Patrice Wendling

It’s becoming clear that it’s not a matter of whether universal pulse oximetry screening for congenital heart disease in newborns will become a reality, but when.

In late September, Health and Human Services (HSS) Secretary Kathleen Sebelius endorsed the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) recommendation that critical congenital heart disease (CCHD) screening be added to the newborn Recommended Uniform Screening Panel.

The endorsement caps off years of work, including a September 2010 recommendation by the SACHDNC to add pulse oximetry screening for CCHD to the uniform screening panel that the HSS secretary deemed not ready for adoption pending an implementation plan from HHS agencies. The SACHDNC had identified seven specific lesions as primary targets for screening: hypoplastic left heart syndrome; pulmonary atresia; tetralogy of Fallot, total anomalous pulmonary venous return, transposition of the great arteries, tricuspid atresia, and truncus arteriosus.

In a 2009 statement, the American Academy of Pediatrics (AAP) and American Heart Association (AHA) offered compelling reasons for adopting pulse oximetry CCHD screening including two large-scale European screening studies in close to 80,000 newborns. The organizations stopped short of recommending universal screening, however, calling instead for further studies on implementation.

A work group was then convened in January 2011 to establish a standard approach to screening, follow-up, and strategies to fill in important knowledge gaps. A white paper outlining the outcomes of the work group has been endorsed by the AAP, AHA, and American College of Cardiology Foundation (ACCF). It is available online and appears in the November 2011 issue of Pediatrics.

"We might still have a way to go, but we are well on our way to universal screening," hospitalist Sandra Cuzzi, and Elizabeth Bradshaw, R.N., of Children’s National Medical Center in Washington, D.C, wrote in an accompanying editorial.

Children’s National has taken a leading role in the fight for universal screening and developed a community-based tool kit on implementing CCHD screening. As to why universal CCHD screening has taken so long to materialize, the tool kit cites a recent survey of 363 American pediatric cardiologists in which overall support for mandated pulse oximetry screening for all newborns was just 55%, despite only 58% of respondents reporting that current practice is adequate for detecting significant congenital heart disease (Pediatr. Cardiol. 2009;30:20-5). The same survey, however, notes that 26% of pediatric cardiologists reported "too many false positives" with pulse oximetry, 21% said the technology is "prone to noise and artifact," and 30% viewed it as "very operator dependent."

In an effort to reduce false-positive results, the work group recommends screening not begin until 24 hours of life, or as late as possible if earlier discharge is planned, and that screening be completed on the second day of life.

"Earlier screening can lead to false-positive results because of the transition from fetal to neonatal circulation and stabilization of systemic oxygen saturation levels, and later screening can miss an opportunity for intervention before closing of the ductus arteriosus," wrote white paper lead author Dr. Alex R. Kemper of the Duke Clinical Research Institute and of the departments of pediatrics and community and family medicine at Duke University, Durham, N.C., and his associates.

The work group recommends that screening be conducted using motion-tolerant pulse oximeters that report functional oxygen saturation, and that have been cleared by the Food and Drug Administration for use in newborns.

Other recommendations include the following:

• Screening should be based on the recommended screening algorithm and be performed by qualified personnel trained in the use of the algorithm and pulse oximetry monitoring of newborns.

• The algorithm cutoffs may need to be adjusted in high-altitude nurseries.

• Any abnormal pattern of low blood oxygen saturation requires a complete clinical evaluation by a licensed, independent practitioner. In the absence of other findings to explain hypoxemia, CCHD needs to be excluded on the basis of a comprehensive echocardiogram interpreted by a pediatric cardiologist before the newborn is discharged from the hospital.

• The results of newborn CCHD screening should be communicated to newborns’ primary care providers. Primary care providers should ensure that newborns in their practice are appropriately screened, and work to make sure there is appropriate follow-up for those diagnosed with CCHD.

• Hospitals and birthing centers should establish partnerships with local and state public health agencies to develop strategies for quality assurance and monitor the impact of screening.

• Standards should be developed for electronic reporting of pulse oximetry monitoring and diagnostic outcomes.

Routine newborn pulse oximetry screening is a concept whose time has come, according to pediatric cardiologist Thomas Johnson of Children’s Hospital at Dartmouth, Manchester, N.H.

"Past concerns about test reliability and the incidence of false-positive tests have been largely laid to rest," he said in an interview. "The AAP/AHA/ACC work group report specifies a protocol and management algorithm that appears to be practical, cost effective, and useful for detecting complex congenital heart lesions that may have a subtle presentation in the first 48 hours of life."

He noted that the New Hampshire legislature is considering similar legislation, known as Parker’s Law, and expects that it will receive very strong support from the medical community. Three states – New Jersey, Maryland, and Indiana – have already passed legislation requiring pulse oximetry screening of all newborns. The Maryland law will not take effect until there are federal recommendations for such screenings.

The work group called on the AAP, AHA, and ACCF to work with the American Medical Association to develop appropriate CPT codes for billing and insurance reimbursement. Current CPT codes for pulse oximetry are only appropriate when accompanied by a diagnostic code for a pulmonary disease associated with hypoxia.

Cost estimates for pulse oximetry compare "quite favorably" with cost estimates for newborn hearing screening, according to the work group. Moreover, Swedish researchers calculated that the savings in health care costs from the prevention of one case of complications of circulatory collapse resulting from undiagnosed CCHD may exceed the cost of screening 2,000 newborns (BMJ 2009;338:a3037).

Finally, the work group recommended the development of a national clearinghouse and technical assistance center, similar to the National Resource Center for Newborn Hearing Screening, to coordinate implementation and evaluation.

"The described infrastructure required to support implementation and compliance with screening guidelines is clearly necessary," editorialists Dr. Cuzzi and Ms. Bradshaw wrote. "However, not all hospitals should feel the need to wait until such infrastructure has been developed. Evidence-based tool kits are already available to facilitate implementation."

Dr. Kemper and his associates, Dr. Cuzzi and Ms. Bradshaw, and Dr. Johnson reported no relevant financial disclosures.

It’s becoming clear that it’s not a matter of whether universal pulse oximetry screening for congenital heart disease in newborns will become a reality, but when.

In late September, Health and Human Services (HSS) Secretary Kathleen Sebelius endorsed the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) recommendation that critical congenital heart disease (CCHD) screening be added to the newborn Recommended Uniform Screening Panel.

The endorsement caps off years of work, including a September 2010 recommendation by the SACHDNC to add pulse oximetry screening for CCHD to the uniform screening panel that the HSS secretary deemed not ready for adoption pending an implementation plan from HHS agencies. The SACHDNC had identified seven specific lesions as primary targets for screening: hypoplastic left heart syndrome; pulmonary atresia; tetralogy of Fallot, total anomalous pulmonary venous return, transposition of the great arteries, tricuspid atresia, and truncus arteriosus.

In a 2009 statement, the American Academy of Pediatrics (AAP) and American Heart Association (AHA) offered compelling reasons for adopting pulse oximetry CCHD screening including two large-scale European screening studies in close to 80,000 newborns. The organizations stopped short of recommending universal screening, however, calling instead for further studies on implementation.

A work group was then convened in January 2011 to establish a standard approach to screening, follow-up, and strategies to fill in important knowledge gaps. A white paper outlining the outcomes of the work group has been endorsed by the AAP, AHA, and American College of Cardiology Foundation (ACCF). It is available online and appears in the November 2011 issue of Pediatrics.

"We might still have a way to go, but we are well on our way to universal screening," hospitalist Sandra Cuzzi, and Elizabeth Bradshaw, R.N., of Children’s National Medical Center in Washington, D.C, wrote in an accompanying editorial.

Children’s National has taken a leading role in the fight for universal screening and developed a community-based tool kit on implementing CCHD screening. As to why universal CCHD screening has taken so long to materialize, the tool kit cites a recent survey of 363 American pediatric cardiologists in which overall support for mandated pulse oximetry screening for all newborns was just 55%, despite only 58% of respondents reporting that current practice is adequate for detecting significant congenital heart disease (Pediatr. Cardiol. 2009;30:20-5). The same survey, however, notes that 26% of pediatric cardiologists reported "too many false positives" with pulse oximetry, 21% said the technology is "prone to noise and artifact," and 30% viewed it as "very operator dependent."

In an effort to reduce false-positive results, the work group recommends screening not begin until 24 hours of life, or as late as possible if earlier discharge is planned, and that screening be completed on the second day of life.

"Earlier screening can lead to false-positive results because of the transition from fetal to neonatal circulation and stabilization of systemic oxygen saturation levels, and later screening can miss an opportunity for intervention before closing of the ductus arteriosus," wrote white paper lead author Dr. Alex R. Kemper of the Duke Clinical Research Institute and of the departments of pediatrics and community and family medicine at Duke University, Durham, N.C., and his associates.

The work group recommends that screening be conducted using motion-tolerant pulse oximeters that report functional oxygen saturation, and that have been cleared by the Food and Drug Administration for use in newborns.

Other recommendations include the following:

• Screening should be based on the recommended screening algorithm and be performed by qualified personnel trained in the use of the algorithm and pulse oximetry monitoring of newborns.

• The algorithm cutoffs may need to be adjusted in high-altitude nurseries.

• Any abnormal pattern of low blood oxygen saturation requires a complete clinical evaluation by a licensed, independent practitioner. In the absence of other findings to explain hypoxemia, CCHD needs to be excluded on the basis of a comprehensive echocardiogram interpreted by a pediatric cardiologist before the newborn is discharged from the hospital.

• The results of newborn CCHD screening should be communicated to newborns’ primary care providers. Primary care providers should ensure that newborns in their practice are appropriately screened, and work to make sure there is appropriate follow-up for those diagnosed with CCHD.

• Hospitals and birthing centers should establish partnerships with local and state public health agencies to develop strategies for quality assurance and monitor the impact of screening.

• Standards should be developed for electronic reporting of pulse oximetry monitoring and diagnostic outcomes.

Routine newborn pulse oximetry screening is a concept whose time has come, according to pediatric cardiologist Thomas Johnson of Children’s Hospital at Dartmouth, Manchester, N.H.

"Past concerns about test reliability and the incidence of false-positive tests have been largely laid to rest," he said in an interview. "The AAP/AHA/ACC work group report specifies a protocol and management algorithm that appears to be practical, cost effective, and useful for detecting complex congenital heart lesions that may have a subtle presentation in the first 48 hours of life."

He noted that the New Hampshire legislature is considering similar legislation, known as Parker’s Law, and expects that it will receive very strong support from the medical community. Three states – New Jersey, Maryland, and Indiana – have already passed legislation requiring pulse oximetry screening of all newborns. The Maryland law will not take effect until there are federal recommendations for such screenings.

The work group called on the AAP, AHA, and ACCF to work with the American Medical Association to develop appropriate CPT codes for billing and insurance reimbursement. Current CPT codes for pulse oximetry are only appropriate when accompanied by a diagnostic code for a pulmonary disease associated with hypoxia.

Cost estimates for pulse oximetry compare "quite favorably" with cost estimates for newborn hearing screening, according to the work group. Moreover, Swedish researchers calculated that the savings in health care costs from the prevention of one case of complications of circulatory collapse resulting from undiagnosed CCHD may exceed the cost of screening 2,000 newborns (BMJ 2009;338:a3037).

Finally, the work group recommended the development of a national clearinghouse and technical assistance center, similar to the National Resource Center for Newborn Hearing Screening, to coordinate implementation and evaluation.

"The described infrastructure required to support implementation and compliance with screening guidelines is clearly necessary," editorialists Dr. Cuzzi and Ms. Bradshaw wrote. "However, not all hospitals should feel the need to wait until such infrastructure has been developed. Evidence-based tool kits are already available to facilitate implementation."

Dr. Kemper and his associates, Dr. Cuzzi and Ms. Bradshaw, and Dr. Johnson reported no relevant financial disclosures.

It’s becoming clear that it’s not a matter of whether universal pulse oximetry screening for congenital heart disease in newborns will become a reality, but when.

In late September, Health and Human Services (HSS) Secretary Kathleen Sebelius endorsed the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) recommendation that critical congenital heart disease (CCHD) screening be added to the newborn Recommended Uniform Screening Panel.

The endorsement caps off years of work, including a September 2010 recommendation by the SACHDNC to add pulse oximetry screening for CCHD to the uniform screening panel that the HSS secretary deemed not ready for adoption pending an implementation plan from HHS agencies. The SACHDNC had identified seven specific lesions as primary targets for screening: hypoplastic left heart syndrome; pulmonary atresia; tetralogy of Fallot, total anomalous pulmonary venous return, transposition of the great arteries, tricuspid atresia, and truncus arteriosus.

In a 2009 statement, the American Academy of Pediatrics (AAP) and American Heart Association (AHA) offered compelling reasons for adopting pulse oximetry CCHD screening including two large-scale European screening studies in close to 80,000 newborns. The organizations stopped short of recommending universal screening, however, calling instead for further studies on implementation.

A work group was then convened in January 2011 to establish a standard approach to screening, follow-up, and strategies to fill in important knowledge gaps. A white paper outlining the outcomes of the work group has been endorsed by the AAP, AHA, and American College of Cardiology Foundation (ACCF). It is available online and appears in the November 2011 issue of Pediatrics.

"We might still have a way to go, but we are well on our way to universal screening," hospitalist Sandra Cuzzi, and Elizabeth Bradshaw, R.N., of Children’s National Medical Center in Washington, D.C, wrote in an accompanying editorial.

Children’s National has taken a leading role in the fight for universal screening and developed a community-based tool kit on implementing CCHD screening. As to why universal CCHD screening has taken so long to materialize, the tool kit cites a recent survey of 363 American pediatric cardiologists in which overall support for mandated pulse oximetry screening for all newborns was just 55%, despite only 58% of respondents reporting that current practice is adequate for detecting significant congenital heart disease (Pediatr. Cardiol. 2009;30:20-5). The same survey, however, notes that 26% of pediatric cardiologists reported "too many false positives" with pulse oximetry, 21% said the technology is "prone to noise and artifact," and 30% viewed it as "very operator dependent."

In an effort to reduce false-positive results, the work group recommends screening not begin until 24 hours of life, or as late as possible if earlier discharge is planned, and that screening be completed on the second day of life.

"Earlier screening can lead to false-positive results because of the transition from fetal to neonatal circulation and stabilization of systemic oxygen saturation levels, and later screening can miss an opportunity for intervention before closing of the ductus arteriosus," wrote white paper lead author Dr. Alex R. Kemper of the Duke Clinical Research Institute and of the departments of pediatrics and community and family medicine at Duke University, Durham, N.C., and his associates.

The work group recommends that screening be conducted using motion-tolerant pulse oximeters that report functional oxygen saturation, and that have been cleared by the Food and Drug Administration for use in newborns.

Other recommendations include the following:

• Screening should be based on the recommended screening algorithm and be performed by qualified personnel trained in the use of the algorithm and pulse oximetry monitoring of newborns.

• The algorithm cutoffs may need to be adjusted in high-altitude nurseries.

• Any abnormal pattern of low blood oxygen saturation requires a complete clinical evaluation by a licensed, independent practitioner. In the absence of other findings to explain hypoxemia, CCHD needs to be excluded on the basis of a comprehensive echocardiogram interpreted by a pediatric cardiologist before the newborn is discharged from the hospital.

• The results of newborn CCHD screening should be communicated to newborns’ primary care providers. Primary care providers should ensure that newborns in their practice are appropriately screened, and work to make sure there is appropriate follow-up for those diagnosed with CCHD.

• Hospitals and birthing centers should establish partnerships with local and state public health agencies to develop strategies for quality assurance and monitor the impact of screening.

• Standards should be developed for electronic reporting of pulse oximetry monitoring and diagnostic outcomes.

Routine newborn pulse oximetry screening is a concept whose time has come, according to pediatric cardiologist Thomas Johnson of Children’s Hospital at Dartmouth, Manchester, N.H.

"Past concerns about test reliability and the incidence of false-positive tests have been largely laid to rest," he said in an interview. "The AAP/AHA/ACC work group report specifies a protocol and management algorithm that appears to be practical, cost effective, and useful for detecting complex congenital heart lesions that may have a subtle presentation in the first 48 hours of life."

He noted that the New Hampshire legislature is considering similar legislation, known as Parker’s Law, and expects that it will receive very strong support from the medical community. Three states – New Jersey, Maryland, and Indiana – have already passed legislation requiring pulse oximetry screening of all newborns. The Maryland law will not take effect until there are federal recommendations for such screenings.

The work group called on the AAP, AHA, and ACCF to work with the American Medical Association to develop appropriate CPT codes for billing and insurance reimbursement. Current CPT codes for pulse oximetry are only appropriate when accompanied by a diagnostic code for a pulmonary disease associated with hypoxia.

Cost estimates for pulse oximetry compare "quite favorably" with cost estimates for newborn hearing screening, according to the work group. Moreover, Swedish researchers calculated that the savings in health care costs from the prevention of one case of complications of circulatory collapse resulting from undiagnosed CCHD may exceed the cost of screening 2,000 newborns (BMJ 2009;338:a3037).

Finally, the work group recommended the development of a national clearinghouse and technical assistance center, similar to the National Resource Center for Newborn Hearing Screening, to coordinate implementation and evaluation.

"The described infrastructure required to support implementation and compliance with screening guidelines is clearly necessary," editorialists Dr. Cuzzi and Ms. Bradshaw wrote. "However, not all hospitals should feel the need to wait until such infrastructure has been developed. Evidence-based tool kits are already available to facilitate implementation."

Dr. Kemper and his associates, Dr. Cuzzi and Ms. Bradshaw, and Dr. Johnson reported no relevant financial disclosures.

MADISON, WIS.  – Cyclic parenteral nutrition may be a viable option in very low birth weight infants requiring parenteral nutrition for several weeks, results of a prospective, randomized trial suggest.

Among 114 neonates weighing no more than 1,500 g, the incidence of cholestasis was nearly double at 24% with continuous parenteral nutrition versus 12.5% with cyclic parenteral nutrition.

Although this did not reach statistical significance at a P value of 0.109, there was a downward trend in direct bilirubin beginning in week 7 favoring cyclic parenteral nutrition that was statistically significant by week 8 (1.4 mg/dL vs. 3.2 mg/dL, P = .042), Dr. Maliha Shareef and her colleagues reported at the annual meeting of the Midwest Society for Pediatric Research.

"While feeding advancement regimens may vary in NICUs, this study indicates cyclic parenteral nutrition as an important option when parenteral nutrition is required for extended periods of time," the authors concluded.

Parenteral nutrition-associated cholestasis can develop in up to 35% of premature infants by 1 month of age and be as high as 67% by 3 months of age. The mortality rate is 3%-14% overall, and even higher in infants with short bowel syndrome.

Cyclic parenteral nutrition (PN) has been shown to be effective in reducing cholestasis in children and adults, but minimal data exist on its use and effects in very low birth weight (VLBW) infants, due primarily to concerns for the risk of hypoglycemia.

Theoretically, cyclic PN is thought to prevent PN-induced fatty infiltration of the liver, decrease hyperinsulinemia seen with continuous infusion of dextrose, prevent lipogenesis, and possibly reduce the respiratory quotient, noted Dr. Shareef, an associate professor of pediatrics and neonatology at Loyola University Chicago, Maywood, Ill.

The researchers enrolled 114 infants weighing no more than 1,500 g at birth, who were hemodynamically and metabolically stable and needed PN for more than 1 week. Their median gestational age was 28 weeks. Median birth weight was 1,000 g in the continuous group and 1,050 g in the cyclic group.

All infants were started on continuous total PN and then were evenly randomized beginning on day 7 to continuous PN or 20 hours of total PN and 4 hours of D10 intravenous solution with sodium, potassium, and calcium to provide the glucose infusion rate (GIR) that is within 30% of GIR in total PN. Serum glucose was checked the first 3 days at 30 and 60 minutes off total PN and 30 minutes before restarting total PN. Weekly liver and basic metabolic panels were also obtained.

Hypoglycemia, defined as a serum glucose level less than 40 mg/dL, did not occur in the cyclic group, Dr. Shareef reported in a poster.

Gastrointestinal complications were observed in eight infants in the continuous PN group and seven in the cyclic group, and gram-negative rod infections in six and eight infants, respectively.

The average number of days on total PN was 31.5 in the continuous group and 29 in the cyclic group.

"Cyclic total PN is tolerated in lower birth weight neonates when glucose infusion rate is supported during off hours," the authors wrote. "Further study is needed to determine when cyclic PN should be initiated."

Dr. Shareef and her associates reported no relevant financial disclosures.

MADISON, WIS.  – Cyclic parenteral nutrition may be a viable option in very low birth weight infants requiring parenteral nutrition for several weeks, results of a prospective, randomized trial suggest.

Among 114 neonates weighing no more than 1,500 g, the incidence of cholestasis was nearly double at 24% with continuous parenteral nutrition versus 12.5% with cyclic parenteral nutrition.

Although this did not reach statistical significance at a P value of 0.109, there was a downward trend in direct bilirubin beginning in week 7 favoring cyclic parenteral nutrition that was statistically significant by week 8 (1.4 mg/dL vs. 3.2 mg/dL, P = .042), Dr. Maliha Shareef and her colleagues reported at the annual meeting of the Midwest Society for Pediatric Research.

"While feeding advancement regimens may vary in NICUs, this study indicates cyclic parenteral nutrition as an important option when parenteral nutrition is required for extended periods of time," the authors concluded.

Parenteral nutrition-associated cholestasis can develop in up to 35% of premature infants by 1 month of age and be as high as 67% by 3 months of age. The mortality rate is 3%-14% overall, and even higher in infants with short bowel syndrome.

Cyclic parenteral nutrition (PN) has been shown to be effective in reducing cholestasis in children and adults, but minimal data exist on its use and effects in very low birth weight (VLBW) infants, due primarily to concerns for the risk of hypoglycemia.

Theoretically, cyclic PN is thought to prevent PN-induced fatty infiltration of the liver, decrease hyperinsulinemia seen with continuous infusion of dextrose, prevent lipogenesis, and possibly reduce the respiratory quotient, noted Dr. Shareef, an associate professor of pediatrics and neonatology at Loyola University Chicago, Maywood, Ill.

The researchers enrolled 114 infants weighing no more than 1,500 g at birth, who were hemodynamically and metabolically stable and needed PN for more than 1 week. Their median gestational age was 28 weeks. Median birth weight was 1,000 g in the continuous group and 1,050 g in the cyclic group.

All infants were started on continuous total PN and then were evenly randomized beginning on day 7 to continuous PN or 20 hours of total PN and 4 hours of D10 intravenous solution with sodium, potassium, and calcium to provide the glucose infusion rate (GIR) that is within 30% of GIR in total PN. Serum glucose was checked the first 3 days at 30 and 60 minutes off total PN and 30 minutes before restarting total PN. Weekly liver and basic metabolic panels were also obtained.

Hypoglycemia, defined as a serum glucose level less than 40 mg/dL, did not occur in the cyclic group, Dr. Shareef reported in a poster.

Gastrointestinal complications were observed in eight infants in the continuous PN group and seven in the cyclic group, and gram-negative rod infections in six and eight infants, respectively.

The average number of days on total PN was 31.5 in the continuous group and 29 in the cyclic group.

"Cyclic total PN is tolerated in lower birth weight neonates when glucose infusion rate is supported during off hours," the authors wrote. "Further study is needed to determine when cyclic PN should be initiated."

Dr. Shareef and her associates reported no relevant financial disclosures.

MADISON, WIS.  – Cyclic parenteral nutrition may be a viable option in very low birth weight infants requiring parenteral nutrition for several weeks, results of a prospective, randomized trial suggest.

Among 114 neonates weighing no more than 1,500 g, the incidence of cholestasis was nearly double at 24% with continuous parenteral nutrition versus 12.5% with cyclic parenteral nutrition.

Although this did not reach statistical significance at a P value of 0.109, there was a downward trend in direct bilirubin beginning in week 7 favoring cyclic parenteral nutrition that was statistically significant by week 8 (1.4 mg/dL vs. 3.2 mg/dL, P = .042), Dr. Maliha Shareef and her colleagues reported at the annual meeting of the Midwest Society for Pediatric Research.

"While feeding advancement regimens may vary in NICUs, this study indicates cyclic parenteral nutrition as an important option when parenteral nutrition is required for extended periods of time," the authors concluded.

Parenteral nutrition-associated cholestasis can develop in up to 35% of premature infants by 1 month of age and be as high as 67% by 3 months of age. The mortality rate is 3%-14% overall, and even higher in infants with short bowel syndrome.

Cyclic parenteral nutrition (PN) has been shown to be effective in reducing cholestasis in children and adults, but minimal data exist on its use and effects in very low birth weight (VLBW) infants, due primarily to concerns for the risk of hypoglycemia.

Theoretically, cyclic PN is thought to prevent PN-induced fatty infiltration of the liver, decrease hyperinsulinemia seen with continuous infusion of dextrose, prevent lipogenesis, and possibly reduce the respiratory quotient, noted Dr. Shareef, an associate professor of pediatrics and neonatology at Loyola University Chicago, Maywood, Ill.

The researchers enrolled 114 infants weighing no more than 1,500 g at birth, who were hemodynamically and metabolically stable and needed PN for more than 1 week. Their median gestational age was 28 weeks. Median birth weight was 1,000 g in the continuous group and 1,050 g in the cyclic group.

All infants were started on continuous total PN and then were evenly randomized beginning on day 7 to continuous PN or 20 hours of total PN and 4 hours of D10 intravenous solution with sodium, potassium, and calcium to provide the glucose infusion rate (GIR) that is within 30% of GIR in total PN. Serum glucose was checked the first 3 days at 30 and 60 minutes off total PN and 30 minutes before restarting total PN. Weekly liver and basic metabolic panels were also obtained.

Hypoglycemia, defined as a serum glucose level less than 40 mg/dL, did not occur in the cyclic group, Dr. Shareef reported in a poster.

Gastrointestinal complications were observed in eight infants in the continuous PN group and seven in the cyclic group, and gram-negative rod infections in six and eight infants, respectively.

The average number of days on total PN was 31.5 in the continuous group and 29 in the cyclic group.

"Cyclic total PN is tolerated in lower birth weight neonates when glucose infusion rate is supported during off hours," the authors wrote. "Further study is needed to determine when cyclic PN should be initiated."

Dr. Shareef and her associates reported no relevant financial disclosures.

STOCKHOLM – Whether or not a woman had a hysterectomy made no impact on survival in a small phase III trial among patients with a complete response after chemoradiation, including brachytherapy, for early-stage ovarian cancer.

The primary end point of the event-free survival rate at 3 years was 72% in women who underwent extrafascial hysterectomy and 89% among those who did not (P = .17). Overall survival rates were also similar at 86% with hysterectomy and 97% without (P = .15), Dr. Philippe Morice reported at the European Multidisciplinary Cancer Congress.

"Even if our conclusion is diminished by the insufficient accrual of patients, in the analysis of 61 patients, we don’t observe any effect of completion hysterectomy on the overall and event-free survival of patients," said Dr. Morice, with the Institût de Cancérologie Gustave Roussy, Villejuif, France.

"With the development of new radiation and brachytherapy that increase the rate of local control, the place of the hysterectomy in this context is very probably disappearing during the next years," he added.

The National Federation of Cancer Campaign Centers GYNECO 02 trial was stopped in 2006 due to poor accrual after randomizing 31 women to hysterectomy after chemoradiotherapy (CRT) and 30 to CRT alone.

The two arms were well balanced, although 11 women in the hysterectomy arm had histologic residual disease in the cervix. Most of the cases were isolated cells, with three other cases having residual disease less than 1 cm and two having disease more than 1 cm, he said.

After a median follow-up of 3.8 years, 11 patients relapsed including 8 randomized to hysterectomy after CRT and 3 randomized to CRT alone.

In the CRT-alone arm, the site of first recurrence was centropelvic alone in two patients and distant without pelvic or nodal involvement in one, he said.

In the hysterectomy arm, the site of recurrence for one patient each was centropelvic alone, centropelvic plus nodal, pelvic node and distant, paraaortic nodes alone, and distant without pelvic or nodal, with three patients having paraaortic nodal involvement and distant recurrence.

"For the patient that undergoes complete treatment with chemoradiation and brachytherapy, we can see in this trial that the problem is not the local control of the disease, but the metastatic control," he said.

"More isn’t always better," observed discussant Dr. Nicholas Reed, a consultant clinical oncologist with Beatson Oncology Centre, Gartnavel General Hospital Glasgow, Scotland.

He suggested that positron emission tomography/computed tomography and other newer imaging modalities have a role in identifying select patients in whom hysterectomy could be avoided. If hysterectomy does not have a central role to play in early ovarian cancer, he suggested that modern imaging techniques and faster computer software systems can improve radiation quality by optimizing the tumor volume to be treated and the dose to organs at risk.

The GYNECO 02 trial asked whether surgery could reduce the risk of local or locoregional relapse in women with stage IB2/II cervical cancer and no extra-pelvic disease treated with pelvic external radiation therapy at 45-50 Gy and concomitant cisplatin 40 mg/m² per week, followed by utero-vaginal brachytherapy at 15 Gy.

A parametrial or nodal boost of 10-15 Gy was possible in cases of parametrial involvement with insufficient regression at the time of brachytherapy or in those with pelvic node involvement on initial imaging, said Dr. Morice. All women had a complete clinical and radiological response, based on magnetic resonance imaging, 6 to 8 weeks after brachytherapy.

The joint congress was sponsored by the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The study was funded by the Federation Nationale des Centres de Lutte Contre le Cancer.

STOCKHOLM – Whether or not a woman had a hysterectomy made no impact on survival in a small phase III trial among patients with a complete response after chemoradiation, including brachytherapy, for early-stage ovarian cancer.

The primary end point of the event-free survival rate at 3 years was 72% in women who underwent extrafascial hysterectomy and 89% among those who did not (P = .17). Overall survival rates were also similar at 86% with hysterectomy and 97% without (P = .15), Dr. Philippe Morice reported at the European Multidisciplinary Cancer Congress.

"Even if our conclusion is diminished by the insufficient accrual of patients, in the analysis of 61 patients, we don’t observe any effect of completion hysterectomy on the overall and event-free survival of patients," said Dr. Morice, with the Institût de Cancérologie Gustave Roussy, Villejuif, France.

"With the development of new radiation and brachytherapy that increase the rate of local control, the place of the hysterectomy in this context is very probably disappearing during the next years," he added.

The National Federation of Cancer Campaign Centers GYNECO 02 trial was stopped in 2006 due to poor accrual after randomizing 31 women to hysterectomy after chemoradiotherapy (CRT) and 30 to CRT alone.

The two arms were well balanced, although 11 women in the hysterectomy arm had histologic residual disease in the cervix. Most of the cases were isolated cells, with three other cases having residual disease less than 1 cm and two having disease more than 1 cm, he said.

After a median follow-up of 3.8 years, 11 patients relapsed including 8 randomized to hysterectomy after CRT and 3 randomized to CRT alone.

In the CRT-alone arm, the site of first recurrence was centropelvic alone in two patients and distant without pelvic or nodal involvement in one, he said.

In the hysterectomy arm, the site of recurrence for one patient each was centropelvic alone, centropelvic plus nodal, pelvic node and distant, paraaortic nodes alone, and distant without pelvic or nodal, with three patients having paraaortic nodal involvement and distant recurrence.

"For the patient that undergoes complete treatment with chemoradiation and brachytherapy, we can see in this trial that the problem is not the local control of the disease, but the metastatic control," he said.

"More isn’t always better," observed discussant Dr. Nicholas Reed, a consultant clinical oncologist with Beatson Oncology Centre, Gartnavel General Hospital Glasgow, Scotland.

He suggested that positron emission tomography/computed tomography and other newer imaging modalities have a role in identifying select patients in whom hysterectomy could be avoided. If hysterectomy does not have a central role to play in early ovarian cancer, he suggested that modern imaging techniques and faster computer software systems can improve radiation quality by optimizing the tumor volume to be treated and the dose to organs at risk.

The GYNECO 02 trial asked whether surgery could reduce the risk of local or locoregional relapse in women with stage IB2/II cervical cancer and no extra-pelvic disease treated with pelvic external radiation therapy at 45-50 Gy and concomitant cisplatin 40 mg/m² per week, followed by utero-vaginal brachytherapy at 15 Gy.

A parametrial or nodal boost of 10-15 Gy was possible in cases of parametrial involvement with insufficient regression at the time of brachytherapy or in those with pelvic node involvement on initial imaging, said Dr. Morice. All women had a complete clinical and radiological response, based on magnetic resonance imaging, 6 to 8 weeks after brachytherapy.

The joint congress was sponsored by the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The study was funded by the Federation Nationale des Centres de Lutte Contre le Cancer.

STOCKHOLM – Whether or not a woman had a hysterectomy made no impact on survival in a small phase III trial among patients with a complete response after chemoradiation, including brachytherapy, for early-stage ovarian cancer.

The primary end point of the event-free survival rate at 3 years was 72% in women who underwent extrafascial hysterectomy and 89% among those who did not (P = .17). Overall survival rates were also similar at 86% with hysterectomy and 97% without (P = .15), Dr. Philippe Morice reported at the European Multidisciplinary Cancer Congress.

"Even if our conclusion is diminished by the insufficient accrual of patients, in the analysis of 61 patients, we don’t observe any effect of completion hysterectomy on the overall and event-free survival of patients," said Dr. Morice, with the Institût de Cancérologie Gustave Roussy, Villejuif, France.

"With the development of new radiation and brachytherapy that increase the rate of local control, the place of the hysterectomy in this context is very probably disappearing during the next years," he added.

The National Federation of Cancer Campaign Centers GYNECO 02 trial was stopped in 2006 due to poor accrual after randomizing 31 women to hysterectomy after chemoradiotherapy (CRT) and 30 to CRT alone.

The two arms were well balanced, although 11 women in the hysterectomy arm had histologic residual disease in the cervix. Most of the cases were isolated cells, with three other cases having residual disease less than 1 cm and two having disease more than 1 cm, he said.

After a median follow-up of 3.8 years, 11 patients relapsed including 8 randomized to hysterectomy after CRT and 3 randomized to CRT alone.

In the CRT-alone arm, the site of first recurrence was centropelvic alone in two patients and distant without pelvic or nodal involvement in one, he said.

In the hysterectomy arm, the site of recurrence for one patient each was centropelvic alone, centropelvic plus nodal, pelvic node and distant, paraaortic nodes alone, and distant without pelvic or nodal, with three patients having paraaortic nodal involvement and distant recurrence.

"For the patient that undergoes complete treatment with chemoradiation and brachytherapy, we can see in this trial that the problem is not the local control of the disease, but the metastatic control," he said.

"More isn’t always better," observed discussant Dr. Nicholas Reed, a consultant clinical oncologist with Beatson Oncology Centre, Gartnavel General Hospital Glasgow, Scotland.

He suggested that positron emission tomography/computed tomography and other newer imaging modalities have a role in identifying select patients in whom hysterectomy could be avoided. If hysterectomy does not have a central role to play in early ovarian cancer, he suggested that modern imaging techniques and faster computer software systems can improve radiation quality by optimizing the tumor volume to be treated and the dose to organs at risk.

The GYNECO 02 trial asked whether surgery could reduce the risk of local or locoregional relapse in women with stage IB2/II cervical cancer and no extra-pelvic disease treated with pelvic external radiation therapy at 45-50 Gy and concomitant cisplatin 40 mg/m² per week, followed by utero-vaginal brachytherapy at 15 Gy.

A parametrial or nodal boost of 10-15 Gy was possible in cases of parametrial involvement with insufficient regression at the time of brachytherapy or in those with pelvic node involvement on initial imaging, said Dr. Morice. All women had a complete clinical and radiological response, based on magnetic resonance imaging, 6 to 8 weeks after brachytherapy.

The joint congress was sponsored by the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

The study was funded by the Federation Nationale des Centres de Lutte Contre le Cancer.

STOCKHOLM – Denosumab prolongs bone metastasis-free survival across a variety of nonmetastatic, castrate-resistant prostate cancer subgroups, according to subanalyses of a phase III study.

Denosumab (Xgeva) improved bone metastasis-free survival compared with placebo in men with dual prostate-specific antigen risk factors (hazard ratio, 0.83; P = .07), a single PSA risk factor (HR, 0.87; P = .20), a Gleason score of 2-7 (HR, 0.85, P = .12), and Gleason score of 8-10 (HR, 0.81; P = .10).

The advantage with denosumab was observed regardless of patient age, geographic region, or race, Dr. Stephane Oudard said at the European Multidisciplinary Cancer Congress.

Overall, the primary end point of bone metastasis-free survival was increased from 25.2 months with placebo to 29.5 months with denosumab. This corresponds to a relative risk reduction of 15% (hazard ratio, 0.85; P = .028).

Dr. Oudard pointed out that nearly all men with prostate cancer develop bone metastases, and that this is "the first randomized study to demonstrate that targeting bone microenvironment prevents bone metastasis in men with prostate cancer."

Denosumab is a monoclonal antibody that inhibits RANK ligand, a key mediator of bone osteoclast activity. The drug was approved in 2010 for the treatment of postmenopausal osteoporosis under the trade name Prolia, and later that year for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

In September 2011, two new indications were added for denosumab: to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, or adjuvant aromatase inhibitor therapy for breast cancer.

The phase III denosumab 147 study evenly randomized 1,432 men with nonmetastatic, castrate-resistant prostate cancer to monthly subcutaneous denosumab 120 mg or placebo. Bone metastases were detected by bone scan and confirmed by scintigraphy.

"[This is] the first randomized study to demonstrate that targeting bone micro-environment prevents bone metastasis in men with prostate cancer."

The men were at high risk of developing bone metastasis as defined by a PSA of 8.0 ng/mL for 3 months prior to randomization or a PSA doubling time of 10 months or less. These dual PSA risk factors were present in 48% of the men. At least one-third of the men had a Gleason score of 8 or more at diagnosis.

The median time from diagnosis was 6 years and duration of androgen-deprivation therapy 4 years, said Dr. Oudard, chief of oncology at Georges Pompidou Hospital in Paris.

Denosumab significantly delayed the time to symptomatic bone metastases (HR, 0.67; P = .01), which translates into a 33% relative risk reduction. Similar benefits were observed for this end point across all disease and patient demographic characteristics, he said.

The overall results of the trial were reported earlier this year at the American Urological Association meeting. Despite delaying bone metastases, patients taking denosumab did not live longer than did those given placebo. Median overall survival was approximately 44 months in both groups (HR, 1.01; P = .91).

Serious adverse event rates were nearly identical at 46% in each arm; hypocalcemia was higher in the denosumab group at 1.7% vs. 0.3% with placebo. Another side effect, osteonecrosis of the jaw, was also slightly increased with denosumab at a cumulative incidence of 1.1% in year 1, 2.9% in year 2, and 4.2% in year 3 vs. 0% for all three years in the placebo group, Dr. Oudard said at the meeting, a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Invited discussant Dr. Joaquim Bellmunt, with Hospital Valle de Hebron in Barcelona, said delaying the development of bone metastasis in men with castrate-resistant prostate cancer represents an important unmet medical need, and that screening for bone metastasis is often inadequate in clinical practice.

He went on to say that long-term quality of life data are needed, since the study showed only that denosumab prolongs the period before metastasis, where the patients’ quality of life has not yet suffered to a great extent.

Finally, Dr. Bellmunt took issue with the lack of survival benefit with denosumab, observing that patients with bone metastases have an almost five-time higher risk of death compared with those patients without.

Prevention of skeletal-related events and pain control are important in multimodality treatment of bone metastasis, he said, but "I want to stress that survival and quality of life is critical in these patients."

The study was funded by Amgen Inc. Disclosures were not presented at the meeting.

Christine Kilgore contributed to this report.

STOCKHOLM – Denosumab prolongs bone metastasis-free survival across a variety of nonmetastatic, castrate-resistant prostate cancer subgroups, according to subanalyses of a phase III study.

Denosumab (Xgeva) improved bone metastasis-free survival compared with placebo in men with dual prostate-specific antigen risk factors (hazard ratio, 0.83; P = .07), a single PSA risk factor (HR, 0.87; P = .20), a Gleason score of 2-7 (HR, 0.85, P = .12), and Gleason score of 8-10 (HR, 0.81; P = .10).

The advantage with denosumab was observed regardless of patient age, geographic region, or race, Dr. Stephane Oudard said at the European Multidisciplinary Cancer Congress.

Overall, the primary end point of bone metastasis-free survival was increased from 25.2 months with placebo to 29.5 months with denosumab. This corresponds to a relative risk reduction of 15% (hazard ratio, 0.85; P = .028).

Dr. Oudard pointed out that nearly all men with prostate cancer develop bone metastases, and that this is "the first randomized study to demonstrate that targeting bone microenvironment prevents bone metastasis in men with prostate cancer."

Denosumab is a monoclonal antibody that inhibits RANK ligand, a key mediator of bone osteoclast activity. The drug was approved in 2010 for the treatment of postmenopausal osteoporosis under the trade name Prolia, and later that year for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

In September 2011, two new indications were added for denosumab: to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, or adjuvant aromatase inhibitor therapy for breast cancer.

The phase III denosumab 147 study evenly randomized 1,432 men with nonmetastatic, castrate-resistant prostate cancer to monthly subcutaneous denosumab 120 mg or placebo. Bone metastases were detected by bone scan and confirmed by scintigraphy.

"[This is] the first randomized study to demonstrate that targeting bone micro-environment prevents bone metastasis in men with prostate cancer."

The men were at high risk of developing bone metastasis as defined by a PSA of 8.0 ng/mL for 3 months prior to randomization or a PSA doubling time of 10 months or less. These dual PSA risk factors were present in 48% of the men. At least one-third of the men had a Gleason score of 8 or more at diagnosis.

The median time from diagnosis was 6 years and duration of androgen-deprivation therapy 4 years, said Dr. Oudard, chief of oncology at Georges Pompidou Hospital in Paris.

Denosumab significantly delayed the time to symptomatic bone metastases (HR, 0.67; P = .01), which translates into a 33% relative risk reduction. Similar benefits were observed for this end point across all disease and patient demographic characteristics, he said.

The overall results of the trial were reported earlier this year at the American Urological Association meeting. Despite delaying bone metastases, patients taking denosumab did not live longer than did those given placebo. Median overall survival was approximately 44 months in both groups (HR, 1.01; P = .91).

Serious adverse event rates were nearly identical at 46% in each arm; hypocalcemia was higher in the denosumab group at 1.7% vs. 0.3% with placebo. Another side effect, osteonecrosis of the jaw, was also slightly increased with denosumab at a cumulative incidence of 1.1% in year 1, 2.9% in year 2, and 4.2% in year 3 vs. 0% for all three years in the placebo group, Dr. Oudard said at the meeting, a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Invited discussant Dr. Joaquim Bellmunt, with Hospital Valle de Hebron in Barcelona, said delaying the development of bone metastasis in men with castrate-resistant prostate cancer represents an important unmet medical need, and that screening for bone metastasis is often inadequate in clinical practice.

He went on to say that long-term quality of life data are needed, since the study showed only that denosumab prolongs the period before metastasis, where the patients’ quality of life has not yet suffered to a great extent.

Finally, Dr. Bellmunt took issue with the lack of survival benefit with denosumab, observing that patients with bone metastases have an almost five-time higher risk of death compared with those patients without.

Prevention of skeletal-related events and pain control are important in multimodality treatment of bone metastasis, he said, but "I want to stress that survival and quality of life is critical in these patients."

The study was funded by Amgen Inc. Disclosures were not presented at the meeting.

Christine Kilgore contributed to this report.

STOCKHOLM – Denosumab prolongs bone metastasis-free survival across a variety of nonmetastatic, castrate-resistant prostate cancer subgroups, according to subanalyses of a phase III study.

Denosumab (Xgeva) improved bone metastasis-free survival compared with placebo in men with dual prostate-specific antigen risk factors (hazard ratio, 0.83; P = .07), a single PSA risk factor (HR, 0.87; P = .20), a Gleason score of 2-7 (HR, 0.85, P = .12), and Gleason score of 8-10 (HR, 0.81; P = .10).

The advantage with denosumab was observed regardless of patient age, geographic region, or race, Dr. Stephane Oudard said at the European Multidisciplinary Cancer Congress.

Overall, the primary end point of bone metastasis-free survival was increased from 25.2 months with placebo to 29.5 months with denosumab. This corresponds to a relative risk reduction of 15% (hazard ratio, 0.85; P = .028).

Dr. Oudard pointed out that nearly all men with prostate cancer develop bone metastases, and that this is "the first randomized study to demonstrate that targeting bone microenvironment prevents bone metastasis in men with prostate cancer."

Denosumab is a monoclonal antibody that inhibits RANK ligand, a key mediator of bone osteoclast activity. The drug was approved in 2010 for the treatment of postmenopausal osteoporosis under the trade name Prolia, and later that year for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

In September 2011, two new indications were added for denosumab: to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, or adjuvant aromatase inhibitor therapy for breast cancer.

The phase III denosumab 147 study evenly randomized 1,432 men with nonmetastatic, castrate-resistant prostate cancer to monthly subcutaneous denosumab 120 mg or placebo. Bone metastases were detected by bone scan and confirmed by scintigraphy.

"[This is] the first randomized study to demonstrate that targeting bone micro-environment prevents bone metastasis in men with prostate cancer."

The men were at high risk of developing bone metastasis as defined by a PSA of 8.0 ng/mL for 3 months prior to randomization or a PSA doubling time of 10 months or less. These dual PSA risk factors were present in 48% of the men. At least one-third of the men had a Gleason score of 8 or more at diagnosis.

The median time from diagnosis was 6 years and duration of androgen-deprivation therapy 4 years, said Dr. Oudard, chief of oncology at Georges Pompidou Hospital in Paris.

Denosumab significantly delayed the time to symptomatic bone metastases (HR, 0.67; P = .01), which translates into a 33% relative risk reduction. Similar benefits were observed for this end point across all disease and patient demographic characteristics, he said.

The overall results of the trial were reported earlier this year at the American Urological Association meeting. Despite delaying bone metastases, patients taking denosumab did not live longer than did those given placebo. Median overall survival was approximately 44 months in both groups (HR, 1.01; P = .91).

Serious adverse event rates were nearly identical at 46% in each arm; hypocalcemia was higher in the denosumab group at 1.7% vs. 0.3% with placebo. Another side effect, osteonecrosis of the jaw, was also slightly increased with denosumab at a cumulative incidence of 1.1% in year 1, 2.9% in year 2, and 4.2% in year 3 vs. 0% for all three years in the placebo group, Dr. Oudard said at the meeting, a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Invited discussant Dr. Joaquim Bellmunt, with Hospital Valle de Hebron in Barcelona, said delaying the development of bone metastasis in men with castrate-resistant prostate cancer represents an important unmet medical need, and that screening for bone metastasis is often inadequate in clinical practice.

He went on to say that long-term quality of life data are needed, since the study showed only that denosumab prolongs the period before metastasis, where the patients’ quality of life has not yet suffered to a great extent.

Finally, Dr. Bellmunt took issue with the lack of survival benefit with denosumab, observing that patients with bone metastases have an almost five-time higher risk of death compared with those patients without.

Prevention of skeletal-related events and pain control are important in multimodality treatment of bone metastasis, he said, but "I want to stress that survival and quality of life is critical in these patients."

The study was funded by Amgen Inc. Disclosures were not presented at the meeting.

Christine Kilgore contributed to this report.

STOCKHOLM – Celecoxib shows no evidence of activity when it’s added to hormone therapy in men with metastatic or high-risk nonmetastatic prostate cancer, according to first results from the six-arm STAMPEDE trial.

The use of celecoxib (Celebrex) plus hormone therapy did not extend failure-free survival, compared with hormone therapy alone (adjusted hazard ratio, 0.98). The 305 failure-free survival events were largely prostate-specific antigen (PSA) failures in 78% of both groups and new metastases in 16% of both groups, Dr. Noel W. Clarke reported on behalf of the STAMPEDE investigators at the European Multidisciplinary Cancer Congress.

Other failure-free survival events were local progression in 2% of both groups, lymph node invasion in 2% of the hormone-only group and in 0% of the hormone-plus-celecoxib group, and prostate cancer-related death in 1% and 4%, respectively.

Toxicity among the 874 patients was not significantly different, with 23% of the hormone-only group and 25% of the celecoxib group experiencing any grade 3-5 toxicity, he said.

Based on the lack of benefit, accrual to the celecoxib arm was halted. Celecoxib treatment was also discontinued in a second arm of the trial that coupled the cyclooxygenase-2 (COX-2) inhibitor with hormone therapy and zoledronic acid (Zometa), said Dr. Clarke, honorary professor of urological cancer at the University of Manchester (England).

STAMPEDE uses a novel and ambitious multiarm, multistage design to simultaneously assess whether the addition of one or two of three agents – docetaxel (Taxotere), zoledronic acid, or celecoxib – improves overall survival in men who have metastatic or high-risk nonmetastatic prostate cancer and are starting long-term hormone therapy. Accrual continues in the remaining arms, and assessment of a new agent, abiraterone (Zytiga), is now underway, he said.

The rationale for using celecoxib is threefold: COX-2 is associated with carcinogenesis in prostate and other cancers, case-control studies show a reduction in the risk of prostate cancer associated with nonsteroidal drugs, and pathological studies show that COX-2 is up-regulated in prostate cancer, Dr. Clarke explained.

Invited discussant Dr. Karim Fizazi of Institut de Cancérologie Gustave Roussy in Villejuif, France, said that the rationale for using celecoxib is much weaker than that for the other agents. Docetaxel has demonstrated an overall survival benefit in castrate-resistant prostate cancer, whereas zoledronic acid is known to delay skeletal-related events in this setting.

He also faulted the study’s heterogeneous population and the inclusion of PSA failure in the definition of failure-free survival, because active agents – such as zoledronic acid, denosumab (Xgeva), and sipuleucel-T (Provenge) – do not typically induce a PSA decrease.

Strengths of STAMPEDE include its ability to accrue almost 70 patients per month, its flexibility in dropping an arm if a drug is inactive rather than starting a separate new trial, and its homogeneous endocrine therapy that included 98% of patients taking LHRH (luteinizing hormone-releasing hormone) agonists, Dr. Fizazi said.

STAMPEDE has randomized 2,043 patients overall, including 583 to standard hormone therapy and 291 to hormone therapy plus celecoxib 400 mg twice daily for up to 1 year, or until a failure-free survival event. The median age in the current analysis was 65 years, and 77% had a performance status of 0. The median PSA was 67 ng/mL in the hormone group and 58 ng/mL in the celecoxib group.

Surprisingly, just 42% of patients who were randomized to celecoxib completed treatment, with a significant number dropping off within the first year because of either disease progression (28%) or excessive toxicity (11%), Dr. Clarke said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).

STAMPEDE is led by Dr. Nicholas James of Queen Elizabeth Hospital in Birmingham, England, and is sponsored by the U.K. Medical Research Council, Cancer Research U.K., Novartis, Sanofi-Aventis, and Pfizer. Dr. Clarke reported no conflicts of interest, although several coauthors are employed by the Medical Research Council. Dr. Fizazi reports serving on advisory boards or as a speaker for Amgen, Dendreon, Exelixis, Janssen, Novartis, and Sanofi-Aventis.

STOCKHOLM – Celecoxib shows no evidence of activity when it’s added to hormone therapy in men with metastatic or high-risk nonmetastatic prostate cancer, according to first results from the six-arm STAMPEDE trial.

The use of celecoxib (Celebrex) plus hormone therapy did not extend failure-free survival, compared with hormone therapy alone (adjusted hazard ratio, 0.98). The 305 failure-free survival events were largely prostate-specific antigen (PSA) failures in 78% of both groups and new metastases in 16% of both groups, Dr. Noel W. Clarke reported on behalf of the STAMPEDE investigators at the European Multidisciplinary Cancer Congress.

Other failure-free survival events were local progression in 2% of both groups, lymph node invasion in 2% of the hormone-only group and in 0% of the hormone-plus-celecoxib group, and prostate cancer-related death in 1% and 4%, respectively.

Toxicity among the 874 patients was not significantly different, with 23% of the hormone-only group and 25% of the celecoxib group experiencing any grade 3-5 toxicity, he said.

Based on the lack of benefit, accrual to the celecoxib arm was halted. Celecoxib treatment was also discontinued in a second arm of the trial that coupled the cyclooxygenase-2 (COX-2) inhibitor with hormone therapy and zoledronic acid (Zometa), said Dr. Clarke, honorary professor of urological cancer at the University of Manchester (England).

STAMPEDE uses a novel and ambitious multiarm, multistage design to simultaneously assess whether the addition of one or two of three agents – docetaxel (Taxotere), zoledronic acid, or celecoxib – improves overall survival in men who have metastatic or high-risk nonmetastatic prostate cancer and are starting long-term hormone therapy. Accrual continues in the remaining arms, and assessment of a new agent, abiraterone (Zytiga), is now underway, he said.

The rationale for using celecoxib is threefold: COX-2 is associated with carcinogenesis in prostate and other cancers, case-control studies show a reduction in the risk of prostate cancer associated with nonsteroidal drugs, and pathological studies show that COX-2 is up-regulated in prostate cancer, Dr. Clarke explained.

Invited discussant Dr. Karim Fizazi of Institut de Cancérologie Gustave Roussy in Villejuif, France, said that the rationale for using celecoxib is much weaker than that for the other agents. Docetaxel has demonstrated an overall survival benefit in castrate-resistant prostate cancer, whereas zoledronic acid is known to delay skeletal-related events in this setting.

He also faulted the study’s heterogeneous population and the inclusion of PSA failure in the definition of failure-free survival, because active agents – such as zoledronic acid, denosumab (Xgeva), and sipuleucel-T (Provenge) – do not typically induce a PSA decrease.

Strengths of STAMPEDE include its ability to accrue almost 70 patients per month, its flexibility in dropping an arm if a drug is inactive rather than starting a separate new trial, and its homogeneous endocrine therapy that included 98% of patients taking LHRH (luteinizing hormone-releasing hormone) agonists, Dr. Fizazi said.

STAMPEDE has randomized 2,043 patients overall, including 583 to standard hormone therapy and 291 to hormone therapy plus celecoxib 400 mg twice daily for up to 1 year, or until a failure-free survival event. The median age in the current analysis was 65 years, and 77% had a performance status of 0. The median PSA was 67 ng/mL in the hormone group and 58 ng/mL in the celecoxib group.

Surprisingly, just 42% of patients who were randomized to celecoxib completed treatment, with a significant number dropping off within the first year because of either disease progression (28%) or excessive toxicity (11%), Dr. Clarke said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).

STAMPEDE is led by Dr. Nicholas James of Queen Elizabeth Hospital in Birmingham, England, and is sponsored by the U.K. Medical Research Council, Cancer Research U.K., Novartis, Sanofi-Aventis, and Pfizer. Dr. Clarke reported no conflicts of interest, although several coauthors are employed by the Medical Research Council. Dr. Fizazi reports serving on advisory boards or as a speaker for Amgen, Dendreon, Exelixis, Janssen, Novartis, and Sanofi-Aventis.

STOCKHOLM – Celecoxib shows no evidence of activity when it’s added to hormone therapy in men with metastatic or high-risk nonmetastatic prostate cancer, according to first results from the six-arm STAMPEDE trial.

The use of celecoxib (Celebrex) plus hormone therapy did not extend failure-free survival, compared with hormone therapy alone (adjusted hazard ratio, 0.98). The 305 failure-free survival events were largely prostate-specific antigen (PSA) failures in 78% of both groups and new metastases in 16% of both groups, Dr. Noel W. Clarke reported on behalf of the STAMPEDE investigators at the European Multidisciplinary Cancer Congress.

Other failure-free survival events were local progression in 2% of both groups, lymph node invasion in 2% of the hormone-only group and in 0% of the hormone-plus-celecoxib group, and prostate cancer-related death in 1% and 4%, respectively.

Toxicity among the 874 patients was not significantly different, with 23% of the hormone-only group and 25% of the celecoxib group experiencing any grade 3-5 toxicity, he said.

Based on the lack of benefit, accrual to the celecoxib arm was halted. Celecoxib treatment was also discontinued in a second arm of the trial that coupled the cyclooxygenase-2 (COX-2) inhibitor with hormone therapy and zoledronic acid (Zometa), said Dr. Clarke, honorary professor of urological cancer at the University of Manchester (England).

STAMPEDE uses a novel and ambitious multiarm, multistage design to simultaneously assess whether the addition of one or two of three agents – docetaxel (Taxotere), zoledronic acid, or celecoxib – improves overall survival in men who have metastatic or high-risk nonmetastatic prostate cancer and are starting long-term hormone therapy. Accrual continues in the remaining arms, and assessment of a new agent, abiraterone (Zytiga), is now underway, he said.

The rationale for using celecoxib is threefold: COX-2 is associated with carcinogenesis in prostate and other cancers, case-control studies show a reduction in the risk of prostate cancer associated with nonsteroidal drugs, and pathological studies show that COX-2 is up-regulated in prostate cancer, Dr. Clarke explained.

Invited discussant Dr. Karim Fizazi of Institut de Cancérologie Gustave Roussy in Villejuif, France, said that the rationale for using celecoxib is much weaker than that for the other agents. Docetaxel has demonstrated an overall survival benefit in castrate-resistant prostate cancer, whereas zoledronic acid is known to delay skeletal-related events in this setting.

He also faulted the study’s heterogeneous population and the inclusion of PSA failure in the definition of failure-free survival, because active agents – such as zoledronic acid, denosumab (Xgeva), and sipuleucel-T (Provenge) – do not typically induce a PSA decrease.

Strengths of STAMPEDE include its ability to accrue almost 70 patients per month, its flexibility in dropping an arm if a drug is inactive rather than starting a separate new trial, and its homogeneous endocrine therapy that included 98% of patients taking LHRH (luteinizing hormone-releasing hormone) agonists, Dr. Fizazi said.

STAMPEDE has randomized 2,043 patients overall, including 583 to standard hormone therapy and 291 to hormone therapy plus celecoxib 400 mg twice daily for up to 1 year, or until a failure-free survival event. The median age in the current analysis was 65 years, and 77% had a performance status of 0. The median PSA was 67 ng/mL in the hormone group and 58 ng/mL in the celecoxib group.

Surprisingly, just 42% of patients who were randomized to celecoxib completed treatment, with a significant number dropping off within the first year because of either disease progression (28%) or excessive toxicity (11%), Dr. Clarke said at the joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).

STAMPEDE is led by Dr. Nicholas James of Queen Elizabeth Hospital in Birmingham, England, and is sponsored by the U.K. Medical Research Council, Cancer Research U.K., Novartis, Sanofi-Aventis, and Pfizer. Dr. Clarke reported no conflicts of interest, although several coauthors are employed by the Medical Research Council. Dr. Fizazi reports serving on advisory boards or as a speaker for Amgen, Dendreon, Exelixis, Janssen, Novartis, and Sanofi-Aventis.

STOCKHOLM – Laparoscopic surgery offers the same radical resection for noninvasive rectal cancer as does open surgery, according to short-term outcomes of the randomized, noninferiority phase III COLOR II trial.

The circumferential resection margin, described as the most important parameter for rectal cancer surgery, was 1.3 cm after laparoscopic and open surgery (P = .16). The distal margin was similar at 3.6 cm (P = .68).

The proximal margin was 17.0 cm in the laparoscopic group and 19.0 cm in the open group. The difference was statistically significant (P less than .001), but "clinically, totally irrelevant since a 17-cm margin is wide enough for a safe tumor resection," lead author Dr. H. Jaap Bonjer said at the European Multidisciplinary Cancer Congress.

COLOR II (Colorectal Cancer Laparoscopic or Open Resection) sought to answer whether laparoscopic total mesorectal excision is as oncologically safe as open surgery is. Removing the entire mesorectum, or fatty tissue around the rectum, is important because the radial spread of rectal cancer is more prominent than is longitudinal spread, explained Dr. Bonjer of the surgery department at Vrije University Medical Centre, Amsterdam.

Researchers at 30 centers in eight countries, including Canada, randomized 1,103 patients with a single rectal carcinoma within 15 cm of the anal verge, staged T1, T2, or T3 with a margin to the endopelvic fascia greater than 2 mm, to laparoscopic or open surgery. The analysis included 699 patients in the laparoscopic arm and 345 in the open surgery arm.

The technically demanding nature of laparoscopic surgery resulted in a longer operating time than with open surgery (median 240 minutes vs. 188 minutes, P less than .001), but blood loss was cut in half (median 200 mL vs. 400 mL, P less than .001), Dr. Bonjer said.

The number of lymph nodes harvested was similar at 13 in the laparoscopic group and 14 in the open group.

The overall positive resection margin rate, defined as less than 2 mm, was 9% in the laparoscopic group and 10% in the open group (P = .078), Dr. Bonjer said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Subgroup analyses showed similar positive resection margin rates in the upper rectum (10% vs. 9%, P = .92) and middle rectum (9% vs. 3%, P = .073), but a significantly better rate in the lower rectum after laparoscopic surgery at 9% vs. 21% after open surgery (P = .013).

The laparoscopic group also had improved postoperative recovery compared with the open group including a shorter time to first bowel movement (2.9 days vs. 3.7 days, P = .001), time to intake of 1 liter of fluid (2.6 days vs. 2.8 days P = .006) and hospital stay (11.9 days vs. 12.1 days, P = .037), he said.

Anastomotic leakage occurred in 7% of patients after laparoscopic surgery and 6% after open surgery (P = .63). One-third of patients had a diverting ileostomy.

Mortality rates within 28 days after surgery did not differ between the laparoscopic and open groups (1.1% vs. 1.7%, P = .41), nor did morbidity (39.5% vs. 36.5%, P = .28), Dr. Bonjer said.

Dr. Peter Naredi, invited discussant and president of the European Society of Surgical Oncology, said COLOR II was very well performed, and that the large number of laparoscopic patients "will make a huge impact on the results of how good laparoscopic surgery is versus open surgery" when added to the current database.

He highlighted a meta-analysis published this spring of six randomized trials enrolling 1,033 patients that showed no difference between the two techniques with regard to number of lymph nodes harvested, involvement of the circumferential resection margin, 3-year-overall survival, and disease-free survival (Int. J. Colorectal. Dis. 2011;26:415-21).

Dr. Naredi, chair of surgery at Umeå (Sweden) University, expressed concern, however, about the 21% positive resection margin rates in the lower rectum for the open group, and said this would likely convert into differences in local recurrence between the two groups. He also stressed the importance of standardization when evaluating multimodal treatments, and pointed out that preoperative radiotherapy was used in 72% of the lower rectal cancer patients treated with laparoscopy and only 63% treated with open surgery.

Ethicon EndoSurgery supported the trial. No individual disclosures were presented.

STOCKHOLM – Laparoscopic surgery offers the same radical resection for noninvasive rectal cancer as does open surgery, according to short-term outcomes of the randomized, noninferiority phase III COLOR II trial.

The circumferential resection margin, described as the most important parameter for rectal cancer surgery, was 1.3 cm after laparoscopic and open surgery (P = .16). The distal margin was similar at 3.6 cm (P = .68).

The proximal margin was 17.0 cm in the laparoscopic group and 19.0 cm in the open group. The difference was statistically significant (P less than .001), but "clinically, totally irrelevant since a 17-cm margin is wide enough for a safe tumor resection," lead author Dr. H. Jaap Bonjer said at the European Multidisciplinary Cancer Congress.

COLOR II (Colorectal Cancer Laparoscopic or Open Resection) sought to answer whether laparoscopic total mesorectal excision is as oncologically safe as open surgery is. Removing the entire mesorectum, or fatty tissue around the rectum, is important because the radial spread of rectal cancer is more prominent than is longitudinal spread, explained Dr. Bonjer of the surgery department at Vrije University Medical Centre, Amsterdam.

Researchers at 30 centers in eight countries, including Canada, randomized 1,103 patients with a single rectal carcinoma within 15 cm of the anal verge, staged T1, T2, or T3 with a margin to the endopelvic fascia greater than 2 mm, to laparoscopic or open surgery. The analysis included 699 patients in the laparoscopic arm and 345 in the open surgery arm.

The technically demanding nature of laparoscopic surgery resulted in a longer operating time than with open surgery (median 240 minutes vs. 188 minutes, P less than .001), but blood loss was cut in half (median 200 mL vs. 400 mL, P less than .001), Dr. Bonjer said.

The number of lymph nodes harvested was similar at 13 in the laparoscopic group and 14 in the open group.

The overall positive resection margin rate, defined as less than 2 mm, was 9% in the laparoscopic group and 10% in the open group (P = .078), Dr. Bonjer said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Subgroup analyses showed similar positive resection margin rates in the upper rectum (10% vs. 9%, P = .92) and middle rectum (9% vs. 3%, P = .073), but a significantly better rate in the lower rectum after laparoscopic surgery at 9% vs. 21% after open surgery (P = .013).

The laparoscopic group also had improved postoperative recovery compared with the open group including a shorter time to first bowel movement (2.9 days vs. 3.7 days, P = .001), time to intake of 1 liter of fluid (2.6 days vs. 2.8 days P = .006) and hospital stay (11.9 days vs. 12.1 days, P = .037), he said.

Anastomotic leakage occurred in 7% of patients after laparoscopic surgery and 6% after open surgery (P = .63). One-third of patients had a diverting ileostomy.

Mortality rates within 28 days after surgery did not differ between the laparoscopic and open groups (1.1% vs. 1.7%, P = .41), nor did morbidity (39.5% vs. 36.5%, P = .28), Dr. Bonjer said.

Dr. Peter Naredi, invited discussant and president of the European Society of Surgical Oncology, said COLOR II was very well performed, and that the large number of laparoscopic patients "will make a huge impact on the results of how good laparoscopic surgery is versus open surgery" when added to the current database.

He highlighted a meta-analysis published this spring of six randomized trials enrolling 1,033 patients that showed no difference between the two techniques with regard to number of lymph nodes harvested, involvement of the circumferential resection margin, 3-year-overall survival, and disease-free survival (Int. J. Colorectal. Dis. 2011;26:415-21).

Dr. Naredi, chair of surgery at Umeå (Sweden) University, expressed concern, however, about the 21% positive resection margin rates in the lower rectum for the open group, and said this would likely convert into differences in local recurrence between the two groups. He also stressed the importance of standardization when evaluating multimodal treatments, and pointed out that preoperative radiotherapy was used in 72% of the lower rectal cancer patients treated with laparoscopy and only 63% treated with open surgery.

Ethicon EndoSurgery supported the trial. No individual disclosures were presented.

STOCKHOLM – Laparoscopic surgery offers the same radical resection for noninvasive rectal cancer as does open surgery, according to short-term outcomes of the randomized, noninferiority phase III COLOR II trial.

The circumferential resection margin, described as the most important parameter for rectal cancer surgery, was 1.3 cm after laparoscopic and open surgery (P = .16). The distal margin was similar at 3.6 cm (P = .68).

The proximal margin was 17.0 cm in the laparoscopic group and 19.0 cm in the open group. The difference was statistically significant (P less than .001), but "clinically, totally irrelevant since a 17-cm margin is wide enough for a safe tumor resection," lead author Dr. H. Jaap Bonjer said at the European Multidisciplinary Cancer Congress.

COLOR II (Colorectal Cancer Laparoscopic or Open Resection) sought to answer whether laparoscopic total mesorectal excision is as oncologically safe as open surgery is. Removing the entire mesorectum, or fatty tissue around the rectum, is important because the radial spread of rectal cancer is more prominent than is longitudinal spread, explained Dr. Bonjer of the surgery department at Vrije University Medical Centre, Amsterdam.

Researchers at 30 centers in eight countries, including Canada, randomized 1,103 patients with a single rectal carcinoma within 15 cm of the anal verge, staged T1, T2, or T3 with a margin to the endopelvic fascia greater than 2 mm, to laparoscopic or open surgery. The analysis included 699 patients in the laparoscopic arm and 345 in the open surgery arm.

The technically demanding nature of laparoscopic surgery resulted in a longer operating time than with open surgery (median 240 minutes vs. 188 minutes, P less than .001), but blood loss was cut in half (median 200 mL vs. 400 mL, P less than .001), Dr. Bonjer said.

The number of lymph nodes harvested was similar at 13 in the laparoscopic group and 14 in the open group.

The overall positive resection margin rate, defined as less than 2 mm, was 9% in the laparoscopic group and 10% in the open group (P = .078), Dr. Bonjer said at the joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.

Subgroup analyses showed similar positive resection margin rates in the upper rectum (10% vs. 9%, P = .92) and middle rectum (9% vs. 3%, P = .073), but a significantly better rate in the lower rectum after laparoscopic surgery at 9% vs. 21% after open surgery (P = .013).

The laparoscopic group also had improved postoperative recovery compared with the open group including a shorter time to first bowel movement (2.9 days vs. 3.7 days, P = .001), time to intake of 1 liter of fluid (2.6 days vs. 2.8 days P = .006) and hospital stay (11.9 days vs. 12.1 days, P = .037), he said.

Anastomotic leakage occurred in 7% of patients after laparoscopic surgery and 6% after open surgery (P = .63). One-third of patients had a diverting ileostomy.

Mortality rates within 28 days after surgery did not differ between the laparoscopic and open groups (1.1% vs. 1.7%, P = .41), nor did morbidity (39.5% vs. 36.5%, P = .28), Dr. Bonjer said.

Dr. Peter Naredi, invited discussant and president of the European Society of Surgical Oncology, said COLOR II was very well performed, and that the large number of laparoscopic patients "will make a huge impact on the results of how good laparoscopic surgery is versus open surgery" when added to the current database.

He highlighted a meta-analysis published this spring of six randomized trials enrolling 1,033 patients that showed no difference between the two techniques with regard to number of lymph nodes harvested, involvement of the circumferential resection margin, 3-year-overall survival, and disease-free survival (Int. J. Colorectal. Dis. 2011;26:415-21).

Dr. Naredi, chair of surgery at Umeå (Sweden) University, expressed concern, however, about the 21% positive resection margin rates in the lower rectum for the open group, and said this would likely convert into differences in local recurrence between the two groups. He also stressed the importance of standardization when evaluating multimodal treatments, and pointed out that preoperative radiotherapy was used in 72% of the lower rectal cancer patients treated with laparoscopy and only 63% treated with open surgery.

Ethicon EndoSurgery supported the trial. No individual disclosures were presented.

PARIS – The heart rate lowering agent, ivabradine, significantly improved left ventricular volume indexes and left ventricular ejection fraction in patients with heart failure and systolic dysfunction, according to the findings of an echocardiography substudy of a large randomized controlled trial.

"These results suggest that ivabradine modifies disease progression in patients with heart failure receiving background therapy," Dr. Jean-Claude Tardif said at the annual congress of the European Society of Cardiology. The results are also clinically important because left ventricular enlargement and reduced ejection fraction are powerful predictors of outcomes in heart failure.

Notably, among the 411 patients analyzed, those who had the greatest reduction in heart rate had better remodeling and outcomes.

Investigators reported at last year’s congress that in SHIFT (Systolic Heart Failure Treatment With the I_f Inhibitor Ivabradine Trial), ivabradine (Procoralan), a selective I_f channel blocker, led to an 18% reduction in the composite primary end point of cardiovascular death and heart failure hospitalization, compared with placebo, in 6,558 patients with chronic heart failure, a left ventricular ejection fraction (LVEF) of 35% or less, and resting heart rate of at least 70 beats per minute (Lancet 2010;376:875-85).

In the prespecified substudy, echocardiography was used to assess left ventricular modeling in 208 patients treated with ivabradine, 5 mg twice daily, and 203 patients given placebo. Baseline background treatment included beta-blockers (92%), an ACE inhibitor/angiotensin-receptor blocker (96%), or an aldosterone antagonist (72%). Their mean LVEF was 32%.

Eight months of treatment with ivabradine resulted in a statistically significant 7 mL/m² reduction in the primary end point of left ventricular end-systolic volume index (LVESVI), compared with a 0.9 mL/m² reduction in the placebo group (P = .0002), reported Dr. Tardif, with the Montreal Heart Institute at the University of Montreal. The change in LVESVI was independent of beta-blocker use, heart failure etiology and baseline LVEF.

A reduction in LVESVI of at least 15% was observed in significantly more patients with ivabradine than placebo (38% vs. 25%, P = .005)

Ivabradine significantly improved the secondary end points of left ventricular end-diastolic volume index (-7.9 mL/m² vs. -1.8 mL/m², P = .002) and LVEF (2.4% vs. -0.1%, P = .0003), he said.

Significantly more patients experienced a clinically relevant improvement in LVEF of 5% or more with ivabradine than placebo (36% vs. 23%, P = .003).

"The significant reductions in LV volumes in favor of ivabradine were parallel with the reduction in heart rate at eight months achieved with ivabradine versus placebo [-14.7 bpm vs. -5.8 bpm, P less than .0001]," Dr. Tardif said.

Discussant Dr. Burkert Pieske, with the division of cardiology at the Medical University of Graz (Austria), said that the substudy findings underscore the importance of reverse remodeling as a marker for improved outcome, and provides solid, mechanistic data to encourage the use of ivabradine as an add-on medication in patients in sinus rhythm and a heart rate above 7 beats/minute.

"The reduction in LVESVI of about 6 mL/m² is more or less comparable with other pharmacologic interventions, and importantly it adds on to the beneficial effect of beta blockers and ACE inhibitors," he said.

In contrast to cardiac resynchronization, ivabradine can be started by every heart failure physician without great expense, Dr. Pieske and his colleague Dr. Friedrich Fruhwald, wrote in an accompanying editorial in the European Heart Journal (Eur. Heart J. 2011 Sept. 2 [doi:10.1093/eurheartj/ehr317]).

They pointed out, however, that ivabradine only works in heart failure patients with sinus rhythm and that relevant reverse modeling was seen in only a third of these patients.

"So, we have to identify the right patients we need to treat with ivabradine," said Dr. Pieske, adding that further testing is warranted in such conditions as acute heart failure or heart failure with preserved ejection fraction.

Findings from a second SHIFT substudy suggest that reduction in heart rate with ivabradine is associated with improved health-related quality of life.

At 12 months, the change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score was significantly greater in the ivabradine group than the placebo group (6.7 vs. 4.3, P less than .001).

This also was true for the KCCQ clinical summary score (5.0 vs. 3.3, P = .018), reported Dr. Inger Ekman from the Institute of Health Care Sciences, Sahlgrenska Academy in Gothenburg, Sweden. A change of 5 units is considered a clinically meaningful change in KCCQ scoring.

The magnitude of heart rate reduction with ivabradine was directly related to the degree of improvement in health-related quality of life, she said.

Among the 1,944 patients in the substudy, the incidence of cardiovascular death or heart failure hospitalization at 12 months was inversely associated with KCCQ scores.

Dr. Ekman pointed out that recommended therapies with survival benefits like beta blockers have no impact on health-related quality of life, while some therapies that improve quality of life like inotropic agents do not improve survival.

Dr. Tardif and Dr. Ekman reported that all the study’s authors have received fees, research grants or both from the study sponsor, Servier. Dr. Pieske reported having no relevant disclosures.

PARIS – The heart rate lowering agent, ivabradine, significantly improved left ventricular volume indexes and left ventricular ejection fraction in patients with heart failure and systolic dysfunction, according to the findings of an echocardiography substudy of a large randomized controlled trial.

"These results suggest that ivabradine modifies disease progression in patients with heart failure receiving background therapy," Dr. Jean-Claude Tardif said at the annual congress of the European Society of Cardiology. The results are also clinically important because left ventricular enlargement and reduced ejection fraction are powerful predictors of outcomes in heart failure.

Notably, among the 411 patients analyzed, those who had the greatest reduction in heart rate had better remodeling and outcomes.

Investigators reported at last year’s congress that in SHIFT (Systolic Heart Failure Treatment With the I_f Inhibitor Ivabradine Trial), ivabradine (Procoralan), a selective I_f channel blocker, led to an 18% reduction in the composite primary end point of cardiovascular death and heart failure hospitalization, compared with placebo, in 6,558 patients with chronic heart failure, a left ventricular ejection fraction (LVEF) of 35% or less, and resting heart rate of at least 70 beats per minute (Lancet 2010;376:875-85).

In the prespecified substudy, echocardiography was used to assess left ventricular modeling in 208 patients treated with ivabradine, 5 mg twice daily, and 203 patients given placebo. Baseline background treatment included beta-blockers (92%), an ACE inhibitor/angiotensin-receptor blocker (96%), or an aldosterone antagonist (72%). Their mean LVEF was 32%.

Eight months of treatment with ivabradine resulted in a statistically significant 7 mL/m² reduction in the primary end point of left ventricular end-systolic volume index (LVESVI), compared with a 0.9 mL/m² reduction in the placebo group (P = .0002), reported Dr. Tardif, with the Montreal Heart Institute at the University of Montreal. The change in LVESVI was independent of beta-blocker use, heart failure etiology and baseline LVEF.

A reduction in LVESVI of at least 15% was observed in significantly more patients with ivabradine than placebo (38% vs. 25%, P = .005)

Ivabradine significantly improved the secondary end points of left ventricular end-diastolic volume index (-7.9 mL/m² vs. -1.8 mL/m², P = .002) and LVEF (2.4% vs. -0.1%, P = .0003), he said.

Significantly more patients experienced a clinically relevant improvement in LVEF of 5% or more with ivabradine than placebo (36% vs. 23%, P = .003).

"The significant reductions in LV volumes in favor of ivabradine were parallel with the reduction in heart rate at eight months achieved with ivabradine versus placebo [-14.7 bpm vs. -5.8 bpm, P less than .0001]," Dr. Tardif said.

Discussant Dr. Burkert Pieske, with the division of cardiology at the Medical University of Graz (Austria), said that the substudy findings underscore the importance of reverse remodeling as a marker for improved outcome, and provides solid, mechanistic data to encourage the use of ivabradine as an add-on medication in patients in sinus rhythm and a heart rate above 7 beats/minute.

"The reduction in LVESVI of about 6 mL/m² is more or less comparable with other pharmacologic interventions, and importantly it adds on to the beneficial effect of beta blockers and ACE inhibitors," he said.

In contrast to cardiac resynchronization, ivabradine can be started by every heart failure physician without great expense, Dr. Pieske and his colleague Dr. Friedrich Fruhwald, wrote in an accompanying editorial in the European Heart Journal (Eur. Heart J. 2011 Sept. 2 [doi:10.1093/eurheartj/ehr317]).

They pointed out, however, that ivabradine only works in heart failure patients with sinus rhythm and that relevant reverse modeling was seen in only a third of these patients.

"So, we have to identify the right patients we need to treat with ivabradine," said Dr. Pieske, adding that further testing is warranted in such conditions as acute heart failure or heart failure with preserved ejection fraction.

Findings from a second SHIFT substudy suggest that reduction in heart rate with ivabradine is associated with improved health-related quality of life.

At 12 months, the change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score was significantly greater in the ivabradine group than the placebo group (6.7 vs. 4.3, P less than .001).

This also was true for the KCCQ clinical summary score (5.0 vs. 3.3, P = .018), reported Dr. Inger Ekman from the Institute of Health Care Sciences, Sahlgrenska Academy in Gothenburg, Sweden. A change of 5 units is considered a clinically meaningful change in KCCQ scoring.

The magnitude of heart rate reduction with ivabradine was directly related to the degree of improvement in health-related quality of life, she said.

Among the 1,944 patients in the substudy, the incidence of cardiovascular death or heart failure hospitalization at 12 months was inversely associated with KCCQ scores.

Dr. Ekman pointed out that recommended therapies with survival benefits like beta blockers have no impact on health-related quality of life, while some therapies that improve quality of life like inotropic agents do not improve survival.

Dr. Tardif and Dr. Ekman reported that all the study’s authors have received fees, research grants or both from the study sponsor, Servier. Dr. Pieske reported having no relevant disclosures.

PARIS – The heart rate lowering agent, ivabradine, significantly improved left ventricular volume indexes and left ventricular ejection fraction in patients with heart failure and systolic dysfunction, according to the findings of an echocardiography substudy of a large randomized controlled trial.

"These results suggest that ivabradine modifies disease progression in patients with heart failure receiving background therapy," Dr. Jean-Claude Tardif said at the annual congress of the European Society of Cardiology. The results are also clinically important because left ventricular enlargement and reduced ejection fraction are powerful predictors of outcomes in heart failure.

Notably, among the 411 patients analyzed, those who had the greatest reduction in heart rate had better remodeling and outcomes.

Investigators reported at last year’s congress that in SHIFT (Systolic Heart Failure Treatment With the I_f Inhibitor Ivabradine Trial), ivabradine (Procoralan), a selective I_f channel blocker, led to an 18% reduction in the composite primary end point of cardiovascular death and heart failure hospitalization, compared with placebo, in 6,558 patients with chronic heart failure, a left ventricular ejection fraction (LVEF) of 35% or less, and resting heart rate of at least 70 beats per minute (Lancet 2010;376:875-85).

In the prespecified substudy, echocardiography was used to assess left ventricular modeling in 208 patients treated with ivabradine, 5 mg twice daily, and 203 patients given placebo. Baseline background treatment included beta-blockers (92%), an ACE inhibitor/angiotensin-receptor blocker (96%), or an aldosterone antagonist (72%). Their mean LVEF was 32%.

Eight months of treatment with ivabradine resulted in a statistically significant 7 mL/m² reduction in the primary end point of left ventricular end-systolic volume index (LVESVI), compared with a 0.9 mL/m² reduction in the placebo group (P = .0002), reported Dr. Tardif, with the Montreal Heart Institute at the University of Montreal. The change in LVESVI was independent of beta-blocker use, heart failure etiology and baseline LVEF.

A reduction in LVESVI of at least 15% was observed in significantly more patients with ivabradine than placebo (38% vs. 25%, P = .005)

Ivabradine significantly improved the secondary end points of left ventricular end-diastolic volume index (-7.9 mL/m² vs. -1.8 mL/m², P = .002) and LVEF (2.4% vs. -0.1%, P = .0003), he said.

Significantly more patients experienced a clinically relevant improvement in LVEF of 5% or more with ivabradine than placebo (36% vs. 23%, P = .003).

"The significant reductions in LV volumes in favor of ivabradine were parallel with the reduction in heart rate at eight months achieved with ivabradine versus placebo [-14.7 bpm vs. -5.8 bpm, P less than .0001]," Dr. Tardif said.

Discussant Dr. Burkert Pieske, with the division of cardiology at the Medical University of Graz (Austria), said that the substudy findings underscore the importance of reverse remodeling as a marker for improved outcome, and provides solid, mechanistic data to encourage the use of ivabradine as an add-on medication in patients in sinus rhythm and a heart rate above 7 beats/minute.

"The reduction in LVESVI of about 6 mL/m² is more or less comparable with other pharmacologic interventions, and importantly it adds on to the beneficial effect of beta blockers and ACE inhibitors," he said.

In contrast to cardiac resynchronization, ivabradine can be started by every heart failure physician without great expense, Dr. Pieske and his colleague Dr. Friedrich Fruhwald, wrote in an accompanying editorial in the European Heart Journal (Eur. Heart J. 2011 Sept. 2 [doi:10.1093/eurheartj/ehr317]).

They pointed out, however, that ivabradine only works in heart failure patients with sinus rhythm and that relevant reverse modeling was seen in only a third of these patients.

"So, we have to identify the right patients we need to treat with ivabradine," said Dr. Pieske, adding that further testing is warranted in such conditions as acute heart failure or heart failure with preserved ejection fraction.

Findings from a second SHIFT substudy suggest that reduction in heart rate with ivabradine is associated with improved health-related quality of life.

At 12 months, the change from baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score was significantly greater in the ivabradine group than the placebo group (6.7 vs. 4.3, P less than .001).

This also was true for the KCCQ clinical summary score (5.0 vs. 3.3, P = .018), reported Dr. Inger Ekman from the Institute of Health Care Sciences, Sahlgrenska Academy in Gothenburg, Sweden. A change of 5 units is considered a clinically meaningful change in KCCQ scoring.

The magnitude of heart rate reduction with ivabradine was directly related to the degree of improvement in health-related quality of life, she said.

Among the 1,944 patients in the substudy, the incidence of cardiovascular death or heart failure hospitalization at 12 months was inversely associated with KCCQ scores.

Dr. Ekman pointed out that recommended therapies with survival benefits like beta blockers have no impact on health-related quality of life, while some therapies that improve quality of life like inotropic agents do not improve survival.

Dr. Tardif and Dr. Ekman reported that all the study’s authors have received fees, research grants or both from the study sponsor, Servier. Dr. Pieske reported having no relevant disclosures.

STOCKHOLM – The experimental oral drug vismodegib provided a "substantial clinical benefit" for patients with locally advanced and metastatic basal cell carcinoma in a phase II trial involving 104 patients.

"Nearly all patients did have some tumor shrinkage," Dr. Luc Dirix said at the European Multidisciplinary Cancer Congress. The overall majority of those with locally advanced disease "had huge responses, with major decreases in tumor size."

The primary end point of overall response rate by independent review was reached in 43% of patients with locally advanced basal cell carcinoma (P less than .0001) and in 30% of those with metastatic disease (P = .0011). Response rates per investigator reached 60% and 45.5%, respectively.

Only a small minority of basal cell carcinomas (BCCs) become locally advanced or metastatic, but the consequences can be disfiguring and ultimately life threatening. For these patients, there is no clear standard of care, and thus this is an unmet medical need, explained Dr. Dirix of the Iridium Kankernetwerk at Sint-Augustinus Hospital in Wilrijk, Belgium.

Vismodegib is a first-in-class small-molecule inhibitor of the hedgehog signaling pathway, which is activated in more than 90% of BCC. Genentech, a member of the Roche group, is studying the drug in a variety of cancers. Based on the current phase II data, it filed a New Drug Application, announced on Sept. 12, 2011, with the Food and Drug Administration for vismodegib in the treatment of advanced, inoperable BCC.

"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma, but I think that long-term tolerance is really an issue," the invited discussant, Dr. Caroline Robert, said at the meeting, which was a joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).

"It’s not a very serious adverse event, but [rather] the chronic effect [of] fatigue, loss of appetite, muscular pain that will impact the patients," said Dr. Robert, chief of dermatology at the Institut Cancérologie Gustave Roussy in Villejuif, France.

"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma."

Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, taste loss, weight loss, and fatigue, but they were mainly grade 1 and 2, Dr. Dirix said.

Serious adverse events were reported in 26 patients (25%), of which four were possibly related to vismodegib. They included cholestasis; dehydration with syncope; pneumonia and cardiac failure; and pulmonary embolism. No fatal events were linked to the drug, he said.

The efficacy analysis was based on 63 patients who had locally advanced BCC that was inoperable or for whom surgery would be significantly disfiguring, and 33 patients with histologically confirmed, RECIST (Response Evaluation Criteria in Solid Tumors)–measurable metastatic BCC.

Patients received 150-mg oral vismodegib daily until disease progression or intolerable toxicity. Their mean age was 61 years.

Three-fourths of patients in both cohorts had a clinical benefit (defined as a response at any time plus stable disease), Dr. Dirix said. The response often occurred before week 8, and lasted a median of 7.6 months in both cohorts, based on independent review.

Median progression-free survival by independent review was 9.5 months in both cohorts.

The current phase II trial, called ERIVANCE BCC, was prompted by a phase I trial reporting a 55% response rate in 33 patients with advanced BCC, including 2 complete responses and 16 partial responses (N. Engl. J. Med. 2009;361:1164-72). Only one patient withdrew because of adverse events.

In a recent unpublished phase II study, however, 28% of 41 patients taking vismodegib for Gorlin's syndrome dropped out because of an adverse event, Dr. Robert said during the presidential session. She called for other treatment modalities for advanced BCC, and suggested that vismodegib may be optimal at lower doses, when used sequentially, or as a 3-month course prior to surgery.

"This is very important, I think, because it may lead us to the use of this drug in the neoadjuvant setting, where we can do surgery after the tumor has already shrunk," she added.

Genentech supported the trial. Dr. Dirix reported that a coauthor is a Genentech employee.

STOCKHOLM – The experimental oral drug vismodegib provided a "substantial clinical benefit" for patients with locally advanced and metastatic basal cell carcinoma in a phase II trial involving 104 patients.

"Nearly all patients did have some tumor shrinkage," Dr. Luc Dirix said at the European Multidisciplinary Cancer Congress. The overall majority of those with locally advanced disease "had huge responses, with major decreases in tumor size."

The primary end point of overall response rate by independent review was reached in 43% of patients with locally advanced basal cell carcinoma (P less than .0001) and in 30% of those with metastatic disease (P = .0011). Response rates per investigator reached 60% and 45.5%, respectively.

Only a small minority of basal cell carcinomas (BCCs) become locally advanced or metastatic, but the consequences can be disfiguring and ultimately life threatening. For these patients, there is no clear standard of care, and thus this is an unmet medical need, explained Dr. Dirix of the Iridium Kankernetwerk at Sint-Augustinus Hospital in Wilrijk, Belgium.

Vismodegib is a first-in-class small-molecule inhibitor of the hedgehog signaling pathway, which is activated in more than 90% of BCC. Genentech, a member of the Roche group, is studying the drug in a variety of cancers. Based on the current phase II data, it filed a New Drug Application, announced on Sept. 12, 2011, with the Food and Drug Administration for vismodegib in the treatment of advanced, inoperable BCC.

"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma, but I think that long-term tolerance is really an issue," the invited discussant, Dr. Caroline Robert, said at the meeting, which was a joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).

"It’s not a very serious adverse event, but [rather] the chronic effect [of] fatigue, loss of appetite, muscular pain that will impact the patients," said Dr. Robert, chief of dermatology at the Institut Cancérologie Gustave Roussy in Villejuif, France.

"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma."

Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, taste loss, weight loss, and fatigue, but they were mainly grade 1 and 2, Dr. Dirix said.

Serious adverse events were reported in 26 patients (25%), of which four were possibly related to vismodegib. They included cholestasis; dehydration with syncope; pneumonia and cardiac failure; and pulmonary embolism. No fatal events were linked to the drug, he said.

The efficacy analysis was based on 63 patients who had locally advanced BCC that was inoperable or for whom surgery would be significantly disfiguring, and 33 patients with histologically confirmed, RECIST (Response Evaluation Criteria in Solid Tumors)–measurable metastatic BCC.

Patients received 150-mg oral vismodegib daily until disease progression or intolerable toxicity. Their mean age was 61 years.

Three-fourths of patients in both cohorts had a clinical benefit (defined as a response at any time plus stable disease), Dr. Dirix said. The response often occurred before week 8, and lasted a median of 7.6 months in both cohorts, based on independent review.

Median progression-free survival by independent review was 9.5 months in both cohorts.

The current phase II trial, called ERIVANCE BCC, was prompted by a phase I trial reporting a 55% response rate in 33 patients with advanced BCC, including 2 complete responses and 16 partial responses (N. Engl. J. Med. 2009;361:1164-72). Only one patient withdrew because of adverse events.

In a recent unpublished phase II study, however, 28% of 41 patients taking vismodegib for Gorlin's syndrome dropped out because of an adverse event, Dr. Robert said during the presidential session. She called for other treatment modalities for advanced BCC, and suggested that vismodegib may be optimal at lower doses, when used sequentially, or as a 3-month course prior to surgery.

"This is very important, I think, because it may lead us to the use of this drug in the neoadjuvant setting, where we can do surgery after the tumor has already shrunk," she added.

Genentech supported the trial. Dr. Dirix reported that a coauthor is a Genentech employee.

STOCKHOLM – The experimental oral drug vismodegib provided a "substantial clinical benefit" for patients with locally advanced and metastatic basal cell carcinoma in a phase II trial involving 104 patients.

"Nearly all patients did have some tumor shrinkage," Dr. Luc Dirix said at the European Multidisciplinary Cancer Congress. The overall majority of those with locally advanced disease "had huge responses, with major decreases in tumor size."

The primary end point of overall response rate by independent review was reached in 43% of patients with locally advanced basal cell carcinoma (P less than .0001) and in 30% of those with metastatic disease (P = .0011). Response rates per investigator reached 60% and 45.5%, respectively.

Only a small minority of basal cell carcinomas (BCCs) become locally advanced or metastatic, but the consequences can be disfiguring and ultimately life threatening. For these patients, there is no clear standard of care, and thus this is an unmet medical need, explained Dr. Dirix of the Iridium Kankernetwerk at Sint-Augustinus Hospital in Wilrijk, Belgium.

Vismodegib is a first-in-class small-molecule inhibitor of the hedgehog signaling pathway, which is activated in more than 90% of BCC. Genentech, a member of the Roche group, is studying the drug in a variety of cancers. Based on the current phase II data, it filed a New Drug Application, announced on Sept. 12, 2011, with the Food and Drug Administration for vismodegib in the treatment of advanced, inoperable BCC.

"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma, but I think that long-term tolerance is really an issue," the invited discussant, Dr. Caroline Robert, said at the meeting, which was a joint congress of the European Cancer Organization (ECCO), the European Society for Medical Oncology (ESMO), and the European Society for Radiotherapy and Oncology (ESTRO).

"It’s not a very serious adverse event, but [rather] the chronic effect [of] fatigue, loss of appetite, muscular pain that will impact the patients," said Dr. Robert, chief of dermatology at the Institut Cancérologie Gustave Roussy in Villejuif, France.

"Vismodegib is really a breakthrough for the treatment of advanced basal cell carcinoma."

Adverse events occurring in more than 30% of patients were muscle spasms, alopecia, taste loss, weight loss, and fatigue, but they were mainly grade 1 and 2, Dr. Dirix said.

Serious adverse events were reported in 26 patients (25%), of which four were possibly related to vismodegib. They included cholestasis; dehydration with syncope; pneumonia and cardiac failure; and pulmonary embolism. No fatal events were linked to the drug, he said.

The efficacy analysis was based on 63 patients who had locally advanced BCC that was inoperable or for whom surgery would be significantly disfiguring, and 33 patients with histologically confirmed, RECIST (Response Evaluation Criteria in Solid Tumors)–measurable metastatic BCC.

Patients received 150-mg oral vismodegib daily until disease progression or intolerable toxicity. Their mean age was 61 years.

Three-fourths of patients in both cohorts had a clinical benefit (defined as a response at any time plus stable disease), Dr. Dirix said. The response often occurred before week 8, and lasted a median of 7.6 months in both cohorts, based on independent review.

Median progression-free survival by independent review was 9.5 months in both cohorts.

The current phase II trial, called ERIVANCE BCC, was prompted by a phase I trial reporting a 55% response rate in 33 patients with advanced BCC, including 2 complete responses and 16 partial responses (N. Engl. J. Med. 2009;361:1164-72). Only one patient withdrew because of adverse events.

In a recent unpublished phase II study, however, 28% of 41 patients taking vismodegib for Gorlin's syndrome dropped out because of an adverse event, Dr. Robert said during the presidential session. She called for other treatment modalities for advanced BCC, and suggested that vismodegib may be optimal at lower doses, when used sequentially, or as a 3-month course prior to surgery.

"This is very important, I think, because it may lead us to the use of this drug in the neoadjuvant setting, where we can do surgery after the tumor has already shrunk," she added.

Genentech supported the trial. Dr. Dirix reported that a coauthor is a Genentech employee.

STOCKHOLM – The experimental cytotoxic agent TAS-102 significantly reduced the risk of death in a placebo-controlled phase II trial of patients with metastatic colorectal cancer refractory to current treatments.

Patients receiving oral TAS-102 plus best supportive care had a median overall survival of 9 months, compared with 6.6 months for placebo and best supportive care (hazard ratio, 0.56; P = .001).

TAS-102 also doubled median progression-free survival from 1 month to 2 months (HR, 0.41; P less than .0001), Dr. Yasutoshi Kuboki reported at the European Multidisciplinary Cancer Congress.

KRAS mutation testing revealed that TAS-102 offers a significant survival advantage for patients harboring a KRAS mutation, a biomarker of nonresponsiveness to the approved targeted agents cetuximab (Erbitux) and panitumumab (Vectibix).

KRAS mutation-positive patients treated with TAS-102 had a median overall survival of 13.0 months, compared with 6.9 months for placebo (HR, 0.44; P = .006,), and a progression-free survival of 2.8 months vs. 1.0 month (HR, 0.34; P less than .0001).

In the KRAS wild-type subset, median overall survival was similar at 7.2 months with TAS-102 and 7.0 months with placebo (HR, 0.70; P = .19), although time to disease progression increased from 1.0 to 1.9 months with TAS-102 (HR, 0.47; P = .0004).

Dr. Kuboki said a phase III trial is needed to confirm the promising results, but that "TAS-102 is the first cytotoxic agent to prolong survival in patients with metastatic colorectal cancer refractory to conventional cytotoxic agents."

Invited discussant Dr. Eric van Cutsem, of the University of Leuven, Belgium, said, "It’s less sexy, less fashionable to talk about cytotoxics in colorectal cancer because we have the impression we’ve seen it all," but the study is important nonetheless and the outcome "very impressive."

"It’s a phase II study, but if we could see similar numbers in a phase III study with hazard rates of 0.56, then we could say we have a new drug," he said.

Dr. van Cutsem pointed out that the hazard ratios observed with TAS-102 in the phase II study are similar to those reported in submission approvals for cetuximab and panitumumab in advanced, chemotherapy-refractory colorectal cancer.

TAS-102 is a novel agent that combines trifluorothymidine and thymidine phosphorylase inhibitor at a molar ratio of 1 to 0.5, explained Dr. Kuboki, with the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo.

Researchers at 10 Japanese centers recruited 172 patients with refractory metastatic colorectal cancer after at least two lines of chemotherapy containing fluoropyrimidine, irinotecan, and oxaliplatin. Prior treatment also included cetuximab in two-thirds and bevacizumab (Avastin) in at least three-fourths of the population.

Patients were randomized double-blind 2:1 to best supportive care plus placebo or TAS-102 70 mg/m² twice daily on days 1-5 and days 8-12 every 4 weeks.

Among 169 evaluable patients, the disease control rate was 43.8% with TAS-102 vs. 10.5% with placebo, Dr. Kuboki said at the meeting, which was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

Treatment with TAS-102 was well tolerated in the heavily pretreated cohort, and there were no treatment-related deaths. Neutropenia was the main side effect (17.6%), but there was no neutropenic sepsis, he said.

Taiho Pharmaceutical Co. sponsored the study. Dr. Kuboki and his coauthors reported no conflicts of interest.

STOCKHOLM – The experimental cytotoxic agent TAS-102 significantly reduced the risk of death in a placebo-controlled phase II trial of patients with metastatic colorectal cancer refractory to current treatments.

Patients receiving oral TAS-102 plus best supportive care had a median overall survival of 9 months, compared with 6.6 months for placebo and best supportive care (hazard ratio, 0.56; P = .001).

TAS-102 also doubled median progression-free survival from 1 month to 2 months (HR, 0.41; P less than .0001), Dr. Yasutoshi Kuboki reported at the European Multidisciplinary Cancer Congress.

KRAS mutation testing revealed that TAS-102 offers a significant survival advantage for patients harboring a KRAS mutation, a biomarker of nonresponsiveness to the approved targeted agents cetuximab (Erbitux) and panitumumab (Vectibix).

KRAS mutation-positive patients treated with TAS-102 had a median overall survival of 13.0 months, compared with 6.9 months for placebo (HR, 0.44; P = .006,), and a progression-free survival of 2.8 months vs. 1.0 month (HR, 0.34; P less than .0001).

In the KRAS wild-type subset, median overall survival was similar at 7.2 months with TAS-102 and 7.0 months with placebo (HR, 0.70; P = .19), although time to disease progression increased from 1.0 to 1.9 months with TAS-102 (HR, 0.47; P = .0004).

Dr. Kuboki said a phase III trial is needed to confirm the promising results, but that "TAS-102 is the first cytotoxic agent to prolong survival in patients with metastatic colorectal cancer refractory to conventional cytotoxic agents."

Invited discussant Dr. Eric van Cutsem, of the University of Leuven, Belgium, said, "It’s less sexy, less fashionable to talk about cytotoxics in colorectal cancer because we have the impression we’ve seen it all," but the study is important nonetheless and the outcome "very impressive."

"It’s a phase II study, but if we could see similar numbers in a phase III study with hazard rates of 0.56, then we could say we have a new drug," he said.

Dr. van Cutsem pointed out that the hazard ratios observed with TAS-102 in the phase II study are similar to those reported in submission approvals for cetuximab and panitumumab in advanced, chemotherapy-refractory colorectal cancer.

TAS-102 is a novel agent that combines trifluorothymidine and thymidine phosphorylase inhibitor at a molar ratio of 1 to 0.5, explained Dr. Kuboki, with the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo.

Researchers at 10 Japanese centers recruited 172 patients with refractory metastatic colorectal cancer after at least two lines of chemotherapy containing fluoropyrimidine, irinotecan, and oxaliplatin. Prior treatment also included cetuximab in two-thirds and bevacizumab (Avastin) in at least three-fourths of the population.

Patients were randomized double-blind 2:1 to best supportive care plus placebo or TAS-102 70 mg/m² twice daily on days 1-5 and days 8-12 every 4 weeks.

Among 169 evaluable patients, the disease control rate was 43.8% with TAS-102 vs. 10.5% with placebo, Dr. Kuboki said at the meeting, which was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

Treatment with TAS-102 was well tolerated in the heavily pretreated cohort, and there were no treatment-related deaths. Neutropenia was the main side effect (17.6%), but there was no neutropenic sepsis, he said.

Taiho Pharmaceutical Co. sponsored the study. Dr. Kuboki and his coauthors reported no conflicts of interest.

STOCKHOLM – The experimental cytotoxic agent TAS-102 significantly reduced the risk of death in a placebo-controlled phase II trial of patients with metastatic colorectal cancer refractory to current treatments.

Patients receiving oral TAS-102 plus best supportive care had a median overall survival of 9 months, compared with 6.6 months for placebo and best supportive care (hazard ratio, 0.56; P = .001).

TAS-102 also doubled median progression-free survival from 1 month to 2 months (HR, 0.41; P less than .0001), Dr. Yasutoshi Kuboki reported at the European Multidisciplinary Cancer Congress.

KRAS mutation testing revealed that TAS-102 offers a significant survival advantage for patients harboring a KRAS mutation, a biomarker of nonresponsiveness to the approved targeted agents cetuximab (Erbitux) and panitumumab (Vectibix).

KRAS mutation-positive patients treated with TAS-102 had a median overall survival of 13.0 months, compared with 6.9 months for placebo (HR, 0.44; P = .006,), and a progression-free survival of 2.8 months vs. 1.0 month (HR, 0.34; P less than .0001).

In the KRAS wild-type subset, median overall survival was similar at 7.2 months with TAS-102 and 7.0 months with placebo (HR, 0.70; P = .19), although time to disease progression increased from 1.0 to 1.9 months with TAS-102 (HR, 0.47; P = .0004).

Dr. Kuboki said a phase III trial is needed to confirm the promising results, but that "TAS-102 is the first cytotoxic agent to prolong survival in patients with metastatic colorectal cancer refractory to conventional cytotoxic agents."

Invited discussant Dr. Eric van Cutsem, of the University of Leuven, Belgium, said, "It’s less sexy, less fashionable to talk about cytotoxics in colorectal cancer because we have the impression we’ve seen it all," but the study is important nonetheless and the outcome "very impressive."

"It’s a phase II study, but if we could see similar numbers in a phase III study with hazard rates of 0.56, then we could say we have a new drug," he said.

Dr. van Cutsem pointed out that the hazard ratios observed with TAS-102 in the phase II study are similar to those reported in submission approvals for cetuximab and panitumumab in advanced, chemotherapy-refractory colorectal cancer.

TAS-102 is a novel agent that combines trifluorothymidine and thymidine phosphorylase inhibitor at a molar ratio of 1 to 0.5, explained Dr. Kuboki, with the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo.

Researchers at 10 Japanese centers recruited 172 patients with refractory metastatic colorectal cancer after at least two lines of chemotherapy containing fluoropyrimidine, irinotecan, and oxaliplatin. Prior treatment also included cetuximab in two-thirds and bevacizumab (Avastin) in at least three-fourths of the population.

Patients were randomized double-blind 2:1 to best supportive care plus placebo or TAS-102 70 mg/m² twice daily on days 1-5 and days 8-12 every 4 weeks.

Among 169 evaluable patients, the disease control rate was 43.8% with TAS-102 vs. 10.5% with placebo, Dr. Kuboki said at the meeting, which was a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society of Radiotherapy and Oncology.

Treatment with TAS-102 was well tolerated in the heavily pretreated cohort, and there were no treatment-related deaths. Neutropenia was the main side effect (17.6%), but there was no neutropenic sepsis, he said.

Taiho Pharmaceutical Co. sponsored the study. Dr. Kuboki and his coauthors reported no conflicts of interest.

CHICAGO – Even though the numbers remain small, fluconazole-resistant Candida albicans vulvovaginitis appears to be emerging as a thorny clinical problem, one expert suggests.

Since its introduction in 1990 as a prophylactic antifungal agent after bone marrow transplantation, fluconazole (Diflucan) has become established as the dominant therapy for vulvovaginal candidiasis (VVC) worldwide. In North America alone, roughly 8 million cases of recurrent vulvovaginitis are reported annually, with more than 90% due to C. albicans.

“So the possibility of resistance is a tremendous problem and concern,” asserted Dr. Jack D. Sobel, chief of the division of infectious diseases and professor of obstetrics and gynecology at Wayne State University in Detroit.

Women with recurrent vulvovaginitis are treated with induction and prolonged, low-dose maintenance fluconazole regimens to achieve an asymptomatic state. Successful control, not cure, is achieved in more than 90%. Susceptibility testing for C. albicans is not standard of care, so there is very little published data on prolonged fluconazole use, Dr. Sobel said at the meeting.

He and his colleagues published the only study to address the issue of resistance, and it failed to identify any evidence of fluconazole resistance in isolates of C. albicans after just 1 year of follow-up (N. Engl. J. Med. 2004;351:876–83).

Clinicians at Wayne State's Vaginitis Clinic, however, have observed an uptick in the frequency of refractory Candida vulvovaginitis cases in the last 10 years among the more than 500 women with recurrent vulvovaginitis that they follow. The women present either on a maintenance fluconazole regimen with a breakthrough of symptoms accompanied by positive cultures or fail to resolve acute symptomatic vulvovaginitis with multidose fluconazole and have increased minimum inhibitory concentration (MIC) in vitro, Dr. Sobel explained.

A retrospective review of patients referred to the Vaginitis Clinic between 2000 and 2010 revealed 25 patients with clinically refractory fluconazole-resistant vulvovaginitis with confirmed in vitro resistance, with an MIC at least 2 mcg/mL (median 8 mcg/mL).

“Two-thirds of these patients were seen in the last 5 years, so the incidence is increasing,” he said.

Eight patients had an MIC of 2 mcg/mL and 17 had MICs ranging from 4 to 128 mcg/mL.

Cross resistance to itraconazole (Sporanox) was present in five women and to ketoconazole (Nizoral) in four.

The cohort consists of married, insured Caucasian women with an average or above average socioeconomic status. Their mean age was 43 years (range 32–56 years). All patients had significant consumption of and recent exposure to fluconazole, with 64% on low-dose, weekly maintenance fluconazole.

Significant risk factors for refractory Candida VVC included more than 10 lifetime sexual partners, recent use of antibiotics, and for mycological failure included increased fluconazole exposure and older age of VVC onset.

Management

Management of refractory VVC is possible, but can be extremely difficult, Dr. Sobel acknowledged.

“When you can't use fluconazole, the closet is pretty empty,” he said.

Dr. Sobel recommends initially using boric acid 600 mg per day for 14 days until an MIC is available. For those with low-level resistance, defined by an MIC of 2–4 mcg/mL, clinicians should increase the fluconazole dose to 150–200 mg twice weekly. Eleven of the 25 patients in the study cohort were controlled on this regimen, with five eventually discontinuing fluconazole.

“In patients with high level resistance, treatment depends on the presence of azole cross-resistance,” he said.

Among eight such patients, three were successfully controlled on 200 mg per day of itraconazole, and four of five were controlled on ketoconazole 100 mg per day, both typically for several months.

One patient required daily gentian violet for 14 days, with cure, and three patients were controlled on boric acid three times per week.

The novel, oral broad-spectrum antifungal, voriconazole (Vfend) is a possibility, but is rarely used because it is so poorly tolerated, Dr. Sobel said. Audience members questioned whether flucytosine (Ancobon), a synthetic antimycotic, can be employed. Specialty pharmacies can formulate it, but at $1,500 to $2,000 per tube is out of reach for most women. The ancient antifungal antibiotic nystatin is a far cheaper alternative, but should be given at 100,000 units daily per vagina only, Dr. Sobel said.

“We urgently need new classes of antifungal agents for Candida vaginitis,” he said.

Dr. Sobel and his colleagues reported no relevant financial disclosures.

This is a photomicrograph of a vaginal smear identifying Candida albicans using a Gram-stain technique.

Source Courtesy CDC/Dr. Stuart Brown

Nystatin: Old is New Again

Although it was patented back in 1957 as the world's first antifungal, antibiotic nystatin upstaged newer antifungal agents when used to treat vulvovaginal candidiasis caused by Candida glabrata in sequential, prospective clinical trials.

On day 7 to day 14 of follow-up, mycological cure of C. glabrata vulvovaginitis was achieved by 15 of 16 women (94%) treated with a nystatin vaginal suppository, compared with 8 of 19 (42%) given a miconazole nitrate vaginal suppository, 5 of 9 (56%) given oral fluconazole (Diflucan) and 7 of 15 (47%) given oral itraconazole (Sporanox). At day 30 to day 35 of follow-up, mycological cure rates, based on a positive or negative Candida culture, were 94%, 33%, 56%, and 40%, respectively.

“Nystatin vaginal suppository could be a therapy choice for vulvovaginal candidiasis caused by Candida glabrata,” Dr. Shangrong Fan said at the meeting.

While C. albicans is the most commonly isolated species, various studies have reported a shift towards infections caused by non-albicans Candida species such as C. glabrata.

The women were enrolled prospectively in separate, sequential, nonrandomized clinical trials and treated with nystatin vaginal suppository at 20 MU per day for 7 days or two 1,200-mg doses of miconazole vaginal suppositories 72 hours apart or oral fluconazole two 150-mg doses 72 hours apart or oral itraconazole 200 mg two times for 1 day.

Dr. Fan, an obstetrician/gynecologist and his colleagues at Peking University Shenzhen Hospital in Shenzhen, China, also conducted an in vitro susceptibility study. The in vitro susceptible rate of C. glabrata on nystatin was 100% (57/57), compared with 90% (51/57) for miconazole, 58% (40/69) for fluconazole, and 87% (58/67) for itraconazole. Resistance to nystatin or miconazole was not observed, and occurred in 3% of strains exposed to fluconazole and 1.5% exposed to itraconazole.

Dr. Fan and his associates reported no relevant financial disclosures.

CHICAGO – Even though the numbers remain small, fluconazole-resistant Candida albicans vulvovaginitis appears to be emerging as a thorny clinical problem, one expert suggests.

Since its introduction in 1990 as a prophylactic antifungal agent after bone marrow transplantation, fluconazole (Diflucan) has become established as the dominant therapy for vulvovaginal candidiasis (VVC) worldwide. In North America alone, roughly 8 million cases of recurrent vulvovaginitis are reported annually, with more than 90% due to C. albicans.

“So the possibility of resistance is a tremendous problem and concern,” asserted Dr. Jack D. Sobel, chief of the division of infectious diseases and professor of obstetrics and gynecology at Wayne State University in Detroit.

Women with recurrent vulvovaginitis are treated with induction and prolonged, low-dose maintenance fluconazole regimens to achieve an asymptomatic state. Successful control, not cure, is achieved in more than 90%. Susceptibility testing for C. albicans is not standard of care, so there is very little published data on prolonged fluconazole use, Dr. Sobel said at the meeting.

He and his colleagues published the only study to address the issue of resistance, and it failed to identify any evidence of fluconazole resistance in isolates of C. albicans after just 1 year of follow-up (N. Engl. J. Med. 2004;351:876–83).

Clinicians at Wayne State's Vaginitis Clinic, however, have observed an uptick in the frequency of refractory Candida vulvovaginitis cases in the last 10 years among the more than 500 women with recurrent vulvovaginitis that they follow. The women present either on a maintenance fluconazole regimen with a breakthrough of symptoms accompanied by positive cultures or fail to resolve acute symptomatic vulvovaginitis with multidose fluconazole and have increased minimum inhibitory concentration (MIC) in vitro, Dr. Sobel explained.

A retrospective review of patients referred to the Vaginitis Clinic between 2000 and 2010 revealed 25 patients with clinically refractory fluconazole-resistant vulvovaginitis with confirmed in vitro resistance, with an MIC at least 2 mcg/mL (median 8 mcg/mL).

“Two-thirds of these patients were seen in the last 5 years, so the incidence is increasing,” he said.

Eight patients had an MIC of 2 mcg/mL and 17 had MICs ranging from 4 to 128 mcg/mL.

Cross resistance to itraconazole (Sporanox) was present in five women and to ketoconazole (Nizoral) in four.

The cohort consists of married, insured Caucasian women with an average or above average socioeconomic status. Their mean age was 43 years (range 32–56 years). All patients had significant consumption of and recent exposure to fluconazole, with 64% on low-dose, weekly maintenance fluconazole.

Significant risk factors for refractory Candida VVC included more than 10 lifetime sexual partners, recent use of antibiotics, and for mycological failure included increased fluconazole exposure and older age of VVC onset.

Management

Management of refractory VVC is possible, but can be extremely difficult, Dr. Sobel acknowledged.

“When you can't use fluconazole, the closet is pretty empty,” he said.

Dr. Sobel recommends initially using boric acid 600 mg per day for 14 days until an MIC is available. For those with low-level resistance, defined by an MIC of 2–4 mcg/mL, clinicians should increase the fluconazole dose to 150–200 mg twice weekly. Eleven of the 25 patients in the study cohort were controlled on this regimen, with five eventually discontinuing fluconazole.

“In patients with high level resistance, treatment depends on the presence of azole cross-resistance,” he said.

Among eight such patients, three were successfully controlled on 200 mg per day of itraconazole, and four of five were controlled on ketoconazole 100 mg per day, both typically for several months.

One patient required daily gentian violet for 14 days, with cure, and three patients were controlled on boric acid three times per week.

The novel, oral broad-spectrum antifungal, voriconazole (Vfend) is a possibility, but is rarely used because it is so poorly tolerated, Dr. Sobel said. Audience members questioned whether flucytosine (Ancobon), a synthetic antimycotic, can be employed. Specialty pharmacies can formulate it, but at $1,500 to $2,000 per tube is out of reach for most women. The ancient antifungal antibiotic nystatin is a far cheaper alternative, but should be given at 100,000 units daily per vagina only, Dr. Sobel said.

“We urgently need new classes of antifungal agents for Candida vaginitis,” he said.

Dr. Sobel and his colleagues reported no relevant financial disclosures.

This is a photomicrograph of a vaginal smear identifying Candida albicans using a Gram-stain technique.

Source Courtesy CDC/Dr. Stuart Brown

Nystatin: Old is New Again

Although it was patented back in 1957 as the world's first antifungal, antibiotic nystatin upstaged newer antifungal agents when used to treat vulvovaginal candidiasis caused by Candida glabrata in sequential, prospective clinical trials.

On day 7 to day 14 of follow-up, mycological cure of C. glabrata vulvovaginitis was achieved by 15 of 16 women (94%) treated with a nystatin vaginal suppository, compared with 8 of 19 (42%) given a miconazole nitrate vaginal suppository, 5 of 9 (56%) given oral fluconazole (Diflucan) and 7 of 15 (47%) given oral itraconazole (Sporanox). At day 30 to day 35 of follow-up, mycological cure rates, based on a positive or negative Candida culture, were 94%, 33%, 56%, and 40%, respectively.

“Nystatin vaginal suppository could be a therapy choice for vulvovaginal candidiasis caused by Candida glabrata,” Dr. Shangrong Fan said at the meeting.

While C. albicans is the most commonly isolated species, various studies have reported a shift towards infections caused by non-albicans Candida species such as C. glabrata.

The women were enrolled prospectively in separate, sequential, nonrandomized clinical trials and treated with nystatin vaginal suppository at 20 MU per day for 7 days or two 1,200-mg doses of miconazole vaginal suppositories 72 hours apart or oral fluconazole two 150-mg doses 72 hours apart or oral itraconazole 200 mg two times for 1 day.

Dr. Fan, an obstetrician/gynecologist and his colleagues at Peking University Shenzhen Hospital in Shenzhen, China, also conducted an in vitro susceptibility study. The in vitro susceptible rate of C. glabrata on nystatin was 100% (57/57), compared with 90% (51/57) for miconazole, 58% (40/69) for fluconazole, and 87% (58/67) for itraconazole. Resistance to nystatin or miconazole was not observed, and occurred in 3% of strains exposed to fluconazole and 1.5% exposed to itraconazole.

Dr. Fan and his associates reported no relevant financial disclosures.

CHICAGO – Even though the numbers remain small, fluconazole-resistant Candida albicans vulvovaginitis appears to be emerging as a thorny clinical problem, one expert suggests.

Since its introduction in 1990 as a prophylactic antifungal agent after bone marrow transplantation, fluconazole (Diflucan) has become established as the dominant therapy for vulvovaginal candidiasis (VVC) worldwide. In North America alone, roughly 8 million cases of recurrent vulvovaginitis are reported annually, with more than 90% due to C. albicans.

“So the possibility of resistance is a tremendous problem and concern,” asserted Dr. Jack D. Sobel, chief of the division of infectious diseases and professor of obstetrics and gynecology at Wayne State University in Detroit.

Women with recurrent vulvovaginitis are treated with induction and prolonged, low-dose maintenance fluconazole regimens to achieve an asymptomatic state. Successful control, not cure, is achieved in more than 90%. Susceptibility testing for C. albicans is not standard of care, so there is very little published data on prolonged fluconazole use, Dr. Sobel said at the meeting.

He and his colleagues published the only study to address the issue of resistance, and it failed to identify any evidence of fluconazole resistance in isolates of C. albicans after just 1 year of follow-up (N. Engl. J. Med. 2004;351:876–83).

Clinicians at Wayne State's Vaginitis Clinic, however, have observed an uptick in the frequency of refractory Candida vulvovaginitis cases in the last 10 years among the more than 500 women with recurrent vulvovaginitis that they follow. The women present either on a maintenance fluconazole regimen with a breakthrough of symptoms accompanied by positive cultures or fail to resolve acute symptomatic vulvovaginitis with multidose fluconazole and have increased minimum inhibitory concentration (MIC) in vitro, Dr. Sobel explained.

A retrospective review of patients referred to the Vaginitis Clinic between 2000 and 2010 revealed 25 patients with clinically refractory fluconazole-resistant vulvovaginitis with confirmed in vitro resistance, with an MIC at least 2 mcg/mL (median 8 mcg/mL).

“Two-thirds of these patients were seen in the last 5 years, so the incidence is increasing,” he said.

Eight patients had an MIC of 2 mcg/mL and 17 had MICs ranging from 4 to 128 mcg/mL.

Cross resistance to itraconazole (Sporanox) was present in five women and to ketoconazole (Nizoral) in four.

The cohort consists of married, insured Caucasian women with an average or above average socioeconomic status. Their mean age was 43 years (range 32–56 years). All patients had significant consumption of and recent exposure to fluconazole, with 64% on low-dose, weekly maintenance fluconazole.

Significant risk factors for refractory Candida VVC included more than 10 lifetime sexual partners, recent use of antibiotics, and for mycological failure included increased fluconazole exposure and older age of VVC onset.

Management

Management of refractory VVC is possible, but can be extremely difficult, Dr. Sobel acknowledged.

“When you can't use fluconazole, the closet is pretty empty,” he said.

Dr. Sobel recommends initially using boric acid 600 mg per day for 14 days until an MIC is available. For those with low-level resistance, defined by an MIC of 2–4 mcg/mL, clinicians should increase the fluconazole dose to 150–200 mg twice weekly. Eleven of the 25 patients in the study cohort were controlled on this regimen, with five eventually discontinuing fluconazole.

“In patients with high level resistance, treatment depends on the presence of azole cross-resistance,” he said.

Among eight such patients, three were successfully controlled on 200 mg per day of itraconazole, and four of five were controlled on ketoconazole 100 mg per day, both typically for several months.

One patient required daily gentian violet for 14 days, with cure, and three patients were controlled on boric acid three times per week.

The novel, oral broad-spectrum antifungal, voriconazole (Vfend) is a possibility, but is rarely used because it is so poorly tolerated, Dr. Sobel said. Audience members questioned whether flucytosine (Ancobon), a synthetic antimycotic, can be employed. Specialty pharmacies can formulate it, but at $1,500 to $2,000 per tube is out of reach for most women. The ancient antifungal antibiotic nystatin is a far cheaper alternative, but should be given at 100,000 units daily per vagina only, Dr. Sobel said.

“We urgently need new classes of antifungal agents for Candida vaginitis,” he said.

Dr. Sobel and his colleagues reported no relevant financial disclosures.

This is a photomicrograph of a vaginal smear identifying Candida albicans using a Gram-stain technique.

Source Courtesy CDC/Dr. Stuart Brown

Nystatin: Old is New Again

Although it was patented back in 1957 as the world's first antifungal, antibiotic nystatin upstaged newer antifungal agents when used to treat vulvovaginal candidiasis caused by Candida glabrata in sequential, prospective clinical trials.

On day 7 to day 14 of follow-up, mycological cure of C. glabrata vulvovaginitis was achieved by 15 of 16 women (94%) treated with a nystatin vaginal suppository, compared with 8 of 19 (42%) given a miconazole nitrate vaginal suppository, 5 of 9 (56%) given oral fluconazole (Diflucan) and 7 of 15 (47%) given oral itraconazole (Sporanox). At day 30 to day 35 of follow-up, mycological cure rates, based on a positive or negative Candida culture, were 94%, 33%, 56%, and 40%, respectively.

“Nystatin vaginal suppository could be a therapy choice for vulvovaginal candidiasis caused by Candida glabrata,” Dr. Shangrong Fan said at the meeting.

While C. albicans is the most commonly isolated species, various studies have reported a shift towards infections caused by non-albicans Candida species such as C. glabrata.

The women were enrolled prospectively in separate, sequential, nonrandomized clinical trials and treated with nystatin vaginal suppository at 20 MU per day for 7 days or two 1,200-mg doses of miconazole vaginal suppositories 72 hours apart or oral fluconazole two 150-mg doses 72 hours apart or oral itraconazole 200 mg two times for 1 day.

Dr. Fan, an obstetrician/gynecologist and his colleagues at Peking University Shenzhen Hospital in Shenzhen, China, also conducted an in vitro susceptibility study. The in vitro susceptible rate of C. glabrata on nystatin was 100% (57/57), compared with 90% (51/57) for miconazole, 58% (40/69) for fluconazole, and 87% (58/67) for itraconazole. Resistance to nystatin or miconazole was not observed, and occurred in 3% of strains exposed to fluconazole and 1.5% exposed to itraconazole.

Dr. Fan and his associates reported no relevant financial disclosures.