Study of Sublobar Resection with or without Brachytherapy Versus Stereotactic Body Radiotherapy in High-Risk Patients with Stage I Non-Small Cell Lung Cancer (ACOSOG-Z4099). See the protocol summary.

Dr. Hiran Fernando Dr. Hiran Fernando

Principal Investigator
Dr. Hiran Fernando, American College of Surgeons Oncology Group

Why This Trial Is Important
For patients with stage I non-small cell lung cancer, surgical removal of the cancer-containing lobe of the lung (lobectomy) or the whole lung (pneumonectomy) can potentially cure their disease and is the current standard of care. However, patients who undergo these operations must be healthy enough to withstand the loss of lung function incurred by losing an entire lobe of a lung or a whole lung.

Stage I lung cancer patients whose medical history indicates that they would not be able to tolerate a lobectomy or a pneumonectomy are categorized as either high-risk operable or medically inoperable. High-risk operable patients can still have surgery to remove a segment of the affected lobe (segmentectomy) or a smaller piece of the lung in which the tumor resides (wedge resection). Although these “sublobar” resections may still cure their disease, the likelihood of recurrence in the affected lobe (local recurrence) or regional lymph nodes is greater than with resection of a whole lobe or the entire lung.

To help prevent local recurrence, some doctors have begun to incorporate a type of radiation therapy called brachytherapy into their treatment approaches. Sublobar resection with brachytherapy involves implanting radioactive seeds after surgery into the area where the tumor had been. Although the addition of brachytherapy has been reported to help prevent local recurrences, the combination of surgery and brachytherapy is not the current standard of care. Researchers hope that the results of a recently completed randomized clinical trial of sublobar resection with or without brachytherapy will help define its role in this patient population. 

Patients with stage I lung cancer who are categorized as medically inoperable (unable to tolerate any surgery) may be treated—and potentially cured—with a form of high-dose radiation treatment called stereotactic body radiation therapy (SBRT). 

A recent phase II trial showed that SBRT resulted in better tumor control and overall survival than what was historically seen in this patient population. Because SBRT typically produces fewer side effects than sublobar resection, doctors are questioning whether SBRT may be preferable to sublobar resection for high-risk operable patients.

Attempting to compare the two therapies by analyzing previous studies is problematic for several reasons, including differences in the way radiation oncologists and surgical oncologists have traditionally defined events such as local recurrence, differences in the patient populations treated by these approaches, and differences in the durations of follow-up in these studies.

In the current trial, patients with high-risk operable stage I lung cancer will be randomly assigned to undergo either sublobar resection (with or without brachytherapy, depending on the standard practice at each treating institution) or SBRT. Doctors will assess overall survival at 3 years and compare local and regional recurrence-free survival, disease-free survival, serious adverse events, and lung function.

“We believe that surgery confers some oncological benefits over SBRT; however, these benefits may be balanced by the lower risks of SBRT, which is a major consideration for patients who are deemed high risk,” said Dr. Fernando. “The primary aim of the study is to demonstrate that survival will not be inferior with SBRT compared to surgery.

“We also want to look at the patterns of recurrence between the two modalities, so we’ve standardized all those definitions that refer to recurrence and tumor control,” he explained. “The use of standardized definitions will allow us to develop a better understanding of how these two very different therapies compare with each other.”

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

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

Community Update

The Leading Edge: Small Businesses Bring Novel Cancer Technologies to Market

Representatives from Firefly BioWorks, Inc., meet with potential strategic partners during a partnering break at the 2012 SBIR Investor Forum.Representatives from Firefly BioWorks, Inc., meet with potential strategic partners during a partnering break at the 2012 SBIR Investor Forum.

Eighteen companies funded by NCI’s Small Business Innovation Research (SBIR) Development Center presented the next generation of cancer therapeutics, diagnostics, and devices at the SBIR 2012 Investor Forum, held April 18 at Agilent Technologies in Santa Clara, CA. Nearly 200 SBIR-funded companies, investors, venture capitalists, and strategic partners attended the meeting.

“Small businesses play a vital role in cancer research in our nation,” said Michael Weingarten, director of the SBIR Development Center. “NCI is committed to fostering public-private partnerships that will help bring new cancer technologies to market to support clinicians and patients in the fight against cancer.”

With $115 million in annual funding, SBIR is one of the largest sources of early-stage funding for small businesses involved in cancer research. SBIR looks for companies on the leading edge of innovation and provides them with the funding necessary to develop their technologies and move them toward commercialization.

In 2010, companies that presented at the Investor Forum raised more than $230 million in funding from third parties. At the 2012 Investor Forum, more than 150 partnering meetings took place that began discussions about future collaborations. Partnerships and funding are critical to help move new cancer technologies through product development and clinical trials.

“The Investor Forum was extraordinarily productive for us,” said Metabolomx CEO Dr. Paul Rhodes. “We made substantive contacts at the conference and have concrete joint projects on the table to discuss with several companies.”

Panelists discuss investor perspectives on future discoveries in cancer research.Panelists discuss investor perspectives on future discoveries in cancer research.

The companies selected to present at the 2012 Investor Forum were chosen based on the strength of their technological and commercial potential by a review panel composed of scientific and life science investment experts.

“We learned a lot [at the forum] about novel cancer technologies that emerging companies are developing,” said Phil Gutry, principal of MPM Capital, a venture capital firm that focuses on the life sciences. “NCI’s SBIR serves a valuable role in the discovery of new cancer innovations and helps to fill a gap to move early-stage research from the lab to the clinic.”  

The presenting SBIR-funded companies are working on technologies that would address significant needs in cancer research and care, including:

  • novel immunotherapeutics
  • a universal biomarker detection platform that would help improve cancer diagnosis and treatment stratification;
  • a testing platform for the early detection of disease at the cellular level;
  • a breath test for lung and other cancers, for use initially as a companion diagnostic and possibly a prospective prescreen;
  • diagnostic medical devices that use optical technologies to noninvasively identify precancerous epithelial tissue; and
  • in vitro assays to improve drug development and testing.

Dr. Ed Harlow, special advisor to NCI Director Dr. Harold Varmus, provided the keynote address. He shared insights and updates on NCI’s Provocative Questions Project, which is intended to engage a diverse range of scientists to define and solve the major understudied problems in cancer research.

Attendees also received an update from Weingarten, who discussed new initiatives, funding opportunities, and how investors and strategic partners can benefit from the SBIR program. Dr. Jodi Black, deputy director of the Division of Extramural Research Activities at the National Heart, Lung, and Blood Institute, talked about that institute’s SBIR program and translational research efforts to support innovations to improve the treatment of heart, lung, and blood diseases.

The forum closed with a panel discussion on emerging trends in the financing of early-stage cancer companies, led by Michael J. O’Donnell, a partner at Morrison Foerster, with panelists Dr. Jeff Settleman of Genentech, Dr. Armen Shanafelt of Lilly Ventures, Dr. Alex de Winter of Mohr Davidow Ventures, and Brian Atwood of Versant Ventures.

More information about the 2012 NCI SBIR Investor Forum, the presenting companies, and their innovative cancer technologies is available online.

FDA Update

FDA Approves New Drug for Advanced Soft Tissue Sarcoma

The Food and Drug Administration (FDA) last week approved pazopanib (Votrient) to treat patients with advanced soft tissue sarcoma who have previously received chemotherapy. Pazopanib is a pill that works by interfering with angiogenesis, the growth of new blood vessels that solid tumors need to grow and survive.

Soft tissue sarcoma—a rare cancer that begins in muscle, fat, fibrous tissue, and other tissues—is diagnosed in about 10,000 people annually in the United States. More than 20 subtypes of sarcoma were included in the clinical trial that led to the approval of pazopanib. The drug is not approved for patients with adipocytic soft tissue sarcoma or gastrointestinal stromal tumors.

“Soft tissue sarcomas are a diverse group of tumors, and the approval of pazopanib for this general class of tumors is the first in decades,” said Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research.

Pazopanib carries a boxed warning alerting patients and health care professionals to the risk of severe or fatal liver damage. Patients should be monitored for liver function, and treatment should be discontinued if liver function declines, the label advises.

Pazopanib was designated an orphan drug for this indication. The designation is given to a drug intended to treat a disease that affects fewer than 200,000 patients in the United States. Pazopanib was first approved in October 2009 for the treatment of advanced kidney cancer.

For more information, see the FDA news release.

Cancer.gov Update

NCI Report Features Cancer Statistics through 2009

The latest SEER Cancer Statistics Review (CSR), a report of the most recent statistics on cancer incidence, mortality, survival, prevalence, and lifetime risk was released on April 16. The report, from NCI’s Surveillance Research Program, includes statistics from 1975 through 2009, the most recent year for which data are available.

These data show a continued decline in the rate of cancer deaths. The four most commonly occurring cancers during this time period were prostate, breast, colorectal, and lung cancer, accounting for more than half of all cancers.

U.S. population data reflecting the 2010 Census were not available when this year’s CSR was published. The 2010 population data are expected in the summer of 2012, at which point NCI will update the rates and trends in the CSR.

There are three ways to access the statistics in the CSR:

  1. Browse the Tables and Figures: Statistics are presented in HTML format based on user selections.
  2. Access Contents in PDF: Statistics are provided in sections by cancer site and topical groupings.
  3. Generate Custom Reports: Individual pages can be extracted and grouped into custom-made PDFs.

2012 Update: SEER Cancer Statistics Review (1975-2009)

You will need Adobe Flash Player 8 or later and JavaScript enabled to view this video.

Dr. Kathy Cronin discusses the SEER Cancer Statistics Review and current trends in cancer statistics.

Notes

Cyber-Seminar Will Explore How to Sustain Community Public Health Programs

Drs. Mary Ann Sheirer, Doug Luke, Susan Tortolero, and Alice AmmermanDrs. Mary Ann Sheirer, Doug Luke, Susan Tortolero, and Alice Ammerman

The May 8 Research-to-Reality (R2R) cyber-seminar, titled “Making It Last: Sustaining Public Health Programs in Your Community,” will focus on how positive public health outcomes can be achieved if effective programs are sustained over time. The seminar will also look at the factors that affect sustainability, including financial and political climates, the organizational setting, and project design and implementation.

Dr. Mary Ann Scheirer will provide an overview of sustainability and a framework for public health programs and research. Dr. Doug Luke will share a new sustainability assessment tool developed for practitioners, and Drs. Susan Tortolero and Alice Ammerman will present examples of how to apply the available tools and sustainability models to public health programs.

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

To find out more about the cyber-seminar series, e-mail ResearchtoReality@mail.nih.gov.

NCI Experts Contribute to HBO's "The Weight of the Nation" Documentary

NCI Cancer Bulletin special issue on obesity and cancer research

More than two-thirds of U.S. adults and one-third of U.S. children are overweight or obese. And obesity contributes to 5 of the 10 leading causes of death in America, including cancer. Later this month, HBO and the Institute of Medicine, in association with the Centers for Disease Control and Prevention, NIH, the Michael & Susan Dell Foundation, and Kaiser Permanente will launch a campaign centered around a four-part documentary series titled “The Weight of the Nation” that will examine the consequences of obesity for health and for the nation, the science and myths surrounding weight loss and dieting, children and obesity, and the driving forces behind the obesity epidemic.

“If we don’t succeed in turning this epidemic around, we are going to face, for the first time in our history, a situation where our children are going to live shorter lives than we do,” said NIH Director Dr. Francis Collins. “If you were told that your child is at risk for cancer, [or] for some sort of brain disease, that would get your attention. Well, obesity should be on that list.”

Because of the expanding research evidence on the important role of obesity, physical activity, and diet on cancer risk and prognosis, NCI and several other NIH institutes provided information on research that helped guide the development of the documentary.

In addition to the documentary, the campaign will include a three-part film series for families, a website and social media campaign, and nationwide outreach to as many as 40,000 community organizations. All films will be broadcast on all HBO channels and available on HBO.com, with free access to HBO provided by some cable carriers.

Free Workshop for Cancer Survivors: Recapturing Joy and Finding Meaning

Drs. Keith Bellizzi, Suzanne Lechner, and William BreitbartDrs. Keith Bellizzi, Suzanne Lechner, and William Breitbart

The tenth annual Cancer Survivorship Series, “Living With, Through, and Beyond Cancer,” will hold the second of four workshops on May 15, from 1:30 to 2:30 p.m. ET. This free series offers cancer survivors, their families, friends, and health care professionals practical information to help them cope with concerns and issues that arise after treatment ends.

Part II of the series, “Recapturing Joy and Finding Meaning,” will feature Dr. Keith Bellizzi of the University of Connecticut, Dr. Suzanne Lechner of the University of Miami Miller School of Medicine, and Dr. William Breitbart of the Weill Cornell Medical College as speakers.

Participants can listen online or by telephone. To register, visit the workshop webpage.

The two remaining workshops will be held from 1:30 to 2:30 p.m. ET on the following dates:

These workshops are presented by CancerCare, in collaboration with NCI, LIVESTRONG, the American Cancer Society, the Intercultural Cancer Council, Living Beyond Breast Cancer, and the National Coalition for Cancer Survivorship.

If you missed part I of the series, “Using Mind/Body Techniques to Cope with the Stress of Survivorship,” a recording is available online.