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Coming soon: CAR T-cell approvals in multiple myeloma
, and will “completely transform oncology,” according to Carl June, MD.
That approval is anticipated sometime in 2019.
“Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells,” Dr. June, the Richard W. Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia, said in an interview.
The first treated patient in a trial of a novel anti-B-cell maturation antigen (BCMA)-specific CAR T-cell therapy (CART-BCMA) developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset.
Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas recently outed himself as that first patient, announcing in a Feb. 14, 2018, UT Southwestern press report that CART-BCMA saved his life.
Dr. Wright, who holds the Southland Financial Corporation Distinguished Chair in Geriatrics at UT Southwestern, was diagnosed with multiple myeloma about 12 years ago and failed 11 prior chemotherapies before he was enrolled in the CART-BCMA trial.
“Now he considers himself cured,” Dr. June said.
More than 2 years after receiving CART-BCMA he remains cancer free, and is now conducting CAR T-cell-related research in his lab at UT Southwestern in an effort to broaden the effectiveness of current CAR T-cell therapies. Specifically, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, as most patients who fail CAR T-cell therapy are elderly patients who might have terminally short telomeres, UT Southwestern reported.
The ongoing University of Pennsylvania trial led by Adam D. Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the American Society of Hematology (ASH) annual meeting in 2016, and multiple companies are currently pursuing registration trials for CAR T therapies in myeloma, Dr. June said.
Among them are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. That product was granted breakthrough therapy designation by the Food and Drug Administration in November 2017, and will thus receive expedited review. It has also been fast-tracked in Europe.
The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial. Updated findings from that trial were presented in December 2017 at ASH and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 106 CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.
Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells.
Janssen Biotech Inc. (a Johnson & Johnson company) and Legend Biotech USA Inc./Legend Biotech Ireland Limited (of Genscript Biotech Corporation) have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr. June said.
The companies announced in December that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate.
LCAR-B38M is currently accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
The “race between companies” for a CAR T myeloma approval will lead to a welcome addition to the treatment armamentarium, because while myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr. June said.
Since many patients live with their disease for a long time, that can mean huge “financial toxicity” associated with treatment and patients still usually have “an awful outcome involving a long death,” he said.
“So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added, explaining that the first CAR T-cell therapy approved (tisagenlecleucel, in August 2017) was for pediatric acute lymphoblastic leukemia that had relapsed at least twice. “That’s only about 600 kids a year in the U.S., so it’s an ultra-orphan market,” he said.
With the subsequent approval of axicabtagene ciloleucel (in October 2017) and the anticipated myeloma approval, CAR T-cell therapy will move away from orphan status.
“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s.
Early on, there were only two places in the country where a patient could get a bone marrow transplant – Fred Hutchinson Cancer Center in Seattle and Johns Hopkins University in Baltimore. “Everyone said ‘you’ll never be able to do it routinely, it’s only at these two referral centers,’ because of the skill needed and the intensity of it,” he said. “But over the years, millions of transplants have now been done; they’re done at many community centers. And it’s the same thing with CARs; Novartis now has 30 centers and people have to be trained. It’s a new skill set, and it will take time,” he said.
That can be particularly frustrating because there are many patients with diseases that “might benefit in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr. June noted.
“There’s more demand than availability, and it’s going to take awhile ... it’s like liver transplants – there aren’t enough donors to go around, so people die, they get on lists, and it’s really hard to see that, but eventually it will get solved,” he said, adding that the solution will most likely involve the complementary use of off-the-shelf CAR T cells in certain patients to induce remission and perhaps provide a bridge to some other definitive therapy, and ultra-personalized CAR T therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.
CRISPR-Cas9 gene editing is also being looked at as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute–funded NYCE study, Dr. June said.
“We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial,” he said. “We just opened and we’re screening patients now.”
Dr. June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.
, and will “completely transform oncology,” according to Carl June, MD.
That approval is anticipated sometime in 2019.
“Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells,” Dr. June, the Richard W. Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia, said in an interview.
The first treated patient in a trial of a novel anti-B-cell maturation antigen (BCMA)-specific CAR T-cell therapy (CART-BCMA) developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset.
Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas recently outed himself as that first patient, announcing in a Feb. 14, 2018, UT Southwestern press report that CART-BCMA saved his life.
Dr. Wright, who holds the Southland Financial Corporation Distinguished Chair in Geriatrics at UT Southwestern, was diagnosed with multiple myeloma about 12 years ago and failed 11 prior chemotherapies before he was enrolled in the CART-BCMA trial.
“Now he considers himself cured,” Dr. June said.
More than 2 years after receiving CART-BCMA he remains cancer free, and is now conducting CAR T-cell-related research in his lab at UT Southwestern in an effort to broaden the effectiveness of current CAR T-cell therapies. Specifically, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, as most patients who fail CAR T-cell therapy are elderly patients who might have terminally short telomeres, UT Southwestern reported.
The ongoing University of Pennsylvania trial led by Adam D. Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the American Society of Hematology (ASH) annual meeting in 2016, and multiple companies are currently pursuing registration trials for CAR T therapies in myeloma, Dr. June said.
Among them are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. That product was granted breakthrough therapy designation by the Food and Drug Administration in November 2017, and will thus receive expedited review. It has also been fast-tracked in Europe.
The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial. Updated findings from that trial were presented in December 2017 at ASH and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 106 CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.
Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells.
Janssen Biotech Inc. (a Johnson & Johnson company) and Legend Biotech USA Inc./Legend Biotech Ireland Limited (of Genscript Biotech Corporation) have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr. June said.
The companies announced in December that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate.
LCAR-B38M is currently accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
The “race between companies” for a CAR T myeloma approval will lead to a welcome addition to the treatment armamentarium, because while myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr. June said.
Since many patients live with their disease for a long time, that can mean huge “financial toxicity” associated with treatment and patients still usually have “an awful outcome involving a long death,” he said.
“So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added, explaining that the first CAR T-cell therapy approved (tisagenlecleucel, in August 2017) was for pediatric acute lymphoblastic leukemia that had relapsed at least twice. “That’s only about 600 kids a year in the U.S., so it’s an ultra-orphan market,” he said.
With the subsequent approval of axicabtagene ciloleucel (in October 2017) and the anticipated myeloma approval, CAR T-cell therapy will move away from orphan status.
“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s.
Early on, there were only two places in the country where a patient could get a bone marrow transplant – Fred Hutchinson Cancer Center in Seattle and Johns Hopkins University in Baltimore. “Everyone said ‘you’ll never be able to do it routinely, it’s only at these two referral centers,’ because of the skill needed and the intensity of it,” he said. “But over the years, millions of transplants have now been done; they’re done at many community centers. And it’s the same thing with CARs; Novartis now has 30 centers and people have to be trained. It’s a new skill set, and it will take time,” he said.
That can be particularly frustrating because there are many patients with diseases that “might benefit in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr. June noted.
“There’s more demand than availability, and it’s going to take awhile ... it’s like liver transplants – there aren’t enough donors to go around, so people die, they get on lists, and it’s really hard to see that, but eventually it will get solved,” he said, adding that the solution will most likely involve the complementary use of off-the-shelf CAR T cells in certain patients to induce remission and perhaps provide a bridge to some other definitive therapy, and ultra-personalized CAR T therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.
CRISPR-Cas9 gene editing is also being looked at as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute–funded NYCE study, Dr. June said.
“We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial,” he said. “We just opened and we’re screening patients now.”
Dr. June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.
, and will “completely transform oncology,” according to Carl June, MD.
That approval is anticipated sometime in 2019.
“Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells,” Dr. June, the Richard W. Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia, said in an interview.
The first treated patient in a trial of a novel anti-B-cell maturation antigen (BCMA)-specific CAR T-cell therapy (CART-BCMA) developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset.
Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas recently outed himself as that first patient, announcing in a Feb. 14, 2018, UT Southwestern press report that CART-BCMA saved his life.
Dr. Wright, who holds the Southland Financial Corporation Distinguished Chair in Geriatrics at UT Southwestern, was diagnosed with multiple myeloma about 12 years ago and failed 11 prior chemotherapies before he was enrolled in the CART-BCMA trial.
“Now he considers himself cured,” Dr. June said.
More than 2 years after receiving CART-BCMA he remains cancer free, and is now conducting CAR T-cell-related research in his lab at UT Southwestern in an effort to broaden the effectiveness of current CAR T-cell therapies. Specifically, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, as most patients who fail CAR T-cell therapy are elderly patients who might have terminally short telomeres, UT Southwestern reported.
The ongoing University of Pennsylvania trial led by Adam D. Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the American Society of Hematology (ASH) annual meeting in 2016, and multiple companies are currently pursuing registration trials for CAR T therapies in myeloma, Dr. June said.
Among them are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. That product was granted breakthrough therapy designation by the Food and Drug Administration in November 2017, and will thus receive expedited review. It has also been fast-tracked in Europe.
The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial. Updated findings from that trial were presented in December 2017 at ASH and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 106 CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.
Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells.
Janssen Biotech Inc. (a Johnson & Johnson company) and Legend Biotech USA Inc./Legend Biotech Ireland Limited (of Genscript Biotech Corporation) have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr. June said.
The companies announced in December that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate.
LCAR-B38M is currently accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
The “race between companies” for a CAR T myeloma approval will lead to a welcome addition to the treatment armamentarium, because while myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr. June said.
Since many patients live with their disease for a long time, that can mean huge “financial toxicity” associated with treatment and patients still usually have “an awful outcome involving a long death,” he said.
“So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added, explaining that the first CAR T-cell therapy approved (tisagenlecleucel, in August 2017) was for pediatric acute lymphoblastic leukemia that had relapsed at least twice. “That’s only about 600 kids a year in the U.S., so it’s an ultra-orphan market,” he said.
With the subsequent approval of axicabtagene ciloleucel (in October 2017) and the anticipated myeloma approval, CAR T-cell therapy will move away from orphan status.
“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s.
Early on, there were only two places in the country where a patient could get a bone marrow transplant – Fred Hutchinson Cancer Center in Seattle and Johns Hopkins University in Baltimore. “Everyone said ‘you’ll never be able to do it routinely, it’s only at these two referral centers,’ because of the skill needed and the intensity of it,” he said. “But over the years, millions of transplants have now been done; they’re done at many community centers. And it’s the same thing with CARs; Novartis now has 30 centers and people have to be trained. It’s a new skill set, and it will take time,” he said.
That can be particularly frustrating because there are many patients with diseases that “might benefit in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr. June noted.
“There’s more demand than availability, and it’s going to take awhile ... it’s like liver transplants – there aren’t enough donors to go around, so people die, they get on lists, and it’s really hard to see that, but eventually it will get solved,” he said, adding that the solution will most likely involve the complementary use of off-the-shelf CAR T cells in certain patients to induce remission and perhaps provide a bridge to some other definitive therapy, and ultra-personalized CAR T therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.
CRISPR-Cas9 gene editing is also being looked at as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute–funded NYCE study, Dr. June said.
“We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial,” he said. “We just opened and we’re screening patients now.”
Dr. June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.
World Trade Center responders face greater cancer burden, including greater risk of multiple myeloma
Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.
In particular, they may be at risk of developing multiple myeloma at an earlier age.
The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.
The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).
“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.
However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.
“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.
A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.
The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.
In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.
Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.
“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.
Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.
The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.
“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.
The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.
The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.
SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.
When the heroes of the World Trade Center are diagnosed with even a common cancer, there is a natural tendency to assume that the diagnosis is the result of their service during the disaster. However, it is important to appreciate that the firefighting profession is known to be associated with higher risks of monoclonal gammopathy of undetermined significance and multiple myelomas, compared with the general population.
Given that, it would have been preferable to compare the World Trade Center–exposed populations with an equally intensively screened, age-matched cohort of firefighters from another major city.
If we apply Sir Richard Doll’s rule that a single epidemiologic study cannot be persuasive until the lower bound of the 95% confidence interval is greater than three, the relative risks in the study by Landgren and colleagues are too small to be persuasive.
The predicted increases in cancers of the prostate, thyroid, and myeloma are interesting, but these have also been previously reported in firefighters from other cities.
Despite this, we owe it to these men and women to find the truth and determine the illnesses that are associated with their service.
Otis W. Brawley, MD, is chief medical and scientific officer and executive vice president of the American Cancer Society and a professor at Emory University, Atlanta. These comments are taken from an accompanying editorial (JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0498.) No conflicts of interest were declared.
When the heroes of the World Trade Center are diagnosed with even a common cancer, there is a natural tendency to assume that the diagnosis is the result of their service during the disaster. However, it is important to appreciate that the firefighting profession is known to be associated with higher risks of monoclonal gammopathy of undetermined significance and multiple myelomas, compared with the general population.
Given that, it would have been preferable to compare the World Trade Center–exposed populations with an equally intensively screened, age-matched cohort of firefighters from another major city.
If we apply Sir Richard Doll’s rule that a single epidemiologic study cannot be persuasive until the lower bound of the 95% confidence interval is greater than three, the relative risks in the study by Landgren and colleagues are too small to be persuasive.
The predicted increases in cancers of the prostate, thyroid, and myeloma are interesting, but these have also been previously reported in firefighters from other cities.
Despite this, we owe it to these men and women to find the truth and determine the illnesses that are associated with their service.
Otis W. Brawley, MD, is chief medical and scientific officer and executive vice president of the American Cancer Society and a professor at Emory University, Atlanta. These comments are taken from an accompanying editorial (JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0498.) No conflicts of interest were declared.
When the heroes of the World Trade Center are diagnosed with even a common cancer, there is a natural tendency to assume that the diagnosis is the result of their service during the disaster. However, it is important to appreciate that the firefighting profession is known to be associated with higher risks of monoclonal gammopathy of undetermined significance and multiple myelomas, compared with the general population.
Given that, it would have been preferable to compare the World Trade Center–exposed populations with an equally intensively screened, age-matched cohort of firefighters from another major city.
If we apply Sir Richard Doll’s rule that a single epidemiologic study cannot be persuasive until the lower bound of the 95% confidence interval is greater than three, the relative risks in the study by Landgren and colleagues are too small to be persuasive.
The predicted increases in cancers of the prostate, thyroid, and myeloma are interesting, but these have also been previously reported in firefighters from other cities.
Despite this, we owe it to these men and women to find the truth and determine the illnesses that are associated with their service.
Otis W. Brawley, MD, is chief medical and scientific officer and executive vice president of the American Cancer Society and a professor at Emory University, Atlanta. These comments are taken from an accompanying editorial (JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0498.) No conflicts of interest were declared.
Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.
In particular, they may be at risk of developing multiple myeloma at an earlier age.
The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.
The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).
“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.
However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.
“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.
A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.
The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.
In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.
Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.
“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.
Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.
The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.
“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.
The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.
The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.
SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.
Rescue and recovery workers who were involved in the aftermath of the World Trade Center disaster may face a greater cancer burden than the general population, according to two studies published in JAMA Oncology.
In particular, they may be at risk of developing multiple myeloma at an earlier age.
The first study was a closed-cohort study of 14,474 employees of the Fire Department of the City of New York (FDNY) who were exposed to the World Trade Center disaster but were cancer-free as of Jan. 1, 2012. The aim was to project cancer incidence from 2012 through 2031, based on data from the FDNY World Trade Center Health Program, and compare those rates with age-, race-, and sex-specific New York cancer rates from the general population.
The modeling projected a “modestly” higher number of cancer cases in the white male subgroup of rescue and recovery workers exposed to the World Trade Center (2,714 vs. 2,596 for the general population of New York; P less than .001). Specifically, the investigators projected significantly higher case counts of prostate cancer (1,437 vs. 863), thyroid cancer (73 vs. 57), and melanoma (201 vs. 131), compared with the general population in New York, but fewer lung (237 vs. 373), colorectal (172 vs. 267), and kidney cancers (66 vs. 132) (P less than .001 for all).
“Our findings suggest that the FDNY WTC-exposed cohort may experience a greater burden of cancer than would be expected from a population with similar demographic characteristics,” wrote Rachel Zeig-Owens, DrPH, from the Montefiore Medical Center and Albert Einstein College of Medicine, both in New York, and coauthors, highlighting prostate cancer as a particular concern.
However, they also acknowledged that the elevated rates observed in people exposed to the World Trade Center disaster could be a result of increased surveillance, even though they did attempt to correct for that, and that firefighters in general might face higher risks.
“It is possible that firefighters have a higher risk of cancer than the general population owing to exposures associated with the occupation,” they wrote. However occupation could also have the opposite effect, as rescue and recovery workers tend to have lower smoking rates, which may explain the relatively low rates of certain cancers such as lung cancer, they said.
A second study examined the effect of the World Trade Center disaster on the risk of multiple myeloma and monoclonal gammopathies in exposed firefighters.
The seroprevalence study of monoclonal gammopathies of undetermined significance (MGUS) in 781 exposed firefighters revealed that the age-standardized prevalence of these was 76% higher in this population than it was in a white male reference population living in Minnesota.
In particular, the age-standardized prevalence of light-chain MGUS was more than threefold higher in exposed firefighters, compared with the reference population.
Researchers also analyzed a case series of 16 exposed white male firefighters who received a diagnosis of multiple myeloma after Sept. 11, 2001. Of the 14 patients for whom data on the monoclonal protein isotype was available, half had light-chain multiple myeloma.
“These findings are of interest due to previously observed associations between light-chain multiple myeloma and light-chain MGUS and exposure to toxins, and chronic immune stimulation,” wrote Ola Landgren, MD, PhD, from the Memorial Sloan Kettering Cancer Center and his coauthors.
Seven patients were also assessed for CD20 expression – a marker of poorer prognosis – and 71% were found to be CD20-positive, a prevalence around 3.5-fold higher than that seen in the general population.
The cohort with multiple myeloma was diagnosed on average 12 years younger than those in the general population. The authors commented that this was unlikely to be caused by lead-time bias because the time from first symptoms to clinical manifestation of the disease is usually around 1 year.
“Taken together, our results show that environmental exposure due to the WTC attacks is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype,” the authors wrote.
The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared.
The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.
SOURCE: Zeig-Owens R et al. JAMA Oncology. 2018 April 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology. 2018 April 16. doi: 10.1001/jamaoncol.2018.0509.
FROM JAMA ONCOLOGY
Key clinical point: Monoclonal gammopathies and multiple myeloma may occur more often and earlier in World Trade Center rescue workers.
Major finding: Prevalence of light-chain monoclonal gammopathies is threefold higher in exposed firefighters than in a reference population of white males.
Study details: A cohort study in 14,474 employees of the Fire Department of the City of New York exposed to the Sept. 11, 2001, World Trade Center disaster, a case series of 16 exposed white male firefighters diagnosed with multiple myeloma, and a seroprevalence study of monoclonal gammopathies of undetermined significance in 781 exposed firefighters.
Disclosures: The first study was supported by the National Institute of Occupational Safety and Health; no conflicts of interest were declared. The second study was supported by the V Foundation for Cancer Research, the Byrne Fund for the benefit of Memorial Sloan-Kettering Cancer Center, the National Cancer Institute, the Albert Einstein Cancer Center, and the National Institute for Occupational Safety and Health; no conflicts of interest were declared.
Source: Zeig-Owens R et al. JAMA Oncology 2018, Apr 26. doi: 10.1001/jamaoncol.2018.0504. Landgren O et al. JAMA Oncology 2018, Apr 26. doi: 10.1001/jamaoncol.2018.0509.
Schizophrenia: Psychiatrists ‘can do much more’ for patients
In this interview, Dr. Lorenzo Norris, of Clinical Psychiatry News, and Dr. Henry A. Nasrallah, of Current Psychiatry, discuss the groundbreaking work of physicians that shows how early schizophrenia can begin manifesting in the brain. And they ask why psychiatry doesn’t seem to be taking the loss of brain tissue seen in schizophrenia and other forms of psychosis more seriously. When it comes to illnesses such as Alzheimer’s, physicians recognize the need to conserve brain tissue. Why is that not the case for schizophrenia?
“We can do much more for our patients than we’re doing right now,” Dr. Nasrallah said. “We’re delaying treatment, and that can lead to more brain damage. We also allow patients to relapse again and again ... it’s like benign neglect.”
Dr. Norris, editor in chief of MdEdge Psychiatry, has no disclosures. Dr. Nasrallah, editor in chief of Current Psychiatry, serves as a consultant and on the advisory boards of several companies, including Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, and Teva. He also serves on speakers bureaus of several companies.
In this interview, Dr. Lorenzo Norris, of Clinical Psychiatry News, and Dr. Henry A. Nasrallah, of Current Psychiatry, discuss the groundbreaking work of physicians that shows how early schizophrenia can begin manifesting in the brain. And they ask why psychiatry doesn’t seem to be taking the loss of brain tissue seen in schizophrenia and other forms of psychosis more seriously. When it comes to illnesses such as Alzheimer’s, physicians recognize the need to conserve brain tissue. Why is that not the case for schizophrenia?
“We can do much more for our patients than we’re doing right now,” Dr. Nasrallah said. “We’re delaying treatment, and that can lead to more brain damage. We also allow patients to relapse again and again ... it’s like benign neglect.”
Dr. Norris, editor in chief of MdEdge Psychiatry, has no disclosures. Dr. Nasrallah, editor in chief of Current Psychiatry, serves as a consultant and on the advisory boards of several companies, including Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, and Teva. He also serves on speakers bureaus of several companies.
In this interview, Dr. Lorenzo Norris, of Clinical Psychiatry News, and Dr. Henry A. Nasrallah, of Current Psychiatry, discuss the groundbreaking work of physicians that shows how early schizophrenia can begin manifesting in the brain. And they ask why psychiatry doesn’t seem to be taking the loss of brain tissue seen in schizophrenia and other forms of psychosis more seriously. When it comes to illnesses such as Alzheimer’s, physicians recognize the need to conserve brain tissue. Why is that not the case for schizophrenia?
“We can do much more for our patients than we’re doing right now,” Dr. Nasrallah said. “We’re delaying treatment, and that can lead to more brain damage. We also allow patients to relapse again and again ... it’s like benign neglect.”
Dr. Norris, editor in chief of MdEdge Psychiatry, has no disclosures. Dr. Nasrallah, editor in chief of Current Psychiatry, serves as a consultant and on the advisory boards of several companies, including Acadia, Alkermes, Allergan, Boehringer-Ingelheim, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, and Teva. He also serves on speakers bureaus of several companies.
IL-22 blocker investigated in phase 2a atopic dermatitis study
Fezakinumab, an interleukin-22 monoclonal antibody, “resulted in consistent improvements in clinical and molecular disease scores as compared with placebo” in a phase 2a study of adults with moderate to severe atopic dermatitis (AD), according to Emma Guttman-Yassky, MD, of Icahn School of Medicine at Mount Sinai, New York, and her associates.
In the double-blind, placebo-controlled trial, 60 patients were randomized to intravenous fezakinumab every 2 weeks for 10 weeks (40 patients) or placebo (20). Beginning at week 4, those who received fezakinumab “showed a consistently stronger and more significant mean SCORAD decline from baseline” compared with those on placebo. This became statistically significant at weeks 6-10 (P less than .05). “Differences between drug and placebo extended beyond the last dose” at week 10, they noted.*
The primary endpoint, the change in the SCORAD score from baseline at 12 weeks, was not statistically significant, however.
In addition, progressive reductions were seen during weeks 14-20, with a significant difference between the drug and placebo arms (P = .049) observed at week 20.
The mean decline in body surface area was “consistently stronger” among those on the biologic, “and was significantly different from the placebo group starting from week 8 until the end of study,” which included the 12th week (P = .009), the researchers noted.
In addition, among those on fezakinumab, mean improvements in Investigator Global Assessment scores compared with baseline were stronger and appeared earlier and were significantly different compared with those on placebo at week 16 (P less than .001).
There were two serious adverse events among those in the treatment group: facial cellulitis after a dental procedure and a pregnancy with elective termination, which were considered “most likely unrelated” to treatment. In the fezakinumab group, four patients had upper respiratory tract infections, the most common adverse event.
“This is the first clinical trial investigating IL-22 blockade in patients with AD, and the first to suggest a pathogenic role of IL-22 in any human disease,” the authors concluded.
SOURCE: Guttman-Yassky et al. J Am Acad Dermatol. 78(5);872-81.
Correction, 4/27/17: An earlier version of this article misstated the statistical significance of the primary endpoint.
Fezakinumab, an interleukin-22 monoclonal antibody, “resulted in consistent improvements in clinical and molecular disease scores as compared with placebo” in a phase 2a study of adults with moderate to severe atopic dermatitis (AD), according to Emma Guttman-Yassky, MD, of Icahn School of Medicine at Mount Sinai, New York, and her associates.
In the double-blind, placebo-controlled trial, 60 patients were randomized to intravenous fezakinumab every 2 weeks for 10 weeks (40 patients) or placebo (20). Beginning at week 4, those who received fezakinumab “showed a consistently stronger and more significant mean SCORAD decline from baseline” compared with those on placebo. This became statistically significant at weeks 6-10 (P less than .05). “Differences between drug and placebo extended beyond the last dose” at week 10, they noted.*
The primary endpoint, the change in the SCORAD score from baseline at 12 weeks, was not statistically significant, however.
In addition, progressive reductions were seen during weeks 14-20, with a significant difference between the drug and placebo arms (P = .049) observed at week 20.
The mean decline in body surface area was “consistently stronger” among those on the biologic, “and was significantly different from the placebo group starting from week 8 until the end of study,” which included the 12th week (P = .009), the researchers noted.
In addition, among those on fezakinumab, mean improvements in Investigator Global Assessment scores compared with baseline were stronger and appeared earlier and were significantly different compared with those on placebo at week 16 (P less than .001).
There were two serious adverse events among those in the treatment group: facial cellulitis after a dental procedure and a pregnancy with elective termination, which were considered “most likely unrelated” to treatment. In the fezakinumab group, four patients had upper respiratory tract infections, the most common adverse event.
“This is the first clinical trial investigating IL-22 blockade in patients with AD, and the first to suggest a pathogenic role of IL-22 in any human disease,” the authors concluded.
SOURCE: Guttman-Yassky et al. J Am Acad Dermatol. 78(5);872-81.
Correction, 4/27/17: An earlier version of this article misstated the statistical significance of the primary endpoint.
Fezakinumab, an interleukin-22 monoclonal antibody, “resulted in consistent improvements in clinical and molecular disease scores as compared with placebo” in a phase 2a study of adults with moderate to severe atopic dermatitis (AD), according to Emma Guttman-Yassky, MD, of Icahn School of Medicine at Mount Sinai, New York, and her associates.
In the double-blind, placebo-controlled trial, 60 patients were randomized to intravenous fezakinumab every 2 weeks for 10 weeks (40 patients) or placebo (20). Beginning at week 4, those who received fezakinumab “showed a consistently stronger and more significant mean SCORAD decline from baseline” compared with those on placebo. This became statistically significant at weeks 6-10 (P less than .05). “Differences between drug and placebo extended beyond the last dose” at week 10, they noted.*
The primary endpoint, the change in the SCORAD score from baseline at 12 weeks, was not statistically significant, however.
In addition, progressive reductions were seen during weeks 14-20, with a significant difference between the drug and placebo arms (P = .049) observed at week 20.
The mean decline in body surface area was “consistently stronger” among those on the biologic, “and was significantly different from the placebo group starting from week 8 until the end of study,” which included the 12th week (P = .009), the researchers noted.
In addition, among those on fezakinumab, mean improvements in Investigator Global Assessment scores compared with baseline were stronger and appeared earlier and were significantly different compared with those on placebo at week 16 (P less than .001).
There were two serious adverse events among those in the treatment group: facial cellulitis after a dental procedure and a pregnancy with elective termination, which were considered “most likely unrelated” to treatment. In the fezakinumab group, four patients had upper respiratory tract infections, the most common adverse event.
“This is the first clinical trial investigating IL-22 blockade in patients with AD, and the first to suggest a pathogenic role of IL-22 in any human disease,” the authors concluded.
SOURCE: Guttman-Yassky et al. J Am Acad Dermatol. 78(5);872-81.
Correction, 4/27/17: An earlier version of this article misstated the statistical significance of the primary endpoint.
FROM THE JOURNAL OF the AMERICAN ACADEMY OF DERMATOLOGY
Climate Change and Skin Disease
The term climate refers to the average weather conditions of a specific geographic location measured over several decades.1 While a certain degree of variation in the Earth’s climate is expected, a persistent warming or cooling trend is not. The factors driving the Earth’s warming remain difficult to prove.2 We know the Earth previously has undergone dramatic climate changes and that natural factors driving these changes are varied (eg, the relationship between the Earth and the Sun, volcanic eruptions, solar irradiance).1,3 These factors ideally change over protracted periods of time in a way that allows organisms to adapt to new environments.
Anthropogenic climate change refers to human-caused climate change. This is thought to be a major driving factor in the Earth’s recent warming trend, partly due to the rapidity of warming in recent years.3 According to climate scientists, the Earth’s temperature has risen 4°C to 7°C over the past 5000 years, but it has risen 0.7°C in just the past 100 years alone.4 Greenhouse gases such as carbon dioxide are emitted by various natural processes and human activities and play a central role in current warming because they trap solar heat and increase ambient temperature.3
In a recent edition of the commonly cited textbook Dermatology, Bolognia et al5 referenced climate change only once in a figure legend regarding the expansion of dengue fever in the Americas. However, climate change may have the potential to cause outright skin disease epidemics worldwide, and the Climate Change Committee of the International Society of Dermatology has called upon dermatologists across the globe to help raise awareness of this issue.6
Much of the literature regarding the effects of climate change on human health focuses on insect-borne diseases, but over the past decade other areas of impact also have been investigated, such as increases in airborne diseases, zoonoses, newly endemic saprophytic and dimorphic fungal infections, fecal-oral diseases, and severe allergic disease.7,8 It is postulated that climate change leads to region-specific increases in human disease because it creates newly favorable habitats for infectious agents, their vectors. and their reservoirs, allowing expansion of their ranges and access to immunologically naïve populations.9 Furthermore, extreme weather events such as heat waves, hurricanes, and flooding, which are expected to increase in frequency as a result of climate change, have all been linked to infectious disease outbreaks.10
Lyme Disease
In the past 20 years, Lyme disease incidence has tripled in the United States.11 It has been hypothesized that the increase may be occurring as a result of the expanding geographic distribution of the Ixodes tick and its mammalian hosts (eg, white-tailed deer) under the influence of climate change.12 Lyme disease is a multisystem disease affecting the skin, joints, heart, and nervous system. Its most characteristic manifestation is cutaneous in the form of erythema migrans. Dermatologists may be called upon to play an increasingly important role in early detection and treatment of this potentially chronic and debilitating condition.
Arboviruses
Arboviruses are transmitted by arthropods and are an important category of climate change–related diseases due to the expansion of the mosquito habitat worldwide. The vectorial capacity for the transmission of dengue fever has increased worldwide by 9.4% via Aedes aegypti and 11.1% via Aedes albopictus since 1950.13 Dengue fever, also known as breakbone fever, presents with intense joint pain, fevers, headaches, and a transient morbilliform rash that desquamates with defervescence and in some cases will incite hemorrhagic skin lesions.14 Dengue fever previously was considered to be a tropical disease but locally acquired cases have been reported in the United States, including Texas, Hawaii, and Florida.15,16
Reports of local transmission of chikungunya, another arbovirus transmitted by A albopictus and A aegypti mosquitoes in Florida, the US Virgin Islands, and Puerto Rico, began in 2014.17 A higher prevalence of these diseases within the United States also may be related to increased globalization, with US travelers returning from endemic regions with infections. Prior to 2014, transmission occurred in traditional endemic regions, primarily in Asia, Africa, or island nations in the Indian Ocean. Like dengue fever, chikungunya causes high fevers, cutaneous manifestations (eg, urticarial papules, morbilliform eruption, hypermelanosis, intertriginous lesions, lymphedema),17 and intense joint pain. Unlike dengue fever, however, joint involvement can be chronic, erosive, and debilitating.
Lastly, New World leishmaniasis, an arboviral disease characterized by mucocutaneous ulcers and transmitted by phlebotomine sand flies, has been acquired locally in Oklahoma and Texas when it was previously considered to be endemic to Mexico and Central and South America.14,18 The habitats of New World Leishmania species are expected to expand northward, with an ecological niche model predicting that they reach southern Canada by the year 2080 due to the expanding habitats of sand fly and rodent vectors.19
Fungal Infections
In the Pacific Northwest, there have been reports of newly endemic Cryptococcus gattii and Coccidioides immitis, both of which previously had been confined to the southwestern United States.8 Endemic ranges of these mycotic pathogens may be expanding for a variety of reasons, with climate change creating new regions conducive to the colonization of these species.8,20,21Coccidioides immitis is a soil-dwelling fungus that usually presents with primary pulmonary disease that can disseminate acutely or even months later. Prompt recognition of disseminated disease may allow life-saving therapy to be initiated. Cryptococcus gattii is a fungus with multiple niches, including oil, trees, and birds.20 This fungus also is acquired via inhalation, with dissemination occurring most commonly in immunosuppressed patients to the central nervous system, bone, and skin. Primary or secondary infection with both of these fungi may present with cutaneous manifestations presenting as polymorphous lesions, including umbilicated or ulcerated papules, indurated nodules, and acneiform pustules.
Final Thoughts
Awareness of the shifting habitats of microorganisms and vectors locally is important in order for clinicians to make correct diagnoses in a timely fashion. Regional or endemic diseases are presenting outside their traditional boundaries due to changing habitats of microbes and vectors and may be easily overlooked, resulting in a delayed diagnosis. Being prepared to diagnose diseases with increasing incidence secondary to climate change and discussing this with patients is an important physician obligation, but it is not the only one. We cannot effectively advocate for the health of patients and the community while ignoring the destruction of the environment. Our additional responsibility is straightforward—being advocates for good stewardship of the Earth’s resources now on both a personal and a policy level.22
- Climate Central. Global Weirdness: Severe Storms, Deadly Heat Waves, Relentless Drought, Rising Seas, and the Weather of the Future. New York, NY: Pantheon Books; 2012.
- Cook J, Nuccitelli D, Green SA, et al. Quantifying the consensus on anthropogenic global warming in the scientific literature. Environ Res Lett. 2013;8:024024.
- A blanket around the Earth. NASA Climate website. https://climate.nasa.gov/causes/. Accessed February 5, 2018.
- How is today’s warming different from the past? NASA Earth Observatory website. https://earthobservatory.nasa.gov/Features/GlobalWarming/page3.php. Accessed February 5, 2018.
- Mancini AJ, Shani-Adir A, Sidbury R. Other viral diseases. In: Bolognia JL, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed. Philadelphia, PA: Elsevier; 2017:1425-1446.
- Andersen LK, Davis MDP. A wake-up call to dermatologists—climate change affects the skin. Int J Dermatol. 2017;56:E198-E199.
- Liang L, Gong P. Climate change and human infectious diseases: a synthesis of research findings from global and spatio-temporal perspectives [published online March 23, 2017]. Environ Int. 2017;103:99-108.
- Lockhart SR, McCotter OZ, Chiller TM. Emerging fungal infections in the Pacific Northwest: the unrecognized burden and geographic range of Cryptococcus gattii and Coccidioides immitis. Microbiol Spectr. 2016;4. doi:10.1128/microbiolspec.EI10-0016-2016.
- Kilpatrick AM, Randolph SE. Drivers, dynamics, and control of emerging vector-borne zoonotic diseases. Lancet. 2012;380:1946-1955.
- McMichael AJ. Extreme weather events and infectious disease outbreaks. Virulence. 2015;6:543-547.
- Lyme disease graphs. CDC website. https://www.cdc.gov/lyme/stats/graphs.html. Updated November 1, 2017. Accessed April 12, 2018.
- Stone BL, Tourand Y, Brissette CA. Brave new worlds: the expanding universe of Lyme disease. Vector Borne Zoonotic Dis. 2017;17:619-629.
- Watts N, Amann M, Ayeb-Karlsson S, et al. The Lancet Countdown on health and climate change: from 25 years of inaction to a global transformation for public health [published online October 30, 2017]. Lancet. doi:10.1016/S0140-6736(17)32464-9.
- Nawas ZY, Tong Y, Kollipara R, et al. Emerging infectious diseases with cutaneous manifestations: viral and bacterial infections. J Am Acad Dermatol. 2016;75:1-16.
- Kaffenberger BH, Shetlar D, Norton SA, et al. The effect of climate change on skin disease in North America. J Am Acad Dermatol. 2017;76:140-147.
- Dengue. CDC website. https://www.cdc.gov/dengue/epidemiology/index.html. Updated June 9, 2014. Accessed April 3, 2018.
- Chikungunya virus in the United States. CDC website. https://www.cdc.gov/chikungunya/geo/united-states.html. Updated October 30, 2017. Accessed April 4, 2018.
- Clarke CF, Bradley KK, Wright JH, et al. Emergence of autochthonous cutaneous leishmaniasis in northeastern Texas and southeastern Oklahoma. Am J Trop Med Hyg. 2013;88:157-61.
- González C, Wang O, Strutz SE, et al. Climate change and risk of leishmaniasis in North America: predictions from ecological niche models of vector and reservoir species. PLoS Negl Trop Dis. 2010;4:E585.
- Chang CC, Chen SC. Colliding epidemics and the rise of cryptococcosis. J Fungi (Basel). 2015;2. doi: 10.3390/jof2010001.
- Marsden-Haug N, Goldoft M, Ralston C, et al. Coccidioidomycosis acquired in Washington state. Clin Infect Dis. 2013;56:847-850.
- Rosenbach M. Climate change & dermatology: what can you do? Paper presented at: American Academy of Dermatology Annual Meeting; March 3-7, 2017; Orlando, FL.
The term climate refers to the average weather conditions of a specific geographic location measured over several decades.1 While a certain degree of variation in the Earth’s climate is expected, a persistent warming or cooling trend is not. The factors driving the Earth’s warming remain difficult to prove.2 We know the Earth previously has undergone dramatic climate changes and that natural factors driving these changes are varied (eg, the relationship between the Earth and the Sun, volcanic eruptions, solar irradiance).1,3 These factors ideally change over protracted periods of time in a way that allows organisms to adapt to new environments.
Anthropogenic climate change refers to human-caused climate change. This is thought to be a major driving factor in the Earth’s recent warming trend, partly due to the rapidity of warming in recent years.3 According to climate scientists, the Earth’s temperature has risen 4°C to 7°C over the past 5000 years, but it has risen 0.7°C in just the past 100 years alone.4 Greenhouse gases such as carbon dioxide are emitted by various natural processes and human activities and play a central role in current warming because they trap solar heat and increase ambient temperature.3
In a recent edition of the commonly cited textbook Dermatology, Bolognia et al5 referenced climate change only once in a figure legend regarding the expansion of dengue fever in the Americas. However, climate change may have the potential to cause outright skin disease epidemics worldwide, and the Climate Change Committee of the International Society of Dermatology has called upon dermatologists across the globe to help raise awareness of this issue.6
Much of the literature regarding the effects of climate change on human health focuses on insect-borne diseases, but over the past decade other areas of impact also have been investigated, such as increases in airborne diseases, zoonoses, newly endemic saprophytic and dimorphic fungal infections, fecal-oral diseases, and severe allergic disease.7,8 It is postulated that climate change leads to region-specific increases in human disease because it creates newly favorable habitats for infectious agents, their vectors. and their reservoirs, allowing expansion of their ranges and access to immunologically naïve populations.9 Furthermore, extreme weather events such as heat waves, hurricanes, and flooding, which are expected to increase in frequency as a result of climate change, have all been linked to infectious disease outbreaks.10
Lyme Disease
In the past 20 years, Lyme disease incidence has tripled in the United States.11 It has been hypothesized that the increase may be occurring as a result of the expanding geographic distribution of the Ixodes tick and its mammalian hosts (eg, white-tailed deer) under the influence of climate change.12 Lyme disease is a multisystem disease affecting the skin, joints, heart, and nervous system. Its most characteristic manifestation is cutaneous in the form of erythema migrans. Dermatologists may be called upon to play an increasingly important role in early detection and treatment of this potentially chronic and debilitating condition.
Arboviruses
Arboviruses are transmitted by arthropods and are an important category of climate change–related diseases due to the expansion of the mosquito habitat worldwide. The vectorial capacity for the transmission of dengue fever has increased worldwide by 9.4% via Aedes aegypti and 11.1% via Aedes albopictus since 1950.13 Dengue fever, also known as breakbone fever, presents with intense joint pain, fevers, headaches, and a transient morbilliform rash that desquamates with defervescence and in some cases will incite hemorrhagic skin lesions.14 Dengue fever previously was considered to be a tropical disease but locally acquired cases have been reported in the United States, including Texas, Hawaii, and Florida.15,16
Reports of local transmission of chikungunya, another arbovirus transmitted by A albopictus and A aegypti mosquitoes in Florida, the US Virgin Islands, and Puerto Rico, began in 2014.17 A higher prevalence of these diseases within the United States also may be related to increased globalization, with US travelers returning from endemic regions with infections. Prior to 2014, transmission occurred in traditional endemic regions, primarily in Asia, Africa, or island nations in the Indian Ocean. Like dengue fever, chikungunya causes high fevers, cutaneous manifestations (eg, urticarial papules, morbilliform eruption, hypermelanosis, intertriginous lesions, lymphedema),17 and intense joint pain. Unlike dengue fever, however, joint involvement can be chronic, erosive, and debilitating.
Lastly, New World leishmaniasis, an arboviral disease characterized by mucocutaneous ulcers and transmitted by phlebotomine sand flies, has been acquired locally in Oklahoma and Texas when it was previously considered to be endemic to Mexico and Central and South America.14,18 The habitats of New World Leishmania species are expected to expand northward, with an ecological niche model predicting that they reach southern Canada by the year 2080 due to the expanding habitats of sand fly and rodent vectors.19
Fungal Infections
In the Pacific Northwest, there have been reports of newly endemic Cryptococcus gattii and Coccidioides immitis, both of which previously had been confined to the southwestern United States.8 Endemic ranges of these mycotic pathogens may be expanding for a variety of reasons, with climate change creating new regions conducive to the colonization of these species.8,20,21Coccidioides immitis is a soil-dwelling fungus that usually presents with primary pulmonary disease that can disseminate acutely or even months later. Prompt recognition of disseminated disease may allow life-saving therapy to be initiated. Cryptococcus gattii is a fungus with multiple niches, including oil, trees, and birds.20 This fungus also is acquired via inhalation, with dissemination occurring most commonly in immunosuppressed patients to the central nervous system, bone, and skin. Primary or secondary infection with both of these fungi may present with cutaneous manifestations presenting as polymorphous lesions, including umbilicated or ulcerated papules, indurated nodules, and acneiform pustules.
Final Thoughts
Awareness of the shifting habitats of microorganisms and vectors locally is important in order for clinicians to make correct diagnoses in a timely fashion. Regional or endemic diseases are presenting outside their traditional boundaries due to changing habitats of microbes and vectors and may be easily overlooked, resulting in a delayed diagnosis. Being prepared to diagnose diseases with increasing incidence secondary to climate change and discussing this with patients is an important physician obligation, but it is not the only one. We cannot effectively advocate for the health of patients and the community while ignoring the destruction of the environment. Our additional responsibility is straightforward—being advocates for good stewardship of the Earth’s resources now on both a personal and a policy level.22
The term climate refers to the average weather conditions of a specific geographic location measured over several decades.1 While a certain degree of variation in the Earth’s climate is expected, a persistent warming or cooling trend is not. The factors driving the Earth’s warming remain difficult to prove.2 We know the Earth previously has undergone dramatic climate changes and that natural factors driving these changes are varied (eg, the relationship between the Earth and the Sun, volcanic eruptions, solar irradiance).1,3 These factors ideally change over protracted periods of time in a way that allows organisms to adapt to new environments.
Anthropogenic climate change refers to human-caused climate change. This is thought to be a major driving factor in the Earth’s recent warming trend, partly due to the rapidity of warming in recent years.3 According to climate scientists, the Earth’s temperature has risen 4°C to 7°C over the past 5000 years, but it has risen 0.7°C in just the past 100 years alone.4 Greenhouse gases such as carbon dioxide are emitted by various natural processes and human activities and play a central role in current warming because they trap solar heat and increase ambient temperature.3
In a recent edition of the commonly cited textbook Dermatology, Bolognia et al5 referenced climate change only once in a figure legend regarding the expansion of dengue fever in the Americas. However, climate change may have the potential to cause outright skin disease epidemics worldwide, and the Climate Change Committee of the International Society of Dermatology has called upon dermatologists across the globe to help raise awareness of this issue.6
Much of the literature regarding the effects of climate change on human health focuses on insect-borne diseases, but over the past decade other areas of impact also have been investigated, such as increases in airborne diseases, zoonoses, newly endemic saprophytic and dimorphic fungal infections, fecal-oral diseases, and severe allergic disease.7,8 It is postulated that climate change leads to region-specific increases in human disease because it creates newly favorable habitats for infectious agents, their vectors. and their reservoirs, allowing expansion of their ranges and access to immunologically naïve populations.9 Furthermore, extreme weather events such as heat waves, hurricanes, and flooding, which are expected to increase in frequency as a result of climate change, have all been linked to infectious disease outbreaks.10
Lyme Disease
In the past 20 years, Lyme disease incidence has tripled in the United States.11 It has been hypothesized that the increase may be occurring as a result of the expanding geographic distribution of the Ixodes tick and its mammalian hosts (eg, white-tailed deer) under the influence of climate change.12 Lyme disease is a multisystem disease affecting the skin, joints, heart, and nervous system. Its most characteristic manifestation is cutaneous in the form of erythema migrans. Dermatologists may be called upon to play an increasingly important role in early detection and treatment of this potentially chronic and debilitating condition.
Arboviruses
Arboviruses are transmitted by arthropods and are an important category of climate change–related diseases due to the expansion of the mosquito habitat worldwide. The vectorial capacity for the transmission of dengue fever has increased worldwide by 9.4% via Aedes aegypti and 11.1% via Aedes albopictus since 1950.13 Dengue fever, also known as breakbone fever, presents with intense joint pain, fevers, headaches, and a transient morbilliform rash that desquamates with defervescence and in some cases will incite hemorrhagic skin lesions.14 Dengue fever previously was considered to be a tropical disease but locally acquired cases have been reported in the United States, including Texas, Hawaii, and Florida.15,16
Reports of local transmission of chikungunya, another arbovirus transmitted by A albopictus and A aegypti mosquitoes in Florida, the US Virgin Islands, and Puerto Rico, began in 2014.17 A higher prevalence of these diseases within the United States also may be related to increased globalization, with US travelers returning from endemic regions with infections. Prior to 2014, transmission occurred in traditional endemic regions, primarily in Asia, Africa, or island nations in the Indian Ocean. Like dengue fever, chikungunya causes high fevers, cutaneous manifestations (eg, urticarial papules, morbilliform eruption, hypermelanosis, intertriginous lesions, lymphedema),17 and intense joint pain. Unlike dengue fever, however, joint involvement can be chronic, erosive, and debilitating.
Lastly, New World leishmaniasis, an arboviral disease characterized by mucocutaneous ulcers and transmitted by phlebotomine sand flies, has been acquired locally in Oklahoma and Texas when it was previously considered to be endemic to Mexico and Central and South America.14,18 The habitats of New World Leishmania species are expected to expand northward, with an ecological niche model predicting that they reach southern Canada by the year 2080 due to the expanding habitats of sand fly and rodent vectors.19
Fungal Infections
In the Pacific Northwest, there have been reports of newly endemic Cryptococcus gattii and Coccidioides immitis, both of which previously had been confined to the southwestern United States.8 Endemic ranges of these mycotic pathogens may be expanding for a variety of reasons, with climate change creating new regions conducive to the colonization of these species.8,20,21Coccidioides immitis is a soil-dwelling fungus that usually presents with primary pulmonary disease that can disseminate acutely or even months later. Prompt recognition of disseminated disease may allow life-saving therapy to be initiated. Cryptococcus gattii is a fungus with multiple niches, including oil, trees, and birds.20 This fungus also is acquired via inhalation, with dissemination occurring most commonly in immunosuppressed patients to the central nervous system, bone, and skin. Primary or secondary infection with both of these fungi may present with cutaneous manifestations presenting as polymorphous lesions, including umbilicated or ulcerated papules, indurated nodules, and acneiform pustules.
Final Thoughts
Awareness of the shifting habitats of microorganisms and vectors locally is important in order for clinicians to make correct diagnoses in a timely fashion. Regional or endemic diseases are presenting outside their traditional boundaries due to changing habitats of microbes and vectors and may be easily overlooked, resulting in a delayed diagnosis. Being prepared to diagnose diseases with increasing incidence secondary to climate change and discussing this with patients is an important physician obligation, but it is not the only one. We cannot effectively advocate for the health of patients and the community while ignoring the destruction of the environment. Our additional responsibility is straightforward—being advocates for good stewardship of the Earth’s resources now on both a personal and a policy level.22
- Climate Central. Global Weirdness: Severe Storms, Deadly Heat Waves, Relentless Drought, Rising Seas, and the Weather of the Future. New York, NY: Pantheon Books; 2012.
- Cook J, Nuccitelli D, Green SA, et al. Quantifying the consensus on anthropogenic global warming in the scientific literature. Environ Res Lett. 2013;8:024024.
- A blanket around the Earth. NASA Climate website. https://climate.nasa.gov/causes/. Accessed February 5, 2018.
- How is today’s warming different from the past? NASA Earth Observatory website. https://earthobservatory.nasa.gov/Features/GlobalWarming/page3.php. Accessed February 5, 2018.
- Mancini AJ, Shani-Adir A, Sidbury R. Other viral diseases. In: Bolognia JL, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed. Philadelphia, PA: Elsevier; 2017:1425-1446.
- Andersen LK, Davis MDP. A wake-up call to dermatologists—climate change affects the skin. Int J Dermatol. 2017;56:E198-E199.
- Liang L, Gong P. Climate change and human infectious diseases: a synthesis of research findings from global and spatio-temporal perspectives [published online March 23, 2017]. Environ Int. 2017;103:99-108.
- Lockhart SR, McCotter OZ, Chiller TM. Emerging fungal infections in the Pacific Northwest: the unrecognized burden and geographic range of Cryptococcus gattii and Coccidioides immitis. Microbiol Spectr. 2016;4. doi:10.1128/microbiolspec.EI10-0016-2016.
- Kilpatrick AM, Randolph SE. Drivers, dynamics, and control of emerging vector-borne zoonotic diseases. Lancet. 2012;380:1946-1955.
- McMichael AJ. Extreme weather events and infectious disease outbreaks. Virulence. 2015;6:543-547.
- Lyme disease graphs. CDC website. https://www.cdc.gov/lyme/stats/graphs.html. Updated November 1, 2017. Accessed April 12, 2018.
- Stone BL, Tourand Y, Brissette CA. Brave new worlds: the expanding universe of Lyme disease. Vector Borne Zoonotic Dis. 2017;17:619-629.
- Watts N, Amann M, Ayeb-Karlsson S, et al. The Lancet Countdown on health and climate change: from 25 years of inaction to a global transformation for public health [published online October 30, 2017]. Lancet. doi:10.1016/S0140-6736(17)32464-9.
- Nawas ZY, Tong Y, Kollipara R, et al. Emerging infectious diseases with cutaneous manifestations: viral and bacterial infections. J Am Acad Dermatol. 2016;75:1-16.
- Kaffenberger BH, Shetlar D, Norton SA, et al. The effect of climate change on skin disease in North America. J Am Acad Dermatol. 2017;76:140-147.
- Dengue. CDC website. https://www.cdc.gov/dengue/epidemiology/index.html. Updated June 9, 2014. Accessed April 3, 2018.
- Chikungunya virus in the United States. CDC website. https://www.cdc.gov/chikungunya/geo/united-states.html. Updated October 30, 2017. Accessed April 4, 2018.
- Clarke CF, Bradley KK, Wright JH, et al. Emergence of autochthonous cutaneous leishmaniasis in northeastern Texas and southeastern Oklahoma. Am J Trop Med Hyg. 2013;88:157-61.
- González C, Wang O, Strutz SE, et al. Climate change and risk of leishmaniasis in North America: predictions from ecological niche models of vector and reservoir species. PLoS Negl Trop Dis. 2010;4:E585.
- Chang CC, Chen SC. Colliding epidemics and the rise of cryptococcosis. J Fungi (Basel). 2015;2. doi: 10.3390/jof2010001.
- Marsden-Haug N, Goldoft M, Ralston C, et al. Coccidioidomycosis acquired in Washington state. Clin Infect Dis. 2013;56:847-850.
- Rosenbach M. Climate change & dermatology: what can you do? Paper presented at: American Academy of Dermatology Annual Meeting; March 3-7, 2017; Orlando, FL.
- Climate Central. Global Weirdness: Severe Storms, Deadly Heat Waves, Relentless Drought, Rising Seas, and the Weather of the Future. New York, NY: Pantheon Books; 2012.
- Cook J, Nuccitelli D, Green SA, et al. Quantifying the consensus on anthropogenic global warming in the scientific literature. Environ Res Lett. 2013;8:024024.
- A blanket around the Earth. NASA Climate website. https://climate.nasa.gov/causes/. Accessed February 5, 2018.
- How is today’s warming different from the past? NASA Earth Observatory website. https://earthobservatory.nasa.gov/Features/GlobalWarming/page3.php. Accessed February 5, 2018.
- Mancini AJ, Shani-Adir A, Sidbury R. Other viral diseases. In: Bolognia JL, Schaffer JV, Cerroni L, eds. Dermatology. 4th ed. Philadelphia, PA: Elsevier; 2017:1425-1446.
- Andersen LK, Davis MDP. A wake-up call to dermatologists—climate change affects the skin. Int J Dermatol. 2017;56:E198-E199.
- Liang L, Gong P. Climate change and human infectious diseases: a synthesis of research findings from global and spatio-temporal perspectives [published online March 23, 2017]. Environ Int. 2017;103:99-108.
- Lockhart SR, McCotter OZ, Chiller TM. Emerging fungal infections in the Pacific Northwest: the unrecognized burden and geographic range of Cryptococcus gattii and Coccidioides immitis. Microbiol Spectr. 2016;4. doi:10.1128/microbiolspec.EI10-0016-2016.
- Kilpatrick AM, Randolph SE. Drivers, dynamics, and control of emerging vector-borne zoonotic diseases. Lancet. 2012;380:1946-1955.
- McMichael AJ. Extreme weather events and infectious disease outbreaks. Virulence. 2015;6:543-547.
- Lyme disease graphs. CDC website. https://www.cdc.gov/lyme/stats/graphs.html. Updated November 1, 2017. Accessed April 12, 2018.
- Stone BL, Tourand Y, Brissette CA. Brave new worlds: the expanding universe of Lyme disease. Vector Borne Zoonotic Dis. 2017;17:619-629.
- Watts N, Amann M, Ayeb-Karlsson S, et al. The Lancet Countdown on health and climate change: from 25 years of inaction to a global transformation for public health [published online October 30, 2017]. Lancet. doi:10.1016/S0140-6736(17)32464-9.
- Nawas ZY, Tong Y, Kollipara R, et al. Emerging infectious diseases with cutaneous manifestations: viral and bacterial infections. J Am Acad Dermatol. 2016;75:1-16.
- Kaffenberger BH, Shetlar D, Norton SA, et al. The effect of climate change on skin disease in North America. J Am Acad Dermatol. 2017;76:140-147.
- Dengue. CDC website. https://www.cdc.gov/dengue/epidemiology/index.html. Updated June 9, 2014. Accessed April 3, 2018.
- Chikungunya virus in the United States. CDC website. https://www.cdc.gov/chikungunya/geo/united-states.html. Updated October 30, 2017. Accessed April 4, 2018.
- Clarke CF, Bradley KK, Wright JH, et al. Emergence of autochthonous cutaneous leishmaniasis in northeastern Texas and southeastern Oklahoma. Am J Trop Med Hyg. 2013;88:157-61.
- González C, Wang O, Strutz SE, et al. Climate change and risk of leishmaniasis in North America: predictions from ecological niche models of vector and reservoir species. PLoS Negl Trop Dis. 2010;4:E585.
- Chang CC, Chen SC. Colliding epidemics and the rise of cryptococcosis. J Fungi (Basel). 2015;2. doi: 10.3390/jof2010001.
- Marsden-Haug N, Goldoft M, Ralston C, et al. Coccidioidomycosis acquired in Washington state. Clin Infect Dis. 2013;56:847-850.
- Rosenbach M. Climate change & dermatology: what can you do? Paper presented at: American Academy of Dermatology Annual Meeting; March 3-7, 2017; Orlando, FL.
Valbenazine Provides Long-Term Benefits for Tardive Dyskinesia
LOS ANGELES—Once-daily treatment with valbenazine for 48 weeks provides substantial improvements on clinician- and patient-reported outcomes in adults with tardive dyskinesia, according to data described at the 70th Annual Meeting of the American Academy of Neurology. The results are consistent with those of previous trials, said the researchers. Valbenazine is well-tolerated and does not raise significant safety concerns.
Valbenazine was approved as a treatment for tardive dyskinesia on the basis of several short-term placebo-controlled trials, a blinded extension study, and the long-term KINECT 4 study. Stewart Factor, DO, Professor of Neurology at Emory University School of Medicine in Atlanta, and colleagues conducted a study to evaluate the long-term effects of once-daily valbenazine on tardive dyskinesia. 
Eligible participants were adults with de novo tardive dyskinesia and those who had participated in prior trials of valbenazine. All participants received 48 weeks of open-label treatment with valbenazine. The initial dose was 40 mg. If an investigator judged that a patient had inadequate clinical response at week four, the dose was increased to 80 mg, based on tolerability. For patients who could not tolerate the 80-mg dose, the dose was decreased to 40 mg.
Dr. Factor and colleagues used the change from baseline in the Abnormal Involuntary Movement Scale (AIMS) total score to assess changes in tardive dyskinesia. Other efficacy assessments included the Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) scales. The investigators applied standard safety methods, including treatment-emergent adverse event reporting.
The safety population included 163 participants. Of this group, 107 participants received and tolerated the 80-mg dose, 45 did not require escalation from the 40-mg dose, and 11 were escalated to 80-mg dose, but later required reduction to the 40-mg dose. The mean change from baseline to week 48 in AIMS total score indicated improvements in tardive dyskinesia in all dose groups. The 80-mg group had a decrease of 11.0 points, the 40-mg group had a decrease of 10.2 points, and the group whose dose was decreased from 80 mg to 40 mg had a decrease of 7.2 points.
At week 48, more than 75% of participants in each study arm had a PGIC score of 2 or lower (ie, much improved or very much improved). This outcome was achieved in 89.2% of the 80-mg group, 90.0% of the 40-mg group, and 77.8% of the group whose dose was decreased from 80 mg to 40 mg. Mean CGI-TD scores at week 48 were 1.6 for the 80-mg group, 1.7 for the 40-mg group, and 2.3 for the group whose dose was reduced from 80 mg to 40 mg. These scores indicated clinically meaningful long-term improvement for all dose groups.
Less than 15% of all participants had a serious treatment-emergent adverse event (12.9%) or treatment-emergent adverse event leading to discontinuation (14.7%).
The study was funded by Neurocrine Biosciences, the manufacturer of valbenazine.
LOS ANGELES—Once-daily treatment with valbenazine for 48 weeks provides substantial improvements on clinician- and patient-reported outcomes in adults with tardive dyskinesia, according to data described at the 70th Annual Meeting of the American Academy of Neurology. The results are consistent with those of previous trials, said the researchers. Valbenazine is well-tolerated and does not raise significant safety concerns.
Valbenazine was approved as a treatment for tardive dyskinesia on the basis of several short-term placebo-controlled trials, a blinded extension study, and the long-term KINECT 4 study. Stewart Factor, DO, Professor of Neurology at Emory University School of Medicine in Atlanta, and colleagues conducted a study to evaluate the long-term effects of once-daily valbenazine on tardive dyskinesia.
Eligible participants were adults with de novo tardive dyskinesia and those who had participated in prior trials of valbenazine. All participants received 48 weeks of open-label treatment with valbenazine. The initial dose was 40 mg. If an investigator judged that a patient had inadequate clinical response at week four, the dose was increased to 80 mg, based on tolerability. For patients who could not tolerate the 80-mg dose, the dose was decreased to 40 mg.
Dr. Factor and colleagues used the change from baseline in the Abnormal Involuntary Movement Scale (AIMS) total score to assess changes in tardive dyskinesia. Other efficacy assessments included the Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) scales. The investigators applied standard safety methods, including treatment-emergent adverse event reporting.
The safety population included 163 participants. Of this group, 107 participants received and tolerated the 80-mg dose, 45 did not require escalation from the 40-mg dose, and 11 were escalated to 80-mg dose, but later required reduction to the 40-mg dose. The mean change from baseline to week 48 in AIMS total score indicated improvements in tardive dyskinesia in all dose groups. The 80-mg group had a decrease of 11.0 points, the 40-mg group had a decrease of 10.2 points, and the group whose dose was decreased from 80 mg to 40 mg had a decrease of 7.2 points.
At week 48, more than 75% of participants in each study arm had a PGIC score of 2 or lower (ie, much improved or very much improved). This outcome was achieved in 89.2% of the 80-mg group, 90.0% of the 40-mg group, and 77.8% of the group whose dose was decreased from 80 mg to 40 mg. Mean CGI-TD scores at week 48 were 1.6 for the 80-mg group, 1.7 for the 40-mg group, and 2.3 for the group whose dose was reduced from 80 mg to 40 mg. These scores indicated clinically meaningful long-term improvement for all dose groups.
Less than 15% of all participants had a serious treatment-emergent adverse event (12.9%) or treatment-emergent adverse event leading to discontinuation (14.7%).
The study was funded by Neurocrine Biosciences, the manufacturer of valbenazine.
LOS ANGELES—Once-daily treatment with valbenazine for 48 weeks provides substantial improvements on clinician- and patient-reported outcomes in adults with tardive dyskinesia, according to data described at the 70th Annual Meeting of the American Academy of Neurology. The results are consistent with those of previous trials, said the researchers. Valbenazine is well-tolerated and does not raise significant safety concerns.
Valbenazine was approved as a treatment for tardive dyskinesia on the basis of several short-term placebo-controlled trials, a blinded extension study, and the long-term KINECT 4 study. Stewart Factor, DO, Professor of Neurology at Emory University School of Medicine in Atlanta, and colleagues conducted a study to evaluate the long-term effects of once-daily valbenazine on tardive dyskinesia.
Eligible participants were adults with de novo tardive dyskinesia and those who had participated in prior trials of valbenazine. All participants received 48 weeks of open-label treatment with valbenazine. The initial dose was 40 mg. If an investigator judged that a patient had inadequate clinical response at week four, the dose was increased to 80 mg, based on tolerability. For patients who could not tolerate the 80-mg dose, the dose was decreased to 40 mg.
Dr. Factor and colleagues used the change from baseline in the Abnormal Involuntary Movement Scale (AIMS) total score to assess changes in tardive dyskinesia. Other efficacy assessments included the Patient Global Impression of Change (PGIC) and Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD) scales. The investigators applied standard safety methods, including treatment-emergent adverse event reporting.
The safety population included 163 participants. Of this group, 107 participants received and tolerated the 80-mg dose, 45 did not require escalation from the 40-mg dose, and 11 were escalated to 80-mg dose, but later required reduction to the 40-mg dose. The mean change from baseline to week 48 in AIMS total score indicated improvements in tardive dyskinesia in all dose groups. The 80-mg group had a decrease of 11.0 points, the 40-mg group had a decrease of 10.2 points, and the group whose dose was decreased from 80 mg to 40 mg had a decrease of 7.2 points.
At week 48, more than 75% of participants in each study arm had a PGIC score of 2 or lower (ie, much improved or very much improved). This outcome was achieved in 89.2% of the 80-mg group, 90.0% of the 40-mg group, and 77.8% of the group whose dose was decreased from 80 mg to 40 mg. Mean CGI-TD scores at week 48 were 1.6 for the 80-mg group, 1.7 for the 40-mg group, and 2.3 for the group whose dose was reduced from 80 mg to 40 mg. These scores indicated clinically meaningful long-term improvement for all dose groups.
Less than 15% of all participants had a serious treatment-emergent adverse event (12.9%) or treatment-emergent adverse event leading to discontinuation (14.7%).
The study was funded by Neurocrine Biosciences, the manufacturer of valbenazine.
2018 Update on cervical disease
In this Update, I outline important findings from several studies published in the past year. First and foremost, what are best practices for performing colposcopy in the United States? The American Society for Colposcopy and Cervical Pathology (ASCCP) released guidelines addressing such practices. Second, what are the implications of repeated negative screening and patients’ acceptance of extended screening intervals? A recent observational cohort study and a large study of Kaiser Permanente’s practices since 2003 shed light on these questions. Last, where do we stand with HPV vaccination? Two studies shed light on the efficacy of vaccination against human papillomavirus (HPV), and subsequent cervical intraepithelial neoplasia (CIN) and cervical cancer.
ASCCP releases updated quality guidelines for performing colposcopy
Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223-229.
Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235-241.
Wentzensen N, Schiffman M, Silver MI, et al. ASCCP colposcopy standards: Risk-based colposcopy practice. J Low Genit Tract Dis. 2017;21(4):230-234.
In October 2017, the ASCCP released a set of standards on the role and performance of colposcopy that represents best practices in women's health care in the United States. The work of these groups comprised a literature search, a national survey of ASCCP members, public comment, and expert consensus, and addressed:
- establishment of a common understanding of 1) the benefits of colposcopy in health maintenance and risk prevention, 2) risks presented by the procedure, and 3) terminology and criteria for reporting results that reduce subjectivity in reporting
- the rationale for, approach to, and recommendations regarding assessment of cervical precancer at colposcopy
- both minimum and comprehensive guidelines for the colposcopic examination, from preprocedure evaluation to follow-up.
Each Working Group performed the analysis and produced its own report and recommendations, published sequentially in a 2017 issue of the Journal of Lower Urinary Tract Disease. The findings and standards that they produced 1) offer essential insight for high- and low-volume coloposcopists and 2) are intended to improve the quality of colposcopy, reduce subjectivity in reporting findings, and improve the sensitivity of the procedure. Aware of the concerns and objectives of payers and hospital credentialing committees, the ASCCP found it important to establish what would be considered US-based minimum quality standards and to present goals that providers and systems could strive to achieve.
Selected details of the 3 guideline reports
The past 6 years have brought us through a great deal of transition in the prevention of cervical precancer, with regard to screening intervals and types of screening (for example, see "HPV−cytology co-testing every 3 years lowers population rates of cervical precancer and cancer," in the 2017 "Cervical Disease Update," OBG Management, May 2017). The most significant change was in 2012, when American Cancer Society/ASCCP guidelines were revised to abandon screening with annual Pap testing on most patients--an effort to strike a balance between the lifesaving value of identifying precancer and the potential harm of excessive colposcopy.
If, as the US Preventive Services Task Force (USPSTF) has declared, excessive colposcopy is a harm of screening, then we should be adapting our practices, especially in terms of the frequency of screening, to 1) reduce the risk of unnecessarily screening and potentially triaging patients to colposcopy and 2) bring the highest standards of performance and reporting to colposcopic practice (see "Why aren't you doing a Pap on me?"). In other words, "This is the way I've always done it" shouldn't characterize efforts to detect disease, when the data are clear that doing less might be more beneficial for our patients. Adherence to extended screening intervals is not yet good enough to balance benefit and risk of harm, as Rendle and colleagues showed in an article this year in Preventive Medicine (discussed in the next section of this "Update"). We need to do better.
Adherence to extended screening intervals means fewer colposcopies and less exposure to risk of attendant harm. But adherence is not purely mechanical: It can be intertwined with how patients feel about the care we provide and about their safety. When a patient moves from years of annual Pap testing to less frequent screening, she might express her concern by challenging your expertise.
In my practice, I have a simple, 1-minute conversation with the patient that is important to wedge into our discussion of her care. I explain that increasing the frequency of screening is only going to increase the chance that I will perform a colposcopy but not increase the chance that I will identify cancer. I conclude by reassuring her that I do not want to harm her, or to cause her anxiety, pain, cramping, or bleeding--or require her to spend time away from work or show her family that she is suffering. Patients are reassured and happy after that, I find. This is a patient-centered discussion that providers need to have if they hope to establish and maintain adherence to recommended screening intervals.
-- Mark H. Einstein, MD, MS
Here is a limited encapsulation of the 3 wide-ranging reports on the ASCCP colposcopy recommendations:
Role of colposcopy; benefits, potential harms, terminology (Khan et al; Working Group 1). The authors provide reinforcement: The strategic benefit of colposcopy is clear--a "drastic" reduction in excisional procedures by limiting them to patients in whom cervical cancer precursors have been confirmed or who present a high risk of occult invasive cervical cancer. Furthermore, the rate of adverse events for colposcopy−including significant bleeding and infection−is low.
Nevertheless, the potential for harm exists when an unskilled provider performs colposcopy; the Working Group emphasizes that proficiency comes with training and experience. Even in skilled hands, however, anxiety and the discomfort of a speculum examination and from acetic acid, as well as cramping and pain, might dissuade some women from receiving regular cervical screening subsequently. The authors cite research showing that educational interventions can help soothe anxiety about colposcopy and potential findings,1,2 although consensus is lacking on the value of such interventions.
The Working Group 1) developed recommended terminology for reporting findings in colposcopy practice in the United States and 2) defined the comprehensive documentation of the procedure as comprising cervix and squamocolumnar junction visibility; acetowhitening; presence of a lesion; lesion visibility, size and location of lesion(s); vascular changes; other features; and colposcopic impression (TABLE 1).3 Minimum criteria for reporting colposcopy results were also proposed, extracted from the comprehensive standards.
Risk-based colposcopy practice (Wentzensen et al). Women referred to colposcopy present with a range of underlying risk of precancer. Assessing that risk at the colposcopy visit allows the provider to modify and individualize the procedure. Risk can be estimated by referral screening tests (eg, cytology, HPV testing) performed in conjunction with the colposcopic impression. As opposed to a lack of standards for a minimum number of biopsies, the Working Group recommends that, as a standard, multiple targeted biopsies (≥2, as many as 4) are needed to improve detection of prevalent precancers. Colposcopic impression alone is not enough to diagnose precancerous cells. Let's face it: Our eyes with a colposcopic magnification of 15X do not make a microscope.
Implementing the Working Group's recommendations is expected to lead to improved detection of cervical precancers at colposcopy and to provide stronger reassurance of negative colposcopy results. Regarding biopsy of lesions, ASCCP did not find added benefit to taking random (nondirected) biopsies for women at low risk for precancer. The sensitivity of biopsy is increased by taking multiple biopsies of suspicious lesions, based on a risk-based approach detailed in the ASCCP guidelines. So, depending on underlying risk (estimated from screening and triage tests), colposcopy practice can be adapted in a useful manner to account for differences in risk:
- When risk of precancer is very high, for example, immediate treatment might reduce cost and prevent the patient from being lost to follow-up. When risk is very low, consider expectant management (serial cytology and HPV testing) with limited need for biopsy. In a setting of intermediate risk, the Working Group proposes, "multiple biopsies of acetowhite lesions lead to increased detection of precancer."
- Perform multiple biopsies that target all areas characterized by 1) acetowhitening, 2) metaplasia, and 3) higher abnormalities.
- Do not perform nontargeted biopsies on patients at the lowest end of risk who have been referred to colposcopy−ie, those with cytology that is less than HSIL; no evidence of HPV types 16/18; and a normal colposcopic impression (ie, no acetowhitening or metaplasia, or other visible abnormality).
- Immediate excision without biopsy confirmation or colposcopy with multiple targeted biopsies is acceptable in nonpregnant women 25 years and older whose risk of precancer is very high (≥2 of the following: HSIL cytology, HPV 16- or HPV 18-positive(or both), and high-grade colposcopy impression). Endocervical sampling should be conducted according to ASCCP's 2012 management guidelines. If biopsies do not show precancer, manage the patient using ASCCP's 2012 management guidelines, the Working Group recommends.
How do we perform colposcopy? Implications for establishing standards (Waxman et al; Working Group 3). To serve as a guide to standardizing colposcopy across the United States, the authors defined and delineated 6 major components (and their constituent parts) of a comprehensive colposcopy:
- precolposcopy evaluation
- the examination
- use of colposcopy adjuncts
- documentation
- biopsy sampling
- postcolposcopy procedures.
The constituent parts of these components are laid out in TABLE 2.4 A set of components for a minimum colposcopy procedure is drawn mostly from the comprehensive protocol.
The Working Group acknowledges that, in the United States, "the accuracy and reproducibility of colposcopy with biopsy as a diagnostic tool are limited." Why? Three contributing factors, the authors write, might be the absence of practice recommendations for colposcopy-biopsy procedures; of measures of quality assurance; and of standardized terminology.
Standards arrive for practice
Minimum quality standards are becoming part of almost everything US health care providers do−whether it is documentation, billing practices, or good care. Our work in gynecology, including colposcopy, is now being assessed as it is in much of the world, where minimum standards are already in place and guidelines must be followed. (In some countries standards require performing a minimum number of colposcopies per year to be identified as a "certified" colposcopist.)
What should be considered "minimum standards" for colposcopy in the United States? These ASCCP reports ask, and deliver answers to that question, bringing a broad range of concerns about high-quality practice into focus. Physicians and advanced-practice clinicians in this country who perform colposcopies have been trained to do so, but they have never had minimum standards by which to model and assess their performance. A procedure that has the potential to lead to additional testing for either cervical cancer, or to surveillance, should have minimum standards by which it is performed and documented in the United States as it is for much of the world that has widespread cervical cancer screening.
Guidance and recommendations developed by ASCCP offer women's health care providers a set of comprehensive and, alternatively, minimum quality standards that should be incorporated into practice across all aspects of the colposcopic exam, including precolposcopy evaluation, how to perform the procedure, how to document and report findings (TABLE 2), biopsy practice, establish quality control and assurance, as well as postprocedure follow-up. In taking the initiative to draw up these standards, ASCCP encourages providers to exceed the minimum requirements.
Read about adherence to cervical cancer screening.
Cervical screening adherence is relatively low, but safe. Extended intervals are very safe.
Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study. Ann Intern Med. 2018;168(1):20-29.
Rendle KA, Schiffman M, Cheung LC, et al. Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. Prev Med. 2018;109:44-50.
Patients who have been screened for cervical cancer for a long time--decades, even--have a diminishing likelihood that cancer will ever be detected. Furthermore, highest-risk patients already have been triaged into further testing or procedures, such as a loop excision electrosurgical procedure or hysterectomy. Two recent studies examined the implications of repeated negative screening and patients' acceptance of extended screening intervals.
Details of the studies
Several negative rounds of cotesting (HPV and cytology) might justify changes to the screening interval. To determine the rate of detection of CIN3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in routine practice after successive negative screening at 3-year intervals, Castle and colleagues looked at records of more than 990,000 women in an integrated health care system who underwent cotesting (HPV and cytology) between 2003 and 2014. They determined that the risk of invasive cervical cancer and ≥CIN3 declined with each round of cotesting; the absolute risk fell more between first and second rounds than between second and third rounds.
At any given round of cotesting, Castle found that the ability to reassure a patient about cancer and cancer risk was similar when looking at an HPV result alone, whatever the cytology or HPV-cytology cotest result was. The investigators concluded that similar patterns of risk would have been seen had stand-alone HPV testing been used, instead of co-testing, (HPV testing alone might have missed a few cases of CIN3 and adenocarcinoma in situ leading to cancer). A single negative cotest was so effective at ruling out ≥CIN3 and cervical cancer that, after a second round of cotesting, they found that no interval cancer cases were detected among women who had a negative HPV result.
Women aged 50 years or older had a 5- to 6-fold lower risk after their third consecutive negative cotest than women aged 30 to 39 years had after their first negative cotest. These data support the ideas, Castle noted, that 1) assigning screening intervals based on both age and number of previous negative screens and 2) extending the screening interval even further than 3 years after 2--perhaps even after 1--negative cotests or HPV tests are worth entertaining. Screening women of this age becomes inefficient and cost-ineffective, even at 5-year intervals.
Is patients' adherence to an extended interval of cotesting reliable enough to change practice? Rendle and colleagues examined the records of more than 491,000 women (in the same integrated health care system that Castle studied) who had undergone routine cervical cancer screening between 2003 and 2015. Their goal was to determine how high adherence had become to the system's recommendation of an every-3-year screening interval--an interval that mirrors long-standing guidelines elsewhere.
In short, researchers observed increasing and relatively rapid clinical adoption of every-3-year cotesting for routine cervical screening over time; between 2003 and 2009, the cohort grew significantly less likely overall to come in early for screening. In this setting, adoption of an extended screeninginterval appears to run counter to earlier understanding that patients are likely to resist such extension.
Women aged 60 to 64 were most likely to screen early across 2 consecutive intervals. What Rendle termed a "modest" decrease in the percentage of late screeners (but still within a 5-year interval) was also noted during adoption of the 3-year interval.
What next?
Molecular-based testing. Research, mostly outside of the United States, is taking us in the direction of molecular-based technologies as at least a component of cervical cancer screening. Today, we rely mostly on Pap tests and colposcopy, but these are subjective screens, with a human operator. With molecular testing (mostly of components of HPV), results are objective--a "Yes" or "No" finding based on clinically validated thresholds. Methods such as genotyping, P16INK4a/Ki-67 gene product dual-stain cytology, and testing for E6 and E7 HPV mRNA transcripts are in development, and hold promise to allow us to screen safely using almost completely molecular testing, thus eliminating human error and subjectivity and enriching the population that needs further management with very sensitive and potentially specific testing.
We are being presented with the possibility that almost all aspects of screening can be done without a provider, until the patient needs treatment.
Access to screening. Research is also looking at improving access, such as self-sampling for primary screening. That includes home cervical and vaginal sampling, with specimens mailed to the laboratory, from where results and follow-up instructions as communicated to patients. The Netherlands and the United Kingdom are moving to self-sampling primary screens; the United States is not--yet. But that is the direction research is taking us.
Modified guidelines. Eyes are on the work of the USPSTF. Last year, the Task Force issued draft recommendations (https://www.uspre ventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2#clinical), followed by a comment period (now closed), for updating 2012 cervical cancer screening guidelines in a way that would trigger a major change in clinical practice. Those draft recommendations and public comments are under review; final recommendations are possible within this calendar year.
Continue to follow current screening guidelines; they are safe and effective for preventing cervical cancer. This assumes adherence to intervals, which is both the provider's and the patient's responsibility: First, less is more; too much screening ("I've always done it this way") can be harmful. Second, screening at intervals set by the guidelines is extremely safe, despite earlier reports or provider concerns that suggest otherwise.
Patients who have undergone several rounds of negative screening have a markedly diminished risk of cervical cancer. Serve them best by performing this underutilized gyn procedure: Sit on your hands.
Be aware that winds of change are blowing: What constitutes appropriate screening intervals is up for discussion this year, and molecular-based testing technologies that are under investigation have the potential to someday be a vast improvement over current good, but subjective, interpretations of results.
Last, promote primary prevention of cervical cancer with HPV vaccination in your practice to increase the percentage of protected patients. Doing so will contribute not only to their long-term health but also, at a societal level, to a herd immunity effect.5 Any positive HPV infection in a future of a well-vaccinated population will be significant, and HPV-targeted technologies to identify the highest risk women will be the most efficient screening.
Read about the safety and efficacy of HPV vaccination.
Primary prevention of cervical cancer with vaccination is critical in any cancer prevention program
Benard VB, Castle PE, Jenison SA, et al; New Mexico HPV Pap Registry Steering Committee. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3(6):833-837.
Luostarinen T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associated cancers. Int J Cancer. 2018;142(10):2186-2187.
The success story of HPV vaccination, after more than a decade of use, continued to unfold in important ways over the past year.
Safety. With tens of millions of doses delivered, we know that the vaccine is safe, and we have retreated on some of the precautions that we once took: For example, we no longer perform a routine pregnancy test before vaccination on reproductive-age women.
Efficacy. We have learned, based on what we see in Australia and Western Europe, that vaccination is highly effective. We are also starting to see evidence of efficacy in areas of the United States, even though the vaccine is voluntary and there are no school-based recommendations. And we know that herd vaccination is very effective. The 2 studies described here add to our understanding of how vaccination is having an impact on endpoints.
Findings of the 2 studies
HPV vaccination has a direct impact on the precursor of cancer, CIN. Benard and colleagues examined data from the New Mexico HPV Pap Registry, a mandatory statewide surveillance system of cervical cancer screening that captured estimates of both screening prevalence and CIN since the time HPV vaccination was introduced in 2007 to 2014. The investigators examined registry data to gauge trends in the rate of CIN and to estimate the effect of HPV vaccination on that rate when adjusted for changes in screening for cervical cancer.
The incidence of CIN declined significantly across all grades in 2 groups between 2007 and 2015: females aged 15 to 19 years and females aged 20 to 24 years (but not in females 25 to 29 years of age). During those years, mean uptake of HPV vaccination among females 13 to 17 years of age reached as high as 40% (in 2014).
Although a reduction in CIN2 and CIN3 precancers "are early benchmarks for achieving this aim [of reducing the rate of cancer]," the investigators note, a reduction in CIN1 is "a direct measure of reductions in HPV infections requisite to the development of almost all invasive cervical cancer."
Benard moves on to conclude that a reduction in clinical outcomes of CIN among groups who are partially vaccinated for HPV is going to change clinical practice and reduce the cost-effectiveness of clinical care that supports prevention of cervical cancer. Of greatest importance, modalities and strategies for screening, and management algorithms, are going to need to evolve as HPV vaccination and cervical screening are integrated in a rational manner. Furthermore, it might be feasible to factor in population-level decreases in CIN among cohorts who are partially vaccinated for HPV when reassessing clinical practice guidelines for cervical cancer screening.
What does this mean? As we start to eliminate HPV from the population, any positive screening result will be that much more meaningful because the outcome--cervical cancer--will be much rarer. The onus will be on providers and public health officials to re-strategize how to screen what is going to be a widely-vaccinated population; more and more, we will be looking for needles in a haystack.
How are we going to someday screen women in their 20s who were vaccinated at 11 or 12 years of age? Likely, screening will start at a later age, and screening will be conducted at longer intervals. Any finding of HPV or disease is going to be highly significant, and likely, far less frequent.
HPV vaccination protects against invasive HPV-associated cancer. Luostarinen and colleagues report proof of highly efficacious protection offered by a population-based HPV vaccination program in Finland, in the form of a decrease in the key endpoint: cases of invasive HPV-associated cancer. Examining vaccinated (3,331 females) and unvaccinated (15,665 females) cohorts in the nationwide Finnish Cancer Registry, the investigators identified 10 cases of HPV-caused cancer (8 cervical, 1 oropharyngeal, 1 vulvar) in the unvaccinated females and 0 cases in vaccinated females--a statistically significant difference.
From the evidence gathered in this first intention-to-treat trial, the investigators conclude that vaccination protects against invasive HPV-associated cancer--what they call "an awaited, pivotal corollary" to high vaccine efficacy against HPV infection.
Summing up
This success story continues to unfold, despite well-organized, antivaccine campaigns. The HPV vaccine has been an easy target: It is novel, it involves a sexually transmitted infection, and the endpoint of protecting against invasive HPV-associated cancer is years--decades--away. But antivaccine groups can no longer argue the point that studies have not been designed to yield evidence of the impact of the vaccine on decisive endpoints, including cervical cancer.
The exciting news that the sought-out endpoint of HPV vaccination -- prevention of invasive HPV-associated cervical cancer -- is being realized. This should all the more energize you to:
- urge vaccination for your patients in whom it is indicated
- emphasize vaccine coverage in the young -- especially for the routinely recommended age group of 11 - and 12-year-olds
- strenuously reject and counter arguments made by segments of the public that HPV vaccination is neither safe nor necessary
- prepare for potential changes down the road in practice guidelines regarding screening (eg, raising the age at which screening begins) as the impact of vaccination on the health of women is felt.
Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.
- Walsh JC, Curtis R, Mylotte M. Anxiety levels in women attending a colposcopy clinic: a randomised trial of an educational intervention using video colposcopy. Patient Educ Couns. 2004;55(2):247–251.
- Tomaino-Brunner C, Freda MC, Damus K, Runowicz CD. Can precolposcopy education increase knowledge and decrease anxiety? J Obstet Gynecol Neonatal Nurs. 1998;27(6):636–645.
- Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223–229.
- Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235–241.
- Wentzensen N, Schiffman M. Accelerating cervical cancer control and prevention. Lancet Public Health. 2018;3(1):e6–e7.
Dr. Einstein is Professor and Chair, Department of Obstetrics, Gynecology and Women’s Health, and Assistant Dean, Clinical Research Unit, Rutgers New Jersey Medical School, Newark, New Jersey. He is coauthor of the 3 articles on ASCCP colposcopy guidelines that are cited and discussed in this Update on cervical disease.
Dr. Einstein has advised, but does not receive an honorarium from any companies. In specific cases his employer has received payment for his consultation from Photocure, Cynvec, Papivax, and PDS Biotechnologies. If travel is required for meetings with any industry, the company pays for Dr. Einstein’s travel-related expenses. Also, his employers have received grant funding for research-related costs of clinical trials that Dr. Einstein has been the overall principal investigator or local principal investigator for the past 12 months from Astra Zeneca, Pfizer, and Inovio.
Dr. Einstein is Professor and Chair, Department of Obstetrics, Gynecology and Women’s Health, and Assistant Dean, Clinical Research Unit, Rutgers New Jersey Medical School, Newark, New Jersey. He is coauthor of the 3 articles on ASCCP colposcopy guidelines that are cited and discussed in this Update on cervical disease.
Dr. Einstein has advised, but does not receive an honorarium from any companies. In specific cases his employer has received payment for his consultation from Photocure, Cynvec, Papivax, and PDS Biotechnologies. If travel is required for meetings with any industry, the company pays for Dr. Einstein’s travel-related expenses. Also, his employers have received grant funding for research-related costs of clinical trials that Dr. Einstein has been the overall principal investigator or local principal investigator for the past 12 months from Astra Zeneca, Pfizer, and Inovio.
Dr. Einstein is Professor and Chair, Department of Obstetrics, Gynecology and Women’s Health, and Assistant Dean, Clinical Research Unit, Rutgers New Jersey Medical School, Newark, New Jersey. He is coauthor of the 3 articles on ASCCP colposcopy guidelines that are cited and discussed in this Update on cervical disease.
Dr. Einstein has advised, but does not receive an honorarium from any companies. In specific cases his employer has received payment for his consultation from Photocure, Cynvec, Papivax, and PDS Biotechnologies. If travel is required for meetings with any industry, the company pays for Dr. Einstein’s travel-related expenses. Also, his employers have received grant funding for research-related costs of clinical trials that Dr. Einstein has been the overall principal investigator or local principal investigator for the past 12 months from Astra Zeneca, Pfizer, and Inovio.
In this Update, I outline important findings from several studies published in the past year. First and foremost, what are best practices for performing colposcopy in the United States? The American Society for Colposcopy and Cervical Pathology (ASCCP) released guidelines addressing such practices. Second, what are the implications of repeated negative screening and patients’ acceptance of extended screening intervals? A recent observational cohort study and a large study of Kaiser Permanente’s practices since 2003 shed light on these questions. Last, where do we stand with HPV vaccination? Two studies shed light on the efficacy of vaccination against human papillomavirus (HPV), and subsequent cervical intraepithelial neoplasia (CIN) and cervical cancer.
ASCCP releases updated quality guidelines for performing colposcopy
Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223-229.
Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235-241.
Wentzensen N, Schiffman M, Silver MI, et al. ASCCP colposcopy standards: Risk-based colposcopy practice. J Low Genit Tract Dis. 2017;21(4):230-234.
In October 2017, the ASCCP released a set of standards on the role and performance of colposcopy that represents best practices in women's health care in the United States. The work of these groups comprised a literature search, a national survey of ASCCP members, public comment, and expert consensus, and addressed:
- establishment of a common understanding of 1) the benefits of colposcopy in health maintenance and risk prevention, 2) risks presented by the procedure, and 3) terminology and criteria for reporting results that reduce subjectivity in reporting
- the rationale for, approach to, and recommendations regarding assessment of cervical precancer at colposcopy
- both minimum and comprehensive guidelines for the colposcopic examination, from preprocedure evaluation to follow-up.
Each Working Group performed the analysis and produced its own report and recommendations, published sequentially in a 2017 issue of the Journal of Lower Urinary Tract Disease. The findings and standards that they produced 1) offer essential insight for high- and low-volume coloposcopists and 2) are intended to improve the quality of colposcopy, reduce subjectivity in reporting findings, and improve the sensitivity of the procedure. Aware of the concerns and objectives of payers and hospital credentialing committees, the ASCCP found it important to establish what would be considered US-based minimum quality standards and to present goals that providers and systems could strive to achieve.
Selected details of the 3 guideline reports
The past 6 years have brought us through a great deal of transition in the prevention of cervical precancer, with regard to screening intervals and types of screening (for example, see "HPV−cytology co-testing every 3 years lowers population rates of cervical precancer and cancer," in the 2017 "Cervical Disease Update," OBG Management, May 2017). The most significant change was in 2012, when American Cancer Society/ASCCP guidelines were revised to abandon screening with annual Pap testing on most patients--an effort to strike a balance between the lifesaving value of identifying precancer and the potential harm of excessive colposcopy.
If, as the US Preventive Services Task Force (USPSTF) has declared, excessive colposcopy is a harm of screening, then we should be adapting our practices, especially in terms of the frequency of screening, to 1) reduce the risk of unnecessarily screening and potentially triaging patients to colposcopy and 2) bring the highest standards of performance and reporting to colposcopic practice (see "Why aren't you doing a Pap on me?"). In other words, "This is the way I've always done it" shouldn't characterize efforts to detect disease, when the data are clear that doing less might be more beneficial for our patients. Adherence to extended screening intervals is not yet good enough to balance benefit and risk of harm, as Rendle and colleagues showed in an article this year in Preventive Medicine (discussed in the next section of this "Update"). We need to do better.
Adherence to extended screening intervals means fewer colposcopies and less exposure to risk of attendant harm. But adherence is not purely mechanical: It can be intertwined with how patients feel about the care we provide and about their safety. When a patient moves from years of annual Pap testing to less frequent screening, she might express her concern by challenging your expertise.
In my practice, I have a simple, 1-minute conversation with the patient that is important to wedge into our discussion of her care. I explain that increasing the frequency of screening is only going to increase the chance that I will perform a colposcopy but not increase the chance that I will identify cancer. I conclude by reassuring her that I do not want to harm her, or to cause her anxiety, pain, cramping, or bleeding--or require her to spend time away from work or show her family that she is suffering. Patients are reassured and happy after that, I find. This is a patient-centered discussion that providers need to have if they hope to establish and maintain adherence to recommended screening intervals.
-- Mark H. Einstein, MD, MS
Here is a limited encapsulation of the 3 wide-ranging reports on the ASCCP colposcopy recommendations:
Role of colposcopy; benefits, potential harms, terminology (Khan et al; Working Group 1). The authors provide reinforcement: The strategic benefit of colposcopy is clear--a "drastic" reduction in excisional procedures by limiting them to patients in whom cervical cancer precursors have been confirmed or who present a high risk of occult invasive cervical cancer. Furthermore, the rate of adverse events for colposcopy−including significant bleeding and infection−is low.
Nevertheless, the potential for harm exists when an unskilled provider performs colposcopy; the Working Group emphasizes that proficiency comes with training and experience. Even in skilled hands, however, anxiety and the discomfort of a speculum examination and from acetic acid, as well as cramping and pain, might dissuade some women from receiving regular cervical screening subsequently. The authors cite research showing that educational interventions can help soothe anxiety about colposcopy and potential findings,1,2 although consensus is lacking on the value of such interventions.
The Working Group 1) developed recommended terminology for reporting findings in colposcopy practice in the United States and 2) defined the comprehensive documentation of the procedure as comprising cervix and squamocolumnar junction visibility; acetowhitening; presence of a lesion; lesion visibility, size and location of lesion(s); vascular changes; other features; and colposcopic impression (TABLE 1).3 Minimum criteria for reporting colposcopy results were also proposed, extracted from the comprehensive standards.
Risk-based colposcopy practice (Wentzensen et al). Women referred to colposcopy present with a range of underlying risk of precancer. Assessing that risk at the colposcopy visit allows the provider to modify and individualize the procedure. Risk can be estimated by referral screening tests (eg, cytology, HPV testing) performed in conjunction with the colposcopic impression. As opposed to a lack of standards for a minimum number of biopsies, the Working Group recommends that, as a standard, multiple targeted biopsies (≥2, as many as 4) are needed to improve detection of prevalent precancers. Colposcopic impression alone is not enough to diagnose precancerous cells. Let's face it: Our eyes with a colposcopic magnification of 15X do not make a microscope.
Implementing the Working Group's recommendations is expected to lead to improved detection of cervical precancers at colposcopy and to provide stronger reassurance of negative colposcopy results. Regarding biopsy of lesions, ASCCP did not find added benefit to taking random (nondirected) biopsies for women at low risk for precancer. The sensitivity of biopsy is increased by taking multiple biopsies of suspicious lesions, based on a risk-based approach detailed in the ASCCP guidelines. So, depending on underlying risk (estimated from screening and triage tests), colposcopy practice can be adapted in a useful manner to account for differences in risk:
- When risk of precancer is very high, for example, immediate treatment might reduce cost and prevent the patient from being lost to follow-up. When risk is very low, consider expectant management (serial cytology and HPV testing) with limited need for biopsy. In a setting of intermediate risk, the Working Group proposes, "multiple biopsies of acetowhite lesions lead to increased detection of precancer."
- Perform multiple biopsies that target all areas characterized by 1) acetowhitening, 2) metaplasia, and 3) higher abnormalities.
- Do not perform nontargeted biopsies on patients at the lowest end of risk who have been referred to colposcopy−ie, those with cytology that is less than HSIL; no evidence of HPV types 16/18; and a normal colposcopic impression (ie, no acetowhitening or metaplasia, or other visible abnormality).
- Immediate excision without biopsy confirmation or colposcopy with multiple targeted biopsies is acceptable in nonpregnant women 25 years and older whose risk of precancer is very high (≥2 of the following: HSIL cytology, HPV 16- or HPV 18-positive(or both), and high-grade colposcopy impression). Endocervical sampling should be conducted according to ASCCP's 2012 management guidelines. If biopsies do not show precancer, manage the patient using ASCCP's 2012 management guidelines, the Working Group recommends.
How do we perform colposcopy? Implications for establishing standards (Waxman et al; Working Group 3). To serve as a guide to standardizing colposcopy across the United States, the authors defined and delineated 6 major components (and their constituent parts) of a comprehensive colposcopy:
- precolposcopy evaluation
- the examination
- use of colposcopy adjuncts
- documentation
- biopsy sampling
- postcolposcopy procedures.
The constituent parts of these components are laid out in TABLE 2.4 A set of components for a minimum colposcopy procedure is drawn mostly from the comprehensive protocol.
The Working Group acknowledges that, in the United States, "the accuracy and reproducibility of colposcopy with biopsy as a diagnostic tool are limited." Why? Three contributing factors, the authors write, might be the absence of practice recommendations for colposcopy-biopsy procedures; of measures of quality assurance; and of standardized terminology.
Standards arrive for practice
Minimum quality standards are becoming part of almost everything US health care providers do−whether it is documentation, billing practices, or good care. Our work in gynecology, including colposcopy, is now being assessed as it is in much of the world, where minimum standards are already in place and guidelines must be followed. (In some countries standards require performing a minimum number of colposcopies per year to be identified as a "certified" colposcopist.)
What should be considered "minimum standards" for colposcopy in the United States? These ASCCP reports ask, and deliver answers to that question, bringing a broad range of concerns about high-quality practice into focus. Physicians and advanced-practice clinicians in this country who perform colposcopies have been trained to do so, but they have never had minimum standards by which to model and assess their performance. A procedure that has the potential to lead to additional testing for either cervical cancer, or to surveillance, should have minimum standards by which it is performed and documented in the United States as it is for much of the world that has widespread cervical cancer screening.
Guidance and recommendations developed by ASCCP offer women's health care providers a set of comprehensive and, alternatively, minimum quality standards that should be incorporated into practice across all aspects of the colposcopic exam, including precolposcopy evaluation, how to perform the procedure, how to document and report findings (TABLE 2), biopsy practice, establish quality control and assurance, as well as postprocedure follow-up. In taking the initiative to draw up these standards, ASCCP encourages providers to exceed the minimum requirements.
Read about adherence to cervical cancer screening.
Cervical screening adherence is relatively low, but safe. Extended intervals are very safe.
Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study. Ann Intern Med. 2018;168(1):20-29.
Rendle KA, Schiffman M, Cheung LC, et al. Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. Prev Med. 2018;109:44-50.
Patients who have been screened for cervical cancer for a long time--decades, even--have a diminishing likelihood that cancer will ever be detected. Furthermore, highest-risk patients already have been triaged into further testing or procedures, such as a loop excision electrosurgical procedure or hysterectomy. Two recent studies examined the implications of repeated negative screening and patients' acceptance of extended screening intervals.
Details of the studies
Several negative rounds of cotesting (HPV and cytology) might justify changes to the screening interval. To determine the rate of detection of CIN3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in routine practice after successive negative screening at 3-year intervals, Castle and colleagues looked at records of more than 990,000 women in an integrated health care system who underwent cotesting (HPV and cytology) between 2003 and 2014. They determined that the risk of invasive cervical cancer and ≥CIN3 declined with each round of cotesting; the absolute risk fell more between first and second rounds than between second and third rounds.
At any given round of cotesting, Castle found that the ability to reassure a patient about cancer and cancer risk was similar when looking at an HPV result alone, whatever the cytology or HPV-cytology cotest result was. The investigators concluded that similar patterns of risk would have been seen had stand-alone HPV testing been used, instead of co-testing, (HPV testing alone might have missed a few cases of CIN3 and adenocarcinoma in situ leading to cancer). A single negative cotest was so effective at ruling out ≥CIN3 and cervical cancer that, after a second round of cotesting, they found that no interval cancer cases were detected among women who had a negative HPV result.
Women aged 50 years or older had a 5- to 6-fold lower risk after their third consecutive negative cotest than women aged 30 to 39 years had after their first negative cotest. These data support the ideas, Castle noted, that 1) assigning screening intervals based on both age and number of previous negative screens and 2) extending the screening interval even further than 3 years after 2--perhaps even after 1--negative cotests or HPV tests are worth entertaining. Screening women of this age becomes inefficient and cost-ineffective, even at 5-year intervals.
Is patients' adherence to an extended interval of cotesting reliable enough to change practice? Rendle and colleagues examined the records of more than 491,000 women (in the same integrated health care system that Castle studied) who had undergone routine cervical cancer screening between 2003 and 2015. Their goal was to determine how high adherence had become to the system's recommendation of an every-3-year screening interval--an interval that mirrors long-standing guidelines elsewhere.
In short, researchers observed increasing and relatively rapid clinical adoption of every-3-year cotesting for routine cervical screening over time; between 2003 and 2009, the cohort grew significantly less likely overall to come in early for screening. In this setting, adoption of an extended screeninginterval appears to run counter to earlier understanding that patients are likely to resist such extension.
Women aged 60 to 64 were most likely to screen early across 2 consecutive intervals. What Rendle termed a "modest" decrease in the percentage of late screeners (but still within a 5-year interval) was also noted during adoption of the 3-year interval.
What next?
Molecular-based testing. Research, mostly outside of the United States, is taking us in the direction of molecular-based technologies as at least a component of cervical cancer screening. Today, we rely mostly on Pap tests and colposcopy, but these are subjective screens, with a human operator. With molecular testing (mostly of components of HPV), results are objective--a "Yes" or "No" finding based on clinically validated thresholds. Methods such as genotyping, P16INK4a/Ki-67 gene product dual-stain cytology, and testing for E6 and E7 HPV mRNA transcripts are in development, and hold promise to allow us to screen safely using almost completely molecular testing, thus eliminating human error and subjectivity and enriching the population that needs further management with very sensitive and potentially specific testing.
We are being presented with the possibility that almost all aspects of screening can be done without a provider, until the patient needs treatment.
Access to screening. Research is also looking at improving access, such as self-sampling for primary screening. That includes home cervical and vaginal sampling, with specimens mailed to the laboratory, from where results and follow-up instructions as communicated to patients. The Netherlands and the United Kingdom are moving to self-sampling primary screens; the United States is not--yet. But that is the direction research is taking us.
Modified guidelines. Eyes are on the work of the USPSTF. Last year, the Task Force issued draft recommendations (https://www.uspre ventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2#clinical), followed by a comment period (now closed), for updating 2012 cervical cancer screening guidelines in a way that would trigger a major change in clinical practice. Those draft recommendations and public comments are under review; final recommendations are possible within this calendar year.
Continue to follow current screening guidelines; they are safe and effective for preventing cervical cancer. This assumes adherence to intervals, which is both the provider's and the patient's responsibility: First, less is more; too much screening ("I've always done it this way") can be harmful. Second, screening at intervals set by the guidelines is extremely safe, despite earlier reports or provider concerns that suggest otherwise.
Patients who have undergone several rounds of negative screening have a markedly diminished risk of cervical cancer. Serve them best by performing this underutilized gyn procedure: Sit on your hands.
Be aware that winds of change are blowing: What constitutes appropriate screening intervals is up for discussion this year, and molecular-based testing technologies that are under investigation have the potential to someday be a vast improvement over current good, but subjective, interpretations of results.
Last, promote primary prevention of cervical cancer with HPV vaccination in your practice to increase the percentage of protected patients. Doing so will contribute not only to their long-term health but also, at a societal level, to a herd immunity effect.5 Any positive HPV infection in a future of a well-vaccinated population will be significant, and HPV-targeted technologies to identify the highest risk women will be the most efficient screening.
Read about the safety and efficacy of HPV vaccination.
Primary prevention of cervical cancer with vaccination is critical in any cancer prevention program
Benard VB, Castle PE, Jenison SA, et al; New Mexico HPV Pap Registry Steering Committee. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3(6):833-837.
Luostarinen T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associated cancers. Int J Cancer. 2018;142(10):2186-2187.
The success story of HPV vaccination, after more than a decade of use, continued to unfold in important ways over the past year.
Safety. With tens of millions of doses delivered, we know that the vaccine is safe, and we have retreated on some of the precautions that we once took: For example, we no longer perform a routine pregnancy test before vaccination on reproductive-age women.
Efficacy. We have learned, based on what we see in Australia and Western Europe, that vaccination is highly effective. We are also starting to see evidence of efficacy in areas of the United States, even though the vaccine is voluntary and there are no school-based recommendations. And we know that herd vaccination is very effective. The 2 studies described here add to our understanding of how vaccination is having an impact on endpoints.
Findings of the 2 studies
HPV vaccination has a direct impact on the precursor of cancer, CIN. Benard and colleagues examined data from the New Mexico HPV Pap Registry, a mandatory statewide surveillance system of cervical cancer screening that captured estimates of both screening prevalence and CIN since the time HPV vaccination was introduced in 2007 to 2014. The investigators examined registry data to gauge trends in the rate of CIN and to estimate the effect of HPV vaccination on that rate when adjusted for changes in screening for cervical cancer.
The incidence of CIN declined significantly across all grades in 2 groups between 2007 and 2015: females aged 15 to 19 years and females aged 20 to 24 years (but not in females 25 to 29 years of age). During those years, mean uptake of HPV vaccination among females 13 to 17 years of age reached as high as 40% (in 2014).
Although a reduction in CIN2 and CIN3 precancers "are early benchmarks for achieving this aim [of reducing the rate of cancer]," the investigators note, a reduction in CIN1 is "a direct measure of reductions in HPV infections requisite to the development of almost all invasive cervical cancer."
Benard moves on to conclude that a reduction in clinical outcomes of CIN among groups who are partially vaccinated for HPV is going to change clinical practice and reduce the cost-effectiveness of clinical care that supports prevention of cervical cancer. Of greatest importance, modalities and strategies for screening, and management algorithms, are going to need to evolve as HPV vaccination and cervical screening are integrated in a rational manner. Furthermore, it might be feasible to factor in population-level decreases in CIN among cohorts who are partially vaccinated for HPV when reassessing clinical practice guidelines for cervical cancer screening.
What does this mean? As we start to eliminate HPV from the population, any positive screening result will be that much more meaningful because the outcome--cervical cancer--will be much rarer. The onus will be on providers and public health officials to re-strategize how to screen what is going to be a widely-vaccinated population; more and more, we will be looking for needles in a haystack.
How are we going to someday screen women in their 20s who were vaccinated at 11 or 12 years of age? Likely, screening will start at a later age, and screening will be conducted at longer intervals. Any finding of HPV or disease is going to be highly significant, and likely, far less frequent.
HPV vaccination protects against invasive HPV-associated cancer. Luostarinen and colleagues report proof of highly efficacious protection offered by a population-based HPV vaccination program in Finland, in the form of a decrease in the key endpoint: cases of invasive HPV-associated cancer. Examining vaccinated (3,331 females) and unvaccinated (15,665 females) cohorts in the nationwide Finnish Cancer Registry, the investigators identified 10 cases of HPV-caused cancer (8 cervical, 1 oropharyngeal, 1 vulvar) in the unvaccinated females and 0 cases in vaccinated females--a statistically significant difference.
From the evidence gathered in this first intention-to-treat trial, the investigators conclude that vaccination protects against invasive HPV-associated cancer--what they call "an awaited, pivotal corollary" to high vaccine efficacy against HPV infection.
Summing up
This success story continues to unfold, despite well-organized, antivaccine campaigns. The HPV vaccine has been an easy target: It is novel, it involves a sexually transmitted infection, and the endpoint of protecting against invasive HPV-associated cancer is years--decades--away. But antivaccine groups can no longer argue the point that studies have not been designed to yield evidence of the impact of the vaccine on decisive endpoints, including cervical cancer.
The exciting news that the sought-out endpoint of HPV vaccination -- prevention of invasive HPV-associated cervical cancer -- is being realized. This should all the more energize you to:
- urge vaccination for your patients in whom it is indicated
- emphasize vaccine coverage in the young -- especially for the routinely recommended age group of 11 - and 12-year-olds
- strenuously reject and counter arguments made by segments of the public that HPV vaccination is neither safe nor necessary
- prepare for potential changes down the road in practice guidelines regarding screening (eg, raising the age at which screening begins) as the impact of vaccination on the health of women is felt.
Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.
In this Update, I outline important findings from several studies published in the past year. First and foremost, what are best practices for performing colposcopy in the United States? The American Society for Colposcopy and Cervical Pathology (ASCCP) released guidelines addressing such practices. Second, what are the implications of repeated negative screening and patients’ acceptance of extended screening intervals? A recent observational cohort study and a large study of Kaiser Permanente’s practices since 2003 shed light on these questions. Last, where do we stand with HPV vaccination? Two studies shed light on the efficacy of vaccination against human papillomavirus (HPV), and subsequent cervical intraepithelial neoplasia (CIN) and cervical cancer.
ASCCP releases updated quality guidelines for performing colposcopy
Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223-229.
Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235-241.
Wentzensen N, Schiffman M, Silver MI, et al. ASCCP colposcopy standards: Risk-based colposcopy practice. J Low Genit Tract Dis. 2017;21(4):230-234.
In October 2017, the ASCCP released a set of standards on the role and performance of colposcopy that represents best practices in women's health care in the United States. The work of these groups comprised a literature search, a national survey of ASCCP members, public comment, and expert consensus, and addressed:
- establishment of a common understanding of 1) the benefits of colposcopy in health maintenance and risk prevention, 2) risks presented by the procedure, and 3) terminology and criteria for reporting results that reduce subjectivity in reporting
- the rationale for, approach to, and recommendations regarding assessment of cervical precancer at colposcopy
- both minimum and comprehensive guidelines for the colposcopic examination, from preprocedure evaluation to follow-up.
Each Working Group performed the analysis and produced its own report and recommendations, published sequentially in a 2017 issue of the Journal of Lower Urinary Tract Disease. The findings and standards that they produced 1) offer essential insight for high- and low-volume coloposcopists and 2) are intended to improve the quality of colposcopy, reduce subjectivity in reporting findings, and improve the sensitivity of the procedure. Aware of the concerns and objectives of payers and hospital credentialing committees, the ASCCP found it important to establish what would be considered US-based minimum quality standards and to present goals that providers and systems could strive to achieve.
Selected details of the 3 guideline reports
The past 6 years have brought us through a great deal of transition in the prevention of cervical precancer, with regard to screening intervals and types of screening (for example, see "HPV−cytology co-testing every 3 years lowers population rates of cervical precancer and cancer," in the 2017 "Cervical Disease Update," OBG Management, May 2017). The most significant change was in 2012, when American Cancer Society/ASCCP guidelines were revised to abandon screening with annual Pap testing on most patients--an effort to strike a balance between the lifesaving value of identifying precancer and the potential harm of excessive colposcopy.
If, as the US Preventive Services Task Force (USPSTF) has declared, excessive colposcopy is a harm of screening, then we should be adapting our practices, especially in terms of the frequency of screening, to 1) reduce the risk of unnecessarily screening and potentially triaging patients to colposcopy and 2) bring the highest standards of performance and reporting to colposcopic practice (see "Why aren't you doing a Pap on me?"). In other words, "This is the way I've always done it" shouldn't characterize efforts to detect disease, when the data are clear that doing less might be more beneficial for our patients. Adherence to extended screening intervals is not yet good enough to balance benefit and risk of harm, as Rendle and colleagues showed in an article this year in Preventive Medicine (discussed in the next section of this "Update"). We need to do better.
Adherence to extended screening intervals means fewer colposcopies and less exposure to risk of attendant harm. But adherence is not purely mechanical: It can be intertwined with how patients feel about the care we provide and about their safety. When a patient moves from years of annual Pap testing to less frequent screening, she might express her concern by challenging your expertise.
In my practice, I have a simple, 1-minute conversation with the patient that is important to wedge into our discussion of her care. I explain that increasing the frequency of screening is only going to increase the chance that I will perform a colposcopy but not increase the chance that I will identify cancer. I conclude by reassuring her that I do not want to harm her, or to cause her anxiety, pain, cramping, or bleeding--or require her to spend time away from work or show her family that she is suffering. Patients are reassured and happy after that, I find. This is a patient-centered discussion that providers need to have if they hope to establish and maintain adherence to recommended screening intervals.
-- Mark H. Einstein, MD, MS
Here is a limited encapsulation of the 3 wide-ranging reports on the ASCCP colposcopy recommendations:
Role of colposcopy; benefits, potential harms, terminology (Khan et al; Working Group 1). The authors provide reinforcement: The strategic benefit of colposcopy is clear--a "drastic" reduction in excisional procedures by limiting them to patients in whom cervical cancer precursors have been confirmed or who present a high risk of occult invasive cervical cancer. Furthermore, the rate of adverse events for colposcopy−including significant bleeding and infection−is low.
Nevertheless, the potential for harm exists when an unskilled provider performs colposcopy; the Working Group emphasizes that proficiency comes with training and experience. Even in skilled hands, however, anxiety and the discomfort of a speculum examination and from acetic acid, as well as cramping and pain, might dissuade some women from receiving regular cervical screening subsequently. The authors cite research showing that educational interventions can help soothe anxiety about colposcopy and potential findings,1,2 although consensus is lacking on the value of such interventions.
The Working Group 1) developed recommended terminology for reporting findings in colposcopy practice in the United States and 2) defined the comprehensive documentation of the procedure as comprising cervix and squamocolumnar junction visibility; acetowhitening; presence of a lesion; lesion visibility, size and location of lesion(s); vascular changes; other features; and colposcopic impression (TABLE 1).3 Minimum criteria for reporting colposcopy results were also proposed, extracted from the comprehensive standards.
Risk-based colposcopy practice (Wentzensen et al). Women referred to colposcopy present with a range of underlying risk of precancer. Assessing that risk at the colposcopy visit allows the provider to modify and individualize the procedure. Risk can be estimated by referral screening tests (eg, cytology, HPV testing) performed in conjunction with the colposcopic impression. As opposed to a lack of standards for a minimum number of biopsies, the Working Group recommends that, as a standard, multiple targeted biopsies (≥2, as many as 4) are needed to improve detection of prevalent precancers. Colposcopic impression alone is not enough to diagnose precancerous cells. Let's face it: Our eyes with a colposcopic magnification of 15X do not make a microscope.
Implementing the Working Group's recommendations is expected to lead to improved detection of cervical precancers at colposcopy and to provide stronger reassurance of negative colposcopy results. Regarding biopsy of lesions, ASCCP did not find added benefit to taking random (nondirected) biopsies for women at low risk for precancer. The sensitivity of biopsy is increased by taking multiple biopsies of suspicious lesions, based on a risk-based approach detailed in the ASCCP guidelines. So, depending on underlying risk (estimated from screening and triage tests), colposcopy practice can be adapted in a useful manner to account for differences in risk:
- When risk of precancer is very high, for example, immediate treatment might reduce cost and prevent the patient from being lost to follow-up. When risk is very low, consider expectant management (serial cytology and HPV testing) with limited need for biopsy. In a setting of intermediate risk, the Working Group proposes, "multiple biopsies of acetowhite lesions lead to increased detection of precancer."
- Perform multiple biopsies that target all areas characterized by 1) acetowhitening, 2) metaplasia, and 3) higher abnormalities.
- Do not perform nontargeted biopsies on patients at the lowest end of risk who have been referred to colposcopy−ie, those with cytology that is less than HSIL; no evidence of HPV types 16/18; and a normal colposcopic impression (ie, no acetowhitening or metaplasia, or other visible abnormality).
- Immediate excision without biopsy confirmation or colposcopy with multiple targeted biopsies is acceptable in nonpregnant women 25 years and older whose risk of precancer is very high (≥2 of the following: HSIL cytology, HPV 16- or HPV 18-positive(or both), and high-grade colposcopy impression). Endocervical sampling should be conducted according to ASCCP's 2012 management guidelines. If biopsies do not show precancer, manage the patient using ASCCP's 2012 management guidelines, the Working Group recommends.
How do we perform colposcopy? Implications for establishing standards (Waxman et al; Working Group 3). To serve as a guide to standardizing colposcopy across the United States, the authors defined and delineated 6 major components (and their constituent parts) of a comprehensive colposcopy:
- precolposcopy evaluation
- the examination
- use of colposcopy adjuncts
- documentation
- biopsy sampling
- postcolposcopy procedures.
The constituent parts of these components are laid out in TABLE 2.4 A set of components for a minimum colposcopy procedure is drawn mostly from the comprehensive protocol.
The Working Group acknowledges that, in the United States, "the accuracy and reproducibility of colposcopy with biopsy as a diagnostic tool are limited." Why? Three contributing factors, the authors write, might be the absence of practice recommendations for colposcopy-biopsy procedures; of measures of quality assurance; and of standardized terminology.
Standards arrive for practice
Minimum quality standards are becoming part of almost everything US health care providers do−whether it is documentation, billing practices, or good care. Our work in gynecology, including colposcopy, is now being assessed as it is in much of the world, where minimum standards are already in place and guidelines must be followed. (In some countries standards require performing a minimum number of colposcopies per year to be identified as a "certified" colposcopist.)
What should be considered "minimum standards" for colposcopy in the United States? These ASCCP reports ask, and deliver answers to that question, bringing a broad range of concerns about high-quality practice into focus. Physicians and advanced-practice clinicians in this country who perform colposcopies have been trained to do so, but they have never had minimum standards by which to model and assess their performance. A procedure that has the potential to lead to additional testing for either cervical cancer, or to surveillance, should have minimum standards by which it is performed and documented in the United States as it is for much of the world that has widespread cervical cancer screening.
Guidance and recommendations developed by ASCCP offer women's health care providers a set of comprehensive and, alternatively, minimum quality standards that should be incorporated into practice across all aspects of the colposcopic exam, including precolposcopy evaluation, how to perform the procedure, how to document and report findings (TABLE 2), biopsy practice, establish quality control and assurance, as well as postprocedure follow-up. In taking the initiative to draw up these standards, ASCCP encourages providers to exceed the minimum requirements.
Read about adherence to cervical cancer screening.
Cervical screening adherence is relatively low, but safe. Extended intervals are very safe.
Castle PE, Kinney WK, Xue X, et al. Effect of several negative rounds of human papillomavirus and cytology co-testing on safety against cervical cancer: an observational cohort study. Ann Intern Med. 2018;168(1):20-29.
Rendle KA, Schiffman M, Cheung LC, et al. Adherence patterns to extended cervical screening intervals in women undergoing human papillomavirus (HPV) and cytology cotesting. Prev Med. 2018;109:44-50.
Patients who have been screened for cervical cancer for a long time--decades, even--have a diminishing likelihood that cancer will ever be detected. Furthermore, highest-risk patients already have been triaged into further testing or procedures, such as a loop excision electrosurgical procedure or hysterectomy. Two recent studies examined the implications of repeated negative screening and patients' acceptance of extended screening intervals.
Details of the studies
Several negative rounds of cotesting (HPV and cytology) might justify changes to the screening interval. To determine the rate of detection of CIN3, adenocarcinoma in situ, and cervical cancer (≥CIN3) in routine practice after successive negative screening at 3-year intervals, Castle and colleagues looked at records of more than 990,000 women in an integrated health care system who underwent cotesting (HPV and cytology) between 2003 and 2014. They determined that the risk of invasive cervical cancer and ≥CIN3 declined with each round of cotesting; the absolute risk fell more between first and second rounds than between second and third rounds.
At any given round of cotesting, Castle found that the ability to reassure a patient about cancer and cancer risk was similar when looking at an HPV result alone, whatever the cytology or HPV-cytology cotest result was. The investigators concluded that similar patterns of risk would have been seen had stand-alone HPV testing been used, instead of co-testing, (HPV testing alone might have missed a few cases of CIN3 and adenocarcinoma in situ leading to cancer). A single negative cotest was so effective at ruling out ≥CIN3 and cervical cancer that, after a second round of cotesting, they found that no interval cancer cases were detected among women who had a negative HPV result.
Women aged 50 years or older had a 5- to 6-fold lower risk after their third consecutive negative cotest than women aged 30 to 39 years had after their first negative cotest. These data support the ideas, Castle noted, that 1) assigning screening intervals based on both age and number of previous negative screens and 2) extending the screening interval even further than 3 years after 2--perhaps even after 1--negative cotests or HPV tests are worth entertaining. Screening women of this age becomes inefficient and cost-ineffective, even at 5-year intervals.
Is patients' adherence to an extended interval of cotesting reliable enough to change practice? Rendle and colleagues examined the records of more than 491,000 women (in the same integrated health care system that Castle studied) who had undergone routine cervical cancer screening between 2003 and 2015. Their goal was to determine how high adherence had become to the system's recommendation of an every-3-year screening interval--an interval that mirrors long-standing guidelines elsewhere.
In short, researchers observed increasing and relatively rapid clinical adoption of every-3-year cotesting for routine cervical screening over time; between 2003 and 2009, the cohort grew significantly less likely overall to come in early for screening. In this setting, adoption of an extended screeninginterval appears to run counter to earlier understanding that patients are likely to resist such extension.
Women aged 60 to 64 were most likely to screen early across 2 consecutive intervals. What Rendle termed a "modest" decrease in the percentage of late screeners (but still within a 5-year interval) was also noted during adoption of the 3-year interval.
What next?
Molecular-based testing. Research, mostly outside of the United States, is taking us in the direction of molecular-based technologies as at least a component of cervical cancer screening. Today, we rely mostly on Pap tests and colposcopy, but these are subjective screens, with a human operator. With molecular testing (mostly of components of HPV), results are objective--a "Yes" or "No" finding based on clinically validated thresholds. Methods such as genotyping, P16INK4a/Ki-67 gene product dual-stain cytology, and testing for E6 and E7 HPV mRNA transcripts are in development, and hold promise to allow us to screen safely using almost completely molecular testing, thus eliminating human error and subjectivity and enriching the population that needs further management with very sensitive and potentially specific testing.
We are being presented with the possibility that almost all aspects of screening can be done without a provider, until the patient needs treatment.
Access to screening. Research is also looking at improving access, such as self-sampling for primary screening. That includes home cervical and vaginal sampling, with specimens mailed to the laboratory, from where results and follow-up instructions as communicated to patients. The Netherlands and the United Kingdom are moving to self-sampling primary screens; the United States is not--yet. But that is the direction research is taking us.
Modified guidelines. Eyes are on the work of the USPSTF. Last year, the Task Force issued draft recommendations (https://www.uspre ventiveservicestaskforce.org/Page/Document/draft-recommendation-statement/cervical-cancer-screening2#clinical), followed by a comment period (now closed), for updating 2012 cervical cancer screening guidelines in a way that would trigger a major change in clinical practice. Those draft recommendations and public comments are under review; final recommendations are possible within this calendar year.
Continue to follow current screening guidelines; they are safe and effective for preventing cervical cancer. This assumes adherence to intervals, which is both the provider's and the patient's responsibility: First, less is more; too much screening ("I've always done it this way") can be harmful. Second, screening at intervals set by the guidelines is extremely safe, despite earlier reports or provider concerns that suggest otherwise.
Patients who have undergone several rounds of negative screening have a markedly diminished risk of cervical cancer. Serve them best by performing this underutilized gyn procedure: Sit on your hands.
Be aware that winds of change are blowing: What constitutes appropriate screening intervals is up for discussion this year, and molecular-based testing technologies that are under investigation have the potential to someday be a vast improvement over current good, but subjective, interpretations of results.
Last, promote primary prevention of cervical cancer with HPV vaccination in your practice to increase the percentage of protected patients. Doing so will contribute not only to their long-term health but also, at a societal level, to a herd immunity effect.5 Any positive HPV infection in a future of a well-vaccinated population will be significant, and HPV-targeted technologies to identify the highest risk women will be the most efficient screening.
Read about the safety and efficacy of HPV vaccination.
Primary prevention of cervical cancer with vaccination is critical in any cancer prevention program
Benard VB, Castle PE, Jenison SA, et al; New Mexico HPV Pap Registry Steering Committee. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol. 2017;3(6):833-837.
Luostarinen T, Apter D, Dillner J, et al. Vaccination protects against invasive HPV-associated cancers. Int J Cancer. 2018;142(10):2186-2187.
The success story of HPV vaccination, after more than a decade of use, continued to unfold in important ways over the past year.
Safety. With tens of millions of doses delivered, we know that the vaccine is safe, and we have retreated on some of the precautions that we once took: For example, we no longer perform a routine pregnancy test before vaccination on reproductive-age women.
Efficacy. We have learned, based on what we see in Australia and Western Europe, that vaccination is highly effective. We are also starting to see evidence of efficacy in areas of the United States, even though the vaccine is voluntary and there are no school-based recommendations. And we know that herd vaccination is very effective. The 2 studies described here add to our understanding of how vaccination is having an impact on endpoints.
Findings of the 2 studies
HPV vaccination has a direct impact on the precursor of cancer, CIN. Benard and colleagues examined data from the New Mexico HPV Pap Registry, a mandatory statewide surveillance system of cervical cancer screening that captured estimates of both screening prevalence and CIN since the time HPV vaccination was introduced in 2007 to 2014. The investigators examined registry data to gauge trends in the rate of CIN and to estimate the effect of HPV vaccination on that rate when adjusted for changes in screening for cervical cancer.
The incidence of CIN declined significantly across all grades in 2 groups between 2007 and 2015: females aged 15 to 19 years and females aged 20 to 24 years (but not in females 25 to 29 years of age). During those years, mean uptake of HPV vaccination among females 13 to 17 years of age reached as high as 40% (in 2014).
Although a reduction in CIN2 and CIN3 precancers "are early benchmarks for achieving this aim [of reducing the rate of cancer]," the investigators note, a reduction in CIN1 is "a direct measure of reductions in HPV infections requisite to the development of almost all invasive cervical cancer."
Benard moves on to conclude that a reduction in clinical outcomes of CIN among groups who are partially vaccinated for HPV is going to change clinical practice and reduce the cost-effectiveness of clinical care that supports prevention of cervical cancer. Of greatest importance, modalities and strategies for screening, and management algorithms, are going to need to evolve as HPV vaccination and cervical screening are integrated in a rational manner. Furthermore, it might be feasible to factor in population-level decreases in CIN among cohorts who are partially vaccinated for HPV when reassessing clinical practice guidelines for cervical cancer screening.
What does this mean? As we start to eliminate HPV from the population, any positive screening result will be that much more meaningful because the outcome--cervical cancer--will be much rarer. The onus will be on providers and public health officials to re-strategize how to screen what is going to be a widely-vaccinated population; more and more, we will be looking for needles in a haystack.
How are we going to someday screen women in their 20s who were vaccinated at 11 or 12 years of age? Likely, screening will start at a later age, and screening will be conducted at longer intervals. Any finding of HPV or disease is going to be highly significant, and likely, far less frequent.
HPV vaccination protects against invasive HPV-associated cancer. Luostarinen and colleagues report proof of highly efficacious protection offered by a population-based HPV vaccination program in Finland, in the form of a decrease in the key endpoint: cases of invasive HPV-associated cancer. Examining vaccinated (3,331 females) and unvaccinated (15,665 females) cohorts in the nationwide Finnish Cancer Registry, the investigators identified 10 cases of HPV-caused cancer (8 cervical, 1 oropharyngeal, 1 vulvar) in the unvaccinated females and 0 cases in vaccinated females--a statistically significant difference.
From the evidence gathered in this first intention-to-treat trial, the investigators conclude that vaccination protects against invasive HPV-associated cancer--what they call "an awaited, pivotal corollary" to high vaccine efficacy against HPV infection.
Summing up
This success story continues to unfold, despite well-organized, antivaccine campaigns. The HPV vaccine has been an easy target: It is novel, it involves a sexually transmitted infection, and the endpoint of protecting against invasive HPV-associated cancer is years--decades--away. But antivaccine groups can no longer argue the point that studies have not been designed to yield evidence of the impact of the vaccine on decisive endpoints, including cervical cancer.
The exciting news that the sought-out endpoint of HPV vaccination -- prevention of invasive HPV-associated cervical cancer -- is being realized. This should all the more energize you to:
- urge vaccination for your patients in whom it is indicated
- emphasize vaccine coverage in the young -- especially for the routinely recommended age group of 11 - and 12-year-olds
- strenuously reject and counter arguments made by segments of the public that HPV vaccination is neither safe nor necessary
- prepare for potential changes down the road in practice guidelines regarding screening (eg, raising the age at which screening begins) as the impact of vaccination on the health of women is felt.
Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.
- Walsh JC, Curtis R, Mylotte M. Anxiety levels in women attending a colposcopy clinic: a randomised trial of an educational intervention using video colposcopy. Patient Educ Couns. 2004;55(2):247–251.
- Tomaino-Brunner C, Freda MC, Damus K, Runowicz CD. Can precolposcopy education increase knowledge and decrease anxiety? J Obstet Gynecol Neonatal Nurs. 1998;27(6):636–645.
- Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223–229.
- Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235–241.
- Wentzensen N, Schiffman M. Accelerating cervical cancer control and prevention. Lancet Public Health. 2018;3(1):e6–e7.
- Walsh JC, Curtis R, Mylotte M. Anxiety levels in women attending a colposcopy clinic: a randomised trial of an educational intervention using video colposcopy. Patient Educ Couns. 2004;55(2):247–251.
- Tomaino-Brunner C, Freda MC, Damus K, Runowicz CD. Can precolposcopy education increase knowledge and decrease anxiety? J Obstet Gynecol Neonatal Nurs. 1998;27(6):636–645.
- Khan MJ, Werner CL, Darragh TM, et al. ASCCP colposcopy standards: Role of colposcopy, benefits, potential harms, and terminology for colposcopic practice. J Low Genit Tract Dis. 2017;21(4):223–229.
- Waxman AG, Conageski C, Silver MI, et al. ASCCP colposcopy standards: How do we perform colposcopy? Implications for establishing standards. J Low Genit Tract Dis. 2017;21(4):235–241.
- Wentzensen N, Schiffman M. Accelerating cervical cancer control and prevention. Lancet Public Health. 2018;3(1):e6–e7.
Lower risk of ICH with dabigatran as compared to warfarin in atrial fibrillation
Clinical question: Is dabigatran superior to warfarin with regards to the risk of intracranial hemorrhage and myocardial infarction in patients with atrial fibrillation?
Background: Several studies – including the RELY trial – have revealed a lower rate of intracranial hemorrhage with dabigatran, compared with warfarin, in patients with atrial fibrillation; however, few of these have been on populations generalizable to clinical practice. Furthermore, there are conflicting data on the association of dabigatran with higher rates of myocardial infarction in patients with atrial fibrillation versus warfarin.
Study design: Retrospective cohort study.
Setting: The Sentinel Program (national surveillance system) including 17 collaborating institutions and health care delivery systems.
Synopsis: In 25,289 propensity score–matched pairs of commercially insured patients aged 21 years or older starting dabigatran or warfarin therapy for atrial fibrillation, dabigatran was associated with a lower rate of intracranial hemorrhage (hazard ratio, 0.89; 95% confidence interval, 0.72-1.09), similar rates of ischemic stroke and extracranial hemorrhage, and a potentially higher rate of myocardial infarction (HR, 1.88; 95% CI, 1.22-2.90). However, the association between dabigatran use and myocardial infarction was smaller and not statistically significant in sensitivity analyses. Also, subgroup analyses demonstrated higher rates of gastrointestinal bleeding with dabigatran than did warfarin in patients aged 75 years or older and those with kidney dysfunction.
Although providing further reassuring evidence about bleeding risks – particularly intracranial hemorrhage – associated with dabigatran use, this observational study fails to clarify the association between dabigatran and myocardial infarction.
Bottom line: Dabigatran, compared with warfarin, in adults with atrial fibrillation is associated with a lower risk of intracranial hemorrhage and similar risk of ischemic stroke and extracranial hemorrhage.
Citation: Go AS et al. Outcomes of dabigatran and warfarin for atrial fibrillation in contemporary practice. Ann Intern Med. 2017 Dec.19;167:845-54.
Dr. Mehta is assistant professor, division of hospital medicine, University of Virginia.
Clinical question: Is dabigatran superior to warfarin with regards to the risk of intracranial hemorrhage and myocardial infarction in patients with atrial fibrillation?
Background: Several studies – including the RELY trial – have revealed a lower rate of intracranial hemorrhage with dabigatran, compared with warfarin, in patients with atrial fibrillation; however, few of these have been on populations generalizable to clinical practice. Furthermore, there are conflicting data on the association of dabigatran with higher rates of myocardial infarction in patients with atrial fibrillation versus warfarin.
Study design: Retrospective cohort study.
Setting: The Sentinel Program (national surveillance system) including 17 collaborating institutions and health care delivery systems.
Synopsis: In 25,289 propensity score–matched pairs of commercially insured patients aged 21 years or older starting dabigatran or warfarin therapy for atrial fibrillation, dabigatran was associated with a lower rate of intracranial hemorrhage (hazard ratio, 0.89; 95% confidence interval, 0.72-1.09), similar rates of ischemic stroke and extracranial hemorrhage, and a potentially higher rate of myocardial infarction (HR, 1.88; 95% CI, 1.22-2.90). However, the association between dabigatran use and myocardial infarction was smaller and not statistically significant in sensitivity analyses. Also, subgroup analyses demonstrated higher rates of gastrointestinal bleeding with dabigatran than did warfarin in patients aged 75 years or older and those with kidney dysfunction.
Although providing further reassuring evidence about bleeding risks – particularly intracranial hemorrhage – associated with dabigatran use, this observational study fails to clarify the association between dabigatran and myocardial infarction.
Bottom line: Dabigatran, compared with warfarin, in adults with atrial fibrillation is associated with a lower risk of intracranial hemorrhage and similar risk of ischemic stroke and extracranial hemorrhage.
Citation: Go AS et al. Outcomes of dabigatran and warfarin for atrial fibrillation in contemporary practice. Ann Intern Med. 2017 Dec.19;167:845-54.
Dr. Mehta is assistant professor, division of hospital medicine, University of Virginia.
Clinical question: Is dabigatran superior to warfarin with regards to the risk of intracranial hemorrhage and myocardial infarction in patients with atrial fibrillation?
Background: Several studies – including the RELY trial – have revealed a lower rate of intracranial hemorrhage with dabigatran, compared with warfarin, in patients with atrial fibrillation; however, few of these have been on populations generalizable to clinical practice. Furthermore, there are conflicting data on the association of dabigatran with higher rates of myocardial infarction in patients with atrial fibrillation versus warfarin.
Study design: Retrospective cohort study.
Setting: The Sentinel Program (national surveillance system) including 17 collaborating institutions and health care delivery systems.
Synopsis: In 25,289 propensity score–matched pairs of commercially insured patients aged 21 years or older starting dabigatran or warfarin therapy for atrial fibrillation, dabigatran was associated with a lower rate of intracranial hemorrhage (hazard ratio, 0.89; 95% confidence interval, 0.72-1.09), similar rates of ischemic stroke and extracranial hemorrhage, and a potentially higher rate of myocardial infarction (HR, 1.88; 95% CI, 1.22-2.90). However, the association between dabigatran use and myocardial infarction was smaller and not statistically significant in sensitivity analyses. Also, subgroup analyses demonstrated higher rates of gastrointestinal bleeding with dabigatran than did warfarin in patients aged 75 years or older and those with kidney dysfunction.
Although providing further reassuring evidence about bleeding risks – particularly intracranial hemorrhage – associated with dabigatran use, this observational study fails to clarify the association between dabigatran and myocardial infarction.
Bottom line: Dabigatran, compared with warfarin, in adults with atrial fibrillation is associated with a lower risk of intracranial hemorrhage and similar risk of ischemic stroke and extracranial hemorrhage.
Citation: Go AS et al. Outcomes of dabigatran and warfarin for atrial fibrillation in contemporary practice. Ann Intern Med. 2017 Dec.19;167:845-54.
Dr. Mehta is assistant professor, division of hospital medicine, University of Virginia.
VIDEO: Meeting stroke screening demand will require systems’ reorganization
In a video interview at the annual meeting of the American Academy of Neurology, Dr. Wechsler described steps being taken at the University of Pittsburgh Medical Center’s comprehensive stroke center to handle the additional workload.
UPMC conducts telemedicine acute stroke evaluations of patients at community hospitals’ primary stroke centers in the greater Pittsburgh area to make sure that only the cases that require mechanical thrombectomy are transferred to them for specialized care, while also continuing to see nontransferred patients via telemedicine for follow-up, said Dr. Wechsler, chair of the department of neurology at UPMC and founder of its Stroke Institute and telestroke network.
This sort of solution may be more feasible and practical for comprehensive stroke centers to implement in order to manage the number of cases, instead of expanding neurology residencies, capping stroke services, adding a nonteaching service, adding advanced practice providers, or increasing the case loads of vascular neurology fellows and attending neurologists, he said.
In just the short time since the DAWN trial results were released in November 2017 and set the new standard for treating eligible patients with large-vessel occlusions with mechanical thrombectomy within 6-24 hours, stroke admissions and transfers to the comprehensive stroke center at UPMC from November 2017 to February 2018 rose 18% from the same time period a year before, including a 5% rise in telemedicine transfers, Dr. Wechsler said in a presentation at the meeting. These additional cases led to a 35% increase in thrombectomy cases.
Putting the matter into additional perspective, in the time period from November 2014 to February 2017, 30% of all 2,667 acute ischemic stroke patients seen at UPMC would have met DAWN trial inclusion criteria with a 6- to 24-hour window, but less than 3% of all the strokes seen at UPMC would have qualified for thrombectomy under criteria from the DAWN and DEFUSE-3 trials. That makes it imperative for comprehensive stroke centers to triage cases and receive only those that require endovascular treatment, he said.
Meeting the already-rising needs for triaging acute ischemic stroke patients arriving in the window of 6-24 hours will be difficult, considering that there are about 800,000 new strokes per year in the United States but only 1,100 vascular neurologists, nearly 1,100 primary stroke centers, and only 110 comprehensive stroke centers at which endovascular thrombectomy treatment may be offered. As of 2016, he noted that there also were only 74 U.S. stroke fellowship programs with 123 positions offered, of which 34% went unfilled.
In a video interview at the annual meeting of the American Academy of Neurology, Dr. Wechsler described steps being taken at the University of Pittsburgh Medical Center’s comprehensive stroke center to handle the additional workload.
UPMC conducts telemedicine acute stroke evaluations of patients at community hospitals’ primary stroke centers in the greater Pittsburgh area to make sure that only the cases that require mechanical thrombectomy are transferred to them for specialized care, while also continuing to see nontransferred patients via telemedicine for follow-up, said Dr. Wechsler, chair of the department of neurology at UPMC and founder of its Stroke Institute and telestroke network.
This sort of solution may be more feasible and practical for comprehensive stroke centers to implement in order to manage the number of cases, instead of expanding neurology residencies, capping stroke services, adding a nonteaching service, adding advanced practice providers, or increasing the case loads of vascular neurology fellows and attending neurologists, he said.
In just the short time since the DAWN trial results were released in November 2017 and set the new standard for treating eligible patients with large-vessel occlusions with mechanical thrombectomy within 6-24 hours, stroke admissions and transfers to the comprehensive stroke center at UPMC from November 2017 to February 2018 rose 18% from the same time period a year before, including a 5% rise in telemedicine transfers, Dr. Wechsler said in a presentation at the meeting. These additional cases led to a 35% increase in thrombectomy cases.
Putting the matter into additional perspective, in the time period from November 2014 to February 2017, 30% of all 2,667 acute ischemic stroke patients seen at UPMC would have met DAWN trial inclusion criteria with a 6- to 24-hour window, but less than 3% of all the strokes seen at UPMC would have qualified for thrombectomy under criteria from the DAWN and DEFUSE-3 trials. That makes it imperative for comprehensive stroke centers to triage cases and receive only those that require endovascular treatment, he said.
Meeting the already-rising needs for triaging acute ischemic stroke patients arriving in the window of 6-24 hours will be difficult, considering that there are about 800,000 new strokes per year in the United States but only 1,100 vascular neurologists, nearly 1,100 primary stroke centers, and only 110 comprehensive stroke centers at which endovascular thrombectomy treatment may be offered. As of 2016, he noted that there also were only 74 U.S. stroke fellowship programs with 123 positions offered, of which 34% went unfilled.
In a video interview at the annual meeting of the American Academy of Neurology, Dr. Wechsler described steps being taken at the University of Pittsburgh Medical Center’s comprehensive stroke center to handle the additional workload.
UPMC conducts telemedicine acute stroke evaluations of patients at community hospitals’ primary stroke centers in the greater Pittsburgh area to make sure that only the cases that require mechanical thrombectomy are transferred to them for specialized care, while also continuing to see nontransferred patients via telemedicine for follow-up, said Dr. Wechsler, chair of the department of neurology at UPMC and founder of its Stroke Institute and telestroke network.
This sort of solution may be more feasible and practical for comprehensive stroke centers to implement in order to manage the number of cases, instead of expanding neurology residencies, capping stroke services, adding a nonteaching service, adding advanced practice providers, or increasing the case loads of vascular neurology fellows and attending neurologists, he said.
In just the short time since the DAWN trial results were released in November 2017 and set the new standard for treating eligible patients with large-vessel occlusions with mechanical thrombectomy within 6-24 hours, stroke admissions and transfers to the comprehensive stroke center at UPMC from November 2017 to February 2018 rose 18% from the same time period a year before, including a 5% rise in telemedicine transfers, Dr. Wechsler said in a presentation at the meeting. These additional cases led to a 35% increase in thrombectomy cases.
Putting the matter into additional perspective, in the time period from November 2014 to February 2017, 30% of all 2,667 acute ischemic stroke patients seen at UPMC would have met DAWN trial inclusion criteria with a 6- to 24-hour window, but less than 3% of all the strokes seen at UPMC would have qualified for thrombectomy under criteria from the DAWN and DEFUSE-3 trials. That makes it imperative for comprehensive stroke centers to triage cases and receive only those that require endovascular treatment, he said.
Meeting the already-rising needs for triaging acute ischemic stroke patients arriving in the window of 6-24 hours will be difficult, considering that there are about 800,000 new strokes per year in the United States but only 1,100 vascular neurologists, nearly 1,100 primary stroke centers, and only 110 comprehensive stroke centers at which endovascular thrombectomy treatment may be offered. As of 2016, he noted that there also were only 74 U.S. stroke fellowship programs with 123 positions offered, of which 34% went unfilled.
REPORTING FROM AAN 2018
How does oral contraceptive use affect one’s risk of ovarian, endometrial, breast, and colorectal cancers?
EXPERT COMMENTARY
Hormonal contraception (HC), including OC, is a central component of women’s health care worldwide. In addition to its many potential health benefits (pregnancy prevention, menstrual symptom management), HC use modifies the risk of various cancers. As we discussed in the February 2018 issue of OBG Management, a recent large population-based study in Denmark showed a small but statistically significant increase in breast cancer risk in HC users.1,2 Conversely, HC use has a long recognized protective effect against ovarian and endometrial cancers. These risk relationships may be altered by other modifiable lifestyle characteristics, such as smoking, alcohol use, obesity, and physical activity.
Details of the study
Michels and colleagues evaluated the association between OC use and multiple cancers, stratifying these risks by duration of use and various modifiable lifestyle characteristics.3 The authors used a prospective survey-based cohort (the NIH-AARP Diet and Health Study) linked with state cancer registries to evaluate this relationship in a diverse population of 196,536 women across 6 US states and 2 metropolitan areas. Women were enrolled in 1995–1996 and followed until 2011. Cancer risks were presented as hazard ratios (HR), which indicate the risk of developing a specific cancer type in OC users compared with nonusers. HRs differ from relative risks (RR) and odds ratios because they compare the instantaneous risk difference between the 2 groups, rather than the cumulative risk difference over the entire study period.4
Duration of OC use and risk reduction
In this study population, OC use was associated with a significantly decreased risk of ovarian cancer, and this risk increased with longer duration of use (TABLE). Similarly, long-term OC use was associated with a decreased risk for endometrial cancer. These effects were true across various lifestyle characteristics, including smoking status, alcohol use, body mass index (BMI), and physical activity level.
There was a nonsignificant trend toward increased risk of breast cancer among OC users. The most significant elevation in breast cancer risk was found in long-term users who were current smokers (HR, 1.21 [95% confidence interval (CI), 1.01–1.44]). OC use had a minimal effect on colorectal cancer risk.
The bottom line. US women using OCs were significantly less likely to develop ovarian and endometrial cancers compared with nonusers. This risk reduction increased with longer duration of OC use and was true regardless of lifestyle. Conversely, there was a trend toward a slightly increased risk of developing breast cancer in OC users.
Study strengths and weaknesses
The effect on breast cancer risk is less pronounced than that reported in a recent large, prospective cohort study in Denmark, which reported an RR of developing breast cancer of 1.20 (95% CI, 1.14–1.26) among all current or recent HC users.1 These differing results may be due to the US study population’s increased heterogeneity compared with the Danish cohort; potential recall bias in the US study (not present in the Danish study because pharmacy records were used); the larger size of the Danish study (that is, ability to detect very small effect sizes); and lack of information on OC formulation, recency of use, and parity in the US study.
Nevertheless, the significant protective effect against ovarian and endometrial cancers (reported previously in numerous studies) should be a part of totality of cancer risk when counseling patients on any potential increased risk of breast cancer with OC use.
According to the study by Michels and colleagues, overall, women using OCs had a decreased risk of ovarian and endometrial cancers and a trend toward a slightly increased risk of breast cancer.3 Based on this and prior estimates, the overall risk of developing any cancer appears to be lower in OC users than in nonusers.5,6
Consider discussing the points below when counseling women on OC use and cancer risk.
Cancer prevention
- OC use was associated with a significantly decreased risk of both ovarian and endometrial cancers. This effect increased with longer duration of use.
- Ovarian cancer risk reduction persisted regardless of smoking status, BMI, alcohol use, or physical activity level.
- The largest reduction in endometrial cancer was seen in current smokers and patients with a BMI greater than 30 kg/m2.
Breast cancer risk
- There was a trend toward a slightly increased risk of breast cancer with OC use of any duration.
- A Danish cohort study showed a significantly higher risk (although still an overall low risk) of breast cancer with HC use (RR, 1.20 [95% CI, 1.14-1.26]).1
- The differences in these 2 results may be related to study design and population characteristic differences.
Overall cancer risk
- The definitive and larger risk reductions in ovarian and endometrial cancer compared with the lesser risk increase in breast cancer suggest a net decrease in developing any cancer for OC users.3,5,6
Risks of pregnancy prevention failure
- OCs are an effective method for preventing unintended pregnancy. Risks of OCs should be weighed against the risks of unintended pregnancy.
- In the United States, the maternal mortality rate (2015) is 26.4 deaths for every 100,000 women.7 The risk of maternal mortality is substantially higher than even the highest published estimates of HC-attributable breast cancer rates (that is, 13 incremental breast cancers for every 100,000 women using HC; 2 incremental breast cancers for every 100,000 women 35 years of age or younger using HC).1
- Unintended pregnancy is a serious maternal-child health problem, and it has substantial health, social, and economic consequences.8-14
- Unintended pregnancies generate a significant economic burden (an estimated $21 billion in direct and indirect costs for the US health care system per year).15 Approximately 42% of unintended pregnancies end in abortion.16
-- Dana M. Scott, MD, and Mark D. Pearlman, MD
Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.
- Mørch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard Ø. Contemporary hormonal contraception and the risk of breast cancer. N Engl J Med. 2017;377(23):2228–2239.
- Scott DM, Pearlman MD. Does hormonal contraception increase the risk of breast cancer? OBG Manag. 2018;30(2):16–17.
- Michels KA, Pfeiffer RM, Brinton LA, Trabert B. Modification of the associations between duration of oral contraceptive use and ovarian, endometrial, breast, and colorectal cancers [published online January 18, 2018]. JAMA Oncol. doi:10.1001/jamaoncol.2017.4942.
- Sedgwick P. Hazards and hazard ratios. BMJ. 2012;345:e5980.
- Bassuk SS, Manson JE. Oral contraceptives and menopausal hormone therapy: relative and attributable risks of cardiovascular disease, cancer, and other health outcomes. Ann Epidemiol. 2015;25(3):193–200.
- Hunter D. Oral contraceptives and the small increased risk of breast cancer. N Engl J Med. 2017;377(23):2276–2277.
- GBD 2015 Maternal Mortality Collaborators. Global, regional, and national levels of maternal mortality, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1775–1812.
- Brown SS, Eisenberg L, eds. The best intentions: unintended pregnancy and the well-being of children and families. Washington, DC: The National Academies Press; 1995:50–90.
- Klein JD; American Academy of Pediatrics Committee on Adolescence. Adolescent pregnancy: current trends and issues. Pediatrics. 2005;116(1):281–286.
- Logan C, Holcombe E, Manlove J, Ryan S; The National Campaign to Prevent Teen Pregnancy and Child Trends. The consequences of unintended childbearing. https://pdfs.semanticscholar.org/b353/b02ae6cad716a7f64ca48b3edae63544c03e.pdf?_ga=2.149310646.1402594583.1524236972-1233479770.1524236972&_gac=1.195699992.1524237056. Accessed April 20, 2018.
- Finer LB, Sonfield A. The evidence mounts on the benefits of preventing unintended pregnancy. Contraception. 2013;87(2):126–127.
- Trussell J, Henry N, Hassan F, Prezioso A, Law A, Filonenko A. Burden of unintended pregnancy in the United States: potential savings with increased use of long-acting reversible contraception. Contraception. 2013;87(2):154–161.
- Sonfield A, Kost K. Public costs from unintended pregnancies and the role of public insurance programs in paying for pregnancy and infant care: estimates for 2008. Guttmacher Institute. https://www.guttmacher.org/sites/default/files/report_pdf/public-costs-of-up.pdf. Published October 2013. Accessed April 20, 2018.
- Forrest JD, Singh S. Public-sector savings resulting from expenditures for contraceptive services. Fam Plann Perspect. 1990;22(1):6–15.
- Sonfield A, Kost K. Public costs from unintended pregnancies and the role of public insurance programs in paying for pregnancy-related care: national and state estimates for 2010. Guttmacher Institute. http://www.guttmacher.org/pubs/public-costs-of-UP-2010.pdf. Published February 2015. Accessed April 20, 2018.
- Finer LB, Zolna MR. Declines in unintended pregnancy in the United States, 2008–2011. N Engl J Med. 2016;374(9):843–852.
- Surveillance, Epidemiology, and End Results Program. Cancer stat facts: ovarian cancer. Bethesda, MD; National Cancer Institute. http://seer.cancer.gov/statfacts/html/ovary.html. Accessed April 20, 2018.
- Surveillance, Epidemiology, and End Results Program. Cancer stat facts: uterine cancer. Bethesda, MD; National Cancer Institute. http://seer.cancer.gov/statfacts/html/corp.html. Accessed April 20, 2018.
- Surveillance, Epidemiology, and End Results Program. Cancer stat facts: female breast cancer. Bethesda, MD; National Cancer Institute. http://seer.cancer.gov/statfacts/html/breast.html. Accessed April 20, 2018.
- Surveillance, Epidemiology, and End Results Program. Cancer stat facts: colorectal cancer. Bethesda, MD; National Cancer Institute. http://seer.cancer.gov/statfacts/html/colorect.html. Accessed April 20, 2018.
EXPERT COMMENTARY
Hormonal contraception (HC), including OC, is a central component of women’s health care worldwide. In addition to its many potential health benefits (pregnancy prevention, menstrual symptom management), HC use modifies the risk of various cancers. As we discussed in the February 2018 issue of OBG Management, a recent large population-based study in Denmark showed a small but statistically significant increase in breast cancer risk in HC users.1,2 Conversely, HC use has a long recognized protective effect against ovarian and endometrial cancers. These risk relationships may be altered by other modifiable lifestyle characteristics, such as smoking, alcohol use, obesity, and physical activity.
Details of the study
Michels and colleagues evaluated the association between OC use and multiple cancers, stratifying these risks by duration of use and various modifiable lifestyle characteristics.3 The authors used a prospective survey-based cohort (the NIH-AARP Diet and Health Study) linked with state cancer registries to evaluate this relationship in a diverse population of 196,536 women across 6 US states and 2 metropolitan areas. Women were enrolled in 1995–1996 and followed until 2011. Cancer risks were presented as hazard ratios (HR), which indicate the risk of developing a specific cancer type in OC users compared with nonusers. HRs differ from relative risks (RR) and odds ratios because they compare the instantaneous risk difference between the 2 groups, rather than the cumulative risk difference over the entire study period.4
Duration of OC use and risk reduction
In this study population, OC use was associated with a significantly decreased risk of ovarian cancer, and this risk increased with longer duration of use (TABLE). Similarly, long-term OC use was associated with a decreased risk for endometrial cancer. These effects were true across various lifestyle characteristics, including smoking status, alcohol use, body mass index (BMI), and physical activity level.
There was a nonsignificant trend toward increased risk of breast cancer among OC users. The most significant elevation in breast cancer risk was found in long-term users who were current smokers (HR, 1.21 [95% confidence interval (CI), 1.01–1.44]). OC use had a minimal effect on colorectal cancer risk.
The bottom line. US women using OCs were significantly less likely to develop ovarian and endometrial cancers compared with nonusers. This risk reduction increased with longer duration of OC use and was true regardless of lifestyle. Conversely, there was a trend toward a slightly increased risk of developing breast cancer in OC users.
Study strengths and weaknesses
The effect on breast cancer risk is less pronounced than that reported in a recent large, prospective cohort study in Denmark, which reported an RR of developing breast cancer of 1.20 (95% CI, 1.14–1.26) among all current or recent HC users.1 These differing results may be due to the US study population’s increased heterogeneity compared with the Danish cohort; potential recall bias in the US study (not present in the Danish study because pharmacy records were used); the larger size of the Danish study (that is, ability to detect very small effect sizes); and lack of information on OC formulation, recency of use, and parity in the US study.
Nevertheless, the significant protective effect against ovarian and endometrial cancers (reported previously in numerous studies) should be a part of totality of cancer risk when counseling patients on any potential increased risk of breast cancer with OC use.
According to the study by Michels and colleagues, overall, women using OCs had a decreased risk of ovarian and endometrial cancers and a trend toward a slightly increased risk of breast cancer.3 Based on this and prior estimates, the overall risk of developing any cancer appears to be lower in OC users than in nonusers.5,6
Consider discussing the points below when counseling women on OC use and cancer risk.
Cancer prevention
- OC use was associated with a significantly decreased risk of both ovarian and endometrial cancers. This effect increased with longer duration of use.
- Ovarian cancer risk reduction persisted regardless of smoking status, BMI, alcohol use, or physical activity level.
- The largest reduction in endometrial cancer was seen in current smokers and patients with a BMI greater than 30 kg/m2.
Breast cancer risk
- There was a trend toward a slightly increased risk of breast cancer with OC use of any duration.
- A Danish cohort study showed a significantly higher risk (although still an overall low risk) of breast cancer with HC use (RR, 1.20 [95% CI, 1.14-1.26]).1
- The differences in these 2 results may be related to study design and population characteristic differences.
Overall cancer risk
- The definitive and larger risk reductions in ovarian and endometrial cancer compared with the lesser risk increase in breast cancer suggest a net decrease in developing any cancer for OC users.3,5,6
Risks of pregnancy prevention failure
- OCs are an effective method for preventing unintended pregnancy. Risks of OCs should be weighed against the risks of unintended pregnancy.
- In the United States, the maternal mortality rate (2015) is 26.4 deaths for every 100,000 women.7 The risk of maternal mortality is substantially higher than even the highest published estimates of HC-attributable breast cancer rates (that is, 13 incremental breast cancers for every 100,000 women using HC; 2 incremental breast cancers for every 100,000 women 35 years of age or younger using HC).1
- Unintended pregnancy is a serious maternal-child health problem, and it has substantial health, social, and economic consequences.8-14
- Unintended pregnancies generate a significant economic burden (an estimated $21 billion in direct and indirect costs for the US health care system per year).15 Approximately 42% of unintended pregnancies end in abortion.16
-- Dana M. Scott, MD, and Mark D. Pearlman, MD
Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.
EXPERT COMMENTARY
Hormonal contraception (HC), including OC, is a central component of women’s health care worldwide. In addition to its many potential health benefits (pregnancy prevention, menstrual symptom management), HC use modifies the risk of various cancers. As we discussed in the February 2018 issue of OBG Management, a recent large population-based study in Denmark showed a small but statistically significant increase in breast cancer risk in HC users.1,2 Conversely, HC use has a long recognized protective effect against ovarian and endometrial cancers. These risk relationships may be altered by other modifiable lifestyle characteristics, such as smoking, alcohol use, obesity, and physical activity.
Details of the study
Michels and colleagues evaluated the association between OC use and multiple cancers, stratifying these risks by duration of use and various modifiable lifestyle characteristics.3 The authors used a prospective survey-based cohort (the NIH-AARP Diet and Health Study) linked with state cancer registries to evaluate this relationship in a diverse population of 196,536 women across 6 US states and 2 metropolitan areas. Women were enrolled in 1995–1996 and followed until 2011. Cancer risks were presented as hazard ratios (HR), which indicate the risk of developing a specific cancer type in OC users compared with nonusers. HRs differ from relative risks (RR) and odds ratios because they compare the instantaneous risk difference between the 2 groups, rather than the cumulative risk difference over the entire study period.4
Duration of OC use and risk reduction
In this study population, OC use was associated with a significantly decreased risk of ovarian cancer, and this risk increased with longer duration of use (TABLE). Similarly, long-term OC use was associated with a decreased risk for endometrial cancer. These effects were true across various lifestyle characteristics, including smoking status, alcohol use, body mass index (BMI), and physical activity level.
There was a nonsignificant trend toward increased risk of breast cancer among OC users. The most significant elevation in breast cancer risk was found in long-term users who were current smokers (HR, 1.21 [95% confidence interval (CI), 1.01–1.44]). OC use had a minimal effect on colorectal cancer risk.
The bottom line. US women using OCs were significantly less likely to develop ovarian and endometrial cancers compared with nonusers. This risk reduction increased with longer duration of OC use and was true regardless of lifestyle. Conversely, there was a trend toward a slightly increased risk of developing breast cancer in OC users.
Study strengths and weaknesses
The effect on breast cancer risk is less pronounced than that reported in a recent large, prospective cohort study in Denmark, which reported an RR of developing breast cancer of 1.20 (95% CI, 1.14–1.26) among all current or recent HC users.1 These differing results may be due to the US study population’s increased heterogeneity compared with the Danish cohort; potential recall bias in the US study (not present in the Danish study because pharmacy records were used); the larger size of the Danish study (that is, ability to detect very small effect sizes); and lack of information on OC formulation, recency of use, and parity in the US study.
Nevertheless, the significant protective effect against ovarian and endometrial cancers (reported previously in numerous studies) should be a part of totality of cancer risk when counseling patients on any potential increased risk of breast cancer with OC use.
According to the study by Michels and colleagues, overall, women using OCs had a decreased risk of ovarian and endometrial cancers and a trend toward a slightly increased risk of breast cancer.3 Based on this and prior estimates, the overall risk of developing any cancer appears to be lower in OC users than in nonusers.5,6
Consider discussing the points below when counseling women on OC use and cancer risk.
Cancer prevention
- OC use was associated with a significantly decreased risk of both ovarian and endometrial cancers. This effect increased with longer duration of use.
- Ovarian cancer risk reduction persisted regardless of smoking status, BMI, alcohol use, or physical activity level.
- The largest reduction in endometrial cancer was seen in current smokers and patients with a BMI greater than 30 kg/m2.
Breast cancer risk
- There was a trend toward a slightly increased risk of breast cancer with OC use of any duration.
- A Danish cohort study showed a significantly higher risk (although still an overall low risk) of breast cancer with HC use (RR, 1.20 [95% CI, 1.14-1.26]).1
- The differences in these 2 results may be related to study design and population characteristic differences.
Overall cancer risk
- The definitive and larger risk reductions in ovarian and endometrial cancer compared with the lesser risk increase in breast cancer suggest a net decrease in developing any cancer for OC users.3,5,6
Risks of pregnancy prevention failure
- OCs are an effective method for preventing unintended pregnancy. Risks of OCs should be weighed against the risks of unintended pregnancy.
- In the United States, the maternal mortality rate (2015) is 26.4 deaths for every 100,000 women.7 The risk of maternal mortality is substantially higher than even the highest published estimates of HC-attributable breast cancer rates (that is, 13 incremental breast cancers for every 100,000 women using HC; 2 incremental breast cancers for every 100,000 women 35 years of age or younger using HC).1
- Unintended pregnancy is a serious maternal-child health problem, and it has substantial health, social, and economic consequences.8-14
- Unintended pregnancies generate a significant economic burden (an estimated $21 billion in direct and indirect costs for the US health care system per year).15 Approximately 42% of unintended pregnancies end in abortion.16
-- Dana M. Scott, MD, and Mark D. Pearlman, MD
Share your thoughts! Send your Letter to the Editor to rbarbieri@mdedge.com. Please include your name and the city and state in which you practice.
- Mørch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard Ø. Contemporary hormonal contraception and the risk of breast cancer. N Engl J Med. 2017;377(23):2228–2239.
- Scott DM, Pearlman MD. Does hormonal contraception increase the risk of breast cancer? OBG Manag. 2018;30(2):16–17.
- Michels KA, Pfeiffer RM, Brinton LA, Trabert B. Modification of the associations between duration of oral contraceptive use and ovarian, endometrial, breast, and colorectal cancers [published online January 18, 2018]. JAMA Oncol. doi:10.1001/jamaoncol.2017.4942.
- Sedgwick P. Hazards and hazard ratios. BMJ. 2012;345:e5980.
- Bassuk SS, Manson JE. Oral contraceptives and menopausal hormone therapy: relative and attributable risks of cardiovascular disease, cancer, and other health outcomes. Ann Epidemiol. 2015;25(3):193–200.
- Hunter D. Oral contraceptives and the small increased risk of breast cancer. N Engl J Med. 2017;377(23):2276–2277.
- GBD 2015 Maternal Mortality Collaborators. Global, regional, and national levels of maternal mortality, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1775–1812.
- Brown SS, Eisenberg L, eds. The best intentions: unintended pregnancy and the well-being of children and families. Washington, DC: The National Academies Press; 1995:50–90.
- Klein JD; American Academy of Pediatrics Committee on Adolescence. Adolescent pregnancy: current trends and issues. Pediatrics. 2005;116(1):281–286.
- Logan C, Holcombe E, Manlove J, Ryan S; The National Campaign to Prevent Teen Pregnancy and Child Trends. The consequences of unintended childbearing. https://pdfs.semanticscholar.org/b353/b02ae6cad716a7f64ca48b3edae63544c03e.pdf?_ga=2.149310646.1402594583.1524236972-1233479770.1524236972&_gac=1.195699992.1524237056. Accessed April 20, 2018.
- Finer LB, Sonfield A. The evidence mounts on the benefits of preventing unintended pregnancy. Contraception. 2013;87(2):126–127.
- Trussell J, Henry N, Hassan F, Prezioso A, Law A, Filonenko A. Burden of unintended pregnancy in the United States: potential savings with increased use of long-acting reversible contraception. Contraception. 2013;87(2):154–161.
- Sonfield A, Kost K. Public costs from unintended pregnancies and the role of public insurance programs in paying for pregnancy and infant care: estimates for 2008. Guttmacher Institute. https://www.guttmacher.org/sites/default/files/report_pdf/public-costs-of-up.pdf. Published October 2013. Accessed April 20, 2018.
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