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May 17, 2011 • Volume 8 / Number 10

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Chemotherapy Regimen Extends Survival in Advanced Pancreatic Cancer Patients

The most common type of pancreatic cancer, an adenocarcinoma (Photo by Ed Uthman) A four-drug chemotherapy regimen has produced the longest improvement in survival ever seen in a phase III clinical trial of patients with metastatic pancreatic cancer, one of the deadliest types of cancer. Patients who received the regimen, called FOLFIRINOX, lived approximately 4 months longer than patients treated with the current standard of care, gemcitabine (11.1 months compared with 6.8 months). Results from the trial, which was conducted at 48 hospitals in France, were published in the May 12 New England Journal of Medicine. Read more > >


NCI Cancer Bulletin Receives First Place NAGC Gold Screen Award

National Association of Government Communicators logo

On May 11, the National Association of Government Communicators (NAGC) awarded the NCI Cancer Bulletin first place in the E-Newsletter category of the 2011 Blue Pencil & Gold Screen Awards. The annual competition recognizes superior government communication products and those who produce them. A complete list of award winners is available here.




  • FDA Update

    • FDA Approves Drug to Treat Pancreatic Neuroendocrine Tumors
  • Legislative Update

    • Senate Appropriators Hold Hearing on President's 2012 Budget Request for NIH
  • Notes

    • Portrait of Former NCI Director Dr. John E. Niederhuber Unveiled
    • Dr. Philip Castle Wins Flemming Award
    • New Resources Raise Awareness about Skin Cancer in Minority Populations
    • Meet NCI Experts at ASCO 2011

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.

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Featured Article

Chemotherapy Regimen Extends Survival in Advanced Pancreatic Cancer Patients

The most common type of pancreatic cancer, an adenocarcinoma (Photo by Ed Uthman) Pathology slide showing the most common type of pancreatic cancer, an adenocarcinoma. Less than 5 percent of patients diagnosed with the disease live more than 5 years. (Photo by Ed Uthman)

A four-drug chemotherapy regimen has produced the longest improvement in survival ever seen in a phase III clinical trial of patients with metastatic pancreatic cancer, one of the deadliest types of cancer. Patients who received the regimen, called FOLFIRINOX, lived approximately 4 months longer than patients treated with the current standard of care, gemcitabine (11.1 months compared with 6.8 months).

Results from the trial, which was conducted at 48 hospitals in France, were published in the May 12 New England Journal of Medicine.

The regimen includes the drugs fluorouracil (also known as 5-FU), leucovorin, irinotecan, and oxaliplatin. Because of serious side effects, the treatment is not suitable for all patients with metastatic disease, several pancreatic cancer researchers cautioned. But for patients who are candidates, based on having what is called a good performance status, the regimen will likely become the standard of care, the researchers noted.

"Clearly these are the best results we've seen to date for advanced pancreatic cancer patients in terms of response rate and overall outcome," said Dr. Al Benson of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, who was not involved with the study. "But this is a potentially very toxic combination," he continued, "so there has to be a note of caution when considering patients for this regimen."

Results from the trial were somewhat unexpected. Over the last few decades, numerous chemotherapy drugs have been tested alone and in various combinations in patients with pancreatic cancer, almost always with little or no impact on disease progression or survival.

Clinicians and patients still have to weigh the risks versus the benefits of treatment, stressed Dr. Jack Welch of NCI's Division of Cancer Treatment and Diagnosis. "But the benefit of the FOLFIRINOX regimen is really hard to overstate in terms of what's been accomplished in pancreatic cancer to date."

Trial Design and Patient Selection

[T]he benefit of the FOLFIRINOX regimen is really hard to overstate in terms of what's been accomplished in pancreatic cancer to date.

—Dr. Jack Welch

The French clinical trial employed an efficient design, Dr. Welch noted. The study eventually enrolled 342 patients but began as a more modest randomized phase II trial. Based on tumor responses seen in the first 88 patients, the French research team expanded the study and was able to include the participants from the phase II trial in the phase III trial population.

All patients in the trial had a performance status of 0 or 1, based on a commonly used scale of 0 to 5. Approximately 20 to 25 percent of patients with metastatic pancreatic cancer likely fall into this category and would be candidates to receive FOLFIRINOX, explained Dr. Philip A. Philip of the Barbara Ann Karmanos Cancer Institute in Detroit.

In addition to the improvement in overall survival, nearly one-third of patients in the FOLFIRINOX arm of the trial had some tumor shrinkage, compared with only 9 percent of patients in the gemcitabine arm.

Based on the presentation of the trial's initial survival results last year at the American Society of Clinical Oncology annual meeting, "community oncologists are increasingly adopting this regimen in day-to-day practice," Dr. Philip said.

The serious side effects associated with the FOLFIRINOX regimen include neutropenia, neuropathy, and gastrointestinal problems. And yet, more patients in the gemcitabine arm dropped out of the study because of side effects, noted the study's lead investigator, Dr. Thierry Conroy of the Centre Alexis Vautrin and Nancy University, in an e-mail.

In addition to performance status, patient age (those younger than 76) and liver function determine which patients are candidates for the regimen, Dr. Conroy explained.

Because of the high risk of neutropenia associated with the FOLFIRINOX regimen, Dr. Benson added, oncologists need to proceed with caution before using it in patients who have a biliary stent. Biliary stents are common in patients with pancreatic cancer, he said, because tumors that form in the head of the pancreas can often obstruct the bile duct, preventing it from feeding properly into the small intestine; a stent is used to alleviate the obstruction.

Neutropenia, Dr. Benson continued, puts patients with biliary stents at increased risk for infections that can lead to sepsis, a potentially fatal blood infection.

Looking for Less-Toxic Combinations

Although the trial results are welcome news, there is still a tremendous amount of work to be done in this disease, Dr. Philip stressed. "New drug development must not ignore the patients with lesser performance status who cannot tolerate this regimen," he said. 

Researchers are now looking to build on the success of the FOLFIRINOX regimen. For example, Dr. Conroy and his colleagues are planning to test it as a post-surgical, or adjuvant, therapy in the small proportion of patients who are diagnosed with earlier-stage disease and who are candidates to have their tumors surgically removed.

FOLFIRNOX's efficacy opens up new avenues of investigation, stressed Dr. Welch, including using it as a backbone on which to piggy back other treatments, particularly targeted therapies that don't have overlapping toxicities. The regimen also needs to be "dissected" and optimized to determine if all four drugs are required or if dosages can be adjusted so that the efficacy can be maintained while alleviating or mitigating some of the regimen's serious side effects.

"For many years all we had as a chemotherapy backbone was gemcitabine," Dr. Welch said. "Now we can be much more flexible in our thinking."

Carmen Phillips

Cancer Research Highlights

Study Finds Colonoscopy Screening Overused in Medicare Beneficiaries

A new study suggests that almost one-quarter of Medicare beneficiaries undergo colorectal cancer screening with colonoscopy more frequently than is recommended, including a large number of beneficiaries 80 years of age or older. Performing potentially unnecessary colonoscopies in such elderly beneficiaries is of "special concern" because the risks associated with the procedure (such as intestinal perforations and infections) can often outweigh the benefits for this age group, the study authors noted.

Dr. James Goodwin of the University of Texas Medical Branch, Galveston, and his colleagues published their findings online May 9 in the Archives of Internal Medicine.

Previous studies have documented the underuse of colorectal cancer screening in general, but this study examined whether colonoscopy was being overused in certain populations based on current recommendations. After a negative result on a screening colonoscopy, cancer organizations and public health groups almost uniformly recommend that most people not have a repeat screening colonoscopy for another 10 years.

For this recent study, the researchers analyzed claims and enrollment data from a random sample of Medicare beneficiaries between 2000 and 2008. The analysis included adjustments to identify initial and repeat screening colonoscopies, since these procedures often are not coded as such on Medicare claims, the study authors noted.

Approximately 46 percent of the more than 24,000 Medicare beneficiaries who had a negative result on the initial screening colonoscopy between 2001 and 2003 underwent another colonoscopy sometime in the next 7 years. In this group, nearly 43 percent had "no clear indication for the early repeated examination," the researchers found, suggesting that the colonoscopies were screening procedures.

A third of people who were 80 years of age or older at their initial negative screening had what appeared to be another screening colonoscopy within 7 years. The analysis revealed "inflection points with noticeable increases in the rate of repeated colonoscopies at 3 and 5 years, suggesting that those procedures might have been routinely scheduled rather than in response to symptoms."

Limiting inappropriate or medically unnecessary colonoscopies is important for a number of reasons, the researchers wrote. Apart from exposing patients to unnecessary risks and incurring extra costs, they continued, unnecessary colonoscopies tie up resources that could otherwise be used "to increase appropriate colonoscopy in inadequately screened populations."

Prostate Cancer Study Provides More Data on Surgery versus Watchful Waiting

Surgery may be the preferred option for men younger than age 65 who are diagnosed with early-stage prostate cancer, according to extended follow-up from a randomized clinical trial. For several reasons, however, the findings may have limited applicability to men in the United States who are diagnosed with early-stage disease, several researchers said.

The results were published in the May 5 New England Journal of Medicine.

The clinical trial, conducted in Sweden, Finland, and Iceland, randomly assigned 695 men newly diagnosed with early-stage prostate cancer to immediate surgical removal of the prostate (radical prostatectomy) or watchful waiting, a less-intensive precursor to what today is typically called active surveillance. Among men younger than age 65, those who underwent immediate surgery had superior overall survival and prostate cancer-specific survival, and their risk of dying from prostate cancer was 51 percent lower than those in the watchful waiting group. (In the 15-year follow-up period, among men younger than 65, 28 men in the surgery group and 49 men in the watchful waiting group died from prostate cancer. The numbers of prostate cancer deaths for all men in the two groups were 55 and 81, respectively.)

Overall, about 15 men had to be treated to prevent one death, reported Dr. Anna Bill-Axelson of the University Hospital, Uppsala, and her colleagues. For men younger than 65, however, the number who needed to be treated to avoid one death was about seven.

The trial "has provided important evidence that effective treatment is both necessary and possible for many men with early-stage prostate cancer," wrote Dr. Matthew R. Smith of the Massachusetts General Hospital Cancer Center in an accompanying editorial. But the findings, he cautioned, "may not be relevant for men with low-risk early-stage prostate cancers identified by PSA screening." In the United States, the vast majority of early-stage prostate cancers are diagnosed by PSA screening, whereas only about 5 percent of cases in the Swedish trial were diagnosed in this manner.

Surgery and other common prostate cancer treatments can have serious side effects, including incontinence and erectile dysfunction, explained Dr. Barry Kramer, editor-in-chief of NCI's Physician Data Query Screening and Prevention Editorial Board. "Because PSA screening can lead to the detection of a large number of tumors that wouldn't have caused any medical problems in the absence of screening," he continued, "the ratio of benefit to risk for immediate surgery can be quite different for men with PSA-detected cancers."

In addition, the watchful waiting protocol used in the trial differs significantly from the more aggressive active surveillance protocol often used in the United States. Men in the watchful waiting arm of the trial were considered for treatment (with transurethral resection of the prostate) only if they had specific symptoms that suggested their disease was progressing.

In contrast, active surveillance programs in the United States can entail twice-yearly checkups that may include PSA testing and digital rectal exams, as well as annual or regular prostate biopsies. These may be followed by curative treatment with surgery or radiation if there is evidence of disease progression.

A recent observational study found that prostate cancer-specific survival rates in men with early-stage disease diagnosed via PSA screening who opted for active surveillance were nearly identical to those of men who opted for immediate treatment.

Results from a large, randomized U.S. trial, called PIVOT, comparing surgery with watchful waiting in men diagnosed with localized prostate cancer, are expected to be available sometime this year. Because the large majority of the men in the trial were diagnosed by PSA screening, the findings should be more applicable to current U.S. practice, Dr. Kramer said.


Findings from the PIVOT trial were presented May 17 at the American Urological Association annual meeting. At 12 years of follow-up, overall and prostate cancer-specific survival were nearly identical in the surgery and watchful waiting arms.

Breast Cancers Arising between Mammograms Have Aggressive Features

Breast cancers that are discovered in the period between regular screening mammograms—known as interval cancers—are more likely to have features associated with aggressive behavior and a poor prognosis than cancers found via screening mammograms. These high-risk features include higher stage and grade, larger size, and lack of estrogen receptors (ER) and progesterone receptors (PR), researchers reported online May 3 in the Journal of the National Cancer Institute.
The results highlight the need for more sensitive screening methods and for women to monitor their breast health between mammograms, concluded Dr. Victoria Kirsh of Cancer Care Ontario and her colleagues.

The researchers compared the traits of breast cancers in women who had been screened in the Ontario Breast Screening Program between 1994 and 2002. The analysis included 87 women who had "missed" interval cancers, 288 women who had true interval cancers, and 450 women whose cancers were detected by screening mammography. Missed interval cancers were cancers that could have been detected by mammography but were overlooked due to error or difficulty in reading the x-ray films. True interval cancers were not detectible at the time of last screening, even on review.

Some clear differences between the tumors were found. Compared with screen-detected cancers, true interval cancers were almost four times as likely to be larger than 2 cm in diameter, more than four times as likely to be stage III or IV instead of stage I, more than three times as likely to be poorly differentiated (to have very abnormal-looking cells), about three times as likely to have a high proliferative rate (to be growing quickly), and about twice as likely to be estrogen receptor negative and progesterone receptor negative. Missed interval cancers were also more likely to be large, to be poorly differentiated, and to have invaded the lymph nodes than screen-detected cancers.

Women in the study were older than age 50 and predominantly white. It is not clear whether these results would be similar in younger women or in a more diverse population.

"A small number of cancers will not be detected by mammography," explained co-author Dr. Anna Chiarelli in an e-mail. This study, she continued, serves as a general reminder that "women should be 'breast aware' and see their health care provider if breast symptoms arise between mammograms."

Patient Reports of Family Cancer History Are Often Inaccurate

Getting an accurate family history of cancer from individuals is important for doctors who make recommendations about cancer screening and prevention strategies based, in part, on this information. But, until now, clinicians have lacked good evidence about the reliability of these histories. A study published online May 11 in the Journal of the National Cancer Institute shows that when people in the general population are asked about the history of specific cancer types in their family their responses are often inaccurate.

Dr. Phuong Mai of NCI's Division of Cancer Epidemiology and Genetics and her colleagues investigated the reliability of reported family histories for the four most common cancers in adults: breast, colorectal, lung, and prostate. Overall, the researchers found that reports of no family history of cancer were highly accurate, but the accuracy of reports of specific cancers among relatives was low to moderate and varied by cancer type. Accuracy was highest for breast cancer, lowest for colorectal cancer, and better overall for first-degree relatives than second-degree relatives.

An accurate family history is important because some cancer screening and prevention recommendations are based on a person's risk level, which is determined in part by family history, noted Dr. Mai. Inaccurate histories can lead to incorrect risk estimates, which may result in unnecessary screening for some people and not enough for others.

The study, begun by Dr. Louise Wideroff, who was part of NCI's Division of Cancer Control and Population Sciences until recently, used information from the 2001 Connecticut Family Health Study, a random telephone survey of households in Connecticut. In the survey, 1,019 Connecticut residents reported on the history of various cancers in a total of 20,578 first- and second-degree relatives.

The researchers then tried to confirm reported cancer cases for a randomly selected subset of 2,605 of those relatives using a number of data resources, including state cancer registries, Medicare databases, the National Death Index, death certificates, and health care facility records, as well as through direct interviews with the relatives or with proxies for those who had died.

"We would strongly encourage people to learn as much as possible about their family history [of disease], cancer or otherwise, and take initiative to collect and preserve these valuable records," said Dr. Mai. "And clinicians need to be aware that when patients report that cancers have occurred in their family, it might require additional validation."

Confirming diagnoses, however, can be time-consuming, expensive, and difficult. In the future such validation may be facilitated by the availability of electronic medical records, Dr. Mai noted.

Physicians need to approach patients' family history information "with healthy skepticism," wrote Drs. Rachel Freedman and Judy Garber of the Dana-Farber Cancer Institute in an accompanying editorial. "Although we should thoughtfully listen to our patients' histories, we must listen even harder to what they 'could' be telling us, especially when specific information could influence their care and the care of their relatives," they concluded.

Special Report

In Rare Skin Cancer, Virus Emerges as Target and Tool

George Campbell, a Merkel cell cancer patient. (Photo courtesy of George Campbell) George Campbell in May 2005. A small bump on his left forearm would later be diagnosed as Merkel cell cancer. (Photo courtesy of George Campbell)

In the spring of 2005, George Campbell was vacationing with his wife in California when he noticed a bump on his left arm. The bump was colorless and painless, but it had not been there before. When the 57-year-old U.S. Air Force retiree returned home to South Carolina, his doctor lanced the growth, and Campbell hoped that would be the end of it.
But a month later, the bump was four times its original size. The doctor then removed the growth and some skin around the area. After eight pathologists analyzed the tissue, Campbell received a diagnosis: Merkel cell carcinoma (MCC), a rare but aggressive form of skin cancer.

This disease tends to occur in people who have compromised immune systems and in older people. Tumors often develop in sun-exposed areas of skin, and UV radiation is a possible risk factor. Approximately 1,600 people in the United States are diagnosed with MCC each year.

Like many patients with MCC, Campbell could not find a local oncologist with experience in treating the disease. So he traveled to Boston, where Dr. Paul Nghiem, then at the Dana-Farber Cancer Institute, and other experts developed a treatment plan. Two weeks later, Campbell underwent surgery, and he has been free of cancer since.

"I am one of the fortunate ones," said Campbell. "Because the cancer was caught early, I fell into the 10 percent of cases that have a low chance of recurrence." Nearly half of all patients with this often fast-growing cancer survive less than 5 years after diagnosis.

Rapid Advances in Research

A new understanding of MCC has emerged since 2008, when researchers discovered a previously unknown virus in 8 of 10 tumors. The finding has been confirmed by many groups, and the virus is now implicated in most—but not all—cases of the cancer.

An electron microphotograph of Merkel cell polyomavirus virus-like particles.An electron microphotograph of Merkel cell polyomavirus virus-like particles.

"In the last 3 years, cancer biologists have turned this disease upside down," said Dr. Patrick Moore of the University of Pittsburgh Cancer Institute, who, with his colleague Dr. Yuan Chang, co-led the team that discovered the virus, now called Merkel cell polyomavirus (MCV).

"When you find a virus that is really causing cancer, the pace of research moves fast," noted Dr. Moore, whose team also discovered the virus that causes Kaposi sarcoma in 1994. "Every new piece of data provides a way of looking at the complex picture of how viruses can cause tumors."

Most people are infected by MCV as children, but the virus causes cancer only rarely. A series of molecular events must occur for tumors to develop, and each of these events is rare. The first step is likely to be the loss of immune control over the virus, Drs. Chang and Moore noted in a recent article on viruses and cancer.

Experimental Blood Test Detects Recurrence

Understanding how a person's immune system responds to the virus could lead to new diagnostic tools and, potentially, treatments. Now at the University of Washington, Dr. Nghiem and his colleagues have developed an experimental blood test that, in a small number of patients, identified a recurrence of the cancer before the disease was clinically detectable.

The test allows researchers to monitor levels of antibodies that a patient produces in response to proteins (antigens) in the virus. These levels tend to fluctuate with the extent of the cancer, falling after treatments and rising with recurrences, the researchers reported last year.

In a recent case, the test showed that a patient's antibody levels were slightly above baseline, though the man felt fine. He had an imaging test, which revealed a mass. "Because of the test, doctors will be able to treat the cancer earlier than they otherwise might have," said Dr. Jayasri Iyer, a research fellow working with Dr. Nghiem.

"The immune response provides a unique window into the disease," said Dr. Nghiem. "We are not aware of another cancer that can be detected via an immune response against tumor antigens." The test needs to be validated in a larger study, he added.

Moving Toward Immune-Based Treatments

In separate work, Dr. Nghiem and his colleagues recently identified a factor that may help explain why some patients fare better than others. Patients whose tumors were infiltrated by immune cells had better outcomes than patients whose tumors were not.

"This tells us that the body's ability to mount an immune response into the tumor is important in determining the outcome and survival in these cases," Dr. Nghiem said.

These findings appeared recently in the Journal of Clinical Oncology with a companion report on MCC. Both studies concluded that immune "readouts" from patients infected by MCV may contain prognostic information.

The studies also "provide more evidence that MCV plays a causal role in this cancer," said Dr. Christopher Buck of NCI's Center for Cancer Research, who co-authored an accompanying editorial with Dr. Douglas Lowy, chief of CCR's Laboratory of Cellular Oncology and deputy director of NCI.

What's more, Dr. Buck continued, the studies provide hope that the human immune system one day could be recruited to help clear tumors in some patients. "Viruses do cause some cancers, but the good news is that a virus can often be a tool in your arsenal for treating the disease," he said.

Dr. Moore agreed. "Now that we know the tumor is caused by the virus, we can look for ways to stimulate virus-specific immunity," he said, noting that his group and others were working on the approach.

For Patients, New Diagnostic Codes

Although immune-based therapies could be years away, patients with MCC have benefited from recent changes in how this disease is reported by doctors. New diagnostic codes that are specific to MCC were approved in 2009. Insurance companies often use these codes in making decisions about coverage.

Under the old codes, MCC was grouped with less aggressive skin cancers that do not require the same extensive tests and imaging studies. Consequently, patients have been denied coverage for tests their doctors ordered.

"The new codes have made a big difference," said Dr. Iyer, who co-led the effort to develop them. "Not only can patients get approval for care from insurance companies, but researchers can now track [the incidence of] MCC more easily."

Connecting Patients with Experts

Dr. David Schuster Dr. David Shuster has blogged about his "battle with Merkel cell cancer" since last year.

Another difference over the last few years has been the increasing use of the Internet as a way for people with rare diseases to share experiences and information. Back in 2005, when George Campbell was recovering from surgery, he decided to create an online discussion and support group for people affected by MCC. Though he initially wondered whether anyone might want to join, the group now has more than 460 active members around the world.

The support group has helped many newly diagnosed patients find experts on the disease; one such patient was Dr. David Shuster, a 70-year-old diagnostic radiologist from California. After he was diagnosed with MCC a year ago, his son discovered the support group and was put in touch with the closest expert, Dr. Nghiem.

A few weeks later, Dr. Shuster flew to Seattle and developed a new treatment plan with the doctors there. He then returned home to receive radiation therapy from his local doctors under Dr. Nghiem's supervision.

The treatment helped, but the disease has recurred twice. Earlier this month, after considering his options, Dr. Shuster started chemotherapy. Support from people on the listserv and readers of his blog, My Battle with Merkel Cell Cancer, has been a comfort, he said.

"When I decided to go ahead with chemotherapy, I thought it might just postpone the inevitable, or just make me sick," he said in an interview. "But there are anecdotal reports from people in the support group who've had chemotherapy alone and survived for years. That gives me hope."

Edward R. Winstead

For more information visit NCI's Web page on MCC

To find the discussion/support group, search Google Groups for "Merkel Cell Cancer."


This is the seventh article in a series of stories related to cancer communications. You can read more articles in the series here.

Straight from the Source: Electronic Patient-Reported Outcomes

Phone buttons (Photo by Chris Campbell) A study found that patients who used an automated phone system to report symptoms to their health care team experienced a faster decline in the symptoms than other patients. (Photo by Chris Campbell)

Patients know what they feel. Whether they are reporting pain caused by cancer or side effects of treatment, a patient's own account of symptoms and other experiences provides a unique perspective. In recognition of this fact, researchers and health care providers increasingly are trying to capture information by patient self-reporting. A 2006 consensus conference at NCI, for example, concluded that a patient's own account of subjective symptoms, such as pain or fatigue, should be routinely collected in clinical research.

For years, researchers have been trying to design electronic systems for collecting patient-reported outcomes (ePRO) that can help improve clinical care as well as clinical research. The hope has been that allowing patients to report distressing symptoms to their health care providers more frequently by computer or phone will enhance communication and decision making between patients and providers.

"If we can use this type of system to stay more acutely attuned to what patients are experiencing, we believe we can both improve patient outcomes and reduce medical care costs by minimizing the occurrence and impact of adverse events during treatment," explained Dr. Bryce Reeve, an associate professor of health policy and management at the University of North Carolina at Chapel Hill.

Preliminary trials examining whether ePRO systems could improve quality of life for patients showed little benefit from electronic monitoring, recounted Dr. Amy Abernethy, associate professor of medicine at Duke University.

"People tried back in the '90s to test some rudimentary electronic quality-of-life monitoring tools, but the problem was that most of them were designed by researchers alone and didn't fit into the way clinical care works," she explained. "But patients have always reported their symptoms and side effects in clinical care, it just wasn't electronic. Now these two pieces are coming together, and we're starting to see electronic patient-reported monitoring that fits into clinical care."

More Talking, Faster Healing?

Two recent randomized trials that tested ePRO systems showed promising improvements in patient care and clinicians' willingness to use the systems. The studies, published in the Journal of Clinical Oncology, also underscore some of the challenges associated with developing and implementing these systems.

In one trial, researchers at the Dana-Farber Cancer Institute and their colleagues tested a system called the Electronic Self-Report Assessment–Cancer (ESRA-C) in 660 patients who were beginning chemotherapy or radiation therapy. The participants completed the ESRA-C questionnaire twice: once before starting treatment and once 4 to 6 weeks later, during treatment.

Although all of the patients completed the questionnaires, the researchers randomly assigned the patients to two groups: half of the patients had their questionnaire answers seen by their health care team, and the other half had their questionnaire answers set aside without their providers seeing the answers. The researchers audio recorded the patients' clinic visits after completion of the second questionnaire to see if receipt of an ESRA-C report increased the discussion of symptoms and treatment side effects.

Overall, doctors who received an ESRA-C report were 30 percent more likely to discuss symptoms that were above a set threshold of severity, including those that related to sexuality and social functioning, which are often awkward for patients and physicians to broach. Patients and doctors still tended to discuss common side effects often, regardless of whether they were of concern to individual patients.

In the second trial, researchers from the University of Texas M. D. Anderson Comprehensive Cancer Center recruited 100 patients to test an automated telephone system for reporting distressing side effects. All patients had undergone thoracotomy for lung cancer or lung metastases, a surgical procedure that can cause many severe symptoms during recovery.

All patients received automatic calls from the system about twice a week for 4 weeks. Before the study began, patients were randomly assigned to either an intervention group or a control group. In the intervention group, if any symptom recorded during the calls exceeded a preset threshold for severity, the system generated an e-mail alert to the patient's medical team. For the control group, symptoms were recorded but no alerts were generated. During the study, severe symptoms declined an average of 19 percent in the intervention group compared with an average of 8 percent in the control group. Moreover, symptoms declined more rapidly in the intervention group.

On a more worrisome note, 16 percent of alerts in the intervention group went unanswered by the health care team. "We've always been concerned that a lot of patient issues are not getting heard," said Dr. Abernethy. At least with ePRO systems, she continued, the clinic knows how many patient requests do not receive a timely response.

Integration in the Real World

"Patients are willing, able, and enthusiastic to provide this information. The real challenge is going to be the integration of this information into clinical work flow," commented Dr. Ethan Basch, an oncologist and patient-reported outcomes researcher at Memorial Sloan-Kettering Cancer Center. "The clinic is very busy, and it can be complicated to introduce new information, particularly real-time reporting of patient data that might be showing up 24/7 if patients are reporting from home."

One selling point for these systems may be their ability to redirect information before it even reaches the oncologist; for example, to send pain management issues straight to an oncology nurse or to have signs of depression trigger a call from the clinic's mental health staff. Such automated distribution could lighten the health provider's clinical burden instead of increasing it, explained Dr. Abernethy.

"Over the past 5 years, the interest in ePRO has grown explosively, and there's a broader movement toward patient-centered care models, where the perspective of the patient is being integrated into care at every level," added Dr. Basch. "With the upsurge in interest from clinicians, it's become easier to integrate this information into the clinic."

Patients need to understand that these tools are meant to enhance, not replace, standard interactions between patients and their care providers, explained Dr. Reeve. This applies particularly to emergency situations. "If patients are experiencing highly distressing symptoms, they should call their doctor or nurse directly or call 911," he stressed, "not log into an ePRO system to report them."

As these systems become more widely used, larger multicenter clinical trials will likely be needed to determine whether this additional communication about the patient experience does indeed translate into better health outcomes for patients, Dr. Reeve explained. Many hospitals are developing customized ePRO systems, which may complicate research studies that seek to combine data across clinics.

However, Dr. Basch does not see this challenge as insurmountable. "We are already seeing big efforts to standardize health care terminology. A number of people around the country and internationally are really interested in this subject, and we're all aware of each other's work," he explained. "We're always thinking about how we can link our data and questionnaires." (See the box below.)

Standards for ePRO data will be important as these systems become more common and undergo more rigorous testing to ensure that they are helping patients, according to Dr. Abernethy.

"While we know that research-designed ePRO systems without attention to the needs of the clinic are going to fail, clinically designed systems without adequate attention to the needs of research would also be inadequate for the future of this field," she concluded.

Sharon Reynolds

NIH Efforts to Standardize ePRO Data Collection

Several NIH-supported initiatives are under way to standardize data collection for ePROs and to disseminate questionnaires validated by research to other interested researchers and clinicians:

A Closer Look

Combining Targeted Cancer Therapies: Much Promise, Many Hurdles

Scientists at work in a research laboratory Obstacles can prevent researchers from testing combinations of investigational targeted agents in clinical trials

A major advance in the treatment of cancer over the past decade has been the introduction of drugs such as imatinib (Gleevec) that target specific abnormalities in cancer cells. But when these drugs are given as single agents, cancer cells often find ways to overcome their anticancer effects. If cancer-promoting signals from one signaling pathway are blocked, for example, tumors activate another.

Evidence from laboratory studies suggests, however, that using combinations of targeted agents to block multiple pathways simultaneously may prevent or slow the development of drug resistance. In some cases, combinations of two investigational targeted agents have had synergistic antitumor effects, even if one or both drugs showed little or no anticancer activity alone. 

However, major obstacles can prevent researchers from testing combinations of investigational targeted agents in clinical trials. The drug development system in the United States is designed to test single agents; first in trials to assess safety, and then in larger studies to evaluate effectiveness. Only after an agent has been approved by the Food and Drug Administration (FDA) can it be tested in combination with a different investigational agent.

Another set of barriers can occur when researchers want to test two investigational agents that belong to different pharmaceutical companies. A situation like that "raises business, legal, liability, and intellectual property issues so thorny no one wants to touch them," said Dr. Michael Caligiuri, director of the NCI-designated Comprehensive Cancer Center at Ohio State University.

Earlier this month, Dr. Caligiuri hosted the Cancer Drug Development Roundtable that brought together representatives of NCI, the FDA, the pharmaceutical industry, and other cancer organizations to develop recommendations for overcoming obstacles to the co-development of two or more promising investigational anticancer agents. The group's recommendations will be announced later this year.

Drafting Guidance

One concern about the co-development of investigational drugs is that the process will provide less information about the safety and effectiveness of these agents than if each were developed and tested individually, according to Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research.

However, she continued, the benefit of getting more effective drug combinations for patients may outweigh this concern. For this reason, a draft guidance published by the FDA in December 2010 proposes allowing clinical trials of two or more investigational agents for use in combination only when:

  • A compelling biological rationale exists for use of the combination—for example, the agents block different targets in the same molecular pathway, block multiple pathways, or block the target in ways that decrease resistance or permit lower doses to be used, thus minimizing toxicity;
  • Preclinical or preliminary clinical studies suggest that the combination provides greater than additive activity or a more durable response compared with using the agents alone; and
  • A compelling reason argues against development of the agents individually—for example, single-agent therapy would lead to resistance or one or both agents would likely be ineffective on its own.

Adaptive Trial Design

The sheer numbers of new targeted agents that could be used in combination challenge the capacity of the current system for developing drugs, explained several speakers at the multi-agency roundtable. Dr. Eric Rubin, vice president for oncology clinical research at Merck Research Laboratories, estimated that testing every possible combination of 10 new drugs in sequential clinical trials would take about 90 years.

With multiple targets, multiple cancers, and multiple active pathways within tumors, we really need to think about how to design trials efficiently.

—Dr. Janet Woodcock

"We can't keep doing one-off trials of single agents that take years to complete," said Dr. Woodcock. "With multiple targets, multiple cancers, and multiple active pathways within tumors, we really need to think about how to design trials efficiently."

Dr. Rubin cited two recent trials as models of the type of "adaptive" trial design needed to address these complexities. In the BATTLE trial, tumor samples from patients with non-small cell lung cancer were tested for specific biomarkers; based on that analysis, the patients were enrolled into one of the trial's four treatment arms, each of which tested a different targeted therapy.

Another trial, called I-SPY2, is using biomarkers to identify women with early-stage breast cancer who might benefit from new investigational drugs that are given along with standard chemotherapy prior to surgery. Participants in that trial have a high risk of recurrence as determined by factors such as estrogen receptor and HER2 status.

Model Agreement

A template developed by NCI's Cancer Therapy Evaluation Program (CTEP) may serve as a model for resolving the intellectual property concerns that often hinder co-development of investigational targeted agents owned by different pharmaceutical companies, said Dr. James H. Doroshow, director of NCI's Division of Cancer Treatment and Diagnosis (DCTD), which oversees CTEP.

Under the CTEP model agreement, all collaborators receive fully paid, nonexclusive, royalty-free licenses to any intellectual property that emerges from combination drug studies. NCI currently holds such collaborative development agreements with more than 80 industry partners for more than 100 investigational agents. CTEP has recently proposed extending such agreements to biomarker studies.

Eleanor Mayfield

Addressing the Scientific Challenges of Co-Developing Targeted Agents

NCI is creating resources for the research community to address some of the scientific challenges to developing combination targeted therapies.

Until now, for example, there haven't been any standardized assays for assessing the clinical effects of targeted therapies. NCI is currently developing more than 50 assays for evaluating the mechanisms of action of molecularly targeted agents. Once validated, these assays will be made available to the research community at no charge.

NCI has also developed "combo plates" specially formatted for researchers to use in testing new compounds in combination with commercially available anticancer drugs. A plated set of about 100 FDA-approved oncology drugs is now available without charge to the research community. Information about this resource and how to obtain it can be found on the DCTD Developmental Therapeutics Program Web site.

Until recently, Dr. Doroshow said, the Department of Health and Human Services' Office of General Counsel prohibited NCI from purchasing or synthesizing patented agents for research purposes. But that policy changed in 2009, and NCI has acquired more than 300 investigational agents for in vitro testing. A program is being established to allow investigators to submit requests for in vitro studies of the effects of specific combinations of investigational agents.

NCI scientists are also modeling estimates of the effectiveness of combining investigational and approved agents in a variety of concentrations across the institute's Human Tumor Cell Line Screen, which includes 60 human cancer cell lines and is used to screen potential anticancer compounds. These data will be publicly available within a year. The most promising combinations will then be studied in animal models to identify those that should progress to clinical trials.

Featured Clinical Trial

Lenalidomide and Radiation for Children with Brain Cancers

Name of the Trial
Phase I Study of Lenalidomide and Radiotherapy in Pediatric Patients with Diffuse Intrinsic Pontine Gliomas or High-Grade Gliomas (NCI-10-C-0219). See the protocol summary.

Dr. Katherine WarrenDr. Katherine Warren

Principal Investigators
Dr. Katherine Warren and Dr. Sean Hipp (Lead Associate Investigator), NCI Center for Cancer Research

Why This Trial Is Important  
Children with aggressive malignant brain tumors, such as high-grade gliomas or diffuse intrinsic pontine gliomas (DIPGs), have very few treatment options. These cancers tend to grow quickly and are usually resistant to treatment. Consequently, most children with these tumors die within a year or two of diagnosis.

Children with high-grade gliomas can undergo surgery, but often their tumors cannot be completely removed (resected). In contrast, DIPGs, which are the most common type of brain stem tumor in children and usually occur between the ages of 5 and 10 years, are inoperable because they involve portions of the brain stem that affect many necessary body functions, such as heart rate and breathing. Treatment for DIPG and high-grade gliomas usually involves radiation therapy to the affected portions of the brain.

Very little is known about the biology of DIPG, in part because the disease is typically diagnosed on the basis of magnetic resonance imaging (MRI) scans without a biopsy to collect tumor tissue. Consequently, there has been little tumor tissue available for study. Recently, however, researchers have begun studying some DIPG tissue obtained at autopsy.

"The problem with studying autopsy tissue is that, while it gives us some biological information, it's after the fact," said Dr. Warren. "Most of the children have received some sort of treatment already, and that alters the biology of the tumor in some way, so the autopsy tissue may not represent the tumor at diagnosis."

Many children with DIPG enroll in clinical trials of experimental therapies so that they can receive treatment after radiation therapy or concurrently with it. However, to date, no chemotherapy agent has demonstrated an effect against DIPG, and there have been no advances in the treatment of this disease since the introduction of radiation therapy more than 30 years ago. Despite these disappointing results, doctors hope that newer molecularly targeted drugs may improve the outcome for these children.

Lenalidomide (Revlimid) is an immunomodulatory drug that stimulates immune cells, inhibits angiogenesis, and triggers cell cycle arrest and apoptosis. Additionally, it is related to the drug thalidomide, which is known to sensitize cancer cells to radiation therapy. In a previous phase I study of lenalidomide alone in pediatric brain tumor patients, researchers were able to administer much greater doses of the drug than can be tolerated by adult patients but did not determine the maximum tolerated dose. Because DIPG and high-grade gliomas are treated with radiation therapy and lenalidomide may enhance the effectiveness of radiation treatment, there is a good rationale for combining these therapies in patients with these cancers.

In this trial, patients up to age 18 who are newly diagnosed with DIPG or who have other high-grade gliomas that could not be completely resected will undergo radiation therapy 5 days a week for 6 weeks and receive oral lenalidomide at increasing doses daily for 6 weeks. Thereafter, the patients will receive oral lenalidomide daily for the first 21 days of each 28-day treatment cycle, for up to 28 treatment cycles in the absence of disease progression or unacceptable toxicity. Doctors want to determine the maximum tolerated dose and safety of lenalidomide combined with radiation therapy in these patients.  

"We're hoping that lenalidomide will improve the effectiveness of the radiation and that the drug's immunomodulatory characteristic will have a greater effect in newly diagnosed patients, whose immune systems haven't yet undergone the assault of multiple anticancer treatments," Dr. Warren explained.

For More Information
See the lists of entry 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

FDA Update

FDA Approves Drug to Treat Pancreatic Neuroendocrine Tumors

The Food and Drug Administration (FDA) has approved everolimus (Afinitor) for the treatment of pancreatic neuroendocrine tumors (PNET) that cannot be surgically removed or that have metastasized. This is only the second drug approved to treat this rare form of pancreatic cancer, which is diagnosed in fewer than 1,000 patients annually in the United States.

The FDA’s approval was based on the results of a recent randomized trial involving patients with advanced PNET. Participants treated with everolimus lived an average of 6.4 months longer without disease progression than those who took a placebo.

Everolimus is also approved for treating renal cell carcinoma and subependymal giant cell astrocytoma, a type of benign brain tumor. The drug is designed to prevent cells from proliferating and tumor blood vessels from forming by inhibiting the mammalian target of rapamycin (mTOR) signaling pathway. Common side effects include rash, diarrhea, fatigue, and abdominal pain; serious complications, including kidney failure, have also been reported.

Everolimus is one of two targeted therapies that the FDA’s Oncologic Drugs Advisory Committee recently recommended for approval to treat PNET.

Further reading: Targeted Therapies May Be Effective Against Rare Pancreatic Cancer

Legislative Update

Senate Appropriators Hold Hearing on President's 2012 Budget Request for NIH

NIH Director Dr. Francis Collins presented his vision for how investment in NIH could yield significant public health and economic benefits at a May 11 hearing before the Senate Appropriations Subcommittee on Labor, Health and Human Services, Education, and Related Agencies. He was joined by NCI Director Dr. Harold Varmus; National Institute of Allergy and Infectious Diseases Director Dr. Anthony Fauci; National Institute of Diabetes and Digestive and Kidney Diseases Director Dr. Griffin Rodgers; and National Heart, Lung, and Blood Institute Acting Director Dr. Susan Shurin. Dr. Collins and the institute directors each submitted written testimony for the record. (A webcast of the hearing and the written testimonies are available online.)

In his remarks, Dr. Collins identified four areas in which recent progress is leading to new opportunities. Using The Cancer Genome Atlas as an example, he described how technological advances are making it possible for scientists “to understand the details of health and disease in breathtaking new ways.” He also discussed how NIH is using the latest science to improve health through disease prevention strategies, highlighting early successes of the Diabetes Prevention Program.

Dr. Collins then focused on NIH’s potential role in enhancing the economy and American competitiveness worldwide. He referenced a new economic impact study published by United for Medical Research, which estimates that NIH investments created 487,900 jobs in fiscal year (FY) 2010. “NIH will be a key engine driving the U.S. economy in the 21st century,” Dr. Collins said.

Finally, the director briefly outlined his plan for accelerating translational sciences through the National Center for Advancing Translational Sciences (NCATS), which was proposed in response to the need for a new approach to therapeutics development. Citing the “deluge of discoveries about the molecular basis of disease,” but also the lengthy development times and high failure rates associated with turning these advances into clinically relevant interventions, Dr. Collins described how be believes NCATS will ultimately help patients by creating a “new paradigm of translation.”

Subcommittee members in attendance voiced bipartisan support for investment in biomedical research. Sen. Tom Harkin (D-IA), the subcommittee chair, said, “NIH research is one of the best investments this country can make.” He expressed his concern that funding cuts for NIH in FY2011—and possible cuts in future years—will result in dramatically lower success rates for researchers seeking NIH support and will undermine American competitiveness in biomedical research.

Sen. Barbara Mikulski (D-MD) praised NIH and its employees for their public service, saying, “I wanted to be here today to say to all the people who work at the institute[s]—all the people who work at the various offices, from the lab techs, the security guards, the fire department—we are really proud of you.”

In addition to offering his support for federal investment in biomedical research, Ranking Member Sen. Richard Shelby (R-AL) requested more information on NCATS, how the re-organization to create the center will affect NIH, and how the center’s budget will be determined. Dr. Collins advised the subcommittee that the only new budgetary consideration in the NCATS plan is associated with the Cures Acceleration Network, which is included in President Obama’s FY2012 budget request. Drs. Fauci and Varmus offered their perspectives on how NCATS will complement and enhance the robust translational research that occurs and will continue to occur across NIH’s institutes.

Sen. Jerry Moran (R-KS) concluded the hearing by asking for information to substantiate his understanding that money spent in biomedical research reduces health care costs. Dr. Collins acknowledged the complexity involved in such an economic analysis and provided examples of economic benefits resulting from research in heart disease and cancer. Dr. Collins told the subcommittee that each time the frequency of cancer decreases by 1 percent, something that is already happening each year, economists say that the resulting reduction in mortality saves Americans $500 billion. “The returns are enormous,” he said.

—Stacye Bruckbauer and Rachel Benkeser

For more information about NCI congressional activity, visit the NCI Office of Government and Congressional Relations Web site.


Portrait of Former NCI Director Dr. John E. Niederhuber Unveiled

Former NCI Director Dr. John E. Niederhuber at the unveiling of his official portrait (Photo by Daniel Sone, NCI) Former NCI Director Dr. John E. Niederhuber at the unveiling of his official portrait (Photo by Daniel Sone, NCI)

The official portrait of former NCI Director Dr. John E. Niederhuber was unveiled May 12 at a ceremony on the NIH main campus in Bethesda, MD. A host of government dignitaries, NCI staff, representatives of the cancer research community, and Dr. Niederhuber himself attended the unveiling.

Dr. Niederhuber, who previously served as chair of the National Cancer Advisory Board (NCAB), joined NCI in 2005 as senior deputy to then-NCI Director Dr. Andrew von Eschenbach. When Dr. von Eschenbach was appointed commissioner of the Food and Drug Administration, Dr. Niederhuber stepped in to head NCI.

Current NCI Director Dr. Harold Varmus thanked Dr. Niederhuber for his leadership from 2006 to 2010. "John was uniquely well qualified to be NCI director," Dr. Varmus noted. "He had run an NCI-designated Cancer Center [at the University of Wisconsin], he was a surgeon, he knew how to take care of patients with skill and compassion, and he was a distinguished investigator of immunotherapy for cancer."

NCI Deputy Director Dr. Douglas Lowy and Dr. James Doroshow, director of the Division of Cancer Treatment and Diagnosis, credited Dr. Niederhuber with commissioning the Institute of Medicine review, which led to a report recommending major reforms to NCI's Clinical Trials Cooperative Group Program. He also launched the NCI Community Cancer Centers Program.

Dr. Niederhuber, who is now CEO of the Inova Translational Medicine Institute, said, "I never expected to be NCI director, and I was deeply honored to serve in what is really the best job in the government." He thanked the "very, very dedicated, excellent" NCI staff and advisors for their support and expert advice during his tenure at the institute. "I couldn't have accomplished anything without each and every one of you," he said.

Dr. Philip Castle Wins Flemming Award

Dr. Philip CastleDr. Philip Castle

Dr. Philip Castle, formerly of the Hormonal and Reproductive Epidemiology Branch in NCI's Division of Cancer Epidemiology and Genetics (DCEG), has been selected for the 2010 Arthur S. Flemming Award for Exceptional Achievement in Federal Government Service. The award acknowledges Dr. Castle's contributions to the epidemiology of the human papillomavirus (HPV) and cervical cancer.

While at DCEG, Dr. Castle's research focused on studying the natural history of HPV and evaluating screening and diagnos­tic technologies for HPV infection, cervical precancer, and cervical cancer, including the development and validation of low-cost strategies in resource-limited areas.

Established in 1948 to honor Arthur Flemming's commitment to public service during a career that spanned 7 decades, the awards have recognized outstanding men and women in the federal government. George Washington University and the Arthur S. Flemming Awards Commission present a total of 12 awards annually in three categories: applied science, engineering, and mathematics; research; and managerial or legal achievement.

Dr. Castle will be honored along with the other 11 award winners at an event at George Washington University next month.

New Resources Raise Awareness about Skin Cancer in Minority Populations

NCI's Division of Cancer Epidemiology and Genetics (DCEG) and Office of Communications and Education (OCE) have developed new educational resources for African American, Asian American, Native American, and Hispanic/Latino audiences to help dispel the belief that only people with light skin are at risk of skin cancer. Although skin cancer is less common among people with darker skin, when the disease does occur in these individuals, it often is detected at later or advanced stages.

A new brochure, titled Anyone Can Get Skin Cancer, discusses how to find skin cancer early, what skin cancer looks like, and how to lower the chance of developing skin cancer. Related content is also available in an NCI Lifelines video and news article. These materials can be accessed in English and Spanish.

View these resources and order a copy of Anyone Can Get Skin Cancer online.

Meet NCI Experts at ASCO 2011

NCI at ASCO 2011 tile

Many NCI staff members will participate in the American Society of Clinical Oncology's (ASCO) 47th Annual Meeting June 3–7, at McCormick Place in Chicago, IL. NCI Director Dr. Harold Varmus will address the opening session on June 4.

Attendees can learn about NCI's programs and Web sites by visiting booth #5017 in the exhibit hall during the meeting. As usual, NCI experts will talk about a wide range of topics. Click here to learn more about NCI-sponsored sessions and activities. Look for highlights from the meeting in the May 31 and June 14 issues of the NCI Cancer Bulletin.