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.
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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."
MASTECTOMY OFFERS NO SURVIVAL ADVANTAGE IN YOUNG WOMEN
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Lumpectomy with adjuvant radiation and mastectomy provide "equivalent" overall and disease-specific survival in young women with early breast cancer, according to a new study presented at a press conference today in advance of the start of the 2011 Breast Cancer Symposium.
Young women "should not choose a mastectomy based on the assumption of improved survival," said lead investigator Usama Mahmood, MD, who was at the University of Maryland in Baltimore when the study was undertaken.
"Young age alone does not mandate mastectomy," commented Andrew Seidman, MD, from Memorial Sloan-Kettering Cancer Center in New York City, who moderated the press briefing. His comments related to this study and another reported at the briefing, which found similar rates of local recurrence with the 2 competing surgical approaches.
Using the Surveillance, Epidemiology, and End Results (SEER) database, Dr. Mahmood and colleagues reviewed outcomes among 14,760 women aged 20 to 39 years who were diagnosed with early-stage breast cancer (T1-2, N0-1, M0) between 1990 and 2007.
The women underwent breast-conserving therapy (45%; lumpectomy and radiation treatment) or mastectomy (55%). Everyone in the breast conservation group received adjuvant radiation, but only 17% of the mastectomy group received radiation.
A multivariable analysis that included tumor characteristics found that breast-conserving therapy resulted in similar overall survival (hazard ratio [HR], 0.93; P = .16) and breast cancer–specific survival (HR, 0.93; P = .26) as mastectomy, said Dr. Mahmood, who is now a fellow in radiation oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
Median follow-up duration was 5.7 years.
A matched-pair analysis involving a subset of 4644 of the patients confirmed no difference in overall survival and disease-specific survival, he also said. The patients were matched according to specific factors such as tumor size, tumor grade, and number of positive nodes.
In this analysis, at 5, 10, and 15 years, the overall survival rates for the breast conservation group were 92.5%, 83.5%, and 77%, respectively. For patients who underwent mastectomy, overall survival rates were 91.9%, 83.6%, and 79.1%, respectively. Breast cancer–specific survival rates were also similar between the 2 groups of women, said Dr. Mahmood.
The study's importance is, in part, due to other research findings, suggested Dr. Mahmood. A series of studies presented in the 1980s comparing breast-conserving therapy and mastectomy found equivalent survival among women with early breast cancer. But the number of young women in those studies was small, he said.
Other research has not encouraged the use of breast-conserving therapy in young women, he suggested.
"Previous studies have shown that young women with breast cancer treated with breast-conservation therapy experience higher local recurrence rates," he said. However, those findings were challenged by another study presented at the press conference. The combination of 2 new studies "should make us question that mastectomy is the only option for young women with breast cancer," said Dr. Seidman, who added the caveat that BRCA status is also a key to decision-making in young women.
The new study "serves as a reminder that women should be counseled appropriately about their treatment options," said Dr. Mahmood.
"The data is the data"
The factors included in the multivariate analysis included year of diagnosis, age, race/ethnicity, tumor grade, progesterone receptor status, tumor size, and lymph node status, noted the study authors. Patients had no more than 3 positive nodes, added Dr. Mahmood.
These are standard factors to consider when assessing breast cancer, suggested Dr. Seidman.
The new analysis did not include a number of factors that might also be used to make treatment decisions in the clinic, he further suggested. For instance, there are biological and luminal subtypes, as well the oncotype recurrence score, all of which may help clinicians and patients in their decision-making, he said.
"But most of us don't think about using that information as a decisive factor in the decision to undergo mastectomy or breast conservation therapy," Dr. Seidman said about these more recently identified breast cancer characteristics and newer tests.
Magnetic resonance imaging (MRI) may or may not have an important role to play in this decision-making process, he suggested. It is used to evaluate breast cancer in the preoperative setting to "better select" patients for the type of surgery, he said.
However, whether or not the use of MRI confers a survival advantage is "not settled," according to Dr. Seidman. "There is an epidemic of breast MRI," he said, quoting his colleague Monica Morrow, MD, from Memorial-Sloan Kettering Cancer Center.
"The data is the data," he said about the study, suggesting that any equivocations about the results and any missing factors in the analysis were not merited.
The investigators have disclosed no relevant financial relationships.
Young women "should not choose a mastectomy based on the assumption of improved survival," said lead investigator Usama Mahmood, MD, who was at the University of Maryland in Baltimore when the study was undertaken.
"Young age alone does not mandate mastectomy," commented Andrew Seidman, MD, from Memorial Sloan-Kettering Cancer Center in New York City, who moderated the press briefing. His comments related to this study and another reported at the briefing, which found similar rates of local recurrence with the 2 competing surgical approaches.
Using the Surveillance, Epidemiology, and End Results (SEER) database, Dr. Mahmood and colleagues reviewed outcomes among 14,760 women aged 20 to 39 years who were diagnosed with early-stage breast cancer (T1-2, N0-1, M0) between 1990 and 2007.
The women underwent breast-conserving therapy (45%; lumpectomy and radiation treatment) or mastectomy (55%). Everyone in the breast conservation group received adjuvant radiation, but only 17% of the mastectomy group received radiation.
A multivariable analysis that included tumor characteristics found that breast-conserving therapy resulted in similar overall survival (hazard ratio [HR], 0.93; P = .16) and breast cancer–specific survival (HR, 0.93; P = .26) as mastectomy, said Dr. Mahmood, who is now a fellow in radiation oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
Median follow-up duration was 5.7 years.
A matched-pair analysis involving a subset of 4644 of the patients confirmed no difference in overall survival and disease-specific survival, he also said. The patients were matched according to specific factors such as tumor size, tumor grade, and number of positive nodes.
In this analysis, at 5, 10, and 15 years, the overall survival rates for the breast conservation group were 92.5%, 83.5%, and 77%, respectively. For patients who underwent mastectomy, overall survival rates were 91.9%, 83.6%, and 79.1%, respectively. Breast cancer–specific survival rates were also similar between the 2 groups of women, said Dr. Mahmood.
The study's importance is, in part, due to other research findings, suggested Dr. Mahmood. A series of studies presented in the 1980s comparing breast-conserving therapy and mastectomy found equivalent survival among women with early breast cancer. But the number of young women in those studies was small, he said.
Other research has not encouraged the use of breast-conserving therapy in young women, he suggested.
"Previous studies have shown that young women with breast cancer treated with breast-conservation therapy experience higher local recurrence rates," he said. However, those findings were challenged by another study presented at the press conference. The combination of 2 new studies "should make us question that mastectomy is the only option for young women with breast cancer," said Dr. Seidman, who added the caveat that BRCA status is also a key to decision-making in young women.
The new study "serves as a reminder that women should be counseled appropriately about their treatment options," said Dr. Mahmood.
"The data is the data"
The factors included in the multivariate analysis included year of diagnosis, age, race/ethnicity, tumor grade, progesterone receptor status, tumor size, and lymph node status, noted the study authors. Patients had no more than 3 positive nodes, added Dr. Mahmood.
These are standard factors to consider when assessing breast cancer, suggested Dr. Seidman.
The new analysis did not include a number of factors that might also be used to make treatment decisions in the clinic, he further suggested. For instance, there are biological and luminal subtypes, as well the oncotype recurrence score, all of which may help clinicians and patients in their decision-making, he said.
"But most of us don't think about using that information as a decisive factor in the decision to undergo mastectomy or breast conservation therapy," Dr. Seidman said about these more recently identified breast cancer characteristics and newer tests.
Magnetic resonance imaging (MRI) may or may not have an important role to play in this decision-making process, he suggested. It is used to evaluate breast cancer in the preoperative setting to "better select" patients for the type of surgery, he said.
However, whether or not the use of MRI confers a survival advantage is "not settled," according to Dr. Seidman. "There is an epidemic of breast MRI," he said, quoting his colleague Monica Morrow, MD, from Memorial-Sloan Kettering Cancer Center.
"The data is the data," he said about the study, suggesting that any equivocations about the results and any missing factors in the analysis were not merited.
The investigators have disclosed no relevant financial relationships.
STATINS-A GOOD MEDICINE
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Long-term results of the Anglo-Scandinavian Cardiac Outcomes--Lipid-Lowering Arm (ASCOT-LLA) study, eight years after the trial officially stopped, showed that treatment with 10 mg of atorvastatin (Lipitor, Pfizer) reduced all-cause mortality compared with placebo, mainly through a reduction in noncardiovascular deaths [1].
Presenting the results at a hot-line session today at the European Society of Cardiology (ESC) 2011 Congress, investigators observed that reductions in the risk of death from respiratory illness and infection contributed to the overall reduction in all-cause mortality. "The numbers are large, the data are convincing, but we have no definitive explanation to date for the hypothesized legacy effect of atorvastatin on noncardiovascular-death risk reduction," said lead investigator Dr Peter Sever (Imperial College, London, UK).
The study was published online August 28, 2011 in the European Heart Journal to coincide with the ESC presentation.
Chair of the hot-line session, Dr George Parcharidis (Aristotle University of Thessaloniki, Greece), asked, somewhat tongue-in-cheek, whether the data were sufficiently strong to support prescribing all young adults a statin for long-term treatment in the hope of reducing all-cause mortality. "They say that one swallow does not make a summer, and I would never advocate atorvastatin to young people on the basis of these findings," responded Sever. "But what these findings do demand is a prospective study in patients at high risk for infection to determine whether the presence of a statin could reduce serious sepsis or death from serious infectious illness."
ASCOT-LLA and the Long-Term Effects of Atorvastatin
The results of ASCOT-LLA were first presented and simultaneously published online in theLancet in 2003 [2]. As reported by heartwire , lipid lowering with atorvastatin resulted in a significant 36% reduction in the primary end point of fatal coronary heart disease and nonfatal MI after a median follow-up of 3.3 years. At the time the study was stopped, there was a nonsignificant trend toward reduction in all-cause mortality. Upon completion of ASCOT-LLA, investigators continued to collect mortality data and evaluated the mortality outcomes in participants originally randomized to atorvastatin or placebo in the ASCOT-LLA arm for a median of 11 years.
At the end of the extended follow-up, all-cause mortality was significantly reduced by 14% (hazard ratio [HR] 0.86; 95% CI 0.76–0.98), and noncardiovascular mortality was significantly reduced by 15% (HR 0.85; 95% CI 0.73–0.99). There was no difference in death from cardiovascular causes.
Looking more closely at deaths from noncardiovascular causes, investigators found that deaths due to cancer were not statistically significant between those treated with atorvastatin vs placebo. There was, however, a significant 36% reduction in deaths due to infection and respiratory illness (HR 0.64; 95% CI 0.42–0.97), driven primarily by deaths due to infection.
During the session, Sever noted there are emerging data on the effects of statins on infection, with preclinical studies showing statins modulate neutrophil function, reduce proinflammatory cytokine release, improve vascular function, have antithrombotic properties, and improve outcomes from pneumonia and sepsis. Results of other observational studies have suggested that prior statin use reduces mortality from sepsis. Despite these observations, Sever said that there is still the possibility of confounding bias in some of the observational studies that have shown a benefit of statins in pneumonia and sepsis and that caution should be used when interpreting such results until a randomized clinical trial is performed.
Serious Decision for Primary Prevention Patients
Dr Guy De Backer (University Hospital, Ghent, Belgium), the discussant who also wrote an editorial that accompanies the published study [3], said that the introduction of statins into primary prevention is a serious decision considering that asymptomatic patients would be advised to take a drug for the rest of their lives and the only treatment benefit would be that "nothing happens." Moreover, there is little long-term safety data. For these primary-prevention trials, the mean patient age is 55 to 66 years old and the median length of statin use is just under five years, and yet primary-prevention patients would likely be treated with a statin for 15 to 20 years.
For this reason, the long-term ASCOT-LLA study is welcome, said De Backer. In primary-prevention studies, the most important clinical outcome is total mortality and quality of life, he added. One of the reassuring results of ASCOT-LLA is that the results confirm the benefits observed in the Scandinavian Simvastatin Survival Study (4S) and West of Scotland Prevention Study (WOSCOPS). In 4S, WOSCOPS, and ASCOT-LLA, there were significant 15%, 12%, and 14% reductions in all-cause mortality, respectively--all achieving statistical significance. He added that data suggesting a therapeutic role for statins in the management of pneumonia and sepsis are supported by observational studies.
Still, De Backer, like Sever, urges caution in interpreting the findings, especially because there is no explanation for the long-term carryover effect of statins on all-cause mortality but not on cardiovascular mortality. The data are essentially a subgroup analysis, and the reduction in all-cause mortality might be the result of chance, De Backer added. Quoting Dr Peter Sleight (Oxford University, UK), De Backer said, "Subgroup analyses are fun to look at, but don't believe them."
Presenting the results at a hot-line session today at the European Society of Cardiology (ESC) 2011 Congress, investigators observed that reductions in the risk of death from respiratory illness and infection contributed to the overall reduction in all-cause mortality. "The numbers are large, the data are convincing, but we have no definitive explanation to date for the hypothesized legacy effect of atorvastatin on noncardiovascular-death risk reduction," said lead investigator Dr Peter Sever (Imperial College, London, UK).
The study was published online August 28, 2011 in the European Heart Journal to coincide with the ESC presentation.
Chair of the hot-line session, Dr George Parcharidis (Aristotle University of Thessaloniki, Greece), asked, somewhat tongue-in-cheek, whether the data were sufficiently strong to support prescribing all young adults a statin for long-term treatment in the hope of reducing all-cause mortality. "They say that one swallow does not make a summer, and I would never advocate atorvastatin to young people on the basis of these findings," responded Sever. "But what these findings do demand is a prospective study in patients at high risk for infection to determine whether the presence of a statin could reduce serious sepsis or death from serious infectious illness."
ASCOT-LLA and the Long-Term Effects of Atorvastatin
The results of ASCOT-LLA were first presented and simultaneously published online in theLancet in 2003 [2]. As reported by heartwire , lipid lowering with atorvastatin resulted in a significant 36% reduction in the primary end point of fatal coronary heart disease and nonfatal MI after a median follow-up of 3.3 years. At the time the study was stopped, there was a nonsignificant trend toward reduction in all-cause mortality. Upon completion of ASCOT-LLA, investigators continued to collect mortality data and evaluated the mortality outcomes in participants originally randomized to atorvastatin or placebo in the ASCOT-LLA arm for a median of 11 years.
At the end of the extended follow-up, all-cause mortality was significantly reduced by 14% (hazard ratio [HR] 0.86; 95% CI 0.76–0.98), and noncardiovascular mortality was significantly reduced by 15% (HR 0.85; 95% CI 0.73–0.99). There was no difference in death from cardiovascular causes.
Looking more closely at deaths from noncardiovascular causes, investigators found that deaths due to cancer were not statistically significant between those treated with atorvastatin vs placebo. There was, however, a significant 36% reduction in deaths due to infection and respiratory illness (HR 0.64; 95% CI 0.42–0.97), driven primarily by deaths due to infection.
During the session, Sever noted there are emerging data on the effects of statins on infection, with preclinical studies showing statins modulate neutrophil function, reduce proinflammatory cytokine release, improve vascular function, have antithrombotic properties, and improve outcomes from pneumonia and sepsis. Results of other observational studies have suggested that prior statin use reduces mortality from sepsis. Despite these observations, Sever said that there is still the possibility of confounding bias in some of the observational studies that have shown a benefit of statins in pneumonia and sepsis and that caution should be used when interpreting such results until a randomized clinical trial is performed.
Serious Decision for Primary Prevention Patients
Dr Guy De Backer (University Hospital, Ghent, Belgium), the discussant who also wrote an editorial that accompanies the published study [3], said that the introduction of statins into primary prevention is a serious decision considering that asymptomatic patients would be advised to take a drug for the rest of their lives and the only treatment benefit would be that "nothing happens." Moreover, there is little long-term safety data. For these primary-prevention trials, the mean patient age is 55 to 66 years old and the median length of statin use is just under five years, and yet primary-prevention patients would likely be treated with a statin for 15 to 20 years.
For this reason, the long-term ASCOT-LLA study is welcome, said De Backer. In primary-prevention studies, the most important clinical outcome is total mortality and quality of life, he added. One of the reassuring results of ASCOT-LLA is that the results confirm the benefits observed in the Scandinavian Simvastatin Survival Study (4S) and West of Scotland Prevention Study (WOSCOPS). In 4S, WOSCOPS, and ASCOT-LLA, there were significant 15%, 12%, and 14% reductions in all-cause mortality, respectively--all achieving statistical significance. He added that data suggesting a therapeutic role for statins in the management of pneumonia and sepsis are supported by observational studies.
Still, De Backer, like Sever, urges caution in interpreting the findings, especially because there is no explanation for the long-term carryover effect of statins on all-cause mortality but not on cardiovascular mortality. The data are essentially a subgroup analysis, and the reduction in all-cause mortality might be the result of chance, De Backer added. Quoting Dr Peter Sleight (Oxford University, UK), De Backer said, "Subgroup analyses are fun to look at, but don't believe them."
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