Mary Ann Moon

Major Finding: Only 43% of patients maintained a “modest” weight loss after LAGB over the long term, and nearly 60% required reoperation.

Data Source: A 13-year follow-up study of 82 patients who underwent LAGB using the perigastric technique during 1994–1997.

Disclosures: Dr. Himpens is a consultant with Ethicon Endosurgery and Covidien, and his associates reported ties to Storz.

The long-term outcomes of laparoscopic adjustable gastric banding appear to be relatively poor, according to a Belgian study.

In a 13-year follow-up study of about half of the obese patients who underwent laparoscopic adjustable gastric banding (LAGB) at one institution between 1994 and 1997, only 43% maintained a loss of excess weight, nearly 60% required reoperation, and obesity-related comorbidities such as diabetes, hypertension, and sleep apnea persisted.

“The high failure rate of LAGB, at least in our hands, could be detrimental to its future continued widespread use as a restrictive weight loss operation,” said Dr. Jacques Himpens and his associates at the European School of Laparoscopic Surgery, Saint Pierre University Hospital, Brussels.

In Europe there has been a marked shift in treatment, away from LAGB in favor of gastric bypass. “In contrast, in the United States, an opposite trend has been noted,” even though some experts contend that LAGB “can result in a mediocre quality of life and a significant number of complications, and … there is a tendency for patients to regain weight after some years,” the investigators noted.

Dr. Himpens and his colleagues performed what they described as the first study of outcomes beyond the 10-year mark in patients who underwent LAGB using the perigastric technique. (The more recent “pars flaccida” technique and the current use of wider, softer bands than those used in the late 1990s may be improving outcomes, but that has not yet been proven, and many surgeons continue to use the perigastric technique, the researchers said.)

During the study period, 151 patients underwent LAGB using the perigastric technique at the hospital, but only 82 were available for a follow-up in 2009. “LAGB patients lost to follow-up are likely to experience very little weight loss. Our results must be viewed from this perspective,” the authors noted.

The 82 study subjects included 74 women and 8 men, with a mean body mass index of 42 kg/m

Fifty patients (59%) developed complications, including 33 major ones such as pouch dilation, band erosion, and band infection. Incisional hernia, port-tubing disconnection, and port infection were considered minor complications.

It is noteworthy that most band erosions and pouch dilations developed “quite late,” at a mean of 4 years after surgery, the authors wrote (Arch. Surg. 2011 March 21 [doi:10.1001/archsurg.2011.45]).

About 60% of patients required at least one reoperation, because of complications or because they failed to lose weight or regained their weight.

Complete weight loss data were available for 70 patients. The mean percentage of excess weight loss was 43% in this group (range 24%–143%).

Overall, weight loss was modest. In the 70 patients, mean weight fell from 114 kg to 93 kg, and mean BMI decreased from 42 to 34. At follow-up, patient weight ranged from 37 to 165 kg, and BMI ranged from 35 to 57.

Hypertension, type 2 diabetes, and sleep apnea persisted or developed anew in 30%, 7%, and 8% of the participants, respectively.

Fourteen patients who switched to gastric bypass surgery after failure of LAGB showed better success with that procedure.

Despite these relatively poor outcomes with LAGB, 47 patients said that they were “pleased” or “very pleased” with the procedure, and their scores on quality-of-life measures were the same as those in a nonsurgical population. This may explain why the public has not yet rejected “lap-band” surgery, wrote the authors.

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Pass These Results On to Patients

“The data in this study, as well as the experience in our own institutions, should influence our choice of procedure [LAGB vs. laparoscopic Rouxen-Y gastric bypass] and the manner in which we inform our patients of the advantages and disadvantages of each procedure,” said Dr. Clifford W. Deveney.

At long-term follow-up, patients who still had the band in place had lost 48% of their excess weight, and those who had had the band removed had lost 22% of their excess weight. Moreover, the number and type of obesity-related comorbidities increased over time. “These data do not shed a favorable light on the use of LAGB,” he noted.

CLIFFORD W. DEVENEY, M.D., is in the department of surgery at Oregon Health and Science University, Portland. These remarks were taken from his “invited critique” accompanying Dr. Himpens' report (Arch. Surg. 2011 March 21[doi:10.1001/archsurg.2011.36]). Dr. Deveney reported no financial disclosures.

Major Finding: Only 43% of patients maintained a “modest” weight loss after LAGB over the long term, and nearly 60% required reoperation.

Data Source: A 13-year follow-up study of 82 patients who underwent LAGB using the perigastric technique during 1994–1997.

Disclosures: Dr. Himpens is a consultant with Ethicon Endosurgery and Covidien, and his associates reported ties to Storz.

The long-term outcomes of laparoscopic adjustable gastric banding appear to be relatively poor, according to a Belgian study.

In a 13-year follow-up study of about half of the obese patients who underwent laparoscopic adjustable gastric banding (LAGB) at one institution between 1994 and 1997, only 43% maintained a loss of excess weight, nearly 60% required reoperation, and obesity-related comorbidities such as diabetes, hypertension, and sleep apnea persisted.

“The high failure rate of LAGB, at least in our hands, could be detrimental to its future continued widespread use as a restrictive weight loss operation,” said Dr. Jacques Himpens and his associates at the European School of Laparoscopic Surgery, Saint Pierre University Hospital, Brussels.

In Europe there has been a marked shift in treatment, away from LAGB in favor of gastric bypass. “In contrast, in the United States, an opposite trend has been noted,” even though some experts contend that LAGB “can result in a mediocre quality of life and a significant number of complications, and … there is a tendency for patients to regain weight after some years,” the investigators noted.

Dr. Himpens and his colleagues performed what they described as the first study of outcomes beyond the 10-year mark in patients who underwent LAGB using the perigastric technique. (The more recent “pars flaccida” technique and the current use of wider, softer bands than those used in the late 1990s may be improving outcomes, but that has not yet been proven, and many surgeons continue to use the perigastric technique, the researchers said.)

During the study period, 151 patients underwent LAGB using the perigastric technique at the hospital, but only 82 were available for a follow-up in 2009. “LAGB patients lost to follow-up are likely to experience very little weight loss. Our results must be viewed from this perspective,” the authors noted.

The 82 study subjects included 74 women and 8 men, with a mean body mass index of 42 kg/m

Fifty patients (59%) developed complications, including 33 major ones such as pouch dilation, band erosion, and band infection. Incisional hernia, port-tubing disconnection, and port infection were considered minor complications.

It is noteworthy that most band erosions and pouch dilations developed “quite late,” at a mean of 4 years after surgery, the authors wrote (Arch. Surg. 2011 March 21 [doi:10.1001/archsurg.2011.45]).

About 60% of patients required at least one reoperation, because of complications or because they failed to lose weight or regained their weight.

Complete weight loss data were available for 70 patients. The mean percentage of excess weight loss was 43% in this group (range 24%–143%).

Overall, weight loss was modest. In the 70 patients, mean weight fell from 114 kg to 93 kg, and mean BMI decreased from 42 to 34. At follow-up, patient weight ranged from 37 to 165 kg, and BMI ranged from 35 to 57.

Hypertension, type 2 diabetes, and sleep apnea persisted or developed anew in 30%, 7%, and 8% of the participants, respectively.

Fourteen patients who switched to gastric bypass surgery after failure of LAGB showed better success with that procedure.

Despite these relatively poor outcomes with LAGB, 47 patients said that they were “pleased” or “very pleased” with the procedure, and their scores on quality-of-life measures were the same as those in a nonsurgical population. This may explain why the public has not yet rejected “lap-band” surgery, wrote the authors.

View on the News

Pass These Results On to Patients

“The data in this study, as well as the experience in our own institutions, should influence our choice of procedure [LAGB vs. laparoscopic Rouxen-Y gastric bypass] and the manner in which we inform our patients of the advantages and disadvantages of each procedure,” said Dr. Clifford W. Deveney.

At long-term follow-up, patients who still had the band in place had lost 48% of their excess weight, and those who had had the band removed had lost 22% of their excess weight. Moreover, the number and type of obesity-related comorbidities increased over time. “These data do not shed a favorable light on the use of LAGB,” he noted.

CLIFFORD W. DEVENEY, M.D., is in the department of surgery at Oregon Health and Science University, Portland. These remarks were taken from his “invited critique” accompanying Dr. Himpens' report (Arch. Surg. 2011 March 21[doi:10.1001/archsurg.2011.36]). Dr. Deveney reported no financial disclosures.

Major Finding: Only 43% of patients maintained a “modest” weight loss after LAGB over the long term, and nearly 60% required reoperation.

Data Source: A 13-year follow-up study of 82 patients who underwent LAGB using the perigastric technique during 1994–1997.

Disclosures: Dr. Himpens is a consultant with Ethicon Endosurgery and Covidien, and his associates reported ties to Storz.

The long-term outcomes of laparoscopic adjustable gastric banding appear to be relatively poor, according to a Belgian study.

In a 13-year follow-up study of about half of the obese patients who underwent laparoscopic adjustable gastric banding (LAGB) at one institution between 1994 and 1997, only 43% maintained a loss of excess weight, nearly 60% required reoperation, and obesity-related comorbidities such as diabetes, hypertension, and sleep apnea persisted.

“The high failure rate of LAGB, at least in our hands, could be detrimental to its future continued widespread use as a restrictive weight loss operation,” said Dr. Jacques Himpens and his associates at the European School of Laparoscopic Surgery, Saint Pierre University Hospital, Brussels.

In Europe there has been a marked shift in treatment, away from LAGB in favor of gastric bypass. “In contrast, in the United States, an opposite trend has been noted,” even though some experts contend that LAGB “can result in a mediocre quality of life and a significant number of complications, and … there is a tendency for patients to regain weight after some years,” the investigators noted.

Dr. Himpens and his colleagues performed what they described as the first study of outcomes beyond the 10-year mark in patients who underwent LAGB using the perigastric technique. (The more recent “pars flaccida” technique and the current use of wider, softer bands than those used in the late 1990s may be improving outcomes, but that has not yet been proven, and many surgeons continue to use the perigastric technique, the researchers said.)

During the study period, 151 patients underwent LAGB using the perigastric technique at the hospital, but only 82 were available for a follow-up in 2009. “LAGB patients lost to follow-up are likely to experience very little weight loss. Our results must be viewed from this perspective,” the authors noted.

The 82 study subjects included 74 women and 8 men, with a mean body mass index of 42 kg/m

Fifty patients (59%) developed complications, including 33 major ones such as pouch dilation, band erosion, and band infection. Incisional hernia, port-tubing disconnection, and port infection were considered minor complications.

It is noteworthy that most band erosions and pouch dilations developed “quite late,” at a mean of 4 years after surgery, the authors wrote (Arch. Surg. 2011 March 21 [doi:10.1001/archsurg.2011.45]).

About 60% of patients required at least one reoperation, because of complications or because they failed to lose weight or regained their weight.

Complete weight loss data were available for 70 patients. The mean percentage of excess weight loss was 43% in this group (range 24%–143%).

Overall, weight loss was modest. In the 70 patients, mean weight fell from 114 kg to 93 kg, and mean BMI decreased from 42 to 34. At follow-up, patient weight ranged from 37 to 165 kg, and BMI ranged from 35 to 57.

Hypertension, type 2 diabetes, and sleep apnea persisted or developed anew in 30%, 7%, and 8% of the participants, respectively.

Fourteen patients who switched to gastric bypass surgery after failure of LAGB showed better success with that procedure.

Despite these relatively poor outcomes with LAGB, 47 patients said that they were “pleased” or “very pleased” with the procedure, and their scores on quality-of-life measures were the same as those in a nonsurgical population. This may explain why the public has not yet rejected “lap-band” surgery, wrote the authors.

View on the News

Pass These Results On to Patients

“The data in this study, as well as the experience in our own institutions, should influence our choice of procedure [LAGB vs. laparoscopic Rouxen-Y gastric bypass] and the manner in which we inform our patients of the advantages and disadvantages of each procedure,” said Dr. Clifford W. Deveney.

At long-term follow-up, patients who still had the band in place had lost 48% of their excess weight, and those who had had the band removed had lost 22% of their excess weight. Moreover, the number and type of obesity-related comorbidities increased over time. “These data do not shed a favorable light on the use of LAGB,” he noted.

CLIFFORD W. DEVENEY, M.D., is in the department of surgery at Oregon Health and Science University, Portland. These remarks were taken from his “invited critique” accompanying Dr. Himpens' report (Arch. Surg. 2011 March 21[doi:10.1001/archsurg.2011.36]). Dr. Deveney reported no financial disclosures.

Major Finding: Men who developed diabetes at or before age 60 and had the disease for at least 8 years had nearly twice the risk of a major cardiovascular event (relative risk 1.95) than did men who developed diabetes at a later age and had it for fewer than 8 years.

Data Source: Analysis of data on 4,045 subjects participating in a prospective study of cardiovascular disease in older, white British men.

Disclosures: The British Regional Heart Study is supported by the British Heart Foundation. No financial conflicts of interest were reported.

Among older white men, coronary heart disease risk is approximately twice as high in those who developed type 2 diabetes relatively early in adulthood and have had the disease for more than 8 years, compared with those who developed it later and have had it for fewer than 8 years, a study has shown.

In older white men with an earlier onset and a longer duration of type 2 diabetes, the risk of CHD events is equivalent to that of nondiabetic men who had already had prior myocardial infarction, said S. Goya Wannamethee, Ph.D., of the department of primary care and population health, University College London, and associates.

“Although diabetes is a well-established risk factor for CHD, whether diabetes alone is a CHD equivalent in assessing the risk of future cardiovascular events [has been] controversial. … Our observations plus prior research [suggest] that CHD risk in patients with diabetes escalates significantly with disease duration and approaches CHD risk equivalence only when disease duration is beyond 8 years,” they noted.

Dr. Wannamethee and colleagues examined the relationship among age of diabetes onset, duration of disease, and cardiovascular risk using data from the British Regional Heart Study (BRHS), a prospective assessment of cardiovascular disease in 7,735 white men aged 40–59 years at enrollment in 1978–1980 who were recruited from general practices in 24 British towns. For this analysis, data were assessed on 4,045 of these subjects who were 60–79 years of age at the 20-year mark of the BRHS and were followed for all-cause mortality and CHD morbidity for a mean of 9 more years.

During that time there were 372 major CHD events, including 263 CHD deaths.

Men with an early onset of type 2 diabetes, with a diagnosis at or before age 60, had a mean duration of disease of 16.7 years. Their CHD risk was approximately twice that of men who had a later onset, with a diagnosis after age 60 and a mean duration of disease of 4.9 years.

“Moreover, the [relative risk] for vascular events and mortality in [men] with early onset of diabetes were comparable to those in men with prior MI, suggesting that a longer duration of diabetes may be necessary to raise risks toward a CHD risk equivalent,” the investigators said (Arch. Intern. Med. 2011;171:404-10).

These findings should go a long way toward resolving the confusion and debate over the issue, and explain why previous studies that did not specifically address age of onset or disease duration have yielded conflicting results, the researchers noted.

“The clinical implication is that, although 10-year CHD risk for newly diagnosed diabetes may not be very high, CHD risk beyond 10 years or indeed lifetime risk will be much higher. This pattern … emphasizes the need to be aggressive with CHD risk reduction [that is, statin use and blood pressure modification] in patients with type 2 diabetes diagnosed at a relatively young age,” Dr. Wannamethee and associates said.

“Finally, neither adjustment for traditional risk factors nor a range of novel risk factors (including markers of inflammation, endothelial dysfunction, and renal dysfunction) explained the excess CHD risk in patients with known diabetes, particularly in those with early onset. These men still showed an almost threefold increase in risk after adjustment,” compared with men who did not have diabetes.

Future studies of this issue must examine whether the findings hold true in women and people of nonwhite ethnicities, they added.

The British Regional Heart Study is supported by the British Heart Foundation. No financial conflicts of interest were reported.

Major Finding: Men who developed diabetes at or before age 60 and had the disease for at least 8 years had nearly twice the risk of a major cardiovascular event (relative risk 1.95) than did men who developed diabetes at a later age and had it for fewer than 8 years.

Data Source: Analysis of data on 4,045 subjects participating in a prospective study of cardiovascular disease in older, white British men.

Disclosures: The British Regional Heart Study is supported by the British Heart Foundation. No financial conflicts of interest were reported.

Among older white men, coronary heart disease risk is approximately twice as high in those who developed type 2 diabetes relatively early in adulthood and have had the disease for more than 8 years, compared with those who developed it later and have had it for fewer than 8 years, a study has shown.

In older white men with an earlier onset and a longer duration of type 2 diabetes, the risk of CHD events is equivalent to that of nondiabetic men who had already had prior myocardial infarction, said S. Goya Wannamethee, Ph.D., of the department of primary care and population health, University College London, and associates.

“Although diabetes is a well-established risk factor for CHD, whether diabetes alone is a CHD equivalent in assessing the risk of future cardiovascular events [has been] controversial. … Our observations plus prior research [suggest] that CHD risk in patients with diabetes escalates significantly with disease duration and approaches CHD risk equivalence only when disease duration is beyond 8 years,” they noted.

Dr. Wannamethee and colleagues examined the relationship among age of diabetes onset, duration of disease, and cardiovascular risk using data from the British Regional Heart Study (BRHS), a prospective assessment of cardiovascular disease in 7,735 white men aged 40–59 years at enrollment in 1978–1980 who were recruited from general practices in 24 British towns. For this analysis, data were assessed on 4,045 of these subjects who were 60–79 years of age at the 20-year mark of the BRHS and were followed for all-cause mortality and CHD morbidity for a mean of 9 more years.

During that time there were 372 major CHD events, including 263 CHD deaths.

Men with an early onset of type 2 diabetes, with a diagnosis at or before age 60, had a mean duration of disease of 16.7 years. Their CHD risk was approximately twice that of men who had a later onset, with a diagnosis after age 60 and a mean duration of disease of 4.9 years.

“Moreover, the [relative risk] for vascular events and mortality in [men] with early onset of diabetes were comparable to those in men with prior MI, suggesting that a longer duration of diabetes may be necessary to raise risks toward a CHD risk equivalent,” the investigators said (Arch. Intern. Med. 2011;171:404-10).

These findings should go a long way toward resolving the confusion and debate over the issue, and explain why previous studies that did not specifically address age of onset or disease duration have yielded conflicting results, the researchers noted.

“The clinical implication is that, although 10-year CHD risk for newly diagnosed diabetes may not be very high, CHD risk beyond 10 years or indeed lifetime risk will be much higher. This pattern … emphasizes the need to be aggressive with CHD risk reduction [that is, statin use and blood pressure modification] in patients with type 2 diabetes diagnosed at a relatively young age,” Dr. Wannamethee and associates said.

“Finally, neither adjustment for traditional risk factors nor a range of novel risk factors (including markers of inflammation, endothelial dysfunction, and renal dysfunction) explained the excess CHD risk in patients with known diabetes, particularly in those with early onset. These men still showed an almost threefold increase in risk after adjustment,” compared with men who did not have diabetes.

Future studies of this issue must examine whether the findings hold true in women and people of nonwhite ethnicities, they added.

The British Regional Heart Study is supported by the British Heart Foundation. No financial conflicts of interest were reported.

Major Finding: Men who developed diabetes at or before age 60 and had the disease for at least 8 years had nearly twice the risk of a major cardiovascular event (relative risk 1.95) than did men who developed diabetes at a later age and had it for fewer than 8 years.

Data Source: Analysis of data on 4,045 subjects participating in a prospective study of cardiovascular disease in older, white British men.

Disclosures: The British Regional Heart Study is supported by the British Heart Foundation. No financial conflicts of interest were reported.

Among older white men, coronary heart disease risk is approximately twice as high in those who developed type 2 diabetes relatively early in adulthood and have had the disease for more than 8 years, compared with those who developed it later and have had it for fewer than 8 years, a study has shown.

In older white men with an earlier onset and a longer duration of type 2 diabetes, the risk of CHD events is equivalent to that of nondiabetic men who had already had prior myocardial infarction, said S. Goya Wannamethee, Ph.D., of the department of primary care and population health, University College London, and associates.

“Although diabetes is a well-established risk factor for CHD, whether diabetes alone is a CHD equivalent in assessing the risk of future cardiovascular events [has been] controversial. … Our observations plus prior research [suggest] that CHD risk in patients with diabetes escalates significantly with disease duration and approaches CHD risk equivalence only when disease duration is beyond 8 years,” they noted.

Dr. Wannamethee and colleagues examined the relationship among age of diabetes onset, duration of disease, and cardiovascular risk using data from the British Regional Heart Study (BRHS), a prospective assessment of cardiovascular disease in 7,735 white men aged 40–59 years at enrollment in 1978–1980 who were recruited from general practices in 24 British towns. For this analysis, data were assessed on 4,045 of these subjects who were 60–79 years of age at the 20-year mark of the BRHS and were followed for all-cause mortality and CHD morbidity for a mean of 9 more years.

During that time there were 372 major CHD events, including 263 CHD deaths.

Men with an early onset of type 2 diabetes, with a diagnosis at or before age 60, had a mean duration of disease of 16.7 years. Their CHD risk was approximately twice that of men who had a later onset, with a diagnosis after age 60 and a mean duration of disease of 4.9 years.

“Moreover, the [relative risk] for vascular events and mortality in [men] with early onset of diabetes were comparable to those in men with prior MI, suggesting that a longer duration of diabetes may be necessary to raise risks toward a CHD risk equivalent,” the investigators said (Arch. Intern. Med. 2011;171:404-10).

These findings should go a long way toward resolving the confusion and debate over the issue, and explain why previous studies that did not specifically address age of onset or disease duration have yielded conflicting results, the researchers noted.

“The clinical implication is that, although 10-year CHD risk for newly diagnosed diabetes may not be very high, CHD risk beyond 10 years or indeed lifetime risk will be much higher. This pattern … emphasizes the need to be aggressive with CHD risk reduction [that is, statin use and blood pressure modification] in patients with type 2 diabetes diagnosed at a relatively young age,” Dr. Wannamethee and associates said.

“Finally, neither adjustment for traditional risk factors nor a range of novel risk factors (including markers of inflammation, endothelial dysfunction, and renal dysfunction) explained the excess CHD risk in patients with known diabetes, particularly in those with early onset. These men still showed an almost threefold increase in risk after adjustment,” compared with men who did not have diabetes.

Future studies of this issue must examine whether the findings hold true in women and people of nonwhite ethnicities, they added.

The British Regional Heart Study is supported by the British Heart Foundation. No financial conflicts of interest were reported.

Major Finding: Compared with placebo, topical nitroglycerin ointment increased bone mineral density in the lumbar spine, total hip, and femoral neck by 7%; decreased bone resorption; and strengthened bone structure to the same or a greater degree than did other available therapies.

Data Source: A single-center, double-blind, placebo-controlled, randomized clinical trial involving 243 postmenopausal women followed for 2 years.

Disclosures: This study was supported by the Canadian Institutes of Health Research and Physicians' Services Inc. Dr. Jamal reported receiving support from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire, and her associates reported ties to numerous drug, device, and technology companies.

Topical nitroglycerin ointment raises bone mineral density, cuts resorption, and alters bone structure so that bone strength is increased, according to results of a double-blind trial in 243 women.

The magnitude of improvement equals or exceeds that observed with other therapies, including teriparatide.

“Together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones such as the hip, legs, and upper arm, which are largely composed of cortical bone,” wrote Dr. Sophie A. Jamal of the University of Toronto and her associates.

In a single-center double-blind clinical trial, they assessed the efficacy of daily application of 2% nitroglycerin ointment over the course of 2 years in increasing bone mineral density (BMD). The study was not large enough to directly determine the drug's effects on fracture risk.

The study subjects were randomly assigned to apply active 15 mg/d nitroglycerin or a matching placebo ointment to a piece of onion skin that was taped to the upper outer arm overnight, every night.

The study subjects were women aged 50 years or older (mean age, 62 years) who were at least 1 year past menopause. None had osteoporosis, but all had BMD T scores of 0 to –2.0 at the lumbar spine and higher than –2.0 at the total hip.

A total of 400 women were enrolled, but only 243 remained in the study long enough to be included in the analysis; 126 in the nitroglycerin group and 117 in the placebo group. A total of 106 subjects dropped out because of headache, nausea, or allergic reaction, and another 51 “lost interest” or became ineligible.

After randomization, another 30 subjects in the nitroglycerin group (24%) and 15 in the placebo group (13%) discontinued treatment or were lost to follow-up, including 26 who cited adverse reactions including headache.

The primary end point was change in lumbar spine areal BMD after 2 years of treatment. Compared with women in the placebo group, those who received active nitroglycerin showed a significant increase of approximately 7% in areal BMD at the lumbar spine.

They also showed comparable increases in areal BMD at the total hip (6%) and femoral neck (7%). Compared with placebo users, the nitroglycerin group also showed increases in volumetric trabecular BMD of 12% at the radius and 8.5% at the tibia; increases in cortical thickness of 14% at the radius and 25% at the tibia; and increases in periosteal circumference of 7% at the radius and 3% at the tibia. The latter finding has not been reported with any other agent, the investigators said (JAMA 2011;305:800-07).

Nitroglycerin therapy also was associated with increases in measures of bone strength, with rises of 11% and 10% in polar section modulus and of 7% and 14.5% in polar moment of inertia at the radius and tibia, respectively. These findings indicate significant improvement in bone bending and twisting strength, which in previous research has correlated with fewer fractures.

Compared with placebo, nitroglycerin treatment was associated with significant increases in bone-specific alkaline phosphatase, a marker of bone formation. This rose 14% at 3 months, 21% at 12 months, and 35% at 24 months.

At the same time, urinary N-telopeptide level, a marker of bone resorption, decreased by 20% at 3 months, 33% at 12 months, and 54% at 24 months.

This concomitant change indicates that nitroglycerin uncouples bone formation from bone resorption. Moreover, “the differential effects of nitroglycerin on formation and resorption appear to widen with time, suggesting that its efficacy continues or even increases during 24 months of use.

In contrast, the effects of other antiresorptives and teriparatide either plateau or wane with time,” Dr. Jamal and her colleagues wrote.

The incidence of serious adverse effects did not differ between the two groups, at 4% in both.

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Next Step: Assess Effect on Fractures

When added to previous research, the findings reported by Dr. Jamal and her associates suggest that nitroglycerin both inhibits bone resorption and stimulates bone formation, which no single drug can do. These results “should set the stage for an adequately powered, larger study using nitroglycerin ointment, with fracture as an outcome,” said Dr. Sundeep Khosla.

“If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis.”

The results of the current study also should spur development of other agents that act as nitric oxide donors, preferably drugs with better adverse effect profiles that don't cause so many headaches.

Future research also should report data on any blood pressure changes associated with nitroglycerin therapy, which Dr. Jamal and her associates did not report on, he added.

DR. KHOSLA is in the endocrine research unit at the Mayo Clinic, Rochester, Minn. He reported serving on a scientific advisory board for Amgen. These remarks were taken from his editorial accompanying Dr. Jamal's report (JAMA 2011:305:826-7).

Major Finding: Compared with placebo, topical nitroglycerin ointment increased bone mineral density in the lumbar spine, total hip, and femoral neck by 7%; decreased bone resorption; and strengthened bone structure to the same or a greater degree than did other available therapies.

Data Source: A single-center, double-blind, placebo-controlled, randomized clinical trial involving 243 postmenopausal women followed for 2 years.

Disclosures: This study was supported by the Canadian Institutes of Health Research and Physicians' Services Inc. Dr. Jamal reported receiving support from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire, and her associates reported ties to numerous drug, device, and technology companies.

Topical nitroglycerin ointment raises bone mineral density, cuts resorption, and alters bone structure so that bone strength is increased, according to results of a double-blind trial in 243 women.

The magnitude of improvement equals or exceeds that observed with other therapies, including teriparatide.

“Together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones such as the hip, legs, and upper arm, which are largely composed of cortical bone,” wrote Dr. Sophie A. Jamal of the University of Toronto and her associates.

In a single-center double-blind clinical trial, they assessed the efficacy of daily application of 2% nitroglycerin ointment over the course of 2 years in increasing bone mineral density (BMD). The study was not large enough to directly determine the drug's effects on fracture risk.

The study subjects were randomly assigned to apply active 15 mg/d nitroglycerin or a matching placebo ointment to a piece of onion skin that was taped to the upper outer arm overnight, every night.

The study subjects were women aged 50 years or older (mean age, 62 years) who were at least 1 year past menopause. None had osteoporosis, but all had BMD T scores of 0 to –2.0 at the lumbar spine and higher than –2.0 at the total hip.

A total of 400 women were enrolled, but only 243 remained in the study long enough to be included in the analysis; 126 in the nitroglycerin group and 117 in the placebo group. A total of 106 subjects dropped out because of headache, nausea, or allergic reaction, and another 51 “lost interest” or became ineligible.

After randomization, another 30 subjects in the nitroglycerin group (24%) and 15 in the placebo group (13%) discontinued treatment or were lost to follow-up, including 26 who cited adverse reactions including headache.

The primary end point was change in lumbar spine areal BMD after 2 years of treatment. Compared with women in the placebo group, those who received active nitroglycerin showed a significant increase of approximately 7% in areal BMD at the lumbar spine.

They also showed comparable increases in areal BMD at the total hip (6%) and femoral neck (7%). Compared with placebo users, the nitroglycerin group also showed increases in volumetric trabecular BMD of 12% at the radius and 8.5% at the tibia; increases in cortical thickness of 14% at the radius and 25% at the tibia; and increases in periosteal circumference of 7% at the radius and 3% at the tibia. The latter finding has not been reported with any other agent, the investigators said (JAMA 2011;305:800-07).

Nitroglycerin therapy also was associated with increases in measures of bone strength, with rises of 11% and 10% in polar section modulus and of 7% and 14.5% in polar moment of inertia at the radius and tibia, respectively. These findings indicate significant improvement in bone bending and twisting strength, which in previous research has correlated with fewer fractures.

Compared with placebo, nitroglycerin treatment was associated with significant increases in bone-specific alkaline phosphatase, a marker of bone formation. This rose 14% at 3 months, 21% at 12 months, and 35% at 24 months.

At the same time, urinary N-telopeptide level, a marker of bone resorption, decreased by 20% at 3 months, 33% at 12 months, and 54% at 24 months.

This concomitant change indicates that nitroglycerin uncouples bone formation from bone resorption. Moreover, “the differential effects of nitroglycerin on formation and resorption appear to widen with time, suggesting that its efficacy continues or even increases during 24 months of use.

In contrast, the effects of other antiresorptives and teriparatide either plateau or wane with time,” Dr. Jamal and her colleagues wrote.

The incidence of serious adverse effects did not differ between the two groups, at 4% in both.

View on the News

Next Step: Assess Effect on Fractures

When added to previous research, the findings reported by Dr. Jamal and her associates suggest that nitroglycerin both inhibits bone resorption and stimulates bone formation, which no single drug can do. These results “should set the stage for an adequately powered, larger study using nitroglycerin ointment, with fracture as an outcome,” said Dr. Sundeep Khosla.

“If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis.”

The results of the current study also should spur development of other agents that act as nitric oxide donors, preferably drugs with better adverse effect profiles that don't cause so many headaches.

Future research also should report data on any blood pressure changes associated with nitroglycerin therapy, which Dr. Jamal and her associates did not report on, he added.

DR. KHOSLA is in the endocrine research unit at the Mayo Clinic, Rochester, Minn. He reported serving on a scientific advisory board for Amgen. These remarks were taken from his editorial accompanying Dr. Jamal's report (JAMA 2011:305:826-7).

Major Finding: Compared with placebo, topical nitroglycerin ointment increased bone mineral density in the lumbar spine, total hip, and femoral neck by 7%; decreased bone resorption; and strengthened bone structure to the same or a greater degree than did other available therapies.

Data Source: A single-center, double-blind, placebo-controlled, randomized clinical trial involving 243 postmenopausal women followed for 2 years.

Disclosures: This study was supported by the Canadian Institutes of Health Research and Physicians' Services Inc. Dr. Jamal reported receiving support from Novartis, Amgen, Warner-Chilcott, Genzyme, and Shire, and her associates reported ties to numerous drug, device, and technology companies.

Topical nitroglycerin ointment raises bone mineral density, cuts resorption, and alters bone structure so that bone strength is increased, according to results of a double-blind trial in 243 women.

The magnitude of improvement equals or exceeds that observed with other therapies, including teriparatide.

“Together, these findings suggest that nitroglycerin may significantly decrease the risk of fractures, including fractures in long bones such as the hip, legs, and upper arm, which are largely composed of cortical bone,” wrote Dr. Sophie A. Jamal of the University of Toronto and her associates.

In a single-center double-blind clinical trial, they assessed the efficacy of daily application of 2% nitroglycerin ointment over the course of 2 years in increasing bone mineral density (BMD). The study was not large enough to directly determine the drug's effects on fracture risk.

The study subjects were randomly assigned to apply active 15 mg/d nitroglycerin or a matching placebo ointment to a piece of onion skin that was taped to the upper outer arm overnight, every night.

The study subjects were women aged 50 years or older (mean age, 62 years) who were at least 1 year past menopause. None had osteoporosis, but all had BMD T scores of 0 to –2.0 at the lumbar spine and higher than –2.0 at the total hip.

A total of 400 women were enrolled, but only 243 remained in the study long enough to be included in the analysis; 126 in the nitroglycerin group and 117 in the placebo group. A total of 106 subjects dropped out because of headache, nausea, or allergic reaction, and another 51 “lost interest” or became ineligible.

After randomization, another 30 subjects in the nitroglycerin group (24%) and 15 in the placebo group (13%) discontinued treatment or were lost to follow-up, including 26 who cited adverse reactions including headache.

The primary end point was change in lumbar spine areal BMD after 2 years of treatment. Compared with women in the placebo group, those who received active nitroglycerin showed a significant increase of approximately 7% in areal BMD at the lumbar spine.

They also showed comparable increases in areal BMD at the total hip (6%) and femoral neck (7%). Compared with placebo users, the nitroglycerin group also showed increases in volumetric trabecular BMD of 12% at the radius and 8.5% at the tibia; increases in cortical thickness of 14% at the radius and 25% at the tibia; and increases in periosteal circumference of 7% at the radius and 3% at the tibia. The latter finding has not been reported with any other agent, the investigators said (JAMA 2011;305:800-07).

Nitroglycerin therapy also was associated with increases in measures of bone strength, with rises of 11% and 10% in polar section modulus and of 7% and 14.5% in polar moment of inertia at the radius and tibia, respectively. These findings indicate significant improvement in bone bending and twisting strength, which in previous research has correlated with fewer fractures.

Compared with placebo, nitroglycerin treatment was associated with significant increases in bone-specific alkaline phosphatase, a marker of bone formation. This rose 14% at 3 months, 21% at 12 months, and 35% at 24 months.

At the same time, urinary N-telopeptide level, a marker of bone resorption, decreased by 20% at 3 months, 33% at 12 months, and 54% at 24 months.

This concomitant change indicates that nitroglycerin uncouples bone formation from bone resorption. Moreover, “the differential effects of nitroglycerin on formation and resorption appear to widen with time, suggesting that its efficacy continues or even increases during 24 months of use.

In contrast, the effects of other antiresorptives and teriparatide either plateau or wane with time,” Dr. Jamal and her colleagues wrote.

The incidence of serious adverse effects did not differ between the two groups, at 4% in both.

View on the News

Next Step: Assess Effect on Fractures

When added to previous research, the findings reported by Dr. Jamal and her associates suggest that nitroglycerin both inhibits bone resorption and stimulates bone formation, which no single drug can do. These results “should set the stage for an adequately powered, larger study using nitroglycerin ointment, with fracture as an outcome,” said Dr. Sundeep Khosla.

“If such a study demonstrates efficacy for reducing fractures, clinicians would have a novel and inexpensive therapy for osteoporosis.”

The results of the current study also should spur development of other agents that act as nitric oxide donors, preferably drugs with better adverse effect profiles that don't cause so many headaches.

Future research also should report data on any blood pressure changes associated with nitroglycerin therapy, which Dr. Jamal and her associates did not report on, he added.

DR. KHOSLA is in the endocrine research unit at the Mayo Clinic, Rochester, Minn. He reported serving on a scientific advisory board for Amgen. These remarks were taken from his editorial accompanying Dr. Jamal's report (JAMA 2011:305:826-7).

Adding the protease inhibitor boceprevir to standard peginterferon-ribavirin therapy for chronic hepatitis C virus type 1 markedly improves the rate of sustained virologic response, according to two reports in the March 31 issue of the New England Journal of Medicine.

The rate of sustained virologic response to standard therapy alone is typically below 50% in these patients, and is even lower (30% or less) in certain groups such as patients of African heritage and those who relapsed after initial treatment. In these separate international phase III randomized clinical trials, the addition of boceprevir boosted that rate to as high as 75%.

Boceprevir was granted priority review status by the Food and Drug Administration earlier this year and has yet to be approved.

In the first trial, 1,097 previously untreated patients were randomly assigned to receive standard peginterferon-ribavirin therapy alone for 44 weeks (363 subjects); response-guided therapy in which peginterferon-ribavirin plus boceprevir were given for 24 weeks and then the standard therapy was continued, along with the addition of a placebo, for another 24 weeks only in those who had detectable HCV RNA levels (368 subjects); or fixed-duration therapy in which patients received 44 weeks of standard therapy plus oral boceprevir (366 subjects).

Because of the marked difference in treatment response between black and nonblack patients, the study cohort was further analyzed by race: 159 black and 938 nonblack subjects, said Dr. Fred Poordad of Cedars-Sinai Medical Center, Los Angeles, and his associates.

A sustained virologic response was attained in 67%-68% of the nonblack patients who received boceprevir, compared with only 40% of the nonblack patients who received standard therapy alone. This represents a relative increase of approximately 70%.

Among blacks, a sustained virologic response was attained in 42%-53% of those who received boceprevir, compared with only 23% of those who received standard therapy alone. This represents a relative increase of approximately 50%.

Both boceprevir regimens were associated with elevated rates of anemia, and nearly twice as many patients given boceprevir (43%) as control subjects (24%) required erythropoietin or showed a hemoglobin level of less than 9.5 g per dL. Dysgeusia also developed twice as often in patients given boceprevir.

However, "neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy," Dr. Poordad and his colleagues said (N. Engl. J. Med. 2011:364:1195-1206).

The use of the second drug regimen allowed the researchers to identify those patients who showed an early treatment response and could be spared from an additional unnecessary 24 weeks of treatment.

In the second study, 403 patients at 80 sites across North America and Europe were randomly assigned to receive standard peginterferon-ribavirin plus placebo for 44 weeks (80 subjects); a response-guided regimen in which standard peginterferon-ribavirin and boceprevir were given for 32 weeks and standard therapy was continued, with the addition of a placebo, for another 12 weeks only in those who had detectable HCV RNA levels (162 subjects); or fixed-duration standard therapy plus boceprevir for 44 weeks (161 subjects).

This study population was different from the first one in that it was particularly "hard to treat," involving patients who had either not responded to an initial course of treatment or who had relapsed after showing an initial response, said Dr. Bruce R. Bacon of Saint Louis University and his associates.

Again, the rates of sustained virologic response were 59%-66% in patients who received boceprevir, compared with only 21% in those who received standard treatment alone.

"The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%," the investigators said (N. Engl. J. Med. 2011;364:1207-17).

"Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33%-34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone," Dr. Bacon and his colleagues said.

As with Dr. Poordad’s study, the second regimen allowed the identification of patients who had an early treatment response and could safely refrain from an additional 12 weeks of therapy.

In this study, patients who received boceprevir had higher rates of serious adverse events and were more likely to discontinue the study medications or require dose modifications than those in the control group. The incidence of anemia was approximately twice as high with boceprevir as without it. Dysgeusia also was more frequent with boceprevir.

In both of these clinical trials, patients who showed undetectable levels of HCV RNA at week 8 also showed a high rate of sustained virologic response, regardless of which treatment they received. This confirms that a strong early response to treatment is predictive of a sustained virologic response, both groups of researchers said.

Both of these studies were funded by Schering-Plough (now part of Merck). Both groups of investigators reported ties to numerous industry sources, including Shering-Plough/Merck.

Adding the protease inhibitor boceprevir to standard peginterferon-ribavirin therapy for chronic hepatitis C virus type 1 markedly improves the rate of sustained virologic response, according to two reports in the March 31 issue of the New England Journal of Medicine.

The rate of sustained virologic response to standard therapy alone is typically below 50% in these patients, and is even lower (30% or less) in certain groups such as patients of African heritage and those who relapsed after initial treatment. In these separate international phase III randomized clinical trials, the addition of boceprevir boosted that rate to as high as 75%.

Boceprevir was granted priority review status by the Food and Drug Administration earlier this year and has yet to be approved.

In the first trial, 1,097 previously untreated patients were randomly assigned to receive standard peginterferon-ribavirin therapy alone for 44 weeks (363 subjects); response-guided therapy in which peginterferon-ribavirin plus boceprevir were given for 24 weeks and then the standard therapy was continued, along with the addition of a placebo, for another 24 weeks only in those who had detectable HCV RNA levels (368 subjects); or fixed-duration therapy in which patients received 44 weeks of standard therapy plus oral boceprevir (366 subjects).

Because of the marked difference in treatment response between black and nonblack patients, the study cohort was further analyzed by race: 159 black and 938 nonblack subjects, said Dr. Fred Poordad of Cedars-Sinai Medical Center, Los Angeles, and his associates.

A sustained virologic response was attained in 67%-68% of the nonblack patients who received boceprevir, compared with only 40% of the nonblack patients who received standard therapy alone. This represents a relative increase of approximately 70%.

Among blacks, a sustained virologic response was attained in 42%-53% of those who received boceprevir, compared with only 23% of those who received standard therapy alone. This represents a relative increase of approximately 50%.

Both boceprevir regimens were associated with elevated rates of anemia, and nearly twice as many patients given boceprevir (43%) as control subjects (24%) required erythropoietin or showed a hemoglobin level of less than 9.5 g per dL. Dysgeusia also developed twice as often in patients given boceprevir.

However, "neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy," Dr. Poordad and his colleagues said (N. Engl. J. Med. 2011:364:1195-1206).

The use of the second drug regimen allowed the researchers to identify those patients who showed an early treatment response and could be spared from an additional unnecessary 24 weeks of treatment.

In the second study, 403 patients at 80 sites across North America and Europe were randomly assigned to receive standard peginterferon-ribavirin plus placebo for 44 weeks (80 subjects); a response-guided regimen in which standard peginterferon-ribavirin and boceprevir were given for 32 weeks and standard therapy was continued, with the addition of a placebo, for another 12 weeks only in those who had detectable HCV RNA levels (162 subjects); or fixed-duration standard therapy plus boceprevir for 44 weeks (161 subjects).

This study population was different from the first one in that it was particularly "hard to treat," involving patients who had either not responded to an initial course of treatment or who had relapsed after showing an initial response, said Dr. Bruce R. Bacon of Saint Louis University and his associates.

Again, the rates of sustained virologic response were 59%-66% in patients who received boceprevir, compared with only 21% in those who received standard treatment alone.

"The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%," the investigators said (N. Engl. J. Med. 2011;364:1207-17).

"Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33%-34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone," Dr. Bacon and his colleagues said.

As with Dr. Poordad’s study, the second regimen allowed the identification of patients who had an early treatment response and could safely refrain from an additional 12 weeks of therapy.

In this study, patients who received boceprevir had higher rates of serious adverse events and were more likely to discontinue the study medications or require dose modifications than those in the control group. The incidence of anemia was approximately twice as high with boceprevir as without it. Dysgeusia also was more frequent with boceprevir.

In both of these clinical trials, patients who showed undetectable levels of HCV RNA at week 8 also showed a high rate of sustained virologic response, regardless of which treatment they received. This confirms that a strong early response to treatment is predictive of a sustained virologic response, both groups of researchers said.

Both of these studies were funded by Schering-Plough (now part of Merck). Both groups of investigators reported ties to numerous industry sources, including Shering-Plough/Merck.

Adding the protease inhibitor boceprevir to standard peginterferon-ribavirin therapy for chronic hepatitis C virus type 1 markedly improves the rate of sustained virologic response, according to two reports in the March 31 issue of the New England Journal of Medicine.

The rate of sustained virologic response to standard therapy alone is typically below 50% in these patients, and is even lower (30% or less) in certain groups such as patients of African heritage and those who relapsed after initial treatment. In these separate international phase III randomized clinical trials, the addition of boceprevir boosted that rate to as high as 75%.

Boceprevir was granted priority review status by the Food and Drug Administration earlier this year and has yet to be approved.

In the first trial, 1,097 previously untreated patients were randomly assigned to receive standard peginterferon-ribavirin therapy alone for 44 weeks (363 subjects); response-guided therapy in which peginterferon-ribavirin plus boceprevir were given for 24 weeks and then the standard therapy was continued, along with the addition of a placebo, for another 24 weeks only in those who had detectable HCV RNA levels (368 subjects); or fixed-duration therapy in which patients received 44 weeks of standard therapy plus oral boceprevir (366 subjects).

Because of the marked difference in treatment response between black and nonblack patients, the study cohort was further analyzed by race: 159 black and 938 nonblack subjects, said Dr. Fred Poordad of Cedars-Sinai Medical Center, Los Angeles, and his associates.

A sustained virologic response was attained in 67%-68% of the nonblack patients who received boceprevir, compared with only 40% of the nonblack patients who received standard therapy alone. This represents a relative increase of approximately 70%.

Among blacks, a sustained virologic response was attained in 42%-53% of those who received boceprevir, compared with only 23% of those who received standard therapy alone. This represents a relative increase of approximately 50%.

Both boceprevir regimens were associated with elevated rates of anemia, and nearly twice as many patients given boceprevir (43%) as control subjects (24%) required erythropoietin or showed a hemoglobin level of less than 9.5 g per dL. Dysgeusia also developed twice as often in patients given boceprevir.

However, "neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy," Dr. Poordad and his colleagues said (N. Engl. J. Med. 2011:364:1195-1206).

The use of the second drug regimen allowed the researchers to identify those patients who showed an early treatment response and could be spared from an additional unnecessary 24 weeks of treatment.

In the second study, 403 patients at 80 sites across North America and Europe were randomly assigned to receive standard peginterferon-ribavirin plus placebo for 44 weeks (80 subjects); a response-guided regimen in which standard peginterferon-ribavirin and boceprevir were given for 32 weeks and standard therapy was continued, with the addition of a placebo, for another 12 weeks only in those who had detectable HCV RNA levels (162 subjects); or fixed-duration standard therapy plus boceprevir for 44 weeks (161 subjects).

This study population was different from the first one in that it was particularly "hard to treat," involving patients who had either not responded to an initial course of treatment or who had relapsed after showing an initial response, said Dr. Bruce R. Bacon of Saint Louis University and his associates.

Again, the rates of sustained virologic response were 59%-66% in patients who received boceprevir, compared with only 21% in those who received standard treatment alone.

"The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%," the investigators said (N. Engl. J. Med. 2011;364:1207-17).

"Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33%-34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone," Dr. Bacon and his colleagues said.

As with Dr. Poordad’s study, the second regimen allowed the identification of patients who had an early treatment response and could safely refrain from an additional 12 weeks of therapy.

In this study, patients who received boceprevir had higher rates of serious adverse events and were more likely to discontinue the study medications or require dose modifications than those in the control group. The incidence of anemia was approximately twice as high with boceprevir as without it. Dysgeusia also was more frequent with boceprevir.

In both of these clinical trials, patients who showed undetectable levels of HCV RNA at week 8 also showed a high rate of sustained virologic response, regardless of which treatment they received. This confirms that a strong early response to treatment is predictive of a sustained virologic response, both groups of researchers said.

Both of these studies were funded by Schering-Plough (now part of Merck). Both groups of investigators reported ties to numerous industry sources, including Shering-Plough/Merck.

Adding the protease inhibitor boceprevir to standard peginterferon-ribavirin therapy for chronic hepatitis C virus type 1 markedly improves the rate of sustained virologic response, according to two reports in the March 31 issue of the New England Journal of Medicine.

The rate of sustained virologic response to standard therapy alone is typically below 50% in these patients, and is even lower (30% or less) in certain groups such as patients of African heritage and those who relapsed after initial treatment. In these separate international phase III randomized clinical trials, the addition of boceprevir boosted that rate to as high as 75%.

Boceprevir was granted priority review status by the Food and Drug Administration earlier this year and has yet to be approved.

In the first trial, 1,097 previously untreated patients were randomly assigned to receive standard peginterferon-ribavirin therapy alone for 44 weeks (363 subjects); response-guided therapy in which peginterferon-ribavirin plus boceprevir were given for 24 weeks and then the standard therapy was continued, along with the addition of a placebo, for another 24 weeks only in those who had detectable HCV RNA levels (368 subjects); or fixed-duration therapy in which patients received 44 weeks of standard therapy plus oral boceprevir (366 subjects).

Because of the marked difference in treatment response between black and nonblack patients, the study cohort was further analyzed by race: 159 black and 938 nonblack subjects, said Dr. Fred Poordad of Cedars-Sinai Medical Center, Los Angeles, and his associates.

A sustained virologic response was attained in 67%-68% of the nonblack patients who received boceprevir, compared with only 40% of the nonblack patients who received standard therapy alone. This represents a relative increase of approximately 70%.

Among blacks, a sustained virologic response was attained in 42%-53% of those who received boceprevir, compared with only 23% of those who received standard therapy alone. This represents a relative increase of approximately 50%.

Both boceprevir regimens were associated with elevated rates of anemia, and nearly twice as many patients given boceprevir (43%) as control subjects (24%) required erythropoietin or showed a hemoglobin level of less than 9.5 g per dL. Dysgeusia also developed twice as often in patients given boceprevir.

However, "neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy," Dr. Poordad and his colleagues said (N. Engl. J. Med. 2011:364:1195-1206).

The use of the second drug regimen allowed the researchers to identify those patients who showed an early treatment response and could be spared from an additional unnecessary 24 weeks of treatment.

In the second study, 403 patients at 80 sites across North America and Europe were randomly assigned to receive standard peginterferon-ribavirin plus placebo for 44 weeks (80 subjects); a response-guided regimen in which standard peginterferon-ribavirin and boceprevir were given for 32 weeks and standard therapy was continued, with the addition of a placebo, for another 12 weeks only in those who had detectable HCV RNA levels (162 subjects); or fixed-duration standard therapy plus boceprevir for 44 weeks (161 subjects).

This study population was different from the first one in that it was particularly "hard to treat," involving patients who had either not responded to an initial course of treatment or who had relapsed after showing an initial response, said Dr. Bruce R. Bacon of Saint Louis University and his associates.

Again, the rates of sustained virologic response were 59%-66% in patients who received boceprevir, compared with only 21% in those who received standard treatment alone.

"The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%," the investigators said (N. Engl. J. Med. 2011;364:1207-17).

"Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33%-34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone," Dr. Bacon and his colleagues said.

As with Dr. Poordad’s study, the second regimen allowed the identification of patients who had an early treatment response and could safely refrain from an additional 12 weeks of therapy.

In this study, patients who received boceprevir had higher rates of serious adverse events and were more likely to discontinue the study medications or require dose modifications than those in the control group. The incidence of anemia was approximately twice as high with boceprevir as without it. Dysgeusia also was more frequent with boceprevir.

In both of these clinical trials, patients who showed undetectable levels of HCV RNA at week 8 also showed a high rate of sustained virologic response, regardless of which treatment they received. This confirms that a strong early response to treatment is predictive of a sustained virologic response, both groups of researchers said.

Both of these studies were funded by Schering-Plough (now part of Merck). Both groups of investigators reported ties to numerous industry sources, including Shering-Plough/Merck.

Adding the protease inhibitor boceprevir to standard peginterferon-ribavirin therapy for chronic hepatitis C virus type 1 markedly improves the rate of sustained virologic response, according to two reports in the March 31 issue of the New England Journal of Medicine.

The rate of sustained virologic response to standard therapy alone is typically below 50% in these patients, and is even lower (30% or less) in certain groups such as patients of African heritage and those who relapsed after initial treatment. In these separate international phase III randomized clinical trials, the addition of boceprevir boosted that rate to as high as 75%.

Boceprevir was granted priority review status by the Food and Drug Administration earlier this year and has yet to be approved.

In the first trial, 1,097 previously untreated patients were randomly assigned to receive standard peginterferon-ribavirin therapy alone for 44 weeks (363 subjects); response-guided therapy in which peginterferon-ribavirin plus boceprevir were given for 24 weeks and then the standard therapy was continued, along with the addition of a placebo, for another 24 weeks only in those who had detectable HCV RNA levels (368 subjects); or fixed-duration therapy in which patients received 44 weeks of standard therapy plus oral boceprevir (366 subjects).

Because of the marked difference in treatment response between black and nonblack patients, the study cohort was further analyzed by race: 159 black and 938 nonblack subjects, said Dr. Fred Poordad of Cedars-Sinai Medical Center, Los Angeles, and his associates.

A sustained virologic response was attained in 67%-68% of the nonblack patients who received boceprevir, compared with only 40% of the nonblack patients who received standard therapy alone. This represents a relative increase of approximately 70%.

Among blacks, a sustained virologic response was attained in 42%-53% of those who received boceprevir, compared with only 23% of those who received standard therapy alone. This represents a relative increase of approximately 50%.

Both boceprevir regimens were associated with elevated rates of anemia, and nearly twice as many patients given boceprevir (43%) as control subjects (24%) required erythropoietin or showed a hemoglobin level of less than 9.5 g per dL. Dysgeusia also developed twice as often in patients given boceprevir.

However, "neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy," Dr. Poordad and his colleagues said (N. Engl. J. Med. 2011:364:1195-1206).

The use of the second drug regimen allowed the researchers to identify those patients who showed an early treatment response and could be spared from an additional unnecessary 24 weeks of treatment.

In the second study, 403 patients at 80 sites across North America and Europe were randomly assigned to receive standard peginterferon-ribavirin plus placebo for 44 weeks (80 subjects); a response-guided regimen in which standard peginterferon-ribavirin and boceprevir were given for 32 weeks and standard therapy was continued, with the addition of a placebo, for another 12 weeks only in those who had detectable HCV RNA levels (162 subjects); or fixed-duration standard therapy plus boceprevir for 44 weeks (161 subjects).

This study population was different from the first one in that it was particularly "hard to treat," involving patients who had either not responded to an initial course of treatment or who had relapsed after showing an initial response, said Dr. Bruce R. Bacon of Saint Louis University and his associates.

Again, the rates of sustained virologic response were 59%-66% in patients who received boceprevir, compared with only 21% in those who received standard treatment alone.

"The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%," the investigators said (N. Engl. J. Med. 2011;364:1207-17).

"Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33%-34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone," Dr. Bacon and his colleagues said.

As with Dr. Poordad’s study, the second regimen allowed the identification of patients who had an early treatment response and could safely refrain from an additional 12 weeks of therapy.

In this study, patients who received boceprevir had higher rates of serious adverse events and were more likely to discontinue the study medications or require dose modifications than those in the control group. The incidence of anemia was approximately twice as high with boceprevir as without it. Dysgeusia also was more frequent with boceprevir.

In both of these clinical trials, patients who showed undetectable levels of HCV RNA at week 8 also showed a high rate of sustained virologic response, regardless of which treatment they received. This confirms that a strong early response to treatment is predictive of a sustained virologic response, both groups of researchers said.

Both of these studies were funded by Schering-Plough (now part of Merck). Both groups of investigators reported ties to numerous industry sources, including Shering-Plough/Merck.

Adding the protease inhibitor boceprevir to standard peginterferon-ribavirin therapy for chronic hepatitis C virus type 1 markedly improves the rate of sustained virologic response, according to two reports in the March 31 issue of the New England Journal of Medicine.

The rate of sustained virologic response to standard therapy alone is typically below 50% in these patients, and is even lower (30% or less) in certain groups such as patients of African heritage and those who relapsed after initial treatment. In these separate international phase III randomized clinical trials, the addition of boceprevir boosted that rate to as high as 75%.

Boceprevir was granted priority review status by the Food and Drug Administration earlier this year and has yet to be approved.

In the first trial, 1,097 previously untreated patients were randomly assigned to receive standard peginterferon-ribavirin therapy alone for 44 weeks (363 subjects); response-guided therapy in which peginterferon-ribavirin plus boceprevir were given for 24 weeks and then the standard therapy was continued, along with the addition of a placebo, for another 24 weeks only in those who had detectable HCV RNA levels (368 subjects); or fixed-duration therapy in which patients received 44 weeks of standard therapy plus oral boceprevir (366 subjects).

Because of the marked difference in treatment response between black and nonblack patients, the study cohort was further analyzed by race: 159 black and 938 nonblack subjects, said Dr. Fred Poordad of Cedars-Sinai Medical Center, Los Angeles, and his associates.

A sustained virologic response was attained in 67%-68% of the nonblack patients who received boceprevir, compared with only 40% of the nonblack patients who received standard therapy alone. This represents a relative increase of approximately 70%.

Among blacks, a sustained virologic response was attained in 42%-53% of those who received boceprevir, compared with only 23% of those who received standard therapy alone. This represents a relative increase of approximately 50%.

Both boceprevir regimens were associated with elevated rates of anemia, and nearly twice as many patients given boceprevir (43%) as control subjects (24%) required erythropoietin or showed a hemoglobin level of less than 9.5 g per dL. Dysgeusia also developed twice as often in patients given boceprevir.

However, "neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy," Dr. Poordad and his colleagues said (N. Engl. J. Med. 2011:364:1195-1206).

The use of the second drug regimen allowed the researchers to identify those patients who showed an early treatment response and could be spared from an additional unnecessary 24 weeks of treatment.

In the second study, 403 patients at 80 sites across North America and Europe were randomly assigned to receive standard peginterferon-ribavirin plus placebo for 44 weeks (80 subjects); a response-guided regimen in which standard peginterferon-ribavirin and boceprevir were given for 32 weeks and standard therapy was continued, with the addition of a placebo, for another 12 weeks only in those who had detectable HCV RNA levels (162 subjects); or fixed-duration standard therapy plus boceprevir for 44 weeks (161 subjects).

This study population was different from the first one in that it was particularly "hard to treat," involving patients who had either not responded to an initial course of treatment or who had relapsed after showing an initial response, said Dr. Bruce R. Bacon of Saint Louis University and his associates.

Again, the rates of sustained virologic response were 59%-66% in patients who received boceprevir, compared with only 21% in those who received standard treatment alone.

"The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%," the investigators said (N. Engl. J. Med. 2011;364:1207-17).

"Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33%-34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone," Dr. Bacon and his colleagues said.

As with Dr. Poordad’s study, the second regimen allowed the identification of patients who had an early treatment response and could safely refrain from an additional 12 weeks of therapy.

In this study, patients who received boceprevir had higher rates of serious adverse events and were more likely to discontinue the study medications or require dose modifications than those in the control group. The incidence of anemia was approximately twice as high with boceprevir as without it. Dysgeusia also was more frequent with boceprevir.

In both of these clinical trials, patients who showed undetectable levels of HCV RNA at week 8 also showed a high rate of sustained virologic response, regardless of which treatment they received. This confirms that a strong early response to treatment is predictive of a sustained virologic response, both groups of researchers said.

Both of these studies were funded by Schering-Plough (now part of Merck). Both groups of investigators reported ties to numerous industry sources, including Shering-Plough/Merck.

Adding the protease inhibitor boceprevir to standard peginterferon-ribavirin therapy for chronic hepatitis C virus type 1 markedly improves the rate of sustained virologic response, according to two reports in the March 31 issue of the New England Journal of Medicine.

The rate of sustained virologic response to standard therapy alone is typically below 50% in these patients, and is even lower (30% or less) in certain groups such as patients of African heritage and those who relapsed after initial treatment. In these separate international phase III randomized clinical trials, the addition of boceprevir boosted that rate to as high as 75%.

Boceprevir was granted priority review status by the Food and Drug Administration earlier this year and has yet to be approved.

In the first trial, 1,097 previously untreated patients were randomly assigned to receive standard peginterferon-ribavirin therapy alone for 44 weeks (363 subjects); response-guided therapy in which peginterferon-ribavirin plus boceprevir were given for 24 weeks and then the standard therapy was continued, along with the addition of a placebo, for another 24 weeks only in those who had detectable HCV RNA levels (368 subjects); or fixed-duration therapy in which patients received 44 weeks of standard therapy plus oral boceprevir (366 subjects).

Because of the marked difference in treatment response between black and nonblack patients, the study cohort was further analyzed by race: 159 black and 938 nonblack subjects, said Dr. Fred Poordad of Cedars-Sinai Medical Center, Los Angeles, and his associates.

A sustained virologic response was attained in 67%-68% of the nonblack patients who received boceprevir, compared with only 40% of the nonblack patients who received standard therapy alone. This represents a relative increase of approximately 70%.

Among blacks, a sustained virologic response was attained in 42%-53% of those who received boceprevir, compared with only 23% of those who received standard therapy alone. This represents a relative increase of approximately 50%.

Both boceprevir regimens were associated with elevated rates of anemia, and nearly twice as many patients given boceprevir (43%) as control subjects (24%) required erythropoietin or showed a hemoglobin level of less than 9.5 g per dL. Dysgeusia also developed twice as often in patients given boceprevir.

However, "neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy," Dr. Poordad and his colleagues said (N. Engl. J. Med. 2011:364:1195-1206).

The use of the second drug regimen allowed the researchers to identify those patients who showed an early treatment response and could be spared from an additional unnecessary 24 weeks of treatment.

In the second study, 403 patients at 80 sites across North America and Europe were randomly assigned to receive standard peginterferon-ribavirin plus placebo for 44 weeks (80 subjects); a response-guided regimen in which standard peginterferon-ribavirin and boceprevir were given for 32 weeks and standard therapy was continued, with the addition of a placebo, for another 12 weeks only in those who had detectable HCV RNA levels (162 subjects); or fixed-duration standard therapy plus boceprevir for 44 weeks (161 subjects).

This study population was different from the first one in that it was particularly "hard to treat," involving patients who had either not responded to an initial course of treatment or who had relapsed after showing an initial response, said Dr. Bruce R. Bacon of Saint Louis University and his associates.

Again, the rates of sustained virologic response were 59%-66% in patients who received boceprevir, compared with only 21% in those who received standard treatment alone.

"The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%," the investigators said (N. Engl. J. Med. 2011;364:1207-17).

"Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33%-34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone," Dr. Bacon and his colleagues said.

As with Dr. Poordad’s study, the second regimen allowed the identification of patients who had an early treatment response and could safely refrain from an additional 12 weeks of therapy.

In this study, patients who received boceprevir had higher rates of serious adverse events and were more likely to discontinue the study medications or require dose modifications than those in the control group. The incidence of anemia was approximately twice as high with boceprevir as without it. Dysgeusia also was more frequent with boceprevir.

In both of these clinical trials, patients who showed undetectable levels of HCV RNA at week 8 also showed a high rate of sustained virologic response, regardless of which treatment they received. This confirms that a strong early response to treatment is predictive of a sustained virologic response, both groups of researchers said.

Both of these studies were funded by Schering-Plough (now part of Merck). Both groups of investigators reported ties to numerous industry sources, including Shering-Plough/Merck.

Adding the protease inhibitor boceprevir to standard peginterferon-ribavirin therapy for chronic hepatitis C virus type 1 markedly improves the rate of sustained virologic response, according to two reports in the March 31 issue of the New England Journal of Medicine.

The rate of sustained virologic response to standard therapy alone is typically below 50% in these patients, and is even lower (30% or less) in certain groups such as patients of African heritage and those who relapsed after initial treatment. In these separate international phase III randomized clinical trials, the addition of boceprevir boosted that rate to as high as 75%.

Boceprevir was granted priority review status by the Food and Drug Administration earlier this year and has yet to be approved.

In the first trial, 1,097 previously untreated patients were randomly assigned to receive standard peginterferon-ribavirin therapy alone for 44 weeks (363 subjects); response-guided therapy in which peginterferon-ribavirin plus boceprevir were given for 24 weeks and then the standard therapy was continued, along with the addition of a placebo, for another 24 weeks only in those who had detectable HCV RNA levels (368 subjects); or fixed-duration therapy in which patients received 44 weeks of standard therapy plus oral boceprevir (366 subjects).

Because of the marked difference in treatment response between black and nonblack patients, the study cohort was further analyzed by race: 159 black and 938 nonblack subjects, said Dr. Fred Poordad of Cedars-Sinai Medical Center, Los Angeles, and his associates.

A sustained virologic response was attained in 67%-68% of the nonblack patients who received boceprevir, compared with only 40% of the nonblack patients who received standard therapy alone. This represents a relative increase of approximately 70%.

Among blacks, a sustained virologic response was attained in 42%-53% of those who received boceprevir, compared with only 23% of those who received standard therapy alone. This represents a relative increase of approximately 50%.

Both boceprevir regimens were associated with elevated rates of anemia, and nearly twice as many patients given boceprevir (43%) as control subjects (24%) required erythropoietin or showed a hemoglobin level of less than 9.5 g per dL. Dysgeusia also developed twice as often in patients given boceprevir.

However, "neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy," Dr. Poordad and his colleagues said (N. Engl. J. Med. 2011:364:1195-1206).

The use of the second drug regimen allowed the researchers to identify those patients who showed an early treatment response and could be spared from an additional unnecessary 24 weeks of treatment.

In the second study, 403 patients at 80 sites across North America and Europe were randomly assigned to receive standard peginterferon-ribavirin plus placebo for 44 weeks (80 subjects); a response-guided regimen in which standard peginterferon-ribavirin and boceprevir were given for 32 weeks and standard therapy was continued, with the addition of a placebo, for another 12 weeks only in those who had detectable HCV RNA levels (162 subjects); or fixed-duration standard therapy plus boceprevir for 44 weeks (161 subjects).

This study population was different from the first one in that it was particularly "hard to treat," involving patients who had either not responded to an initial course of treatment or who had relapsed after showing an initial response, said Dr. Bruce R. Bacon of Saint Louis University and his associates.

Again, the rates of sustained virologic response were 59%-66% in patients who received boceprevir, compared with only 21% in those who received standard treatment alone.

"The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%," the investigators said (N. Engl. J. Med. 2011;364:1207-17).

"Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33%-34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone," Dr. Bacon and his colleagues said.

As with Dr. Poordad’s study, the second regimen allowed the identification of patients who had an early treatment response and could safely refrain from an additional 12 weeks of therapy.

In this study, patients who received boceprevir had higher rates of serious adverse events and were more likely to discontinue the study medications or require dose modifications than those in the control group. The incidence of anemia was approximately twice as high with boceprevir as without it. Dysgeusia also was more frequent with boceprevir.

In both of these clinical trials, patients who showed undetectable levels of HCV RNA at week 8 also showed a high rate of sustained virologic response, regardless of which treatment they received. This confirms that a strong early response to treatment is predictive of a sustained virologic response, both groups of researchers said.

Both of these studies were funded by Schering-Plough (now part of Merck). Both groups of investigators reported ties to numerous industry sources, including Shering-Plough/Merck.

Adding the protease inhibitor boceprevir to standard peginterferon-ribavirin therapy for chronic hepatitis C virus type 1 markedly improves the rate of sustained virologic response, according to two reports in the March 31 issue of the New England Journal of Medicine.

The rate of sustained virologic response to standard therapy alone is typically below 50% in these patients, and is even lower (30% or less) in certain groups such as patients of African heritage and those who relapsed after initial treatment. In these separate international phase III randomized clinical trials, the addition of boceprevir boosted that rate to as high as 75%.

Boceprevir was granted priority review status by the Food and Drug Administration earlier this year and has yet to be approved.

In the first trial, 1,097 previously untreated patients were randomly assigned to receive standard peginterferon-ribavirin therapy alone for 44 weeks (363 subjects); response-guided therapy in which peginterferon-ribavirin plus boceprevir were given for 24 weeks and then the standard therapy was continued, along with the addition of a placebo, for another 24 weeks only in those who had detectable HCV RNA levels (368 subjects); or fixed-duration therapy in which patients received 44 weeks of standard therapy plus oral boceprevir (366 subjects).

Because of the marked difference in treatment response between black and nonblack patients, the study cohort was further analyzed by race: 159 black and 938 nonblack subjects, said Dr. Fred Poordad of Cedars-Sinai Medical Center, Los Angeles, and his associates.

A sustained virologic response was attained in 67%-68% of the nonblack patients who received boceprevir, compared with only 40% of the nonblack patients who received standard therapy alone. This represents a relative increase of approximately 70%.

Among blacks, a sustained virologic response was attained in 42%-53% of those who received boceprevir, compared with only 23% of those who received standard therapy alone. This represents a relative increase of approximately 50%.

Both boceprevir regimens were associated with elevated rates of anemia, and nearly twice as many patients given boceprevir (43%) as control subjects (24%) required erythropoietin or showed a hemoglobin level of less than 9.5 g per dL. Dysgeusia also developed twice as often in patients given boceprevir.

However, "neither the incidence of serious adverse events nor the frequency of discontinuation owing to an adverse event differed significantly between patients receiving boceprevir and those receiving standard therapy," Dr. Poordad and his colleagues said (N. Engl. J. Med. 2011:364:1195-1206).

The use of the second drug regimen allowed the researchers to identify those patients who showed an early treatment response and could be spared from an additional unnecessary 24 weeks of treatment.

In the second study, 403 patients at 80 sites across North America and Europe were randomly assigned to receive standard peginterferon-ribavirin plus placebo for 44 weeks (80 subjects); a response-guided regimen in which standard peginterferon-ribavirin and boceprevir were given for 32 weeks and standard therapy was continued, with the addition of a placebo, for another 12 weeks only in those who had detectable HCV RNA levels (162 subjects); or fixed-duration standard therapy plus boceprevir for 44 weeks (161 subjects).

This study population was different from the first one in that it was particularly "hard to treat," involving patients who had either not responded to an initial course of treatment or who had relapsed after showing an initial response, said Dr. Bruce R. Bacon of Saint Louis University and his associates.

Again, the rates of sustained virologic response were 59%-66% in patients who received boceprevir, compared with only 21% in those who received standard treatment alone.

"The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%," the investigators said (N. Engl. J. Med. 2011;364:1207-17).

"Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33%-34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone," Dr. Bacon and his colleagues said.

As with Dr. Poordad’s study, the second regimen allowed the identification of patients who had an early treatment response and could safely refrain from an additional 12 weeks of therapy.

In this study, patients who received boceprevir had higher rates of serious adverse events and were more likely to discontinue the study medications or require dose modifications than those in the control group. The incidence of anemia was approximately twice as high with boceprevir as without it. Dysgeusia also was more frequent with boceprevir.

In both of these clinical trials, patients who showed undetectable levels of HCV RNA at week 8 also showed a high rate of sustained virologic response, regardless of which treatment they received. This confirms that a strong early response to treatment is predictive of a sustained virologic response, both groups of researchers said.

Both of these studies were funded by Schering-Plough (now part of Merck). Both groups of investigators reported ties to numerous industry sources, including Shering-Plough/Merck.

Adding ultralow-dose estrogen to growth hormone therapy in young girls with Turner’s syndrome improves adult height attainment and might provide additional neurocognitive and behavioral benefits, according to a report in the March 31 issue of the New England Journal of Medicine.

Carefully individualized ultralow-dose estrogen, given before puberty, appears to have a modest synergistic effect with growth hormone in promoting height velocity. Reportedly, some patients also have shown improvements in nonverbal processing speed, motor performance, verbal and nonverbal memory, and self-image with the dual therapy, said Dr. Judith L. Ross of Thomas Jefferson University, Philadelphia, and her associates.

The purpose of their study was twofold: to provide objective evidence from the first randomized, double-blind clinical trial that the accepted practice of giving growth hormone to girls with Turner’s syndrome in mid-childhood improves their markedly short stature, and to determine whether ultralow-dose estrogen at this age is beneficial or detrimental to height attainment.

Even though estrogen deficiency in Turner’s syndrome begins in infancy, "common clinical practice has been to postpone estrogen-replacement therapy until the mid-teens because of the widely held view that estrogen reduces height by accelerating epiphyseal fusion," the investigators noted.

Their findings suggest that to the contrary, this practice of delaying estrogen therapy "should be reconsidered."

"Although estrogen replacement during mid-childhood (prepuberty) may seem counterintuitive, this approach has a physiological rationale: the normal mid-childhood ovary is not entirely quiescent – plasma estradiol concentrations in healthy prepubertal girls, albeit low, are up to eight times as high as those in prepubescent boys," Dr. Ross and her colleagues said.

The study involved 149 girls aged 5-13 years who had Turner’s syndrome confirmed by karyotyping, breast development at Tanner stage 1-2, and height at or below the 10th percentile of that in the general population. The study subjects were enrolled between 1987 and 1996 and were followed through 2003.

The patients were randomly assigned to receive placebo injections plus oral estrogen (40 subjects), growth hormone injections plus oral placebo (35 subjects), growth hormone injections plus oral estrogen (35 subjects), or oral placebo plus placebo injections (39 subjects). They were assessed at 6-month intervals until they reached their adult height, which was defined as an annualized height velocity of less than 1.5 cm per year, and were assessed again approximately 1 year after completing the protocol.

Girls who received active growth hormone injections achieved significantly greater height than did those who received placebo injections, by approximately 5 cm. The height gain was even greater for girls given both active growth hormone and active estrogen, by an additional 2.3 cm.

Moreover, 79% of the girls who received both growth hormone and estrogen achieved significant gains in height, compared with only 65% of the girls who received growth hormone alone, 32% of the girls who received estrogen alone, and 15% of the girls who received double placebos, Dr. Ross and her associates wrote (N. Engl. J. Med. 2011;364:1230-42).

Serious adverse events were reported in 27 patients, including gynecologic disorders, pain, scoliosis, and thyroid disorders. However, "there were no new or unexpected safety findings with respect to growth hormone or estrogen treatment in this study," they added.

The researchers noted that, because this study was begun in the 1980s, the growth hormone regimen "may be considered suboptimal by current standards." The dose they used was 20% lower than the currently approved dose, and the three-times per week injection schedule they used is less effective than the daily injections that are currently recommended.

Similarly, the doses of estrogen that were deemed "ultralow-dose" 20 years ago when the study began, would now be considered excessive. At the time, "we aim[ed] to approximate the estrogen milieu in healthy prepubertal girls." However, it is now known that even lower doses would "minimize premature pubertal development and undue skeletal maturation."

The investigators emphasized that some girls with Turner’s syndrome don’t need estrogen supplementation, at least initially, because pubertal development can sometimes occur spontaneously. Approximately 13% of the girls in this study who received oral placebo instead of oral estrogen showed spontaneous breast development.

Taken together, the study findings demonstrate that "a regimen combining carefully individualized childhood estrogen replacement with growth hormone ... has the potential not only to optimize adult height but also to provide the neurocognitive and behavioral benefits of early estrogen administration," Dr. Ross and her colleagues said.

Adding ultralow-dose estrogen to growth hormone therapy in young girls with Turner’s syndrome improves adult height attainment and might provide additional neurocognitive and behavioral benefits, according to a report in the March 31 issue of the New England Journal of Medicine.

Carefully individualized ultralow-dose estrogen, given before puberty, appears to have a modest synergistic effect with growth hormone in promoting height velocity. Reportedly, some patients also have shown improvements in nonverbal processing speed, motor performance, verbal and nonverbal memory, and self-image with the dual therapy, said Dr. Judith L. Ross of Thomas Jefferson University, Philadelphia, and her associates.

The purpose of their study was twofold: to provide objective evidence from the first randomized, double-blind clinical trial that the accepted practice of giving growth hormone to girls with Turner’s syndrome in mid-childhood improves their markedly short stature, and to determine whether ultralow-dose estrogen at this age is beneficial or detrimental to height attainment.

Even though estrogen deficiency in Turner’s syndrome begins in infancy, "common clinical practice has been to postpone estrogen-replacement therapy until the mid-teens because of the widely held view that estrogen reduces height by accelerating epiphyseal fusion," the investigators noted.

Their findings suggest that to the contrary, this practice of delaying estrogen therapy "should be reconsidered."

"Although estrogen replacement during mid-childhood (prepuberty) may seem counterintuitive, this approach has a physiological rationale: the normal mid-childhood ovary is not entirely quiescent – plasma estradiol concentrations in healthy prepubertal girls, albeit low, are up to eight times as high as those in prepubescent boys," Dr. Ross and her colleagues said.

The study involved 149 girls aged 5-13 years who had Turner’s syndrome confirmed by karyotyping, breast development at Tanner stage 1-2, and height at or below the 10th percentile of that in the general population. The study subjects were enrolled between 1987 and 1996 and were followed through 2003.

The patients were randomly assigned to receive placebo injections plus oral estrogen (40 subjects), growth hormone injections plus oral placebo (35 subjects), growth hormone injections plus oral estrogen (35 subjects), or oral placebo plus placebo injections (39 subjects). They were assessed at 6-month intervals until they reached their adult height, which was defined as an annualized height velocity of less than 1.5 cm per year, and were assessed again approximately 1 year after completing the protocol.

Girls who received active growth hormone injections achieved significantly greater height than did those who received placebo injections, by approximately 5 cm. The height gain was even greater for girls given both active growth hormone and active estrogen, by an additional 2.3 cm.

Moreover, 79% of the girls who received both growth hormone and estrogen achieved significant gains in height, compared with only 65% of the girls who received growth hormone alone, 32% of the girls who received estrogen alone, and 15% of the girls who received double placebos, Dr. Ross and her associates wrote (N. Engl. J. Med. 2011;364:1230-42).

Serious adverse events were reported in 27 patients, including gynecologic disorders, pain, scoliosis, and thyroid disorders. However, "there were no new or unexpected safety findings with respect to growth hormone or estrogen treatment in this study," they added.

The researchers noted that, because this study was begun in the 1980s, the growth hormone regimen "may be considered suboptimal by current standards." The dose they used was 20% lower than the currently approved dose, and the three-times per week injection schedule they used is less effective than the daily injections that are currently recommended.

Similarly, the doses of estrogen that were deemed "ultralow-dose" 20 years ago when the study began, would now be considered excessive. At the time, "we aim[ed] to approximate the estrogen milieu in healthy prepubertal girls." However, it is now known that even lower doses would "minimize premature pubertal development and undue skeletal maturation."

The investigators emphasized that some girls with Turner’s syndrome don’t need estrogen supplementation, at least initially, because pubertal development can sometimes occur spontaneously. Approximately 13% of the girls in this study who received oral placebo instead of oral estrogen showed spontaneous breast development.

Taken together, the study findings demonstrate that "a regimen combining carefully individualized childhood estrogen replacement with growth hormone ... has the potential not only to optimize adult height but also to provide the neurocognitive and behavioral benefits of early estrogen administration," Dr. Ross and her colleagues said.

Adding ultralow-dose estrogen to growth hormone therapy in young girls with Turner’s syndrome improves adult height attainment and might provide additional neurocognitive and behavioral benefits, according to a report in the March 31 issue of the New England Journal of Medicine.

Carefully individualized ultralow-dose estrogen, given before puberty, appears to have a modest synergistic effect with growth hormone in promoting height velocity. Reportedly, some patients also have shown improvements in nonverbal processing speed, motor performance, verbal and nonverbal memory, and self-image with the dual therapy, said Dr. Judith L. Ross of Thomas Jefferson University, Philadelphia, and her associates.

The purpose of their study was twofold: to provide objective evidence from the first randomized, double-blind clinical trial that the accepted practice of giving growth hormone to girls with Turner’s syndrome in mid-childhood improves their markedly short stature, and to determine whether ultralow-dose estrogen at this age is beneficial or detrimental to height attainment.

Even though estrogen deficiency in Turner’s syndrome begins in infancy, "common clinical practice has been to postpone estrogen-replacement therapy until the mid-teens because of the widely held view that estrogen reduces height by accelerating epiphyseal fusion," the investigators noted.

Their findings suggest that to the contrary, this practice of delaying estrogen therapy "should be reconsidered."

"Although estrogen replacement during mid-childhood (prepuberty) may seem counterintuitive, this approach has a physiological rationale: the normal mid-childhood ovary is not entirely quiescent – plasma estradiol concentrations in healthy prepubertal girls, albeit low, are up to eight times as high as those in prepubescent boys," Dr. Ross and her colleagues said.

The study involved 149 girls aged 5-13 years who had Turner’s syndrome confirmed by karyotyping, breast development at Tanner stage 1-2, and height at or below the 10th percentile of that in the general population. The study subjects were enrolled between 1987 and 1996 and were followed through 2003.

The patients were randomly assigned to receive placebo injections plus oral estrogen (40 subjects), growth hormone injections plus oral placebo (35 subjects), growth hormone injections plus oral estrogen (35 subjects), or oral placebo plus placebo injections (39 subjects). They were assessed at 6-month intervals until they reached their adult height, which was defined as an annualized height velocity of less than 1.5 cm per year, and were assessed again approximately 1 year after completing the protocol.

Girls who received active growth hormone injections achieved significantly greater height than did those who received placebo injections, by approximately 5 cm. The height gain was even greater for girls given both active growth hormone and active estrogen, by an additional 2.3 cm.

Moreover, 79% of the girls who received both growth hormone and estrogen achieved significant gains in height, compared with only 65% of the girls who received growth hormone alone, 32% of the girls who received estrogen alone, and 15% of the girls who received double placebos, Dr. Ross and her associates wrote (N. Engl. J. Med. 2011;364:1230-42).

Serious adverse events were reported in 27 patients, including gynecologic disorders, pain, scoliosis, and thyroid disorders. However, "there were no new or unexpected safety findings with respect to growth hormone or estrogen treatment in this study," they added.

The researchers noted that, because this study was begun in the 1980s, the growth hormone regimen "may be considered suboptimal by current standards." The dose they used was 20% lower than the currently approved dose, and the three-times per week injection schedule they used is less effective than the daily injections that are currently recommended.

Similarly, the doses of estrogen that were deemed "ultralow-dose" 20 years ago when the study began, would now be considered excessive. At the time, "we aim[ed] to approximate the estrogen milieu in healthy prepubertal girls." However, it is now known that even lower doses would "minimize premature pubertal development and undue skeletal maturation."

The investigators emphasized that some girls with Turner’s syndrome don’t need estrogen supplementation, at least initially, because pubertal development can sometimes occur spontaneously. Approximately 13% of the girls in this study who received oral placebo instead of oral estrogen showed spontaneous breast development.

Taken together, the study findings demonstrate that "a regimen combining carefully individualized childhood estrogen replacement with growth hormone ... has the potential not only to optimize adult height but also to provide the neurocognitive and behavioral benefits of early estrogen administration," Dr. Ross and her colleagues said.

Adding ultralow-dose estrogen to growth hormone therapy in young girls with Turner’s syndrome improves adult height attainment and might provide additional neurocognitive and behavioral benefits, according to a report in the March 31 issue of the New England Journal of Medicine.

Carefully individualized ultralow-dose estrogen, given before puberty, appears to have a modest synergistic effect with growth hormone in promoting height velocity. Reportedly, some patients also have shown improvements in nonverbal processing speed, motor performance, verbal and nonverbal memory, and self-image with the dual therapy, said Dr. Judith L. Ross of Thomas Jefferson University, Philadelphia, and her associates.

The purpose of their study was twofold: to provide objective evidence from the first randomized, double-blind clinical trial that the accepted practice of giving growth hormone to girls with Turner’s syndrome in mid-childhood improves their markedly short stature, and to determine whether ultralow-dose estrogen at this age is beneficial or detrimental to height attainment.

Even though estrogen deficiency in Turner’s syndrome begins in infancy, "common clinical practice has been to postpone estrogen-replacement therapy until the mid-teens because of the widely held view that estrogen reduces height by accelerating epiphyseal fusion," the investigators noted.

Their findings suggest that to the contrary, this practice of delaying estrogen therapy "should be reconsidered."

"Although estrogen replacement during mid-childhood (prepuberty) may seem counterintuitive, this approach has a physiological rationale: the normal mid-childhood ovary is not entirely quiescent – plasma estradiol concentrations in healthy prepubertal girls, albeit low, are up to eight times as high as those in prepubescent boys," Dr. Ross and her colleagues said.

The study involved 149 girls aged 5-13 years who had Turner’s syndrome confirmed by karyotyping, breast development at Tanner stage 1-2, and height at or below the 10th percentile of that in the general population. The study subjects were enrolled between 1987 and 1996 and were followed through 2003.

The patients were randomly assigned to receive placebo injections plus oral estrogen (40 subjects), growth hormone injections plus oral placebo (35 subjects), growth hormone injections plus oral estrogen (35 subjects), or oral placebo plus placebo injections (39 subjects). They were assessed at 6-month intervals until they reached their adult height, which was defined as an annualized height velocity of less than 1.5 cm per year, and were assessed again approximately 1 year after completing the protocol.

Girls who received active growth hormone injections achieved significantly greater height than did those who received placebo injections, by approximately 5 cm. The height gain was even greater for girls given both active growth hormone and active estrogen, by an additional 2.3 cm.

Moreover, 79% of the girls who received both growth hormone and estrogen achieved significant gains in height, compared with only 65% of the girls who received growth hormone alone, 32% of the girls who received estrogen alone, and 15% of the girls who received double placebos, Dr. Ross and her associates wrote (N. Engl. J. Med. 2011;364:1230-42).

Serious adverse events were reported in 27 patients, including gynecologic disorders, pain, scoliosis, and thyroid disorders. However, "there were no new or unexpected safety findings with respect to growth hormone or estrogen treatment in this study," they added.

The researchers noted that, because this study was begun in the 1980s, the growth hormone regimen "may be considered suboptimal by current standards." The dose they used was 20% lower than the currently approved dose, and the three-times per week injection schedule they used is less effective than the daily injections that are currently recommended.

Similarly, the doses of estrogen that were deemed "ultralow-dose" 20 years ago when the study began, would now be considered excessive. At the time, "we aim[ed] to approximate the estrogen milieu in healthy prepubertal girls." However, it is now known that even lower doses would "minimize premature pubertal development and undue skeletal maturation."

The investigators emphasized that some girls with Turner’s syndrome don’t need estrogen supplementation, at least initially, because pubertal development can sometimes occur spontaneously. Approximately 13% of the girls in this study who received oral placebo instead of oral estrogen showed spontaneous breast development.

Taken together, the study findings demonstrate that "a regimen combining carefully individualized childhood estrogen replacement with growth hormone ... has the potential not only to optimize adult height but also to provide the neurocognitive and behavioral benefits of early estrogen administration," Dr. Ross and her colleagues said.

Adding ultralow-dose estrogen to growth hormone therapy in young girls with Turner’s syndrome improves adult height attainment and might provide additional neurocognitive and behavioral benefits, according to a report in the March 31 issue of the New England Journal of Medicine.

Carefully individualized ultralow-dose estrogen, given before puberty, appears to have a modest synergistic effect with growth hormone in promoting height velocity. Reportedly, some patients also have shown improvements in nonverbal processing speed, motor performance, verbal and nonverbal memory, and self-image with the dual therapy, said Dr. Judith L. Ross of Thomas Jefferson University, Philadelphia, and her associates.

The purpose of their study was twofold: to provide objective evidence from the first randomized, double-blind clinical trial that the accepted practice of giving growth hormone to girls with Turner’s syndrome in mid-childhood improves their markedly short stature, and to determine whether ultralow-dose estrogen at this age is beneficial or detrimental to height attainment.

Even though estrogen deficiency in Turner’s syndrome begins in infancy, "common clinical practice has been to postpone estrogen-replacement therapy until the mid-teens because of the widely held view that estrogen reduces height by accelerating epiphyseal fusion," the investigators noted.

Their findings suggest that to the contrary, this practice of delaying estrogen therapy "should be reconsidered."

"Although estrogen replacement during mid-childhood (prepuberty) may seem counterintuitive, this approach has a physiological rationale: the normal mid-childhood ovary is not entirely quiescent – plasma estradiol concentrations in healthy prepubertal girls, albeit low, are up to eight times as high as those in prepubescent boys," Dr. Ross and her colleagues said.

The study involved 149 girls aged 5-13 years who had Turner’s syndrome confirmed by karyotyping, breast development at Tanner stage 1-2, and height at or below the 10th percentile of that in the general population. The study subjects were enrolled between 1987 and 1996 and were followed through 2003.

The patients were randomly assigned to receive placebo injections plus oral estrogen (40 subjects), growth hormone injections plus oral placebo (35 subjects), growth hormone injections plus oral estrogen (35 subjects), or oral placebo plus placebo injections (39 subjects). They were assessed at 6-month intervals until they reached their adult height, which was defined as an annualized height velocity of less than 1.5 cm per year, and were assessed again approximately 1 year after completing the protocol.

Girls who received active growth hormone injections achieved significantly greater height than did those who received placebo injections, by approximately 5 cm. The height gain was even greater for girls given both active growth hormone and active estrogen, by an additional 2.3 cm.

Moreover, 79% of the girls who received both growth hormone and estrogen achieved significant gains in height, compared with only 65% of the girls who received growth hormone alone, 32% of the girls who received estrogen alone, and 15% of the girls who received double placebos, Dr. Ross and her associates wrote (N. Engl. J. Med. 2011;364:1230-42).

Serious adverse events were reported in 27 patients, including gynecologic disorders, pain, scoliosis, and thyroid disorders. However, "there were no new or unexpected safety findings with respect to growth hormone or estrogen treatment in this study," they added.

The researchers noted that, because this study was begun in the 1980s, the growth hormone regimen "may be considered suboptimal by current standards." The dose they used was 20% lower than the currently approved dose, and the three-times per week injection schedule they used is less effective than the daily injections that are currently recommended.

Similarly, the doses of estrogen that were deemed "ultralow-dose" 20 years ago when the study began, would now be considered excessive. At the time, "we aim[ed] to approximate the estrogen milieu in healthy prepubertal girls." However, it is now known that even lower doses would "minimize premature pubertal development and undue skeletal maturation."

The investigators emphasized that some girls with Turner’s syndrome don’t need estrogen supplementation, at least initially, because pubertal development can sometimes occur spontaneously. Approximately 13% of the girls in this study who received oral placebo instead of oral estrogen showed spontaneous breast development.

Taken together, the study findings demonstrate that "a regimen combining carefully individualized childhood estrogen replacement with growth hormone ... has the potential not only to optimize adult height but also to provide the neurocognitive and behavioral benefits of early estrogen administration," Dr. Ross and her colleagues said.

Adding ultralow-dose estrogen to growth hormone therapy in young girls with Turner’s syndrome improves adult height attainment and might provide additional neurocognitive and behavioral benefits, according to a report in the March 31 issue of the New England Journal of Medicine.

Carefully individualized ultralow-dose estrogen, given before puberty, appears to have a modest synergistic effect with growth hormone in promoting height velocity. Reportedly, some patients also have shown improvements in nonverbal processing speed, motor performance, verbal and nonverbal memory, and self-image with the dual therapy, said Dr. Judith L. Ross of Thomas Jefferson University, Philadelphia, and her associates.

The purpose of their study was twofold: to provide objective evidence from the first randomized, double-blind clinical trial that the accepted practice of giving growth hormone to girls with Turner’s syndrome in mid-childhood improves their markedly short stature, and to determine whether ultralow-dose estrogen at this age is beneficial or detrimental to height attainment.

Even though estrogen deficiency in Turner’s syndrome begins in infancy, "common clinical practice has been to postpone estrogen-replacement therapy until the mid-teens because of the widely held view that estrogen reduces height by accelerating epiphyseal fusion," the investigators noted.

Their findings suggest that to the contrary, this practice of delaying estrogen therapy "should be reconsidered."

"Although estrogen replacement during mid-childhood (prepuberty) may seem counterintuitive, this approach has a physiological rationale: the normal mid-childhood ovary is not entirely quiescent – plasma estradiol concentrations in healthy prepubertal girls, albeit low, are up to eight times as high as those in prepubescent boys," Dr. Ross and her colleagues said.

The study involved 149 girls aged 5-13 years who had Turner’s syndrome confirmed by karyotyping, breast development at Tanner stage 1-2, and height at or below the 10th percentile of that in the general population. The study subjects were enrolled between 1987 and 1996 and were followed through 2003.

The patients were randomly assigned to receive placebo injections plus oral estrogen (40 subjects), growth hormone injections plus oral placebo (35 subjects), growth hormone injections plus oral estrogen (35 subjects), or oral placebo plus placebo injections (39 subjects). They were assessed at 6-month intervals until they reached their adult height, which was defined as an annualized height velocity of less than 1.5 cm per year, and were assessed again approximately 1 year after completing the protocol.

Girls who received active growth hormone injections achieved significantly greater height than did those who received placebo injections, by approximately 5 cm. The height gain was even greater for girls given both active growth hormone and active estrogen, by an additional 2.3 cm.

Moreover, 79% of the girls who received both growth hormone and estrogen achieved significant gains in height, compared with only 65% of the girls who received growth hormone alone, 32% of the girls who received estrogen alone, and 15% of the girls who received double placebos, Dr. Ross and her associates wrote (N. Engl. J. Med. 2011;364:1230-42).

Serious adverse events were reported in 27 patients, including gynecologic disorders, pain, scoliosis, and thyroid disorders. However, "there were no new or unexpected safety findings with respect to growth hormone or estrogen treatment in this study," they added.

The researchers noted that, because this study was begun in the 1980s, the growth hormone regimen "may be considered suboptimal by current standards." The dose they used was 20% lower than the currently approved dose, and the three-times per week injection schedule they used is less effective than the daily injections that are currently recommended.

Similarly, the doses of estrogen that were deemed "ultralow-dose" 20 years ago when the study began, would now be considered excessive. At the time, "we aim[ed] to approximate the estrogen milieu in healthy prepubertal girls." However, it is now known that even lower doses would "minimize premature pubertal development and undue skeletal maturation."

The investigators emphasized that some girls with Turner’s syndrome don’t need estrogen supplementation, at least initially, because pubertal development can sometimes occur spontaneously. Approximately 13% of the girls in this study who received oral placebo instead of oral estrogen showed spontaneous breast development.

Taken together, the study findings demonstrate that "a regimen combining carefully individualized childhood estrogen replacement with growth hormone ... has the potential not only to optimize adult height but also to provide the neurocognitive and behavioral benefits of early estrogen administration," Dr. Ross and her colleagues said.

It appears that only 8% of second solid cancers can be attributed to radiotherapy for a first cancer, according to a report published online March 30 in the Lancet.

This figure varies somewhat according to the site of the first solid tumor, with the lowest attributable risk (4%) in cancers of the eye or orbit and the highest attributable risk (24%) in cancers of the testes.

Given that only a small proportion of second cancers among adult survivors are likely to be related to radiotherapy, it follows that most second cancers arise from other causes, such as genetics or lifestyle factors, said Amy Berrington de Gonzalez, D.Phil., of the National Cancer Institute, and her associates.

"These findings can be used by physicians and patients to put the risk of radiation-related cancer into perspective when compared with the probable benefits of treatment," the researchers noted.

Many studies have shown an association between receiving radiotherapy for a first solid tumor and subsequently developing a second solid tumor. However, the proportion of second cancers that might be related to radiotherapy has not been investigated before, they said.

Dr. Berrington de Gonzalez and her colleagues used data from the U.S. SEER (Surveillance, Epidemiology, and End Results) cancer registry to perform "a comprehensive and systematic analysis of all first solid cancer sites in adults that are routinely treated with radiotherapy." They included 647,672 patients who were 5-year cancer survivors and were aged 20 years and older when they were diagnosed with a first primary invasive solid cancer in 1973-2002. The participants were followed for 5-34 years (mean follow-up, 12 years) for the development of a second solid cancer.

The study included 15 possible sites of solid cancer that usually receive radiotherapy as the first course of treatment: oral/pharynx, salivary gland, rectum, anus, larynx, lung, soft tissue, female breast, cervix, endometrial, prostate, testes, eye/orbit, brain/central nervous system (CNS), and thyroid. "We excluded hematological cancers from both the first and second cancer sites because of potential confounding by chemotherapy," the investigators said.

A total of 60,271 study subjects (9%) developed a second solid cancer. "There were an estimated 3,266 excess second solid cancers that could be related to radiotherapy ... in our analysis; more than half of these were in breast and prostate cancer survivors," they said (Lancet 2011 March 30 [doi:10.1016/S1470-2045(11)70061-4]).

"We estimate that 8% of the 42,294 second solid cancers diagnosed in patients that survived longer than 1 year could be related to radiotherapy. ... For every 1,000 patients treated with radiotherapy, we estimated [three excess] cancers by 10 years after first cancer diagnosis, and [five excess] cancers by 15 years," they added.

Attributable risk was highest for seminomas (24%) and cancers of the cervix (17%), nonlimb soft tissue (15%), salivary gland (12%), and anus and prostate (10% each); it was lowest for cancers of the eye or orbit (4%), and oral/pharynx, larynx, and female breast (5% each). Attributable risk was intermediate for cancers of the lung (6%), rectum and thyroid (7% each), and endometrium and brain/CNS (9%).

In general, attributable risks followed expected patterns: They were higher for sites that are typically exposed to higher doses of radiation, for patients who were younger when they were exposed to the radiation, and for patients who had survived the longest time since diagnosis of the first cancer.

The strengths of this study were its large sample population and long follow-up. Weaknesses included the lack of data on smoking status and on the use of chemotherapy or hormone therapy, which could confound the results.

In addition, "since all the patients were treated before 2003, the effect of the widespread introduction of intensity-modulated radiotherapy (IMRT) could not be assessed. There is concern that IMRT might actually increase second-cancer risks because of the greater volume of tissue that receives low-level radiation exposure, and it will be important to study this directly in the future," Dr. Berrington de Gonzalez and her associates said.

Overall, the study results demonstrate that the risks of developing a second cancer after receiving radiotherapy in adulthood "are relatively small, especially when compared with the treatment benefits," they added.

This study was funded by the National Cancer Institute. No financial conflicts of interest were reported.

It appears that only 8% of second solid cancers can be attributed to radiotherapy for a first cancer, according to a report published online March 30 in the Lancet.

This figure varies somewhat according to the site of the first solid tumor, with the lowest attributable risk (4%) in cancers of the eye or orbit and the highest attributable risk (24%) in cancers of the testes.

Given that only a small proportion of second cancers among adult survivors are likely to be related to radiotherapy, it follows that most second cancers arise from other causes, such as genetics or lifestyle factors, said Amy Berrington de Gonzalez, D.Phil., of the National Cancer Institute, and her associates.

"These findings can be used by physicians and patients to put the risk of radiation-related cancer into perspective when compared with the probable benefits of treatment," the researchers noted.

Many studies have shown an association between receiving radiotherapy for a first solid tumor and subsequently developing a second solid tumor. However, the proportion of second cancers that might be related to radiotherapy has not been investigated before, they said.

Dr. Berrington de Gonzalez and her colleagues used data from the U.S. SEER (Surveillance, Epidemiology, and End Results) cancer registry to perform "a comprehensive and systematic analysis of all first solid cancer sites in adults that are routinely treated with radiotherapy." They included 647,672 patients who were 5-year cancer survivors and were aged 20 years and older when they were diagnosed with a first primary invasive solid cancer in 1973-2002. The participants were followed for 5-34 years (mean follow-up, 12 years) for the development of a second solid cancer.

The study included 15 possible sites of solid cancer that usually receive radiotherapy as the first course of treatment: oral/pharynx, salivary gland, rectum, anus, larynx, lung, soft tissue, female breast, cervix, endometrial, prostate, testes, eye/orbit, brain/central nervous system (CNS), and thyroid. "We excluded hematological cancers from both the first and second cancer sites because of potential confounding by chemotherapy," the investigators said.

A total of 60,271 study subjects (9%) developed a second solid cancer. "There were an estimated 3,266 excess second solid cancers that could be related to radiotherapy ... in our analysis; more than half of these were in breast and prostate cancer survivors," they said (Lancet 2011 March 30 [doi:10.1016/S1470-2045(11)70061-4]).

"We estimate that 8% of the 42,294 second solid cancers diagnosed in patients that survived longer than 1 year could be related to radiotherapy. ... For every 1,000 patients treated with radiotherapy, we estimated [three excess] cancers by 10 years after first cancer diagnosis, and [five excess] cancers by 15 years," they added.

Attributable risk was highest for seminomas (24%) and cancers of the cervix (17%), nonlimb soft tissue (15%), salivary gland (12%), and anus and prostate (10% each); it was lowest for cancers of the eye or orbit (4%), and oral/pharynx, larynx, and female breast (5% each). Attributable risk was intermediate for cancers of the lung (6%), rectum and thyroid (7% each), and endometrium and brain/CNS (9%).

In general, attributable risks followed expected patterns: They were higher for sites that are typically exposed to higher doses of radiation, for patients who were younger when they were exposed to the radiation, and for patients who had survived the longest time since diagnosis of the first cancer.

The strengths of this study were its large sample population and long follow-up. Weaknesses included the lack of data on smoking status and on the use of chemotherapy or hormone therapy, which could confound the results.

In addition, "since all the patients were treated before 2003, the effect of the widespread introduction of intensity-modulated radiotherapy (IMRT) could not be assessed. There is concern that IMRT might actually increase second-cancer risks because of the greater volume of tissue that receives low-level radiation exposure, and it will be important to study this directly in the future," Dr. Berrington de Gonzalez and her associates said.

Overall, the study results demonstrate that the risks of developing a second cancer after receiving radiotherapy in adulthood "are relatively small, especially when compared with the treatment benefits," they added.

This study was funded by the National Cancer Institute. No financial conflicts of interest were reported.

It appears that only 8% of second solid cancers can be attributed to radiotherapy for a first cancer, according to a report published online March 30 in the Lancet.

This figure varies somewhat according to the site of the first solid tumor, with the lowest attributable risk (4%) in cancers of the eye or orbit and the highest attributable risk (24%) in cancers of the testes.

Given that only a small proportion of second cancers among adult survivors are likely to be related to radiotherapy, it follows that most second cancers arise from other causes, such as genetics or lifestyle factors, said Amy Berrington de Gonzalez, D.Phil., of the National Cancer Institute, and her associates.

"These findings can be used by physicians and patients to put the risk of radiation-related cancer into perspective when compared with the probable benefits of treatment," the researchers noted.

Many studies have shown an association between receiving radiotherapy for a first solid tumor and subsequently developing a second solid tumor. However, the proportion of second cancers that might be related to radiotherapy has not been investigated before, they said.

Dr. Berrington de Gonzalez and her colleagues used data from the U.S. SEER (Surveillance, Epidemiology, and End Results) cancer registry to perform "a comprehensive and systematic analysis of all first solid cancer sites in adults that are routinely treated with radiotherapy." They included 647,672 patients who were 5-year cancer survivors and were aged 20 years and older when they were diagnosed with a first primary invasive solid cancer in 1973-2002. The participants were followed for 5-34 years (mean follow-up, 12 years) for the development of a second solid cancer.

The study included 15 possible sites of solid cancer that usually receive radiotherapy as the first course of treatment: oral/pharynx, salivary gland, rectum, anus, larynx, lung, soft tissue, female breast, cervix, endometrial, prostate, testes, eye/orbit, brain/central nervous system (CNS), and thyroid. "We excluded hematological cancers from both the first and second cancer sites because of potential confounding by chemotherapy," the investigators said.

A total of 60,271 study subjects (9%) developed a second solid cancer. "There were an estimated 3,266 excess second solid cancers that could be related to radiotherapy ... in our analysis; more than half of these were in breast and prostate cancer survivors," they said (Lancet 2011 March 30 [doi:10.1016/S1470-2045(11)70061-4]).

"We estimate that 8% of the 42,294 second solid cancers diagnosed in patients that survived longer than 1 year could be related to radiotherapy. ... For every 1,000 patients treated with radiotherapy, we estimated [three excess] cancers by 10 years after first cancer diagnosis, and [five excess] cancers by 15 years," they added.

Attributable risk was highest for seminomas (24%) and cancers of the cervix (17%), nonlimb soft tissue (15%), salivary gland (12%), and anus and prostate (10% each); it was lowest for cancers of the eye or orbit (4%), and oral/pharynx, larynx, and female breast (5% each). Attributable risk was intermediate for cancers of the lung (6%), rectum and thyroid (7% each), and endometrium and brain/CNS (9%).

In general, attributable risks followed expected patterns: They were higher for sites that are typically exposed to higher doses of radiation, for patients who were younger when they were exposed to the radiation, and for patients who had survived the longest time since diagnosis of the first cancer.

The strengths of this study were its large sample population and long follow-up. Weaknesses included the lack of data on smoking status and on the use of chemotherapy or hormone therapy, which could confound the results.

In addition, "since all the patients were treated before 2003, the effect of the widespread introduction of intensity-modulated radiotherapy (IMRT) could not be assessed. There is concern that IMRT might actually increase second-cancer risks because of the greater volume of tissue that receives low-level radiation exposure, and it will be important to study this directly in the future," Dr. Berrington de Gonzalez and her associates said.

Overall, the study results demonstrate that the risks of developing a second cancer after receiving radiotherapy in adulthood "are relatively small, especially when compared with the treatment benefits," they added.

This study was funded by the National Cancer Institute. No financial conflicts of interest were reported.

It appears that only 8% of second solid cancers can be attributed to radiotherapy for a first cancer, according to a report published online March 30 in the Lancet.

This figure varies somewhat according to the site of the first solid tumor, with the lowest attributable risk (4%) in cancers of the eye or orbit and the highest attributable risk (24%) in cancers of the testes.

Given that only a small proportion of second cancers among adult survivors are likely to be related to radiotherapy, it follows that most second cancers arise from other causes, such as genetics or lifestyle factors, said Amy Berrington de Gonzalez, D.Phil., of the National Cancer Institute, and her associates.

"These findings can be used by physicians and patients to put the risk of radiation-related cancer into perspective when compared with the probable benefits of treatment," the researchers noted.

Many studies have shown an association between receiving radiotherapy for a first solid tumor and subsequently developing a second solid tumor. However, the proportion of second cancers that might be related to radiotherapy has not been investigated before, they said.

Dr. Berrington de Gonzalez and her colleagues used data from the U.S. SEER (Surveillance, Epidemiology, and End Results) cancer registry to perform "a comprehensive and systematic analysis of all first solid cancer sites in adults that are routinely treated with radiotherapy." They included 647,672 patients who were 5-year cancer survivors and were aged 20 years and older when they were diagnosed with a first primary invasive solid cancer in 1973-2002. The participants were followed for 5-34 years (mean follow-up, 12 years) for the development of a second solid cancer.

The study included 15 possible sites of solid cancer that usually receive radiotherapy as the first course of treatment: oral/pharynx, salivary gland, rectum, anus, larynx, lung, soft tissue, female breast, cervix, endometrial, prostate, testes, eye/orbit, brain/central nervous system (CNS), and thyroid. "We excluded hematological cancers from both the first and second cancer sites because of potential confounding by chemotherapy," the investigators said.

A total of 60,271 study subjects (9%) developed a second solid cancer. "There were an estimated 3,266 excess second solid cancers that could be related to radiotherapy ... in our analysis; more than half of these were in breast and prostate cancer survivors," they said (Lancet 2011 March 30 [doi:10.1016/S1470-2045(11)70061-4]).

"We estimate that 8% of the 42,294 second solid cancers diagnosed in patients that survived longer than 1 year could be related to radiotherapy. ... For every 1,000 patients treated with radiotherapy, we estimated [three excess] cancers by 10 years after first cancer diagnosis, and [five excess] cancers by 15 years," they added.

Attributable risk was highest for seminomas (24%) and cancers of the cervix (17%), nonlimb soft tissue (15%), salivary gland (12%), and anus and prostate (10% each); it was lowest for cancers of the eye or orbit (4%), and oral/pharynx, larynx, and female breast (5% each). Attributable risk was intermediate for cancers of the lung (6%), rectum and thyroid (7% each), and endometrium and brain/CNS (9%).

In general, attributable risks followed expected patterns: They were higher for sites that are typically exposed to higher doses of radiation, for patients who were younger when they were exposed to the radiation, and for patients who had survived the longest time since diagnosis of the first cancer.

The strengths of this study were its large sample population and long follow-up. Weaknesses included the lack of data on smoking status and on the use of chemotherapy or hormone therapy, which could confound the results.

In addition, "since all the patients were treated before 2003, the effect of the widespread introduction of intensity-modulated radiotherapy (IMRT) could not be assessed. There is concern that IMRT might actually increase second-cancer risks because of the greater volume of tissue that receives low-level radiation exposure, and it will be important to study this directly in the future," Dr. Berrington de Gonzalez and her associates said.

Overall, the study results demonstrate that the risks of developing a second cancer after receiving radiotherapy in adulthood "are relatively small, especially when compared with the treatment benefits," they added.

This study was funded by the National Cancer Institute. No financial conflicts of interest were reported.

It appears that only 8% of second solid cancers can be attributed to radiotherapy for a first cancer, according to a report published online March 30 in the Lancet.

This figure varies somewhat according to the site of the first solid tumor, with the lowest attributable risk (4%) in cancers of the eye or orbit and the highest attributable risk (24%) in cancers of the testes.

Given that only a small proportion of second cancers among adult survivors are likely to be related to radiotherapy, it follows that most second cancers arise from other causes, such as genetics or lifestyle factors, said Amy Berrington de Gonzalez, D.Phil., of the National Cancer Institute, and her associates.

"These findings can be used by physicians and patients to put the risk of radiation-related cancer into perspective when compared with the probable benefits of treatment," the researchers noted.

Many studies have shown an association between receiving radiotherapy for a first solid tumor and subsequently developing a second solid tumor. However, the proportion of second cancers that might be related to radiotherapy has not been investigated before, they said.

Dr. Berrington de Gonzalez and her colleagues used data from the U.S. SEER (Surveillance, Epidemiology, and End Results) cancer registry to perform "a comprehensive and systematic analysis of all first solid cancer sites in adults that are routinely treated with radiotherapy." They included 647,672 patients who were 5-year cancer survivors and were aged 20 years and older when they were diagnosed with a first primary invasive solid cancer in 1973-2002. The participants were followed for 5-34 years (mean follow-up, 12 years) for the development of a second solid cancer.

The study included 15 possible sites of solid cancer that usually receive radiotherapy as the first course of treatment: oral/pharynx, salivary gland, rectum, anus, larynx, lung, soft tissue, female breast, cervix, endometrial, prostate, testes, eye/orbit, brain/central nervous system (CNS), and thyroid. "We excluded hematological cancers from both the first and second cancer sites because of potential confounding by chemotherapy," the investigators said.

A total of 60,271 study subjects (9%) developed a second solid cancer. "There were an estimated 3,266 excess second solid cancers that could be related to radiotherapy ... in our analysis; more than half of these were in breast and prostate cancer survivors," they said (Lancet 2011 March 30 [doi:10.1016/S1470-2045(11)70061-4]).

"We estimate that 8% of the 42,294 second solid cancers diagnosed in patients that survived longer than 1 year could be related to radiotherapy. ... For every 1,000 patients treated with radiotherapy, we estimated [three excess] cancers by 10 years after first cancer diagnosis, and [five excess] cancers by 15 years," they added.

Attributable risk was highest for seminomas (24%) and cancers of the cervix (17%), nonlimb soft tissue (15%), salivary gland (12%), and anus and prostate (10% each); it was lowest for cancers of the eye or orbit (4%), and oral/pharynx, larynx, and female breast (5% each). Attributable risk was intermediate for cancers of the lung (6%), rectum and thyroid (7% each), and endometrium and brain/CNS (9%).

In general, attributable risks followed expected patterns: They were higher for sites that are typically exposed to higher doses of radiation, for patients who were younger when they were exposed to the radiation, and for patients who had survived the longest time since diagnosis of the first cancer.

The strengths of this study were its large sample population and long follow-up. Weaknesses included the lack of data on smoking status and on the use of chemotherapy or hormone therapy, which could confound the results.

In addition, "since all the patients were treated before 2003, the effect of the widespread introduction of intensity-modulated radiotherapy (IMRT) could not be assessed. There is concern that IMRT might actually increase second-cancer risks because of the greater volume of tissue that receives low-level radiation exposure, and it will be important to study this directly in the future," Dr. Berrington de Gonzalez and her associates said.

Overall, the study results demonstrate that the risks of developing a second cancer after receiving radiotherapy in adulthood "are relatively small, especially when compared with the treatment benefits," they added.

This study was funded by the National Cancer Institute. No financial conflicts of interest were reported.

It appears that only 8% of second solid cancers can be attributed to radiotherapy for a first cancer, according to a report published online March 30 in the Lancet.

This figure varies somewhat according to the site of the first solid tumor, with the lowest attributable risk (4%) in cancers of the eye or orbit and the highest attributable risk (24%) in cancers of the testes.

Given that only a small proportion of second cancers among adult survivors are likely to be related to radiotherapy, it follows that most second cancers arise from other causes, such as genetics or lifestyle factors, said Amy Berrington de Gonzalez, D.Phil., of the National Cancer Institute, and her associates.

"These findings can be used by physicians and patients to put the risk of radiation-related cancer into perspective when compared with the probable benefits of treatment," the researchers noted.

Many studies have shown an association between receiving radiotherapy for a first solid tumor and subsequently developing a second solid tumor. However, the proportion of second cancers that might be related to radiotherapy has not been investigated before, they said.

Dr. Berrington de Gonzalez and her colleagues used data from the U.S. SEER (Surveillance, Epidemiology, and End Results) cancer registry to perform "a comprehensive and systematic analysis of all first solid cancer sites in adults that are routinely treated with radiotherapy." They included 647,672 patients who were 5-year cancer survivors and were aged 20 years and older when they were diagnosed with a first primary invasive solid cancer in 1973-2002. The participants were followed for 5-34 years (mean follow-up, 12 years) for the development of a second solid cancer.

The study included 15 possible sites of solid cancer that usually receive radiotherapy as the first course of treatment: oral/pharynx, salivary gland, rectum, anus, larynx, lung, soft tissue, female breast, cervix, endometrial, prostate, testes, eye/orbit, brain/central nervous system (CNS), and thyroid. "We excluded hematological cancers from both the first and second cancer sites because of potential confounding by chemotherapy," the investigators said.

A total of 60,271 study subjects (9%) developed a second solid cancer. "There were an estimated 3,266 excess second solid cancers that could be related to radiotherapy ... in our analysis; more than half of these were in breast and prostate cancer survivors," they said (Lancet 2011 March 30 [doi:10.1016/S1470-2045(11)70061-4]).

"We estimate that 8% of the 42,294 second solid cancers diagnosed in patients that survived longer than 1 year could be related to radiotherapy. ... For every 1,000 patients treated with radiotherapy, we estimated [three excess] cancers by 10 years after first cancer diagnosis, and [five excess] cancers by 15 years," they added.

Attributable risk was highest for seminomas (24%) and cancers of the cervix (17%), nonlimb soft tissue (15%), salivary gland (12%), and anus and prostate (10% each); it was lowest for cancers of the eye or orbit (4%), and oral/pharynx, larynx, and female breast (5% each). Attributable risk was intermediate for cancers of the lung (6%), rectum and thyroid (7% each), and endometrium and brain/CNS (9%).

In general, attributable risks followed expected patterns: They were higher for sites that are typically exposed to higher doses of radiation, for patients who were younger when they were exposed to the radiation, and for patients who had survived the longest time since diagnosis of the first cancer.

The strengths of this study were its large sample population and long follow-up. Weaknesses included the lack of data on smoking status and on the use of chemotherapy or hormone therapy, which could confound the results.

In addition, "since all the patients were treated before 2003, the effect of the widespread introduction of intensity-modulated radiotherapy (IMRT) could not be assessed. There is concern that IMRT might actually increase second-cancer risks because of the greater volume of tissue that receives low-level radiation exposure, and it will be important to study this directly in the future," Dr. Berrington de Gonzalez and her associates said.

Overall, the study results demonstrate that the risks of developing a second cancer after receiving radiotherapy in adulthood "are relatively small, especially when compared with the treatment benefits," they added.

This study was funded by the National Cancer Institute. No financial conflicts of interest were reported.