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CHS Research News
Vol 19, Issue 2, Spring/Summer 2007

Feature Article

Gut reaction:
Gastrointestinal cancer research requires collaboration and foresight

By Katie Saunders

Ask Group Health Center for Health Studies (CHS) Associate Investigator Margaret “Meg” Mandelson, PhD, about her research in gastrointestinal cancers and one theme emerges: collaboration. Whether she’s talking about longtime research partners such as John Potter, MD, PhD, director of the Public Health Sciences Division at the Fred Hutchinson Cancer Research Center (FHCRC), or the gastroenterologists and oncologists at Group Health, she understands that solid population-health research is a team sport.

But it’s the Group Health patients to whom she seems most grateful. Recalling a study that required blood draws, tissue samples, biopsies, surveys, and medical record review, she said she was “stunned” by the patients’ reactions. “Given the burden, we thought the response rate would be low, but we were reminded how members value Group Health’s commitment to research and transforming health care,” Mandelson said.

Perhaps the study participants share Mandelson’s optimism that research into prevention, screening, and treatment can make a difference. Her work at CHS over the past 15 years has been focused on:

• Identifying biomarkers to develop easier colorectal cancer screening
• Studying the feasibility of screening colonoscopy in the general population aged 50 to 69, and comparing it to fecal occult blood testing (FOBT)
• Determining whether hyperplastic polyps in the colon are markers for future development of colorectal cancer
• Investigating barriers to state-of-the-art colorectal cancer care
• Performing rapid surveillance of pancreatic cancer cases to learn about family history, medical history, and possible risk factors

Biomarker research may lead to easier colorectal cancer screening

“Although colorectal cancer is the third most commonly diagnosed cancer in the United States and the second most common cause of cancer death, it’s a cancer that’s very amenable to screening,” says Mandelson. FOBT, flexible sigmoidoscopy, and colonoscopy (see sidebar at upper right) are tests that can prevent disease through the detection and removal of precancerous growths called adenomas. “By removing the adenoma or precursor lesion, you can prevent most cancer,” explains Mandelson.

Colorectal cancer screening also lends itself to secondary prevention, or early detection, of the disease. More than 90 percent of patients with early-stage colorectal cancer survive more than five years, compared to only 10 percent of those with cancer that is diagnosed at a late stage.

“The single most important step to curing cancer is to catch it early. If all colorectal cancer cases were now detected at the earliest stages, five-year survival rates for the disease would jump from 64 to over 90 percent,” Mandelson says.

But there are many problems with current screening tests. Despite the persuasive case that can be made for colorectal cancer screening, compliance is low. In one Group Health study, Mandelson found that only 48 percent of women aged 50 to 80 years had had an FOBT in the last two years. (Guidelines recommend annual testing in this age group.) This compares with a 51 percent rate nationally.

The unpleasantness and discomfort associated with the screening tests are partly to blame, says Mandelson. In addition, experts view the current screening tests as less than ideal. Mandelson explains that FOBT is neither highly sensitive nor highly specific; it misses true colorectal cancer cases while erroneously identifying many disease-free patients as possible cases. FOBT with flexible sigmoidoscopy performs better and has some cost and logistical advantages over colonoscopy, but sigmoidoscopy only examines one-third of the colon.

Colonoscopy is a highly effective screening test for colorectal cancer. However, colonoscopy may not be an ideal screening tool for the general population, according to Mandelson. She cites several reasons: anticipated discomfort with the procedure and prep, invasiveness, cost, lost work productivity, and the need for specialized facilities, resources, and personnel.

“Screening could be vastly improved by better risk assessment and by using new technologies to develop easy-to-administer tests that can detect cancer from DNA in blood or stool,” Mandelson explains.

This need led to a study of early detection biomarkers, begun in 1998 and funded by the National Cancer Institute (NCI). Mandelson collaborated with Principal Investigator John Potter of FHCRC, who is also a CHS affiliate investigator. The idea was to identify biomarkers from a sample that would be easily obtained in a primary care physician’s office,” she explains. “That would allow clinicians to distinguish between patients with adenomas or early cancer who need a colonoscopy and patients who are not currently at risk.”
 
To accomplish this, the study recruited almost 800 Group Health members who were scheduled to undergo colonoscopy for any reason. Participants completed a risk-factor questionnaire, gave a blood sample, and underwent research biopsies at the time of the colonoscopy. The researchers are now in the process of examining the tissue samples.

Improving current programs: Screening colonoscopy vs. FOBT

Meanwhile, scientists are studying how best to implement the existing colorectal cancer screening methods. Mandelson has collaborated for the last several years with scientists at the Memorial Sloan-Kettering Cancer Center on the National Colonoscopy Study of the feasibility of screening colonoscopy in the general population of men and women aged 50 to 69. More recently, she and her collaborators have been comparing colonoscopy to screening by annual FOBT. These two strategies have never been pitted against each other before in a randomized trial. The goal is to determine which screening test is more effective for the general population.

Colonoscopy may appear to have two advantages over FOBT for colorectal cancer screening. That’s because treatment (i.e., polyp removal) can be accomplished at the same time as the screening test and patient adherence may be better because of the less frequent screening interval generally recommended (every decade for colonoscopy vs. every year for FOBT). However, it may be that the rate of advanced cancer detected by screening colonoscopy in the general population is too low to justify the cost, possible complications, and burden on resources.

The trial, which is taking place at Group Health, the University of Minnesota, and Louisiana State University, should provide answers.

Do hyperplastic polyps lead to cancer?

Another CHS study that could affect colorectal cancer screening practices looks into the underlying biology and risk factors for hyperplastic polyps found in the colon. Experts have historically considered these growths, in contrast to adenomas, to have no malignant potential. As a result, current practice guidelines say they can safely be ignored. However, some evidence points to the contrary. Mandelson explains that, for a subset of patients, hyperplastic polyps may represent an alternative pathway to colorectal cancer—a deviation from the traditional adenoma-carcinoma pathway. Or the polyps could be an earlier event on that traditional pathway. In any case, if hyperplastic polyps do play a role in the natural history of colorectal cancer, this discovery will have implications for primary prevention and screening strategies.

The research team (Mandelson, Principal Investigator Polly Newcombe, PhD, from the FHCRC, and colleagues) is recruiting 2,100 Group Health members who have undergone colonoscopy for any reason and who are categorized one of three groups post-procedure: (1) no pathologic findings; (2) hyperplastic polyps only; or (3) adenomas. The researchers will identify risk factors and biologic characteristics associated with the three groups and will assess whether the traits of hyperplastic polyps more closely resemble those of adenomas or normal tissue.

What are barriers to the best cancer care?

While most of Mandelson’s research in colorectal cancer relates to the early biology and early detection of the disease, she also studies cancer treatment through participation in CanCORS, a large collaborative study led by eight teams of investigators at 22 sites nationwide. CanCORS, which stands for Cancer Care Outcomes Research and Surveillance Consortium, is investigating treatment patterns and outcomes in a national sample of patients with lung or colorectal cancer. Mandelson explains that most of the prior treatment studies have been conducted in specialized cancer-center settings where neither the patients nor the treatments may represent care in community settings, such as Group Health. Yet community settings provide about 85 percent of treatment for cancer patients.

The main goal of CanCORS is to identify barriers to receiving state-of-the-art care for colorectal cancer and lung cancer as defined by previous randomized trials. A major focus is on racial disparities. Several studies have documented that minorities with colorectal cancer generally receive less treatment and later treatment and experience poorer outcomes than do whites with the disease. CanCORS is investigating several possible reasons for such disparities, including patient beliefs regarding treatment, provider specialty referral practices, and delivery-system shortcomings, such as inadequate reminder systems.

To better understand the entire spectrum of treatment, all colorectal cancer patients were interviewed—those with newly diagnosed, early-stage disease and those with more advanced colorectal cancer. Providers were also interviewed about decision-making and treatment preferences for colorectal cancer. “I think this is going to be the definitive study in understanding cancer treatment patterns and outcomes, best practices, and what constitutes quality care for these cancers—both nationally and at Group Health,” says Mandelson.

Rapid surveillance to discover risk factors for pancreatic cancer

In addition to colorectal cancer, several of Mandelson’s joint projects with researchers at FHCRC have involved another gastrointestinal disease and the fifth leading cause of U.S. cancer deaths—pancreatic cancer. In contrast to colorectal cancer, little is known about its epidemiology and biology. This knowledge gap can be traced to the typically short interval between diagnosis and death; most people die within four months of diagnosis—meaning there is scant opportunity to interview patients.

Ultra-rapid case ascertainment is key. To that end, Mandelson, Potter, and colleagues received a $6 million grant from the NCI that features daily surveillance of Group Health’s and Kaiser Permanente Northern California’s automated lab, radiology, and pathology records for possible pancreatic cancer cases. “Group Health and Kaiser Northern California are two of just a handful of research institutions that have the capacity to do this ‘ultra-rapid case identification’ that the study requires,” says Mandelson.

Study participants, who are matched to control cases from the same institution, are asked to give a blood sample and complete a survey about their family history, medical history, and possible risk factors. Several risk factors have been implicated in the development of colorectal cancer, including family history, physical inactivity, and a diet heavy on red meat. But for pancreatic cancer, there are few well-established links so far. The grant will investigate a wide range of factors suspected to be associated with the disease and will analyze study specimens to advance understanding of biologic measures of risk.

Discovering such key information could lead to better cancer prevention. This, along with Mandelson’s research into providing improved cancer screening and treatment, will contribute to better health outcomes at Group Health, at FHCRC, and around the globe.

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