Noninvasive DNA Test for Colorectal Cancer Gets FDA Thumbs-up

Among cancers that affect both men and women, colorectal cancer is the third most common cancer and the second leading cause of cancer-related death in the United States, according to the CDC. The agency estimates that if everyone age 50 or older participated in recommended colorectal cancer screening(www.cdc.gov), at least 60 percent of colorectal cancer deaths could be avoided.

Now, family physicians and other clinicians have a singular new option for detecting this life-threatening condition. Moreover, CMS has already laid the groundwork for Medicare coverage for the test.

On Aug. 11, the FDA approved Cologuard, a stool-based colorectal screening test that detects red blood cells and DNA mutations that can indicate the presence of abnormal, possibly precancerous growths, according to an FDA news release(www.fda.gov). It is the first fecal DNA test for colorectal cancer to receive the agency's thumbs-up; previous candidates have lacked adequate sensitivity and specificity.

Specifically, Cologuard detects hemoglobin and mutations associated with colorectal cancer in DNA of cells shed by advanced adenomas as stool moves through the large intestine and rectum. Patients who receive a positive test result are advised to undergo a diagnostic colonoscopy.

"This approval offers patients and physicians another option to screen for colorectal cancer," said Alberto Gutierrez, Ph.D., director of the Office of In Vitro Diagnostics and Radiological Health at the FDA's Center for Devices and Radiological Health (CDRH), in the news release. "Fecal blood testing is a well-established screening tool, and the clinical data showed that (Cologuard) detected more cancers than a commonly used fecal occult test."

The FDA's approval of Madison, Wisc.-based Exact Sciences' Cologuard expands the options for colorectal cancer screening but does not change current related guidelines. The U.S. Preventive Services Task Force (USPSTF) does not recommend stool DNA testing as a method to screen for colorectal cancer. The USPSTF's current screening recommendation(www.uspreventiveservicestaskforce.org) for average-risk adults ages 50 to 75 calls for using fecal occult blood testing (FOBT), sigmoidoscopy or colonoscopy.

However, the USPSTF currently is reviewing its colorectal cancer screening recommendations; evaluation of fecal DNA screening was specifically included in the systematic evidence review(www.ncbi.nlm.nih.gov) the task force is using to inform that update.

Cologuard Study

A recent study(www.nejm.org) published in the New England Journal of Medicineexamined the safety and effectiveness of Cologuard, screening almost 10,000 asymptomatic participants ages 50 to 84 who were at average risk for colorectal cancer and were scheduled to undergo a screening colonoscopy. The trial compared Cologuard to fecal immunochemical testing (FIT).

Compared with FIT, Cologuard was more accurate in detecting colorectal cancers (92 percent versus 74 percent) and advanced adenomas (42 percent versus 24 percent). It was less accurate than FIT, however, at correctly identifying subjects negative for colorectal cancer or advanced adenomas (87 percent versus 95 percent).

Family physician Richard Wender, M.D., who is chair of the National Colorectal Cancer Roundtable and chief cancer control officer for the American Cancer Society (ACS), told AAFP News he was impressed with the sensitivity of Cologuard in the clinical trial. He added that a precursor to Cologuard had at one time been on an ACS-recommended list of colorectal cancer screening options, but the test is no longer available.

"Cologuard has more robust data than the older stool DNA test and better performance," Wender said, "so a good argument for including the test in guidelines can be made."

CMS Coverage

Cologuard is the first product to be reviewed through a joint FDA-CMS pilot program for parallel review,(www.fda.gov) under which the agencies concurrently review certain premarket medical devices to reduce the time between FDA approval and Medicare coverage.

"Parallel review allows the last part of the FDA process to run at the same time as the CMS process, cutting as many as six months from the time of study initiation to coverage," said Nancy Stade, CDRH's deputy director for policy, in the news release.

CMS proposes to cover the Cologuard test once every three years for asymptomatic individuals ages 50 to 85 who are at average risk of developing colorectal cancer.

"This new process (of parallel review) is a good step in developing a more efficient and streamlined approach to test approval," Wender said. "I applaud the FDA and CMS for developing this innovative process to accelerate the availability of the test.

"I think it is fair to say that having both agencies join in approving the test and paying for the test does constitute additional endorsement of the test."

The Future for Cologuard

For Cologuard to become widely used, it will need to be added to the USPSTF and other major colorectal cancer screening guidelines, Wender said. Otherwise, the test may not be covered by some commercial insurers.

As to Cologuard's limitations, Wender said that although CMS has decided to pay for the test every three years, the ideal testing interval has not yet been determined. Furthermore, at a cost of $500 (the preliminary payment amount established by CMS), the test is likely to be cost-effective but its relative cost-effectiveness compared to other screening options is unclear. Finally, the acceptability of the test to clinicians and patients also is not fully known.

Wender said it's important for physicians to remember that there are already two widely used screening options: colonoscopy every 10 years or FIT every year. He added that high-sensitivity guaiac FOBT and CT colonoscopy are additional options to consider. The variety of options should help the ACS reach its "80% by 2018"(nccrt.org) initiative's goal to have 80 percent of adults ages 50 and older screened for colorectal cancer by 2018.

"In short, we already have both more and less invasive, more and less costly options to screen everyone for colorectal cancer," said Wender. "We can achieve the 80 percent goal using available tests. But it is conceivable that having Cologuard available and approved may place the 80 percent goal more within our reach."

Tomado de: http://www.aafp.org/

Referencias:: American Cancer Society: How to Increase Colorectal Cancer Screening Rates in Practice: A Primary Care Clinician's Evidence-Based Toolbox and Guide 2008(www.cancer.org)

Fecal immunochemical tests detect most colorectal cancers

Fecal immunochemical tests have an overall diagnostic accuracy of 95% for the detection of colorectal cancer, according to the results of a meta-analysis just published in the Annals of Internal Medicine.

The tests, which have already begun to replace the fecal occult blood test (FOBT) in national screening programs in the United States, Europe, and Asia, were found to be 79% sensitive and 94% specific for CRC.

"This systematic review and meta-analysis suggests that FITs [fecal immunochemical tests] have high accuracy, high specificity, and moderately high sensitivity for detection of CRC," Dr. Douglas Corley of the Kaiser Permanente division of research in Oakland, Calif., and his associates wrote (Ann. Intern. Med. 2014;160:171-81).

FITs are more sensitive at detecting both CRC and adenomas than the FOBT, they maintained, and are also more practical for people to perform at home, requiring only one or two stool samples and no special dietary or medication restrictions.

Despite a greater potential ease of use for mass screening, reports on the diagnostic performance of FITs have been inconsistent, the investigators explained. They therefore performed the meta-analysis to determine the overall diagnostic accuracy and factors affecting the tests’ performance. Nineteen trials were included that involved more than 113,000 individuals and provided data on eight different FITs available for use in the United States.

In addition to the sensitivities and specificities of FITs, positive and negative likelihood ratios (LR) were calculated to assess the ability of the tests to respectively "rule in" or "rule out" a diagnosis of CRC. The threshold set for a positive LR was a value above 5 and for a negative LR was 0.2. Pooled data from the trials showed a positive LR of 13.10 and a negative LR of 0.23.

Increasing the number of FIT samples did not affect the pooled sensitivities, specificities, positive LRs, or negative LRs of FITs for CRC. There also was no great difference in performance between the FIT brands evaluated in the studies. Dr. Corley and his associates pointed out, however, that head-to-head comparisons were not included in most studies so this finding should be interpreted with caution.

Diagnostic performance was affected by the cutoff values used to define a positive test, which might influence which test health systems decide to use, the researchers said.

"Health systems wishing to optimize use of a quantitative FIT should consider the tradeoff between increasing sensitivity (by lowering the cutoff threshold for a positive test) and the resulting increase in the number of positive results," they wrote. The latter could significantly impact colonoscopy resources if more procedures were indicated by a positive test.

The researchers recommended that health systems also look at individual studies comparing single or repeat testing, as the current data do not provide a definitive answer on the effect of sample number on the performance of FITs.

The National Institute of Diabetes and Digestive and Kidney Diseases and the National Cancer Institute funded the research.

By: SARA FREEMAN, Family Practice News Digital Network

Inflammatory markers associated with IBD colon cancer risk

As C-reactive protein levels and erythrocyte sedimentation rates go up in patients with inflammatory bowel disease, the risk of colorectal cancer goes up, too, a finding that suggests a role for both as markers of colon cancer risk, Boston investigators reported in a prospective study published online Jan. 6 in Clinical Gastroenterology and Hepatology.

The team divided 3,145 IBD patients into quartiles based on median C-reactive protein (CRP) levels, and 4,008 others into quartiles based on median erythrocyte sedimentation rates (ESR), then followed them for a median of 6 years.

On multivariate analysis, there was a significant increase in the risk of colorectal cancer (CRC) across quartiles of CRP elevation (P fortrend = .017). Higher median ESR was also independently associated with higher risk of CRC across quartiles (P for trend = .007) (Clin. Gastroenterol. Hepatol. 2014 Jan. 6 [doi: 10.1016/j.cgh.2013.12.030]).

"This association adds another clinical variable to help stratify patients into risk categories. There is an important need to identify high-risk subgroups that may benefit from continued intensive surveillance strategies while allowing for less frequent colonoscopies in patients at low risk of CRC. We believe that our findings ... suggest that an individual patient’s severity of inflammation may be helpful in further personalizing surveillance recommendations," and might even help monitor other outcomes, including treatment response, said the authors, led by Dr. Ashwin Ananthakrishnan, a gastroenterologist at Massachusetts General Hospital, Boston.

After adjustment for age, sex, race, IBD type, and other factors, the patients in the highest CRP quartile had more than double the risk of colorectal cancer compared with those in the lowest quartile (OR 2.72, 95% CI 0.95-7.76). The strength of association was similar in men and women, and in Crohn’s disease and ulcerative colitis.

Similarly, patients in the highest ESR quartile had double the risk compared with those in the lowest (OR 2.06, 95% CI 1.14-3.74). The correlation was strongest in ulcerative colitis patients and men.

The median CRP values in each of the quartiles were 0.8, 2.7, 7.5, and 32.8 mg/L. In the ESR group, the median quartile values were 7, 14, 25, and 50 mm/hr.

Overall, 33 patients in the CRP cohort and 102 patients in the ESR cohort developed colorectal cancer at a median age of 55 years. The median number of CRP measurements was three, and median number of ESR measurements six. More than half the subjects were women, most were white, and ulcerative colitis was slightly more common than was Crohn’s disease.

Adjusting for number of colonoscopies, intensity of health care utilization, use of corticosteroids, and other factors did not change results for either the CRP or ESR cohorts.

The National Institutes of Health funded the work. The investigators have no disclosures.

Tomado de Internalmedicinenews.com

By: M. ALEXANDER OTTO, 

Sigmoidoscopy may not be enough for older patients

Colon cancer screening with sigmoidoscopy alone could miss up to 50% of colon polyps in older patients.

As people age, polyps seem to develop more and more proximally, Dr. Victor Tsirline said at the annual clinical congress of the American College of Surgeons. His review of more than 120,000 colonoscopies found that a flexible sigmoidoscopy alone could miss 44% of polyps in patients aged 60-69 years and 50% in those aged 70-79 years.

"We found that proximal colon polyps are more frequent with advanced age than previously considered," said Dr. Tsirline of Carolinas Medical Center, Charlotte, N.C. "So if this is true, what happens if we use sigmoidoscopy instead of colonoscopy? If we had, we would have missed 22,800 polyps, and 16,800 of those would have been adenomatous. In [patients 59 and younger] 32%-36% would be missed and in the older patients, 45%-50%."

Dr. Tsirline obtained his data from the Provation MD endoscopy transcription system. He obtained information on 120,365 colonoscopies that were performed from 2003 to 2011.

He cross-referenced this with CoPathPlus, a pathology reporting system. This allowed him to cross-reference polyp pathology (adenoma vs. hyperplasia) by computer algorithm. There was complete information available on 43,833 polyps.

Because of the large sample size, he set his level of statistical significance at P = less than 0.01.

The patients in the study were aged 20-90 years. Of the entire group of procedures, 53,492 colonoscopies (44%) identified polyps. Most studies (64%) found a single polyp; 25% found two, and 11% found three or more. A subset of the colonoscopies was only for average risk screening (44,806). Of these, 46% identified polyps.

Overall, 48% of polyps were adenomatous; 37% were hyperplastic. Pathology was not available for the remainder.

The polyps were fairly evenly distributed throughout the colon: rectum, 18%; sigmoid, 26%; descending, 14%; transverse, 16%; ascending, 15%; cecum, 11%.

However, when broken down by patient age, the distribution changed significantly. With every advancing decade of life, patients were:

• 22% less likely to have polyps in the rectum or sigmoid.

• 7% more likely to have polyps in the descending colon.

• 19% more likely to have polyps in the transverse colon.

• 30% more likely to have polyps in the ascending colon.

• 22% more likely to have polyps in the cecum.

All of these risks were statistically significant, and they held for both adenomatous and hyperplastic polyps.

The findings led Dr. Tsirline to conclude that flexible sigmoidoscopy should not be relied upon as an effective colon cancer screening method in patients older than 60 years. The U.S. Preventive Services Task Force states that sigmoidoscopy every 5 years combined with high-sensitivity fecal occult blood testing every 3 years is an adequate screening alternative.

"From this study, it’s pretty apparent that sigmoidoscopy should not be used for colon cancer screening in older patients," he said.

During a discussion, Dr. Tsirline fielded a question about screening the very elderly – patients in their 80s and 90s. The study group did include a small number of these patients, he said.

"I think the argument for not screening older individuals is based on the question of whether finding a colon cancer would change anything. Most people think the risks of screening and treatment would outweigh the benefits. Yes, you may find anything, but what are you going to do about it?"

Tomado de internalmedicinenews.com

Long-term Efficacy Data on CRC Screening Methods

Screening can reduce colorectal cancer mortality, as well as the incidence of the disease, but it is has been unclear which screening method is the best.

Two long-term studies confirm the effectiveness of major screening technologies, but leave the question of superiority up in the air. Both appear in the September 19 issue of the New England of Medicine.

In one study with a 22-year follow-up period, colonoscopy was shown to have advantages over sigmoidoscopy for the prevention of colorectal cancer. In addition, screening colonoscopy reduced the risk for any colorectal-cancer-associated death, whereas sigmoidoscopy lowered the risk of dying only from left-side tumors.

"Our data support the use of colonoscopy as a the preferred screening option for patients if the primary consideration is maximal reduction in risk of colorectal cancer," said study coauthor Andrew Chan, MD, MPH, associate professor of medicine, gastroenterology, at the Massachusetts General Hospital in Boston.

In the second study, which has a 30-year follow-up period, annual and biennial screening with fecal occult blood testing reduced the risk for death from colorectal cancer. The risk for death from colorectal cancer was 32% lower with annual screening, compared with no screening, and 22% lower with biennial screening.

The Best Method?

But how does colonoscopy compare to fecal occult blood screening?

Both of these tests are effective for colorectal cancer screening, and both these studies support current screening guidelines, according to an accompanying editorial by Theodore R. Levin, MD, and Douglas A. Corley, MD, PhD, from Kaiser Permanente Medical Centers in California.

In addition, the screening tests have improved since the trial participants first used them.

The editorialists emphasize that these studies are quite different from one another, which makes it difficult to make direct comparisons of effectiveness.

"It would be tempting to use these 2 studies to draw conclusions about which test is more effective," they write.

The reduction in mortality was better with colonoscopy than with annual fecal occult blood testing (68% vs 32%). However, it is a mistake to directly compare these results, the editorialists point out. "The 2 study populations are not comparable: one was a randomized trial, the other an observational study of volunteers, and both tests have undergone improvements since the studies were performed."

To date, no completed studies directly compare fecal occult blood testing with colonoscopy, although randomized trials are ongoing.

Although the performance of colonoscopy has probably improved because of the greater recognition of nonpolypoid colorectal neoplasia, and it "appears to have a performance edge over the old guaiac fecal occult blood test, fecal occult blood testing has largely been replaced by the more effective fecal immunochemical test (FIT)," they note. This newer test has better sensitivity than the guaiac fecal occult blood testing used in that study.

Of importance, recent data show that individuals were more likely to "complete screening if they were offered guaiac fecal occult blood tests, a choice between colonoscopy and guaiac fecal occult blood tests, or FIT alone, as compared with being offered colonoscopy alone," they write.

In the Kaiser Permanente Northern California health system, where both editorialists practice, a combined approach is used, and substantial improvement in rates of colorectal cancer screening has been achieved.

Colonoscopy vs Sigmoidoscopy

In the first study, Dr. Chan and colleagues evaluated the association between the use of lower endoscopy (updated biennially from 1988 to 2008) and colorectal cancer incidence (to June 2010) and mortality (to June 2012). The cohort involved 88,902 individuals who participated in the Nurses' Health Study and the Health Professionals Follow-up Study.

Over a follow-up period of 22 years, there were 1815 documented cases of colorectal cancers and 474 colorectal-cancer-specific deaths.

When endoscopy screening was compared with no screening, multivariate hazard ratios (HRs) for colorectal cancer were 0.57 after polypectomy, 0.60 after negative sigmoidoscopy, and 0.44 after negative colonoscopy.

A negative colonoscopy was associated with a reduced incidence of proximal colon cancer (multivariate HR, 0.73), and the rate of mortality from proximal colon cancer was lower after screening colonoscopy (multivariate HR, 0.47), but not after sigmoidoscopy.

The multivariate HRs for colorectal cancer mortality were 0.59 after screening sigmoidoscopy and 0.32 after screening colonoscopy.

Even though colonoscopy appears to have some advantages over sigmoidoscopy, there are reasons patients might opt for the latter. "A screening sigmoidoscopy generally does not require a full bowel preparation or the administration of sedation, so patients undergoing the procedure can generally expect to miss less work," Dr. Chan told Medscape Medical News.

"In addition, although serious complications from both colonoscopy and sigmoidoscopy are quite rare — generally about 1 to 3 per 1000 patients — they do occur at a higher rate with colonoscopy than with sigmoidoscopy," he noted.

Dr. Chan and colleagues point out that although randomized controlled trials have shown that screening with flexible sigmoidoscopy reduces the incidence of colorectal cancer and associated mortality, comparable data for screening colonoscopy are not yet available.

"I think that, based on the data assembled so far and the widespread availability of colonoscopy, we should continue our current practice of recommending colonoscopy as one of a few screening options, with a full discussion of the risks, benefits, and areas of uncertainty associated with each test," said Dr. Chan.

Reduces Long-term Risk

In the second study, Aasma Shaukat, MD, MPH, from the University of Minnesota in Minneapolis, and colleagues provide an update to the Minnesota Colon Cancer Control Study, which assessed the long-term effect of fecal occult blood test screening on all-cause and colorectal cancer mortality.

The initial cohort involved 46,551 participants 50 to 80 years of age who were randomized to usual care or to annual or biennial screening with fecal occult blood testing. Screening tests were performed from 1976 to 1982 and from 1986 to 1992.

The researchers used the National Death Index to obtain updated information about the participants and to determine cause of death.

A total of 33,020 participants (70.9%) died from any cause during the 30-year follow-up period; 732 of the deaths were attributable to colorectal cancer.

Table. Deaths From Colorectal Cancer in the Study Groups

Deaths	Annual Screening (n = 11,072)	Biennial Screening (n = 11,004)	Usual Care (n = 10,944)
n (%)	200 (1.8%)	237 (2.2%)	295 (2.7%)

Annual screening lowered colorectal cancer mortality (relative risk [RR], 0.68), as did biennial screening (RR, 0.78). There was no reduction in all-cause mortality with annual screening (RR, 1.00) or with biennial screening (RR, 0.99).

Men 60 to 69 years of age got the most benefit from screening. RR for death from colorectal cancer was 0.46 with annual screening, 0.42 with biennial screening, and 0.44 for either screening.

The overall reduction in colorectal cancer death associated with biennial screening was greater for men than women (P = .04 for interaction). This difference was not observed with annual screening (P = .30 for interaction) or with the 2 screening methods combined (P = .06 for interaction).

"The reductions in colorectal cancer mortality in the Minnesota Colon Cancer Control Study are comparable to those reported in randomized clinical trials of screening with flexible sigmoidoscopy, suggesting that fecal occult blood testing remains an effective and acceptable method of screening," the authors write. "Stool-based tests for colorectal cancer screening are an active area of current research, with development and testing of new stool-based tests."

Tomado de: medscape.com
Referencia: N Engl J Med. 2013; 369:1095-1105, 1106-1114, 1164-1166