Neil Osterweil

BOSTON — The route of hormonal contraceptive administration—transdermal or oral—does not make a difference in terms of the hormone's effect on plasma lipids and lipoproteins, according to the findings of a randomized crossover trial.

In the study, women on either a standard or extended-release contraceptive patch had higher levels of HDL cholesterol and its constituent apolipoprotein A1 (ApoA-1), compared with when they were taking oral contraceptives; however, the effects of patch and oral formulations on atherogenic lipoproteins were similar, Dr. Elizabeth Chan reported at a symposium sponsored by the International Atherosclerosis Society.

“Patch contraception results in 60% higher estrogen levels than oral contraception. It is the estrogen/progestin ratio that determines the overall lipoprotein effects in hormonal contraception formulations,” according to Dr. Chan, of the University of Washington Division of Cardiology in Seattle, and her colleagues.

Estrogen is known to increase triglycerides and HDL cholesterol, and progestin has been shown to increase LDL and decrease HDL, the authors explained. If differences in these effects do exist among the various administration methods, the cumulative effect could be considerable given women often remain on hormonal contraceptives for decades.

For the study, 35 healthy premenopausal women had a 2-month phase-in period on an oral contraceptive (Ortho-Cyclen; 35 mcg ethinyl estradiol and 0.25 mg norgestimate) and were then randomly assigned in a three-way crossover design to 2 months on either the oral contraceptive, a patch formulation (Ortho-Evra; approximating a daily dose of 20 mcg ethinyl estradiol and 150 mcg norelgestromin), or an extended-release patch (Extended Ortho-Evra). A total of 31 women completed all three treatments and were available for the final analysis.

The investigators found that the use of the standard patch formulation resulted in significantly higher levels of favorable lipids—HDL and ApoA1—compared with oral administration. The extended patch also had a significantly greater effect on HDL and ApoA1, compared with the standard patch.

But for all other lipid parameters—LDL, non-HDL cholesterol, apolipoprotein B, and triglycerides—there were no significant differences among the three contraceptive formulations.

The findings “do not provide compelling evidence for selection of one method of hormonal contraception versus another regarding their effects on lipids and lipoproteins,” the authors said.

The researchers reported having no conflicts of interest related to the study, which was supported by Ortho-McNeil, maker of the contraceptives tested.

BOSTON — The route of hormonal contraceptive administration—transdermal or oral—does not make a difference in terms of the hormone's effect on plasma lipids and lipoproteins, according to the findings of a randomized crossover trial.

In the study, women on either a standard or extended-release contraceptive patch had higher levels of HDL cholesterol and its constituent apolipoprotein A1 (ApoA-1), compared with when they were taking oral contraceptives; however, the effects of patch and oral formulations on atherogenic lipoproteins were similar, Dr. Elizabeth Chan reported at a symposium sponsored by the International Atherosclerosis Society.

“Patch contraception results in 60% higher estrogen levels than oral contraception. It is the estrogen/progestin ratio that determines the overall lipoprotein effects in hormonal contraception formulations,” according to Dr. Chan, of the University of Washington Division of Cardiology in Seattle, and her colleagues.

Estrogen is known to increase triglycerides and HDL cholesterol, and progestin has been shown to increase LDL and decrease HDL, the authors explained. If differences in these effects do exist among the various administration methods, the cumulative effect could be considerable given women often remain on hormonal contraceptives for decades.

For the study, 35 healthy premenopausal women had a 2-month phase-in period on an oral contraceptive (Ortho-Cyclen; 35 mcg ethinyl estradiol and 0.25 mg norgestimate) and were then randomly assigned in a three-way crossover design to 2 months on either the oral contraceptive, a patch formulation (Ortho-Evra; approximating a daily dose of 20 mcg ethinyl estradiol and 150 mcg norelgestromin), or an extended-release patch (Extended Ortho-Evra). A total of 31 women completed all three treatments and were available for the final analysis.

The investigators found that the use of the standard patch formulation resulted in significantly higher levels of favorable lipids—HDL and ApoA1—compared with oral administration. The extended patch also had a significantly greater effect on HDL and ApoA1, compared with the standard patch.

But for all other lipid parameters—LDL, non-HDL cholesterol, apolipoprotein B, and triglycerides—there were no significant differences among the three contraceptive formulations.

The findings “do not provide compelling evidence for selection of one method of hormonal contraception versus another regarding their effects on lipids and lipoproteins,” the authors said.

The researchers reported having no conflicts of interest related to the study, which was supported by Ortho-McNeil, maker of the contraceptives tested.

BOSTON — The route of hormonal contraceptive administration—transdermal or oral—does not make a difference in terms of the hormone's effect on plasma lipids and lipoproteins, according to the findings of a randomized crossover trial.

In the study, women on either a standard or extended-release contraceptive patch had higher levels of HDL cholesterol and its constituent apolipoprotein A1 (ApoA-1), compared with when they were taking oral contraceptives; however, the effects of patch and oral formulations on atherogenic lipoproteins were similar, Dr. Elizabeth Chan reported at a symposium sponsored by the International Atherosclerosis Society.

“Patch contraception results in 60% higher estrogen levels than oral contraception. It is the estrogen/progestin ratio that determines the overall lipoprotein effects in hormonal contraception formulations,” according to Dr. Chan, of the University of Washington Division of Cardiology in Seattle, and her colleagues.

Estrogen is known to increase triglycerides and HDL cholesterol, and progestin has been shown to increase LDL and decrease HDL, the authors explained. If differences in these effects do exist among the various administration methods, the cumulative effect could be considerable given women often remain on hormonal contraceptives for decades.

For the study, 35 healthy premenopausal women had a 2-month phase-in period on an oral contraceptive (Ortho-Cyclen; 35 mcg ethinyl estradiol and 0.25 mg norgestimate) and were then randomly assigned in a three-way crossover design to 2 months on either the oral contraceptive, a patch formulation (Ortho-Evra; approximating a daily dose of 20 mcg ethinyl estradiol and 150 mcg norelgestromin), or an extended-release patch (Extended Ortho-Evra). A total of 31 women completed all three treatments and were available for the final analysis.

The investigators found that the use of the standard patch formulation resulted in significantly higher levels of favorable lipids—HDL and ApoA1—compared with oral administration. The extended patch also had a significantly greater effect on HDL and ApoA1, compared with the standard patch.

But for all other lipid parameters—LDL, non-HDL cholesterol, apolipoprotein B, and triglycerides—there were no significant differences among the three contraceptive formulations.

The findings “do not provide compelling evidence for selection of one method of hormonal contraception versus another regarding their effects on lipids and lipoproteins,” the authors said.

The researchers reported having no conflicts of interest related to the study, which was supported by Ortho-McNeil, maker of the contraceptives tested.

BOSTON — The most successful diet for weight loss is the one that patients will stick with, provided that it has a balance of protein, fats, and carbohydrates.

“Successful diets for weight loss can emphasize a large range of macronutrient intakes,” Dr. Frank Sacks said at a symposium sponsored by the International Atherosclerosis Society.

“Diets should be made with foods that reduce the risk of cardiovascular events in and of themselves,” added Dr. Sacks, professor of cardiovascular disease prevention at the Harvard School of Public Health in Boston.

In one study, a low-carbohydrate ketogenic (Atkins) diet produced a greater degree of weight loss over 6 months than did a low-fat diet. But the ketogenic diet was associated with more adverse events, including constipation, halitosis, myalgia, and headache (Ann. Intern. Med. 2004;140:769-77).

In a separate, 1-year trial comparing a low-carbohydrate Atkins-style diet with a low-fat diet, patients on the former lost weight more quickly during the first 6 months, but then began to gain it back. Patients on the low-fat diet had a steady and continual decline in weight over 1 year, with the two curves converging so that weight loss between the groups was similar at the end of the study (Ann. Intern. Med. 2004;140;778-85).

“You wonder if the curves are going to converge at some point, and is the tortoise going to catch up with the hare,” Dr. Sacks said in commenting on that study.

Dr. Sacks and his colleagues took a different approach in a 2001 pilot study that compared a Mediterranean-style diet with moderate fat levels to a low-fat diet (Int. J. Obes. Relat. Metab. Disord. 2001;25:1503-11).

Dieters in both groups lost a mean of about 13.5 pounds within 6 months. But patients on the low-fat diet began to regain more weight, and at 18 months their mean weight loss was only about 6 pounds from baseline, while patients on the moderate-fat diet maintained a mean weight loss of 11 pounds from baseline. Only 20% of patients randomized to the low-fat diet were still on it 18 months later, compared with 54% of those randomized to the moderate-fat arm. In both arms, patients who dropped out had a net gain of 9 pounds over starting weight at 18 months, while those who stayed in the program—low-fat or high-fat—had a net loss of 11 pounds.

A common problem with comparative weight-loss trials is that there is no obvious pattern of results favoring a specific fat, carbohydrate, or protein content for weight loss. Also, many diets induce weight loss over 3-6 months, but the loss is not sustained for 1 or 2 years. In addition, up to half of all participants in some studies drop out, and study results may be influenced by the novelty of diets, marketing, or media attention, he said.

To try to cut through the background noise, Dr. Sacks and his colleagues conducted the 2-year PoundsLost study comparing four diets (N. Engl. J. Med. 2009;360:859-73) The investigators randomly assigned 811 overweight adults to one of four diets, with targeted percentages of energy derived from fat, protein, and carbohydrates, respectively, of 20%, 15%, and 65%; 20%, 25%, and 55%; 40%, 15%, and 45%; or 40%, 25%, and 35%. Foods were similar among the four diets, and participants were offered group and individual weight-loss instruction sessions for the duration of the study.

At 2 years, there were no significant differences in weight loss between the 20% and 40% fat-content diets, 15% and 25% protein-content diets, or 35% and 65% carbohydrate diet. About 80% of all participants completed the study, and satiety, hunger, satisfaction with the diet, and attendance at group sessions were similar among all diet groups. The authors found that educational support was a strong predictor of weight loss, with each session attended associated with an average 0.2 kg weight loss. All of the diets improved lipid levels and fasting insulin levels.

“We feel these results have an optimistic message for people,” Dr. Sacks said. “Successful diets for weight loss can be tailored to an individual's personal and cultural preferences to achieve long-term success. It's not so important to focus on particular contents of fat or protein, but more on what people feel comfortable with and can sustain for the long run.”

Dr. Sacks reported that he has received consulting fees and/or performed contracted research for ISIS and Genzyme.

BOSTON — The most successful diet for weight loss is the one that patients will stick with, provided that it has a balance of protein, fats, and carbohydrates.

“Successful diets for weight loss can emphasize a large range of macronutrient intakes,” Dr. Frank Sacks said at a symposium sponsored by the International Atherosclerosis Society.

“Diets should be made with foods that reduce the risk of cardiovascular events in and of themselves,” added Dr. Sacks, professor of cardiovascular disease prevention at the Harvard School of Public Health in Boston.

In one study, a low-carbohydrate ketogenic (Atkins) diet produced a greater degree of weight loss over 6 months than did a low-fat diet. But the ketogenic diet was associated with more adverse events, including constipation, halitosis, myalgia, and headache (Ann. Intern. Med. 2004;140:769-77).

In a separate, 1-year trial comparing a low-carbohydrate Atkins-style diet with a low-fat diet, patients on the former lost weight more quickly during the first 6 months, but then began to gain it back. Patients on the low-fat diet had a steady and continual decline in weight over 1 year, with the two curves converging so that weight loss between the groups was similar at the end of the study (Ann. Intern. Med. 2004;140;778-85).

“You wonder if the curves are going to converge at some point, and is the tortoise going to catch up with the hare,” Dr. Sacks said in commenting on that study.

Dr. Sacks and his colleagues took a different approach in a 2001 pilot study that compared a Mediterranean-style diet with moderate fat levels to a low-fat diet (Int. J. Obes. Relat. Metab. Disord. 2001;25:1503-11).

Dieters in both groups lost a mean of about 13.5 pounds within 6 months. But patients on the low-fat diet began to regain more weight, and at 18 months their mean weight loss was only about 6 pounds from baseline, while patients on the moderate-fat diet maintained a mean weight loss of 11 pounds from baseline. Only 20% of patients randomized to the low-fat diet were still on it 18 months later, compared with 54% of those randomized to the moderate-fat arm. In both arms, patients who dropped out had a net gain of 9 pounds over starting weight at 18 months, while those who stayed in the program—low-fat or high-fat—had a net loss of 11 pounds.

A common problem with comparative weight-loss trials is that there is no obvious pattern of results favoring a specific fat, carbohydrate, or protein content for weight loss. Also, many diets induce weight loss over 3-6 months, but the loss is not sustained for 1 or 2 years. In addition, up to half of all participants in some studies drop out, and study results may be influenced by the novelty of diets, marketing, or media attention, he said.

To try to cut through the background noise, Dr. Sacks and his colleagues conducted the 2-year PoundsLost study comparing four diets (N. Engl. J. Med. 2009;360:859-73) The investigators randomly assigned 811 overweight adults to one of four diets, with targeted percentages of energy derived from fat, protein, and carbohydrates, respectively, of 20%, 15%, and 65%; 20%, 25%, and 55%; 40%, 15%, and 45%; or 40%, 25%, and 35%. Foods were similar among the four diets, and participants were offered group and individual weight-loss instruction sessions for the duration of the study.

At 2 years, there were no significant differences in weight loss between the 20% and 40% fat-content diets, 15% and 25% protein-content diets, or 35% and 65% carbohydrate diet. About 80% of all participants completed the study, and satiety, hunger, satisfaction with the diet, and attendance at group sessions were similar among all diet groups. The authors found that educational support was a strong predictor of weight loss, with each session attended associated with an average 0.2 kg weight loss. All of the diets improved lipid levels and fasting insulin levels.

“We feel these results have an optimistic message for people,” Dr. Sacks said. “Successful diets for weight loss can be tailored to an individual's personal and cultural preferences to achieve long-term success. It's not so important to focus on particular contents of fat or protein, but more on what people feel comfortable with and can sustain for the long run.”

Dr. Sacks reported that he has received consulting fees and/or performed contracted research for ISIS and Genzyme.

BOSTON — The most successful diet for weight loss is the one that patients will stick with, provided that it has a balance of protein, fats, and carbohydrates.

“Successful diets for weight loss can emphasize a large range of macronutrient intakes,” Dr. Frank Sacks said at a symposium sponsored by the International Atherosclerosis Society.

“Diets should be made with foods that reduce the risk of cardiovascular events in and of themselves,” added Dr. Sacks, professor of cardiovascular disease prevention at the Harvard School of Public Health in Boston.

In one study, a low-carbohydrate ketogenic (Atkins) diet produced a greater degree of weight loss over 6 months than did a low-fat diet. But the ketogenic diet was associated with more adverse events, including constipation, halitosis, myalgia, and headache (Ann. Intern. Med. 2004;140:769-77).

In a separate, 1-year trial comparing a low-carbohydrate Atkins-style diet with a low-fat diet, patients on the former lost weight more quickly during the first 6 months, but then began to gain it back. Patients on the low-fat diet had a steady and continual decline in weight over 1 year, with the two curves converging so that weight loss between the groups was similar at the end of the study (Ann. Intern. Med. 2004;140;778-85).

“You wonder if the curves are going to converge at some point, and is the tortoise going to catch up with the hare,” Dr. Sacks said in commenting on that study.

Dr. Sacks and his colleagues took a different approach in a 2001 pilot study that compared a Mediterranean-style diet with moderate fat levels to a low-fat diet (Int. J. Obes. Relat. Metab. Disord. 2001;25:1503-11).

Dieters in both groups lost a mean of about 13.5 pounds within 6 months. But patients on the low-fat diet began to regain more weight, and at 18 months their mean weight loss was only about 6 pounds from baseline, while patients on the moderate-fat diet maintained a mean weight loss of 11 pounds from baseline. Only 20% of patients randomized to the low-fat diet were still on it 18 months later, compared with 54% of those randomized to the moderate-fat arm. In both arms, patients who dropped out had a net gain of 9 pounds over starting weight at 18 months, while those who stayed in the program—low-fat or high-fat—had a net loss of 11 pounds.

A common problem with comparative weight-loss trials is that there is no obvious pattern of results favoring a specific fat, carbohydrate, or protein content for weight loss. Also, many diets induce weight loss over 3-6 months, but the loss is not sustained for 1 or 2 years. In addition, up to half of all participants in some studies drop out, and study results may be influenced by the novelty of diets, marketing, or media attention, he said.

To try to cut through the background noise, Dr. Sacks and his colleagues conducted the 2-year PoundsLost study comparing four diets (N. Engl. J. Med. 2009;360:859-73) The investigators randomly assigned 811 overweight adults to one of four diets, with targeted percentages of energy derived from fat, protein, and carbohydrates, respectively, of 20%, 15%, and 65%; 20%, 25%, and 55%; 40%, 15%, and 45%; or 40%, 25%, and 35%. Foods were similar among the four diets, and participants were offered group and individual weight-loss instruction sessions for the duration of the study.

At 2 years, there were no significant differences in weight loss between the 20% and 40% fat-content diets, 15% and 25% protein-content diets, or 35% and 65% carbohydrate diet. About 80% of all participants completed the study, and satiety, hunger, satisfaction with the diet, and attendance at group sessions were similar among all diet groups. The authors found that educational support was a strong predictor of weight loss, with each session attended associated with an average 0.2 kg weight loss. All of the diets improved lipid levels and fasting insulin levels.

“We feel these results have an optimistic message for people,” Dr. Sacks said. “Successful diets for weight loss can be tailored to an individual's personal and cultural preferences to achieve long-term success. It's not so important to focus on particular contents of fat or protein, but more on what people feel comfortable with and can sustain for the long run.”

Dr. Sacks reported that he has received consulting fees and/or performed contracted research for ISIS and Genzyme.

BOSTON — Proponents of the Atkins low-carbohydrate/high-saturated-fat diet say that you can have your steak and eat it, too, and still lose weight.

But the adverse metabolic consequences are too heavy a price to pay, Australian investigators reported at a symposium sponsored by the International Atherosclerosis Society.

After 1 year, overweight and obese patients randomly assigned to the Atkins diet or to a low-saturated-fat, high-carbohydrate diet lost similar amounts of weight. But patients on the Atkins diet had a deterioration in flow-mediated arterial dilatation, a marker for cardiovascular disease, and higher levels of LDL cholesterol than at baseline, reported Dr. Peter Clifton of the Commonwealth Scientific and Industrial Research Organization (CSIRO) in Adelaide, South Australia.

“What I really want to know is, does the early elevation of HDL, which has been shown convincingly [with the Atkins diet], and lowering of triglycerides plus the lowering of blood pressure and glucose outweigh the rise in LDL cholesterol that you see in some individuals in some studies?” he said.

“Of course, there are no Atkins end point studies, which is a bit disappointing since there are a fair number of advocates of the Atkins diet,” he added.

Dr. Clifton and his colleagues analyzed the effects of two diets on flow-mediated dilatation (FMD), a measurement of the ability of blood vessels to dilate in response to increases in blood flow. FMD is reduced in both cardiovascular disease and diabetes, but whether it improves with significant weight loss is unclear; if so, it might be related to either decreases in glucose or in LDL, Dr. Clifton said.

The study's aim was to evaluate the effects on markers of endothelial dysfunction and cardiovascular disease risk of a very-low-carbohydrate/high-saturated-fat diet, and an isocaloric high-carbohydrate/low-saturated fat diet.

The outcomes were FMD and markers of endothelial dysfunction, including cellular adhesion molecules, inhibitors and promoters of fibrinolysis, adiponectin, glucose, insulin, C-reactive protein (CRP), lipids, and apolipoprotein B.

The study involved 70 men and women aged 16-60 years with body mass index between 27 and 40 kg/m

The Atkins diet consisted of 35% protein, 61% fat (20% saturated fat), and 4% carbohydrates. The low-fat diet was composed of 30% fat (less than 8% saturated), 46% carbohydrates, and 24% protein.

“We managed to keep people on the Atkins diet for a year without too many complaints, and certainly they had no constipation or halitosis,” Dr. Clifton said. These effects often result from the ketogenic state induced by the Atkins diet.

After 1 year, the 33 patients on the Atkins diet lost slightly more weight on average (14.5 kg) than did the 36 patients on the low-fat diet (11.5 kg), but this difference was not significant. Body fat decreased by a mean 11.3 kg among the Atkins dieters, and by 9.4 kg among the low-fat dieters, a difference that was not significant. Loss of muscle mass was significantly greater among those on the meat-heavy diet, at a mean of 3.2 vs. 2.3 kg for the low-fat, high-carb diet.

There was no diet-specific effect on blood pressure, glucose, insulin, or CRP, but the Atkins diet was superior to the low-fat diet at decreasing triglycerides and increasing HDL. The Atkins diet also was associated with increases in LDL levels. In addition, apolipoprotein B, a marker for cardiovascular disease, increased with the Atkins diet and declined with the low-fat diet, although this difference was not significant.

Overall, 49 patients (26 on the Atkins diet, 23 on the low-fat diet) underwent FMD assessment. Endothelial function decreased by almost half from baseline among patients on the Atkins diet, compared with no change among patients on the low-fat diet. Pulse-wave velocity, a measure of arterial stiffness, improved significantly over baseline in both groups, with no diet-specific effect; another measure of stiffness, augmentation index, did not change in either group.

“So overall, FMD deteriorated after 12 months on a high-saturated-fat Atkins diet, despite their fantastic weight loss and improvement in all those other things,” Dr. Clifton said. “Solely because the LDL increased, it outweighed all the other measures of weight loss. The other measures of endothelial function that we took actually improved except ICAM-1 on the Atkins diet, so there seems to be a separation of endothelial functions as expressed by nitric oxide and these other endothelial markers.

“This really calls into question that fantastic elevation of HDL [with the Atkins diet] as being a good thing or having anything much to do with cardiovascular health,” he added, noting that when changes in HDL in clinical trials are adjusted for LDL changes, any potential relationship of HDL to cardiovascular disease outcomes disappears.

Dr. Clifton disclosed that he has coauthored diet books, but they do not include the information he presented.

Flow-mediated dilatation “deteriorated after 12 months on a high-saturated-fat Atkins diet, despite [patients'] fantastic weight loss and improvement” on other measures.

Source ©Graça Victoria/Fotolia.com

BOSTON — Proponents of the Atkins low-carbohydrate/high-saturated-fat diet say that you can have your steak and eat it, too, and still lose weight.

But the adverse metabolic consequences are too heavy a price to pay, Australian investigators reported at a symposium sponsored by the International Atherosclerosis Society.

After 1 year, overweight and obese patients randomly assigned to the Atkins diet or to a low-saturated-fat, high-carbohydrate diet lost similar amounts of weight. But patients on the Atkins diet had a deterioration in flow-mediated arterial dilatation, a marker for cardiovascular disease, and higher levels of LDL cholesterol than at baseline, reported Dr. Peter Clifton of the Commonwealth Scientific and Industrial Research Organization (CSIRO) in Adelaide, South Australia.

“What I really want to know is, does the early elevation of HDL, which has been shown convincingly [with the Atkins diet], and lowering of triglycerides plus the lowering of blood pressure and glucose outweigh the rise in LDL cholesterol that you see in some individuals in some studies?” he said.

“Of course, there are no Atkins end point studies, which is a bit disappointing since there are a fair number of advocates of the Atkins diet,” he added.

Dr. Clifton and his colleagues analyzed the effects of two diets on flow-mediated dilatation (FMD), a measurement of the ability of blood vessels to dilate in response to increases in blood flow. FMD is reduced in both cardiovascular disease and diabetes, but whether it improves with significant weight loss is unclear; if so, it might be related to either decreases in glucose or in LDL, Dr. Clifton said.

The study's aim was to evaluate the effects on markers of endothelial dysfunction and cardiovascular disease risk of a very-low-carbohydrate/high-saturated-fat diet, and an isocaloric high-carbohydrate/low-saturated fat diet.

The outcomes were FMD and markers of endothelial dysfunction, including cellular adhesion molecules, inhibitors and promoters of fibrinolysis, adiponectin, glucose, insulin, C-reactive protein (CRP), lipids, and apolipoprotein B.

The study involved 70 men and women aged 16-60 years with body mass index between 27 and 40 kg/m

The Atkins diet consisted of 35% protein, 61% fat (20% saturated fat), and 4% carbohydrates. The low-fat diet was composed of 30% fat (less than 8% saturated), 46% carbohydrates, and 24% protein.

“We managed to keep people on the Atkins diet for a year without too many complaints, and certainly they had no constipation or halitosis,” Dr. Clifton said. These effects often result from the ketogenic state induced by the Atkins diet.

After 1 year, the 33 patients on the Atkins diet lost slightly more weight on average (14.5 kg) than did the 36 patients on the low-fat diet (11.5 kg), but this difference was not significant. Body fat decreased by a mean 11.3 kg among the Atkins dieters, and by 9.4 kg among the low-fat dieters, a difference that was not significant. Loss of muscle mass was significantly greater among those on the meat-heavy diet, at a mean of 3.2 vs. 2.3 kg for the low-fat, high-carb diet.

There was no diet-specific effect on blood pressure, glucose, insulin, or CRP, but the Atkins diet was superior to the low-fat diet at decreasing triglycerides and increasing HDL. The Atkins diet also was associated with increases in LDL levels. In addition, apolipoprotein B, a marker for cardiovascular disease, increased with the Atkins diet and declined with the low-fat diet, although this difference was not significant.

Overall, 49 patients (26 on the Atkins diet, 23 on the low-fat diet) underwent FMD assessment. Endothelial function decreased by almost half from baseline among patients on the Atkins diet, compared with no change among patients on the low-fat diet. Pulse-wave velocity, a measure of arterial stiffness, improved significantly over baseline in both groups, with no diet-specific effect; another measure of stiffness, augmentation index, did not change in either group.

“So overall, FMD deteriorated after 12 months on a high-saturated-fat Atkins diet, despite their fantastic weight loss and improvement in all those other things,” Dr. Clifton said. “Solely because the LDL increased, it outweighed all the other measures of weight loss. The other measures of endothelial function that we took actually improved except ICAM-1 on the Atkins diet, so there seems to be a separation of endothelial functions as expressed by nitric oxide and these other endothelial markers.

“This really calls into question that fantastic elevation of HDL [with the Atkins diet] as being a good thing or having anything much to do with cardiovascular health,” he added, noting that when changes in HDL in clinical trials are adjusted for LDL changes, any potential relationship of HDL to cardiovascular disease outcomes disappears.

Dr. Clifton disclosed that he has coauthored diet books, but they do not include the information he presented.

Flow-mediated dilatation “deteriorated after 12 months on a high-saturated-fat Atkins diet, despite [patients'] fantastic weight loss and improvement” on other measures.

Source ©Graça Victoria/Fotolia.com

BOSTON — Proponents of the Atkins low-carbohydrate/high-saturated-fat diet say that you can have your steak and eat it, too, and still lose weight.

But the adverse metabolic consequences are too heavy a price to pay, Australian investigators reported at a symposium sponsored by the International Atherosclerosis Society.

After 1 year, overweight and obese patients randomly assigned to the Atkins diet or to a low-saturated-fat, high-carbohydrate diet lost similar amounts of weight. But patients on the Atkins diet had a deterioration in flow-mediated arterial dilatation, a marker for cardiovascular disease, and higher levels of LDL cholesterol than at baseline, reported Dr. Peter Clifton of the Commonwealth Scientific and Industrial Research Organization (CSIRO) in Adelaide, South Australia.

“What I really want to know is, does the early elevation of HDL, which has been shown convincingly [with the Atkins diet], and lowering of triglycerides plus the lowering of blood pressure and glucose outweigh the rise in LDL cholesterol that you see in some individuals in some studies?” he said.

“Of course, there are no Atkins end point studies, which is a bit disappointing since there are a fair number of advocates of the Atkins diet,” he added.

Dr. Clifton and his colleagues analyzed the effects of two diets on flow-mediated dilatation (FMD), a measurement of the ability of blood vessels to dilate in response to increases in blood flow. FMD is reduced in both cardiovascular disease and diabetes, but whether it improves with significant weight loss is unclear; if so, it might be related to either decreases in glucose or in LDL, Dr. Clifton said.

The study's aim was to evaluate the effects on markers of endothelial dysfunction and cardiovascular disease risk of a very-low-carbohydrate/high-saturated-fat diet, and an isocaloric high-carbohydrate/low-saturated fat diet.

The outcomes were FMD and markers of endothelial dysfunction, including cellular adhesion molecules, inhibitors and promoters of fibrinolysis, adiponectin, glucose, insulin, C-reactive protein (CRP), lipids, and apolipoprotein B.

The study involved 70 men and women aged 16-60 years with body mass index between 27 and 40 kg/m

The Atkins diet consisted of 35% protein, 61% fat (20% saturated fat), and 4% carbohydrates. The low-fat diet was composed of 30% fat (less than 8% saturated), 46% carbohydrates, and 24% protein.

“We managed to keep people on the Atkins diet for a year without too many complaints, and certainly they had no constipation or halitosis,” Dr. Clifton said. These effects often result from the ketogenic state induced by the Atkins diet.

After 1 year, the 33 patients on the Atkins diet lost slightly more weight on average (14.5 kg) than did the 36 patients on the low-fat diet (11.5 kg), but this difference was not significant. Body fat decreased by a mean 11.3 kg among the Atkins dieters, and by 9.4 kg among the low-fat dieters, a difference that was not significant. Loss of muscle mass was significantly greater among those on the meat-heavy diet, at a mean of 3.2 vs. 2.3 kg for the low-fat, high-carb diet.

There was no diet-specific effect on blood pressure, glucose, insulin, or CRP, but the Atkins diet was superior to the low-fat diet at decreasing triglycerides and increasing HDL. The Atkins diet also was associated with increases in LDL levels. In addition, apolipoprotein B, a marker for cardiovascular disease, increased with the Atkins diet and declined with the low-fat diet, although this difference was not significant.

Overall, 49 patients (26 on the Atkins diet, 23 on the low-fat diet) underwent FMD assessment. Endothelial function decreased by almost half from baseline among patients on the Atkins diet, compared with no change among patients on the low-fat diet. Pulse-wave velocity, a measure of arterial stiffness, improved significantly over baseline in both groups, with no diet-specific effect; another measure of stiffness, augmentation index, did not change in either group.

“So overall, FMD deteriorated after 12 months on a high-saturated-fat Atkins diet, despite their fantastic weight loss and improvement in all those other things,” Dr. Clifton said. “Solely because the LDL increased, it outweighed all the other measures of weight loss. The other measures of endothelial function that we took actually improved except ICAM-1 on the Atkins diet, so there seems to be a separation of endothelial functions as expressed by nitric oxide and these other endothelial markers.

“This really calls into question that fantastic elevation of HDL [with the Atkins diet] as being a good thing or having anything much to do with cardiovascular health,” he added, noting that when changes in HDL in clinical trials are adjusted for LDL changes, any potential relationship of HDL to cardiovascular disease outcomes disappears.

Dr. Clifton disclosed that he has coauthored diet books, but they do not include the information he presented.

Flow-mediated dilatation “deteriorated after 12 months on a high-saturated-fat Atkins diet, despite [patients'] fantastic weight loss and improvement” on other measures.

Source ©Graça Victoria/Fotolia.com

ORLANDO — Although ulcerated primary melanomas are notorious for having a poor prognosis, the presence of ulceration may be a signal that the tumor is one of a small proportion of melanomas that are sensitive to adjuvant interferon, European researchers suggested at the annual meeting of the American Society of Clinical Oncology.

A meta-analysis of two large published studies of adjuvant interferon therapy indicates that interferon treatment of ulcerated primary melanoma is associated with about a 25% reduction in the risk for distant metastases and about a 40% decrease in the risk of death, compared with interferon treatment of nonulcerated primary melanomas.

"After 20 years of adjuvant interferon trials, it took a [previous] meta-analysis in over 10,000 patients to demonstrate a 3% overall survival benefit," said Dr. Alexander M.M. Eggermont, professor of surgical oncology at Erasmus University, Rotterdam, the Netherlands. Most trials showed a significant impact on relapse-free survival, he said, but not on overall survival—leading to the suspicion that a fraction of patients are sensitive to interferon.

By identifying those patients who respond to interferon, clinicians can protect the majority of patients from "unjustified" exposure to interferon. Ulcerated primary tumors may be the sign that everyone's looking for, said Dr. Eggermont, speaking on behalf of colleagues in the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group.

Ulcerated melanoma is a distinct biological entity with much worse prognosis, he said, pointing to an analysis by Dr. Charles M. Balch and colleagues of prognostic factors among 17,600 melanoma patients, which showed that for tumors of the same thickness, overall survival was much worse if the primary was ulcerated (J. Clin. Oncol. 2001; 19:3622-34).

Earlier analyses of data from the EORTC 18952 and 18991 studies in the new meta-analysis suggested that tumor burden and ulcerated primaries were both likely determinants of interferon sensitivity, whereas autoimmune antibodies were not, Dr. Eggermont said.

The 18991 study involved 1,256 patients with resected stage III melanoma who were randomly assigned to long-term therapy with pegylated interferon alfa-2b or observation. The study included an 8-week induction period, followed by weekly maintenance for 5 years or until distant metastases were detected.

The 18952 study involved 1,388 patients with resected stage IIb or III melanoma who were randomized to observation or to intermediate doses of peginterferon alfa-2b (induction with 10 million IU daily for 4 weeks, followed by maintenance with either 10 million IU thrice weekly for 12 months or 5 million IU thrice weekly for 24 months).

Analysis of the 18991 study, which used peginterferon, showed that ulcerated primary melanoma was associated with a 23% reduction in risk for distant metastasis vs. observation, and the difference was even greater in patients with ulceration and one involved node. They had a 41% reduction vs. patients with ulcerated N1 tumors who underwent observation.

"For nonulcerated primaries, all primary end points were nonsignificant. The exposure of adjuvant interferon did not translate into a benefit," Dr. Eggermont said. "But if the primary was ulcerated, relapse-free survival, distant metastasis-free survival, and overall survival" were all significantly impacted.

This finding prompted the investigators to conduct the meta-analysis including all 2,624 patients in the combined trials. Looking at relapse-free survival by treatment group according to ulceration status, they found that, among all patients with primary tumors, there was no significant difference between the patients who were treated with interferon or those randomized to observation only.

But when they compared relapse-free survival among patients with ulcerated primaries, they saw that interferon-treated patients had a hazard ratio for relapse of 0.75, compared with similar patients who underwent observation only. There was also a significant benefit for interferon therapy of ulcerated stage IIB and III-N1 tumors, compared with observation, but not for patients with stage IIB or II N1 nonulcerated primaries.

In the combined studies, there was no overall survival advantage for interferon therapy over observation alone in patients with nonulcerated tumors. In contrast, interferon treatment significantly benefitted patients with ulcerations.

Ulceration also held up as a significant determinant of overall survival when the two studies were considered separately. Interferon conferred a survival advantage compared with observation in each study. "In these studies, with interferon given these ways, ulceration did seem to be a very powerful indicator of outcome," said Dr. Thomas F. Gajewski of the cancer research center at the University of Chicago, who was the invited discussant.

"Ulceration may be trying to tell us something about the biology of melanoma," he said.

Ulcerated primaries tend to express at higher levels genes linked to cell cycle, DNA repair, and epigenetics, and may also be linked to a vascular invasion phenotype that makes them more sensitive than nonulcerated tumors to interferon, he said.

Dr. Eggermont had no conflict of interest disclosures. Dr. Gajewski disclosed receiving honoraria and/or research funding from Bristol-Myers Squibb Co., Genentech Inc., GlaxoSmithKline, and Pfizer Inc.

Ulcerated melanoma is a distinct biological entity with much worse prognosis.

Source DR. EGGERMONT

ORLANDO — Although ulcerated primary melanomas are notorious for having a poor prognosis, the presence of ulceration may be a signal that the tumor is one of a small proportion of melanomas that are sensitive to adjuvant interferon, European researchers suggested at the annual meeting of the American Society of Clinical Oncology.

A meta-analysis of two large published studies of adjuvant interferon therapy indicates that interferon treatment of ulcerated primary melanoma is associated with about a 25% reduction in the risk for distant metastases and about a 40% decrease in the risk of death, compared with interferon treatment of nonulcerated primary melanomas.

"After 20 years of adjuvant interferon trials, it took a [previous] meta-analysis in over 10,000 patients to demonstrate a 3% overall survival benefit," said Dr. Alexander M.M. Eggermont, professor of surgical oncology at Erasmus University, Rotterdam, the Netherlands. Most trials showed a significant impact on relapse-free survival, he said, but not on overall survival—leading to the suspicion that a fraction of patients are sensitive to interferon.

By identifying those patients who respond to interferon, clinicians can protect the majority of patients from "unjustified" exposure to interferon. Ulcerated primary tumors may be the sign that everyone's looking for, said Dr. Eggermont, speaking on behalf of colleagues in the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group.

Ulcerated melanoma is a distinct biological entity with much worse prognosis, he said, pointing to an analysis by Dr. Charles M. Balch and colleagues of prognostic factors among 17,600 melanoma patients, which showed that for tumors of the same thickness, overall survival was much worse if the primary was ulcerated (J. Clin. Oncol. 2001; 19:3622-34).

Earlier analyses of data from the EORTC 18952 and 18991 studies in the new meta-analysis suggested that tumor burden and ulcerated primaries were both likely determinants of interferon sensitivity, whereas autoimmune antibodies were not, Dr. Eggermont said.

The 18991 study involved 1,256 patients with resected stage III melanoma who were randomly assigned to long-term therapy with pegylated interferon alfa-2b or observation. The study included an 8-week induction period, followed by weekly maintenance for 5 years or until distant metastases were detected.

The 18952 study involved 1,388 patients with resected stage IIb or III melanoma who were randomized to observation or to intermediate doses of peginterferon alfa-2b (induction with 10 million IU daily for 4 weeks, followed by maintenance with either 10 million IU thrice weekly for 12 months or 5 million IU thrice weekly for 24 months).

Analysis of the 18991 study, which used peginterferon, showed that ulcerated primary melanoma was associated with a 23% reduction in risk for distant metastasis vs. observation, and the difference was even greater in patients with ulceration and one involved node. They had a 41% reduction vs. patients with ulcerated N1 tumors who underwent observation.

"For nonulcerated primaries, all primary end points were nonsignificant. The exposure of adjuvant interferon did not translate into a benefit," Dr. Eggermont said. "But if the primary was ulcerated, relapse-free survival, distant metastasis-free survival, and overall survival" were all significantly impacted.

This finding prompted the investigators to conduct the meta-analysis including all 2,624 patients in the combined trials. Looking at relapse-free survival by treatment group according to ulceration status, they found that, among all patients with primary tumors, there was no significant difference between the patients who were treated with interferon or those randomized to observation only.

But when they compared relapse-free survival among patients with ulcerated primaries, they saw that interferon-treated patients had a hazard ratio for relapse of 0.75, compared with similar patients who underwent observation only. There was also a significant benefit for interferon therapy of ulcerated stage IIB and III-N1 tumors, compared with observation, but not for patients with stage IIB or II N1 nonulcerated primaries.

In the combined studies, there was no overall survival advantage for interferon therapy over observation alone in patients with nonulcerated tumors. In contrast, interferon treatment significantly benefitted patients with ulcerations.

Ulceration also held up as a significant determinant of overall survival when the two studies were considered separately. Interferon conferred a survival advantage compared with observation in each study. "In these studies, with interferon given these ways, ulceration did seem to be a very powerful indicator of outcome," said Dr. Thomas F. Gajewski of the cancer research center at the University of Chicago, who was the invited discussant.

"Ulceration may be trying to tell us something about the biology of melanoma," he said.

Ulcerated primaries tend to express at higher levels genes linked to cell cycle, DNA repair, and epigenetics, and may also be linked to a vascular invasion phenotype that makes them more sensitive than nonulcerated tumors to interferon, he said.

Dr. Eggermont had no conflict of interest disclosures. Dr. Gajewski disclosed receiving honoraria and/or research funding from Bristol-Myers Squibb Co., Genentech Inc., GlaxoSmithKline, and Pfizer Inc.

Ulcerated melanoma is a distinct biological entity with much worse prognosis.

Source DR. EGGERMONT

ORLANDO — Although ulcerated primary melanomas are notorious for having a poor prognosis, the presence of ulceration may be a signal that the tumor is one of a small proportion of melanomas that are sensitive to adjuvant interferon, European researchers suggested at the annual meeting of the American Society of Clinical Oncology.

A meta-analysis of two large published studies of adjuvant interferon therapy indicates that interferon treatment of ulcerated primary melanoma is associated with about a 25% reduction in the risk for distant metastases and about a 40% decrease in the risk of death, compared with interferon treatment of nonulcerated primary melanomas.

"After 20 years of adjuvant interferon trials, it took a [previous] meta-analysis in over 10,000 patients to demonstrate a 3% overall survival benefit," said Dr. Alexander M.M. Eggermont, professor of surgical oncology at Erasmus University, Rotterdam, the Netherlands. Most trials showed a significant impact on relapse-free survival, he said, but not on overall survival—leading to the suspicion that a fraction of patients are sensitive to interferon.

By identifying those patients who respond to interferon, clinicians can protect the majority of patients from "unjustified" exposure to interferon. Ulcerated primary tumors may be the sign that everyone's looking for, said Dr. Eggermont, speaking on behalf of colleagues in the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group.

Ulcerated melanoma is a distinct biological entity with much worse prognosis, he said, pointing to an analysis by Dr. Charles M. Balch and colleagues of prognostic factors among 17,600 melanoma patients, which showed that for tumors of the same thickness, overall survival was much worse if the primary was ulcerated (J. Clin. Oncol. 2001; 19:3622-34).

Earlier analyses of data from the EORTC 18952 and 18991 studies in the new meta-analysis suggested that tumor burden and ulcerated primaries were both likely determinants of interferon sensitivity, whereas autoimmune antibodies were not, Dr. Eggermont said.

The 18991 study involved 1,256 patients with resected stage III melanoma who were randomly assigned to long-term therapy with pegylated interferon alfa-2b or observation. The study included an 8-week induction period, followed by weekly maintenance for 5 years or until distant metastases were detected.

The 18952 study involved 1,388 patients with resected stage IIb or III melanoma who were randomized to observation or to intermediate doses of peginterferon alfa-2b (induction with 10 million IU daily for 4 weeks, followed by maintenance with either 10 million IU thrice weekly for 12 months or 5 million IU thrice weekly for 24 months).

Analysis of the 18991 study, which used peginterferon, showed that ulcerated primary melanoma was associated with a 23% reduction in risk for distant metastasis vs. observation, and the difference was even greater in patients with ulceration and one involved node. They had a 41% reduction vs. patients with ulcerated N1 tumors who underwent observation.

"For nonulcerated primaries, all primary end points were nonsignificant. The exposure of adjuvant interferon did not translate into a benefit," Dr. Eggermont said. "But if the primary was ulcerated, relapse-free survival, distant metastasis-free survival, and overall survival" were all significantly impacted.

This finding prompted the investigators to conduct the meta-analysis including all 2,624 patients in the combined trials. Looking at relapse-free survival by treatment group according to ulceration status, they found that, among all patients with primary tumors, there was no significant difference between the patients who were treated with interferon or those randomized to observation only.

But when they compared relapse-free survival among patients with ulcerated primaries, they saw that interferon-treated patients had a hazard ratio for relapse of 0.75, compared with similar patients who underwent observation only. There was also a significant benefit for interferon therapy of ulcerated stage IIB and III-N1 tumors, compared with observation, but not for patients with stage IIB or II N1 nonulcerated primaries.

In the combined studies, there was no overall survival advantage for interferon therapy over observation alone in patients with nonulcerated tumors. In contrast, interferon treatment significantly benefitted patients with ulcerations.

Ulceration also held up as a significant determinant of overall survival when the two studies were considered separately. Interferon conferred a survival advantage compared with observation in each study. "In these studies, with interferon given these ways, ulceration did seem to be a very powerful indicator of outcome," said Dr. Thomas F. Gajewski of the cancer research center at the University of Chicago, who was the invited discussant.

"Ulceration may be trying to tell us something about the biology of melanoma," he said.

Ulcerated primaries tend to express at higher levels genes linked to cell cycle, DNA repair, and epigenetics, and may also be linked to a vascular invasion phenotype that makes them more sensitive than nonulcerated tumors to interferon, he said.

Dr. Eggermont had no conflict of interest disclosures. Dr. Gajewski disclosed receiving honoraria and/or research funding from Bristol-Myers Squibb Co., Genentech Inc., GlaxoSmithKline, and Pfizer Inc.

Ulcerated melanoma is a distinct biological entity with much worse prognosis.

Source DR. EGGERMONT

PHOENIX — Call it visionary, hubris, or heresy, but University of Arkansas cancer surgeons assert that radiotherapy may not be necessary to prevent local recurrence of breast cancer in some women.

Instead—in a select population of patients with early breast cancer—they propose the use of local excision followed by intraoperative radiofrequency thermal ablation to effectively extend surgical margins an additional 1 cm.

“Short-term follow-up suggests that for patients with favorable breast cancer or those who don't or won't take breast irradiation, excision followed by radiofrequency ablation [RFA] can reduce local recurrence without the need for—or complications of—radiation,” said Dr. V. Suzanne Klimberg of the University of Arkansas in Little Rock. But that assertion did not sit well with many of the oncologic surgeons attending a symposium sponsored by the Society of Surgical Oncology.

“There have been multiple prospective randomized trials that have asked the question, 'Can we identify a subgroup of women who don't need radiation?' and the answer to that has always been 'No,'” said Dr. Monica Morrow, chief of the breast service at Memorial Sloan-Kettering Cancer Center, New York, in an interview. Dr. Morrow was not involved in the study.

“Given the fact that we now know that every form of local recurrence prevented translates into one life saved from breast cancer, we need to be very careful about things that maintain local control,” she added. “And why radiofrequency ablation to achieve a negative margin should be any different from large surgical resection to achieve a negative margin, I don't know. So that would be my concern about this study.”

“Lumpectomy followed by radiation is no doubt the standard of care and the preferred method for treating breast cancer,” Dr. Klimberg acknowledged. But she also said that radiotherapy, performed to ensure that any residual malignancy in the tumor bed is destroyed, does not always give the best cosmetic result.

Whole-breast radiation only reduces recurrence at the tumor bed, and brachytherapy “only gives a 100% dose 1 cm around the cavity, and that's what we shoot for, because [according to] several studies, most disease is within a centimeter of a T1 mass,” said Dr. Klimberg.

The goal of excision plus RFA, then, is for the surgeon to perform the best possible surgical excision, followed by insertion of an RFA probe into the incision to deliver thermal energy to the tumor margins.

Dr. Klimberg and her colleagues performed a phase II trial of the technique in 94 women with breast cancer who expressed a preference for treatment with lumpectomy. The mean patient age was 67 years. Ductal carcinoma in situ was diagnosed in 32 patients and invasive cancer in 62 patients, 6 of whom also had node-positive disease. The tumors were grade I in 48 patients, grade II in 26, grade III in 19, and of unknown grade in 1.

Pathology showed that 71 of the tumors were estrogen receptor positive and 10 were negative; the remaining 13 were not tested for ER status. Sixty of the samples were HER2 (human epidermal growth factor receptor 2) negative, 14 were positive, and 20 were not tested for HER2 status.

The women underwent lumpectomy followed by RFA with a probe placed 1 cm circumferentially into the lumpectomy cavity and maintained at 100° C for 15 minutes. The surgeons used intraoperative Doppler ultrasound to follow the thermal ablation through detection of nitrogen off-gassing.

In all, 24 patients had inadequate margin resection (defined as less than 2 mm); of these, 8 had grossly positive margins and 4 had focally positive margins. Eight of the patients, who underwent a second resection, were excluded from the analysis.

Postoperative complications included one burn, which prompted the addition of ultrasound to monitor the margins of ablation; one hematoma; two cases of wound dehiscence; and one wound infection, which was treated with antibiotics only.

The women did not receive adjuvant radiation therapy, but most received systemic therapy with tamoxifen (25 patients), an aromatase inhibitor (26), a tamoxifen/AI combination (9), chemotherapy (7), or trastuzumab (1). The remaining 26 underwent observation only.

Cosmesis, scored according to Radiation Therapy Oncology Group criteria in 62 patients 2 weeks after surgery, showed excellent results in 28 patients, good in 25, and fair in 9.

After a mean 23 months of follow-up, there were no local recurrences in the tumor bed. Four “elsewhere” recurrences (defined as a recurrence greater than 5 cm away from the primary tumor) were observed, three in the same breast and one in the contralateral breast. All recurrences were seen within 1 year of surgery “and therefore they were probably there to begin with,” Dr. Klimberg commented.

Disease-free survival was 95% at 3 years, regardless of whether patients had ductal carcinoma in situ or invasive pathologies, but the lack of a difference may be due to small numbers, she noted.

Dr. Klimberg concluded that excision plus RFA “may represent a new paradigm in achieving optimal breast conservation without radiation.”

Dr. Morrow remained unconvinced: “This was a feasibility study in a highly selected group of patients, and we need longer-term follow-up, and this is certainly not something that is ready for routine clinical use, in my opinion.”

Dr. Klimberg disclosed that she owns stock and has received research support from RITA Medical Systems Inc., a maker of RFA equipment.

Dr. V. Suzanne Klimberg cited the merits of RFA plus excision in select patients. University of Arkansas for Medical Sciences

PHOENIX — Call it visionary, hubris, or heresy, but University of Arkansas cancer surgeons assert that radiotherapy may not be necessary to prevent local recurrence of breast cancer in some women.

Instead—in a select population of patients with early breast cancer—they propose the use of local excision followed by intraoperative radiofrequency thermal ablation to effectively extend surgical margins an additional 1 cm.

“Short-term follow-up suggests that for patients with favorable breast cancer or those who don't or won't take breast irradiation, excision followed by radiofrequency ablation [RFA] can reduce local recurrence without the need for—or complications of—radiation,” said Dr. V. Suzanne Klimberg of the University of Arkansas in Little Rock. But that assertion did not sit well with many of the oncologic surgeons attending a symposium sponsored by the Society of Surgical Oncology.

“There have been multiple prospective randomized trials that have asked the question, 'Can we identify a subgroup of women who don't need radiation?' and the answer to that has always been 'No,'” said Dr. Monica Morrow, chief of the breast service at Memorial Sloan-Kettering Cancer Center, New York, in an interview. Dr. Morrow was not involved in the study.

“Given the fact that we now know that every form of local recurrence prevented translates into one life saved from breast cancer, we need to be very careful about things that maintain local control,” she added. “And why radiofrequency ablation to achieve a negative margin should be any different from large surgical resection to achieve a negative margin, I don't know. So that would be my concern about this study.”

“Lumpectomy followed by radiation is no doubt the standard of care and the preferred method for treating breast cancer,” Dr. Klimberg acknowledged. But she also said that radiotherapy, performed to ensure that any residual malignancy in the tumor bed is destroyed, does not always give the best cosmetic result.

Whole-breast radiation only reduces recurrence at the tumor bed, and brachytherapy “only gives a 100% dose 1 cm around the cavity, and that's what we shoot for, because [according to] several studies, most disease is within a centimeter of a T1 mass,” said Dr. Klimberg.

The goal of excision plus RFA, then, is for the surgeon to perform the best possible surgical excision, followed by insertion of an RFA probe into the incision to deliver thermal energy to the tumor margins.

Dr. Klimberg and her colleagues performed a phase II trial of the technique in 94 women with breast cancer who expressed a preference for treatment with lumpectomy. The mean patient age was 67 years. Ductal carcinoma in situ was diagnosed in 32 patients and invasive cancer in 62 patients, 6 of whom also had node-positive disease. The tumors were grade I in 48 patients, grade II in 26, grade III in 19, and of unknown grade in 1.

Pathology showed that 71 of the tumors were estrogen receptor positive and 10 were negative; the remaining 13 were not tested for ER status. Sixty of the samples were HER2 (human epidermal growth factor receptor 2) negative, 14 were positive, and 20 were not tested for HER2 status.

The women underwent lumpectomy followed by RFA with a probe placed 1 cm circumferentially into the lumpectomy cavity and maintained at 100° C for 15 minutes. The surgeons used intraoperative Doppler ultrasound to follow the thermal ablation through detection of nitrogen off-gassing.

In all, 24 patients had inadequate margin resection (defined as less than 2 mm); of these, 8 had grossly positive margins and 4 had focally positive margins. Eight of the patients, who underwent a second resection, were excluded from the analysis.

Postoperative complications included one burn, which prompted the addition of ultrasound to monitor the margins of ablation; one hematoma; two cases of wound dehiscence; and one wound infection, which was treated with antibiotics only.

The women did not receive adjuvant radiation therapy, but most received systemic therapy with tamoxifen (25 patients), an aromatase inhibitor (26), a tamoxifen/AI combination (9), chemotherapy (7), or trastuzumab (1). The remaining 26 underwent observation only.

Cosmesis, scored according to Radiation Therapy Oncology Group criteria in 62 patients 2 weeks after surgery, showed excellent results in 28 patients, good in 25, and fair in 9.

After a mean 23 months of follow-up, there were no local recurrences in the tumor bed. Four “elsewhere” recurrences (defined as a recurrence greater than 5 cm away from the primary tumor) were observed, three in the same breast and one in the contralateral breast. All recurrences were seen within 1 year of surgery “and therefore they were probably there to begin with,” Dr. Klimberg commented.

Disease-free survival was 95% at 3 years, regardless of whether patients had ductal carcinoma in situ or invasive pathologies, but the lack of a difference may be due to small numbers, she noted.

Dr. Klimberg concluded that excision plus RFA “may represent a new paradigm in achieving optimal breast conservation without radiation.”

Dr. Morrow remained unconvinced: “This was a feasibility study in a highly selected group of patients, and we need longer-term follow-up, and this is certainly not something that is ready for routine clinical use, in my opinion.”

Dr. Klimberg disclosed that she owns stock and has received research support from RITA Medical Systems Inc., a maker of RFA equipment.

Dr. V. Suzanne Klimberg cited the merits of RFA plus excision in select patients. University of Arkansas for Medical Sciences

PHOENIX — Call it visionary, hubris, or heresy, but University of Arkansas cancer surgeons assert that radiotherapy may not be necessary to prevent local recurrence of breast cancer in some women.

Instead—in a select population of patients with early breast cancer—they propose the use of local excision followed by intraoperative radiofrequency thermal ablation to effectively extend surgical margins an additional 1 cm.

“Short-term follow-up suggests that for patients with favorable breast cancer or those who don't or won't take breast irradiation, excision followed by radiofrequency ablation [RFA] can reduce local recurrence without the need for—or complications of—radiation,” said Dr. V. Suzanne Klimberg of the University of Arkansas in Little Rock. But that assertion did not sit well with many of the oncologic surgeons attending a symposium sponsored by the Society of Surgical Oncology.

“There have been multiple prospective randomized trials that have asked the question, 'Can we identify a subgroup of women who don't need radiation?' and the answer to that has always been 'No,'” said Dr. Monica Morrow, chief of the breast service at Memorial Sloan-Kettering Cancer Center, New York, in an interview. Dr. Morrow was not involved in the study.

“Given the fact that we now know that every form of local recurrence prevented translates into one life saved from breast cancer, we need to be very careful about things that maintain local control,” she added. “And why radiofrequency ablation to achieve a negative margin should be any different from large surgical resection to achieve a negative margin, I don't know. So that would be my concern about this study.”

“Lumpectomy followed by radiation is no doubt the standard of care and the preferred method for treating breast cancer,” Dr. Klimberg acknowledged. But she also said that radiotherapy, performed to ensure that any residual malignancy in the tumor bed is destroyed, does not always give the best cosmetic result.

Whole-breast radiation only reduces recurrence at the tumor bed, and brachytherapy “only gives a 100% dose 1 cm around the cavity, and that's what we shoot for, because [according to] several studies, most disease is within a centimeter of a T1 mass,” said Dr. Klimberg.

The goal of excision plus RFA, then, is for the surgeon to perform the best possible surgical excision, followed by insertion of an RFA probe into the incision to deliver thermal energy to the tumor margins.

Dr. Klimberg and her colleagues performed a phase II trial of the technique in 94 women with breast cancer who expressed a preference for treatment with lumpectomy. The mean patient age was 67 years. Ductal carcinoma in situ was diagnosed in 32 patients and invasive cancer in 62 patients, 6 of whom also had node-positive disease. The tumors were grade I in 48 patients, grade II in 26, grade III in 19, and of unknown grade in 1.

Pathology showed that 71 of the tumors were estrogen receptor positive and 10 were negative; the remaining 13 were not tested for ER status. Sixty of the samples were HER2 (human epidermal growth factor receptor 2) negative, 14 were positive, and 20 were not tested for HER2 status.

The women underwent lumpectomy followed by RFA with a probe placed 1 cm circumferentially into the lumpectomy cavity and maintained at 100° C for 15 minutes. The surgeons used intraoperative Doppler ultrasound to follow the thermal ablation through detection of nitrogen off-gassing.

In all, 24 patients had inadequate margin resection (defined as less than 2 mm); of these, 8 had grossly positive margins and 4 had focally positive margins. Eight of the patients, who underwent a second resection, were excluded from the analysis.

Postoperative complications included one burn, which prompted the addition of ultrasound to monitor the margins of ablation; one hematoma; two cases of wound dehiscence; and one wound infection, which was treated with antibiotics only.

The women did not receive adjuvant radiation therapy, but most received systemic therapy with tamoxifen (25 patients), an aromatase inhibitor (26), a tamoxifen/AI combination (9), chemotherapy (7), or trastuzumab (1). The remaining 26 underwent observation only.

Cosmesis, scored according to Radiation Therapy Oncology Group criteria in 62 patients 2 weeks after surgery, showed excellent results in 28 patients, good in 25, and fair in 9.

After a mean 23 months of follow-up, there were no local recurrences in the tumor bed. Four “elsewhere” recurrences (defined as a recurrence greater than 5 cm away from the primary tumor) were observed, three in the same breast and one in the contralateral breast. All recurrences were seen within 1 year of surgery “and therefore they were probably there to begin with,” Dr. Klimberg commented.

Disease-free survival was 95% at 3 years, regardless of whether patients had ductal carcinoma in situ or invasive pathologies, but the lack of a difference may be due to small numbers, she noted.

Dr. Klimberg concluded that excision plus RFA “may represent a new paradigm in achieving optimal breast conservation without radiation.”

Dr. Morrow remained unconvinced: “This was a feasibility study in a highly selected group of patients, and we need longer-term follow-up, and this is certainly not something that is ready for routine clinical use, in my opinion.”

Dr. Klimberg disclosed that she owns stock and has received research support from RITA Medical Systems Inc., a maker of RFA equipment.

Dr. V. Suzanne Klimberg cited the merits of RFA plus excision in select patients. University of Arkansas for Medical Sciences

CHICAGO — Six or more months of continuous androgen deprivation therapy was associated with significantly increased risk of fragility fractures and type 2 diabetes in an observational study of nearly 20,000 men aged 66 years and older with prostate cancer, reported investigators at the annual meeting of the American Society of Clinical Oncology.

Continuous androgen deprivation was not associated with elevated risk for either acute myocardial infarction or hypercholesterolemia, however. There was actually a slight decrease in risk for dyslipidemia, and nonsignificant trends toward lower rates of AMI and sudden cardiac death, said Dr. Shabbir M.H. Alibhai.

Concern about adverse effects of androgen deprivation therapy on bone is based on four retrospective studies and a case-control study showing an increase risk for both fragility fractures and nonfragility fractures with its use, according to Dr. Alibhai, a research scientist in the department of medicine at Princess Margaret Hospital and the University of Toronto.

A large prospective study by Dr. Nancy L. Keating and her coauthors at Brigham and Women's Hospital in Boston showed use of a gonadotropin-releasing hormone agonist was associated with a 44% increased risk of incident diabetes, 16% increase each in risk of coronary heart disease and sudden cardiac death, and an 11% rise in risk of MI (J. Clin. Oncol. 2006 20;24:4448–56).

“These findings are worrisome, but at the same time, there are some limitations that must be kept in mind,” said Dr. Alibhai. “The findings are not entirely consistent among studies. Some studies suggested, for example, increased rate of fatal myocardial infarction, but no overall increased rate of myocardial infarction. And another study suggested that while androgen deprivation increased the risk of MI, diabetes, and hypertension, paradoxically, it did not seem to in that cohort.”

Dr. Alibhai and his colleagues looked at data on 19,709 men in Ontario (Canada), who had continuous androgen deprivation therapy for at least 6 months or had undergone bilateral orchiectomy, and an identical number of controls. The treated patients were matched by age and prior prostate cancer therapy to other men who did not receive androgen deprivation.

The primary end points were fragility fractures, incident diabetes, incident dyslipidemia, acute MI, and sudden cardiac death. Secondary outcomes were any fracture, heart failure, stroke, use of diagnostic cardiac catheterization, and cardiac revascularization with either angioplasty or coronary artery bypass graft surgery.

The investigators found in a time-to-event analysis that after a mean of 6.47 years, use of androgen deprivation was associated with a hazard ratio for fragility fractures of 1.65 (P less than .001), and a 1.26 hazard ratio for incident diabetes (P less than .001).

In contrast, there was a 14% lower risk for incident dyslipidemia (HR 0.86, P less than .001), and nonsignificant trends toward lower MI risk (HR 0.92, P = .059) and time to sudden cardiac death (HR 0.96, P = .53).

In analysis of secondary outcomes, androgen deprivation was significantly associated with higher risk of any fracture (HR 1.46) and lower risk for stroke (HR 0.88), cardiac catheterization (HR 0.88), and cardiac revascularization (HR 0.87).

Dr. Alibhai acknowledged that the study was limited by its restriction to men 66 years and older, possible undercoding of some comorbidities or minor fractures, lack of information on tumor stage or grade, the fact that the outcomes of dyslipidemia were not validated, and that propensity analysis lessens but does not eliminate the potential for confounding.

“In men who are age 66 [years] or older, on continuous androgen deprivation for at least 6 months,” Dr. Alibhai said in his conclusion, “this therapy was associated with an increased risk of fragility fracture—of course as well as any fracture—a decreased risk of dyslipidemia … and no appreciable impact on myocardial infarction. And, if anything, there was a slight decrease in acute myocardial infarction in this cohort, which goes against the previously published studies to date.”

The study was supported by the Toronto General and Toronto Western Hospital Foundation and the National Cancer Institute of Canada. Dr. Alibhai reported no financial conflict of interest.

CHICAGO — Six or more months of continuous androgen deprivation therapy was associated with significantly increased risk of fragility fractures and type 2 diabetes in an observational study of nearly 20,000 men aged 66 years and older with prostate cancer, reported investigators at the annual meeting of the American Society of Clinical Oncology.

Continuous androgen deprivation was not associated with elevated risk for either acute myocardial infarction or hypercholesterolemia, however. There was actually a slight decrease in risk for dyslipidemia, and nonsignificant trends toward lower rates of AMI and sudden cardiac death, said Dr. Shabbir M.H. Alibhai.

Concern about adverse effects of androgen deprivation therapy on bone is based on four retrospective studies and a case-control study showing an increase risk for both fragility fractures and nonfragility fractures with its use, according to Dr. Alibhai, a research scientist in the department of medicine at Princess Margaret Hospital and the University of Toronto.

A large prospective study by Dr. Nancy L. Keating and her coauthors at Brigham and Women's Hospital in Boston showed use of a gonadotropin-releasing hormone agonist was associated with a 44% increased risk of incident diabetes, 16% increase each in risk of coronary heart disease and sudden cardiac death, and an 11% rise in risk of MI (J. Clin. Oncol. 2006 20;24:4448–56).

“These findings are worrisome, but at the same time, there are some limitations that must be kept in mind,” said Dr. Alibhai. “The findings are not entirely consistent among studies. Some studies suggested, for example, increased rate of fatal myocardial infarction, but no overall increased rate of myocardial infarction. And another study suggested that while androgen deprivation increased the risk of MI, diabetes, and hypertension, paradoxically, it did not seem to in that cohort.”

Dr. Alibhai and his colleagues looked at data on 19,709 men in Ontario (Canada), who had continuous androgen deprivation therapy for at least 6 months or had undergone bilateral orchiectomy, and an identical number of controls. The treated patients were matched by age and prior prostate cancer therapy to other men who did not receive androgen deprivation.

The primary end points were fragility fractures, incident diabetes, incident dyslipidemia, acute MI, and sudden cardiac death. Secondary outcomes were any fracture, heart failure, stroke, use of diagnostic cardiac catheterization, and cardiac revascularization with either angioplasty or coronary artery bypass graft surgery.

The investigators found in a time-to-event analysis that after a mean of 6.47 years, use of androgen deprivation was associated with a hazard ratio for fragility fractures of 1.65 (P less than .001), and a 1.26 hazard ratio for incident diabetes (P less than .001).

In contrast, there was a 14% lower risk for incident dyslipidemia (HR 0.86, P less than .001), and nonsignificant trends toward lower MI risk (HR 0.92, P = .059) and time to sudden cardiac death (HR 0.96, P = .53).

In analysis of secondary outcomes, androgen deprivation was significantly associated with higher risk of any fracture (HR 1.46) and lower risk for stroke (HR 0.88), cardiac catheterization (HR 0.88), and cardiac revascularization (HR 0.87).

Dr. Alibhai acknowledged that the study was limited by its restriction to men 66 years and older, possible undercoding of some comorbidities or minor fractures, lack of information on tumor stage or grade, the fact that the outcomes of dyslipidemia were not validated, and that propensity analysis lessens but does not eliminate the potential for confounding.

“In men who are age 66 [years] or older, on continuous androgen deprivation for at least 6 months,” Dr. Alibhai said in his conclusion, “this therapy was associated with an increased risk of fragility fracture—of course as well as any fracture—a decreased risk of dyslipidemia … and no appreciable impact on myocardial infarction. And, if anything, there was a slight decrease in acute myocardial infarction in this cohort, which goes against the previously published studies to date.”

The study was supported by the Toronto General and Toronto Western Hospital Foundation and the National Cancer Institute of Canada. Dr. Alibhai reported no financial conflict of interest.

CHICAGO — Six or more months of continuous androgen deprivation therapy was associated with significantly increased risk of fragility fractures and type 2 diabetes in an observational study of nearly 20,000 men aged 66 years and older with prostate cancer, reported investigators at the annual meeting of the American Society of Clinical Oncology.

Continuous androgen deprivation was not associated with elevated risk for either acute myocardial infarction or hypercholesterolemia, however. There was actually a slight decrease in risk for dyslipidemia, and nonsignificant trends toward lower rates of AMI and sudden cardiac death, said Dr. Shabbir M.H. Alibhai.

Concern about adverse effects of androgen deprivation therapy on bone is based on four retrospective studies and a case-control study showing an increase risk for both fragility fractures and nonfragility fractures with its use, according to Dr. Alibhai, a research scientist in the department of medicine at Princess Margaret Hospital and the University of Toronto.

A large prospective study by Dr. Nancy L. Keating and her coauthors at Brigham and Women's Hospital in Boston showed use of a gonadotropin-releasing hormone agonist was associated with a 44% increased risk of incident diabetes, 16% increase each in risk of coronary heart disease and sudden cardiac death, and an 11% rise in risk of MI (J. Clin. Oncol. 2006 20;24:4448–56).

“These findings are worrisome, but at the same time, there are some limitations that must be kept in mind,” said Dr. Alibhai. “The findings are not entirely consistent among studies. Some studies suggested, for example, increased rate of fatal myocardial infarction, but no overall increased rate of myocardial infarction. And another study suggested that while androgen deprivation increased the risk of MI, diabetes, and hypertension, paradoxically, it did not seem to in that cohort.”

Dr. Alibhai and his colleagues looked at data on 19,709 men in Ontario (Canada), who had continuous androgen deprivation therapy for at least 6 months or had undergone bilateral orchiectomy, and an identical number of controls. The treated patients were matched by age and prior prostate cancer therapy to other men who did not receive androgen deprivation.

The primary end points were fragility fractures, incident diabetes, incident dyslipidemia, acute MI, and sudden cardiac death. Secondary outcomes were any fracture, heart failure, stroke, use of diagnostic cardiac catheterization, and cardiac revascularization with either angioplasty or coronary artery bypass graft surgery.

The investigators found in a time-to-event analysis that after a mean of 6.47 years, use of androgen deprivation was associated with a hazard ratio for fragility fractures of 1.65 (P less than .001), and a 1.26 hazard ratio for incident diabetes (P less than .001).

In contrast, there was a 14% lower risk for incident dyslipidemia (HR 0.86, P less than .001), and nonsignificant trends toward lower MI risk (HR 0.92, P = .059) and time to sudden cardiac death (HR 0.96, P = .53).

In analysis of secondary outcomes, androgen deprivation was significantly associated with higher risk of any fracture (HR 1.46) and lower risk for stroke (HR 0.88), cardiac catheterization (HR 0.88), and cardiac revascularization (HR 0.87).

Dr. Alibhai acknowledged that the study was limited by its restriction to men 66 years and older, possible undercoding of some comorbidities or minor fractures, lack of information on tumor stage or grade, the fact that the outcomes of dyslipidemia were not validated, and that propensity analysis lessens but does not eliminate the potential for confounding.

“In men who are age 66 [years] or older, on continuous androgen deprivation for at least 6 months,” Dr. Alibhai said in his conclusion, “this therapy was associated with an increased risk of fragility fracture—of course as well as any fracture—a decreased risk of dyslipidemia … and no appreciable impact on myocardial infarction. And, if anything, there was a slight decrease in acute myocardial infarction in this cohort, which goes against the previously published studies to date.”

The study was supported by the Toronto General and Toronto Western Hospital Foundation and the National Cancer Institute of Canada. Dr. Alibhai reported no financial conflict of interest.

CHICAGO — A twofold to threefold increase in the incidence of tonsillar cancer over several decades was paralleled by a similar rise in the incidence of tumors positive for the human papillomavirus, the results of a Swedish cohort study indicate.

Survival rates among patients with tonsillar cancer also increased, possibly because of the higher proportion of HPV-positive cancers, which tend to have a much better prognosis than other oral cancers, Dr. Hanna Dahlstrand said at the annual meeting of the American Society of Clinical Oncology.

The reasons for the increase in HPV-positive tumors are not known, she said.

In the United States, the incidence of HPV-related oropharyngeal squamous cell carcinomas has increased since 1973, while the incidence of squamous cell carcinomas at other oral sites has remained constant or declined, said Dr. Dahlstrand of the department of oncology-pathology at the Karolinska Institute in Stockholm.

HPV DNA has been shown to be present in 40%–75% of oropharyngeal cancers, compared with about 25% of all head and neck cancers. “It is only the high-risk types of HPV that are found, with at least 90% dominance of HPV-16, and the oncogenes on HPV, E6 and E7 are transcribed,” she said, “Exposure to HPV-16 precedes by at least 9 years the diagnosis, and has been shown to be a strong risk factor for tumor development.”

HPV-positive oropharyngeal cancers tend to occur more often among nonsmokers and younger patients. Risk factors include multiple sexual partners, younger age at first intercourse, and oral sex. Studies have shown that the presence of HPV positivity is associated with about a 50% reduction in 5-year mortality, she noted.

Dr. Dahlstrand and her colleagues at the Karolinska Institute conducted a nationwide cohort study to see whether there has been an increase in the incidence of tonsillar cancer in Sweden; to determine whether such an increase, if present, could be linked to the proportion of HPV-positive tumors; and to see whether the incidence of HPV-positive tonsillar cancers would have an effect on survival.

They identified a total of 2,165 incident cases of tonsillar squamous cell carcinoma from 1960 through 2003, using the Swedish National Cancer Registry. To determine survival, the investigators used records from the Swedish Causes of Death Register, and checked them against the Swedish Emigration Registry from 1960 to 2001 to ensure that cohort members were not lost to follow-up. They identified a total of 1,800 survivors as of 2003.

The investigators also assessed the incidence of tonsillar cancer from 1970 to 2001 and survival in a Stockholm cohort, and used this cohort to control for treatment, tumor-nodes-metastasis stage, and cause of death. They identified 515 cases in this cohort, and 337 survivors as of 2001.

They were able to obtain 203 biopsy samples and screened them for HPV using polymerase chain reaction testing; they then typed and sequenced the HPV to determine expression of the E6 and E7 oncogenes and expression of HPV-16.

In the nationwide cohort, there was a twofold increase in the incidence of tonsillar cancers, from 1.2/100,000 population to 2.4/100,000, from 1960 to 2003. There was no parallel increase in cancers of the oral cavity, Dr. Dahlstrand reported.

In the Stockholm cohort, tonsillar cancers increased from 1.3/100,000 to 3.6/100,000, or 2.8-fold, from 1970 to 2002, while there was a 2.9-fold increase in the proportion of HPV-positive tonsillar cancers. During the 1970s, 23% of cases were HPV positive, which increased to 28% in the 1980s, 57% in the 1990s, and to 68% into the 21st century.

The mean 5-year relative survival rate among men with tonsillar cancer also increased in Sweden since the 1960s, from 32% to 53% in 1990–2001. In the Stockholm cohort, in a Cox multivariate analysis adjusted for age, gender, stage, and treatment, the investigators found a similar significant increase in relative 5-year survival, with a relative hazard ratio of 0.54 for 1990–2001, compared with 1970–1979. The presence of a lower proportion of stage I and II tumors in the 1990s, compared with the 1970s, suggests that the improvement in survival over the years cannot be explained by earlier diagnosis, Dr. Dahlstrand said.

Dr. Dahlstrand stated that she had no relevant financial disclosures.

CHICAGO — A twofold to threefold increase in the incidence of tonsillar cancer over several decades was paralleled by a similar rise in the incidence of tumors positive for the human papillomavirus, the results of a Swedish cohort study indicate.

Survival rates among patients with tonsillar cancer also increased, possibly because of the higher proportion of HPV-positive cancers, which tend to have a much better prognosis than other oral cancers, Dr. Hanna Dahlstrand said at the annual meeting of the American Society of Clinical Oncology.

The reasons for the increase in HPV-positive tumors are not known, she said.

In the United States, the incidence of HPV-related oropharyngeal squamous cell carcinomas has increased since 1973, while the incidence of squamous cell carcinomas at other oral sites has remained constant or declined, said Dr. Dahlstrand of the department of oncology-pathology at the Karolinska Institute in Stockholm.

HPV DNA has been shown to be present in 40%–75% of oropharyngeal cancers, compared with about 25% of all head and neck cancers. “It is only the high-risk types of HPV that are found, with at least 90% dominance of HPV-16, and the oncogenes on HPV, E6 and E7 are transcribed,” she said, “Exposure to HPV-16 precedes by at least 9 years the diagnosis, and has been shown to be a strong risk factor for tumor development.”

HPV-positive oropharyngeal cancers tend to occur more often among nonsmokers and younger patients. Risk factors include multiple sexual partners, younger age at first intercourse, and oral sex. Studies have shown that the presence of HPV positivity is associated with about a 50% reduction in 5-year mortality, she noted.

Dr. Dahlstrand and her colleagues at the Karolinska Institute conducted a nationwide cohort study to see whether there has been an increase in the incidence of tonsillar cancer in Sweden; to determine whether such an increase, if present, could be linked to the proportion of HPV-positive tumors; and to see whether the incidence of HPV-positive tonsillar cancers would have an effect on survival.

They identified a total of 2,165 incident cases of tonsillar squamous cell carcinoma from 1960 through 2003, using the Swedish National Cancer Registry. To determine survival, the investigators used records from the Swedish Causes of Death Register, and checked them against the Swedish Emigration Registry from 1960 to 2001 to ensure that cohort members were not lost to follow-up. They identified a total of 1,800 survivors as of 2003.

The investigators also assessed the incidence of tonsillar cancer from 1970 to 2001 and survival in a Stockholm cohort, and used this cohort to control for treatment, tumor-nodes-metastasis stage, and cause of death. They identified 515 cases in this cohort, and 337 survivors as of 2001.

They were able to obtain 203 biopsy samples and screened them for HPV using polymerase chain reaction testing; they then typed and sequenced the HPV to determine expression of the E6 and E7 oncogenes and expression of HPV-16.

In the nationwide cohort, there was a twofold increase in the incidence of tonsillar cancers, from 1.2/100,000 population to 2.4/100,000, from 1960 to 2003. There was no parallel increase in cancers of the oral cavity, Dr. Dahlstrand reported.

In the Stockholm cohort, tonsillar cancers increased from 1.3/100,000 to 3.6/100,000, or 2.8-fold, from 1970 to 2002, while there was a 2.9-fold increase in the proportion of HPV-positive tonsillar cancers. During the 1970s, 23% of cases were HPV positive, which increased to 28% in the 1980s, 57% in the 1990s, and to 68% into the 21st century.

The mean 5-year relative survival rate among men with tonsillar cancer also increased in Sweden since the 1960s, from 32% to 53% in 1990–2001. In the Stockholm cohort, in a Cox multivariate analysis adjusted for age, gender, stage, and treatment, the investigators found a similar significant increase in relative 5-year survival, with a relative hazard ratio of 0.54 for 1990–2001, compared with 1970–1979. The presence of a lower proportion of stage I and II tumors in the 1990s, compared with the 1970s, suggests that the improvement in survival over the years cannot be explained by earlier diagnosis, Dr. Dahlstrand said.

Dr. Dahlstrand stated that she had no relevant financial disclosures.

CHICAGO — A twofold to threefold increase in the incidence of tonsillar cancer over several decades was paralleled by a similar rise in the incidence of tumors positive for the human papillomavirus, the results of a Swedish cohort study indicate.

Survival rates among patients with tonsillar cancer also increased, possibly because of the higher proportion of HPV-positive cancers, which tend to have a much better prognosis than other oral cancers, Dr. Hanna Dahlstrand said at the annual meeting of the American Society of Clinical Oncology.

The reasons for the increase in HPV-positive tumors are not known, she said.

In the United States, the incidence of HPV-related oropharyngeal squamous cell carcinomas has increased since 1973, while the incidence of squamous cell carcinomas at other oral sites has remained constant or declined, said Dr. Dahlstrand of the department of oncology-pathology at the Karolinska Institute in Stockholm.

HPV DNA has been shown to be present in 40%–75% of oropharyngeal cancers, compared with about 25% of all head and neck cancers. “It is only the high-risk types of HPV that are found, with at least 90% dominance of HPV-16, and the oncogenes on HPV, E6 and E7 are transcribed,” she said, “Exposure to HPV-16 precedes by at least 9 years the diagnosis, and has been shown to be a strong risk factor for tumor development.”

HPV-positive oropharyngeal cancers tend to occur more often among nonsmokers and younger patients. Risk factors include multiple sexual partners, younger age at first intercourse, and oral sex. Studies have shown that the presence of HPV positivity is associated with about a 50% reduction in 5-year mortality, she noted.

Dr. Dahlstrand and her colleagues at the Karolinska Institute conducted a nationwide cohort study to see whether there has been an increase in the incidence of tonsillar cancer in Sweden; to determine whether such an increase, if present, could be linked to the proportion of HPV-positive tumors; and to see whether the incidence of HPV-positive tonsillar cancers would have an effect on survival.

They identified a total of 2,165 incident cases of tonsillar squamous cell carcinoma from 1960 through 2003, using the Swedish National Cancer Registry. To determine survival, the investigators used records from the Swedish Causes of Death Register, and checked them against the Swedish Emigration Registry from 1960 to 2001 to ensure that cohort members were not lost to follow-up. They identified a total of 1,800 survivors as of 2003.

The investigators also assessed the incidence of tonsillar cancer from 1970 to 2001 and survival in a Stockholm cohort, and used this cohort to control for treatment, tumor-nodes-metastasis stage, and cause of death. They identified 515 cases in this cohort, and 337 survivors as of 2001.

They were able to obtain 203 biopsy samples and screened them for HPV using polymerase chain reaction testing; they then typed and sequenced the HPV to determine expression of the E6 and E7 oncogenes and expression of HPV-16.

In the nationwide cohort, there was a twofold increase in the incidence of tonsillar cancers, from 1.2/100,000 population to 2.4/100,000, from 1960 to 2003. There was no parallel increase in cancers of the oral cavity, Dr. Dahlstrand reported.

In the Stockholm cohort, tonsillar cancers increased from 1.3/100,000 to 3.6/100,000, or 2.8-fold, from 1970 to 2002, while there was a 2.9-fold increase in the proportion of HPV-positive tonsillar cancers. During the 1970s, 23% of cases were HPV positive, which increased to 28% in the 1980s, 57% in the 1990s, and to 68% into the 21st century.

The mean 5-year relative survival rate among men with tonsillar cancer also increased in Sweden since the 1960s, from 32% to 53% in 1990–2001. In the Stockholm cohort, in a Cox multivariate analysis adjusted for age, gender, stage, and treatment, the investigators found a similar significant increase in relative 5-year survival, with a relative hazard ratio of 0.54 for 1990–2001, compared with 1970–1979. The presence of a lower proportion of stage I and II tumors in the 1990s, compared with the 1970s, suggests that the improvement in survival over the years cannot be explained by earlier diagnosis, Dr. Dahlstrand said.

Dr. Dahlstrand stated that she had no relevant financial disclosures.

CHICAGO — A twofold to threefold increase in the incidence of tonsillar cancer over several decades was paralleled by a similar rise in the incidence of tumors positive for the human papillomavirus, the results of a Swedish cohort study indicate.

At the same time, however, survival rates among patients with tonsillar cancer also increased, possibly because of the higher proportion of HPV-positive cancers, which tend to have a much better prognosis than other oral cancers, Dr. Hanna Dahlstrand said at the annual meeting of the American Society of Clinical Oncology.

The reasons for the increase in HPV-positive tumors are not known, although they could be related to a possible increase in sexual behaviors, particularly in urban centers, Dr. Dahlstrand said.

Although Sweden is a relatively small nation, the results may be applicable to other countries, she noted. In the United States, for example, the incidence of HPV-related oropharyngeal squamous cell carcinomas has increased since 1973, while the incidence of squamous cell carcinomas at other oral sites has either remained constant or declined. In Finland, the incidence of tonsillar cancers doubled from 1956 through 2000, said Dr. Dahlstrand of the department of oncology-pathology at the Karolinska Institute in Stockholm.

HPV DNA has been shown to be present in 40%-75% of oropharyngeal cancers, compared with about 25% of all head and neck cancers.

"It is only the high-risk types of HPV that are found, with at least 90% dominance of HPV-16, and the oncogenes on HPV, E6 and E7 are transcribed," she said, "And importantly, there is a temporal connection: Exposure to HPV-16 precedes by at least 9 years the diagnosis, and has been shown to be a strong risk factor for tumor development."

HPV-positive oropharyngeal cancers tend to occur more often among nonsmokers and younger patients. Risk factors include multiple sexual partners, younger age at first intercourse, and oral sex. Several studies have shown that the presence of HPV positivity is associated with about a 50% reduction in 5-year mortality, Dr. Dahlstrand noted.

She and her colleagues at the Karolinska Institute conducted a nationwide cohort study using the exhaustive clinical and demographic databases available to Swedish investigators. Their goals were to see whether there has been an increase in the incidence of tonsillar cancer in Sweden; to determine whether such an increase, if present, could be linked to the proportion of HPV-positive tumors; and to see whether the incidence of HPV-positive tonsillar cancers would have an effect on survival.

They identified a total of 2,165 incident cases of tonsillar squamous cell carcinoma from 1960 through 2003, using the Swedish National Cancer Registry.

To determine survival, the investigators used records from the Swedish Causes of Death Register, and checked them against the Swedish Emigration Registry from 1960 to 2001 to ensure that cohort members were not lost to follow-up. They identified a total of 1,800 survivors as of 2003.

The investigators also assessed the incidence of tonsillar cancer from 1970 to 2001 and survival in a Stockholm cohort, and used this cohort to control for treatment, tumor-nodes-metastasis stage, and cause of death. They identified 515 cases in this cohort, and 337 survivors as of 2001.

They were able to obtain 203 biopsy samples and screened them for HPV using polymerase chain reaction testing; they then typed and sequenced the HPV to determine expression of the E6 and E7 oncogenes and expression of HPV-16.

In the nationwide cohort, there was a twofold increase in the incidence of tonsillar cancers, from 1.2/100,000 population to 2.4/100,000, from 1960 to 2003. There was no parallel increase in cancers of the oral cavity (for example, mobile tongue or floor of the mouth), however.

In the Stockholm cohort, tonsillar cancers increased from 1.3/100,000 to 3.6/100,000, or 2.8-fold, from 1970 to 2002. There was also a 2.9-fold increase in the proportion of HPV-positive tonsillar cancers during that same time period. This increase became significant for the 1990-1999 period, compared with 1970-1979, and remained significant for 2000-2002. During the 1970s, 23% of cases were HPV positive, which increased to 28% in the 1980s, 57% in the 1990s, and to 68% into the 21st century.

The mean 5-year relative survival rate among men with tonsillar cancer also increased in Sweden since the 1960s, from 32% to 53% in 1990-2001. In the Stockholm cohort, in a Cox multivariate analysis adjusted for age, gender, stage, and treatment, the investigators found a similar significant increase in relative 5-year survival, with a relative hazard ratio of 0.54 for 1990-2001, compared with 1970-1979. The presence of a lower proportion of stage I and II tumors in the 1990s, compared with the 1970s, suggests that the improvement in survival over the years cannot be explained by earlier diagnosis, Dr. Dahlstrand said.

Dr. Dahlstrand stated that she had no relevant financial disclosures.

CHICAGO — A twofold to threefold increase in the incidence of tonsillar cancer over several decades was paralleled by a similar rise in the incidence of tumors positive for the human papillomavirus, the results of a Swedish cohort study indicate.

At the same time, however, survival rates among patients with tonsillar cancer also increased, possibly because of the higher proportion of HPV-positive cancers, which tend to have a much better prognosis than other oral cancers, Dr. Hanna Dahlstrand said at the annual meeting of the American Society of Clinical Oncology.

The reasons for the increase in HPV-positive tumors are not known, although they could be related to a possible increase in sexual behaviors, particularly in urban centers, Dr. Dahlstrand said.

Although Sweden is a relatively small nation, the results may be applicable to other countries, she noted. In the United States, for example, the incidence of HPV-related oropharyngeal squamous cell carcinomas has increased since 1973, while the incidence of squamous cell carcinomas at other oral sites has either remained constant or declined. In Finland, the incidence of tonsillar cancers doubled from 1956 through 2000, said Dr. Dahlstrand of the department of oncology-pathology at the Karolinska Institute in Stockholm.

HPV DNA has been shown to be present in 40%-75% of oropharyngeal cancers, compared with about 25% of all head and neck cancers.

"It is only the high-risk types of HPV that are found, with at least 90% dominance of HPV-16, and the oncogenes on HPV, E6 and E7 are transcribed," she said, "And importantly, there is a temporal connection: Exposure to HPV-16 precedes by at least 9 years the diagnosis, and has been shown to be a strong risk factor for tumor development."

HPV-positive oropharyngeal cancers tend to occur more often among nonsmokers and younger patients. Risk factors include multiple sexual partners, younger age at first intercourse, and oral sex. Several studies have shown that the presence of HPV positivity is associated with about a 50% reduction in 5-year mortality, Dr. Dahlstrand noted.

She and her colleagues at the Karolinska Institute conducted a nationwide cohort study using the exhaustive clinical and demographic databases available to Swedish investigators. Their goals were to see whether there has been an increase in the incidence of tonsillar cancer in Sweden; to determine whether such an increase, if present, could be linked to the proportion of HPV-positive tumors; and to see whether the incidence of HPV-positive tonsillar cancers would have an effect on survival.

They identified a total of 2,165 incident cases of tonsillar squamous cell carcinoma from 1960 through 2003, using the Swedish National Cancer Registry.

To determine survival, the investigators used records from the Swedish Causes of Death Register, and checked them against the Swedish Emigration Registry from 1960 to 2001 to ensure that cohort members were not lost to follow-up. They identified a total of 1,800 survivors as of 2003.

The investigators also assessed the incidence of tonsillar cancer from 1970 to 2001 and survival in a Stockholm cohort, and used this cohort to control for treatment, tumor-nodes-metastasis stage, and cause of death. They identified 515 cases in this cohort, and 337 survivors as of 2001.

They were able to obtain 203 biopsy samples and screened them for HPV using polymerase chain reaction testing; they then typed and sequenced the HPV to determine expression of the E6 and E7 oncogenes and expression of HPV-16.

In the nationwide cohort, there was a twofold increase in the incidence of tonsillar cancers, from 1.2/100,000 population to 2.4/100,000, from 1960 to 2003. There was no parallel increase in cancers of the oral cavity (for example, mobile tongue or floor of the mouth), however.

In the Stockholm cohort, tonsillar cancers increased from 1.3/100,000 to 3.6/100,000, or 2.8-fold, from 1970 to 2002. There was also a 2.9-fold increase in the proportion of HPV-positive tonsillar cancers during that same time period. This increase became significant for the 1990-1999 period, compared with 1970-1979, and remained significant for 2000-2002. During the 1970s, 23% of cases were HPV positive, which increased to 28% in the 1980s, 57% in the 1990s, and to 68% into the 21st century.

The mean 5-year relative survival rate among men with tonsillar cancer also increased in Sweden since the 1960s, from 32% to 53% in 1990-2001. In the Stockholm cohort, in a Cox multivariate analysis adjusted for age, gender, stage, and treatment, the investigators found a similar significant increase in relative 5-year survival, with a relative hazard ratio of 0.54 for 1990-2001, compared with 1970-1979. The presence of a lower proportion of stage I and II tumors in the 1990s, compared with the 1970s, suggests that the improvement in survival over the years cannot be explained by earlier diagnosis, Dr. Dahlstrand said.

Dr. Dahlstrand stated that she had no relevant financial disclosures.

CHICAGO — A twofold to threefold increase in the incidence of tonsillar cancer over several decades was paralleled by a similar rise in the incidence of tumors positive for the human papillomavirus, the results of a Swedish cohort study indicate.

At the same time, however, survival rates among patients with tonsillar cancer also increased, possibly because of the higher proportion of HPV-positive cancers, which tend to have a much better prognosis than other oral cancers, Dr. Hanna Dahlstrand said at the annual meeting of the American Society of Clinical Oncology.

The reasons for the increase in HPV-positive tumors are not known, although they could be related to a possible increase in sexual behaviors, particularly in urban centers, Dr. Dahlstrand said.

Although Sweden is a relatively small nation, the results may be applicable to other countries, she noted. In the United States, for example, the incidence of HPV-related oropharyngeal squamous cell carcinomas has increased since 1973, while the incidence of squamous cell carcinomas at other oral sites has either remained constant or declined. In Finland, the incidence of tonsillar cancers doubled from 1956 through 2000, said Dr. Dahlstrand of the department of oncology-pathology at the Karolinska Institute in Stockholm.

HPV DNA has been shown to be present in 40%-75% of oropharyngeal cancers, compared with about 25% of all head and neck cancers.

"It is only the high-risk types of HPV that are found, with at least 90% dominance of HPV-16, and the oncogenes on HPV, E6 and E7 are transcribed," she said, "And importantly, there is a temporal connection: Exposure to HPV-16 precedes by at least 9 years the diagnosis, and has been shown to be a strong risk factor for tumor development."

HPV-positive oropharyngeal cancers tend to occur more often among nonsmokers and younger patients. Risk factors include multiple sexual partners, younger age at first intercourse, and oral sex. Several studies have shown that the presence of HPV positivity is associated with about a 50% reduction in 5-year mortality, Dr. Dahlstrand noted.

She and her colleagues at the Karolinska Institute conducted a nationwide cohort study using the exhaustive clinical and demographic databases available to Swedish investigators. Their goals were to see whether there has been an increase in the incidence of tonsillar cancer in Sweden; to determine whether such an increase, if present, could be linked to the proportion of HPV-positive tumors; and to see whether the incidence of HPV-positive tonsillar cancers would have an effect on survival.

They identified a total of 2,165 incident cases of tonsillar squamous cell carcinoma from 1960 through 2003, using the Swedish National Cancer Registry.

To determine survival, the investigators used records from the Swedish Causes of Death Register, and checked them against the Swedish Emigration Registry from 1960 to 2001 to ensure that cohort members were not lost to follow-up. They identified a total of 1,800 survivors as of 2003.

The investigators also assessed the incidence of tonsillar cancer from 1970 to 2001 and survival in a Stockholm cohort, and used this cohort to control for treatment, tumor-nodes-metastasis stage, and cause of death. They identified 515 cases in this cohort, and 337 survivors as of 2001.

They were able to obtain 203 biopsy samples and screened them for HPV using polymerase chain reaction testing; they then typed and sequenced the HPV to determine expression of the E6 and E7 oncogenes and expression of HPV-16.

In the nationwide cohort, there was a twofold increase in the incidence of tonsillar cancers, from 1.2/100,000 population to 2.4/100,000, from 1960 to 2003. There was no parallel increase in cancers of the oral cavity (for example, mobile tongue or floor of the mouth), however.

In the Stockholm cohort, tonsillar cancers increased from 1.3/100,000 to 3.6/100,000, or 2.8-fold, from 1970 to 2002. There was also a 2.9-fold increase in the proportion of HPV-positive tonsillar cancers during that same time period. This increase became significant for the 1990-1999 period, compared with 1970-1979, and remained significant for 2000-2002. During the 1970s, 23% of cases were HPV positive, which increased to 28% in the 1980s, 57% in the 1990s, and to 68% into the 21st century.

The mean 5-year relative survival rate among men with tonsillar cancer also increased in Sweden since the 1960s, from 32% to 53% in 1990-2001. In the Stockholm cohort, in a Cox multivariate analysis adjusted for age, gender, stage, and treatment, the investigators found a similar significant increase in relative 5-year survival, with a relative hazard ratio of 0.54 for 1990-2001, compared with 1970-1979. The presence of a lower proportion of stage I and II tumors in the 1990s, compared with the 1970s, suggests that the improvement in survival over the years cannot be explained by earlier diagnosis, Dr. Dahlstrand said.

Dr. Dahlstrand stated that she had no relevant financial disclosures.

CHICAGO — Cetuximab can be added safely and apparently to good effect when giving a standard induction regimen to patients with newly diagnosed, locally advanced head and neck cancer, reported investigators at the annual meeting of the American Society of Clinical Oncology.

In a phase I study looking at the addition of cetuximab (Erbitux) to induction chemotherapy with docetaxel (Taxotere), cisplatin, and 5-fluorouracil (the TPF regimen), 14 of 19 treated patients had a complete clinical response, 5 had a partial clinical response, and all 19 had a partial radiographic response, reported Dr. Robert I. Haddad, who is a clinical investigator in the Head and Neck Cancer Center at the Dana Farber Cancer Institute in Boston.

"The preliminary efficacy data [are] encouraging in this patient population with fairly advanced presentation," Dr. Haddad said.

The TPF regimen is both a new standard for induction chemotherapy in patients with previously untreated squamous cell carcinomas of the head and neck, and a platform for testing new agents such as cetuximab, which has been shown to have efficacy in head and neck cancer as a single agent and in combination with radiation therapy and cistplatin/5-fluorouracil (PF) chemotherapy, Dr. Haddad said.

He and his colleagues conducted a phase I study of the maximum tolerated dose of 5-fluorouracil (5-FU) in the TPF regimen when cetuximab was added. Secondary goals of the study included a toxicity assessment and response rates.

They enrolled 28 patients with biopsy-proven squamous cell carcinoma of the head and neck, with primary tumor sites in the oral cavity, oropharynx, nasopharynx, hypopharynx, or larynx. Patients with unknown primary site squamous cell carcinomas were also eligible.

The patients had to have stage III or IV disease with no evidence of distant metastases, and they had to have no prior chemotherapy, radiation therapy, or surgery, measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors). In addition, patients needed to have good Eastern Cooperative Oncology Group performance status (0 or 1), and normal hematologic, renal, and liver function.

Patients received 400 mg/m

The treatment plan called for three cycles of induction chemotherapy, with TPF every 21 days, plus weekly cetuximab in doses of 250 mg/m

At the end of induction, restaging was performed and then patients underwent definitive chemoradiotherapy with a platinum-based regimen according to the institution's standard.

One of the patients withdrew consent before toxicity could be assessed, leaving 27 available for the analysis. Of these patients, 19 had completed chemoradiotherapy at the time Dr. Haddad presented the data.

There were no dose-limiting toxicities after the first cycle of cetuximab/TPF with 5-FU at 750 or 850 mg/m

But in that expanded cohort, there were two cases of gastrointestinal bleeding and one of febrile neutropenia, causing the investigators to reconsider 5-FU dosing, and they instead settled on 850 mg as the maximum tolerated dose. Of the 10 patients planned for enrollment in the expanded cohort at this dose, nine had enrolled at the time of the analysis. Only one dose-limiting toxicity was reported: mucositis.

Among the 12 patients in total enrolled at the 850-mg dose (3 from the original cohort, plus 9 additionally enrolled), there were four cases of grade 4 neutropenia and one of grade 4 diarrhea. Grade 3 events include three cases of neutropenia, two of febrile neutropenia, one mucositis (dose limiting), one fatigue, and one syncope. Skin toxicities included acneiform rash (seven grade 2 and one grade 3), and four cases of grade 2 nail fissuring and/or paronychial infection.

At the time of the data presentation, 19 of 27 patients had completed chemoradiotherapy with a platinum-based agent, and 8 remained on treatment. All but one of the patients received 70-Gy radiation over 7 weeks; the remaining patients received 59 Gy over 10 weeks.

An analysis of the best overall response showed a clinical complete response in 14 patients, and partial response in 5. Radiographic evaluation at the end of induction but before radiation showed a partial response in all 19 patients.

"All of these patients had still-persistent abnormalities on CT or PET," Dr. Haddad said. "Keep in mind these patients have fairly advanced nodal presentations, and often the CT scan or imaging is not normalized for these patients."

Among the 13 patients who underwent primary site biopsy after induction, 11 had pathologic complete response, and 2 had a partial response.

All patients were alive at 6-month follow-up; one patient with a stage T4 N2b cancer of the base of the tongue had local/regional recurrence and is currently on palliative chemotherapy. Two patients had neck dissections performed after chemoradiotherapy, and neither had pathologic evidence of residual cancer in the surgical specimen.

A randomized multicenter phase II study is being planned to compare the cetuximab and TPF combination with the M.D. Anderson Cancer Center induction regimen consisting of carboplatin, paclitaxel, and cetiuximab, Dr. Haddad said.

The study was supported by Bristol-Myers Squibb. Dr. Haddad disclosed receiving honoraria and research support from the company, and honoraria from Sanofi-Aventis and Imclone Systems.

CHICAGO — Cetuximab can be added safely and apparently to good effect when giving a standard induction regimen to patients with newly diagnosed, locally advanced head and neck cancer, reported investigators at the annual meeting of the American Society of Clinical Oncology.

In a phase I study looking at the addition of cetuximab (Erbitux) to induction chemotherapy with docetaxel (Taxotere), cisplatin, and 5-fluorouracil (the TPF regimen), 14 of 19 treated patients had a complete clinical response, 5 had a partial clinical response, and all 19 had a partial radiographic response, reported Dr. Robert I. Haddad, who is a clinical investigator in the Head and Neck Cancer Center at the Dana Farber Cancer Institute in Boston.

"The preliminary efficacy data [are] encouraging in this patient population with fairly advanced presentation," Dr. Haddad said.

The TPF regimen is both a new standard for induction chemotherapy in patients with previously untreated squamous cell carcinomas of the head and neck, and a platform for testing new agents such as cetuximab, which has been shown to have efficacy in head and neck cancer as a single agent and in combination with radiation therapy and cistplatin/5-fluorouracil (PF) chemotherapy, Dr. Haddad said.

He and his colleagues conducted a phase I study of the maximum tolerated dose of 5-fluorouracil (5-FU) in the TPF regimen when cetuximab was added. Secondary goals of the study included a toxicity assessment and response rates.

They enrolled 28 patients with biopsy-proven squamous cell carcinoma of the head and neck, with primary tumor sites in the oral cavity, oropharynx, nasopharynx, hypopharynx, or larynx. Patients with unknown primary site squamous cell carcinomas were also eligible.

The patients had to have stage III or IV disease with no evidence of distant metastases, and they had to have no prior chemotherapy, radiation therapy, or surgery, measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors). In addition, patients needed to have good Eastern Cooperative Oncology Group performance status (0 or 1), and normal hematologic, renal, and liver function.

Patients received 400 mg/m

The treatment plan called for three cycles of induction chemotherapy, with TPF every 21 days, plus weekly cetuximab in doses of 250 mg/m

At the end of induction, restaging was performed and then patients underwent definitive chemoradiotherapy with a platinum-based regimen according to the institution's standard.

One of the patients withdrew consent before toxicity could be assessed, leaving 27 available for the analysis. Of these patients, 19 had completed chemoradiotherapy at the time Dr. Haddad presented the data.

There were no dose-limiting toxicities after the first cycle of cetuximab/TPF with 5-FU at 750 or 850 mg/m

But in that expanded cohort, there were two cases of gastrointestinal bleeding and one of febrile neutropenia, causing the investigators to reconsider 5-FU dosing, and they instead settled on 850 mg as the maximum tolerated dose. Of the 10 patients planned for enrollment in the expanded cohort at this dose, nine had enrolled at the time of the analysis. Only one dose-limiting toxicity was reported: mucositis.

Among the 12 patients in total enrolled at the 850-mg dose (3 from the original cohort, plus 9 additionally enrolled), there were four cases of grade 4 neutropenia and one of grade 4 diarrhea. Grade 3 events include three cases of neutropenia, two of febrile neutropenia, one mucositis (dose limiting), one fatigue, and one syncope. Skin toxicities included acneiform rash (seven grade 2 and one grade 3), and four cases of grade 2 nail fissuring and/or paronychial infection.

At the time of the data presentation, 19 of 27 patients had completed chemoradiotherapy with a platinum-based agent, and 8 remained on treatment. All but one of the patients received 70-Gy radiation over 7 weeks; the remaining patients received 59 Gy over 10 weeks.

An analysis of the best overall response showed a clinical complete response in 14 patients, and partial response in 5. Radiographic evaluation at the end of induction but before radiation showed a partial response in all 19 patients.

"All of these patients had still-persistent abnormalities on CT or PET," Dr. Haddad said. "Keep in mind these patients have fairly advanced nodal presentations, and often the CT scan or imaging is not normalized for these patients."

Among the 13 patients who underwent primary site biopsy after induction, 11 had pathologic complete response, and 2 had a partial response.

All patients were alive at 6-month follow-up; one patient with a stage T4 N2b cancer of the base of the tongue had local/regional recurrence and is currently on palliative chemotherapy. Two patients had neck dissections performed after chemoradiotherapy, and neither had pathologic evidence of residual cancer in the surgical specimen.

A randomized multicenter phase II study is being planned to compare the cetuximab and TPF combination with the M.D. Anderson Cancer Center induction regimen consisting of carboplatin, paclitaxel, and cetiuximab, Dr. Haddad said.

The study was supported by Bristol-Myers Squibb. Dr. Haddad disclosed receiving honoraria and research support from the company, and honoraria from Sanofi-Aventis and Imclone Systems.

CHICAGO — Cetuximab can be added safely and apparently to good effect when giving a standard induction regimen to patients with newly diagnosed, locally advanced head and neck cancer, reported investigators at the annual meeting of the American Society of Clinical Oncology.

In a phase I study looking at the addition of cetuximab (Erbitux) to induction chemotherapy with docetaxel (Taxotere), cisplatin, and 5-fluorouracil (the TPF regimen), 14 of 19 treated patients had a complete clinical response, 5 had a partial clinical response, and all 19 had a partial radiographic response, reported Dr. Robert I. Haddad, who is a clinical investigator in the Head and Neck Cancer Center at the Dana Farber Cancer Institute in Boston.

"The preliminary efficacy data [are] encouraging in this patient population with fairly advanced presentation," Dr. Haddad said.

The TPF regimen is both a new standard for induction chemotherapy in patients with previously untreated squamous cell carcinomas of the head and neck, and a platform for testing new agents such as cetuximab, which has been shown to have efficacy in head and neck cancer as a single agent and in combination with radiation therapy and cistplatin/5-fluorouracil (PF) chemotherapy, Dr. Haddad said.

He and his colleagues conducted a phase I study of the maximum tolerated dose of 5-fluorouracil (5-FU) in the TPF regimen when cetuximab was added. Secondary goals of the study included a toxicity assessment and response rates.

They enrolled 28 patients with biopsy-proven squamous cell carcinoma of the head and neck, with primary tumor sites in the oral cavity, oropharynx, nasopharynx, hypopharynx, or larynx. Patients with unknown primary site squamous cell carcinomas were also eligible.

The patients had to have stage III or IV disease with no evidence of distant metastases, and they had to have no prior chemotherapy, radiation therapy, or surgery, measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors). In addition, patients needed to have good Eastern Cooperative Oncology Group performance status (0 or 1), and normal hematologic, renal, and liver function.

Patients received 400 mg/m

The treatment plan called for three cycles of induction chemotherapy, with TPF every 21 days, plus weekly cetuximab in doses of 250 mg/m

At the end of induction, restaging was performed and then patients underwent definitive chemoradiotherapy with a platinum-based regimen according to the institution's standard.

One of the patients withdrew consent before toxicity could be assessed, leaving 27 available for the analysis. Of these patients, 19 had completed chemoradiotherapy at the time Dr. Haddad presented the data.

There were no dose-limiting toxicities after the first cycle of cetuximab/TPF with 5-FU at 750 or 850 mg/m

But in that expanded cohort, there were two cases of gastrointestinal bleeding and one of febrile neutropenia, causing the investigators to reconsider 5-FU dosing, and they instead settled on 850 mg as the maximum tolerated dose. Of the 10 patients planned for enrollment in the expanded cohort at this dose, nine had enrolled at the time of the analysis. Only one dose-limiting toxicity was reported: mucositis.

Among the 12 patients in total enrolled at the 850-mg dose (3 from the original cohort, plus 9 additionally enrolled), there were four cases of grade 4 neutropenia and one of grade 4 diarrhea. Grade 3 events include three cases of neutropenia, two of febrile neutropenia, one mucositis (dose limiting), one fatigue, and one syncope. Skin toxicities included acneiform rash (seven grade 2 and one grade 3), and four cases of grade 2 nail fissuring and/or paronychial infection.

At the time of the data presentation, 19 of 27 patients had completed chemoradiotherapy with a platinum-based agent, and 8 remained on treatment. All but one of the patients received 70-Gy radiation over 7 weeks; the remaining patients received 59 Gy over 10 weeks.

An analysis of the best overall response showed a clinical complete response in 14 patients, and partial response in 5. Radiographic evaluation at the end of induction but before radiation showed a partial response in all 19 patients.

"All of these patients had still-persistent abnormalities on CT or PET," Dr. Haddad said. "Keep in mind these patients have fairly advanced nodal presentations, and often the CT scan or imaging is not normalized for these patients."

Among the 13 patients who underwent primary site biopsy after induction, 11 had pathologic complete response, and 2 had a partial response.

All patients were alive at 6-month follow-up; one patient with a stage T4 N2b cancer of the base of the tongue had local/regional recurrence and is currently on palliative chemotherapy. Two patients had neck dissections performed after chemoradiotherapy, and neither had pathologic evidence of residual cancer in the surgical specimen.

A randomized multicenter phase II study is being planned to compare the cetuximab and TPF combination with the M.D. Anderson Cancer Center induction regimen consisting of carboplatin, paclitaxel, and cetiuximab, Dr. Haddad said.

The study was supported by Bristol-Myers Squibb. Dr. Haddad disclosed receiving honoraria and research support from the company, and honoraria from Sanofi-Aventis and Imclone Systems.

CHICAGO — A threefold increase in the incidence of tonsillar cancer over 3 decades in Sweden was paralleled by a similar rise in the incidence of tumors positive for the human papillomavirus, the results of a cohort study indicate.

At the same time, however, survival rates in patients with tonsillar cancer also increased, possibly because of the higher proportion of HPV-positive cancers, which tend to have a better prognosis than other oral cancers, Dr. Hanna Dahlstrand said at the annual meeting of the American Society of Clinical Oncology.

The reasons for the increase in HPV-positive tumors are not known, although they could be related to a possible increase in sexual behaviors, particularly in urban centers, Dr. Dahlstrand said.

Sweden is a relatively small nation, but the results may be applicable to other countries, she noted. In the United States, for example, the incidence of HPV-related oropharyngeal squamous cell carcinomas has risen since 1973, whereas the incidence of squamous cell carcinomas at other oral sites has either remained constant or declined. In Finland, the incidence of tonsillar cancers doubled from 1956 through 2000.

HPV DNA has been shown to be present in 40%–75% of oro- pharyngeal cancers, compared with about 25% of all head and neck cancers.

“It is only the high-risk types of HPV that are found, with at least 90% dominance of HPV-16, and the oncogenes on HPV, E6 and E7 are transcribed,” she said, “And there is a temporal connection: Exposure to HPV-16 precedes by at least 9 years the diagnosis, and has been shown to be a strong risk factor for tumor development.”

HPV-positive oropharyngeal cancers tend to occur more often in nonsmokers and younger patients. Risk factors include multiple sexual partners, younger age at first intercourse, and oral sex. Several studies have shown that the presence of HPV positivity is associated with about a 50% reduction in 5-year mortality, said Dr. Dahlstrand of the department of oncology-pathology at the Karo- linska Institute in Stockholm.

She and her colleagues conducted a nationwide cohort study using the exhaustive clinical and demographic databases available to Swedish investigators. Their goals were to see whether there has been an increase in the incidence of tonsillar cancer in Sweden; to determine whether such an increase, if present, could be linked to the proportion of HPV-positive tumors; and to see whether the incidence of HPV-positive tonsillar cancers would have an effect on survival.

They identified a total of 2,165 incident cases of tonsillar squamous cell carcinoma from 1960 through 2003, using the Swedish National Cancer Registry.

To determine survival, the investigators used records from the Swedish Causes of Death Register, and checked them against the Swedish Emigration Registry from 1960 to 2001 to ensure that cohort members were not lost to follow-up. They identified a total of 1,800 survivors as of 2003.

The investigators also assessed the incidence of tonsillar cancer from 1970 to 2001 and survival in a Stockholm cohort, and used this cohort to control for treatment, tumor-nodes-metastasis stage, and cause of death. They identified 515 cases in this cohort, and 337 survivors as of 2001.

They were able to obtain 203 biopsy samples and screened them for HPV using polymerase chain reaction testing; they then typed and sequenced the HPV to determine expression of the E6 and E7 oncogenes and expression of HPV-16.

In the nationwide cohort, there was a 2.04-fold increase in the incidence of tonsillar cancers, from 1.2/100,000 population to 2.4/ 100,000, from 1960 to 2003. There was no parallel increase in cancers of the oral cavity (for example, mobile tongue or floor of the mouth), however.

In the Stockholm cohort, tonsillar cancers increased from 1.3/100,000 to 3.6/ 100,000, or 2.8-fold, from 1970 to 2002. There was also a 2.9-fold increase in the proportion of HPV-positive tonsillar cancers during that same time period. This increase became significant for the 1990–1999 period, compared with 1970–1979 (P = .0025), and remained significant for 2000–2002 (P less than .0001). During the ′70s, 23% of cases were HPV positive, which increased to 28% in the ′80s, 57% in the ′90s, and to 68% into the 21st century.

The mean 5-year relative survival rate in men with tonsillar cancer also increased in Sweden since the 1960s, from 32% to 53% in 1990–2001. The relative hazard ratio for death for the latest decade vs. the earliest was 0.50. Women had a slightly better survival rate than men then and now, with the rate increasing from 45% in the ′60s to 60% in the ′90s and into 2001. Because women had better survival early on, however, the difference in relative hazard ratios was not quite as large as that for the cohort as a whole.

In the Stockholm cohort, in a Cox multivariate analysis adjusted for age, gender, stage, and treatment, the researchers found a similar significant rise in relative 5-year survival, with a relative hazard ratio of 0.54 for 1990–2001, compared with 1970–1979. A lower proportion of stage I and II tumors in the ′90s, compared with the ′70s, suggests the improvement in survival over the years can't be explained by earlier diagnosis, Dr. Dahlstrand said.

Finally, when the investigators looked at survival by HPV status in the Stockholm cohort, they found that independent of age, gender, and tumor stage, the hazard ratio for patients with HPV-positive tumors was 0.17.

In all, 49% of cases from 1973 to 2008 were HPV positive, and the E6 and/or E7 mRNA were found in 94% of assessable HPV-positive samples, Dr. Dahlstrand noted.

The findings show that about a threefold increase in the incidence of tonsillar cancer was accompanied by about a threefold rise in the rate of HPV-positive tonsillar cancers. The presence of the E6 and E7 oncogenes provides further evidence linking HPV to tonsillar cancers, she said.

The study funding source was not provided. Dr. Dahlstrand said she has no relevant financial disclosures.

CHICAGO — A threefold increase in the incidence of tonsillar cancer over 3 decades in Sweden was paralleled by a similar rise in the incidence of tumors positive for the human papillomavirus, the results of a cohort study indicate.

At the same time, however, survival rates in patients with tonsillar cancer also increased, possibly because of the higher proportion of HPV-positive cancers, which tend to have a better prognosis than other oral cancers, Dr. Hanna Dahlstrand said at the annual meeting of the American Society of Clinical Oncology.

The reasons for the increase in HPV-positive tumors are not known, although they could be related to a possible increase in sexual behaviors, particularly in urban centers, Dr. Dahlstrand said.

Sweden is a relatively small nation, but the results may be applicable to other countries, she noted. In the United States, for example, the incidence of HPV-related oropharyngeal squamous cell carcinomas has risen since 1973, whereas the incidence of squamous cell carcinomas at other oral sites has either remained constant or declined. In Finland, the incidence of tonsillar cancers doubled from 1956 through 2000.

HPV DNA has been shown to be present in 40%–75% of oro- pharyngeal cancers, compared with about 25% of all head and neck cancers.

“It is only the high-risk types of HPV that are found, with at least 90% dominance of HPV-16, and the oncogenes on HPV, E6 and E7 are transcribed,” she said, “And there is a temporal connection: Exposure to HPV-16 precedes by at least 9 years the diagnosis, and has been shown to be a strong risk factor for tumor development.”

HPV-positive oropharyngeal cancers tend to occur more often in nonsmokers and younger patients. Risk factors include multiple sexual partners, younger age at first intercourse, and oral sex. Several studies have shown that the presence of HPV positivity is associated with about a 50% reduction in 5-year mortality, said Dr. Dahlstrand of the department of oncology-pathology at the Karo- linska Institute in Stockholm.

She and her colleagues conducted a nationwide cohort study using the exhaustive clinical and demographic databases available to Swedish investigators. Their goals were to see whether there has been an increase in the incidence of tonsillar cancer in Sweden; to determine whether such an increase, if present, could be linked to the proportion of HPV-positive tumors; and to see whether the incidence of HPV-positive tonsillar cancers would have an effect on survival.

They identified a total of 2,165 incident cases of tonsillar squamous cell carcinoma from 1960 through 2003, using the Swedish National Cancer Registry.

To determine survival, the investigators used records from the Swedish Causes of Death Register, and checked them against the Swedish Emigration Registry from 1960 to 2001 to ensure that cohort members were not lost to follow-up. They identified a total of 1,800 survivors as of 2003.

The investigators also assessed the incidence of tonsillar cancer from 1970 to 2001 and survival in a Stockholm cohort, and used this cohort to control for treatment, tumor-nodes-metastasis stage, and cause of death. They identified 515 cases in this cohort, and 337 survivors as of 2001.

They were able to obtain 203 biopsy samples and screened them for HPV using polymerase chain reaction testing; they then typed and sequenced the HPV to determine expression of the E6 and E7 oncogenes and expression of HPV-16.

In the nationwide cohort, there was a 2.04-fold increase in the incidence of tonsillar cancers, from 1.2/100,000 population to 2.4/ 100,000, from 1960 to 2003. There was no parallel increase in cancers of the oral cavity (for example, mobile tongue or floor of the mouth), however.

In the Stockholm cohort, tonsillar cancers increased from 1.3/100,000 to 3.6/ 100,000, or 2.8-fold, from 1970 to 2002. There was also a 2.9-fold increase in the proportion of HPV-positive tonsillar cancers during that same time period. This increase became significant for the 1990–1999 period, compared with 1970–1979 (P = .0025), and remained significant for 2000–2002 (P less than .0001). During the ′70s, 23% of cases were HPV positive, which increased to 28% in the ′80s, 57% in the ′90s, and to 68% into the 21st century.

The mean 5-year relative survival rate in men with tonsillar cancer also increased in Sweden since the 1960s, from 32% to 53% in 1990–2001. The relative hazard ratio for death for the latest decade vs. the earliest was 0.50. Women had a slightly better survival rate than men then and now, with the rate increasing from 45% in the ′60s to 60% in the ′90s and into 2001. Because women had better survival early on, however, the difference in relative hazard ratios was not quite as large as that for the cohort as a whole.

In the Stockholm cohort, in a Cox multivariate analysis adjusted for age, gender, stage, and treatment, the researchers found a similar significant rise in relative 5-year survival, with a relative hazard ratio of 0.54 for 1990–2001, compared with 1970–1979. A lower proportion of stage I and II tumors in the ′90s, compared with the ′70s, suggests the improvement in survival over the years can't be explained by earlier diagnosis, Dr. Dahlstrand said.

Finally, when the investigators looked at survival by HPV status in the Stockholm cohort, they found that independent of age, gender, and tumor stage, the hazard ratio for patients with HPV-positive tumors was 0.17.

In all, 49% of cases from 1973 to 2008 were HPV positive, and the E6 and/or E7 mRNA were found in 94% of assessable HPV-positive samples, Dr. Dahlstrand noted.

The findings show that about a threefold increase in the incidence of tonsillar cancer was accompanied by about a threefold rise in the rate of HPV-positive tonsillar cancers. The presence of the E6 and E7 oncogenes provides further evidence linking HPV to tonsillar cancers, she said.

The study funding source was not provided. Dr. Dahlstrand said she has no relevant financial disclosures.

CHICAGO — A threefold increase in the incidence of tonsillar cancer over 3 decades in Sweden was paralleled by a similar rise in the incidence of tumors positive for the human papillomavirus, the results of a cohort study indicate.

At the same time, however, survival rates in patients with tonsillar cancer also increased, possibly because of the higher proportion of HPV-positive cancers, which tend to have a better prognosis than other oral cancers, Dr. Hanna Dahlstrand said at the annual meeting of the American Society of Clinical Oncology.

The reasons for the increase in HPV-positive tumors are not known, although they could be related to a possible increase in sexual behaviors, particularly in urban centers, Dr. Dahlstrand said.

Sweden is a relatively small nation, but the results may be applicable to other countries, she noted. In the United States, for example, the incidence of HPV-related oropharyngeal squamous cell carcinomas has risen since 1973, whereas the incidence of squamous cell carcinomas at other oral sites has either remained constant or declined. In Finland, the incidence of tonsillar cancers doubled from 1956 through 2000.

HPV DNA has been shown to be present in 40%–75% of oro- pharyngeal cancers, compared with about 25% of all head and neck cancers.

“It is only the high-risk types of HPV that are found, with at least 90% dominance of HPV-16, and the oncogenes on HPV, E6 and E7 are transcribed,” she said, “And there is a temporal connection: Exposure to HPV-16 precedes by at least 9 years the diagnosis, and has been shown to be a strong risk factor for tumor development.”

HPV-positive oropharyngeal cancers tend to occur more often in nonsmokers and younger patients. Risk factors include multiple sexual partners, younger age at first intercourse, and oral sex. Several studies have shown that the presence of HPV positivity is associated with about a 50% reduction in 5-year mortality, said Dr. Dahlstrand of the department of oncology-pathology at the Karo- linska Institute in Stockholm.

She and her colleagues conducted a nationwide cohort study using the exhaustive clinical and demographic databases available to Swedish investigators. Their goals were to see whether there has been an increase in the incidence of tonsillar cancer in Sweden; to determine whether such an increase, if present, could be linked to the proportion of HPV-positive tumors; and to see whether the incidence of HPV-positive tonsillar cancers would have an effect on survival.

They identified a total of 2,165 incident cases of tonsillar squamous cell carcinoma from 1960 through 2003, using the Swedish National Cancer Registry.

To determine survival, the investigators used records from the Swedish Causes of Death Register, and checked them against the Swedish Emigration Registry from 1960 to 2001 to ensure that cohort members were not lost to follow-up. They identified a total of 1,800 survivors as of 2003.

The investigators also assessed the incidence of tonsillar cancer from 1970 to 2001 and survival in a Stockholm cohort, and used this cohort to control for treatment, tumor-nodes-metastasis stage, and cause of death. They identified 515 cases in this cohort, and 337 survivors as of 2001.

They were able to obtain 203 biopsy samples and screened them for HPV using polymerase chain reaction testing; they then typed and sequenced the HPV to determine expression of the E6 and E7 oncogenes and expression of HPV-16.

In the nationwide cohort, there was a 2.04-fold increase in the incidence of tonsillar cancers, from 1.2/100,000 population to 2.4/ 100,000, from 1960 to 2003. There was no parallel increase in cancers of the oral cavity (for example, mobile tongue or floor of the mouth), however.

In the Stockholm cohort, tonsillar cancers increased from 1.3/100,000 to 3.6/ 100,000, or 2.8-fold, from 1970 to 2002. There was also a 2.9-fold increase in the proportion of HPV-positive tonsillar cancers during that same time period. This increase became significant for the 1990–1999 period, compared with 1970–1979 (P = .0025), and remained significant for 2000–2002 (P less than .0001). During the ′70s, 23% of cases were HPV positive, which increased to 28% in the ′80s, 57% in the ′90s, and to 68% into the 21st century.

The mean 5-year relative survival rate in men with tonsillar cancer also increased in Sweden since the 1960s, from 32% to 53% in 1990–2001. The relative hazard ratio for death for the latest decade vs. the earliest was 0.50. Women had a slightly better survival rate than men then and now, with the rate increasing from 45% in the ′60s to 60% in the ′90s and into 2001. Because women had better survival early on, however, the difference in relative hazard ratios was not quite as large as that for the cohort as a whole.

In the Stockholm cohort, in a Cox multivariate analysis adjusted for age, gender, stage, and treatment, the researchers found a similar significant rise in relative 5-year survival, with a relative hazard ratio of 0.54 for 1990–2001, compared with 1970–1979. A lower proportion of stage I and II tumors in the ′90s, compared with the ′70s, suggests the improvement in survival over the years can't be explained by earlier diagnosis, Dr. Dahlstrand said.

Finally, when the investigators looked at survival by HPV status in the Stockholm cohort, they found that independent of age, gender, and tumor stage, the hazard ratio for patients with HPV-positive tumors was 0.17.

In all, 49% of cases from 1973 to 2008 were HPV positive, and the E6 and/or E7 mRNA were found in 94% of assessable HPV-positive samples, Dr. Dahlstrand noted.

The findings show that about a threefold increase in the incidence of tonsillar cancer was accompanied by about a threefold rise in the rate of HPV-positive tonsillar cancers. The presence of the E6 and E7 oncogenes provides further evidence linking HPV to tonsillar cancers, she said.

The study funding source was not provided. Dr. Dahlstrand said she has no relevant financial disclosures.