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May 29, 2012 • Volume 9 / Number 11

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NEWS

Medical illustration of a sigmoidoscope in the colon. (Illustration by Terese Winslow for NCI)Sigmoidoscopy Proves to Be Effective Screening Tool for Colorectal Cancer

In a large randomized trial in healthy men and women aged 55 to 74, sigmoidoscopy substantially reduced the incidence of and mortality from colorectal cancer. Newly diagnosed cases of the disease fell by 21 percent and colorectal cancer deaths fell by 26 percent after a median of 12 years of follow-up. 

The findings, from the NCI-funded Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial appeared online May 21 in the New England Journal of Medicine. Read more > >

A MESSAGE TO READERS

Meet NCI Experts at ASCO 2012

NCI at ASCO banner NCI staff will participate in the upcoming American Society of Clinical Oncology's (ASCO) 48th Annual Meeting on June 1–5 at McCormick Place in Chicago, IL.
 
Attendees can learn about NCI's programs and resources by visiting booth #2047 in the exhibit hall during the meeting. Learn more about NCI-sponsored sessions and activities online, and look for additional highlights from the meeting in the June 12 issue of the NCI Cancer Bulletin.

IN DEPTH

UPDATES

  • Notes

    • In Memoriam: Cedric Long, Assistant Director of NCI's Division of Extramural Activities
    • NCI's Advanced Technology Research Facility Opens
    • NCI and China Cancer Institute Discuss Research Issues and Medical Journalism
    • Paula Jacobs Appointed Associate Director in NCI's Division of Cancer Treatment and Diagnosis
    • Proposals Sought for Use of PLCO Data and Biospecimens
    • Cyber-Seminar Will Examine Cancer Control at the State and Local Level


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

Sigmoidoscopy Proves to Be Effective Screening Tool for Colorectal Cancer

Medical illustrations of a sigmoidoscope and a colonoscope in the colon. (Illustrations by Terese Winslow for NCI)During a sigmoidoscopy (left), a thin, lighted tube is inserted through the anus and rectum and into the lower part of the colon to look for abnormal areas. During a colonoscopy (right), a similar instrument is used to visualize the entire colon. (Illustrations by Terese Winslow for NCI) [Enlarge]

In a large randomized trial involving healthy men and women aged 55 to 74, sigmoidoscopy substantially reduced the incidence of and mortality from colorectal cancer. Newly diagnosed cases of the disease fell by 21 percent and colorectal cancer deaths fell by 26 percent after a median of 12 years of follow-up. The findings, from the NCI-funded Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial appeared online May 21 in the New England Journal of Medicine.

The results add to a growing body of evidence that endoscopic screening with sigmoidoscopy or colonoscopy can prevent deaths from colorectal cancer. In 2010, a large trial in the United Kingdom found that a single sigmoidoscopy exam between the ages of 55 and 64 substantially reduced colorectal cancer incidence and mortality.

In the PLCO trial, Dr. Robert Schoen of the University of Pittsburgh Cancer Institute and his colleagues did not remove polyps during sigmoidoscopy; instead, participants who were found to have a polyp or suspected cancer during the screening examination were referred for colonoscopy. Polyps could then be removed during colonoscopy. (Smaller polyps in the distal colon—on the left side; closer to the rectum—can be removed by sigmoidoscopy, but this wasn't done in the PLCO trial.)

"In large measure, the efficacy [seen in the PLCO trial] was due to the colonoscopies that were triggered by sigmoidoscopy," explained Dr. Barry Kramer, director of NCI's Division of Cancer Prevention and a PLCO investigator.

From 1993 to 2001, PLCO investigators randomly assigned nearly 155,000 people at average risk of colorectal cancer to receive either screening with sigmoidoscopy at study entry, followed by a repeat exam 3 or 5 years later, or usual care.

Ongoing Randomized Trials of Screening Colonoscopy

Earlier this year, long-term follow-up from a U.S. study of patients at higher-than-average risk of colorectal cancer showed that colonoscopy and polyp removal reduced deaths from colorectal cancer.

Large trials evaluating screening colonoscopy in people at average risk for the disease are under way, including:

Of the 77,445 people assigned to the sigmoidoscopy group, 84 percent underwent a first sigmoidoscopy and 54 percent returned for a second exam. About 80 percent of participants with an abnormal sigmoidoscopy result had a diagnostic procedure—in most cases, a colonoscopy—within 1 year of the abnormal screening exam.

Overall, 22 percent of patients assigned to the screening group had a colonoscopy as a direct consequence of an abnormal result on their sigmoidoscopy.

Because acceptance of colorectal cancer screening in the United States rose as the PLCO trial was being conducted, almost half of the participants in the usual care group also received an endoscopic colorectal cancer screening exam outside the trial. This "contamination" likely lessened the magnitude of the screening effect, explained Dr. Christine Berg, chief of NCI's Early Detection Research Group and project officer for the PLCO trial. Nevertheless, incidence of and mortality from colorectal cancer were substantially lower in the screening group.

Interestingly, although sigmoidoscopy and subsequent colonoscopy reduced colorectal cancer incidence in both the distal and proximal colon (right side; closer to the small intestine), sigmoidoscopy screening reduced mortality only for cancers in the distal colon.

Colonoscopy may be "more effective for reducing deaths from cancer in the left side of the colon—the portion of the colon that sigmoidoscopy reaches—than in the right side of the colon," explained Dr. Kramer.

One possible reason for this is a higher frequency of flat polyps—which are harder to detect with endoscopy—in the proximal colon. Genetic changes driving the polyps in the proximal colon could also lead to more aggressive cancers, noted Dr. John Inadomi of the University of Washington in an accompanying editorial.

Colon polyps (Illustration by Terese Winslow for NCI) Colon polyps are growths that can lead to colon cancer. They can be flat or have stalks. (Illustration by Terese Winslow for NCI)

Currently, the U.S. Preventive Services Task Force recommends three colorectal cancer screening tests: sigmoidoscopy, colonoscopy, and high-sensitivity fecal occult blood testing (FOBT)—a noninvasive test that can detect colorectal cancer but not smaller precancerous polyps—for adults aged 50 to 75.

Having more than one effective screening option is important, said Dr. Kramer, because "patient preferences for screening tests should be identified and respected. Some patients may be more willing to undergo FOBT or sigmoidoscopy than colonoscopy. But whichever commonly available screening test they choose to get, the mounting evidence is that it's going to be effective."

"[People] shouldn't neglect colorectal cancer screening altogether just because they don't want colonoscopy," urged Dr. Berg.

Further research is needed to determine optimal screening practices and intervals, she added. For example, could some patients at low risk of colorectal cancer be safely screened with colonoscopy only once in their life? And can noninvasive, less-sensitive tests like FOBT or fecal immunochemical testing find more cancers in a population, since they may be performed more frequently and be accepted by more patients?

In the last decade, use of sigmoidoscopy has decreased in the United States. In a recent study, 53 percent of primary care physicians surveyed reported that their sigmoidoscopy volume had fallen either substantially or somewhat since 2003.

This abandonment of the technique may be premature: "High-quality evidence must show the superiority of colonoscopy over other screening tests before we dismiss the use of flexible sigmoidoscopy and fecal occult-blood testing, both of which have randomized, controlled trials supporting their benefit," concluded Dr. Inadomi.

Sharon Reynolds

Also in the Journals: Laxative-Free CT Colonography Detects Large Polyps

CT colonography, also called virtual colonoscopy, typically requires the same laxative preparation to empty the colon as traditional optical colonoscopy. In a study published May 15 in the Annals of Internal Medicine, researchers found that a laxative-free CT colonography technique found a similar number of large polyps as optical colonoscopy with laxative preparation.

The 605 participants ate a low-fiber diet for several days and drank a contrast material that allowed computer software to tag and "remove" stool in the scans. All participants also received a standard optical colonoscopy so that the accuracy of the two exams could be compared.

Laxative-free CT colonography detected adenomas 10 mm or larger as well as optical colonoscopy but was less effective at finding smaller polyps. Of the 465 participants who rated both procedures, 62 percent preferred laxative-free CT colonography for future exams. CT colonography is not covered by Medicare as a screening procedure.

Further reading: "Virtual Colonoscopy Identifies Large Polyps"

Cancer Research Highlights

Panel Reviews Benefits and Harms of CT Scans for Lung Cancer Screening

A panel of experts has reviewed the evidence regarding the benefits and harms of screening for lung cancer with low-dose computed tomography (CT) and concluded that the technology may benefit some individuals at high risk for lung cancer. But the panel cautioned that many questions remain about the potential harms of screening and how to translate screening into clinical practice.

The review, published in JAMA on May 20, was a collaborative effort by the American Cancer Society, the American College of Chest Physicians (ACCP), the American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network.

"We found that CT screening has the potential to reduce lung cancer deaths in some smokers and former smokers when utilized appropriately, but there are many unanswered questions about its risks and whether it will work as well in clinical practice as it has in carefully conducted trials," lead author Dr. Peter B. Bach of Memorial Sloan-Kettering Cancer Center said in a statement.

Based on the results, ASCO and ACCP issued a clinical practice guideline for physicians. The guideline suggests that screening be offered to smokers and former smokers aged 55 to 74 who have smoked for 30 pack years and either continue to smoke or have quit smoking within the past 15 years. Individuals who do not belong to these categories or who have serious health conditions that would limit their life expectancy, rule out curative treatment for lung cancer, or both, should not be offered screening.

In addition, screening should be done at facilities that can deliver the level of care provided to participants in the National Lung Screening Trial (NLST).  Results from that trial, which were published last year, showed that screening with low-dose CT led to a 20 percent reduction in lung cancer deaths compared with chest x-ray screening.

The NLST investigators noted that the harms of screening should be considered in future clinical recommendations. Potential harms include false-positive results and unnecessary follow-up procedures, such as needle biopsies and bronchoscopies.

Dr. Bach and his colleagues categorized the strength of the recommendations in the new guideline as "weak" based on "moderate" or "low" quality research data. However, additional results from the NLST and from European studies will appear in the coming years. When these data become available, the clinical practice guidelines will be reassessed, Dr. Bach explained.

"As we understand more about the risks and the benefits [of low-dose CT screening], the calculus is very likely to change," he wrote in an e-mail message. "In which direction, it is impossible to predict."

Further reading: "Crunching Numbers: What Cancer Screening Statistics Really Tell Us"

Lung Cancer Drug Shows Promise against Several Childhood Cancers

Preliminary results from a phase I clinical trial suggest that the targeted drug crizotinib (Xalkori) may be effective in children with cancer whose tumors harbor genetic alterations in the ALK gene. In some children, the drug caused all signs of the disease to disappear (complete response). Crizotinib is already approved by the Food and Drug Administration to treat patients with lung cancer whose tumors have ALK mutations.

The findings were presented at a press briefing on May 16 in advance of the American Society of Clinical Oncology (ASCO) annual meeting.

Sponsored by the Children's Oncology Group (COG) Phase I Consortium, the study included 70 children whose cancers had progressed on standard treatments. Many had one of three diseases that have been associated with abnormalities in the ALK gene: anaplastic large cell lymphoma (ALCL), neuroblastoma, or a rare type of sarcoma, called inflammatory myofibroblastic tumor (IMT). All of the patients in the trial had seen their disease progress following standard therapy.

When possible, the researchers tested patients' tumors for ALK mutations, but this was not required for enrollment. The study assessed the safety of the drug, which is given as a pill, and established an optimal dose. "Overall, this drug is extremely well tolerated," said Dr. Yael Mossé of Children's Hospital of Philadelphia and the University of Pennsylvania at the press briefing.

Seven of the eight children with ALCL had complete responses. Some remained on the drug without the disease progressing for as long as 18 months. Most cases of ALCL in children are driven by ALK mutations, and COG researchers are developing a new clinical trial to learn how to effectively use crizotinib in children newly diagnosed with that disease. 

Of the eight patients with aggressive neuroblastomas, two had complete responses. These two patients, who had documented ALK abnormalities, remained on therapy for 9 months to more than 2 years without the disease progressing, Dr. Mossé noted.

The researchers also reported that the drug had antitumor activity in some patients with IMT. No effective treatments are available for patients with this disease, but about half of IMTs have ALK abnormalities.

This study shows that by understanding "the molecular driver of the tumor, we have the prospect of seeing dramatic responses [in patients]," said ASCO President Dr. Michael P. Link.

The ALK gene appears to be expressed early in development and then shut down after birth, explained Dr. Mossé. This makes the gene an appealing therapeutic target, she added, because it is normally switched off in the body.

Approximately 200 to 250 children are diagnosed with one of these cancers in the United States each year and would be candidates for this treatment based on abnormalities in the ALK gene, Dr. Mossé estimated.

Further reading: "Crizotinib Continues to Show Promise for Some Lung Tumors, Faces Challenge of Drug Resistance"

Antipsychotic Drug Controls "Breakthrough" Nausea and Vomiting after Chemotherapy

In a phase III clinical trial, the antipsychotic drug olanzapine (Zyprexa) was significantly more effective than metoclopramide (Reglan) in controlling chemotherapy-induced nausea and vomiting (CINV) that occurs in some patients despite preventive treatment for these side effects. (Olanzapine is approved by the Food and Drug Administration to treat schizophrenia and bipolar disorder.) Dr. Rudolph Navari of Indiana University School of Medicine-South Bend presented the results at a May 16 press briefing held in advance of the American Society of Clinical Oncology (ASCO) annual meeting.

The double-blinded randomized trial is the first study to demonstrate an effective treatment for "breakthrough" CINV, defined as nausea and vomiting that persist despite preventive treatments. About 30 to 40 percent of patients receiving certain chemotherapy drugs experience breakthrough CINV, which usually develops 2 to 4 days after treatment.

Dr. Navari and his colleagues studied 80 patients who developed breakthrough vomiting or nausea after treatment with chemotherapies that are known to induce vomiting, such as cisplatin, cyclophosphamide, and doxorubicin. Patients were randomly assigned to receive either daily oral olanzapine (10 mg) for 3 days or oral metoclopramide (10 mg) three times per day for 3 days.

During the 72-hour follow-up period, 71 percent of patients receiving olanzapine had no vomiting, compared with 32 percent of patients receiving metoclopramide. Olanzapine prevented nausea in 67 percent of patients, versus 24 percent for metoclopramide. The differences between the two treatment groups were statistically significant, and neither drug caused severe side effects.

"The recommendation from ASCO and other international guidelines is to use your best antiemetics up front," explained Dr. Navari. "Then, if patients develop breakthrough nausea and vomiting, there really haven't been any good options." Metoclopromide is often used in such cases, "but it hasn't been that effective," he said.

The results "are a great step forward for quality of life for our patients," Dr. Sandra Swain, ASCO president-elect, said at the press briefing. For some patients, breakthrough CINV is so debilitating that they will "opt out of curative treatment," she added.

Targeted Drug Shows Potential in Advanced Solid Tumors and Brain Metastases

Results from two early-phase studies of dabrafenib, given alone or combined with another targeted drug, show that the drug is safe and may be effective for patients with advanced melanoma, melanoma brain metastases, and other solid tumors with mutations in the BRAF gene.

The first study, a phase I trial published online May 17 in The Lancet, included 184 patients with melanoma or advanced solid tumors. Of these, 179 patients had BRAF mutations in their tumors. The patients received varying amounts of oral dabrafenib to establish a safe, tolerable dose for use in further studies.

Of the 36 patients with BRAF-mutated metastatic melanoma, but no brain metastases, who received 150 mg of dabrafenib twice a day (the recommended phase II dose), half had a partial or complete response, reported Dr. Gerald S. Falchook of the University of Texas MD Anderson Cancer Center and his colleagues. But most patients developed drug resistance, with a median time to disease progression of 5.5 months.

Dabrafenib at any dose led to partial responses in patients with papillary thyroid and non-small cell lung cancer, as well as in one patient with colorectal cancer. Seven other patients with colorectal cancer, a patient with ovarian cancer, and another with a gastrointestinal stromal tumor had stable disease.

The 150 mg dose of dabrafenib taken twice per day also shrank asymptomatic brain lesions in nine of ten patients with advanced melanoma, completely eliminating them in four of these patients. The median time to disease progression for patients with brain metastases was 4.2 months. All 10 patients were alive at 5 months, and two survived beyond a year. (Patients with brain metastases typically survive for fewer than 5 months.) The researchers suggested that dabrafenib may enter the brain when metastases disrupt the blood-brain barrier, which normally keeps drugs out of the brain.

The most common adverse effects of dabrafenib treatment were skin lesions, fatigue, and fever.

Further trials of dabrafenib, including a phase II study in patients with asymptomatic brain metastases and a phase III randomized controlled study of dabrafenib versus dacarbazine in patients with BRAF-mutant advanced or metastatic melanoma, are under way. 

The second trial tested dabrafenib in combination with trametinib, which targets the MEK protein, in patients with BRAF-mutant metastatic melanoma. In preclinical studies, the combination was more effective than either drug alone. Dr. Jeffrey Weber of the H. Lee Moffitt Cancer Center discussed preliminary results of the phase I/II trial at a May 16 press briefing held prior to the American Society of Clinical Oncology annual meeting.

Of the 77 patients treated with any of four doses of the drug combination, 8 percent had a complete response, 49 percent had a partial response, and 38 percent had stable disease. Among the 24 patients taking 150 mg of dabrafenib twice a day and 2 mg of trametinib once a day (the dose that will be used in the phase II study), 8 percent of patients had a complete response, 54 percent a partial response, and 38 percent stable disease. In this subset of patients, the time to disease progression was 10.8 months.

Dr. Weber noted that only 3 percent of patients who received both drugs developed squamous cell cancers, compared with 15 to 25 percent of patients in previous studies who took dabrafenib or another BRAF inhibitor alone. Although 22 percent of patients who received both drugs developed a rash, there was an almost complete absence of the acneform rash usually seen with MEK inhibitors. However, high fever was more common among patients taking the combination than in patients in previous studies who took a single BRAF inhibitor, and in some cases high fever led to a dose reduction or treatment delay.

"Obviously, we have to be cautious—it's only a cohort of 24 patients—but [the finding] looks extremely encouraging," said Dr. Weber. A phase III trial testing the drug combination in patients with advanced melanoma has just begun.

Also in the Journals: Program Helps Older, Overweight Cancer Survivors Lose Weight, Eat Better

A tailored, home-based program has helped older cancer survivors who were overweight or obese eat better, get more exercise, lose weight, and maintain these improvements over time, according to findings from the Reach Out to Enhance Wellness (RENEW) study. Dr. Wendy Demark-Wahnefried of the University of Alabama at Birmingham and her colleagues reported their results May 21 in the Journal of Clinical Oncology.

The study included more than 600 survivors of breast, prostate, or colorectal cancer who were older than age 65, sedentary, and overweight or obese. Participants received tailored print materials and telephone counseling at regular intervals over the course of a year.

Further research to improve older cancer survivors' health and quality of life is important, the study authors noted, because this population numbers over 7 million and is increasing rapidly.

Also in the Journals: Coffee Drinking May Be Associated With Lower Risk of Death

Results from a large study of older adults suggest that coffee drinking may be associated with a lower risk of death. Those who reported at the start of the study that they drank coffee (whether caffeinated or decaffeinated) had a slightly lower risk of death from heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections—but not cancer—than those who did not report drinking coffee.

Compared with people who did not drink coffee, those who consumed three or more cups of coffee per day had approximately a 10 percent lower risk of death.

The study, led by Dr. Neal Freedman of NCI's Division of Cancer Epidemiology and Genetics, was observational and could not determine whether coffee drinking actually reduced the risk of death. The findings appeared May 17 in the New England Journal of Medicine.

Special Report

U.S. Preventive Services Task Force Advises against PSA Screening

Vials of blood The debate about the value and appropriate use of the PSA blood test to screen for prostate cancer is likely to continue for some time.

A long-awaited update from the U.S. Preventive Services Task Force (USPSTF) recommends against screening men for prostate cancer with the prostate-specific antigen (PSA) test. The task force's 2008 recommendation advised only against screening men aged 75 and older; the update has extended that guidance to include all men.

The recommendation—published May 21 in the Annals of Internal Medicine and on the USPSTF website—does not apply to PSA testing to monitor prostate cancer progression after diagnosis or treatment.

"All men deserve to know what the science tells us about PSA screening: There is a very small potential benefit and significant potential harms," the task force's co-chair, Dr. Michael LeFevre, explained in a statement on the new recommendation.

Based on some of the responses to the recommendation, however, the debate about the value and appropriate use of PSA screening is likely to continue for some time.

Dr. Sushil Lacy, the current president of the American Urological Association, said the organization was unhappy that the task force had failed to revise its recommendation to "more adequately [reflect] the benefits of the PSA test in the diagnosis of prostate cancer."

And in an accompanying editorial in Annals, Dr. William Catalona, director of the Clinical Prostate Cancer Program at the Robert H. Lurie Comprehensive Cancer Center in Chicago, and his colleagues from several other institutions argued that the task force had "underestimated the benefits and overestimated the harms of prostate cancer screening."

Although task force Chair Dr. Virginia Moyer of the Baylor College of Medicine said that the USPSTF recommendation essentially advises physicians not to suggest PSA screening for their patients, she added that there is no disagreement about the need for shared decision-making among patients and physicians.

"We're not saying, 'Don't respond to your patients who ask about screening,'" she said. "Physicians need to have the right information available, so when patients do ask they can give them accurate information and help them make the best decision."

A Tale of Two Trials

The task force relied heavily on findings from two randomized clinical trials of PSA screening: the NCI-funded Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and the European Randomized Study of Screening for Prostate Cancer (ERSPC).

In January, the most recent update from the PLCO trial, based on 13 years of follow-up in nearly 60 percent of the trial participants, showed that regular PSA screening did not lead to fewer prostate cancer deaths. On the other hand, in the ERSPC trial, men who were screened had an approximately 20 percent lower risk of dying of prostate cancer after 9 years of follow-up.

All men deserve to know what the science tells us about PSA screening: There is a very small potential benefit and significant potential harms.

—Dr. Michael LeFevre

The PLCO and ERSPC trials differed in design, however, and both had shortcomings that may have influenced the findings, the task force acknowledged.

The PLCO trial, for example, had a substantial amount of "contamination." That is, about half of the men assigned to usual care (the control arm) had at least one PSA test during the trial.

Although there was a lower contamination rate in the ERSPC trial, the reduced mortality risk in the screening arm was driven almost entirely by participants from just two of the seven countries involved in the trial: Sweden and the Netherlands. And, Dr. Moyer noted, the vast majority of patients in the screening arms were treated at academic medical centers, while nearly all of those in the control arm were treated in community health facilities. This could have biased the results in favor of the screening arm of the study.

Based on an analysis of these and other studies, the USPSTF concluded that no more than 1 death would be avoided for every 1,000 men aged 55 to 69 years screened every 1 to 4 years for a decade.

The task force also pointed to the potential harms that can occur as a result of screening, such as overdiagnosis, psychological harms of false-positive results, and biopsy-related infections. For every 1,000 men treated, Dr. Moyer noted, 200 to 300 will have long-term problems with incontinence, erectile dysfunction, or both.

Recommendations Criticized

In addition to what they called the "methodological flaws" of the two large screening trials, Dr. Catalona and his colleagues argued that it is still too soon to draw firm conclusions on mortality reduction from either trial because the benefits of screening for a slow-growing disease like prostate cancer may take years to become evident.

And the task force "gave little weight," wrote the editorialists, to a PSA screening trial conducted in Göteborg, Sweden, which had longer follow-up than the PLCO and ERSPC trials, but far fewer participants. That trial—which was part of the larger ERSPC trial—showed a 40 percent relative reduction in mortality in men aged 50 to 64 who underwent regular PSA screening.

PSA screening likely played a substantial role in the 40 percent reduction in prostate cancer mortality in the United States since the early 1990s, around the time when PSA screening began to proliferate, said Dr. H. Ballantine Carter, who directs the active surveillance program for men with prostate cancer at the Johns Hopkins University Brady Urological Institute.

"I don't think you can ignore those benefits," Dr. Carter said.

Dr. Moyer noted, however, that there would have been a substantial lag period, as long as 10 years, before any impact on mortality would have been seen from PSA screening. Nevertheless, a 2008 modeling study funded through NCI's Cancer Surveillance and Intervention Modeling Network, suggested that PSA screening could account for anywhere from 45 to 70 percent of the observed drop in prostate cancer mortality.

Despite the disagreement the recommendations have caused, Dr. Carter believes the end result may be beneficial. "I think this starts a conversation that we needed to have about harms and overtreatment, because for a long time those conversations haven't happened," he said. "I think it will move the field toward more targeted screening."

Carmen Phillips

A Failing Grade

The USPSTF makes its recommendations based on a grading system. The task force gave PSA screening for prostate cancer a grade of D, which means the evidence indicates "moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits." 

Under the previous recommendation, issued in 2008, PSA screening for men younger than 75 was given an I grade, meaning the task force concluded that the available evidence was insufficient to judge whether screening had a net benefit or harm.

The task force issued a draft of the updated recommendation last fall for public comment, and some who commented suggested that PSA screening be given a C grade, meaning physicians may advise individual patients to have a screening test or treatment because the evidence suggests there may be a small benefit.

But under the task force's rules, "We really didn't have any choice about this recommendation," Dr. Moyer explained. "When we put all of the evidence together, under the most optimistic view, the potential benefit of screening was very small. And the potential harm was substantial. So the net [impact of PSA screening] comes out negative."

Featured Clinical Trial

Combining Angiogenesis-Targeted Treatments for Liver Cancer

Name of the Trial
Phase I/II Study of TRC105 in Combination with Sorafenib in Hepatocellular Carcinoma (NCI-11-C-0102). See the protocol summary.

Dr. Tim Greten Dr. Tim Greten

Principal Investigator
Dr. Tim Greten, NCI Center for Cancer Research

Why This Trial Is Important
Hepatocellular carcinoma is the most common form of primary liver cancer in adults. Surgery to remove the tumor (resection) is the preferred treatment for patients with limited disease, but many patients are ineligible for resection because of the location of the tumor within the liver, coexisting medical conditions, or both. Options to treat people with unresectable, localized liver cancer include radiofrequency ablation, transarterial chemoembolization, or liver transplantation, but, again, not all patients are eligible for these procedures.

In 2008, the results of a phase III clinical trial established the drug sorafenib as the first systemic agent to improve the survival of patients with unresectable hepatocellular carcinoma. In that study, patients treated with sorafenib lived almost 3 months longer than those who received a placebo. Sorafenib is a targeted drug that interferes with several molecular pathways important for tumor growth and metastasis, including pathways involved in the development of new blood vessels needed to nourish the tumor (tumor angiogenesis). Doctors are eager to see if combining sorafenib with other agents will enhance the benefits seen with sorafenib alone.

An experimental biological agent called TRC105 may also be effective against hepatocellular carcinoma. It too interferes with the development and recruitment of new blood vessels to a tumor, but it does so by blocking a pathway that is different from the ones affected by sorafenib. TRC105 blocks the activity of a protein called endoglin (CD105), which is overexpressed by the endothelial cells of tumor blood vessels. TRC105 is being tested in a phase II study as a single agent for patients with unresectable hepatocellular carcinoma that progressed despite treatment with sorafenib.

In this trial, patients with unresectable hepatocellular carcinoma who are ineligible for a liver transplant or other local therapies will be given oral sorafenib at the standard approved dose and intravenous TRC105. In the first, or phase I, part of the trial, successive groups of patients will be given escalating doses of TRC105 to determine its maximum tolerated dose when combined with standard-dose sorafenib. In the second, or phase II, part of the trial, doctors will treat patients who have not had prior systemic therapy with standard-dose sorafenib and TRC105 at the previously determined maximum tolerated dose. Patients will receive this combined treatment as long as there is no tumor growth and the side effects remain tolerable. Doctors will measure the time it takes for the patients' tumors to begin growing again (that is, until disease progression).

"TRC105 is a [monoclonal] antibody that recognizes and binds to endoglin, which is expressed on the proliferating endothelial cells of the tumor vasculature," said Dr. Greten. "The reason we believe that angiogenesis is a valid target in hepatocellular carcinoma is that these tumors are highly vascularized, so much so that radiologists can diagnose hepatocellular carcinoma by recognizing the imaging pattern in the blood vessels of the liver.

"We know from our preclinical studies that endoglin is upregulated by treatment with sorafenib, meaning there is more of that protein expressed, so there is a strong rationale for combining the endoglin-targeting agent with sorafenib and blocking angiogenesis through two independent pathways," he explained.

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.

Community Update

Community Update


This article is part of a series of stories related to the NCI-designated cancer centers. Look for the icon when we run the next article in the series.

Bridging the Charles River to Find Novel Approaches to Cancer Research

Dana-Farber/Harvard Cancer Center (DF/HCC) and the Massachusetts Institute of Technology's (MIT) Koch Institute for Integrative Cancer Research (Koch) recently announced the Bridge Project, a comprehensive joint collaboration. The goal is to bring together clinical translational scientists from DF/HCC and biologists and bioengineers from Koch to address the "most intractable challenges in cancer." Initial awards totaling $1.3 million for several interdisciplinary research projects will address pancreatic cancer and glioblastoma.

The Bridge Project evolved from discussions between DF/HCC Deputy Director Dr. David Livingston and Koch Director Dr. Tyler Jacks. The idea attracted private donor interest from MIT alumni Arthur Gelb and Thomas Peterson, as well as financial support from the Lustgarten Foundation for pancreatic cancer and the National Brain Tumor Society. The Commonwealth Foundation for Cancer Research joined in 2012 to contribute to the upcoming grant cycle.

Harvard Bridge over the Charles River and the MIT campus (Photo by Dominick Reuter) The Harvard Bridge over the Charles River connects the MIT (pictured above) and Dana-Farber campuses. (Photo by Dominick Reuter)

"Dana-Farber/Harvard Cancer Center and Koch investigators [already] had a number of collaborations going on," commented DF/HCC Deputy Associate Director Dr. Sarah Weiler. "This initiative has formalized and expanded that." As W. David Lee, integrative program officer at Koch, explained, "The idea is to bring together novel technologies with unmet needs on the clinical side." Scientists from the two centers are talking to each other about their work and identifying "riskier" projects they might not have otherwise pursued, he explained.

The initial grant recipients were selected by an external advisory team that provided rigorous, expert review. The four project teams, which will each receive $325,000 over 2 years, will work on

  • Single-cell functional, genomic, and RNA analysis in glioblastoma;
  • A novel approach to improve drug delivery in the treatment of pancreatic cancer;
  • A pancreatobiliary eluting stent for delivering chemotherapy to pancreatic ductal adenocarcinomas; and
  • Novel immunotherapies against pancreatic cancer.

These collaborative projects were forged during two workshops conducted last summer; one on each side of the Charles River, which separates the DF/HCC and MIT campuses. In the first session, DF/HCC clinician-scientists made presentations to Koch and MIT faculty on specific challenges related to pancreatic cancer and glioblastoma, two of the most lethal and least treatable cancers.

The idea is to bring together novel technologies with unmet needs on the clinical side.

—W. David Lee

The second workshop brought the Koch and MIT biologists and engineers to DF/HCC. "We highlighted a number of MIT cutting-edge technologies that we thought the clinicians and researchers over there might not know about, including transgenic mouse models and nanotechnologies capable of analyzing single cells," Lee recalled. "It was a little bit like a very elegant trade show."

Both workshops drew hundreds of faculty from each institution for several hours of intense discussions and networking. The initial solicitation for the Bridge Project brought in 15 proposals from cross-institutional teams that ranged from DF/HCC and Koch investigators who'd never met before last year to scientists with established working relationships who were collaborating on the two target cancers for the first time.

DF/HCC and Koch plan a second round of workshops and awards this year to expand the Bridge Project to include lung, melanoma, and ovarian cancers and hope to grant $50 million over the next 3 to 5 years. "DF/HCC brings the translational scientists, the hospitals, and the patients," Dr. Weiler said. "Koch has strong [expertise in] basic science and engineering. What's neat about this is bringing these strengths together to address some fundamental problems in cancer therapy that really need attention, to try to put some engineering thought behind what we're doing in the clinic."

"Many [NCI-supported cancer] centers have collaborations," noted Dr. Linda Weiss, director of the NCI Office of Cancer Centers. "But I'm not aware of any that are like this in terms of participants, scale, and focus. It's exciting."

Bill Robinson

Notes

In Memoriam: Cedric Long, Assistant Director of NCI's Division of Extramural Activities

Dr. Cedric Long Dr. Cedric Long

Dr. Cedric W. Long, assistant director of NCI's Division of Extramural Activities (DEA), passed away unexpectedly on May 3; he was 75.

Dr. Long spent his 32-year federal career at NCI, including 15 years with DEA. As DEA's assistant director, he oversaw the management of NCI's advisory committees and research integrity compliance. He also served as project officer for the contract supporting operations of the presidentially appointed National Cancer Advisory Board (NCAB) and NCI's Board of Scientific Advisors. Dr. Long was an advisor to the DEA director on extramural policies, including those involving the interface between extramural, intramural, and contract operations.

Over the course of his career, Dr. Long held many leadership positions, and he published more than 90 original papers and abstracts. His research projects spanned the fields of enzymology, protein chemistry, cell biology, virology, immunology, and nucleic acid chemistry. He also studied the factors controlling the expression of leukemia and sarcoma viruses and how these factors relate to cell growth and the transformation of normal tissue into malignant tissue.

Dr. Long was a member of the American Society of Biological Chemists, the American Association for the Advancement of Science, and Sigma Xi. He served as a referee for the Journal of the National Cancer Institute, Analytical Biochemistry, International Journal of Cancer, and the National Science Foundation. Dr. Long was also a member of the NCI Cancer Bulletin Executive Editorial Committee.

A memorial service will be held on June 14 at 2:00 p.m. at the Neuroscience Center Building in conference rooms C and D, located at 6001 Executive Boulevard, in North Bethesda, MD.

NCI's Advanced Technology Research Facility Opens

NCI's Advanced Technology Research Facility in Frederick, MD NCI's Advanced Technology Research Facility in Frederick, MD

On May 21, more than 700 guests attended a ribbon-cutting ceremony to mark the opening of NCI's Advanced Technology Research Facility (ATRF) in Frederick, MD. NCI's Deputy Director for Management John Czajkowski, SAIC President and CEO John Jumper, SAIC-Frederick CEO David Heimbrook, and Rep. Roscoe Bartlett (R-MD) joined representatives of the Frederick County Chamber of Commerce at the ceremony.

The event, hosted by the Chamber, was held in the three-story open atrium of the 330,000-square-foot research and development facility that will house staff from the Frederick National Laboratory for Cancer Research. The ATRF includes laboratories for studying genetics, genomics, proteomics, advanced biomedical imaging, nanotechnology, and clinical-grade drug development and manufacturing for first-in-human studies.

The facility will be a centerpiece of NCI's efforts to develop partnerships that bring together collaborators from government, industry, academia, and the nonprofit sector. These efforts can accelerate the translation of basic research findings into clinical technologies, diagnostics, and treatments for patients with cancer and AIDS. About 40,000 square feet of the interior space will be reserved for partnership projects and start-up companies coming out of the projects.

"This building is designed to facilitate collaboration," said Dr. Heimbrook, in his opening remarks. "Within a few short months, these hallways will be filled with scientists from NCI, SAIC-Frederick, and our partners, doing research and development work to further NCI's mission to provide new hope to patients afflicted with cancer and AIDS."

The work done at the ATRF will pave the way for doctors to "provide the right drug, to the right patient, at the right time," he added.

NCI and China Cancer Institute Discuss Research Issues and Medical Journalism

Scientists, clinicians, and government officials from the United States and China met earlier this month in Beijing for a workshop sponsored by NCI's Center for Global Health and the Cancer Institute and Hospital of the Chinese Academy of Medical Sciences (CICAMS). Participants discussed research on cancer prevention, screening, and biomarkers. At the meeting, held May 9–11, speakers reviewed the status of research in both countries and explored a broad range of opportunities for future collaboration.

Other topics included cancer biomarker research for early diagnosis and prevention, NCI-supported studies of esophageal cancer in China, and U.S.-China collaborations by tumor site. NCI and Chinese government officials highlighted funding opportunities and grant procedures for cancer researchers. In addition, participants explored a proposal to translate NCI's Physician Data Query (PDQ) online summaries of cancer-related information into Chinese.

"The quality of science presented by both CICAMS and U.S. investigators was invigorating. Just as important, plans for collaborations in several areas of high priority for both countries in the areas of cancer biomarker and screening research were a major topic of discussion," said Dr. Barry Kramer, director of NCI's Division of Cancer Prevention, who attended the workshop.

CICAMS Director of Cancer Epidemiology Dr. You-Lin Qiao noted, "The extensive discussion and recommendations for community-based screening of four priority cancers (lung, esophageal, breast, and cervical cancers) provides a great collaboration opportunity for scientists of both countries in the context of China's increased investment in health-related projects."

NCI and CICAMS also hosted a May 8 workshop on medical journalism and cancer research for Chinese editors and reporters to learn how to better evaluate, interpret, and summarize cancer research topics for a lay audience. The session helped participants determine which studies are newsworthy and how to present scientific results accurately to the public.

Paula Jacobs Appointed Associate Director in NCI's Division of Cancer Treatment and Diagnosis

Dr. Paula Jacobs Dr. Paula Jacobs

Dr. Paula Jacobs has been appointed associate director in NCI's Division of Cancer Treatment and Diagnosis and will be responsible for the Cancer Imaging Program. Dr. Jacobs began working at NCI after 30 years in the private sector, where she developed ultrasmall superparamagnetic iron oxide drugs as magnetic resonance imaging agents and iron replacement therapies.

Her research at NCI has focused on lowering the scientific, logistical, and regulatory barriers to investigational use of PET radiopharmaceuticals for therapeutic drug development. She works to standardize imaging techniques to make them more reliable and conducts exploratory research to correlate genomic information about tumors with tumor imaging data.

Proposals Sought for Use of PLCO Data and Biospecimens

Data and biospecimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial are available to qualified researchers through a peer-review process. The Etiology and Early Marker Studies (EEMS) program accepts proposals for access to PLCO biospecimens twice a year. Proposals for the next cycle will be accepted between June 1 and July 16, 2012.

By collecting biologic materials and information about risk factors from trial participants before the diagnosis of disease, EEMS—a component of the PLCO—provides a resource for cancer researchers who are studying the causes and origins of cancer and/or early detection of the disease. Etiologic studies investigate environmental, biochemical, and genetic risk factors for cancer. Early detection studies aim to develop reproducible, reliable biomarkers of early disease.

Details of the review process and application materials are available online. Questions may be directed to parplcohelpdesk@westat.com or 240-314-2313.

Cyber-Seminar Will Examine Cancer Control at State and Local Level

Brandie Adams, Bruce Behringer, and Della Rhoades Brandie Adams, Bruce Behringer, and Della Rhoades

The June 12 NCI Research to Reality (R2R) cyber-seminar will feature examples of successful cancer control coalitions that have used evidence-based public health practice to implement state cancer plans in local jurisdictions. 

The seminar will explore state and local health department perspectives. Bruce Behringer of the Tennessee Department of Health and Della Rhoades of Nodaway County Health Center in Missouri will share their stories of success, lessons learned, and opportunities. In addition, Brandie Adams of the National Association of County and City Health Officials will present the association's new resource guides. These guides are designed to support local implementation of comprehensive cancer control work through local, community-based coalitions.

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 a week after the presentation. 

For more information on the cyber-seminar series, please e-mail ResearchtoReality@mail.nih.gov.