Patrice Wendling

The investigational anti-PCSK9 antibody AMG145 significantly lowers LDL cholesterol in high-risk patients unable to tolerate statins, the phase II GAUSS trial showed.

Three subcutaneous injections of AMG145 at varying doses reduced LDL cholesterol by up to 51% when used as monotherapy, and by 63% when combined with ezetimibe (Zetia), compared with an expected 15% reduction with ezetimibe and placebo.

These reductions are comparable with those achieved with maximal doses of the most efficacious statins.

If the results are confirmed in larger and longer-term studies, AMG145 could provide a new therapeutic option for high-risk patients who currently have few treatment options, Dr. Evan Stein reported at the annual scientific sessions of the American Heart Association in Los Angeles.

In GAUSS (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects), 84% of all patients were unable to tolerate even low doses of any statin.

Overall, about 10%-20% of people can’t tolerate statins at all or the higher doses needed to achieve recommended LDL cholesterol goals, primarily because of muscle-related side effects. Ezetimibe is frequently used as an alternative for these patients, but without great success.

Evidence and enthusiasm are growing, however, for the use of monoclonal antibodies that block proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that binds to and destroys LDL receptors. It is thought that blocking the destructive capacity of PCSK9 can lead to more LDL receptors on cells and lower cholesterol levels.

Dr. Stein and his associates recently reported that another PCSK9 monoclonal antibody, REGN727 (Regeneron Pharmaceuticals), significantly lowered LDL cholesterol in three early-phase trials involving healthy volunteers and patients with familial or nonfamilial forms of hypercholesterolemia (N. Engl. J. Med. 2012;366:1108-18). GAUSS investigators at 33 sites in North America, Australia, and Europe enrolled patients, aged 18-75 years, with hypercholesterolemia who were considered intolerant to at least one statin because of muscle-related events and had LDL cholesterol levels above risk-based goals set by the National Cholesterol Education Program (NCEP). At baseline, the average LDL cholesterol level was 193 mg/dL, 50% of patients were at high or moderately high cardiovascular risk according to NCEP categories, and 24% had clinical atherosclerotic disease. Their average age was 62.

In all, 160 patients were randomly assigned to AMG145 monotherapy at doses of 280 mg, 350 mg, or 420 mg every 4 weeks, or 450 mg AMG145 every 4 weeks plus daily oral ezetimibe 10 mg, or placebo every 4 weeks plus ezetimibe 10 mg.

At week 12, the mean change from baseline in LDL cholesterol was –41% in the AMG 280-mg group, –43% in the 350-mg group, –51% in the 420-mg group, and –63% in the AMG plus ezetimibe group, compared with –15% in the placebo plus ezetimibe group, all highly significant differences, reported Dr. Stein of the Metabolic and Atherosclerosis Research Center in Cincinnati.

Notably, the reductions in LDL cholesterol levels with AMG145 monotherapy given every 4 weeks are comparable to those obtained with REGN727 given in addition to statins every 2 weeks.

AMG145 produced modest increases in HDL cholesterol that were statistically significant only in the combination group, and nonsignificant reductions in triglycerides.

Myalgia was the most common treatment-related adverse event, reported in five patients in the 280-mg group, one each in the 350-mg and 420-mg groups, six in the AMG145/ezetimibe group, and one in the placebo/ezetimibe group. Fewer than 5% of patients taking AMG145, with or without ezetimibe, reported fatigue, muscle fatigue, or muscle spasm.

There were four serious adverse events reported in patients given AMG 145 – coronary artery disease, acute pancreatitis, hip fracture, and syncope. These patients did not require treatment discontinuation; these adverse events are not known to be linked to the mechanism of action of PCSK9 inhibition, the authors, led by Dr. David Sullivan of Royal Prince Alfred Hospital, Camperdown, Australia, reported in the paper, simultaneously published online (JAMA 2012;308 [doi:10.1001/jama.2012.25790]).

GAUSS was funded by Amgen, which participated in the design and conduct of the study, as well as the collection and management of data. Dr. Stein and Dr. Sullivan reported financial relationships with Amgen and other firms, and four coauthors are employees of Amgen.

The investigational anti-PCSK9 antibody AMG145 significantly lowers LDL cholesterol in high-risk patients unable to tolerate statins, the phase II GAUSS trial showed.

Three subcutaneous injections of AMG145 at varying doses reduced LDL cholesterol by up to 51% when used as monotherapy, and by 63% when combined with ezetimibe (Zetia), compared with an expected 15% reduction with ezetimibe and placebo.

These reductions are comparable with those achieved with maximal doses of the most efficacious statins.

If the results are confirmed in larger and longer-term studies, AMG145 could provide a new therapeutic option for high-risk patients who currently have few treatment options, Dr. Evan Stein reported at the annual scientific sessions of the American Heart Association in Los Angeles.

In GAUSS (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects), 84% of all patients were unable to tolerate even low doses of any statin.

Overall, about 10%-20% of people can’t tolerate statins at all or the higher doses needed to achieve recommended LDL cholesterol goals, primarily because of muscle-related side effects. Ezetimibe is frequently used as an alternative for these patients, but without great success.

Evidence and enthusiasm are growing, however, for the use of monoclonal antibodies that block proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that binds to and destroys LDL receptors. It is thought that blocking the destructive capacity of PCSK9 can lead to more LDL receptors on cells and lower cholesterol levels.

Dr. Stein and his associates recently reported that another PCSK9 monoclonal antibody, REGN727 (Regeneron Pharmaceuticals), significantly lowered LDL cholesterol in three early-phase trials involving healthy volunteers and patients with familial or nonfamilial forms of hypercholesterolemia (N. Engl. J. Med. 2012;366:1108-18). GAUSS investigators at 33 sites in North America, Australia, and Europe enrolled patients, aged 18-75 years, with hypercholesterolemia who were considered intolerant to at least one statin because of muscle-related events and had LDL cholesterol levels above risk-based goals set by the National Cholesterol Education Program (NCEP). At baseline, the average LDL cholesterol level was 193 mg/dL, 50% of patients were at high or moderately high cardiovascular risk according to NCEP categories, and 24% had clinical atherosclerotic disease. Their average age was 62.

In all, 160 patients were randomly assigned to AMG145 monotherapy at doses of 280 mg, 350 mg, or 420 mg every 4 weeks, or 450 mg AMG145 every 4 weeks plus daily oral ezetimibe 10 mg, or placebo every 4 weeks plus ezetimibe 10 mg.

At week 12, the mean change from baseline in LDL cholesterol was –41% in the AMG 280-mg group, –43% in the 350-mg group, –51% in the 420-mg group, and –63% in the AMG plus ezetimibe group, compared with –15% in the placebo plus ezetimibe group, all highly significant differences, reported Dr. Stein of the Metabolic and Atherosclerosis Research Center in Cincinnati.

Notably, the reductions in LDL cholesterol levels with AMG145 monotherapy given every 4 weeks are comparable to those obtained with REGN727 given in addition to statins every 2 weeks.

AMG145 produced modest increases in HDL cholesterol that were statistically significant only in the combination group, and nonsignificant reductions in triglycerides.

Myalgia was the most common treatment-related adverse event, reported in five patients in the 280-mg group, one each in the 350-mg and 420-mg groups, six in the AMG145/ezetimibe group, and one in the placebo/ezetimibe group. Fewer than 5% of patients taking AMG145, with or without ezetimibe, reported fatigue, muscle fatigue, or muscle spasm.

There were four serious adverse events reported in patients given AMG 145 – coronary artery disease, acute pancreatitis, hip fracture, and syncope. These patients did not require treatment discontinuation; these adverse events are not known to be linked to the mechanism of action of PCSK9 inhibition, the authors, led by Dr. David Sullivan of Royal Prince Alfred Hospital, Camperdown, Australia, reported in the paper, simultaneously published online (JAMA 2012;308 [doi:10.1001/jama.2012.25790]).

GAUSS was funded by Amgen, which participated in the design and conduct of the study, as well as the collection and management of data. Dr. Stein and Dr. Sullivan reported financial relationships with Amgen and other firms, and four coauthors are employees of Amgen.

The investigational anti-PCSK9 antibody AMG145 significantly lowers LDL cholesterol in high-risk patients unable to tolerate statins, the phase II GAUSS trial showed.

Three subcutaneous injections of AMG145 at varying doses reduced LDL cholesterol by up to 51% when used as monotherapy, and by 63% when combined with ezetimibe (Zetia), compared with an expected 15% reduction with ezetimibe and placebo.

These reductions are comparable with those achieved with maximal doses of the most efficacious statins.

If the results are confirmed in larger and longer-term studies, AMG145 could provide a new therapeutic option for high-risk patients who currently have few treatment options, Dr. Evan Stein reported at the annual scientific sessions of the American Heart Association in Los Angeles.

In GAUSS (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects), 84% of all patients were unable to tolerate even low doses of any statin.

Overall, about 10%-20% of people can’t tolerate statins at all or the higher doses needed to achieve recommended LDL cholesterol goals, primarily because of muscle-related side effects. Ezetimibe is frequently used as an alternative for these patients, but without great success.

Evidence and enthusiasm are growing, however, for the use of monoclonal antibodies that block proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that binds to and destroys LDL receptors. It is thought that blocking the destructive capacity of PCSK9 can lead to more LDL receptors on cells and lower cholesterol levels.

Dr. Stein and his associates recently reported that another PCSK9 monoclonal antibody, REGN727 (Regeneron Pharmaceuticals), significantly lowered LDL cholesterol in three early-phase trials involving healthy volunteers and patients with familial or nonfamilial forms of hypercholesterolemia (N. Engl. J. Med. 2012;366:1108-18). GAUSS investigators at 33 sites in North America, Australia, and Europe enrolled patients, aged 18-75 years, with hypercholesterolemia who were considered intolerant to at least one statin because of muscle-related events and had LDL cholesterol levels above risk-based goals set by the National Cholesterol Education Program (NCEP). At baseline, the average LDL cholesterol level was 193 mg/dL, 50% of patients were at high or moderately high cardiovascular risk according to NCEP categories, and 24% had clinical atherosclerotic disease. Their average age was 62.

In all, 160 patients were randomly assigned to AMG145 monotherapy at doses of 280 mg, 350 mg, or 420 mg every 4 weeks, or 450 mg AMG145 every 4 weeks plus daily oral ezetimibe 10 mg, or placebo every 4 weeks plus ezetimibe 10 mg.

At week 12, the mean change from baseline in LDL cholesterol was –41% in the AMG 280-mg group, –43% in the 350-mg group, –51% in the 420-mg group, and –63% in the AMG plus ezetimibe group, compared with –15% in the placebo plus ezetimibe group, all highly significant differences, reported Dr. Stein of the Metabolic and Atherosclerosis Research Center in Cincinnati.

Notably, the reductions in LDL cholesterol levels with AMG145 monotherapy given every 4 weeks are comparable to those obtained with REGN727 given in addition to statins every 2 weeks.

AMG145 produced modest increases in HDL cholesterol that were statistically significant only in the combination group, and nonsignificant reductions in triglycerides.

Myalgia was the most common treatment-related adverse event, reported in five patients in the 280-mg group, one each in the 350-mg and 420-mg groups, six in the AMG145/ezetimibe group, and one in the placebo/ezetimibe group. Fewer than 5% of patients taking AMG145, with or without ezetimibe, reported fatigue, muscle fatigue, or muscle spasm.

There were four serious adverse events reported in patients given AMG 145 – coronary artery disease, acute pancreatitis, hip fracture, and syncope. These patients did not require treatment discontinuation; these adverse events are not known to be linked to the mechanism of action of PCSK9 inhibition, the authors, led by Dr. David Sullivan of Royal Prince Alfred Hospital, Camperdown, Australia, reported in the paper, simultaneously published online (JAMA 2012;308 [doi:10.1001/jama.2012.25790]).

GAUSS was funded by Amgen, which participated in the design and conduct of the study, as well as the collection and management of data. Dr. Stein and Dr. Sullivan reported financial relationships with Amgen and other firms, and four coauthors are employees of Amgen.

MINNEAPOLIS – Odanacatib added bone density in postmenopausal women with osteoporosis previously treated with alendronate, according to results from a study presented at the annual meeting of the American Society for Bone and Mineral Research.

In a phase II trial involving 243 patients, the investigational oral cathepsin K inhibitor began to distinguish itself from placebo at 12 months. At 2 years, the change from baseline in femoral neck bone mineral density (BMD) was significantly increased by 1.73%, compared with a loss of 0.94% for placebo (P less than .001).

Merck Research Laboratories

BMD changes in the treatment group at 2 years were also significantly different from placebo at the trochanter (1.83% vs. –1.35%) and for the total hip (0.83% vs. –1.87%, both P less than .001).

All of the women studied had received alendronate (Fosamax) for at least 3 years. Patients could have been off the bisphosphonate for up to 3 months prior to enrollment, but many switched directly over to odanacatib, said study coauthor Dr. Albert Leung, executive director of clinical research at Merck Research Laboratories.

"This drug has the potential to give additional benefits when [patients] have been treated with alendronate for a number of years and the treatment effect has reached a plateau and they may need a different treatment," he said in an interview.

In July 2012, a pivotal 16,731-patient, phase III trial of odanacatib was stopped early after an interim analysis showed a "favorable benefit-risk profile" for fracture risk reduction in postmenopausal women with previously untreated osteoporosis.

"It could be quite a population that may benefit from this drug," Dr. Leung remarked.

The study’s data monitoring committee, however, flagged safety concerns in "certain selected areas" for further follow-up. Those safety risks have not been identified as the trial is still closing, but will be monitored along with efficacy in a double-blind, placebo-controlled, extension trial going out to 5 years of treatment, he said.

Merck, which plans to submit regulatory applications for odanacatib in the United States and Europe in the first half of 2013, has high hopes for odanacatib despite competition from generic drugs because of its novel mechanism of action.

Odanacatib inhibits cathepsin K, the primary protease in osteoclasts that breaks down bone collagen during bone resorption. Unlike traditional antiresorptive drugs like bisphosphonates, however, odanacatib does not interfere with the function of the entire osteoclast or reduce the number of osteoclasts. This characteristic is important, as osteoclasts secrete signaling factors to stimulate osteoblasts, the cells responsible for bone formation. As a result, there is greater bone formation with odanacatib, Dr. Leung explained.

The phase II trial enrolled women at least 60 years of age (mean 71 years) with a BMD T score of –2.5 to more than –3.5 at any hip site without a prior fragility fracture or those with a history of fragility fracture (except hip fracture), and a BMD T score of –1.5 and more than –3.5 at any hip site. The women were randomly assigned to odanacatib 50 mg once weekly or placebo for 24 months, as well as 5,600 IU of vitamin D₃ per week and calcium at dosages up to 1,200 mg/day. The study was not powered to assess fractures.

At 24 months, the change in BMD at the lumbar spine was significant at 2.28% for odanacatib vs. a loss of 0.30% with placebo (P less than .001).

BMD change was not significant at the distal forearm, with losses of 0.92% vs. 1.14%, respectively.

As expected, urinary collagen type I cross-linked N-telopeptide, a biomarker of bone resorption, increased with placebo, compared with a significant 47% decrease with odanacatib.

The bone formation marker, serum type I procollagen, rose inexplicably with placebo, but this increase was surpassed by a significant gain of 31.2% with odanacatib.

Most unexpected, however, was an increase in the resorption marker collagen type I cross-linked C-telopeptide (sCTx) with once-weekly odanacatib. Dr. Leung said the finding appears to correlate with the bone density changes because sCTx levels remained relatively stable during the first 12 months of treatment before rising in the second year of the study.

Finally, adverse events were similar in both groups. The most common adverse events in the odanacatib and placebo arms were urinary tract infection (11.5% vs. 16.5%, respectively), back pain (11.5% vs. 9.9%), arthralgia (9% vs. 9.9%), and fractures (4.9% vs. 13.2%). Treatment discontinuation rates due to adverse events were 9% vs. 3.3%, he said.

Dr. Leung and several of his coauthors are employees of Merck, the trial sponsor.

MINNEAPOLIS – Odanacatib added bone density in postmenopausal women with osteoporosis previously treated with alendronate, according to results from a study presented at the annual meeting of the American Society for Bone and Mineral Research.

In a phase II trial involving 243 patients, the investigational oral cathepsin K inhibitor began to distinguish itself from placebo at 12 months. At 2 years, the change from baseline in femoral neck bone mineral density (BMD) was significantly increased by 1.73%, compared with a loss of 0.94% for placebo (P less than .001).

Merck Research Laboratories

BMD changes in the treatment group at 2 years were also significantly different from placebo at the trochanter (1.83% vs. –1.35%) and for the total hip (0.83% vs. –1.87%, both P less than .001).

All of the women studied had received alendronate (Fosamax) for at least 3 years. Patients could have been off the bisphosphonate for up to 3 months prior to enrollment, but many switched directly over to odanacatib, said study coauthor Dr. Albert Leung, executive director of clinical research at Merck Research Laboratories.

"This drug has the potential to give additional benefits when [patients] have been treated with alendronate for a number of years and the treatment effect has reached a plateau and they may need a different treatment," he said in an interview.

In July 2012, a pivotal 16,731-patient, phase III trial of odanacatib was stopped early after an interim analysis showed a "favorable benefit-risk profile" for fracture risk reduction in postmenopausal women with previously untreated osteoporosis.

"It could be quite a population that may benefit from this drug," Dr. Leung remarked.

The study’s data monitoring committee, however, flagged safety concerns in "certain selected areas" for further follow-up. Those safety risks have not been identified as the trial is still closing, but will be monitored along with efficacy in a double-blind, placebo-controlled, extension trial going out to 5 years of treatment, he said.

Merck, which plans to submit regulatory applications for odanacatib in the United States and Europe in the first half of 2013, has high hopes for odanacatib despite competition from generic drugs because of its novel mechanism of action.

Odanacatib inhibits cathepsin K, the primary protease in osteoclasts that breaks down bone collagen during bone resorption. Unlike traditional antiresorptive drugs like bisphosphonates, however, odanacatib does not interfere with the function of the entire osteoclast or reduce the number of osteoclasts. This characteristic is important, as osteoclasts secrete signaling factors to stimulate osteoblasts, the cells responsible for bone formation. As a result, there is greater bone formation with odanacatib, Dr. Leung explained.

The phase II trial enrolled women at least 60 years of age (mean 71 years) with a BMD T score of –2.5 to more than –3.5 at any hip site without a prior fragility fracture or those with a history of fragility fracture (except hip fracture), and a BMD T score of –1.5 and more than –3.5 at any hip site. The women were randomly assigned to odanacatib 50 mg once weekly or placebo for 24 months, as well as 5,600 IU of vitamin D₃ per week and calcium at dosages up to 1,200 mg/day. The study was not powered to assess fractures.

At 24 months, the change in BMD at the lumbar spine was significant at 2.28% for odanacatib vs. a loss of 0.30% with placebo (P less than .001).

BMD change was not significant at the distal forearm, with losses of 0.92% vs. 1.14%, respectively.

As expected, urinary collagen type I cross-linked N-telopeptide, a biomarker of bone resorption, increased with placebo, compared with a significant 47% decrease with odanacatib.

The bone formation marker, serum type I procollagen, rose inexplicably with placebo, but this increase was surpassed by a significant gain of 31.2% with odanacatib.

Most unexpected, however, was an increase in the resorption marker collagen type I cross-linked C-telopeptide (sCTx) with once-weekly odanacatib. Dr. Leung said the finding appears to correlate with the bone density changes because sCTx levels remained relatively stable during the first 12 months of treatment before rising in the second year of the study.

Finally, adverse events were similar in both groups. The most common adverse events in the odanacatib and placebo arms were urinary tract infection (11.5% vs. 16.5%, respectively), back pain (11.5% vs. 9.9%), arthralgia (9% vs. 9.9%), and fractures (4.9% vs. 13.2%). Treatment discontinuation rates due to adverse events were 9% vs. 3.3%, he said.

Dr. Leung and several of his coauthors are employees of Merck, the trial sponsor.

MINNEAPOLIS – Odanacatib added bone density in postmenopausal women with osteoporosis previously treated with alendronate, according to results from a study presented at the annual meeting of the American Society for Bone and Mineral Research.

In a phase II trial involving 243 patients, the investigational oral cathepsin K inhibitor began to distinguish itself from placebo at 12 months. At 2 years, the change from baseline in femoral neck bone mineral density (BMD) was significantly increased by 1.73%, compared with a loss of 0.94% for placebo (P less than .001).

Merck Research Laboratories

BMD changes in the treatment group at 2 years were also significantly different from placebo at the trochanter (1.83% vs. –1.35%) and for the total hip (0.83% vs. –1.87%, both P less than .001).

All of the women studied had received alendronate (Fosamax) for at least 3 years. Patients could have been off the bisphosphonate for up to 3 months prior to enrollment, but many switched directly over to odanacatib, said study coauthor Dr. Albert Leung, executive director of clinical research at Merck Research Laboratories.

"This drug has the potential to give additional benefits when [patients] have been treated with alendronate for a number of years and the treatment effect has reached a plateau and they may need a different treatment," he said in an interview.

In July 2012, a pivotal 16,731-patient, phase III trial of odanacatib was stopped early after an interim analysis showed a "favorable benefit-risk profile" for fracture risk reduction in postmenopausal women with previously untreated osteoporosis.

"It could be quite a population that may benefit from this drug," Dr. Leung remarked.

The study’s data monitoring committee, however, flagged safety concerns in "certain selected areas" for further follow-up. Those safety risks have not been identified as the trial is still closing, but will be monitored along with efficacy in a double-blind, placebo-controlled, extension trial going out to 5 years of treatment, he said.

Merck, which plans to submit regulatory applications for odanacatib in the United States and Europe in the first half of 2013, has high hopes for odanacatib despite competition from generic drugs because of its novel mechanism of action.

Odanacatib inhibits cathepsin K, the primary protease in osteoclasts that breaks down bone collagen during bone resorption. Unlike traditional antiresorptive drugs like bisphosphonates, however, odanacatib does not interfere with the function of the entire osteoclast or reduce the number of osteoclasts. This characteristic is important, as osteoclasts secrete signaling factors to stimulate osteoblasts, the cells responsible for bone formation. As a result, there is greater bone formation with odanacatib, Dr. Leung explained.

The phase II trial enrolled women at least 60 years of age (mean 71 years) with a BMD T score of –2.5 to more than –3.5 at any hip site without a prior fragility fracture or those with a history of fragility fracture (except hip fracture), and a BMD T score of –1.5 and more than –3.5 at any hip site. The women were randomly assigned to odanacatib 50 mg once weekly or placebo for 24 months, as well as 5,600 IU of vitamin D₃ per week and calcium at dosages up to 1,200 mg/day. The study was not powered to assess fractures.

At 24 months, the change in BMD at the lumbar spine was significant at 2.28% for odanacatib vs. a loss of 0.30% with placebo (P less than .001).

BMD change was not significant at the distal forearm, with losses of 0.92% vs. 1.14%, respectively.

As expected, urinary collagen type I cross-linked N-telopeptide, a biomarker of bone resorption, increased with placebo, compared with a significant 47% decrease with odanacatib.

The bone formation marker, serum type I procollagen, rose inexplicably with placebo, but this increase was surpassed by a significant gain of 31.2% with odanacatib.

Most unexpected, however, was an increase in the resorption marker collagen type I cross-linked C-telopeptide (sCTx) with once-weekly odanacatib. Dr. Leung said the finding appears to correlate with the bone density changes because sCTx levels remained relatively stable during the first 12 months of treatment before rising in the second year of the study.

Finally, adverse events were similar in both groups. The most common adverse events in the odanacatib and placebo arms were urinary tract infection (11.5% vs. 16.5%, respectively), back pain (11.5% vs. 9.9%), arthralgia (9% vs. 9.9%), and fractures (4.9% vs. 13.2%). Treatment discontinuation rates due to adverse events were 9% vs. 3.3%, he said.

Dr. Leung and several of his coauthors are employees of Merck, the trial sponsor.

VIENNA – A second prospective randomized trial has confirmed the benefits of continuing bevacizumab beyond tumor progression in metastatic colorectal cancer.

The median time to progression in the phase II BEBYP trial was 4.9 months with second-line 5-fluorouracil–based chemotherapy alone vs. 6.7 months with chemotherapy and bevacizumab (Avastin) continued without interruption from first-line therapy (hazard ratio, 0.65; P = .0062).

Patrice Wendling/IMNG Medical Media

The benefit of continuous bevacizumab was consistent across all subgroups, including mutant and wildtype KRAS, Dr. Gianluca Masi reported on behalf of the Gruppo Oncologico Nord Ovest, which conducted the trial.

Earlier this year, the prospective, phase III 820-patient Treatment Across Multiple Lines (TML) trial reported a hazard ratio of 0.68 for progression or death and a modest 19% improvement in overall survival with continuous bevacizumab and chemotherapy in second-line metastatic colorectal cancer.

Overall survival data from BEBYP are still immature, with 52 events reported in the chemotherapy-alone arm and 46 in the bevacizumab arm after a median follow-up of 18 months, said Dr. Masi of Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. The trial was stopped early in May 2012 after results of TML were made public. BEBYP had randomized just 185 of the 262 planned patients.

Invited discussant Dr. Jean-Yves Douillard, professor of medical oncology at the University of Nantes and ICO R. Gauducheau, St. Herblain France, said, "These studies validate the use of bevacizumab beyond progression with all chemo combinations, in selected patients initially responding to bevacizumab."

He described the median progression-free survival as "quite good," particularly since the enrollment criteria for BEBYP were less strict than for TML and patients were less selected for bevacizumab sensitivity.

Still, Dr. Douillard cautioned that the 1.8-month gain in progression-free survival with the monoclonal antibody comes at a price. He highlighted an article estimating that the cost of new drugs to treat patients with metastatic colorectal cancer is $150,000-$200,000 for an additional year of life, compared with fluorouracil plus leucovorin alone (J. Clin. Oncol. 2007;25:180-6).

"There is a rising curve each time a new drug is added, and I don’t know how long we will be able to afford that," he said.

Patients in BEBYP had unresectable and measurable metastatic disease that had progressed after or during first-line chemotherapy with fluoropyrimidine, FOLFIRI, FOLFOX, or FOLFOXIRI plus bevacizumab. They were randomized to second-line FOLFIRI or modified FOLFOX-6 chemotherapy repeated every 2 weeks with or without bevacizumab 5 mg/kg on day 1 and repeated every 2 weeks. One patient was randomized twice, leaving 184 patients evaluable for analysis.

FOLFIRI was the most common first-line therapy, used in about 58% of patients. Median time to progression-free survival was 10.3 months in both arms.

Compared with second-line chemotherapy alone, the addition of bevacizumab did not significantly impact the overall response rate (18% vs. 21%) or disease control rate (62% vs. 71%), Dr. Masi said.

BEBYP was supported by the Agenzia Italiana del Farmaco. Dr. Masi disclosed honoraria from Roche, Merck-Serono, and Amgen, and research funding from Roche. Dr. Douillard reported serving as a consultant, an adviser, or a speaker for Roche and Sanofi-Aventis and as a consultant, an adviser, and a data safety monitoring board chair for Bayer.

VIENNA – A second prospective randomized trial has confirmed the benefits of continuing bevacizumab beyond tumor progression in metastatic colorectal cancer.

The median time to progression in the phase II BEBYP trial was 4.9 months with second-line 5-fluorouracil–based chemotherapy alone vs. 6.7 months with chemotherapy and bevacizumab (Avastin) continued without interruption from first-line therapy (hazard ratio, 0.65; P = .0062).

Patrice Wendling/IMNG Medical Media

The benefit of continuous bevacizumab was consistent across all subgroups, including mutant and wildtype KRAS, Dr. Gianluca Masi reported on behalf of the Gruppo Oncologico Nord Ovest, which conducted the trial.

Earlier this year, the prospective, phase III 820-patient Treatment Across Multiple Lines (TML) trial reported a hazard ratio of 0.68 for progression or death and a modest 19% improvement in overall survival with continuous bevacizumab and chemotherapy in second-line metastatic colorectal cancer.

Overall survival data from BEBYP are still immature, with 52 events reported in the chemotherapy-alone arm and 46 in the bevacizumab arm after a median follow-up of 18 months, said Dr. Masi of Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. The trial was stopped early in May 2012 after results of TML were made public. BEBYP had randomized just 185 of the 262 planned patients.

Invited discussant Dr. Jean-Yves Douillard, professor of medical oncology at the University of Nantes and ICO R. Gauducheau, St. Herblain France, said, "These studies validate the use of bevacizumab beyond progression with all chemo combinations, in selected patients initially responding to bevacizumab."

He described the median progression-free survival as "quite good," particularly since the enrollment criteria for BEBYP were less strict than for TML and patients were less selected for bevacizumab sensitivity.

Still, Dr. Douillard cautioned that the 1.8-month gain in progression-free survival with the monoclonal antibody comes at a price. He highlighted an article estimating that the cost of new drugs to treat patients with metastatic colorectal cancer is $150,000-$200,000 for an additional year of life, compared with fluorouracil plus leucovorin alone (J. Clin. Oncol. 2007;25:180-6).

"There is a rising curve each time a new drug is added, and I don’t know how long we will be able to afford that," he said.

Patients in BEBYP had unresectable and measurable metastatic disease that had progressed after or during first-line chemotherapy with fluoropyrimidine, FOLFIRI, FOLFOX, or FOLFOXIRI plus bevacizumab. They were randomized to second-line FOLFIRI or modified FOLFOX-6 chemotherapy repeated every 2 weeks with or without bevacizumab 5 mg/kg on day 1 and repeated every 2 weeks. One patient was randomized twice, leaving 184 patients evaluable for analysis.

FOLFIRI was the most common first-line therapy, used in about 58% of patients. Median time to progression-free survival was 10.3 months in both arms.

Compared with second-line chemotherapy alone, the addition of bevacizumab did not significantly impact the overall response rate (18% vs. 21%) or disease control rate (62% vs. 71%), Dr. Masi said.

BEBYP was supported by the Agenzia Italiana del Farmaco. Dr. Masi disclosed honoraria from Roche, Merck-Serono, and Amgen, and research funding from Roche. Dr. Douillard reported serving as a consultant, an adviser, or a speaker for Roche and Sanofi-Aventis and as a consultant, an adviser, and a data safety monitoring board chair for Bayer.

VIENNA – A second prospective randomized trial has confirmed the benefits of continuing bevacizumab beyond tumor progression in metastatic colorectal cancer.

The median time to progression in the phase II BEBYP trial was 4.9 months with second-line 5-fluorouracil–based chemotherapy alone vs. 6.7 months with chemotherapy and bevacizumab (Avastin) continued without interruption from first-line therapy (hazard ratio, 0.65; P = .0062).

Patrice Wendling/IMNG Medical Media

The benefit of continuous bevacizumab was consistent across all subgroups, including mutant and wildtype KRAS, Dr. Gianluca Masi reported on behalf of the Gruppo Oncologico Nord Ovest, which conducted the trial.

Earlier this year, the prospective, phase III 820-patient Treatment Across Multiple Lines (TML) trial reported a hazard ratio of 0.68 for progression or death and a modest 19% improvement in overall survival with continuous bevacizumab and chemotherapy in second-line metastatic colorectal cancer.

Overall survival data from BEBYP are still immature, with 52 events reported in the chemotherapy-alone arm and 46 in the bevacizumab arm after a median follow-up of 18 months, said Dr. Masi of Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. The trial was stopped early in May 2012 after results of TML were made public. BEBYP had randomized just 185 of the 262 planned patients.

Invited discussant Dr. Jean-Yves Douillard, professor of medical oncology at the University of Nantes and ICO R. Gauducheau, St. Herblain France, said, "These studies validate the use of bevacizumab beyond progression with all chemo combinations, in selected patients initially responding to bevacizumab."

He described the median progression-free survival as "quite good," particularly since the enrollment criteria for BEBYP were less strict than for TML and patients were less selected for bevacizumab sensitivity.

Still, Dr. Douillard cautioned that the 1.8-month gain in progression-free survival with the monoclonal antibody comes at a price. He highlighted an article estimating that the cost of new drugs to treat patients with metastatic colorectal cancer is $150,000-$200,000 for an additional year of life, compared with fluorouracil plus leucovorin alone (J. Clin. Oncol. 2007;25:180-6).

"There is a rising curve each time a new drug is added, and I don’t know how long we will be able to afford that," he said.

Patients in BEBYP had unresectable and measurable metastatic disease that had progressed after or during first-line chemotherapy with fluoropyrimidine, FOLFIRI, FOLFOX, or FOLFOXIRI plus bevacizumab. They were randomized to second-line FOLFIRI or modified FOLFOX-6 chemotherapy repeated every 2 weeks with or without bevacizumab 5 mg/kg on day 1 and repeated every 2 weeks. One patient was randomized twice, leaving 184 patients evaluable for analysis.

FOLFIRI was the most common first-line therapy, used in about 58% of patients. Median time to progression-free survival was 10.3 months in both arms.

Compared with second-line chemotherapy alone, the addition of bevacizumab did not significantly impact the overall response rate (18% vs. 21%) or disease control rate (62% vs. 71%), Dr. Masi said.

BEBYP was supported by the Agenzia Italiana del Farmaco. Dr. Masi disclosed honoraria from Roche, Merck-Serono, and Amgen, and research funding from Roche. Dr. Douillard reported serving as a consultant, an adviser, or a speaker for Roche and Sanofi-Aventis and as a consultant, an adviser, and a data safety monitoring board chair for Bayer.

VIENNA – Gefitinib failed to improve overall survival in advanced esophageal cancer but could prove beneficial in a setting in which palliative care is the standard of care.

Gefitinib (Iressa) significantly improved progression-free survival and provided some dramatic and durable responses in palliation in the first-ever randomized trial of second-line therapy for esophageal cancer, Dr. David Ferry said at the European Society for Medical Oncology Congress.

In addition, the Cancer Oesophagus Gefitinib (COG) trial demonstrated a striking effect of performance status on survival in 450 patients treated with the epidermal growth factor receptor inhibitor.

Median overall survival increased significantly from 1.97 months in patients with a performance status (PS) of 2 to 3.93 months and 6.03 months, respectively, in those with PS 1 and PS 0 (P value less than .0001; hazard ratios, 1.00, 1.40, 2.98, respectively).

"We can now look at performance status as a prognostic factor for patients with this disease," said Dr. Ferry, of New Cross Hospital, Wolverhampton, England.

The next step lies in the ongoing, companion translational research project, TRANS-COG, analyzing predictive biomarkers in more than 300 of the 450 patients’ biopsies in an effort to identify a molecularly defined subgroup of patients most likely to benefit from gefitinib.

"If we can identify a subgroup of patients – and I think we’re fairly optimistic we can – then we will move on to another trial where placebo will be the control arm and a different targeted agent will be the experimental arm," Dr. Ferry said at a press briefing held at the congress.

He would not say what targeted agent that might be and added that there’s not sufficient benefit in an unselected population for clinicians to begin using gefitinib in their patients with advanced esophageal cancer, "no matter how tempted you might be."

More Study Details

The Cancer Oesophagus Gefitinib was prompted by a round of promising single-agent phase II trials involving the epidermal growth factor receptor inhibitors gefitinib and erlotinib reporting responses in the second-line setting for esophageal cancer. Roughly 50%-70% of esophageal cancers overexpress epidermal growth factor receptor.

At the moment, there is no systemic therapy that has significantly altered the natural history of metastatic esophageal cancer progressing after chemotherapy.

Investigators at 51 centers in the United Kingdom evenly randomized 450 patients with metastatic esophageal cancers and type I/II junctional tumors to once-daily oral gefitinib 500 mg or placebo until progression.

Patients with stable brain metastases who had received prior cranial irradiation were not excluded from the trial.

Three-fourths of patients had adenocarcinoma, 80% had esophageal involvement, and one-third had received at least two prior treatments.

PS was balanced between the placebo and gefitinib arms, with 25% and 26% at PS 0, 55% and 52% at PS 1 and 20% and 22% at PS 2. They were a median age of 64 years.

Progression-free survival was 1.17 months in the placebo arm and 1.60 months in the gefitinib arm, which was statistically significant (P = .017; HR, 0.79), Dr. Ferry said.

Exploratory subgroup analyses showed that all patients, regardless of cytology, disease site, age, sex, and time since diagnosis, benefited equally.

This positive effect on progression did not translate into an overall survival benefit, with a median overall survival of 3.60 months for placebo and 3.73 months for gefitinib (P = .285; HR, 0.90).

At 4 weeks, patients receiving gefitinib reported significant improvements in difficulty swallowing (P = .004), but not in global health quality of life, dysphagia, or difficulty eating, the three other prespecified health-related quality of life outcomes.

Disease control rates at 8 weeks, however, significantly favored gefitinib over placebo (26% vs. 16%, P = .014), he said. True partial responses occurred in 3.1% vs. 0.4%, respectively.

Dr. Ferry presented images illustrating rapid and durable radiologic responses that were associated with palliation in patients with adenocarcinoma and squamous cancers. Patient receiving gefitinib experienced weight gain, increased appetite, and reduced chest wall pain, with responses lasting 18 months in one patient.

There were no new safety signals with gefitinib, although there was an excess of diarrhea and skin toxicity, he said.

Discussant Arnaud D. Roth of Geneva University Hospital told the audience it would be easy to write COG off as another boring, negative study in esophageal cancer but pointed out that deeper analyses of molecular and clinical factors turned the initially negative PETACC-3 trial in colon cancer into a success story.

"A study of this size is a fantastic opportunity to learn more about esophageal cancer biology," he said, remarking that gefitinib in esophageal cancer is "just the beginning of a spicy story," said Dr. Roth, chief of oncosurgery at the hospital.

Cancer Research UK sponsored the trial. Dr. Ferry reported grant support, honoraria, and an advisory relationship with AstraZeneca in the development of gefitinib.

VIENNA – Gefitinib failed to improve overall survival in advanced esophageal cancer but could prove beneficial in a setting in which palliative care is the standard of care.

Gefitinib (Iressa) significantly improved progression-free survival and provided some dramatic and durable responses in palliation in the first-ever randomized trial of second-line therapy for esophageal cancer, Dr. David Ferry said at the European Society for Medical Oncology Congress.

In addition, the Cancer Oesophagus Gefitinib (COG) trial demonstrated a striking effect of performance status on survival in 450 patients treated with the epidermal growth factor receptor inhibitor.

Median overall survival increased significantly from 1.97 months in patients with a performance status (PS) of 2 to 3.93 months and 6.03 months, respectively, in those with PS 1 and PS 0 (P value less than .0001; hazard ratios, 1.00, 1.40, 2.98, respectively).

"We can now look at performance status as a prognostic factor for patients with this disease," said Dr. Ferry, of New Cross Hospital, Wolverhampton, England.

The next step lies in the ongoing, companion translational research project, TRANS-COG, analyzing predictive biomarkers in more than 300 of the 450 patients’ biopsies in an effort to identify a molecularly defined subgroup of patients most likely to benefit from gefitinib.

"If we can identify a subgroup of patients – and I think we’re fairly optimistic we can – then we will move on to another trial where placebo will be the control arm and a different targeted agent will be the experimental arm," Dr. Ferry said at a press briefing held at the congress.

He would not say what targeted agent that might be and added that there’s not sufficient benefit in an unselected population for clinicians to begin using gefitinib in their patients with advanced esophageal cancer, "no matter how tempted you might be."

More Study Details

The Cancer Oesophagus Gefitinib was prompted by a round of promising single-agent phase II trials involving the epidermal growth factor receptor inhibitors gefitinib and erlotinib reporting responses in the second-line setting for esophageal cancer. Roughly 50%-70% of esophageal cancers overexpress epidermal growth factor receptor.

At the moment, there is no systemic therapy that has significantly altered the natural history of metastatic esophageal cancer progressing after chemotherapy.

Investigators at 51 centers in the United Kingdom evenly randomized 450 patients with metastatic esophageal cancers and type I/II junctional tumors to once-daily oral gefitinib 500 mg or placebo until progression.

Patients with stable brain metastases who had received prior cranial irradiation were not excluded from the trial.

Three-fourths of patients had adenocarcinoma, 80% had esophageal involvement, and one-third had received at least two prior treatments.

PS was balanced between the placebo and gefitinib arms, with 25% and 26% at PS 0, 55% and 52% at PS 1 and 20% and 22% at PS 2. They were a median age of 64 years.

Progression-free survival was 1.17 months in the placebo arm and 1.60 months in the gefitinib arm, which was statistically significant (P = .017; HR, 0.79), Dr. Ferry said.

Exploratory subgroup analyses showed that all patients, regardless of cytology, disease site, age, sex, and time since diagnosis, benefited equally.

This positive effect on progression did not translate into an overall survival benefit, with a median overall survival of 3.60 months for placebo and 3.73 months for gefitinib (P = .285; HR, 0.90).

At 4 weeks, patients receiving gefitinib reported significant improvements in difficulty swallowing (P = .004), but not in global health quality of life, dysphagia, or difficulty eating, the three other prespecified health-related quality of life outcomes.

Disease control rates at 8 weeks, however, significantly favored gefitinib over placebo (26% vs. 16%, P = .014), he said. True partial responses occurred in 3.1% vs. 0.4%, respectively.

Dr. Ferry presented images illustrating rapid and durable radiologic responses that were associated with palliation in patients with adenocarcinoma and squamous cancers. Patient receiving gefitinib experienced weight gain, increased appetite, and reduced chest wall pain, with responses lasting 18 months in one patient.

There were no new safety signals with gefitinib, although there was an excess of diarrhea and skin toxicity, he said.

Discussant Arnaud D. Roth of Geneva University Hospital told the audience it would be easy to write COG off as another boring, negative study in esophageal cancer but pointed out that deeper analyses of molecular and clinical factors turned the initially negative PETACC-3 trial in colon cancer into a success story.

"A study of this size is a fantastic opportunity to learn more about esophageal cancer biology," he said, remarking that gefitinib in esophageal cancer is "just the beginning of a spicy story," said Dr. Roth, chief of oncosurgery at the hospital.

Cancer Research UK sponsored the trial. Dr. Ferry reported grant support, honoraria, and an advisory relationship with AstraZeneca in the development of gefitinib.

VIENNA – Gefitinib failed to improve overall survival in advanced esophageal cancer but could prove beneficial in a setting in which palliative care is the standard of care.

Gefitinib (Iressa) significantly improved progression-free survival and provided some dramatic and durable responses in palliation in the first-ever randomized trial of second-line therapy for esophageal cancer, Dr. David Ferry said at the European Society for Medical Oncology Congress.

In addition, the Cancer Oesophagus Gefitinib (COG) trial demonstrated a striking effect of performance status on survival in 450 patients treated with the epidermal growth factor receptor inhibitor.

Median overall survival increased significantly from 1.97 months in patients with a performance status (PS) of 2 to 3.93 months and 6.03 months, respectively, in those with PS 1 and PS 0 (P value less than .0001; hazard ratios, 1.00, 1.40, 2.98, respectively).

"We can now look at performance status as a prognostic factor for patients with this disease," said Dr. Ferry, of New Cross Hospital, Wolverhampton, England.

The next step lies in the ongoing, companion translational research project, TRANS-COG, analyzing predictive biomarkers in more than 300 of the 450 patients’ biopsies in an effort to identify a molecularly defined subgroup of patients most likely to benefit from gefitinib.

"If we can identify a subgroup of patients – and I think we’re fairly optimistic we can – then we will move on to another trial where placebo will be the control arm and a different targeted agent will be the experimental arm," Dr. Ferry said at a press briefing held at the congress.

He would not say what targeted agent that might be and added that there’s not sufficient benefit in an unselected population for clinicians to begin using gefitinib in their patients with advanced esophageal cancer, "no matter how tempted you might be."

More Study Details

The Cancer Oesophagus Gefitinib was prompted by a round of promising single-agent phase II trials involving the epidermal growth factor receptor inhibitors gefitinib and erlotinib reporting responses in the second-line setting for esophageal cancer. Roughly 50%-70% of esophageal cancers overexpress epidermal growth factor receptor.

At the moment, there is no systemic therapy that has significantly altered the natural history of metastatic esophageal cancer progressing after chemotherapy.

Investigators at 51 centers in the United Kingdom evenly randomized 450 patients with metastatic esophageal cancers and type I/II junctional tumors to once-daily oral gefitinib 500 mg or placebo until progression.

Patients with stable brain metastases who had received prior cranial irradiation were not excluded from the trial.

Three-fourths of patients had adenocarcinoma, 80% had esophageal involvement, and one-third had received at least two prior treatments.

PS was balanced between the placebo and gefitinib arms, with 25% and 26% at PS 0, 55% and 52% at PS 1 and 20% and 22% at PS 2. They were a median age of 64 years.

Progression-free survival was 1.17 months in the placebo arm and 1.60 months in the gefitinib arm, which was statistically significant (P = .017; HR, 0.79), Dr. Ferry said.

Exploratory subgroup analyses showed that all patients, regardless of cytology, disease site, age, sex, and time since diagnosis, benefited equally.

This positive effect on progression did not translate into an overall survival benefit, with a median overall survival of 3.60 months for placebo and 3.73 months for gefitinib (P = .285; HR, 0.90).

At 4 weeks, patients receiving gefitinib reported significant improvements in difficulty swallowing (P = .004), but not in global health quality of life, dysphagia, or difficulty eating, the three other prespecified health-related quality of life outcomes.

Disease control rates at 8 weeks, however, significantly favored gefitinib over placebo (26% vs. 16%, P = .014), he said. True partial responses occurred in 3.1% vs. 0.4%, respectively.

Dr. Ferry presented images illustrating rapid and durable radiologic responses that were associated with palliation in patients with adenocarcinoma and squamous cancers. Patient receiving gefitinib experienced weight gain, increased appetite, and reduced chest wall pain, with responses lasting 18 months in one patient.

There were no new safety signals with gefitinib, although there was an excess of diarrhea and skin toxicity, he said.

Discussant Arnaud D. Roth of Geneva University Hospital told the audience it would be easy to write COG off as another boring, negative study in esophageal cancer but pointed out that deeper analyses of molecular and clinical factors turned the initially negative PETACC-3 trial in colon cancer into a success story.

"A study of this size is a fantastic opportunity to learn more about esophageal cancer biology," he said, remarking that gefitinib in esophageal cancer is "just the beginning of a spicy story," said Dr. Roth, chief of oncosurgery at the hospital.

Cancer Research UK sponsored the trial. Dr. Ferry reported grant support, honoraria, and an advisory relationship with AstraZeneca in the development of gefitinib.

VIENNA – Maintenance therapy with the investigational immunomodulator MGN1703 reduced the risk of progression in patients with metastatic colorectal cancer in the phase II/III IMPACT trial.

Median progression-free survival from the start of maintenance therapy was 2.8 months with MGN1703 and 2.6 months with placebo. This was not statistically significant (P = .06) but represented a 47% reduction in the risk of progression (hazard ratio, 0.53).

Patrice Wendling/IMNG Medical Media

The benefit was even greater in a subgroup of good-risk patients, where the risk of progression was reduced 61% and the median time to progression more than doubled from 2.7 to 5.8 months with MGN1703 (HR, .39; P = .013).

"The findings indicate a potential new approach in the management of metastatic colorectal cancer patients," investigator Dr. Dirk Arnold said at the European Society for Medical Oncology Congress.

MGN1703 is an immunomodulator and toll-like receptor (TLR) 9 agonist that activates all components of the innate and adaptive immune system.

TLR9 agonists have shown activity in clinical trials in renal cell carcinoma, cutaneous T-cell lymphoma, and non-Hodgkin’s lymphoma. In a prior study, a TLR9 agonist combined with first-line taxane-plus-platinum chemotherapy reduced the risk of death from advanced-stage non–small cell lung cancer by 26% (J. Clin. Oncol. 2008;26:3979-86).

Dr. Jean-Yves Douillard, who was invited to discuss the study, agreed that immunomodulation represents a new approach to metastatic colorectal cancer.

"This is an additional set of data showing activity with TLR9 agonists, but this is the first time in metastatic colorectal cancer, which has never been considered a really immunosensitive type of tumor," he said. "The tolerance profile is excellent and this type of approach certainly deserves further evaluation in a larger sample to be convincing."

IMPACT was stopped early after an interim analysis of 55 patients because of slow accrual and observed benefit with MGN1703 in a subgroup of patients with no signs of tumor progression.

The 55 patients had achieved disease control after standard first-line chemotherapy and were randomized in a 2:1 fashion to subcutaneous 60 mg MGN1703 or placebo twice weekly until disease progression.

The good-risk subgroup was composed of 46 patients with two of three previously identified factors: carcinoembryonic antigen less than 30 times the upper limit of normal (ULN); gamma glutamyl transpeptidase less than two times the ULN; or alkaline phosphatase less than two times the ULN.

First-line therapy was: FOLFOX/XELOX or FOLFIRI/XELIRI chemotherapy combined with a standard dose of bevacizumab or FOLFOX/XELOX alone; these regimens were given over an average of 5 months and completed within 2 weeks before treatment with MGN1703.

Complete or partial responses to induction therapy had been observed in 72% of the 40 patients in the MGN1703 arm and 93% of the placebo arm. "This is very unusual and we are dealing here with a very chemo-sensitive population," remarked Dr. Douillard, professor of medical oncology at the University of Nantes and ICO R. Gauducheau, St. Herblain, France.

The secondary end point of progression-free survival from the start of induction reached a median of 9 months in the experimental arm and 8.6 months in the control arm, representing a significant risk reduction of 50% (HR, 0.50; P = .047), reported Dr. Arnold of University Cancer Center Hamburg, Germany.

In all, 33% of patients in both arms reporting a drug-related adverse event. Tolerability was good, with only two patients reporting grade 3 hypertension and two reporting grade 4 ileus, he said.

A further clinical study of MGN1703 is being planning, and the drug is also in development for non–small cell lung cancer.

Based on the data now available, Dr. Douillard said patients can no longer be randomized to placebo and that more effective strategies such as those used in the Treatment Across Multiple Lines (TML) trial could be used as a reference arm to be improved by the immunostimulant.

IMPACT was sponsored by Mologen AG, which is developing MGN1703. Dr. Arnold reported no conflicts, but several of his co-authors reported relationships with Mologen including employment. Dr. Douillard reported serving as a consultant, adviser, or speaker for Roche and Sanofi Aventis, and serving as a consultant, adviser, and data safety monitoring board chair for Bayer.

VIENNA – Maintenance therapy with the investigational immunomodulator MGN1703 reduced the risk of progression in patients with metastatic colorectal cancer in the phase II/III IMPACT trial.

Median progression-free survival from the start of maintenance therapy was 2.8 months with MGN1703 and 2.6 months with placebo. This was not statistically significant (P = .06) but represented a 47% reduction in the risk of progression (hazard ratio, 0.53).

Patrice Wendling/IMNG Medical Media

The benefit was even greater in a subgroup of good-risk patients, where the risk of progression was reduced 61% and the median time to progression more than doubled from 2.7 to 5.8 months with MGN1703 (HR, .39; P = .013).

"The findings indicate a potential new approach in the management of metastatic colorectal cancer patients," investigator Dr. Dirk Arnold said at the European Society for Medical Oncology Congress.

MGN1703 is an immunomodulator and toll-like receptor (TLR) 9 agonist that activates all components of the innate and adaptive immune system.

TLR9 agonists have shown activity in clinical trials in renal cell carcinoma, cutaneous T-cell lymphoma, and non-Hodgkin’s lymphoma. In a prior study, a TLR9 agonist combined with first-line taxane-plus-platinum chemotherapy reduced the risk of death from advanced-stage non–small cell lung cancer by 26% (J. Clin. Oncol. 2008;26:3979-86).

Dr. Jean-Yves Douillard, who was invited to discuss the study, agreed that immunomodulation represents a new approach to metastatic colorectal cancer.

"This is an additional set of data showing activity with TLR9 agonists, but this is the first time in metastatic colorectal cancer, which has never been considered a really immunosensitive type of tumor," he said. "The tolerance profile is excellent and this type of approach certainly deserves further evaluation in a larger sample to be convincing."

IMPACT was stopped early after an interim analysis of 55 patients because of slow accrual and observed benefit with MGN1703 in a subgroup of patients with no signs of tumor progression.

The 55 patients had achieved disease control after standard first-line chemotherapy and were randomized in a 2:1 fashion to subcutaneous 60 mg MGN1703 or placebo twice weekly until disease progression.

The good-risk subgroup was composed of 46 patients with two of three previously identified factors: carcinoembryonic antigen less than 30 times the upper limit of normal (ULN); gamma glutamyl transpeptidase less than two times the ULN; or alkaline phosphatase less than two times the ULN.

First-line therapy was: FOLFOX/XELOX or FOLFIRI/XELIRI chemotherapy combined with a standard dose of bevacizumab or FOLFOX/XELOX alone; these regimens were given over an average of 5 months and completed within 2 weeks before treatment with MGN1703.

Complete or partial responses to induction therapy had been observed in 72% of the 40 patients in the MGN1703 arm and 93% of the placebo arm. "This is very unusual and we are dealing here with a very chemo-sensitive population," remarked Dr. Douillard, professor of medical oncology at the University of Nantes and ICO R. Gauducheau, St. Herblain, France.

The secondary end point of progression-free survival from the start of induction reached a median of 9 months in the experimental arm and 8.6 months in the control arm, representing a significant risk reduction of 50% (HR, 0.50; P = .047), reported Dr. Arnold of University Cancer Center Hamburg, Germany.

In all, 33% of patients in both arms reporting a drug-related adverse event. Tolerability was good, with only two patients reporting grade 3 hypertension and two reporting grade 4 ileus, he said.

A further clinical study of MGN1703 is being planning, and the drug is also in development for non–small cell lung cancer.

Based on the data now available, Dr. Douillard said patients can no longer be randomized to placebo and that more effective strategies such as those used in the Treatment Across Multiple Lines (TML) trial could be used as a reference arm to be improved by the immunostimulant.

IMPACT was sponsored by Mologen AG, which is developing MGN1703. Dr. Arnold reported no conflicts, but several of his co-authors reported relationships with Mologen including employment. Dr. Douillard reported serving as a consultant, adviser, or speaker for Roche and Sanofi Aventis, and serving as a consultant, adviser, and data safety monitoring board chair for Bayer.

VIENNA – Maintenance therapy with the investigational immunomodulator MGN1703 reduced the risk of progression in patients with metastatic colorectal cancer in the phase II/III IMPACT trial.

Median progression-free survival from the start of maintenance therapy was 2.8 months with MGN1703 and 2.6 months with placebo. This was not statistically significant (P = .06) but represented a 47% reduction in the risk of progression (hazard ratio, 0.53).

Patrice Wendling/IMNG Medical Media

The benefit was even greater in a subgroup of good-risk patients, where the risk of progression was reduced 61% and the median time to progression more than doubled from 2.7 to 5.8 months with MGN1703 (HR, .39; P = .013).

"The findings indicate a potential new approach in the management of metastatic colorectal cancer patients," investigator Dr. Dirk Arnold said at the European Society for Medical Oncology Congress.

MGN1703 is an immunomodulator and toll-like receptor (TLR) 9 agonist that activates all components of the innate and adaptive immune system.

TLR9 agonists have shown activity in clinical trials in renal cell carcinoma, cutaneous T-cell lymphoma, and non-Hodgkin’s lymphoma. In a prior study, a TLR9 agonist combined with first-line taxane-plus-platinum chemotherapy reduced the risk of death from advanced-stage non–small cell lung cancer by 26% (J. Clin. Oncol. 2008;26:3979-86).

Dr. Jean-Yves Douillard, who was invited to discuss the study, agreed that immunomodulation represents a new approach to metastatic colorectal cancer.

"This is an additional set of data showing activity with TLR9 agonists, but this is the first time in metastatic colorectal cancer, which has never been considered a really immunosensitive type of tumor," he said. "The tolerance profile is excellent and this type of approach certainly deserves further evaluation in a larger sample to be convincing."

IMPACT was stopped early after an interim analysis of 55 patients because of slow accrual and observed benefit with MGN1703 in a subgroup of patients with no signs of tumor progression.

The 55 patients had achieved disease control after standard first-line chemotherapy and were randomized in a 2:1 fashion to subcutaneous 60 mg MGN1703 or placebo twice weekly until disease progression.

The good-risk subgroup was composed of 46 patients with two of three previously identified factors: carcinoembryonic antigen less than 30 times the upper limit of normal (ULN); gamma glutamyl transpeptidase less than two times the ULN; or alkaline phosphatase less than two times the ULN.

First-line therapy was: FOLFOX/XELOX or FOLFIRI/XELIRI chemotherapy combined with a standard dose of bevacizumab or FOLFOX/XELOX alone; these regimens were given over an average of 5 months and completed within 2 weeks before treatment with MGN1703.

Complete or partial responses to induction therapy had been observed in 72% of the 40 patients in the MGN1703 arm and 93% of the placebo arm. "This is very unusual and we are dealing here with a very chemo-sensitive population," remarked Dr. Douillard, professor of medical oncology at the University of Nantes and ICO R. Gauducheau, St. Herblain, France.

The secondary end point of progression-free survival from the start of induction reached a median of 9 months in the experimental arm and 8.6 months in the control arm, representing a significant risk reduction of 50% (HR, 0.50; P = .047), reported Dr. Arnold of University Cancer Center Hamburg, Germany.

In all, 33% of patients in both arms reporting a drug-related adverse event. Tolerability was good, with only two patients reporting grade 3 hypertension and two reporting grade 4 ileus, he said.

A further clinical study of MGN1703 is being planning, and the drug is also in development for non–small cell lung cancer.

Based on the data now available, Dr. Douillard said patients can no longer be randomized to placebo and that more effective strategies such as those used in the Treatment Across Multiple Lines (TML) trial could be used as a reference arm to be improved by the immunostimulant.

IMPACT was sponsored by Mologen AG, which is developing MGN1703. Dr. Arnold reported no conflicts, but several of his co-authors reported relationships with Mologen including employment. Dr. Douillard reported serving as a consultant, adviser, or speaker for Roche and Sanofi Aventis, and serving as a consultant, adviser, and data safety monitoring board chair for Bayer.

VIENNA – Trastuzumab appears to have a limited impact on advanced HER2-positive bladder cancer, despite its transformative role in HER2-positive breast cancer.

In a multicenter, randomized phase II trial, no difference was observed in response, survival, or quality of life when gemcitabine (Gemzar) plus platinum-based chemotherapy was compared with the same gemcitabine-plus-platinum regimen plus trastuzumab (Herceptin) in 61 patients with stage IV advanced or metastatic urothelial cancer overexpressing HER2.

There was, however, the intriguing finding that overall survival was related to baseline platinum treatment, which included cisplatin or carboplatin.

Patients receiving cisplatin chemotherapy plus trastuzumab lived a median of 33.1 months, compared with 14.5 months in those receiving cisplatin without trastuzumab and just 9.4 months for patients given carboplatin chemotherapy with trastuzumab, Dr. Stéphane Oudard reported at the European Society for Medical Oncology Congress.

"Trastuzumab could have a synergistic effect with cisplatinum, leading to a longer overall survival," he said.

Urothelial cancer is the fourth most common cancer among men, with about 111,000 new cases reported in 2011. It has proven difficult to target with novel agents, despite the variety of molecular pathways that play a significant role in the formation of these tumors. The incidence of HER2 overexpression and/or amplification remains uncertain, ranging from 23% to 80% in various publications, Dr. Oudard observed.

An earlier phase II trial reported a response rate of 70%, including five complete and 26 partial responses, when trastuzumab was added to paclitaxel (Taxol), carboplatin, and gemcitabine chemotherapy in 44 patients with advanced urothelial cancer not previously treated with chemotherapy for metastasis. Median survival was 14 months, but 22% of patients experienced grades 1-3 cardiac toxicity (J. Clin. Oncol. 2007;25:2218-24).

A more recent phase II double-blind trial reported that adding the oral tyrosine kinase inhibitor vandetanib (Caprelsa) to second-line docetaxel (Taxotere) in advanced urothelial cancer did not significantly improve the overall response rate, progression-free survival, or overall survival, which reached a median of just 7 months (J. Clin. Oncol. 2012;30:507-512).

Treatment in the current trial included gemcitabine 1,000 mg/m² on days 1 and 8 every 21 days plus cisplatin 70 mg/m² on day 1 if creatinine clearance was more than 60 mL/min or carboplatin area under the curve (AUC) 5 on day 1 every 21 days if creatinine clearance was 60 mL/min or less, or the same chemotherapy regimen plus trastuzumab at a loading dose of 8 mg/kg then 6 mg/kg every 21 days until progression.

Prior neoadjuvant or adjuvant chemotherapy was allowed if it occurred at least 6 months prior to study entry. Prior trastuzumab therapy was not permitted.

Of the 563 patients tested for HER2 status, only 75 patients (13.3%) were positive on immunohistochemistry, and 14 of these were excluded from the trial for various reasons. The remaining 61 patients had an ECOG performance status of 2 or less, three-fourths had metastatic disease, and half received cisplatin-based chemotherapy.

The 32 patients in the trastuzumab arm received a median of eight chemotherapy cycles vs. a median of six cycles for the 29 patients in the control group, and their median time on therapy was longer, at 5.3 months vs. 3.9 months. Trastuzumab was given for a median of 10 months. Median follow-up was 33.3 months.

The median time to progression was 10.5 months in the control group and 8.3 months with trastuzumab (P = .33), and median overall survival was 15.7 months vs. 14.2 months (P = .56), said Dr. Oudard, of the Georges Pompidou European Hospital, Paris.

Using a Cox regression analysis, baseline serum HER2 was found to be predictive of progression-free survival, whatever the treatment arm (P = .03).

In multivariate Cox regression analysis, the main predictive factors for progression-free survival were ECOG performance status 0-1 vs. 2 (hazard ratio, 3.66) and baseline serum HER2 (HR, 1.01). Trastuzumab was not predictive (P = .49), nor was platinum analogue cisplatin vs. carboplatin (P = .77), he said.

Patients treated with trastuzumab did not have improved quality of life scores, and experienced more grade 3/4 febrile neutropenia (6.5% vs. 0%), dyspnea (3.2% vs. 0%), and decreased left ventricular ejection fraction (3.2% vs. 0%).

Future urothelial cancer trials with HER2-targeting therapy should be performed, but it is unclear whether a trastuzumab combination should be proposed for patients who can only receive cisplatin chemotherapy, whether patient selection should be based on baseline serum HER2, or whether a more powerful drug such as T-DM1 should be used, Dr. Oudard said.

Dr. Oudard reported honoraria from Sanofi-Aventis, Bayer, and other companies.

VIENNA – Trastuzumab appears to have a limited impact on advanced HER2-positive bladder cancer, despite its transformative role in HER2-positive breast cancer.

In a multicenter, randomized phase II trial, no difference was observed in response, survival, or quality of life when gemcitabine (Gemzar) plus platinum-based chemotherapy was compared with the same gemcitabine-plus-platinum regimen plus trastuzumab (Herceptin) in 61 patients with stage IV advanced or metastatic urothelial cancer overexpressing HER2.

There was, however, the intriguing finding that overall survival was related to baseline platinum treatment, which included cisplatin or carboplatin.

Patients receiving cisplatin chemotherapy plus trastuzumab lived a median of 33.1 months, compared with 14.5 months in those receiving cisplatin without trastuzumab and just 9.4 months for patients given carboplatin chemotherapy with trastuzumab, Dr. Stéphane Oudard reported at the European Society for Medical Oncology Congress.

"Trastuzumab could have a synergistic effect with cisplatinum, leading to a longer overall survival," he said.

Urothelial cancer is the fourth most common cancer among men, with about 111,000 new cases reported in 2011. It has proven difficult to target with novel agents, despite the variety of molecular pathways that play a significant role in the formation of these tumors. The incidence of HER2 overexpression and/or amplification remains uncertain, ranging from 23% to 80% in various publications, Dr. Oudard observed.

An earlier phase II trial reported a response rate of 70%, including five complete and 26 partial responses, when trastuzumab was added to paclitaxel (Taxol), carboplatin, and gemcitabine chemotherapy in 44 patients with advanced urothelial cancer not previously treated with chemotherapy for metastasis. Median survival was 14 months, but 22% of patients experienced grades 1-3 cardiac toxicity (J. Clin. Oncol. 2007;25:2218-24).

A more recent phase II double-blind trial reported that adding the oral tyrosine kinase inhibitor vandetanib (Caprelsa) to second-line docetaxel (Taxotere) in advanced urothelial cancer did not significantly improve the overall response rate, progression-free survival, or overall survival, which reached a median of just 7 months (J. Clin. Oncol. 2012;30:507-512).

Treatment in the current trial included gemcitabine 1,000 mg/m² on days 1 and 8 every 21 days plus cisplatin 70 mg/m² on day 1 if creatinine clearance was more than 60 mL/min or carboplatin area under the curve (AUC) 5 on day 1 every 21 days if creatinine clearance was 60 mL/min or less, or the same chemotherapy regimen plus trastuzumab at a loading dose of 8 mg/kg then 6 mg/kg every 21 days until progression.

Prior neoadjuvant or adjuvant chemotherapy was allowed if it occurred at least 6 months prior to study entry. Prior trastuzumab therapy was not permitted.

Of the 563 patients tested for HER2 status, only 75 patients (13.3%) were positive on immunohistochemistry, and 14 of these were excluded from the trial for various reasons. The remaining 61 patients had an ECOG performance status of 2 or less, three-fourths had metastatic disease, and half received cisplatin-based chemotherapy.

The 32 patients in the trastuzumab arm received a median of eight chemotherapy cycles vs. a median of six cycles for the 29 patients in the control group, and their median time on therapy was longer, at 5.3 months vs. 3.9 months. Trastuzumab was given for a median of 10 months. Median follow-up was 33.3 months.

The median time to progression was 10.5 months in the control group and 8.3 months with trastuzumab (P = .33), and median overall survival was 15.7 months vs. 14.2 months (P = .56), said Dr. Oudard, of the Georges Pompidou European Hospital, Paris.

Using a Cox regression analysis, baseline serum HER2 was found to be predictive of progression-free survival, whatever the treatment arm (P = .03).

In multivariate Cox regression analysis, the main predictive factors for progression-free survival were ECOG performance status 0-1 vs. 2 (hazard ratio, 3.66) and baseline serum HER2 (HR, 1.01). Trastuzumab was not predictive (P = .49), nor was platinum analogue cisplatin vs. carboplatin (P = .77), he said.

Patients treated with trastuzumab did not have improved quality of life scores, and experienced more grade 3/4 febrile neutropenia (6.5% vs. 0%), dyspnea (3.2% vs. 0%), and decreased left ventricular ejection fraction (3.2% vs. 0%).

Future urothelial cancer trials with HER2-targeting therapy should be performed, but it is unclear whether a trastuzumab combination should be proposed for patients who can only receive cisplatin chemotherapy, whether patient selection should be based on baseline serum HER2, or whether a more powerful drug such as T-DM1 should be used, Dr. Oudard said.

Dr. Oudard reported honoraria from Sanofi-Aventis, Bayer, and other companies.

VIENNA – Trastuzumab appears to have a limited impact on advanced HER2-positive bladder cancer, despite its transformative role in HER2-positive breast cancer.

In a multicenter, randomized phase II trial, no difference was observed in response, survival, or quality of life when gemcitabine (Gemzar) plus platinum-based chemotherapy was compared with the same gemcitabine-plus-platinum regimen plus trastuzumab (Herceptin) in 61 patients with stage IV advanced or metastatic urothelial cancer overexpressing HER2.

There was, however, the intriguing finding that overall survival was related to baseline platinum treatment, which included cisplatin or carboplatin.

Patients receiving cisplatin chemotherapy plus trastuzumab lived a median of 33.1 months, compared with 14.5 months in those receiving cisplatin without trastuzumab and just 9.4 months for patients given carboplatin chemotherapy with trastuzumab, Dr. Stéphane Oudard reported at the European Society for Medical Oncology Congress.

"Trastuzumab could have a synergistic effect with cisplatinum, leading to a longer overall survival," he said.

Urothelial cancer is the fourth most common cancer among men, with about 111,000 new cases reported in 2011. It has proven difficult to target with novel agents, despite the variety of molecular pathways that play a significant role in the formation of these tumors. The incidence of HER2 overexpression and/or amplification remains uncertain, ranging from 23% to 80% in various publications, Dr. Oudard observed.

An earlier phase II trial reported a response rate of 70%, including five complete and 26 partial responses, when trastuzumab was added to paclitaxel (Taxol), carboplatin, and gemcitabine chemotherapy in 44 patients with advanced urothelial cancer not previously treated with chemotherapy for metastasis. Median survival was 14 months, but 22% of patients experienced grades 1-3 cardiac toxicity (J. Clin. Oncol. 2007;25:2218-24).

A more recent phase II double-blind trial reported that adding the oral tyrosine kinase inhibitor vandetanib (Caprelsa) to second-line docetaxel (Taxotere) in advanced urothelial cancer did not significantly improve the overall response rate, progression-free survival, or overall survival, which reached a median of just 7 months (J. Clin. Oncol. 2012;30:507-512).

Treatment in the current trial included gemcitabine 1,000 mg/m² on days 1 and 8 every 21 days plus cisplatin 70 mg/m² on day 1 if creatinine clearance was more than 60 mL/min or carboplatin area under the curve (AUC) 5 on day 1 every 21 days if creatinine clearance was 60 mL/min or less, or the same chemotherapy regimen plus trastuzumab at a loading dose of 8 mg/kg then 6 mg/kg every 21 days until progression.

Prior neoadjuvant or adjuvant chemotherapy was allowed if it occurred at least 6 months prior to study entry. Prior trastuzumab therapy was not permitted.

Of the 563 patients tested for HER2 status, only 75 patients (13.3%) were positive on immunohistochemistry, and 14 of these were excluded from the trial for various reasons. The remaining 61 patients had an ECOG performance status of 2 or less, three-fourths had metastatic disease, and half received cisplatin-based chemotherapy.

The 32 patients in the trastuzumab arm received a median of eight chemotherapy cycles vs. a median of six cycles for the 29 patients in the control group, and their median time on therapy was longer, at 5.3 months vs. 3.9 months. Trastuzumab was given for a median of 10 months. Median follow-up was 33.3 months.

The median time to progression was 10.5 months in the control group and 8.3 months with trastuzumab (P = .33), and median overall survival was 15.7 months vs. 14.2 months (P = .56), said Dr. Oudard, of the Georges Pompidou European Hospital, Paris.

Using a Cox regression analysis, baseline serum HER2 was found to be predictive of progression-free survival, whatever the treatment arm (P = .03).

In multivariate Cox regression analysis, the main predictive factors for progression-free survival were ECOG performance status 0-1 vs. 2 (hazard ratio, 3.66) and baseline serum HER2 (HR, 1.01). Trastuzumab was not predictive (P = .49), nor was platinum analogue cisplatin vs. carboplatin (P = .77), he said.

Patients treated with trastuzumab did not have improved quality of life scores, and experienced more grade 3/4 febrile neutropenia (6.5% vs. 0%), dyspnea (3.2% vs. 0%), and decreased left ventricular ejection fraction (3.2% vs. 0%).

Future urothelial cancer trials with HER2-targeting therapy should be performed, but it is unclear whether a trastuzumab combination should be proposed for patients who can only receive cisplatin chemotherapy, whether patient selection should be based on baseline serum HER2, or whether a more powerful drug such as T-DM1 should be used, Dr. Oudard said.

Dr. Oudard reported honoraria from Sanofi-Aventis, Bayer, and other companies.

VIENNA – The mammalian target of rapamycin inhibitors temsirolimus and everolimus have racked up a trio of negative trials in advanced renal cell carcinoma.

The phase IIIb INTORACT and phase II RECORD-2 trials show that combinations of bevacizumab (Avastin) and temsirolimus (Torisel) or everolimus (Afinitor) offer no response or survival advantage over existing first-line treatments. In addition, temsirolimus was not superior to sorafenib (Nexavar) as second-line therapy in the phase III INTORSECT trial.

All three trials were reported at the European Society for Medical Oncology Congress.

INTORACT: Temsirolimus

INTORACT randomly assigned 791 treatment naive patients with advanced, predominantly clear cell renal cell carcinoma (RCC) to bevacizumab 10 mg/kg every two weeks plus temsirolimus 25 mg IV weekly or bevacizumab plus interferon-alfa 9 MU three times per week until progression or unacceptable toxicity. Two-thirds of patients were Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate risk, three-fourths were male, and about 85% had undergone a prior nephrectomy.

In INTORACT, the primary end point of progression free-survival by independent review reached 9.1 months with temsirolimus and bevacizumab and 9.3 months with interferon and bevacizumab (hazard ratio, 1.07; P = .759).

Median overall survival was nearly identical at 25.8 months with the temsirolimus combination and 25.5 months with interferon (HR, 1.04; P = .638), as were objective response rates at 27% and 28% (P = .965).

Median duration of response was longer in the interferon arm (17 months vs. 11 months), reported Dr. Brian Rini of the Cleveland Clinic.

According to a subset analysis, patients with a prior nephrectomy had a longer time to progression than did those without nephrectomy in the interferon arm (median 10.9 months vs. 6.8 months), but not in the temsirolimus arm (9.1 months vs. 9.2 months). Progression-free survival was similar between arms based on MSKCC risk status.

Temsirolimus is approved for the treatment of advanced RCC.

Patients receiving temsirolimus had significantly more grade 3/4 mucosal inflammation (8% vs. 0.3%), stomatitis (7% vs. 2%), as well as hypercholesterolemia, hyperglycemia and hypophosphatemia (all 6% vs. 1%). Pneumonitis was lower than expected based on previous trials (1% vs. 0%), he said.

Grade 3/4 neutropenia (8% vs. 2%), fatigue (11% vs. 5%), lymphopenia (6% vs. 3%) and asthenia (10% vs. 6%) were significantly more common in the interferon arm.

"Interferon plus bevacizumab remains a valid treatment option in metastatic renal cell carcinoma, but other combination therapies remain investigational," Dr. Rini concluded.

RECORD-2: Everolimus

The phase II, open-label RECORD-2 (Renal Cell Cancer Treatment With Oral RAD001 given daily–2) trial had a similar design, randomizing 365 treatment-naive patients metastatic RCC patients to bevacizumab 10 mg/kg every two weeks plus everolimus 10 mg/day or to bevacizumab plus interferon alfa-2a 3 to 9 MU three times/week. All patients had a prior nephrectomy, and more than 90% had a good to intermediate MSKCC performance status.

There was no significant difference between the everolimus and interferon groups in objective response rates (27% vs. 28%) or median progression-free survival based on central review (9.3 months vs. 10 months; HR, 0.91; P = .485).

Patients receiving bevacizumab with interferon lived for a median of 26 months, while the median was not yet available for those given everolimus and bevacizumab, reported Dr. Alain Ravaud of Bordeaux University Victor Segalen in France.

The combination of everolimus with bevacizumab was generally well tolerated and resulted in significantly better physical functioning on two quality of life measures, although no significant difference was observed between arms in a time to definitive deterioration analysis. Final overall survival and safety updates are expected later this year, he said.

Everolimus is approved for treatment of advanced RCC after failure of sunitinib (Sutent) or sorafenib.

Results Show Feasibility, Not Efficacy

Invited discussant Dr. Christian Kollmannsberger, senior scientist with the British Columbia Cancer Agency in Vancouver, said the two studies confirm phase I data that combining an mTOR inhibitor with bevacizumab is feasible, whereas combining bevacizumab with tyrosine kinase inhibitors or TKIs with mTOR inhibitors has proven too toxic because of overlapping toxicity profiles.

He said the current results clearly, and inexplicably, also contrast with the recently published French phase II TORAVA trial reporting treatment-limiting toxicity with temsirolimus plus bevacizumab and less clinical activity than the benefit expected from sequential use of each targeted therapy (Lancet Oncol. 2011;12:673-80).

Dr. Kollmannsberger said the overall negative results aren’t surprising since the rationale behind the INTORSECT and RECORD-2 combinations was based on very small phase I/II trials without complete responses and an absence of preclinical data showing an additive or synergistic effect with an mTOR inhibitor and bevacizumab.

He said future trials should combine agents with multiple mechanisms, and that vertical blockade of a single signaling pathway, in this case the vascular endothelial growth factor (VEGF) pathway, "is certainly not the way to go" with currently available agents because it is either too toxic or lacks convincing efficacy.

INTORSECT: Striking Finding

INTORSECT, the first head-to-head phase III trial comparing an mTOR inhibitor and a VEGF receptor inhibitor in second-line RCC, provided no easy answers regarding the optimal treatment sequence after sunitinib in advanced RCC.

The trial randomly assigned 512 patients to temsirolimus 25 mg weekly or sorafenib 400 mg twice daily until progressive disease or unacceptable toxicity. All patients had received first-line sunitinib, and about 82% had clear cell histology.

The confirmed objective response rates were 8% for both the temsirolimus and sorafenib groups, with stable disease reported in 61% of all patients.

Although patients receiving temsirolimus had a numerically longer progression-free survival by independent assessment (median 4.2 months vs. 3.9; HR 0.87; P = .193), those given sorafenib lived a median of four months longer (16.64 months vs. 12.27 months; HR 1.31, P = .014), reported Dr. Thomas Hutson, Pharm.D., of the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas.

Dr. Kollmannsberger described this as the most striking finding of the trial, and said it is likely the longest survival time observed in a randomized trial. The difference in survival is unlikely to be explained by patient characteristics, discontinuations because of adverse events with temsirolimus and sorafenib (17% vs. 14%), or subsequent therapies, since few patients had third-line therapy.

One possible explanation may be that prior VEGF therapy alters the biology of the disease. This hypothesis is supported by a recent analysis of sequential tissue samples suggesting that the protein expression in metastatic cell RCC changes with sunitinib therapy, Dr. Kollmannsberger said.

"I think in the end, the significant survival difference remains to be conclusively explained, but it at least gives rise to the hypothesis that the sequence of drugs does actually matter and matters more than we may think at the present time," he said.

INTORACT was sponsored by Pfizer Inc., which also provided funding for editorial support by Peloton Advantage. Dr. Rini reported research funding from and consulting for Pfizer. RECORD-2 was sponsored by Novartis. Dr. Ravaud reported financial ties with several firms including Pfizer and Novartis. Dr. Hutson reported serving as an adviser and investigator for Aveo, Bayer, GlaxoSmithKline, Novartis, and Pfizer, which sponsored INTORSECT. Dr. Kollmannsberger reported being an investigator on the INTORSECT study, and serving as an advisor for and travel support from Pfizer, Novartis and GSK.

VIENNA – The mammalian target of rapamycin inhibitors temsirolimus and everolimus have racked up a trio of negative trials in advanced renal cell carcinoma.

The phase IIIb INTORACT and phase II RECORD-2 trials show that combinations of bevacizumab (Avastin) and temsirolimus (Torisel) or everolimus (Afinitor) offer no response or survival advantage over existing first-line treatments. In addition, temsirolimus was not superior to sorafenib (Nexavar) as second-line therapy in the phase III INTORSECT trial.

All three trials were reported at the European Society for Medical Oncology Congress.

INTORACT: Temsirolimus

INTORACT randomly assigned 791 treatment naive patients with advanced, predominantly clear cell renal cell carcinoma (RCC) to bevacizumab 10 mg/kg every two weeks plus temsirolimus 25 mg IV weekly or bevacizumab plus interferon-alfa 9 MU three times per week until progression or unacceptable toxicity. Two-thirds of patients were Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate risk, three-fourths were male, and about 85% had undergone a prior nephrectomy.

In INTORACT, the primary end point of progression free-survival by independent review reached 9.1 months with temsirolimus and bevacizumab and 9.3 months with interferon and bevacizumab (hazard ratio, 1.07; P = .759).

Median overall survival was nearly identical at 25.8 months with the temsirolimus combination and 25.5 months with interferon (HR, 1.04; P = .638), as were objective response rates at 27% and 28% (P = .965).

Median duration of response was longer in the interferon arm (17 months vs. 11 months), reported Dr. Brian Rini of the Cleveland Clinic.

According to a subset analysis, patients with a prior nephrectomy had a longer time to progression than did those without nephrectomy in the interferon arm (median 10.9 months vs. 6.8 months), but not in the temsirolimus arm (9.1 months vs. 9.2 months). Progression-free survival was similar between arms based on MSKCC risk status.

Temsirolimus is approved for the treatment of advanced RCC.

Patients receiving temsirolimus had significantly more grade 3/4 mucosal inflammation (8% vs. 0.3%), stomatitis (7% vs. 2%), as well as hypercholesterolemia, hyperglycemia and hypophosphatemia (all 6% vs. 1%). Pneumonitis was lower than expected based on previous trials (1% vs. 0%), he said.

Grade 3/4 neutropenia (8% vs. 2%), fatigue (11% vs. 5%), lymphopenia (6% vs. 3%) and asthenia (10% vs. 6%) were significantly more common in the interferon arm.

"Interferon plus bevacizumab remains a valid treatment option in metastatic renal cell carcinoma, but other combination therapies remain investigational," Dr. Rini concluded.

RECORD-2: Everolimus

The phase II, open-label RECORD-2 (Renal Cell Cancer Treatment With Oral RAD001 given daily–2) trial had a similar design, randomizing 365 treatment-naive patients metastatic RCC patients to bevacizumab 10 mg/kg every two weeks plus everolimus 10 mg/day or to bevacizumab plus interferon alfa-2a 3 to 9 MU three times/week. All patients had a prior nephrectomy, and more than 90% had a good to intermediate MSKCC performance status.

There was no significant difference between the everolimus and interferon groups in objective response rates (27% vs. 28%) or median progression-free survival based on central review (9.3 months vs. 10 months; HR, 0.91; P = .485).

Patients receiving bevacizumab with interferon lived for a median of 26 months, while the median was not yet available for those given everolimus and bevacizumab, reported Dr. Alain Ravaud of Bordeaux University Victor Segalen in France.

The combination of everolimus with bevacizumab was generally well tolerated and resulted in significantly better physical functioning on two quality of life measures, although no significant difference was observed between arms in a time to definitive deterioration analysis. Final overall survival and safety updates are expected later this year, he said.

Everolimus is approved for treatment of advanced RCC after failure of sunitinib (Sutent) or sorafenib.

Results Show Feasibility, Not Efficacy

Invited discussant Dr. Christian Kollmannsberger, senior scientist with the British Columbia Cancer Agency in Vancouver, said the two studies confirm phase I data that combining an mTOR inhibitor with bevacizumab is feasible, whereas combining bevacizumab with tyrosine kinase inhibitors or TKIs with mTOR inhibitors has proven too toxic because of overlapping toxicity profiles.

He said the current results clearly, and inexplicably, also contrast with the recently published French phase II TORAVA trial reporting treatment-limiting toxicity with temsirolimus plus bevacizumab and less clinical activity than the benefit expected from sequential use of each targeted therapy (Lancet Oncol. 2011;12:673-80).

Dr. Kollmannsberger said the overall negative results aren’t surprising since the rationale behind the INTORSECT and RECORD-2 combinations was based on very small phase I/II trials without complete responses and an absence of preclinical data showing an additive or synergistic effect with an mTOR inhibitor and bevacizumab.

He said future trials should combine agents with multiple mechanisms, and that vertical blockade of a single signaling pathway, in this case the vascular endothelial growth factor (VEGF) pathway, "is certainly not the way to go" with currently available agents because it is either too toxic or lacks convincing efficacy.

INTORSECT: Striking Finding

INTORSECT, the first head-to-head phase III trial comparing an mTOR inhibitor and a VEGF receptor inhibitor in second-line RCC, provided no easy answers regarding the optimal treatment sequence after sunitinib in advanced RCC.

The trial randomly assigned 512 patients to temsirolimus 25 mg weekly or sorafenib 400 mg twice daily until progressive disease or unacceptable toxicity. All patients had received first-line sunitinib, and about 82% had clear cell histology.

The confirmed objective response rates were 8% for both the temsirolimus and sorafenib groups, with stable disease reported in 61% of all patients.

Although patients receiving temsirolimus had a numerically longer progression-free survival by independent assessment (median 4.2 months vs. 3.9; HR 0.87; P = .193), those given sorafenib lived a median of four months longer (16.64 months vs. 12.27 months; HR 1.31, P = .014), reported Dr. Thomas Hutson, Pharm.D., of the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas.

Dr. Kollmannsberger described this as the most striking finding of the trial, and said it is likely the longest survival time observed in a randomized trial. The difference in survival is unlikely to be explained by patient characteristics, discontinuations because of adverse events with temsirolimus and sorafenib (17% vs. 14%), or subsequent therapies, since few patients had third-line therapy.

One possible explanation may be that prior VEGF therapy alters the biology of the disease. This hypothesis is supported by a recent analysis of sequential tissue samples suggesting that the protein expression in metastatic cell RCC changes with sunitinib therapy, Dr. Kollmannsberger said.

"I think in the end, the significant survival difference remains to be conclusively explained, but it at least gives rise to the hypothesis that the sequence of drugs does actually matter and matters more than we may think at the present time," he said.

INTORACT was sponsored by Pfizer Inc., which also provided funding for editorial support by Peloton Advantage. Dr. Rini reported research funding from and consulting for Pfizer. RECORD-2 was sponsored by Novartis. Dr. Ravaud reported financial ties with several firms including Pfizer and Novartis. Dr. Hutson reported serving as an adviser and investigator for Aveo, Bayer, GlaxoSmithKline, Novartis, and Pfizer, which sponsored INTORSECT. Dr. Kollmannsberger reported being an investigator on the INTORSECT study, and serving as an advisor for and travel support from Pfizer, Novartis and GSK.

VIENNA – The mammalian target of rapamycin inhibitors temsirolimus and everolimus have racked up a trio of negative trials in advanced renal cell carcinoma.

The phase IIIb INTORACT and phase II RECORD-2 trials show that combinations of bevacizumab (Avastin) and temsirolimus (Torisel) or everolimus (Afinitor) offer no response or survival advantage over existing first-line treatments. In addition, temsirolimus was not superior to sorafenib (Nexavar) as second-line therapy in the phase III INTORSECT trial.

All three trials were reported at the European Society for Medical Oncology Congress.

INTORACT: Temsirolimus

INTORACT randomly assigned 791 treatment naive patients with advanced, predominantly clear cell renal cell carcinoma (RCC) to bevacizumab 10 mg/kg every two weeks plus temsirolimus 25 mg IV weekly or bevacizumab plus interferon-alfa 9 MU three times per week until progression or unacceptable toxicity. Two-thirds of patients were Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate risk, three-fourths were male, and about 85% had undergone a prior nephrectomy.

In INTORACT, the primary end point of progression free-survival by independent review reached 9.1 months with temsirolimus and bevacizumab and 9.3 months with interferon and bevacizumab (hazard ratio, 1.07; P = .759).

Median overall survival was nearly identical at 25.8 months with the temsirolimus combination and 25.5 months with interferon (HR, 1.04; P = .638), as were objective response rates at 27% and 28% (P = .965).

Median duration of response was longer in the interferon arm (17 months vs. 11 months), reported Dr. Brian Rini of the Cleveland Clinic.

According to a subset analysis, patients with a prior nephrectomy had a longer time to progression than did those without nephrectomy in the interferon arm (median 10.9 months vs. 6.8 months), but not in the temsirolimus arm (9.1 months vs. 9.2 months). Progression-free survival was similar between arms based on MSKCC risk status.

Temsirolimus is approved for the treatment of advanced RCC.

Patients receiving temsirolimus had significantly more grade 3/4 mucosal inflammation (8% vs. 0.3%), stomatitis (7% vs. 2%), as well as hypercholesterolemia, hyperglycemia and hypophosphatemia (all 6% vs. 1%). Pneumonitis was lower than expected based on previous trials (1% vs. 0%), he said.

Grade 3/4 neutropenia (8% vs. 2%), fatigue (11% vs. 5%), lymphopenia (6% vs. 3%) and asthenia (10% vs. 6%) were significantly more common in the interferon arm.

"Interferon plus bevacizumab remains a valid treatment option in metastatic renal cell carcinoma, but other combination therapies remain investigational," Dr. Rini concluded.

RECORD-2: Everolimus

The phase II, open-label RECORD-2 (Renal Cell Cancer Treatment With Oral RAD001 given daily–2) trial had a similar design, randomizing 365 treatment-naive patients metastatic RCC patients to bevacizumab 10 mg/kg every two weeks plus everolimus 10 mg/day or to bevacizumab plus interferon alfa-2a 3 to 9 MU three times/week. All patients had a prior nephrectomy, and more than 90% had a good to intermediate MSKCC performance status.

There was no significant difference between the everolimus and interferon groups in objective response rates (27% vs. 28%) or median progression-free survival based on central review (9.3 months vs. 10 months; HR, 0.91; P = .485).

Patients receiving bevacizumab with interferon lived for a median of 26 months, while the median was not yet available for those given everolimus and bevacizumab, reported Dr. Alain Ravaud of Bordeaux University Victor Segalen in France.

The combination of everolimus with bevacizumab was generally well tolerated and resulted in significantly better physical functioning on two quality of life measures, although no significant difference was observed between arms in a time to definitive deterioration analysis. Final overall survival and safety updates are expected later this year, he said.

Everolimus is approved for treatment of advanced RCC after failure of sunitinib (Sutent) or sorafenib.

Results Show Feasibility, Not Efficacy

Invited discussant Dr. Christian Kollmannsberger, senior scientist with the British Columbia Cancer Agency in Vancouver, said the two studies confirm phase I data that combining an mTOR inhibitor with bevacizumab is feasible, whereas combining bevacizumab with tyrosine kinase inhibitors or TKIs with mTOR inhibitors has proven too toxic because of overlapping toxicity profiles.

He said the current results clearly, and inexplicably, also contrast with the recently published French phase II TORAVA trial reporting treatment-limiting toxicity with temsirolimus plus bevacizumab and less clinical activity than the benefit expected from sequential use of each targeted therapy (Lancet Oncol. 2011;12:673-80).

Dr. Kollmannsberger said the overall negative results aren’t surprising since the rationale behind the INTORSECT and RECORD-2 combinations was based on very small phase I/II trials without complete responses and an absence of preclinical data showing an additive or synergistic effect with an mTOR inhibitor and bevacizumab.

He said future trials should combine agents with multiple mechanisms, and that vertical blockade of a single signaling pathway, in this case the vascular endothelial growth factor (VEGF) pathway, "is certainly not the way to go" with currently available agents because it is either too toxic or lacks convincing efficacy.

INTORSECT: Striking Finding

INTORSECT, the first head-to-head phase III trial comparing an mTOR inhibitor and a VEGF receptor inhibitor in second-line RCC, provided no easy answers regarding the optimal treatment sequence after sunitinib in advanced RCC.

The trial randomly assigned 512 patients to temsirolimus 25 mg weekly or sorafenib 400 mg twice daily until progressive disease or unacceptable toxicity. All patients had received first-line sunitinib, and about 82% had clear cell histology.

The confirmed objective response rates were 8% for both the temsirolimus and sorafenib groups, with stable disease reported in 61% of all patients.

Although patients receiving temsirolimus had a numerically longer progression-free survival by independent assessment (median 4.2 months vs. 3.9; HR 0.87; P = .193), those given sorafenib lived a median of four months longer (16.64 months vs. 12.27 months; HR 1.31, P = .014), reported Dr. Thomas Hutson, Pharm.D., of the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas.

Dr. Kollmannsberger described this as the most striking finding of the trial, and said it is likely the longest survival time observed in a randomized trial. The difference in survival is unlikely to be explained by patient characteristics, discontinuations because of adverse events with temsirolimus and sorafenib (17% vs. 14%), or subsequent therapies, since few patients had third-line therapy.

One possible explanation may be that prior VEGF therapy alters the biology of the disease. This hypothesis is supported by a recent analysis of sequential tissue samples suggesting that the protein expression in metastatic cell RCC changes with sunitinib therapy, Dr. Kollmannsberger said.

"I think in the end, the significant survival difference remains to be conclusively explained, but it at least gives rise to the hypothesis that the sequence of drugs does actually matter and matters more than we may think at the present time," he said.

INTORACT was sponsored by Pfizer Inc., which also provided funding for editorial support by Peloton Advantage. Dr. Rini reported research funding from and consulting for Pfizer. RECORD-2 was sponsored by Novartis. Dr. Ravaud reported financial ties with several firms including Pfizer and Novartis. Dr. Hutson reported serving as an adviser and investigator for Aveo, Bayer, GlaxoSmithKline, Novartis, and Pfizer, which sponsored INTORSECT. Dr. Kollmannsberger reported being an investigator on the INTORSECT study, and serving as an advisor for and travel support from Pfizer, Novartis and GSK.

MINNEAPOLIS – The risk of hip fracture among elderly patients spikes shortly after starting antihypertensive medications, judging from the findings of a large self-controlled, case series analysis.

Overall, elderly community-dwelling patients had a 43% increased risk of hip fracture within 45 days of initiating an antihypertensive therapy (incidence rate ratio, 1.41; 95% confidence interval, 1.19-1.72).

The risk was significantly higher only for two of the five classes of commonly used antihypertensive drugs: ACE inhibitors and beta-blockers.

Patrice Wendling/IMNG Medical Media

The risk of early fracture rose by 53% for patients started on an ACE inhibitor (IRR, 1.53; 95% CI, 1.12-2.10) and by 58% for those on beta-blockers (IRR, 1.58; 95% CI, 1.01-2.48), Dr. Debra Butt reported at the annual meeting of the American Society of Bone and Mineral Research.

This is the first large population-based study to report such an association, and the evidence is conflicting regarding the association between antihypertensives and fracture risk. The majority of studies evaluate long exposure periods, where the underlying mechanism is thought to be related to bone mass.

On the other hand, there are studies of immediate increased risk of falls in the elderly started on antihypertensive drugs, where orthostatic hypotension is thought to be the underlying mechanism. One recently updated analysis reported that the effect on falls in the elderly was strongest in the first 3 weeks of a thiazide diuretic prescription (IRR, 2.80), after taking into account confounding factors (Pharmacoepidemiol. Drug Saf. 2011;20:879-84).

The current analysis used six health care administrative databases to identify 301,591 newly treated hypertensive patients at least 66 years of age living in Ontario and link them with hip fractures occurring from April 1, 2000, to March 31, 2009. The risk period was the first 45 days following initiation of monotherapy antihypertensive therapy, with control periods before and after treatment in a 450-day observation period.

The study excluded long-term care residents and patients with conditions other than hypertension for which an antihypertensive drug may have been prescribed such as diabetes, myocardial infarction, heart failure, angina, cardiomyopathy and transient ischemic attack.

At baseline, only 3% of patients had had a fall in the past year requiring hospital care and 6% had a history of past hip fracture. The majority of patients were female (81%) and the median age was 80.8 years.

Antihypertensive drugs included thiazide diuretics (23%), ACE inhibitors (30%), angiotensin receptor blockers (4%), calcium channel blockers (17%) and beta blockers (26%).

During the observation period, 1,463 hip fractures were identified, according to Dr. Butt of the department of family and community medicine, University of Toronto.

A sensitivity analysis that excluded use of other potential fall-causing drugs and psychotropic drugs that can trigger falls, confirmed the initial association between antihypertensive drug initiation and early hip fracture with a nearly identical incidence ratio of 1.42.

"Based on this finding, caution is advised when initiating antihypertensive drugs in the elderly," she said.

During a discussion of the study, however, concerns were raised about what to advise patients without knowing the absolute risk of falling and the risk of hip fracture while on antihypertensive medications vs. the benefits of treating hypertension.

One audience member said the study alerts clinicians to the risk but that it’s hard to draw any practical, clinical recommendations without more information such as when the falls occurred, whether the patient was standing or sitting down at the time of the fracture, or the magnitude of the hypertension decrease from baseline.

"In order to develop clinical recommendations, you have to start by demonstrating an association and that’s what our study does," Dr. Butt responded. "It’s a start, in an area where we have few studies that exist."

The government of Ontario funded the study. Dr. Butt reported no relevant conflicts of interest.

MINNEAPOLIS – The risk of hip fracture among elderly patients spikes shortly after starting antihypertensive medications, judging from the findings of a large self-controlled, case series analysis.

Overall, elderly community-dwelling patients had a 43% increased risk of hip fracture within 45 days of initiating an antihypertensive therapy (incidence rate ratio, 1.41; 95% confidence interval, 1.19-1.72).

The risk was significantly higher only for two of the five classes of commonly used antihypertensive drugs: ACE inhibitors and beta-blockers.

Patrice Wendling/IMNG Medical Media

The risk of early fracture rose by 53% for patients started on an ACE inhibitor (IRR, 1.53; 95% CI, 1.12-2.10) and by 58% for those on beta-blockers (IRR, 1.58; 95% CI, 1.01-2.48), Dr. Debra Butt reported at the annual meeting of the American Society of Bone and Mineral Research.

This is the first large population-based study to report such an association, and the evidence is conflicting regarding the association between antihypertensives and fracture risk. The majority of studies evaluate long exposure periods, where the underlying mechanism is thought to be related to bone mass.

On the other hand, there are studies of immediate increased risk of falls in the elderly started on antihypertensive drugs, where orthostatic hypotension is thought to be the underlying mechanism. One recently updated analysis reported that the effect on falls in the elderly was strongest in the first 3 weeks of a thiazide diuretic prescription (IRR, 2.80), after taking into account confounding factors (Pharmacoepidemiol. Drug Saf. 2011;20:879-84).

The current analysis used six health care administrative databases to identify 301,591 newly treated hypertensive patients at least 66 years of age living in Ontario and link them with hip fractures occurring from April 1, 2000, to March 31, 2009. The risk period was the first 45 days following initiation of monotherapy antihypertensive therapy, with control periods before and after treatment in a 450-day observation period.

The study excluded long-term care residents and patients with conditions other than hypertension for which an antihypertensive drug may have been prescribed such as diabetes, myocardial infarction, heart failure, angina, cardiomyopathy and transient ischemic attack.

At baseline, only 3% of patients had had a fall in the past year requiring hospital care and 6% had a history of past hip fracture. The majority of patients were female (81%) and the median age was 80.8 years.

Antihypertensive drugs included thiazide diuretics (23%), ACE inhibitors (30%), angiotensin receptor blockers (4%), calcium channel blockers (17%) and beta blockers (26%).

During the observation period, 1,463 hip fractures were identified, according to Dr. Butt of the department of family and community medicine, University of Toronto.

A sensitivity analysis that excluded use of other potential fall-causing drugs and psychotropic drugs that can trigger falls, confirmed the initial association between antihypertensive drug initiation and early hip fracture with a nearly identical incidence ratio of 1.42.

"Based on this finding, caution is advised when initiating antihypertensive drugs in the elderly," she said.

During a discussion of the study, however, concerns were raised about what to advise patients without knowing the absolute risk of falling and the risk of hip fracture while on antihypertensive medications vs. the benefits of treating hypertension.

One audience member said the study alerts clinicians to the risk but that it’s hard to draw any practical, clinical recommendations without more information such as when the falls occurred, whether the patient was standing or sitting down at the time of the fracture, or the magnitude of the hypertension decrease from baseline.

"In order to develop clinical recommendations, you have to start by demonstrating an association and that’s what our study does," Dr. Butt responded. "It’s a start, in an area where we have few studies that exist."

The government of Ontario funded the study. Dr. Butt reported no relevant conflicts of interest.

MINNEAPOLIS – The risk of hip fracture among elderly patients spikes shortly after starting antihypertensive medications, judging from the findings of a large self-controlled, case series analysis.

Overall, elderly community-dwelling patients had a 43% increased risk of hip fracture within 45 days of initiating an antihypertensive therapy (incidence rate ratio, 1.41; 95% confidence interval, 1.19-1.72).

The risk was significantly higher only for two of the five classes of commonly used antihypertensive drugs: ACE inhibitors and beta-blockers.

Patrice Wendling/IMNG Medical Media

The risk of early fracture rose by 53% for patients started on an ACE inhibitor (IRR, 1.53; 95% CI, 1.12-2.10) and by 58% for those on beta-blockers (IRR, 1.58; 95% CI, 1.01-2.48), Dr. Debra Butt reported at the annual meeting of the American Society of Bone and Mineral Research.

This is the first large population-based study to report such an association, and the evidence is conflicting regarding the association between antihypertensives and fracture risk. The majority of studies evaluate long exposure periods, where the underlying mechanism is thought to be related to bone mass.

On the other hand, there are studies of immediate increased risk of falls in the elderly started on antihypertensive drugs, where orthostatic hypotension is thought to be the underlying mechanism. One recently updated analysis reported that the effect on falls in the elderly was strongest in the first 3 weeks of a thiazide diuretic prescription (IRR, 2.80), after taking into account confounding factors (Pharmacoepidemiol. Drug Saf. 2011;20:879-84).

The current analysis used six health care administrative databases to identify 301,591 newly treated hypertensive patients at least 66 years of age living in Ontario and link them with hip fractures occurring from April 1, 2000, to March 31, 2009. The risk period was the first 45 days following initiation of monotherapy antihypertensive therapy, with control periods before and after treatment in a 450-day observation period.

The study excluded long-term care residents and patients with conditions other than hypertension for which an antihypertensive drug may have been prescribed such as diabetes, myocardial infarction, heart failure, angina, cardiomyopathy and transient ischemic attack.

At baseline, only 3% of patients had had a fall in the past year requiring hospital care and 6% had a history of past hip fracture. The majority of patients were female (81%) and the median age was 80.8 years.

Antihypertensive drugs included thiazide diuretics (23%), ACE inhibitors (30%), angiotensin receptor blockers (4%), calcium channel blockers (17%) and beta blockers (26%).

During the observation period, 1,463 hip fractures were identified, according to Dr. Butt of the department of family and community medicine, University of Toronto.

A sensitivity analysis that excluded use of other potential fall-causing drugs and psychotropic drugs that can trigger falls, confirmed the initial association between antihypertensive drug initiation and early hip fracture with a nearly identical incidence ratio of 1.42.

"Based on this finding, caution is advised when initiating antihypertensive drugs in the elderly," she said.

During a discussion of the study, however, concerns were raised about what to advise patients without knowing the absolute risk of falling and the risk of hip fracture while on antihypertensive medications vs. the benefits of treating hypertension.

One audience member said the study alerts clinicians to the risk but that it’s hard to draw any practical, clinical recommendations without more information such as when the falls occurred, whether the patient was standing or sitting down at the time of the fracture, or the magnitude of the hypertension decrease from baseline.

"In order to develop clinical recommendations, you have to start by demonstrating an association and that’s what our study does," Dr. Butt responded. "It’s a start, in an area where we have few studies that exist."

The government of Ontario funded the study. Dr. Butt reported no relevant conflicts of interest.

When the U.S. Preventive Services Task Force recommended against prostate-specific antigen-based screening in men of any age this spring, an uproar swiftly followed. Evidence was dissected; cancer survivors and stakeholders lambasted the decision as shortsighted, and still others endorsed the recommendation as a long overdue nod to science.

Similar fallout erupted in November 2009 when the task force recommended against routine screening mammography in women younger than age 50 years. Only this time, critics charged that science had taken a back seat to politics, characterizing the decision as a harbinger of rationing under President Obama’s health care reform.

Less contentious so far are new recommendations that the annual Pap smear screening for cervical cancer should be pushed back to every 3 years and that low-dose lung CT screening be offered to heavy smokers. Time will tell whether the former is accepted in clinical practice and the latter can make the leap from clinical trial strategy to national guideline.

Given the complicated, emotionally charged nature of cancer screening and the political forces still at play, could another maelstrom be far off?

"There are a lot of misconceptions out there, in part because for so many decades, the messages have been so strong, they sometimes leaped ahead of the evidence," Dr. Barnett Kramer, director of the division of cancer prevention at the National Cancer Institute (NCI), Bethesda, Md., said in an interview.

When advocacy groups such as the American Cancer Society (ACS) first formed, strong, simple messages were needed to get Americans even to utter the word cancer out loud.

Over time, cancer screening messages have evolved into sound bites that almost always follow the very strong presumption that early detection means a better chance for survival, said Dr. Kramer, who described this as a serious oversimplification of the principles of screening. By its very nature, a screening test will always advance the date of diagnosis, but this may not benefit the patient.

"Simply saying that screening increases survival doesn’t convey any useful information," he said. "You really need to know what the effect of the screening test is on the risk of dying – that is the mortality rate, and that’s a different calculation from simply measuring the duration of life from the day of diagnosis to death."

Dr. Virginia Moyer, chair of the U.S. Preventive Services Task Force (USPSTF), agreed that some advocacy groups "absolutely oversell the benefits of screening and completely ignore the harms" that screening and medical interventions can cause. The perception among the general public is that if you screen and find something, you have therefore saved a life.

She argued in an interview that scientific groups such as the task force have provided a more balanced message, but admits the scientific community has made its own mistakes.

"Our concept at the time that PSA screening was developed was that if you had cancer in you, it would inevitably grow and kill you if you didn’t do something about it," she said. "That’s what we thought all cancer was about and we just turned out to be wrong. A huge proportion of cancers never do anything and that’s the piece we didn’t know."

Some physicians, however, may still not know. Dr. Moyer pointed out that risk communication experts recently reported that about one half (47%) of U.S. primary care physicians surveyed incorrectly said that finding more cases of cancer in screened vs. unscreened populations, "proves that screening saves lives" (Ann. Intern. Med. 2012;156:340-9).

The Push-Pull of Politics

Dr. Handel Reynolds, breast radiologist with Piedmont Hospital in Atlanta and author of the new book, "The Big Squeeze: A Social and Political History of the Controversial Mammogram," said in an interview that a series of crucial decisions made by health professionals set up screening mammography to be the controversial test it is today.

The first of these came in 1973 when, based on a single trial showing a mortality benefit in women under 50, the ACS and NCI decided to include women as young as 35 years in the National Breast Cancer Detection Demonstration Project (BCDDP), the first large-scale use of mammography as a screening tool involving some 280,000 women over 5 years (J. Natl. Cancer Inst. 1988;80:1540-7).

Just 3 years later, the National Institutes of Health (NIH) convened its first consensus conference to address screening in younger women, even though the BCDDP was not a clinical trial and demonstration projects are typically performed to show that activities with proven efficacy in clinical trials can be done on a large scale.

"1976 was the first time we had this huge blow-up about women under 50, and it has not gone away. In fact, it has become more acrimonious with each subsequent iteration," Dr. Reynolds said.

The most egregious example of political interference occurred in 1997. The NCI had broken with the ACS four years earlier and dropped its recommendation for mammography in women under 50. In 1997, however, the NCI reversed its position after a series of high-profile hearings held by then Sen. Arlen Specter (R-PA.), who chaired the subcommittee controlling funding for the NCI and who openly supported screening for women under 50, Dr. Reynolds said.

"The 1997 episode established the primacy of politics over science in the mammography debate and made it so much easier then for the 2009 controversy to be resolved in a matter of weeks," he contends.

Pap Test Changes Fly Under the Radar

Politics played a huge role in the uproar that surrounded the 2003 cervical cancer guidelines, said Dr. Alan G. Waxman, who recalled being accused of hating his mother because the 2003 guidelines he helped pen urged less frequent screening for cervical cancer.

Although the 2012 cervical screening guidelines essentially retire the annual Pap smear, Dr. Waxman said that he’s not expecting a huge backlash. Things have been relatively quiet since two separate groups released updates this March. The change between guidelines has been incremental, and women trust the science because it hasn’t gone through the permutations and "fluctuating truth" observed with the mammography data.

"With the Pap smear, the science has been pretty much in lockstep," said Dr. Waxman, president of the American Society for Colposcopy and Cervical Pathology, which partnered with the ACS and American Society for Clinical Pathology to release its guidelines in tandem with similar recommendations from the USPSTF.

Money Makes Its Voice Heard

The relative quiet following the changes to cervical cancer screening recommendations may also reflect the numbers. Only about 12,000 new cases of cervical cancer are diagnosed annually, compared with 214,633 new cases of prostate cancer in 2008, the most recent year for which numbers are available. Similarly, mammograms were ordered or provided in 20.3 million physician office visits and 2.3 million hospital outpatient department visits in 2009 alone.

The financial stakes are high in prostate and breast cancer and the rhetoric proportionate.

The American Urological Association expressed outrage after the release of the UPSTF PSA recommendation, warning that it could potentially turn back the clock to a time before PSA testing when "men presented with high-grade, metastatic disease for which there was little or no treatment beyond palliative care."

Dr. Otis Brawley, chief medical officer of the American Cancer Society, defended the USPSTF in a recent commentary, saying that unlike many of their critics, USPSTF members are ideally suited to assess the science objectively because they have no "emotional, ideological, or financial conflicts of interest" and understand the complicated science of screening.

He also expressed hope that the new PSA recommendations will end mass screenings, a "lucrative business" that offers tests outside the physician-patient relationship, often in shopping malls and parking lots with sponsorship from hospitals, medical practices, and even an adult diaper company.

For his part, Dr. Richard Albin, who discovered PSA, has been quoted as saying, "I never dreamed that my discovery 4 decades ago would lead to such a profit-driven public health disaster."

Some urologists have criticized the USPSTF for failing to include urologists on the panel and for the absence of a cost analysis.

"If you’re not saving any lives, then any money you’re spending is wasted, and you don’t need a complicated cost-effectiveness analysis to figure that out," countered Dr. Moyer.

Physicians and patients, however, may need a scorecard to wade through the rhetoric and conflicting data, frequently cherry-picked to argue for or against a particular screening test. In a recent study, 30% of women reported that the 2009 USPSTF mammography guidelines confused more than they helped them understand when to get a mammogram (Am. J. Prev. Med. 2011;40:497-504)

A More Nuanced Conversation

There’s little doubt that the task force’s recent decisions will dramatically reshape mammography and PSA screening in the United States, but the question is by how much.

"Largely what we’ve communicated is all the benefit, but I think the U.S. Preventive Services Task Force is communicating all the harms. And the right place is somewhere in between," Dr. Therese Bartholomew Bevers, medical director of the Cancer Prevention Center at the University of Texas M.D. Anderson Cancer Center in Houston, said in an interview.

What’s important is having a more balanced, nuanced conversation with patients. But is the American public ready for discussions of mortality rates or the changing calculus of risk/benefit ratios of screening as they age?

Nearly half of all American adults – 90 million people – have difficulty understanding and using health information, according to an Institute of Medicine report. In addition, the 2000 census counted 20 million people who speak poor English and 10 million who speak none.

The public is quite intelligent, but that part of the problem is that physicians don’t always know or understand the data. And if even when physicians understand the data, they often do not know how to communicate them in a way their patients can understand, says Dr. Bevers.

"That’s where there is a huge opportunity to create decision-making tools," she says.

With the help of communication experts, Dr. Bevers and her colleagues are developing a computerized tool that reviews the data from the National Lung Screening Trial (NLST) and spells out the benefits and harms of low-dose computed tomography screening for lung cancer in a very simplified fashion, using smiley faces for benefits and frowning faces for risks.

"It really advances my discussion when I walk in the room," said Dr. Bevers, a coinvestigator for the NLST. "I’m not explaining about the 20% mortality reduction, the associated harms. I’m now talking about: ‘What did you think about that?’ ‘What did you think about the harms?’ ‘How did it influence your decision about this?’ It’s a much more advanced discussion, and that’s helpful in a busy practice."

Another tool could then be used to walk patients through the next step of care to give physicians a sense of what concerns their patients most; for example, the risk of dying or that their cancer will return, she said.

The New Kid on the Block

Most experts agree that low-dose CT lung cancer screening is something of an anomaly in the cancer screening wars. Prior nonrandomized trials suggested a benefit with low-dose CT, but practice did not leapfrog the evidence. Only now that the randomized NLST has been completed is the screening machinery gearing up, but with significant questions about cost and high false-positive rates still unanswered (N. Engl. J. Med. 2011;365:395-409)

Moreover, CT lung screening would be an additional service offered to high-risk individuals, rather than the retraction of an entrenched screening practice.

The NCI has developed its own one-page, online NLST study guide for patients and physicians that provides specific data on low-dose CT vs. chest x-ray screening, "take-home" messages, and an educational component directing patients not to smoke.

"We don’t want to oversell the harms and undersell the benefits," said the NCI’s Dr. Kramer. "We don’t want the pendulum to swing completely in the opposite direction, and I think this sheet goes a long way."

In a busy primary care office, no doubt the various new recommendations will shift the conversation with patients, many of whom have been given the simple message for years to come back each year for their annual mammogram or PSA test. Depending on which recommendations their physicians advocate and what patients choose to follow, it will ultimately tip the balance sheet and outcomes data for years to come.

None of the physicians interviewed reported having relevant conflicts of interest.

When the U.S. Preventive Services Task Force recommended against prostate-specific antigen-based screening in men of any age this spring, an uproar swiftly followed. Evidence was dissected; cancer survivors and stakeholders lambasted the decision as shortsighted, and still others endorsed the recommendation as a long overdue nod to science.

Similar fallout erupted in November 2009 when the task force recommended against routine screening mammography in women younger than age 50 years. Only this time, critics charged that science had taken a back seat to politics, characterizing the decision as a harbinger of rationing under President Obama’s health care reform.

Less contentious so far are new recommendations that the annual Pap smear screening for cervical cancer should be pushed back to every 3 years and that low-dose lung CT screening be offered to heavy smokers. Time will tell whether the former is accepted in clinical practice and the latter can make the leap from clinical trial strategy to national guideline.

Given the complicated, emotionally charged nature of cancer screening and the political forces still at play, could another maelstrom be far off?

"There are a lot of misconceptions out there, in part because for so many decades, the messages have been so strong, they sometimes leaped ahead of the evidence," Dr. Barnett Kramer, director of the division of cancer prevention at the National Cancer Institute (NCI), Bethesda, Md., said in an interview.

When advocacy groups such as the American Cancer Society (ACS) first formed, strong, simple messages were needed to get Americans even to utter the word cancer out loud.

Over time, cancer screening messages have evolved into sound bites that almost always follow the very strong presumption that early detection means a better chance for survival, said Dr. Kramer, who described this as a serious oversimplification of the principles of screening. By its very nature, a screening test will always advance the date of diagnosis, but this may not benefit the patient.

"Simply saying that screening increases survival doesn’t convey any useful information," he said. "You really need to know what the effect of the screening test is on the risk of dying – that is the mortality rate, and that’s a different calculation from simply measuring the duration of life from the day of diagnosis to death."

Dr. Virginia Moyer, chair of the U.S. Preventive Services Task Force (USPSTF), agreed that some advocacy groups "absolutely oversell the benefits of screening and completely ignore the harms" that screening and medical interventions can cause. The perception among the general public is that if you screen and find something, you have therefore saved a life.

She argued in an interview that scientific groups such as the task force have provided a more balanced message, but admits the scientific community has made its own mistakes.

"Our concept at the time that PSA screening was developed was that if you had cancer in you, it would inevitably grow and kill you if you didn’t do something about it," she said. "That’s what we thought all cancer was about and we just turned out to be wrong. A huge proportion of cancers never do anything and that’s the piece we didn’t know."

Some physicians, however, may still not know. Dr. Moyer pointed out that risk communication experts recently reported that about one half (47%) of U.S. primary care physicians surveyed incorrectly said that finding more cases of cancer in screened vs. unscreened populations, "proves that screening saves lives" (Ann. Intern. Med. 2012;156:340-9).

The Push-Pull of Politics

Dr. Handel Reynolds, breast radiologist with Piedmont Hospital in Atlanta and author of the new book, "The Big Squeeze: A Social and Political History of the Controversial Mammogram," said in an interview that a series of crucial decisions made by health professionals set up screening mammography to be the controversial test it is today.

The first of these came in 1973 when, based on a single trial showing a mortality benefit in women under 50, the ACS and NCI decided to include women as young as 35 years in the National Breast Cancer Detection Demonstration Project (BCDDP), the first large-scale use of mammography as a screening tool involving some 280,000 women over 5 years (J. Natl. Cancer Inst. 1988;80:1540-7).

Just 3 years later, the National Institutes of Health (NIH) convened its first consensus conference to address screening in younger women, even though the BCDDP was not a clinical trial and demonstration projects are typically performed to show that activities with proven efficacy in clinical trials can be done on a large scale.

"1976 was the first time we had this huge blow-up about women under 50, and it has not gone away. In fact, it has become more acrimonious with each subsequent iteration," Dr. Reynolds said.

The most egregious example of political interference occurred in 1997. The NCI had broken with the ACS four years earlier and dropped its recommendation for mammography in women under 50. In 1997, however, the NCI reversed its position after a series of high-profile hearings held by then Sen. Arlen Specter (R-PA.), who chaired the subcommittee controlling funding for the NCI and who openly supported screening for women under 50, Dr. Reynolds said.

"The 1997 episode established the primacy of politics over science in the mammography debate and made it so much easier then for the 2009 controversy to be resolved in a matter of weeks," he contends.

Pap Test Changes Fly Under the Radar

Politics played a huge role in the uproar that surrounded the 2003 cervical cancer guidelines, said Dr. Alan G. Waxman, who recalled being accused of hating his mother because the 2003 guidelines he helped pen urged less frequent screening for cervical cancer.

Although the 2012 cervical screening guidelines essentially retire the annual Pap smear, Dr. Waxman said that he’s not expecting a huge backlash. Things have been relatively quiet since two separate groups released updates this March. The change between guidelines has been incremental, and women trust the science because it hasn’t gone through the permutations and "fluctuating truth" observed with the mammography data.

"With the Pap smear, the science has been pretty much in lockstep," said Dr. Waxman, president of the American Society for Colposcopy and Cervical Pathology, which partnered with the ACS and American Society for Clinical Pathology to release its guidelines in tandem with similar recommendations from the USPSTF.

Money Makes Its Voice Heard

The relative quiet following the changes to cervical cancer screening recommendations may also reflect the numbers. Only about 12,000 new cases of cervical cancer are diagnosed annually, compared with 214,633 new cases of prostate cancer in 2008, the most recent year for which numbers are available. Similarly, mammograms were ordered or provided in 20.3 million physician office visits and 2.3 million hospital outpatient department visits in 2009 alone.

The financial stakes are high in prostate and breast cancer and the rhetoric proportionate.

The American Urological Association expressed outrage after the release of the UPSTF PSA recommendation, warning that it could potentially turn back the clock to a time before PSA testing when "men presented with high-grade, metastatic disease for which there was little or no treatment beyond palliative care."

Dr. Otis Brawley, chief medical officer of the American Cancer Society, defended the USPSTF in a recent commentary, saying that unlike many of their critics, USPSTF members are ideally suited to assess the science objectively because they have no "emotional, ideological, or financial conflicts of interest" and understand the complicated science of screening.

He also expressed hope that the new PSA recommendations will end mass screenings, a "lucrative business" that offers tests outside the physician-patient relationship, often in shopping malls and parking lots with sponsorship from hospitals, medical practices, and even an adult diaper company.

For his part, Dr. Richard Albin, who discovered PSA, has been quoted as saying, "I never dreamed that my discovery 4 decades ago would lead to such a profit-driven public health disaster."

Some urologists have criticized the USPSTF for failing to include urologists on the panel and for the absence of a cost analysis.

"If you’re not saving any lives, then any money you’re spending is wasted, and you don’t need a complicated cost-effectiveness analysis to figure that out," countered Dr. Moyer.

Physicians and patients, however, may need a scorecard to wade through the rhetoric and conflicting data, frequently cherry-picked to argue for or against a particular screening test. In a recent study, 30% of women reported that the 2009 USPSTF mammography guidelines confused more than they helped them understand when to get a mammogram (Am. J. Prev. Med. 2011;40:497-504)

A More Nuanced Conversation

There’s little doubt that the task force’s recent decisions will dramatically reshape mammography and PSA screening in the United States, but the question is by how much.

"Largely what we’ve communicated is all the benefit, but I think the U.S. Preventive Services Task Force is communicating all the harms. And the right place is somewhere in between," Dr. Therese Bartholomew Bevers, medical director of the Cancer Prevention Center at the University of Texas M.D. Anderson Cancer Center in Houston, said in an interview.

What’s important is having a more balanced, nuanced conversation with patients. But is the American public ready for discussions of mortality rates or the changing calculus of risk/benefit ratios of screening as they age?

Nearly half of all American adults – 90 million people – have difficulty understanding and using health information, according to an Institute of Medicine report. In addition, the 2000 census counted 20 million people who speak poor English and 10 million who speak none.

The public is quite intelligent, but that part of the problem is that physicians don’t always know or understand the data. And if even when physicians understand the data, they often do not know how to communicate them in a way their patients can understand, says Dr. Bevers.

"That’s where there is a huge opportunity to create decision-making tools," she says.

With the help of communication experts, Dr. Bevers and her colleagues are developing a computerized tool that reviews the data from the National Lung Screening Trial (NLST) and spells out the benefits and harms of low-dose computed tomography screening for lung cancer in a very simplified fashion, using smiley faces for benefits and frowning faces for risks.

"It really advances my discussion when I walk in the room," said Dr. Bevers, a coinvestigator for the NLST. "I’m not explaining about the 20% mortality reduction, the associated harms. I’m now talking about: ‘What did you think about that?’ ‘What did you think about the harms?’ ‘How did it influence your decision about this?’ It’s a much more advanced discussion, and that’s helpful in a busy practice."

Another tool could then be used to walk patients through the next step of care to give physicians a sense of what concerns their patients most; for example, the risk of dying or that their cancer will return, she said.

The New Kid on the Block

Most experts agree that low-dose CT lung cancer screening is something of an anomaly in the cancer screening wars. Prior nonrandomized trials suggested a benefit with low-dose CT, but practice did not leapfrog the evidence. Only now that the randomized NLST has been completed is the screening machinery gearing up, but with significant questions about cost and high false-positive rates still unanswered (N. Engl. J. Med. 2011;365:395-409)

Moreover, CT lung screening would be an additional service offered to high-risk individuals, rather than the retraction of an entrenched screening practice.

The NCI has developed its own one-page, online NLST study guide for patients and physicians that provides specific data on low-dose CT vs. chest x-ray screening, "take-home" messages, and an educational component directing patients not to smoke.

"We don’t want to oversell the harms and undersell the benefits," said the NCI’s Dr. Kramer. "We don’t want the pendulum to swing completely in the opposite direction, and I think this sheet goes a long way."

In a busy primary care office, no doubt the various new recommendations will shift the conversation with patients, many of whom have been given the simple message for years to come back each year for their annual mammogram or PSA test. Depending on which recommendations their physicians advocate and what patients choose to follow, it will ultimately tip the balance sheet and outcomes data for years to come.

None of the physicians interviewed reported having relevant conflicts of interest.

When the U.S. Preventive Services Task Force recommended against prostate-specific antigen-based screening in men of any age this spring, an uproar swiftly followed. Evidence was dissected; cancer survivors and stakeholders lambasted the decision as shortsighted, and still others endorsed the recommendation as a long overdue nod to science.

Similar fallout erupted in November 2009 when the task force recommended against routine screening mammography in women younger than age 50 years. Only this time, critics charged that science had taken a back seat to politics, characterizing the decision as a harbinger of rationing under President Obama’s health care reform.

Less contentious so far are new recommendations that the annual Pap smear screening for cervical cancer should be pushed back to every 3 years and that low-dose lung CT screening be offered to heavy smokers. Time will tell whether the former is accepted in clinical practice and the latter can make the leap from clinical trial strategy to national guideline.

Given the complicated, emotionally charged nature of cancer screening and the political forces still at play, could another maelstrom be far off?

"There are a lot of misconceptions out there, in part because for so many decades, the messages have been so strong, they sometimes leaped ahead of the evidence," Dr. Barnett Kramer, director of the division of cancer prevention at the National Cancer Institute (NCI), Bethesda, Md., said in an interview.

When advocacy groups such as the American Cancer Society (ACS) first formed, strong, simple messages were needed to get Americans even to utter the word cancer out loud.

Over time, cancer screening messages have evolved into sound bites that almost always follow the very strong presumption that early detection means a better chance for survival, said Dr. Kramer, who described this as a serious oversimplification of the principles of screening. By its very nature, a screening test will always advance the date of diagnosis, but this may not benefit the patient.

"Simply saying that screening increases survival doesn’t convey any useful information," he said. "You really need to know what the effect of the screening test is on the risk of dying – that is the mortality rate, and that’s a different calculation from simply measuring the duration of life from the day of diagnosis to death."

Dr. Virginia Moyer, chair of the U.S. Preventive Services Task Force (USPSTF), agreed that some advocacy groups "absolutely oversell the benefits of screening and completely ignore the harms" that screening and medical interventions can cause. The perception among the general public is that if you screen and find something, you have therefore saved a life.

She argued in an interview that scientific groups such as the task force have provided a more balanced message, but admits the scientific community has made its own mistakes.

"Our concept at the time that PSA screening was developed was that if you had cancer in you, it would inevitably grow and kill you if you didn’t do something about it," she said. "That’s what we thought all cancer was about and we just turned out to be wrong. A huge proportion of cancers never do anything and that’s the piece we didn’t know."

Some physicians, however, may still not know. Dr. Moyer pointed out that risk communication experts recently reported that about one half (47%) of U.S. primary care physicians surveyed incorrectly said that finding more cases of cancer in screened vs. unscreened populations, "proves that screening saves lives" (Ann. Intern. Med. 2012;156:340-9).

The Push-Pull of Politics

Dr. Handel Reynolds, breast radiologist with Piedmont Hospital in Atlanta and author of the new book, "The Big Squeeze: A Social and Political History of the Controversial Mammogram," said in an interview that a series of crucial decisions made by health professionals set up screening mammography to be the controversial test it is today.

The first of these came in 1973 when, based on a single trial showing a mortality benefit in women under 50, the ACS and NCI decided to include women as young as 35 years in the National Breast Cancer Detection Demonstration Project (BCDDP), the first large-scale use of mammography as a screening tool involving some 280,000 women over 5 years (J. Natl. Cancer Inst. 1988;80:1540-7).

Just 3 years later, the National Institutes of Health (NIH) convened its first consensus conference to address screening in younger women, even though the BCDDP was not a clinical trial and demonstration projects are typically performed to show that activities with proven efficacy in clinical trials can be done on a large scale.

"1976 was the first time we had this huge blow-up about women under 50, and it has not gone away. In fact, it has become more acrimonious with each subsequent iteration," Dr. Reynolds said.

The most egregious example of political interference occurred in 1997. The NCI had broken with the ACS four years earlier and dropped its recommendation for mammography in women under 50. In 1997, however, the NCI reversed its position after a series of high-profile hearings held by then Sen. Arlen Specter (R-PA.), who chaired the subcommittee controlling funding for the NCI and who openly supported screening for women under 50, Dr. Reynolds said.

"The 1997 episode established the primacy of politics over science in the mammography debate and made it so much easier then for the 2009 controversy to be resolved in a matter of weeks," he contends.

Pap Test Changes Fly Under the Radar

Politics played a huge role in the uproar that surrounded the 2003 cervical cancer guidelines, said Dr. Alan G. Waxman, who recalled being accused of hating his mother because the 2003 guidelines he helped pen urged less frequent screening for cervical cancer.

Although the 2012 cervical screening guidelines essentially retire the annual Pap smear, Dr. Waxman said that he’s not expecting a huge backlash. Things have been relatively quiet since two separate groups released updates this March. The change between guidelines has been incremental, and women trust the science because it hasn’t gone through the permutations and "fluctuating truth" observed with the mammography data.

"With the Pap smear, the science has been pretty much in lockstep," said Dr. Waxman, president of the American Society for Colposcopy and Cervical Pathology, which partnered with the ACS and American Society for Clinical Pathology to release its guidelines in tandem with similar recommendations from the USPSTF.

Money Makes Its Voice Heard

The relative quiet following the changes to cervical cancer screening recommendations may also reflect the numbers. Only about 12,000 new cases of cervical cancer are diagnosed annually, compared with 214,633 new cases of prostate cancer in 2008, the most recent year for which numbers are available. Similarly, mammograms were ordered or provided in 20.3 million physician office visits and 2.3 million hospital outpatient department visits in 2009 alone.

The financial stakes are high in prostate and breast cancer and the rhetoric proportionate.

The American Urological Association expressed outrage after the release of the UPSTF PSA recommendation, warning that it could potentially turn back the clock to a time before PSA testing when "men presented with high-grade, metastatic disease for which there was little or no treatment beyond palliative care."

Dr. Otis Brawley, chief medical officer of the American Cancer Society, defended the USPSTF in a recent commentary, saying that unlike many of their critics, USPSTF members are ideally suited to assess the science objectively because they have no "emotional, ideological, or financial conflicts of interest" and understand the complicated science of screening.

He also expressed hope that the new PSA recommendations will end mass screenings, a "lucrative business" that offers tests outside the physician-patient relationship, often in shopping malls and parking lots with sponsorship from hospitals, medical practices, and even an adult diaper company.

For his part, Dr. Richard Albin, who discovered PSA, has been quoted as saying, "I never dreamed that my discovery 4 decades ago would lead to such a profit-driven public health disaster."

Some urologists have criticized the USPSTF for failing to include urologists on the panel and for the absence of a cost analysis.

"If you’re not saving any lives, then any money you’re spending is wasted, and you don’t need a complicated cost-effectiveness analysis to figure that out," countered Dr. Moyer.

Physicians and patients, however, may need a scorecard to wade through the rhetoric and conflicting data, frequently cherry-picked to argue for or against a particular screening test. In a recent study, 30% of women reported that the 2009 USPSTF mammography guidelines confused more than they helped them understand when to get a mammogram (Am. J. Prev. Med. 2011;40:497-504)

A More Nuanced Conversation

There’s little doubt that the task force’s recent decisions will dramatically reshape mammography and PSA screening in the United States, but the question is by how much.

"Largely what we’ve communicated is all the benefit, but I think the U.S. Preventive Services Task Force is communicating all the harms. And the right place is somewhere in between," Dr. Therese Bartholomew Bevers, medical director of the Cancer Prevention Center at the University of Texas M.D. Anderson Cancer Center in Houston, said in an interview.

What’s important is having a more balanced, nuanced conversation with patients. But is the American public ready for discussions of mortality rates or the changing calculus of risk/benefit ratios of screening as they age?

Nearly half of all American adults – 90 million people – have difficulty understanding and using health information, according to an Institute of Medicine report. In addition, the 2000 census counted 20 million people who speak poor English and 10 million who speak none.

The public is quite intelligent, but that part of the problem is that physicians don’t always know or understand the data. And if even when physicians understand the data, they often do not know how to communicate them in a way their patients can understand, says Dr. Bevers.

"That’s where there is a huge opportunity to create decision-making tools," she says.

With the help of communication experts, Dr. Bevers and her colleagues are developing a computerized tool that reviews the data from the National Lung Screening Trial (NLST) and spells out the benefits and harms of low-dose computed tomography screening for lung cancer in a very simplified fashion, using smiley faces for benefits and frowning faces for risks.

"It really advances my discussion when I walk in the room," said Dr. Bevers, a coinvestigator for the NLST. "I’m not explaining about the 20% mortality reduction, the associated harms. I’m now talking about: ‘What did you think about that?’ ‘What did you think about the harms?’ ‘How did it influence your decision about this?’ It’s a much more advanced discussion, and that’s helpful in a busy practice."

Another tool could then be used to walk patients through the next step of care to give physicians a sense of what concerns their patients most; for example, the risk of dying or that their cancer will return, she said.

The New Kid on the Block

Most experts agree that low-dose CT lung cancer screening is something of an anomaly in the cancer screening wars. Prior nonrandomized trials suggested a benefit with low-dose CT, but practice did not leapfrog the evidence. Only now that the randomized NLST has been completed is the screening machinery gearing up, but with significant questions about cost and high false-positive rates still unanswered (N. Engl. J. Med. 2011;365:395-409)

Moreover, CT lung screening would be an additional service offered to high-risk individuals, rather than the retraction of an entrenched screening practice.

The NCI has developed its own one-page, online NLST study guide for patients and physicians that provides specific data on low-dose CT vs. chest x-ray screening, "take-home" messages, and an educational component directing patients not to smoke.

"We don’t want to oversell the harms and undersell the benefits," said the NCI’s Dr. Kramer. "We don’t want the pendulum to swing completely in the opposite direction, and I think this sheet goes a long way."

In a busy primary care office, no doubt the various new recommendations will shift the conversation with patients, many of whom have been given the simple message for years to come back each year for their annual mammogram or PSA test. Depending on which recommendations their physicians advocate and what patients choose to follow, it will ultimately tip the balance sheet and outcomes data for years to come.

None of the physicians interviewed reported having relevant conflicts of interest.

MINNEAPOLIS – Combining the antiresorptive denosumab with the anabolic agent teriparatide increased bone mineral density more than either drug alone in postmenopausal women at high fracture risk in the ongoing DATA study.

At 12 months, the combination of denosumab (Prolia) and teriparatide (Forteo) significantly increased bone mineral density (BMD) by 8.9% at the spine, 4.5% at the femoral neck, and 4.9% at the total hip.

Patrice Wendling/IMNG Medical Media

The increases in BMD observed in the combination group are larger than those seen in prior combination anabolic and antiresorptive trials, Dr. Benjamin Z. Leder reported at the annual meeting of the American Society for Bone and Mineral Research.

The DATA (Denosumab, Teriparatide or Both for the Treatment of Postmenopausal Osteoporosis) trial is the first to study denosumab in combination with an anabolic agent. Prior trials combining teriparatide and bisphosphonates have shown inconsistent effects on BMD or, in some cases, a blunting effect of the anabolic agent.

The mechanisms underlying the additive effects of denosumab and teriparatide are unclear, but they may be related to the ability of denosumab to fully block teriparatide’s pro-resorptive effects while still allowing for continued modeling-based bone formation and, perhaps, an expansion of the anabolic window, said Dr. Leder, an endocrinologist with Massachusetts General Hospital in Boston.

"If these results persist in the second year of therapy and are confirmed in larger studies, the combination of these two agents may eventually prove to be a beneficial treatment in patients who are at particularly high risk of fracture," he said.

The trial randomized 100 women aged 45 years or older who were at least 3 years post menopause to daily teriparatide 20 mcg subcutaneous or denosumab 60 mg subcutaneous every 6 months or both. All patients received calcium 1,200 mg and vitamin D 400 IU.

Enrollment criteria were a BMD T-score of –2.5 or less at any anatomic site or a T-score of –2 or less with one risk factor (fracture or parental hip fracture after age 50, prior hyperthyroidism, inability to rise from a chair with arms elevated, or current smoker) or a T-score of –1 or less with a history of fragility fracture.

Patients were excluded if they had received oral bisphosphonates in the past 6 months; glucocorticoids for more than 14 days in the past 6 months; and any prior use of teriparatide, strontium, or parenteral bisphosphonates.

Patients were stratified by age and spine BMD. The 94 evaluable patients had an average age of 66 years.

At 12 months, the average increase in total hip BMD was 0.7% with teriparatide, 2.5% with denosumab, and 4.9% with combination therapy. Femoral neck BMD increased 0.8%, 2.1%, and 4.5% and spine BMD increased 6.2%, 5.5%, and 8.9%, respectively.

At the distal one-third of the radius, there was a decrease in BMD of 1.8% with teriparatide, an increase of 1.7% with denosumab, and a gain of 2.5% with the combination, Dr. Leder said. The difference in BMD was significant between the combination and teriparatide groups (P less than .001) but not between the combination and denosumab groups.

Changes in bone density were not significantly different between bisphosphonate-naive patients and those with prior bisphosphonate exposure.

Bone formation biomarker analysis showed significant suppression of osteocalcium with denosumab monotherapy at 3 months that continued through the 12-month study, while there was no change at 3 months and a more modest suppression thereafter in the combination group, he said.

Denosumab monotherapy significantly inhibited procollagen type I N-terminal propeptide at 3 and 6 months, but both groups were similar at 12 months.

The data on bone turnover marker C-telopeptide of type I collagen were distinct, with suppression identical in the denosumab alone and combination groups, Dr. Leder observed.

During a discussion of the study, Dr. Leder said bone biopsies were not available but that data at the distal radius and tibia that have not yet been analyzed "may provide some additional idea of what is going on, specifically in the trabecular and cortical compartments."

Session comoderator Dr. Aliya Khan, director of the calcium disorders clinic at St. Joseph’s Healthcare, McMaster University in Hamilton, Ont., said in an interview that the results shouldn’t be universally applied, but "if someone has a fracture, we can certainly consider this approach."

She went on to say that "combination therapy may be a way to improve bone strength, and it may actually enable us to avoid conditions such as atypical femoral fractures, which appear to be associated with oversuppression of bone remodeling."

Eli Lilly and Amgen sponsored the trial. Dr. Leder reported consulting for Amgen and Merck. Dr. Khan reported no disclosures.

MINNEAPOLIS – Combining the antiresorptive denosumab with the anabolic agent teriparatide increased bone mineral density more than either drug alone in postmenopausal women at high fracture risk in the ongoing DATA study.

At 12 months, the combination of denosumab (Prolia) and teriparatide (Forteo) significantly increased bone mineral density (BMD) by 8.9% at the spine, 4.5% at the femoral neck, and 4.9% at the total hip.

Patrice Wendling/IMNG Medical Media

The increases in BMD observed in the combination group are larger than those seen in prior combination anabolic and antiresorptive trials, Dr. Benjamin Z. Leder reported at the annual meeting of the American Society for Bone and Mineral Research.

The DATA (Denosumab, Teriparatide or Both for the Treatment of Postmenopausal Osteoporosis) trial is the first to study denosumab in combination with an anabolic agent. Prior trials combining teriparatide and bisphosphonates have shown inconsistent effects on BMD or, in some cases, a blunting effect of the anabolic agent.

The mechanisms underlying the additive effects of denosumab and teriparatide are unclear, but they may be related to the ability of denosumab to fully block teriparatide’s pro-resorptive effects while still allowing for continued modeling-based bone formation and, perhaps, an expansion of the anabolic window, said Dr. Leder, an endocrinologist with Massachusetts General Hospital in Boston.

"If these results persist in the second year of therapy and are confirmed in larger studies, the combination of these two agents may eventually prove to be a beneficial treatment in patients who are at particularly high risk of fracture," he said.

The trial randomized 100 women aged 45 years or older who were at least 3 years post menopause to daily teriparatide 20 mcg subcutaneous or denosumab 60 mg subcutaneous every 6 months or both. All patients received calcium 1,200 mg and vitamin D 400 IU.

Enrollment criteria were a BMD T-score of –2.5 or less at any anatomic site or a T-score of –2 or less with one risk factor (fracture or parental hip fracture after age 50, prior hyperthyroidism, inability to rise from a chair with arms elevated, or current smoker) or a T-score of –1 or less with a history of fragility fracture.

Patients were excluded if they had received oral bisphosphonates in the past 6 months; glucocorticoids for more than 14 days in the past 6 months; and any prior use of teriparatide, strontium, or parenteral bisphosphonates.

Patients were stratified by age and spine BMD. The 94 evaluable patients had an average age of 66 years.

At 12 months, the average increase in total hip BMD was 0.7% with teriparatide, 2.5% with denosumab, and 4.9% with combination therapy. Femoral neck BMD increased 0.8%, 2.1%, and 4.5% and spine BMD increased 6.2%, 5.5%, and 8.9%, respectively.

At the distal one-third of the radius, there was a decrease in BMD of 1.8% with teriparatide, an increase of 1.7% with denosumab, and a gain of 2.5% with the combination, Dr. Leder said. The difference in BMD was significant between the combination and teriparatide groups (P less than .001) but not between the combination and denosumab groups.

Changes in bone density were not significantly different between bisphosphonate-naive patients and those with prior bisphosphonate exposure.

Bone formation biomarker analysis showed significant suppression of osteocalcium with denosumab monotherapy at 3 months that continued through the 12-month study, while there was no change at 3 months and a more modest suppression thereafter in the combination group, he said.

Denosumab monotherapy significantly inhibited procollagen type I N-terminal propeptide at 3 and 6 months, but both groups were similar at 12 months.

The data on bone turnover marker C-telopeptide of type I collagen were distinct, with suppression identical in the denosumab alone and combination groups, Dr. Leder observed.

During a discussion of the study, Dr. Leder said bone biopsies were not available but that data at the distal radius and tibia that have not yet been analyzed "may provide some additional idea of what is going on, specifically in the trabecular and cortical compartments."

Session comoderator Dr. Aliya Khan, director of the calcium disorders clinic at St. Joseph’s Healthcare, McMaster University in Hamilton, Ont., said in an interview that the results shouldn’t be universally applied, but "if someone has a fracture, we can certainly consider this approach."

She went on to say that "combination therapy may be a way to improve bone strength, and it may actually enable us to avoid conditions such as atypical femoral fractures, which appear to be associated with oversuppression of bone remodeling."

Eli Lilly and Amgen sponsored the trial. Dr. Leder reported consulting for Amgen and Merck. Dr. Khan reported no disclosures.

MINNEAPOLIS – Combining the antiresorptive denosumab with the anabolic agent teriparatide increased bone mineral density more than either drug alone in postmenopausal women at high fracture risk in the ongoing DATA study.

At 12 months, the combination of denosumab (Prolia) and teriparatide (Forteo) significantly increased bone mineral density (BMD) by 8.9% at the spine, 4.5% at the femoral neck, and 4.9% at the total hip.

Patrice Wendling/IMNG Medical Media

The increases in BMD observed in the combination group are larger than those seen in prior combination anabolic and antiresorptive trials, Dr. Benjamin Z. Leder reported at the annual meeting of the American Society for Bone and Mineral Research.

The DATA (Denosumab, Teriparatide or Both for the Treatment of Postmenopausal Osteoporosis) trial is the first to study denosumab in combination with an anabolic agent. Prior trials combining teriparatide and bisphosphonates have shown inconsistent effects on BMD or, in some cases, a blunting effect of the anabolic agent.

The mechanisms underlying the additive effects of denosumab and teriparatide are unclear, but they may be related to the ability of denosumab to fully block teriparatide’s pro-resorptive effects while still allowing for continued modeling-based bone formation and, perhaps, an expansion of the anabolic window, said Dr. Leder, an endocrinologist with Massachusetts General Hospital in Boston.

"If these results persist in the second year of therapy and are confirmed in larger studies, the combination of these two agents may eventually prove to be a beneficial treatment in patients who are at particularly high risk of fracture," he said.

The trial randomized 100 women aged 45 years or older who were at least 3 years post menopause to daily teriparatide 20 mcg subcutaneous or denosumab 60 mg subcutaneous every 6 months or both. All patients received calcium 1,200 mg and vitamin D 400 IU.

Enrollment criteria were a BMD T-score of –2.5 or less at any anatomic site or a T-score of –2 or less with one risk factor (fracture or parental hip fracture after age 50, prior hyperthyroidism, inability to rise from a chair with arms elevated, or current smoker) or a T-score of –1 or less with a history of fragility fracture.

Patients were excluded if they had received oral bisphosphonates in the past 6 months; glucocorticoids for more than 14 days in the past 6 months; and any prior use of teriparatide, strontium, or parenteral bisphosphonates.

Patients were stratified by age and spine BMD. The 94 evaluable patients had an average age of 66 years.

At 12 months, the average increase in total hip BMD was 0.7% with teriparatide, 2.5% with denosumab, and 4.9% with combination therapy. Femoral neck BMD increased 0.8%, 2.1%, and 4.5% and spine BMD increased 6.2%, 5.5%, and 8.9%, respectively.

At the distal one-third of the radius, there was a decrease in BMD of 1.8% with teriparatide, an increase of 1.7% with denosumab, and a gain of 2.5% with the combination, Dr. Leder said. The difference in BMD was significant between the combination and teriparatide groups (P less than .001) but not between the combination and denosumab groups.

Changes in bone density were not significantly different between bisphosphonate-naive patients and those with prior bisphosphonate exposure.

Bone formation biomarker analysis showed significant suppression of osteocalcium with denosumab monotherapy at 3 months that continued through the 12-month study, while there was no change at 3 months and a more modest suppression thereafter in the combination group, he said.

Denosumab monotherapy significantly inhibited procollagen type I N-terminal propeptide at 3 and 6 months, but both groups were similar at 12 months.

The data on bone turnover marker C-telopeptide of type I collagen were distinct, with suppression identical in the denosumab alone and combination groups, Dr. Leder observed.

During a discussion of the study, Dr. Leder said bone biopsies were not available but that data at the distal radius and tibia that have not yet been analyzed "may provide some additional idea of what is going on, specifically in the trabecular and cortical compartments."

Session comoderator Dr. Aliya Khan, director of the calcium disorders clinic at St. Joseph’s Healthcare, McMaster University in Hamilton, Ont., said in an interview that the results shouldn’t be universally applied, but "if someone has a fracture, we can certainly consider this approach."

She went on to say that "combination therapy may be a way to improve bone strength, and it may actually enable us to avoid conditions such as atypical femoral fractures, which appear to be associated with oversuppression of bone remodeling."

Eli Lilly and Amgen sponsored the trial. Dr. Leder reported consulting for Amgen and Merck. Dr. Khan reported no disclosures.