Many fabulous prizes are now available for bidding. The Society for Vascular Surgery has compiled nearly 70 packages for items graciously donated for the silent auction portion of the ‘Vascular Spectacular’ gala. The event takes place at the Vascular Annual Meeting on Friday, June 14, in National Harbor, MD. Everyone, including non-attendees, may participate in the silent auction until it closes during the gala itself. Sign up to participate in the auction here.

Many fabulous prizes are now available for bidding. The Society for Vascular Surgery has compiled nearly 70 packages for items graciously donated for the silent auction portion of the ‘Vascular Spectacular’ gala. The event takes place at the Vascular Annual Meeting on Friday, June 14, in National Harbor, MD. Everyone, including non-attendees, may participate in the silent auction until it closes during the gala itself. Sign up to participate in the auction here.

Many fabulous prizes are now available for bidding. The Society for Vascular Surgery has compiled nearly 70 packages for items graciously donated for the silent auction portion of the ‘Vascular Spectacular’ gala. The event takes place at the Vascular Annual Meeting on Friday, June 14, in National Harbor, MD. Everyone, including non-attendees, may participate in the silent auction until it closes during the gala itself. Sign up to participate in the auction here.

TORONTO – Oral methotrexate therapy was associated with significant reductions in knee osteoarthritis pain, stiffness, and functional impairment, compared with placebo at 6 months in the randomized, double-blind PROMOTE trial, Philip G. Conaghan, MD, PhD, reported at the OARSI 2019 World Congress.

Bruce Jancin/MDedge News

There is, however, an asterisk attached to these findings. “Despite a moderate standard effect size, the treatment effect was smaller than some of the thresholds for what is considered clinically meaningful,” he noted at the meeting sponsored by the Osteoarthritis Research Society International.

That being said, the rheumatologist is convinced further investigation of methotrexate in osteoarthritis is warranted.

“I have to say that, unlike our earlier hydroxychloroquine trial, which was robustly negative with nothing more to say, I think there is a signal in this study. I need to understand the results of this trial better to understand if there is a subgroup we could treat with methotrexate. It’s a cheap drug, it’s readily available, and we’ve got a lot of experience with it,” noted Dr. Conaghan, professor of musculoskeletal medicine at the University of Leeds (England) and director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine.

The rationale for the 15-center PROMOTE trial is that synovitis is common in OA. Synovitis is associated with pain, methotrexate is the gold-standard treatment for synovitis in inflammatory forms of arthritis, and current treatments for OA are, to say the least, severely limited. Also, an earlier 30-patient, open-label pilot study of methotrexate in patients with painful knee OA conducted by Dr. Conaghan and coworkers suggested the drug was promising (Rheumatology [Oxford]. 2013 May;52[5]:888-92).

PROMOTE included 134 patients with symptomatic and radiographic knee OA who were randomized in double-blind fashion to 6 months of oral methotrexate at 10 mg titrated to a target dose of 25 mg/week or to placebo. All patients also received usual care with oral NSAIDs and/or acetaminophen. Their mean baseline knee pain on a 0-10 numeric rating scale was 6.6.

The primary endpoint, assessed at 6 months, was the difference between the two study arms in average knee pain during the previous week on a 0-10 scale. The score was 5.1 in the methotrexate group and 6.2 in the placebo arm, for a baseline-adjusted treatment difference of 0.83 points, which works out to a standard effect size of 0.36. When the data were reanalyzed after excluding the 15 patients who missed more than four doses of medication within any 3-month period, the between-group difference in pain scores increased to 0.95 points in favor of the methotrexate group.

A significant difference in favor of the methotrexate group was documented in the OARSI-OMERACT response rate at 6 months: 45% in the methotrexate group and 26% in the controls. Some secondary endpoints were positive as well, with statistically significant differences seen at 6 months in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) stiffness, WOMAC physical function, and several other endpoints. But there were no significant differences in WOMAC pain, SF-12 physical component or SF-12 mental component scores, or in an OA quality of life measure.

The mean dose of methotrexate used in the study was about 17 mg/week. Dr. Conaghan said that if he could do the trial over again, he would have used subcutaneous methotrexate.

“It’s a more reliable way of getting a dose into people and probably of getting a slightly higher dose into people. In the rheumatoid arthritis world, we use a lot more subcutaneous methotrexate now than we did 10 years ago because it gets around a lot of the minor side effects and helps compliance,” he said.

One audience member suggested that one potentially useful way to zero in on a subgroup of knee OA patients likely to derive the most benefit from methotrexate would be to have screened potential study participants for comorbid fibromyalgia and exclude those with the disorder. Dr. Conaghan replied that the PROMOTE investigators did gather data on participants’ pain at sites other than the knee. That data can be used to identify those at increased likelihood of fibromyalgia, and he agreed that’s worth looking into.

Dr. Conaghan reported having no financial conflicts regarding PROMOTE, which was funded by the U.K. National Institute for Health Research and Versus Arthritis.

bjancin@mdedge.com

SOURCE: Conaghan PG et al. OARSI 2019, Abstract 86.

TORONTO – Oral methotrexate therapy was associated with significant reductions in knee osteoarthritis pain, stiffness, and functional impairment, compared with placebo at 6 months in the randomized, double-blind PROMOTE trial, Philip G. Conaghan, MD, PhD, reported at the OARSI 2019 World Congress.

Bruce Jancin/MDedge News

There is, however, an asterisk attached to these findings. “Despite a moderate standard effect size, the treatment effect was smaller than some of the thresholds for what is considered clinically meaningful,” he noted at the meeting sponsored by the Osteoarthritis Research Society International.

That being said, the rheumatologist is convinced further investigation of methotrexate in osteoarthritis is warranted.

“I have to say that, unlike our earlier hydroxychloroquine trial, which was robustly negative with nothing more to say, I think there is a signal in this study. I need to understand the results of this trial better to understand if there is a subgroup we could treat with methotrexate. It’s a cheap drug, it’s readily available, and we’ve got a lot of experience with it,” noted Dr. Conaghan, professor of musculoskeletal medicine at the University of Leeds (England) and director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine.

The rationale for the 15-center PROMOTE trial is that synovitis is common in OA. Synovitis is associated with pain, methotrexate is the gold-standard treatment for synovitis in inflammatory forms of arthritis, and current treatments for OA are, to say the least, severely limited. Also, an earlier 30-patient, open-label pilot study of methotrexate in patients with painful knee OA conducted by Dr. Conaghan and coworkers suggested the drug was promising (Rheumatology [Oxford]. 2013 May;52[5]:888-92).

PROMOTE included 134 patients with symptomatic and radiographic knee OA who were randomized in double-blind fashion to 6 months of oral methotrexate at 10 mg titrated to a target dose of 25 mg/week or to placebo. All patients also received usual care with oral NSAIDs and/or acetaminophen. Their mean baseline knee pain on a 0-10 numeric rating scale was 6.6.

The primary endpoint, assessed at 6 months, was the difference between the two study arms in average knee pain during the previous week on a 0-10 scale. The score was 5.1 in the methotrexate group and 6.2 in the placebo arm, for a baseline-adjusted treatment difference of 0.83 points, which works out to a standard effect size of 0.36. When the data were reanalyzed after excluding the 15 patients who missed more than four doses of medication within any 3-month period, the between-group difference in pain scores increased to 0.95 points in favor of the methotrexate group.

A significant difference in favor of the methotrexate group was documented in the OARSI-OMERACT response rate at 6 months: 45% in the methotrexate group and 26% in the controls. Some secondary endpoints were positive as well, with statistically significant differences seen at 6 months in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) stiffness, WOMAC physical function, and several other endpoints. But there were no significant differences in WOMAC pain, SF-12 physical component or SF-12 mental component scores, or in an OA quality of life measure.

The mean dose of methotrexate used in the study was about 17 mg/week. Dr. Conaghan said that if he could do the trial over again, he would have used subcutaneous methotrexate.

“It’s a more reliable way of getting a dose into people and probably of getting a slightly higher dose into people. In the rheumatoid arthritis world, we use a lot more subcutaneous methotrexate now than we did 10 years ago because it gets around a lot of the minor side effects and helps compliance,” he said.

One audience member suggested that one potentially useful way to zero in on a subgroup of knee OA patients likely to derive the most benefit from methotrexate would be to have screened potential study participants for comorbid fibromyalgia and exclude those with the disorder. Dr. Conaghan replied that the PROMOTE investigators did gather data on participants’ pain at sites other than the knee. That data can be used to identify those at increased likelihood of fibromyalgia, and he agreed that’s worth looking into.

Dr. Conaghan reported having no financial conflicts regarding PROMOTE, which was funded by the U.K. National Institute for Health Research and Versus Arthritis.

bjancin@mdedge.com

SOURCE: Conaghan PG et al. OARSI 2019, Abstract 86.

TORONTO – Oral methotrexate therapy was associated with significant reductions in knee osteoarthritis pain, stiffness, and functional impairment, compared with placebo at 6 months in the randomized, double-blind PROMOTE trial, Philip G. Conaghan, MD, PhD, reported at the OARSI 2019 World Congress.

Bruce Jancin/MDedge News

There is, however, an asterisk attached to these findings. “Despite a moderate standard effect size, the treatment effect was smaller than some of the thresholds for what is considered clinically meaningful,” he noted at the meeting sponsored by the Osteoarthritis Research Society International.

That being said, the rheumatologist is convinced further investigation of methotrexate in osteoarthritis is warranted.

“I have to say that, unlike our earlier hydroxychloroquine trial, which was robustly negative with nothing more to say, I think there is a signal in this study. I need to understand the results of this trial better to understand if there is a subgroup we could treat with methotrexate. It’s a cheap drug, it’s readily available, and we’ve got a lot of experience with it,” noted Dr. Conaghan, professor of musculoskeletal medicine at the University of Leeds (England) and director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine.

The rationale for the 15-center PROMOTE trial is that synovitis is common in OA. Synovitis is associated with pain, methotrexate is the gold-standard treatment for synovitis in inflammatory forms of arthritis, and current treatments for OA are, to say the least, severely limited. Also, an earlier 30-patient, open-label pilot study of methotrexate in patients with painful knee OA conducted by Dr. Conaghan and coworkers suggested the drug was promising (Rheumatology [Oxford]. 2013 May;52[5]:888-92).

PROMOTE included 134 patients with symptomatic and radiographic knee OA who were randomized in double-blind fashion to 6 months of oral methotrexate at 10 mg titrated to a target dose of 25 mg/week or to placebo. All patients also received usual care with oral NSAIDs and/or acetaminophen. Their mean baseline knee pain on a 0-10 numeric rating scale was 6.6.

The primary endpoint, assessed at 6 months, was the difference between the two study arms in average knee pain during the previous week on a 0-10 scale. The score was 5.1 in the methotrexate group and 6.2 in the placebo arm, for a baseline-adjusted treatment difference of 0.83 points, which works out to a standard effect size of 0.36. When the data were reanalyzed after excluding the 15 patients who missed more than four doses of medication within any 3-month period, the between-group difference in pain scores increased to 0.95 points in favor of the methotrexate group.

A significant difference in favor of the methotrexate group was documented in the OARSI-OMERACT response rate at 6 months: 45% in the methotrexate group and 26% in the controls. Some secondary endpoints were positive as well, with statistically significant differences seen at 6 months in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) stiffness, WOMAC physical function, and several other endpoints. But there were no significant differences in WOMAC pain, SF-12 physical component or SF-12 mental component scores, or in an OA quality of life measure.

The mean dose of methotrexate used in the study was about 17 mg/week. Dr. Conaghan said that if he could do the trial over again, he would have used subcutaneous methotrexate.

“It’s a more reliable way of getting a dose into people and probably of getting a slightly higher dose into people. In the rheumatoid arthritis world, we use a lot more subcutaneous methotrexate now than we did 10 years ago because it gets around a lot of the minor side effects and helps compliance,” he said.

One audience member suggested that one potentially useful way to zero in on a subgroup of knee OA patients likely to derive the most benefit from methotrexate would be to have screened potential study participants for comorbid fibromyalgia and exclude those with the disorder. Dr. Conaghan replied that the PROMOTE investigators did gather data on participants’ pain at sites other than the knee. That data can be used to identify those at increased likelihood of fibromyalgia, and he agreed that’s worth looking into.

Dr. Conaghan reported having no financial conflicts regarding PROMOTE, which was funded by the U.K. National Institute for Health Research and Versus Arthritis.

bjancin@mdedge.com

SOURCE: Conaghan PG et al. OARSI 2019, Abstract 86.

SEATTLE – Among patients with active relapsing-remitting multiple sclerosis (MS) who have been treated with interferon beta-1a, switching to alemtuzumab improves clinical and MRI outcomes, according to an analysis presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. These outcomes may be maintained for 6 years without continuous treatment, said the investigators.

The CARE-MS II study demonstrated alemtuzumab’s superior efficacy, compared with subcutaneous interferon beta-1a, over 2 years in patients with active relapsing-remitting MS who had had an inadequate response to previous therapy. The trial was followed by a 4-year extension, during which patients who had received interferon beta-1a were given the option of discontinuing that therapy and initiating alemtuzumab. The alemtuzumab regimen for these patients was 12 mg/day for 5 consecutive days at baseline, and the same dose for 3 consecutive days at 1 year. Additional annual alemtuzumab as needed for disease activity was allowed. At investigators’ discretion, patients could receive other disease-modifying therapy (DMT) at any time. After the 4-year extension, patients could continue in the 5-year TOPAZ extension.

Carolina Ionete, MD, a neurologist at University of Massachusetts Memorial Medical Center in Worcester, and colleagues examined data from the TOPAZ extension study to evaluate the efficacy and safety of alemtuzumab over 6 years in patients with relapsing-remitting MS from CARE-MS II who discontinued interferon beta-1a. In TOPAZ, patients can receive additional alemtuzumab (12 mg/day on 3 consecutive days at 12 or more months after the most recent course) or other DMTs at any time at investigators’ discretion.

In all, 143 patients started alemtuzumab in the extension study. Of this group 117 patients (82%) completed year 2 of TOPAZ (i.e., year 6 after initiating alemtuzumab). The annualized relapse rate at year 6 was 0.19, and the annual rate of freedom from relapse ranged from 83% to 90% during years 1 through 6. At year 6, Expanded Disability Status Scale (EDSS) scores were stable (51%) or improved (17%) in 68% of patients, compared with the baseline of the main study. At year 6, the mean EDSS score change was 0.43. Over 6 years, 69% of patients were free from 6-month confirmed disability worsening, and 23% achieved 6-month confirmed disability improvement.

In addition, 69% of patients were free of MRI disease activity in year 6. The median percent cumulative brain volume loss from alemtuzumab initiation through year 6 was 0.53%, compared with 0.81% over 2 years with interferon beta-1a. Brain volume loss was 0.32% or less annually during years 2 through 6 after initiating alemtuzumab (0.04% at year 2, 0.15% at year 3, 0.14% at year 4, 0.07% at year 5, and 0.32% at year 6). These efficacy outcomes were observed as 57% of patients received neither additional alemtuzumab nor another DMT through year 6. Safety results were consistent with those for the alemtuzumab-treated patients in the core and extension studies.

Sanofi and Bayer HealthCare Pharmaceuticals supported this study. Dr. Ionete received research support from Biogen, Roche, and Sanofi. She reported receiving compensation for advisory board participation from Sanofi.

egreb@mdedge.com

SEATTLE – Among patients with active relapsing-remitting multiple sclerosis (MS) who have been treated with interferon beta-1a, switching to alemtuzumab improves clinical and MRI outcomes, according to an analysis presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. These outcomes may be maintained for 6 years without continuous treatment, said the investigators.

The CARE-MS II study demonstrated alemtuzumab’s superior efficacy, compared with subcutaneous interferon beta-1a, over 2 years in patients with active relapsing-remitting MS who had had an inadequate response to previous therapy. The trial was followed by a 4-year extension, during which patients who had received interferon beta-1a were given the option of discontinuing that therapy and initiating alemtuzumab. The alemtuzumab regimen for these patients was 12 mg/day for 5 consecutive days at baseline, and the same dose for 3 consecutive days at 1 year. Additional annual alemtuzumab as needed for disease activity was allowed. At investigators’ discretion, patients could receive other disease-modifying therapy (DMT) at any time. After the 4-year extension, patients could continue in the 5-year TOPAZ extension.

Carolina Ionete, MD, a neurologist at University of Massachusetts Memorial Medical Center in Worcester, and colleagues examined data from the TOPAZ extension study to evaluate the efficacy and safety of alemtuzumab over 6 years in patients with relapsing-remitting MS from CARE-MS II who discontinued interferon beta-1a. In TOPAZ, patients can receive additional alemtuzumab (12 mg/day on 3 consecutive days at 12 or more months after the most recent course) or other DMTs at any time at investigators’ discretion.

In all, 143 patients started alemtuzumab in the extension study. Of this group 117 patients (82%) completed year 2 of TOPAZ (i.e., year 6 after initiating alemtuzumab). The annualized relapse rate at year 6 was 0.19, and the annual rate of freedom from relapse ranged from 83% to 90% during years 1 through 6. At year 6, Expanded Disability Status Scale (EDSS) scores were stable (51%) or improved (17%) in 68% of patients, compared with the baseline of the main study. At year 6, the mean EDSS score change was 0.43. Over 6 years, 69% of patients were free from 6-month confirmed disability worsening, and 23% achieved 6-month confirmed disability improvement.

In addition, 69% of patients were free of MRI disease activity in year 6. The median percent cumulative brain volume loss from alemtuzumab initiation through year 6 was 0.53%, compared with 0.81% over 2 years with interferon beta-1a. Brain volume loss was 0.32% or less annually during years 2 through 6 after initiating alemtuzumab (0.04% at year 2, 0.15% at year 3, 0.14% at year 4, 0.07% at year 5, and 0.32% at year 6). These efficacy outcomes were observed as 57% of patients received neither additional alemtuzumab nor another DMT through year 6. Safety results were consistent with those for the alemtuzumab-treated patients in the core and extension studies.

Sanofi and Bayer HealthCare Pharmaceuticals supported this study. Dr. Ionete received research support from Biogen, Roche, and Sanofi. She reported receiving compensation for advisory board participation from Sanofi.

egreb@mdedge.com

SEATTLE – Among patients with active relapsing-remitting multiple sclerosis (MS) who have been treated with interferon beta-1a, switching to alemtuzumab improves clinical and MRI outcomes, according to an analysis presented at the annual meeting of the Consortium of Multiple Sclerosis Centers. These outcomes may be maintained for 6 years without continuous treatment, said the investigators.

The CARE-MS II study demonstrated alemtuzumab’s superior efficacy, compared with subcutaneous interferon beta-1a, over 2 years in patients with active relapsing-remitting MS who had had an inadequate response to previous therapy. The trial was followed by a 4-year extension, during which patients who had received interferon beta-1a were given the option of discontinuing that therapy and initiating alemtuzumab. The alemtuzumab regimen for these patients was 12 mg/day for 5 consecutive days at baseline, and the same dose for 3 consecutive days at 1 year. Additional annual alemtuzumab as needed for disease activity was allowed. At investigators’ discretion, patients could receive other disease-modifying therapy (DMT) at any time. After the 4-year extension, patients could continue in the 5-year TOPAZ extension.

Carolina Ionete, MD, a neurologist at University of Massachusetts Memorial Medical Center in Worcester, and colleagues examined data from the TOPAZ extension study to evaluate the efficacy and safety of alemtuzumab over 6 years in patients with relapsing-remitting MS from CARE-MS II who discontinued interferon beta-1a. In TOPAZ, patients can receive additional alemtuzumab (12 mg/day on 3 consecutive days at 12 or more months after the most recent course) or other DMTs at any time at investigators’ discretion.

In all, 143 patients started alemtuzumab in the extension study. Of this group 117 patients (82%) completed year 2 of TOPAZ (i.e., year 6 after initiating alemtuzumab). The annualized relapse rate at year 6 was 0.19, and the annual rate of freedom from relapse ranged from 83% to 90% during years 1 through 6. At year 6, Expanded Disability Status Scale (EDSS) scores were stable (51%) or improved (17%) in 68% of patients, compared with the baseline of the main study. At year 6, the mean EDSS score change was 0.43. Over 6 years, 69% of patients were free from 6-month confirmed disability worsening, and 23% achieved 6-month confirmed disability improvement.

In addition, 69% of patients were free of MRI disease activity in year 6. The median percent cumulative brain volume loss from alemtuzumab initiation through year 6 was 0.53%, compared with 0.81% over 2 years with interferon beta-1a. Brain volume loss was 0.32% or less annually during years 2 through 6 after initiating alemtuzumab (0.04% at year 2, 0.15% at year 3, 0.14% at year 4, 0.07% at year 5, and 0.32% at year 6). These efficacy outcomes were observed as 57% of patients received neither additional alemtuzumab nor another DMT through year 6. Safety results were consistent with those for the alemtuzumab-treated patients in the core and extension studies.

Sanofi and Bayer HealthCare Pharmaceuticals supported this study. Dr. Ionete received research support from Biogen, Roche, and Sanofi. She reported receiving compensation for advisory board participation from Sanofi.

egreb@mdedge.com

CHICAGO – For decades investigators have documented racial disparities in access to cancer care and in clinical outcomes, with socioeconomic factors suspected – but not conclusively proven – to play a role

Now a new study based on electronic health record (EHR) data shows that after Medicaid expansion under the Affordable Care Act (ACA), racial differences in timely cancer treatment effectively disappeared. Before Medicaid expansion, African Americans were 4.8% less likely than whites to receive timely cancer treatment, defined as treatment starting within 30 days of diagnosis of an advanced or metastatic solid tumor. After Medicaid expansion, however, the difference between the racial groups had dwindled to just 0.8% and was no longer statistically significant.

The findings suggest that the expanded availability of health insurance has had a salutary effect on cancer care.

In this video interview, co-authors Amy J. Davidoff, PhD, MS, from the Yale Cancer Center in New Haven Connecticut, and Blythe J.S. Adamson, PhD, from Flatiron Health in New York, New York, discuss the study findings and the possible implications for health care policy in the United States.

The study was funded by Flatiron Health. Dr. Adamson is an employee of the company. Dr. Davidoff disclosed consulting or advisory roles with and honoraria from several pharmaceutical companies.

CHICAGO – For decades investigators have documented racial disparities in access to cancer care and in clinical outcomes, with socioeconomic factors suspected – but not conclusively proven – to play a role

Now a new study based on electronic health record (EHR) data shows that after Medicaid expansion under the Affordable Care Act (ACA), racial differences in timely cancer treatment effectively disappeared. Before Medicaid expansion, African Americans were 4.8% less likely than whites to receive timely cancer treatment, defined as treatment starting within 30 days of diagnosis of an advanced or metastatic solid tumor. After Medicaid expansion, however, the difference between the racial groups had dwindled to just 0.8% and was no longer statistically significant.

The findings suggest that the expanded availability of health insurance has had a salutary effect on cancer care.

In this video interview, co-authors Amy J. Davidoff, PhD, MS, from the Yale Cancer Center in New Haven Connecticut, and Blythe J.S. Adamson, PhD, from Flatiron Health in New York, New York, discuss the study findings and the possible implications for health care policy in the United States.

The study was funded by Flatiron Health. Dr. Adamson is an employee of the company. Dr. Davidoff disclosed consulting or advisory roles with and honoraria from several pharmaceutical companies.

CHICAGO – For decades investigators have documented racial disparities in access to cancer care and in clinical outcomes, with socioeconomic factors suspected – but not conclusively proven – to play a role

Now a new study based on electronic health record (EHR) data shows that after Medicaid expansion under the Affordable Care Act (ACA), racial differences in timely cancer treatment effectively disappeared. Before Medicaid expansion, African Americans were 4.8% less likely than whites to receive timely cancer treatment, defined as treatment starting within 30 days of diagnosis of an advanced or metastatic solid tumor. After Medicaid expansion, however, the difference between the racial groups had dwindled to just 0.8% and was no longer statistically significant.

The findings suggest that the expanded availability of health insurance has had a salutary effect on cancer care.

In this video interview, co-authors Amy J. Davidoff, PhD, MS, from the Yale Cancer Center in New Haven Connecticut, and Blythe J.S. Adamson, PhD, from Flatiron Health in New York, New York, discuss the study findings and the possible implications for health care policy in the United States.

The study was funded by Flatiron Health. Dr. Adamson is an employee of the company. Dr. Davidoff disclosed consulting or advisory roles with and honoraria from several pharmaceutical companies.

CHICAGO – In 2014, the average time from diagnosis to treatment initiation for new cancer patients at the Cleveland Clinic was 29-41 days, depending on whether the patient was diagnosed internally or externally. That figure was not acceptable, said Brian J. Bolwell, MD, chairman of the Cleveland Clinic’s Taussig Cancer Institute.

Since then, the time-to-treat metric has improved dramatically, dropping 33%. Today, time to treat for new cancer patients is 25-31 days, depending on the site of diagnosis.

To get there, leaders at the cancer center examined the causes of delay within each of their disease programs. The analysis revealed that less than 20% of the time it was patient preferences that slowed down the initiation of treatment, but that more than 80% of the time the delay was on the part of their institution.

Dr. Bolwell said this led them to start tracking every newly diagnosed patient who came through the cancer center to ensure they didn’t fall through the cracks, and that they were treated as rapidly as possible.

But figuring out how to get patients to treatment quicker depended on the type of cancer they had, since each type of cancer had different challenges and different points of entry to the health care system.

“So for breast cancer, it turns out a lot of the challenges might be coordination of surgery because sometimes a general surgeon has to work with a reconstructive-plastic surgeon and coordinating the surgical schedules might drastically lengthen time to treat,” he said during an interview at the annual meeting of the American Society of Clinical Oncology.

They helped address that problem by scheduling breast cancer patients for surgery by the next available operating room slot, rather than doing the scheduling by surgeon.

There are additional barriers to achieving a rapid time to treat standard, including prior authorization, Dr. Bolwell said. But they are continuing to chip away at the metric, working within each cancer type to lower the obstacles to treatment. “I don’t think we’ll ever be satisfied with where we are,” Dr. Bolwell said.

Dr. Bolwell reported having no relevant financial disclosures.

mschneider@mdedge.com

CHICAGO – In 2014, the average time from diagnosis to treatment initiation for new cancer patients at the Cleveland Clinic was 29-41 days, depending on whether the patient was diagnosed internally or externally. That figure was not acceptable, said Brian J. Bolwell, MD, chairman of the Cleveland Clinic’s Taussig Cancer Institute.

Since then, the time-to-treat metric has improved dramatically, dropping 33%. Today, time to treat for new cancer patients is 25-31 days, depending on the site of diagnosis.

To get there, leaders at the cancer center examined the causes of delay within each of their disease programs. The analysis revealed that less than 20% of the time it was patient preferences that slowed down the initiation of treatment, but that more than 80% of the time the delay was on the part of their institution.

Dr. Bolwell said this led them to start tracking every newly diagnosed patient who came through the cancer center to ensure they didn’t fall through the cracks, and that they were treated as rapidly as possible.

But figuring out how to get patients to treatment quicker depended on the type of cancer they had, since each type of cancer had different challenges and different points of entry to the health care system.

“So for breast cancer, it turns out a lot of the challenges might be coordination of surgery because sometimes a general surgeon has to work with a reconstructive-plastic surgeon and coordinating the surgical schedules might drastically lengthen time to treat,” he said during an interview at the annual meeting of the American Society of Clinical Oncology.

They helped address that problem by scheduling breast cancer patients for surgery by the next available operating room slot, rather than doing the scheduling by surgeon.

There are additional barriers to achieving a rapid time to treat standard, including prior authorization, Dr. Bolwell said. But they are continuing to chip away at the metric, working within each cancer type to lower the obstacles to treatment. “I don’t think we’ll ever be satisfied with where we are,” Dr. Bolwell said.

Dr. Bolwell reported having no relevant financial disclosures.

mschneider@mdedge.com

CHICAGO – In 2014, the average time from diagnosis to treatment initiation for new cancer patients at the Cleveland Clinic was 29-41 days, depending on whether the patient was diagnosed internally or externally. That figure was not acceptable, said Brian J. Bolwell, MD, chairman of the Cleveland Clinic’s Taussig Cancer Institute.

Since then, the time-to-treat metric has improved dramatically, dropping 33%. Today, time to treat for new cancer patients is 25-31 days, depending on the site of diagnosis.

To get there, leaders at the cancer center examined the causes of delay within each of their disease programs. The analysis revealed that less than 20% of the time it was patient preferences that slowed down the initiation of treatment, but that more than 80% of the time the delay was on the part of their institution.

Dr. Bolwell said this led them to start tracking every newly diagnosed patient who came through the cancer center to ensure they didn’t fall through the cracks, and that they were treated as rapidly as possible.

But figuring out how to get patients to treatment quicker depended on the type of cancer they had, since each type of cancer had different challenges and different points of entry to the health care system.

“So for breast cancer, it turns out a lot of the challenges might be coordination of surgery because sometimes a general surgeon has to work with a reconstructive-plastic surgeon and coordinating the surgical schedules might drastically lengthen time to treat,” he said during an interview at the annual meeting of the American Society of Clinical Oncology.

They helped address that problem by scheduling breast cancer patients for surgery by the next available operating room slot, rather than doing the scheduling by surgeon.

There are additional barriers to achieving a rapid time to treat standard, including prior authorization, Dr. Bolwell said. But they are continuing to chip away at the metric, working within each cancer type to lower the obstacles to treatment. “I don’t think we’ll ever be satisfied with where we are,” Dr. Bolwell said.

Dr. Bolwell reported having no relevant financial disclosures.

mschneider@mdedge.com

SAN DIEGO – There is no significant increased risk of dementia among patients who use proton pump inhibitors, compared with those who don’t, results from a systematic meta-analysis suggest.

Doug Brunk/MDedge News

The finding runs counter to recent studies, including a large pharmacoepidemiological claims data analysis from Germany, that propose an association between proton pump inhibitor (PPI) use and the development of dementia (JAMA Neurol. 2016;73[4]:410-6). “The issue with these studies is that they’re based on retrospective claims data and pharmacoepidemiological studies and insurance databases that don’t really give you a good causality basis,” lead study author Saad Alrajhi, MD, said in an interview at the annual Digestive Disease Week.

In an effort to better characterize the association between PPI exposure and dementia, Dr. Alrajhi, a gastroenterology fellow at McGill University, Montreal, and colleagues conducted a meta-analysis of all fully published randomized clinical trials or observational studies comparing use of PPIs and occurrence of dementia. The researchers queried Embase, MEDLINE, and ISI Web of Knowledge for relevant studies that were published from 1995 through September 2018. Next, they assessed the quality of the studies by using the Cochrane risk assessment tool for RCTs or the Newcastle-Ottawa Scale for observational studies.

As the primary outcome, the researchers compared dementia incidence after PPI exposure (experimental group) versus no PPI exposure (control group). Development of Alzheimer’s dementia was a secondary outcome. Sensitivity analyses consisted of excluding one study at a time, and assessing results among studies of highest qualities. Subgroup analyses included stratifying patients by age. To report odds ratios, Dr. Alrajhi and colleagues used fixed or random effects models based on the absence or presence of heterogeneity.


Of 549 studies assessed, 5 met the criteria for inclusion in the final analysis: 3 case-control studies and 2 cohort studies, with a total of 472,933 patients. All of the studies scored 8 or 9 on the Newcastle-Ottawa scale, indicating high quality. Significant heterogeneity was noted for all analyses. The researchers found that the incidence of dementia was not significantly increased among patients in the PPI-exposed group (odd ratio, 1.08 (95% confidence interval, 0.97-1.20; P = .18). Sensitivity analyses confirmed the robustness of the results. Subgroup analysis showed no between-group differences among studies that included a minimum age above 65 years (three studies) or less than age 65 (two studies). PPI exposure was not associated with the development of Alzheimer’s dementia (two studies) (OR, 1.32 (95% CI, 0.80-2.17; P = .27).

“In the absence of randomized trial evidence, a PPI prescribing approach based on appropriate utilization of guideline-based prescription should be done without the extra fear of the association of dementia,” Dr. Alrajhi said.

The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SAN DIEGO – There is no significant increased risk of dementia among patients who use proton pump inhibitors, compared with those who don’t, results from a systematic meta-analysis suggest.

Doug Brunk/MDedge News

The finding runs counter to recent studies, including a large pharmacoepidemiological claims data analysis from Germany, that propose an association between proton pump inhibitor (PPI) use and the development of dementia (JAMA Neurol. 2016;73[4]:410-6). “The issue with these studies is that they’re based on retrospective claims data and pharmacoepidemiological studies and insurance databases that don’t really give you a good causality basis,” lead study author Saad Alrajhi, MD, said in an interview at the annual Digestive Disease Week.

In an effort to better characterize the association between PPI exposure and dementia, Dr. Alrajhi, a gastroenterology fellow at McGill University, Montreal, and colleagues conducted a meta-analysis of all fully published randomized clinical trials or observational studies comparing use of PPIs and occurrence of dementia. The researchers queried Embase, MEDLINE, and ISI Web of Knowledge for relevant studies that were published from 1995 through September 2018. Next, they assessed the quality of the studies by using the Cochrane risk assessment tool for RCTs or the Newcastle-Ottawa Scale for observational studies.

As the primary outcome, the researchers compared dementia incidence after PPI exposure (experimental group) versus no PPI exposure (control group). Development of Alzheimer’s dementia was a secondary outcome. Sensitivity analyses consisted of excluding one study at a time, and assessing results among studies of highest qualities. Subgroup analyses included stratifying patients by age. To report odds ratios, Dr. Alrajhi and colleagues used fixed or random effects models based on the absence or presence of heterogeneity.


Of 549 studies assessed, 5 met the criteria for inclusion in the final analysis: 3 case-control studies and 2 cohort studies, with a total of 472,933 patients. All of the studies scored 8 or 9 on the Newcastle-Ottawa scale, indicating high quality. Significant heterogeneity was noted for all analyses. The researchers found that the incidence of dementia was not significantly increased among patients in the PPI-exposed group (odd ratio, 1.08 (95% confidence interval, 0.97-1.20; P = .18). Sensitivity analyses confirmed the robustness of the results. Subgroup analysis showed no between-group differences among studies that included a minimum age above 65 years (three studies) or less than age 65 (two studies). PPI exposure was not associated with the development of Alzheimer’s dementia (two studies) (OR, 1.32 (95% CI, 0.80-2.17; P = .27).

“In the absence of randomized trial evidence, a PPI prescribing approach based on appropriate utilization of guideline-based prescription should be done without the extra fear of the association of dementia,” Dr. Alrajhi said.

The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SAN DIEGO – There is no significant increased risk of dementia among patients who use proton pump inhibitors, compared with those who don’t, results from a systematic meta-analysis suggest.

Doug Brunk/MDedge News

The finding runs counter to recent studies, including a large pharmacoepidemiological claims data analysis from Germany, that propose an association between proton pump inhibitor (PPI) use and the development of dementia (JAMA Neurol. 2016;73[4]:410-6). “The issue with these studies is that they’re based on retrospective claims data and pharmacoepidemiological studies and insurance databases that don’t really give you a good causality basis,” lead study author Saad Alrajhi, MD, said in an interview at the annual Digestive Disease Week.

In an effort to better characterize the association between PPI exposure and dementia, Dr. Alrajhi, a gastroenterology fellow at McGill University, Montreal, and colleagues conducted a meta-analysis of all fully published randomized clinical trials or observational studies comparing use of PPIs and occurrence of dementia. The researchers queried Embase, MEDLINE, and ISI Web of Knowledge for relevant studies that were published from 1995 through September 2018. Next, they assessed the quality of the studies by using the Cochrane risk assessment tool for RCTs or the Newcastle-Ottawa Scale for observational studies.

As the primary outcome, the researchers compared dementia incidence after PPI exposure (experimental group) versus no PPI exposure (control group). Development of Alzheimer’s dementia was a secondary outcome. Sensitivity analyses consisted of excluding one study at a time, and assessing results among studies of highest qualities. Subgroup analyses included stratifying patients by age. To report odds ratios, Dr. Alrajhi and colleagues used fixed or random effects models based on the absence or presence of heterogeneity.


Of 549 studies assessed, 5 met the criteria for inclusion in the final analysis: 3 case-control studies and 2 cohort studies, with a total of 472,933 patients. All of the studies scored 8 or 9 on the Newcastle-Ottawa scale, indicating high quality. Significant heterogeneity was noted for all analyses. The researchers found that the incidence of dementia was not significantly increased among patients in the PPI-exposed group (odd ratio, 1.08 (95% confidence interval, 0.97-1.20; P = .18). Sensitivity analyses confirmed the robustness of the results. Subgroup analysis showed no between-group differences among studies that included a minimum age above 65 years (three studies) or less than age 65 (two studies). PPI exposure was not associated with the development of Alzheimer’s dementia (two studies) (OR, 1.32 (95% CI, 0.80-2.17; P = .27).

“In the absence of randomized trial evidence, a PPI prescribing approach based on appropriate utilization of guideline-based prescription should be done without the extra fear of the association of dementia,” Dr. Alrajhi said.

The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SEATTLE – Failed in-vitro fertilization (IVF) treatment appears to boost the risk of relapse in women with multiple sclerosis (MS). Does successful IVF have the same effect? The preliminary results of a new study suggests it does, a finding that may influence how physicians track patients during pregnancy.

“We found that IVF can still cause a relapse even if it is successful,” study lead author Maria Claudia Manieri, a graduate student at Harvard Medical School’s Partners MS Center, said in an interview at the annual meeting of the Consortium of Multiple Sclerosis Centers, where she presented the findings.

Multiple studies have linked infertility treatment in women with MS to relapses. In a 2013 review, researchers analyzed several papers, and “all of them reported an increase in annualized relapse rate after ART [assisted reproductive treatment]. Furthermore, in a recent study, clinical worsening was associated with an increase in MRI activity” (Clin Immunol. 2013 Nov;149(2):219-24).

For the new report, based on statistics from the New England Multiple Sclerosis Pregnancy Prospective Cohort Study, Ms. Manieri and colleagues collected data on 91 women (mean age = 33). Eleven were unsuccessful in conceiving, and 80 successfully conceived.

Three of the 91 women (3%) used intrauterine insemination as a fertility treatment. Another 9 (10%) relied on ART; all used IVF except for 1 who underwent intracytoplasmic sperm injection.

The new report is a preliminary analysis of early data, Ms. Manieri said. The study has recruited about one-sixth of its participants, she said, and will track women beyond pregnancy to explore long-term outcomes in their children.

Eleven women relapsed during pregnancy, including 9 who were using fertility treatment (P = .003). Of those 9, 7 women (78%) used ART.

No other factor other than fertility treatment predicted intrapartum relapses. The relapses during pregnancy started at 21 weeks (± 12 weeks) of gestational age and lasted for 4 weeks (± 2 weeks).

Of those who successfully conceived, 4 of 5 (80%) who used fertility treatment relapsed, compared with 7 of 64 (11%) who didn’t use fertility treatment. Of women who did not successfully conceive, 2 of 3 (67%) relapsed among those who used fertility treatment vs. 1 of 7 (14%) of those who didn’t.

It’s not clear how infertility treatment may be boosting MS relapse in women, but the 2013 review offered these possibilities: “temporary interruption of disease modified therapies, stressful events associated with infertility, and immunological changes induced by hormones such as increase in pro-inflammatory cytokines and anti-MOG antibodies, as well as an increase in immune cell migration across the blood-brain-barrier.”

MS tends to improve during pregnancy, and it’s common for neurologists to not see patients for extended periods, Ms. Manieri said. In light of the findings, she said, it may be wise for neurologists to continue follow-up appointments during pregnancy. “Avoid delaying care and keep monitoring the patient,” she advised.

The study was funded by Sanofi Genzyme and a gift from Michelle and Christopher Rondeau. The study authors report no relevant disclosures.

SEATTLE – Failed in-vitro fertilization (IVF) treatment appears to boost the risk of relapse in women with multiple sclerosis (MS). Does successful IVF have the same effect? The preliminary results of a new study suggests it does, a finding that may influence how physicians track patients during pregnancy.

“We found that IVF can still cause a relapse even if it is successful,” study lead author Maria Claudia Manieri, a graduate student at Harvard Medical School’s Partners MS Center, said in an interview at the annual meeting of the Consortium of Multiple Sclerosis Centers, where she presented the findings.

Multiple studies have linked infertility treatment in women with MS to relapses. In a 2013 review, researchers analyzed several papers, and “all of them reported an increase in annualized relapse rate after ART [assisted reproductive treatment]. Furthermore, in a recent study, clinical worsening was associated with an increase in MRI activity” (Clin Immunol. 2013 Nov;149(2):219-24).

For the new report, based on statistics from the New England Multiple Sclerosis Pregnancy Prospective Cohort Study, Ms. Manieri and colleagues collected data on 91 women (mean age = 33). Eleven were unsuccessful in conceiving, and 80 successfully conceived.

Three of the 91 women (3%) used intrauterine insemination as a fertility treatment. Another 9 (10%) relied on ART; all used IVF except for 1 who underwent intracytoplasmic sperm injection.

The new report is a preliminary analysis of early data, Ms. Manieri said. The study has recruited about one-sixth of its participants, she said, and will track women beyond pregnancy to explore long-term outcomes in their children.

Eleven women relapsed during pregnancy, including 9 who were using fertility treatment (P = .003). Of those 9, 7 women (78%) used ART.

No other factor other than fertility treatment predicted intrapartum relapses. The relapses during pregnancy started at 21 weeks (± 12 weeks) of gestational age and lasted for 4 weeks (± 2 weeks).

Of those who successfully conceived, 4 of 5 (80%) who used fertility treatment relapsed, compared with 7 of 64 (11%) who didn’t use fertility treatment. Of women who did not successfully conceive, 2 of 3 (67%) relapsed among those who used fertility treatment vs. 1 of 7 (14%) of those who didn’t.

It’s not clear how infertility treatment may be boosting MS relapse in women, but the 2013 review offered these possibilities: “temporary interruption of disease modified therapies, stressful events associated with infertility, and immunological changes induced by hormones such as increase in pro-inflammatory cytokines and anti-MOG antibodies, as well as an increase in immune cell migration across the blood-brain-barrier.”

MS tends to improve during pregnancy, and it’s common for neurologists to not see patients for extended periods, Ms. Manieri said. In light of the findings, she said, it may be wise for neurologists to continue follow-up appointments during pregnancy. “Avoid delaying care and keep monitoring the patient,” she advised.

The study was funded by Sanofi Genzyme and a gift from Michelle and Christopher Rondeau. The study authors report no relevant disclosures.

SEATTLE – Failed in-vitro fertilization (IVF) treatment appears to boost the risk of relapse in women with multiple sclerosis (MS). Does successful IVF have the same effect? The preliminary results of a new study suggests it does, a finding that may influence how physicians track patients during pregnancy.

“We found that IVF can still cause a relapse even if it is successful,” study lead author Maria Claudia Manieri, a graduate student at Harvard Medical School’s Partners MS Center, said in an interview at the annual meeting of the Consortium of Multiple Sclerosis Centers, where she presented the findings.

Multiple studies have linked infertility treatment in women with MS to relapses. In a 2013 review, researchers analyzed several papers, and “all of them reported an increase in annualized relapse rate after ART [assisted reproductive treatment]. Furthermore, in a recent study, clinical worsening was associated with an increase in MRI activity” (Clin Immunol. 2013 Nov;149(2):219-24).

For the new report, based on statistics from the New England Multiple Sclerosis Pregnancy Prospective Cohort Study, Ms. Manieri and colleagues collected data on 91 women (mean age = 33). Eleven were unsuccessful in conceiving, and 80 successfully conceived.

Three of the 91 women (3%) used intrauterine insemination as a fertility treatment. Another 9 (10%) relied on ART; all used IVF except for 1 who underwent intracytoplasmic sperm injection.

The new report is a preliminary analysis of early data, Ms. Manieri said. The study has recruited about one-sixth of its participants, she said, and will track women beyond pregnancy to explore long-term outcomes in their children.

Eleven women relapsed during pregnancy, including 9 who were using fertility treatment (P = .003). Of those 9, 7 women (78%) used ART.

No other factor other than fertility treatment predicted intrapartum relapses. The relapses during pregnancy started at 21 weeks (± 12 weeks) of gestational age and lasted for 4 weeks (± 2 weeks).

Of those who successfully conceived, 4 of 5 (80%) who used fertility treatment relapsed, compared with 7 of 64 (11%) who didn’t use fertility treatment. Of women who did not successfully conceive, 2 of 3 (67%) relapsed among those who used fertility treatment vs. 1 of 7 (14%) of those who didn’t.

It’s not clear how infertility treatment may be boosting MS relapse in women, but the 2013 review offered these possibilities: “temporary interruption of disease modified therapies, stressful events associated with infertility, and immunological changes induced by hormones such as increase in pro-inflammatory cytokines and anti-MOG antibodies, as well as an increase in immune cell migration across the blood-brain-barrier.”

MS tends to improve during pregnancy, and it’s common for neurologists to not see patients for extended periods, Ms. Manieri said. In light of the findings, she said, it may be wise for neurologists to continue follow-up appointments during pregnancy. “Avoid delaying care and keep monitoring the patient,” she advised.

The study was funded by Sanofi Genzyme and a gift from Michelle and Christopher Rondeau. The study authors report no relevant disclosures.

Cediranib was found to confer sensitivity to olaparib through downregulation of the homology-directed DNA repair (HDR) pathway in tumor cells, investigators report.

“The objective of this study was to define the effects of cediranib on the HDR pathway of DNA repair,” wrote Alanna R. Kaplan, MD, of Yale University, New Haven, Conn., and colleagues. The report is in Science Translational Medicine.

The researchers explored the effects of combination cediranib and olaparib therapy at the molecular level using various in vitro and in vivo experiments. Tumor growth studies were conducted in a mouse model with sample sizes selected based on prior experience.

“In vitro experiments were performed in biological triplicate unless otherwise stated,” the researchers wrote. “For in vivo experiments, mice were randomly assigned to treatment groups,” they added.

After analysis, the researchers found that cediranib provides sensitivity to olaparib through suppression of the HDR pathway in malignant cells. The downregulation was explained in part by the inducement of hypoxia, which inhibited gene expression of certain factors in the pathway.

“We noted a decrease in the expression of HDR factors BRCA1, BRCA2, and RAD51 in the cediranib-treated groups compared to controls,” the researchers explained.

In addition, the team reported that cediranib alone exhibits direct effects on the HDR pathway outside of mechanisms related to tumor hypoxia.

“This downregulation was seen in mouse tumor xenografts but not in mouse bone marrow, providing a therapeutic window for combining cediranib and olaparib in cancer therapy,” the team wrote.

The researchers acknowledged that a key limitation of the study was the lack of inquiry into the effects of other mutations on the HDR pathway, which could possibly influence the effects of cediranib in tumor cells.

“These findings identify a pathway by which cediranib can alter the DNA repair capacity of cancer cells that has implications for the design of cancer therapies,” the authors concluded.

The study was supported by grant funding from the National Institutes of Health. One of the researchers reported financial affiliations with Trucode Gene Repair, Cybrexa Therapeutics, and Patrys.

SOURCE: Kaplan AR et al. Sci Transl Med. 2019 May 15. doi: 10.1126/scitranslmed.aav4508.

Cediranib was found to confer sensitivity to olaparib through downregulation of the homology-directed DNA repair (HDR) pathway in tumor cells, investigators report.

“The objective of this study was to define the effects of cediranib on the HDR pathway of DNA repair,” wrote Alanna R. Kaplan, MD, of Yale University, New Haven, Conn., and colleagues. The report is in Science Translational Medicine.

The researchers explored the effects of combination cediranib and olaparib therapy at the molecular level using various in vitro and in vivo experiments. Tumor growth studies were conducted in a mouse model with sample sizes selected based on prior experience.

“In vitro experiments were performed in biological triplicate unless otherwise stated,” the researchers wrote. “For in vivo experiments, mice were randomly assigned to treatment groups,” they added.

After analysis, the researchers found that cediranib provides sensitivity to olaparib through suppression of the HDR pathway in malignant cells. The downregulation was explained in part by the inducement of hypoxia, which inhibited gene expression of certain factors in the pathway.

“We noted a decrease in the expression of HDR factors BRCA1, BRCA2, and RAD51 in the cediranib-treated groups compared to controls,” the researchers explained.

In addition, the team reported that cediranib alone exhibits direct effects on the HDR pathway outside of mechanisms related to tumor hypoxia.

“This downregulation was seen in mouse tumor xenografts but not in mouse bone marrow, providing a therapeutic window for combining cediranib and olaparib in cancer therapy,” the team wrote.

The researchers acknowledged that a key limitation of the study was the lack of inquiry into the effects of other mutations on the HDR pathway, which could possibly influence the effects of cediranib in tumor cells.

“These findings identify a pathway by which cediranib can alter the DNA repair capacity of cancer cells that has implications for the design of cancer therapies,” the authors concluded.

The study was supported by grant funding from the National Institutes of Health. One of the researchers reported financial affiliations with Trucode Gene Repair, Cybrexa Therapeutics, and Patrys.

SOURCE: Kaplan AR et al. Sci Transl Med. 2019 May 15. doi: 10.1126/scitranslmed.aav4508.

Cediranib was found to confer sensitivity to olaparib through downregulation of the homology-directed DNA repair (HDR) pathway in tumor cells, investigators report.

“The objective of this study was to define the effects of cediranib on the HDR pathway of DNA repair,” wrote Alanna R. Kaplan, MD, of Yale University, New Haven, Conn., and colleagues. The report is in Science Translational Medicine.

The researchers explored the effects of combination cediranib and olaparib therapy at the molecular level using various in vitro and in vivo experiments. Tumor growth studies were conducted in a mouse model with sample sizes selected based on prior experience.

“In vitro experiments were performed in biological triplicate unless otherwise stated,” the researchers wrote. “For in vivo experiments, mice were randomly assigned to treatment groups,” they added.

After analysis, the researchers found that cediranib provides sensitivity to olaparib through suppression of the HDR pathway in malignant cells. The downregulation was explained in part by the inducement of hypoxia, which inhibited gene expression of certain factors in the pathway.

“We noted a decrease in the expression of HDR factors BRCA1, BRCA2, and RAD51 in the cediranib-treated groups compared to controls,” the researchers explained.

In addition, the team reported that cediranib alone exhibits direct effects on the HDR pathway outside of mechanisms related to tumor hypoxia.

“This downregulation was seen in mouse tumor xenografts but not in mouse bone marrow, providing a therapeutic window for combining cediranib and olaparib in cancer therapy,” the team wrote.

The researchers acknowledged that a key limitation of the study was the lack of inquiry into the effects of other mutations on the HDR pathway, which could possibly influence the effects of cediranib in tumor cells.

“These findings identify a pathway by which cediranib can alter the DNA repair capacity of cancer cells that has implications for the design of cancer therapies,” the authors concluded.

The study was supported by grant funding from the National Institutes of Health. One of the researchers reported financial affiliations with Trucode Gene Repair, Cybrexa Therapeutics, and Patrys.

SOURCE: Kaplan AR et al. Sci Transl Med. 2019 May 15. doi: 10.1126/scitranslmed.aav4508.

Measles, an ancient, highly contagious disease with a history of successful control by vaccination, is now threatening to have an epidemic resurgence. Until recently, measles vaccination largely controlled outbreaks in the United States. The Global Vaccine Action Plan under the World Health Organization aimed to eliminate measles worldwide. Nonetheless, the vaccine refusal movement and slow rollout of vaccine programs globally have interfered with control of the virus. A record number of measles cases have emerged in recent months: more than 700 since January 2019.¹ Approximately 70% of recent cases were in unvaccinated patients, and almost all were in US residents.

This update reviews the history, presentation and diagnosis, complications, management, contagion control, and emerging threat of a measles epidemic. It concludes with recommendations for clinical practice in the context of the current measles outbreaks.

FROM UBIQUITOUS TO ERADICATED—AND BACK

Before the measles vaccine was developed and became available in the 1960s, outbreaks of measles occurred predictably every year in the United States and other temperate regions. During yearly outbreaks, measles was so contagious that household contacts had attack rates above 95%. Most cases occurred in very young children, and because infection with the virus causes lifelong immunity, it could be safely assumed that by adulthood, everyone was immune. In an outbreak in the Faroe Islands in 1846, no one who had been alive in the last major outbreak 65 years earlier became ill, but everyone under age 65 was at high risk with “high attack rates,” estimated as 99% from other outbreaks (reviewed by Krugman et al²).

In isolated regions previously free of measles, adults did not have immunity, and when exposed, they often developed severe disease. When European settlers brought measles and smallpox to the Americas beginning in the late 15th century, these diseases decimated whole populations of native peoples who had never been exposed to them.

From the US Centers for Disease Control and Prevention.

That was premature. A number of outbreaks have occurred since then; the largest in the United States (before 2019) was in 2000. Over half of the 667 cases reported during that outbreak were in an underimmunized Amish community in Ohio.³

Now it emerges again.

PRESENTATION CAN VARY

From the US Centers for Disease Control and Prevention.

From the US Centers for Disease Control and Prevention.

The presentation varies somewhat among certain groups.

Nonimmune pregnant women have an especially severe course, likely related to the relative immune suppression of pregnancy.

In immune-suppressed states, measles is not only more severe, it is also difficult to diagnose because the rash can be absent.

In partially vaccinated children and adults, the disease may present atypically, without cough, conjunctivitis, and coryza, and it may be milder, lacking some of the extreme malaise typical of measles and with a shortened course. Measles infection in people who received the inactivated measles vaccine that was briefly available from 1963 to 1967 is also associated with atypical measles syndrome, a severe hypersensitivity reaction to the measles virus. Atypical measles can be prevented by revaccination with a live-virus vaccine.

 

 

DIAGNOSIS MAY NEED TO BE CONFIRMED

The diagnosis of measles is straightforward when all of the signs and symptoms are present. In partially vaccinated populations, however, the diagnosis may need to be confirmed by serologic or polymerase chain reaction (PCR) testing.

Differential diagnosis

The differential diagnosis of the fever and a rash typical of measles in children, especially when accompanied by severe malaise, includes the following:

Kawasaki disease. However, the red eyes of Kawasaki are an injection of the bulbar conjunctivae with sparing of the limbus. No eye exudate is present, and respiratory illness is not part of the disease.

Drug eruptions can present with a morbilliform rash and sometimes fever, but not the other signs of measles in either adults or children.

Scarlet fever has a different rash, the sandpaper rash typical of toxin-mediated disease.

Rubella tends to cause mild respiratory symptoms and illness rather than the severe disease of measles and other rash-causing viral infections in children and infants.

Confirmation in confusing cases

To confirm a diagnosis of measles, samples from throat, nasal, and posterior nasopharyngeal swabs should be collected with a blood specimen for serology and sent to the state public health laboratory.⁴ The US Centers for Disease Control and Prevention gives instructions on who should be tested and with which tests.⁴

Most testing now uses PCR for viral RNA, as viral culture is more costly and takes longer. For accurate diagnosis, samples for PCR must be obtained during the acute illness.

The serologic gold standard for diagnosis is a 4-fold rise or fall in immunoglobulin G (IgG) titer of paired serum samples sent 10 days to 2 weeks apart around the illness. The IgM test may be negative initially, and a negative test cannot be used to rule out the diagnosis. Confirmed cases should be reported to public health authorities.

COMPLICATIONS: EARLY AND LATE

Frequent complications of measles infection include those related to the primary viral infection of respiratory tract mucosal surfaces, as well as bacterial superinfections. Complications are most likely in children under age 5, nonimmune adults, pregnant women, and immunocompromised people. Typical complications include otitis media, laryngotracheobronchitis (presenting as a croupy cough), pneumonia, and diarrhea.

Late sequelae of measles infection are related in part to serious mucosal damage and generalized immune suppression caused by the virus. Even after recovery from acute infection, children can have persistent diarrhea and failure to thrive, with increased mortality risk in the months after infection. Tuberculosis can reactivate in patients already infected, and new tuberculosis infection can be especially severe. Further, tuberculosis skin tests become less reliable immediately after measles infection. Severe disease and fatalities are increased in populations that have baseline vitamin A deficiency and malnutrition.

Death from measles is most often caused by viral pneumonia, secondary bacterial pneumonia, and postviral encephalitis. Before the vaccine era, measles encephalitis occurred in the United States in about 1 in 1,000 measles cases.

Subacute sclerosing panencephalitis is a rare, late, and often fatal complication of measles that presents 7 to 10 years after acute measles infection, usually in adolescence. Beginning with myoclonic jerks, stiffening, and slow mental deterioration, it progresses over 1 to 3 years, with a relentless degenerative course leading to death. Since the introduction of the measles vaccine in 1957, this disease has essentially disappeared in the United States.

SUPPORTIVE CARE, INFECTION CONTROL

Management of measles and its complications is primarily supportive.

Preventing contagion

Measles infection has an incubation period of 8 to 12 days. Individuals are contagious 4 days before to 4 days after rash onset in the normal host but longer in those lacking immune function. Cases can occur up to 21 days after exposure during the contagious period.

The disease is highly contagious, so hospitalized patients should be cared for with airborne precautions. It is crucial that caretakers be vaccinated properly, so that they can care for patients safely. Recommendations for preventing secondary cases by prompt vaccination and giving immune globulin are detailed below, including specific recommendations for individuals with immune system suppression.

The current US public health policy regarding measles vaccine booster doses began in response to the widespread measles outbreak in the United States from 1989 to 1991. Cases occurred more commonly in unvaccinated individuals and in young adults who had received only 1 dose of vaccine.

Today, the policy in areas where measles has been controlled is to vaccinate between 12 and 15 months of age and to boost with a second dose before starting kindergarten. In outbreak situations, the first dose should be given at 6 months of age, with a repeat dose at 12 to 15 months of age and the usual booster before starting kindergarten.

Those born before 1957 can be presumed to have had natural measles, which confers lifelong immunity (Table 3).⁷

 

 

CURRENT THREAT

In 2000, measles was considered controlled in the United States, thanks to the national vaccination policy. But despite overall control, small numbers of cases continued to occur each year, related to exposure to cases imported from areas of the world endemic with measles.

Within the last year, however, major outbreaks have emerged. Incompletely vaccinated populations and unvaccinated individuals are the reason for the progression of current outbreaks.⁸

Until there is broader acceptance of the vaccine and better adherence to vaccine policies nationally and globally, measles cannot be completely eradicated. But with high vaccination rates, it is predicted that this infection can be controlled and ultimately eradicated.

RECOMMENDATIONS

In the midst of an outbreak and with rising public awareness of the threat of measles, it is important to recognize that MMR vaccination is the most effective way to prevent spread of the virus and maintain measles elimination in the United States. With this in mind, there are several key facts and recommendations regarding vaccination:

Recommendations on vaccination

• In measles-controlled populations, all children should be vaccinated between 12 and 15 months of age and again before kindergarten.
• In outbreak settings, children should receive a first vaccine dose at 6 months of age, a second at 12 to 15 months of age, and a third before kindergarten.
• Children who have received 2 measles vaccine doses can be assumed to be fully vaccinated and thus protected as long as the first dose was after 12 months of age. If the first dose was before 12 months of age, a child needs 3 doses.
• Adults born before 1957 can be assumed to have had measles infection and to be immune.
• Adults who were immunized with the inactivated measles vaccine available between 1963 and 1967 should receive 1 dose of live virus vaccine.
• Boosters are recommended for young adults who did not receive a second dose of vaccine and for adults with an uncertain history of immunization. There is no need to check titers before giving a booster, but if a positive titer is available in an adult, a booster is not needed.
• Heathcare providers should vaccinate unvaccinated or undervaccinated US residents traveling internationally (as long as they do not have contraindications) or traveling within the country to areas with outbreaks of measles.

Recommendations on vaccination after exposure to measles

• Vaccine is recommended for a nonimmune contact, including anyone with a history of only a single dose of vaccine.
• If a child got a first dose of vaccine before 12 months of age, give the second dose as soon as he or she turns 1 year old, or at least 28 days after the first dose.
• Vaccine must be given within 72 hours of exposure to confer protection (or at least decrease disease severity).
• The second dose of vaccine should be given at least 28 days after the first dose.

Recommendations on immune globulin after exposure to measles

• Immune globulin is recommended for anyone with exposure and no history of vaccination or immunity.
• Immune globulin can be given up to 6 days after exposure to prevent or decrease the severity of measles in immunocompromised hosts who have not been previously vaccinated. It is best to give it as early as possible.
• Immune globulin is given intramuscularly at 0.5 mL/kg, up to a to maximum dose of 15 mL.
• Pregnant women and immunocompromised hosts without immunity should receive immunoglobulin intravenously. Children and adults who have had a recent bone marrow transplant and likely do not yet have a reconstituted immune system should be treated with immune globulin to prevent infection, as vaccine cannot be given immediately after transplant. This is also true for other immunocompromised individuals who have not been vaccinated and who are not candidates for vaccine because of the severity of their immune suppression.
• Children with human immunodeficiency virus infection are routinely vaccinated. As long as they have evidence of serologic immunity, they do not need additional treatment.

Measles, an ancient, highly contagious disease with a history of successful control by vaccination, is now threatening to have an epidemic resurgence. Until recently, measles vaccination largely controlled outbreaks in the United States. The Global Vaccine Action Plan under the World Health Organization aimed to eliminate measles worldwide. Nonetheless, the vaccine refusal movement and slow rollout of vaccine programs globally have interfered with control of the virus. A record number of measles cases have emerged in recent months: more than 700 since January 2019.¹ Approximately 70% of recent cases were in unvaccinated patients, and almost all were in US residents.

This update reviews the history, presentation and diagnosis, complications, management, contagion control, and emerging threat of a measles epidemic. It concludes with recommendations for clinical practice in the context of the current measles outbreaks.

FROM UBIQUITOUS TO ERADICATED—AND BACK

Before the measles vaccine was developed and became available in the 1960s, outbreaks of measles occurred predictably every year in the United States and other temperate regions. During yearly outbreaks, measles was so contagious that household contacts had attack rates above 95%. Most cases occurred in very young children, and because infection with the virus causes lifelong immunity, it could be safely assumed that by adulthood, everyone was immune. In an outbreak in the Faroe Islands in 1846, no one who had been alive in the last major outbreak 65 years earlier became ill, but everyone under age 65 was at high risk with “high attack rates,” estimated as 99% from other outbreaks (reviewed by Krugman et al²).

In isolated regions previously free of measles, adults did not have immunity, and when exposed, they often developed severe disease. When European settlers brought measles and smallpox to the Americas beginning in the late 15th century, these diseases decimated whole populations of native peoples who had never been exposed to them.

From the US Centers for Disease Control and Prevention.

That was premature. A number of outbreaks have occurred since then; the largest in the United States (before 2019) was in 2000. Over half of the 667 cases reported during that outbreak were in an underimmunized Amish community in Ohio.³

Now it emerges again.

PRESENTATION CAN VARY

From the US Centers for Disease Control and Prevention.

From the US Centers for Disease Control and Prevention.

The presentation varies somewhat among certain groups.

Nonimmune pregnant women have an especially severe course, likely related to the relative immune suppression of pregnancy.

In immune-suppressed states, measles is not only more severe, it is also difficult to diagnose because the rash can be absent.

In partially vaccinated children and adults, the disease may present atypically, without cough, conjunctivitis, and coryza, and it may be milder, lacking some of the extreme malaise typical of measles and with a shortened course. Measles infection in people who received the inactivated measles vaccine that was briefly available from 1963 to 1967 is also associated with atypical measles syndrome, a severe hypersensitivity reaction to the measles virus. Atypical measles can be prevented by revaccination with a live-virus vaccine.

 

 

DIAGNOSIS MAY NEED TO BE CONFIRMED

The diagnosis of measles is straightforward when all of the signs and symptoms are present. In partially vaccinated populations, however, the diagnosis may need to be confirmed by serologic or polymerase chain reaction (PCR) testing.

Differential diagnosis

The differential diagnosis of the fever and a rash typical of measles in children, especially when accompanied by severe malaise, includes the following:

Kawasaki disease. However, the red eyes of Kawasaki are an injection of the bulbar conjunctivae with sparing of the limbus. No eye exudate is present, and respiratory illness is not part of the disease.

Drug eruptions can present with a morbilliform rash and sometimes fever, but not the other signs of measles in either adults or children.

Scarlet fever has a different rash, the sandpaper rash typical of toxin-mediated disease.

Rubella tends to cause mild respiratory symptoms and illness rather than the severe disease of measles and other rash-causing viral infections in children and infants.

Confirmation in confusing cases

To confirm a diagnosis of measles, samples from throat, nasal, and posterior nasopharyngeal swabs should be collected with a blood specimen for serology and sent to the state public health laboratory.⁴ The US Centers for Disease Control and Prevention gives instructions on who should be tested and with which tests.⁴

Most testing now uses PCR for viral RNA, as viral culture is more costly and takes longer. For accurate diagnosis, samples for PCR must be obtained during the acute illness.

The serologic gold standard for diagnosis is a 4-fold rise or fall in immunoglobulin G (IgG) titer of paired serum samples sent 10 days to 2 weeks apart around the illness. The IgM test may be negative initially, and a negative test cannot be used to rule out the diagnosis. Confirmed cases should be reported to public health authorities.

COMPLICATIONS: EARLY AND LATE

Frequent complications of measles infection include those related to the primary viral infection of respiratory tract mucosal surfaces, as well as bacterial superinfections. Complications are most likely in children under age 5, nonimmune adults, pregnant women, and immunocompromised people. Typical complications include otitis media, laryngotracheobronchitis (presenting as a croupy cough), pneumonia, and diarrhea.

Late sequelae of measles infection are related in part to serious mucosal damage and generalized immune suppression caused by the virus. Even after recovery from acute infection, children can have persistent diarrhea and failure to thrive, with increased mortality risk in the months after infection. Tuberculosis can reactivate in patients already infected, and new tuberculosis infection can be especially severe. Further, tuberculosis skin tests become less reliable immediately after measles infection. Severe disease and fatalities are increased in populations that have baseline vitamin A deficiency and malnutrition.

Death from measles is most often caused by viral pneumonia, secondary bacterial pneumonia, and postviral encephalitis. Before the vaccine era, measles encephalitis occurred in the United States in about 1 in 1,000 measles cases.

Subacute sclerosing panencephalitis is a rare, late, and often fatal complication of measles that presents 7 to 10 years after acute measles infection, usually in adolescence. Beginning with myoclonic jerks, stiffening, and slow mental deterioration, it progresses over 1 to 3 years, with a relentless degenerative course leading to death. Since the introduction of the measles vaccine in 1957, this disease has essentially disappeared in the United States.

SUPPORTIVE CARE, INFECTION CONTROL

Management of measles and its complications is primarily supportive.

Preventing contagion

Measles infection has an incubation period of 8 to 12 days. Individuals are contagious 4 days before to 4 days after rash onset in the normal host but longer in those lacking immune function. Cases can occur up to 21 days after exposure during the contagious period.

The disease is highly contagious, so hospitalized patients should be cared for with airborne precautions. It is crucial that caretakers be vaccinated properly, so that they can care for patients safely. Recommendations for preventing secondary cases by prompt vaccination and giving immune globulin are detailed below, including specific recommendations for individuals with immune system suppression.

The current US public health policy regarding measles vaccine booster doses began in response to the widespread measles outbreak in the United States from 1989 to 1991. Cases occurred more commonly in unvaccinated individuals and in young adults who had received only 1 dose of vaccine.

Today, the policy in areas where measles has been controlled is to vaccinate between 12 and 15 months of age and to boost with a second dose before starting kindergarten. In outbreak situations, the first dose should be given at 6 months of age, with a repeat dose at 12 to 15 months of age and the usual booster before starting kindergarten.

Those born before 1957 can be presumed to have had natural measles, which confers lifelong immunity (Table 3).⁷

 

 

CURRENT THREAT

In 2000, measles was considered controlled in the United States, thanks to the national vaccination policy. But despite overall control, small numbers of cases continued to occur each year, related to exposure to cases imported from areas of the world endemic with measles.

Within the last year, however, major outbreaks have emerged. Incompletely vaccinated populations and unvaccinated individuals are the reason for the progression of current outbreaks.⁸

Until there is broader acceptance of the vaccine and better adherence to vaccine policies nationally and globally, measles cannot be completely eradicated. But with high vaccination rates, it is predicted that this infection can be controlled and ultimately eradicated.

RECOMMENDATIONS

In the midst of an outbreak and with rising public awareness of the threat of measles, it is important to recognize that MMR vaccination is the most effective way to prevent spread of the virus and maintain measles elimination in the United States. With this in mind, there are several key facts and recommendations regarding vaccination:

Recommendations on vaccination

• In measles-controlled populations, all children should be vaccinated between 12 and 15 months of age and again before kindergarten.
• In outbreak settings, children should receive a first vaccine dose at 6 months of age, a second at 12 to 15 months of age, and a third before kindergarten.
• Children who have received 2 measles vaccine doses can be assumed to be fully vaccinated and thus protected as long as the first dose was after 12 months of age. If the first dose was before 12 months of age, a child needs 3 doses.
• Adults born before 1957 can be assumed to have had measles infection and to be immune.
• Adults who were immunized with the inactivated measles vaccine available between 1963 and 1967 should receive 1 dose of live virus vaccine.
• Boosters are recommended for young adults who did not receive a second dose of vaccine and for adults with an uncertain history of immunization. There is no need to check titers before giving a booster, but if a positive titer is available in an adult, a booster is not needed.
• Heathcare providers should vaccinate unvaccinated or undervaccinated US residents traveling internationally (as long as they do not have contraindications) or traveling within the country to areas with outbreaks of measles.

Recommendations on vaccination after exposure to measles

• Vaccine is recommended for a nonimmune contact, including anyone with a history of only a single dose of vaccine.
• If a child got a first dose of vaccine before 12 months of age, give the second dose as soon as he or she turns 1 year old, or at least 28 days after the first dose.
• Vaccine must be given within 72 hours of exposure to confer protection (or at least decrease disease severity).
• The second dose of vaccine should be given at least 28 days after the first dose.

Recommendations on immune globulin after exposure to measles

• Immune globulin is recommended for anyone with exposure and no history of vaccination or immunity.
• Immune globulin can be given up to 6 days after exposure to prevent or decrease the severity of measles in immunocompromised hosts who have not been previously vaccinated. It is best to give it as early as possible.
• Immune globulin is given intramuscularly at 0.5 mL/kg, up to a to maximum dose of 15 mL.
• Pregnant women and immunocompromised hosts without immunity should receive immunoglobulin intravenously. Children and adults who have had a recent bone marrow transplant and likely do not yet have a reconstituted immune system should be treated with immune globulin to prevent infection, as vaccine cannot be given immediately after transplant. This is also true for other immunocompromised individuals who have not been vaccinated and who are not candidates for vaccine because of the severity of their immune suppression.
• Children with human immunodeficiency virus infection are routinely vaccinated. As long as they have evidence of serologic immunity, they do not need additional treatment.

Measles, an ancient, highly contagious disease with a history of successful control by vaccination, is now threatening to have an epidemic resurgence. Until recently, measles vaccination largely controlled outbreaks in the United States. The Global Vaccine Action Plan under the World Health Organization aimed to eliminate measles worldwide. Nonetheless, the vaccine refusal movement and slow rollout of vaccine programs globally have interfered with control of the virus. A record number of measles cases have emerged in recent months: more than 700 since January 2019.¹ Approximately 70% of recent cases were in unvaccinated patients, and almost all were in US residents.

This update reviews the history, presentation and diagnosis, complications, management, contagion control, and emerging threat of a measles epidemic. It concludes with recommendations for clinical practice in the context of the current measles outbreaks.

FROM UBIQUITOUS TO ERADICATED—AND BACK

Before the measles vaccine was developed and became available in the 1960s, outbreaks of measles occurred predictably every year in the United States and other temperate regions. During yearly outbreaks, measles was so contagious that household contacts had attack rates above 95%. Most cases occurred in very young children, and because infection with the virus causes lifelong immunity, it could be safely assumed that by adulthood, everyone was immune. In an outbreak in the Faroe Islands in 1846, no one who had been alive in the last major outbreak 65 years earlier became ill, but everyone under age 65 was at high risk with “high attack rates,” estimated as 99% from other outbreaks (reviewed by Krugman et al²).

In isolated regions previously free of measles, adults did not have immunity, and when exposed, they often developed severe disease. When European settlers brought measles and smallpox to the Americas beginning in the late 15th century, these diseases decimated whole populations of native peoples who had never been exposed to them.

From the US Centers for Disease Control and Prevention.

That was premature. A number of outbreaks have occurred since then; the largest in the United States (before 2019) was in 2000. Over half of the 667 cases reported during that outbreak were in an underimmunized Amish community in Ohio.³

Now it emerges again.

PRESENTATION CAN VARY

From the US Centers for Disease Control and Prevention.

From the US Centers for Disease Control and Prevention.

The presentation varies somewhat among certain groups.

Nonimmune pregnant women have an especially severe course, likely related to the relative immune suppression of pregnancy.

In immune-suppressed states, measles is not only more severe, it is also difficult to diagnose because the rash can be absent.

In partially vaccinated children and adults, the disease may present atypically, without cough, conjunctivitis, and coryza, and it may be milder, lacking some of the extreme malaise typical of measles and with a shortened course. Measles infection in people who received the inactivated measles vaccine that was briefly available from 1963 to 1967 is also associated with atypical measles syndrome, a severe hypersensitivity reaction to the measles virus. Atypical measles can be prevented by revaccination with a live-virus vaccine.

 

 

DIAGNOSIS MAY NEED TO BE CONFIRMED

The diagnosis of measles is straightforward when all of the signs and symptoms are present. In partially vaccinated populations, however, the diagnosis may need to be confirmed by serologic or polymerase chain reaction (PCR) testing.

Differential diagnosis

The differential diagnosis of the fever and a rash typical of measles in children, especially when accompanied by severe malaise, includes the following:

Kawasaki disease. However, the red eyes of Kawasaki are an injection of the bulbar conjunctivae with sparing of the limbus. No eye exudate is present, and respiratory illness is not part of the disease.

Drug eruptions can present with a morbilliform rash and sometimes fever, but not the other signs of measles in either adults or children.

Scarlet fever has a different rash, the sandpaper rash typical of toxin-mediated disease.

Rubella tends to cause mild respiratory symptoms and illness rather than the severe disease of measles and other rash-causing viral infections in children and infants.

Confirmation in confusing cases

To confirm a diagnosis of measles, samples from throat, nasal, and posterior nasopharyngeal swabs should be collected with a blood specimen for serology and sent to the state public health laboratory.⁴ The US Centers for Disease Control and Prevention gives instructions on who should be tested and with which tests.⁴

Most testing now uses PCR for viral RNA, as viral culture is more costly and takes longer. For accurate diagnosis, samples for PCR must be obtained during the acute illness.

The serologic gold standard for diagnosis is a 4-fold rise or fall in immunoglobulin G (IgG) titer of paired serum samples sent 10 days to 2 weeks apart around the illness. The IgM test may be negative initially, and a negative test cannot be used to rule out the diagnosis. Confirmed cases should be reported to public health authorities.

COMPLICATIONS: EARLY AND LATE

Frequent complications of measles infection include those related to the primary viral infection of respiratory tract mucosal surfaces, as well as bacterial superinfections. Complications are most likely in children under age 5, nonimmune adults, pregnant women, and immunocompromised people. Typical complications include otitis media, laryngotracheobronchitis (presenting as a croupy cough), pneumonia, and diarrhea.

Late sequelae of measles infection are related in part to serious mucosal damage and generalized immune suppression caused by the virus. Even after recovery from acute infection, children can have persistent diarrhea and failure to thrive, with increased mortality risk in the months after infection. Tuberculosis can reactivate in patients already infected, and new tuberculosis infection can be especially severe. Further, tuberculosis skin tests become less reliable immediately after measles infection. Severe disease and fatalities are increased in populations that have baseline vitamin A deficiency and malnutrition.

Death from measles is most often caused by viral pneumonia, secondary bacterial pneumonia, and postviral encephalitis. Before the vaccine era, measles encephalitis occurred in the United States in about 1 in 1,000 measles cases.

Subacute sclerosing panencephalitis is a rare, late, and often fatal complication of measles that presents 7 to 10 years after acute measles infection, usually in adolescence. Beginning with myoclonic jerks, stiffening, and slow mental deterioration, it progresses over 1 to 3 years, with a relentless degenerative course leading to death. Since the introduction of the measles vaccine in 1957, this disease has essentially disappeared in the United States.

SUPPORTIVE CARE, INFECTION CONTROL

Management of measles and its complications is primarily supportive.

Preventing contagion

Measles infection has an incubation period of 8 to 12 days. Individuals are contagious 4 days before to 4 days after rash onset in the normal host but longer in those lacking immune function. Cases can occur up to 21 days after exposure during the contagious period.

The disease is highly contagious, so hospitalized patients should be cared for with airborne precautions. It is crucial that caretakers be vaccinated properly, so that they can care for patients safely. Recommendations for preventing secondary cases by prompt vaccination and giving immune globulin are detailed below, including specific recommendations for individuals with immune system suppression.

The current US public health policy regarding measles vaccine booster doses began in response to the widespread measles outbreak in the United States from 1989 to 1991. Cases occurred more commonly in unvaccinated individuals and in young adults who had received only 1 dose of vaccine.

Today, the policy in areas where measles has been controlled is to vaccinate between 12 and 15 months of age and to boost with a second dose before starting kindergarten. In outbreak situations, the first dose should be given at 6 months of age, with a repeat dose at 12 to 15 months of age and the usual booster before starting kindergarten.

Those born before 1957 can be presumed to have had natural measles, which confers lifelong immunity (Table 3).⁷

 

 

CURRENT THREAT

In 2000, measles was considered controlled in the United States, thanks to the national vaccination policy. But despite overall control, small numbers of cases continued to occur each year, related to exposure to cases imported from areas of the world endemic with measles.

Within the last year, however, major outbreaks have emerged. Incompletely vaccinated populations and unvaccinated individuals are the reason for the progression of current outbreaks.⁸

Until there is broader acceptance of the vaccine and better adherence to vaccine policies nationally and globally, measles cannot be completely eradicated. But with high vaccination rates, it is predicted that this infection can be controlled and ultimately eradicated.

RECOMMENDATIONS

In the midst of an outbreak and with rising public awareness of the threat of measles, it is important to recognize that MMR vaccination is the most effective way to prevent spread of the virus and maintain measles elimination in the United States. With this in mind, there are several key facts and recommendations regarding vaccination:

Recommendations on vaccination

• In measles-controlled populations, all children should be vaccinated between 12 and 15 months of age and again before kindergarten.
• In outbreak settings, children should receive a first vaccine dose at 6 months of age, a second at 12 to 15 months of age, and a third before kindergarten.
• Children who have received 2 measles vaccine doses can be assumed to be fully vaccinated and thus protected as long as the first dose was after 12 months of age. If the first dose was before 12 months of age, a child needs 3 doses.
• Adults born before 1957 can be assumed to have had measles infection and to be immune.
• Adults who were immunized with the inactivated measles vaccine available between 1963 and 1967 should receive 1 dose of live virus vaccine.
• Boosters are recommended for young adults who did not receive a second dose of vaccine and for adults with an uncertain history of immunization. There is no need to check titers before giving a booster, but if a positive titer is available in an adult, a booster is not needed.
• Heathcare providers should vaccinate unvaccinated or undervaccinated US residents traveling internationally (as long as they do not have contraindications) or traveling within the country to areas with outbreaks of measles.

Recommendations on vaccination after exposure to measles

• Vaccine is recommended for a nonimmune contact, including anyone with a history of only a single dose of vaccine.
• If a child got a first dose of vaccine before 12 months of age, give the second dose as soon as he or she turns 1 year old, or at least 28 days after the first dose.
• Vaccine must be given within 72 hours of exposure to confer protection (or at least decrease disease severity).
• The second dose of vaccine should be given at least 28 days after the first dose.

Recommendations on immune globulin after exposure to measles

• Immune globulin is recommended for anyone with exposure and no history of vaccination or immunity.
• Immune globulin can be given up to 6 days after exposure to prevent or decrease the severity of measles in immunocompromised hosts who have not been previously vaccinated. It is best to give it as early as possible.
• Immune globulin is given intramuscularly at 0.5 mL/kg, up to a to maximum dose of 15 mL.
• Pregnant women and immunocompromised hosts without immunity should receive immunoglobulin intravenously. Children and adults who have had a recent bone marrow transplant and likely do not yet have a reconstituted immune system should be treated with immune globulin to prevent infection, as vaccine cannot be given immediately after transplant. This is also true for other immunocompromised individuals who have not been vaccinated and who are not candidates for vaccine because of the severity of their immune suppression.
• Children with human immunodeficiency virus infection are routinely vaccinated. As long as they have evidence of serologic immunity, they do not need additional treatment.

Screening can help prevent colorectal cancer. The United States has seen a steady decline in colorectal cancer incidence and mortality, thanks in large part to screening. Screening rates can be increased with good patient-physician dialogue and by choosing a method the patient prefers and is most likely to complete.

In this article, we review a general approach to screening, focusing on the most commonly used methods in the United States, ie, the guaiac-based fecal occult blood test (FOBT), the fecal immunochemical test (FIT), and colonoscopy. We discuss current colorectal cancer incidence rates, screening recommendations, and how to choose the appropriate screening test.

This article does not discuss patients at high risk of polyps or cancer due to hereditary colon cancer syndromes, a personal history of colorectal neoplasia, inflammatory bowel disease, or primary sclerosing cholangitis.

TRENDS IN INCIDENCE

Colorectal cancer is the second most common type of cancer and cause of cancer-related deaths in the United States, responsible for an estimated 50,000 deaths in 2017. The lifetime risk of its occurrence is estimated to be 1 in 21 men and 1 in 23 women.¹ Encouragingly, the incidence has declined by 24% over the last 30 years,² and by 3% per year from 2004 to 2013.¹ Also, as a result of screening and advances in treatment, 5-year survival rates for patients with colorectal cancer have increased, from 48.6% in 1975 to 66.4% in 2009.²

When detected at a localized stage, the 5-year survival rate in colorectal cancer is greater than 90%. Unfortunately, it is diagnosed early in only 39% of patients. And despite advances in treatment and a doubling of the 5-year survival rate in patients with advanced cancers since 1990,³ the latter is only 14%. In most patients, cancer is diagnosed when it has spread to the lymph nodes (36%) or to distant organs (22%), and the survival rate declines to 71% after lymph-node spread, and 14% after metastasis to distant organs.

It is essential to screen people who have no symptoms, as symptoms such as gastrointestinal bleeding, unexplained abdominal pain or weight loss, a persistent change in bowel movements, and bowel obstruction typically do not arise until the disease is advanced and less amenable to cure.

Increasing prevalence in younger adults

Curiously, the incidence of colorectal cancer is increasing in white US adults under age 50. Over the last 30 years, incidence rates have increased from 1.0% to 2.4% annually in adults ages 20 to 39.⁴ Based on current trends, colon cancer rates are expected to increase by 90% for patients ages 20 to 34 and by 28% for patients 35 to 49 by 2030.⁵

Although recommendations vary for colorectal cancer screening in patients under age 50, clinicians should investigate symptoms such as rectal bleeding, unexplained iron deficiency anemia, progressive abdominal pain, and persistent changes in bowel movements.

Other challenges

Despite the benefits of screening, it is underutilized. Although rates of compliance with screening recommendations have increased 10% over the last 10 years, only 65% of eligible adults currently comply.^1,6

Additionally, certain areas of the country such as Appalachia and the Mississippi Delta have not benefited from the decline in the national rate of colorectal cancer.⁷

SCREENING GUIDELINES

Most guidelines say that colorectal cancer screening should begin at age 50 in people at average risk with no symptoms. However, the American College of Gastroenterology (ACG) recommends beginning screening at age 45 in African Americans, as this group has higher incidence and mortality rates of colorectal cancer.⁸ Also, the American Cancer Society recently recommended beginning screening at age 45 for all individuals.⁹

Screening can stop at age 75 for most patients, according to the ACG,⁸ the US Multi-Society Task Force on Colorectal Cancer,¹⁰ and the US Preventive Services Task Force  (USPSTF).¹¹ However, the decision should be individualized for patients ages 76 to 85. Patients within that age group who are in good health and have not previously been screened are more likely to benefit than those who have previously been screened and had a negative screening test. Patients over age 85 should not begin or continue screening, because of diminished benefit of screening in this age group, shorter life expectancy, advanced comorbid conditions, and the risks of colonoscopy and cancer treatment.

Patients and clinicians are encouraged to collaborate in deciding which screening method is appropriate. Patients adhere better when they are given a choice in the matter.^12–14 And adherence is the key to effective colorectal cancer screening.

Familiarity with the key characteristics of currently available colorectal cancer screening tests will facilitate discussion with patients.

Opportunistic vs programmatic screening

Screening can be classified according to the approach to the patient or population and the intent of the test. Most screening in the United States is opportunistic rather than programmatic—that is, the physician offers the patient screening at the point of service without systematic follow-up or patient re-engagement.

In a programmatic approach, the patient is offered screening through an organized program that streamlines services, reduces overscreening, and provides systematic follow-up of testing.

 

 

DISCUSSING THE OPTIONS

Stool studies such as FOBT and FIT do not reliably detect cancer precursors such as adenomas and serrated neoplasms. If an FOBT is positive, follow-up diagnostic colonoscopy is required. Unlike screening colonoscopy, diagnostic colonoscopy requires a copayment for Medicare patients, and this should be explained to the patient.

FIT and FOBT detect hemolyzed blood within a stool sample, FOBT by a chemical reaction, and FIT by detecting a globin-specific antibody. Colorectal cancer and some large adenomatous polyps may intermittently bleed and result in occult blood in the stool, iron deficiency anemia, or hematochezia.¹⁵

Fecal occult blood testing

Historically, FOBT was the stool test of choice for screening. It uses an indirect enzymatic reaction to detect hemolyzed blood in the stool. When a specimen containing hemoglobin is added to guaiac paper and a drop of hydrogen peroxide is added to “develop” it, the peroxidase activity of hemoglobin turns the guaiac blue.

Screening with FOBT involves annual testing of 3 consecutively passed stools from different days; FOBT should not be performed at the time of digital rectal examination or if the patient is having overt rectal, urinary, or menstrual bleeding.

Dietary and medication restrictions before and during the testing period are critical, as red meat contains hemoglobin, and certain vegetables (eg, radishes, turnips, cauliflower, cucumbers) contain peroxidase, all of which can cause a false-positive result. Waiting 3 days after the stool sample is collected to develop it can mitigate the peroxidase activity of vegetables.¹⁶ Vitamin C inhibits heme peroxidase activity and leads to false-negative results. Aspirin and high-dose nonsteroidal anti-inflammatory drugs can promote bleeding throughout the intestinal tract.¹⁷

In randomized controlled trials,^18–21 screening with FOBT reduced colorectal cancer mortality rates by 15% to 33%. The 30-year follow-up of a large US trial²² found a 32% relative reduction in mortality rates in patients randomized to annual screening, and a 22% relative reduction in those randomized to screening every 2 years. Despite the many possibilities for false-positive results, the specificity for detecting cancer has ranged from 86.7% to 97.3%, and the sensitivity from 37.1% to 79.4%, highlighting the benefit of colorectal cancer screening programs in unscreened populations.^23–26

FIT vs FOBT in current practice

FIT should replace FOBT as the preferred stool screening method. Instead of an enzymatic reaction that can be altered by food or medication, FIT utilizes an antibody specific to human globin to directly detect hemolyzed blood, thus eliminating the need to modify the diet or medications.²⁷ Additionally, only 1 stool specimen is needed, which may explain why the adherence rate was about 20% higher with FIT than with FOBT in most studies.^28–30

FIT has a sensitivity of 69% to 86% for colorectal cancer and a specificity of 92% to 95%.³¹ The sensitivity can be improved by lowering the threshold value for a positive test, but this is associated with a decrease in specificity. A single FIT has the same sensitivity and specificity as several samples.³²

In a large retrospective US cohort study of programmatic screening with FIT, Jensen et al³³ reported that 48% of 670,841 people who were offered testing actually did the test. Of the 48% who participated in the first round and remained eligible, 75% to 86% participated in subsequent rounds over 4 years. Those who had a positive result on FIT were supposed to undergo colonoscopy, but 22% did not.

The US Multi-Society Task Force on Colorectal Cancer³⁴ suggests that FIT-based screening programs aim for a target FIT completion rate of more than 60% and a target colonoscopy completion rate of more than 80% of patients with positive FITs. These benchmarks were derived from adherence rates in international FIT screening studies in average-risk populations.^35–39 (Note that the large US cohort described above³³ did not meet these goals.) Ideally, every patient with a positive FIT should undergo diagnostic colonoscopy, but in reality only 50% to 83% actually do. Methods shown to improve adherence include structured screening programs with routine performance reports, provider feedback, and involvement of patient navigators.^40–42

Accordingly, several aspects of stool-based testing need to be stressed with patients. Understanding that FOBT is recommended yearly is integral for optimal impact on colorectal cancer incidence and mortality rates.

Additionally, patients should be advised to undergo colonoscopy soon after a positive FIT, because delaying colonoscopy could give precancerous lesions time to progress in stage. The acceptable time between a positive FIT and colonoscopy has yet to be determined. However, a retrospective cohort study of 1.26 million screened patients with 107,000 positive FIT results demonstrated that the rates of cancer discovered on colonoscopy were similar when performed within 30 days or up to 10 months after a positive test. Detection rates increased from 3% to 4.8% at 10 months and to 7.9% at 12 months.⁴³

In modeling studies, Meester et al⁴⁴ showed the estimated lifetime risk and mortality rates from colorectal cancer and life-years gained from screening are significantly better when colonoscopy is completed within 2 weeks rather than 1 year after a positive FIT. Each additional month after 2 weeks incrementally affected these outcomes, with a 1.4% increase in cancer mortality. These data suggest that colonoscopy should be done soon after a positive FIT result and at a maximum of 10 months.^43,44

Screening with FOBT is a multistep process for patients that includes receiving the test kit, collecting the sample, preparing it, returning it, undergoing colonoscopy after a positive test, and repeating in 1 year if negative. The screening program should identify patients at average risk in whom screening is appropriate, ensure delivery of the test, verify the quality of collected samples for laboratory testing against the manufacturer’s recommendations, and report results. Report of a positive FOBT result should provide recommendations for follow-up.

Though evidence clearly supports screening annually or biennially (every 2 years) with FOBT, the ideal interval for FIT is undetermined. Modeling studies utilized by the USPSTF and Multi-Society Task Force demonstrate that colonoscopy and annual FIT result in similar life-years gained, while 2 population-based screening programs have demonstrated that a 2- or 3-year interval may be equally efficacious by lowering the threshold for a positive test.^38,45

Randomized controlled trials of screening colonoscopy vs annual and biennial FIT are currently under way. Cost-effectiveness analysis has shown that offering single-sample FITs at more frequent (annual) intervals performs better than multisample testing at less frequent intervals.^45–47

 

 

Colonoscopy

Compared with stool-based screening, colonoscopy has advantages, including a 10-year screening interval if bowel preparation is adequate and the examination shows no neoplasia, the ability to inspect the entire colon, and the ability to diagnose and treat lesions in the same session.

Screening colonoscopy visualizes the entire colon in more than 98% of cases, although it requires adequate bowel preparation for maximal polyp detection. It can be done safely with or without sedation.⁴⁸

While there are no available randomized controlled trial data on the impact of screening colonoscopy on cancer incidence or mortality, extensive case-control and cohort studies consistently show that screening colonoscopy reduces cancer incidence and mortality rates.^49–54 A US Veterans Administration study of more than 32,000 patients reported a 50% reduction in overall colorectal cancer mortality.⁵⁵ In a microsimulation modeling study that assumed 100% adherence, colonoscopy every 10 years and annual FIT in individuals ages 50 to 75 provided similar life-years gained per 1,000 people screened (270 for colonoscopy, 244 for FIT).⁵⁶

Well-established metrics for maximizing the effectiveness and quality of colonoscopy have been established (Table 2). The most important include the mucosa inspection time (withdrawal time) and adenoma detection rate.⁵⁷ Withdrawal time is directly correlated with adenoma detection, and a 6-minute minimum withdrawal time is recommended in screening colonoscopy examinations of patients at average risk when no polyps are found.⁵⁸ The adenoma detection rate is the strongest evidence-based metric, as each 1% increase in the adenoma detection rate over 19% is associated with a 3% decrease in the risk of colorectal cancer and a 5% decrease in death rate.⁵⁹ The average-risk screening adenoma detection rate differs based on sex: the rate is greater than 20% for women and greater than 30% for men.

Complications from screening, diagnostic, or therapeutic colonoscopy are infrequent but include perforation (4/10,000) and significant intestinal bleeding (8/10,000).^56–62

Patients with a first-degree relative under age 60 with advanced adenomas or colorectal cancer are considered at high risk and should begin screening colonoscopy at age 40, with repeat colonoscopy at 5-year intervals, given a trend toward advanced neoplasia detection compared with FIT.⁶³

Guidelines recently published by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association also support starting screening in high-risk individuals at age 40, with a surveillance interval of 5 to 10 years based on the number of first-degree relatives with colorectal cancer or adenomas.⁶⁴ Consensus statements were based on retrospective cohort, prospective case-controlled, and cross-sectional studies comparing the risk of colorectal cancer in individuals with a family history against those without a family history.

Randomized clinical trials comparing colonoscopy and FIT are under way. Interim analysis of a European trial in which asymptomatic adults ages 50 to 69 were randomized to 1-time colonoscopy (26,703 patients) vs FIT every 2 years (26,599 patients) found significantly higher participation rates in the FIT arm (34.2% vs 24.6%) but higher rates of nonadvanced adenomas (4.2% vs 0.4%) and advanced neoplasia (1.9% vs 0.9%) in the colonoscopy arm.⁶⁵ Cancer was detected in 0.1% in each arm. These findings correlate with those of another study showing higher participation with FIT but higher advanced neoplasia detection rates with colonoscopy.⁶⁶

Detection of precursor lesions is vital, as removing neoplasms is the main strategy to reduce colorectal cancer incidence. Accordingly, the advantage of colonoscopy was illustrated by a study that determined that 53 patients would need to undergo screening colonoscopy to detect 1 advanced adenoma or cancerous lesion, compared with 264 for FIT.⁶⁷

STARTING SCREEING AT AGE 45

The American Cancer Society recently provided a qualified recommendation to start colorectal cancer screening in all individuals at age 45 rather than 50.⁹ This recommendation was based on modeling studies demonstrating that starting screening at age 45 with colonoscopy every 10 years resulted in 25 life-years gained at the cost of 610 colonoscopies per 1,000 individuals. Alternative strategies included FIT, which resulted in an additional 26 life-years gained per 1,000 individuals screened, flexible sigmoidoscopy (23 life-years gained), and computed tomographic colonoscopy (22 life-years gained).

Rates of colorectal cancer are rising in adults under age 50, and 10,000 new cases are anticipated this year.^2,3 Currently, 22 million US adults are between the ages of 45 and 50. The system and support needed to perform screening in all adults over age 45 and a lack of direct evidence to support its benefits in the young population need to be considered before widespread acceptance of the American Cancer Society recommendations. However, if screening is considered, FIT with or without sigmoidoscopy may be appropriate, given that most cancers diagnosed in individuals under age 50 are left-sided.^4,5

Screening has not been proven to reduce all-cause mortality. Randomized controlled trials of FOBT and observational studies of colonoscopy show that screening reduces cancer incidence and mortality. Until the currently ongoing randomized controlled trials comparing colonoscopy with FIT are completed, their comparative impact on colorectal cancer end points is unknown.

PATIENT ADHERENCE IS KEY

FIT and colonoscopy are the most prevalent screening methods in the United States. Careful attention should be given to offer the screening option the patient is most likely to complete, as adherence is key to the benefit from colorectal cancer screening.

The National Colorectal Cancer Roundtable (nccrt.org), established in 1997 by the American Cancer Society and the US Centers for Disease Control and Prevention, is a national coalition of public and private organizations dedicated to reducing colorectal cancer incidence and mortality. The Roundtable waged a national campaign to achieve a colorectal cancer screening rate of 80% in eligible adults by 2018, a goal that was not met. Still, the potential for a substantial impact is a compelling reason to endorse adherence to colorectal cancer screening. The Roundtable provides many resources for physicians to enhance screening in their practice.

The United States has seen a steady decline in colorectal cancer incidence and mortality, mainly as a result of screening. Colorectal cancer is preventable with ensuring patients’ adherence to screening. Screening rates have been shown to increase with patient-provider dialogue and with selection of a screening program the patient prefers and is most likely to complete.

Screening can help prevent colorectal cancer. The United States has seen a steady decline in colorectal cancer incidence and mortality, thanks in large part to screening. Screening rates can be increased with good patient-physician dialogue and by choosing a method the patient prefers and is most likely to complete.

In this article, we review a general approach to screening, focusing on the most commonly used methods in the United States, ie, the guaiac-based fecal occult blood test (FOBT), the fecal immunochemical test (FIT), and colonoscopy. We discuss current colorectal cancer incidence rates, screening recommendations, and how to choose the appropriate screening test.

This article does not discuss patients at high risk of polyps or cancer due to hereditary colon cancer syndromes, a personal history of colorectal neoplasia, inflammatory bowel disease, or primary sclerosing cholangitis.

TRENDS IN INCIDENCE

Colorectal cancer is the second most common type of cancer and cause of cancer-related deaths in the United States, responsible for an estimated 50,000 deaths in 2017. The lifetime risk of its occurrence is estimated to be 1 in 21 men and 1 in 23 women.¹ Encouragingly, the incidence has declined by 24% over the last 30 years,² and by 3% per year from 2004 to 2013.¹ Also, as a result of screening and advances in treatment, 5-year survival rates for patients with colorectal cancer have increased, from 48.6% in 1975 to 66.4% in 2009.²

When detected at a localized stage, the 5-year survival rate in colorectal cancer is greater than 90%. Unfortunately, it is diagnosed early in only 39% of patients. And despite advances in treatment and a doubling of the 5-year survival rate in patients with advanced cancers since 1990,³ the latter is only 14%. In most patients, cancer is diagnosed when it has spread to the lymph nodes (36%) or to distant organs (22%), and the survival rate declines to 71% after lymph-node spread, and 14% after metastasis to distant organs.

It is essential to screen people who have no symptoms, as symptoms such as gastrointestinal bleeding, unexplained abdominal pain or weight loss, a persistent change in bowel movements, and bowel obstruction typically do not arise until the disease is advanced and less amenable to cure.

Increasing prevalence in younger adults

Curiously, the incidence of colorectal cancer is increasing in white US adults under age 50. Over the last 30 years, incidence rates have increased from 1.0% to 2.4% annually in adults ages 20 to 39.⁴ Based on current trends, colon cancer rates are expected to increase by 90% for patients ages 20 to 34 and by 28% for patients 35 to 49 by 2030.⁵

Although recommendations vary for colorectal cancer screening in patients under age 50, clinicians should investigate symptoms such as rectal bleeding, unexplained iron deficiency anemia, progressive abdominal pain, and persistent changes in bowel movements.

Other challenges

Despite the benefits of screening, it is underutilized. Although rates of compliance with screening recommendations have increased 10% over the last 10 years, only 65% of eligible adults currently comply.^1,6

Additionally, certain areas of the country such as Appalachia and the Mississippi Delta have not benefited from the decline in the national rate of colorectal cancer.⁷

SCREENING GUIDELINES

Most guidelines say that colorectal cancer screening should begin at age 50 in people at average risk with no symptoms. However, the American College of Gastroenterology (ACG) recommends beginning screening at age 45 in African Americans, as this group has higher incidence and mortality rates of colorectal cancer.⁸ Also, the American Cancer Society recently recommended beginning screening at age 45 for all individuals.⁹

Screening can stop at age 75 for most patients, according to the ACG,⁸ the US Multi-Society Task Force on Colorectal Cancer,¹⁰ and the US Preventive Services Task Force  (USPSTF).¹¹ However, the decision should be individualized for patients ages 76 to 85. Patients within that age group who are in good health and have not previously been screened are more likely to benefit than those who have previously been screened and had a negative screening test. Patients over age 85 should not begin or continue screening, because of diminished benefit of screening in this age group, shorter life expectancy, advanced comorbid conditions, and the risks of colonoscopy and cancer treatment.

Patients and clinicians are encouraged to collaborate in deciding which screening method is appropriate. Patients adhere better when they are given a choice in the matter.^12–14 And adherence is the key to effective colorectal cancer screening.

Familiarity with the key characteristics of currently available colorectal cancer screening tests will facilitate discussion with patients.

Opportunistic vs programmatic screening

Screening can be classified according to the approach to the patient or population and the intent of the test. Most screening in the United States is opportunistic rather than programmatic—that is, the physician offers the patient screening at the point of service without systematic follow-up or patient re-engagement.

In a programmatic approach, the patient is offered screening through an organized program that streamlines services, reduces overscreening, and provides systematic follow-up of testing.

 

 

DISCUSSING THE OPTIONS

Stool studies such as FOBT and FIT do not reliably detect cancer precursors such as adenomas and serrated neoplasms. If an FOBT is positive, follow-up diagnostic colonoscopy is required. Unlike screening colonoscopy, diagnostic colonoscopy requires a copayment for Medicare patients, and this should be explained to the patient.

FIT and FOBT detect hemolyzed blood within a stool sample, FOBT by a chemical reaction, and FIT by detecting a globin-specific antibody. Colorectal cancer and some large adenomatous polyps may intermittently bleed and result in occult blood in the stool, iron deficiency anemia, or hematochezia.¹⁵

Fecal occult blood testing

Historically, FOBT was the stool test of choice for screening. It uses an indirect enzymatic reaction to detect hemolyzed blood in the stool. When a specimen containing hemoglobin is added to guaiac paper and a drop of hydrogen peroxide is added to “develop” it, the peroxidase activity of hemoglobin turns the guaiac blue.

Screening with FOBT involves annual testing of 3 consecutively passed stools from different days; FOBT should not be performed at the time of digital rectal examination or if the patient is having overt rectal, urinary, or menstrual bleeding.

Dietary and medication restrictions before and during the testing period are critical, as red meat contains hemoglobin, and certain vegetables (eg, radishes, turnips, cauliflower, cucumbers) contain peroxidase, all of which can cause a false-positive result. Waiting 3 days after the stool sample is collected to develop it can mitigate the peroxidase activity of vegetables.¹⁶ Vitamin C inhibits heme peroxidase activity and leads to false-negative results. Aspirin and high-dose nonsteroidal anti-inflammatory drugs can promote bleeding throughout the intestinal tract.¹⁷

In randomized controlled trials,^18–21 screening with FOBT reduced colorectal cancer mortality rates by 15% to 33%. The 30-year follow-up of a large US trial²² found a 32% relative reduction in mortality rates in patients randomized to annual screening, and a 22% relative reduction in those randomized to screening every 2 years. Despite the many possibilities for false-positive results, the specificity for detecting cancer has ranged from 86.7% to 97.3%, and the sensitivity from 37.1% to 79.4%, highlighting the benefit of colorectal cancer screening programs in unscreened populations.^23–26

FIT vs FOBT in current practice

FIT should replace FOBT as the preferred stool screening method. Instead of an enzymatic reaction that can be altered by food or medication, FIT utilizes an antibody specific to human globin to directly detect hemolyzed blood, thus eliminating the need to modify the diet or medications.²⁷ Additionally, only 1 stool specimen is needed, which may explain why the adherence rate was about 20% higher with FIT than with FOBT in most studies.^28–30

FIT has a sensitivity of 69% to 86% for colorectal cancer and a specificity of 92% to 95%.³¹ The sensitivity can be improved by lowering the threshold value for a positive test, but this is associated with a decrease in specificity. A single FIT has the same sensitivity and specificity as several samples.³²

In a large retrospective US cohort study of programmatic screening with FIT, Jensen et al³³ reported that 48% of 670,841 people who were offered testing actually did the test. Of the 48% who participated in the first round and remained eligible, 75% to 86% participated in subsequent rounds over 4 years. Those who had a positive result on FIT were supposed to undergo colonoscopy, but 22% did not.

The US Multi-Society Task Force on Colorectal Cancer³⁴ suggests that FIT-based screening programs aim for a target FIT completion rate of more than 60% and a target colonoscopy completion rate of more than 80% of patients with positive FITs. These benchmarks were derived from adherence rates in international FIT screening studies in average-risk populations.^35–39 (Note that the large US cohort described above³³ did not meet these goals.) Ideally, every patient with a positive FIT should undergo diagnostic colonoscopy, but in reality only 50% to 83% actually do. Methods shown to improve adherence include structured screening programs with routine performance reports, provider feedback, and involvement of patient navigators.^40–42

Accordingly, several aspects of stool-based testing need to be stressed with patients. Understanding that FOBT is recommended yearly is integral for optimal impact on colorectal cancer incidence and mortality rates.

Additionally, patients should be advised to undergo colonoscopy soon after a positive FIT, because delaying colonoscopy could give precancerous lesions time to progress in stage. The acceptable time between a positive FIT and colonoscopy has yet to be determined. However, a retrospective cohort study of 1.26 million screened patients with 107,000 positive FIT results demonstrated that the rates of cancer discovered on colonoscopy were similar when performed within 30 days or up to 10 months after a positive test. Detection rates increased from 3% to 4.8% at 10 months and to 7.9% at 12 months.⁴³

In modeling studies, Meester et al⁴⁴ showed the estimated lifetime risk and mortality rates from colorectal cancer and life-years gained from screening are significantly better when colonoscopy is completed within 2 weeks rather than 1 year after a positive FIT. Each additional month after 2 weeks incrementally affected these outcomes, with a 1.4% increase in cancer mortality. These data suggest that colonoscopy should be done soon after a positive FIT result and at a maximum of 10 months.^43,44

Screening with FOBT is a multistep process for patients that includes receiving the test kit, collecting the sample, preparing it, returning it, undergoing colonoscopy after a positive test, and repeating in 1 year if negative. The screening program should identify patients at average risk in whom screening is appropriate, ensure delivery of the test, verify the quality of collected samples for laboratory testing against the manufacturer’s recommendations, and report results. Report of a positive FOBT result should provide recommendations for follow-up.

Though evidence clearly supports screening annually or biennially (every 2 years) with FOBT, the ideal interval for FIT is undetermined. Modeling studies utilized by the USPSTF and Multi-Society Task Force demonstrate that colonoscopy and annual FIT result in similar life-years gained, while 2 population-based screening programs have demonstrated that a 2- or 3-year interval may be equally efficacious by lowering the threshold for a positive test.^38,45

Randomized controlled trials of screening colonoscopy vs annual and biennial FIT are currently under way. Cost-effectiveness analysis has shown that offering single-sample FITs at more frequent (annual) intervals performs better than multisample testing at less frequent intervals.^45–47

 

 

Colonoscopy

Compared with stool-based screening, colonoscopy has advantages, including a 10-year screening interval if bowel preparation is adequate and the examination shows no neoplasia, the ability to inspect the entire colon, and the ability to diagnose and treat lesions in the same session.

Screening colonoscopy visualizes the entire colon in more than 98% of cases, although it requires adequate bowel preparation for maximal polyp detection. It can be done safely with or without sedation.⁴⁸

While there are no available randomized controlled trial data on the impact of screening colonoscopy on cancer incidence or mortality, extensive case-control and cohort studies consistently show that screening colonoscopy reduces cancer incidence and mortality rates.^49–54 A US Veterans Administration study of more than 32,000 patients reported a 50% reduction in overall colorectal cancer mortality.⁵⁵ In a microsimulation modeling study that assumed 100% adherence, colonoscopy every 10 years and annual FIT in individuals ages 50 to 75 provided similar life-years gained per 1,000 people screened (270 for colonoscopy, 244 for FIT).⁵⁶

Well-established metrics for maximizing the effectiveness and quality of colonoscopy have been established (Table 2). The most important include the mucosa inspection time (withdrawal time) and adenoma detection rate.⁵⁷ Withdrawal time is directly correlated with adenoma detection, and a 6-minute minimum withdrawal time is recommended in screening colonoscopy examinations of patients at average risk when no polyps are found.⁵⁸ The adenoma detection rate is the strongest evidence-based metric, as each 1% increase in the adenoma detection rate over 19% is associated with a 3% decrease in the risk of colorectal cancer and a 5% decrease in death rate.⁵⁹ The average-risk screening adenoma detection rate differs based on sex: the rate is greater than 20% for women and greater than 30% for men.

Complications from screening, diagnostic, or therapeutic colonoscopy are infrequent but include perforation (4/10,000) and significant intestinal bleeding (8/10,000).^56–62

Patients with a first-degree relative under age 60 with advanced adenomas or colorectal cancer are considered at high risk and should begin screening colonoscopy at age 40, with repeat colonoscopy at 5-year intervals, given a trend toward advanced neoplasia detection compared with FIT.⁶³

Guidelines recently published by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association also support starting screening in high-risk individuals at age 40, with a surveillance interval of 5 to 10 years based on the number of first-degree relatives with colorectal cancer or adenomas.⁶⁴ Consensus statements were based on retrospective cohort, prospective case-controlled, and cross-sectional studies comparing the risk of colorectal cancer in individuals with a family history against those without a family history.

Randomized clinical trials comparing colonoscopy and FIT are under way. Interim analysis of a European trial in which asymptomatic adults ages 50 to 69 were randomized to 1-time colonoscopy (26,703 patients) vs FIT every 2 years (26,599 patients) found significantly higher participation rates in the FIT arm (34.2% vs 24.6%) but higher rates of nonadvanced adenomas (4.2% vs 0.4%) and advanced neoplasia (1.9% vs 0.9%) in the colonoscopy arm.⁶⁵ Cancer was detected in 0.1% in each arm. These findings correlate with those of another study showing higher participation with FIT but higher advanced neoplasia detection rates with colonoscopy.⁶⁶

Detection of precursor lesions is vital, as removing neoplasms is the main strategy to reduce colorectal cancer incidence. Accordingly, the advantage of colonoscopy was illustrated by a study that determined that 53 patients would need to undergo screening colonoscopy to detect 1 advanced adenoma or cancerous lesion, compared with 264 for FIT.⁶⁷

STARTING SCREEING AT AGE 45

The American Cancer Society recently provided a qualified recommendation to start colorectal cancer screening in all individuals at age 45 rather than 50.⁹ This recommendation was based on modeling studies demonstrating that starting screening at age 45 with colonoscopy every 10 years resulted in 25 life-years gained at the cost of 610 colonoscopies per 1,000 individuals. Alternative strategies included FIT, which resulted in an additional 26 life-years gained per 1,000 individuals screened, flexible sigmoidoscopy (23 life-years gained), and computed tomographic colonoscopy (22 life-years gained).

Rates of colorectal cancer are rising in adults under age 50, and 10,000 new cases are anticipated this year.^2,3 Currently, 22 million US adults are between the ages of 45 and 50. The system and support needed to perform screening in all adults over age 45 and a lack of direct evidence to support its benefits in the young population need to be considered before widespread acceptance of the American Cancer Society recommendations. However, if screening is considered, FIT with or without sigmoidoscopy may be appropriate, given that most cancers diagnosed in individuals under age 50 are left-sided.^4,5

Screening has not been proven to reduce all-cause mortality. Randomized controlled trials of FOBT and observational studies of colonoscopy show that screening reduces cancer incidence and mortality. Until the currently ongoing randomized controlled trials comparing colonoscopy with FIT are completed, their comparative impact on colorectal cancer end points is unknown.

PATIENT ADHERENCE IS KEY

FIT and colonoscopy are the most prevalent screening methods in the United States. Careful attention should be given to offer the screening option the patient is most likely to complete, as adherence is key to the benefit from colorectal cancer screening.

The National Colorectal Cancer Roundtable (nccrt.org), established in 1997 by the American Cancer Society and the US Centers for Disease Control and Prevention, is a national coalition of public and private organizations dedicated to reducing colorectal cancer incidence and mortality. The Roundtable waged a national campaign to achieve a colorectal cancer screening rate of 80% in eligible adults by 2018, a goal that was not met. Still, the potential for a substantial impact is a compelling reason to endorse adherence to colorectal cancer screening. The Roundtable provides many resources for physicians to enhance screening in their practice.

The United States has seen a steady decline in colorectal cancer incidence and mortality, mainly as a result of screening. Colorectal cancer is preventable with ensuring patients’ adherence to screening. Screening rates have been shown to increase with patient-provider dialogue and with selection of a screening program the patient prefers and is most likely to complete.

Screening can help prevent colorectal cancer. The United States has seen a steady decline in colorectal cancer incidence and mortality, thanks in large part to screening. Screening rates can be increased with good patient-physician dialogue and by choosing a method the patient prefers and is most likely to complete.

In this article, we review a general approach to screening, focusing on the most commonly used methods in the United States, ie, the guaiac-based fecal occult blood test (FOBT), the fecal immunochemical test (FIT), and colonoscopy. We discuss current colorectal cancer incidence rates, screening recommendations, and how to choose the appropriate screening test.

This article does not discuss patients at high risk of polyps or cancer due to hereditary colon cancer syndromes, a personal history of colorectal neoplasia, inflammatory bowel disease, or primary sclerosing cholangitis.

TRENDS IN INCIDENCE

Colorectal cancer is the second most common type of cancer and cause of cancer-related deaths in the United States, responsible for an estimated 50,000 deaths in 2017. The lifetime risk of its occurrence is estimated to be 1 in 21 men and 1 in 23 women.¹ Encouragingly, the incidence has declined by 24% over the last 30 years,² and by 3% per year from 2004 to 2013.¹ Also, as a result of screening and advances in treatment, 5-year survival rates for patients with colorectal cancer have increased, from 48.6% in 1975 to 66.4% in 2009.²

When detected at a localized stage, the 5-year survival rate in colorectal cancer is greater than 90%. Unfortunately, it is diagnosed early in only 39% of patients. And despite advances in treatment and a doubling of the 5-year survival rate in patients with advanced cancers since 1990,³ the latter is only 14%. In most patients, cancer is diagnosed when it has spread to the lymph nodes (36%) or to distant organs (22%), and the survival rate declines to 71% after lymph-node spread, and 14% after metastasis to distant organs.

It is essential to screen people who have no symptoms, as symptoms such as gastrointestinal bleeding, unexplained abdominal pain or weight loss, a persistent change in bowel movements, and bowel obstruction typically do not arise until the disease is advanced and less amenable to cure.

Increasing prevalence in younger adults

Curiously, the incidence of colorectal cancer is increasing in white US adults under age 50. Over the last 30 years, incidence rates have increased from 1.0% to 2.4% annually in adults ages 20 to 39.⁴ Based on current trends, colon cancer rates are expected to increase by 90% for patients ages 20 to 34 and by 28% for patients 35 to 49 by 2030.⁵

Although recommendations vary for colorectal cancer screening in patients under age 50, clinicians should investigate symptoms such as rectal bleeding, unexplained iron deficiency anemia, progressive abdominal pain, and persistent changes in bowel movements.

Other challenges

Despite the benefits of screening, it is underutilized. Although rates of compliance with screening recommendations have increased 10% over the last 10 years, only 65% of eligible adults currently comply.^1,6

Additionally, certain areas of the country such as Appalachia and the Mississippi Delta have not benefited from the decline in the national rate of colorectal cancer.⁷

SCREENING GUIDELINES

Most guidelines say that colorectal cancer screening should begin at age 50 in people at average risk with no symptoms. However, the American College of Gastroenterology (ACG) recommends beginning screening at age 45 in African Americans, as this group has higher incidence and mortality rates of colorectal cancer.⁸ Also, the American Cancer Society recently recommended beginning screening at age 45 for all individuals.⁹

Screening can stop at age 75 for most patients, according to the ACG,⁸ the US Multi-Society Task Force on Colorectal Cancer,¹⁰ and the US Preventive Services Task Force  (USPSTF).¹¹ However, the decision should be individualized for patients ages 76 to 85. Patients within that age group who are in good health and have not previously been screened are more likely to benefit than those who have previously been screened and had a negative screening test. Patients over age 85 should not begin or continue screening, because of diminished benefit of screening in this age group, shorter life expectancy, advanced comorbid conditions, and the risks of colonoscopy and cancer treatment.

Patients and clinicians are encouraged to collaborate in deciding which screening method is appropriate. Patients adhere better when they are given a choice in the matter.^12–14 And adherence is the key to effective colorectal cancer screening.

Familiarity with the key characteristics of currently available colorectal cancer screening tests will facilitate discussion with patients.

Opportunistic vs programmatic screening

Screening can be classified according to the approach to the patient or population and the intent of the test. Most screening in the United States is opportunistic rather than programmatic—that is, the physician offers the patient screening at the point of service without systematic follow-up or patient re-engagement.

In a programmatic approach, the patient is offered screening through an organized program that streamlines services, reduces overscreening, and provides systematic follow-up of testing.

 

 

DISCUSSING THE OPTIONS

Stool studies such as FOBT and FIT do not reliably detect cancer precursors such as adenomas and serrated neoplasms. If an FOBT is positive, follow-up diagnostic colonoscopy is required. Unlike screening colonoscopy, diagnostic colonoscopy requires a copayment for Medicare patients, and this should be explained to the patient.

FIT and FOBT detect hemolyzed blood within a stool sample, FOBT by a chemical reaction, and FIT by detecting a globin-specific antibody. Colorectal cancer and some large adenomatous polyps may intermittently bleed and result in occult blood in the stool, iron deficiency anemia, or hematochezia.¹⁵

Fecal occult blood testing

Historically, FOBT was the stool test of choice for screening. It uses an indirect enzymatic reaction to detect hemolyzed blood in the stool. When a specimen containing hemoglobin is added to guaiac paper and a drop of hydrogen peroxide is added to “develop” it, the peroxidase activity of hemoglobin turns the guaiac blue.

Screening with FOBT involves annual testing of 3 consecutively passed stools from different days; FOBT should not be performed at the time of digital rectal examination or if the patient is having overt rectal, urinary, or menstrual bleeding.

Dietary and medication restrictions before and during the testing period are critical, as red meat contains hemoglobin, and certain vegetables (eg, radishes, turnips, cauliflower, cucumbers) contain peroxidase, all of which can cause a false-positive result. Waiting 3 days after the stool sample is collected to develop it can mitigate the peroxidase activity of vegetables.¹⁶ Vitamin C inhibits heme peroxidase activity and leads to false-negative results. Aspirin and high-dose nonsteroidal anti-inflammatory drugs can promote bleeding throughout the intestinal tract.¹⁷

In randomized controlled trials,^18–21 screening with FOBT reduced colorectal cancer mortality rates by 15% to 33%. The 30-year follow-up of a large US trial²² found a 32% relative reduction in mortality rates in patients randomized to annual screening, and a 22% relative reduction in those randomized to screening every 2 years. Despite the many possibilities for false-positive results, the specificity for detecting cancer has ranged from 86.7% to 97.3%, and the sensitivity from 37.1% to 79.4%, highlighting the benefit of colorectal cancer screening programs in unscreened populations.^23–26

FIT vs FOBT in current practice

FIT should replace FOBT as the preferred stool screening method. Instead of an enzymatic reaction that can be altered by food or medication, FIT utilizes an antibody specific to human globin to directly detect hemolyzed blood, thus eliminating the need to modify the diet or medications.²⁷ Additionally, only 1 stool specimen is needed, which may explain why the adherence rate was about 20% higher with FIT than with FOBT in most studies.^28–30

FIT has a sensitivity of 69% to 86% for colorectal cancer and a specificity of 92% to 95%.³¹ The sensitivity can be improved by lowering the threshold value for a positive test, but this is associated with a decrease in specificity. A single FIT has the same sensitivity and specificity as several samples.³²

In a large retrospective US cohort study of programmatic screening with FIT, Jensen et al³³ reported that 48% of 670,841 people who were offered testing actually did the test. Of the 48% who participated in the first round and remained eligible, 75% to 86% participated in subsequent rounds over 4 years. Those who had a positive result on FIT were supposed to undergo colonoscopy, but 22% did not.

The US Multi-Society Task Force on Colorectal Cancer³⁴ suggests that FIT-based screening programs aim for a target FIT completion rate of more than 60% and a target colonoscopy completion rate of more than 80% of patients with positive FITs. These benchmarks were derived from adherence rates in international FIT screening studies in average-risk populations.^35–39 (Note that the large US cohort described above³³ did not meet these goals.) Ideally, every patient with a positive FIT should undergo diagnostic colonoscopy, but in reality only 50% to 83% actually do. Methods shown to improve adherence include structured screening programs with routine performance reports, provider feedback, and involvement of patient navigators.^40–42

Accordingly, several aspects of stool-based testing need to be stressed with patients. Understanding that FOBT is recommended yearly is integral for optimal impact on colorectal cancer incidence and mortality rates.

Additionally, patients should be advised to undergo colonoscopy soon after a positive FIT, because delaying colonoscopy could give precancerous lesions time to progress in stage. The acceptable time between a positive FIT and colonoscopy has yet to be determined. However, a retrospective cohort study of 1.26 million screened patients with 107,000 positive FIT results demonstrated that the rates of cancer discovered on colonoscopy were similar when performed within 30 days or up to 10 months after a positive test. Detection rates increased from 3% to 4.8% at 10 months and to 7.9% at 12 months.⁴³

In modeling studies, Meester et al⁴⁴ showed the estimated lifetime risk and mortality rates from colorectal cancer and life-years gained from screening are significantly better when colonoscopy is completed within 2 weeks rather than 1 year after a positive FIT. Each additional month after 2 weeks incrementally affected these outcomes, with a 1.4% increase in cancer mortality. These data suggest that colonoscopy should be done soon after a positive FIT result and at a maximum of 10 months.^43,44

Screening with FOBT is a multistep process for patients that includes receiving the test kit, collecting the sample, preparing it, returning it, undergoing colonoscopy after a positive test, and repeating in 1 year if negative. The screening program should identify patients at average risk in whom screening is appropriate, ensure delivery of the test, verify the quality of collected samples for laboratory testing against the manufacturer’s recommendations, and report results. Report of a positive FOBT result should provide recommendations for follow-up.

Though evidence clearly supports screening annually or biennially (every 2 years) with FOBT, the ideal interval for FIT is undetermined. Modeling studies utilized by the USPSTF and Multi-Society Task Force demonstrate that colonoscopy and annual FIT result in similar life-years gained, while 2 population-based screening programs have demonstrated that a 2- or 3-year interval may be equally efficacious by lowering the threshold for a positive test.^38,45

Randomized controlled trials of screening colonoscopy vs annual and biennial FIT are currently under way. Cost-effectiveness analysis has shown that offering single-sample FITs at more frequent (annual) intervals performs better than multisample testing at less frequent intervals.^45–47

 

 

Colonoscopy

Compared with stool-based screening, colonoscopy has advantages, including a 10-year screening interval if bowel preparation is adequate and the examination shows no neoplasia, the ability to inspect the entire colon, and the ability to diagnose and treat lesions in the same session.

Screening colonoscopy visualizes the entire colon in more than 98% of cases, although it requires adequate bowel preparation for maximal polyp detection. It can be done safely with or without sedation.⁴⁸

While there are no available randomized controlled trial data on the impact of screening colonoscopy on cancer incidence or mortality, extensive case-control and cohort studies consistently show that screening colonoscopy reduces cancer incidence and mortality rates.^49–54 A US Veterans Administration study of more than 32,000 patients reported a 50% reduction in overall colorectal cancer mortality.⁵⁵ In a microsimulation modeling study that assumed 100% adherence, colonoscopy every 10 years and annual FIT in individuals ages 50 to 75 provided similar life-years gained per 1,000 people screened (270 for colonoscopy, 244 for FIT).⁵⁶

Well-established metrics for maximizing the effectiveness and quality of colonoscopy have been established (Table 2). The most important include the mucosa inspection time (withdrawal time) and adenoma detection rate.⁵⁷ Withdrawal time is directly correlated with adenoma detection, and a 6-minute minimum withdrawal time is recommended in screening colonoscopy examinations of patients at average risk when no polyps are found.⁵⁸ The adenoma detection rate is the strongest evidence-based metric, as each 1% increase in the adenoma detection rate over 19% is associated with a 3% decrease in the risk of colorectal cancer and a 5% decrease in death rate.⁵⁹ The average-risk screening adenoma detection rate differs based on sex: the rate is greater than 20% for women and greater than 30% for men.

Complications from screening, diagnostic, or therapeutic colonoscopy are infrequent but include perforation (4/10,000) and significant intestinal bleeding (8/10,000).^56–62

Patients with a first-degree relative under age 60 with advanced adenomas or colorectal cancer are considered at high risk and should begin screening colonoscopy at age 40, with repeat colonoscopy at 5-year intervals, given a trend toward advanced neoplasia detection compared with FIT.⁶³

Guidelines recently published by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association also support starting screening in high-risk individuals at age 40, with a surveillance interval of 5 to 10 years based on the number of first-degree relatives with colorectal cancer or adenomas.⁶⁴ Consensus statements were based on retrospective cohort, prospective case-controlled, and cross-sectional studies comparing the risk of colorectal cancer in individuals with a family history against those without a family history.

Randomized clinical trials comparing colonoscopy and FIT are under way. Interim analysis of a European trial in which asymptomatic adults ages 50 to 69 were randomized to 1-time colonoscopy (26,703 patients) vs FIT every 2 years (26,599 patients) found significantly higher participation rates in the FIT arm (34.2% vs 24.6%) but higher rates of nonadvanced adenomas (4.2% vs 0.4%) and advanced neoplasia (1.9% vs 0.9%) in the colonoscopy arm.⁶⁵ Cancer was detected in 0.1% in each arm. These findings correlate with those of another study showing higher participation with FIT but higher advanced neoplasia detection rates with colonoscopy.⁶⁶

Detection of precursor lesions is vital, as removing neoplasms is the main strategy to reduce colorectal cancer incidence. Accordingly, the advantage of colonoscopy was illustrated by a study that determined that 53 patients would need to undergo screening colonoscopy to detect 1 advanced adenoma or cancerous lesion, compared with 264 for FIT.⁶⁷

STARTING SCREEING AT AGE 45

The American Cancer Society recently provided a qualified recommendation to start colorectal cancer screening in all individuals at age 45 rather than 50.⁹ This recommendation was based on modeling studies demonstrating that starting screening at age 45 with colonoscopy every 10 years resulted in 25 life-years gained at the cost of 610 colonoscopies per 1,000 individuals. Alternative strategies included FIT, which resulted in an additional 26 life-years gained per 1,000 individuals screened, flexible sigmoidoscopy (23 life-years gained), and computed tomographic colonoscopy (22 life-years gained).

Rates of colorectal cancer are rising in adults under age 50, and 10,000 new cases are anticipated this year.^2,3 Currently, 22 million US adults are between the ages of 45 and 50. The system and support needed to perform screening in all adults over age 45 and a lack of direct evidence to support its benefits in the young population need to be considered before widespread acceptance of the American Cancer Society recommendations. However, if screening is considered, FIT with or without sigmoidoscopy may be appropriate, given that most cancers diagnosed in individuals under age 50 are left-sided.^4,5

Screening has not been proven to reduce all-cause mortality. Randomized controlled trials of FOBT and observational studies of colonoscopy show that screening reduces cancer incidence and mortality. Until the currently ongoing randomized controlled trials comparing colonoscopy with FIT are completed, their comparative impact on colorectal cancer end points is unknown.

PATIENT ADHERENCE IS KEY

FIT and colonoscopy are the most prevalent screening methods in the United States. Careful attention should be given to offer the screening option the patient is most likely to complete, as adherence is key to the benefit from colorectal cancer screening.

The National Colorectal Cancer Roundtable (nccrt.org), established in 1997 by the American Cancer Society and the US Centers for Disease Control and Prevention, is a national coalition of public and private organizations dedicated to reducing colorectal cancer incidence and mortality. The Roundtable waged a national campaign to achieve a colorectal cancer screening rate of 80% in eligible adults by 2018, a goal that was not met. Still, the potential for a substantial impact is a compelling reason to endorse adherence to colorectal cancer screening. The Roundtable provides many resources for physicians to enhance screening in their practice.

The United States has seen a steady decline in colorectal cancer incidence and mortality, mainly as a result of screening. Colorectal cancer is preventable with ensuring patients’ adherence to screening. Screening rates have been shown to increase with patient-provider dialogue and with selection of a screening program the patient prefers and is most likely to complete.