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Some Children Outgrow ADHD, Imaging Shows
SANTA FE, N.M. – Twenty years of brain imaging studies in children are leading National Institute of Mental Health investigators to explore whether they can distinguish youngsters who will outgrow attention-deficit/hyperactivity disorder from those for whom it will be a persistent problem.
This new work is built on evidence that normal brain development occurs with a 3-year delay in children with ADHD. In pilot data, the researchers have found a hint that the brains of youngsters who have “good” clinical outcomes compensate for this delay, whereas those of youngsters with “poor” outcomes take a different developmental trajectory.
“Approximately half of them grow up, and follow what their grandmothers said all along: 'He will grow out of it,'” Dr. Judith L. Rapoport, chief of the Child Psychiatry Branch at the NIMH, told attendees at an annual psychiatric symposium sponsored by the University of Arizona.
Her group has accumulated more than 6,000 anatomic MRIs of children whose brains were scanned every 2 years starting at age 4 in a longitudinal study, she said. The subjects were not selected for any particular psychiatric condition, but 300 were subsequently diagnosed with ADHD. In addition, the investigators received 3,000 referrals of children with suspected childhood-onset schizophrenia, among whom it found and scanned 107 children with the rare disorder.
By mapping the normal course of cortical development, the study revealed a process of cortical thinning from ages 5 to 20 that can be seen in Dr. Rapoport's words as “a back-to-front wave of cortical maturation” (PNAS 2004;101:8174-9; Nat. Neurosci. 1999;2:861-3). Comparison of high-intelligence children with those of high and average intelligence subsequently showed the children with high IQs had a developmental trajectory in which key measures were reached 2-3 years later than in the other children.”
“We were simply astonished to find out the real difference was between the superior intelligence group and the rest, and it was in the frontal lobes,” Dr. Rapoport recalled, adding that this is “one example that later at least in some brain regions is not associated with deficit and may be associated with the opposite.”
The investigators were soon deluged with tales of geniuses who did not talk until late (Albert Einstein famously among them), she added, speculating that perhaps the late maturity coincided with more complexity in input to the brain. The cerebellum with its abundance of neurons may be “the last frontier in terms of therapy and understanding,” she suggested. It is the last part of the brain to mature, she noted, and the least heritable.
Subsequent work showed later cortical development in the brains of children with ADHD (PNAS 2007;104:19649-54), and that the trajectory of baseline thinning also differed in ADHD between children with better outcomes and those with poor outcomes. Among the findings were that brain asymmetry is not as pronounced in ADHD as in non-ADHD children and that the right parietal cortex–a little region that “looks like a freckle”–develops differently in ADHD.
One study showed that cortical thickness “normalizes” in the right parietal cortex of 48 children with ADHD who have “good” outcomes. The difference at a key point in the developmental trajectory was statistically significant when these children were compared with 51 children with poor outcomes and to 161 healthy children without ADHD. The finding “suggests compensatory plastic response for good-outcome subjects,” Dr. Rapoport said of the ongoing study.
Further work suggests that some children with ADHD reach a developmental milestone by their adolescent years, but others do not.
She cautioned that her group has not published what it considers “just pilot data” in this regard, but has started to follow 80 hyperactive 5-year-olds in the hope of developing a predictive test based on brain development trajectories that will distinguish the children who are going to outgrow ADHD from “those who are going to continue to have problems.”
The study should produce results in about 5 years, she said, forecasting that such a test might help clinicians “single out people for whom resources are really needed, and let us relax more for people for whom, no matter what you do, it is going to turn out fine.”
Treating ADHD with stimulants remains controversial, and there is not good evidence supporting benefit from long-term use, she noted. Her group has found no difference in brain development trajectories when children on stimulants are compared with children not treated with stimulants, she said: “They were absolutely identical. A researcher couldn't have planned it better in terms of the mean and standard deviation.”
That said, in the short term, she suggested, “Kids' memories of grade school are happier [when given stimulants], because they weren't at odds with everyone all the time.”
For now, Dr. Rapoport strongly discourages parents from spending money on brain imaging tests to diagnose ADHD. While useful for research, the tests currently available are unlikely to have sufficient sensitivity or specificity “that you would want anyone to pay for,” she said.
“I am sad to see that there are colleagues all over the country … selling, in our already overtaxed health care system, brain imaging tests of various sorts for diagnosis of ADHD,” she lamented.
Dr. Rapoport also questioned whether the findings still to come will render premature the work going into the much-anticipated DSM-V.
She and her colleagues already have a theoretical classification scheme for DSM-VI that incorporates evidence of key cortical milestones occurring early in autism and late in ADHD when compared with normal development.
“At some point, you may be able to argue that brain development trajectories may turn out to be as important as any classification in psychiatry,” she said.
Predicting Schizophrenia in Womb
Prenatal screening based on variations in the numbers of certain key genes might be able to identify the carriers of childhood-onset schizophrenia and other psychiatric disorders, according to Dr. Rapoport.
About 9% of children with childhood-onset schizophrenia have been found to have genetic abnormalities, Dr. Rapoport explained. When children with multiple copies or deletions of key genes are counted, the proportion with possible genetic markers rises to 36%.
Moreover, many of the genes also are implicated in autism. Both conditions are associated with ahead-of-normal brain development, she said, and the timing of certain milestones might determine which of these or other disorders develops. Of note, three children referred to the team as possibly having childhood-onset schizophrenia subsequently developed bipolar disorder instead.
“I think the world is going to be stood on its head diagnostically when these things get sorted out,” Dr. Rapoport said, estimating that as many as 50% of children with early neurodevelopmental abnormalities could have copy number variants.
SANTA FE, N.M. – Twenty years of brain imaging studies in children are leading National Institute of Mental Health investigators to explore whether they can distinguish youngsters who will outgrow attention-deficit/hyperactivity disorder from those for whom it will be a persistent problem.
This new work is built on evidence that normal brain development occurs with a 3-year delay in children with ADHD. In pilot data, the researchers have found a hint that the brains of youngsters who have “good” clinical outcomes compensate for this delay, whereas those of youngsters with “poor” outcomes take a different developmental trajectory.
“Approximately half of them grow up, and follow what their grandmothers said all along: 'He will grow out of it,'” Dr. Judith L. Rapoport, chief of the Child Psychiatry Branch at the NIMH, told attendees at an annual psychiatric symposium sponsored by the University of Arizona.
Her group has accumulated more than 6,000 anatomic MRIs of children whose brains were scanned every 2 years starting at age 4 in a longitudinal study, she said. The subjects were not selected for any particular psychiatric condition, but 300 were subsequently diagnosed with ADHD. In addition, the investigators received 3,000 referrals of children with suspected childhood-onset schizophrenia, among whom it found and scanned 107 children with the rare disorder.
By mapping the normal course of cortical development, the study revealed a process of cortical thinning from ages 5 to 20 that can be seen in Dr. Rapoport's words as “a back-to-front wave of cortical maturation” (PNAS 2004;101:8174-9; Nat. Neurosci. 1999;2:861-3). Comparison of high-intelligence children with those of high and average intelligence subsequently showed the children with high IQs had a developmental trajectory in which key measures were reached 2-3 years later than in the other children.”
“We were simply astonished to find out the real difference was between the superior intelligence group and the rest, and it was in the frontal lobes,” Dr. Rapoport recalled, adding that this is “one example that later at least in some brain regions is not associated with deficit and may be associated with the opposite.”
The investigators were soon deluged with tales of geniuses who did not talk until late (Albert Einstein famously among them), she added, speculating that perhaps the late maturity coincided with more complexity in input to the brain. The cerebellum with its abundance of neurons may be “the last frontier in terms of therapy and understanding,” she suggested. It is the last part of the brain to mature, she noted, and the least heritable.
Subsequent work showed later cortical development in the brains of children with ADHD (PNAS 2007;104:19649-54), and that the trajectory of baseline thinning also differed in ADHD between children with better outcomes and those with poor outcomes. Among the findings were that brain asymmetry is not as pronounced in ADHD as in non-ADHD children and that the right parietal cortex–a little region that “looks like a freckle”–develops differently in ADHD.
One study showed that cortical thickness “normalizes” in the right parietal cortex of 48 children with ADHD who have “good” outcomes. The difference at a key point in the developmental trajectory was statistically significant when these children were compared with 51 children with poor outcomes and to 161 healthy children without ADHD. The finding “suggests compensatory plastic response for good-outcome subjects,” Dr. Rapoport said of the ongoing study.
Further work suggests that some children with ADHD reach a developmental milestone by their adolescent years, but others do not.
She cautioned that her group has not published what it considers “just pilot data” in this regard, but has started to follow 80 hyperactive 5-year-olds in the hope of developing a predictive test based on brain development trajectories that will distinguish the children who are going to outgrow ADHD from “those who are going to continue to have problems.”
The study should produce results in about 5 years, she said, forecasting that such a test might help clinicians “single out people for whom resources are really needed, and let us relax more for people for whom, no matter what you do, it is going to turn out fine.”
Treating ADHD with stimulants remains controversial, and there is not good evidence supporting benefit from long-term use, she noted. Her group has found no difference in brain development trajectories when children on stimulants are compared with children not treated with stimulants, she said: “They were absolutely identical. A researcher couldn't have planned it better in terms of the mean and standard deviation.”
That said, in the short term, she suggested, “Kids' memories of grade school are happier [when given stimulants], because they weren't at odds with everyone all the time.”
For now, Dr. Rapoport strongly discourages parents from spending money on brain imaging tests to diagnose ADHD. While useful for research, the tests currently available are unlikely to have sufficient sensitivity or specificity “that you would want anyone to pay for,” she said.
“I am sad to see that there are colleagues all over the country … selling, in our already overtaxed health care system, brain imaging tests of various sorts for diagnosis of ADHD,” she lamented.
Dr. Rapoport also questioned whether the findings still to come will render premature the work going into the much-anticipated DSM-V.
She and her colleagues already have a theoretical classification scheme for DSM-VI that incorporates evidence of key cortical milestones occurring early in autism and late in ADHD when compared with normal development.
“At some point, you may be able to argue that brain development trajectories may turn out to be as important as any classification in psychiatry,” she said.
Predicting Schizophrenia in Womb
Prenatal screening based on variations in the numbers of certain key genes might be able to identify the carriers of childhood-onset schizophrenia and other psychiatric disorders, according to Dr. Rapoport.
About 9% of children with childhood-onset schizophrenia have been found to have genetic abnormalities, Dr. Rapoport explained. When children with multiple copies or deletions of key genes are counted, the proportion with possible genetic markers rises to 36%.
Moreover, many of the genes also are implicated in autism. Both conditions are associated with ahead-of-normal brain development, she said, and the timing of certain milestones might determine which of these or other disorders develops. Of note, three children referred to the team as possibly having childhood-onset schizophrenia subsequently developed bipolar disorder instead.
“I think the world is going to be stood on its head diagnostically when these things get sorted out,” Dr. Rapoport said, estimating that as many as 50% of children with early neurodevelopmental abnormalities could have copy number variants.
SANTA FE, N.M. – Twenty years of brain imaging studies in children are leading National Institute of Mental Health investigators to explore whether they can distinguish youngsters who will outgrow attention-deficit/hyperactivity disorder from those for whom it will be a persistent problem.
This new work is built on evidence that normal brain development occurs with a 3-year delay in children with ADHD. In pilot data, the researchers have found a hint that the brains of youngsters who have “good” clinical outcomes compensate for this delay, whereas those of youngsters with “poor” outcomes take a different developmental trajectory.
“Approximately half of them grow up, and follow what their grandmothers said all along: 'He will grow out of it,'” Dr. Judith L. Rapoport, chief of the Child Psychiatry Branch at the NIMH, told attendees at an annual psychiatric symposium sponsored by the University of Arizona.
Her group has accumulated more than 6,000 anatomic MRIs of children whose brains were scanned every 2 years starting at age 4 in a longitudinal study, she said. The subjects were not selected for any particular psychiatric condition, but 300 were subsequently diagnosed with ADHD. In addition, the investigators received 3,000 referrals of children with suspected childhood-onset schizophrenia, among whom it found and scanned 107 children with the rare disorder.
By mapping the normal course of cortical development, the study revealed a process of cortical thinning from ages 5 to 20 that can be seen in Dr. Rapoport's words as “a back-to-front wave of cortical maturation” (PNAS 2004;101:8174-9; Nat. Neurosci. 1999;2:861-3). Comparison of high-intelligence children with those of high and average intelligence subsequently showed the children with high IQs had a developmental trajectory in which key measures were reached 2-3 years later than in the other children.”
“We were simply astonished to find out the real difference was between the superior intelligence group and the rest, and it was in the frontal lobes,” Dr. Rapoport recalled, adding that this is “one example that later at least in some brain regions is not associated with deficit and may be associated with the opposite.”
The investigators were soon deluged with tales of geniuses who did not talk until late (Albert Einstein famously among them), she added, speculating that perhaps the late maturity coincided with more complexity in input to the brain. The cerebellum with its abundance of neurons may be “the last frontier in terms of therapy and understanding,” she suggested. It is the last part of the brain to mature, she noted, and the least heritable.
Subsequent work showed later cortical development in the brains of children with ADHD (PNAS 2007;104:19649-54), and that the trajectory of baseline thinning also differed in ADHD between children with better outcomes and those with poor outcomes. Among the findings were that brain asymmetry is not as pronounced in ADHD as in non-ADHD children and that the right parietal cortex–a little region that “looks like a freckle”–develops differently in ADHD.
One study showed that cortical thickness “normalizes” in the right parietal cortex of 48 children with ADHD who have “good” outcomes. The difference at a key point in the developmental trajectory was statistically significant when these children were compared with 51 children with poor outcomes and to 161 healthy children without ADHD. The finding “suggests compensatory plastic response for good-outcome subjects,” Dr. Rapoport said of the ongoing study.
Further work suggests that some children with ADHD reach a developmental milestone by their adolescent years, but others do not.
She cautioned that her group has not published what it considers “just pilot data” in this regard, but has started to follow 80 hyperactive 5-year-olds in the hope of developing a predictive test based on brain development trajectories that will distinguish the children who are going to outgrow ADHD from “those who are going to continue to have problems.”
The study should produce results in about 5 years, she said, forecasting that such a test might help clinicians “single out people for whom resources are really needed, and let us relax more for people for whom, no matter what you do, it is going to turn out fine.”
Treating ADHD with stimulants remains controversial, and there is not good evidence supporting benefit from long-term use, she noted. Her group has found no difference in brain development trajectories when children on stimulants are compared with children not treated with stimulants, she said: “They were absolutely identical. A researcher couldn't have planned it better in terms of the mean and standard deviation.”
That said, in the short term, she suggested, “Kids' memories of grade school are happier [when given stimulants], because they weren't at odds with everyone all the time.”
For now, Dr. Rapoport strongly discourages parents from spending money on brain imaging tests to diagnose ADHD. While useful for research, the tests currently available are unlikely to have sufficient sensitivity or specificity “that you would want anyone to pay for,” she said.
“I am sad to see that there are colleagues all over the country … selling, in our already overtaxed health care system, brain imaging tests of various sorts for diagnosis of ADHD,” she lamented.
Dr. Rapoport also questioned whether the findings still to come will render premature the work going into the much-anticipated DSM-V.
She and her colleagues already have a theoretical classification scheme for DSM-VI that incorporates evidence of key cortical milestones occurring early in autism and late in ADHD when compared with normal development.
“At some point, you may be able to argue that brain development trajectories may turn out to be as important as any classification in psychiatry,” she said.
Predicting Schizophrenia in Womb
Prenatal screening based on variations in the numbers of certain key genes might be able to identify the carriers of childhood-onset schizophrenia and other psychiatric disorders, according to Dr. Rapoport.
About 9% of children with childhood-onset schizophrenia have been found to have genetic abnormalities, Dr. Rapoport explained. When children with multiple copies or deletions of key genes are counted, the proportion with possible genetic markers rises to 36%.
Moreover, many of the genes also are implicated in autism. Both conditions are associated with ahead-of-normal brain development, she said, and the timing of certain milestones might determine which of these or other disorders develops. Of note, three children referred to the team as possibly having childhood-onset schizophrenia subsequently developed bipolar disorder instead.
“I think the world is going to be stood on its head diagnostically when these things get sorted out,” Dr. Rapoport said, estimating that as many as 50% of children with early neurodevelopmental abnormalities could have copy number variants.
Skin Regimen Prevents Cancer Tx-Related Rashes
ORLANDO A prophylactic skin care regimen may prevent the severe rashes that afflict cancer patients treated with epidermal growth factor receptor inhibitors, according to a physician who conducted a randomized, controlled trial in 95 colon cancer patients.
Not only did the intervention reduce moderate to severe dermatologic side effects by more than half during the 6-week study, but investigators also were surprised to see adverse events such as diarrhea and neutropenia sharply reduced.
"Everything is cost effective," Dr. Edith P. Mitchell said, listing the generic products in the regimen during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented.
The regimen includes sunscreen (for patients going out in the sun), a moisturizer, topical 1% hydrocortisone cream, and 100 mg of oral doxycycline, all given twice a day, explained Dr. Mitchell, program leader in gastrointestinal oncology at Thomas Jefferson University in Philadelphia.
Treatment should commence at least 24 hours before the start of anti-epidermal growth factor receptor (EGFR) therapy and continue throughout treatment, she said. One patient stayed on the prophylactic regimen for a year.
All patients in the STEPP (Skin Toxicity Evaluation Plan with Panitumumab) study were being treated with panitumumab (Vectibix), a monoclonal antibody approved as monotherapy for metastatic colorectal carcinoma that has progressed after standard chemotherapy. Although cetuximab (Erbitux), another EGFR inhibitor, was not involved in the trial, Dr. Mitchell said rash is a class effect of EGFR inhibitors. She also uses the regimen in patients receiving cetuximab.
Investigators randomized 48 patients to the prophylactic regimen and 47 patients to receive skin treatment reactively if they developed a rash. Dr. Mitchell reported 14 patients (29%) in the prophylactic group developed grade 2 or higher skin toxicity, compared with 29 patients (62%) in the control group.
Just 3 patients had grade 3 or higher dermatologic toxicity, compared with 10 patients in the control group. Those toxicities included dermatitis acneiform, pruritus, and pustular rash. None of the patients in either group had a grade 4 or 5 event.
Although the prophylactic group received more panitumumab doses (155 vs. 141) during the study, they had fewer doses of panitumumab delayed (1 vs. 9). That is considered important, because EGFR rashes are a problem affecting 90% of patients, causing some to delay and even to stop treatment, according to Dr. Mitchell. There have even been deaths due to infections associated with those rashes, she said.
A concern going into the study was that eliminating rash would interfere with the effectiveness of panitumumab.
Dr. Mitchell reported the regimen had no impact on efficacy of the colon cancer therapy. The overall response rate was 15% in the prophylactic arm and 11% in the control group; progression-free survival was 4.7 and 4.1 months, respectively.
The analysis also saw no difference between the two study arms when patients were analyzed for KRAS status.
Nondermatologic toxicities including grade 3 nausea, vomiting, fatigue, diarrhea, neutropenia, hypomagnesemia, and dehydration occurred less frequently in the prophylactic arm, as did grade 4 neutropenia. Neither group had any grade 5 toxicities.
Dr. Mitchell and many of her co-investigators disclosed financial relationships with Amgen, Inc., which makes panitumumab.
'Everything iscost effective,' and the skin care regimen had no impact on the cancer drug's efficacy. DR. MITCHELL
ORLANDO A prophylactic skin care regimen may prevent the severe rashes that afflict cancer patients treated with epidermal growth factor receptor inhibitors, according to a physician who conducted a randomized, controlled trial in 95 colon cancer patients.
Not only did the intervention reduce moderate to severe dermatologic side effects by more than half during the 6-week study, but investigators also were surprised to see adverse events such as diarrhea and neutropenia sharply reduced.
"Everything is cost effective," Dr. Edith P. Mitchell said, listing the generic products in the regimen during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented.
The regimen includes sunscreen (for patients going out in the sun), a moisturizer, topical 1% hydrocortisone cream, and 100 mg of oral doxycycline, all given twice a day, explained Dr. Mitchell, program leader in gastrointestinal oncology at Thomas Jefferson University in Philadelphia.
Treatment should commence at least 24 hours before the start of anti-epidermal growth factor receptor (EGFR) therapy and continue throughout treatment, she said. One patient stayed on the prophylactic regimen for a year.
All patients in the STEPP (Skin Toxicity Evaluation Plan with Panitumumab) study were being treated with panitumumab (Vectibix), a monoclonal antibody approved as monotherapy for metastatic colorectal carcinoma that has progressed after standard chemotherapy. Although cetuximab (Erbitux), another EGFR inhibitor, was not involved in the trial, Dr. Mitchell said rash is a class effect of EGFR inhibitors. She also uses the regimen in patients receiving cetuximab.
Investigators randomized 48 patients to the prophylactic regimen and 47 patients to receive skin treatment reactively if they developed a rash. Dr. Mitchell reported 14 patients (29%) in the prophylactic group developed grade 2 or higher skin toxicity, compared with 29 patients (62%) in the control group.
Just 3 patients had grade 3 or higher dermatologic toxicity, compared with 10 patients in the control group. Those toxicities included dermatitis acneiform, pruritus, and pustular rash. None of the patients in either group had a grade 4 or 5 event.
Although the prophylactic group received more panitumumab doses (155 vs. 141) during the study, they had fewer doses of panitumumab delayed (1 vs. 9). That is considered important, because EGFR rashes are a problem affecting 90% of patients, causing some to delay and even to stop treatment, according to Dr. Mitchell. There have even been deaths due to infections associated with those rashes, she said.
A concern going into the study was that eliminating rash would interfere with the effectiveness of panitumumab.
Dr. Mitchell reported the regimen had no impact on efficacy of the colon cancer therapy. The overall response rate was 15% in the prophylactic arm and 11% in the control group; progression-free survival was 4.7 and 4.1 months, respectively.
The analysis also saw no difference between the two study arms when patients were analyzed for KRAS status.
Nondermatologic toxicities including grade 3 nausea, vomiting, fatigue, diarrhea, neutropenia, hypomagnesemia, and dehydration occurred less frequently in the prophylactic arm, as did grade 4 neutropenia. Neither group had any grade 5 toxicities.
Dr. Mitchell and many of her co-investigators disclosed financial relationships with Amgen, Inc., which makes panitumumab.
'Everything iscost effective,' and the skin care regimen had no impact on the cancer drug's efficacy. DR. MITCHELL
ORLANDO A prophylactic skin care regimen may prevent the severe rashes that afflict cancer patients treated with epidermal growth factor receptor inhibitors, according to a physician who conducted a randomized, controlled trial in 95 colon cancer patients.
Not only did the intervention reduce moderate to severe dermatologic side effects by more than half during the 6-week study, but investigators also were surprised to see adverse events such as diarrhea and neutropenia sharply reduced.
"Everything is cost effective," Dr. Edith P. Mitchell said, listing the generic products in the regimen during a press briefing at the annual meeting of the American Society of Clinical Oncology, where the study was presented.
The regimen includes sunscreen (for patients going out in the sun), a moisturizer, topical 1% hydrocortisone cream, and 100 mg of oral doxycycline, all given twice a day, explained Dr. Mitchell, program leader in gastrointestinal oncology at Thomas Jefferson University in Philadelphia.
Treatment should commence at least 24 hours before the start of anti-epidermal growth factor receptor (EGFR) therapy and continue throughout treatment, she said. One patient stayed on the prophylactic regimen for a year.
All patients in the STEPP (Skin Toxicity Evaluation Plan with Panitumumab) study were being treated with panitumumab (Vectibix), a monoclonal antibody approved as monotherapy for metastatic colorectal carcinoma that has progressed after standard chemotherapy. Although cetuximab (Erbitux), another EGFR inhibitor, was not involved in the trial, Dr. Mitchell said rash is a class effect of EGFR inhibitors. She also uses the regimen in patients receiving cetuximab.
Investigators randomized 48 patients to the prophylactic regimen and 47 patients to receive skin treatment reactively if they developed a rash. Dr. Mitchell reported 14 patients (29%) in the prophylactic group developed grade 2 or higher skin toxicity, compared with 29 patients (62%) in the control group.
Just 3 patients had grade 3 or higher dermatologic toxicity, compared with 10 patients in the control group. Those toxicities included dermatitis acneiform, pruritus, and pustular rash. None of the patients in either group had a grade 4 or 5 event.
Although the prophylactic group received more panitumumab doses (155 vs. 141) during the study, they had fewer doses of panitumumab delayed (1 vs. 9). That is considered important, because EGFR rashes are a problem affecting 90% of patients, causing some to delay and even to stop treatment, according to Dr. Mitchell. There have even been deaths due to infections associated with those rashes, she said.
A concern going into the study was that eliminating rash would interfere with the effectiveness of panitumumab.
Dr. Mitchell reported the regimen had no impact on efficacy of the colon cancer therapy. The overall response rate was 15% in the prophylactic arm and 11% in the control group; progression-free survival was 4.7 and 4.1 months, respectively.
The analysis also saw no difference between the two study arms when patients were analyzed for KRAS status.
Nondermatologic toxicities including grade 3 nausea, vomiting, fatigue, diarrhea, neutropenia, hypomagnesemia, and dehydration occurred less frequently in the prophylactic arm, as did grade 4 neutropenia. Neither group had any grade 5 toxicities.
Dr. Mitchell and many of her co-investigators disclosed financial relationships with Amgen, Inc., which makes panitumumab.
'Everything iscost effective,' and the skin care regimen had no impact on the cancer drug's efficacy. DR. MITCHELL
Endometrial Ca: Progression-Free Interval Predicts Survival, 'Limited' Clinical Value
SAN ANTONIO — The length of time between the starts of primary and secondary treatment for advanced or recurrent endometrial cancer is a statistically significant predictor of a woman's risk of death 6 months after resuming treatment, according to a review of phase III trials conducted over the last 20 years.
A progression-free interval lasting more than 6 months reduced the risk of death by 30% in the Gynecologic Oncology Group (GOG) studies. The finding was statistically significant with a P value of .0001, but investigators concluded it had “limited” clinical value. Compared with women whose disease progressed within 6 months or less, patients gained about 3 months of life when they went longer before restarting treatment. Moreover, platinum sensitivity did not make much difference in the impact of second-line treatments on survival.
“Ten months versus 7 months—that's not a very useful prognostic indication,” lead investigator Kathleen M. Moore said in an interview, referring to the median probability of survival after second-line treatment with the longer progression-free interval versus a shorter span. “For endometrial cancer, it really doesn't change what you are going to do for that patient. It doesn't change how you are going to counsel that patient about progression.”
Dr. Moore of the University of Oklahoma, Oklahoma City, presented the results at the annual meeting of the Society of Gynecologic Oncologists.
The ancillary data analysis compared outcomes relative to progression-free intervals among 586 women who participated in GOG protocols 107, 122, 139, 163, and 177, which tested a variety of chemotherapy regimens. The women had a median age of 64 years, and nearly two-thirds had recurrent disease in this first part of the study. Most received platinum-based regimens as first-line therapy; their median progression-free interval was 6.7 months.
Investigators also reviewed treatment-free intervals from completion of the first regimen to progression for 275 women in the GOG protocol 129 series of trials. This group's median age was 66 years, and 89% of the women had been given platinum-based regimens as first-line therapy.
The women in this part of the study had a median treatment-free interval of 2.9 months. A treatment-free interval greater than 3 months was associated with a 25% reduction in risk of death (P = .014), but the investigators again saw little clinical value. Median survival from the start of therapy was 10.22 months with the longer treatment-free interval and 7.39 months for those who stayed off treatment for less than 3 months.
The findings were “very disappointing,” Dr. Moore said. Investigators had hoped to see a difference comparable to ovarian cancer, a disease in which some women gain 2 years of life, with median survival improving from 12 months to 36 months, if they remained progression free for more than 6 months after first-line treatment. She attributed the differences in predictive value of progression-free interval in part to underlying differences in response to first-line therapy. Women with ovarian cancer are typically in remission after completing their first chemotherapy, she said. This is not the case in women with endometrial cancer: “Only 15% had a complete clinical response—the majority finished their first chemotherapy with measurable disease.”
Moreover, the second-line treatments that can significantly prolong survival in ovarian cancer are lacking in endometrial cancer, she said, describing continued drug development as key to improving survival. Dr. Moore disclosed no conflicts of interest.
SAN ANTONIO — The length of time between the starts of primary and secondary treatment for advanced or recurrent endometrial cancer is a statistically significant predictor of a woman's risk of death 6 months after resuming treatment, according to a review of phase III trials conducted over the last 20 years.
A progression-free interval lasting more than 6 months reduced the risk of death by 30% in the Gynecologic Oncology Group (GOG) studies. The finding was statistically significant with a P value of .0001, but investigators concluded it had “limited” clinical value. Compared with women whose disease progressed within 6 months or less, patients gained about 3 months of life when they went longer before restarting treatment. Moreover, platinum sensitivity did not make much difference in the impact of second-line treatments on survival.
“Ten months versus 7 months—that's not a very useful prognostic indication,” lead investigator Kathleen M. Moore said in an interview, referring to the median probability of survival after second-line treatment with the longer progression-free interval versus a shorter span. “For endometrial cancer, it really doesn't change what you are going to do for that patient. It doesn't change how you are going to counsel that patient about progression.”
Dr. Moore of the University of Oklahoma, Oklahoma City, presented the results at the annual meeting of the Society of Gynecologic Oncologists.
The ancillary data analysis compared outcomes relative to progression-free intervals among 586 women who participated in GOG protocols 107, 122, 139, 163, and 177, which tested a variety of chemotherapy regimens. The women had a median age of 64 years, and nearly two-thirds had recurrent disease in this first part of the study. Most received platinum-based regimens as first-line therapy; their median progression-free interval was 6.7 months.
Investigators also reviewed treatment-free intervals from completion of the first regimen to progression for 275 women in the GOG protocol 129 series of trials. This group's median age was 66 years, and 89% of the women had been given platinum-based regimens as first-line therapy.
The women in this part of the study had a median treatment-free interval of 2.9 months. A treatment-free interval greater than 3 months was associated with a 25% reduction in risk of death (P = .014), but the investigators again saw little clinical value. Median survival from the start of therapy was 10.22 months with the longer treatment-free interval and 7.39 months for those who stayed off treatment for less than 3 months.
The findings were “very disappointing,” Dr. Moore said. Investigators had hoped to see a difference comparable to ovarian cancer, a disease in which some women gain 2 years of life, with median survival improving from 12 months to 36 months, if they remained progression free for more than 6 months after first-line treatment. She attributed the differences in predictive value of progression-free interval in part to underlying differences in response to first-line therapy. Women with ovarian cancer are typically in remission after completing their first chemotherapy, she said. This is not the case in women with endometrial cancer: “Only 15% had a complete clinical response—the majority finished their first chemotherapy with measurable disease.”
Moreover, the second-line treatments that can significantly prolong survival in ovarian cancer are lacking in endometrial cancer, she said, describing continued drug development as key to improving survival. Dr. Moore disclosed no conflicts of interest.
SAN ANTONIO — The length of time between the starts of primary and secondary treatment for advanced or recurrent endometrial cancer is a statistically significant predictor of a woman's risk of death 6 months after resuming treatment, according to a review of phase III trials conducted over the last 20 years.
A progression-free interval lasting more than 6 months reduced the risk of death by 30% in the Gynecologic Oncology Group (GOG) studies. The finding was statistically significant with a P value of .0001, but investigators concluded it had “limited” clinical value. Compared with women whose disease progressed within 6 months or less, patients gained about 3 months of life when they went longer before restarting treatment. Moreover, platinum sensitivity did not make much difference in the impact of second-line treatments on survival.
“Ten months versus 7 months—that's not a very useful prognostic indication,” lead investigator Kathleen M. Moore said in an interview, referring to the median probability of survival after second-line treatment with the longer progression-free interval versus a shorter span. “For endometrial cancer, it really doesn't change what you are going to do for that patient. It doesn't change how you are going to counsel that patient about progression.”
Dr. Moore of the University of Oklahoma, Oklahoma City, presented the results at the annual meeting of the Society of Gynecologic Oncologists.
The ancillary data analysis compared outcomes relative to progression-free intervals among 586 women who participated in GOG protocols 107, 122, 139, 163, and 177, which tested a variety of chemotherapy regimens. The women had a median age of 64 years, and nearly two-thirds had recurrent disease in this first part of the study. Most received platinum-based regimens as first-line therapy; their median progression-free interval was 6.7 months.
Investigators also reviewed treatment-free intervals from completion of the first regimen to progression for 275 women in the GOG protocol 129 series of trials. This group's median age was 66 years, and 89% of the women had been given platinum-based regimens as first-line therapy.
The women in this part of the study had a median treatment-free interval of 2.9 months. A treatment-free interval greater than 3 months was associated with a 25% reduction in risk of death (P = .014), but the investigators again saw little clinical value. Median survival from the start of therapy was 10.22 months with the longer treatment-free interval and 7.39 months for those who stayed off treatment for less than 3 months.
The findings were “very disappointing,” Dr. Moore said. Investigators had hoped to see a difference comparable to ovarian cancer, a disease in which some women gain 2 years of life, with median survival improving from 12 months to 36 months, if they remained progression free for more than 6 months after first-line treatment. She attributed the differences in predictive value of progression-free interval in part to underlying differences in response to first-line therapy. Women with ovarian cancer are typically in remission after completing their first chemotherapy, she said. This is not the case in women with endometrial cancer: “Only 15% had a complete clinical response—the majority finished their first chemotherapy with measurable disease.”
Moreover, the second-line treatments that can significantly prolong survival in ovarian cancer are lacking in endometrial cancer, she said, describing continued drug development as key to improving survival. Dr. Moore disclosed no conflicts of interest.
Rectovaginal Nodularity, Bowel Perforations Tied
SAN ANTONIO — Rectovaginal nodularity turned out to be the only significant risk factor for bowel complications in a retrospective single-institution study of 112 women treated with bevacizumab for recurrent epithelial ovarian cancer.
Ten women (9%) developed bowel perforations in the study, and five died within 30 days—a mortality rate of 50% for this serious complication. Fistulas were diagnosed in two patients (1.8%): one enterocutaneous fistula and one fistula-in-ano.
To the investigators' surprise, a host of potential causes—among them, the number of previous bevacizumab (Avastin) regimens, carcinomatosis, bowel involvement on CT scan, and history of small bowel obstruction—produced no significant associations with bowel complications. Rectovaginal nodularity increased risk more than threefold (odds ratio 3.64, P = .04), however.
After hearing the data presented at the Society of Gynecologic Oncologists' annual meeting on women's cancer, an audience member asked Dr. Debra L. Richardson, the lead author, whether the 50% mortality rate she reported was excessive. Most of the patients were heavily pretreated, she responded, and three patients chose not to pursue any further interventions at a late stage in their disease.
Though potentially deadly, the risk of bevacizumab-related bowel complications should not preclude use of the agent in advanced ovarian cancer, Dr. Richardson added in an interview. If other treatment options are available, she might hold off introducing bevacizumab. If not, she would discuss the risk with the patient.
“If bevacizumab is the only treatment option, I think it still may be worthwhile as long as the patient is well counseled about this risk,” she said.
Dr. Richardson and her coauthors at the Ohio State University in Columbus undertook the chart review because high rates of bowel complications have been seen when bevacizumab is used in patients with recurrent epithelial ovarian cancer. Bowel perforation and fistula have been reported in 0%–11% of patients given monotherapy, and 0%–9% of patients when bevacizumab is used in combination with other cytotoxic agents. Of particular concern, these rates are higher than with bevacizumab use in other cancers, including colorectal cancers.
Despite this toxicity, she noted, bevacizumab continues to be used because it has produced response rates of 10%–21% as monotherapy and 24%–78% when used in combination with other drugs for recurrent ovarian cancer.
The chart review looked at all patients treated with at least one dose of bevacizumab. Dr. Richardson reported that 112 patients (median age 60 years) who met study requirements received 160 different bevacizumab regimens. Nearly a third, 31%, had received more than one bevacizumab regimen. The most common cytotoxic combination was with weekly paclitaxel (34%) followed by combinations of bevacizumab with gemcitabine and carboplatin or cisplatin.
Patients had a median of four prior chemotherapy regimens, and they received a median of six cycles of bevacizumab with a median total dose of 8,313 mg. The population included 18 patients with a history of small bowel obstruction, 31 with rectovaginal nodularity, 78 with a CT scan prior to starting bevacizumab, 10 with a CT scan showing bowel involvement, and 21 with carcinomatosis.
The bowel perforations occurred 2–25 days (0.5–5 cycles) after starting bevacizumab, Dr. Richardson reported. Three of the patients who developed perforations had previously been treated with bevacizumab, and 30% of perforated patients died within 7 days. After the perforations were diagnosed, she continued, four patients opted for surgery and three of them survived 30 days as did two patients treated with intravenous antibiotics.
As for why rectovaginal nodularity turned out to be the only significant risk factor, Dr. Richardson cited the small size of the study as one possibility. Another is that only large-volume disease is associated with bevacizumab-related bowel perforation, she said, and yet another that current imaging is not large enough to detect bowel involvement.
Dr. Richardson disclosed no conflicts of interest.
Bevacizumab continues to be used because it has produced response rates of 10%–21% as monotherapy. DR. RICHARDSON
SAN ANTONIO — Rectovaginal nodularity turned out to be the only significant risk factor for bowel complications in a retrospective single-institution study of 112 women treated with bevacizumab for recurrent epithelial ovarian cancer.
Ten women (9%) developed bowel perforations in the study, and five died within 30 days—a mortality rate of 50% for this serious complication. Fistulas were diagnosed in two patients (1.8%): one enterocutaneous fistula and one fistula-in-ano.
To the investigators' surprise, a host of potential causes—among them, the number of previous bevacizumab (Avastin) regimens, carcinomatosis, bowel involvement on CT scan, and history of small bowel obstruction—produced no significant associations with bowel complications. Rectovaginal nodularity increased risk more than threefold (odds ratio 3.64, P = .04), however.
After hearing the data presented at the Society of Gynecologic Oncologists' annual meeting on women's cancer, an audience member asked Dr. Debra L. Richardson, the lead author, whether the 50% mortality rate she reported was excessive. Most of the patients were heavily pretreated, she responded, and three patients chose not to pursue any further interventions at a late stage in their disease.
Though potentially deadly, the risk of bevacizumab-related bowel complications should not preclude use of the agent in advanced ovarian cancer, Dr. Richardson added in an interview. If other treatment options are available, she might hold off introducing bevacizumab. If not, she would discuss the risk with the patient.
“If bevacizumab is the only treatment option, I think it still may be worthwhile as long as the patient is well counseled about this risk,” she said.
Dr. Richardson and her coauthors at the Ohio State University in Columbus undertook the chart review because high rates of bowel complications have been seen when bevacizumab is used in patients with recurrent epithelial ovarian cancer. Bowel perforation and fistula have been reported in 0%–11% of patients given monotherapy, and 0%–9% of patients when bevacizumab is used in combination with other cytotoxic agents. Of particular concern, these rates are higher than with bevacizumab use in other cancers, including colorectal cancers.
Despite this toxicity, she noted, bevacizumab continues to be used because it has produced response rates of 10%–21% as monotherapy and 24%–78% when used in combination with other drugs for recurrent ovarian cancer.
The chart review looked at all patients treated with at least one dose of bevacizumab. Dr. Richardson reported that 112 patients (median age 60 years) who met study requirements received 160 different bevacizumab regimens. Nearly a third, 31%, had received more than one bevacizumab regimen. The most common cytotoxic combination was with weekly paclitaxel (34%) followed by combinations of bevacizumab with gemcitabine and carboplatin or cisplatin.
Patients had a median of four prior chemotherapy regimens, and they received a median of six cycles of bevacizumab with a median total dose of 8,313 mg. The population included 18 patients with a history of small bowel obstruction, 31 with rectovaginal nodularity, 78 with a CT scan prior to starting bevacizumab, 10 with a CT scan showing bowel involvement, and 21 with carcinomatosis.
The bowel perforations occurred 2–25 days (0.5–5 cycles) after starting bevacizumab, Dr. Richardson reported. Three of the patients who developed perforations had previously been treated with bevacizumab, and 30% of perforated patients died within 7 days. After the perforations were diagnosed, she continued, four patients opted for surgery and three of them survived 30 days as did two patients treated with intravenous antibiotics.
As for why rectovaginal nodularity turned out to be the only significant risk factor, Dr. Richardson cited the small size of the study as one possibility. Another is that only large-volume disease is associated with bevacizumab-related bowel perforation, she said, and yet another that current imaging is not large enough to detect bowel involvement.
Dr. Richardson disclosed no conflicts of interest.
Bevacizumab continues to be used because it has produced response rates of 10%–21% as monotherapy. DR. RICHARDSON
SAN ANTONIO — Rectovaginal nodularity turned out to be the only significant risk factor for bowel complications in a retrospective single-institution study of 112 women treated with bevacizumab for recurrent epithelial ovarian cancer.
Ten women (9%) developed bowel perforations in the study, and five died within 30 days—a mortality rate of 50% for this serious complication. Fistulas were diagnosed in two patients (1.8%): one enterocutaneous fistula and one fistula-in-ano.
To the investigators' surprise, a host of potential causes—among them, the number of previous bevacizumab (Avastin) regimens, carcinomatosis, bowel involvement on CT scan, and history of small bowel obstruction—produced no significant associations with bowel complications. Rectovaginal nodularity increased risk more than threefold (odds ratio 3.64, P = .04), however.
After hearing the data presented at the Society of Gynecologic Oncologists' annual meeting on women's cancer, an audience member asked Dr. Debra L. Richardson, the lead author, whether the 50% mortality rate she reported was excessive. Most of the patients were heavily pretreated, she responded, and three patients chose not to pursue any further interventions at a late stage in their disease.
Though potentially deadly, the risk of bevacizumab-related bowel complications should not preclude use of the agent in advanced ovarian cancer, Dr. Richardson added in an interview. If other treatment options are available, she might hold off introducing bevacizumab. If not, she would discuss the risk with the patient.
“If bevacizumab is the only treatment option, I think it still may be worthwhile as long as the patient is well counseled about this risk,” she said.
Dr. Richardson and her coauthors at the Ohio State University in Columbus undertook the chart review because high rates of bowel complications have been seen when bevacizumab is used in patients with recurrent epithelial ovarian cancer. Bowel perforation and fistula have been reported in 0%–11% of patients given monotherapy, and 0%–9% of patients when bevacizumab is used in combination with other cytotoxic agents. Of particular concern, these rates are higher than with bevacizumab use in other cancers, including colorectal cancers.
Despite this toxicity, she noted, bevacizumab continues to be used because it has produced response rates of 10%–21% as monotherapy and 24%–78% when used in combination with other drugs for recurrent ovarian cancer.
The chart review looked at all patients treated with at least one dose of bevacizumab. Dr. Richardson reported that 112 patients (median age 60 years) who met study requirements received 160 different bevacizumab regimens. Nearly a third, 31%, had received more than one bevacizumab regimen. The most common cytotoxic combination was with weekly paclitaxel (34%) followed by combinations of bevacizumab with gemcitabine and carboplatin or cisplatin.
Patients had a median of four prior chemotherapy regimens, and they received a median of six cycles of bevacizumab with a median total dose of 8,313 mg. The population included 18 patients with a history of small bowel obstruction, 31 with rectovaginal nodularity, 78 with a CT scan prior to starting bevacizumab, 10 with a CT scan showing bowel involvement, and 21 with carcinomatosis.
The bowel perforations occurred 2–25 days (0.5–5 cycles) after starting bevacizumab, Dr. Richardson reported. Three of the patients who developed perforations had previously been treated with bevacizumab, and 30% of perforated patients died within 7 days. After the perforations were diagnosed, she continued, four patients opted for surgery and three of them survived 30 days as did two patients treated with intravenous antibiotics.
As for why rectovaginal nodularity turned out to be the only significant risk factor, Dr. Richardson cited the small size of the study as one possibility. Another is that only large-volume disease is associated with bevacizumab-related bowel perforation, she said, and yet another that current imaging is not large enough to detect bowel involvement.
Dr. Richardson disclosed no conflicts of interest.
Bevacizumab continues to be used because it has produced response rates of 10%–21% as monotherapy. DR. RICHARDSON
CA 125 Level Predicts Survival in Ovarian Cancer Patients
SAN ANTONIO — Elevated cancer antigen 125 levels measured after surgery but before chemotherapy are an independent prognostic indicator of recurrence and worse survival in women with high-risk, early-stage epithelial ovarian cancer, according to results of a Gynecologic Oncology Group study.
Moreover, the highest recurrence and worst 5-year survival rates were seen in a subgroup of women whose high postsurgery CA 125 levels persisted after they started treatment, perhaps suggesting a poor response to chemotherapy, Dr. Joshua P. Kesterson reported at the annual meeting of the Society of Gynecologic Oncologists.
Serum CA 125 levels are used to assess response to therapy and to detect recurrences, mainly in advanced epithelial ovarian cancer. Some studies have looked at CA 125 levels before chemotherapy in stage I disease. The current study, in 350 women, is the first to look at CA 125 levels after surgery but before chemotherapy, said Dr. Kesterson of a cancer research and treatment center in Buffalo, N.Y.
Looking at the primary end points, Dr. Kesterson reported 5-year recurrence-free survival rates of 86% in women who had normal CA 125 levels after surgery, and 75% in those with high levels at that point. The 5-year overall survival rate was likewise higher when women had normal CA 125 levels before chemotherapy, compared with those who had high levels (88% vs. 82%).
Information for the current analysis came from a phase III clinical trial (GOG-157) that compared three vs. six cycles of adjuvant chemotherapy with paclitaxel and carboplatin in surgically staged women with stage IA/B grade 3 or stage IC or stage II epithelial ovarian cancer. Investigators deemed CA 125 levels that were 35 U/mL or lower to be normal.
Preclinical data were available on 350 of 427 eligible patients: 110 women (31%) who had a normal CA 125 level before chemotherapy, and 240 (69%) with elevated CA 125 at that point. The median level was 65 U/mL after primary surgery.
White women were more likely to have elevated CA 125 than were nonwhites, but this difference was not statistically significant. Nor were any significant differences observed in comparisons by performance status grade (0 vs. 1 or 2), tumor stage (I vs. II), cell type, cytology, rupture, or patient age.
Ascites was associated with a trend toward elevated CA 125 after surgery; it was present in 76% of women with elevated levels vs. 24% with normal levels.
The investigators observed that about three-fourths of patients had normal CA 125 levels after the first cycle of chemotherapy. This led to a stratification of the population into the following three groups based on CA 125 levels:
▸ Normal before and after chemotherapy. The best outcomes were seen in women who had normal levels before and after one cycle of chemotherapy; in all, 87% were recurrence free, and 92% were alive 5 years later.
▸ Elevated before and normal after chemotherapy. In comparison, the women who had elevated levels and fell into the normal range after one cycle fared not quite as well, with 5-year recurrence and overall survival rates of 80% and 88%, respectively.
▸ Elevated before and after chemotherapy. When high CA 125 levels remained elevated after the start of chemotherapy, only 68% of women stayed recurrence free, and just 77% were alive 5 years later. These differences were statistically significant.
Dr. Kesterson said the study's limitations included a lack of information on how recurrences were treated and possible selection bias in that all cases were high risk. Among its strengths was that all patients were treated by gynecologic oncologists with comprehensive staging, central pathology review, standardized adjuvant treatment, and extended follow-up of a large number of patients.
In response to questions, he said the researchers found that whether patients received three or six cycles of chemotherapy did not affect the conclusion that an elevated CA 125 level after surgery is a significant prognostic factor for recurrence and for survival. Still to be examined, he said, is whether the interval between surgery and the start of chemotherapy could have influenced the findings.
The study was funded by the Society of Gynecologic Oncologists and the Ovarian Cancer Research Foundation.
ELSEVIER GLOBAL MEDICAL NEWS
SAN ANTONIO — Elevated cancer antigen 125 levels measured after surgery but before chemotherapy are an independent prognostic indicator of recurrence and worse survival in women with high-risk, early-stage epithelial ovarian cancer, according to results of a Gynecologic Oncology Group study.
Moreover, the highest recurrence and worst 5-year survival rates were seen in a subgroup of women whose high postsurgery CA 125 levels persisted after they started treatment, perhaps suggesting a poor response to chemotherapy, Dr. Joshua P. Kesterson reported at the annual meeting of the Society of Gynecologic Oncologists.
Serum CA 125 levels are used to assess response to therapy and to detect recurrences, mainly in advanced epithelial ovarian cancer. Some studies have looked at CA 125 levels before chemotherapy in stage I disease. The current study, in 350 women, is the first to look at CA 125 levels after surgery but before chemotherapy, said Dr. Kesterson of a cancer research and treatment center in Buffalo, N.Y.
Looking at the primary end points, Dr. Kesterson reported 5-year recurrence-free survival rates of 86% in women who had normal CA 125 levels after surgery, and 75% in those with high levels at that point. The 5-year overall survival rate was likewise higher when women had normal CA 125 levels before chemotherapy, compared with those who had high levels (88% vs. 82%).
Information for the current analysis came from a phase III clinical trial (GOG-157) that compared three vs. six cycles of adjuvant chemotherapy with paclitaxel and carboplatin in surgically staged women with stage IA/B grade 3 or stage IC or stage II epithelial ovarian cancer. Investigators deemed CA 125 levels that were 35 U/mL or lower to be normal.
Preclinical data were available on 350 of 427 eligible patients: 110 women (31%) who had a normal CA 125 level before chemotherapy, and 240 (69%) with elevated CA 125 at that point. The median level was 65 U/mL after primary surgery.
White women were more likely to have elevated CA 125 than were nonwhites, but this difference was not statistically significant. Nor were any significant differences observed in comparisons by performance status grade (0 vs. 1 or 2), tumor stage (I vs. II), cell type, cytology, rupture, or patient age.
Ascites was associated with a trend toward elevated CA 125 after surgery; it was present in 76% of women with elevated levels vs. 24% with normal levels.
The investigators observed that about three-fourths of patients had normal CA 125 levels after the first cycle of chemotherapy. This led to a stratification of the population into the following three groups based on CA 125 levels:
▸ Normal before and after chemotherapy. The best outcomes were seen in women who had normal levels before and after one cycle of chemotherapy; in all, 87% were recurrence free, and 92% were alive 5 years later.
▸ Elevated before and normal after chemotherapy. In comparison, the women who had elevated levels and fell into the normal range after one cycle fared not quite as well, with 5-year recurrence and overall survival rates of 80% and 88%, respectively.
▸ Elevated before and after chemotherapy. When high CA 125 levels remained elevated after the start of chemotherapy, only 68% of women stayed recurrence free, and just 77% were alive 5 years later. These differences were statistically significant.
Dr. Kesterson said the study's limitations included a lack of information on how recurrences were treated and possible selection bias in that all cases were high risk. Among its strengths was that all patients were treated by gynecologic oncologists with comprehensive staging, central pathology review, standardized adjuvant treatment, and extended follow-up of a large number of patients.
In response to questions, he said the researchers found that whether patients received three or six cycles of chemotherapy did not affect the conclusion that an elevated CA 125 level after surgery is a significant prognostic factor for recurrence and for survival. Still to be examined, he said, is whether the interval between surgery and the start of chemotherapy could have influenced the findings.
The study was funded by the Society of Gynecologic Oncologists and the Ovarian Cancer Research Foundation.
ELSEVIER GLOBAL MEDICAL NEWS
SAN ANTONIO — Elevated cancer antigen 125 levels measured after surgery but before chemotherapy are an independent prognostic indicator of recurrence and worse survival in women with high-risk, early-stage epithelial ovarian cancer, according to results of a Gynecologic Oncology Group study.
Moreover, the highest recurrence and worst 5-year survival rates were seen in a subgroup of women whose high postsurgery CA 125 levels persisted after they started treatment, perhaps suggesting a poor response to chemotherapy, Dr. Joshua P. Kesterson reported at the annual meeting of the Society of Gynecologic Oncologists.
Serum CA 125 levels are used to assess response to therapy and to detect recurrences, mainly in advanced epithelial ovarian cancer. Some studies have looked at CA 125 levels before chemotherapy in stage I disease. The current study, in 350 women, is the first to look at CA 125 levels after surgery but before chemotherapy, said Dr. Kesterson of a cancer research and treatment center in Buffalo, N.Y.
Looking at the primary end points, Dr. Kesterson reported 5-year recurrence-free survival rates of 86% in women who had normal CA 125 levels after surgery, and 75% in those with high levels at that point. The 5-year overall survival rate was likewise higher when women had normal CA 125 levels before chemotherapy, compared with those who had high levels (88% vs. 82%).
Information for the current analysis came from a phase III clinical trial (GOG-157) that compared three vs. six cycles of adjuvant chemotherapy with paclitaxel and carboplatin in surgically staged women with stage IA/B grade 3 or stage IC or stage II epithelial ovarian cancer. Investigators deemed CA 125 levels that were 35 U/mL or lower to be normal.
Preclinical data were available on 350 of 427 eligible patients: 110 women (31%) who had a normal CA 125 level before chemotherapy, and 240 (69%) with elevated CA 125 at that point. The median level was 65 U/mL after primary surgery.
White women were more likely to have elevated CA 125 than were nonwhites, but this difference was not statistically significant. Nor were any significant differences observed in comparisons by performance status grade (0 vs. 1 or 2), tumor stage (I vs. II), cell type, cytology, rupture, or patient age.
Ascites was associated with a trend toward elevated CA 125 after surgery; it was present in 76% of women with elevated levels vs. 24% with normal levels.
The investigators observed that about three-fourths of patients had normal CA 125 levels after the first cycle of chemotherapy. This led to a stratification of the population into the following three groups based on CA 125 levels:
▸ Normal before and after chemotherapy. The best outcomes were seen in women who had normal levels before and after one cycle of chemotherapy; in all, 87% were recurrence free, and 92% were alive 5 years later.
▸ Elevated before and normal after chemotherapy. In comparison, the women who had elevated levels and fell into the normal range after one cycle fared not quite as well, with 5-year recurrence and overall survival rates of 80% and 88%, respectively.
▸ Elevated before and after chemotherapy. When high CA 125 levels remained elevated after the start of chemotherapy, only 68% of women stayed recurrence free, and just 77% were alive 5 years later. These differences were statistically significant.
Dr. Kesterson said the study's limitations included a lack of information on how recurrences were treated and possible selection bias in that all cases were high risk. Among its strengths was that all patients were treated by gynecologic oncologists with comprehensive staging, central pathology review, standardized adjuvant treatment, and extended follow-up of a large number of patients.
In response to questions, he said the researchers found that whether patients received three or six cycles of chemotherapy did not affect the conclusion that an elevated CA 125 level after surgery is a significant prognostic factor for recurrence and for survival. Still to be examined, he said, is whether the interval between surgery and the start of chemotherapy could have influenced the findings.
The study was funded by the Society of Gynecologic Oncologists and the Ovarian Cancer Research Foundation.
ELSEVIER GLOBAL MEDICAL NEWS
ROMA Tool More Sensitive Than RMI to Predict Ovarian Ca
SAN ANTONIO — A novel algorithm has been shown to be more sensitive than a widely used risk of malignancy index for predicting epithelial ovarian cancers in women who present with a pelvic mass or ovarian cyst.
The Risk of Ovarian Malignancy Algorithm (ROMA) stratifies women at high or low risk for epithelial ovarian cancer based on menopausal status and preoperative serum levels of human epididymis protein 4 (HE4) and cancer antigen 125 (CA 125). The algorithm correctly classified 94% of women with epithelial ovarian cancer in a prospective, double-blind, multicenter trial with 457 evaluable patients, researchers said (Gynecol. Oncol. 2009;112:40–6).
A new secondary analysis of trial data comparing patients with benign disease and all stages of epithelial ovarian cancer determined ROMA's sensitivity to be 94.3%, vs. 83.7% for the risk of malignancy index (RMI), when specificity for both was set at 75%. ROMA also was more sensitive than RMI in a comparison of patients with benign disease, tumors with a low potential for malignancy, and epithelial ovarian cancer (89% vs. 80.7%).
“This tool can be used to triage patients to physicians and centers that are experienced in the care and management of patients with ovarian cancer,” Dr. Richard G. Moore said at the annual meeting of the Society of Gynecologic Oncologists. High-risk women should be referred to gynecologic oncologists and centers that have been shown to treat ovarian cancer with better survival outcomes and less morbidity, Dr. Moore said.
The investigators do not see ROMA as replacing the Society of Gynecologic Oncologists/American College of Obstetricians and Gynecologists referral guidelines for pelvic masses, he said, adding that they would like to see ROMA incorporated into the guidelines.
“Clinical findings and impressions are very important, but I think these markers can really help us to triage these patients,” said Dr. Moore of Women and Infants Hospital and Brown University, Providence, R.I. Gynecologists now operate on fewer than half of women with ovarian cancers, he said.
The investigators compared ROMA to RMI because the latter is a validated, well-accepted tool currently in use, he said in an interview. The RMI is based on menopausal status, CA 125 levels, and ultrasound scores of 0–5.
ROMA has one formula for premenopausal and another for postmenopausal women. Both include HE4 and CA 125 levels, but the premenopausal formula weighs HE4 more heavily. “In premenopausal patients, there are many benign diseases that cause elevated CA 125, and there is no cancer,” Dr. Moore said.
The algorithm was based on pooled data from a pilot study at Women and Infants Hospital and a retrospective case-control study at Massachusetts General Hospital, Boston. The prospective trial enrolled 566 women who presented at 12 centers with pelvic masses that were documented on imaging and for which surgery was planned.
Three independent reviewers assigned an RMI score for each evaluable patient based on a preoperative ultrasound, CT, or MRI scan. Patients were included if at least two reviewers agreed on the imaging score; correlation between reviewers was 78.4%. They were blinded to tumor marker values and pathology.
The final population included 212 premenopausal and 245 postmenopausal women. All told, 123 women had epithelial ovarian cancers (80 of which were stage III), 22 had tumors with a low potential for malignancy, and 312 had benign disease.
The investigators did not report sensitivity by histology, but Dr. Moore said it was close to or at 100% in all but mucinous tumors. ROMA was much less sensitive in mucinous tumors, identifying only about half of them, he said.
Although ROMA was significantly more sensitive in other comparisons based on tumor stage, Dr. Moore did not report benign vs. stage I results because only 17 patients were stage I. Even with such small numbers, the comparison trended in favor of ROMA, he said.
The prospective trial was supported by Fujirebio Diagnostics Inc. and grants from the National Cancer Institute. Seven authors, including Dr. Moore, served as consultants to and were on the scientific advisory board for Fujirebio.
The ROMA tool correctly classified 94% of women with epithelial ovarian cancer, said Dr. Richard G. Moore, here with Dr. Geralyn Messerlian. ©David Witbeck
SAN ANTONIO — A novel algorithm has been shown to be more sensitive than a widely used risk of malignancy index for predicting epithelial ovarian cancers in women who present with a pelvic mass or ovarian cyst.
The Risk of Ovarian Malignancy Algorithm (ROMA) stratifies women at high or low risk for epithelial ovarian cancer based on menopausal status and preoperative serum levels of human epididymis protein 4 (HE4) and cancer antigen 125 (CA 125). The algorithm correctly classified 94% of women with epithelial ovarian cancer in a prospective, double-blind, multicenter trial with 457 evaluable patients, researchers said (Gynecol. Oncol. 2009;112:40–6).
A new secondary analysis of trial data comparing patients with benign disease and all stages of epithelial ovarian cancer determined ROMA's sensitivity to be 94.3%, vs. 83.7% for the risk of malignancy index (RMI), when specificity for both was set at 75%. ROMA also was more sensitive than RMI in a comparison of patients with benign disease, tumors with a low potential for malignancy, and epithelial ovarian cancer (89% vs. 80.7%).
“This tool can be used to triage patients to physicians and centers that are experienced in the care and management of patients with ovarian cancer,” Dr. Richard G. Moore said at the annual meeting of the Society of Gynecologic Oncologists. High-risk women should be referred to gynecologic oncologists and centers that have been shown to treat ovarian cancer with better survival outcomes and less morbidity, Dr. Moore said.
The investigators do not see ROMA as replacing the Society of Gynecologic Oncologists/American College of Obstetricians and Gynecologists referral guidelines for pelvic masses, he said, adding that they would like to see ROMA incorporated into the guidelines.
“Clinical findings and impressions are very important, but I think these markers can really help us to triage these patients,” said Dr. Moore of Women and Infants Hospital and Brown University, Providence, R.I. Gynecologists now operate on fewer than half of women with ovarian cancers, he said.
The investigators compared ROMA to RMI because the latter is a validated, well-accepted tool currently in use, he said in an interview. The RMI is based on menopausal status, CA 125 levels, and ultrasound scores of 0–5.
ROMA has one formula for premenopausal and another for postmenopausal women. Both include HE4 and CA 125 levels, but the premenopausal formula weighs HE4 more heavily. “In premenopausal patients, there are many benign diseases that cause elevated CA 125, and there is no cancer,” Dr. Moore said.
The algorithm was based on pooled data from a pilot study at Women and Infants Hospital and a retrospective case-control study at Massachusetts General Hospital, Boston. The prospective trial enrolled 566 women who presented at 12 centers with pelvic masses that were documented on imaging and for which surgery was planned.
Three independent reviewers assigned an RMI score for each evaluable patient based on a preoperative ultrasound, CT, or MRI scan. Patients were included if at least two reviewers agreed on the imaging score; correlation between reviewers was 78.4%. They were blinded to tumor marker values and pathology.
The final population included 212 premenopausal and 245 postmenopausal women. All told, 123 women had epithelial ovarian cancers (80 of which were stage III), 22 had tumors with a low potential for malignancy, and 312 had benign disease.
The investigators did not report sensitivity by histology, but Dr. Moore said it was close to or at 100% in all but mucinous tumors. ROMA was much less sensitive in mucinous tumors, identifying only about half of them, he said.
Although ROMA was significantly more sensitive in other comparisons based on tumor stage, Dr. Moore did not report benign vs. stage I results because only 17 patients were stage I. Even with such small numbers, the comparison trended in favor of ROMA, he said.
The prospective trial was supported by Fujirebio Diagnostics Inc. and grants from the National Cancer Institute. Seven authors, including Dr. Moore, served as consultants to and were on the scientific advisory board for Fujirebio.
The ROMA tool correctly classified 94% of women with epithelial ovarian cancer, said Dr. Richard G. Moore, here with Dr. Geralyn Messerlian. ©David Witbeck
SAN ANTONIO — A novel algorithm has been shown to be more sensitive than a widely used risk of malignancy index for predicting epithelial ovarian cancers in women who present with a pelvic mass or ovarian cyst.
The Risk of Ovarian Malignancy Algorithm (ROMA) stratifies women at high or low risk for epithelial ovarian cancer based on menopausal status and preoperative serum levels of human epididymis protein 4 (HE4) and cancer antigen 125 (CA 125). The algorithm correctly classified 94% of women with epithelial ovarian cancer in a prospective, double-blind, multicenter trial with 457 evaluable patients, researchers said (Gynecol. Oncol. 2009;112:40–6).
A new secondary analysis of trial data comparing patients with benign disease and all stages of epithelial ovarian cancer determined ROMA's sensitivity to be 94.3%, vs. 83.7% for the risk of malignancy index (RMI), when specificity for both was set at 75%. ROMA also was more sensitive than RMI in a comparison of patients with benign disease, tumors with a low potential for malignancy, and epithelial ovarian cancer (89% vs. 80.7%).
“This tool can be used to triage patients to physicians and centers that are experienced in the care and management of patients with ovarian cancer,” Dr. Richard G. Moore said at the annual meeting of the Society of Gynecologic Oncologists. High-risk women should be referred to gynecologic oncologists and centers that have been shown to treat ovarian cancer with better survival outcomes and less morbidity, Dr. Moore said.
The investigators do not see ROMA as replacing the Society of Gynecologic Oncologists/American College of Obstetricians and Gynecologists referral guidelines for pelvic masses, he said, adding that they would like to see ROMA incorporated into the guidelines.
“Clinical findings and impressions are very important, but I think these markers can really help us to triage these patients,” said Dr. Moore of Women and Infants Hospital and Brown University, Providence, R.I. Gynecologists now operate on fewer than half of women with ovarian cancers, he said.
The investigators compared ROMA to RMI because the latter is a validated, well-accepted tool currently in use, he said in an interview. The RMI is based on menopausal status, CA 125 levels, and ultrasound scores of 0–5.
ROMA has one formula for premenopausal and another for postmenopausal women. Both include HE4 and CA 125 levels, but the premenopausal formula weighs HE4 more heavily. “In premenopausal patients, there are many benign diseases that cause elevated CA 125, and there is no cancer,” Dr. Moore said.
The algorithm was based on pooled data from a pilot study at Women and Infants Hospital and a retrospective case-control study at Massachusetts General Hospital, Boston. The prospective trial enrolled 566 women who presented at 12 centers with pelvic masses that were documented on imaging and for which surgery was planned.
Three independent reviewers assigned an RMI score for each evaluable patient based on a preoperative ultrasound, CT, or MRI scan. Patients were included if at least two reviewers agreed on the imaging score; correlation between reviewers was 78.4%. They were blinded to tumor marker values and pathology.
The final population included 212 premenopausal and 245 postmenopausal women. All told, 123 women had epithelial ovarian cancers (80 of which were stage III), 22 had tumors with a low potential for malignancy, and 312 had benign disease.
The investigators did not report sensitivity by histology, but Dr. Moore said it was close to or at 100% in all but mucinous tumors. ROMA was much less sensitive in mucinous tumors, identifying only about half of them, he said.
Although ROMA was significantly more sensitive in other comparisons based on tumor stage, Dr. Moore did not report benign vs. stage I results because only 17 patients were stage I. Even with such small numbers, the comparison trended in favor of ROMA, he said.
The prospective trial was supported by Fujirebio Diagnostics Inc. and grants from the National Cancer Institute. Seven authors, including Dr. Moore, served as consultants to and were on the scientific advisory board for Fujirebio.
The ROMA tool correctly classified 94% of women with epithelial ovarian cancer, said Dr. Richard G. Moore, here with Dr. Geralyn Messerlian. ©David Witbeck
Algorithm Predicts Epithelial Ovarian Cancer Risk
SAN ANTONIO — A novel algorithm has been shown to be more sensitive than a widely used risk of malignancy index for predicting epithelial ovarian cancers in women who present with a pelvic mass or ovarian cyst.
The Risk of Ovarian Malignancy Algorithm (ROMA) stratifies women as being at high or low risk for epithelial ovarian cancer based on menopausal status and preoperative serum levels of two biomarkers: human epididymis protein 4 (HE4) and cancer antigen 125 (CA 125). Investigators found that the algorithm correctly classified 94% of women with epithelial ovarian cancer in a prospective, double-blind, multicenter trial with 457 evaluable patients (Gynecol. Oncol. 2009;112:40–6).
A new secondary analysis of trial data comparing patients with benign disease and all stages of epithelial ovarian cancer determined ROMA's sensitivity to be 94.3%, vs. 83.7% for the risk of malignancy index (RMI), when specificity for both was set at 75%. ROMA also was more sensitive than RMI in a comparison of patients with benign disease, tumors with a low potential for malignancy, and epithelial ovarian cancer (89% vs. 80.7%).
“This tool can be used to triage patients to physicians and centers that are experienced in the care and management of patients with ovarian cancer,” Dr. Richard G. Moore said at the annual meeting of the Society of Gynecologic Oncologists.
High-risk women should be referred to gynecologic oncologists and centers that have been shown to treat ovarian cancer with better survival outcomes and less morbidity, according to Dr. Moore. Low-risk women do not need that level of care and may be treated in their communities.
The investigators do not see ROMA as replacing the Society of Gynecologic Oncologists'/American College of Obstetricians and Gynecologists' referral guidelines for pelvic masses, he said in response to a question during a discussion of the study. Rather, Dr. Moore and his associates would like to see ROMA incorporated into the guidelines.
“Clinical findings and impressions are very important, but I think these markers can really help us to triage these patients,” said Dr. Moore of Women and Infants Hospital and Brown University, both in Providence, R.I.
The investigators compared ROMA vs. RMI because the latter is a validated, well-accepted tool that is currently in use, he added in an interview. The RMI is based on menopausal status, CA 125 levels, and ultrasound scores of 0–5.
ROMA has two formulas, one for premenopausal and another for postmenopausal women. Both include HE4 and CA 125 levels, but the premenopausal formula weighs HE4 more heavily. “In premenopausal patients, there are many benign diseases that cause elevated CA 125, and there is no cancer,” Dr. Moore explained, describing the two markers as complementary.
The algorithm was developed based on pooled data from a pilot study at Women and Infants Hospital and a retrospective case-control study at Massachusetts General Hospital in Boston. The prospective trial enrolled 566 women, who presented at 12 centers with pelvic masses that were documented on imaging and for which surgery was planned.
The investigators did not report sensitivity by histology, but Dr. Moore said it was close to or at 100% in all but mucinous tumors. ROMA was much less sensitive in mucinous tumors, identifying only about half of them, he said.
The prospective trial was supported by Fujirebio Diagnostics Inc. and grants from the National Cancer Institute. Seven authors, including Dr. Moore, served as consultants to and were on the scientific advisory board for Fujirebio.
This tool can help triage patients to centers that are experienced in the management of patients with ovarian cancer. DR. MOORE
SAN ANTONIO — A novel algorithm has been shown to be more sensitive than a widely used risk of malignancy index for predicting epithelial ovarian cancers in women who present with a pelvic mass or ovarian cyst.
The Risk of Ovarian Malignancy Algorithm (ROMA) stratifies women as being at high or low risk for epithelial ovarian cancer based on menopausal status and preoperative serum levels of two biomarkers: human epididymis protein 4 (HE4) and cancer antigen 125 (CA 125). Investigators found that the algorithm correctly classified 94% of women with epithelial ovarian cancer in a prospective, double-blind, multicenter trial with 457 evaluable patients (Gynecol. Oncol. 2009;112:40–6).
A new secondary analysis of trial data comparing patients with benign disease and all stages of epithelial ovarian cancer determined ROMA's sensitivity to be 94.3%, vs. 83.7% for the risk of malignancy index (RMI), when specificity for both was set at 75%. ROMA also was more sensitive than RMI in a comparison of patients with benign disease, tumors with a low potential for malignancy, and epithelial ovarian cancer (89% vs. 80.7%).
“This tool can be used to triage patients to physicians and centers that are experienced in the care and management of patients with ovarian cancer,” Dr. Richard G. Moore said at the annual meeting of the Society of Gynecologic Oncologists.
High-risk women should be referred to gynecologic oncologists and centers that have been shown to treat ovarian cancer with better survival outcomes and less morbidity, according to Dr. Moore. Low-risk women do not need that level of care and may be treated in their communities.
The investigators do not see ROMA as replacing the Society of Gynecologic Oncologists'/American College of Obstetricians and Gynecologists' referral guidelines for pelvic masses, he said in response to a question during a discussion of the study. Rather, Dr. Moore and his associates would like to see ROMA incorporated into the guidelines.
“Clinical findings and impressions are very important, but I think these markers can really help us to triage these patients,” said Dr. Moore of Women and Infants Hospital and Brown University, both in Providence, R.I.
The investigators compared ROMA vs. RMI because the latter is a validated, well-accepted tool that is currently in use, he added in an interview. The RMI is based on menopausal status, CA 125 levels, and ultrasound scores of 0–5.
ROMA has two formulas, one for premenopausal and another for postmenopausal women. Both include HE4 and CA 125 levels, but the premenopausal formula weighs HE4 more heavily. “In premenopausal patients, there are many benign diseases that cause elevated CA 125, and there is no cancer,” Dr. Moore explained, describing the two markers as complementary.
The algorithm was developed based on pooled data from a pilot study at Women and Infants Hospital and a retrospective case-control study at Massachusetts General Hospital in Boston. The prospective trial enrolled 566 women, who presented at 12 centers with pelvic masses that were documented on imaging and for which surgery was planned.
The investigators did not report sensitivity by histology, but Dr. Moore said it was close to or at 100% in all but mucinous tumors. ROMA was much less sensitive in mucinous tumors, identifying only about half of them, he said.
The prospective trial was supported by Fujirebio Diagnostics Inc. and grants from the National Cancer Institute. Seven authors, including Dr. Moore, served as consultants to and were on the scientific advisory board for Fujirebio.
This tool can help triage patients to centers that are experienced in the management of patients with ovarian cancer. DR. MOORE
SAN ANTONIO — A novel algorithm has been shown to be more sensitive than a widely used risk of malignancy index for predicting epithelial ovarian cancers in women who present with a pelvic mass or ovarian cyst.
The Risk of Ovarian Malignancy Algorithm (ROMA) stratifies women as being at high or low risk for epithelial ovarian cancer based on menopausal status and preoperative serum levels of two biomarkers: human epididymis protein 4 (HE4) and cancer antigen 125 (CA 125). Investigators found that the algorithm correctly classified 94% of women with epithelial ovarian cancer in a prospective, double-blind, multicenter trial with 457 evaluable patients (Gynecol. Oncol. 2009;112:40–6).
A new secondary analysis of trial data comparing patients with benign disease and all stages of epithelial ovarian cancer determined ROMA's sensitivity to be 94.3%, vs. 83.7% for the risk of malignancy index (RMI), when specificity for both was set at 75%. ROMA also was more sensitive than RMI in a comparison of patients with benign disease, tumors with a low potential for malignancy, and epithelial ovarian cancer (89% vs. 80.7%).
“This tool can be used to triage patients to physicians and centers that are experienced in the care and management of patients with ovarian cancer,” Dr. Richard G. Moore said at the annual meeting of the Society of Gynecologic Oncologists.
High-risk women should be referred to gynecologic oncologists and centers that have been shown to treat ovarian cancer with better survival outcomes and less morbidity, according to Dr. Moore. Low-risk women do not need that level of care and may be treated in their communities.
The investigators do not see ROMA as replacing the Society of Gynecologic Oncologists'/American College of Obstetricians and Gynecologists' referral guidelines for pelvic masses, he said in response to a question during a discussion of the study. Rather, Dr. Moore and his associates would like to see ROMA incorporated into the guidelines.
“Clinical findings and impressions are very important, but I think these markers can really help us to triage these patients,” said Dr. Moore of Women and Infants Hospital and Brown University, both in Providence, R.I.
The investigators compared ROMA vs. RMI because the latter is a validated, well-accepted tool that is currently in use, he added in an interview. The RMI is based on menopausal status, CA 125 levels, and ultrasound scores of 0–5.
ROMA has two formulas, one for premenopausal and another for postmenopausal women. Both include HE4 and CA 125 levels, but the premenopausal formula weighs HE4 more heavily. “In premenopausal patients, there are many benign diseases that cause elevated CA 125, and there is no cancer,” Dr. Moore explained, describing the two markers as complementary.
The algorithm was developed based on pooled data from a pilot study at Women and Infants Hospital and a retrospective case-control study at Massachusetts General Hospital in Boston. The prospective trial enrolled 566 women, who presented at 12 centers with pelvic masses that were documented on imaging and for which surgery was planned.
The investigators did not report sensitivity by histology, but Dr. Moore said it was close to or at 100% in all but mucinous tumors. ROMA was much less sensitive in mucinous tumors, identifying only about half of them, he said.
The prospective trial was supported by Fujirebio Diagnostics Inc. and grants from the National Cancer Institute. Seven authors, including Dr. Moore, served as consultants to and were on the scientific advisory board for Fujirebio.
This tool can help triage patients to centers that are experienced in the management of patients with ovarian cancer. DR. MOORE
Liver Enzyme Spike After Weight Loss Deemed Transient
PHOENIX — Increases in liver enzymes after substantial weight loss are common, transient, and not cause for alarm, suggest study results presented at the annual scientific meeting of the Obesity Society.
Dr. James W. Anderson assessed liver function tests in 91 obese and 94 severely obese patients who were participating in a rapid weight loss program at the University of Kentucky, Lexington, where he is medical director of the Health Management Resources weight loss program.
About a quarter of both groups had elevated alanine aminotransferase (ALT) levels at baseline. Mean ALT levels increased within 3-6 weeks of starting the program in nearly all patients. By 16 weeks, however, ALT levels had returned to normal in 98% of the population.
“What we found systematically is that the levels increase, but they come back down below where they started. So we think this is therapeutic, of great value,” he said in a poster-side interview, rejecting the hypothesis that weight loss could trigger or worsen liver disease.
Generally speaking, about a third of obese individuals have elevated ALT before weight loss, Dr. Anderson said. Moreover, approximately two-thirds of obese individuals and about 90% of severely obese individuals have steatosis, according to one report (N. Engl. J. Med. 2002;346:1221).
The 91 obese individuals studied by Dr. Anderson had a baseline body mass index of 42 kg/m
Less than half, 47%, of the 94 severely obese individuals were women, and the group was slightly younger with an average age of 43 years. The severely obese cohort started with a baseline BMI of 53 kg/m
Dr. Anderson reported that in 70 severely obese patients with baseline ALT values of 40 U/L or less, those values rose from 25 U/L to 60 U/L at 6 weeks but then fell to 30 U/L at 16 weeks and were below baseline at 40 weeks. The mean peak and final ALT values in this group were 81 U/L and 24 U/L, respectively.
Another 24 severely obese patients had abnormal initial ALT values that increased from 61 U/L to 81 U/L at 2 weeks before falling to 34 U/L by 16 weeks. The mean peak and final ALT values in this group were 97 U/L and 28 U/L, respectively.
In the obese group, the changes were not as dramatic, but a similar pattern was observed. In these patients, the initial ALTvalue was 33 U/L, and the final value fell to 29 U/L.
“These observations suggest most of our patients had benign steatosis that benefited from rapid and significant weight loss,” the authors concluded in the poster.
Dr. Anderson speculated that liver enzyme levels might go up when people start losing weight because fat moves out of the liver so fast that “it drags some enzymes with it.”
To prove benefit conclusively would require biopsy data, and that would require an unnecessary invasive procedure, he added.
“We think we are doing a good thing here, but this is clinical judgment,” he said. “We don't have solid biopsy data.”
Dr. Anderson disclosed no conflicts of interest.
'Most of our patients had benign steatosis that benefited from rapid and significant weight loss.' DR. ANDERSON
PHOENIX — Increases in liver enzymes after substantial weight loss are common, transient, and not cause for alarm, suggest study results presented at the annual scientific meeting of the Obesity Society.
Dr. James W. Anderson assessed liver function tests in 91 obese and 94 severely obese patients who were participating in a rapid weight loss program at the University of Kentucky, Lexington, where he is medical director of the Health Management Resources weight loss program.
About a quarter of both groups had elevated alanine aminotransferase (ALT) levels at baseline. Mean ALT levels increased within 3-6 weeks of starting the program in nearly all patients. By 16 weeks, however, ALT levels had returned to normal in 98% of the population.
“What we found systematically is that the levels increase, but they come back down below where they started. So we think this is therapeutic, of great value,” he said in a poster-side interview, rejecting the hypothesis that weight loss could trigger or worsen liver disease.
Generally speaking, about a third of obese individuals have elevated ALT before weight loss, Dr. Anderson said. Moreover, approximately two-thirds of obese individuals and about 90% of severely obese individuals have steatosis, according to one report (N. Engl. J. Med. 2002;346:1221).
The 91 obese individuals studied by Dr. Anderson had a baseline body mass index of 42 kg/m
Less than half, 47%, of the 94 severely obese individuals were women, and the group was slightly younger with an average age of 43 years. The severely obese cohort started with a baseline BMI of 53 kg/m
Dr. Anderson reported that in 70 severely obese patients with baseline ALT values of 40 U/L or less, those values rose from 25 U/L to 60 U/L at 6 weeks but then fell to 30 U/L at 16 weeks and were below baseline at 40 weeks. The mean peak and final ALT values in this group were 81 U/L and 24 U/L, respectively.
Another 24 severely obese patients had abnormal initial ALT values that increased from 61 U/L to 81 U/L at 2 weeks before falling to 34 U/L by 16 weeks. The mean peak and final ALT values in this group were 97 U/L and 28 U/L, respectively.
In the obese group, the changes were not as dramatic, but a similar pattern was observed. In these patients, the initial ALTvalue was 33 U/L, and the final value fell to 29 U/L.
“These observations suggest most of our patients had benign steatosis that benefited from rapid and significant weight loss,” the authors concluded in the poster.
Dr. Anderson speculated that liver enzyme levels might go up when people start losing weight because fat moves out of the liver so fast that “it drags some enzymes with it.”
To prove benefit conclusively would require biopsy data, and that would require an unnecessary invasive procedure, he added.
“We think we are doing a good thing here, but this is clinical judgment,” he said. “We don't have solid biopsy data.”
Dr. Anderson disclosed no conflicts of interest.
'Most of our patients had benign steatosis that benefited from rapid and significant weight loss.' DR. ANDERSON
PHOENIX — Increases in liver enzymes after substantial weight loss are common, transient, and not cause for alarm, suggest study results presented at the annual scientific meeting of the Obesity Society.
Dr. James W. Anderson assessed liver function tests in 91 obese and 94 severely obese patients who were participating in a rapid weight loss program at the University of Kentucky, Lexington, where he is medical director of the Health Management Resources weight loss program.
About a quarter of both groups had elevated alanine aminotransferase (ALT) levels at baseline. Mean ALT levels increased within 3-6 weeks of starting the program in nearly all patients. By 16 weeks, however, ALT levels had returned to normal in 98% of the population.
“What we found systematically is that the levels increase, but they come back down below where they started. So we think this is therapeutic, of great value,” he said in a poster-side interview, rejecting the hypothesis that weight loss could trigger or worsen liver disease.
Generally speaking, about a third of obese individuals have elevated ALT before weight loss, Dr. Anderson said. Moreover, approximately two-thirds of obese individuals and about 90% of severely obese individuals have steatosis, according to one report (N. Engl. J. Med. 2002;346:1221).
The 91 obese individuals studied by Dr. Anderson had a baseline body mass index of 42 kg/m
Less than half, 47%, of the 94 severely obese individuals were women, and the group was slightly younger with an average age of 43 years. The severely obese cohort started with a baseline BMI of 53 kg/m
Dr. Anderson reported that in 70 severely obese patients with baseline ALT values of 40 U/L or less, those values rose from 25 U/L to 60 U/L at 6 weeks but then fell to 30 U/L at 16 weeks and were below baseline at 40 weeks. The mean peak and final ALT values in this group were 81 U/L and 24 U/L, respectively.
Another 24 severely obese patients had abnormal initial ALT values that increased from 61 U/L to 81 U/L at 2 weeks before falling to 34 U/L by 16 weeks. The mean peak and final ALT values in this group were 97 U/L and 28 U/L, respectively.
In the obese group, the changes were not as dramatic, but a similar pattern was observed. In these patients, the initial ALTvalue was 33 U/L, and the final value fell to 29 U/L.
“These observations suggest most of our patients had benign steatosis that benefited from rapid and significant weight loss,” the authors concluded in the poster.
Dr. Anderson speculated that liver enzyme levels might go up when people start losing weight because fat moves out of the liver so fast that “it drags some enzymes with it.”
To prove benefit conclusively would require biopsy data, and that would require an unnecessary invasive procedure, he added.
“We think we are doing a good thing here, but this is clinical judgment,” he said. “We don't have solid biopsy data.”
Dr. Anderson disclosed no conflicts of interest.
'Most of our patients had benign steatosis that benefited from rapid and significant weight loss.' DR. ANDERSON
IVF Appears to Increase Risk of Ovarian Cancer
SAN ANTONIO — Ovarian stimulation for in vitro fertilization was linked to an increased risk of ovarian cancer 15 years later in a large cohort study that followed thousands of women in the Netherlands.
Compared with controls who had fertility problems but did not undergo in vitro fertilization (IVF), women who underwent IVF were more than four times as likely to develop “borderline” tumors and 1.5 times more likely to develop invasive ovarian cancer. Overall, IVF conferred a relative risk of 2.05 for all ovarian malignancies.
The “borderline” tumors, also known as low-malignant-potential tumors, tended to occur earlier than the invasive ovarian cancers—for which an increase in incidence did not become apparent until 15 years after treatment, Dr. Curt W. Burger reported at the Society of Gynecologic Oncologists' annual meeting.
Whether borderline tumors eventually become invasive is subject to debate, noted Dr. Burger, a gynecologist at Erasmus University Medical Center in Rotterdam, the Netherlands.
“The clinical implications are modest,” he said, estimating the cumulative individual risk of developing an ovarian tumor before age 55 years as 0.45% for the general population and 0.71% for women who have undergone IVF.
Dr. Wendy R. Brewster of the University of North Carolina, Chapel Hill, called the results “quite troubling” in a discussion of the study.
Both Dr. Brewster and Dr. Burger reviewed a long line of studies that failed to prove increased incidence of ovarian cancer after ovarian stimulation. Among the earlier reports were two by Dr. Burger, based on shorter follow-up.
All 12 IVF centers in the Netherlands participated in the study. The initial cohort comprised 18,970 women who received IVF treatment between 1983 and 1995, and a control group of 7,536 subfertile women who sought help but were not treated with IVF.
About two-thirds of the women—67% of the total population and 74% of the IVF group—responded to questionnaires on reproductive risk factors between 1997 and 1999. The investigators reviewed their medical records and, with written permission, followed their cancer diagnoses through linkage with the Netherlands Cancer Registry through 2007.
At a median follow-up of 14.7 years, he reported 61 ovarian cancers were observed in the IVF group and 16 in the control group versus expectations of 38.4 and 15.6, respectively, in those populations. The standardized incidence ratio (SIR) for the IVF group was 1.59.
In the IVF group the SIR for invasive cancers peaked in the first year, probably because of screening after IVF, and at or after 15 years (3.94 and 3.22, respectively). Borderline tumors also showed a peak the first year, and most were found within 10 years of treatment; between years 5 and 9 after treatment, 12 were found (SIR 2.18).
All told, 55 ovarian cancers (SIR 1.49) were found after the first year in the IVF group: 28 invasive cancers (SIR 1.30) and 27 borderline tumors (SIR 1.76).
Dr. Glenn L. Schattman, chairperson of the Practice Committee of the Society for Assisted Reproductive Technology, affiliate of the American Society for Reproductive Medicine, called the study interesting but noted that it 'does not take into account whether the IVF patients were successful in achieving a pregnancy or what their previous pregnancy histories and ovarian cancer risk factors were. It also does not give the dosages of the stimulant drugs they took. It was a retrospective study, and such studies have limitations.”
SAN ANTONIO — Ovarian stimulation for in vitro fertilization was linked to an increased risk of ovarian cancer 15 years later in a large cohort study that followed thousands of women in the Netherlands.
Compared with controls who had fertility problems but did not undergo in vitro fertilization (IVF), women who underwent IVF were more than four times as likely to develop “borderline” tumors and 1.5 times more likely to develop invasive ovarian cancer. Overall, IVF conferred a relative risk of 2.05 for all ovarian malignancies.
The “borderline” tumors, also known as low-malignant-potential tumors, tended to occur earlier than the invasive ovarian cancers—for which an increase in incidence did not become apparent until 15 years after treatment, Dr. Curt W. Burger reported at the Society of Gynecologic Oncologists' annual meeting.
Whether borderline tumors eventually become invasive is subject to debate, noted Dr. Burger, a gynecologist at Erasmus University Medical Center in Rotterdam, the Netherlands.
“The clinical implications are modest,” he said, estimating the cumulative individual risk of developing an ovarian tumor before age 55 years as 0.45% for the general population and 0.71% for women who have undergone IVF.
Dr. Wendy R. Brewster of the University of North Carolina, Chapel Hill, called the results “quite troubling” in a discussion of the study.
Both Dr. Brewster and Dr. Burger reviewed a long line of studies that failed to prove increased incidence of ovarian cancer after ovarian stimulation. Among the earlier reports were two by Dr. Burger, based on shorter follow-up.
All 12 IVF centers in the Netherlands participated in the study. The initial cohort comprised 18,970 women who received IVF treatment between 1983 and 1995, and a control group of 7,536 subfertile women who sought help but were not treated with IVF.
About two-thirds of the women—67% of the total population and 74% of the IVF group—responded to questionnaires on reproductive risk factors between 1997 and 1999. The investigators reviewed their medical records and, with written permission, followed their cancer diagnoses through linkage with the Netherlands Cancer Registry through 2007.
At a median follow-up of 14.7 years, he reported 61 ovarian cancers were observed in the IVF group and 16 in the control group versus expectations of 38.4 and 15.6, respectively, in those populations. The standardized incidence ratio (SIR) for the IVF group was 1.59.
In the IVF group the SIR for invasive cancers peaked in the first year, probably because of screening after IVF, and at or after 15 years (3.94 and 3.22, respectively). Borderline tumors also showed a peak the first year, and most were found within 10 years of treatment; between years 5 and 9 after treatment, 12 were found (SIR 2.18).
All told, 55 ovarian cancers (SIR 1.49) were found after the first year in the IVF group: 28 invasive cancers (SIR 1.30) and 27 borderline tumors (SIR 1.76).
Dr. Glenn L. Schattman, chairperson of the Practice Committee of the Society for Assisted Reproductive Technology, affiliate of the American Society for Reproductive Medicine, called the study interesting but noted that it 'does not take into account whether the IVF patients were successful in achieving a pregnancy or what their previous pregnancy histories and ovarian cancer risk factors were. It also does not give the dosages of the stimulant drugs they took. It was a retrospective study, and such studies have limitations.”
SAN ANTONIO — Ovarian stimulation for in vitro fertilization was linked to an increased risk of ovarian cancer 15 years later in a large cohort study that followed thousands of women in the Netherlands.
Compared with controls who had fertility problems but did not undergo in vitro fertilization (IVF), women who underwent IVF were more than four times as likely to develop “borderline” tumors and 1.5 times more likely to develop invasive ovarian cancer. Overall, IVF conferred a relative risk of 2.05 for all ovarian malignancies.
The “borderline” tumors, also known as low-malignant-potential tumors, tended to occur earlier than the invasive ovarian cancers—for which an increase in incidence did not become apparent until 15 years after treatment, Dr. Curt W. Burger reported at the Society of Gynecologic Oncologists' annual meeting.
Whether borderline tumors eventually become invasive is subject to debate, noted Dr. Burger, a gynecologist at Erasmus University Medical Center in Rotterdam, the Netherlands.
“The clinical implications are modest,” he said, estimating the cumulative individual risk of developing an ovarian tumor before age 55 years as 0.45% for the general population and 0.71% for women who have undergone IVF.
Dr. Wendy R. Brewster of the University of North Carolina, Chapel Hill, called the results “quite troubling” in a discussion of the study.
Both Dr. Brewster and Dr. Burger reviewed a long line of studies that failed to prove increased incidence of ovarian cancer after ovarian stimulation. Among the earlier reports were two by Dr. Burger, based on shorter follow-up.
All 12 IVF centers in the Netherlands participated in the study. The initial cohort comprised 18,970 women who received IVF treatment between 1983 and 1995, and a control group of 7,536 subfertile women who sought help but were not treated with IVF.
About two-thirds of the women—67% of the total population and 74% of the IVF group—responded to questionnaires on reproductive risk factors between 1997 and 1999. The investigators reviewed their medical records and, with written permission, followed their cancer diagnoses through linkage with the Netherlands Cancer Registry through 2007.
At a median follow-up of 14.7 years, he reported 61 ovarian cancers were observed in the IVF group and 16 in the control group versus expectations of 38.4 and 15.6, respectively, in those populations. The standardized incidence ratio (SIR) for the IVF group was 1.59.
In the IVF group the SIR for invasive cancers peaked in the first year, probably because of screening after IVF, and at or after 15 years (3.94 and 3.22, respectively). Borderline tumors also showed a peak the first year, and most were found within 10 years of treatment; between years 5 and 9 after treatment, 12 were found (SIR 2.18).
All told, 55 ovarian cancers (SIR 1.49) were found after the first year in the IVF group: 28 invasive cancers (SIR 1.30) and 27 borderline tumors (SIR 1.76).
Dr. Glenn L. Schattman, chairperson of the Practice Committee of the Society for Assisted Reproductive Technology, affiliate of the American Society for Reproductive Medicine, called the study interesting but noted that it 'does not take into account whether the IVF patients were successful in achieving a pregnancy or what their previous pregnancy histories and ovarian cancer risk factors were. It also does not give the dosages of the stimulant drugs they took. It was a retrospective study, and such studies have limitations.”
IVF Regimen Linked to Ovarian Cancer Risk
SAN ANTONIO — Ovarian stimulation for in vitro fertilization was linked to an increased risk of ovarian cancer 15 years later in a large cohort study that followed thousands of women in the Netherlands.
Compared with a control group of women who had fertility problems but did not undergo in vitro fertilization (IVF), women who underwent IVF had a relative risk of 4.40 for “borderline” (low-malignant-potential) tumors and 1.51 for invasive ovarian cancer. Overall, IVF conferred a relative risk of 2.05 for all ovarian malignancies, Dr. Curt W. Burger reported at the annual meeting of the Society of Gynecologic Oncologists.
Whether borderline tumors eventually become invasive is subject to debate, noted Dr. Burger, a gynecologist at Erasmus University Medical Center in Rotterdam, the Netherlands.
“The clinical implications are modest,” he said, estimating the cumulative individual risk of developing an ovarian tumor before age 55 years as 0.45% for the general population and 0.71% for women who have undergone IVF.
Dr. Wendy R. Brewster of the University of North Carolina, Chapel Hill, called the results “quite troubling” in a discussion of the study.
“We have to advise our patients that there is some risk of ovarian cancer,” Dr. Brewster said. The risk of developing breast cancer may be greater, “but, still, to develop ovarian cancer, your life is much more at risk.”
Two earlier reports by Dr. Burger were based on shorter follow-up of women in the current study. At 7.4 years, he reported increased incidence of borderline tumors in subfertile women regardless of whether they had undergone IVF, and said this was not related to IVF.
All 12 IVF centers in the Netherlands participated in the study. The initial cohort comprised 18,970 women who received IVF treatment between 1983 and 1995, and a control group of 7,536 subfertile women who sought help but were not treated with IVF. Agents used were clomiphene (Clomid), clomiphene/human menopausal gonadotrophin, and follicle-stimulating hormone/human menopausal gonadotrophin.
About two-thirds of the women—67% of the total population and 74% of the IVF group—responded to questionnaires on reproductive risk factors between 1997 and 1999. The investigators reviewed their medical records and, with written permission, followed their cancer diagnoses through linkage with The Netherlands Cancer Registry through 2007.
At a median follow-up of 14.7 years, 61 ovarian cancers were observed in the IVF group and 16 in the control group vs. expectations of 38.4 and 15.6, respectively, in those populations, he said.
Dr. Glenn L. Schattman, chair of the practice committee of the Society for Assisted Reproductive Technology, called the study interesting, but noted that “it does not take into account whether the IVF patients were successful in achieving a pregnancy or what their previous pregnancy histories and ovarian cancer risk factors were. It also does not give the dosages of the stimulant drugs they took. It was a retrospective study, and such studies have limitations and are subject to recall bias.”
In general, there is evidence that infertile women who achieve pregnancy “reduce their risk of ovarian cancer by that factor alone,” said Dr. Schattman, associate professor of ob.gyn. at Weill Cornell Medical College, New York.
In fact, he said, a more comprehensive study that looked at use of specific fertility drugs found no overall increase in ovarian cancer risk (BMJ 2009 Feb. 5 [doi:10.1136/bmj.b249]).
Individual risk is 0.45% for the general population vs. 0.71% for women who have undergone IVF. DR. BURGER
SAN ANTONIO — Ovarian stimulation for in vitro fertilization was linked to an increased risk of ovarian cancer 15 years later in a large cohort study that followed thousands of women in the Netherlands.
Compared with a control group of women who had fertility problems but did not undergo in vitro fertilization (IVF), women who underwent IVF had a relative risk of 4.40 for “borderline” (low-malignant-potential) tumors and 1.51 for invasive ovarian cancer. Overall, IVF conferred a relative risk of 2.05 for all ovarian malignancies, Dr. Curt W. Burger reported at the annual meeting of the Society of Gynecologic Oncologists.
Whether borderline tumors eventually become invasive is subject to debate, noted Dr. Burger, a gynecologist at Erasmus University Medical Center in Rotterdam, the Netherlands.
“The clinical implications are modest,” he said, estimating the cumulative individual risk of developing an ovarian tumor before age 55 years as 0.45% for the general population and 0.71% for women who have undergone IVF.
Dr. Wendy R. Brewster of the University of North Carolina, Chapel Hill, called the results “quite troubling” in a discussion of the study.
“We have to advise our patients that there is some risk of ovarian cancer,” Dr. Brewster said. The risk of developing breast cancer may be greater, “but, still, to develop ovarian cancer, your life is much more at risk.”
Two earlier reports by Dr. Burger were based on shorter follow-up of women in the current study. At 7.4 years, he reported increased incidence of borderline tumors in subfertile women regardless of whether they had undergone IVF, and said this was not related to IVF.
All 12 IVF centers in the Netherlands participated in the study. The initial cohort comprised 18,970 women who received IVF treatment between 1983 and 1995, and a control group of 7,536 subfertile women who sought help but were not treated with IVF. Agents used were clomiphene (Clomid), clomiphene/human menopausal gonadotrophin, and follicle-stimulating hormone/human menopausal gonadotrophin.
About two-thirds of the women—67% of the total population and 74% of the IVF group—responded to questionnaires on reproductive risk factors between 1997 and 1999. The investigators reviewed their medical records and, with written permission, followed their cancer diagnoses through linkage with The Netherlands Cancer Registry through 2007.
At a median follow-up of 14.7 years, 61 ovarian cancers were observed in the IVF group and 16 in the control group vs. expectations of 38.4 and 15.6, respectively, in those populations, he said.
Dr. Glenn L. Schattman, chair of the practice committee of the Society for Assisted Reproductive Technology, called the study interesting, but noted that “it does not take into account whether the IVF patients were successful in achieving a pregnancy or what their previous pregnancy histories and ovarian cancer risk factors were. It also does not give the dosages of the stimulant drugs they took. It was a retrospective study, and such studies have limitations and are subject to recall bias.”
In general, there is evidence that infertile women who achieve pregnancy “reduce their risk of ovarian cancer by that factor alone,” said Dr. Schattman, associate professor of ob.gyn. at Weill Cornell Medical College, New York.
In fact, he said, a more comprehensive study that looked at use of specific fertility drugs found no overall increase in ovarian cancer risk (BMJ 2009 Feb. 5 [doi:10.1136/bmj.b249]).
Individual risk is 0.45% for the general population vs. 0.71% for women who have undergone IVF. DR. BURGER
SAN ANTONIO — Ovarian stimulation for in vitro fertilization was linked to an increased risk of ovarian cancer 15 years later in a large cohort study that followed thousands of women in the Netherlands.
Compared with a control group of women who had fertility problems but did not undergo in vitro fertilization (IVF), women who underwent IVF had a relative risk of 4.40 for “borderline” (low-malignant-potential) tumors and 1.51 for invasive ovarian cancer. Overall, IVF conferred a relative risk of 2.05 for all ovarian malignancies, Dr. Curt W. Burger reported at the annual meeting of the Society of Gynecologic Oncologists.
Whether borderline tumors eventually become invasive is subject to debate, noted Dr. Burger, a gynecologist at Erasmus University Medical Center in Rotterdam, the Netherlands.
“The clinical implications are modest,” he said, estimating the cumulative individual risk of developing an ovarian tumor before age 55 years as 0.45% for the general population and 0.71% for women who have undergone IVF.
Dr. Wendy R. Brewster of the University of North Carolina, Chapel Hill, called the results “quite troubling” in a discussion of the study.
“We have to advise our patients that there is some risk of ovarian cancer,” Dr. Brewster said. The risk of developing breast cancer may be greater, “but, still, to develop ovarian cancer, your life is much more at risk.”
Two earlier reports by Dr. Burger were based on shorter follow-up of women in the current study. At 7.4 years, he reported increased incidence of borderline tumors in subfertile women regardless of whether they had undergone IVF, and said this was not related to IVF.
All 12 IVF centers in the Netherlands participated in the study. The initial cohort comprised 18,970 women who received IVF treatment between 1983 and 1995, and a control group of 7,536 subfertile women who sought help but were not treated with IVF. Agents used were clomiphene (Clomid), clomiphene/human menopausal gonadotrophin, and follicle-stimulating hormone/human menopausal gonadotrophin.
About two-thirds of the women—67% of the total population and 74% of the IVF group—responded to questionnaires on reproductive risk factors between 1997 and 1999. The investigators reviewed their medical records and, with written permission, followed their cancer diagnoses through linkage with The Netherlands Cancer Registry through 2007.
At a median follow-up of 14.7 years, 61 ovarian cancers were observed in the IVF group and 16 in the control group vs. expectations of 38.4 and 15.6, respectively, in those populations, he said.
Dr. Glenn L. Schattman, chair of the practice committee of the Society for Assisted Reproductive Technology, called the study interesting, but noted that “it does not take into account whether the IVF patients were successful in achieving a pregnancy or what their previous pregnancy histories and ovarian cancer risk factors were. It also does not give the dosages of the stimulant drugs they took. It was a retrospective study, and such studies have limitations and are subject to recall bias.”
In general, there is evidence that infertile women who achieve pregnancy “reduce their risk of ovarian cancer by that factor alone,” said Dr. Schattman, associate professor of ob.gyn. at Weill Cornell Medical College, New York.
In fact, he said, a more comprehensive study that looked at use of specific fertility drugs found no overall increase in ovarian cancer risk (BMJ 2009 Feb. 5 [doi:10.1136/bmj.b249]).
Individual risk is 0.45% for the general population vs. 0.71% for women who have undergone IVF. DR. BURGER