Are oral oncology drugs being mislabeled? Maybe.
Most oral cancer drugs stipulate that they should be taken in a fasting state, but some actually have better bioavailability when taken with food. This is particularly true for the new prostate cancer drug abiraterone acetate (Zytiga), which has a greater interaction with food than any other marketed drug, yet it is labeled to be taken when fasting.
These points are highlighted in a comment published in the October 20 issue of the Journal of Clinical Oncology by Mark J. Ratain, MD, professor of medicine and director of the Center for Personalized Therapeutics at the University of Chicago, Illinois.
"My major concern is safety," Dr. Ratain told Medscape Medical News. "Very few patients would anticipate that the consequences of taking their medications with food...would be an effective overdose."
In the case of abiraterone acetate, the dose of the drug could be increased 10-fold by eating breakfast half an hour after taking the drug, he writes.
Dr. Ratain notes that food interactions are described in the labeling of many drugs, but are notably absent in the labeling of new oral cancer agents.
Most drugs can be taken either with or without food, he explains, because the effects of food are not clinically significant to drug absorption. There are cases in which absorption is decreased by food; generally, the labeling on those drugs instructs that they be taken on an empty stomach. Similarly, labeling on drugs for which absorption is enhanced by food typically instructs that they be ingested with meals.
"However, a recent study of oral agents approved by the US Food and Drug Administration [FDA] in the last 10 years demonstrated that oral oncology drugs have generally been labeled fasting, despite food effects as large as a 4-fold increase in bioavailability," Dr. Ratain notes.
Bias in Labeling?
This apparent bias for fasting labeling in cancer drugs is exemplified with abiraterone, he notes. Abiraterone, which was approved earlier this year in the United States for the treatment of metastatic prostate cancer, has a greater food interaction than any drug currently on the market. Depending on the fat content, food can increase drug exposure 5- to 10-fold, yet it is labeled to be taken in a fasting state, Dr. Ratain points out.
The effect of a high-fat meal indicates "that absolute bioavailability in the fasting state is no more than 10%," says Dr. Ratain, and is likely due to the low absorption rate under fasting conditions; 77% of the drug is excreted as abiraterone (or its prodrug acetate) in the stool.
"In addition, there is marked interindividual pharmacokinetic variability, with a coefficient of variation in the plasma concentration area under the curve of 59% under labeled conditions," he notes.
It is unclear why this faulty labeling is occurring, or why the FDA has not been more stringent about proper labeling for oral oncology drugs, Dr. Ratain said. He told Medscape Medical Newsthat the FDA has not responded to his inquiries and "essentially stonewalled" him because of the confidentiality of their discussions with sponsors.
"The blame could be assigned to sponsors, the Office of Oncology Drug Products, and/or the Office of Clinical Pharmacology and Biopharmaceutics," he said. "Given that there are multiple sponsors, all of whom who have a different approach to oncology..., the evidence points to an FDA origin."
Oral Drugs Relatively New
Alex Adjei, MD, PhD, who was approached by Medscape Medical News for independent comment, explained that until recently, oncology drugs have generally been given intravenously; for other diseases, oral drugs have been in common use for many years.
Perhaps that is why there has not been that much attention on the food-effect data, Dr. Adjei hypothesized. He is chair of the Department of Medicine at Roswell Park Cancer Institute, in Buffalo, New York.
"In clinical trials, we tend to give the drugs on an empty stomach," he said. "So that was how the drug was tested and that was how it was approved. We don't go back and change the label."
Dr. Adjei pointed out that unlike intravenous drugs, there is considerable variation in the way oral drugs are absorbed. "We try to simplify it by giving them on an empty stomach," he said.
Food-Effect Data Ignored
In a study published last year (Clin Cancer Res. 2010;16:4446-4451), Dr. Ratain and his colleague, Soonmo Peter Kang, MD, also from the University of Chicago, evaluated the effect of food on 99 oral agents that received FDA approval from January 2000 to May 2009. They compared food-labeling patterns between oncology and nononcology drugs using Fisher's exact test.
Food had a significant effect on drug bioavailability in 34 of the 99 drugs evaluated. In cases where food markedly enhanced bioavailability, 8 of 9 nononcology drugs were labeled to be taken with food to take advantage of the food–drug interaction. However, all oncology agents were labeled to be taken in "fasted" states (P = .01).
"The food-labeling pattern of recently approved oral oncology drug products is inconsistent with fundamental principles of oral drug delivery," they write. "The labels of 3 agents (erlotinib, nilotinib, and lapatinib) minimized bioavailability through food restrictions, which is in contrast to the labeling principles used for all other classes of oral agents."
In an editorial that accompanied the study by Drs. Ratain and Kang (Clin Cancer Res. 2010;16:4305-4307), Rajul K. Jain, MD, from the University of Texas M.D. Anderson Cancer Center, Houston, and colleagues explained that the effects of food are complex, and that multiple factors determine final labeling recommendations. "When analyzing the label given to any product or product class, all of the potential influencing factors should be considered," they said.
They also noted that "sponsors are encouraged to conduct food-effect studies early in a product's development so the results can be implemented into larger clinical trials."
In his comment, Dr. Ratain refers back to that editorial, and points out that the agency has "expressed concern about the potential for high intraindividual variability in cancer patients resulting from variability in oral intake secondary to disease or concurrent medications." This appears to indicate a preference for labeling drugs to be used when fasting, even if their bioavailability would be substantially increased when taken with food.
He explains that there isn't any evidence that this concern applies to all oral oncology drugs, and that there is no evidence that intraindividual variability in diet is greater for cancer patients than for those with other life-threatening conditions who also take daily oral drugs.
"If the US Food and Drug Administration were truly concerned about intraindividual variability in diet, why has this never come up in the labeling of nononcology drugs?" he asks.
He notes that the FDA was aware of the food-effect data from early studies of abiraterone and could have required at least 1 randomized study to be conducted to review this, so that it could have been labeled to be taken with food. The FDA has the authority to require such studies as a postmarketing requirement, but chose not to.
With the risk for poor adherence to food-effect labeling, there is a risk for overdose or underdose of a given drug, with the more serious being overdose, Dr. Ratain says.
In addition to this safety issue, there are economic implications, Dr. Ratain notes.
The standard dose of abiraterone for men without liver problems is 1000 mg once daily. But because the bioavailability of the drug is greatly increased when taken with food, it would be interesting to have studies of abiraterone at a dose of 250 mg once daily, administered with a standard breakfast. If this approach is shown to be safe and effective, it could save patients and their payers approximately $3750 per month at current prices.
"It also would send a message to the pharmaceutical industry that flawed drug development has financial consequences," he notes, "along with potential risks of product liability because of defective labeling."
He concludes: "After all, given the high attrition rate for oncology drugs, do we really need to flush our few successful products down the toilet?"
Impracticalities of Dosing and Diet
Lawrence J. Lesko, PhD, FCP, former director of the Office of Clinical Pharmacology at the FDA's Center for Drug Evaluation and Research, and a coauthor of the editorial by Dr. Jain, pointed out that the principal of labeling is consistent safety.
"The most consistent way to take drugs is on an empty stomach," said Dr. Lesko, who is now at the Department of Pharmaceutics at the College of Pharmacy at the University of Florida in Gainesville. "It would be impractical to expect that patients are going to adhere to a specific diet when taking these drugs. And it is often unclear what 'food' may mean to the patient. Is it a glass of juice, breakfast cereal, a cheeseburger?"
The goal is to minimize the variability, he told Medscape Medical News. "Food studies are generally conducted in healthy volunteers and not cancer patients. Labeling can't be done on a theoretical basis; it has to reflect what was done in the study."
Dr. Lesko noted that another problem with tying an oral drug dose to food is that many cancer patients have problems with appetite, nausea and vomiting, and gastrointestinal motility. "Their appetite can change on any given day," he said. "Some days, they may not be able to tolerate a high-fat meal, for example, which raises the bioavailability of abiraterone. It would just be impractical to do this on a day-to-day basis."
The other issue that Dr. Ratain focuses on in his comment is the comparison of oncology and nononcology drugs, Dr. Lesko pointed out. "But you really can't compare them."
For most nononcologic agents, food doesn't matter, so it isn't that important how the product is labeled, he said.
But that is not the case with oral oncologic agents. "Every drug in oncology has a narrow therapeutic index, and taking the drug with food could affect the therapeutic range," he said. "The labels are intended to minimize variability and mimic approval data."
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CANCER DEATHS OVERTAKE HEART DISEASE IN CANADA
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For the first time, cancer has overtaken heart disease as the number-one cause of death across Canada, according to the latest statistics here [1].
According to numbers released yesterday, cancer accounted for 29.6% of deaths (70 558) in 2008--the latest year for which stats have been made available by heath authorities. Heart disease caused 21.3% of deaths (50 722).
Stroke, in third place, caused 5.8% (13 870) of deaths.
Statistics from the previous year had cancer leading heart disease in every province and territory with the exception of Prince Edward Island and the Northwest Territories. In the 2008 statistics, heart disease has now moved into second place in every province/territory, with the exception of Nunavut, where suicide ranks second.
Between 2007 and 2008, cancer deaths climbed 1.4% nationally, continuing a trend seen since 2000. By contrast, heart-disease deaths declined between 2000 and 2006 but actually crept upward between 2007 and 2008.
Preliminary US numbers published by the US Centers for Disease Control and Prevention show that heart disease was still the leading cause of death for both 2008 and 2009, followed by malignant neoplasms, with both diseases declining in this period, although that decline was three times greater for heart disease [2].
In the UK, which has published 2010 causes of death for England and Wales, it is more difficult to draw comparisons, due to how diseases are grouped by statisticians there [3]. "Circulatory diseases" (which include heart disease and stroke, as well as venous and arterial diseases) were the leading cause of death and had declined since 2009. By contrast, deaths due to cancers and neoplasms, in the number-two position, had climbed slightly over the past year.
Commenting on the newly released Canadian statistics for heartwire , Dr Paul Armstrong(University of Calgary, AB) observed that there is both good news and bad in the numbers.
"I guess it's good news that we're making some progress in cardiovascular disease. And obviously if the burden of cardiovascular disease is relieved such that you are living longer, it's more likely that you're going to die of something else," he said.
But before anyone celebrates these numbers, Armstrong points out that despite progress in controlling risk factors such as hypertension and elevated cholesterol, Canada and other countries have not done so well in curbing the upward march of obesity and diabetes. Diabetes, he points out, is the number-six cause of death in Canada, and the number of diabetes deaths has climbed since 2000.
"I worry we could still see a second wave of [increased] heart-disease deaths as a result of the increasing prevalence of diabetes and obesity, although it's too soon to know," Armstrong said.
In response to a poll question on theheart.org this summer, 52% of respondents said they expected cancer to surpass heart disease as the world's number-one killer within the next 10 years.
According to numbers released yesterday, cancer accounted for 29.6% of deaths (70 558) in 2008--the latest year for which stats have been made available by heath authorities. Heart disease caused 21.3% of deaths (50 722).
Stroke, in third place, caused 5.8% (13 870) of deaths.
Statistics from the previous year had cancer leading heart disease in every province and territory with the exception of Prince Edward Island and the Northwest Territories. In the 2008 statistics, heart disease has now moved into second place in every province/territory, with the exception of Nunavut, where suicide ranks second.
Between 2007 and 2008, cancer deaths climbed 1.4% nationally, continuing a trend seen since 2000. By contrast, heart-disease deaths declined between 2000 and 2006 but actually crept upward between 2007 and 2008.
Preliminary US numbers published by the US Centers for Disease Control and Prevention show that heart disease was still the leading cause of death for both 2008 and 2009, followed by malignant neoplasms, with both diseases declining in this period, although that decline was three times greater for heart disease [2].
In the UK, which has published 2010 causes of death for England and Wales, it is more difficult to draw comparisons, due to how diseases are grouped by statisticians there [3]. "Circulatory diseases" (which include heart disease and stroke, as well as venous and arterial diseases) were the leading cause of death and had declined since 2009. By contrast, deaths due to cancers and neoplasms, in the number-two position, had climbed slightly over the past year.
Commenting on the newly released Canadian statistics for heartwire , Dr Paul Armstrong(University of Calgary, AB) observed that there is both good news and bad in the numbers.
"I guess it's good news that we're making some progress in cardiovascular disease. And obviously if the burden of cardiovascular disease is relieved such that you are living longer, it's more likely that you're going to die of something else," he said.
But before anyone celebrates these numbers, Armstrong points out that despite progress in controlling risk factors such as hypertension and elevated cholesterol, Canada and other countries have not done so well in curbing the upward march of obesity and diabetes. Diabetes, he points out, is the number-six cause of death in Canada, and the number of diabetes deaths has climbed since 2000.
"I worry we could still see a second wave of [increased] heart-disease deaths as a result of the increasing prevalence of diabetes and obesity, although it's too soon to know," Armstrong said.
In response to a poll question on theheart.org this summer, 52% of respondents said they expected cancer to surpass heart disease as the world's number-one killer within the next 10 years.
NEW GUIDELINES FOR REIRRADIATION OF HEAD AND NECK CANCER
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When head and neck cancer recurs and surgery is not an option, reirradiation provides the only potentially curative option. However, because the tumor often recurs in the same place or very close to tissue that has already been irradiated, this treatment approach represents a "significant challenge."
For this reason, it should be handled at a tertiary-care center, according to a new guideline issued by the American College of Radiology. Specifically, it stipulates that the tertiary center should have a head and neck oncology team that is equipped with the resources and the experience to manage the complexities and toxicities of retreatment.
In the guideline, published in the International Journal of Radiation Oncology, Biology and Physics, a panel of experts outline appropriateness criteria for various clinical scenarios that arise with such patients.
"This is an important document because it is the first set of guidelines for the potentially curative treatment of patients who have regrowth of head and neck tumors. It provides a consensus on how patients should be managed," coauthor Madhur Kumar Garg, MD, said in a statement. Dr. Garg is from the Department of Radiation Oncology at Montefiore Medical Center, in the Bronx, New York, where about a dozen reirradiation procedures are performed annually.
Commitment to Retreatment
Retreatment is justified because clinical trial results have shown that local treatment improves overall survival, the panel of experts notes.
However, they emphasize that, before a commitment to retreatment is made, patients presenting with recurrent or second primary tumors need to undergo careful restaging evaluation. In addition to computed tomography (CT) or magnetic resonance imaging to evaluate the extent of the recurrent tumor, the panel urges that strong consideration be given to positron emission tomography with CT to evaluate for metastatic disease, or "at a minimum, a CT scan of the chest should be performed."
In addition, a detailed history and assessment is needed, which includes documentation of the sequelae of previous treatment, such as fibrosis, carotid stenosis, dysphagia, xerostomia, and osteoradionecrosis.
Retreatment options include surgical resection and palliative chemotherapy — both are regarded as standard of care, the panel writes. But for patients with unresectable disease, reirradiation is the "only potentially curative treatment," they add.
Two phase 2 clinical trials conducted by the Radiation Therapy Oncology Group (RTOG) have shown survival outcomes with reirradiation plus chemotherapy that appear to be superior to those seen with chemotherapy alone in other studies. However, "whether this apparent improvement is the result of selection bias is uncertain," the panel explains. A larger phase 3 comparing reirradiation plus chemotherapy with chemotherapy alone was closed because of poor accrual.
In terms of the dose of radiation delivered in the second treatment course, it appears that at least 50 to 60 Gy is needed, the experts report. Both of the phase 2 studies conducted by the RTOG delivered a total dose of 60 Gy, using an accelerated hyperfractionated regimen delivering 1.4 Gy twice daily in 4 week-on/week-off cycles. Multiple single-institution reports of reirradiation have used once-daily standard fractionation in a planned continuous treatment course with less toxicity, they note. However, differences in study designs and in the chemotherapy regimens make it difficult to discern what independent effect, if any, differences in radiation fractionation had on the toxicity that was seen.
For this reason, it should be handled at a tertiary-care center, according to a new guideline issued by the American College of Radiology. Specifically, it stipulates that the tertiary center should have a head and neck oncology team that is equipped with the resources and the experience to manage the complexities and toxicities of retreatment.
In the guideline, published in the International Journal of Radiation Oncology, Biology and Physics, a panel of experts outline appropriateness criteria for various clinical scenarios that arise with such patients.
"This is an important document because it is the first set of guidelines for the potentially curative treatment of patients who have regrowth of head and neck tumors. It provides a consensus on how patients should be managed," coauthor Madhur Kumar Garg, MD, said in a statement. Dr. Garg is from the Department of Radiation Oncology at Montefiore Medical Center, in the Bronx, New York, where about a dozen reirradiation procedures are performed annually.
Commitment to Retreatment
Retreatment is justified because clinical trial results have shown that local treatment improves overall survival, the panel of experts notes.
However, they emphasize that, before a commitment to retreatment is made, patients presenting with recurrent or second primary tumors need to undergo careful restaging evaluation. In addition to computed tomography (CT) or magnetic resonance imaging to evaluate the extent of the recurrent tumor, the panel urges that strong consideration be given to positron emission tomography with CT to evaluate for metastatic disease, or "at a minimum, a CT scan of the chest should be performed."
In addition, a detailed history and assessment is needed, which includes documentation of the sequelae of previous treatment, such as fibrosis, carotid stenosis, dysphagia, xerostomia, and osteoradionecrosis.
Retreatment options include surgical resection and palliative chemotherapy — both are regarded as standard of care, the panel writes. But for patients with unresectable disease, reirradiation is the "only potentially curative treatment," they add.
Two phase 2 clinical trials conducted by the Radiation Therapy Oncology Group (RTOG) have shown survival outcomes with reirradiation plus chemotherapy that appear to be superior to those seen with chemotherapy alone in other studies. However, "whether this apparent improvement is the result of selection bias is uncertain," the panel explains. A larger phase 3 comparing reirradiation plus chemotherapy with chemotherapy alone was closed because of poor accrual.
In terms of the dose of radiation delivered in the second treatment course, it appears that at least 50 to 60 Gy is needed, the experts report. Both of the phase 2 studies conducted by the RTOG delivered a total dose of 60 Gy, using an accelerated hyperfractionated regimen delivering 1.4 Gy twice daily in 4 week-on/week-off cycles. Multiple single-institution reports of reirradiation have used once-daily standard fractionation in a planned continuous treatment course with less toxicity, they note. However, differences in study designs and in the chemotherapy regimens make it difficult to discern what independent effect, if any, differences in radiation fractionation had on the toxicity that was seen.
CHEMOTHERAPY CAN BE USED SAFELY AFTER FIRST TRIMESTER OF PREGNANCY
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A cancer diagnosis can be devastating, but is even more traumatic when the patient is pregnant. A new study offers some reassurance to pregnant patients and their physicians.
The results of the small study, presented during a presidential session here at the 2011 European Multidisciplinary Cancer Congress, show that children who were exposed to chemotherapy in utero did not appear to suffer any detrimental effects in terms of general health and neurologic and cardiac functioning.
Treating cancer in pregnant women is complex. One issue, in particular, is the ethics of treating a woman with chemotherapy, "but there are no good data that describe the ethics," said lead author Frederic Amant, MD, PhD, assistant professor, gynecologic oncologist, and head of the scientific section of gynecologic oncology at Katholieke Universiteit in Leuven, Belgium.
In Europe, there are approximately 2500 to 5000 cases of cancer diagnosed during pregnancy every year; however, it remains unclear how systemic chemotherapy affects the development of the fetus, he said.
This is a common situation, and one that many doctors face, said Michael Baumann, MD, PhD, a radiation oncologist from the University of Technology, Dresden, Germany, and president of the European CanCer Organisation. "That is why this study is so important," he said.
There are a lot of data related to radiotherapy and its use in pregnancy, said Dr. Baumann, who moderated a press briefing during which the highlights of this study were presented. " That there are now good data on chemotherapy.... This is a paradigm shift that we see here."
Neuro and Cardiac Function Normal
In their study, Dr. Amant and colleagues looked at the potential negative effects of in utero exposure to chemotherapy. Participants ranged in age from 18 months to 18 years. Of the 140 children currently in the study, complete data are available for 70.
The children were all evaluated at birth and approximately every 2 years after. Their general health was assessed, and they underwent neuropsychologic testing to assess intelligence, verbal and nonverbal memory, attention, working memory, and behavior.
The mean gestational age at cancer diagnosis was 18.1 weeks, and a total of 236 cycles of chemotherapy were given in the cohort.
About half of the women were diagnosed with breast cancer (51%), and 26% were diagnosed with hematologic cancers. Other diagnoses included cervical cancer, ovarian cancer, and malignancies of the brain, skin, and colorectum. Half of the patients (50%) received chemotherapy, and 38% underwent surgery and received chemotherapy. Treatment was given at a median gestational age of 17 weeks (range, 12 to 37 weeks).
The median gestational age of the children at birth was 35.7 weeks, and intrauterine growth retardation was observed in almost 21% of the children.
Cardiac function was evaluated by electrocardiography and echocardiography. It was necessary to assess for possible cardiac problems because the majority of these women were given anthracyclines, explained Dr. Amant. In breast and gynecologic cancers, "anthracyclines are very important. The majority of children — almost 80% — were exposed to anthracyclines, which can pass through the placenta, so it is very important to assess heart function."
The median follow-up was almost 2 years, although some were followed for up to 18 years.
At birth, no congenital heart defects were observed, and cardiac function was normal. Most of the children had adequate neurologic function and normal cardiac function, explained Dr. Amant; rates were similar to those seen in the general population.
High Rate of Premature Birth
Premature birth was very common in this population, with 47 of the 70 children born before 40 weeks of gestation (66%), and 7 born at 26 to 32 weeks.
Although cognitive development was in the normal range for the majority of the cohort, children who fell below the normal parameters tended to be premature. Because developmental delay is common in children who are premature, Dr. Amant explained, they are unable to tell if these issues are related to chemotherapy exposure.
"We can't exclude the effects of chemotherapy in preterm children," he told Medscape Medical News. "They do worse, we know that, but whether it's the prematurity or the chemotherapy — that is an unanswered question."
Because the majority of the children have done well, Dr. Amant surmised that the cognitive issues in those born premature are not related to the chemotherapy.
Normal findings were observed in 64 children (91.4%), which conforms to the general population.
Developmental Issues in Twins
Two serious problems emerged with a set of twins who were born at 32.5 weeks of gestation. The mother had been treated for leukemia. The male twin was autistic and had other serious neurodevelopmental delays and problems; the female twin also had some degree of neurodevelopmental delay.
Although prenatal exposure to chemotherapeutic agents cannot be completely ruled out, Dr. Amant feels that it was probably not the cause of the severe problems observed in the male twin. Geneticists who studied the data tend to think that the child had some sort of syndrome, he pointed out, which was not related to the chemotherapy. "But we can't rule it out right now," he said.
The high rate of prematurity seen in this study was not caused by chemotherapy, but was most likely related to the strategy of delivering the baby as soon as it becomes viable and then beginning chemotherapy, explained Dr. Amant.
Chemotherapy Should Not Be Feared
"Our message is that we prefer to give chemotherapy until the baby is mature; after the baby is delivered, we continue maternal treatment," said Dr. Amant. "The baby loses 2.5 IQ points for each week that he or she is delivered early."
"We think that the baby has less trauma from chemotherapy than from prematurity," he explained. "In our setting, this changes how we treat patients."
This is not a perfect study, Dr. Amant acknowledged; it was both retrospective and prospective, and had a relatively short follow-up.
"But we think that the fear of chemotherapy should no longer be an indication to terminate a pregnancy, and it should no longer be a reason to delay maternal treatment, which can affect maternal prognosis," Dr. Amant explained.
More Data Needed
"We are quite confident that these children will continue to perform normally, but we need more follow-up and more children," he said. "Right now, the group is too small to make a statement on clinical practice change."
George Pentheroudakis, MD, PhD, who acted as discussant for the paper, agrees that a longer follow-up is needed.
Although the study showed that chemotherapy can be administered with reasonable safety after the first trimester of pregnancy, there are still a number of unanswered questions, noted Dr. Pentheroudakis, who is from the University of Ioannina, Greece.
There are a few children in the study with severe neurocognitive deficits, he pointed out, noting that more careful interpretation of the results is needed. In addition, the "course of these deficits over time" need to be determined.
Undetected cardiac toxicity is a potential problem for these children. Although the electrocardiogram and echocardiogram are good tools, they might not be sensitive enough for the early detection of subclinical cardiac damage, he said.
Also, there was a high incidence of prematurity in the cohort. "What are the causes of prematurity," he wondered. "Is it maternal age, the presence of cancer,...or the cancer treatment that was administered?
Much is still unknown about the long-term effects of chemotherapy exposure, said Dr. Pentheroudakis. "We don't know about fertility or germ cell mutagenesis in the children and their future offspring. More data are needed."
For now, on the basis of these data, the fear of chemotherapy is not a reason to delay treatment that can affect maternal prognosis, he said. "It seems that chemotherapy can be administered with reasonable safety after the first trimester, and there is emerging evidence that the mid- and long-term health of these children is normal."
The results of the small study, presented during a presidential session here at the 2011 European Multidisciplinary Cancer Congress, show that children who were exposed to chemotherapy in utero did not appear to suffer any detrimental effects in terms of general health and neurologic and cardiac functioning.
Treating cancer in pregnant women is complex. One issue, in particular, is the ethics of treating a woman with chemotherapy, "but there are no good data that describe the ethics," said lead author Frederic Amant, MD, PhD, assistant professor, gynecologic oncologist, and head of the scientific section of gynecologic oncology at Katholieke Universiteit in Leuven, Belgium.
In Europe, there are approximately 2500 to 5000 cases of cancer diagnosed during pregnancy every year; however, it remains unclear how systemic chemotherapy affects the development of the fetus, he said.
This is a common situation, and one that many doctors face, said Michael Baumann, MD, PhD, a radiation oncologist from the University of Technology, Dresden, Germany, and president of the European CanCer Organisation. "That is why this study is so important," he said.
There are a lot of data related to radiotherapy and its use in pregnancy, said Dr. Baumann, who moderated a press briefing during which the highlights of this study were presented. " That there are now good data on chemotherapy.... This is a paradigm shift that we see here."
Neuro and Cardiac Function Normal
In their study, Dr. Amant and colleagues looked at the potential negative effects of in utero exposure to chemotherapy. Participants ranged in age from 18 months to 18 years. Of the 140 children currently in the study, complete data are available for 70.
The children were all evaluated at birth and approximately every 2 years after. Their general health was assessed, and they underwent neuropsychologic testing to assess intelligence, verbal and nonverbal memory, attention, working memory, and behavior.
The mean gestational age at cancer diagnosis was 18.1 weeks, and a total of 236 cycles of chemotherapy were given in the cohort.
About half of the women were diagnosed with breast cancer (51%), and 26% were diagnosed with hematologic cancers. Other diagnoses included cervical cancer, ovarian cancer, and malignancies of the brain, skin, and colorectum. Half of the patients (50%) received chemotherapy, and 38% underwent surgery and received chemotherapy. Treatment was given at a median gestational age of 17 weeks (range, 12 to 37 weeks).
The median gestational age of the children at birth was 35.7 weeks, and intrauterine growth retardation was observed in almost 21% of the children.
Cardiac function was evaluated by electrocardiography and echocardiography. It was necessary to assess for possible cardiac problems because the majority of these women were given anthracyclines, explained Dr. Amant. In breast and gynecologic cancers, "anthracyclines are very important. The majority of children — almost 80% — were exposed to anthracyclines, which can pass through the placenta, so it is very important to assess heart function."
The median follow-up was almost 2 years, although some were followed for up to 18 years.
At birth, no congenital heart defects were observed, and cardiac function was normal. Most of the children had adequate neurologic function and normal cardiac function, explained Dr. Amant; rates were similar to those seen in the general population.
High Rate of Premature Birth
Premature birth was very common in this population, with 47 of the 70 children born before 40 weeks of gestation (66%), and 7 born at 26 to 32 weeks.
Although cognitive development was in the normal range for the majority of the cohort, children who fell below the normal parameters tended to be premature. Because developmental delay is common in children who are premature, Dr. Amant explained, they are unable to tell if these issues are related to chemotherapy exposure.
"We can't exclude the effects of chemotherapy in preterm children," he told Medscape Medical News. "They do worse, we know that, but whether it's the prematurity or the chemotherapy — that is an unanswered question."
Because the majority of the children have done well, Dr. Amant surmised that the cognitive issues in those born premature are not related to the chemotherapy.
Normal findings were observed in 64 children (91.4%), which conforms to the general population.
Developmental Issues in Twins
Two serious problems emerged with a set of twins who were born at 32.5 weeks of gestation. The mother had been treated for leukemia. The male twin was autistic and had other serious neurodevelopmental delays and problems; the female twin also had some degree of neurodevelopmental delay.
Although prenatal exposure to chemotherapeutic agents cannot be completely ruled out, Dr. Amant feels that it was probably not the cause of the severe problems observed in the male twin. Geneticists who studied the data tend to think that the child had some sort of syndrome, he pointed out, which was not related to the chemotherapy. "But we can't rule it out right now," he said.
The high rate of prematurity seen in this study was not caused by chemotherapy, but was most likely related to the strategy of delivering the baby as soon as it becomes viable and then beginning chemotherapy, explained Dr. Amant.
Chemotherapy Should Not Be Feared
"Our message is that we prefer to give chemotherapy until the baby is mature; after the baby is delivered, we continue maternal treatment," said Dr. Amant. "The baby loses 2.5 IQ points for each week that he or she is delivered early."
"We think that the baby has less trauma from chemotherapy than from prematurity," he explained. "In our setting, this changes how we treat patients."
This is not a perfect study, Dr. Amant acknowledged; it was both retrospective and prospective, and had a relatively short follow-up.
"But we think that the fear of chemotherapy should no longer be an indication to terminate a pregnancy, and it should no longer be a reason to delay maternal treatment, which can affect maternal prognosis," Dr. Amant explained.
More Data Needed
"We are quite confident that these children will continue to perform normally, but we need more follow-up and more children," he said. "Right now, the group is too small to make a statement on clinical practice change."
George Pentheroudakis, MD, PhD, who acted as discussant for the paper, agrees that a longer follow-up is needed.
Although the study showed that chemotherapy can be administered with reasonable safety after the first trimester of pregnancy, there are still a number of unanswered questions, noted Dr. Pentheroudakis, who is from the University of Ioannina, Greece.
There are a few children in the study with severe neurocognitive deficits, he pointed out, noting that more careful interpretation of the results is needed. In addition, the "course of these deficits over time" need to be determined.
Undetected cardiac toxicity is a potential problem for these children. Although the electrocardiogram and echocardiogram are good tools, they might not be sensitive enough for the early detection of subclinical cardiac damage, he said.
Also, there was a high incidence of prematurity in the cohort. "What are the causes of prematurity," he wondered. "Is it maternal age, the presence of cancer,...or the cancer treatment that was administered?
Much is still unknown about the long-term effects of chemotherapy exposure, said Dr. Pentheroudakis. "We don't know about fertility or germ cell mutagenesis in the children and their future offspring. More data are needed."
For now, on the basis of these data, the fear of chemotherapy is not a reason to delay treatment that can affect maternal prognosis, he said. "It seems that chemotherapy can be administered with reasonable safety after the first trimester, and there is emerging evidence that the mid- and long-term health of these children is normal."
TWICE DAILY ASPIRIN MAY BE BETTER FOR DIABETICS
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Twice-daily aspirin administration, but not a once-daily doubling of the dose, appears to provide good inhibition of platelet cyclooxygenase (COX)-1 in diabetic patients who have rapid recovery of COX-1 activity and might enhance cardiovascular protection, Francesco Zaccardi, MD, a diabetology fellow at Catholic University of Sacred Heart in Rome, Italy, reported here at the European Association for the Study of Diabetes (EASD) 47th Annual Meeting.
Aspirin is currently recommended for cardiovascular protection for patients with type 2 diabetes mellitus, regardless of prior vascular events. But primary prevention trials have failed to demonstrate its efficacy in this population, possibly because of incomplete platelet inhibition. Italian researchers, led by Dr. Zaccardi, investigated glycemic control and other factors as possible reasons for the incomplete inhibition of thromboxane A2 by low-dose aspirin over 24 hours. Thromboxane A2, a product of COX-1 activity, is prothrombotic.
The investigators recruited 100 patients with type 2 diabetes who were taking 100 mg of aspirin daily. They measured thromboxane B2, the hydrolysis product of thromboxane A2 and a marker of platelet COX-1 activity, every 3 hours, between 12 and 24 hours after an observed aspirin administration, to assess the kinetics of recovery of COX-1 activity. In addition, a subset of 46 patients underwent 24-hour continuous glucose monitoring. Of them, the 33 patients with the steepest slopes of recovery of COX-1 activity were randomly assigned to receive aspirin 100 mg daily (n = 11), 200 mg daily (n = 11), or 100 mg twice daily for 28 days (n = 11). Recovery of COX-1 activity was determined on day 29 during the 12- to 24-hour dosing period.
The researchers found that COX-1 activity showed linear kinetics with large variability among individuals in the slope of recovery of enzyme activity. For the patients in the lowest tertile of recovery of activity, serum thromboxane B2 increased in the 12- to 24-hour period by 0.02 ng/mL per hour (range, 0.01 to 0.03 ng/mL per hour), compared with an increase of 0.14 ng/mL per hour (range, 0.11 to 0.20 ng/mL per hour) for the tertile with the fastest recovery.
Independent predictors of the slope of thromboxane B2 recovery were mean platelet volume (MPV) (P < .0001), higher body mass index (BMI) (P = .007), and age (P = .049). None of the parameters studied in continuous glucose monitoring (e.g., mean 24-hour glycemic value, mean amplitude of glycemic excursions), nor glycated hemoglobin or fasting glucose level, predicted the slope of recovery of thromboxane B2.
In the cohort with the steepest slopes of return of COX-1 activity, the subjects taking 100 mg of aspirin twice daily showed complete normalization of the slope of platelet COX-1 activity; the administration of 200 mg daily did not have such an effect. Compared with 100 mg once daily, the once-daily administration of 200 mg of aspirin reduced the slope of the recovery line by 55%, and 100 mg of aspirin twice daily reduced the slope by 88% (P < .05 for each vs 100 mg once daily).
Considering the predictive effect of MPV, Dr. Zaccardi surmised that the interindividual variability in the return of COX-1 activity probably reflects abnormal megakaryopoiesis associated with type 2 diabetes. Furthermore, BMI might affect the pharmacokinetics after aspirin dosing. He concluded that twice-daily aspirin administration can overcome the inadequate thromboxane B2 inhibition seen with once-daily dosing. He advised performing larger, randomized clinical trials to test the safety and effectiveness of this approach.
Since it is not feasible to measure COX-1 activity or thromboxane B2 in routine clinical practice, Dr. Zaccardi told Medscape Medical News that in the future, we will likely "have to focus more attention on BMI, on age, and on MPV, because it's very easy to measure BMI and to obtain the value of MPV from a single blood analysis."
In summary, he said that an important finding of the study is that "one third of type 2 diabetic patients are poor responders to aspirin, and probably they need twice-daily administration of aspirin." He speculated that the one third of patients who are poor responders to aspirin might have diluted out an effect in the other two thirds in primary prevention trials, possibly accounting for the failure of those trials to show efficacy.
With twice-daily dosing, compliance could be a problem. A slow-release formulation of 200 mg of aspirin could be helpful, but does not now exist, Dr. Zaccardi said. Session cochair Michael Cummings, MD, professor of diabetes and endocrinology in Portsmouth, United Kingdom, said he doubts that adding 1 more pill a day for an elderly type 2 diabetic patient on multiple medications already would present much of an additional problem.
He noted that guidelines in the United States and in Europe focus on using once-daily aspirin, so the study is intriguing for its use of twice-daily dosing, which has not been studied previously. "The implications of the study could be that a simple change to the way that we dose aspirin at the moment — [twice-daily] dosing — could lead to different clinical outcomes, and could perhaps have more pronounced cardiovascular benefits than we're seeing with once-daily aspirin," he said, "particularly in patients with type 2 diabetes."
Dr. Cummings noted that it is becoming increasingly apparent that how and when drugs are administered can change outcomes. As an example, he cited recent work showing that nighttime dosing of antihypertension drugs is probably better than taking them in the morning.
Dr. Cummings advised that future trials of aspirin in people with type 2 diabetes will need to look at cardiovascular outcomes, not just mechanisms of platelet inhibition. Dr. Zaccardi agreed, and said that in light of current good regimens for glycemic, cholesterol, and blood pressure control, "what we have to improve is the problem of [platelet] aggregation in diabetic patients. It is probable that this study could represent a solution...[to] the reduced ability of aspirin to block COX-1."
Aspirin is currently recommended for cardiovascular protection for patients with type 2 diabetes mellitus, regardless of prior vascular events. But primary prevention trials have failed to demonstrate its efficacy in this population, possibly because of incomplete platelet inhibition. Italian researchers, led by Dr. Zaccardi, investigated glycemic control and other factors as possible reasons for the incomplete inhibition of thromboxane A2 by low-dose aspirin over 24 hours. Thromboxane A2, a product of COX-1 activity, is prothrombotic.
The investigators recruited 100 patients with type 2 diabetes who were taking 100 mg of aspirin daily. They measured thromboxane B2, the hydrolysis product of thromboxane A2 and a marker of platelet COX-1 activity, every 3 hours, between 12 and 24 hours after an observed aspirin administration, to assess the kinetics of recovery of COX-1 activity. In addition, a subset of 46 patients underwent 24-hour continuous glucose monitoring. Of them, the 33 patients with the steepest slopes of recovery of COX-1 activity were randomly assigned to receive aspirin 100 mg daily (n = 11), 200 mg daily (n = 11), or 100 mg twice daily for 28 days (n = 11). Recovery of COX-1 activity was determined on day 29 during the 12- to 24-hour dosing period.
The researchers found that COX-1 activity showed linear kinetics with large variability among individuals in the slope of recovery of enzyme activity. For the patients in the lowest tertile of recovery of activity, serum thromboxane B2 increased in the 12- to 24-hour period by 0.02 ng/mL per hour (range, 0.01 to 0.03 ng/mL per hour), compared with an increase of 0.14 ng/mL per hour (range, 0.11 to 0.20 ng/mL per hour) for the tertile with the fastest recovery.
Independent predictors of the slope of thromboxane B2 recovery were mean platelet volume (MPV) (P < .0001), higher body mass index (BMI) (P = .007), and age (P = .049). None of the parameters studied in continuous glucose monitoring (e.g., mean 24-hour glycemic value, mean amplitude of glycemic excursions), nor glycated hemoglobin or fasting glucose level, predicted the slope of recovery of thromboxane B2.
In the cohort with the steepest slopes of return of COX-1 activity, the subjects taking 100 mg of aspirin twice daily showed complete normalization of the slope of platelet COX-1 activity; the administration of 200 mg daily did not have such an effect. Compared with 100 mg once daily, the once-daily administration of 200 mg of aspirin reduced the slope of the recovery line by 55%, and 100 mg of aspirin twice daily reduced the slope by 88% (P < .05 for each vs 100 mg once daily).
Considering the predictive effect of MPV, Dr. Zaccardi surmised that the interindividual variability in the return of COX-1 activity probably reflects abnormal megakaryopoiesis associated with type 2 diabetes. Furthermore, BMI might affect the pharmacokinetics after aspirin dosing. He concluded that twice-daily aspirin administration can overcome the inadequate thromboxane B2 inhibition seen with once-daily dosing. He advised performing larger, randomized clinical trials to test the safety and effectiveness of this approach.
Since it is not feasible to measure COX-1 activity or thromboxane B2 in routine clinical practice, Dr. Zaccardi told Medscape Medical News that in the future, we will likely "have to focus more attention on BMI, on age, and on MPV, because it's very easy to measure BMI and to obtain the value of MPV from a single blood analysis."
In summary, he said that an important finding of the study is that "one third of type 2 diabetic patients are poor responders to aspirin, and probably they need twice-daily administration of aspirin." He speculated that the one third of patients who are poor responders to aspirin might have diluted out an effect in the other two thirds in primary prevention trials, possibly accounting for the failure of those trials to show efficacy.
With twice-daily dosing, compliance could be a problem. A slow-release formulation of 200 mg of aspirin could be helpful, but does not now exist, Dr. Zaccardi said. Session cochair Michael Cummings, MD, professor of diabetes and endocrinology in Portsmouth, United Kingdom, said he doubts that adding 1 more pill a day for an elderly type 2 diabetic patient on multiple medications already would present much of an additional problem.
He noted that guidelines in the United States and in Europe focus on using once-daily aspirin, so the study is intriguing for its use of twice-daily dosing, which has not been studied previously. "The implications of the study could be that a simple change to the way that we dose aspirin at the moment — [twice-daily] dosing — could lead to different clinical outcomes, and could perhaps have more pronounced cardiovascular benefits than we're seeing with once-daily aspirin," he said, "particularly in patients with type 2 diabetes."
Dr. Cummings noted that it is becoming increasingly apparent that how and when drugs are administered can change outcomes. As an example, he cited recent work showing that nighttime dosing of antihypertension drugs is probably better than taking them in the morning.
Dr. Cummings advised that future trials of aspirin in people with type 2 diabetes will need to look at cardiovascular outcomes, not just mechanisms of platelet inhibition. Dr. Zaccardi agreed, and said that in light of current good regimens for glycemic, cholesterol, and blood pressure control, "what we have to improve is the problem of [platelet] aggregation in diabetic patients. It is probable that this study could represent a solution...[to] the reduced ability of aspirin to block COX-1."
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