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March 6, 2012 • Volume 9 / Number 5

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NEWS

Heavy Diesel Exhaust Linked to Lung Cancer Deaths in Miners

Diesel-powered equipment used in underground mining Long-awaited results from an epidemiological study of workers in non-metal mines suggest that exposure to exhaust from diesel-powered equipment in mines is associated with an increased risk of lung cancer. Even exposure to moderate levels of diesel exhaust was associated with some increased risk of death from the disease among underground miners. The findings are from the Diesel Exhaust in Miners Study (DEMS). Read more > >

COMMENTARY

Roger Daltry of The Who

A Conversation with The Who's Roger Daltrey about Teen Cancer Centers

For the past 12 years, the rock singer has been an outspoken advocate for teens and young adults with cancer. He spoke recently with the NCI Cancer Bulletin about his latest activities and the importance of this often overlooked segment of the cancer patient community.

IN DEPTH

UPDATES

  • Cancer.gov Update

    • NCI's Cancer.gov Goes Mobile
    • NCI Launches Smokefree Texting Service in Spanish
  • Notes

    • In Memoriam: Dr. Renato Dulbecco
    • Cyberseminar Will Explore How to Customize Health Materials
    • Public Comment Sought on Genetic Testing for Breast and Ovarian Cancer
    • National Cancer Advisory Board Holds First Meeting of 2012

A MESSAGE TO READERS

Coverage of AACR Annual Meeting

NCI at AACR 2012 tileThe American Association for Cancer Research's 103rd Annual Meeting will take place March 31–April 4 in Chicago, IL. Click on the tile to learn more about sessions with NCI staff and activities at the NCI exhibit booth. Look for highlights from the meeting in the April 3 issue of the NCI Cancer Bulletin.

 


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

Heavy Diesel Exhaust Linked to Lung Cancer Deaths in Miners

Diesel-powered equipment used in underground miningExhaust from diesel-powered equipment used in underground mines may increase workers’ risk of lung cancer.

Long-awaited results from an epidemiological study of workers in nonmetal mines suggest that exposure to exhaust from diesel-powered equipment in mines is associated with an increased risk of lung cancer. Even exposure to moderate levels of diesel exhaust was associated with some increased risk of death from the disease among underground miners in the study, researchers reported March 2 in the Journal of the National Cancer Institute. (See the first analysis, second analysis, and editorial.)

The findings are from the Diesel Exhaust in Miners Study (DEMS). Launched in 1992 by researchers from NCI and the National Institute for Occupational Safety and Health (NIOSH), the study was designed to clarify the relationship between exposure to diesel engine exhaust and the risk of death from lung cancer. DEMS includes more than 12,000 miners exposed to different levels of diesel exhaust.

Based on the data, the researchers concluded that underground mine workers exposed to the highest levels of diesel exhaust were more likely to die from lung cancer than their colleagues who worked above ground, as well as those who worked underground and were exposed to lower levels of diesel exhaust.

“The results also show that the risk of death from lung cancer grew with increasing exposure to exhaust,” said one of the lead investigators, Dr. Michael Attfield, formerly of NIOSH. This phenomenon is known as an exposure-response relationship, he explained. 

Many Studies, No Consensus

Diesel engine exhaust contains fine particles that enter the body through the nose and mouth and can leave deposits in the lungs. But even after some 35 prior studies investigating lung cancer risk in relation to diesel engine exhaust, the evidence was unclear.

"The results show that the risk of death from lung cancer grew with increasing exposure to exhaust."

—Dr. Michael Attfield

A majority of the studies suggested a modest, but consistent, increased risk of lung cancer associated with this exposure. Many of these studies, however, had important limitations. In some cases, researchers inferred exposure levels based on a subject’s job title, such as truck driver, rather than quantifying subjects’ actual exposures.

To overcome these limitations, Dr. Debra Silverman of NCI’s Division of Cancer Epidemiology and Genetics (DCEG), Dr. Attfield, and their colleagues designed two studies based on DEMS. The first analysis was carried out in the full cohort of 12,315 miners from eight U.S. nonmetal mines. (The analyses did not include metal mine workers because they are often exposed to radon, which could contribute to lung cancer risk and confound the effect of diesel exhaust.)

For each participant, the researchers developed a quantitative estimate of occupational exposure to diesel exhaust based on many sources of information, including mining company records and air samples collected in seven of the eight mines. In addition, they reviewed records on inventories of diesel equipment at each mine, including the year a machine came into use, and ventilation data over time.

Smoking and Diesel Exhaust: A Puzzling Interaction

One of the unexpected findings of the case-control analysis was an apparent interaction between smoking and diesel exhaust among the most heavily exposed workers. Each of these factors was attenuated in the presence of the other factor.

"This was very interesting," said Dr. Silverman, noting that the finding is the first report of this interaction and needs to be replicated in other populations.

The researchers offered a number of possible explanations for the tapering off of smokers' risk at high levels of diesel exhaust exposure. "It may be that smokers are more likely to clear diesel exhaust particulate matter from their lungs than nonsmokers," said Dr. Silverman.

The analysis of the full cohort showed statistically significant increases in the risk of lung cancer mortality among underground workers as the level of diesel exposure increased, especially in those who worked for more than 5 years.

In a second analysis, researchers conducted a nested case-control study, in which subjects who died from lung cancer in the full cohort were compared with matched control subjects from the cohort. For the 198 workers in the study who died from this disease, as well as the matched comparison subjects, the researchers collected additional data, including information about workers’ history of smoking, employment in jobs associated with a high risk for lung cancer, and nonmalignant respiratory disease. Information on smoking and other factors often came from interviews with a worker’s next of kin.

The results of the second analysis showed that workers with heavy exposure to diesel exhaust were three times more likely to die from lung cancer than workers with the lowest exposures, after taking smoking and other lung cancer risk factors into account.

DEMS is the first study to show a statistically significant exposure-response of increasing lung cancer risk associated with increasing exposure to diesel exhaust based on quantitative levels of workers’ exposure, after adjusting for confounding factors such as cigarette smoking, the authors noted.

“Diesel exhaust appeared to have a strong effect on nonsmokers, although this is based on small numbers of nonsmoking cases,” Dr. Silverman said. Among nonsmokers in the study, exposure to high levels of diesel exhaust resulted in seven times the risk of death from lung cancer, compared with exposure to low levels. (For information on smokers and diesel exhaust, see the sidebar.)

The new studies are “an important contribution to the body of evidence about diesel engine exhaust,” wrote Dr. Lesley Rushton of Imperial College London in an accompanying editorial. The findings are also timely, because the International Agency for Research on Cancer (IARC) will meet this year to review the evidence linking diesel engine exhaust to cancer. In 1989, the agency classified the exhaust as a “probable” carcinogen.

Environmental Exposures and Urban Areas

The new findings are important not just for miners, but also for the 1.4 million American workers and millions more worldwide who are exposed to diesel exhaust in the workplace and for people who live in cities with high levels of diesel exhaust, the study authors noted.

Diesel-powered equipment used in underground miningA diesel-powered machine that inserts bolts into mine roofs to strengthen them

Their results suggest that in some urban areas high air concentrations of elemental carbon, which is considered the best index of diesel exhaust, may confer an increased risk of lung cancer. Dr. Silverman and her colleagues estimated that people who live in highly polluted cities may have about the same lifetime exposure to diesel exhaust as underground miners with low exposures in their study.

Based on these reports and other results, “stringent occupational and particularly environmental standards for diesel engine exhaust should be set and compliance ensured to have an impact on health outcomes,” Dr. Rushton wrote.

“Society should endeavor to minimize exposures to diesel exhaust, and diesel engine manufacturers are already working on this,” said Dr. Attfield. Diesel engines tend to last a long time, however, so many people will likely be exposed to exhaust from older engines for years to come. 

Newer, cleaner diesel engines have been developed only recently, Dr. Silverman noted. “Our study addresses the health effects of exhaust from diesel engines that are currently in use around the world—predominantly the old technology,” she added.

—Edward R. Winstead

Cancer Research Highlights

Vemurafenib Improves Survival for Patients with Metastatic Melanoma

Patients with metastatic melanoma whose tumors harbor a specific genetic mutation have improved overall survival with the targeted therapy vemurafenib (Zelboraf), according to longer-term follow-up data from a phase II clinical trial published in the February 23 issue of the New England Journal of Medicine. The mutation, the V600 mutation in the BRAF gene, is found in approximately half of patients diagnosed with melanoma.

After a median follow-up of almost 13 months, median overall survival was nearly 16 months in the trial of 132 patients whose cancer was no longer responding to standard treatments—a substantial improvement over the 6- to 10-month median survival traditionally seen in patients with metastatic melanoma. The median progression-free survival was 6.8 months.

Last year, based on the impressive early results of a large phase III trial, the Food and Drug Administration approved vemurafenib for the treatment of patients with metastatic disease whose tumors have this mutation.

In the current trial—funded by the drug’s manufacturer, Roche—a tumor response was observed in more than half of the patients, with 6 percent of patients experiencing a complete response. Most patients whose tumors responded to treatment saw their tumors shrink within 2 months.

Most patients taking the drug will ultimately develop resistance, said the study’s lead author, Dr. Jeffrey Sosman of Vanderbilt-Ingram Cancer Center in Tennessee. But a subset of patients, he noted, have shown no signs of progression even 2 years after beginning treatment.

The drug is generally well tolerated, the researchers reported. Nevertheless, 45 percent of patients had their dose of the drug reduced, and nearly two-thirds had to have their treatments temporarily stopped, because of side effects. Common side effects included rash, joint pain, and extreme sensitivity to light. And, as has been seen in other trials of vemurafenib, approximately one-quarter of patients developed cancerous or precancerous non-melanoma skin lesions.

In most of these patients, only one or two lesions were found, and in all cases they could be removed easily with surgery, Dr. Sosman said.

Less-Invasive Colorectal Screening Test May Detect Cancer as Effectively as Colonoscopy

Initial findings from a European clinical trial show that colonoscopy and fecal immunochemical testing (FIT), a type of stool test, detect a similar number of colorectal cancers. Investigators leading the COLONPREV trial are testing whether screening average-risk individuals only once with colonoscopy can reduce the number of deaths from colorectal cancer compared with biennial screening with FIT. The results from the trial’s first round of screening appeared February 23 in the New England Journal of Medicine.

More participants in the FIT group than the colonoscopy group complied with screening, 34.2 percent versus 24.6 percent. The two tests had similar cancer detection rates, and the stage of the cancers found did not differ between the groups. Colonoscopy, however, was better than FIT at detecting both advanced and, especially, nonadvanced adenomas. But the extent to which nonadvanced adenomas are likely to progress to more advanced disease is not yet known.

“Since the primary outcome of this trial is the reduction in the rate of death from colorectal cancer at 10 years, the relative benefits and risks of the two strategies will be assessed at the end of the trial,” explained the authors. Follow-up will continue through 2021.

These results hold promise, noted Dr. Barry Kramer, director of NCI’s Division of Cancer Prevention, because the less-invasive FIT—which had better screening participation—picked up the same number of cancers as colonoscopy during the initial period of the trial.

“The final proof will be mortality, but it’s certainly conceivable that, as the trial goes on, FIT will continue to pick up potentially lethal cancers that are missed by a one-time [colonoscopy],” he explained. In the COLONPREV design, patients assigned to colonoscopy get a single test, whereas patients assigned to FIT receive the stool test every 2 years over a 10-year period.

Chemotherapy Can Impair Cognition More than Two Decades Later

More than 20 years after treatment, breast cancer patients who received adjuvant chemotherapy exhibited cognitive deficits compared with women who were never diagnosed with cancer. The results, which appeared online February 27 in the Journal of Clinical Oncology, suggest that the phenomenon known as chemobrain can persist for decades after cancer treatment ends and may become more common as the number of cancer survivors grows.

To investigate chemotherapy’s long-term effects on cognition, Dr. Vincent Koppelmans of Erasmus MC University Medical Center in Rotterdam, the Netherlands, and his colleagues identified 196 eligible breast cancer patients from two Dutch hospital registries and invited them to participate in tests that measured learning, memory, information processing, and psychomotor abilities.

All of the patients had received six cycles of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) on average 21 years earlier and were between 50 and 80 years old when recruited to the trial. Women who had experienced a relapse, second primary tumor, or distant metastases, and those who used adjuvant endocrine therapy were excluded from the study.

The 1,509 women in the reference group were selected from the Rotterdam Study, a population-based study also being conducted in the Netherlands. These women had no history of cancer and were also between 50 and 80 years old when they were tested.

Although the researchers observed no difference between the two groups in a dementia screening test, the breast cancer survivors performed worse on some tests of delayed verbal memory, processing speed, and psychomotor speed. The survivors also had more memory complaints but fewer symptoms of depression.

This pattern of deficits is similar to those from other trials conducted closer to the time patients finished chemotherapy. But it is unclear whether the results of this study are representative of the long-term effects of other chemotherapy regimens.

Although newer regimens are now available for women with early-stage breast cancer, the authors noted, “[CMF] was the standard regimen up to the 1990s... [and] cyclophosphamide and fluorouracil continue to be incorporated into currently used regimens.”

“This work is an important reminder that it is not enough to focus on the cure and control of cancer,” commented Dr. Julia Rowland, director of NCI’s Office of Cancer Survivorship. “We must also attend to the impact of therapy on the long-term health and function of our growing population of survivors.”

See also: “Delving Into Possible Mechanisms for Chemobrain

Gene Mutation Implicated in Heightened Breast Cancer Risk in Some Families

An inherited mutation in the Abraxas gene, which encodes a protein that interacts with BRCA1 and other DNA-repair proteins, is associated with an increased risk of breast cancer in some families, new study results show. The findings were published February 22 in Science Translational Medicine.

Inherited mutations in BRCA1 and BRCA2 are the strongest known genetic risk factors for breast and ovarian cancer, but these mutations do not account for all familial breast cancers worldwide.

To determine whether mutations in Abraxas might influence breast cancer risk, a team of Finnish and U.S. researchers screened breast cancer patients from 125 Northern Finnish families with a history of breast cancer for hereditary mutations in the Abraxas gene. Several gene-sequence variants were found, one of which was likely to result in altered protein function.

Three of the families were found to carry this mutation, as did one additional woman from an unselected group of breast cancer patients who turned out to have a family history of the disease. In the two families in which this analysis could be performed, the mutation was found to occur together with breast cancer. The researchers did not find the Abraxas mutation in 868 healthy Northern Finnish women.

The Abraxas protein binds directly to the BRCA1 protein and is responsible for delivering BRCA1 to sites of DNA damage in the cell nucleus, explained Dr. Roger Greenberg of the University of Pennsylvania, a co-author of the study with Dr. Robert Winqvist of the University of Oulu in Finland. “The mutant protein still interacted with BRCA1 and other DNA-repair proteins but prevented them from getting to DNA damage sites,” Dr. Greenberg said.

Defects in the DNA repair process lead to changes in a cell’s genetic material that can increase the risk of breast cancer and other cancers. Indeed, the researchers found several cancer types besides breast cancer in two of the families with Abraxas mutations, suggesting that the gene may play a role in other cancers, as does the BRCA1 gene.

Because the study looked only at people in Northern Finland, “it will be important…to investigate Abraxas mutations in other populations,” Dr. Greenberg said. Eventually, he added, Abraxas could be one of several genes tested for mutations in families with a history of breast and ovarian cancer.

Furthermore, noted Dr. Richard Pelroy of NCI’s Division of Cancer Biology, the information gleaned on how Abraxas works in concert with BRCA1 could aid development of treatments that target BRCA1 defects.

Study Details Cancer-Promoting Activity of mTOR Protein

The mTOR protein, a regulator of protein translation that is overactive in many cancers, increases the production of a specific group of proteins that help cancer cells escape tumors and invade other tissues, according to a new study published online February 22 in Nature. The same study found that, in mouse models of metastatic prostate cancer, an investigational drug called INK128 that potently blocks mTOR’s activity shrank tumors and prevented metastasis more effectively than other mTOR inhibitors.

Because of its mechanism of action, INK128 and other drugs in development that target mTOR in a similar way may be particularly effective in treating metastatic disease, noted the study’s lead investigator, Dr. Davide Ruggero of the University of California, San Francisco.

Using a new technique called ribosome profiling that shows which messenger RNAs are being translated into proteins by the ribosomes in a cell, the research team pinpointed a group of four proteins—all of which cluster together in a signaling “node”—in advanced prostate cancer cell lines whose translation was altered by mTOR inhibition.

The technology, Dr. Ruggero explained, allows researchers to analyze what is happening at the functional level in cells, particularly the production of proteins, which are the primary drivers of cellular activity. “These four proteins were really most affected downstream [of mTOR] at the translational level,” he continued. “And we show, one by one, their functional role in making tumor cells more metastatic or more invasive.”

In the mouse models, “treatment with INK128 completely blocked the progression of invasive prostate cancer locally in the prostate gland, and profoundly inhibited the total number and size of distant metastases,” the study authors wrote.

Several study authors are from the California-based company Intellikine, which is developing INK128. The drug is being tested in several phase I trials.


Also in the News: Judge Rules against Graphic Warnings on Cigarette Packages

U.S. District Judge Richard Leon ruled last week that the Food and Drug Administration (FDA) regulation requiring cigarette packages and displays to carry graphic warnings of the consequences of smoking violated tobacco companies’ free speech rights under the First Amendment. The same judge temporarily blocked the regulation last fall. The government has appealed that decision and will have 60 days to appeal the new decision.

The FDA rule was scheduled to take effect this fall but is now on hold pending the outcomes of the government’s appeals. The Department of Health and Human Services, under which the FDA falls, released a brief statement that read: “This Administration is determined to do everything we can to warn young people about the dangers of smoking, which remains the leading cause of preventable death in America. …We are confident that efforts to stop these important warnings from going forward will ultimately fail.”



Also in the Journals: Questioning the Use of Progression-Free Survival as a Clinical Trial Endpoint

A comment paper published in the Journal of Clinical Oncology last week argues that the cancer research community should consider more carefully the use of progression-free survival (PFS) as an endpoint in clinical trials. Drs. Christopher Booth and Elizabeth Eisenhauer of the National Cancer Institute of Canada noted that growing numbers of trials are using PFS as an endpoint and that drugs are being approved based on the results of such trials.

Although PFS is easily measured, it is unclear whether an improvement in PFS signals improvement in overall survival or quality of life, the authors wrote, leading them to question whether using PFS merely lowers the bar for approving new drugs without real benefit for patients.

See also: “Progression-free Survival: Patient Benefit or Lower Standard?

A Conversation With

A Conversation with The Who's Roger Daltrey about Teen Cancer Centers

Roger Daltrey of The Who joins teenagers with cancer at the launch of the UCLA Daltrey/Townshend Teen and Young Adult Cancer ProgramRoger Daltrey of The Who joins teenagers with cancer at the launch of the UCLA Daltrey/Townshend Teen and Young Adult Cancer Program.

Roger Daltrey, lead singer of the rock band The Who, has been an active spokesperson for the creation of specialized cancer treatment centers for teenagers and young adults in the United Kingdom for the past 12 years. Last fall, he and The Who guitarist and songwriter Pete Townshend, along with other well-known musicians, supported the launch of the UCLA Daltrey/Townshend Teen and Young Adult Cancer Program, which serves teen and young adult cancer patients at the Ronald Reagan UCLA Medical Center. (See the box at the bottom of the page.)

How did you get involved with teenagers and young adults with cancer?

My doctor and his wife, Drs. Adrian and Myrna Whiteson, had the idea to set up the Teenage Cancer Trust in the early 1990s to create specialist treatment units for teens with cancer, and they enlisted me as a patron. Using the first rule of patient care—observation—they noticed that teenagers with cancer were suffering needlessly because the medical profession had failed to realize that teenagers aren’t children, and they’re certainly not adults. They are a completely separate group and need to be treated in an environment of their own that is teen friendly.

Eventually, I thought it was such a great idea that I decided to get more hands on. By 2000, the Trust had built six treatment units, and I got heavily involved after I learned that two of the six units were due to be pulled down because they were located in Victorian-era hospitals. It felt like we were going backward, in a way.

See the special issue of the NCI Cancer Bulletin on Adolescents and Young Adults

The Who did a 2-night charity show at the Royal Albert Hall with a lot of guests, including Eddie Vedder, Bryan Adams, Noel Gallagher, Kelly Jones, and Stereophonics. It was fabulous, and we gave the Teenage Cancer Trust the rights for the concert DVD and the live album. They made enough money to replace the two treatment units. The financial success of these shows was great, but the publicity generated was an added bonus for bringing the issue to the public’s attention in the U.K. The Trust was gaining a stronger profile, and we’re now in our 12th year of running these charity shows.

The Teenage Cancer Trust has to pay for every nut, bolt, brick, door, and window, as well as the furnishings, with the average cost now running at about $5 million. As of today, we’ve built 17 hospital wards within our National Health Service for teen and young adult cancer patients, with a further 10 wards under construction. It’s been a phenomenal success.

What is unique about these teen treatment centers?

We get teenagers involved in designing the centers. We make spaces for them to be quiet when they want to be quiet, noisy when they want to be noisy, in teenage-friendly surroundings. We have areas where they can carry on their studies, so they don’t fall behind in their schooling. There are kitchens where they can cook for themselves and facilities for parents—because, as you know, parents of cancer patients need an awful lot of support as well during this time.

Any parent who has had teenagers will tell you, the hardest thing to get teenagers to do is talk to you. There are high rates of misdiagnosis or delayed diagnosis of their cancers. They also suffer from very rare forms of cancer and the disease can be extremely aggressive, and so it’s a bad situation all around. They’re hammered with these diseases right at that stage of life where even a pimple on your nose is a disaster.

When you’re losing your hair or your leg or, even worse, your life, it's important to open up, but a lot of teenagers withdraw instead. When we put teens together, they really do support each other. They talk to each other very, very openly and honestly, and that’s a psychological boost. You can only get that by putting them together. They’re very secretive around adults. It’s part of the teenage process, isn’t it?

What impact have the centers had on young patients?

What is wonderful about our system in the U.K. is that, because we have nationalized medical care, everybody gets the same medical treatments, including the teens in our special units. We’ve now got figures over almost a 20-year period where we can compare the teenagers who went through our units to teenagers who were unfortunate enough not to have that access.

Members of the pediatric medical profession are finding that our teens appear to do better than teens outside our centers who receive the same treatments. That impact continues to be studied and, if it’s confirmed by more data, that improvement can only be due to the psychological benefit for the teens who are treated in our units.

How did you get involved in the UCLA teen cancer center?

About 2 years ago, I did a benefit for an autism charity in Los Angeles, where I met the head of the UCLA Health System, Dr. David Feinberg. I told him about my work with the Teenage Cancer Trust, and within 2 months they had a team from their hospital come to England. After thoroughly looking over our units, they said, “This is the gold standard for treating teens and young adults, and UCLA has got to have it.”

They made space available in the UCLA hospital to set up a unit. In November 2011, I performed at a concert with Robert Plant and Dave Grohl to raise the funds to furnish the facility.

I also had the pleasure of welcoming and meeting [the unit’s] first patients. I think it will be the first of many such centers in the United States. We’re already talking to medical center leaders at Yale University and Duke University. With the help of the American public and, I hope, more people in the music business—who rely on teenagers for a large part of their revenue—these facilities can be available to every teen and young adult in America.

—Interviewed by Bill Robinson

For more information on adolescent and young adult cancers, see the NCI Cancer Bulletin’s 2011 special issue on the topic.

UCLA Teen and Young Adult Cancer Program to Open New Facility

Boosted by the success of the fund-raising concert last fall by The Who lead singer Roger Daltrey and other well-known musicians, the UCLA Daltrey/Townshend Teen and Young Adult Cancer Program will begin construction this spring on a specially designed inpatient/outpatient facility for adolescent and young adult (AYA) cancer patients at the Santa Monica–UCLA Medical Center.

The new unit is modeled on the AYA centers established by the Teenage Cancer Trust in the United Kingdom. “We’ll have an eight-bed AYA unit with a social zone at the center for the patients to hang out together,” said Dr. Jacqueline Casillas, director of the UCLA program. “One thing we’ve learned from the U.K. teen centers is to try to think outside the box of traditional health care delivery for this patient population.”

That includes seeking feedback from UCLA’s Teenage and Young Adult Advisory Group, Dr. Casillas noted. “They asked us to take the word ‘cancer’ off the sign on the door to the AYA unit,” she recalled. “They told us: ‘You really don’t need to say 'cancer' on the front of the door!’”

The Santa Monica unit will also provide outpatient chemotherapy services in the social zone, so that patients can receive treatment in a supportive environment and during extended hours more adapted to teenage lifestyles.

Dr. David Feinberg, CEO of the UCLA Health System, commented: “We feel confident that this first Daltrey/Townshend Teen and Young Adult Cancer Program in America will establish a more healing environment for our adolescent patients and set the stage for an expansion of the program to medical institutions across the United States.”

Special Report

Colonoscopy Reduces Risk of Death from Colorectal Cancer in High-Risk Patients

Colon polypDuring a colonoscopy, physicians can find and remove polyps, such as this one, in the colon.

Long-term results from a study of colonoscopy for patients at higher-than-average risk of colorectal cancer confirm that removing precancerous adenomas can not only reduce the risk of colorectal cancer but also reduce the number of deaths from the disease by more than half, according to this study. The findings appeared February 23 in the New England Journal of Medicine.

These results, from the National Polyp Study, may not apply to the general, average-risk population. However, the findings provide reassurance that removing precancerous adenomas decreases the risk of death from colorectal cancer in people at higher-than average risk, noted lead author Dr. Ann Zauber of Memorial Sloan-Kettering Cancer Center.

“In screening, what you’re going to pick up for the most part is adenomas, not cancers, so I think it’s really important to know the impact [on mortality] of taking out those adenomas when you do a colonoscopy,” said Dr. Zauber. (The benefit of colorectal cancer screening for average-risk individuals is being tested in several randomized trials. See the sidebar.)

Earlier results from the National Polyp Study showed that colonoscopy and removal of adenomas found during the procedure was associated with a reduced incidence of colorectal cancer. However, whether the reduction in incidence found in the study would translate into fewer deaths could be determined only with longer follow-up.  

If the study hadn’t shown a reduction in mortality, explained Dr. Zauber, that would have indicated that colonoscopy mostly picks up adenomas that would not progress to the aggressive cancers that lead to death from the disease. Instead, the finding that colonoscopy and adenoma removal reduced deaths from colorectal cancer by more than half over two decades of follow-up indicates that at least some of the adenomas that were detected would have progressed to cancer if they had not been removed.

Substantial Reduction in Deaths

In 1980, Principal Investigator Dr. Sidney Winawer of Memorial Sloan-Kettering and his co-investigators began the National Polyp Study at seven clinical centers. The study was designed to determine the appropriate interval for follow-up colonoscopy after adenoma removal. 

Of the more than 9,000 original participants, 3,778 had at least one polyp removed; of those, 2,632 had adenomas. The other 776 patients, with benign polyps, served as an internal control group for the follow-up portion of the study, to track survival in people who did not have any adenomas at the time of initial colonoscopy.

Current Colorectal Cancer Screening Trials

The median follow-up for all patients was almost 16 years. The researchers compared the number of deaths from colorectal cancer in the group that had adenomas removed with the number of deaths in the internal control group without adenomas. They also compared the number of deaths in the adenoma group with the number of deaths expected to have occurred in the general population, calculated from NCI’s Surveillance, Epidemiology, and End Results database, the National Center for Health Statistics database, and the National Death Index.

Over the follow-up period, 12 patients in the adenoma group died of colorectal cancer, compared with an expected 25.4 deaths from the disease in the general population. This translates to an estimated 53 percent reduction in the risk of death from colorectal cancer following the removal of precancerous adenomas during colonoscopy.

Only one patient in the nonadenoma group died of colorectal cancer during the follow-up period. In the first 10 years after initial colonoscopy, the risk of death from colorectal cancer was approximately the same between the patients who had precancerous adenomas removed and those without adenomas. “We felt that was a powerful result,” said Dr. Zauber.

Modeling the Natural History of Adenoma Removal

To determine the actual mortality benefit of adenoma removal, the ideal randomized trial would compare colorectal cancer mortality in a group of patients who have had adenomas removed with that in a group of patients who have had adenomas detected but not removed, explained Dr. Asad Umar, chief of the Gastrointestinal and Other Cancers Research Group in NCI’s Division of Cancer Prevention (DCP). But, he added, such a study would be unethical because the evidence is clear that between 10 and 24 percent of adenomas will progress to cancer.

Because this type of comparison could never be performed, Dr. Zauber and her colleagues also used a computer model in their study called MISCAN-Colon to estimate the number of deaths that would have occurred in a population of the same age and with the same number of detected adenomas as the National Polyp Study group, but who did not have those adenomas removed.

The model, created by the NCI-sponsored Cancer Intervention and Surveillance Modeling Network (CISNET), uses validated data on the natural progression of adenomas to cancer in order to calculate the risk of death from colorectal cancer in a hypothetical population. 

Based on MISCAN-Colon, the researchers estimated that 145 patients whose adenomas had not been removed would have died, whereas only 12 patients whose adenomas were removed died of colorectal cancer in the study. This model suggests a 92 percent reduction in mortality from colonoscopy and adenoma removal in this group of high-risk patients.

Future Questions

To establish optimal surveillance strategies for the general population, other studies will be needed to determine the best ways to identify patients with adenomas that are at low risk versus high risk of progression to colorectal cancer, said Dr. Zauber. Recent studies have shown that many high-risk patients do not receive adequate follow-up, whereas many low-risk patients receive too many surveillance colonoscopies. “We need to use surveillance judiciously because colonoscopy does have risks,” she added.

In the first 10 years after initial colonoscopy, the risk of death from colorectal cancer was approximately the same between the patients who had precancerous adenomas removed and those without adenomas.

She also believes that colonoscopy quality and standards need to be improved. “We really think that our high-quality baseline colonoscopy [in the National Polyp Study] contributed to the strong reduction in both incidence and mortality that we observed,” she added.

For now, this study “adds evidence to support the widespread assumption—that I think is correct—that colonoscopy decreases the risk of colorectal cancer and decreases colorectal cancer mortality,” said Dr. Barry Kramer, director of DCP.

The 50 percent reduction in risk observed in this study may not apply outside this particular study population. "The participants were healthier overall than the average population, which could have lowered their risk of death, but they harbored adenomatous polyps, which could have increased their risk of death," explained Dr. Kramer.

“While this study was not randomized, and it is very difficult to match a study cohort using population data, this study confirms qualitatively that colonoscopy decreases mortality from colorectal cancer,” said Dr. Kramer. “However, we still can’t answer the question with precision: In the [general] public, what would be the absolute decrease in colorectal cancer mortality?”

Mature results of several large population-based colorectal cancer screening trials will not be available until after 2020, he added, although some preliminary results indicate that screening colonoscopy may reduce colorectal cancer mortality in the general public.

Sharon Reynolds

Featured Clinical Trial

Exploring the Anticancer Potential of Valproic Acid in Advanced Thyroid Cancer

Dr. Electron KebebewDr. Electron Kebebew

Name of the Trial
Phase II Trial of Valproic Acid in Patients with Advanced Thyroid Cancers of Follicular Cell Origin (NCI-10-C-0041). See the protocol summary.

Principal Investigators
Dr. Electron Kebebew, NCI Center for Cancer Research   

Why This Trial Is Important
Most thyroid cancers, especially when found early, are highly treatable and usually curable. About 90 percent of thyroid cancers are either of the papillary or the follicular type, both of which arise in the follicular cells of the thyroid. The cells of these tumors are usually well differentiated, meaning that they appear more similar to regular thyroid cells than cells of the rarer and more aggressive medullary and anaplastic types. Differentiated thyroid cancers are usually amenable to surgical resection and systemic therapy with radioactive iodine, which is readily taken up by the thyroid.

Patients with more advanced differentiated thyroid cancer may also be treated with radioactive iodine; however, some of these patients have tumors that fail to take up radioactive iodine adequately. External-beam radiation therapy and thyroid hormone suppression therapy may be alternative treatment options, but the long-term survival of these patients is low. Thus, it is important to identify better treatments for these patients.

A drug called valproic acid has been used for decades to treat people with mood or seizure disorders. Recently, researchers have begun studying this drug as a possible treatment for cancer. Valproic acid may act against cancer cells in a number of ways, and studies of the drug in tumor models support its clinical testing in people with cancer.

“Valproic acid has been in clinical use as a mood stabilizer and anticonvulsant for a very long time,” said Dr. Kebebew. “Eventually, researchers discovered that it has other mechanisms of action, including as a histone deacetylase inhibitor, or HDAC inhibitor, which is a class of drugs known to have anticancer activity. When it was tested subsequently in the laboratory with cancer cell lines, valproic acid was found to inhibit the growth and invasiveness of thyroid cancer cells.

“These studies also revealed that the drug could affect the differentiation of cancer cells. This is very important in thyroid cancer because even metastatic sites of disease are quite effectively treated with radioactive iodine,” Dr. Kebebew explained. “But that entirely depends on the thyroid cell being able to preferentially trap radioactive iodine. As thyroid cancer cells become dedifferentiated, they lose, or at least decrease expression of, a gene required for iodine uptake. So, the second effect of valproic acid in thyroid cancer is that it can actually increase the expression of this gene and allow the cancer to be treated with radioactive iodine.”

In this trial, patients with advanced thyroid cancers of follicular cell origin whose tumors are not sensitive to radioactive iodine therapy will take valproic acid tablets for 10 weeks and then undergo a radioactive iodine uptake test. Patients whose tumors show increased uptake of radioactive iodine at 10 weeks will receive radioactive iodine therapy, whereas those whose tumors do not show increased iodine uptake will receive an additional 6 weeks of treatment with valproic acid. Doctors want to see if valproic acid will cause thyroid cancer cells to die, or at least stop growing, and if it will cause thyroid tumors to increase their uptake of radioactive iodine.

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

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

Cancer.gov Update

NCI's Cancer.gov Goes Mobile

smartphone

NCI has launched a new mobile web initiative that will improve access to its website, cancer.gov.

Designed specifically for mobile users, m.cancer.gov is available in English and Spanish and offers credible, current information about a wide range of cancer types, diagnosis and treatment, side effects, and other topics. Mobile users can also access cancer news, a dictionary of cancer terms that includes audio pronunciations, and a one-touch-connection to NCI’s Cancer Information Service call center at 1-800-4-CANCER, where they can talk directly with an NCI cancer information specialist.

In line with national trends, NCI has seen a substantial increase in the number of people accessing its website from mobile devices. From May to December 2011, mobile visits to cancer.gov nearly doubled, and that trend is likely to continue.

Arranged for simple navigation from any mobile device, the site provides cancer patients, their loved ones, and their caregivers with easy access to the information they need. Content for NCI's mobile site was selected by closely reviewing web analytics data on the areas of cancer.gov that mobile users were accessing most frequently.

In the future, more content, including information about clinical trials, will be added to m.cancer.gov.

NCI Launches Smokefree Texting Service in Spanish

Smokefree TXT en Español logo

NCI has released SmokefreeTXT en Español, a mobile phone-based service that provides scientific information, tips, and support for quitting smoking to Spanish speakers. Users can receive text messages leading up to and following a scheduled quit date, as well as on-demand support at any time of the day or night.

Approximately 16 percent of Hispanic adults and 22 percent of Hispanic high school students in the United States smoke, and smoking-related illnesses are the leading cause of death for Hispanics in the United States. Recent national surveys indicate that Hispanics are less likely than people of other racial or ethnic groups to receive advice about quitting from a health professional or to use proven smoking cessation treatments such as medications and counseling. This highlights the need to find novel ways to engage Hispanic smokers, including those whose primary language is Spanish.

SmokefreeTXT en Español is one of the major features of a new website, Smokefree Español. Users can enroll in the free texting service by signing up online or by texting LIBRE to 47848. 

This new tool adds to NCI’s existing English-language web-based and mobile cessation resources for smokers who want to quit.

Notes

In Memoriam: Dr. Renato Dulbecco

Dr. Renato DulbeccoDr. Renato Dulbecco

Dr. Renato Dulbecco—a Nobel laureate, founding member of the Salk Institute, and influential proponent of the Human Genome Project—died in La Jolla, CA, on February 19.

Dr. Dulbecco shared the 1975 Nobel Prize in Physiology or Medicine for “discoveries concerning the interaction between tumor viruses and the genetic material of the cell.” In the 1950s, he had discovered that when viruses infect cells, genetic material from the virus is incorporated into the cell’s genetic material, which can cause the cell to become malignant. This was the first solid evidence that cancer is caused by mutations, and the finding opened important new avenues in cancer research.

Following his early work in cancer research, Dr. Dulbecco and long-time collaborator Dr. Marguerite Vogt also developed a way to grow animal viruses in culture and a method to measure the concentration of virus in a sample. Called the plaque technique, the method was used in the development of the polio vaccine.

Later in his career, Dr. Dulbecco was the first to use monoclonal antibodies to identify cancer cells by their genetic signature—that is, by the proteins displayed on their surface. Monoclonal antibodies are now used in several cancer treatments.

In 1986, he published an influential perspective piece in Science that urged the sequencing of the human genome. He noted that such an effort “would have to be a national effort. Its significance would be comparable to that of the effort that led to the conquest of space, and it should be carried out with the same spirit.” The Human Genome Project was launched in 1990 and completed in 2003. Today, the tumors of many newly diagnosed cancer patients are sequenced to help doctors choose the most effective treatments.

Born and educated in Italy, Dr. Dulbecco earned an M.D. degree from the University of Turin in 1936. During World War II, he served as a medical officer in the Italian army. After being wounded, he was sent home to recuperate but soon joined the anti-German resistance forces in Italy.

After the war, he was invited to work at Indiana University, where he shared a lab with Dr. James Watson, co-discoverer of the DNA double helix. Dr. Dulbecco’s work at Indiana University caught the eye of Dr. Max Delbrück, who recruited him to the California Institute of Technology in 1949.

In 1963, Dr. Jonas Salk invited Dr. Dulbecco to join the new Salk Institute for Biological Studies in La Jolla, CA. Apart from a stint at the Imperial Cancer Research Fund in London in the 1970s, Dr. Dulbecco spent much of the rest of his career at the Salk, serving as president from 1988 to 1992.

Dr. Dulbecco was awarded the Albert Lasker Basic Medical Research Award in 1964. He was elected to the National Academy of Sciences, the Royal Society of London, and the Accademia Nazionale dei Lincei of Italy.

Cyberseminar Will Explore How to Customize Health Materials

Dr. Matthew Kreuter, Gena Hodge, and Angela McFallDr. Matthew Kreuter, Gena Hodge, and Angela McFall

NCI’s March Research-to-Reality (R2R) cyber-seminar will explore how to develop, tailor, and promote health materials for communities and audiences. Make It Your Own (MIYO), created in 2008 by the Health Communication Research Lab at Washington University in St. Louis, is a web-based system that gives community partners the tools to create customized, culturally appropriate health materials targeted to their audiences without having to develop them from scratch.

Dr. Matthew Kreuter, one of MIYO’s developers, will provide an overview of the tool, how it can be used, and the potential benefits for communities and organizations. Gena Hodge and Angela McFall, who implemented MIYO in their colorectal cancer control programs in Iowa and Michigan, will share their experiences with using MIYO, including lessons learned and the potential implications of this resource for other health departments and organizations.

For more information and to register for the March 13 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.

Public Comment Sought on Genetic Testing for Breast and Ovarian Cancer

The U.S. Preventive Services Task Force (USPSTF) would like the public’s input and feedback on its draft research plan on genetic risk assessment and BRCA mutation testing for breast and ovarian cancer susceptibility. The draft research plan will be available online for public comment until March 27.

USPSTF researchers will review all of the comments they receive and revise the draft plan. The final research plan will serve as a framework to guide the scope, conduct, and content for an evidence review. The resulting evidence report will form the basis of the final, updated USPSTF recommendation statement on this topic, which will be published in a peer-reviewed journal or posted on the USPSTF website. 

The current recommendation statement was released in September 2005.

National Cancer Advisory Board Holds First Meeting of 2012

The National Cancer Advisory Board (NCAB) convened its first meeting of the year on February 27–28 in Bethesda, MD. 

NCI Director Dr. Harold Varmus, Deputy Director Dr. Doug Lowy, and Deputy Director for Clinical and Translational Research Dr. James Doroshow presented the NCI Director’s Report, highlighting various institute activities, including those in the areas of global health, genomics, and team science.

In addition, Dr. Barbara Rimer, the new chairperson of the President’s Cancer Panel, outlined the panel’s strategy for engaging key elements of the research community in the coming year. She also announced the panel’s first priority of 2012, “Accelerating Progress in Cancer Prevention: The HPV Vaccine Example.”   

Other meeting presentations included an overview of current and future perspectives on cancer prevention research by Dr. Barry Kramer, director of NCI’s Division of Cancer Prevention, and an update on cooperative group reorganization by Dr. Jeff Abrams, associate director of NCI’s Cancer Therapy Evaluation Program.

The full agenda and a videocast of the meeting are available online.