The link between dementia and weight loss has been established: Weight loss is associated with even mild dementia, increasing with advancing disease severity and duration. But with a large multicountry study, researchers from the National Institutes of Health in Bethesda, Maryland, King’s College London and Newcastle University, both in the United Kingdom, and Universidad Nacional Pedro Henriquez Ureña in Santo Domingo, Dominican Republic, add new information about the universality of the association.

The researchers surveyed 16,538 older adults, asking them or a caregiver whether the patient had lost ≥ 10 pounds in the previous 3 months. The prevalence of weight loss ranged from 2% in China to 26% in the Dominican Republic and was lowest for participants with no dementia and highest in those with a Clinical Dementia Rating Scale Severity of two-thirds in all countries. The association increased and strengthened linearly through stages of dementia severity in all the study countries.

Weight loss in people with dementia can lead to further morbidity, worse prognosis, and death, the researchers note. They call for more studies, but in the meantime, they emphasize that treating and preventing weight loss is critical, particularly for institutionalized dementia patients.

One intervention that could help is giving patients nutritionally complete oral supplements, say researchers from The Royal Berkshire Hospital NHS Foundation Trust and the University of Reading, both in the United Kingdom. They reviewed 12 studies involving 1,824 patients. Most interventions, which ranged from 3 weeks to 1 year, were compared with a normal diet and care.

Two findings had to do with how weight loss is measured in older people. Skin-fold thickness and arm muscle circumference are not affected by supplement use, the researchers found. They add that those anthropometric measurements have a low level of reproducibility and are not an accurate method for obtaining evidence of changes in body composition (mid-arm muscle circumference is calculated from the skin-fold measurements). Further, measuring by body mass index (BMI) is less accurate in older patients, they note, when determining fat mass and subsequent nutritional status due to changes in height and age-related redistribution of fat mass.

However, the studies were short enough to allow BMI and weight measurements to detect the influence of the supplements. And the conclusion was that the nutritional supplement drinks had positive effects on weight gain and BMI. Overall, the consumption was “fairly good”; however, consumption was lowest in one of the longest studies. That might have been due to changes in staff behavior—increased vigilance and verbal prompting, common in the shorter studies, may have dropped off in longer studies.

Supplement use was significantly associated with improved overall energy intake and a small but statistically significant change in weight and BMI (P < .0001). However, where the control was a macro- or micronutrient supplement, findings were less positive. That may indicate that comparisons of nutritional supplements to vitamin/mineral tablets and high protein-calorie shots needs more research, the researchers conclude.

Sources
Albanese E, Taylor C, Siervo M, Stewart R, Prince MJ, Acosta D. Alzheimer’s Dement. 2013;9(6):649-656.
doi: 10.1016/j.jalz.2012.11.014.
Allen VJ, Methven L, Gosney MA. Clin Nutr. 2013;32(6):950-957.
doi: 10.1016/j.clnu.2013.03.015.

The link between dementia and weight loss has been established: Weight loss is associated with even mild dementia, increasing with advancing disease severity and duration. But with a large multicountry study, researchers from the National Institutes of Health in Bethesda, Maryland, King’s College London and Newcastle University, both in the United Kingdom, and Universidad Nacional Pedro Henriquez Ureña in Santo Domingo, Dominican Republic, add new information about the universality of the association.

The researchers surveyed 16,538 older adults, asking them or a caregiver whether the patient had lost ≥ 10 pounds in the previous 3 months. The prevalence of weight loss ranged from 2% in China to 26% in the Dominican Republic and was lowest for participants with no dementia and highest in those with a Clinical Dementia Rating Scale Severity of two-thirds in all countries. The association increased and strengthened linearly through stages of dementia severity in all the study countries.

Weight loss in people with dementia can lead to further morbidity, worse prognosis, and death, the researchers note. They call for more studies, but in the meantime, they emphasize that treating and preventing weight loss is critical, particularly for institutionalized dementia patients.

One intervention that could help is giving patients nutritionally complete oral supplements, say researchers from The Royal Berkshire Hospital NHS Foundation Trust and the University of Reading, both in the United Kingdom. They reviewed 12 studies involving 1,824 patients. Most interventions, which ranged from 3 weeks to 1 year, were compared with a normal diet and care.

Two findings had to do with how weight loss is measured in older people. Skin-fold thickness and arm muscle circumference are not affected by supplement use, the researchers found. They add that those anthropometric measurements have a low level of reproducibility and are not an accurate method for obtaining evidence of changes in body composition (mid-arm muscle circumference is calculated from the skin-fold measurements). Further, measuring by body mass index (BMI) is less accurate in older patients, they note, when determining fat mass and subsequent nutritional status due to changes in height and age-related redistribution of fat mass.

However, the studies were short enough to allow BMI and weight measurements to detect the influence of the supplements. And the conclusion was that the nutritional supplement drinks had positive effects on weight gain and BMI. Overall, the consumption was “fairly good”; however, consumption was lowest in one of the longest studies. That might have been due to changes in staff behavior—increased vigilance and verbal prompting, common in the shorter studies, may have dropped off in longer studies.

Supplement use was significantly associated with improved overall energy intake and a small but statistically significant change in weight and BMI (P < .0001). However, where the control was a macro- or micronutrient supplement, findings were less positive. That may indicate that comparisons of nutritional supplements to vitamin/mineral tablets and high protein-calorie shots needs more research, the researchers conclude.

Sources
Albanese E, Taylor C, Siervo M, Stewart R, Prince MJ, Acosta D. Alzheimer’s Dement. 2013;9(6):649-656.
doi: 10.1016/j.jalz.2012.11.014.
Allen VJ, Methven L, Gosney MA. Clin Nutr. 2013;32(6):950-957.
doi: 10.1016/j.clnu.2013.03.015.

The link between dementia and weight loss has been established: Weight loss is associated with even mild dementia, increasing with advancing disease severity and duration. But with a large multicountry study, researchers from the National Institutes of Health in Bethesda, Maryland, King’s College London and Newcastle University, both in the United Kingdom, and Universidad Nacional Pedro Henriquez Ureña in Santo Domingo, Dominican Republic, add new information about the universality of the association.

The researchers surveyed 16,538 older adults, asking them or a caregiver whether the patient had lost ≥ 10 pounds in the previous 3 months. The prevalence of weight loss ranged from 2% in China to 26% in the Dominican Republic and was lowest for participants with no dementia and highest in those with a Clinical Dementia Rating Scale Severity of two-thirds in all countries. The association increased and strengthened linearly through stages of dementia severity in all the study countries.

Weight loss in people with dementia can lead to further morbidity, worse prognosis, and death, the researchers note. They call for more studies, but in the meantime, they emphasize that treating and preventing weight loss is critical, particularly for institutionalized dementia patients.

One intervention that could help is giving patients nutritionally complete oral supplements, say researchers from The Royal Berkshire Hospital NHS Foundation Trust and the University of Reading, both in the United Kingdom. They reviewed 12 studies involving 1,824 patients. Most interventions, which ranged from 3 weeks to 1 year, were compared with a normal diet and care.

Two findings had to do with how weight loss is measured in older people. Skin-fold thickness and arm muscle circumference are not affected by supplement use, the researchers found. They add that those anthropometric measurements have a low level of reproducibility and are not an accurate method for obtaining evidence of changes in body composition (mid-arm muscle circumference is calculated from the skin-fold measurements). Further, measuring by body mass index (BMI) is less accurate in older patients, they note, when determining fat mass and subsequent nutritional status due to changes in height and age-related redistribution of fat mass.

However, the studies were short enough to allow BMI and weight measurements to detect the influence of the supplements. And the conclusion was that the nutritional supplement drinks had positive effects on weight gain and BMI. Overall, the consumption was “fairly good”; however, consumption was lowest in one of the longest studies. That might have been due to changes in staff behavior—increased vigilance and verbal prompting, common in the shorter studies, may have dropped off in longer studies.

Supplement use was significantly associated with improved overall energy intake and a small but statistically significant change in weight and BMI (P < .0001). However, where the control was a macro- or micronutrient supplement, findings were less positive. That may indicate that comparisons of nutritional supplements to vitamin/mineral tablets and high protein-calorie shots needs more research, the researchers conclude.

Sources
Albanese E, Taylor C, Siervo M, Stewart R, Prince MJ, Acosta D. Alzheimer’s Dement. 2013;9(6):649-656.
doi: 10.1016/j.jalz.2012.11.014.
Allen VJ, Methven L, Gosney MA. Clin Nutr. 2013;32(6):950-957.
doi: 10.1016/j.clnu.2013.03.015.

Candida albicans

The US Food and Drug Administration has approved an intravenous formulation of posaconazole (Noxafil), which is expected to be available at wholesalers in mid-April.

The antifungal agent is already available as delayed-release tablets and in an oral suspension formulation.

In any formulation, posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients who are at high risk of developing these infections.

This includes patients who have developed graft-vs-host disease after hematopoietic stem cell transplant and patients with hematologic malignancies who have prolonged neutropenia resulting from chemotherapy.

Posaconazole injection is indicated for use in patients 18 years of age and older. The delayed-release tablets and oral suspension are indicated for patients 13 years of age and older.

Posaconazole injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by slow intravenous infusion over approximately 90 minutes.

Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole injection should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2-8 degrees C (36-46 degrees F).

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

In clinical trials, the adverse reactions reported for posaconazole injection were generally similar to those reported in trials of posaconazole oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

Patients who are allergic to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given along with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

For more details, see the complete prescribing information. Posaconazole is marketed as Noxafil by Merck.

Candida albicans

The US Food and Drug Administration has approved an intravenous formulation of posaconazole (Noxafil), which is expected to be available at wholesalers in mid-April.

The antifungal agent is already available as delayed-release tablets and in an oral suspension formulation.

In any formulation, posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients who are at high risk of developing these infections.

This includes patients who have developed graft-vs-host disease after hematopoietic stem cell transplant and patients with hematologic malignancies who have prolonged neutropenia resulting from chemotherapy.

Posaconazole injection is indicated for use in patients 18 years of age and older. The delayed-release tablets and oral suspension are indicated for patients 13 years of age and older.

Posaconazole injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by slow intravenous infusion over approximately 90 minutes.

Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole injection should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2-8 degrees C (36-46 degrees F).

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

In clinical trials, the adverse reactions reported for posaconazole injection were generally similar to those reported in trials of posaconazole oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

Patients who are allergic to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given along with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

For more details, see the complete prescribing information. Posaconazole is marketed as Noxafil by Merck.

Candida albicans

The US Food and Drug Administration has approved an intravenous formulation of posaconazole (Noxafil), which is expected to be available at wholesalers in mid-April.

The antifungal agent is already available as delayed-release tablets and in an oral suspension formulation.

In any formulation, posaconazole is indicated for prophylaxis of invasive Aspergillus and Candida infections in immunocompromised patients who are at high risk of developing these infections.

This includes patients who have developed graft-vs-host disease after hematopoietic stem cell transplant and patients with hematologic malignancies who have prolonged neutropenia resulting from chemotherapy.

Posaconazole injection is indicated for use in patients 18 years of age and older. The delayed-release tablets and oral suspension are indicated for patients 13 years of age and older.

Posaconazole injection is administered with a loading dose of 300 mg (one 300 mg vial) twice a day on the first day of therapy, then 300 mg once a day thereafter. It is given through a central venous line by slow intravenous infusion over approximately 90 minutes.

Once combined with a mixture of intravenous solution (150 mL of 5% dextrose in water or sodium chloride 0.9%), posaconazole injection should be administered immediately. If not used immediately, the solution can be stored up to 24 hours if refrigerated at 2-8 degrees C (36-46 degrees F).

Co-administration of drugs that can decrease the plasma concentration of posaconazole should be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections.

In clinical trials, the adverse reactions reported for posaconazole injection were generally similar to those reported in trials of posaconazole oral suspension. The most frequently reported adverse reactions with an onset during the posaconazole intravenous phase of dosing 300 mg once-daily therapy were diarrhea (32%), hypokalemia (22%), fever (21%), and nausea (19%).

Patients who are allergic to posaconazole or other azole antifungal medicines should not receive posaconazole. The drug should not be given along with sirolimus, pimozide, quinidine, atorvastatin, lovastatin, simvastatin, or ergot alkaloids.

Drugs such as cyclosporine and tacrolimus require dose adjustments and frequent blood monitoring when administered with posaconazole. Serious side effects, including nephrotoxicity, leukoencephalopathy, and death, have been reported in patients with increased cyclosporine or tacrolimus blood levels.

Healthcare professionals should use caution when administering posaconazole to patients at risk of developing an irregular heart rhythm, as the drug has been shown to prolong the QT interval, and cases of potentially fatal irregular heart rhythm (torsades de pointes) have been reported in patients taking posaconazole.

For more details, see the complete prescribing information. Posaconazole is marketed as Noxafil by Merck.

Drugs in vials

Credit: Bill Branson

The UK’s National Institute for Health and Care Excellence (NICE) has asked the manufacturer of eculizumab (Soliris) to explain the high cost of the drug.

Research has suggested that eculizumab can be effective against atypical hemolytic uremic syndrome (aHUS), a rare disease that often proves difficult to treat.

So the National Health Service (NHS) has made eculizumab available for these patients on an interim basis, pending NICE appraisal.

However, an advisory committee for NICE has estimated that routine use of eculizumab would cost the NHS about £58 million in the first year, and costs would exceed £80 million in 5 years.

Therefore, in its draft guidance for eculizumab, the committee has asked the drug’s manufacturer, Alexion Pharma, to explain its costs.

“[The committee has] asked for clarification from the company on aspects of the manufacturing, research, and development costs of a medicinal product for the treatment of a very rare condition,” said Sir Andrew Dillon, Chief Executive at NICE.

“It has also asked NHS England for clarification on treatment costs for a highly specialized technology in the context of a highly specialized service. The information provided will be considered at the next meeting of the evaluation committee in April.”

The committee will also consider comments on its draft guidance at the meeting. The guidance is available for public comment until midday on March 25.

About aHUS

Estimated to affect more than 200 people in England, aHUS is a chronic condition that causes severe inflammation of blood vessels and thrombus formation in small blood vessels throughout the body.

Patients with aHUS can experience significant kidney impairment, thrombosis, heart failure, and brain injury. In about 70% of patients, aHUS is associated with an underlying genetic or acquired abnormality of proteins in the complement immune system.

Before eculizumab became available, plasma therapy (infusion and/or exchange) was the main treatment for aHUS. However, not all patients with aHUS respond to plasma therapy. And up to 40% of patients may die or progress to end-stage renal failure and require dialysis with the first clinical aHUS manifestation, despite the use of plasma therapy.

Some patients may be eligible for a kidney or combined kidney-liver transplantation. However, there is a high risk of organ rejection following recurrent disease.

Eculizumab in aHUS: Treatment and cost

Eculizumab inhibits the disease process by blocking pro-thrombotic and pro-inflammatory processes that can lead to cellular damage in small blood vessels throughout the body, renal failure, and damage to other organs.

Eculizumab is given intravenously in adults as initial treatment at a dose of 900 mg for 4 weeks, then as maintenance treatment at a dose of 1200 mg on week 5 and then every 12 to 16 days. The summary of product characteristics for eculizumab states that treatment should be continued for the patient’s lifetime, unless discontinuation is clinically indicated.

Eculizumab costs £3150 per 30 mL vial, excluding tax, according to the British National Formulary.

“Alexion insisted that its information about the overall cost of eculizumab be kept confidential, and so NICE is unable to share these details of the Alexion submission with stakeholders,” Dillon said.

However, to allow consultees and commentators to properly engage in the consultation process, NICE has prepared an estimate of the possible budget impact eculizumab might have, using information available in the public domain.

This is based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumes a patient cohort of 170, as estimated by NHS England in its interim commissioning policy.

Assuming all of these patients receive eculizumab, the budget impact for the first year would be £57.8 million. If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 million), the budget impact will rise to £62.5 million. That is assuming all new patients are treated and all existing patients continue to be treated at the maintenance cost of £327,600 per year.

Using the same assumptions, the budget impact will rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients) and £82 million in year 5 (230 existing and 20 new patients).

Drugs in vials

Credit: Bill Branson

The UK’s National Institute for Health and Care Excellence (NICE) has asked the manufacturer of eculizumab (Soliris) to explain the high cost of the drug.

Research has suggested that eculizumab can be effective against atypical hemolytic uremic syndrome (aHUS), a rare disease that often proves difficult to treat.

So the National Health Service (NHS) has made eculizumab available for these patients on an interim basis, pending NICE appraisal.

However, an advisory committee for NICE has estimated that routine use of eculizumab would cost the NHS about £58 million in the first year, and costs would exceed £80 million in 5 years.

Therefore, in its draft guidance for eculizumab, the committee has asked the drug’s manufacturer, Alexion Pharma, to explain its costs.

“[The committee has] asked for clarification from the company on aspects of the manufacturing, research, and development costs of a medicinal product for the treatment of a very rare condition,” said Sir Andrew Dillon, Chief Executive at NICE.

“It has also asked NHS England for clarification on treatment costs for a highly specialized technology in the context of a highly specialized service. The information provided will be considered at the next meeting of the evaluation committee in April.”

The committee will also consider comments on its draft guidance at the meeting. The guidance is available for public comment until midday on March 25.

About aHUS

Estimated to affect more than 200 people in England, aHUS is a chronic condition that causes severe inflammation of blood vessels and thrombus formation in small blood vessels throughout the body.

Patients with aHUS can experience significant kidney impairment, thrombosis, heart failure, and brain injury. In about 70% of patients, aHUS is associated with an underlying genetic or acquired abnormality of proteins in the complement immune system.

Before eculizumab became available, plasma therapy (infusion and/or exchange) was the main treatment for aHUS. However, not all patients with aHUS respond to plasma therapy. And up to 40% of patients may die or progress to end-stage renal failure and require dialysis with the first clinical aHUS manifestation, despite the use of plasma therapy.

Some patients may be eligible for a kidney or combined kidney-liver transplantation. However, there is a high risk of organ rejection following recurrent disease.

Eculizumab in aHUS: Treatment and cost

Eculizumab inhibits the disease process by blocking pro-thrombotic and pro-inflammatory processes that can lead to cellular damage in small blood vessels throughout the body, renal failure, and damage to other organs.

Eculizumab is given intravenously in adults as initial treatment at a dose of 900 mg for 4 weeks, then as maintenance treatment at a dose of 1200 mg on week 5 and then every 12 to 16 days. The summary of product characteristics for eculizumab states that treatment should be continued for the patient’s lifetime, unless discontinuation is clinically indicated.

Eculizumab costs £3150 per 30 mL vial, excluding tax, according to the British National Formulary.

“Alexion insisted that its information about the overall cost of eculizumab be kept confidential, and so NICE is unable to share these details of the Alexion submission with stakeholders,” Dillon said.

However, to allow consultees and commentators to properly engage in the consultation process, NICE has prepared an estimate of the possible budget impact eculizumab might have, using information available in the public domain.

This is based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumes a patient cohort of 170, as estimated by NHS England in its interim commissioning policy.

Assuming all of these patients receive eculizumab, the budget impact for the first year would be £57.8 million. If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 million), the budget impact will rise to £62.5 million. That is assuming all new patients are treated and all existing patients continue to be treated at the maintenance cost of £327,600 per year.

Using the same assumptions, the budget impact will rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients) and £82 million in year 5 (230 existing and 20 new patients).

Drugs in vials

Credit: Bill Branson

The UK’s National Institute for Health and Care Excellence (NICE) has asked the manufacturer of eculizumab (Soliris) to explain the high cost of the drug.

Research has suggested that eculizumab can be effective against atypical hemolytic uremic syndrome (aHUS), a rare disease that often proves difficult to treat.

So the National Health Service (NHS) has made eculizumab available for these patients on an interim basis, pending NICE appraisal.

However, an advisory committee for NICE has estimated that routine use of eculizumab would cost the NHS about £58 million in the first year, and costs would exceed £80 million in 5 years.

Therefore, in its draft guidance for eculizumab, the committee has asked the drug’s manufacturer, Alexion Pharma, to explain its costs.

“[The committee has] asked for clarification from the company on aspects of the manufacturing, research, and development costs of a medicinal product for the treatment of a very rare condition,” said Sir Andrew Dillon, Chief Executive at NICE.

“It has also asked NHS England for clarification on treatment costs for a highly specialized technology in the context of a highly specialized service. The information provided will be considered at the next meeting of the evaluation committee in April.”

The committee will also consider comments on its draft guidance at the meeting. The guidance is available for public comment until midday on March 25.

About aHUS

Estimated to affect more than 200 people in England, aHUS is a chronic condition that causes severe inflammation of blood vessels and thrombus formation in small blood vessels throughout the body.

Patients with aHUS can experience significant kidney impairment, thrombosis, heart failure, and brain injury. In about 70% of patients, aHUS is associated with an underlying genetic or acquired abnormality of proteins in the complement immune system.

Before eculizumab became available, plasma therapy (infusion and/or exchange) was the main treatment for aHUS. However, not all patients with aHUS respond to plasma therapy. And up to 40% of patients may die or progress to end-stage renal failure and require dialysis with the first clinical aHUS manifestation, despite the use of plasma therapy.

Some patients may be eligible for a kidney or combined kidney-liver transplantation. However, there is a high risk of organ rejection following recurrent disease.

Eculizumab in aHUS: Treatment and cost

Eculizumab inhibits the disease process by blocking pro-thrombotic and pro-inflammatory processes that can lead to cellular damage in small blood vessels throughout the body, renal failure, and damage to other organs.

Eculizumab is given intravenously in adults as initial treatment at a dose of 900 mg for 4 weeks, then as maintenance treatment at a dose of 1200 mg on week 5 and then every 12 to 16 days. The summary of product characteristics for eculizumab states that treatment should be continued for the patient’s lifetime, unless discontinuation is clinically indicated.

Eculizumab costs £3150 per 30 mL vial, excluding tax, according to the British National Formulary.

“Alexion insisted that its information about the overall cost of eculizumab be kept confidential, and so NICE is unable to share these details of the Alexion submission with stakeholders,” Dillon said.

However, to allow consultees and commentators to properly engage in the consultation process, NICE has prepared an estimate of the possible budget impact eculizumab might have, using information available in the public domain.

This is based on a treatment cost of £340,200 per adult patient in the first year (based on the acquisition cost of the drug and the recommended dosing for an adult), and assumes a patient cohort of 170, as estimated by NHS England in its interim commissioning policy.

Assuming all of these patients receive eculizumab, the budget impact for the first year would be £57.8 million. If an additional 20 new patients are treated the following year (based on a worldwide incidence of 0.4 million), the budget impact will rise to £62.5 million. That is assuming all new patients are treated and all existing patients continue to be treated at the maintenance cost of £327,600 per year.

Using the same assumptions, the budget impact will rise to £69 million in year 3 (190 existing and 20 new patients), £75 million in year 4 (210 existing and 20 new patients) and £82 million in year 5 (230 existing and 20 new patients).

Angiogenesis; Credit: Louis

Heiser & Robert Ackland

Multiple mutations drive the development of angiosarcoma, according to a study published in Nature Genetics.

Researchers identified driver mutations in several genes associated with angiogenesis, including PTPRB and PLCG1.

They also found that PLCG1 mutations only occurred alongside mutations in PTPRB.

The investigators believe these findings may explain why angiosarcoma therapies directed at a single target fail to eradicate the disease.

Angiosarcoma is a rare cancer of the blood vessels that can occur spontaneously or develop after radiotherapy or chronic lymphedema.

Previous research indicated that aberrant angiogenesis, including somatic mutations in angiogenesis-signaling genes, drives angiosarcoma. So researchers developed drugs targeting pathways involved in angiogenesis, but these drugs have had little or no success.

“Because this cancer doesn’t respond well to traditional chemotherapy and radiotherapy, it makes sense to develop drugs that target pathways that control blood vessel formation,” said study author Peter Campbell, MD, PhD, of the Wellcome Trust Sanger Institute in the UK.

“We found 2 novel cancer genes that control blood vessel formation which are mutated in this cancer and which could be targeted for treatment of this highly aggressive cancer.”

To identify these genes, Dr Campbell and his colleagues performed whole-genome, whole-exome, and targeted sequencing in samples from patients with angiosarcoma.

Thirty-eight percent of the samples (15/39) carried mutations in genes that control angiogenesis, including PLCG1 and PTPRB.

The researchers identified 14 PTPRB mutations in 10 samples. This included 8 nonsense variants, 3 missense variants, 2 essential splice-site variants, and 1 frameshift insertion.

The investigators also discovered a recurrent mutation in PLCG1, a missense variant encoding p.Arg707Gln, which was present in 3 patient samples. All 3 PLCG1 mutations co-occurred with PTPRB mutations.

The researchers said this discovery may explain why drugs developed for a single target are ineffective in some angiosarcoma patients.

“Not only does our study change the way people view the biology of this tumor, it acts as a guide for future drug trials in angiosarcoma patients,” said study author Adrian Harris, MD, DPhil, of the University of Oxford in the UK.

He noted that researchers can use information from this study to determine if existing drugs could be effective against angiosarcoma.

Angiogenesis; Credit: Louis

Heiser & Robert Ackland

Multiple mutations drive the development of angiosarcoma, according to a study published in Nature Genetics.

Researchers identified driver mutations in several genes associated with angiogenesis, including PTPRB and PLCG1.

They also found that PLCG1 mutations only occurred alongside mutations in PTPRB.

The investigators believe these findings may explain why angiosarcoma therapies directed at a single target fail to eradicate the disease.

Angiosarcoma is a rare cancer of the blood vessels that can occur spontaneously or develop after radiotherapy or chronic lymphedema.

Previous research indicated that aberrant angiogenesis, including somatic mutations in angiogenesis-signaling genes, drives angiosarcoma. So researchers developed drugs targeting pathways involved in angiogenesis, but these drugs have had little or no success.

“Because this cancer doesn’t respond well to traditional chemotherapy and radiotherapy, it makes sense to develop drugs that target pathways that control blood vessel formation,” said study author Peter Campbell, MD, PhD, of the Wellcome Trust Sanger Institute in the UK.

“We found 2 novel cancer genes that control blood vessel formation which are mutated in this cancer and which could be targeted for treatment of this highly aggressive cancer.”

To identify these genes, Dr Campbell and his colleagues performed whole-genome, whole-exome, and targeted sequencing in samples from patients with angiosarcoma.

Thirty-eight percent of the samples (15/39) carried mutations in genes that control angiogenesis, including PLCG1 and PTPRB.

The researchers identified 14 PTPRB mutations in 10 samples. This included 8 nonsense variants, 3 missense variants, 2 essential splice-site variants, and 1 frameshift insertion.

The investigators also discovered a recurrent mutation in PLCG1, a missense variant encoding p.Arg707Gln, which was present in 3 patient samples. All 3 PLCG1 mutations co-occurred with PTPRB mutations.

The researchers said this discovery may explain why drugs developed for a single target are ineffective in some angiosarcoma patients.

“Not only does our study change the way people view the biology of this tumor, it acts as a guide for future drug trials in angiosarcoma patients,” said study author Adrian Harris, MD, DPhil, of the University of Oxford in the UK.

He noted that researchers can use information from this study to determine if existing drugs could be effective against angiosarcoma.

Angiogenesis; Credit: Louis

Heiser & Robert Ackland

Multiple mutations drive the development of angiosarcoma, according to a study published in Nature Genetics.

Researchers identified driver mutations in several genes associated with angiogenesis, including PTPRB and PLCG1.

They also found that PLCG1 mutations only occurred alongside mutations in PTPRB.

The investigators believe these findings may explain why angiosarcoma therapies directed at a single target fail to eradicate the disease.

Angiosarcoma is a rare cancer of the blood vessels that can occur spontaneously or develop after radiotherapy or chronic lymphedema.

Previous research indicated that aberrant angiogenesis, including somatic mutations in angiogenesis-signaling genes, drives angiosarcoma. So researchers developed drugs targeting pathways involved in angiogenesis, but these drugs have had little or no success.

“Because this cancer doesn’t respond well to traditional chemotherapy and radiotherapy, it makes sense to develop drugs that target pathways that control blood vessel formation,” said study author Peter Campbell, MD, PhD, of the Wellcome Trust Sanger Institute in the UK.

“We found 2 novel cancer genes that control blood vessel formation which are mutated in this cancer and which could be targeted for treatment of this highly aggressive cancer.”

To identify these genes, Dr Campbell and his colleagues performed whole-genome, whole-exome, and targeted sequencing in samples from patients with angiosarcoma.

Thirty-eight percent of the samples (15/39) carried mutations in genes that control angiogenesis, including PLCG1 and PTPRB.

The researchers identified 14 PTPRB mutations in 10 samples. This included 8 nonsense variants, 3 missense variants, 2 essential splice-site variants, and 1 frameshift insertion.

The investigators also discovered a recurrent mutation in PLCG1, a missense variant encoding p.Arg707Gln, which was present in 3 patient samples. All 3 PLCG1 mutations co-occurred with PTPRB mutations.

The researchers said this discovery may explain why drugs developed for a single target are ineffective in some angiosarcoma patients.

“Not only does our study change the way people view the biology of this tumor, it acts as a guide for future drug trials in angiosarcoma patients,” said study author Adrian Harris, MD, DPhil, of the University of Oxford in the UK.

He noted that researchers can use information from this study to determine if existing drugs could be effective against angiosarcoma.

Drug release in a cancer cell

Credit: PNAS

Researchers say they’ve discovered how a class of diabetes drugs known as biguanides exerts anticancer properties in certain malignancies.

The team identified a mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments.

By finding cancer cells with defects in this pathway or impaired glucose utilization, the researchers found they could predict which cancers would be sensitive to drugs that inhibit this pathway.

And follow-up experiments confirmed that lymphoma, leukemia, and myeloma tumors were among those sensitive to treatment.

Kivanç Birsoy, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues reported these findings in Nature.

To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, the researchers developed a system that circulates low-nutrient media continuously around cells.

Of the 30 cancer cell lines the team tested within this system, most appeared unaffected by a lack of glucose. However, a few of the cells lines thrived and reproduced rapidly, while others struggled.

Specifically, a low-glucose environment prompted an increase in proliferation for the Burkitt lymphoma cell line Raji, as well as in medulloblastoma, lung, and stomach cancer cell lines.

However, the lymphoma cell lines U-937 and MC116, as well as the myeloma cell lines NCI-H929 and KMS-26, saw significant decreases in proliferation in a low-glucose environment. The leukemia cell line Jurkat was moderately sensitive to a low-glucose environment.

“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” said study author Richard Possemato, PhD, also of the Whitehead Institute.

To gain more insight, the researchers screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation.

The team hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer.

If true, the hypothesis would suggest that further impairing mitochondrial function with biguanides, which are known oxidative phosphorylation inhibitors, could push the mitochondria beyond their limits, to the detriment of the cancer cells.

The researchers first tested this hypothesis in vitro on cell lines with glucose utilization defects (NCI-H929, KMS-26, LP-1, L-363, MOLP-8, D341Med, and KMS-28BM) or mitochondrial DNA (mtDNA) mutations (U-937, BxPC3, Cal-62, HCC-1438, HCC-827, and NU-DHL-1).

They found that, in a low-glucose environment, cell lines with mtDNA mutations or impaired glucose utilization were 5 to 20 times more susceptible to phenformin, a more potent biguanide than metformin, when compared to control cancer cell lines or an immortalized B-cell line.

The team then tested phenformin in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the growth of tumors derived from cancer cells with mtDNA mutations (Cal-62 and U-937) or poor glucose consumption (KMS-26 and NCI-H929) but not from cells lacking these defects (NCI-H2171 and NCI-H82).

“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” Dr Birsoy said.

“And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”

To confirm the accuracy of their proposed biomarkers, the researchers now want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.

Drug release in a cancer cell

Credit: PNAS

Researchers say they’ve discovered how a class of diabetes drugs known as biguanides exerts anticancer properties in certain malignancies.

The team identified a mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments.

By finding cancer cells with defects in this pathway or impaired glucose utilization, the researchers found they could predict which cancers would be sensitive to drugs that inhibit this pathway.

And follow-up experiments confirmed that lymphoma, leukemia, and myeloma tumors were among those sensitive to treatment.

Kivanç Birsoy, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues reported these findings in Nature.

To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, the researchers developed a system that circulates low-nutrient media continuously around cells.

Of the 30 cancer cell lines the team tested within this system, most appeared unaffected by a lack of glucose. However, a few of the cells lines thrived and reproduced rapidly, while others struggled.

Specifically, a low-glucose environment prompted an increase in proliferation for the Burkitt lymphoma cell line Raji, as well as in medulloblastoma, lung, and stomach cancer cell lines.

However, the lymphoma cell lines U-937 and MC116, as well as the myeloma cell lines NCI-H929 and KMS-26, saw significant decreases in proliferation in a low-glucose environment. The leukemia cell line Jurkat was moderately sensitive to a low-glucose environment.

“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” said study author Richard Possemato, PhD, also of the Whitehead Institute.

To gain more insight, the researchers screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation.

The team hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer.

If true, the hypothesis would suggest that further impairing mitochondrial function with biguanides, which are known oxidative phosphorylation inhibitors, could push the mitochondria beyond their limits, to the detriment of the cancer cells.

The researchers first tested this hypothesis in vitro on cell lines with glucose utilization defects (NCI-H929, KMS-26, LP-1, L-363, MOLP-8, D341Med, and KMS-28BM) or mitochondrial DNA (mtDNA) mutations (U-937, BxPC3, Cal-62, HCC-1438, HCC-827, and NU-DHL-1).

They found that, in a low-glucose environment, cell lines with mtDNA mutations or impaired glucose utilization were 5 to 20 times more susceptible to phenformin, a more potent biguanide than metformin, when compared to control cancer cell lines or an immortalized B-cell line.

The team then tested phenformin in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the growth of tumors derived from cancer cells with mtDNA mutations (Cal-62 and U-937) or poor glucose consumption (KMS-26 and NCI-H929) but not from cells lacking these defects (NCI-H2171 and NCI-H82).

“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” Dr Birsoy said.

“And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”

To confirm the accuracy of their proposed biomarkers, the researchers now want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.

Drug release in a cancer cell

Credit: PNAS

Researchers say they’ve discovered how a class of diabetes drugs known as biguanides exerts anticancer properties in certain malignancies.

The team identified a mitochondrial pathway that imbues cancer cells with the ability to survive in low-glucose environments.

By finding cancer cells with defects in this pathway or impaired glucose utilization, the researchers found they could predict which cancers would be sensitive to drugs that inhibit this pathway.

And follow-up experiments confirmed that lymphoma, leukemia, and myeloma tumors were among those sensitive to treatment.

Kivanç Birsoy, PhD, of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, and his colleagues reported these findings in Nature.

To study how cancer cells survive in the kind of low-glucose environment found within cancerous tumors, the researchers developed a system that circulates low-nutrient media continuously around cells.

Of the 30 cancer cell lines the team tested within this system, most appeared unaffected by a lack of glucose. However, a few of the cells lines thrived and reproduced rapidly, while others struggled.

Specifically, a low-glucose environment prompted an increase in proliferation for the Burkitt lymphoma cell line Raji, as well as in medulloblastoma, lung, and stomach cancer cell lines.

However, the lymphoma cell lines U-937 and MC116, as well as the myeloma cell lines NCI-H929 and KMS-26, saw significant decreases in proliferation in a low-glucose environment. The leukemia cell line Jurkat was moderately sensitive to a low-glucose environment.

“No one really understood why cancer cells had these responses or whether they were important for the formation of the tumor,” said study author Richard Possemato, PhD, also of the Whitehead Institute.

To gain more insight, the researchers screened overly distressed cells for genes whose suppression improved or further hindered the cells’ survival rates. The screen flagged genes involved in glucose transportation and oxidative phosphorylation.

The team hypothesized that cancer cells with mutations in these genes are over-taxing their mitochondria under normal conditions. When placed in a harsh, low-glucose environment, the mitochondria are maxed out, and the cells suffer.

If true, the hypothesis would suggest that further impairing mitochondrial function with biguanides, which are known oxidative phosphorylation inhibitors, could push the mitochondria beyond their limits, to the detriment of the cancer cells.

The researchers first tested this hypothesis in vitro on cell lines with glucose utilization defects (NCI-H929, KMS-26, LP-1, L-363, MOLP-8, D341Med, and KMS-28BM) or mitochondrial DNA (mtDNA) mutations (U-937, BxPC3, Cal-62, HCC-1438, HCC-827, and NU-DHL-1).

They found that, in a low-glucose environment, cell lines with mtDNA mutations or impaired glucose utilization were 5 to 20 times more susceptible to phenformin, a more potent biguanide than metformin, when compared to control cancer cell lines or an immortalized B-cell line.

The team then tested phenformin in mice implanted with tumors derived from low-glucose-sensitive cancer cells. The drug inhibited the growth of tumors derived from cancer cells with mtDNA mutations (Cal-62 and U-937) or poor glucose consumption (KMS-26 and NCI-H929) but not from cells lacking these defects (NCI-H2171 and NCI-H82).

“These results show that mitochondrial DNA mutations and glucose import defects can be used as biomarkers for biguanide sensitivity to determine if a cancer patient might benefit from these drugs,” Dr Birsoy said.

“And this is the first time that anyone has shown that the direct cytotoxic effects of this class of drugs, including metformin and phenformin, on cancer cells are mediated through their effect on mitochondria.”

To confirm the accuracy of their proposed biomarkers, the researchers now want to analyze previous clinical trials to see if cancer patients with the proposed biomarkers fared better with metformin treatment than patients without the biomarkers.

The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.

The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.

For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).

Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.

Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.

The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.

"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."

Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.

"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."

To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.

"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."

QOL

Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.

"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."

Breast cancer

For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.

Lung cancer

The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.

Colon cancer

The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.

Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.

"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.

She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.

Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."

Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.

[email protected]

The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.

The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.

For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).

Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.

Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.

The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.

"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."

Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.

"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."

To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.

"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."

QOL

Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.

"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."

Breast cancer

For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.

Lung cancer

The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.

Colon cancer

The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.

Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.

"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.

She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.

Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."

Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.

[email protected]

The American Society of Clinical Oncology is pressing cancer researchers to rethink the design of future clinical trials to achieve larger gains in four common cancers.

The final recommendations, which come after months of deliberations and public comment, try to hit the sweet spot between proposing guidelines that are not obtainable, and thus ignored, and having ambitious yet realistic goals.

For pancreatic cancer, for example, the experts recommended that clinical trials seek to improve median overall survival by 50%, or 4-5 months, for patients eligible for FOLFIRINOX (leucovorin, fluorouracil, irinotecan, and oxaliplatin) and by 3-4 months for those eligible for gemcitabine (Gemzar) with or without nab-paclitaxel (Abraxane).

Overall survival (OS) was selected over progression-free survival as the primary endpoint, although it was acknowledged that OS poses challenges such as the need for longer follow-up, the potential confounding effect of post-study therapies, and use of second-line therapies for secondary mutations identified after progression during first-line targeted therapy.

Ultimately, an improvement in median OS of 2.5-6 months, depending on the setting, was identified as the minimum incremental improvement over standard therapy that would define a clinically meaningful outcome.

The recommendations, published March 17 in the Journal of Clinical Oncology (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.53.8009]), also note that incremental improvements should be accompanied by little to no added toxicity over current treatments, and that a highly toxic regimen should produce the greatest OS gains to be considered clinically meaningful.

"We expect that sponsors will appreciate the need for raising the bar with regard to clinical trial goals, but that they will be conservative in their adoption of the recommendations," Dr. Lee M. Ellis, committee chair and professor of surgery at the University of Texas M.D. Anderson Cancer Center, Houston, said in an interview. "Trials designed with less ambitious goals may still be of benefit to individual patients if trial endpoints are met and if we can develop methods to identify patients most likely to benefit from the intervention."

Achieving the "smaller and smarter" trials envisioned by the committee rests on the ability to select patients for targeted therapy based on the molecular drivers of their tumors, rather than enrolling all comers. Unfortunately, in many cases, targeted agents continue to be developed without complete understanding of the drug target and, therefore, companion diagnostics to aid in patient selection, the experts observed.

"It is difficult to hit a target when it is not certain where it is or if it is valid," agreed Dr. David M. Dilts, codirector of the Center for Management Research in Healthcare, Oregon Health & Science University, Portland, in an accompanying editorial (J. Clin. Oncol. 2014 Mar. 17 [doi:10.1200/JCO.2013.54.5277]). "This, not insubstantial risk, should be ameliorated in the near future as major clinical research organizations are banking specimens, some of which are highly annotated, and as technology to analyze such specimens becomes faster, better, and cheaper."

To further this goal, the expert committee calls on trial sponsors to develop comprehensive biospecimen banks for each trial.

"Obstacles to developing these banks include cost and the willingness and ability of trial sponsors to foot the bill," Dr. Ellis said. "However, we believe the investment will pay off in increasing our ability to understand the molecular drivers of cancer and, as a result, more appropriate targeted therapies for people with cancer."

QOL

Though quality of life was a common theme that arose in all working group discussions, the recommendations lack hard targets in this area. Instead, the working groups cited the 2011 approval of the Janus kinase 1 and 2 inhibitor ruxolitinib (Jakavi) for myelofibrosis as an example of how serial assessment of specific cancer-related symptoms can define a clinically meaningful outcome for patients.

"It is not enough to just mention how important quality of life is. A clinical trial must be designed with a suite of thoughtful, feasible, validated patient-reported outcome measures that capture clinical benefit," Ms. Musa Mayer, a long-time advocate for patients with metastatic breast cancer, said in an interview. "Observed adverse events can never fully account for the lived experience of a given treatment."

Breast cancer

For breast cancer, the committee selected metastatic triple-negative breast cancer that was previously untreated for metastatic disease. They recommend clinical trials aim for an increase in OS of 4.5-6 months, although it was noted that consensus was not achieved by the breast cancer group on the magnitude of the benefit that would be considered clinically meaningful. The current median overall survival in this poor-prognosis population is 18 months.

Lung cancer

The committee addressed two lung cancer populations: nonsquamous cell carcinoma and squamous cell carcinoma. They recommend clinical trials seek to improve OS by 3.25-4 months and by 2.5-3 months, respectively. Current baseline median OS in these groups is 13 and 10 months.

Colon cancer

The recommendations for colon cancer target patients with disease progression with all prior therapies, or who are not candidates for standard second- or third-line options. Here, the goal is to improve OS by 3-5 months over the current baseline median OS of 4-6 months.

Notably, the cost of delivering the recommended targets for all four cancers was not addressed by the committee. The ASCO Value of Cancer Care Task Force, however, is already tasked with evaluating the efficacy, toxicity, and cost of specific oncology treatments.

"The working group provided thoughtful recommendations for the topics considered, although the specific recommendations were limited," Ms. Patricia Haugen, breast cancer survivor and current member and previous chair of the Department of Defense Congressionally Directed Breast Cancer Research Program Integration Panel, said in an interview.

She is hopeful that the new recommendations will be followed, but said there needs to be broad support and commitment to changes that produce more meaningful clinical benefit. "That commitment must be real and must come from all parties involved in the clinical trials process, so that clinical trials that do not meet a high bar are not considered, funded, nor implemented," she said.

Editorialist Dr. Dilts agreed that advocates from many areas are needed if the recommended goals are to be reached and suggested what might be required is "a more DARPA [Defense Advanced Research Projects Agency] approach, where answering high-risk questions are fostered and supported."

Dr. Ellis reported a consultant/advisory role with Genentech, Roche, Imclone, Eli Lilly, and Amgen. Ms. Mayer, Ms. Haugen, and Dr. Dilts reported no potential conflicts of interest.

[email protected]

The American Academy’s 2014 annual meeting in Denver will feature new CME sessions and updates on the latest dermatology research.

This year’s program features expert commentary on key issues in medical dermatology, including "Melanoma Multidisciplinary Care 2014: What You Need to Know" on Sunday, March 23, from 1 p.m. to 3 p.m. in Room 705/707 and "Dermatologic Manifestations of New Oncology Drugs," also on Sunday, March 23, from 1 p.m. to 3 p.m. in the Mile High Ballroom 3B. Looking for the latest in aesthetic dermatology? Check out the "Advanced Botulinum Toxin" live demonstration session on Saturday, March 22, from 2 p.m. to 5 p.m. in the Bellco Theater.

There will be expert sessions on pregnancy dermatoses, cutaneous T-cell lymphoma, pediatric dermatology, skin of color, and the latest on treatments for hair and nail conditions. The full scientific session list is available online.

A series of practice management lectures includes topics such as "How to Have an Unforgettably Positive Office Visit" on Saturday, March 22, from 10:00 a.m. to 12:00 p.m. in Room 709/7111 and "Hot Buttons: Recognizing What Sets You Off and Managing Your Triggers" on Sunday, March 23, from 1:00 p.m. to 3:00 p.m. in Room 702.

There is also a mobile device app that meeting attendees can download that contains session schedules, exhibitor and attendee lists, and more.

Can’t attend the meeting? Visit www.eDermatologyNews.com for live conference coverage.

[email protected]

On Twitter @Sknews

The American Academy’s 2014 annual meeting in Denver will feature new CME sessions and updates on the latest dermatology research.

This year’s program features expert commentary on key issues in medical dermatology, including "Melanoma Multidisciplinary Care 2014: What You Need to Know" on Sunday, March 23, from 1 p.m. to 3 p.m. in Room 705/707 and "Dermatologic Manifestations of New Oncology Drugs," also on Sunday, March 23, from 1 p.m. to 3 p.m. in the Mile High Ballroom 3B. Looking for the latest in aesthetic dermatology? Check out the "Advanced Botulinum Toxin" live demonstration session on Saturday, March 22, from 2 p.m. to 5 p.m. in the Bellco Theater.

There will be expert sessions on pregnancy dermatoses, cutaneous T-cell lymphoma, pediatric dermatology, skin of color, and the latest on treatments for hair and nail conditions. The full scientific session list is available online.

A series of practice management lectures includes topics such as "How to Have an Unforgettably Positive Office Visit" on Saturday, March 22, from 10:00 a.m. to 12:00 p.m. in Room 709/7111 and "Hot Buttons: Recognizing What Sets You Off and Managing Your Triggers" on Sunday, March 23, from 1:00 p.m. to 3:00 p.m. in Room 702.

There is also a mobile device app that meeting attendees can download that contains session schedules, exhibitor and attendee lists, and more.

Can’t attend the meeting? Visit www.eDermatologyNews.com for live conference coverage.

[email protected]

On Twitter @Sknews

The American Academy’s 2014 annual meeting in Denver will feature new CME sessions and updates on the latest dermatology research.

This year’s program features expert commentary on key issues in medical dermatology, including "Melanoma Multidisciplinary Care 2014: What You Need to Know" on Sunday, March 23, from 1 p.m. to 3 p.m. in Room 705/707 and "Dermatologic Manifestations of New Oncology Drugs," also on Sunday, March 23, from 1 p.m. to 3 p.m. in the Mile High Ballroom 3B. Looking for the latest in aesthetic dermatology? Check out the "Advanced Botulinum Toxin" live demonstration session on Saturday, March 22, from 2 p.m. to 5 p.m. in the Bellco Theater.

There will be expert sessions on pregnancy dermatoses, cutaneous T-cell lymphoma, pediatric dermatology, skin of color, and the latest on treatments for hair and nail conditions. The full scientific session list is available online.

A series of practice management lectures includes topics such as "How to Have an Unforgettably Positive Office Visit" on Saturday, March 22, from 10:00 a.m. to 12:00 p.m. in Room 709/7111 and "Hot Buttons: Recognizing What Sets You Off and Managing Your Triggers" on Sunday, March 23, from 1:00 p.m. to 3:00 p.m. in Room 702.

There is also a mobile device app that meeting attendees can download that contains session schedules, exhibitor and attendee lists, and more.

Can’t attend the meeting? Visit www.eDermatologyNews.com for live conference coverage.

[email protected]

On Twitter @Sknews

WAIKOLOA, HAWAII – A key point to understand about Juvederm Voluma XC, the recently approved filler for age-related midface volume deficit, is that it’s a pillar or lift product, according to Dr. Sue Ellen Cox.

"Voluma loves to lift. It works great when placed on bone, such as the malar bone. With a supraperiosteal vertical puncture, you’ll see the skin lift right in front of your eyes," said Dr. Cox, a dermatologist at the University of North Carolina at Chapel Hill and principal investigator in the pivotal clinical trial that led to Food and Drug Administration approval of Voluma.

This characteristic of the highly cohesive 20-mg/mL hyaluronic acid filler has important implications for the product’s optimal use and achieving maximal patient satisfaction. For one, Voluma absolutely should not be used for patients with thin skin. For these patients, a more effective option is a product containing monophasic monodensified hyaluronic acids, such as Juvederm Ultra or Ultra Plus, Dr. Cox said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

As a rule of thumb, approximately 40% of Voluma is needed compared with the amount of monophasic monodensified hyaluronic acid fillers dermatologists are accustomed to working with, she said.

It’s crucial to inject Voluma extremely slowly, Dr. Cox emphasized. She advised scheduling 30 minutes for a patient’s first volumizing session. It’s also important to avoid using a large bolus, and be sure not to overcorrect. Voluma loves water and will draw it from tissue, Dr. Cox noted. Therefore it’s important to use the exact correction. Remember that at 9 months post treatment, 50% or more of the original correction will remain, so the 9-month mark is a good time to schedule a touch-up, she added.

Another pearl: Inject struts or pillars from the periostium; then blend and mold them, Dr. Cox continued.

She urged her colleagues to be conservative in using Voluma around the eyes. In her experience, too much Voluma in this area causes the product to migrate anteriorly on the cheek, which could result in an unwelcome doughy appearance.

To achieve improvement in the submalar area, it’s best to utilize tangential microdroplets of Voluma after reconstitution with saline so the filler doesn’t affect the nerve and cause a lip drop, according to Dr. Cox.

Should it become necessary to dissolve Voluma, use twice as much hyaluronidase (Hylenex).

Dr. Cox reported serving as a consultant to Allergan and Medicis and serving as principal investigator in trials funded by those companies, as well as in studies funded by Revance and Kythera.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – A key point to understand about Juvederm Voluma XC, the recently approved filler for age-related midface volume deficit, is that it’s a pillar or lift product, according to Dr. Sue Ellen Cox.

"Voluma loves to lift. It works great when placed on bone, such as the malar bone. With a supraperiosteal vertical puncture, you’ll see the skin lift right in front of your eyes," said Dr. Cox, a dermatologist at the University of North Carolina at Chapel Hill and principal investigator in the pivotal clinical trial that led to Food and Drug Administration approval of Voluma.

This characteristic of the highly cohesive 20-mg/mL hyaluronic acid filler has important implications for the product’s optimal use and achieving maximal patient satisfaction. For one, Voluma absolutely should not be used for patients with thin skin. For these patients, a more effective option is a product containing monophasic monodensified hyaluronic acids, such as Juvederm Ultra or Ultra Plus, Dr. Cox said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

As a rule of thumb, approximately 40% of Voluma is needed compared with the amount of monophasic monodensified hyaluronic acid fillers dermatologists are accustomed to working with, she said.

It’s crucial to inject Voluma extremely slowly, Dr. Cox emphasized. She advised scheduling 30 minutes for a patient’s first volumizing session. It’s also important to avoid using a large bolus, and be sure not to overcorrect. Voluma loves water and will draw it from tissue, Dr. Cox noted. Therefore it’s important to use the exact correction. Remember that at 9 months post treatment, 50% or more of the original correction will remain, so the 9-month mark is a good time to schedule a touch-up, she added.

Another pearl: Inject struts or pillars from the periostium; then blend and mold them, Dr. Cox continued.

She urged her colleagues to be conservative in using Voluma around the eyes. In her experience, too much Voluma in this area causes the product to migrate anteriorly on the cheek, which could result in an unwelcome doughy appearance.

To achieve improvement in the submalar area, it’s best to utilize tangential microdroplets of Voluma after reconstitution with saline so the filler doesn’t affect the nerve and cause a lip drop, according to Dr. Cox.

Should it become necessary to dissolve Voluma, use twice as much hyaluronidase (Hylenex).

Dr. Cox reported serving as a consultant to Allergan and Medicis and serving as principal investigator in trials funded by those companies, as well as in studies funded by Revance and Kythera.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – A key point to understand about Juvederm Voluma XC, the recently approved filler for age-related midface volume deficit, is that it’s a pillar or lift product, according to Dr. Sue Ellen Cox.

"Voluma loves to lift. It works great when placed on bone, such as the malar bone. With a supraperiosteal vertical puncture, you’ll see the skin lift right in front of your eyes," said Dr. Cox, a dermatologist at the University of North Carolina at Chapel Hill and principal investigator in the pivotal clinical trial that led to Food and Drug Administration approval of Voluma.

This characteristic of the highly cohesive 20-mg/mL hyaluronic acid filler has important implications for the product’s optimal use and achieving maximal patient satisfaction. For one, Voluma absolutely should not be used for patients with thin skin. For these patients, a more effective option is a product containing monophasic monodensified hyaluronic acids, such as Juvederm Ultra or Ultra Plus, Dr. Cox said at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

As a rule of thumb, approximately 40% of Voluma is needed compared with the amount of monophasic monodensified hyaluronic acid fillers dermatologists are accustomed to working with, she said.

It’s crucial to inject Voluma extremely slowly, Dr. Cox emphasized. She advised scheduling 30 minutes for a patient’s first volumizing session. It’s also important to avoid using a large bolus, and be sure not to overcorrect. Voluma loves water and will draw it from tissue, Dr. Cox noted. Therefore it’s important to use the exact correction. Remember that at 9 months post treatment, 50% or more of the original correction will remain, so the 9-month mark is a good time to schedule a touch-up, she added.

Another pearl: Inject struts or pillars from the periostium; then blend and mold them, Dr. Cox continued.

She urged her colleagues to be conservative in using Voluma around the eyes. In her experience, too much Voluma in this area causes the product to migrate anteriorly on the cheek, which could result in an unwelcome doughy appearance.

To achieve improvement in the submalar area, it’s best to utilize tangential microdroplets of Voluma after reconstitution with saline so the filler doesn’t affect the nerve and cause a lip drop, according to Dr. Cox.

Should it become necessary to dissolve Voluma, use twice as much hyaluronidase (Hylenex).

Dr. Cox reported serving as a consultant to Allergan and Medicis and serving as principal investigator in trials funded by those companies, as well as in studies funded by Revance and Kythera.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – Juvederm Voluma XC continues to show significant results in extended follow-up data from the pivotal phase III trial that earned the product marketing approval from the Food and Drug Administration late last year as the first filler indicated specifically for treating age-related midface volume deficit.

One of the notable new findings: At 6 months post treatment, 73% of Voluma-treated study participants rated themselves as looking younger than at baseline – and by an average of 5 years less than their mean baseline chronologic age of 56 years. Moreover, at 24 months, 55% of patients said they felt that they still looked younger by an average of 3 years, Dr. Sue Ellen Cox reported at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

"The improvement was really profound. What was also profound was how long it lasted. I’m now 3 years out seeing these patients and they still have retention of their product. So I am a believer," said Dr. Cox, a dermatologist at the University of North Carolina at Chapel Hill, who was principal investigator in the pivotal phase III trial.

Dr. Cox shared highlights of the extended follow-up data, along with her personal observations regarding how to use Voluma most effectively.

Voluma XC is a highly cohesive volumizing hyaluronic acid filler formulated at a concentration of 20 mg/mL. It fills what has been widely regarded as a major unmet need in aesthetic dermatology, said Dr. Cox

"It’s a wonderful filler we’re all really going to enjoy using. I think it’s going to prove to be everything we want it to be," she said.

The pivotal data reviewed by the FDA came from a 15-center, randomized, single-blind clinical trial including 235 Voluma-treated patients and 47 no-treatment controls. All patients had moderate or severe baseline midface volume deficits as reflected by scores of 3-5 on a standardized 0-5 scoring system. The active treatment group received one treatment with the option of a touch-up session a month later.

The primary study endpoint prespecified by the FDA was an improvement of at least 1 point between baseline and 6 months on the Mid-Facial Volume Deficit Scale (MFVDS). This endpoint was achieved in 86% of the Voluma group and 39% of controls. Moreover, 51% of the active treatment group had an improvement of 2 points or greater compared with 11% of controls. And 26% of the Voluma group, but none of the controls, showed a 2.5-point improvement or better.

The durability of the treatment response was noteworthy, Dr. Cox added. At 2 years, 67% of patients in the Voluma group maintained a clinically significant improvement based upon MFVDS scores.

Every 3 months for the 2 years of follow-up, patients were asked how they felt about their appearance. As Dr. Cox noted, this is the true litmus test for any aesthetic dermatology procedure. At 6 months, 90% of patients pronounced themselves satisfied with the improvement in their facial appearance. At 12 months, 82% said they were satisfied; and at 2 years post treatment, 76% of patients remained satisfied with their facial appearance.

At baseline, 67% of patients rated their midface appearance as making them look "very much" older; at 6 months post treatment, only 12% of patients felt that way. Similarly, at baseline 55%-66% of patients characterized their midface appearance as variously "very much" unattractive, sad, and/or tired; at 6 months post treatment, only 9%-11% of subjects did so.

Treatment of the nasolabial folds and tear ducts was not permitted in the pivotal trial. Yet by investigator assessment at 6 months’ follow-up 32% of the active treatment group had a clinically meaningful improvement of at least 1 point on the 5-point Nasolabial Fold Photo Severity Scale, compared with 8% of controls, said Dr. Cox. Moreover, 54% of Voluma-treated patients rated themselves as moderately, very much, or completely satisfied with the appearance of their tear trough area, a marked improvement over the 17% rate at baseline. These findings underscore the point that effectively reinflating the midface and reestablishing optimal proportion provides ancillary benefits that may render treatment of the tear troughs and nasolabial folds unnecessary, she said.

Common treatment side effects consisted of mild to moderate injection site tenderness, swelling, bruising, lumps and bumps, and pain. All cases of side effects resolved within 30 days, and most resolved within 2 weeks.

Dr. Cox reported acting as a consultant to Allergan and Medicis and serving as principal investigator in trials funded by those companies, as well as in studies funded by Revance and Kythera.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – Juvederm Voluma XC continues to show significant results in extended follow-up data from the pivotal phase III trial that earned the product marketing approval from the Food and Drug Administration late last year as the first filler indicated specifically for treating age-related midface volume deficit.

One of the notable new findings: At 6 months post treatment, 73% of Voluma-treated study participants rated themselves as looking younger than at baseline – and by an average of 5 years less than their mean baseline chronologic age of 56 years. Moreover, at 24 months, 55% of patients said they felt that they still looked younger by an average of 3 years, Dr. Sue Ellen Cox reported at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

"The improvement was really profound. What was also profound was how long it lasted. I’m now 3 years out seeing these patients and they still have retention of their product. So I am a believer," said Dr. Cox, a dermatologist at the University of North Carolina at Chapel Hill, who was principal investigator in the pivotal phase III trial.

Dr. Cox shared highlights of the extended follow-up data, along with her personal observations regarding how to use Voluma most effectively.

Voluma XC is a highly cohesive volumizing hyaluronic acid filler formulated at a concentration of 20 mg/mL. It fills what has been widely regarded as a major unmet need in aesthetic dermatology, said Dr. Cox

"It’s a wonderful filler we’re all really going to enjoy using. I think it’s going to prove to be everything we want it to be," she said.

The pivotal data reviewed by the FDA came from a 15-center, randomized, single-blind clinical trial including 235 Voluma-treated patients and 47 no-treatment controls. All patients had moderate or severe baseline midface volume deficits as reflected by scores of 3-5 on a standardized 0-5 scoring system. The active treatment group received one treatment with the option of a touch-up session a month later.

The primary study endpoint prespecified by the FDA was an improvement of at least 1 point between baseline and 6 months on the Mid-Facial Volume Deficit Scale (MFVDS). This endpoint was achieved in 86% of the Voluma group and 39% of controls. Moreover, 51% of the active treatment group had an improvement of 2 points or greater compared with 11% of controls. And 26% of the Voluma group, but none of the controls, showed a 2.5-point improvement or better.

The durability of the treatment response was noteworthy, Dr. Cox added. At 2 years, 67% of patients in the Voluma group maintained a clinically significant improvement based upon MFVDS scores.

Every 3 months for the 2 years of follow-up, patients were asked how they felt about their appearance. As Dr. Cox noted, this is the true litmus test for any aesthetic dermatology procedure. At 6 months, 90% of patients pronounced themselves satisfied with the improvement in their facial appearance. At 12 months, 82% said they were satisfied; and at 2 years post treatment, 76% of patients remained satisfied with their facial appearance.

At baseline, 67% of patients rated their midface appearance as making them look "very much" older; at 6 months post treatment, only 12% of patients felt that way. Similarly, at baseline 55%-66% of patients characterized their midface appearance as variously "very much" unattractive, sad, and/or tired; at 6 months post treatment, only 9%-11% of subjects did so.

Treatment of the nasolabial folds and tear ducts was not permitted in the pivotal trial. Yet by investigator assessment at 6 months’ follow-up 32% of the active treatment group had a clinically meaningful improvement of at least 1 point on the 5-point Nasolabial Fold Photo Severity Scale, compared with 8% of controls, said Dr. Cox. Moreover, 54% of Voluma-treated patients rated themselves as moderately, very much, or completely satisfied with the appearance of their tear trough area, a marked improvement over the 17% rate at baseline. These findings underscore the point that effectively reinflating the midface and reestablishing optimal proportion provides ancillary benefits that may render treatment of the tear troughs and nasolabial folds unnecessary, she said.

Common treatment side effects consisted of mild to moderate injection site tenderness, swelling, bruising, lumps and bumps, and pain. All cases of side effects resolved within 30 days, and most resolved within 2 weeks.

Dr. Cox reported acting as a consultant to Allergan and Medicis and serving as principal investigator in trials funded by those companies, as well as in studies funded by Revance and Kythera.

SDEF and this news organization are owned by the same parent company.

[email protected]

WAIKOLOA, HAWAII – Juvederm Voluma XC continues to show significant results in extended follow-up data from the pivotal phase III trial that earned the product marketing approval from the Food and Drug Administration late last year as the first filler indicated specifically for treating age-related midface volume deficit.

One of the notable new findings: At 6 months post treatment, 73% of Voluma-treated study participants rated themselves as looking younger than at baseline – and by an average of 5 years less than their mean baseline chronologic age of 56 years. Moreover, at 24 months, 55% of patients said they felt that they still looked younger by an average of 3 years, Dr. Sue Ellen Cox reported at the Hawaii Dermatology Seminar sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

"The improvement was really profound. What was also profound was how long it lasted. I’m now 3 years out seeing these patients and they still have retention of their product. So I am a believer," said Dr. Cox, a dermatologist at the University of North Carolina at Chapel Hill, who was principal investigator in the pivotal phase III trial.

Dr. Cox shared highlights of the extended follow-up data, along with her personal observations regarding how to use Voluma most effectively.

Voluma XC is a highly cohesive volumizing hyaluronic acid filler formulated at a concentration of 20 mg/mL. It fills what has been widely regarded as a major unmet need in aesthetic dermatology, said Dr. Cox

"It’s a wonderful filler we’re all really going to enjoy using. I think it’s going to prove to be everything we want it to be," she said.

The pivotal data reviewed by the FDA came from a 15-center, randomized, single-blind clinical trial including 235 Voluma-treated patients and 47 no-treatment controls. All patients had moderate or severe baseline midface volume deficits as reflected by scores of 3-5 on a standardized 0-5 scoring system. The active treatment group received one treatment with the option of a touch-up session a month later.

The primary study endpoint prespecified by the FDA was an improvement of at least 1 point between baseline and 6 months on the Mid-Facial Volume Deficit Scale (MFVDS). This endpoint was achieved in 86% of the Voluma group and 39% of controls. Moreover, 51% of the active treatment group had an improvement of 2 points or greater compared with 11% of controls. And 26% of the Voluma group, but none of the controls, showed a 2.5-point improvement or better.

The durability of the treatment response was noteworthy, Dr. Cox added. At 2 years, 67% of patients in the Voluma group maintained a clinically significant improvement based upon MFVDS scores.

Every 3 months for the 2 years of follow-up, patients were asked how they felt about their appearance. As Dr. Cox noted, this is the true litmus test for any aesthetic dermatology procedure. At 6 months, 90% of patients pronounced themselves satisfied with the improvement in their facial appearance. At 12 months, 82% said they were satisfied; and at 2 years post treatment, 76% of patients remained satisfied with their facial appearance.

At baseline, 67% of patients rated their midface appearance as making them look "very much" older; at 6 months post treatment, only 12% of patients felt that way. Similarly, at baseline 55%-66% of patients characterized their midface appearance as variously "very much" unattractive, sad, and/or tired; at 6 months post treatment, only 9%-11% of subjects did so.

Treatment of the nasolabial folds and tear ducts was not permitted in the pivotal trial. Yet by investigator assessment at 6 months’ follow-up 32% of the active treatment group had a clinically meaningful improvement of at least 1 point on the 5-point Nasolabial Fold Photo Severity Scale, compared with 8% of controls, said Dr. Cox. Moreover, 54% of Voluma-treated patients rated themselves as moderately, very much, or completely satisfied with the appearance of their tear trough area, a marked improvement over the 17% rate at baseline. These findings underscore the point that effectively reinflating the midface and reestablishing optimal proportion provides ancillary benefits that may render treatment of the tear troughs and nasolabial folds unnecessary, she said.

Common treatment side effects consisted of mild to moderate injection site tenderness, swelling, bruising, lumps and bumps, and pain. All cases of side effects resolved within 30 days, and most resolved within 2 weeks.

Dr. Cox reported acting as a consultant to Allergan and Medicis and serving as principal investigator in trials funded by those companies, as well as in studies funded by Revance and Kythera.

SDEF and this news organization are owned by the same parent company.

[email protected]