Percutaneous coronary intervention with a sirolimus-eluting stent showed comparable rates of death, myocardial infarction and stroke to coronary artery bypass grafting in patients with coronary artery stenosis after 5 years in a randomized trial.

The PRECOMBAT (Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease) study randomized trial in 600 patients with unprotected left main coronary artery stenosis – 300 of whom were randomized to PCI and the rest to CABG – showed no significant difference in major adverse cardiac or cerebrovascular events (hazard ratio, 1.27; 95% confidence interval, 0.84-1.90; P = 0.26), according to a presentation at the American College of Cardiology meeting in San Diego.

However, the study did observe a twofold increase in the rate of ischemia-driven target vessel revascularization among patients treated with PCI, compared to those who underwent CABG (HR, 2.11; 95% CI, 1.16-3.84; P = 0.012), although the authors pointed out that this did not appear to impact the study’s harder endpoints.

“Given a higher rate of repeat revascularization even after the use of second-generation drug-eluting stents for unprotected left main coronary artery stenosis, frequent repeat revascularization could be an inherent weakness of stent-related treatments,” wrote Dr. Jung-Min Ahn, from the Asan Medical Center, Seoul, and coauthors (J. Am. Coll. Cardiol. 2015; March 15 [doi:10.1016/j.jacc.2015.03.033]).

The study was supported by the CardioVascular Research Foundation, Cordis, Johnson and Johnson, and the Korean Ministry of Health & Welfare. No conflicts of interest were disclosed.

Percutaneous coronary intervention with a sirolimus-eluting stent showed comparable rates of death, myocardial infarction and stroke to coronary artery bypass grafting in patients with coronary artery stenosis after 5 years in a randomized trial.

The PRECOMBAT (Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease) study randomized trial in 600 patients with unprotected left main coronary artery stenosis – 300 of whom were randomized to PCI and the rest to CABG – showed no significant difference in major adverse cardiac or cerebrovascular events (hazard ratio, 1.27; 95% confidence interval, 0.84-1.90; P = 0.26), according to a presentation at the American College of Cardiology meeting in San Diego.

However, the study did observe a twofold increase in the rate of ischemia-driven target vessel revascularization among patients treated with PCI, compared to those who underwent CABG (HR, 2.11; 95% CI, 1.16-3.84; P = 0.012), although the authors pointed out that this did not appear to impact the study’s harder endpoints.

“Given a higher rate of repeat revascularization even after the use of second-generation drug-eluting stents for unprotected left main coronary artery stenosis, frequent repeat revascularization could be an inherent weakness of stent-related treatments,” wrote Dr. Jung-Min Ahn, from the Asan Medical Center, Seoul, and coauthors (J. Am. Coll. Cardiol. 2015; March 15 [doi:10.1016/j.jacc.2015.03.033]).

The study was supported by the CardioVascular Research Foundation, Cordis, Johnson and Johnson, and the Korean Ministry of Health & Welfare. No conflicts of interest were disclosed.

Percutaneous coronary intervention with a sirolimus-eluting stent showed comparable rates of death, myocardial infarction and stroke to coronary artery bypass grafting in patients with coronary artery stenosis after 5 years in a randomized trial.

The PRECOMBAT (Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease) study randomized trial in 600 patients with unprotected left main coronary artery stenosis – 300 of whom were randomized to PCI and the rest to CABG – showed no significant difference in major adverse cardiac or cerebrovascular events (hazard ratio, 1.27; 95% confidence interval, 0.84-1.90; P = 0.26), according to a presentation at the American College of Cardiology meeting in San Diego.

However, the study did observe a twofold increase in the rate of ischemia-driven target vessel revascularization among patients treated with PCI, compared to those who underwent CABG (HR, 2.11; 95% CI, 1.16-3.84; P = 0.012), although the authors pointed out that this did not appear to impact the study’s harder endpoints.

“Given a higher rate of repeat revascularization even after the use of second-generation drug-eluting stents for unprotected left main coronary artery stenosis, frequent repeat revascularization could be an inherent weakness of stent-related treatments,” wrote Dr. Jung-Min Ahn, from the Asan Medical Center, Seoul, and coauthors (J. Am. Coll. Cardiol. 2015; March 15 [doi:10.1016/j.jacc.2015.03.033]).

The study was supported by the CardioVascular Research Foundation, Cordis, Johnson and Johnson, and the Korean Ministry of Health & Welfare. No conflicts of interest were disclosed.

SAN DIEGO – The idea that patients with established coronary disease can derive important, secondary-prevention benefit from prolonged dual-antiplatelet therapy received a major boost with the results of a major, international, controlled trial with more than 21,000 patients.

Results from the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) showed putting post-myocardial infarction patients on dual-antiplatelet therapy (DAPT) with aspirin and the thienopyridine ticagrelor (Brilinta) for a median of 33 months cut the combined incidence of cardiovascular death, MI, or stroke by a relative 15%, compared with patients on aspirin alone as well as the other standard treatments used for post-MI patients, Dr. Marc S. Sabatine reported at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

The findings added to the growing body of evidence that long-term – and possibly lifelong – DAPT is a key part of secondary prevention. Last year, results from the DAPT (Dual Antiplatelet Therapy) trial (N. Engl. J. Med. 2014;371:2155-66) supplied evidence for this in acute coronary syndrome patients who had undergone percutaneous coronary intervention (PCI). The PEGASUS-TIMI 54 trial did not require that enrolled post-MI patients had undergone PCI, but the reality is that this is the way most MI patients get managed, and in PEGASUS-TIMI 54 roughly 83% of the patients had a PCI history.

The new findings also highlighted the risk-benefit trade-off that DAPT means for patients. In PEGASUS-TIMI 54 the increased incidence of major bleeding events roughly matched the decreased rate of major cardiovascular events prevented. But while the incidence of bleeds categorized as TIMI major bleeds more than doubled in the patients randomized to DAPT compared with those on aspirin only, the prolonged treatment with ticagrelor did not result in an increase in fatal bleeds or in intracranial hemorrhages, the two most feared types of TIMI major bleeds.

“I’d much rather prevent cardiovascular deaths, MIs, and strokes even at the expense of causing reversible, nonfatal bleeding events,” said Dr. Sabatine, professor of medicine at Harvard Medical School in Boston and chairman of the TIMI Study Group at Brigham and Women’s Hospital.

Another notable adverse effect from ticagrelor treatment was a roughly threefold increased incidence of dyspnea, which led to drug discontinuation in 5%-7% of patients, depending on whether they received ticagrelor at 60 mg b.i.d. or 90 mg b.i.d. The study results showed a reduced rate of both bleeding and dyspnea in patients randomized to receive the 60-mg b.i.d. dosage, compared with those who received the 90-mg b.i.d. dosage, which is the standard ticagrelor dosage and the formulation now sold. At the same time, the efficacy of the 60-mg b.i.d. dosage for preventing ischemic events equaled that of the higher dosage. But as of today, it is impossible for a physician to prescribe a 60-mg formulation of ticagrelor because the manufacturer does not sell it.

Mitchel L. Zoler/Frontline Medical News

Several cardiologists PEGASUS-TIMI 54 at the meeting said that they agreed with Dr. Sabatine and felt that the benefits from prolonged DAPT with ticagrelor outweighed the downside of an increased bleeding risk.

“I think that the benefit is greater than the risk. None of us wants to see patients experience bleeding, but I was encouraged that fatal bleeds and intracranial hemorrhages were no different,” commented Dr. Elliott M. Antman, a professor of medicine at Harvard.

“The benefits outweigh the bleeding risk, but I wouldn’t trivialize the bleeding risk. Assessing a patient’s bleeding risk is really important,” commented Dr. Robert Harrington, professor of medicine at Stanford (Calif.) University.

But others at the meeting said that the elevated bleeding risk gave them pause. “There clearly is a price to be paid even if extended-duration DAPT reduces MI and stent thrombosis. I believe only the highest risk patients – those with acute coronary syndrome and ST-elevation MI – are the ones for whom I’d even consider it. Unless we can reduce bleeding risk, maybe with even lower doses [of ticagrelor], stopping aspirin, or using a reversal agent, we will be causing bleeds that are very relevant to patients,” commented Dr. Ajay J. Kirtane, an interventional cardiologist at Columbia University in New York.

Mitchel L. Zoler/Frontline Medical News

Dr. Kirtane also questioned whether TIMI major bleeds was the appropriate measure of bleeding risk in the context of a study like PEGASUS-TIMI 54. “Historically, TIMI major bleeding was derived from studies of acute heart attack patients getting fibrinolytic therapy. That is a very different population from this one. In my mind, the combination of TIMI major and minor bleeding would be more encompassing, and for patients the bleeding risks of these therapies are real and have been associated with bad sequelae,” he said in an interview.

When placed in the context of prior reports the new findings also raise the possibility that the generic, and hence much cheaper, thienopyridine clopidogrel might provide roughly the same long-term benefit as more expensive ticagrelor, especially for patients without a genetic profile that makes them poor clopidogrel metabolizers. This may be an attractive option for patients who have a problem paying for ticagrelor long term.

“I’d rather prescribe a patient a cheaper medication that might be a bit less effective than create an economic hardship,” Dr. Harrington said in an interview. The results from the DAPT trial, which included some post-PCI patients who received long-term DAPT with clopidogrel plus aspirin “give you a certain comfort” with the idea of substituting clopidogrel for ticagrelor when affordability is a major concern, Dr. Harrington noted.

PEGASUS-TIMI 54 enrolled 21, 162 patients who were 1-3 years out from a prior myocardial infarction at 1,161 sites in 31 countries. Enrolled patients also had to be at least 50 years old, and have at least one additional risk factor for ischemic events such as age 65 years or older, diabetes, multivessel coronary artery disease, or chronic renal dysfunction. The enrolled patients averaged 1.7 years out from their index MI. Randomization assigned patients to treatment with 90 mg ticagrelor b.i.d., 60 mg ticagrelor b.i.d., or placebo, and all patients also received daily treatment with 75-150 mg aspirin.

After a median follow-up of 33 months on treatment, the combined rate of cardiovascular death, myocardial infarction, or stroke – the study’s primary endpoint – occurred in 7.85% of patients on the 90-mg ticagrelor dosage, 7.77% of those on the 60-mg dosage, and in 9.04% of patients on placebo receiving aspirin only, statistically significant differences for the study’s primary endpoint for each of the two ticagrelor dosages. Concurrent with the report at the meeting the results also appeared online (N. Engl. J. Med. 2015; [doi:10.1056/nejmoa1500857]). This translated into hazard ratios of 0.85 for the 90 mg dosage and 0.84 for the 60 mg dosage compared with placebo.

The study’s primary safety outcome was the incidence of TIMI major bleeding events, which occurred in 2.60% of patients on the higher ticagrelor dosage, 2.30% of those on the 60 mg dosage, and in 1.06% of those on placebo, which converted into hazard ratios of 2.69 for the 90-mg dosage and 2.32 for the lower dosage for TIMI major bleeds compared with aspirin alone.

[email protected]

On Twitter @mitchelzoler

SAN DIEGO – The idea that patients with established coronary disease can derive important, secondary-prevention benefit from prolonged dual-antiplatelet therapy received a major boost with the results of a major, international, controlled trial with more than 21,000 patients.

Results from the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) showed putting post-myocardial infarction patients on dual-antiplatelet therapy (DAPT) with aspirin and the thienopyridine ticagrelor (Brilinta) for a median of 33 months cut the combined incidence of cardiovascular death, MI, or stroke by a relative 15%, compared with patients on aspirin alone as well as the other standard treatments used for post-MI patients, Dr. Marc S. Sabatine reported at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

The findings added to the growing body of evidence that long-term – and possibly lifelong – DAPT is a key part of secondary prevention. Last year, results from the DAPT (Dual Antiplatelet Therapy) trial (N. Engl. J. Med. 2014;371:2155-66) supplied evidence for this in acute coronary syndrome patients who had undergone percutaneous coronary intervention (PCI). The PEGASUS-TIMI 54 trial did not require that enrolled post-MI patients had undergone PCI, but the reality is that this is the way most MI patients get managed, and in PEGASUS-TIMI 54 roughly 83% of the patients had a PCI history.

The new findings also highlighted the risk-benefit trade-off that DAPT means for patients. In PEGASUS-TIMI 54 the increased incidence of major bleeding events roughly matched the decreased rate of major cardiovascular events prevented. But while the incidence of bleeds categorized as TIMI major bleeds more than doubled in the patients randomized to DAPT compared with those on aspirin only, the prolonged treatment with ticagrelor did not result in an increase in fatal bleeds or in intracranial hemorrhages, the two most feared types of TIMI major bleeds.

“I’d much rather prevent cardiovascular deaths, MIs, and strokes even at the expense of causing reversible, nonfatal bleeding events,” said Dr. Sabatine, professor of medicine at Harvard Medical School in Boston and chairman of the TIMI Study Group at Brigham and Women’s Hospital.

Another notable adverse effect from ticagrelor treatment was a roughly threefold increased incidence of dyspnea, which led to drug discontinuation in 5%-7% of patients, depending on whether they received ticagrelor at 60 mg b.i.d. or 90 mg b.i.d. The study results showed a reduced rate of both bleeding and dyspnea in patients randomized to receive the 60-mg b.i.d. dosage, compared with those who received the 90-mg b.i.d. dosage, which is the standard ticagrelor dosage and the formulation now sold. At the same time, the efficacy of the 60-mg b.i.d. dosage for preventing ischemic events equaled that of the higher dosage. But as of today, it is impossible for a physician to prescribe a 60-mg formulation of ticagrelor because the manufacturer does not sell it.

Mitchel L. Zoler/Frontline Medical News

Several cardiologists PEGASUS-TIMI 54 at the meeting said that they agreed with Dr. Sabatine and felt that the benefits from prolonged DAPT with ticagrelor outweighed the downside of an increased bleeding risk.

“I think that the benefit is greater than the risk. None of us wants to see patients experience bleeding, but I was encouraged that fatal bleeds and intracranial hemorrhages were no different,” commented Dr. Elliott M. Antman, a professor of medicine at Harvard.

“The benefits outweigh the bleeding risk, but I wouldn’t trivialize the bleeding risk. Assessing a patient’s bleeding risk is really important,” commented Dr. Robert Harrington, professor of medicine at Stanford (Calif.) University.

But others at the meeting said that the elevated bleeding risk gave them pause. “There clearly is a price to be paid even if extended-duration DAPT reduces MI and stent thrombosis. I believe only the highest risk patients – those with acute coronary syndrome and ST-elevation MI – are the ones for whom I’d even consider it. Unless we can reduce bleeding risk, maybe with even lower doses [of ticagrelor], stopping aspirin, or using a reversal agent, we will be causing bleeds that are very relevant to patients,” commented Dr. Ajay J. Kirtane, an interventional cardiologist at Columbia University in New York.

Mitchel L. Zoler/Frontline Medical News

Dr. Kirtane also questioned whether TIMI major bleeds was the appropriate measure of bleeding risk in the context of a study like PEGASUS-TIMI 54. “Historically, TIMI major bleeding was derived from studies of acute heart attack patients getting fibrinolytic therapy. That is a very different population from this one. In my mind, the combination of TIMI major and minor bleeding would be more encompassing, and for patients the bleeding risks of these therapies are real and have been associated with bad sequelae,” he said in an interview.

When placed in the context of prior reports the new findings also raise the possibility that the generic, and hence much cheaper, thienopyridine clopidogrel might provide roughly the same long-term benefit as more expensive ticagrelor, especially for patients without a genetic profile that makes them poor clopidogrel metabolizers. This may be an attractive option for patients who have a problem paying for ticagrelor long term.

“I’d rather prescribe a patient a cheaper medication that might be a bit less effective than create an economic hardship,” Dr. Harrington said in an interview. The results from the DAPT trial, which included some post-PCI patients who received long-term DAPT with clopidogrel plus aspirin “give you a certain comfort” with the idea of substituting clopidogrel for ticagrelor when affordability is a major concern, Dr. Harrington noted.

PEGASUS-TIMI 54 enrolled 21, 162 patients who were 1-3 years out from a prior myocardial infarction at 1,161 sites in 31 countries. Enrolled patients also had to be at least 50 years old, and have at least one additional risk factor for ischemic events such as age 65 years or older, diabetes, multivessel coronary artery disease, or chronic renal dysfunction. The enrolled patients averaged 1.7 years out from their index MI. Randomization assigned patients to treatment with 90 mg ticagrelor b.i.d., 60 mg ticagrelor b.i.d., or placebo, and all patients also received daily treatment with 75-150 mg aspirin.

After a median follow-up of 33 months on treatment, the combined rate of cardiovascular death, myocardial infarction, or stroke – the study’s primary endpoint – occurred in 7.85% of patients on the 90-mg ticagrelor dosage, 7.77% of those on the 60-mg dosage, and in 9.04% of patients on placebo receiving aspirin only, statistically significant differences for the study’s primary endpoint for each of the two ticagrelor dosages. Concurrent with the report at the meeting the results also appeared online (N. Engl. J. Med. 2015; [doi:10.1056/nejmoa1500857]). This translated into hazard ratios of 0.85 for the 90 mg dosage and 0.84 for the 60 mg dosage compared with placebo.

The study’s primary safety outcome was the incidence of TIMI major bleeding events, which occurred in 2.60% of patients on the higher ticagrelor dosage, 2.30% of those on the 60 mg dosage, and in 1.06% of those on placebo, which converted into hazard ratios of 2.69 for the 90-mg dosage and 2.32 for the lower dosage for TIMI major bleeds compared with aspirin alone.

[email protected]

On Twitter @mitchelzoler

SAN DIEGO – The idea that patients with established coronary disease can derive important, secondary-prevention benefit from prolonged dual-antiplatelet therapy received a major boost with the results of a major, international, controlled trial with more than 21,000 patients.

Results from the PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54) showed putting post-myocardial infarction patients on dual-antiplatelet therapy (DAPT) with aspirin and the thienopyridine ticagrelor (Brilinta) for a median of 33 months cut the combined incidence of cardiovascular death, MI, or stroke by a relative 15%, compared with patients on aspirin alone as well as the other standard treatments used for post-MI patients, Dr. Marc S. Sabatine reported at the annual meeting of the American College of Cardiology.

Nick Piegari/Frontline Medical News

The findings added to the growing body of evidence that long-term – and possibly lifelong – DAPT is a key part of secondary prevention. Last year, results from the DAPT (Dual Antiplatelet Therapy) trial (N. Engl. J. Med. 2014;371:2155-66) supplied evidence for this in acute coronary syndrome patients who had undergone percutaneous coronary intervention (PCI). The PEGASUS-TIMI 54 trial did not require that enrolled post-MI patients had undergone PCI, but the reality is that this is the way most MI patients get managed, and in PEGASUS-TIMI 54 roughly 83% of the patients had a PCI history.

The new findings also highlighted the risk-benefit trade-off that DAPT means for patients. In PEGASUS-TIMI 54 the increased incidence of major bleeding events roughly matched the decreased rate of major cardiovascular events prevented. But while the incidence of bleeds categorized as TIMI major bleeds more than doubled in the patients randomized to DAPT compared with those on aspirin only, the prolonged treatment with ticagrelor did not result in an increase in fatal bleeds or in intracranial hemorrhages, the two most feared types of TIMI major bleeds.

“I’d much rather prevent cardiovascular deaths, MIs, and strokes even at the expense of causing reversible, nonfatal bleeding events,” said Dr. Sabatine, professor of medicine at Harvard Medical School in Boston and chairman of the TIMI Study Group at Brigham and Women’s Hospital.

Another notable adverse effect from ticagrelor treatment was a roughly threefold increased incidence of dyspnea, which led to drug discontinuation in 5%-7% of patients, depending on whether they received ticagrelor at 60 mg b.i.d. or 90 mg b.i.d. The study results showed a reduced rate of both bleeding and dyspnea in patients randomized to receive the 60-mg b.i.d. dosage, compared with those who received the 90-mg b.i.d. dosage, which is the standard ticagrelor dosage and the formulation now sold. At the same time, the efficacy of the 60-mg b.i.d. dosage for preventing ischemic events equaled that of the higher dosage. But as of today, it is impossible for a physician to prescribe a 60-mg formulation of ticagrelor because the manufacturer does not sell it.

Mitchel L. Zoler/Frontline Medical News

Several cardiologists PEGASUS-TIMI 54 at the meeting said that they agreed with Dr. Sabatine and felt that the benefits from prolonged DAPT with ticagrelor outweighed the downside of an increased bleeding risk.

“I think that the benefit is greater than the risk. None of us wants to see patients experience bleeding, but I was encouraged that fatal bleeds and intracranial hemorrhages were no different,” commented Dr. Elliott M. Antman, a professor of medicine at Harvard.

“The benefits outweigh the bleeding risk, but I wouldn’t trivialize the bleeding risk. Assessing a patient’s bleeding risk is really important,” commented Dr. Robert Harrington, professor of medicine at Stanford (Calif.) University.

But others at the meeting said that the elevated bleeding risk gave them pause. “There clearly is a price to be paid even if extended-duration DAPT reduces MI and stent thrombosis. I believe only the highest risk patients – those with acute coronary syndrome and ST-elevation MI – are the ones for whom I’d even consider it. Unless we can reduce bleeding risk, maybe with even lower doses [of ticagrelor], stopping aspirin, or using a reversal agent, we will be causing bleeds that are very relevant to patients,” commented Dr. Ajay J. Kirtane, an interventional cardiologist at Columbia University in New York.

Mitchel L. Zoler/Frontline Medical News

Dr. Kirtane also questioned whether TIMI major bleeds was the appropriate measure of bleeding risk in the context of a study like PEGASUS-TIMI 54. “Historically, TIMI major bleeding was derived from studies of acute heart attack patients getting fibrinolytic therapy. That is a very different population from this one. In my mind, the combination of TIMI major and minor bleeding would be more encompassing, and for patients the bleeding risks of these therapies are real and have been associated with bad sequelae,” he said in an interview.

When placed in the context of prior reports the new findings also raise the possibility that the generic, and hence much cheaper, thienopyridine clopidogrel might provide roughly the same long-term benefit as more expensive ticagrelor, especially for patients without a genetic profile that makes them poor clopidogrel metabolizers. This may be an attractive option for patients who have a problem paying for ticagrelor long term.

“I’d rather prescribe a patient a cheaper medication that might be a bit less effective than create an economic hardship,” Dr. Harrington said in an interview. The results from the DAPT trial, which included some post-PCI patients who received long-term DAPT with clopidogrel plus aspirin “give you a certain comfort” with the idea of substituting clopidogrel for ticagrelor when affordability is a major concern, Dr. Harrington noted.

PEGASUS-TIMI 54 enrolled 21, 162 patients who were 1-3 years out from a prior myocardial infarction at 1,161 sites in 31 countries. Enrolled patients also had to be at least 50 years old, and have at least one additional risk factor for ischemic events such as age 65 years or older, diabetes, multivessel coronary artery disease, or chronic renal dysfunction. The enrolled patients averaged 1.7 years out from their index MI. Randomization assigned patients to treatment with 90 mg ticagrelor b.i.d., 60 mg ticagrelor b.i.d., or placebo, and all patients also received daily treatment with 75-150 mg aspirin.

After a median follow-up of 33 months on treatment, the combined rate of cardiovascular death, myocardial infarction, or stroke – the study’s primary endpoint – occurred in 7.85% of patients on the 90-mg ticagrelor dosage, 7.77% of those on the 60-mg dosage, and in 9.04% of patients on placebo receiving aspirin only, statistically significant differences for the study’s primary endpoint for each of the two ticagrelor dosages. Concurrent with the report at the meeting the results also appeared online (N. Engl. J. Med. 2015; [doi:10.1056/nejmoa1500857]). This translated into hazard ratios of 0.85 for the 90 mg dosage and 0.84 for the 60 mg dosage compared with placebo.

The study’s primary safety outcome was the incidence of TIMI major bleeding events, which occurred in 2.60% of patients on the higher ticagrelor dosage, 2.30% of those on the 60 mg dosage, and in 1.06% of those on placebo, which converted into hazard ratios of 2.69 for the 90-mg dosage and 2.32 for the lower dosage for TIMI major bleeds compared with aspirin alone.

[email protected]

On Twitter @mitchelzoler

SAN DIEGO– The risk of developing cancer is significantly higher in survivors of an acute MI compared to the general population, according to a large Danish national registry study.

“Greater focus on long-term cancer risk is warranted in MI survivors. This could potentially have implications on future patient care for MI patients, outpatient follow-up strategies, and distribution of health care resources,” Morten Winther Malmborg said at the annual meeting of the American College of Cardiology.

He presented a nationwide cohort study including 3,005,734 Danish adults with no baseline history of MI or cancer who were followed for up to 17 years in the comprehensive Danish National Patient Registry. During the study period, 125,926 of these individuals had a nonfatal MI.

The subsequent incidence of cancer in the MI survivors was 167 cases per 10,000 person-years compared with 95 per 10,000 person-years in the control group, reported Mr. Malmborg, a fourth-year medical student at the University of Copenhagen.

Cancer diagnoses of all types were highest by far in the first 6 months post-MI, which he attributed to surveillance bias, since that was a period of increased medical contact. However, after he and his coinvestigators excluded the cancers diagnosed during that initial 6-month period, the post-MI group still had a highly significant 11% increased relative risk for cancer overall during the period from 6 months through 17 years post-MI.

The younger a patient was when the MI occurred, the greater the subsequent cancer risk. Individuals who had a nonfatal MI at age 30-54 had a 44% greater risk of cancer overall at 6 months–17 years post-MI compared, with the control group. Those who had an MI at age 55-69 had a 19% increased cancer risk compared to controls, while those whose MI occurred at age 70-99 had a modest but still statistically significant 5% increase in cancer risk.

Particularly striking, according to Mr. Malmborg, was the MI survivors’ 44% increased relative risk for lung cancer and 31% increase in bladder cancer during the period from 6 months–17 years post-MI compared with the general population. In contrast, rates of breast, prostate, and colon cancer weren’t significantly different between MI survivors and the general population with no history of MI.

This observational study didn’t address the mechanisms involved in MI survivors’ increased cancer risk. Although the Danish registry didn’t include information of smoking status, Mr. Malmborg speculated that smoking may figure prominently, since it is a major shared risk factor for cardiovascular disease as well as lung and bladder cancer in particular. Other shared risk factors for cardiovascular disease and cancer include obesity, sedentary lifestyle, and excessive alcohol use.

This is the first large-scale study to look at cancer risk post-MI. It’s an increasingly relevant issue because the advances in cardiac care that have brought improved long-term survival following acute MI means more patients with a history of MI are likely to die from noncardiac causes, Mr. Malmborg observed.

He and his coinvestigators are now performing a number-needed-to-screen analysis to help them determine whether structured, formal creening for cancer following an MI should be done routinely.

The study was supported by Danish national medical research funds. The presenter reported having no financial conflicts.

[email protected]

SAN DIEGO– The risk of developing cancer is significantly higher in survivors of an acute MI compared to the general population, according to a large Danish national registry study.

“Greater focus on long-term cancer risk is warranted in MI survivors. This could potentially have implications on future patient care for MI patients, outpatient follow-up strategies, and distribution of health care resources,” Morten Winther Malmborg said at the annual meeting of the American College of Cardiology.

He presented a nationwide cohort study including 3,005,734 Danish adults with no baseline history of MI or cancer who were followed for up to 17 years in the comprehensive Danish National Patient Registry. During the study period, 125,926 of these individuals had a nonfatal MI.

The subsequent incidence of cancer in the MI survivors was 167 cases per 10,000 person-years compared with 95 per 10,000 person-years in the control group, reported Mr. Malmborg, a fourth-year medical student at the University of Copenhagen.

Cancer diagnoses of all types were highest by far in the first 6 months post-MI, which he attributed to surveillance bias, since that was a period of increased medical contact. However, after he and his coinvestigators excluded the cancers diagnosed during that initial 6-month period, the post-MI group still had a highly significant 11% increased relative risk for cancer overall during the period from 6 months through 17 years post-MI.

The younger a patient was when the MI occurred, the greater the subsequent cancer risk. Individuals who had a nonfatal MI at age 30-54 had a 44% greater risk of cancer overall at 6 months–17 years post-MI compared, with the control group. Those who had an MI at age 55-69 had a 19% increased cancer risk compared to controls, while those whose MI occurred at age 70-99 had a modest but still statistically significant 5% increase in cancer risk.

Particularly striking, according to Mr. Malmborg, was the MI survivors’ 44% increased relative risk for lung cancer and 31% increase in bladder cancer during the period from 6 months–17 years post-MI compared with the general population. In contrast, rates of breast, prostate, and colon cancer weren’t significantly different between MI survivors and the general population with no history of MI.

This observational study didn’t address the mechanisms involved in MI survivors’ increased cancer risk. Although the Danish registry didn’t include information of smoking status, Mr. Malmborg speculated that smoking may figure prominently, since it is a major shared risk factor for cardiovascular disease as well as lung and bladder cancer in particular. Other shared risk factors for cardiovascular disease and cancer include obesity, sedentary lifestyle, and excessive alcohol use.

This is the first large-scale study to look at cancer risk post-MI. It’s an increasingly relevant issue because the advances in cardiac care that have brought improved long-term survival following acute MI means more patients with a history of MI are likely to die from noncardiac causes, Mr. Malmborg observed.

He and his coinvestigators are now performing a number-needed-to-screen analysis to help them determine whether structured, formal creening for cancer following an MI should be done routinely.

The study was supported by Danish national medical research funds. The presenter reported having no financial conflicts.

[email protected]

SAN DIEGO– The risk of developing cancer is significantly higher in survivors of an acute MI compared to the general population, according to a large Danish national registry study.

“Greater focus on long-term cancer risk is warranted in MI survivors. This could potentially have implications on future patient care for MI patients, outpatient follow-up strategies, and distribution of health care resources,” Morten Winther Malmborg said at the annual meeting of the American College of Cardiology.

He presented a nationwide cohort study including 3,005,734 Danish adults with no baseline history of MI or cancer who were followed for up to 17 years in the comprehensive Danish National Patient Registry. During the study period, 125,926 of these individuals had a nonfatal MI.

The subsequent incidence of cancer in the MI survivors was 167 cases per 10,000 person-years compared with 95 per 10,000 person-years in the control group, reported Mr. Malmborg, a fourth-year medical student at the University of Copenhagen.

Cancer diagnoses of all types were highest by far in the first 6 months post-MI, which he attributed to surveillance bias, since that was a period of increased medical contact. However, after he and his coinvestigators excluded the cancers diagnosed during that initial 6-month period, the post-MI group still had a highly significant 11% increased relative risk for cancer overall during the period from 6 months through 17 years post-MI.

The younger a patient was when the MI occurred, the greater the subsequent cancer risk. Individuals who had a nonfatal MI at age 30-54 had a 44% greater risk of cancer overall at 6 months–17 years post-MI compared, with the control group. Those who had an MI at age 55-69 had a 19% increased cancer risk compared to controls, while those whose MI occurred at age 70-99 had a modest but still statistically significant 5% increase in cancer risk.

Particularly striking, according to Mr. Malmborg, was the MI survivors’ 44% increased relative risk for lung cancer and 31% increase in bladder cancer during the period from 6 months–17 years post-MI compared with the general population. In contrast, rates of breast, prostate, and colon cancer weren’t significantly different between MI survivors and the general population with no history of MI.

This observational study didn’t address the mechanisms involved in MI survivors’ increased cancer risk. Although the Danish registry didn’t include information of smoking status, Mr. Malmborg speculated that smoking may figure prominently, since it is a major shared risk factor for cardiovascular disease as well as lung and bladder cancer in particular. Other shared risk factors for cardiovascular disease and cancer include obesity, sedentary lifestyle, and excessive alcohol use.

This is the first large-scale study to look at cancer risk post-MI. It’s an increasingly relevant issue because the advances in cardiac care that have brought improved long-term survival following acute MI means more patients with a history of MI are likely to die from noncardiac causes, Mr. Malmborg observed.

He and his coinvestigators are now performing a number-needed-to-screen analysis to help them determine whether structured, formal creening for cancer following an MI should be done routinely.

The study was supported by Danish national medical research funds. The presenter reported having no financial conflicts.

[email protected]

Colony of iPSCs

Image courtesy of the Salk

Institute of Biological Studies

Researchers say they have devised a way to correct a genetic defect in cells from a patient with X-linked severe combined immunodeficiency (SCID-X1).

The group generated induced pluripotent stem cells (iPSCs) using a sample from an infant with SCID-X1, then used the gene-editing technique TALEN to correct the defect in those iPSCs.

And this allowed the iPSCs to generate mature natural killer (NK) cells and T-cell precursors.

The researchers said this is the first evidence of genomic correction of iPSCs derived from a patient with SCID-X1 that resulted in the regeneration of mature lymphoid cells in vitro.

And the work, which is published in Cell Stem Cell, holds promise for the development of new treatments for this disease.

“This work demonstrates a new method that could lead to a more effective and less invasive treatment for this devastating disease,” said study author Inder Verma, PhD, of The Salk Institute of Biological Studies in La Jolla, California.

“It also has the potential to lay the foundation to cure other deadly and rare blood disorders.”

Dr Verma and his colleagues began this research by securing a sample of bone marrow from a deceased infant with SCID-X1. The subject harbored a novel splice-site mutation (c.468+3A > C) of the IL-2Rγ gene, which results in a lack of functional NK and T cells.

The researchers used the subject’s sample to create iPSC lines and used TALEN to correct the mutation in those iPSCs.

“We use TALEN-based genome editing to change just one nucleotide in one gene to correct the deficiency,” said study author Tushar Menon, PhD, also of the Salk Institute. “The technique is literally that precise.”

The team then compared the corrected iPSCs to uncorrected SCID-X1 iPSCs and control iPSCs generated from cord-blood-derived endothelial cells and dermal fibroblasts.

Like control cells, the corrected iPSCs were able to differentiate into mature NK cells that expressed both inhibitory and activating receptors (KIR/CD158b and CD16, respectively).

The corrected iPSCs could also differentiate into T-cell precursors but not mature T cells. The researchers are currently working on producing mature T cells.

“Ultimately, we hope these efforts will help lead to the ‘holy grail’ in the field: the ability to create stem cells from iPSCs capable of generating all types of blood and immune cells,” Dr Verma said.

He and his colleagues noted, however, that further improvements of their protocol will be needed to obtain sufficient cells for clinical use.

Colony of iPSCs

Image courtesy of the Salk

Institute of Biological Studies

Researchers say they have devised a way to correct a genetic defect in cells from a patient with X-linked severe combined immunodeficiency (SCID-X1).

The group generated induced pluripotent stem cells (iPSCs) using a sample from an infant with SCID-X1, then used the gene-editing technique TALEN to correct the defect in those iPSCs.

And this allowed the iPSCs to generate mature natural killer (NK) cells and T-cell precursors.

The researchers said this is the first evidence of genomic correction of iPSCs derived from a patient with SCID-X1 that resulted in the regeneration of mature lymphoid cells in vitro.

And the work, which is published in Cell Stem Cell, holds promise for the development of new treatments for this disease.

“This work demonstrates a new method that could lead to a more effective and less invasive treatment for this devastating disease,” said study author Inder Verma, PhD, of The Salk Institute of Biological Studies in La Jolla, California.

“It also has the potential to lay the foundation to cure other deadly and rare blood disorders.”

Dr Verma and his colleagues began this research by securing a sample of bone marrow from a deceased infant with SCID-X1. The subject harbored a novel splice-site mutation (c.468+3A > C) of the IL-2Rγ gene, which results in a lack of functional NK and T cells.

The researchers used the subject’s sample to create iPSC lines and used TALEN to correct the mutation in those iPSCs.

“We use TALEN-based genome editing to change just one nucleotide in one gene to correct the deficiency,” said study author Tushar Menon, PhD, also of the Salk Institute. “The technique is literally that precise.”

The team then compared the corrected iPSCs to uncorrected SCID-X1 iPSCs and control iPSCs generated from cord-blood-derived endothelial cells and dermal fibroblasts.

Like control cells, the corrected iPSCs were able to differentiate into mature NK cells that expressed both inhibitory and activating receptors (KIR/CD158b and CD16, respectively).

The corrected iPSCs could also differentiate into T-cell precursors but not mature T cells. The researchers are currently working on producing mature T cells.

“Ultimately, we hope these efforts will help lead to the ‘holy grail’ in the field: the ability to create stem cells from iPSCs capable of generating all types of blood and immune cells,” Dr Verma said.

He and his colleagues noted, however, that further improvements of their protocol will be needed to obtain sufficient cells for clinical use.

Colony of iPSCs

Image courtesy of the Salk

Institute of Biological Studies

Researchers say they have devised a way to correct a genetic defect in cells from a patient with X-linked severe combined immunodeficiency (SCID-X1).

The group generated induced pluripotent stem cells (iPSCs) using a sample from an infant with SCID-X1, then used the gene-editing technique TALEN to correct the defect in those iPSCs.

And this allowed the iPSCs to generate mature natural killer (NK) cells and T-cell precursors.

The researchers said this is the first evidence of genomic correction of iPSCs derived from a patient with SCID-X1 that resulted in the regeneration of mature lymphoid cells in vitro.

And the work, which is published in Cell Stem Cell, holds promise for the development of new treatments for this disease.

“This work demonstrates a new method that could lead to a more effective and less invasive treatment for this devastating disease,” said study author Inder Verma, PhD, of The Salk Institute of Biological Studies in La Jolla, California.

“It also has the potential to lay the foundation to cure other deadly and rare blood disorders.”

Dr Verma and his colleagues began this research by securing a sample of bone marrow from a deceased infant with SCID-X1. The subject harbored a novel splice-site mutation (c.468+3A > C) of the IL-2Rγ gene, which results in a lack of functional NK and T cells.

The researchers used the subject’s sample to create iPSC lines and used TALEN to correct the mutation in those iPSCs.

“We use TALEN-based genome editing to change just one nucleotide in one gene to correct the deficiency,” said study author Tushar Menon, PhD, also of the Salk Institute. “The technique is literally that precise.”

The team then compared the corrected iPSCs to uncorrected SCID-X1 iPSCs and control iPSCs generated from cord-blood-derived endothelial cells and dermal fibroblasts.

Like control cells, the corrected iPSCs were able to differentiate into mature NK cells that expressed both inhibitory and activating receptors (KIR/CD158b and CD16, respectively).

The corrected iPSCs could also differentiate into T-cell precursors but not mature T cells. The researchers are currently working on producing mature T cells.

“Ultimately, we hope these efforts will help lead to the ‘holy grail’ in the field: the ability to create stem cells from iPSCs capable of generating all types of blood and immune cells,” Dr Verma said.

He and his colleagues noted, however, that further improvements of their protocol will be needed to obtain sufficient cells for clinical use.

SAN DIEGO – Current guidelines call for treating acute coronary syndrome patients with dual antiplatelet therapy (aspirin plus a thienopyridine) for at least 1 year following their event, but results from recent large, randomized trials suggest that many patients continue to benefit from treatment that extends beyond the first year, Dr. Richard C. Becker said during an interview at the annual meeting of the American College of Cardiology.

New results reported at the meeting from the PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction) 54 trial highlight the long-term risk for ischemic events faced by patients following an acute coronary syndrome (N. Engl. J. Med. 2025;[doi: 10.1056/NEJMoa0904327]. The results also underscore the importance of risk assessment, and the importance of tailoring treatment to ACS patients based not only on their long-term risk from their cardiovascular disease but also their risk for adverse bleeding events secondary to prolonged, aggressive antiplatelet therapy. The PEGASUS-TIMI 54 results complement the findings reported last year from the DAPT (Dual Antiplatelet Therapy) trial (N. Engl. J. Med. 2014;371:2155-66), he said.

Based on the accumulated evidence, ACS patients who have done well clinically on DAPT after 1 year and are deemed at low risk for bleeding and other complications are good candidates for more prolonged DAPT treatment, said Dr. Becker, professor and director of the University of Cincinnati Heart, Lung & Vascular Institute.

PEGASUS-TIMI 54 ws sponsored by AstraZeneca, which markets ticagrelor (Brilinta). Dr. Becker has been a consultant to and received research support from AstraZeneca.

[email protected]

On Twitter @mitchelzoler

SAN DIEGO – Current guidelines call for treating acute coronary syndrome patients with dual antiplatelet therapy (aspirin plus a thienopyridine) for at least 1 year following their event, but results from recent large, randomized trials suggest that many patients continue to benefit from treatment that extends beyond the first year, Dr. Richard C. Becker said during an interview at the annual meeting of the American College of Cardiology.

New results reported at the meeting from the PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction) 54 trial highlight the long-term risk for ischemic events faced by patients following an acute coronary syndrome (N. Engl. J. Med. 2025;[doi: 10.1056/NEJMoa0904327]. The results also underscore the importance of risk assessment, and the importance of tailoring treatment to ACS patients based not only on their long-term risk from their cardiovascular disease but also their risk for adverse bleeding events secondary to prolonged, aggressive antiplatelet therapy. The PEGASUS-TIMI 54 results complement the findings reported last year from the DAPT (Dual Antiplatelet Therapy) trial (N. Engl. J. Med. 2014;371:2155-66), he said.

Based on the accumulated evidence, ACS patients who have done well clinically on DAPT after 1 year and are deemed at low risk for bleeding and other complications are good candidates for more prolonged DAPT treatment, said Dr. Becker, professor and director of the University of Cincinnati Heart, Lung & Vascular Institute.

PEGASUS-TIMI 54 ws sponsored by AstraZeneca, which markets ticagrelor (Brilinta). Dr. Becker has been a consultant to and received research support from AstraZeneca.

[email protected]

On Twitter @mitchelzoler

SAN DIEGO – Current guidelines call for treating acute coronary syndrome patients with dual antiplatelet therapy (aspirin plus a thienopyridine) for at least 1 year following their event, but results from recent large, randomized trials suggest that many patients continue to benefit from treatment that extends beyond the first year, Dr. Richard C. Becker said during an interview at the annual meeting of the American College of Cardiology.

New results reported at the meeting from the PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction) 54 trial highlight the long-term risk for ischemic events faced by patients following an acute coronary syndrome (N. Engl. J. Med. 2025;[doi: 10.1056/NEJMoa0904327]. The results also underscore the importance of risk assessment, and the importance of tailoring treatment to ACS patients based not only on their long-term risk from their cardiovascular disease but also their risk for adverse bleeding events secondary to prolonged, aggressive antiplatelet therapy. The PEGASUS-TIMI 54 results complement the findings reported last year from the DAPT (Dual Antiplatelet Therapy) trial (N. Engl. J. Med. 2014;371:2155-66), he said.

Based on the accumulated evidence, ACS patients who have done well clinically on DAPT after 1 year and are deemed at low risk for bleeding and other complications are good candidates for more prolonged DAPT treatment, said Dr. Becker, professor and director of the University of Cincinnati Heart, Lung & Vascular Institute.

PEGASUS-TIMI 54 ws sponsored by AstraZeneca, which markets ticagrelor (Brilinta). Dr. Becker has been a consultant to and received research support from AstraZeneca.

[email protected]

On Twitter @mitchelzoler

SAN DIEGO – Digoxin increases the risk of death by 27% in patients with atrial fibrillation, a meta-analysis of 19 studies showed.

Patients with AF and kidney failure faced a 60% to 70 % increase in mortality compared to their counterparts not taking digoxin, according to a press release on the study.

A weaker association between digoxin and death was observed in AF patients who also had heart failure, a finding the authors suggest warrants further investigation.

“Until further research can be done, I would suggest physicians use caution when prescribing digoxin for patients with atrial fibrillation, especially given that there are alternative drugs available that might be safer,” lead author Dr. Waqas Qureshi said in a statement.

The results were released in advance of their March 15 presentation at the annual meeting of the American College of Cardiology in San Diego.

About 5.6 million Americans have atrial fibrillation (AF) and roughly 1 in 5 are prescribed digoxin for heart rate control.

Current guidelines recommend digoxin as first-line therapy in patients who aren’t physically active and as a second-line drug for more active patients.

“Based on consistent results coming out of many studies, our results suggest digoxin should be downgraded from its position as a front-line agent for certain patients with atrial fibrillation,” Dr. Qureshi, a clinical and research cardiology fellow at Wake Forest School of Medicine in Winston-Salem, N.C., recommended.

The authors reviewed 19 studies including five cohort and randomized controlled trials involving 501,681 patients. Of these, 458,311 patients had AF and 111,978 were prescribed digoxin.

In a random effects model, digoxin was associated with an increased risk of mortality, with a pooled hazard ratio of 1.27 (95% confidence interval 1.19-1.36; P value < .001).

Several studies in the meta-analysis suggest that higher blood levels of digoxin increase the risk of death. The mechanism behind the increased mortality is not known, although previous studies have suggested digoxin increases the risk of thromboembolism.

The meta-analysis accounted for risk factors and co-morbidities reported in the various studies, but it’s possible that some confounding factors may not have been accounted for, the authors acknowledge.

“The study points to the need for a well-structured, targeted trial to investigate digoxin’s safety,” Dr. Qureshi stated.

[email protected]

SAN DIEGO – Digoxin increases the risk of death by 27% in patients with atrial fibrillation, a meta-analysis of 19 studies showed.

Patients with AF and kidney failure faced a 60% to 70 % increase in mortality compared to their counterparts not taking digoxin, according to a press release on the study.

A weaker association between digoxin and death was observed in AF patients who also had heart failure, a finding the authors suggest warrants further investigation.

“Until further research can be done, I would suggest physicians use caution when prescribing digoxin for patients with atrial fibrillation, especially given that there are alternative drugs available that might be safer,” lead author Dr. Waqas Qureshi said in a statement.

The results were released in advance of their March 15 presentation at the annual meeting of the American College of Cardiology in San Diego.

About 5.6 million Americans have atrial fibrillation (AF) and roughly 1 in 5 are prescribed digoxin for heart rate control.

Current guidelines recommend digoxin as first-line therapy in patients who aren’t physically active and as a second-line drug for more active patients.

“Based on consistent results coming out of many studies, our results suggest digoxin should be downgraded from its position as a front-line agent for certain patients with atrial fibrillation,” Dr. Qureshi, a clinical and research cardiology fellow at Wake Forest School of Medicine in Winston-Salem, N.C., recommended.

The authors reviewed 19 studies including five cohort and randomized controlled trials involving 501,681 patients. Of these, 458,311 patients had AF and 111,978 were prescribed digoxin.

In a random effects model, digoxin was associated with an increased risk of mortality, with a pooled hazard ratio of 1.27 (95% confidence interval 1.19-1.36; P value < .001).

Several studies in the meta-analysis suggest that higher blood levels of digoxin increase the risk of death. The mechanism behind the increased mortality is not known, although previous studies have suggested digoxin increases the risk of thromboembolism.

The meta-analysis accounted for risk factors and co-morbidities reported in the various studies, but it’s possible that some confounding factors may not have been accounted for, the authors acknowledge.

“The study points to the need for a well-structured, targeted trial to investigate digoxin’s safety,” Dr. Qureshi stated.

[email protected]

SAN DIEGO – Digoxin increases the risk of death by 27% in patients with atrial fibrillation, a meta-analysis of 19 studies showed.

Patients with AF and kidney failure faced a 60% to 70 % increase in mortality compared to their counterparts not taking digoxin, according to a press release on the study.

A weaker association between digoxin and death was observed in AF patients who also had heart failure, a finding the authors suggest warrants further investigation.

“Until further research can be done, I would suggest physicians use caution when prescribing digoxin for patients with atrial fibrillation, especially given that there are alternative drugs available that might be safer,” lead author Dr. Waqas Qureshi said in a statement.

The results were released in advance of their March 15 presentation at the annual meeting of the American College of Cardiology in San Diego.

About 5.6 million Americans have atrial fibrillation (AF) and roughly 1 in 5 are prescribed digoxin for heart rate control.

Current guidelines recommend digoxin as first-line therapy in patients who aren’t physically active and as a second-line drug for more active patients.

“Based on consistent results coming out of many studies, our results suggest digoxin should be downgraded from its position as a front-line agent for certain patients with atrial fibrillation,” Dr. Qureshi, a clinical and research cardiology fellow at Wake Forest School of Medicine in Winston-Salem, N.C., recommended.

The authors reviewed 19 studies including five cohort and randomized controlled trials involving 501,681 patients. Of these, 458,311 patients had AF and 111,978 were prescribed digoxin.

In a random effects model, digoxin was associated with an increased risk of mortality, with a pooled hazard ratio of 1.27 (95% confidence interval 1.19-1.36; P value < .001).

Several studies in the meta-analysis suggest that higher blood levels of digoxin increase the risk of death. The mechanism behind the increased mortality is not known, although previous studies have suggested digoxin increases the risk of thromboembolism.

The meta-analysis accounted for risk factors and co-morbidities reported in the various studies, but it’s possible that some confounding factors may not have been accounted for, the authors acknowledge.

“The study points to the need for a well-structured, targeted trial to investigate digoxin’s safety,” Dr. Qureshi stated.

[email protected]

Diagnosis: Bleomycin-induced flagellate hyperpigmentation

Bleomycin is an antineoplastic agent. Most reported side effects involve the lung and skin since these organs have lower concentrations of the enzyme that detoxifies bleomycin. Other dermatologic side effects of bleomycin include Raynaud's phenomenon, hyperkeratosis, nailbed changes, and peeling of the skin on the palmar and plantar surfaces.

Flagellate erythema has been described in relation to bleomycin treatment along with other reported associations with peplomycin (a bleomycin derivative), docetaxel, dermatomyositis, adult-onset Still's disease, and shiitake mushroom dermatitis. The rash may appear following administration of bleomycin by any route and has been shown to be dose independent. Onset occurs anytime from 1 day to several months after exposure to the offending agent. Patients typically present with history of itching followed by the appearance of red linear streaks, which are most commonly found on the trunk. Over time, the erythema will resolve to postinflammatory hyperpigmentation.

The exact cause is unknown, but it is thought that scratching causes vasodilation with bleomycin accumulating in the skin. Diagnosis is made by physical examination of the characteristic appearance of the rash along with the history of chemotherapy. A skin biopsy may be performed. In most cases, the rash resolves spontaneously within 6-8 months. Severe rashes may warrant discontinuation of bleomycin. Using antihistamines and topical and oral corticosteroids in conjunction with bleomycin may reduce the incidence of flagellate erythema/hyperpigmentation.

Diagnosis: Bleomycin-induced flagellate hyperpigmentation

Bleomycin is an antineoplastic agent. Most reported side effects involve the lung and skin since these organs have lower concentrations of the enzyme that detoxifies bleomycin. Other dermatologic side effects of bleomycin include Raynaud's phenomenon, hyperkeratosis, nailbed changes, and peeling of the skin on the palmar and plantar surfaces.

Flagellate erythema has been described in relation to bleomycin treatment along with other reported associations with peplomycin (a bleomycin derivative), docetaxel, dermatomyositis, adult-onset Still's disease, and shiitake mushroom dermatitis. The rash may appear following administration of bleomycin by any route and has been shown to be dose independent. Onset occurs anytime from 1 day to several months after exposure to the offending agent. Patients typically present with history of itching followed by the appearance of red linear streaks, which are most commonly found on the trunk. Over time, the erythema will resolve to postinflammatory hyperpigmentation.

The exact cause is unknown, but it is thought that scratching causes vasodilation with bleomycin accumulating in the skin. Diagnosis is made by physical examination of the characteristic appearance of the rash along with the history of chemotherapy. A skin biopsy may be performed. In most cases, the rash resolves spontaneously within 6-8 months. Severe rashes may warrant discontinuation of bleomycin. Using antihistamines and topical and oral corticosteroids in conjunction with bleomycin may reduce the incidence of flagellate erythema/hyperpigmentation.

Diagnosis: Bleomycin-induced flagellate hyperpigmentation

Bleomycin is an antineoplastic agent. Most reported side effects involve the lung and skin since these organs have lower concentrations of the enzyme that detoxifies bleomycin. Other dermatologic side effects of bleomycin include Raynaud's phenomenon, hyperkeratosis, nailbed changes, and peeling of the skin on the palmar and plantar surfaces.

Flagellate erythema has been described in relation to bleomycin treatment along with other reported associations with peplomycin (a bleomycin derivative), docetaxel, dermatomyositis, adult-onset Still's disease, and shiitake mushroom dermatitis. The rash may appear following administration of bleomycin by any route and has been shown to be dose independent. Onset occurs anytime from 1 day to several months after exposure to the offending agent. Patients typically present with history of itching followed by the appearance of red linear streaks, which are most commonly found on the trunk. Over time, the erythema will resolve to postinflammatory hyperpigmentation.

The exact cause is unknown, but it is thought that scratching causes vasodilation with bleomycin accumulating in the skin. Diagnosis is made by physical examination of the characteristic appearance of the rash along with the history of chemotherapy. A skin biopsy may be performed. In most cases, the rash resolves spontaneously within 6-8 months. Severe rashes may warrant discontinuation of bleomycin. Using antihistamines and topical and oral corticosteroids in conjunction with bleomycin may reduce the incidence of flagellate erythema/hyperpigmentation.

Irish setter, a breed of dog

that can develop hemophilia B

Gene therapy that produces a potent clotting factor holds promise for treating hemophilia B, researchers have reported in Blood.

The group administered adeno-associated viral-8 (AAV-8) vectors encoding the clotting factor FIX-Padua to mice and dogs with hemophilia B.

The treatment appeared to be safe and effective, did not prompt the formation of inhibitory antibodies, and even eradicated pre-existing inhibitors in one of the dogs.

“Our findings may provide a new approach to gene therapy for hemophilia and perhaps other genetic diseases that have similar complications from inhibiting antibodies,” said study author Valder R. Arruda, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

For years, researchers have investigated gene therapy strategies that deliver DNA sequences carrying genetic code to produce clotting factor in patients. But this approach has been hindered by the body’s immune response against vectors.

Those responses, which defeated initial benefits seen in experimental human gene therapy, were dose-dependent. So Dr Arruda and his colleagues decided to test gene therapy that used lower doses of AAV-8 vector to produce FIX-Padua.

Dr Arruda was part of a team that discovered FIX-Padua in a young Italian man with thrombophilia. A mutation in the factor IX gene produced the clotting factor, which was named after the patient’s city of residence.

FIX-Padua is hyperfunctional, clotting blood 8 to 12 times more strongly than wild-type factor IX. Therefore, in the current study, the researchers needed to strike a balance—to relieve severe hemophilia in dogs by using a dose strong enough to allow clotting but not enough to cause thrombosis or stimulate immune reactions.

“Our ultimate goal is to translate this approach to humans by adapting this variant protein found in one patient to benefit other patients with the opposite disease,” Dr Arruda said

He and his colleagues tested the safety of canine FIX-Padua (AAV-cFIX-Padua) in 3 dogs, all with naturally occurring types of hemophilia B.

Two of the dogs had never been exposed to clotting factor and had never developed antibodies. Injections of AAV-cFIX-Padua changed their hemophilia from severe to mild. They had no bleeding episodes for up to 2 years and did not develop inhibitory antibodies or thrombosis.

The third dog, Wiley, already had inhibitory antibodies before receiving AAV-cFIX-Padua. Like his peers, Wiley responded to the treatment, and that response persisted for 3 years. AAV-cFIX-Padua also eradicated his inhibitors, which marks the first time this occurred in an animal model with pre-existing antibodies.

Another set of experiments in mice suggested the gene therapy is safe and effective. Mice that received AAV encoding human FIX-Padua (AAV-hFIX-Padua) did not develop antibodies.

And the researchers found that AAV-hFIX-Padua was comparable to wild-type human FIX with regard to long-term expression and toxicity.

Dr Arruda noted that larger studies are needed in dogs with pre-existing inhibitors to confirm these encouraging early results.

In the meantime, at least one clinical trial is making use of FIX-Padua in adult patients with hemophilia B—at the University of North Carolina at Chapel Hill, under Paul Monahan, MD. Leaders of a separate trial being planned at Spark Therapeutics in Philadelphia, under Katherine A. High, MD, are contemplating using FIX-Padua as well.

Irish setter, a breed of dog

that can develop hemophilia B

Gene therapy that produces a potent clotting factor holds promise for treating hemophilia B, researchers have reported in Blood.

The group administered adeno-associated viral-8 (AAV-8) vectors encoding the clotting factor FIX-Padua to mice and dogs with hemophilia B.

The treatment appeared to be safe and effective, did not prompt the formation of inhibitory antibodies, and even eradicated pre-existing inhibitors in one of the dogs.

“Our findings may provide a new approach to gene therapy for hemophilia and perhaps other genetic diseases that have similar complications from inhibiting antibodies,” said study author Valder R. Arruda, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

For years, researchers have investigated gene therapy strategies that deliver DNA sequences carrying genetic code to produce clotting factor in patients. But this approach has been hindered by the body’s immune response against vectors.

Those responses, which defeated initial benefits seen in experimental human gene therapy, were dose-dependent. So Dr Arruda and his colleagues decided to test gene therapy that used lower doses of AAV-8 vector to produce FIX-Padua.

Dr Arruda was part of a team that discovered FIX-Padua in a young Italian man with thrombophilia. A mutation in the factor IX gene produced the clotting factor, which was named after the patient’s city of residence.

FIX-Padua is hyperfunctional, clotting blood 8 to 12 times more strongly than wild-type factor IX. Therefore, in the current study, the researchers needed to strike a balance—to relieve severe hemophilia in dogs by using a dose strong enough to allow clotting but not enough to cause thrombosis or stimulate immune reactions.

“Our ultimate goal is to translate this approach to humans by adapting this variant protein found in one patient to benefit other patients with the opposite disease,” Dr Arruda said

He and his colleagues tested the safety of canine FIX-Padua (AAV-cFIX-Padua) in 3 dogs, all with naturally occurring types of hemophilia B.

Two of the dogs had never been exposed to clotting factor and had never developed antibodies. Injections of AAV-cFIX-Padua changed their hemophilia from severe to mild. They had no bleeding episodes for up to 2 years and did not develop inhibitory antibodies or thrombosis.

The third dog, Wiley, already had inhibitory antibodies before receiving AAV-cFIX-Padua. Like his peers, Wiley responded to the treatment, and that response persisted for 3 years. AAV-cFIX-Padua also eradicated his inhibitors, which marks the first time this occurred in an animal model with pre-existing antibodies.

Another set of experiments in mice suggested the gene therapy is safe and effective. Mice that received AAV encoding human FIX-Padua (AAV-hFIX-Padua) did not develop antibodies.

And the researchers found that AAV-hFIX-Padua was comparable to wild-type human FIX with regard to long-term expression and toxicity.

Dr Arruda noted that larger studies are needed in dogs with pre-existing inhibitors to confirm these encouraging early results.

In the meantime, at least one clinical trial is making use of FIX-Padua in adult patients with hemophilia B—at the University of North Carolina at Chapel Hill, under Paul Monahan, MD. Leaders of a separate trial being planned at Spark Therapeutics in Philadelphia, under Katherine A. High, MD, are contemplating using FIX-Padua as well.

Irish setter, a breed of dog

that can develop hemophilia B

Gene therapy that produces a potent clotting factor holds promise for treating hemophilia B, researchers have reported in Blood.

The group administered adeno-associated viral-8 (AAV-8) vectors encoding the clotting factor FIX-Padua to mice and dogs with hemophilia B.

The treatment appeared to be safe and effective, did not prompt the formation of inhibitory antibodies, and even eradicated pre-existing inhibitors in one of the dogs.

“Our findings may provide a new approach to gene therapy for hemophilia and perhaps other genetic diseases that have similar complications from inhibiting antibodies,” said study author Valder R. Arruda, MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania.

For years, researchers have investigated gene therapy strategies that deliver DNA sequences carrying genetic code to produce clotting factor in patients. But this approach has been hindered by the body’s immune response against vectors.

Those responses, which defeated initial benefits seen in experimental human gene therapy, were dose-dependent. So Dr Arruda and his colleagues decided to test gene therapy that used lower doses of AAV-8 vector to produce FIX-Padua.

Dr Arruda was part of a team that discovered FIX-Padua in a young Italian man with thrombophilia. A mutation in the factor IX gene produced the clotting factor, which was named after the patient’s city of residence.

FIX-Padua is hyperfunctional, clotting blood 8 to 12 times more strongly than wild-type factor IX. Therefore, in the current study, the researchers needed to strike a balance—to relieve severe hemophilia in dogs by using a dose strong enough to allow clotting but not enough to cause thrombosis or stimulate immune reactions.

“Our ultimate goal is to translate this approach to humans by adapting this variant protein found in one patient to benefit other patients with the opposite disease,” Dr Arruda said

He and his colleagues tested the safety of canine FIX-Padua (AAV-cFIX-Padua) in 3 dogs, all with naturally occurring types of hemophilia B.

Two of the dogs had never been exposed to clotting factor and had never developed antibodies. Injections of AAV-cFIX-Padua changed their hemophilia from severe to mild. They had no bleeding episodes for up to 2 years and did not develop inhibitory antibodies or thrombosis.

The third dog, Wiley, already had inhibitory antibodies before receiving AAV-cFIX-Padua. Like his peers, Wiley responded to the treatment, and that response persisted for 3 years. AAV-cFIX-Padua also eradicated his inhibitors, which marks the first time this occurred in an animal model with pre-existing antibodies.

Another set of experiments in mice suggested the gene therapy is safe and effective. Mice that received AAV encoding human FIX-Padua (AAV-hFIX-Padua) did not develop antibodies.

And the researchers found that AAV-hFIX-Padua was comparable to wild-type human FIX with regard to long-term expression and toxicity.

Dr Arruda noted that larger studies are needed in dogs with pre-existing inhibitors to confirm these encouraging early results.

In the meantime, at least one clinical trial is making use of FIX-Padua in adult patients with hemophilia B—at the University of North Carolina at Chapel Hill, under Paul Monahan, MD. Leaders of a separate trial being planned at Spark Therapeutics in Philadelphia, under Katherine A. High, MD, are contemplating using FIX-Padua as well.

From the Boston University School of Medicine, Boston, MA.

Abstract

• Objective: To review recommendations for colorectal cancer (CRC) screening.
• Methods: Review of the literature.
• Results: In the United States, CRC is the third most commonly diagnosed cancer and the third leading cause of cancer death. CRC screening can reduce mortality through the detection of early-stage disease and the detection and removal of adenomatous polyps. There are several modalities for CRC screening, with current technology falling into 2 general categories: stool tests, which include tests for occult blood or exfoliated DNA; and structural exams, which include flexible sigmoidoscopy, colonoscopy, double-contrast barium enema, and CT colonography. The preferred CRC prevention test for average-risk individuals is colonoscopy starting at age 50 with subsequent examinations every 10 years. Patients unwilling to undergo screening colonoscopy may be offered flexible sigmoidoscopy, CT colonography, or fecal immunohistochemical test. Surveillance examinations should occur based on polyp findings on index colonoscopy. There is no recommendation to continue screening after age 75, though physicians can make a determination based on a patient’s health and risk/benefit profile. Current guidelines recommend against offering screening to patients over age 85.
• Conclusion: Increasing access to and utilization of CRC screening tests is likely to lead to improvements in mortality reduction, as only about half of people aged 50 or older report having received CRC testing consistent with current guidelines.

In the United States, colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death in both men and women [1]. In 2014, an estimated 136,830 people were diagnosed with CRC and about 50,310 people died of the disease [2]. Colorectal cancer usually develops slowly over a period of 10 to 15 years. The tumor typically begins as a noncancerous polyp, classically an adenomatous polyp or adenoma, though fewer than 10% of adenomas will progress to cancer [3]. Adenomas are common; an estimated one-third to one-half of all individuals will eventually develop 1 or more adenomas [4,5]. In the United States, the lifetime risk of being diagnosed with CRC is approximately 5% for both men and women [6]. Incidence rates for CRC increase with age, with an incidence rate more than 15 times higher in adults aged 50 years and older compared with those aged 20 to 49 years [7].

Certain demographic subgroups have been shown to be at higher risk. Overall, CRC incidence and mortality rates are about 35% to 40% higher in men than in women. The reasons for this are not completely understood but likely reflect complex interactions between gender-related differences in exposure to hormones and risk factors [8]. CRC incidence and mortality rates are highest in African-American men and women; incidence rates are 20% higher and mortality rates are about 45% higher than those in whites. Prior to 1989, incidence rates were predominantly higher in white men than in African American men and were similar for women of both races. Since that time, although incidence rates have declined as a whole [9], incidence rates have been higher for African Americans than whites in both men and women This crossover likely reflects a combination of greater access to and utilization of recommended screening tests among whites (resulting in detection and removal of precancerous polyps), as well as racial differences in trends for CRC risk factors [10].

CRC screening can reduce mortality through the detection of early-stage disease and the detection and removal of ademomatous polyps [11]. Increasing access to and utilization of CRC screening tests is likely to lead to improvements in mortality reduction, as only about half of people aged 50 or older report having received CRC testing consistent with current guidelines [1].

Case Study

Initial Presentation

A 55-year-old white male presents for a routine visit and asks about colon cancer screening. His father was diagnosed with colon cancer at the age of 78. Overall, he feels well and does not have any particular complaints. His bowel habits are normal and he denies melena and hematochezia. His past medical history is significant for diabetes, hypertension, and obesity. He was a previous smoker and has a few alcoholic drinks on the weekends. His physical exam is unremarkable. Results of recent blood work are normal and there is no evidence of anemia.

• What are this patient’s risk factors for developing colon cancer?

Risk Factors for CRC

There are numerous factors that are thought to influence risk for CRC. Nonmodifiable risk factors include a personal or family history of CRC or adenomatous polyps, and a personal history of chronic inflammatory bowel disease. Modifiable risk factors that have been associated with an increased risk of CRC in epidemiologic studies include physical inactivity, obesity, high consumption of red or processed meats, smoking, and moderate-to-heavy alcohol consumption. In fact, a prospective study showed that up to 23% of colorectal cancers were considered to be potentially avoidable by adhering to multiple healthy lifestyle recommendations including maintaining a healthy weight, being physically active at least 30 minutes per day, eating a healthy diet, and avoiding smoking and drinking excessive amounts of alcohol [12].

People with a first-degree relative (parent, sibling, or offspring) who has had CRC have 2 to 3 times the risk of developing the disease compared with individuals with no family history; if the relative was diagnosed at a young age or if there is more than 1 affected relative, risk increases to 3 to 6 times that of the general population [13,14]. About 5% of patients with CRC have a well-defined genetic syndrome that causes the disease [15]. The most common of these is Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC), which accounts for 2% to 4% of all CRC cases [16]. Although individuals with Lynch syndrome are predisposed to numerous types of cancer, risk of CRC is highest. A recent study of CRC in 147 Lynch syndrome families in the United States found lifetime risk of CRC to be 66% in men and 43% in women, with a median age at diagnosis of 42 years and 47 years, respectively [17]. Familial adenomatous polyposis (FAP) is the second most common predisposing genetic syndrome; for these individuals, the lifetime risk of CRC approaches 100% without intervention (eg, colectomy) [16].

People who have inflammatory bowel disease of the colon (both ulcerative colitis and Crohn’s disease) have an increased risk of developing CRC that correlates with the extent and the duration of the inflammation [18]. It is estimated that 18% of patients with a 30-year history of ulcerative colitis will develop CRC [19]. In addition, several studies have found an association between diabetes and increased risk of CRC [20,21]. Though adult-onset type 2 diabetes (the most common type) and CRC share similar risk factors, including physical inactivity and obesity, a positive association between diabetes and CRC has been found even after accounting for physical activity, body mass index, and waist circumference [22].

Being overweight or obese is also associated with a higher risk of CRC, with stronger associations more consistently observed in men than in women. Obesity increases the risk of CRC independent of physical activity. Abdominal obesity (measured by waist circumference) may be a more important risk factor for colon cancer than overall obesity in both men and women [23–25]. Diet and lifestyle strongly influence CRC risk; however, research on the role of specific dietary elements on CRC risk is still accumulating. Several studies, including one by the American Cancer Society, have found that high consumption of red and/or processed meat increases the risk of both colon and rectal cancer [23,26,27]. Further analyses indicate that the association between CRC and red meat may be related to the cooking process, because a higher risk of CRC is observed particularly among those individuals who consume meat that has been cooked at a high temperature for a long period of time [28]. In contrast to findings from earlier research, more recent large, prospective studies do not indicate a major relationship between CRC and vegetable, fruit, or fiber consumption [28,29]. However, some studies suggest that people with very low fruit and vegetable intake are at above-average risk for CRC [30,31]. Consumption of milk and calcium may decrease the risk of developing CRC [28,29,32].

In November 2009, the International Agency for Research on Cancer reported that there is now sufficient evidence to conclude that tobacco smoking causes CRC [33]. Colorectal cancer has been linked to even moderate alcohol use. Individuals who have a lifetime average of 2 to 4 alcoholic drinks per day have a 23% higher risk of CRC than those who consume less than 1 drink per day [34].

Protective Factors

One of the most consistently reported relationships between colon cancer risk and behavior is the protective effect of physical activity [35]. Based on these findings, as well as the numerous other health benefits of regular physical activity, the American Cancer Society recommends engaging in at least moderate activity for 30 minutes or more on 5 or more days per week.

Accumulating research suggests that aspirin-like drugs, postmenopausal hormones, and calcium supplements may help prevent CRC. Extensive evidence suggests that long-term, regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is asso-ciated with lower risk of CRC. The American Cancer Society does not currently recommend use of these drugs as chemoprevention because of the potential side effects of gastrointestinal bleeding from aspirin and other traditional NSAIDs and heart attacks from selective cyclooxygenase-2 (COX-2) inhibitors. However, people who are already taking NSAIDs for chronic arthritis or aspirin for heart disease prevention may have a lower risk of CRC as a positive side effect [36,37].

There is substantial evidence that women who use postmenopausal hormones have lower rates of CRC than those who do not. A decreased risk of CRC is especially evident in women who use hormones long-term, although the risk returns to that of nonusers within 3 years of cessation. Despite its positive effect on CRC risk, the use of postmenopausal hormones increases the risk of breast and other cancers as well as cardiovascular disease, and therefore it is not recommended for the prevention of CRC. At present, the American Cancer Society does not recommend any medications or supplements to prevent CRC because of uncertainties about their effectiveness, appropriate dosing, and potential toxicity [38–40].

Case Continued

The physician tells the patient that there are several environmental factors that may predispose him to developing CRC. He recommends that the patient follow a healthy lifestyle, including eating 5 servings of fruits and vegetables daily, minimizing consumption of red meats, exercising for 30 minutes at least 5 days per week, drinking only moderate amounts of alcohol, and continuing to take his aspirin in the setting of his diabetes. He also asks the patient if he would be interested in talking about weight loss and working together to make a plan.

The patient is appreciative of this information and wants to know what CRC creening test the physician recommends.

• What screening test should be recommended?

Screening Options

There are several modalities for CRC screening, with current technology falling into 2 general categories: stool tests, which include tests for occult blood or exfoliated DNA; and structural exams, which include flexible sigmoidoscopy, colonoscopy, double-contrast barium enema (DCBE), and computed tomographic (CT) colonography. Stool tests are best suited for the detection of CRC, although they also will deliver positive findings for some advanced adenomas, while the structural exams can achieve both detection and prevention of CRC through identification and removal of adenomatous polyps [41]. These tests may be used alone or in combination to improve sensitivity or, in some instances, to ensure a complete examination of the colon if the initial test cannot be completed.

In principle, all adults should have access to the full range of options for CRC screening, and the availability of lower-cost, less invasive options in most practice settings is a public health advantage [11]. However, the availability of multiple testing options can overwhelm the primary care provider and presents challenges for practices in trying to support an office policy that can manage a broad range of testing choices, their follow-up requirements, and shared decision making related to the options. Shared decision making around CRC screening options is both demanding and time consuming and is complicated by the different characteristics of the tests and the test-specific requirements for individuals undergoing screening [42].

Recommended Tests

The joint guideline on screening for CRC from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology (the MSTF guideline) [11] is of the strong opinion that tests designed to detect early cancer and prevent cancer through the detection and removal of adenomatous polyps (the structural exams) should be encouraged if resources are available and patients are willing to undergo an invasive test [11]. In clinical settings in which economic issues preclude primary screening with colonoscopy, or for patients who decline invasive tests, clinicians may offer stool- based testing. However, providers and patients should understand that these tests are less likely to prevent cancer compared with the invasive tests, they must be repeated at regular intervals to be effective (ie, programmatic sensitivity), and if the test is abnormal, a colonoscopy will be needed to follow up. Therefore, if patients are not willing to have repeated testing or pursue colonoscopy if the test is abnormal, these programs will not be effective and should not be recommended [11].

Stool-Based Testing

Stool blood tests are conventionally known as fecal occult blood tests (FOBT) because they are designed to detect the presence of occult blood in stool. FOBT falls into 2 primary categories based on the detected analyte: guaiac-based and FIT. Blood in the stool is a nonspecific finding but may originate from CRC or larger (> 1 to 2 cm) polyps. Because small adenomatous polyps do not tend to bleed and bleeding from cancers or large polyps may be intermittent or undetectable in a single sample of stool, the proper use of stool blood tests requires annual testing that consists of collecting specimens (2 or 3, depending on the product) from consecutive bowel movements [45–47].

Guaiac-based FOBT

Guaiac-based FOBT (gFOBT) is the most common stool blood test for CRC screening and the only CRC screening test for which there is evidence of efficacy from randomized controlled trials [11]. The usual gFOBT protocol consists of collecting 2 samples from each of 3 consecutive bowel movements at home. Prior to testing with a sensitive guaiac-based test, individuals usually will be instructed to avoid aspirin and other NSAIDs, vitamin C, red meat, poultry, fish, and some raw vegetables because of diet-test interactions that can increase the risk of both false-positive and false-negative (specifically, vitamin C) results [48]. Collection of all 3 samples is important because test sensitivity improves with each additional stool sample [41]. Three large randomized controlled trials with gFOBT have demonstrated that screened patients have cancers detected at an early and more curable stage than unscreened patients. Over time (8 to 13 years), each of the trials demonstrated significant reductions in CRC mortality of 15% to 33% [49–51]. However, the reported sensitivity of a single gFOBT varies considerably [52].

FIT

FIT has several technological advantages when compared with gFOBT. FIT detects human globin, a protein that along with heme constitutes human hemoglobin. Thus, FIT is more specific for human blood than guaiac-based tests, which rely on detection of peroxidase in human blood and also react to the peroxidase that is present in dietary constituents such as rare red meat, cruciferous vegetables, and some fruits [53]. Furthermore, unlike gFOBT, FIT is not subject to false-negative results in the presence of high-dose vitamin C supplements, which block the peroxidase reaction. In addition, because globin is degraded by digestive enzymes in the upper gastrointestinal tract, FIT is also more specific for lower gastrointestinal bleeding, thus improving the specificity for CRC. Finally, the sample collection process for patients for some variants of FIT are less demanding than gFOBT, requiring fewer samples or less direct handling of stool, which may increase FIT’s appeal. Although FIT has superior performance characteristics when compared with older guaiac-based Hemoccult II cards [54–56], the spectrum of benefits, limitations, and harms is similar to a gFOBT with high sensitivity [41]. As for adherence with FIT, there were 10% and 12% gains in adherence with FIT in the first 2 randomized controlled trials comparing FIT with guaiac-based testing [57,58]. Therefore, FIT is preferred over Hemoccult Sensa and is the preferred annual cancer detection test when colonoscopy is not an option [43]. The American College of Gastroenterology supports the joint guideline recommendation [11] that older guaiac-based fecal occult blood testing be abandoned as a method for CRC screening.

sDNA

Fecal DNA testing uses knowledge of molecular genomics and provides the basis of a new method of CRC screening that tests stool for the presence of known DNA alterations in the adenoma-carcinoma sequence of colorectal carcinogenesis [11]. Three different types of fecal DNA testing kits have been evaluated. The sensitivity for cancer in each version was superior to traditional guaiac-based occult blood testing, but the sensitivities ranged from 52%–87%, with the specificities ranging from 82%–95%. Based on the accumulation of evidence since the last update of joint guideline, the joint guideline panel concluded that there now are sufficient data to include sDNA as an acceptable option for CRC screening [11].

As for overall recommendations for stool-based testing, the ACG supports the joint guideline recommendation that older guaiac-based fecal occult blood testing be abandoned as a method for CRC screening. Because of more extensive data (compared with Hemoccult Sensa), and the high cost of fecal DNA testing, the American College of Gastroenterology recommends FIT as the preferred cancer detection test in cases where colonoscopy is not an option [43].

Invasive Tests Other than Colonoscopy

The use of flexible sigmoidoscopy for CRC screening is supported by high-quality case-control and cohort studies [46]. The chief advantage of flexible sigmoidoscopy is that it can be performed with a simple preparation (2 enemas), without sedation, and by a variety of practitioners in diverse settings. The main limitation of the procedure is that it does not examine the entire colon but only the rectum, sigmoid, and descending colon. The effectiveness of a flexible sigmoidoscopy program is based on the assumption that if an adenoma is detected during the procedure, the patient would be referred for colonoscopy to examine the entire colon.

DCBE is an imaging modality which can evaluate the entire colon in almost all cases and can detect most cancers and the majority of significant polyps. However, the lower sensitivity for significant adenomas when compared with colonoscopy may result in less favorable outcomes regarding CRC morbidity and mortality. Double-contrast barium enema is no longer recommended as an alternative CRC prevention test because its use has declined dramatically and also as its effectiveness for polyp detection is less than CT colonography [43].

CT Colonography

CT colonography every 5 years is endorsed as an alternative to colonoscopy every 10 years because of its recent performance in the American College of Imaging Network Trial 6664 (also known as the National CT Colonography Trial) [59]. The principle performance feature that justifies inclusion of CT colonography as a viable alternative in patients who decline colonoscopy is that the sensitivity for polyps ≥ 1 cm in size was 90% in the most recent multicenter US trial [59]. In this study, 25% of radiologists who were tested for entry into the trial but performed poorly were excluded from participation, and thus lower sensitivity might be expected in actual clinical practice. CT colonography probably has a lower risk of perforation than colonoscopy in most settings, but for several reasons it is not considered the equivalent of colonoscopy as a screening strategy. First, the evidence to support an effect of endoscopic screening on prevention of incident CRC and mortality is overwhelming compared with that for CT colonography. Second, the inability of CT colonography to adequately detect polyps 5 mm and smaller, which constitutes 80% of colorectal neoplasms, and whose natural history is still not understood, necessitates performance of the test at 5-year rather than 10-year intervals [43]. Finally, false-positives are common, and the specificity for polyps ≥ 1 cm in size was only 86% in the National CT Colonography Trial, with a positive predictive value of 23% [59]. The American College of Gastroenterology recommends that asymptomatic patients be informed of the possibility of radiation risk associated with one or repeated CT colonography studies, though the exact risk associated with radiation is unclear [60,61].

The value of extracolonic findings detected by CT colonography is mixed, with substantial costs associated with incidental findings, but occasional important extracolonic findings are detected, such as asymptomatic cancers and large abdominal aortic aneurysms. As a final point, the ACG is also concerned about the potential impact of CT colonography on adherence with follow-up colonoscopy and thus on polypectomy rates. Thus, if CT colonography substantially improves adherence, it should improve polypectomy rates and thereby reduce CRC, even if only large polyps are detected and referred for colonoscopy. On the other hand, if CT colonography largely displaces patients who would otherwise be willing to undergo colonoscopy, then polypectomy rates will fall substantially, which could significantly increase the CRC incidence [62]. Thus, for multiple reasons and pending additional study, CT colonography should be offered to patients who decline colonoscopy. It should be noted that CT colonography should only be offered for the purposes of CRC screening and should not be used for diagnostic workup of symptoms (eg, patient with active bleeding or inflammatory bowel disease).

• When should screening begin?

The American College of Gastroenterology continues to recommend that screening begin at age 50 years in average-risk persons (ie, those without a family history of colorectal neoplasia), except for African Americans, in whom it should begin at age 45 years [43]. The USPSTF does not currently provide specific recommendations based on race or ethnicity, but certain other subgroups of the average-risk population might warrant initiation of screening at an earlier or later age, depending on their risk. For example, the incident risk of CRC has been described to be greater in men than women [63]. In reviewing the literature, the writing committee also identified heavy cigarette smoking and obesity as linked to an increased risk of CRC and to the development of CRC at an earlier age.

For patients with a family history of CRC or adenomatous polyps, the 2008 MSTF guideline recommends initiation of screening at age 40 [11]. The American College of Gastroenterology recommendations for screening in patients with a family history are shown in Table 1. From a practical perspective, many clinicians have found that patients are often not aware of whether their first-degree relatives had advanced adenomas vs. small tubular adenomas, or whether their family members had non-neoplastic vs. neoplastic polyps. Given these difficulties, the American College of Gastroenterology now recommends that adenomas only be counted as equal to a family history of cancer when there is a clear history, or medical report containing evidence, or other evidence to indicate that family members had advanced adenomas (an adenoma ≥ 1 cm in size, or with high-grade dysplasia, or with villous elements) [43]. Continuation of the old recommendation to screen first-degree relatives of patients with only small tubular adenomas could result in most of the population being screened at age 40, with doubtful benefit.

• What are screening considerations in patients with genetic syndromes?

Patients with features of an inherited CRC syndrome should be advised to pursue genetic counseling with a licensed genetic counselor and, if appropriate, genetic testing. Individuals with FAP should undergo adenomatous polyposis coli (APC) mutation testing and, if negative, MYH mutation testing. Patients with FAP or at risk of FAP based upon family history should undergo annual colonoscopy until colectomy is deemed by both physician and patient as the best treatment [64]. Patients with a retained rectum after total colectomy and ileorectal anastomosis, ileal pouch, after total proctocolectomy and ileal pouch anal anastomosis, or stoma after total proctocolectomy and end ileostomy, should undergo endoscopic assessment approximately every 6 to 12 months after surgery, depending on the polyp burden seen. Individuals with oligopolyposis (< 100 colorectal polyps) should be sent for genetic counseling, consideration of APC and MYH mutation testing, and individualized colonoscopy surveillance depending on the size, number, and pathology of polyps seen. Upper endoscopic surveillance is recommended in individuals with FAP, but there are no established guidelines for endoscopic surveillance in MAP (MYH-associated polyposis) [43].

Patients who meet the Bethesda criteria for HNPCC [65] can be screened by 2 different mechanisms. One is a DNA-based test for microsatellite instability of either the patient’s or a family member’s tumor. The other mechanism is to assess by immunohistochemical staining for evidence of mismatch repair proteins (eg, MLH1, MSH2, MSH6). In those patients in whom deleterious mutations are found, the affected individual should undergo colonoscopy every 2 years beginning at age 20 to 25 years until age 40 years, then annually thereafter [43]. If genetic testing is negative (ie, no deleterious mutation is found), but the patient is still felt to clinically have Lynch syndrome, then they should still be surveyed in the same way.

Case Continued

The physician recommends colonoscopy as the screening modality as it is the most efficient and accurate way of finding precancerous lesions and the most effective way of preventing CRC by removing precancerous lesions. He also explains that because the patient’s father developed CRC after the age of 60, this does not place the patient in a higher risk category and he can follow screening recommendations for “average-risk” individuals.

Screening

The patient undergoes colonoscopy. Two 5-mm adenomas in the transverse colon are detected and removed.

• When should he have a repeat colonoscopy?

Surveillance Intervals

New data have recently emerged on the risk of interval cancer after colonoscopy. The overall rate of interval cancer is estimated to be 1.1–2.7 per 1000 person-years of follow-up. There are several reasons that may account for why patients develop interval cancers: (1) important lesions may be missed at baseline colonoscopy, (2) adenomas may be incompletely removed at the time of baseline colonoscopy, and (3) interval CRC may be biologically different or more aggressive than prevalent CRC. In order to minimize the risk of interval cancer development, it is important to perform a high-quality baseline screening colonoscopy examination as this is associated with lowering the risk of interval cancer [66]. A high-quality colonoscopy entails completion of the procedure to the cecum (with photodocumentation of the appendiceal orifice and ileocecal valve) with careful inspection of folds including adequate bowel cleanliness and a withdrawal time > 6 minutes.

Baseline Colonoscopy Findings

No Polyps

Several prospective observational studies in different populations have shown that the risk of advanced adenomas within 5 years after negative findings on colonoscopy is low (1.3%–2.4%) relative to the rate on initial screening examination (4%–10%) [68–73]. In these studies, interval cancers were rare within 5 years. A sigmoidoscopy randomized controlled trial performed in the United Kingdom demonstrated a reduction in CRC incidence and mortality at 10 years in patients who received one-time sigmoidoscopy compared with controls—a benefit limited to the distal colon [46]. This is the first randomized study to show the effectiveness of endoscopic screening, an effect that appears to have at least a 10-year duration [74]. Thus, in patients who have a baseline colonoscopic evaluation without any adenomas or polyps and are average-risk individuals, the recommendation for the next examination is in 10 years [66].

Distal Hyperplastic Polyps < 10 mm

There is considerable evidence that patients with only rectal or sigmoid hyperplastic polyps (HPs) appear to represent a low-risk cohort. Studies have focused on whether the finding in the distal colon was a marker of risk for advanced neoplasia elsewhere and most studies show no such relationship [67]. Prior and current evidence suggests that distal HPs <10 mm are benign without neoplastic potential. If the most advanced lesions at baseline colonoscopy are distal HPs <10 mm, the interval for colonoscopic follow-up should be 10 years [66].

1-2 Tubular Adenomas < 10 mm

Prior evidence suggested that patients with low-risk adenomas (<10 mm, no villous histology or high-grade dysplasia) had a lower risk of developing advanced adenomas during follow-up compared with patients with high risk adenomas (≥ 10mm, villous histology or high -grade dysplasia). At that time in 2006, consensus on the task force was that an interval of 5 years would be acceptable in this low-risk group [75]. Data published since 2006 endorse the assessment that patients with 1–2 tubular adenomas with low-grade dysplasia <10 mm represent a low-risk group. Three new studies suggest that this group may have only a small, nonsignificant increase in risk of advanced neoplasia within 5 years compared with individuals with no baseline neoplasia. The evidence now supports a surveillance interval of longer than 5 years for most patients and can be extended to 10 years based on the quality of the preparation and colonoscopy [66].

3–10 Tubular Adenomas

Two independent meta-analyses in 2006 found that patients with 3 or more adenomas at baseline had an increased RR for adenomas during surveillance, ranging from 1.7 to 4.8 [47,75]. New information from the VA study and the National Cancer Institute Pooling Project also support these prior findings. Patients with 3 or more adenomas have a level of risk for advanced neoplasia similar to other patients with advanced neoplasia (adenoma >10 mm, adenoma with high grade dysplasia) and thus, repeat examination should be performed in 3 years [66,68,76].

> 10 Adenomas

Only a small proportion of patients undergoing screening colonoscopy will have >10 adenomas. The 2006 guidelines for colonoscopy surveillance after polypectomy noted that such patients should be considered for evaluation of hereditary CRC syndromes [67]. Early follow-up surveillance colonoscopy is based on clinical judgment because there is little evidence to support a firm recommendation. At present, the recommendation is to consider follow-up in less than 3 years after a baseline colonoscopy [66].

1 or More Tubular Adenomas ≥ 10mm

The 2006 MSTF guideline reviewed data related to adenoma size, demonstrating that most studies showed a 2- to 5-fold increased risk of advanced neoplasia during follow-up if the baseline examination had one or more adenomas ≥ 10 mm [67]. Newer, additional data shows that patients with one or more adenomas ≥ 10 mm have an increased risk of advanced neoplasia during surveillance compared with those with no neoplasia or small (< 10 mm) adenomas [68,76]. Thus, the recommendations remains that repeat examination should be performed in 3 years [66]. If there is question about complete removal of an adenoma (ie, piecemeal resection), early follow-up colonoscopy is warranted [66].

1 or More Villous Adenomas

The 2006 MSTF guideline considers adenomas with villous histology to be high risk [67]. The NCI Pooling Project analyzed polyp histology as a risk factor for development of interval advanced neoplasia. Compared with patients with tubular adenomas, those with baseline polyp(s) showing adenomas with villous or tubulovillous histology (TVA) had increased risk of advanced neoplasia during follow-up (16.8% vs 9.7%; adjusted OR, 1.28; 95% CI, 1.07–1.52) [76]. Patients with one or more adenomas with villous histology were also found to have an increased risk of advanced neoplasia during surveillance compared with those with no neoplasia or small (<10 mm) tubular adenomas. Thus, the recommendation remains that repeat examination should be performed in 3 years [66].

Adenoma with High-Grade Dysplasia (HGD)

The 2006 MSTF guideline concluded that the presence of HGD in an adenoma was associated with both villous histology and larger size, which are both risk factors for advanced neoplasia during surveillance [67]. In a univariate analysis from the NCI Pooling Project, HGD was strongly associated with risk of advanced neoplasia during surveillance (OR, 1.77; 95% CI, 1.41–2.22) [76]. Thus, the recommendation remains that repeat examination should be performed in 3 years [66].

Serrated Lesions

A total of 20% to 30% of CRCs arise through a molecular pathway characterized by hypermethylation of genes, known as CgG Island Methylator Phenotype (CIMP) [77]. Precursors are believed to be serrated polyps. Tumors in this pathway have a high frequency of BRAF mutation, and up to 50% are microsatellite unstable. CIMP-positive tumors are overrepresented in interval cancers, particularly in the proximal colon. The principal precursor of hypermethylated cancers is probably the sessile serrated polyp (synonymous with sessile serrated adenoma). These polyps are difficult to detect at endoscopy. They may be the same color as surrounding colonic mucosa, have indiscrete edges, are nearly always flat or sessile, and may have a layer of adherent mucus and obscure the vascular pattern.

Recent studies show that proximal colon location or size ≥ 10 mm may be markers of risk for synchronous advanced adenomas elsewhere in the colon [78,79]. Surveillance after colonoscopy was evaluated in one study, which found that coexisting serrated polyps and high-risk adenomas (HRA; ie, size ≥ 10 mm, villous histology, or presence of HGD) is associated with a higher risk of advanced neoplasia at surveillance [78]. This study also found that if small proximal serrated polyps are the only finding at baseline, the risk of adenomas during surveillance is similar to that of patients with low-risk adenomas (LRA; ie, 1–2 small adenomas).

The current evidence suggests that size (>10 mm), histology (a sessile serrated polyp is a more significant lesion than an HP; a sessile serrated polyp with cytological dysplasia is more advanced than a sessile serrated polyp without dysplasia), and location (proximal to the sigmoid colon) are risk factors that might be associated with higher risk of CRC. A sessile serrated polyp ≥ 10 mm and a sessile serrated polyp with cytological dysplasia should be managed like a HRA with repeat colonoscopy occurring in 3 years. Serrated polyps that are <10 mm in size and do not have cytological dysplasia may have lower risk and can be managed like LRA with repeat colonoscopy occurring in 5 years [66].

Follow-up After Surveillance

In a 2009 study, 564 participants underwent 2 surveillance colonoscopies after an index procedure and 10.3% had high-risk findings at the third study examination. If the second examination showed high-risk findings, then results from the first examination added no significant information about the probability of high-risk findings on the third examination (18.2% for high-risk findings on the first examination vs. 20.0% for low-risk findings on the first examination; P = 0.78). If the second examination showed no adenomas, then the results from the first examination added significant information about the probability of high-risk findings on the third exam-ination (12.3% if the first examination had high-risk findings vs. 4.9% if the first examination had low-risk findings; P = 0.015) [80]. Thus, information from 2 previous colonoscopies appears to be helpful in defining the risk of neoplasia for individual patients and in the future, guidelines might consider accounting for the results of 2 exams to tailor surveillance intervals for patients.

• When should screening / surveillance be stopped?

There is considerable new evidence that the risks of colonoscopy increase with advancing age [81,82]. Neither surveillance nor screening colonoscopy should be performed when the risk of the preparation, sedation, or procedure outweighs the potential benefit. For patients aged 75–85 years, the USPSTF recommends against routine screening but argues for individualization based on comorbidities and findings on any prior colonoscopy. The USPSTF recommends against continued screening after age 85 years because risk could exceed potential benefit [44].

In terms of surveillance of prior adenomas, the 75-85 year age group may still benefit from surveillance because patients with prior HRA are at higher risk for developing advanced neoplasia compared with average-risk screenees. However, the decision to continue surveillance in this population should be individualized and based on an assessment of benefit and risk in the context of the person’s estimated life expectancy [66]. More importantly, it should be noted that an individual’s most important and impactful screening colonoscopy is his or her first one and therefore, from a public health standpoint, great effort should be taken to increase the number of people in a population who undergo screening rather than simply targeting those who need surveillance for prior polyps. This is ever true in settings with limited resources.

Case Conclusion

The physician discusses the findings from the colonoscopy (2 small adenomas) with the patient and recommends a repeat colonoscopy in 5 to 10 years.

Summary

Colorectal cancer is one of the leading causes of cancer-related death in the United States. Since the advent of colonoscopy and the implementation of CRC screening efforts, the rates of CRC have started to decline. There are several environmental factors which have been associated with the development of CRC including obesity, dietary intake, physical activity and smoking. At present, there are multiple tools available for CRC prevention, but the most accurate and effective method is currently colonoscopy. Stool-based tests like FIT should be offered when a patient declines colonoscopy. For those interested in colonoscopy, average-risk individuals should be screened starting at the age of 50 with subsequent examinations every 10 years. Surveillance examinations should occur based on polyp findings on index colonoscopy. There is no recommendation to continue screening after the age of 75, though physicians can determine this based on patients health and risk/benefit profile. Current guidelines recommend against offering any screening to patients over the age of 85. Despite these recommendations, almost half of the eligible screening population has yet to undergo appropriate CRC screening. Future work should include public health efforts to improve access and appeal of widespread CRC screening regardless of modality. While colonoscopy is considered the most effective screening test, the best test is still the one the patient gets.

Corresponding author: Audrey H. Calderwood, MD, MS, 85 E. Concord St., Rm. 7724, Boston, MA 02118, [email protected].

Financial disclosures: None.

From the Boston University School of Medicine, Boston, MA.

Abstract

• Objective: To review recommendations for colorectal cancer (CRC) screening.
• Methods: Review of the literature.
• Results: In the United States, CRC is the third most commonly diagnosed cancer and the third leading cause of cancer death. CRC screening can reduce mortality through the detection of early-stage disease and the detection and removal of adenomatous polyps. There are several modalities for CRC screening, with current technology falling into 2 general categories: stool tests, which include tests for occult blood or exfoliated DNA; and structural exams, which include flexible sigmoidoscopy, colonoscopy, double-contrast barium enema, and CT colonography. The preferred CRC prevention test for average-risk individuals is colonoscopy starting at age 50 with subsequent examinations every 10 years. Patients unwilling to undergo screening colonoscopy may be offered flexible sigmoidoscopy, CT colonography, or fecal immunohistochemical test. Surveillance examinations should occur based on polyp findings on index colonoscopy. There is no recommendation to continue screening after age 75, though physicians can make a determination based on a patient’s health and risk/benefit profile. Current guidelines recommend against offering screening to patients over age 85.
• Conclusion: Increasing access to and utilization of CRC screening tests is likely to lead to improvements in mortality reduction, as only about half of people aged 50 or older report having received CRC testing consistent with current guidelines.

In the United States, colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death in both men and women [1]. In 2014, an estimated 136,830 people were diagnosed with CRC and about 50,310 people died of the disease [2]. Colorectal cancer usually develops slowly over a period of 10 to 15 years. The tumor typically begins as a noncancerous polyp, classically an adenomatous polyp or adenoma, though fewer than 10% of adenomas will progress to cancer [3]. Adenomas are common; an estimated one-third to one-half of all individuals will eventually develop 1 or more adenomas [4,5]. In the United States, the lifetime risk of being diagnosed with CRC is approximately 5% for both men and women [6]. Incidence rates for CRC increase with age, with an incidence rate more than 15 times higher in adults aged 50 years and older compared with those aged 20 to 49 years [7].

Certain demographic subgroups have been shown to be at higher risk. Overall, CRC incidence and mortality rates are about 35% to 40% higher in men than in women. The reasons for this are not completely understood but likely reflect complex interactions between gender-related differences in exposure to hormones and risk factors [8]. CRC incidence and mortality rates are highest in African-American men and women; incidence rates are 20% higher and mortality rates are about 45% higher than those in whites. Prior to 1989, incidence rates were predominantly higher in white men than in African American men and were similar for women of both races. Since that time, although incidence rates have declined as a whole [9], incidence rates have been higher for African Americans than whites in both men and women This crossover likely reflects a combination of greater access to and utilization of recommended screening tests among whites (resulting in detection and removal of precancerous polyps), as well as racial differences in trends for CRC risk factors [10].

CRC screening can reduce mortality through the detection of early-stage disease and the detection and removal of ademomatous polyps [11]. Increasing access to and utilization of CRC screening tests is likely to lead to improvements in mortality reduction, as only about half of people aged 50 or older report having received CRC testing consistent with current guidelines [1].

Case Study

Initial Presentation

A 55-year-old white male presents for a routine visit and asks about colon cancer screening. His father was diagnosed with colon cancer at the age of 78. Overall, he feels well and does not have any particular complaints. His bowel habits are normal and he denies melena and hematochezia. His past medical history is significant for diabetes, hypertension, and obesity. He was a previous smoker and has a few alcoholic drinks on the weekends. His physical exam is unremarkable. Results of recent blood work are normal and there is no evidence of anemia.

• What are this patient’s risk factors for developing colon cancer?

Risk Factors for CRC

There are numerous factors that are thought to influence risk for CRC. Nonmodifiable risk factors include a personal or family history of CRC or adenomatous polyps, and a personal history of chronic inflammatory bowel disease. Modifiable risk factors that have been associated with an increased risk of CRC in epidemiologic studies include physical inactivity, obesity, high consumption of red or processed meats, smoking, and moderate-to-heavy alcohol consumption. In fact, a prospective study showed that up to 23% of colorectal cancers were considered to be potentially avoidable by adhering to multiple healthy lifestyle recommendations including maintaining a healthy weight, being physically active at least 30 minutes per day, eating a healthy diet, and avoiding smoking and drinking excessive amounts of alcohol [12].

People with a first-degree relative (parent, sibling, or offspring) who has had CRC have 2 to 3 times the risk of developing the disease compared with individuals with no family history; if the relative was diagnosed at a young age or if there is more than 1 affected relative, risk increases to 3 to 6 times that of the general population [13,14]. About 5% of patients with CRC have a well-defined genetic syndrome that causes the disease [15]. The most common of these is Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC), which accounts for 2% to 4% of all CRC cases [16]. Although individuals with Lynch syndrome are predisposed to numerous types of cancer, risk of CRC is highest. A recent study of CRC in 147 Lynch syndrome families in the United States found lifetime risk of CRC to be 66% in men and 43% in women, with a median age at diagnosis of 42 years and 47 years, respectively [17]. Familial adenomatous polyposis (FAP) is the second most common predisposing genetic syndrome; for these individuals, the lifetime risk of CRC approaches 100% without intervention (eg, colectomy) [16].

People who have inflammatory bowel disease of the colon (both ulcerative colitis and Crohn’s disease) have an increased risk of developing CRC that correlates with the extent and the duration of the inflammation [18]. It is estimated that 18% of patients with a 30-year history of ulcerative colitis will develop CRC [19]. In addition, several studies have found an association between diabetes and increased risk of CRC [20,21]. Though adult-onset type 2 diabetes (the most common type) and CRC share similar risk factors, including physical inactivity and obesity, a positive association between diabetes and CRC has been found even after accounting for physical activity, body mass index, and waist circumference [22].

Being overweight or obese is also associated with a higher risk of CRC, with stronger associations more consistently observed in men than in women. Obesity increases the risk of CRC independent of physical activity. Abdominal obesity (measured by waist circumference) may be a more important risk factor for colon cancer than overall obesity in both men and women [23–25]. Diet and lifestyle strongly influence CRC risk; however, research on the role of specific dietary elements on CRC risk is still accumulating. Several studies, including one by the American Cancer Society, have found that high consumption of red and/or processed meat increases the risk of both colon and rectal cancer [23,26,27]. Further analyses indicate that the association between CRC and red meat may be related to the cooking process, because a higher risk of CRC is observed particularly among those individuals who consume meat that has been cooked at a high temperature for a long period of time [28]. In contrast to findings from earlier research, more recent large, prospective studies do not indicate a major relationship between CRC and vegetable, fruit, or fiber consumption [28,29]. However, some studies suggest that people with very low fruit and vegetable intake are at above-average risk for CRC [30,31]. Consumption of milk and calcium may decrease the risk of developing CRC [28,29,32].

In November 2009, the International Agency for Research on Cancer reported that there is now sufficient evidence to conclude that tobacco smoking causes CRC [33]. Colorectal cancer has been linked to even moderate alcohol use. Individuals who have a lifetime average of 2 to 4 alcoholic drinks per day have a 23% higher risk of CRC than those who consume less than 1 drink per day [34].

Protective Factors

One of the most consistently reported relationships between colon cancer risk and behavior is the protective effect of physical activity [35]. Based on these findings, as well as the numerous other health benefits of regular physical activity, the American Cancer Society recommends engaging in at least moderate activity for 30 minutes or more on 5 or more days per week.

Accumulating research suggests that aspirin-like drugs, postmenopausal hormones, and calcium supplements may help prevent CRC. Extensive evidence suggests that long-term, regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is asso-ciated with lower risk of CRC. The American Cancer Society does not currently recommend use of these drugs as chemoprevention because of the potential side effects of gastrointestinal bleeding from aspirin and other traditional NSAIDs and heart attacks from selective cyclooxygenase-2 (COX-2) inhibitors. However, people who are already taking NSAIDs for chronic arthritis or aspirin for heart disease prevention may have a lower risk of CRC as a positive side effect [36,37].

There is substantial evidence that women who use postmenopausal hormones have lower rates of CRC than those who do not. A decreased risk of CRC is especially evident in women who use hormones long-term, although the risk returns to that of nonusers within 3 years of cessation. Despite its positive effect on CRC risk, the use of postmenopausal hormones increases the risk of breast and other cancers as well as cardiovascular disease, and therefore it is not recommended for the prevention of CRC. At present, the American Cancer Society does not recommend any medications or supplements to prevent CRC because of uncertainties about their effectiveness, appropriate dosing, and potential toxicity [38–40].

Case Continued

The physician tells the patient that there are several environmental factors that may predispose him to developing CRC. He recommends that the patient follow a healthy lifestyle, including eating 5 servings of fruits and vegetables daily, minimizing consumption of red meats, exercising for 30 minutes at least 5 days per week, drinking only moderate amounts of alcohol, and continuing to take his aspirin in the setting of his diabetes. He also asks the patient if he would be interested in talking about weight loss and working together to make a plan.

The patient is appreciative of this information and wants to know what CRC creening test the physician recommends.

• What screening test should be recommended?

Screening Options

There are several modalities for CRC screening, with current technology falling into 2 general categories: stool tests, which include tests for occult blood or exfoliated DNA; and structural exams, which include flexible sigmoidoscopy, colonoscopy, double-contrast barium enema (DCBE), and computed tomographic (CT) colonography. Stool tests are best suited for the detection of CRC, although they also will deliver positive findings for some advanced adenomas, while the structural exams can achieve both detection and prevention of CRC through identification and removal of adenomatous polyps [41]. These tests may be used alone or in combination to improve sensitivity or, in some instances, to ensure a complete examination of the colon if the initial test cannot be completed.

In principle, all adults should have access to the full range of options for CRC screening, and the availability of lower-cost, less invasive options in most practice settings is a public health advantage [11]. However, the availability of multiple testing options can overwhelm the primary care provider and presents challenges for practices in trying to support an office policy that can manage a broad range of testing choices, their follow-up requirements, and shared decision making related to the options. Shared decision making around CRC screening options is both demanding and time consuming and is complicated by the different characteristics of the tests and the test-specific requirements for individuals undergoing screening [42].

Recommended Tests

The joint guideline on screening for CRC from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology (the MSTF guideline) [11] is of the strong opinion that tests designed to detect early cancer and prevent cancer through the detection and removal of adenomatous polyps (the structural exams) should be encouraged if resources are available and patients are willing to undergo an invasive test [11]. In clinical settings in which economic issues preclude primary screening with colonoscopy, or for patients who decline invasive tests, clinicians may offer stool- based testing. However, providers and patients should understand that these tests are less likely to prevent cancer compared with the invasive tests, they must be repeated at regular intervals to be effective (ie, programmatic sensitivity), and if the test is abnormal, a colonoscopy will be needed to follow up. Therefore, if patients are not willing to have repeated testing or pursue colonoscopy if the test is abnormal, these programs will not be effective and should not be recommended [11].

Stool-Based Testing

Stool blood tests are conventionally known as fecal occult blood tests (FOBT) because they are designed to detect the presence of occult blood in stool. FOBT falls into 2 primary categories based on the detected analyte: guaiac-based and FIT. Blood in the stool is a nonspecific finding but may originate from CRC or larger (> 1 to 2 cm) polyps. Because small adenomatous polyps do not tend to bleed and bleeding from cancers or large polyps may be intermittent or undetectable in a single sample of stool, the proper use of stool blood tests requires annual testing that consists of collecting specimens (2 or 3, depending on the product) from consecutive bowel movements [45–47].

Guaiac-based FOBT

Guaiac-based FOBT (gFOBT) is the most common stool blood test for CRC screening and the only CRC screening test for which there is evidence of efficacy from randomized controlled trials [11]. The usual gFOBT protocol consists of collecting 2 samples from each of 3 consecutive bowel movements at home. Prior to testing with a sensitive guaiac-based test, individuals usually will be instructed to avoid aspirin and other NSAIDs, vitamin C, red meat, poultry, fish, and some raw vegetables because of diet-test interactions that can increase the risk of both false-positive and false-negative (specifically, vitamin C) results [48]. Collection of all 3 samples is important because test sensitivity improves with each additional stool sample [41]. Three large randomized controlled trials with gFOBT have demonstrated that screened patients have cancers detected at an early and more curable stage than unscreened patients. Over time (8 to 13 years), each of the trials demonstrated significant reductions in CRC mortality of 15% to 33% [49–51]. However, the reported sensitivity of a single gFOBT varies considerably [52].

FIT

FIT has several technological advantages when compared with gFOBT. FIT detects human globin, a protein that along with heme constitutes human hemoglobin. Thus, FIT is more specific for human blood than guaiac-based tests, which rely on detection of peroxidase in human blood and also react to the peroxidase that is present in dietary constituents such as rare red meat, cruciferous vegetables, and some fruits [53]. Furthermore, unlike gFOBT, FIT is not subject to false-negative results in the presence of high-dose vitamin C supplements, which block the peroxidase reaction. In addition, because globin is degraded by digestive enzymes in the upper gastrointestinal tract, FIT is also more specific for lower gastrointestinal bleeding, thus improving the specificity for CRC. Finally, the sample collection process for patients for some variants of FIT are less demanding than gFOBT, requiring fewer samples or less direct handling of stool, which may increase FIT’s appeal. Although FIT has superior performance characteristics when compared with older guaiac-based Hemoccult II cards [54–56], the spectrum of benefits, limitations, and harms is similar to a gFOBT with high sensitivity [41]. As for adherence with FIT, there were 10% and 12% gains in adherence with FIT in the first 2 randomized controlled trials comparing FIT with guaiac-based testing [57,58]. Therefore, FIT is preferred over Hemoccult Sensa and is the preferred annual cancer detection test when colonoscopy is not an option [43]. The American College of Gastroenterology supports the joint guideline recommendation [11] that older guaiac-based fecal occult blood testing be abandoned as a method for CRC screening.

sDNA

Fecal DNA testing uses knowledge of molecular genomics and provides the basis of a new method of CRC screening that tests stool for the presence of known DNA alterations in the adenoma-carcinoma sequence of colorectal carcinogenesis [11]. Three different types of fecal DNA testing kits have been evaluated. The sensitivity for cancer in each version was superior to traditional guaiac-based occult blood testing, but the sensitivities ranged from 52%–87%, with the specificities ranging from 82%–95%. Based on the accumulation of evidence since the last update of joint guideline, the joint guideline panel concluded that there now are sufficient data to include sDNA as an acceptable option for CRC screening [11].

As for overall recommendations for stool-based testing, the ACG supports the joint guideline recommendation that older guaiac-based fecal occult blood testing be abandoned as a method for CRC screening. Because of more extensive data (compared with Hemoccult Sensa), and the high cost of fecal DNA testing, the American College of Gastroenterology recommends FIT as the preferred cancer detection test in cases where colonoscopy is not an option [43].

Invasive Tests Other than Colonoscopy

The use of flexible sigmoidoscopy for CRC screening is supported by high-quality case-control and cohort studies [46]. The chief advantage of flexible sigmoidoscopy is that it can be performed with a simple preparation (2 enemas), without sedation, and by a variety of practitioners in diverse settings. The main limitation of the procedure is that it does not examine the entire colon but only the rectum, sigmoid, and descending colon. The effectiveness of a flexible sigmoidoscopy program is based on the assumption that if an adenoma is detected during the procedure, the patient would be referred for colonoscopy to examine the entire colon.

DCBE is an imaging modality which can evaluate the entire colon in almost all cases and can detect most cancers and the majority of significant polyps. However, the lower sensitivity for significant adenomas when compared with colonoscopy may result in less favorable outcomes regarding CRC morbidity and mortality. Double-contrast barium enema is no longer recommended as an alternative CRC prevention test because its use has declined dramatically and also as its effectiveness for polyp detection is less than CT colonography [43].

CT Colonography

CT colonography every 5 years is endorsed as an alternative to colonoscopy every 10 years because of its recent performance in the American College of Imaging Network Trial 6664 (also known as the National CT Colonography Trial) [59]. The principle performance feature that justifies inclusion of CT colonography as a viable alternative in patients who decline colonoscopy is that the sensitivity for polyps ≥ 1 cm in size was 90% in the most recent multicenter US trial [59]. In this study, 25% of radiologists who were tested for entry into the trial but performed poorly were excluded from participation, and thus lower sensitivity might be expected in actual clinical practice. CT colonography probably has a lower risk of perforation than colonoscopy in most settings, but for several reasons it is not considered the equivalent of colonoscopy as a screening strategy. First, the evidence to support an effect of endoscopic screening on prevention of incident CRC and mortality is overwhelming compared with that for CT colonography. Second, the inability of CT colonography to adequately detect polyps 5 mm and smaller, which constitutes 80% of colorectal neoplasms, and whose natural history is still not understood, necessitates performance of the test at 5-year rather than 10-year intervals [43]. Finally, false-positives are common, and the specificity for polyps ≥ 1 cm in size was only 86% in the National CT Colonography Trial, with a positive predictive value of 23% [59]. The American College of Gastroenterology recommends that asymptomatic patients be informed of the possibility of radiation risk associated with one or repeated CT colonography studies, though the exact risk associated with radiation is unclear [60,61].

The value of extracolonic findings detected by CT colonography is mixed, with substantial costs associated with incidental findings, but occasional important extracolonic findings are detected, such as asymptomatic cancers and large abdominal aortic aneurysms. As a final point, the ACG is also concerned about the potential impact of CT colonography on adherence with follow-up colonoscopy and thus on polypectomy rates. Thus, if CT colonography substantially improves adherence, it should improve polypectomy rates and thereby reduce CRC, even if only large polyps are detected and referred for colonoscopy. On the other hand, if CT colonography largely displaces patients who would otherwise be willing to undergo colonoscopy, then polypectomy rates will fall substantially, which could significantly increase the CRC incidence [62]. Thus, for multiple reasons and pending additional study, CT colonography should be offered to patients who decline colonoscopy. It should be noted that CT colonography should only be offered for the purposes of CRC screening and should not be used for diagnostic workup of symptoms (eg, patient with active bleeding or inflammatory bowel disease).

• When should screening begin?

The American College of Gastroenterology continues to recommend that screening begin at age 50 years in average-risk persons (ie, those without a family history of colorectal neoplasia), except for African Americans, in whom it should begin at age 45 years [43]. The USPSTF does not currently provide specific recommendations based on race or ethnicity, but certain other subgroups of the average-risk population might warrant initiation of screening at an earlier or later age, depending on their risk. For example, the incident risk of CRC has been described to be greater in men than women [63]. In reviewing the literature, the writing committee also identified heavy cigarette smoking and obesity as linked to an increased risk of CRC and to the development of CRC at an earlier age.

For patients with a family history of CRC or adenomatous polyps, the 2008 MSTF guideline recommends initiation of screening at age 40 [11]. The American College of Gastroenterology recommendations for screening in patients with a family history are shown in Table 1. From a practical perspective, many clinicians have found that patients are often not aware of whether their first-degree relatives had advanced adenomas vs. small tubular adenomas, or whether their family members had non-neoplastic vs. neoplastic polyps. Given these difficulties, the American College of Gastroenterology now recommends that adenomas only be counted as equal to a family history of cancer when there is a clear history, or medical report containing evidence, or other evidence to indicate that family members had advanced adenomas (an adenoma ≥ 1 cm in size, or with high-grade dysplasia, or with villous elements) [43]. Continuation of the old recommendation to screen first-degree relatives of patients with only small tubular adenomas could result in most of the population being screened at age 40, with doubtful benefit.

• What are screening considerations in patients with genetic syndromes?

Patients with features of an inherited CRC syndrome should be advised to pursue genetic counseling with a licensed genetic counselor and, if appropriate, genetic testing. Individuals with FAP should undergo adenomatous polyposis coli (APC) mutation testing and, if negative, MYH mutation testing. Patients with FAP or at risk of FAP based upon family history should undergo annual colonoscopy until colectomy is deemed by both physician and patient as the best treatment [64]. Patients with a retained rectum after total colectomy and ileorectal anastomosis, ileal pouch, after total proctocolectomy and ileal pouch anal anastomosis, or stoma after total proctocolectomy and end ileostomy, should undergo endoscopic assessment approximately every 6 to 12 months after surgery, depending on the polyp burden seen. Individuals with oligopolyposis (< 100 colorectal polyps) should be sent for genetic counseling, consideration of APC and MYH mutation testing, and individualized colonoscopy surveillance depending on the size, number, and pathology of polyps seen. Upper endoscopic surveillance is recommended in individuals with FAP, but there are no established guidelines for endoscopic surveillance in MAP (MYH-associated polyposis) [43].

Patients who meet the Bethesda criteria for HNPCC [65] can be screened by 2 different mechanisms. One is a DNA-based test for microsatellite instability of either the patient’s or a family member’s tumor. The other mechanism is to assess by immunohistochemical staining for evidence of mismatch repair proteins (eg, MLH1, MSH2, MSH6). In those patients in whom deleterious mutations are found, the affected individual should undergo colonoscopy every 2 years beginning at age 20 to 25 years until age 40 years, then annually thereafter [43]. If genetic testing is negative (ie, no deleterious mutation is found), but the patient is still felt to clinically have Lynch syndrome, then they should still be surveyed in the same way.

Case Continued

The physician recommends colonoscopy as the screening modality as it is the most efficient and accurate way of finding precancerous lesions and the most effective way of preventing CRC by removing precancerous lesions. He also explains that because the patient’s father developed CRC after the age of 60, this does not place the patient in a higher risk category and he can follow screening recommendations for “average-risk” individuals.

Screening

The patient undergoes colonoscopy. Two 5-mm adenomas in the transverse colon are detected and removed.

• When should he have a repeat colonoscopy?

Surveillance Intervals

New data have recently emerged on the risk of interval cancer after colonoscopy. The overall rate of interval cancer is estimated to be 1.1–2.7 per 1000 person-years of follow-up. There are several reasons that may account for why patients develop interval cancers: (1) important lesions may be missed at baseline colonoscopy, (2) adenomas may be incompletely removed at the time of baseline colonoscopy, and (3) interval CRC may be biologically different or more aggressive than prevalent CRC. In order to minimize the risk of interval cancer development, it is important to perform a high-quality baseline screening colonoscopy examination as this is associated with lowering the risk of interval cancer [66]. A high-quality colonoscopy entails completion of the procedure to the cecum (with photodocumentation of the appendiceal orifice and ileocecal valve) with careful inspection of folds including adequate bowel cleanliness and a withdrawal time > 6 minutes.

Baseline Colonoscopy Findings

No Polyps

Several prospective observational studies in different populations have shown that the risk of advanced adenomas within 5 years after negative findings on colonoscopy is low (1.3%–2.4%) relative to the rate on initial screening examination (4%–10%) [68–73]. In these studies, interval cancers were rare within 5 years. A sigmoidoscopy randomized controlled trial performed in the United Kingdom demonstrated a reduction in CRC incidence and mortality at 10 years in patients who received one-time sigmoidoscopy compared with controls—a benefit limited to the distal colon [46]. This is the first randomized study to show the effectiveness of endoscopic screening, an effect that appears to have at least a 10-year duration [74]. Thus, in patients who have a baseline colonoscopic evaluation without any adenomas or polyps and are average-risk individuals, the recommendation for the next examination is in 10 years [66].

Distal Hyperplastic Polyps < 10 mm

There is considerable evidence that patients with only rectal or sigmoid hyperplastic polyps (HPs) appear to represent a low-risk cohort. Studies have focused on whether the finding in the distal colon was a marker of risk for advanced neoplasia elsewhere and most studies show no such relationship [67]. Prior and current evidence suggests that distal HPs <10 mm are benign without neoplastic potential. If the most advanced lesions at baseline colonoscopy are distal HPs <10 mm, the interval for colonoscopic follow-up should be 10 years [66].

1-2 Tubular Adenomas < 10 mm

Prior evidence suggested that patients with low-risk adenomas (<10 mm, no villous histology or high-grade dysplasia) had a lower risk of developing advanced adenomas during follow-up compared with patients with high risk adenomas (≥ 10mm, villous histology or high -grade dysplasia). At that time in 2006, consensus on the task force was that an interval of 5 years would be acceptable in this low-risk group [75]. Data published since 2006 endorse the assessment that patients with 1–2 tubular adenomas with low-grade dysplasia <10 mm represent a low-risk group. Three new studies suggest that this group may have only a small, nonsignificant increase in risk of advanced neoplasia within 5 years compared with individuals with no baseline neoplasia. The evidence now supports a surveillance interval of longer than 5 years for most patients and can be extended to 10 years based on the quality of the preparation and colonoscopy [66].

3–10 Tubular Adenomas

Two independent meta-analyses in 2006 found that patients with 3 or more adenomas at baseline had an increased RR for adenomas during surveillance, ranging from 1.7 to 4.8 [47,75]. New information from the VA study and the National Cancer Institute Pooling Project also support these prior findings. Patients with 3 or more adenomas have a level of risk for advanced neoplasia similar to other patients with advanced neoplasia (adenoma >10 mm, adenoma with high grade dysplasia) and thus, repeat examination should be performed in 3 years [66,68,76].

> 10 Adenomas

Only a small proportion of patients undergoing screening colonoscopy will have >10 adenomas. The 2006 guidelines for colonoscopy surveillance after polypectomy noted that such patients should be considered for evaluation of hereditary CRC syndromes [67]. Early follow-up surveillance colonoscopy is based on clinical judgment because there is little evidence to support a firm recommendation. At present, the recommendation is to consider follow-up in less than 3 years after a baseline colonoscopy [66].

1 or More Tubular Adenomas ≥ 10mm

The 2006 MSTF guideline reviewed data related to adenoma size, demonstrating that most studies showed a 2- to 5-fold increased risk of advanced neoplasia during follow-up if the baseline examination had one or more adenomas ≥ 10 mm [67]. Newer, additional data shows that patients with one or more adenomas ≥ 10 mm have an increased risk of advanced neoplasia during surveillance compared with those with no neoplasia or small (< 10 mm) adenomas [68,76]. Thus, the recommendations remains that repeat examination should be performed in 3 years [66]. If there is question about complete removal of an adenoma (ie, piecemeal resection), early follow-up colonoscopy is warranted [66].

1 or More Villous Adenomas

The 2006 MSTF guideline considers adenomas with villous histology to be high risk [67]. The NCI Pooling Project analyzed polyp histology as a risk factor for development of interval advanced neoplasia. Compared with patients with tubular adenomas, those with baseline polyp(s) showing adenomas with villous or tubulovillous histology (TVA) had increased risk of advanced neoplasia during follow-up (16.8% vs 9.7%; adjusted OR, 1.28; 95% CI, 1.07–1.52) [76]. Patients with one or more adenomas with villous histology were also found to have an increased risk of advanced neoplasia during surveillance compared with those with no neoplasia or small (<10 mm) tubular adenomas. Thus, the recommendation remains that repeat examination should be performed in 3 years [66].

Adenoma with High-Grade Dysplasia (HGD)

The 2006 MSTF guideline concluded that the presence of HGD in an adenoma was associated with both villous histology and larger size, which are both risk factors for advanced neoplasia during surveillance [67]. In a univariate analysis from the NCI Pooling Project, HGD was strongly associated with risk of advanced neoplasia during surveillance (OR, 1.77; 95% CI, 1.41–2.22) [76]. Thus, the recommendation remains that repeat examination should be performed in 3 years [66].

Serrated Lesions

A total of 20% to 30% of CRCs arise through a molecular pathway characterized by hypermethylation of genes, known as CgG Island Methylator Phenotype (CIMP) [77]. Precursors are believed to be serrated polyps. Tumors in this pathway have a high frequency of BRAF mutation, and up to 50% are microsatellite unstable. CIMP-positive tumors are overrepresented in interval cancers, particularly in the proximal colon. The principal precursor of hypermethylated cancers is probably the sessile serrated polyp (synonymous with sessile serrated adenoma). These polyps are difficult to detect at endoscopy. They may be the same color as surrounding colonic mucosa, have indiscrete edges, are nearly always flat or sessile, and may have a layer of adherent mucus and obscure the vascular pattern.

Recent studies show that proximal colon location or size ≥ 10 mm may be markers of risk for synchronous advanced adenomas elsewhere in the colon [78,79]. Surveillance after colonoscopy was evaluated in one study, which found that coexisting serrated polyps and high-risk adenomas (HRA; ie, size ≥ 10 mm, villous histology, or presence of HGD) is associated with a higher risk of advanced neoplasia at surveillance [78]. This study also found that if small proximal serrated polyps are the only finding at baseline, the risk of adenomas during surveillance is similar to that of patients with low-risk adenomas (LRA; ie, 1–2 small adenomas).

The current evidence suggests that size (>10 mm), histology (a sessile serrated polyp is a more significant lesion than an HP; a sessile serrated polyp with cytological dysplasia is more advanced than a sessile serrated polyp without dysplasia), and location (proximal to the sigmoid colon) are risk factors that might be associated with higher risk of CRC. A sessile serrated polyp ≥ 10 mm and a sessile serrated polyp with cytological dysplasia should be managed like a HRA with repeat colonoscopy occurring in 3 years. Serrated polyps that are <10 mm in size and do not have cytological dysplasia may have lower risk and can be managed like LRA with repeat colonoscopy occurring in 5 years [66].

Follow-up After Surveillance

In a 2009 study, 564 participants underwent 2 surveillance colonoscopies after an index procedure and 10.3% had high-risk findings at the third study examination. If the second examination showed high-risk findings, then results from the first examination added no significant information about the probability of high-risk findings on the third examination (18.2% for high-risk findings on the first examination vs. 20.0% for low-risk findings on the first examination; P = 0.78). If the second examination showed no adenomas, then the results from the first examination added significant information about the probability of high-risk findings on the third exam-ination (12.3% if the first examination had high-risk findings vs. 4.9% if the first examination had low-risk findings; P = 0.015) [80]. Thus, information from 2 previous colonoscopies appears to be helpful in defining the risk of neoplasia for individual patients and in the future, guidelines might consider accounting for the results of 2 exams to tailor surveillance intervals for patients.

• When should screening / surveillance be stopped?

There is considerable new evidence that the risks of colonoscopy increase with advancing age [81,82]. Neither surveillance nor screening colonoscopy should be performed when the risk of the preparation, sedation, or procedure outweighs the potential benefit. For patients aged 75–85 years, the USPSTF recommends against routine screening but argues for individualization based on comorbidities and findings on any prior colonoscopy. The USPSTF recommends against continued screening after age 85 years because risk could exceed potential benefit [44].

In terms of surveillance of prior adenomas, the 75-85 year age group may still benefit from surveillance because patients with prior HRA are at higher risk for developing advanced neoplasia compared with average-risk screenees. However, the decision to continue surveillance in this population should be individualized and based on an assessment of benefit and risk in the context of the person’s estimated life expectancy [66]. More importantly, it should be noted that an individual’s most important and impactful screening colonoscopy is his or her first one and therefore, from a public health standpoint, great effort should be taken to increase the number of people in a population who undergo screening rather than simply targeting those who need surveillance for prior polyps. This is ever true in settings with limited resources.

Case Conclusion

The physician discusses the findings from the colonoscopy (2 small adenomas) with the patient and recommends a repeat colonoscopy in 5 to 10 years.

Summary

Colorectal cancer is one of the leading causes of cancer-related death in the United States. Since the advent of colonoscopy and the implementation of CRC screening efforts, the rates of CRC have started to decline. There are several environmental factors which have been associated with the development of CRC including obesity, dietary intake, physical activity and smoking. At present, there are multiple tools available for CRC prevention, but the most accurate and effective method is currently colonoscopy. Stool-based tests like FIT should be offered when a patient declines colonoscopy. For those interested in colonoscopy, average-risk individuals should be screened starting at the age of 50 with subsequent examinations every 10 years. Surveillance examinations should occur based on polyp findings on index colonoscopy. There is no recommendation to continue screening after the age of 75, though physicians can determine this based on patients health and risk/benefit profile. Current guidelines recommend against offering any screening to patients over the age of 85. Despite these recommendations, almost half of the eligible screening population has yet to undergo appropriate CRC screening. Future work should include public health efforts to improve access and appeal of widespread CRC screening regardless of modality. While colonoscopy is considered the most effective screening test, the best test is still the one the patient gets.

Corresponding author: Audrey H. Calderwood, MD, MS, 85 E. Concord St., Rm. 7724, Boston, MA 02118, [email protected].

Financial disclosures: None.

From the Boston University School of Medicine, Boston, MA.

Abstract

• Objective: To review recommendations for colorectal cancer (CRC) screening.
• Methods: Review of the literature.
• Results: In the United States, CRC is the third most commonly diagnosed cancer and the third leading cause of cancer death. CRC screening can reduce mortality through the detection of early-stage disease and the detection and removal of adenomatous polyps. There are several modalities for CRC screening, with current technology falling into 2 general categories: stool tests, which include tests for occult blood or exfoliated DNA; and structural exams, which include flexible sigmoidoscopy, colonoscopy, double-contrast barium enema, and CT colonography. The preferred CRC prevention test for average-risk individuals is colonoscopy starting at age 50 with subsequent examinations every 10 years. Patients unwilling to undergo screening colonoscopy may be offered flexible sigmoidoscopy, CT colonography, or fecal immunohistochemical test. Surveillance examinations should occur based on polyp findings on index colonoscopy. There is no recommendation to continue screening after age 75, though physicians can make a determination based on a patient’s health and risk/benefit profile. Current guidelines recommend against offering screening to patients over age 85.
• Conclusion: Increasing access to and utilization of CRC screening tests is likely to lead to improvements in mortality reduction, as only about half of people aged 50 or older report having received CRC testing consistent with current guidelines.

In the United States, colorectal cancer (CRC) is the third most commonly diagnosed cancer and the third leading cause of cancer death in both men and women [1]. In 2014, an estimated 136,830 people were diagnosed with CRC and about 50,310 people died of the disease [2]. Colorectal cancer usually develops slowly over a period of 10 to 15 years. The tumor typically begins as a noncancerous polyp, classically an adenomatous polyp or adenoma, though fewer than 10% of adenomas will progress to cancer [3]. Adenomas are common; an estimated one-third to one-half of all individuals will eventually develop 1 or more adenomas [4,5]. In the United States, the lifetime risk of being diagnosed with CRC is approximately 5% for both men and women [6]. Incidence rates for CRC increase with age, with an incidence rate more than 15 times higher in adults aged 50 years and older compared with those aged 20 to 49 years [7].

Certain demographic subgroups have been shown to be at higher risk. Overall, CRC incidence and mortality rates are about 35% to 40% higher in men than in women. The reasons for this are not completely understood but likely reflect complex interactions between gender-related differences in exposure to hormones and risk factors [8]. CRC incidence and mortality rates are highest in African-American men and women; incidence rates are 20% higher and mortality rates are about 45% higher than those in whites. Prior to 1989, incidence rates were predominantly higher in white men than in African American men and were similar for women of both races. Since that time, although incidence rates have declined as a whole [9], incidence rates have been higher for African Americans than whites in both men and women This crossover likely reflects a combination of greater access to and utilization of recommended screening tests among whites (resulting in detection and removal of precancerous polyps), as well as racial differences in trends for CRC risk factors [10].

CRC screening can reduce mortality through the detection of early-stage disease and the detection and removal of ademomatous polyps [11]. Increasing access to and utilization of CRC screening tests is likely to lead to improvements in mortality reduction, as only about half of people aged 50 or older report having received CRC testing consistent with current guidelines [1].

Case Study

Initial Presentation

A 55-year-old white male presents for a routine visit and asks about colon cancer screening. His father was diagnosed with colon cancer at the age of 78. Overall, he feels well and does not have any particular complaints. His bowel habits are normal and he denies melena and hematochezia. His past medical history is significant for diabetes, hypertension, and obesity. He was a previous smoker and has a few alcoholic drinks on the weekends. His physical exam is unremarkable. Results of recent blood work are normal and there is no evidence of anemia.

• What are this patient’s risk factors for developing colon cancer?

Risk Factors for CRC

There are numerous factors that are thought to influence risk for CRC. Nonmodifiable risk factors include a personal or family history of CRC or adenomatous polyps, and a personal history of chronic inflammatory bowel disease. Modifiable risk factors that have been associated with an increased risk of CRC in epidemiologic studies include physical inactivity, obesity, high consumption of red or processed meats, smoking, and moderate-to-heavy alcohol consumption. In fact, a prospective study showed that up to 23% of colorectal cancers were considered to be potentially avoidable by adhering to multiple healthy lifestyle recommendations including maintaining a healthy weight, being physically active at least 30 minutes per day, eating a healthy diet, and avoiding smoking and drinking excessive amounts of alcohol [12].

People with a first-degree relative (parent, sibling, or offspring) who has had CRC have 2 to 3 times the risk of developing the disease compared with individuals with no family history; if the relative was diagnosed at a young age or if there is more than 1 affected relative, risk increases to 3 to 6 times that of the general population [13,14]. About 5% of patients with CRC have a well-defined genetic syndrome that causes the disease [15]. The most common of these is Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC), which accounts for 2% to 4% of all CRC cases [16]. Although individuals with Lynch syndrome are predisposed to numerous types of cancer, risk of CRC is highest. A recent study of CRC in 147 Lynch syndrome families in the United States found lifetime risk of CRC to be 66% in men and 43% in women, with a median age at diagnosis of 42 years and 47 years, respectively [17]. Familial adenomatous polyposis (FAP) is the second most common predisposing genetic syndrome; for these individuals, the lifetime risk of CRC approaches 100% without intervention (eg, colectomy) [16].

People who have inflammatory bowel disease of the colon (both ulcerative colitis and Crohn’s disease) have an increased risk of developing CRC that correlates with the extent and the duration of the inflammation [18]. It is estimated that 18% of patients with a 30-year history of ulcerative colitis will develop CRC [19]. In addition, several studies have found an association between diabetes and increased risk of CRC [20,21]. Though adult-onset type 2 diabetes (the most common type) and CRC share similar risk factors, including physical inactivity and obesity, a positive association between diabetes and CRC has been found even after accounting for physical activity, body mass index, and waist circumference [22].

Being overweight or obese is also associated with a higher risk of CRC, with stronger associations more consistently observed in men than in women. Obesity increases the risk of CRC independent of physical activity. Abdominal obesity (measured by waist circumference) may be a more important risk factor for colon cancer than overall obesity in both men and women [23–25]. Diet and lifestyle strongly influence CRC risk; however, research on the role of specific dietary elements on CRC risk is still accumulating. Several studies, including one by the American Cancer Society, have found that high consumption of red and/or processed meat increases the risk of both colon and rectal cancer [23,26,27]. Further analyses indicate that the association between CRC and red meat may be related to the cooking process, because a higher risk of CRC is observed particularly among those individuals who consume meat that has been cooked at a high temperature for a long period of time [28]. In contrast to findings from earlier research, more recent large, prospective studies do not indicate a major relationship between CRC and vegetable, fruit, or fiber consumption [28,29]. However, some studies suggest that people with very low fruit and vegetable intake are at above-average risk for CRC [30,31]. Consumption of milk and calcium may decrease the risk of developing CRC [28,29,32].

In November 2009, the International Agency for Research on Cancer reported that there is now sufficient evidence to conclude that tobacco smoking causes CRC [33]. Colorectal cancer has been linked to even moderate alcohol use. Individuals who have a lifetime average of 2 to 4 alcoholic drinks per day have a 23% higher risk of CRC than those who consume less than 1 drink per day [34].

Protective Factors

One of the most consistently reported relationships between colon cancer risk and behavior is the protective effect of physical activity [35]. Based on these findings, as well as the numerous other health benefits of regular physical activity, the American Cancer Society recommends engaging in at least moderate activity for 30 minutes or more on 5 or more days per week.

Accumulating research suggests that aspirin-like drugs, postmenopausal hormones, and calcium supplements may help prevent CRC. Extensive evidence suggests that long-term, regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is asso-ciated with lower risk of CRC. The American Cancer Society does not currently recommend use of these drugs as chemoprevention because of the potential side effects of gastrointestinal bleeding from aspirin and other traditional NSAIDs and heart attacks from selective cyclooxygenase-2 (COX-2) inhibitors. However, people who are already taking NSAIDs for chronic arthritis or aspirin for heart disease prevention may have a lower risk of CRC as a positive side effect [36,37].

There is substantial evidence that women who use postmenopausal hormones have lower rates of CRC than those who do not. A decreased risk of CRC is especially evident in women who use hormones long-term, although the risk returns to that of nonusers within 3 years of cessation. Despite its positive effect on CRC risk, the use of postmenopausal hormones increases the risk of breast and other cancers as well as cardiovascular disease, and therefore it is not recommended for the prevention of CRC. At present, the American Cancer Society does not recommend any medications or supplements to prevent CRC because of uncertainties about their effectiveness, appropriate dosing, and potential toxicity [38–40].

Case Continued

The physician tells the patient that there are several environmental factors that may predispose him to developing CRC. He recommends that the patient follow a healthy lifestyle, including eating 5 servings of fruits and vegetables daily, minimizing consumption of red meats, exercising for 30 minutes at least 5 days per week, drinking only moderate amounts of alcohol, and continuing to take his aspirin in the setting of his diabetes. He also asks the patient if he would be interested in talking about weight loss and working together to make a plan.

The patient is appreciative of this information and wants to know what CRC creening test the physician recommends.

• What screening test should be recommended?

Screening Options

There are several modalities for CRC screening, with current technology falling into 2 general categories: stool tests, which include tests for occult blood or exfoliated DNA; and structural exams, which include flexible sigmoidoscopy, colonoscopy, double-contrast barium enema (DCBE), and computed tomographic (CT) colonography. Stool tests are best suited for the detection of CRC, although they also will deliver positive findings for some advanced adenomas, while the structural exams can achieve both detection and prevention of CRC through identification and removal of adenomatous polyps [41]. These tests may be used alone or in combination to improve sensitivity or, in some instances, to ensure a complete examination of the colon if the initial test cannot be completed.

In principle, all adults should have access to the full range of options for CRC screening, and the availability of lower-cost, less invasive options in most practice settings is a public health advantage [11]. However, the availability of multiple testing options can overwhelm the primary care provider and presents challenges for practices in trying to support an office policy that can manage a broad range of testing choices, their follow-up requirements, and shared decision making related to the options. Shared decision making around CRC screening options is both demanding and time consuming and is complicated by the different characteristics of the tests and the test-specific requirements for individuals undergoing screening [42].

Recommended Tests

The joint guideline on screening for CRC from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology (the MSTF guideline) [11] is of the strong opinion that tests designed to detect early cancer and prevent cancer through the detection and removal of adenomatous polyps (the structural exams) should be encouraged if resources are available and patients are willing to undergo an invasive test [11]. In clinical settings in which economic issues preclude primary screening with colonoscopy, or for patients who decline invasive tests, clinicians may offer stool- based testing. However, providers and patients should understand that these tests are less likely to prevent cancer compared with the invasive tests, they must be repeated at regular intervals to be effective (ie, programmatic sensitivity), and if the test is abnormal, a colonoscopy will be needed to follow up. Therefore, if patients are not willing to have repeated testing or pursue colonoscopy if the test is abnormal, these programs will not be effective and should not be recommended [11].

Stool-Based Testing

Stool blood tests are conventionally known as fecal occult blood tests (FOBT) because they are designed to detect the presence of occult blood in stool. FOBT falls into 2 primary categories based on the detected analyte: guaiac-based and FIT. Blood in the stool is a nonspecific finding but may originate from CRC or larger (> 1 to 2 cm) polyps. Because small adenomatous polyps do not tend to bleed and bleeding from cancers or large polyps may be intermittent or undetectable in a single sample of stool, the proper use of stool blood tests requires annual testing that consists of collecting specimens (2 or 3, depending on the product) from consecutive bowel movements [45–47].

Guaiac-based FOBT

Guaiac-based FOBT (gFOBT) is the most common stool blood test for CRC screening and the only CRC screening test for which there is evidence of efficacy from randomized controlled trials [11]. The usual gFOBT protocol consists of collecting 2 samples from each of 3 consecutive bowel movements at home. Prior to testing with a sensitive guaiac-based test, individuals usually will be instructed to avoid aspirin and other NSAIDs, vitamin C, red meat, poultry, fish, and some raw vegetables because of diet-test interactions that can increase the risk of both false-positive and false-negative (specifically, vitamin C) results [48]. Collection of all 3 samples is important because test sensitivity improves with each additional stool sample [41]. Three large randomized controlled trials with gFOBT have demonstrated that screened patients have cancers detected at an early and more curable stage than unscreened patients. Over time (8 to 13 years), each of the trials demonstrated significant reductions in CRC mortality of 15% to 33% [49–51]. However, the reported sensitivity of a single gFOBT varies considerably [52].

FIT

FIT has several technological advantages when compared with gFOBT. FIT detects human globin, a protein that along with heme constitutes human hemoglobin. Thus, FIT is more specific for human blood than guaiac-based tests, which rely on detection of peroxidase in human blood and also react to the peroxidase that is present in dietary constituents such as rare red meat, cruciferous vegetables, and some fruits [53]. Furthermore, unlike gFOBT, FIT is not subject to false-negative results in the presence of high-dose vitamin C supplements, which block the peroxidase reaction. In addition, because globin is degraded by digestive enzymes in the upper gastrointestinal tract, FIT is also more specific for lower gastrointestinal bleeding, thus improving the specificity for CRC. Finally, the sample collection process for patients for some variants of FIT are less demanding than gFOBT, requiring fewer samples or less direct handling of stool, which may increase FIT’s appeal. Although FIT has superior performance characteristics when compared with older guaiac-based Hemoccult II cards [54–56], the spectrum of benefits, limitations, and harms is similar to a gFOBT with high sensitivity [41]. As for adherence with FIT, there were 10% and 12% gains in adherence with FIT in the first 2 randomized controlled trials comparing FIT with guaiac-based testing [57,58]. Therefore, FIT is preferred over Hemoccult Sensa and is the preferred annual cancer detection test when colonoscopy is not an option [43]. The American College of Gastroenterology supports the joint guideline recommendation [11] that older guaiac-based fecal occult blood testing be abandoned as a method for CRC screening.

sDNA

Fecal DNA testing uses knowledge of molecular genomics and provides the basis of a new method of CRC screening that tests stool for the presence of known DNA alterations in the adenoma-carcinoma sequence of colorectal carcinogenesis [11]. Three different types of fecal DNA testing kits have been evaluated. The sensitivity for cancer in each version was superior to traditional guaiac-based occult blood testing, but the sensitivities ranged from 52%–87%, with the specificities ranging from 82%–95%. Based on the accumulation of evidence since the last update of joint guideline, the joint guideline panel concluded that there now are sufficient data to include sDNA as an acceptable option for CRC screening [11].

As for overall recommendations for stool-based testing, the ACG supports the joint guideline recommendation that older guaiac-based fecal occult blood testing be abandoned as a method for CRC screening. Because of more extensive data (compared with Hemoccult Sensa), and the high cost of fecal DNA testing, the American College of Gastroenterology recommends FIT as the preferred cancer detection test in cases where colonoscopy is not an option [43].

Invasive Tests Other than Colonoscopy

The use of flexible sigmoidoscopy for CRC screening is supported by high-quality case-control and cohort studies [46]. The chief advantage of flexible sigmoidoscopy is that it can be performed with a simple preparation (2 enemas), without sedation, and by a variety of practitioners in diverse settings. The main limitation of the procedure is that it does not examine the entire colon but only the rectum, sigmoid, and descending colon. The effectiveness of a flexible sigmoidoscopy program is based on the assumption that if an adenoma is detected during the procedure, the patient would be referred for colonoscopy to examine the entire colon.

DCBE is an imaging modality which can evaluate the entire colon in almost all cases and can detect most cancers and the majority of significant polyps. However, the lower sensitivity for significant adenomas when compared with colonoscopy may result in less favorable outcomes regarding CRC morbidity and mortality. Double-contrast barium enema is no longer recommended as an alternative CRC prevention test because its use has declined dramatically and also as its effectiveness for polyp detection is less than CT colonography [43].

CT Colonography

CT colonography every 5 years is endorsed as an alternative to colonoscopy every 10 years because of its recent performance in the American College of Imaging Network Trial 6664 (also known as the National CT Colonography Trial) [59]. The principle performance feature that justifies inclusion of CT colonography as a viable alternative in patients who decline colonoscopy is that the sensitivity for polyps ≥ 1 cm in size was 90% in the most recent multicenter US trial [59]. In this study, 25% of radiologists who were tested for entry into the trial but performed poorly were excluded from participation, and thus lower sensitivity might be expected in actual clinical practice. CT colonography probably has a lower risk of perforation than colonoscopy in most settings, but for several reasons it is not considered the equivalent of colonoscopy as a screening strategy. First, the evidence to support an effect of endoscopic screening on prevention of incident CRC and mortality is overwhelming compared with that for CT colonography. Second, the inability of CT colonography to adequately detect polyps 5 mm and smaller, which constitutes 80% of colorectal neoplasms, and whose natural history is still not understood, necessitates performance of the test at 5-year rather than 10-year intervals [43]. Finally, false-positives are common, and the specificity for polyps ≥ 1 cm in size was only 86% in the National CT Colonography Trial, with a positive predictive value of 23% [59]. The American College of Gastroenterology recommends that asymptomatic patients be informed of the possibility of radiation risk associated with one or repeated CT colonography studies, though the exact risk associated with radiation is unclear [60,61].

The value of extracolonic findings detected by CT colonography is mixed, with substantial costs associated with incidental findings, but occasional important extracolonic findings are detected, such as asymptomatic cancers and large abdominal aortic aneurysms. As a final point, the ACG is also concerned about the potential impact of CT colonography on adherence with follow-up colonoscopy and thus on polypectomy rates. Thus, if CT colonography substantially improves adherence, it should improve polypectomy rates and thereby reduce CRC, even if only large polyps are detected and referred for colonoscopy. On the other hand, if CT colonography largely displaces patients who would otherwise be willing to undergo colonoscopy, then polypectomy rates will fall substantially, which could significantly increase the CRC incidence [62]. Thus, for multiple reasons and pending additional study, CT colonography should be offered to patients who decline colonoscopy. It should be noted that CT colonography should only be offered for the purposes of CRC screening and should not be used for diagnostic workup of symptoms (eg, patient with active bleeding or inflammatory bowel disease).

• When should screening begin?

The American College of Gastroenterology continues to recommend that screening begin at age 50 years in average-risk persons (ie, those without a family history of colorectal neoplasia), except for African Americans, in whom it should begin at age 45 years [43]. The USPSTF does not currently provide specific recommendations based on race or ethnicity, but certain other subgroups of the average-risk population might warrant initiation of screening at an earlier or later age, depending on their risk. For example, the incident risk of CRC has been described to be greater in men than women [63]. In reviewing the literature, the writing committee also identified heavy cigarette smoking and obesity as linked to an increased risk of CRC and to the development of CRC at an earlier age.

For patients with a family history of CRC or adenomatous polyps, the 2008 MSTF guideline recommends initiation of screening at age 40 [11]. The American College of Gastroenterology recommendations for screening in patients with a family history are shown in Table 1. From a practical perspective, many clinicians have found that patients are often not aware of whether their first-degree relatives had advanced adenomas vs. small tubular adenomas, or whether their family members had non-neoplastic vs. neoplastic polyps. Given these difficulties, the American College of Gastroenterology now recommends that adenomas only be counted as equal to a family history of cancer when there is a clear history, or medical report containing evidence, or other evidence to indicate that family members had advanced adenomas (an adenoma ≥ 1 cm in size, or with high-grade dysplasia, or with villous elements) [43]. Continuation of the old recommendation to screen first-degree relatives of patients with only small tubular adenomas could result in most of the population being screened at age 40, with doubtful benefit.

• What are screening considerations in patients with genetic syndromes?

Patients with features of an inherited CRC syndrome should be advised to pursue genetic counseling with a licensed genetic counselor and, if appropriate, genetic testing. Individuals with FAP should undergo adenomatous polyposis coli (APC) mutation testing and, if negative, MYH mutation testing. Patients with FAP or at risk of FAP based upon family history should undergo annual colonoscopy until colectomy is deemed by both physician and patient as the best treatment [64]. Patients with a retained rectum after total colectomy and ileorectal anastomosis, ileal pouch, after total proctocolectomy and ileal pouch anal anastomosis, or stoma after total proctocolectomy and end ileostomy, should undergo endoscopic assessment approximately every 6 to 12 months after surgery, depending on the polyp burden seen. Individuals with oligopolyposis (< 100 colorectal polyps) should be sent for genetic counseling, consideration of APC and MYH mutation testing, and individualized colonoscopy surveillance depending on the size, number, and pathology of polyps seen. Upper endoscopic surveillance is recommended in individuals with FAP, but there are no established guidelines for endoscopic surveillance in MAP (MYH-associated polyposis) [43].

Patients who meet the Bethesda criteria for HNPCC [65] can be screened by 2 different mechanisms. One is a DNA-based test for microsatellite instability of either the patient’s or a family member’s tumor. The other mechanism is to assess by immunohistochemical staining for evidence of mismatch repair proteins (eg, MLH1, MSH2, MSH6). In those patients in whom deleterious mutations are found, the affected individual should undergo colonoscopy every 2 years beginning at age 20 to 25 years until age 40 years, then annually thereafter [43]. If genetic testing is negative (ie, no deleterious mutation is found), but the patient is still felt to clinically have Lynch syndrome, then they should still be surveyed in the same way.

Case Continued

The physician recommends colonoscopy as the screening modality as it is the most efficient and accurate way of finding precancerous lesions and the most effective way of preventing CRC by removing precancerous lesions. He also explains that because the patient’s father developed CRC after the age of 60, this does not place the patient in a higher risk category and he can follow screening recommendations for “average-risk” individuals.

Screening

The patient undergoes colonoscopy. Two 5-mm adenomas in the transverse colon are detected and removed.

• When should he have a repeat colonoscopy?

Surveillance Intervals

New data have recently emerged on the risk of interval cancer after colonoscopy. The overall rate of interval cancer is estimated to be 1.1–2.7 per 1000 person-years of follow-up. There are several reasons that may account for why patients develop interval cancers: (1) important lesions may be missed at baseline colonoscopy, (2) adenomas may be incompletely removed at the time of baseline colonoscopy, and (3) interval CRC may be biologically different or more aggressive than prevalent CRC. In order to minimize the risk of interval cancer development, it is important to perform a high-quality baseline screening colonoscopy examination as this is associated with lowering the risk of interval cancer [66]. A high-quality colonoscopy entails completion of the procedure to the cecum (with photodocumentation of the appendiceal orifice and ileocecal valve) with careful inspection of folds including adequate bowel cleanliness and a withdrawal time > 6 minutes.

Baseline Colonoscopy Findings

No Polyps

Several prospective observational studies in different populations have shown that the risk of advanced adenomas within 5 years after negative findings on colonoscopy is low (1.3%–2.4%) relative to the rate on initial screening examination (4%–10%) [68–73]. In these studies, interval cancers were rare within 5 years. A sigmoidoscopy randomized controlled trial performed in the United Kingdom demonstrated a reduction in CRC incidence and mortality at 10 years in patients who received one-time sigmoidoscopy compared with controls—a benefit limited to the distal colon [46]. This is the first randomized study to show the effectiveness of endoscopic screening, an effect that appears to have at least a 10-year duration [74]. Thus, in patients who have a baseline colonoscopic evaluation without any adenomas or polyps and are average-risk individuals, the recommendation for the next examination is in 10 years [66].

Distal Hyperplastic Polyps < 10 mm

There is considerable evidence that patients with only rectal or sigmoid hyperplastic polyps (HPs) appear to represent a low-risk cohort. Studies have focused on whether the finding in the distal colon was a marker of risk for advanced neoplasia elsewhere and most studies show no such relationship [67]. Prior and current evidence suggests that distal HPs <10 mm are benign without neoplastic potential. If the most advanced lesions at baseline colonoscopy are distal HPs <10 mm, the interval for colonoscopic follow-up should be 10 years [66].

1-2 Tubular Adenomas < 10 mm

Prior evidence suggested that patients with low-risk adenomas (<10 mm, no villous histology or high-grade dysplasia) had a lower risk of developing advanced adenomas during follow-up compared with patients with high risk adenomas (≥ 10mm, villous histology or high -grade dysplasia). At that time in 2006, consensus on the task force was that an interval of 5 years would be acceptable in this low-risk group [75]. Data published since 2006 endorse the assessment that patients with 1–2 tubular adenomas with low-grade dysplasia <10 mm represent a low-risk group. Three new studies suggest that this group may have only a small, nonsignificant increase in risk of advanced neoplasia within 5 years compared with individuals with no baseline neoplasia. The evidence now supports a surveillance interval of longer than 5 years for most patients and can be extended to 10 years based on the quality of the preparation and colonoscopy [66].

3–10 Tubular Adenomas

Two independent meta-analyses in 2006 found that patients with 3 or more adenomas at baseline had an increased RR for adenomas during surveillance, ranging from 1.7 to 4.8 [47,75]. New information from the VA study and the National Cancer Institute Pooling Project also support these prior findings. Patients with 3 or more adenomas have a level of risk for advanced neoplasia similar to other patients with advanced neoplasia (adenoma >10 mm, adenoma with high grade dysplasia) and thus, repeat examination should be performed in 3 years [66,68,76].

> 10 Adenomas

Only a small proportion of patients undergoing screening colonoscopy will have >10 adenomas. The 2006 guidelines for colonoscopy surveillance after polypectomy noted that such patients should be considered for evaluation of hereditary CRC syndromes [67]. Early follow-up surveillance colonoscopy is based on clinical judgment because there is little evidence to support a firm recommendation. At present, the recommendation is to consider follow-up in less than 3 years after a baseline colonoscopy [66].

1 or More Tubular Adenomas ≥ 10mm

The 2006 MSTF guideline reviewed data related to adenoma size, demonstrating that most studies showed a 2- to 5-fold increased risk of advanced neoplasia during follow-up if the baseline examination had one or more adenomas ≥ 10 mm [67]. Newer, additional data shows that patients with one or more adenomas ≥ 10 mm have an increased risk of advanced neoplasia during surveillance compared with those with no neoplasia or small (< 10 mm) adenomas [68,76]. Thus, the recommendations remains that repeat examination should be performed in 3 years [66]. If there is question about complete removal of an adenoma (ie, piecemeal resection), early follow-up colonoscopy is warranted [66].

1 or More Villous Adenomas

The 2006 MSTF guideline considers adenomas with villous histology to be high risk [67]. The NCI Pooling Project analyzed polyp histology as a risk factor for development of interval advanced neoplasia. Compared with patients with tubular adenomas, those with baseline polyp(s) showing adenomas with villous or tubulovillous histology (TVA) had increased risk of advanced neoplasia during follow-up (16.8% vs 9.7%; adjusted OR, 1.28; 95% CI, 1.07–1.52) [76]. Patients with one or more adenomas with villous histology were also found to have an increased risk of advanced neoplasia during surveillance compared with those with no neoplasia or small (<10 mm) tubular adenomas. Thus, the recommendation remains that repeat examination should be performed in 3 years [66].

Adenoma with High-Grade Dysplasia (HGD)

The 2006 MSTF guideline concluded that the presence of HGD in an adenoma was associated with both villous histology and larger size, which are both risk factors for advanced neoplasia during surveillance [67]. In a univariate analysis from the NCI Pooling Project, HGD was strongly associated with risk of advanced neoplasia during surveillance (OR, 1.77; 95% CI, 1.41–2.22) [76]. Thus, the recommendation remains that repeat examination should be performed in 3 years [66].

Serrated Lesions

A total of 20% to 30% of CRCs arise through a molecular pathway characterized by hypermethylation of genes, known as CgG Island Methylator Phenotype (CIMP) [77]. Precursors are believed to be serrated polyps. Tumors in this pathway have a high frequency of BRAF mutation, and up to 50% are microsatellite unstable. CIMP-positive tumors are overrepresented in interval cancers, particularly in the proximal colon. The principal precursor of hypermethylated cancers is probably the sessile serrated polyp (synonymous with sessile serrated adenoma). These polyps are difficult to detect at endoscopy. They may be the same color as surrounding colonic mucosa, have indiscrete edges, are nearly always flat or sessile, and may have a layer of adherent mucus and obscure the vascular pattern.

Recent studies show that proximal colon location or size ≥ 10 mm may be markers of risk for synchronous advanced adenomas elsewhere in the colon [78,79]. Surveillance after colonoscopy was evaluated in one study, which found that coexisting serrated polyps and high-risk adenomas (HRA; ie, size ≥ 10 mm, villous histology, or presence of HGD) is associated with a higher risk of advanced neoplasia at surveillance [78]. This study also found that if small proximal serrated polyps are the only finding at baseline, the risk of adenomas during surveillance is similar to that of patients with low-risk adenomas (LRA; ie, 1–2 small adenomas).

The current evidence suggests that size (>10 mm), histology (a sessile serrated polyp is a more significant lesion than an HP; a sessile serrated polyp with cytological dysplasia is more advanced than a sessile serrated polyp without dysplasia), and location (proximal to the sigmoid colon) are risk factors that might be associated with higher risk of CRC. A sessile serrated polyp ≥ 10 mm and a sessile serrated polyp with cytological dysplasia should be managed like a HRA with repeat colonoscopy occurring in 3 years. Serrated polyps that are <10 mm in size and do not have cytological dysplasia may have lower risk and can be managed like LRA with repeat colonoscopy occurring in 5 years [66].

Follow-up After Surveillance

In a 2009 study, 564 participants underwent 2 surveillance colonoscopies after an index procedure and 10.3% had high-risk findings at the third study examination. If the second examination showed high-risk findings, then results from the first examination added no significant information about the probability of high-risk findings on the third examination (18.2% for high-risk findings on the first examination vs. 20.0% for low-risk findings on the first examination; P = 0.78). If the second examination showed no adenomas, then the results from the first examination added significant information about the probability of high-risk findings on the third exam-ination (12.3% if the first examination had high-risk findings vs. 4.9% if the first examination had low-risk findings; P = 0.015) [80]. Thus, information from 2 previous colonoscopies appears to be helpful in defining the risk of neoplasia for individual patients and in the future, guidelines might consider accounting for the results of 2 exams to tailor surveillance intervals for patients.

• When should screening / surveillance be stopped?

There is considerable new evidence that the risks of colonoscopy increase with advancing age [81,82]. Neither surveillance nor screening colonoscopy should be performed when the risk of the preparation, sedation, or procedure outweighs the potential benefit. For patients aged 75–85 years, the USPSTF recommends against routine screening but argues for individualization based on comorbidities and findings on any prior colonoscopy. The USPSTF recommends against continued screening after age 85 years because risk could exceed potential benefit [44].

In terms of surveillance of prior adenomas, the 75-85 year age group may still benefit from surveillance because patients with prior HRA are at higher risk for developing advanced neoplasia compared with average-risk screenees. However, the decision to continue surveillance in this population should be individualized and based on an assessment of benefit and risk in the context of the person’s estimated life expectancy [66]. More importantly, it should be noted that an individual’s most important and impactful screening colonoscopy is his or her first one and therefore, from a public health standpoint, great effort should be taken to increase the number of people in a population who undergo screening rather than simply targeting those who need surveillance for prior polyps. This is ever true in settings with limited resources.

Case Conclusion

The physician discusses the findings from the colonoscopy (2 small adenomas) with the patient and recommends a repeat colonoscopy in 5 to 10 years.

Summary

Colorectal cancer is one of the leading causes of cancer-related death in the United States. Since the advent of colonoscopy and the implementation of CRC screening efforts, the rates of CRC have started to decline. There are several environmental factors which have been associated with the development of CRC including obesity, dietary intake, physical activity and smoking. At present, there are multiple tools available for CRC prevention, but the most accurate and effective method is currently colonoscopy. Stool-based tests like FIT should be offered when a patient declines colonoscopy. For those interested in colonoscopy, average-risk individuals should be screened starting at the age of 50 with subsequent examinations every 10 years. Surveillance examinations should occur based on polyp findings on index colonoscopy. There is no recommendation to continue screening after the age of 75, though physicians can determine this based on patients health and risk/benefit profile. Current guidelines recommend against offering any screening to patients over the age of 85. Despite these recommendations, almost half of the eligible screening population has yet to undergo appropriate CRC screening. Future work should include public health efforts to improve access and appeal of widespread CRC screening regardless of modality. While colonoscopy is considered the most effective screening test, the best test is still the one the patient gets.

Corresponding author: Audrey H. Calderwood, MD, MS, 85 E. Concord St., Rm. 7724, Boston, MA 02118, [email protected].

Financial disclosures: None.

Study Overview

Objective. To identify psychosocial predictors of weight loss maintenance in a multi-site clinical trial following a group-based weight loss program.

Design. Secondary analysis of a 2-phase randomized controlled trial. The first phase was a 6-month group-based weight loss program and the second phase was a 30-month trial comparing weight loss maintenance strategies.

Setting and participants. The patients studied were participants in the Weight Loss Maintenance trial [1], which was conducted at 4 US clinical centers. Eligible participants were overweight and obese adults with a BMI between 25 to 45 who were actively taking medication for hypertension, dyslipidemia, or both. 1685 patients were recruited into the weight-loss phase, and those who lost at least 4 kg (n = 1032) were then randomly assigned to 1 of the 3 maintenance arms: (a) self-directed with minimal intervention (control), (b) interactive technology that consisted of unlimited, interactive study website access, or (c) personal contact consisting of monthly, personalized telephone calls and quarterly face-to-face contact with a study interventionist. There was 1 death in each treatment group, so a total of 1029 participants were included in the analyses.

Main outcome measures. The researchers examined the associations between psychosocial variables and weight change outcomes at 12 and 30 months. Patients completed 5 self-report measures at the time of randomization into phase 2 of the study: a social support and exercise survey, a social support and eating habits survey, the SF-36, the Patient Health Questionnaire Depression Scale, and the Perceived Stress Scale.

Results. Of the 1029 participants initially included for analyses, 2 failed to provide complete data on the social support scales and 2 were identified as outliers at both 12 and 30 months. This resulted in a final sample size of 1025 participants; 63% were women, 61% were non-Latino white, and 38% were black. The mean age was 55.6 years. All groups regained weight, with the personal contact group having the least amount of gain. However, the mean weight at 30 months remained significantly lower than the mean weight at entry into phase 1.

Only 3 psychosocial variables were significantly related to weight loss at 12 and 30 months. At both time marks, less weight regain was associated with higher SF-36 mental health composite scores (P < 0.01). Interestingly, for black participants at the 12-month mark, more weight regain was associated with higher exercise encouragement from friends (P < 0.05). At 30 months, more weight regain was associated with friends’ encouragement for healthy eating (P < 0.05).

Conclusion. The psychosocial variables that were self-reported upon entering phase 2 may predict the ability of an individual to maintain weight loss at 12 and 30 months. The significant, complex interactions between these variables, race, sex, and treatment interventions need to be further studied for proper incorporation into a weight loss maintenance program.

Commentary

The case for the obesity epidemic has been long established. Unfortunately, the causes for weight gain can be complicated and multifactorial. Factors associated with weight gain include nonmodifiable factors such as age, sex, and race as well as modifiable factors like lifestyle, eating habits, and perceived stress [2]. The CDC states that about 78.6 million American adults are overweight or obese [3], and about 25% to 40% of US adults attempt to lose weight each year [4]. It is unclear what proportion of those who lose weight are successful at maintaining their weight loss [5,6].

Researchers and practitioners alike understand that maintaining weight loss is difficult. Most studies on weight regain have focused on biological and lifestyle factors [7]. This article did a good job in detailing gaps in knowledge and supporting the need for further study of psychosocial variables. The results demonstrated complex, interactive relationships between multiple factors. Three psychosocial variables were found to be statistically significant in relation to weight loss, but more significant relationships were found between race, perceived stress, and weight loss.

As a secondary analysis, this study carries the strengths of the initial study, including a 30-month study duration. In addition, this study was randomized and included 3 different treatment arms. Lastly, there was a large representation of black participants, and the authors suggested that the results may offer and initial characterization of this population.

A limitation of this study was the use of self-reported data, which may be subject to be bias and be less reliable than direct measured data. Also, these measures were apparently taken only once prior to the beginning of phase 2 with no rationale provided. Psychosocial variables such as social support, quality of life, and perceived stress are dynamic and cannot be accurately encapsulated in isolated moments in time. The sample’s diversity was also lacking as there were few Hispanics and no Asian
participants.

Applications for Clinical Practice

A few significant, interactive relationships were discovered in this examination and require further study. Continued research and a better understanding of these complex relationships are needed.

—Angela M. Godwin Beoku-Betts, MSN, FNP–BC

Study Overview

Objective. To identify psychosocial predictors of weight loss maintenance in a multi-site clinical trial following a group-based weight loss program.

Design. Secondary analysis of a 2-phase randomized controlled trial. The first phase was a 6-month group-based weight loss program and the second phase was a 30-month trial comparing weight loss maintenance strategies.

Setting and participants. The patients studied were participants in the Weight Loss Maintenance trial [1], which was conducted at 4 US clinical centers. Eligible participants were overweight and obese adults with a BMI between 25 to 45 who were actively taking medication for hypertension, dyslipidemia, or both. 1685 patients were recruited into the weight-loss phase, and those who lost at least 4 kg (n = 1032) were then randomly assigned to 1 of the 3 maintenance arms: (a) self-directed with minimal intervention (control), (b) interactive technology that consisted of unlimited, interactive study website access, or (c) personal contact consisting of monthly, personalized telephone calls and quarterly face-to-face contact with a study interventionist. There was 1 death in each treatment group, so a total of 1029 participants were included in the analyses.

Main outcome measures. The researchers examined the associations between psychosocial variables and weight change outcomes at 12 and 30 months. Patients completed 5 self-report measures at the time of randomization into phase 2 of the study: a social support and exercise survey, a social support and eating habits survey, the SF-36, the Patient Health Questionnaire Depression Scale, and the Perceived Stress Scale.

Results. Of the 1029 participants initially included for analyses, 2 failed to provide complete data on the social support scales and 2 were identified as outliers at both 12 and 30 months. This resulted in a final sample size of 1025 participants; 63% were women, 61% were non-Latino white, and 38% were black. The mean age was 55.6 years. All groups regained weight, with the personal contact group having the least amount of gain. However, the mean weight at 30 months remained significantly lower than the mean weight at entry into phase 1.

Only 3 psychosocial variables were significantly related to weight loss at 12 and 30 months. At both time marks, less weight regain was associated with higher SF-36 mental health composite scores (P < 0.01). Interestingly, for black participants at the 12-month mark, more weight regain was associated with higher exercise encouragement from friends (P < 0.05). At 30 months, more weight regain was associated with friends’ encouragement for healthy eating (P < 0.05).

Conclusion. The psychosocial variables that were self-reported upon entering phase 2 may predict the ability of an individual to maintain weight loss at 12 and 30 months. The significant, complex interactions between these variables, race, sex, and treatment interventions need to be further studied for proper incorporation into a weight loss maintenance program.

Commentary

The case for the obesity epidemic has been long established. Unfortunately, the causes for weight gain can be complicated and multifactorial. Factors associated with weight gain include nonmodifiable factors such as age, sex, and race as well as modifiable factors like lifestyle, eating habits, and perceived stress [2]. The CDC states that about 78.6 million American adults are overweight or obese [3], and about 25% to 40% of US adults attempt to lose weight each year [4]. It is unclear what proportion of those who lose weight are successful at maintaining their weight loss [5,6].

Researchers and practitioners alike understand that maintaining weight loss is difficult. Most studies on weight regain have focused on biological and lifestyle factors [7]. This article did a good job in detailing gaps in knowledge and supporting the need for further study of psychosocial variables. The results demonstrated complex, interactive relationships between multiple factors. Three psychosocial variables were found to be statistically significant in relation to weight loss, but more significant relationships were found between race, perceived stress, and weight loss.

As a secondary analysis, this study carries the strengths of the initial study, including a 30-month study duration. In addition, this study was randomized and included 3 different treatment arms. Lastly, there was a large representation of black participants, and the authors suggested that the results may offer and initial characterization of this population.

A limitation of this study was the use of self-reported data, which may be subject to be bias and be less reliable than direct measured data. Also, these measures were apparently taken only once prior to the beginning of phase 2 with no rationale provided. Psychosocial variables such as social support, quality of life, and perceived stress are dynamic and cannot be accurately encapsulated in isolated moments in time. The sample’s diversity was also lacking as there were few Hispanics and no Asian
participants.

Applications for Clinical Practice

A few significant, interactive relationships were discovered in this examination and require further study. Continued research and a better understanding of these complex relationships are needed.

—Angela M. Godwin Beoku-Betts, MSN, FNP–BC

Study Overview

Objective. To identify psychosocial predictors of weight loss maintenance in a multi-site clinical trial following a group-based weight loss program.

Design. Secondary analysis of a 2-phase randomized controlled trial. The first phase was a 6-month group-based weight loss program and the second phase was a 30-month trial comparing weight loss maintenance strategies.

Setting and participants. The patients studied were participants in the Weight Loss Maintenance trial [1], which was conducted at 4 US clinical centers. Eligible participants were overweight and obese adults with a BMI between 25 to 45 who were actively taking medication for hypertension, dyslipidemia, or both. 1685 patients were recruited into the weight-loss phase, and those who lost at least 4 kg (n = 1032) were then randomly assigned to 1 of the 3 maintenance arms: (a) self-directed with minimal intervention (control), (b) interactive technology that consisted of unlimited, interactive study website access, or (c) personal contact consisting of monthly, personalized telephone calls and quarterly face-to-face contact with a study interventionist. There was 1 death in each treatment group, so a total of 1029 participants were included in the analyses.

Main outcome measures. The researchers examined the associations between psychosocial variables and weight change outcomes at 12 and 30 months. Patients completed 5 self-report measures at the time of randomization into phase 2 of the study: a social support and exercise survey, a social support and eating habits survey, the SF-36, the Patient Health Questionnaire Depression Scale, and the Perceived Stress Scale.

Results. Of the 1029 participants initially included for analyses, 2 failed to provide complete data on the social support scales and 2 were identified as outliers at both 12 and 30 months. This resulted in a final sample size of 1025 participants; 63% were women, 61% were non-Latino white, and 38% were black. The mean age was 55.6 years. All groups regained weight, with the personal contact group having the least amount of gain. However, the mean weight at 30 months remained significantly lower than the mean weight at entry into phase 1.

Only 3 psychosocial variables were significantly related to weight loss at 12 and 30 months. At both time marks, less weight regain was associated with higher SF-36 mental health composite scores (P < 0.01). Interestingly, for black participants at the 12-month mark, more weight regain was associated with higher exercise encouragement from friends (P < 0.05). At 30 months, more weight regain was associated with friends’ encouragement for healthy eating (P < 0.05).

Conclusion. The psychosocial variables that were self-reported upon entering phase 2 may predict the ability of an individual to maintain weight loss at 12 and 30 months. The significant, complex interactions between these variables, race, sex, and treatment interventions need to be further studied for proper incorporation into a weight loss maintenance program.

Commentary

The case for the obesity epidemic has been long established. Unfortunately, the causes for weight gain can be complicated and multifactorial. Factors associated with weight gain include nonmodifiable factors such as age, sex, and race as well as modifiable factors like lifestyle, eating habits, and perceived stress [2]. The CDC states that about 78.6 million American adults are overweight or obese [3], and about 25% to 40% of US adults attempt to lose weight each year [4]. It is unclear what proportion of those who lose weight are successful at maintaining their weight loss [5,6].

Researchers and practitioners alike understand that maintaining weight loss is difficult. Most studies on weight regain have focused on biological and lifestyle factors [7]. This article did a good job in detailing gaps in knowledge and supporting the need for further study of psychosocial variables. The results demonstrated complex, interactive relationships between multiple factors. Three psychosocial variables were found to be statistically significant in relation to weight loss, but more significant relationships were found between race, perceived stress, and weight loss.

As a secondary analysis, this study carries the strengths of the initial study, including a 30-month study duration. In addition, this study was randomized and included 3 different treatment arms. Lastly, there was a large representation of black participants, and the authors suggested that the results may offer and initial characterization of this population.

A limitation of this study was the use of self-reported data, which may be subject to be bias and be less reliable than direct measured data. Also, these measures were apparently taken only once prior to the beginning of phase 2 with no rationale provided. Psychosocial variables such as social support, quality of life, and perceived stress are dynamic and cannot be accurately encapsulated in isolated moments in time. The sample’s diversity was also lacking as there were few Hispanics and no Asian
participants.

Applications for Clinical Practice

A few significant, interactive relationships were discovered in this examination and require further study. Continued research and a better understanding of these complex relationships are needed.

—Angela M. Godwin Beoku-Betts, MSN, FNP–BC