Sara Freeman

VIENNA – As the severity of nonalcoholic fatty liver disease (NAFLD) increases, so does the risk for death and cardiovascular disease, according to data from a large population study reported at the meeting sponsored by the European Association for the Study of the Liver.

There was a 50% increase in the adjusted all-cause morality rate when comparing patients who developed nonalcoholic steatohepatitis (NASH) with those who had NAFLD (hazard ratio of 1.5).

The risk of death was also five times as high when comparing patients with NASH-related cirrhosis to those with NAFLD, with an adjusted HR of 5.1.

Heart failure (HF), atrial fibrillation (AF), type 2 diabetes mellitus, and chronic kidney disease (CKD) rates were also increased in patients with NAFLD, compared with those in the healthy population.*

“Nonalcoholic fatty liver disease has got a strong association with cardiovascular disease; it may be an independent risk factor for cardiovascular disease, but that is still open to debate,” said study investigator Dr. Jake Mann, who is an academic clinical fellow in pediatrics at the University of Cambridge (England).

“What isn’t quite so clear is whether or not there is progressively increasing risk of cardiovascular comorbidities as you move from NAFLD to NASH to NASH cirrhosis,” he added at the meeting, which was sponsored by the European Association for the Study of the Liver (EASL).

To investigate this further, Dr. Mann and collaborators therefore obtained data collected on more than 929,465 patients with NAFLD-related diseases included in the U.K. ACALM (Algorithm for Comorbidities, Associations, Length of stay, and Mortality) study database. ICD-10 codes were used to identify patients with NAFLD, NASH, cryptogenic (NASH)-cirrhosis, and cardiovascular morbidities.

During the 14-year follow-up period, 1,294 patients were diagnosed with NAFLD, 122 with NASH, and 1,285 with cirrhosis. Around 57% of patients in each group were male, with the mean age rising from 50.6 years in the NAFLD patients to 51.6% in the NASH patients to 59.2% in the patients with cirrhosis. Most (76%-80%) patients were white, with around 10%-12% being of Asian ethnicity.

HF was more prevalent in patients with NASH (9% vs. 3.8%, P < .01) and cirrhosis (6.6% vs. 3.8%; P < .001) than in those with NAFLD. The prevalence of AF was increased progressing from NAFLD to NASH (4.9% vs. 8.2%) and NAFLD to cirrhosis (4.9% vs. 8.3%; P < .0001). Rates for diabetes were 20.9%, 24.6%, and 31.2% and for CKD were 2.1%, 4.9%, and 6.9% progressing from NAFLD to NASH to cirrhosis.

Hyperlipidemia and hypertension rates for NAFLD, NASH, and cirrhosis were 12.1%, 17.2%, and 5%, and 29.4%, 34.4%, and 27.3%, respectively.

Crude mortality rates were 11.5% for the general population and 14.5% for NAFLD, 22.1% for NASH, and 53.1% for cirrhosis. “Unfortunately we do not have disease-specific mortality data,” Dr. Mann said.

There are of course several limitations that need consideration, including assuming NASH was a biopsy-proven diagnosis. The findings are also reliant on data coding and of course it is possible that patients with NASH are included in the NAFLD group, and non-NASH cirrhosis could be included in the cryptogenic cirrhosis group.

There is also the chance of underdiagnosis and undercoding, Dr. Mann said. The overall prevalence of NAFLD-spectrum disease was 2.5%, which is perhaps somewhat lower than might be expected in a large U.K. population.

Other limiting factors were that the patients with the cryptogenic cirrhosis group were older than those in the other groups and also that these findings could be describing the natural history of the disease rather than implying causation.

Nevertheless, this is the largest study of its kind, Dr. Mann said, and shows that there is a trend towards increasing mortality and burden of CVD with increasing severity of NAFLD-spectrum disease.

“The take-home message is that clinicians should be very aware of this association, such that hepatologists should consider that patients are at very high risk of heart disease, and as they currently do, they should screen for cardiovascular disease and refer on as appropriate,” Dr. Mann said in an interview.

“Likewise, cardiologists and general practitioners should be very aware that patients with cardiac disease are at risk of NAFLD and equally would refer to GI and liver teams,” Dr. Mann said.

“These findings clearly link the severity of [nonalcoholic fatty liver disease] with the increased risk of cardiovascular disease and death,” Dr. Laurent Castera of Hôpital Beaujon in France said in a press release issued by the EASL.

Dr. Castera, who is the vice-secretary of the association added: “It is therefore imperative that we identify people in the early stages of [the disease] so they can be treated through diet and lifestyle interventions before their condition becomes potentially deadly.”

*A correction was made to this sentence on 5/22/2015.

VIENNA – As the severity of nonalcoholic fatty liver disease (NAFLD) increases, so does the risk for death and cardiovascular disease, according to data from a large population study reported at the meeting sponsored by the European Association for the Study of the Liver.

There was a 50% increase in the adjusted all-cause morality rate when comparing patients who developed nonalcoholic steatohepatitis (NASH) with those who had NAFLD (hazard ratio of 1.5).

The risk of death was also five times as high when comparing patients with NASH-related cirrhosis to those with NAFLD, with an adjusted HR of 5.1.

Heart failure (HF), atrial fibrillation (AF), type 2 diabetes mellitus, and chronic kidney disease (CKD) rates were also increased in patients with NAFLD, compared with those in the healthy population.*

“Nonalcoholic fatty liver disease has got a strong association with cardiovascular disease; it may be an independent risk factor for cardiovascular disease, but that is still open to debate,” said study investigator Dr. Jake Mann, who is an academic clinical fellow in pediatrics at the University of Cambridge (England).

“What isn’t quite so clear is whether or not there is progressively increasing risk of cardiovascular comorbidities as you move from NAFLD to NASH to NASH cirrhosis,” he added at the meeting, which was sponsored by the European Association for the Study of the Liver (EASL).

To investigate this further, Dr. Mann and collaborators therefore obtained data collected on more than 929,465 patients with NAFLD-related diseases included in the U.K. ACALM (Algorithm for Comorbidities, Associations, Length of stay, and Mortality) study database. ICD-10 codes were used to identify patients with NAFLD, NASH, cryptogenic (NASH)-cirrhosis, and cardiovascular morbidities.

During the 14-year follow-up period, 1,294 patients were diagnosed with NAFLD, 122 with NASH, and 1,285 with cirrhosis. Around 57% of patients in each group were male, with the mean age rising from 50.6 years in the NAFLD patients to 51.6% in the NASH patients to 59.2% in the patients with cirrhosis. Most (76%-80%) patients were white, with around 10%-12% being of Asian ethnicity.

HF was more prevalent in patients with NASH (9% vs. 3.8%, P < .01) and cirrhosis (6.6% vs. 3.8%; P < .001) than in those with NAFLD. The prevalence of AF was increased progressing from NAFLD to NASH (4.9% vs. 8.2%) and NAFLD to cirrhosis (4.9% vs. 8.3%; P < .0001). Rates for diabetes were 20.9%, 24.6%, and 31.2% and for CKD were 2.1%, 4.9%, and 6.9% progressing from NAFLD to NASH to cirrhosis.

Hyperlipidemia and hypertension rates for NAFLD, NASH, and cirrhosis were 12.1%, 17.2%, and 5%, and 29.4%, 34.4%, and 27.3%, respectively.

Crude mortality rates were 11.5% for the general population and 14.5% for NAFLD, 22.1% for NASH, and 53.1% for cirrhosis. “Unfortunately we do not have disease-specific mortality data,” Dr. Mann said.

There are of course several limitations that need consideration, including assuming NASH was a biopsy-proven diagnosis. The findings are also reliant on data coding and of course it is possible that patients with NASH are included in the NAFLD group, and non-NASH cirrhosis could be included in the cryptogenic cirrhosis group.

There is also the chance of underdiagnosis and undercoding, Dr. Mann said. The overall prevalence of NAFLD-spectrum disease was 2.5%, which is perhaps somewhat lower than might be expected in a large U.K. population.

Other limiting factors were that the patients with the cryptogenic cirrhosis group were older than those in the other groups and also that these findings could be describing the natural history of the disease rather than implying causation.

Nevertheless, this is the largest study of its kind, Dr. Mann said, and shows that there is a trend towards increasing mortality and burden of CVD with increasing severity of NAFLD-spectrum disease.

“The take-home message is that clinicians should be very aware of this association, such that hepatologists should consider that patients are at very high risk of heart disease, and as they currently do, they should screen for cardiovascular disease and refer on as appropriate,” Dr. Mann said in an interview.

“Likewise, cardiologists and general practitioners should be very aware that patients with cardiac disease are at risk of NAFLD and equally would refer to GI and liver teams,” Dr. Mann said.

“These findings clearly link the severity of [nonalcoholic fatty liver disease] with the increased risk of cardiovascular disease and death,” Dr. Laurent Castera of Hôpital Beaujon in France said in a press release issued by the EASL.

Dr. Castera, who is the vice-secretary of the association added: “It is therefore imperative that we identify people in the early stages of [the disease] so they can be treated through diet and lifestyle interventions before their condition becomes potentially deadly.”

*A correction was made to this sentence on 5/22/2015.

VIENNA – As the severity of nonalcoholic fatty liver disease (NAFLD) increases, so does the risk for death and cardiovascular disease, according to data from a large population study reported at the meeting sponsored by the European Association for the Study of the Liver.

There was a 50% increase in the adjusted all-cause morality rate when comparing patients who developed nonalcoholic steatohepatitis (NASH) with those who had NAFLD (hazard ratio of 1.5).

The risk of death was also five times as high when comparing patients with NASH-related cirrhosis to those with NAFLD, with an adjusted HR of 5.1.

Heart failure (HF), atrial fibrillation (AF), type 2 diabetes mellitus, and chronic kidney disease (CKD) rates were also increased in patients with NAFLD, compared with those in the healthy population.*

“Nonalcoholic fatty liver disease has got a strong association with cardiovascular disease; it may be an independent risk factor for cardiovascular disease, but that is still open to debate,” said study investigator Dr. Jake Mann, who is an academic clinical fellow in pediatrics at the University of Cambridge (England).

“What isn’t quite so clear is whether or not there is progressively increasing risk of cardiovascular comorbidities as you move from NAFLD to NASH to NASH cirrhosis,” he added at the meeting, which was sponsored by the European Association for the Study of the Liver (EASL).

To investigate this further, Dr. Mann and collaborators therefore obtained data collected on more than 929,465 patients with NAFLD-related diseases included in the U.K. ACALM (Algorithm for Comorbidities, Associations, Length of stay, and Mortality) study database. ICD-10 codes were used to identify patients with NAFLD, NASH, cryptogenic (NASH)-cirrhosis, and cardiovascular morbidities.

During the 14-year follow-up period, 1,294 patients were diagnosed with NAFLD, 122 with NASH, and 1,285 with cirrhosis. Around 57% of patients in each group were male, with the mean age rising from 50.6 years in the NAFLD patients to 51.6% in the NASH patients to 59.2% in the patients with cirrhosis. Most (76%-80%) patients were white, with around 10%-12% being of Asian ethnicity.

HF was more prevalent in patients with NASH (9% vs. 3.8%, P < .01) and cirrhosis (6.6% vs. 3.8%; P < .001) than in those with NAFLD. The prevalence of AF was increased progressing from NAFLD to NASH (4.9% vs. 8.2%) and NAFLD to cirrhosis (4.9% vs. 8.3%; P < .0001). Rates for diabetes were 20.9%, 24.6%, and 31.2% and for CKD were 2.1%, 4.9%, and 6.9% progressing from NAFLD to NASH to cirrhosis.

Hyperlipidemia and hypertension rates for NAFLD, NASH, and cirrhosis were 12.1%, 17.2%, and 5%, and 29.4%, 34.4%, and 27.3%, respectively.

Crude mortality rates were 11.5% for the general population and 14.5% for NAFLD, 22.1% for NASH, and 53.1% for cirrhosis. “Unfortunately we do not have disease-specific mortality data,” Dr. Mann said.

There are of course several limitations that need consideration, including assuming NASH was a biopsy-proven diagnosis. The findings are also reliant on data coding and of course it is possible that patients with NASH are included in the NAFLD group, and non-NASH cirrhosis could be included in the cryptogenic cirrhosis group.

There is also the chance of underdiagnosis and undercoding, Dr. Mann said. The overall prevalence of NAFLD-spectrum disease was 2.5%, which is perhaps somewhat lower than might be expected in a large U.K. population.

Other limiting factors were that the patients with the cryptogenic cirrhosis group were older than those in the other groups and also that these findings could be describing the natural history of the disease rather than implying causation.

Nevertheless, this is the largest study of its kind, Dr. Mann said, and shows that there is a trend towards increasing mortality and burden of CVD with increasing severity of NAFLD-spectrum disease.

“The take-home message is that clinicians should be very aware of this association, such that hepatologists should consider that patients are at very high risk of heart disease, and as they currently do, they should screen for cardiovascular disease and refer on as appropriate,” Dr. Mann said in an interview.

“Likewise, cardiologists and general practitioners should be very aware that patients with cardiac disease are at risk of NAFLD and equally would refer to GI and liver teams,” Dr. Mann said.

“These findings clearly link the severity of [nonalcoholic fatty liver disease] with the increased risk of cardiovascular disease and death,” Dr. Laurent Castera of Hôpital Beaujon in France said in a press release issued by the EASL.

Dr. Castera, who is the vice-secretary of the association added: “It is therefore imperative that we identify people in the early stages of [the disease] so they can be treated through diet and lifestyle interventions before their condition becomes potentially deadly.”

*A correction was made to this sentence on 5/22/2015.

MANCHESTER, U.K. – Tocilizumab showed signs of improving skin and other symptoms in patients with systemic sclerosis (SSc) in an ongoing proof-of-concept study.

Although the primary endpoint of a significant change in the modified Rodan skin score (mRSS) at 24 weeks was not met, there was a numerically greater decrease in mRSS among patients who took tocilizumab versus those who took placebo. The mean change in mRSS was –3.92 units vs. –1.22 units, respectively, giving a difference of –2.70 units (P = .09).

“We were more encouraged by the 48-week data because we saw a much clearer fall in the mRSS,” said Dr. Christopher P. Denton, who presented these early findings from the phase II/III faSScinate trial at the British Society for Rheumatology annual conference.

At 48 weeks, there was a decrease of 6.33 units in the tocilizumab-treated patients vs. a decrease of 2.77 units in the placebo arm (mean change of –3.55 units; P = .06). A drop of 4 units in the mRSS is deemed to be a minimally clinically important difference.

“There is a reasonable rationale for looking at the IL [interleukin]-6 axis in systemic sclerosis as a target for therapy,” explained Dr. Denton, who is a consultant rheumatologist and professor of experimental rheumatology at University College London.

Indeed, preclinical data have indicated that IL-6 expression is elevated in SSc skin and that an antibody targeting IL-6 inhibited collagen synthesis in cultured fibroblasts and IL-6 receptor antibody reduced skin fibrosis in an animal model.

There also were early clinical data in SSc patients from Dr. Denton’s group that supported conducting a phase II study with tocilizumab (Ann. Rheum. Dis. 2012;71:1235-42).

The faSScinate trial started in 2012 and included 87 patients with active diffuse SSc of 5 years’ or less duration. For inclusion, patients had to have an mRSS of between 15 and 40 units at baseline and elevated acute phase reactants. Patients were randomized to treatment with tocilizumab, which was given at a dose of 162 mg by subcutaneous injection every week, or matching placebo. Treatment was blinded for 48 weeks, followed by an open-label period for a further 48 weeks, during which all patients received tocilizumab.

Dr. Denton said that there were clear and consistent trends towards continuous improvement in skin scores from baseline out to week 48 in the tocilizumab arm. There also were “encouraging trends” favoring tocilizumab in improvement in a number of secondary endpoints, including the Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Clinician Global Assessment, FACIT-Fatigue score, and pruritus measured using the 5-D Itch Scale.

More patients treated with placebo than with tocilizumab experienced a worsening in lung function during the trial. This was an exploratory endpoint with an “intriguing” result, Dr. Denton said. A clinically meaningful drop of 10% or more in forced vital capacity was seen in just 3.3% of tocilizumab-treated patients, compared with 19.4% of placebo-treated patients (P = .009).

“Treatment was not entirely benign,” he acknowledged, adding that “noninfective adverse events were more common in the placebo-treatment arm and infective adverse events were more common in the tocilizumab-treated arm.” The increase in infective side effects was not surprising and generally treatable, he said, and serious adverse events were potentially due to complications of SSc rather than treatment.

“This was a small study, but relatively large for a proof-of-concept trial in systemic sclerosis,” Dr. Denton observed.

“We do feel the benefit-to-safety ratio does favor further investigation and that tocilizumab is likely to benefit a subset of patients with SSc who would otherwise have a particularly poor outcome.”

A phase III study is now being planned, with recruitment likely to start later this year.

Tocilizumab is currently indicated for use in the United States as Actemra and in Europe as RoActemra in combination with methotrexate for the treatment of severe, active, and progressive rheumatoid arthritis and for active juvenile idiopathic systemic or polyarthritis.

The faSScinate study was funded by F. Hoffman La Roche. Dr. Denton has acted as a consultant for Actelion Pharmaceuticals US, Biogen-Idec, CSL Behring, Genentech/Roche, GlaxoSmithKline, and Sanofi-Aventis. His coinvestigators also reported financial relationships with other pharmaceutical companies, including Roche.

MANCHESTER, U.K. – Tocilizumab showed signs of improving skin and other symptoms in patients with systemic sclerosis (SSc) in an ongoing proof-of-concept study.

Although the primary endpoint of a significant change in the modified Rodan skin score (mRSS) at 24 weeks was not met, there was a numerically greater decrease in mRSS among patients who took tocilizumab versus those who took placebo. The mean change in mRSS was –3.92 units vs. –1.22 units, respectively, giving a difference of –2.70 units (P = .09).

“We were more encouraged by the 48-week data because we saw a much clearer fall in the mRSS,” said Dr. Christopher P. Denton, who presented these early findings from the phase II/III faSScinate trial at the British Society for Rheumatology annual conference.

At 48 weeks, there was a decrease of 6.33 units in the tocilizumab-treated patients vs. a decrease of 2.77 units in the placebo arm (mean change of –3.55 units; P = .06). A drop of 4 units in the mRSS is deemed to be a minimally clinically important difference.

“There is a reasonable rationale for looking at the IL [interleukin]-6 axis in systemic sclerosis as a target for therapy,” explained Dr. Denton, who is a consultant rheumatologist and professor of experimental rheumatology at University College London.

Indeed, preclinical data have indicated that IL-6 expression is elevated in SSc skin and that an antibody targeting IL-6 inhibited collagen synthesis in cultured fibroblasts and IL-6 receptor antibody reduced skin fibrosis in an animal model.

There also were early clinical data in SSc patients from Dr. Denton’s group that supported conducting a phase II study with tocilizumab (Ann. Rheum. Dis. 2012;71:1235-42).

The faSScinate trial started in 2012 and included 87 patients with active diffuse SSc of 5 years’ or less duration. For inclusion, patients had to have an mRSS of between 15 and 40 units at baseline and elevated acute phase reactants. Patients were randomized to treatment with tocilizumab, which was given at a dose of 162 mg by subcutaneous injection every week, or matching placebo. Treatment was blinded for 48 weeks, followed by an open-label period for a further 48 weeks, during which all patients received tocilizumab.

Dr. Denton said that there were clear and consistent trends towards continuous improvement in skin scores from baseline out to week 48 in the tocilizumab arm. There also were “encouraging trends” favoring tocilizumab in improvement in a number of secondary endpoints, including the Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Clinician Global Assessment, FACIT-Fatigue score, and pruritus measured using the 5-D Itch Scale.

More patients treated with placebo than with tocilizumab experienced a worsening in lung function during the trial. This was an exploratory endpoint with an “intriguing” result, Dr. Denton said. A clinically meaningful drop of 10% or more in forced vital capacity was seen in just 3.3% of tocilizumab-treated patients, compared with 19.4% of placebo-treated patients (P = .009).

“Treatment was not entirely benign,” he acknowledged, adding that “noninfective adverse events were more common in the placebo-treatment arm and infective adverse events were more common in the tocilizumab-treated arm.” The increase in infective side effects was not surprising and generally treatable, he said, and serious adverse events were potentially due to complications of SSc rather than treatment.

“This was a small study, but relatively large for a proof-of-concept trial in systemic sclerosis,” Dr. Denton observed.

“We do feel the benefit-to-safety ratio does favor further investigation and that tocilizumab is likely to benefit a subset of patients with SSc who would otherwise have a particularly poor outcome.”

A phase III study is now being planned, with recruitment likely to start later this year.

Tocilizumab is currently indicated for use in the United States as Actemra and in Europe as RoActemra in combination with methotrexate for the treatment of severe, active, and progressive rheumatoid arthritis and for active juvenile idiopathic systemic or polyarthritis.

The faSScinate study was funded by F. Hoffman La Roche. Dr. Denton has acted as a consultant for Actelion Pharmaceuticals US, Biogen-Idec, CSL Behring, Genentech/Roche, GlaxoSmithKline, and Sanofi-Aventis. His coinvestigators also reported financial relationships with other pharmaceutical companies, including Roche.

MANCHESTER, U.K. – Tocilizumab showed signs of improving skin and other symptoms in patients with systemic sclerosis (SSc) in an ongoing proof-of-concept study.

Although the primary endpoint of a significant change in the modified Rodan skin score (mRSS) at 24 weeks was not met, there was a numerically greater decrease in mRSS among patients who took tocilizumab versus those who took placebo. The mean change in mRSS was –3.92 units vs. –1.22 units, respectively, giving a difference of –2.70 units (P = .09).

“We were more encouraged by the 48-week data because we saw a much clearer fall in the mRSS,” said Dr. Christopher P. Denton, who presented these early findings from the phase II/III faSScinate trial at the British Society for Rheumatology annual conference.

At 48 weeks, there was a decrease of 6.33 units in the tocilizumab-treated patients vs. a decrease of 2.77 units in the placebo arm (mean change of –3.55 units; P = .06). A drop of 4 units in the mRSS is deemed to be a minimally clinically important difference.

“There is a reasonable rationale for looking at the IL [interleukin]-6 axis in systemic sclerosis as a target for therapy,” explained Dr. Denton, who is a consultant rheumatologist and professor of experimental rheumatology at University College London.

Indeed, preclinical data have indicated that IL-6 expression is elevated in SSc skin and that an antibody targeting IL-6 inhibited collagen synthesis in cultured fibroblasts and IL-6 receptor antibody reduced skin fibrosis in an animal model.

There also were early clinical data in SSc patients from Dr. Denton’s group that supported conducting a phase II study with tocilizumab (Ann. Rheum. Dis. 2012;71:1235-42).

The faSScinate trial started in 2012 and included 87 patients with active diffuse SSc of 5 years’ or less duration. For inclusion, patients had to have an mRSS of between 15 and 40 units at baseline and elevated acute phase reactants. Patients were randomized to treatment with tocilizumab, which was given at a dose of 162 mg by subcutaneous injection every week, or matching placebo. Treatment was blinded for 48 weeks, followed by an open-label period for a further 48 weeks, during which all patients received tocilizumab.

Dr. Denton said that there were clear and consistent trends towards continuous improvement in skin scores from baseline out to week 48 in the tocilizumab arm. There also were “encouraging trends” favoring tocilizumab in improvement in a number of secondary endpoints, including the Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Clinician Global Assessment, FACIT-Fatigue score, and pruritus measured using the 5-D Itch Scale.

More patients treated with placebo than with tocilizumab experienced a worsening in lung function during the trial. This was an exploratory endpoint with an “intriguing” result, Dr. Denton said. A clinically meaningful drop of 10% or more in forced vital capacity was seen in just 3.3% of tocilizumab-treated patients, compared with 19.4% of placebo-treated patients (P = .009).

“Treatment was not entirely benign,” he acknowledged, adding that “noninfective adverse events were more common in the placebo-treatment arm and infective adverse events were more common in the tocilizumab-treated arm.” The increase in infective side effects was not surprising and generally treatable, he said, and serious adverse events were potentially due to complications of SSc rather than treatment.

“This was a small study, but relatively large for a proof-of-concept trial in systemic sclerosis,” Dr. Denton observed.

“We do feel the benefit-to-safety ratio does favor further investigation and that tocilizumab is likely to benefit a subset of patients with SSc who would otherwise have a particularly poor outcome.”

A phase III study is now being planned, with recruitment likely to start later this year.

Tocilizumab is currently indicated for use in the United States as Actemra and in Europe as RoActemra in combination with methotrexate for the treatment of severe, active, and progressive rheumatoid arthritis and for active juvenile idiopathic systemic or polyarthritis.

The faSScinate study was funded by F. Hoffman La Roche. Dr. Denton has acted as a consultant for Actelion Pharmaceuticals US, Biogen-Idec, CSL Behring, Genentech/Roche, GlaxoSmithKline, and Sanofi-Aventis. His coinvestigators also reported financial relationships with other pharmaceutical companies, including Roche.

MANCHESTER, ENGLAND – Results of the Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients with Rheumatoid Arthritis (TRACE-RA) suggest that daily treatment with atorvastatin may have a primary protective effect on the development of cardiovascular disease in patients with rheumatoid arthritis.

There was a 34% reduction in the primary composite cardiovascular endpoint, which, although not significant, showed a trend for benefit that was similar to that seen with other statin studies in the general population, according to Dr. George Kitas, a consultant rheumatologist and director of research and development at the Dudley (England) Group NHS Foundation Trust.

Sara Freeman/Frontline Medical News

“The event rate we observed was actually lower than we had calculated on,” Dr. Kitas said in an interview at the British Society for Rheumatology annual conference. The anticipated event rate was 1.8%, but the observed event rate was 0.76%, he explained. As a result, the trial was terminated early as there would not be sufficient events over the planned time course of the trial.

“However, if you correct for a couple of baseline differences, particularly smoking and ethnicity, and also for compliance, the effect on the CVD event rate is actually statistically significant,” Dr. Kitas observed.

He noted that low-density lipoprotein cholesterol (LDL-C) was lowered by a significant 1.07 mmol/L (19.26 mg/dL) in the 1,492 patients randomized to atorvastatin versus a 0.14 mmol/L (2.52 mg/dL) decrease in the 1,492 patients randomized to placebo (P < .001).

Statins are established as a means of both primary and secondary prevention of CVD in the general population, but few patients with RA were included in the seminal statin trials. The aim of TRACE-RA was therefore to look at statins as a possible means for primary prevention in patients with high-grade inflammation such as RA.

TRACE-RA was a prospective, double-blind trial of 2,986 patients with RA aged 50 years or older or who had a disease duration of more than 10 years and who had been recruited at 102 participating centers between 2007 and 2012.

Patients had been randomized to treatment with atorvastatin 40 mg/day or placebo for the primary prevention of cardiovascular events and the median follow-up was 2.53 years, with an overall 7,908 years of patient follow-up. All patients were given lifestyle advice on how to reduce their cardiovascular risk.

The primary endpoint was a composite of CVD death, nonfatal myocardial infarction, cerebrovascular accident (excluding hemorrhagic stroke), transient ischemic attack, hospitalized angina, and coronary and noncoronary revascularization. A total of 33 of these CVD events occurred in 24 atorvastatin-treated patients and 52 events occurred in 36 patients on placebo. Of these, the majority were coronary events.

Adverse event rates in the atorvastatin and placebo arms were a respective 19.7% and 19.5%. “The side effects that were observed in the statin arm were virtually identical to the side effects that were observed in the placebo arm,” Dr. Kitas noted.

“So, what we think we can say from TRACE-RA is firstly that statins are ‘safe’ in people with rheumatoid arthritis. Secondly, that they have virtually identical effects, both in terms of LDL-C reduction and in terms of hard cardiovascular events, as what one would expect with equivalent doses of statins in the general population,” Dr. Kitas said.

“In practical terms, I would suggest that we all assess our patients regularly for their cardiovascular risk and make sure that we do not hesitate to start a statin in those who fulfill criteria according to the relevant national guidelines.”

Commenting on the study, Dr. Ernest Choy of Cardiff University, Wales, said that this is the largest randomized, controlled trial to look at preventing cardiovascular mortality in patients with RA.

“The message is that cardiovascular risk can potentially be reduced by a statin, especially in high-risk patients,” Dr. Choy said, noting that it also “highlights the importance of monitoring for cardiovascular disease.”

TRACE-RA was funded by Arthritis Research UK and the British Heart Foundation. Pfizer UK provided the study medication and an unrestricted grant for the TRACE-RA biobank. Dr. Kitas had no financial conflicts of interest to disclose.

MANCHESTER, ENGLAND – Results of the Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients with Rheumatoid Arthritis (TRACE-RA) suggest that daily treatment with atorvastatin may have a primary protective effect on the development of cardiovascular disease in patients with rheumatoid arthritis.

There was a 34% reduction in the primary composite cardiovascular endpoint, which, although not significant, showed a trend for benefit that was similar to that seen with other statin studies in the general population, according to Dr. George Kitas, a consultant rheumatologist and director of research and development at the Dudley (England) Group NHS Foundation Trust.

Sara Freeman/Frontline Medical News

“The event rate we observed was actually lower than we had calculated on,” Dr. Kitas said in an interview at the British Society for Rheumatology annual conference. The anticipated event rate was 1.8%, but the observed event rate was 0.76%, he explained. As a result, the trial was terminated early as there would not be sufficient events over the planned time course of the trial.

“However, if you correct for a couple of baseline differences, particularly smoking and ethnicity, and also for compliance, the effect on the CVD event rate is actually statistically significant,” Dr. Kitas observed.

He noted that low-density lipoprotein cholesterol (LDL-C) was lowered by a significant 1.07 mmol/L (19.26 mg/dL) in the 1,492 patients randomized to atorvastatin versus a 0.14 mmol/L (2.52 mg/dL) decrease in the 1,492 patients randomized to placebo (P < .001).

Statins are established as a means of both primary and secondary prevention of CVD in the general population, but few patients with RA were included in the seminal statin trials. The aim of TRACE-RA was therefore to look at statins as a possible means for primary prevention in patients with high-grade inflammation such as RA.

TRACE-RA was a prospective, double-blind trial of 2,986 patients with RA aged 50 years or older or who had a disease duration of more than 10 years and who had been recruited at 102 participating centers between 2007 and 2012.

Patients had been randomized to treatment with atorvastatin 40 mg/day or placebo for the primary prevention of cardiovascular events and the median follow-up was 2.53 years, with an overall 7,908 years of patient follow-up. All patients were given lifestyle advice on how to reduce their cardiovascular risk.

The primary endpoint was a composite of CVD death, nonfatal myocardial infarction, cerebrovascular accident (excluding hemorrhagic stroke), transient ischemic attack, hospitalized angina, and coronary and noncoronary revascularization. A total of 33 of these CVD events occurred in 24 atorvastatin-treated patients and 52 events occurred in 36 patients on placebo. Of these, the majority were coronary events.

Adverse event rates in the atorvastatin and placebo arms were a respective 19.7% and 19.5%. “The side effects that were observed in the statin arm were virtually identical to the side effects that were observed in the placebo arm,” Dr. Kitas noted.

“So, what we think we can say from TRACE-RA is firstly that statins are ‘safe’ in people with rheumatoid arthritis. Secondly, that they have virtually identical effects, both in terms of LDL-C reduction and in terms of hard cardiovascular events, as what one would expect with equivalent doses of statins in the general population,” Dr. Kitas said.

“In practical terms, I would suggest that we all assess our patients regularly for their cardiovascular risk and make sure that we do not hesitate to start a statin in those who fulfill criteria according to the relevant national guidelines.”

Commenting on the study, Dr. Ernest Choy of Cardiff University, Wales, said that this is the largest randomized, controlled trial to look at preventing cardiovascular mortality in patients with RA.

“The message is that cardiovascular risk can potentially be reduced by a statin, especially in high-risk patients,” Dr. Choy said, noting that it also “highlights the importance of monitoring for cardiovascular disease.”

TRACE-RA was funded by Arthritis Research UK and the British Heart Foundation. Pfizer UK provided the study medication and an unrestricted grant for the TRACE-RA biobank. Dr. Kitas had no financial conflicts of interest to disclose.

MANCHESTER, ENGLAND – Results of the Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients with Rheumatoid Arthritis (TRACE-RA) suggest that daily treatment with atorvastatin may have a primary protective effect on the development of cardiovascular disease in patients with rheumatoid arthritis.

There was a 34% reduction in the primary composite cardiovascular endpoint, which, although not significant, showed a trend for benefit that was similar to that seen with other statin studies in the general population, according to Dr. George Kitas, a consultant rheumatologist and director of research and development at the Dudley (England) Group NHS Foundation Trust.

Sara Freeman/Frontline Medical News

“The event rate we observed was actually lower than we had calculated on,” Dr. Kitas said in an interview at the British Society for Rheumatology annual conference. The anticipated event rate was 1.8%, but the observed event rate was 0.76%, he explained. As a result, the trial was terminated early as there would not be sufficient events over the planned time course of the trial.

“However, if you correct for a couple of baseline differences, particularly smoking and ethnicity, and also for compliance, the effect on the CVD event rate is actually statistically significant,” Dr. Kitas observed.

He noted that low-density lipoprotein cholesterol (LDL-C) was lowered by a significant 1.07 mmol/L (19.26 mg/dL) in the 1,492 patients randomized to atorvastatin versus a 0.14 mmol/L (2.52 mg/dL) decrease in the 1,492 patients randomized to placebo (P < .001).

Statins are established as a means of both primary and secondary prevention of CVD in the general population, but few patients with RA were included in the seminal statin trials. The aim of TRACE-RA was therefore to look at statins as a possible means for primary prevention in patients with high-grade inflammation such as RA.

TRACE-RA was a prospective, double-blind trial of 2,986 patients with RA aged 50 years or older or who had a disease duration of more than 10 years and who had been recruited at 102 participating centers between 2007 and 2012.

Patients had been randomized to treatment with atorvastatin 40 mg/day or placebo for the primary prevention of cardiovascular events and the median follow-up was 2.53 years, with an overall 7,908 years of patient follow-up. All patients were given lifestyle advice on how to reduce their cardiovascular risk.

The primary endpoint was a composite of CVD death, nonfatal myocardial infarction, cerebrovascular accident (excluding hemorrhagic stroke), transient ischemic attack, hospitalized angina, and coronary and noncoronary revascularization. A total of 33 of these CVD events occurred in 24 atorvastatin-treated patients and 52 events occurred in 36 patients on placebo. Of these, the majority were coronary events.

Adverse event rates in the atorvastatin and placebo arms were a respective 19.7% and 19.5%. “The side effects that were observed in the statin arm were virtually identical to the side effects that were observed in the placebo arm,” Dr. Kitas noted.

“So, what we think we can say from TRACE-RA is firstly that statins are ‘safe’ in people with rheumatoid arthritis. Secondly, that they have virtually identical effects, both in terms of LDL-C reduction and in terms of hard cardiovascular events, as what one would expect with equivalent doses of statins in the general population,” Dr. Kitas said.

“In practical terms, I would suggest that we all assess our patients regularly for their cardiovascular risk and make sure that we do not hesitate to start a statin in those who fulfill criteria according to the relevant national guidelines.”

Commenting on the study, Dr. Ernest Choy of Cardiff University, Wales, said that this is the largest randomized, controlled trial to look at preventing cardiovascular mortality in patients with RA.

“The message is that cardiovascular risk can potentially be reduced by a statin, especially in high-risk patients,” Dr. Choy said, noting that it also “highlights the importance of monitoring for cardiovascular disease.”

TRACE-RA was funded by Arthritis Research UK and the British Heart Foundation. Pfizer UK provided the study medication and an unrestricted grant for the TRACE-RA biobank. Dr. Kitas had no financial conflicts of interest to disclose.

VIENNA– In addition to dramatically increasing the risk of liver cancer more than 68-fold, chronic hepatitis C virus (HCV) infection more than doubled or tripled the risk of a host of other solid tumors and hematologic malignancies in a large retrospective, cross-sectional study.

Data from the Kaiser Permanente Southern California HMO accounting for more than 145,000 patient-years of follow-up for HCV-infected individuals and 14,000,000 patient-years of follow-up for non–HCV-infected individuals showed the crude rate ratio for the development of all cancers including hepatocellular carcinoma (HCC) was 2.33 (P < .0001), and excluding HCC, was 1.84.

The crude rate ratios for individual cancers in HCV-infected, compared with non–HCV-infected individuals were 68.67 for hepatocellular carcinoma (HCC); 3.59 for non-Hodgkin’s lymphoma (NHL); 3.41 for multiple myeloma; 3.05 for renal cancer; 3.03 for stomach cancer; 2.79 for pancreatic cancer; 2.56 for head and neck cancer; 2.51 for esophageal cancer; 2.44 for lung cancer; 2.05 for prostate cancer; and 1.88 for colorectal cancer.

Courtesy ILC 2015

“We need to interpret these results cautiously,” Dr. Anders Nyberg, a hepatologist at Kaiser Permanente Southern California in San Diego, acknowledged at the International Liver Congress sponsored by the European Association for the Study of the Liver.

“The strength of the study is that it is a large database in a ‘real-world’ population,” but one limitation is that it cannot establish causality and how chronic HCV infection might be linked to the increased risk of these cancers.

The link between chronic HCV infection and liver cancer is well established, and Swedish researchers have also previously reported a link with NHL and multiple myeloma (Hepatology 2005;13:652-9; doi:10.1002/hep.20608). Dr. Nyberg noted, however, that there are sporadic data on HCV and other cancer types.

The objective of the present study was therefore to look further at the possible association between HCV infection and cancer in a large population by linking the Kaiser Permanente Southern California data to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. Patients were included if they had HCV diagnosed between 2008 and 2012 and were aged 18 years or older but excluded if they had HIV coinfection or a history of solid organ or bone marrow transplantation.

The study population consisted of 1,831 patients with a mean age of 62 years who had chronic HCV and a cancer diagnosis, 33,881 patients aged a mean of 59 years who had HCV but no cancer diagnosis, and 5,297,191 individuals aged 72 years without HCV. Dr. Nyberg noted that study subjects were predominantly male (around 50%-60%) and from white or Hispanic backgrounds.

Baseline comorbidities were more common in patients with HCV and cancer, with a Charlson Comorbidity Index of 2.1, than in those with HCV but no cancer (Charlson index of 1.5) or those in the non–HCV-infected cohort (Charlson index 0.5). There was a higher percentage of patients who smoked tobacco or with alcohol abuse in the HCV vs. non–HCV-infected cohort groups, and HCV patients were more likely to have diabetes mellitus and cirrhosis, but a lower body mass index.

When HCV and non–HCV-infected cohorts were stratified according to tobacco use, alcohol abuse, diabetes mellitus, and body weight, the increase in the cancer rate ratio for all cancer sites remained significant, as did the increase in rate of HCC and NHL.

“In the absence of alcohol abuse, tobacco use, and diabetes mellitus, there was an increase in the rate of many cancer types among those with HCV,” Dr. Nyberg said. However, when those variables were present, HCV had a more moderate effect on the cancer rates than the variables themselves, but rates were still increased.

“I interpret these data that the increased overall cancer rate is multifactorial. It may be related to hepatitis C, but it is also related to alcohol abuse, tobacco use, and diabetes mellitus,” Dr. Nyberg said at a press conference. “In the short term, my take-home message is that we can take HCV out of the equation.”

He qualified this further in an interview saying, “It is important not to just address the hepatitis C but also to address the other risk factors like stopping smoking, cutting down on drinking, reducing weight, and trying to prevent diabetes.”

This is a descriptive study, Dr. Nyberg added, and more research will be needed to further evaluate the findings.

The study was supported by a grant from Gilead Sciences paid to Kaiser Permanente Southern California. Dr. Anders Nyberg and Dr. Lisa Nyberg are employees of Kaiser Permanente Southern California but had no personal financial conflicts of interest.

VIENNA– In addition to dramatically increasing the risk of liver cancer more than 68-fold, chronic hepatitis C virus (HCV) infection more than doubled or tripled the risk of a host of other solid tumors and hematologic malignancies in a large retrospective, cross-sectional study.

Data from the Kaiser Permanente Southern California HMO accounting for more than 145,000 patient-years of follow-up for HCV-infected individuals and 14,000,000 patient-years of follow-up for non–HCV-infected individuals showed the crude rate ratio for the development of all cancers including hepatocellular carcinoma (HCC) was 2.33 (P < .0001), and excluding HCC, was 1.84.

The crude rate ratios for individual cancers in HCV-infected, compared with non–HCV-infected individuals were 68.67 for hepatocellular carcinoma (HCC); 3.59 for non-Hodgkin’s lymphoma (NHL); 3.41 for multiple myeloma; 3.05 for renal cancer; 3.03 for stomach cancer; 2.79 for pancreatic cancer; 2.56 for head and neck cancer; 2.51 for esophageal cancer; 2.44 for lung cancer; 2.05 for prostate cancer; and 1.88 for colorectal cancer.

Courtesy ILC 2015

“We need to interpret these results cautiously,” Dr. Anders Nyberg, a hepatologist at Kaiser Permanente Southern California in San Diego, acknowledged at the International Liver Congress sponsored by the European Association for the Study of the Liver.

“The strength of the study is that it is a large database in a ‘real-world’ population,” but one limitation is that it cannot establish causality and how chronic HCV infection might be linked to the increased risk of these cancers.

The link between chronic HCV infection and liver cancer is well established, and Swedish researchers have also previously reported a link with NHL and multiple myeloma (Hepatology 2005;13:652-9; doi:10.1002/hep.20608). Dr. Nyberg noted, however, that there are sporadic data on HCV and other cancer types.

The objective of the present study was therefore to look further at the possible association between HCV infection and cancer in a large population by linking the Kaiser Permanente Southern California data to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. Patients were included if they had HCV diagnosed between 2008 and 2012 and were aged 18 years or older but excluded if they had HIV coinfection or a history of solid organ or bone marrow transplantation.

The study population consisted of 1,831 patients with a mean age of 62 years who had chronic HCV and a cancer diagnosis, 33,881 patients aged a mean of 59 years who had HCV but no cancer diagnosis, and 5,297,191 individuals aged 72 years without HCV. Dr. Nyberg noted that study subjects were predominantly male (around 50%-60%) and from white or Hispanic backgrounds.

Baseline comorbidities were more common in patients with HCV and cancer, with a Charlson Comorbidity Index of 2.1, than in those with HCV but no cancer (Charlson index of 1.5) or those in the non–HCV-infected cohort (Charlson index 0.5). There was a higher percentage of patients who smoked tobacco or with alcohol abuse in the HCV vs. non–HCV-infected cohort groups, and HCV patients were more likely to have diabetes mellitus and cirrhosis, but a lower body mass index.

When HCV and non–HCV-infected cohorts were stratified according to tobacco use, alcohol abuse, diabetes mellitus, and body weight, the increase in the cancer rate ratio for all cancer sites remained significant, as did the increase in rate of HCC and NHL.

“In the absence of alcohol abuse, tobacco use, and diabetes mellitus, there was an increase in the rate of many cancer types among those with HCV,” Dr. Nyberg said. However, when those variables were present, HCV had a more moderate effect on the cancer rates than the variables themselves, but rates were still increased.

“I interpret these data that the increased overall cancer rate is multifactorial. It may be related to hepatitis C, but it is also related to alcohol abuse, tobacco use, and diabetes mellitus,” Dr. Nyberg said at a press conference. “In the short term, my take-home message is that we can take HCV out of the equation.”

He qualified this further in an interview saying, “It is important not to just address the hepatitis C but also to address the other risk factors like stopping smoking, cutting down on drinking, reducing weight, and trying to prevent diabetes.”

This is a descriptive study, Dr. Nyberg added, and more research will be needed to further evaluate the findings.

The study was supported by a grant from Gilead Sciences paid to Kaiser Permanente Southern California. Dr. Anders Nyberg and Dr. Lisa Nyberg are employees of Kaiser Permanente Southern California but had no personal financial conflicts of interest.

VIENNA– In addition to dramatically increasing the risk of liver cancer more than 68-fold, chronic hepatitis C virus (HCV) infection more than doubled or tripled the risk of a host of other solid tumors and hematologic malignancies in a large retrospective, cross-sectional study.

Data from the Kaiser Permanente Southern California HMO accounting for more than 145,000 patient-years of follow-up for HCV-infected individuals and 14,000,000 patient-years of follow-up for non–HCV-infected individuals showed the crude rate ratio for the development of all cancers including hepatocellular carcinoma (HCC) was 2.33 (P < .0001), and excluding HCC, was 1.84.

The crude rate ratios for individual cancers in HCV-infected, compared with non–HCV-infected individuals were 68.67 for hepatocellular carcinoma (HCC); 3.59 for non-Hodgkin’s lymphoma (NHL); 3.41 for multiple myeloma; 3.05 for renal cancer; 3.03 for stomach cancer; 2.79 for pancreatic cancer; 2.56 for head and neck cancer; 2.51 for esophageal cancer; 2.44 for lung cancer; 2.05 for prostate cancer; and 1.88 for colorectal cancer.

Courtesy ILC 2015

“We need to interpret these results cautiously,” Dr. Anders Nyberg, a hepatologist at Kaiser Permanente Southern California in San Diego, acknowledged at the International Liver Congress sponsored by the European Association for the Study of the Liver.

“The strength of the study is that it is a large database in a ‘real-world’ population,” but one limitation is that it cannot establish causality and how chronic HCV infection might be linked to the increased risk of these cancers.

The link between chronic HCV infection and liver cancer is well established, and Swedish researchers have also previously reported a link with NHL and multiple myeloma (Hepatology 2005;13:652-9; doi:10.1002/hep.20608). Dr. Nyberg noted, however, that there are sporadic data on HCV and other cancer types.

The objective of the present study was therefore to look further at the possible association between HCV infection and cancer in a large population by linking the Kaiser Permanente Southern California data to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. Patients were included if they had HCV diagnosed between 2008 and 2012 and were aged 18 years or older but excluded if they had HIV coinfection or a history of solid organ or bone marrow transplantation.

The study population consisted of 1,831 patients with a mean age of 62 years who had chronic HCV and a cancer diagnosis, 33,881 patients aged a mean of 59 years who had HCV but no cancer diagnosis, and 5,297,191 individuals aged 72 years without HCV. Dr. Nyberg noted that study subjects were predominantly male (around 50%-60%) and from white or Hispanic backgrounds.

Baseline comorbidities were more common in patients with HCV and cancer, with a Charlson Comorbidity Index of 2.1, than in those with HCV but no cancer (Charlson index of 1.5) or those in the non–HCV-infected cohort (Charlson index 0.5). There was a higher percentage of patients who smoked tobacco or with alcohol abuse in the HCV vs. non–HCV-infected cohort groups, and HCV patients were more likely to have diabetes mellitus and cirrhosis, but a lower body mass index.

When HCV and non–HCV-infected cohorts were stratified according to tobacco use, alcohol abuse, diabetes mellitus, and body weight, the increase in the cancer rate ratio for all cancer sites remained significant, as did the increase in rate of HCC and NHL.

“In the absence of alcohol abuse, tobacco use, and diabetes mellitus, there was an increase in the rate of many cancer types among those with HCV,” Dr. Nyberg said. However, when those variables were present, HCV had a more moderate effect on the cancer rates than the variables themselves, but rates were still increased.

“I interpret these data that the increased overall cancer rate is multifactorial. It may be related to hepatitis C, but it is also related to alcohol abuse, tobacco use, and diabetes mellitus,” Dr. Nyberg said at a press conference. “In the short term, my take-home message is that we can take HCV out of the equation.”

He qualified this further in an interview saying, “It is important not to just address the hepatitis C but also to address the other risk factors like stopping smoking, cutting down on drinking, reducing weight, and trying to prevent diabetes.”

This is a descriptive study, Dr. Nyberg added, and more research will be needed to further evaluate the findings.

The study was supported by a grant from Gilead Sciences paid to Kaiser Permanente Southern California. Dr. Anders Nyberg and Dr. Lisa Nyberg are employees of Kaiser Permanente Southern California but had no personal financial conflicts of interest.

VIENNA– In addition to dramatically increasing the risk of liver cancer more than 68-fold, chronic hepatitis C virus (HCV) infection more than doubled or tripled the risk of a host of other solid tumors and hematologic malignancies in a large retrospective, cross-sectional study.

Data from the Kaiser Permanente Southern California HMO accounting for more than 145,000 patient-years of follow-up for HCV-infected individuals and 14,000,000 patient-years of follow-up for non–HCV-infected individuals showed the crude rate ratio for the development of all cancers including hepatocellular carcinoma (HCC) was 2.33 (P < .0001), and excluding HCC, was 1.84.

The crude rate ratios for individual cancers in HCV-infected, compared with non–HCV-infected individuals were 68.67 for hepatocellular carcinoma (HCC); 3.59 for non-Hodgkin’s lymphoma (NHL); 3.41 for multiple myeloma; 3.05 for renal cancer; 3.03 for stomach cancer; 2.79 for pancreatic cancer; 2.56 for head and neck cancer; 2.51 for esophageal cancer; 2.44 for lung cancer; 2.05 for prostate cancer; and 1.88 for colorectal cancer.

Courtesy ILC 2015

“We need to interpret these results cautiously,” Dr. Anders Nyberg, a hepatologist at Kaiser Permanente Southern California in San Diego, acknowledged at the International Liver Congress sponsored by the European Association for the Study of the Liver.

“The strength of the study is that it is a large database in a ‘real-world’ population,” but one limitation is that it cannot establish causality and how chronic HCV infection might be linked to the increased risk of these cancers.

The link between chronic HCV infection and liver cancer is well established, and Swedish researchers have also previously reported a link with NHL and multiple myeloma (Hepatology 2005;13:652-9; doi:10.1002/hep.20608). Dr. Nyberg noted, however, that there are sporadic data on HCV and other cancer types.

The objective of the present study was therefore to look further at the possible association between HCV infection and cancer in a large population by linking the Kaiser Permanente Southern California data to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. Patients were included if they had HCV diagnosed between 2008 and 2012 and were aged 18 years or older but excluded if they had HIV coinfection or a history of solid organ or bone marrow transplantation.

The study population consisted of 1,831 patients with a mean age of 62 years who had chronic HCV and a cancer diagnosis, 33,881 patients aged a mean of 59 years who had HCV but no cancer diagnosis, and 5,297,191 individuals aged 72 years without HCV. Dr. Nyberg noted that study subjects were predominantly male (around 50%-60%) and from white or Hispanic backgrounds.

Baseline comorbidities were more common in patients with HCV and cancer, with a Charlson Comorbidity Index of 2.1, than in those with HCV but no cancer (Charlson index of 1.5) or those in the non–HCV-infected cohort (Charlson index 0.5). There was a higher percentage of patients who smoked tobacco or with alcohol abuse in the HCV vs. non–HCV-infected cohort groups, and HCV patients were more likely to have diabetes mellitus and cirrhosis, but a lower body mass index.

When HCV and non–HCV-infected cohorts were stratified according to tobacco use, alcohol abuse, diabetes mellitus, and body weight, the increase in the cancer rate ratio for all cancer sites remained significant, as did the increase in rate of HCC and NHL.

“In the absence of alcohol abuse, tobacco use, and diabetes mellitus, there was an increase in the rate of many cancer types among those with HCV,” Dr. Nyberg said. However, when those variables were present, HCV had a more moderate effect on the cancer rates than the variables themselves, but rates were still increased.

“I interpret these data that the increased overall cancer rate is multifactorial. It may be related to hepatitis C, but it is also related to alcohol abuse, tobacco use, and diabetes mellitus,” Dr. Nyberg said at a press conference. “In the short term, my take-home message is that we can take HCV out of the equation.”

He qualified this further in an interview saying, “It is important not to just address the hepatitis C but also to address the other risk factors like stopping smoking, cutting down on drinking, reducing weight, and trying to prevent diabetes.”

This is a descriptive study, Dr. Nyberg added, and more research will be needed to further evaluate the findings.

The study was supported by a grant from Gilead Sciences paid to Kaiser Permanente Southern California. Dr. Anders Nyberg and Dr. Lisa Nyberg are employees of Kaiser Permanente Southern California but had no personal financial conflicts of interest.

VIENNA– In addition to dramatically increasing the risk of liver cancer more than 68-fold, chronic hepatitis C virus (HCV) infection more than doubled or tripled the risk of a host of other solid tumors and hematologic malignancies in a large retrospective, cross-sectional study.

Data from the Kaiser Permanente Southern California HMO accounting for more than 145,000 patient-years of follow-up for HCV-infected individuals and 14,000,000 patient-years of follow-up for non–HCV-infected individuals showed the crude rate ratio for the development of all cancers including hepatocellular carcinoma (HCC) was 2.33 (P < .0001), and excluding HCC, was 1.84.

The crude rate ratios for individual cancers in HCV-infected, compared with non–HCV-infected individuals were 68.67 for hepatocellular carcinoma (HCC); 3.59 for non-Hodgkin’s lymphoma (NHL); 3.41 for multiple myeloma; 3.05 for renal cancer; 3.03 for stomach cancer; 2.79 for pancreatic cancer; 2.56 for head and neck cancer; 2.51 for esophageal cancer; 2.44 for lung cancer; 2.05 for prostate cancer; and 1.88 for colorectal cancer.

Courtesy ILC 2015

“We need to interpret these results cautiously,” Dr. Anders Nyberg, a hepatologist at Kaiser Permanente Southern California in San Diego, acknowledged at the International Liver Congress sponsored by the European Association for the Study of the Liver.

“The strength of the study is that it is a large database in a ‘real-world’ population,” but one limitation is that it cannot establish causality and how chronic HCV infection might be linked to the increased risk of these cancers.

The link between chronic HCV infection and liver cancer is well established, and Swedish researchers have also previously reported a link with NHL and multiple myeloma (Hepatology 2005;13:652-9; doi:10.1002/hep.20608). Dr. Nyberg noted, however, that there are sporadic data on HCV and other cancer types.

The objective of the present study was therefore to look further at the possible association between HCV infection and cancer in a large population by linking the Kaiser Permanente Southern California data to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. Patients were included if they had HCV diagnosed between 2008 and 2012 and were aged 18 years or older but excluded if they had HIV coinfection or a history of solid organ or bone marrow transplantation.

The study population consisted of 1,831 patients with a mean age of 62 years who had chronic HCV and a cancer diagnosis, 33,881 patients aged a mean of 59 years who had HCV but no cancer diagnosis, and 5,297,191 individuals aged 72 years without HCV. Dr. Nyberg noted that study subjects were predominantly male (around 50%-60%) and from white or Hispanic backgrounds.

Baseline comorbidities were more common in patients with HCV and cancer, with a Charlson Comorbidity Index of 2.1, than in those with HCV but no cancer (Charlson index of 1.5) or those in the non–HCV-infected cohort (Charlson index 0.5). There was a higher percentage of patients who smoked tobacco or with alcohol abuse in the HCV vs. non–HCV-infected cohort groups, and HCV patients were more likely to have diabetes mellitus and cirrhosis, but a lower body mass index.

When HCV and non–HCV-infected cohorts were stratified according to tobacco use, alcohol abuse, diabetes mellitus, and body weight, the increase in the cancer rate ratio for all cancer sites remained significant, as did the increase in rate of HCC and NHL.

“In the absence of alcohol abuse, tobacco use, and diabetes mellitus, there was an increase in the rate of many cancer types among those with HCV,” Dr. Nyberg said. However, when those variables were present, HCV had a more moderate effect on the cancer rates than the variables themselves, but rates were still increased.

“I interpret these data that the increased overall cancer rate is multifactorial. It may be related to hepatitis C, but it is also related to alcohol abuse, tobacco use, and diabetes mellitus,” Dr. Nyberg said at a press conference. “In the short term, my take-home message is that we can take HCV out of the equation.”

He qualified this further in an interview saying, “It is important not to just address the hepatitis C but also to address the other risk factors like stopping smoking, cutting down on drinking, reducing weight, and trying to prevent diabetes.”

This is a descriptive study, Dr. Nyberg added, and more research will be needed to further evaluate the findings.

The study was supported by a grant from Gilead Sciences paid to Kaiser Permanente Southern California. Dr. Anders Nyberg and Dr. Lisa Nyberg are employees of Kaiser Permanente Southern California but had no personal financial conflicts of interest.

VIENNA– In addition to dramatically increasing the risk of liver cancer more than 68-fold, chronic hepatitis C virus (HCV) infection more than doubled or tripled the risk of a host of other solid tumors and hematologic malignancies in a large retrospective, cross-sectional study.

Data from the Kaiser Permanente Southern California HMO accounting for more than 145,000 patient-years of follow-up for HCV-infected individuals and 14,000,000 patient-years of follow-up for non–HCV-infected individuals showed the crude rate ratio for the development of all cancers including hepatocellular carcinoma (HCC) was 2.33 (P < .0001), and excluding HCC, was 1.84.

The crude rate ratios for individual cancers in HCV-infected, compared with non–HCV-infected individuals were 68.67 for hepatocellular carcinoma (HCC); 3.59 for non-Hodgkin’s lymphoma (NHL); 3.41 for multiple myeloma; 3.05 for renal cancer; 3.03 for stomach cancer; 2.79 for pancreatic cancer; 2.56 for head and neck cancer; 2.51 for esophageal cancer; 2.44 for lung cancer; 2.05 for prostate cancer; and 1.88 for colorectal cancer.

Courtesy ILC 2015

“We need to interpret these results cautiously,” Dr. Anders Nyberg, a hepatologist at Kaiser Permanente Southern California in San Diego, acknowledged at the International Liver Congress sponsored by the European Association for the Study of the Liver.

“The strength of the study is that it is a large database in a ‘real-world’ population,” but one limitation is that it cannot establish causality and how chronic HCV infection might be linked to the increased risk of these cancers.

The link between chronic HCV infection and liver cancer is well established, and Swedish researchers have also previously reported a link with NHL and multiple myeloma (Hepatology 2005;13:652-9; doi:10.1002/hep.20608). Dr. Nyberg noted, however, that there are sporadic data on HCV and other cancer types.

The objective of the present study was therefore to look further at the possible association between HCV infection and cancer in a large population by linking the Kaiser Permanente Southern California data to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. Patients were included if they had HCV diagnosed between 2008 and 2012 and were aged 18 years or older but excluded if they had HIV coinfection or a history of solid organ or bone marrow transplantation.

The study population consisted of 1,831 patients with a mean age of 62 years who had chronic HCV and a cancer diagnosis, 33,881 patients aged a mean of 59 years who had HCV but no cancer diagnosis, and 5,297,191 individuals aged 72 years without HCV. Dr. Nyberg noted that study subjects were predominantly male (around 50%-60%) and from white or Hispanic backgrounds.

Baseline comorbidities were more common in patients with HCV and cancer, with a Charlson Comorbidity Index of 2.1, than in those with HCV but no cancer (Charlson index of 1.5) or those in the non–HCV-infected cohort (Charlson index 0.5). There was a higher percentage of patients who smoked tobacco or with alcohol abuse in the HCV vs. non–HCV-infected cohort groups, and HCV patients were more likely to have diabetes mellitus and cirrhosis, but a lower body mass index.

When HCV and non–HCV-infected cohorts were stratified according to tobacco use, alcohol abuse, diabetes mellitus, and body weight, the increase in the cancer rate ratio for all cancer sites remained significant, as did the increase in rate of HCC and NHL.

“In the absence of alcohol abuse, tobacco use, and diabetes mellitus, there was an increase in the rate of many cancer types among those with HCV,” Dr. Nyberg said. However, when those variables were present, HCV had a more moderate effect on the cancer rates than the variables themselves, but rates were still increased.

“I interpret these data that the increased overall cancer rate is multifactorial. It may be related to hepatitis C, but it is also related to alcohol abuse, tobacco use, and diabetes mellitus,” Dr. Nyberg said at a press conference. “In the short term, my take-home message is that we can take HCV out of the equation.”

He qualified this further in an interview saying, “It is important not to just address the hepatitis C but also to address the other risk factors like stopping smoking, cutting down on drinking, reducing weight, and trying to prevent diabetes.”

This is a descriptive study, Dr. Nyberg added, and more research will be needed to further evaluate the findings.

The study was supported by a grant from Gilead Sciences paid to Kaiser Permanente Southern California. Dr. Anders Nyberg and Dr. Lisa Nyberg are employees of Kaiser Permanente Southern California but had no personal financial conflicts of interest.

PARIS – Health status should be evaluated when determining how best to treat an older man with prostate cancer, attendees at an international congress on anticancer treatment were told.

According to recently updated guidelines issued by the International Society of Geriatric Oncology (SIOG), patient preferences should also be a priority when deciding upon prostate cancer treatment, but not their chronological age.

“In the first SIOG guidelines [Crit. Rev. Oncol. Hematol. 2010;731:68-91], we introduced an approach for assessing health status that was somewhat difficult to use by urologists or medical oncologists who had no training in geriatric oncology,” Dr. John-Pierre Droz, professor emeritus of medical oncology at Université Claude Bernard in Lyon, France, said in an interview.

In the updated guidelines (Lancet Oncol. 2014;15:e404-14), however, the use of the G-8 simplified health assessment tool is recommended that takes just 4 minutes to compete and can be used to determine if further health status assessments are necessary.

“This assessment can be performed by a trained nurse,” Dr. Droz said, making the assessment much easier to integrate into clinician’s daily practice.

The G-8 screening tool (Ann. Oncol. 2012;23:2166-72) consists of eight items that take into account patients’ food intake and weight loss in the past 3 months, their body mass index, mobility, prescription drug use, and neuropsychological status. Their age and assessment of their perceived health status in comparison to people of the same age are also included.

A score above 14 is favorable on the G-8 and patients can be categorized as being “fit” and no further geriatric assessment is suggested. But the guidelines recommend a more comprehensive geriatric assessment if a score below this threshold is obtained, which includes comorbidities measured via the Cumulative Illness Rating Scale-Geriatric, evaluation of nutritional status, and patients’ cognitive and physical functions. The latter includes using the familiar concepts of activities of daily living and independent activities of daily living.

Based on these further assessments elderly patients can be categorized as vulnerable, where the health status parameters are potentially improved with appropriate measures; or frail,when changes to health status are deemed permanent or irreversible.

In general, elderly men with prostate cancer who fall into the “fit” health assessment category should have the same treatment options as younger patients. Patients who fall into the “vulnerable” category should be able to receive standard treatment after measures are taken to address any reversible impairments such as malnutrition. Adapted treatment might be more appropriate in senior men who fall into the “frail” category, and palliative care is recommended for those identified with terminal illness.

The potential for side effects to occur and patients’ willingness to accept these is vital to consider when selecting treatments, perhaps more so in elderly individuals who may be more prone to experience adverse events, particularly if they have comorbid disease. Age marginally influences genitourinary and gastrointestinal toxicity seen with external beam radiation therapy, for example, but increases the risk for erectile dysfunction in older men.

Considering first-line treatment for metastatic castrate-resistant prostate cancer disease, “This is exactly the same as in younger patients,” Dr. Droz said. So, docetaxel at the usual dose of 75 mg/m² given three times a week should be suitable for the treatment of both fit and vulnerable patients. A reduced frequency docetaxel regimen, such as weekly or twice weekly, may be more suitable in a frail patient.

Abiraterone acetate is also suitable in the first-line setting in asymptomatic or mildly symptomatic patients who do not have liver metastases. Bone-targeted drugs can also be used to prevent bone loss and for the treatment of bone metastases.

As for second-line treatment, cabazitaxel, abiraterone, and enzalutamide are available, but careful monitoring is needed in older patients, advised Dr. Droz. As in younger men, the optimal sequence of these therapies needs further research.

Dr. Droz commented that the efficacy of treatments for both localized and advanced prostate cancer in older men is similar to that in younger men. However, “the critical issue in the decision-making process is the competition between the risk of death due to prostate cancer and the risk of death due to health status,” he observed.

Dr. Droz has received honoraria from Sanofi.

PARIS – Health status should be evaluated when determining how best to treat an older man with prostate cancer, attendees at an international congress on anticancer treatment were told.

According to recently updated guidelines issued by the International Society of Geriatric Oncology (SIOG), patient preferences should also be a priority when deciding upon prostate cancer treatment, but not their chronological age.

“In the first SIOG guidelines [Crit. Rev. Oncol. Hematol. 2010;731:68-91], we introduced an approach for assessing health status that was somewhat difficult to use by urologists or medical oncologists who had no training in geriatric oncology,” Dr. John-Pierre Droz, professor emeritus of medical oncology at Université Claude Bernard in Lyon, France, said in an interview.

In the updated guidelines (Lancet Oncol. 2014;15:e404-14), however, the use of the G-8 simplified health assessment tool is recommended that takes just 4 minutes to compete and can be used to determine if further health status assessments are necessary.

“This assessment can be performed by a trained nurse,” Dr. Droz said, making the assessment much easier to integrate into clinician’s daily practice.

The G-8 screening tool (Ann. Oncol. 2012;23:2166-72) consists of eight items that take into account patients’ food intake and weight loss in the past 3 months, their body mass index, mobility, prescription drug use, and neuropsychological status. Their age and assessment of their perceived health status in comparison to people of the same age are also included.

A score above 14 is favorable on the G-8 and patients can be categorized as being “fit” and no further geriatric assessment is suggested. But the guidelines recommend a more comprehensive geriatric assessment if a score below this threshold is obtained, which includes comorbidities measured via the Cumulative Illness Rating Scale-Geriatric, evaluation of nutritional status, and patients’ cognitive and physical functions. The latter includes using the familiar concepts of activities of daily living and independent activities of daily living.

Based on these further assessments elderly patients can be categorized as vulnerable, where the health status parameters are potentially improved with appropriate measures; or frail,when changes to health status are deemed permanent or irreversible.

In general, elderly men with prostate cancer who fall into the “fit” health assessment category should have the same treatment options as younger patients. Patients who fall into the “vulnerable” category should be able to receive standard treatment after measures are taken to address any reversible impairments such as malnutrition. Adapted treatment might be more appropriate in senior men who fall into the “frail” category, and palliative care is recommended for those identified with terminal illness.

The potential for side effects to occur and patients’ willingness to accept these is vital to consider when selecting treatments, perhaps more so in elderly individuals who may be more prone to experience adverse events, particularly if they have comorbid disease. Age marginally influences genitourinary and gastrointestinal toxicity seen with external beam radiation therapy, for example, but increases the risk for erectile dysfunction in older men.

Considering first-line treatment for metastatic castrate-resistant prostate cancer disease, “This is exactly the same as in younger patients,” Dr. Droz said. So, docetaxel at the usual dose of 75 mg/m² given three times a week should be suitable for the treatment of both fit and vulnerable patients. A reduced frequency docetaxel regimen, such as weekly or twice weekly, may be more suitable in a frail patient.

Abiraterone acetate is also suitable in the first-line setting in asymptomatic or mildly symptomatic patients who do not have liver metastases. Bone-targeted drugs can also be used to prevent bone loss and for the treatment of bone metastases.

As for second-line treatment, cabazitaxel, abiraterone, and enzalutamide are available, but careful monitoring is needed in older patients, advised Dr. Droz. As in younger men, the optimal sequence of these therapies needs further research.

Dr. Droz commented that the efficacy of treatments for both localized and advanced prostate cancer in older men is similar to that in younger men. However, “the critical issue in the decision-making process is the competition between the risk of death due to prostate cancer and the risk of death due to health status,” he observed.

Dr. Droz has received honoraria from Sanofi.

PARIS – Health status should be evaluated when determining how best to treat an older man with prostate cancer, attendees at an international congress on anticancer treatment were told.

According to recently updated guidelines issued by the International Society of Geriatric Oncology (SIOG), patient preferences should also be a priority when deciding upon prostate cancer treatment, but not their chronological age.

“In the first SIOG guidelines [Crit. Rev. Oncol. Hematol. 2010;731:68-91], we introduced an approach for assessing health status that was somewhat difficult to use by urologists or medical oncologists who had no training in geriatric oncology,” Dr. John-Pierre Droz, professor emeritus of medical oncology at Université Claude Bernard in Lyon, France, said in an interview.

In the updated guidelines (Lancet Oncol. 2014;15:e404-14), however, the use of the G-8 simplified health assessment tool is recommended that takes just 4 minutes to compete and can be used to determine if further health status assessments are necessary.

“This assessment can be performed by a trained nurse,” Dr. Droz said, making the assessment much easier to integrate into clinician’s daily practice.

The G-8 screening tool (Ann. Oncol. 2012;23:2166-72) consists of eight items that take into account patients’ food intake and weight loss in the past 3 months, their body mass index, mobility, prescription drug use, and neuropsychological status. Their age and assessment of their perceived health status in comparison to people of the same age are also included.

A score above 14 is favorable on the G-8 and patients can be categorized as being “fit” and no further geriatric assessment is suggested. But the guidelines recommend a more comprehensive geriatric assessment if a score below this threshold is obtained, which includes comorbidities measured via the Cumulative Illness Rating Scale-Geriatric, evaluation of nutritional status, and patients’ cognitive and physical functions. The latter includes using the familiar concepts of activities of daily living and independent activities of daily living.

Based on these further assessments elderly patients can be categorized as vulnerable, where the health status parameters are potentially improved with appropriate measures; or frail,when changes to health status are deemed permanent or irreversible.

In general, elderly men with prostate cancer who fall into the “fit” health assessment category should have the same treatment options as younger patients. Patients who fall into the “vulnerable” category should be able to receive standard treatment after measures are taken to address any reversible impairments such as malnutrition. Adapted treatment might be more appropriate in senior men who fall into the “frail” category, and palliative care is recommended for those identified with terminal illness.

The potential for side effects to occur and patients’ willingness to accept these is vital to consider when selecting treatments, perhaps more so in elderly individuals who may be more prone to experience adverse events, particularly if they have comorbid disease. Age marginally influences genitourinary and gastrointestinal toxicity seen with external beam radiation therapy, for example, but increases the risk for erectile dysfunction in older men.

Considering first-line treatment for metastatic castrate-resistant prostate cancer disease, “This is exactly the same as in younger patients,” Dr. Droz said. So, docetaxel at the usual dose of 75 mg/m² given three times a week should be suitable for the treatment of both fit and vulnerable patients. A reduced frequency docetaxel regimen, such as weekly or twice weekly, may be more suitable in a frail patient.

Abiraterone acetate is also suitable in the first-line setting in asymptomatic or mildly symptomatic patients who do not have liver metastases. Bone-targeted drugs can also be used to prevent bone loss and for the treatment of bone metastases.

As for second-line treatment, cabazitaxel, abiraterone, and enzalutamide are available, but careful monitoring is needed in older patients, advised Dr. Droz. As in younger men, the optimal sequence of these therapies needs further research.

Dr. Droz commented that the efficacy of treatments for both localized and advanced prostate cancer in older men is similar to that in younger men. However, “the critical issue in the decision-making process is the competition between the risk of death due to prostate cancer and the risk of death due to health status,” he observed.

Dr. Droz has received honoraria from Sanofi.

PARIS – Outcomes for women with progressive or relapsed ovarian carcinoma are significantly improving due to the availability of new molecularly targeted treatments and evolving treatment modalities, medical oncologist Peter Harper said at an international conference on anticancer treatment.

Dr. Harper, who is in private practice in London, said in an interview that the effects of these new approaches were “very significant, such that [clinicians] are now probably doubling the survival, but not doubling the cure rate” in women with advanced disease.

The question for further research, however, is whether using targeted treatments and newer modalities earlier in the course of the disease could make any additional difference to patient outcomes. “As soon as you see a 30%-40% response rate in second-line treatment, when you add that treatment to first-line, you [should also] have a benefit, and that’s happened in all tumor types,” Dr. Harper said.

Around 75% of patients with ovarian cancer will develop recurrent or progressive disease at some point in the course of their disease, he said during his presentation, noting that the disease can be difficult to treat once it has gone past stage I to stage II. Relapse can occur within a few months to a year in patients who do not respond or who are resistant to first-line platinum-based chemotherapy.

But how do you define and know when to treat a patient in relapse? Do you wait until they are symptomatic or do you treat the moment their serum levels of cancer antigen 125 (CA-125) start to rise? Rising CA-125 can be an early signal of relapse, but this is a highly variable time, Dr. Harper said. “Some patients will just have smoldering disease which doesn’t do them any harm for a long time, but for others, there can be a rapid progression.”

Data show that treating patients early in the course of relapse based on their CA-125 levels alone does not influence the outcome. Indeed, similar overall survival (OS) was seen in the OV 05/EORTC 55959 trial (Lancet 2010;376:1155–1163) regardless of whether treatment was initiated early on the basis of rising CA-125 levels or delayed.

Thus treatment should be based on a combination of clinical determinants, symptoms, and radiologic findings, but perhaps not the level of CA-125 on its own, Dr. Harper suggested, and it is important not to forget the psychological burden for patients in knowing their CA-125 result.

Chemotherapy is the standard option for treating platinum-sensitive disease in relapse, with combination therapy generally improving progression-free survival (PFS) and sometimes OS over single-agents, although using combinations can be associated with greater toxicity.

Surgery may be possible Dr. Harper said but “you’ve got to have big eyes.” If there is an obvious obstruction then investigation with a view to surgical removal might be the best course of action.

As for treating platinum-resistant disease or patients with disease that is refractory to first-line therapy, the addition of molecularly targeted agents to chemotherapy is showing great promise.

A host of molecularly targeted drugs have been investigated in the treatment of advanced ovarian carcinoma, including those inhibiting vascular endothelial growth factor (VEGF) or its receptor (VEGFR), and polymerase poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors.

The VEGF inhibitor bevacizumab (Avastin) is the most studied, with data from the OCEANS (J. Clin. Oncol. 2012;30:2039-45) and AURELIA (N. Engl. J. Med. 2011;365:2484-96) trials showing that it can increase overall response rates and PFS in both platinum-sensitive and platinum-resistant relapse when added to chemotherapy. No OS benefit was seen in either trial but there was a high (30%-40%) rate of crossover in these trials, and in OCEANS patients received multiple lines of therapy.

“Long postprogression survival means detection of differences in OS is harder and requires a much larger sample size,” Dr. Harper observed. “The reason for stressing this is because we’ve had a lot of trouble with regulators who do not like progression-free survival as an endpoint and want overall survival, and you’re simply not going to see that.”

VEGFR inhibitors evaluated in advanced ovarian cancer in combination with chemotherapy include sorafenib (Nexavar), pazopanib (Votrient), nintedanib (Ofev), and cediranib. Early trial data show these drugs added to chemotherapy can increase PFS in comparison to chemotherapy alone, perhaps even improve OS in the case of cediranib. In the phase II ICON-6 trial, cediranib was added to platinum-based chemotherapy in patients with platinum-sensitive, relapsed disease.

Like bevacizumab, VEGFR-targeting drugs can be associated with a spectrum of side effects, from hypertension to diarrhea, “but you can get quite good at using them and can really minimize side effects”.

Dr. Harper highlighted the potential role of the PARP inhibitor olaparib (Lynparza) as maintenance therapy in patients with platinum-sensitive ovarian cancer. Data from a phase II study (N. Engl. J. Med. 2012:366:1382-92) suggest that it too can improve PFS, with the potential for women to do better if they have the BRCA1 or BRCA2 mutations.

As for immunotherapy, “PD-L1 is very interesting,” Dr. Harper observed. “We know the trials are taking place in ovarian cancer, but it’s much further down the line than in other tumors as ovarian cancer accounts for only 5%-6% of all female cancers, so obviously they’ve tried it in breast cancer and lung cancer first.” Overall, “it’s very hopeful that treatments which are now being used in relapse will be introduced first line and will make a difference,” Dr. Harper said.

PARIS – Outcomes for women with progressive or relapsed ovarian carcinoma are significantly improving due to the availability of new molecularly targeted treatments and evolving treatment modalities, medical oncologist Peter Harper said at an international conference on anticancer treatment.

Dr. Harper, who is in private practice in London, said in an interview that the effects of these new approaches were “very significant, such that [clinicians] are now probably doubling the survival, but not doubling the cure rate” in women with advanced disease.

The question for further research, however, is whether using targeted treatments and newer modalities earlier in the course of the disease could make any additional difference to patient outcomes. “As soon as you see a 30%-40% response rate in second-line treatment, when you add that treatment to first-line, you [should also] have a benefit, and that’s happened in all tumor types,” Dr. Harper said.

Around 75% of patients with ovarian cancer will develop recurrent or progressive disease at some point in the course of their disease, he said during his presentation, noting that the disease can be difficult to treat once it has gone past stage I to stage II. Relapse can occur within a few months to a year in patients who do not respond or who are resistant to first-line platinum-based chemotherapy.

But how do you define and know when to treat a patient in relapse? Do you wait until they are symptomatic or do you treat the moment their serum levels of cancer antigen 125 (CA-125) start to rise? Rising CA-125 can be an early signal of relapse, but this is a highly variable time, Dr. Harper said. “Some patients will just have smoldering disease which doesn’t do them any harm for a long time, but for others, there can be a rapid progression.”

Data show that treating patients early in the course of relapse based on their CA-125 levels alone does not influence the outcome. Indeed, similar overall survival (OS) was seen in the OV 05/EORTC 55959 trial (Lancet 2010;376:1155–1163) regardless of whether treatment was initiated early on the basis of rising CA-125 levels or delayed.

Thus treatment should be based on a combination of clinical determinants, symptoms, and radiologic findings, but perhaps not the level of CA-125 on its own, Dr. Harper suggested, and it is important not to forget the psychological burden for patients in knowing their CA-125 result.

Chemotherapy is the standard option for treating platinum-sensitive disease in relapse, with combination therapy generally improving progression-free survival (PFS) and sometimes OS over single-agents, although using combinations can be associated with greater toxicity.

Surgery may be possible Dr. Harper said but “you’ve got to have big eyes.” If there is an obvious obstruction then investigation with a view to surgical removal might be the best course of action.

As for treating platinum-resistant disease or patients with disease that is refractory to first-line therapy, the addition of molecularly targeted agents to chemotherapy is showing great promise.

A host of molecularly targeted drugs have been investigated in the treatment of advanced ovarian carcinoma, including those inhibiting vascular endothelial growth factor (VEGF) or its receptor (VEGFR), and polymerase poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors.

The VEGF inhibitor bevacizumab (Avastin) is the most studied, with data from the OCEANS (J. Clin. Oncol. 2012;30:2039-45) and AURELIA (N. Engl. J. Med. 2011;365:2484-96) trials showing that it can increase overall response rates and PFS in both platinum-sensitive and platinum-resistant relapse when added to chemotherapy. No OS benefit was seen in either trial but there was a high (30%-40%) rate of crossover in these trials, and in OCEANS patients received multiple lines of therapy.

“Long postprogression survival means detection of differences in OS is harder and requires a much larger sample size,” Dr. Harper observed. “The reason for stressing this is because we’ve had a lot of trouble with regulators who do not like progression-free survival as an endpoint and want overall survival, and you’re simply not going to see that.”

VEGFR inhibitors evaluated in advanced ovarian cancer in combination with chemotherapy include sorafenib (Nexavar), pazopanib (Votrient), nintedanib (Ofev), and cediranib. Early trial data show these drugs added to chemotherapy can increase PFS in comparison to chemotherapy alone, perhaps even improve OS in the case of cediranib. In the phase II ICON-6 trial, cediranib was added to platinum-based chemotherapy in patients with platinum-sensitive, relapsed disease.

Like bevacizumab, VEGFR-targeting drugs can be associated with a spectrum of side effects, from hypertension to diarrhea, “but you can get quite good at using them and can really minimize side effects”.

Dr. Harper highlighted the potential role of the PARP inhibitor olaparib (Lynparza) as maintenance therapy in patients with platinum-sensitive ovarian cancer. Data from a phase II study (N. Engl. J. Med. 2012:366:1382-92) suggest that it too can improve PFS, with the potential for women to do better if they have the BRCA1 or BRCA2 mutations.

As for immunotherapy, “PD-L1 is very interesting,” Dr. Harper observed. “We know the trials are taking place in ovarian cancer, but it’s much further down the line than in other tumors as ovarian cancer accounts for only 5%-6% of all female cancers, so obviously they’ve tried it in breast cancer and lung cancer first.” Overall, “it’s very hopeful that treatments which are now being used in relapse will be introduced first line and will make a difference,” Dr. Harper said.

PARIS – Outcomes for women with progressive or relapsed ovarian carcinoma are significantly improving due to the availability of new molecularly targeted treatments and evolving treatment modalities, medical oncologist Peter Harper said at an international conference on anticancer treatment.

Dr. Harper, who is in private practice in London, said in an interview that the effects of these new approaches were “very significant, such that [clinicians] are now probably doubling the survival, but not doubling the cure rate” in women with advanced disease.

The question for further research, however, is whether using targeted treatments and newer modalities earlier in the course of the disease could make any additional difference to patient outcomes. “As soon as you see a 30%-40% response rate in second-line treatment, when you add that treatment to first-line, you [should also] have a benefit, and that’s happened in all tumor types,” Dr. Harper said.

Around 75% of patients with ovarian cancer will develop recurrent or progressive disease at some point in the course of their disease, he said during his presentation, noting that the disease can be difficult to treat once it has gone past stage I to stage II. Relapse can occur within a few months to a year in patients who do not respond or who are resistant to first-line platinum-based chemotherapy.

But how do you define and know when to treat a patient in relapse? Do you wait until they are symptomatic or do you treat the moment their serum levels of cancer antigen 125 (CA-125) start to rise? Rising CA-125 can be an early signal of relapse, but this is a highly variable time, Dr. Harper said. “Some patients will just have smoldering disease which doesn’t do them any harm for a long time, but for others, there can be a rapid progression.”

Data show that treating patients early in the course of relapse based on their CA-125 levels alone does not influence the outcome. Indeed, similar overall survival (OS) was seen in the OV 05/EORTC 55959 trial (Lancet 2010;376:1155–1163) regardless of whether treatment was initiated early on the basis of rising CA-125 levels or delayed.

Thus treatment should be based on a combination of clinical determinants, symptoms, and radiologic findings, but perhaps not the level of CA-125 on its own, Dr. Harper suggested, and it is important not to forget the psychological burden for patients in knowing their CA-125 result.

Chemotherapy is the standard option for treating platinum-sensitive disease in relapse, with combination therapy generally improving progression-free survival (PFS) and sometimes OS over single-agents, although using combinations can be associated with greater toxicity.

Surgery may be possible Dr. Harper said but “you’ve got to have big eyes.” If there is an obvious obstruction then investigation with a view to surgical removal might be the best course of action.

As for treating platinum-resistant disease or patients with disease that is refractory to first-line therapy, the addition of molecularly targeted agents to chemotherapy is showing great promise.

A host of molecularly targeted drugs have been investigated in the treatment of advanced ovarian carcinoma, including those inhibiting vascular endothelial growth factor (VEGF) or its receptor (VEGFR), and polymerase poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors.

The VEGF inhibitor bevacizumab (Avastin) is the most studied, with data from the OCEANS (J. Clin. Oncol. 2012;30:2039-45) and AURELIA (N. Engl. J. Med. 2011;365:2484-96) trials showing that it can increase overall response rates and PFS in both platinum-sensitive and platinum-resistant relapse when added to chemotherapy. No OS benefit was seen in either trial but there was a high (30%-40%) rate of crossover in these trials, and in OCEANS patients received multiple lines of therapy.

“Long postprogression survival means detection of differences in OS is harder and requires a much larger sample size,” Dr. Harper observed. “The reason for stressing this is because we’ve had a lot of trouble with regulators who do not like progression-free survival as an endpoint and want overall survival, and you’re simply not going to see that.”

VEGFR inhibitors evaluated in advanced ovarian cancer in combination with chemotherapy include sorafenib (Nexavar), pazopanib (Votrient), nintedanib (Ofev), and cediranib. Early trial data show these drugs added to chemotherapy can increase PFS in comparison to chemotherapy alone, perhaps even improve OS in the case of cediranib. In the phase II ICON-6 trial, cediranib was added to platinum-based chemotherapy in patients with platinum-sensitive, relapsed disease.

Like bevacizumab, VEGFR-targeting drugs can be associated with a spectrum of side effects, from hypertension to diarrhea, “but you can get quite good at using them and can really minimize side effects”.

Dr. Harper highlighted the potential role of the PARP inhibitor olaparib (Lynparza) as maintenance therapy in patients with platinum-sensitive ovarian cancer. Data from a phase II study (N. Engl. J. Med. 2012:366:1382-92) suggest that it too can improve PFS, with the potential for women to do better if they have the BRCA1 or BRCA2 mutations.

As for immunotherapy, “PD-L1 is very interesting,” Dr. Harper observed. “We know the trials are taking place in ovarian cancer, but it’s much further down the line than in other tumors as ovarian cancer accounts for only 5%-6% of all female cancers, so obviously they’ve tried it in breast cancer and lung cancer first.” Overall, “it’s very hopeful that treatments which are now being used in relapse will be introduced first line and will make a difference,” Dr. Harper said.

PARIS – Treatment algorithms for metastatic colorectal cancer are “dynamic and fast changing” in order to keep up with the multiple cytotoxic and biologic options that are currently or will soon be available, Dr. Eric Van Cutsem said at an international congress on anticancer treatment.

“We are making progress. If you look at the past 10-15 years you see that the median survival is going up with the introduction of different agents and with the results of different trials,” Dr. Van Cutsem of University Hospitals Leuven, Belgium, said.

It is becoming increasingly clear that mCRC is “not one disease” and that patient and tumor characteristics vary wildly. Multiple molecular alterations have been identified and there are many molecular signaling pathways known to be involved in tumor progression.

Recent work by the SAGE Colorectal Cancer Subtyping Consortium suggest that there are four or five molecular subtypes of mCRC (Ann. Oncol. 2014;25:iii1-iii9). While it is too early to determine if each subtype might require a different therapeutic strategy, it is another step along the path to achieving the goal of personalized medicine in the disease.

“Treatment choice depends on more than efficacy,” Dr. Van Cutsem said. Together with tumor characteristics (clinical presentation, tumor biology, RAS and BRAF mutation status), patient characteristics (age, performance status, prior adjuvant treatment and comorbidities) and their preferences (expectations, toxicities, socioeconomic factors, and quality of life) need to be incorporated into the treatment plan.

In terms of optimizing the use of targeted treatments in mCRC, Dr. Van Cutsem noted that are three antiangiogenic agents currently approved for use in Europe – bevacizumab (Avastin), aflibercept (Zaltrap), and regorafenib (Stivarga) – and two epidermal growth factor receptor inhibitors, cetuximab (Erbitux) and panitumumab (Vectibix). Promising data from the phase III RAISE trial recently presented at ASCO GI mean that another antiangiogenic agent, ramucirumab (Cyramza), could soon be added to this list.

How to best choose between these agents remains an area of active research but data already show that patients’ RAS status can determine if they might respond to anti-epidermal growth factor receptor monoclonal antibody treatment. BRAF analysis remains more experimental but it can be performed alongside RAS testing with limited extra effort and cost.

Dr. Van Cutsem gave highlights of an expert discussion on mCRC held at the 2014 ESMO/World Congress on Gastrointestinal Cancer in Barcelona, where it was agreed that while chemotherapy remains the backbone of first-line treatment, biologics are also indicated as first-line treatment in most patients, unless there are specific contraindications.

As yet, there is no unequivocal evidence that one biologic agent is superior to another as a first-line choice and the decision to use bevacizumab or an anti-EGFR monoclonal antibody will depend on the subsequent strategy if treatment fails, as well as likely toxicities and patient quality of life.

According to current European Society of Medical Oncology guidelines (Ann. Oncol. 2014;25: iii1–iii9) dividing patients into four categories may help direct the therapeutic strategy. Category 0 patients are those with resectable disease and category 1 patients have potentially resectable disease. Category 2 patients have nonresectable tumors with a heavy tumor load and aggressive biology and Category 3 patients are those who are nonresectable, nonaggressive, and asymptomatic disease.

The categories are not perfect, however, and will be refined in the next iteration of the guidelines due out later this year, Dr. Van Cutsem commented. He added that patients do not always need high-intensity treatment; it depends on what is trying to be achieved. For example, treatment may be more intense at the start when the goal may be to try to shrink tumors to allow surgery and less intense when the aim is to provide good disease control with low toxicity.

In potentially resectable patients in which conversion to surgery is the goal, there is uncertainty on the best combination of cytotoxic and biologic agents to use, with different combinations suggested in RAS mutant and RAS wild-type patients.

In RAS mutant patients, for example, doublet chemotherapy plus bevacizumab or FOLFOXIRI with or without bevacizumab may be reasonable choices, whereas in RAS wild-type patients doublet chemotherapy maybe be combined with an anti-EGFR monoclonal antibody. Another front-line option in the future may be ramucirumab added to FOLFIRI but this has yet to be approved and incorporated into the guidelines. Reevaluation of treatment is important so that patients with resectable disease are not overtreated.

Second-line options may include bevacizumab or aflibercept added to chemotherapy, with third- and later lines of treatment including anti-EGFR monoclonal antibodies possibly used alone in RAS wild-type patients or with irinotecan in the case of cetuximab, and regorafenib in patients who are refractory to other therapies.

Another “new kid on the block” yet to be approved and incorporated into the guidelines is TAS-102, an oral fluoropyrimidine. Data from the recent RECOURSE study (Refractory Colorectal Cancer Study) showed an overall survival benefit of the novel drug vs. placebo when added to best supportive care after two or more prior regimens for mCRC (Ann. Oncol. 2014;25-4: Abstr. LBA13).

Dr. Van Cutsem has received research funding from Amgen, Bayer, Boehringer, Lilly, Merck, Merck Serono, Novartis, Roche, and Sanofi.

PARIS – Treatment algorithms for metastatic colorectal cancer are “dynamic and fast changing” in order to keep up with the multiple cytotoxic and biologic options that are currently or will soon be available, Dr. Eric Van Cutsem said at an international congress on anticancer treatment.

“We are making progress. If you look at the past 10-15 years you see that the median survival is going up with the introduction of different agents and with the results of different trials,” Dr. Van Cutsem of University Hospitals Leuven, Belgium, said.

It is becoming increasingly clear that mCRC is “not one disease” and that patient and tumor characteristics vary wildly. Multiple molecular alterations have been identified and there are many molecular signaling pathways known to be involved in tumor progression.

Recent work by the SAGE Colorectal Cancer Subtyping Consortium suggest that there are four or five molecular subtypes of mCRC (Ann. Oncol. 2014;25:iii1-iii9). While it is too early to determine if each subtype might require a different therapeutic strategy, it is another step along the path to achieving the goal of personalized medicine in the disease.

“Treatment choice depends on more than efficacy,” Dr. Van Cutsem said. Together with tumor characteristics (clinical presentation, tumor biology, RAS and BRAF mutation status), patient characteristics (age, performance status, prior adjuvant treatment and comorbidities) and their preferences (expectations, toxicities, socioeconomic factors, and quality of life) need to be incorporated into the treatment plan.

In terms of optimizing the use of targeted treatments in mCRC, Dr. Van Cutsem noted that are three antiangiogenic agents currently approved for use in Europe – bevacizumab (Avastin), aflibercept (Zaltrap), and regorafenib (Stivarga) – and two epidermal growth factor receptor inhibitors, cetuximab (Erbitux) and panitumumab (Vectibix). Promising data from the phase III RAISE trial recently presented at ASCO GI mean that another antiangiogenic agent, ramucirumab (Cyramza), could soon be added to this list.

How to best choose between these agents remains an area of active research but data already show that patients’ RAS status can determine if they might respond to anti-epidermal growth factor receptor monoclonal antibody treatment. BRAF analysis remains more experimental but it can be performed alongside RAS testing with limited extra effort and cost.

Dr. Van Cutsem gave highlights of an expert discussion on mCRC held at the 2014 ESMO/World Congress on Gastrointestinal Cancer in Barcelona, where it was agreed that while chemotherapy remains the backbone of first-line treatment, biologics are also indicated as first-line treatment in most patients, unless there are specific contraindications.

As yet, there is no unequivocal evidence that one biologic agent is superior to another as a first-line choice and the decision to use bevacizumab or an anti-EGFR monoclonal antibody will depend on the subsequent strategy if treatment fails, as well as likely toxicities and patient quality of life.

According to current European Society of Medical Oncology guidelines (Ann. Oncol. 2014;25: iii1–iii9) dividing patients into four categories may help direct the therapeutic strategy. Category 0 patients are those with resectable disease and category 1 patients have potentially resectable disease. Category 2 patients have nonresectable tumors with a heavy tumor load and aggressive biology and Category 3 patients are those who are nonresectable, nonaggressive, and asymptomatic disease.

The categories are not perfect, however, and will be refined in the next iteration of the guidelines due out later this year, Dr. Van Cutsem commented. He added that patients do not always need high-intensity treatment; it depends on what is trying to be achieved. For example, treatment may be more intense at the start when the goal may be to try to shrink tumors to allow surgery and less intense when the aim is to provide good disease control with low toxicity.

In potentially resectable patients in which conversion to surgery is the goal, there is uncertainty on the best combination of cytotoxic and biologic agents to use, with different combinations suggested in RAS mutant and RAS wild-type patients.

In RAS mutant patients, for example, doublet chemotherapy plus bevacizumab or FOLFOXIRI with or without bevacizumab may be reasonable choices, whereas in RAS wild-type patients doublet chemotherapy maybe be combined with an anti-EGFR monoclonal antibody. Another front-line option in the future may be ramucirumab added to FOLFIRI but this has yet to be approved and incorporated into the guidelines. Reevaluation of treatment is important so that patients with resectable disease are not overtreated.

Second-line options may include bevacizumab or aflibercept added to chemotherapy, with third- and later lines of treatment including anti-EGFR monoclonal antibodies possibly used alone in RAS wild-type patients or with irinotecan in the case of cetuximab, and regorafenib in patients who are refractory to other therapies.

Another “new kid on the block” yet to be approved and incorporated into the guidelines is TAS-102, an oral fluoropyrimidine. Data from the recent RECOURSE study (Refractory Colorectal Cancer Study) showed an overall survival benefit of the novel drug vs. placebo when added to best supportive care after two or more prior regimens for mCRC (Ann. Oncol. 2014;25-4: Abstr. LBA13).

Dr. Van Cutsem has received research funding from Amgen, Bayer, Boehringer, Lilly, Merck, Merck Serono, Novartis, Roche, and Sanofi.

PARIS – Treatment algorithms for metastatic colorectal cancer are “dynamic and fast changing” in order to keep up with the multiple cytotoxic and biologic options that are currently or will soon be available, Dr. Eric Van Cutsem said at an international congress on anticancer treatment.

“We are making progress. If you look at the past 10-15 years you see that the median survival is going up with the introduction of different agents and with the results of different trials,” Dr. Van Cutsem of University Hospitals Leuven, Belgium, said.

It is becoming increasingly clear that mCRC is “not one disease” and that patient and tumor characteristics vary wildly. Multiple molecular alterations have been identified and there are many molecular signaling pathways known to be involved in tumor progression.

Recent work by the SAGE Colorectal Cancer Subtyping Consortium suggest that there are four or five molecular subtypes of mCRC (Ann. Oncol. 2014;25:iii1-iii9). While it is too early to determine if each subtype might require a different therapeutic strategy, it is another step along the path to achieving the goal of personalized medicine in the disease.

“Treatment choice depends on more than efficacy,” Dr. Van Cutsem said. Together with tumor characteristics (clinical presentation, tumor biology, RAS and BRAF mutation status), patient characteristics (age, performance status, prior adjuvant treatment and comorbidities) and their preferences (expectations, toxicities, socioeconomic factors, and quality of life) need to be incorporated into the treatment plan.

In terms of optimizing the use of targeted treatments in mCRC, Dr. Van Cutsem noted that are three antiangiogenic agents currently approved for use in Europe – bevacizumab (Avastin), aflibercept (Zaltrap), and regorafenib (Stivarga) – and two epidermal growth factor receptor inhibitors, cetuximab (Erbitux) and panitumumab (Vectibix). Promising data from the phase III RAISE trial recently presented at ASCO GI mean that another antiangiogenic agent, ramucirumab (Cyramza), could soon be added to this list.

How to best choose between these agents remains an area of active research but data already show that patients’ RAS status can determine if they might respond to anti-epidermal growth factor receptor monoclonal antibody treatment. BRAF analysis remains more experimental but it can be performed alongside RAS testing with limited extra effort and cost.

Dr. Van Cutsem gave highlights of an expert discussion on mCRC held at the 2014 ESMO/World Congress on Gastrointestinal Cancer in Barcelona, where it was agreed that while chemotherapy remains the backbone of first-line treatment, biologics are also indicated as first-line treatment in most patients, unless there are specific contraindications.

As yet, there is no unequivocal evidence that one biologic agent is superior to another as a first-line choice and the decision to use bevacizumab or an anti-EGFR monoclonal antibody will depend on the subsequent strategy if treatment fails, as well as likely toxicities and patient quality of life.

According to current European Society of Medical Oncology guidelines (Ann. Oncol. 2014;25: iii1–iii9) dividing patients into four categories may help direct the therapeutic strategy. Category 0 patients are those with resectable disease and category 1 patients have potentially resectable disease. Category 2 patients have nonresectable tumors with a heavy tumor load and aggressive biology and Category 3 patients are those who are nonresectable, nonaggressive, and asymptomatic disease.

The categories are not perfect, however, and will be refined in the next iteration of the guidelines due out later this year, Dr. Van Cutsem commented. He added that patients do not always need high-intensity treatment; it depends on what is trying to be achieved. For example, treatment may be more intense at the start when the goal may be to try to shrink tumors to allow surgery and less intense when the aim is to provide good disease control with low toxicity.

In potentially resectable patients in which conversion to surgery is the goal, there is uncertainty on the best combination of cytotoxic and biologic agents to use, with different combinations suggested in RAS mutant and RAS wild-type patients.

In RAS mutant patients, for example, doublet chemotherapy plus bevacizumab or FOLFOXIRI with or without bevacizumab may be reasonable choices, whereas in RAS wild-type patients doublet chemotherapy maybe be combined with an anti-EGFR monoclonal antibody. Another front-line option in the future may be ramucirumab added to FOLFIRI but this has yet to be approved and incorporated into the guidelines. Reevaluation of treatment is important so that patients with resectable disease are not overtreated.

Second-line options may include bevacizumab or aflibercept added to chemotherapy, with third- and later lines of treatment including anti-EGFR monoclonal antibodies possibly used alone in RAS wild-type patients or with irinotecan in the case of cetuximab, and regorafenib in patients who are refractory to other therapies.

Another “new kid on the block” yet to be approved and incorporated into the guidelines is TAS-102, an oral fluoropyrimidine. Data from the recent RECOURSE study (Refractory Colorectal Cancer Study) showed an overall survival benefit of the novel drug vs. placebo when added to best supportive care after two or more prior regimens for mCRC (Ann. Oncol. 2014;25-4: Abstr. LBA13).

Dr. Van Cutsem has received research funding from Amgen, Bayer, Boehringer, Lilly, Merck, Merck Serono, Novartis, Roche, and Sanofi.

PARIS – Successful head and neck cancer management can be achieved only if a multidisciplinary approach is taken, experts emphasized at a recent international conference on anticancer treatment.

Because of its very location and complex anatomy, squamous cell cancer of the head and neck (SCCHN) is a difficult tumor to treat, Dr. Jean-Pierre Lefebvre of Centre Oscar Lambret in Lille, France, explained. Two-thirds of tumors are diagnosed at a late stage and often require a combination of therapeutic approaches and thus “combined toxicities.” Patients also frequently have comorbid illnesses that can affect their compliance and tolerance to treatments.

“There is only one solution: a multidisciplinary approach at any time of the management,” Dr. Lefebvre said.

The multidisciplinary approach requires a tight-knit team of imaging specialists; biologists and pathologists; anesthesiologists and surgeons; medical and radiation oncologists; nurses, general practitioners, and other support professions, such as dentists, dietitians, psychologists, speech and physical therapy specialists; and of course, the patients themselves.

Dr. Lefebvre noted that it was vital to provide patients with good information about their disease and its treatment, from the time of diagnosis to explain the various management decisions made by the multidisciplinary team and likely outcomes of the recommended interventions.

The primary goals of treatment are to control disease above the clavicles and to ensure survival, Dr. Lefebvre observed. Other treatment goals include preserving organ function, controlling symptoms, and creating a minimal impact on a patient’s quality of life by providing treatments that offer minimal long-term toxicity, good tolerability, and perhaps most important, good patient satisfaction.

Selecting treatment can be challenging and cannot be done without a multidisciplinary decision. The two main pathways are a surgery-based or radiotherapy-based treatment, but within each there are multiple options and combinations that need careful consideration on a case-by-case basis.

“It’s not a cookbook decision,” agreed Dr. Jan B. Vermorken, emeritus professor of oncology at Antwerp University Hospital, Belgium, who discussed the systemic treatment of head and neck cancer in a separate lecture. He agreed that head and neck cancer treatment is a multidisciplinary challenge that needs to balance the efficacy and tolerability of treatment on an individual basis, and always while considering the patient’s preferences.

“Patients can be very well informed,” Dr. Vermorken noted and suggested that clinicians need to be prepared to help patients understand the information that they find themselves in order to be able to counter any misinformation they might have found.

“There is no treatment without side effects,” Dr. Vermorken stressed. “When there are no side effects, [the treatment] doesn’t work. So you have to warn patients there are always side effects of the treatment they will be given.”

In addition to the importance of the multidisciplinary team in the management of head and neck cancer, understanding the biology of the disease and using systemic treatment are important for treatment, he said. Recent advances in this area include the recognition of the human papillomavirus as a risk factor for and strong predictor of survival in oropharyngeal cancer, and the role of epidermal growth factor receptor to enable targeting with anti-EGFR drugs, such as cetuximab (Erbitux). Systemic treatment for locally advanced disease includes concurrent chemoradiotherapy (CCRT), bioradiotherapy (BRT) with cetuximab and sequential chemotherapy (induction chemotherapy followed by CCRT or BRT).

In most cases of locally advanced SCCHN, the recommended chemotherapy of choice is high-dose cisplatin, given every 3 weeks. Although alternatives to this have been proposed – such as lowering the dose of cisplatin or using carboplatin or cetuximab instead – they have been insufficiently studied and many questions remain unanswered at the moment.

As for the treatment of recurrent or metastatic SCCHN, if it is resectable, then this would be followed by radiotherapy or CCRT. In patients deemed fit enough to handle the regimen, a combination of a platinum agent, 5-fluorouracil (5-FU) and cetuximab) is a new standard first-line regimen, although the role of maintenance cetuximab is unclear.

Better chemotherapy partners for cetuximab or alternatives for anti-EGFR–targeting agents are under investigation. This includes using docetaxel (Taxotere) instead of 5-FU with cetuximab or using lapatinib (Tykerb), afatinib (Gilotrif) or dacomitinib to block multiple human epidermal growth factor receptors or a variety of monoclonal antibodies to try to overcome resistance to anti-EGFR drugs.

Reactivation of immune surveillance by blocking the PD-1 pathway with drugs such as nivolumab (Opdivo) and pembrolizumab (Keytruda) seems to be a promising approach for treating head and neck cancer and is under investigation in other tumors, including non–small cell lung cancer, triple-negative breast cancer, and melanoma, Dr. Vermorken said.Dr. Lefebvre has acted as a consultant to Merck Serono and Sanofi. Dr. Vermorken has participated in advisory boards of AstraZeneca; Boehringer Ingelheim; Debiopharm; Genentech; Merck Serono; Merck, Sharp & Dohme; Oncolytics Biotech; Pierre Fabre; and Vaccinogen; and received lecturer fees from Merck Serono.

PARIS – Successful head and neck cancer management can be achieved only if a multidisciplinary approach is taken, experts emphasized at a recent international conference on anticancer treatment.

Because of its very location and complex anatomy, squamous cell cancer of the head and neck (SCCHN) is a difficult tumor to treat, Dr. Jean-Pierre Lefebvre of Centre Oscar Lambret in Lille, France, explained. Two-thirds of tumors are diagnosed at a late stage and often require a combination of therapeutic approaches and thus “combined toxicities.” Patients also frequently have comorbid illnesses that can affect their compliance and tolerance to treatments.

“There is only one solution: a multidisciplinary approach at any time of the management,” Dr. Lefebvre said.

The multidisciplinary approach requires a tight-knit team of imaging specialists; biologists and pathologists; anesthesiologists and surgeons; medical and radiation oncologists; nurses, general practitioners, and other support professions, such as dentists, dietitians, psychologists, speech and physical therapy specialists; and of course, the patients themselves.

Dr. Lefebvre noted that it was vital to provide patients with good information about their disease and its treatment, from the time of diagnosis to explain the various management decisions made by the multidisciplinary team and likely outcomes of the recommended interventions.

The primary goals of treatment are to control disease above the clavicles and to ensure survival, Dr. Lefebvre observed. Other treatment goals include preserving organ function, controlling symptoms, and creating a minimal impact on a patient’s quality of life by providing treatments that offer minimal long-term toxicity, good tolerability, and perhaps most important, good patient satisfaction.

Selecting treatment can be challenging and cannot be done without a multidisciplinary decision. The two main pathways are a surgery-based or radiotherapy-based treatment, but within each there are multiple options and combinations that need careful consideration on a case-by-case basis.

“It’s not a cookbook decision,” agreed Dr. Jan B. Vermorken, emeritus professor of oncology at Antwerp University Hospital, Belgium, who discussed the systemic treatment of head and neck cancer in a separate lecture. He agreed that head and neck cancer treatment is a multidisciplinary challenge that needs to balance the efficacy and tolerability of treatment on an individual basis, and always while considering the patient’s preferences.

“Patients can be very well informed,” Dr. Vermorken noted and suggested that clinicians need to be prepared to help patients understand the information that they find themselves in order to be able to counter any misinformation they might have found.

“There is no treatment without side effects,” Dr. Vermorken stressed. “When there are no side effects, [the treatment] doesn’t work. So you have to warn patients there are always side effects of the treatment they will be given.”

In addition to the importance of the multidisciplinary team in the management of head and neck cancer, understanding the biology of the disease and using systemic treatment are important for treatment, he said. Recent advances in this area include the recognition of the human papillomavirus as a risk factor for and strong predictor of survival in oropharyngeal cancer, and the role of epidermal growth factor receptor to enable targeting with anti-EGFR drugs, such as cetuximab (Erbitux). Systemic treatment for locally advanced disease includes concurrent chemoradiotherapy (CCRT), bioradiotherapy (BRT) with cetuximab and sequential chemotherapy (induction chemotherapy followed by CCRT or BRT).

In most cases of locally advanced SCCHN, the recommended chemotherapy of choice is high-dose cisplatin, given every 3 weeks. Although alternatives to this have been proposed – such as lowering the dose of cisplatin or using carboplatin or cetuximab instead – they have been insufficiently studied and many questions remain unanswered at the moment.

As for the treatment of recurrent or metastatic SCCHN, if it is resectable, then this would be followed by radiotherapy or CCRT. In patients deemed fit enough to handle the regimen, a combination of a platinum agent, 5-fluorouracil (5-FU) and cetuximab) is a new standard first-line regimen, although the role of maintenance cetuximab is unclear.

Better chemotherapy partners for cetuximab or alternatives for anti-EGFR–targeting agents are under investigation. This includes using docetaxel (Taxotere) instead of 5-FU with cetuximab or using lapatinib (Tykerb), afatinib (Gilotrif) or dacomitinib to block multiple human epidermal growth factor receptors or a variety of monoclonal antibodies to try to overcome resistance to anti-EGFR drugs.

Reactivation of immune surveillance by blocking the PD-1 pathway with drugs such as nivolumab (Opdivo) and pembrolizumab (Keytruda) seems to be a promising approach for treating head and neck cancer and is under investigation in other tumors, including non–small cell lung cancer, triple-negative breast cancer, and melanoma, Dr. Vermorken said.Dr. Lefebvre has acted as a consultant to Merck Serono and Sanofi. Dr. Vermorken has participated in advisory boards of AstraZeneca; Boehringer Ingelheim; Debiopharm; Genentech; Merck Serono; Merck, Sharp & Dohme; Oncolytics Biotech; Pierre Fabre; and Vaccinogen; and received lecturer fees from Merck Serono.

PARIS – Successful head and neck cancer management can be achieved only if a multidisciplinary approach is taken, experts emphasized at a recent international conference on anticancer treatment.

Because of its very location and complex anatomy, squamous cell cancer of the head and neck (SCCHN) is a difficult tumor to treat, Dr. Jean-Pierre Lefebvre of Centre Oscar Lambret in Lille, France, explained. Two-thirds of tumors are diagnosed at a late stage and often require a combination of therapeutic approaches and thus “combined toxicities.” Patients also frequently have comorbid illnesses that can affect their compliance and tolerance to treatments.

“There is only one solution: a multidisciplinary approach at any time of the management,” Dr. Lefebvre said.

The multidisciplinary approach requires a tight-knit team of imaging specialists; biologists and pathologists; anesthesiologists and surgeons; medical and radiation oncologists; nurses, general practitioners, and other support professions, such as dentists, dietitians, psychologists, speech and physical therapy specialists; and of course, the patients themselves.

Dr. Lefebvre noted that it was vital to provide patients with good information about their disease and its treatment, from the time of diagnosis to explain the various management decisions made by the multidisciplinary team and likely outcomes of the recommended interventions.

The primary goals of treatment are to control disease above the clavicles and to ensure survival, Dr. Lefebvre observed. Other treatment goals include preserving organ function, controlling symptoms, and creating a minimal impact on a patient’s quality of life by providing treatments that offer minimal long-term toxicity, good tolerability, and perhaps most important, good patient satisfaction.

Selecting treatment can be challenging and cannot be done without a multidisciplinary decision. The two main pathways are a surgery-based or radiotherapy-based treatment, but within each there are multiple options and combinations that need careful consideration on a case-by-case basis.

“It’s not a cookbook decision,” agreed Dr. Jan B. Vermorken, emeritus professor of oncology at Antwerp University Hospital, Belgium, who discussed the systemic treatment of head and neck cancer in a separate lecture. He agreed that head and neck cancer treatment is a multidisciplinary challenge that needs to balance the efficacy and tolerability of treatment on an individual basis, and always while considering the patient’s preferences.

“Patients can be very well informed,” Dr. Vermorken noted and suggested that clinicians need to be prepared to help patients understand the information that they find themselves in order to be able to counter any misinformation they might have found.

“There is no treatment without side effects,” Dr. Vermorken stressed. “When there are no side effects, [the treatment] doesn’t work. So you have to warn patients there are always side effects of the treatment they will be given.”

In addition to the importance of the multidisciplinary team in the management of head and neck cancer, understanding the biology of the disease and using systemic treatment are important for treatment, he said. Recent advances in this area include the recognition of the human papillomavirus as a risk factor for and strong predictor of survival in oropharyngeal cancer, and the role of epidermal growth factor receptor to enable targeting with anti-EGFR drugs, such as cetuximab (Erbitux). Systemic treatment for locally advanced disease includes concurrent chemoradiotherapy (CCRT), bioradiotherapy (BRT) with cetuximab and sequential chemotherapy (induction chemotherapy followed by CCRT or BRT).

In most cases of locally advanced SCCHN, the recommended chemotherapy of choice is high-dose cisplatin, given every 3 weeks. Although alternatives to this have been proposed – such as lowering the dose of cisplatin or using carboplatin or cetuximab instead – they have been insufficiently studied and many questions remain unanswered at the moment.

As for the treatment of recurrent or metastatic SCCHN, if it is resectable, then this would be followed by radiotherapy or CCRT. In patients deemed fit enough to handle the regimen, a combination of a platinum agent, 5-fluorouracil (5-FU) and cetuximab) is a new standard first-line regimen, although the role of maintenance cetuximab is unclear.

Better chemotherapy partners for cetuximab or alternatives for anti-EGFR–targeting agents are under investigation. This includes using docetaxel (Taxotere) instead of 5-FU with cetuximab or using lapatinib (Tykerb), afatinib (Gilotrif) or dacomitinib to block multiple human epidermal growth factor receptors or a variety of monoclonal antibodies to try to overcome resistance to anti-EGFR drugs.

Reactivation of immune surveillance by blocking the PD-1 pathway with drugs such as nivolumab (Opdivo) and pembrolizumab (Keytruda) seems to be a promising approach for treating head and neck cancer and is under investigation in other tumors, including non–small cell lung cancer, triple-negative breast cancer, and melanoma, Dr. Vermorken said.Dr. Lefebvre has acted as a consultant to Merck Serono and Sanofi. Dr. Vermorken has participated in advisory boards of AstraZeneca; Boehringer Ingelheim; Debiopharm; Genentech; Merck Serono; Merck, Sharp & Dohme; Oncolytics Biotech; Pierre Fabre; and Vaccinogen; and received lecturer fees from Merck Serono.

PARIS – Although survival remains relatively poor, the options for the management of metastatic, recurrent, or persistent cervical cancer have increased in recent years, with bevacizumab-enhanced, platinum-based, combination chemotherapy becoming the “new standard” for many women according to medical oncologist Isabelle Ray-Coquard.

Speaking at a recent international conference on anticancer treatment, Dr. Ray-Coquard of Centre Léon Bérard in Lyon, France, noted that there are several questions that the medical oncologists must address before prescribing treatment. These are: Would the patient benefit from chemotherapy and if so, should a single-agent or a combination be used? Is the patient a candidate for a new or novel agent? Or would palliative care be the best option? How can patients best be selected for treatment?

“We have some strong data to support the use of cisplatin first line,” she observed. “Cisplatin is probably the first actor in the management of cervix cancer.” Response rates using single-agent cisplatin have ranged from 18% to 25% in women with recurrent and advanced carcinoma of the cervix.

“The question is what is the best partner for cisplatin?” Dr. Ray-Coquard asked. She highlighted several studies showing the activity of other cytotoxic chemotherapies as single agents, with the highest responses seen with paclitaxel (Taxol, at 19% of patients), followed by vinorelbine (Navelbine, 18%), irinotecan (Campto, 17%), topotecan (Hycamtin, 16%), docetaxel (Taxotere, 13%), and the lowest with gemcitabine (Gemzar, 8%).

Both paclitaxel and topotecan have been studied in combination with cisplatin vs. cisplatin alone and been shown to confer survival benefits. In the Gynecologic Oncology Group (GOG) 169 study (J. Clin. Oncol. 2004;22:3113-9), for example, paclitaxel plus cisplatin was associated with a significant (P < .001) increase in progression-free survival (PFS) of 4.8 vs. 2.8 months, although overall survival (OS) was not statistically different (9.7 vs. 8.8 months). Dr. Ray-Coquard noted, however, that paclitaxel had been given to women randomized to cisplatin at relapse, which might have clouded the OS benefit.

Similar benefits were seen when topotecan and cisplatin were combined and compared against single agent cisplatin in the GOG 179 study (J. Clin. Oncol. 2005;23:4626-33), with median PFS of 4.6 vs 2.9 months (P = .014) and median OS of 9.4 and 6.5 months (P = .017).

The toxicity of combining chemotherapies is important, and looking at the combination of topotecan and cisplatin vs. cisplatin alone in the GOG 179 study, Dr. Ray-Coquard noted that grade 3 & 4 side effects such as neutropenia, thrombocytopenia, nausea, and vomiting occurred much more frequently.

Data from the GOG 204 study (J. Clin. Oncol. 2009;27:4649-55) suggested that both paclitaxel and topotecan were good partners for cisplatin, with perhaps an advantage for paclitaxel. The latter combination can be inconvenient for patients, however, as it requires infusion of paclitaxel over 24 hours and hydration is required to prevent renal toxicity associated with the cisplatin. The combination is also quite toxic and hasn’t been shown to significantly relieve pain or to improve quality of life.

Phase II trial findings (Gynecol. Oncol. 2012;125:307-11) suggest that carboplatin might be an effective and less toxic alternative to cisplatin in combination with paclitaxel. There may also be a slight advantage of using carboplatin in patients who have already received prior platinum therapy but not in those who have not received cisplatin before.

“If we want to increase the overall survival, we need to also explore new compounds,” Dr. Ray-Coquard said. Drugs targeting the human epidermal growth factor receptor (HER) and angiogenesis have been tested, with lapatinib (Tykerb) and pazopanib (Votrient) found to be too toxic to use in combination but perhaps have an effect on survival when used alone. Cediranib (tentative trade name Recentin) in combination with paclitaxel and cisplatin also improved PFS in a phase II trial.

The best evidence in support of using targeted therapy to date is for bevacizumab. Using bevacizumab in combination with platinum-based combination chemotherapy is supported by the positive findings of the GOG 240 study (N. Engl. J. Med. 2014;370:734-43). This trial tested two hypotheses: first, if a nonplatinum chemotherapy doublet of paclitaxel and topotecan (Hycamtin) would be better than a platinum-based couplet (cisplatin plus paclitaxel); second if receiving additional antiangiogenic therapy with bevacizumab (Avastin) would confer any benefit over these combined chemotherapy regimens.

The results showed that combining topotecan with paclitaxel was not superior to cisplatin plus paclitaxel. When bevacizumab was combined with chemotherapy, however, there were PFS and OS benefits. Bevacizumab conferred an almost 4-month gain in OS, Dr. Ray-Coquard said.

Several factors including age, performance status, and previous treatment and toxicities need to be considered when selecting this or other treatment, she explained in an interview.

Women who have a very poor (≥ 2) performance status or who are symptomatic may not be suitable for the bevacizumab-enhanced therapy, as they may not be able to tolerate the toxicities associated with this regimen.

Notable toxicities reported with the regimen in the GOG 240 study included gastrointestinal fistula and perforation, neutropenia, including febrile neutropenia, hypertension, thrombosis and an increased risk for bleeding in the GI tract.

Understandably, care needs to be taken when considering this regimen for women who may have residual toxicity from other treatments, such as enteritis or cystitis caused by radiotherapy, and those with bowel, bladder, or vaginal involvement.

Women with vaginal bleeding or renal impairment may also not be able to tolerate combined antiangiogenic and chemotherapeutic treatment very well, and women with uncontrolled hypertension might not be good candidates.

Perhaps some of these women could still receive platinum-based chemotherapy without the bevacizumab, but, unfortunately, there will still be women for whom best supportive or palliative care may be the only option, Dr. Ray-Coquard said.

Dr. Ray-Coquard has served on advisory boards convened by Roche and AstraZeneca.

PARIS – Although survival remains relatively poor, the options for the management of metastatic, recurrent, or persistent cervical cancer have increased in recent years, with bevacizumab-enhanced, platinum-based, combination chemotherapy becoming the “new standard” for many women according to medical oncologist Isabelle Ray-Coquard.

Speaking at a recent international conference on anticancer treatment, Dr. Ray-Coquard of Centre Léon Bérard in Lyon, France, noted that there are several questions that the medical oncologists must address before prescribing treatment. These are: Would the patient benefit from chemotherapy and if so, should a single-agent or a combination be used? Is the patient a candidate for a new or novel agent? Or would palliative care be the best option? How can patients best be selected for treatment?

“We have some strong data to support the use of cisplatin first line,” she observed. “Cisplatin is probably the first actor in the management of cervix cancer.” Response rates using single-agent cisplatin have ranged from 18% to 25% in women with recurrent and advanced carcinoma of the cervix.

“The question is what is the best partner for cisplatin?” Dr. Ray-Coquard asked. She highlighted several studies showing the activity of other cytotoxic chemotherapies as single agents, with the highest responses seen with paclitaxel (Taxol, at 19% of patients), followed by vinorelbine (Navelbine, 18%), irinotecan (Campto, 17%), topotecan (Hycamtin, 16%), docetaxel (Taxotere, 13%), and the lowest with gemcitabine (Gemzar, 8%).

Both paclitaxel and topotecan have been studied in combination with cisplatin vs. cisplatin alone and been shown to confer survival benefits. In the Gynecologic Oncology Group (GOG) 169 study (J. Clin. Oncol. 2004;22:3113-9), for example, paclitaxel plus cisplatin was associated with a significant (P < .001) increase in progression-free survival (PFS) of 4.8 vs. 2.8 months, although overall survival (OS) was not statistically different (9.7 vs. 8.8 months). Dr. Ray-Coquard noted, however, that paclitaxel had been given to women randomized to cisplatin at relapse, which might have clouded the OS benefit.

Similar benefits were seen when topotecan and cisplatin were combined and compared against single agent cisplatin in the GOG 179 study (J. Clin. Oncol. 2005;23:4626-33), with median PFS of 4.6 vs 2.9 months (P = .014) and median OS of 9.4 and 6.5 months (P = .017).

The toxicity of combining chemotherapies is important, and looking at the combination of topotecan and cisplatin vs. cisplatin alone in the GOG 179 study, Dr. Ray-Coquard noted that grade 3 & 4 side effects such as neutropenia, thrombocytopenia, nausea, and vomiting occurred much more frequently.

Data from the GOG 204 study (J. Clin. Oncol. 2009;27:4649-55) suggested that both paclitaxel and topotecan were good partners for cisplatin, with perhaps an advantage for paclitaxel. The latter combination can be inconvenient for patients, however, as it requires infusion of paclitaxel over 24 hours and hydration is required to prevent renal toxicity associated with the cisplatin. The combination is also quite toxic and hasn’t been shown to significantly relieve pain or to improve quality of life.

Phase II trial findings (Gynecol. Oncol. 2012;125:307-11) suggest that carboplatin might be an effective and less toxic alternative to cisplatin in combination with paclitaxel. There may also be a slight advantage of using carboplatin in patients who have already received prior platinum therapy but not in those who have not received cisplatin before.

“If we want to increase the overall survival, we need to also explore new compounds,” Dr. Ray-Coquard said. Drugs targeting the human epidermal growth factor receptor (HER) and angiogenesis have been tested, with lapatinib (Tykerb) and pazopanib (Votrient) found to be too toxic to use in combination but perhaps have an effect on survival when used alone. Cediranib (tentative trade name Recentin) in combination with paclitaxel and cisplatin also improved PFS in a phase II trial.

The best evidence in support of using targeted therapy to date is for bevacizumab. Using bevacizumab in combination with platinum-based combination chemotherapy is supported by the positive findings of the GOG 240 study (N. Engl. J. Med. 2014;370:734-43). This trial tested two hypotheses: first, if a nonplatinum chemotherapy doublet of paclitaxel and topotecan (Hycamtin) would be better than a platinum-based couplet (cisplatin plus paclitaxel); second if receiving additional antiangiogenic therapy with bevacizumab (Avastin) would confer any benefit over these combined chemotherapy regimens.

The results showed that combining topotecan with paclitaxel was not superior to cisplatin plus paclitaxel. When bevacizumab was combined with chemotherapy, however, there were PFS and OS benefits. Bevacizumab conferred an almost 4-month gain in OS, Dr. Ray-Coquard said.

Several factors including age, performance status, and previous treatment and toxicities need to be considered when selecting this or other treatment, she explained in an interview.

Women who have a very poor (≥ 2) performance status or who are symptomatic may not be suitable for the bevacizumab-enhanced therapy, as they may not be able to tolerate the toxicities associated with this regimen.

Notable toxicities reported with the regimen in the GOG 240 study included gastrointestinal fistula and perforation, neutropenia, including febrile neutropenia, hypertension, thrombosis and an increased risk for bleeding in the GI tract.

Understandably, care needs to be taken when considering this regimen for women who may have residual toxicity from other treatments, such as enteritis or cystitis caused by radiotherapy, and those with bowel, bladder, or vaginal involvement.

Women with vaginal bleeding or renal impairment may also not be able to tolerate combined antiangiogenic and chemotherapeutic treatment very well, and women with uncontrolled hypertension might not be good candidates.

Perhaps some of these women could still receive platinum-based chemotherapy without the bevacizumab, but, unfortunately, there will still be women for whom best supportive or palliative care may be the only option, Dr. Ray-Coquard said.

Dr. Ray-Coquard has served on advisory boards convened by Roche and AstraZeneca.

PARIS – Although survival remains relatively poor, the options for the management of metastatic, recurrent, or persistent cervical cancer have increased in recent years, with bevacizumab-enhanced, platinum-based, combination chemotherapy becoming the “new standard” for many women according to medical oncologist Isabelle Ray-Coquard.

Speaking at a recent international conference on anticancer treatment, Dr. Ray-Coquard of Centre Léon Bérard in Lyon, France, noted that there are several questions that the medical oncologists must address before prescribing treatment. These are: Would the patient benefit from chemotherapy and if so, should a single-agent or a combination be used? Is the patient a candidate for a new or novel agent? Or would palliative care be the best option? How can patients best be selected for treatment?

“We have some strong data to support the use of cisplatin first line,” she observed. “Cisplatin is probably the first actor in the management of cervix cancer.” Response rates using single-agent cisplatin have ranged from 18% to 25% in women with recurrent and advanced carcinoma of the cervix.

“The question is what is the best partner for cisplatin?” Dr. Ray-Coquard asked. She highlighted several studies showing the activity of other cytotoxic chemotherapies as single agents, with the highest responses seen with paclitaxel (Taxol, at 19% of patients), followed by vinorelbine (Navelbine, 18%), irinotecan (Campto, 17%), topotecan (Hycamtin, 16%), docetaxel (Taxotere, 13%), and the lowest with gemcitabine (Gemzar, 8%).

Both paclitaxel and topotecan have been studied in combination with cisplatin vs. cisplatin alone and been shown to confer survival benefits. In the Gynecologic Oncology Group (GOG) 169 study (J. Clin. Oncol. 2004;22:3113-9), for example, paclitaxel plus cisplatin was associated with a significant (P < .001) increase in progression-free survival (PFS) of 4.8 vs. 2.8 months, although overall survival (OS) was not statistically different (9.7 vs. 8.8 months). Dr. Ray-Coquard noted, however, that paclitaxel had been given to women randomized to cisplatin at relapse, which might have clouded the OS benefit.

Similar benefits were seen when topotecan and cisplatin were combined and compared against single agent cisplatin in the GOG 179 study (J. Clin. Oncol. 2005;23:4626-33), with median PFS of 4.6 vs 2.9 months (P = .014) and median OS of 9.4 and 6.5 months (P = .017).

The toxicity of combining chemotherapies is important, and looking at the combination of topotecan and cisplatin vs. cisplatin alone in the GOG 179 study, Dr. Ray-Coquard noted that grade 3 & 4 side effects such as neutropenia, thrombocytopenia, nausea, and vomiting occurred much more frequently.

Data from the GOG 204 study (J. Clin. Oncol. 2009;27:4649-55) suggested that both paclitaxel and topotecan were good partners for cisplatin, with perhaps an advantage for paclitaxel. The latter combination can be inconvenient for patients, however, as it requires infusion of paclitaxel over 24 hours and hydration is required to prevent renal toxicity associated with the cisplatin. The combination is also quite toxic and hasn’t been shown to significantly relieve pain or to improve quality of life.

Phase II trial findings (Gynecol. Oncol. 2012;125:307-11) suggest that carboplatin might be an effective and less toxic alternative to cisplatin in combination with paclitaxel. There may also be a slight advantage of using carboplatin in patients who have already received prior platinum therapy but not in those who have not received cisplatin before.

“If we want to increase the overall survival, we need to also explore new compounds,” Dr. Ray-Coquard said. Drugs targeting the human epidermal growth factor receptor (HER) and angiogenesis have been tested, with lapatinib (Tykerb) and pazopanib (Votrient) found to be too toxic to use in combination but perhaps have an effect on survival when used alone. Cediranib (tentative trade name Recentin) in combination with paclitaxel and cisplatin also improved PFS in a phase II trial.

The best evidence in support of using targeted therapy to date is for bevacizumab. Using bevacizumab in combination with platinum-based combination chemotherapy is supported by the positive findings of the GOG 240 study (N. Engl. J. Med. 2014;370:734-43). This trial tested two hypotheses: first, if a nonplatinum chemotherapy doublet of paclitaxel and topotecan (Hycamtin) would be better than a platinum-based couplet (cisplatin plus paclitaxel); second if receiving additional antiangiogenic therapy with bevacizumab (Avastin) would confer any benefit over these combined chemotherapy regimens.

The results showed that combining topotecan with paclitaxel was not superior to cisplatin plus paclitaxel. When bevacizumab was combined with chemotherapy, however, there were PFS and OS benefits. Bevacizumab conferred an almost 4-month gain in OS, Dr. Ray-Coquard said.

Several factors including age, performance status, and previous treatment and toxicities need to be considered when selecting this or other treatment, she explained in an interview.

Women who have a very poor (≥ 2) performance status or who are symptomatic may not be suitable for the bevacizumab-enhanced therapy, as they may not be able to tolerate the toxicities associated with this regimen.

Notable toxicities reported with the regimen in the GOG 240 study included gastrointestinal fistula and perforation, neutropenia, including febrile neutropenia, hypertension, thrombosis and an increased risk for bleeding in the GI tract.

Understandably, care needs to be taken when considering this regimen for women who may have residual toxicity from other treatments, such as enteritis or cystitis caused by radiotherapy, and those with bowel, bladder, or vaginal involvement.

Women with vaginal bleeding or renal impairment may also not be able to tolerate combined antiangiogenic and chemotherapeutic treatment very well, and women with uncontrolled hypertension might not be good candidates.

Perhaps some of these women could still receive platinum-based chemotherapy without the bevacizumab, but, unfortunately, there will still be women for whom best supportive or palliative care may be the only option, Dr. Ray-Coquard said.

Dr. Ray-Coquard has served on advisory boards convened by Roche and AstraZeneca.