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Mitchel is a reporter for MDedge based in the Philadelphia area. He started with the company in 1992, when it was International Medical News Group (IMNG), and has since covered a range of medical specialties. Mitchel trained as a virologist at Roswell Park Memorial Institute in Buffalo, and then worked briefly as a researcher at Boston Children's Hospital before pivoting to journalism as a AAAS Mass Media Fellow in 1980. His first reporting job was with Science Digest magazine, and from the mid-1980s to early-1990s he was a reporter with Medical World News. @mitchelzoler
Oral oligonucleotide shows efficacy, safety in Crohn’s
VIENNA – Fourteen days of daily treatment with mongersen, an oral, antisense oligonucleotide, safely produced remissions in two-thirds of patients with Crohn’s disease in a phase II study with a total of 163 patients.
The responses were also durable, with patients in remission continuing to show low disease activity at 10 weeks after they received their last dose of mongersen, Dr. Giovanni Monteleone reported at he United European Gastroenterology Global Congress.
The durability of patient response was not a surprise as similar findings occurred during phase I testing, he said. Mongensen “is not an anti-inflammatory drug. It removes a brake on the normal immunosupressant mechanism in the gut, and that is why the effect is long lasting. It allows TGF [transforming growth factor]-beta to work again [as an endogenous immunosuppressant] and promote healing,” said Dr. Monteleone, a professor of gastroenterology at the University of Rome Tor Vergata.
Dr. Silvio Danese, director of the IBD center at the Humanitis Research Hospital in Milan, said he was impressed by the frequent, durable, and apparently safe remissions achieved by mongensen treatment. “If the phase III studies show efficacy, mongersen will probably be a game changer” for treating inflammatory bowel disease, he commented.
Dr. Monteleone traced development on mongensen to work he published 13 years ago, which showed that oligonucleotide blockade of the production of the Smad7 intracellular protein prevented the inhibitory effect of Smad7 on TGF-beta and thus allowed TGF-beta to inhibit cytokine production and T lymphocyte signaling (J. Clin. Invest. 2001;108:601-9). His work also showed that patients with inflammatory bowel disease have elevated Smad7 levels in their intestinal mucosa, suggesting the potential for therapeutically cutting Smad7 levels in the gut of patients with inflammatory bowel disease.
The study he reported at the meeting included 163 patients with active Crohn’s disease at about a dozen hospitals in Italy. Patients had a Crohn’s disease activity index (CDAI) score of 221-400, were steroid dependent, steroid resistant, or both, and had documented lesions in their terminal ileum, right colon, or both. Patients randomized to active treatment received a daily pill for 14 days with one of three dosages of mongersen formulated into a tablet with a pH dependent coating designed to release the drug in the terminal ileum and right colon and avoid systemic absorption. The researchers then followed patients for an additional 70 days during which they received usual care but no additional treatment with mongersen or placebo.
The study’s primary endpoint was the frequency of remission, designed as a CDAI score of less than 150 on day 15 (the day after their last investigational dose) that was then maintained through day 28 of the study. This endpoint occurred in 65% of the 43 patients who received the highest mongersen dosage, 160 mg/day, in 55% of patients who received 40 mg/day of mongersen, in 12% of patients who received 10 mg/day of mongersen, and in 10% of placebo patients. The differences were statistically significant for the two highest drug dosages.
At 84 days into the study, 10 weeks after receiving their final dosage of mongersen, the rate of patients who were given the highest dosage and continued to have a CDAI of less than 150 stood at 67%, Dr. Monteleone reported. An additional analysis focused on the 61% of patients who entered the study with a C-reactive protein level greater than 3 mg/L. Within this subgroup, 68% of patients who received the highest mongersen dosage achieved remission compared with 12% of patients who received placebo, a statistically significant difference.
The safety analysis showed that mongersen was safe and well tolerated, with low rates of total and serious adverse events that were similar across all four treatment arms. Patient follow-up also showed no clinically meaningful changes in laboratory values, vital signs, physical findings, or strictures.
Celgene has stated that it will proceed into phase III testing of mongersen.
The study was sponsored by Nogra, and then subsequently by Celgene which acquired a license for morgensen from Nogra. Dr. Monteleone has received research support from Nogra and from several other companies and has been a speaker on behalf of AbbVie and Zambon. Dr. Danese has been a consultant to several drug companies.
On Twitter @mitchelzoler
VIENNA – Fourteen days of daily treatment with mongersen, an oral, antisense oligonucleotide, safely produced remissions in two-thirds of patients with Crohn’s disease in a phase II study with a total of 163 patients.
The responses were also durable, with patients in remission continuing to show low disease activity at 10 weeks after they received their last dose of mongersen, Dr. Giovanni Monteleone reported at he United European Gastroenterology Global Congress.
The durability of patient response was not a surprise as similar findings occurred during phase I testing, he said. Mongensen “is not an anti-inflammatory drug. It removes a brake on the normal immunosupressant mechanism in the gut, and that is why the effect is long lasting. It allows TGF [transforming growth factor]-beta to work again [as an endogenous immunosuppressant] and promote healing,” said Dr. Monteleone, a professor of gastroenterology at the University of Rome Tor Vergata.
Dr. Silvio Danese, director of the IBD center at the Humanitis Research Hospital in Milan, said he was impressed by the frequent, durable, and apparently safe remissions achieved by mongensen treatment. “If the phase III studies show efficacy, mongersen will probably be a game changer” for treating inflammatory bowel disease, he commented.
Dr. Monteleone traced development on mongensen to work he published 13 years ago, which showed that oligonucleotide blockade of the production of the Smad7 intracellular protein prevented the inhibitory effect of Smad7 on TGF-beta and thus allowed TGF-beta to inhibit cytokine production and T lymphocyte signaling (J. Clin. Invest. 2001;108:601-9). His work also showed that patients with inflammatory bowel disease have elevated Smad7 levels in their intestinal mucosa, suggesting the potential for therapeutically cutting Smad7 levels in the gut of patients with inflammatory bowel disease.
The study he reported at the meeting included 163 patients with active Crohn’s disease at about a dozen hospitals in Italy. Patients had a Crohn’s disease activity index (CDAI) score of 221-400, were steroid dependent, steroid resistant, or both, and had documented lesions in their terminal ileum, right colon, or both. Patients randomized to active treatment received a daily pill for 14 days with one of three dosages of mongersen formulated into a tablet with a pH dependent coating designed to release the drug in the terminal ileum and right colon and avoid systemic absorption. The researchers then followed patients for an additional 70 days during which they received usual care but no additional treatment with mongersen or placebo.
The study’s primary endpoint was the frequency of remission, designed as a CDAI score of less than 150 on day 15 (the day after their last investigational dose) that was then maintained through day 28 of the study. This endpoint occurred in 65% of the 43 patients who received the highest mongersen dosage, 160 mg/day, in 55% of patients who received 40 mg/day of mongersen, in 12% of patients who received 10 mg/day of mongersen, and in 10% of placebo patients. The differences were statistically significant for the two highest drug dosages.
At 84 days into the study, 10 weeks after receiving their final dosage of mongersen, the rate of patients who were given the highest dosage and continued to have a CDAI of less than 150 stood at 67%, Dr. Monteleone reported. An additional analysis focused on the 61% of patients who entered the study with a C-reactive protein level greater than 3 mg/L. Within this subgroup, 68% of patients who received the highest mongersen dosage achieved remission compared with 12% of patients who received placebo, a statistically significant difference.
The safety analysis showed that mongersen was safe and well tolerated, with low rates of total and serious adverse events that were similar across all four treatment arms. Patient follow-up also showed no clinically meaningful changes in laboratory values, vital signs, physical findings, or strictures.
Celgene has stated that it will proceed into phase III testing of mongersen.
The study was sponsored by Nogra, and then subsequently by Celgene which acquired a license for morgensen from Nogra. Dr. Monteleone has received research support from Nogra and from several other companies and has been a speaker on behalf of AbbVie and Zambon. Dr. Danese has been a consultant to several drug companies.
On Twitter @mitchelzoler
VIENNA – Fourteen days of daily treatment with mongersen, an oral, antisense oligonucleotide, safely produced remissions in two-thirds of patients with Crohn’s disease in a phase II study with a total of 163 patients.
The responses were also durable, with patients in remission continuing to show low disease activity at 10 weeks after they received their last dose of mongersen, Dr. Giovanni Monteleone reported at he United European Gastroenterology Global Congress.
The durability of patient response was not a surprise as similar findings occurred during phase I testing, he said. Mongensen “is not an anti-inflammatory drug. It removes a brake on the normal immunosupressant mechanism in the gut, and that is why the effect is long lasting. It allows TGF [transforming growth factor]-beta to work again [as an endogenous immunosuppressant] and promote healing,” said Dr. Monteleone, a professor of gastroenterology at the University of Rome Tor Vergata.
Dr. Silvio Danese, director of the IBD center at the Humanitis Research Hospital in Milan, said he was impressed by the frequent, durable, and apparently safe remissions achieved by mongensen treatment. “If the phase III studies show efficacy, mongersen will probably be a game changer” for treating inflammatory bowel disease, he commented.
Dr. Monteleone traced development on mongensen to work he published 13 years ago, which showed that oligonucleotide blockade of the production of the Smad7 intracellular protein prevented the inhibitory effect of Smad7 on TGF-beta and thus allowed TGF-beta to inhibit cytokine production and T lymphocyte signaling (J. Clin. Invest. 2001;108:601-9). His work also showed that patients with inflammatory bowel disease have elevated Smad7 levels in their intestinal mucosa, suggesting the potential for therapeutically cutting Smad7 levels in the gut of patients with inflammatory bowel disease.
The study he reported at the meeting included 163 patients with active Crohn’s disease at about a dozen hospitals in Italy. Patients had a Crohn’s disease activity index (CDAI) score of 221-400, were steroid dependent, steroid resistant, or both, and had documented lesions in their terminal ileum, right colon, or both. Patients randomized to active treatment received a daily pill for 14 days with one of three dosages of mongersen formulated into a tablet with a pH dependent coating designed to release the drug in the terminal ileum and right colon and avoid systemic absorption. The researchers then followed patients for an additional 70 days during which they received usual care but no additional treatment with mongersen or placebo.
The study’s primary endpoint was the frequency of remission, designed as a CDAI score of less than 150 on day 15 (the day after their last investigational dose) that was then maintained through day 28 of the study. This endpoint occurred in 65% of the 43 patients who received the highest mongersen dosage, 160 mg/day, in 55% of patients who received 40 mg/day of mongersen, in 12% of patients who received 10 mg/day of mongersen, and in 10% of placebo patients. The differences were statistically significant for the two highest drug dosages.
At 84 days into the study, 10 weeks after receiving their final dosage of mongersen, the rate of patients who were given the highest dosage and continued to have a CDAI of less than 150 stood at 67%, Dr. Monteleone reported. An additional analysis focused on the 61% of patients who entered the study with a C-reactive protein level greater than 3 mg/L. Within this subgroup, 68% of patients who received the highest mongersen dosage achieved remission compared with 12% of patients who received placebo, a statistically significant difference.
The safety analysis showed that mongersen was safe and well tolerated, with low rates of total and serious adverse events that were similar across all four treatment arms. Patient follow-up also showed no clinically meaningful changes in laboratory values, vital signs, physical findings, or strictures.
Celgene has stated that it will proceed into phase III testing of mongersen.
The study was sponsored by Nogra, and then subsequently by Celgene which acquired a license for morgensen from Nogra. Dr. Monteleone has received research support from Nogra and from several other companies and has been a speaker on behalf of AbbVie and Zambon. Dr. Danese has been a consultant to several drug companies.
On Twitter @mitchelzoler
AT UEG WEEK VIENNA 2014
Key clinical point: Mongersen may prove to be an effective oral therapy that can be used on a short-term basis to produce durable remissions in Crohn’s.
Major finding: Two weeks of oral treatment with mongersen produced remissions in 65% of Crohn’s disease patients while the remission rate was 10% in placebo-treated controls.
Data source: A multicenter, placebo-controlled phase II study that included 163 patients.
Disclosures: The study was sponsored by Nogra, and then subsequently by Celgene which acquired a license for morgensen from Nogra. Dr. Monteleone has received research support from Nogra and from several other companies and has been a speaker on behalf of AbbVie and Zambon. Dr. Danese has been a consultant to several drug companies.
Psoriasiform lesions linked to anti-TNF treatment
VIENNA – Patients treated with an anti–tumor necrosis factor drug had a 5% annual rate of developing one or more psoriasiform skin lesions in a review of more than 400 patients who received these drugs to treat inflammatory bowel disease at a single center in Rome.
The cohort review confirmed prior reports that smoking is a risk factor for the appearance of psoriasislike skin lesions on patients being treated with an anti–tumor necrosis factor (TNF) drug, such as infliximab (Remicade) or adalimumab (Humira). The Rome experience also showed that in 28 of the 42 patients who developed a psoriasiform lesion, the eruption responded to topical treatment without need to stop or change the anti-TNF regimen. Ten of the 42 patients ultimately had to stop their anti-TNF regimen, Dr. Daniela Pugliese said at the United European Gastroenterology Global Congress.
“There have been several case reports of this, but this is the largest cohort review yet reported by one center,” said Dr. Pugliese, a gastroenterologist in the inflammatory bowel disease (IBD) unit of Complesso Integrato Columbus, Catholic University in Rome.
The review included 402 patients treated with an anti-TNF drug at the unit during 2008-2013, with a median follow-up of 17 months. During follow-up, 42 patients developed a psoriasiform lesion with a biopsy-proven diagnosis, a rate of 5 cases/100 person-years on anti-TNF treatment. The IBD patients averaged 40 years old, and 60% had Crohn’s disease and 40% had ulcerative colitis. About 60% received infliximab treatment, and 40% adalimumab. Most lesions appeared in predilection sites, as well as on palmoplantar surfaces or on the scalp; nearly half the patients had lesions in two or more locations.
A multivariate regression analysis that assessed several demographic and clinical features of all 402 patients identified two parameters that significantly linked with lesion development. Smoking linked with a greater than twofold increased risk for having a psoriasiform lesion (78 of the patients, 19%, smoked), and concurrent treatment with a thiopurine such as azathioprine, linked with a 67% reduced rate of lesion development (85 patients, 21%, were on concurrent thiopurine treatment). All IBD patients seen at the Rome unit who smoked were counseled regarding smoking cessation, Dr. Pugliese said in an interview.
Among the patients who did not respond to topical treatment, four received some benefit from starting treatment with ustekinumab (Stelara), which especially benefited patients who were otherwise difficult to treat, Dr. Pugliese said. Other patients benefited from starting treatment with cyclosporine, methotrexate, or a transient treatment with an oral steroid. Two patients who developed lesions on infliximab switched to adalimumab, and two other patients who had lesions on adalimumab switched to infliximab.
Dr. Pugliese and her associates did not have a good explanation of why patients on anti-TNF drugs develop these lesions, which Dr. Pugliese called “paradoxical.” One possible etiology is that inhibition of TNF-alpha results in uncontrolled production of interferon-alpha by plasmacytoid dendritic cells and this then triggers the psoriasiform eruptions.
A key element in managing these lesions may be early detection and topical treatment while they remain small, commented Dr. C. Janneke van der Woude, head of the IBD unit at Erasmus University Medical Center in Rotterdam, the Netherlands. “Every time we see an IBD patient who is on an anti-TNF drug, we ask whether they have had any itching, allergic reaction, arthritis, eye problem, or headache,” to facilitate early detection of an adverse effect from treatment, she said in an interview.
Dr. Pugliese had no disclosures. Dr. van der Woude said that she has been an adviser to Dr Falk, AbbVie, Janssen, Johnson & Johnson, and Cosmo.
On Twitter@mitchelzoler
VIENNA – Patients treated with an anti–tumor necrosis factor drug had a 5% annual rate of developing one or more psoriasiform skin lesions in a review of more than 400 patients who received these drugs to treat inflammatory bowel disease at a single center in Rome.
The cohort review confirmed prior reports that smoking is a risk factor for the appearance of psoriasislike skin lesions on patients being treated with an anti–tumor necrosis factor (TNF) drug, such as infliximab (Remicade) or adalimumab (Humira). The Rome experience also showed that in 28 of the 42 patients who developed a psoriasiform lesion, the eruption responded to topical treatment without need to stop or change the anti-TNF regimen. Ten of the 42 patients ultimately had to stop their anti-TNF regimen, Dr. Daniela Pugliese said at the United European Gastroenterology Global Congress.
“There have been several case reports of this, but this is the largest cohort review yet reported by one center,” said Dr. Pugliese, a gastroenterologist in the inflammatory bowel disease (IBD) unit of Complesso Integrato Columbus, Catholic University in Rome.
The review included 402 patients treated with an anti-TNF drug at the unit during 2008-2013, with a median follow-up of 17 months. During follow-up, 42 patients developed a psoriasiform lesion with a biopsy-proven diagnosis, a rate of 5 cases/100 person-years on anti-TNF treatment. The IBD patients averaged 40 years old, and 60% had Crohn’s disease and 40% had ulcerative colitis. About 60% received infliximab treatment, and 40% adalimumab. Most lesions appeared in predilection sites, as well as on palmoplantar surfaces or on the scalp; nearly half the patients had lesions in two or more locations.
A multivariate regression analysis that assessed several demographic and clinical features of all 402 patients identified two parameters that significantly linked with lesion development. Smoking linked with a greater than twofold increased risk for having a psoriasiform lesion (78 of the patients, 19%, smoked), and concurrent treatment with a thiopurine such as azathioprine, linked with a 67% reduced rate of lesion development (85 patients, 21%, were on concurrent thiopurine treatment). All IBD patients seen at the Rome unit who smoked were counseled regarding smoking cessation, Dr. Pugliese said in an interview.
Among the patients who did not respond to topical treatment, four received some benefit from starting treatment with ustekinumab (Stelara), which especially benefited patients who were otherwise difficult to treat, Dr. Pugliese said. Other patients benefited from starting treatment with cyclosporine, methotrexate, or a transient treatment with an oral steroid. Two patients who developed lesions on infliximab switched to adalimumab, and two other patients who had lesions on adalimumab switched to infliximab.
Dr. Pugliese and her associates did not have a good explanation of why patients on anti-TNF drugs develop these lesions, which Dr. Pugliese called “paradoxical.” One possible etiology is that inhibition of TNF-alpha results in uncontrolled production of interferon-alpha by plasmacytoid dendritic cells and this then triggers the psoriasiform eruptions.
A key element in managing these lesions may be early detection and topical treatment while they remain small, commented Dr. C. Janneke van der Woude, head of the IBD unit at Erasmus University Medical Center in Rotterdam, the Netherlands. “Every time we see an IBD patient who is on an anti-TNF drug, we ask whether they have had any itching, allergic reaction, arthritis, eye problem, or headache,” to facilitate early detection of an adverse effect from treatment, she said in an interview.
Dr. Pugliese had no disclosures. Dr. van der Woude said that she has been an adviser to Dr Falk, AbbVie, Janssen, Johnson & Johnson, and Cosmo.
On Twitter@mitchelzoler
VIENNA – Patients treated with an anti–tumor necrosis factor drug had a 5% annual rate of developing one or more psoriasiform skin lesions in a review of more than 400 patients who received these drugs to treat inflammatory bowel disease at a single center in Rome.
The cohort review confirmed prior reports that smoking is a risk factor for the appearance of psoriasislike skin lesions on patients being treated with an anti–tumor necrosis factor (TNF) drug, such as infliximab (Remicade) or adalimumab (Humira). The Rome experience also showed that in 28 of the 42 patients who developed a psoriasiform lesion, the eruption responded to topical treatment without need to stop or change the anti-TNF regimen. Ten of the 42 patients ultimately had to stop their anti-TNF regimen, Dr. Daniela Pugliese said at the United European Gastroenterology Global Congress.
“There have been several case reports of this, but this is the largest cohort review yet reported by one center,” said Dr. Pugliese, a gastroenterologist in the inflammatory bowel disease (IBD) unit of Complesso Integrato Columbus, Catholic University in Rome.
The review included 402 patients treated with an anti-TNF drug at the unit during 2008-2013, with a median follow-up of 17 months. During follow-up, 42 patients developed a psoriasiform lesion with a biopsy-proven diagnosis, a rate of 5 cases/100 person-years on anti-TNF treatment. The IBD patients averaged 40 years old, and 60% had Crohn’s disease and 40% had ulcerative colitis. About 60% received infliximab treatment, and 40% adalimumab. Most lesions appeared in predilection sites, as well as on palmoplantar surfaces or on the scalp; nearly half the patients had lesions in two or more locations.
A multivariate regression analysis that assessed several demographic and clinical features of all 402 patients identified two parameters that significantly linked with lesion development. Smoking linked with a greater than twofold increased risk for having a psoriasiform lesion (78 of the patients, 19%, smoked), and concurrent treatment with a thiopurine such as azathioprine, linked with a 67% reduced rate of lesion development (85 patients, 21%, were on concurrent thiopurine treatment). All IBD patients seen at the Rome unit who smoked were counseled regarding smoking cessation, Dr. Pugliese said in an interview.
Among the patients who did not respond to topical treatment, four received some benefit from starting treatment with ustekinumab (Stelara), which especially benefited patients who were otherwise difficult to treat, Dr. Pugliese said. Other patients benefited from starting treatment with cyclosporine, methotrexate, or a transient treatment with an oral steroid. Two patients who developed lesions on infliximab switched to adalimumab, and two other patients who had lesions on adalimumab switched to infliximab.
Dr. Pugliese and her associates did not have a good explanation of why patients on anti-TNF drugs develop these lesions, which Dr. Pugliese called “paradoxical.” One possible etiology is that inhibition of TNF-alpha results in uncontrolled production of interferon-alpha by plasmacytoid dendritic cells and this then triggers the psoriasiform eruptions.
A key element in managing these lesions may be early detection and topical treatment while they remain small, commented Dr. C. Janneke van der Woude, head of the IBD unit at Erasmus University Medical Center in Rotterdam, the Netherlands. “Every time we see an IBD patient who is on an anti-TNF drug, we ask whether they have had any itching, allergic reaction, arthritis, eye problem, or headache,” to facilitate early detection of an adverse effect from treatment, she said in an interview.
Dr. Pugliese had no disclosures. Dr. van der Woude said that she has been an adviser to Dr Falk, AbbVie, Janssen, Johnson & Johnson, and Cosmo.
On Twitter@mitchelzoler
AT UEG WEEK VIENNA 2014
Key clinical point: Inflammatory bowel disease patients on anti–tumor necrosis factor treatment often develop psoriasiform skin lesions.
Major finding: Patients receiving an anti-TNF drug developed psoriasiform lesions at an annual rate of 5%.
Data source: Retrospective review of 402 patients with inflammatory bowel disease treated with an anti-TNF drug at one center in Rome.
Disclosures: Dr. Pugliese had no disclosures. Dr. van der Woude said that she has been an adviser to Dr Falk, AbbVie, Janssen, Johnson & Johnson, and Cosmo.
Uncomplicated diverticulitis patients safely avoid routine antibiotics
VIENNA – Patients with first-episode, uncomplicated diverticulitis can safely be managed by observation alone without routine antibiotic treatment, based on results from a prospective, controlled, multicenter Dutch trial with 528 patients.
Coupled with similar results from a 2012 Swedish randomized trial, the new findings show that an observational approach without up-front antibiotic treatment is safe and effective for routine practice for patients with a modified Hinchey stage 1 classification, the most common diverticulitis presentation, Dr. Lidewine Daniels said at the United European Gastroenterology Global Congress.
The 2012 trial, done in Sweden and Iceland, randomized 623 patients with acute, uncomplicated diverticulitis, and found no statistically significant difference in the rate of recovery without complications during 12 months of follow-up, regardless of whether or not patients received routine antibiotic treatment at the time of initial diagnosis (Br. J. Surg. 2012;99:532-9).
This approach “can now be adopted into guidelines,” said Dr. Daniels, a researcher in the surgery department at the Academic Medical Center in Amsterdam. This would shift current practice recommendations, such as those published earlier this year by the American College of Colon and Rectal Surgeons (Dis. Colon Rectum 2014;57:284-94), which have generally called for routine antibiotic management of these types of diverticulitis patients, Dr. Daniels said.
The DIABOLO (Multicenter Randomized Clinical Trial Investigating the Cost-effectiveness of Treatment Strategies With or Without Antibiotics for Uncomplicated Acute Diverticulitis) trial enrolled patients with CT-proven, left-sided, first-episode, uncomplicated diverticulitis at 22 Dutch centers. All patients were classified as having stage 1 disease by the modified Hinchey criteria (Int. J. Colorectal Dis. 2012;27:207-14), with about 92% of patients classified as Hinchey 1a.
The 266 patients randomized to initial antibiotic treatment began at least 2 days on intravenous treatment with amoxicillin and clavulanic acid, followed by a switch to oral delivery of the same combination when appropriate for a total of 10 days on the antibiotic.
Patients remained hospitalized until they switched from intravenous to oral treatment. The 262 patients randomized to no initial antibiotic treatment were hospitalized and observed, and received supportive treatment until they were judged ready for discharge by being able to eat a normal diet, had a temperature of less than 38 °C, and had a self-rated pain score of less than 4 on a visual analog scale of 0-10 without use of pain medication; in addition, the patient’s agreement was needed for discharge.
During 6 months of follow-up, the median time to complete recovery – defined as the criteria for hospital discharge plus a return to normal activity – occurred after a median of 12 days among patients in the antibiotic group and 14 days among those in the observation group, a difference that was not statistically significant for the study’s primary endpoint.
The results also showed no statistically significant differences between the two study arms for almost all the other outcomes assessed, including need for readmission, complications, need for surgery, morbidities, serious morbidities, and deaths. The only significant differences in outcomes were a decreased rate of hospitalization at the time of initial treatment among patients in the observation-only arm, and fewer hospitalized days among the observation-only patients.
“Observational treatment is without short- or long-term repercussions,” Dr. Daniels concluded.
Dr. Daniels had no disclosures.
On Twitter @mitchelzoler
VIENNA – Patients with first-episode, uncomplicated diverticulitis can safely be managed by observation alone without routine antibiotic treatment, based on results from a prospective, controlled, multicenter Dutch trial with 528 patients.
Coupled with similar results from a 2012 Swedish randomized trial, the new findings show that an observational approach without up-front antibiotic treatment is safe and effective for routine practice for patients with a modified Hinchey stage 1 classification, the most common diverticulitis presentation, Dr. Lidewine Daniels said at the United European Gastroenterology Global Congress.
The 2012 trial, done in Sweden and Iceland, randomized 623 patients with acute, uncomplicated diverticulitis, and found no statistically significant difference in the rate of recovery without complications during 12 months of follow-up, regardless of whether or not patients received routine antibiotic treatment at the time of initial diagnosis (Br. J. Surg. 2012;99:532-9).
This approach “can now be adopted into guidelines,” said Dr. Daniels, a researcher in the surgery department at the Academic Medical Center in Amsterdam. This would shift current practice recommendations, such as those published earlier this year by the American College of Colon and Rectal Surgeons (Dis. Colon Rectum 2014;57:284-94), which have generally called for routine antibiotic management of these types of diverticulitis patients, Dr. Daniels said.
The DIABOLO (Multicenter Randomized Clinical Trial Investigating the Cost-effectiveness of Treatment Strategies With or Without Antibiotics for Uncomplicated Acute Diverticulitis) trial enrolled patients with CT-proven, left-sided, first-episode, uncomplicated diverticulitis at 22 Dutch centers. All patients were classified as having stage 1 disease by the modified Hinchey criteria (Int. J. Colorectal Dis. 2012;27:207-14), with about 92% of patients classified as Hinchey 1a.
The 266 patients randomized to initial antibiotic treatment began at least 2 days on intravenous treatment with amoxicillin and clavulanic acid, followed by a switch to oral delivery of the same combination when appropriate for a total of 10 days on the antibiotic.
Patients remained hospitalized until they switched from intravenous to oral treatment. The 262 patients randomized to no initial antibiotic treatment were hospitalized and observed, and received supportive treatment until they were judged ready for discharge by being able to eat a normal diet, had a temperature of less than 38 °C, and had a self-rated pain score of less than 4 on a visual analog scale of 0-10 without use of pain medication; in addition, the patient’s agreement was needed for discharge.
During 6 months of follow-up, the median time to complete recovery – defined as the criteria for hospital discharge plus a return to normal activity – occurred after a median of 12 days among patients in the antibiotic group and 14 days among those in the observation group, a difference that was not statistically significant for the study’s primary endpoint.
The results also showed no statistically significant differences between the two study arms for almost all the other outcomes assessed, including need for readmission, complications, need for surgery, morbidities, serious morbidities, and deaths. The only significant differences in outcomes were a decreased rate of hospitalization at the time of initial treatment among patients in the observation-only arm, and fewer hospitalized days among the observation-only patients.
“Observational treatment is without short- or long-term repercussions,” Dr. Daniels concluded.
Dr. Daniels had no disclosures.
On Twitter @mitchelzoler
VIENNA – Patients with first-episode, uncomplicated diverticulitis can safely be managed by observation alone without routine antibiotic treatment, based on results from a prospective, controlled, multicenter Dutch trial with 528 patients.
Coupled with similar results from a 2012 Swedish randomized trial, the new findings show that an observational approach without up-front antibiotic treatment is safe and effective for routine practice for patients with a modified Hinchey stage 1 classification, the most common diverticulitis presentation, Dr. Lidewine Daniels said at the United European Gastroenterology Global Congress.
The 2012 trial, done in Sweden and Iceland, randomized 623 patients with acute, uncomplicated diverticulitis, and found no statistically significant difference in the rate of recovery without complications during 12 months of follow-up, regardless of whether or not patients received routine antibiotic treatment at the time of initial diagnosis (Br. J. Surg. 2012;99:532-9).
This approach “can now be adopted into guidelines,” said Dr. Daniels, a researcher in the surgery department at the Academic Medical Center in Amsterdam. This would shift current practice recommendations, such as those published earlier this year by the American College of Colon and Rectal Surgeons (Dis. Colon Rectum 2014;57:284-94), which have generally called for routine antibiotic management of these types of diverticulitis patients, Dr. Daniels said.
The DIABOLO (Multicenter Randomized Clinical Trial Investigating the Cost-effectiveness of Treatment Strategies With or Without Antibiotics for Uncomplicated Acute Diverticulitis) trial enrolled patients with CT-proven, left-sided, first-episode, uncomplicated diverticulitis at 22 Dutch centers. All patients were classified as having stage 1 disease by the modified Hinchey criteria (Int. J. Colorectal Dis. 2012;27:207-14), with about 92% of patients classified as Hinchey 1a.
The 266 patients randomized to initial antibiotic treatment began at least 2 days on intravenous treatment with amoxicillin and clavulanic acid, followed by a switch to oral delivery of the same combination when appropriate for a total of 10 days on the antibiotic.
Patients remained hospitalized until they switched from intravenous to oral treatment. The 262 patients randomized to no initial antibiotic treatment were hospitalized and observed, and received supportive treatment until they were judged ready for discharge by being able to eat a normal diet, had a temperature of less than 38 °C, and had a self-rated pain score of less than 4 on a visual analog scale of 0-10 without use of pain medication; in addition, the patient’s agreement was needed for discharge.
During 6 months of follow-up, the median time to complete recovery – defined as the criteria for hospital discharge plus a return to normal activity – occurred after a median of 12 days among patients in the antibiotic group and 14 days among those in the observation group, a difference that was not statistically significant for the study’s primary endpoint.
The results also showed no statistically significant differences between the two study arms for almost all the other outcomes assessed, including need for readmission, complications, need for surgery, morbidities, serious morbidities, and deaths. The only significant differences in outcomes were a decreased rate of hospitalization at the time of initial treatment among patients in the observation-only arm, and fewer hospitalized days among the observation-only patients.
“Observational treatment is without short- or long-term repercussions,” Dr. Daniels concluded.
Dr. Daniels had no disclosures.
On Twitter @mitchelzoler
AT UEG WEEK VIENNA 2014
Key clinical point: Observation-only worked as well as routine antibiotic treatment for patients with uncomplicated diverticulitis.
Major finding: Median time to full recovery was 12 days for antibiotic-treated patients and 14 days for observation-only patients.
Data source: The DIABOLO study, which randomized 528 patients with first-time, CT-proven, acute, uncomplicated diverticulitis at 22 Dutch centers.
Disclosures: Dr. Daniels had no disclosures.
Liquid biopsies: High potential but are they ready for prime time?
MADRID – Liquid biopsies to track genetic changes in a patient’s tumor by serial blood specimens rather than multiple tissue biopsies seem poised to enter routine clinical use. But several experts speaking at a session on the topic agreed that liquid biopsy technologies largely remain too unproven to enter everyday practice right now.
“I have no doubt [liquid biopsy] will become routine, but right now the evidence is lacking,” said Alberto Bardelli, Ph.D., summarizing a session he cochaired at the European Society for Medical Oncology Congress.
“I think the potential is very high to use liquid biopsy to monitor residual disease in patients with breast cancer or other tumor types. There is also the possibility of using CTCs [circulating tumor cells] to interrogate the genome of single tumor cells or to grow the cells and use them functionally” to, for example, help identify effective treatments against the tumor, said Dr. Bardelli, a molecular biologist at the University of Torino, Italy.
Liquid biopsies are generally divided into two categories. One approach involves the isolation and analysis of individual, living tumor cells that slough off a primary tumor or metastasis and can be isolated from a patient’s peripheral blood, although tumor cell concentrations are very low, on the order of one tumor cell in a million normal blood cells or even 10- to 100-fold more dilute than that.
In 2004, the Food and Drug Administration approved CellSearch, a commercial test that quantifies CTCs in patients with metastatic breast cancer to predict the likelihood of survival. CellSearch remains the only FDA-approved liquid biopsy assay for cancer, though its use has expanded to patients with prostate or colorectal cancer as well as breast cancer.
Circulating tumor DNA
The second option is to isolate and analyze the DNA that slips out of dead tumor cells and enters a patient’s circulation. One advantage of focusing on circulating tumor DNA (ctDNA) is that it is more than 100 times as common in a patent’s blood as tumor cells; however, tumor DNA is limited to providing a broad-brush average of what is going on genetically in a primary tumor and its metastases at any time, rather than giving the specificity of a genome isolated from a single, circulating tumor cell.
Both approaches seem to have value, and both seem on course to continue in development and be used in complementary ways.
An example of the potential benefit of analyzing ctDNA came in a study published last year, in which investigators identified genetic alterations that they could use to follow patients with metastatic breast cancer. They found ctDNA in the blood of 29 out of 52 women, and saw a strong, inverse relationship between increased levels of ctDNA and survival. Patients with a below-average level of ctDNA had significantly better survival, while patients with relatively higher ctDNA levels had significantly worse survival, the British researchers reported last year (New Engl. J. Med. 2013;368:1199-209). The study results also showed that quantifying ctDNA provided better correlation with changes in tumor burden than did quantifying CTCs or measuring an immune marker for breast cancer, CA 15-3.
More recently, these investigators expanded the mutation panel they use to identify ctDNA, and now can find a single-nucleotide or structural variant in the DNAs of 48 of these 52 patients, Dr. Carlos Caldas, one of the investigators, said in a talk at the meeting. Dr. Caldas added that he and his associates have now seen a patient from this series with triple-negative breast cancer and an elevated level of ctDNA who then showed a dramatic reduction in ctDNA level following several treatment cycles. This drop in ctDNA level tracked with the patient’s complete pathological response to treatment.
“This is preliminary evidence that you can use ctDNA as a very early marker of treatment response,” said Dr. Caldas, professor of cancer medicine at the University of Cambridge, England.
Other advantages of measuring ctDNA, especially compared with tracking a tumor using CTCs, is that it is simple and relatively inexpensive, with no need for special isolation technology, and it reflects the patient’s total tumor burden, noted Dr. Gerald Prager, an oncologist at the Medical University of Vienna. He cited a recent example of the power of ctDNA analysis in a report on 106 patients with colorectal cancer, who underwent ctDNA analysis for KRAS and BRAF mutations. Comparison of results from the ctDNA analysis and conventional mutation determinations showed 100% sensitivity and specificity for detecting tumors with the BRAF V600E mutation, and 98% specificity and 92% sensitivity for detecting any of seven KRAS point mutations (Nature Med. 2014;20:430-5).
“We think that liquid biopsies can help deliver the right treatment to a patient at the right time, and less invasively” than tissue biopsies, Dr. Prager said in a talk at the meeting. “They are useful for monitoring tumor growth and therapeutic activity.” He and his associates now have a study in progress evaluating the ability of serial ctDNA analysis to improve treatment with regorafenib in patients with metastatic colorectal cancer.
Analyses using ctDNA “are accurate, but we need to perform clinical trials to know what we should do with the information,” Dr. Prager said in an interview. “When we see a clone has been selected, should we change treatment before we see actual disease progression? This question has not yet been answered,” he said.
Circulating tumor cells
Liquid biopsy for CTCs has the advantage over ctDNA of having an FDA-approved test, which uses epithelial-marker antigens on the surface of CTCs to isolate the cells from a 7.5-mL specimen of blood. Study results showed a clear link between increased numbers of CTCs in patients and their rate of metastatic progression. For example, a meta-analysis published this year summarized data on CTC analysis in 1,944 patients with metastatic breast cancer evaluated in 20 separate studies done at 17 European centers. This meta-analysis showed that 47% of patients had a CTC count at baseline of 5 cells or more in a 7.5-mL specimen, and that this was significantly linked to diminished overall survival (hazard ratio, 1.92; 95% confidence interval, 1.73-2.14; P < .0001) (Lancet Oncol. 2014;15:406-14). The data also showed significantly reduced survival when CTC count increased either 3-5 weeks after treatment started or 6-8 weeks after treatment started. All these findings “confirm the independent, prognostic effect of CTC count on progression-free survival and overall survival,” the authors concluded.
This report confirmed the added value of CTC number, which was first reported using the same CellSearch technology a decade before (New Engl. J. Med. 2004;351:781-91).
The 2014 meta-analysis “provides level I evidence that CTC detection with CellSearch is an adverse prognostic factor in metastatic breast cancer,” said Dr. Michail Ignatiadis, an oncologist at the Jules Bordet Institute in Brussels.
But while CTC number “gives us very good prognostication, what we want is to know whether a treatment is working, and [whether we] can we get enough information from these cells to decide on what treatment to use. That is more challenging,” said Dr. Klaus Pantel, a professor of oncology and director of tumor biology at the University of Hamburg, Germany.
“We can now say, by monitoring CTCs in blood, whether or not treatment is going in the right direction; and it is important to have an early indicator of treatment response, but the challenge is to get a good picture” of the tumor to guide drug selection, Dr. Pantel said in an interview. He has recently used a new approach to collect CTCs developed by Gilupi that employs a receptor-coated needle placed in a patient’s blood vessel and left there for 30 minutes, during which roughly a liter of blood passes by the needle, allowing for collection of many more CTCs than is possible from a 7.5-mL specimen.
Another question about CTCs is that collection works well in metastatic-stage disease, when CTCs are relatively plentiful, but can it also play a role in assessing mortality risk in patients with early-stage cancer? Dr. Pantel and his associates recently addressed this question by using the CellSearch assay in 2,026 patients with early-stage breast cancer prior to treatment with adjuvant chemotherapy, and 1,492 patients after chemotherapy. The results showed that the presence of CTCs was linked to worse prognosis, with the worst outcomes occurring in women with 5 or more CTCs in 30 mL of blood (J. Natl. Cancer Inst. 2014;106:dju066 [doi: 10.1093/jnci/dju066]). The findings are the first “to provide strong evidence for the prognostic relevance of CTCs in early breast cancer before and after adjuvant chemotherapy in a large patient cohort,” Dr. Pantel and his coauthors concluded. “Our data offer support for the clinical potential of CTCs to assess the individual risk of patients at the time of primary diagnosis.”
Coupling liquid biopsies with better treatments
One of the challenges of using liquid biopsies to improve cancer treatment is the inherent limitation researchers often encounter of having to rely on inadequate treatment regimens with limited efficacy, Dr. Ignatiadis noted. That limitation came into play in a recent report of a study that used CTCs to stratify risk in patients with metastatic breast cancer and randomize them to either of two different treatment regimens. The results confirmed the prognostic significance of CTC number but failed to show that changing treatment based on CTC number improved outcomes, likely because the alternative regimen applied offered no real advantages over the comparator, the researchers concluded (J. Clin. Oncol. 2014 June 2 [doi: 10.1200/JCO.2014.56.2561]).
Studies now in progress have been designed to specifically test the efficacy of new treatment approaches in cancer populations selected for their CTC or ctDNA profile, such as the TREAT CTC trial, which is evaluating the efficacy of trastuzumab for treating women with detectable CTCs and HER2-negative primary breast cancer. Another example is the DETECT III trial, which is investigating the efficacy of lapatinib in patients with metastatic breast cancer who have HER2-positive CTCs.
“Until now we have mostly had proof-of-principle studies. Now we need to see how CTCs and ctDNA work in real practice” and in coordination with new approaches to treatment, Dr. Pantel said.
Dr. Bardelli is a shareholder in Horizon Discovery and has been an adviser to Biocartis, Trovagene, and HD. Dr. Caldas had no disclosures. Dr. Prager has been an adviser and consultant to Bayer, Roche, Amgen, Merck Serono, and Sanofi-Aventis. Dr. Ignatiadis has received educational grants from Janssen Diagnostics and Roche. Dr. Pantel has been an adviser to Veridex/Janssen, Alere, and Gilupi.
On Twitter @mitchelzoler
MADRID – Liquid biopsies to track genetic changes in a patient’s tumor by serial blood specimens rather than multiple tissue biopsies seem poised to enter routine clinical use. But several experts speaking at a session on the topic agreed that liquid biopsy technologies largely remain too unproven to enter everyday practice right now.
“I have no doubt [liquid biopsy] will become routine, but right now the evidence is lacking,” said Alberto Bardelli, Ph.D., summarizing a session he cochaired at the European Society for Medical Oncology Congress.
“I think the potential is very high to use liquid biopsy to monitor residual disease in patients with breast cancer or other tumor types. There is also the possibility of using CTCs [circulating tumor cells] to interrogate the genome of single tumor cells or to grow the cells and use them functionally” to, for example, help identify effective treatments against the tumor, said Dr. Bardelli, a molecular biologist at the University of Torino, Italy.
Liquid biopsies are generally divided into two categories. One approach involves the isolation and analysis of individual, living tumor cells that slough off a primary tumor or metastasis and can be isolated from a patient’s peripheral blood, although tumor cell concentrations are very low, on the order of one tumor cell in a million normal blood cells or even 10- to 100-fold more dilute than that.
In 2004, the Food and Drug Administration approved CellSearch, a commercial test that quantifies CTCs in patients with metastatic breast cancer to predict the likelihood of survival. CellSearch remains the only FDA-approved liquid biopsy assay for cancer, though its use has expanded to patients with prostate or colorectal cancer as well as breast cancer.
Circulating tumor DNA
The second option is to isolate and analyze the DNA that slips out of dead tumor cells and enters a patient’s circulation. One advantage of focusing on circulating tumor DNA (ctDNA) is that it is more than 100 times as common in a patent’s blood as tumor cells; however, tumor DNA is limited to providing a broad-brush average of what is going on genetically in a primary tumor and its metastases at any time, rather than giving the specificity of a genome isolated from a single, circulating tumor cell.
Both approaches seem to have value, and both seem on course to continue in development and be used in complementary ways.
An example of the potential benefit of analyzing ctDNA came in a study published last year, in which investigators identified genetic alterations that they could use to follow patients with metastatic breast cancer. They found ctDNA in the blood of 29 out of 52 women, and saw a strong, inverse relationship between increased levels of ctDNA and survival. Patients with a below-average level of ctDNA had significantly better survival, while patients with relatively higher ctDNA levels had significantly worse survival, the British researchers reported last year (New Engl. J. Med. 2013;368:1199-209). The study results also showed that quantifying ctDNA provided better correlation with changes in tumor burden than did quantifying CTCs or measuring an immune marker for breast cancer, CA 15-3.
More recently, these investigators expanded the mutation panel they use to identify ctDNA, and now can find a single-nucleotide or structural variant in the DNAs of 48 of these 52 patients, Dr. Carlos Caldas, one of the investigators, said in a talk at the meeting. Dr. Caldas added that he and his associates have now seen a patient from this series with triple-negative breast cancer and an elevated level of ctDNA who then showed a dramatic reduction in ctDNA level following several treatment cycles. This drop in ctDNA level tracked with the patient’s complete pathological response to treatment.
“This is preliminary evidence that you can use ctDNA as a very early marker of treatment response,” said Dr. Caldas, professor of cancer medicine at the University of Cambridge, England.
Other advantages of measuring ctDNA, especially compared with tracking a tumor using CTCs, is that it is simple and relatively inexpensive, with no need for special isolation technology, and it reflects the patient’s total tumor burden, noted Dr. Gerald Prager, an oncologist at the Medical University of Vienna. He cited a recent example of the power of ctDNA analysis in a report on 106 patients with colorectal cancer, who underwent ctDNA analysis for KRAS and BRAF mutations. Comparison of results from the ctDNA analysis and conventional mutation determinations showed 100% sensitivity and specificity for detecting tumors with the BRAF V600E mutation, and 98% specificity and 92% sensitivity for detecting any of seven KRAS point mutations (Nature Med. 2014;20:430-5).
“We think that liquid biopsies can help deliver the right treatment to a patient at the right time, and less invasively” than tissue biopsies, Dr. Prager said in a talk at the meeting. “They are useful for monitoring tumor growth and therapeutic activity.” He and his associates now have a study in progress evaluating the ability of serial ctDNA analysis to improve treatment with regorafenib in patients with metastatic colorectal cancer.
Analyses using ctDNA “are accurate, but we need to perform clinical trials to know what we should do with the information,” Dr. Prager said in an interview. “When we see a clone has been selected, should we change treatment before we see actual disease progression? This question has not yet been answered,” he said.
Circulating tumor cells
Liquid biopsy for CTCs has the advantage over ctDNA of having an FDA-approved test, which uses epithelial-marker antigens on the surface of CTCs to isolate the cells from a 7.5-mL specimen of blood. Study results showed a clear link between increased numbers of CTCs in patients and their rate of metastatic progression. For example, a meta-analysis published this year summarized data on CTC analysis in 1,944 patients with metastatic breast cancer evaluated in 20 separate studies done at 17 European centers. This meta-analysis showed that 47% of patients had a CTC count at baseline of 5 cells or more in a 7.5-mL specimen, and that this was significantly linked to diminished overall survival (hazard ratio, 1.92; 95% confidence interval, 1.73-2.14; P < .0001) (Lancet Oncol. 2014;15:406-14). The data also showed significantly reduced survival when CTC count increased either 3-5 weeks after treatment started or 6-8 weeks after treatment started. All these findings “confirm the independent, prognostic effect of CTC count on progression-free survival and overall survival,” the authors concluded.
This report confirmed the added value of CTC number, which was first reported using the same CellSearch technology a decade before (New Engl. J. Med. 2004;351:781-91).
The 2014 meta-analysis “provides level I evidence that CTC detection with CellSearch is an adverse prognostic factor in metastatic breast cancer,” said Dr. Michail Ignatiadis, an oncologist at the Jules Bordet Institute in Brussels.
But while CTC number “gives us very good prognostication, what we want is to know whether a treatment is working, and [whether we] can we get enough information from these cells to decide on what treatment to use. That is more challenging,” said Dr. Klaus Pantel, a professor of oncology and director of tumor biology at the University of Hamburg, Germany.
“We can now say, by monitoring CTCs in blood, whether or not treatment is going in the right direction; and it is important to have an early indicator of treatment response, but the challenge is to get a good picture” of the tumor to guide drug selection, Dr. Pantel said in an interview. He has recently used a new approach to collect CTCs developed by Gilupi that employs a receptor-coated needle placed in a patient’s blood vessel and left there for 30 minutes, during which roughly a liter of blood passes by the needle, allowing for collection of many more CTCs than is possible from a 7.5-mL specimen.
Another question about CTCs is that collection works well in metastatic-stage disease, when CTCs are relatively plentiful, but can it also play a role in assessing mortality risk in patients with early-stage cancer? Dr. Pantel and his associates recently addressed this question by using the CellSearch assay in 2,026 patients with early-stage breast cancer prior to treatment with adjuvant chemotherapy, and 1,492 patients after chemotherapy. The results showed that the presence of CTCs was linked to worse prognosis, with the worst outcomes occurring in women with 5 or more CTCs in 30 mL of blood (J. Natl. Cancer Inst. 2014;106:dju066 [doi: 10.1093/jnci/dju066]). The findings are the first “to provide strong evidence for the prognostic relevance of CTCs in early breast cancer before and after adjuvant chemotherapy in a large patient cohort,” Dr. Pantel and his coauthors concluded. “Our data offer support for the clinical potential of CTCs to assess the individual risk of patients at the time of primary diagnosis.”
Coupling liquid biopsies with better treatments
One of the challenges of using liquid biopsies to improve cancer treatment is the inherent limitation researchers often encounter of having to rely on inadequate treatment regimens with limited efficacy, Dr. Ignatiadis noted. That limitation came into play in a recent report of a study that used CTCs to stratify risk in patients with metastatic breast cancer and randomize them to either of two different treatment regimens. The results confirmed the prognostic significance of CTC number but failed to show that changing treatment based on CTC number improved outcomes, likely because the alternative regimen applied offered no real advantages over the comparator, the researchers concluded (J. Clin. Oncol. 2014 June 2 [doi: 10.1200/JCO.2014.56.2561]).
Studies now in progress have been designed to specifically test the efficacy of new treatment approaches in cancer populations selected for their CTC or ctDNA profile, such as the TREAT CTC trial, which is evaluating the efficacy of trastuzumab for treating women with detectable CTCs and HER2-negative primary breast cancer. Another example is the DETECT III trial, which is investigating the efficacy of lapatinib in patients with metastatic breast cancer who have HER2-positive CTCs.
“Until now we have mostly had proof-of-principle studies. Now we need to see how CTCs and ctDNA work in real practice” and in coordination with new approaches to treatment, Dr. Pantel said.
Dr. Bardelli is a shareholder in Horizon Discovery and has been an adviser to Biocartis, Trovagene, and HD. Dr. Caldas had no disclosures. Dr. Prager has been an adviser and consultant to Bayer, Roche, Amgen, Merck Serono, and Sanofi-Aventis. Dr. Ignatiadis has received educational grants from Janssen Diagnostics and Roche. Dr. Pantel has been an adviser to Veridex/Janssen, Alere, and Gilupi.
On Twitter @mitchelzoler
MADRID – Liquid biopsies to track genetic changes in a patient’s tumor by serial blood specimens rather than multiple tissue biopsies seem poised to enter routine clinical use. But several experts speaking at a session on the topic agreed that liquid biopsy technologies largely remain too unproven to enter everyday practice right now.
“I have no doubt [liquid biopsy] will become routine, but right now the evidence is lacking,” said Alberto Bardelli, Ph.D., summarizing a session he cochaired at the European Society for Medical Oncology Congress.
“I think the potential is very high to use liquid biopsy to monitor residual disease in patients with breast cancer or other tumor types. There is also the possibility of using CTCs [circulating tumor cells] to interrogate the genome of single tumor cells or to grow the cells and use them functionally” to, for example, help identify effective treatments against the tumor, said Dr. Bardelli, a molecular biologist at the University of Torino, Italy.
Liquid biopsies are generally divided into two categories. One approach involves the isolation and analysis of individual, living tumor cells that slough off a primary tumor or metastasis and can be isolated from a patient’s peripheral blood, although tumor cell concentrations are very low, on the order of one tumor cell in a million normal blood cells or even 10- to 100-fold more dilute than that.
In 2004, the Food and Drug Administration approved CellSearch, a commercial test that quantifies CTCs in patients with metastatic breast cancer to predict the likelihood of survival. CellSearch remains the only FDA-approved liquid biopsy assay for cancer, though its use has expanded to patients with prostate or colorectal cancer as well as breast cancer.
Circulating tumor DNA
The second option is to isolate and analyze the DNA that slips out of dead tumor cells and enters a patient’s circulation. One advantage of focusing on circulating tumor DNA (ctDNA) is that it is more than 100 times as common in a patent’s blood as tumor cells; however, tumor DNA is limited to providing a broad-brush average of what is going on genetically in a primary tumor and its metastases at any time, rather than giving the specificity of a genome isolated from a single, circulating tumor cell.
Both approaches seem to have value, and both seem on course to continue in development and be used in complementary ways.
An example of the potential benefit of analyzing ctDNA came in a study published last year, in which investigators identified genetic alterations that they could use to follow patients with metastatic breast cancer. They found ctDNA in the blood of 29 out of 52 women, and saw a strong, inverse relationship between increased levels of ctDNA and survival. Patients with a below-average level of ctDNA had significantly better survival, while patients with relatively higher ctDNA levels had significantly worse survival, the British researchers reported last year (New Engl. J. Med. 2013;368:1199-209). The study results also showed that quantifying ctDNA provided better correlation with changes in tumor burden than did quantifying CTCs or measuring an immune marker for breast cancer, CA 15-3.
More recently, these investigators expanded the mutation panel they use to identify ctDNA, and now can find a single-nucleotide or structural variant in the DNAs of 48 of these 52 patients, Dr. Carlos Caldas, one of the investigators, said in a talk at the meeting. Dr. Caldas added that he and his associates have now seen a patient from this series with triple-negative breast cancer and an elevated level of ctDNA who then showed a dramatic reduction in ctDNA level following several treatment cycles. This drop in ctDNA level tracked with the patient’s complete pathological response to treatment.
“This is preliminary evidence that you can use ctDNA as a very early marker of treatment response,” said Dr. Caldas, professor of cancer medicine at the University of Cambridge, England.
Other advantages of measuring ctDNA, especially compared with tracking a tumor using CTCs, is that it is simple and relatively inexpensive, with no need for special isolation technology, and it reflects the patient’s total tumor burden, noted Dr. Gerald Prager, an oncologist at the Medical University of Vienna. He cited a recent example of the power of ctDNA analysis in a report on 106 patients with colorectal cancer, who underwent ctDNA analysis for KRAS and BRAF mutations. Comparison of results from the ctDNA analysis and conventional mutation determinations showed 100% sensitivity and specificity for detecting tumors with the BRAF V600E mutation, and 98% specificity and 92% sensitivity for detecting any of seven KRAS point mutations (Nature Med. 2014;20:430-5).
“We think that liquid biopsies can help deliver the right treatment to a patient at the right time, and less invasively” than tissue biopsies, Dr. Prager said in a talk at the meeting. “They are useful for monitoring tumor growth and therapeutic activity.” He and his associates now have a study in progress evaluating the ability of serial ctDNA analysis to improve treatment with regorafenib in patients with metastatic colorectal cancer.
Analyses using ctDNA “are accurate, but we need to perform clinical trials to know what we should do with the information,” Dr. Prager said in an interview. “When we see a clone has been selected, should we change treatment before we see actual disease progression? This question has not yet been answered,” he said.
Circulating tumor cells
Liquid biopsy for CTCs has the advantage over ctDNA of having an FDA-approved test, which uses epithelial-marker antigens on the surface of CTCs to isolate the cells from a 7.5-mL specimen of blood. Study results showed a clear link between increased numbers of CTCs in patients and their rate of metastatic progression. For example, a meta-analysis published this year summarized data on CTC analysis in 1,944 patients with metastatic breast cancer evaluated in 20 separate studies done at 17 European centers. This meta-analysis showed that 47% of patients had a CTC count at baseline of 5 cells or more in a 7.5-mL specimen, and that this was significantly linked to diminished overall survival (hazard ratio, 1.92; 95% confidence interval, 1.73-2.14; P < .0001) (Lancet Oncol. 2014;15:406-14). The data also showed significantly reduced survival when CTC count increased either 3-5 weeks after treatment started or 6-8 weeks after treatment started. All these findings “confirm the independent, prognostic effect of CTC count on progression-free survival and overall survival,” the authors concluded.
This report confirmed the added value of CTC number, which was first reported using the same CellSearch technology a decade before (New Engl. J. Med. 2004;351:781-91).
The 2014 meta-analysis “provides level I evidence that CTC detection with CellSearch is an adverse prognostic factor in metastatic breast cancer,” said Dr. Michail Ignatiadis, an oncologist at the Jules Bordet Institute in Brussels.
But while CTC number “gives us very good prognostication, what we want is to know whether a treatment is working, and [whether we] can we get enough information from these cells to decide on what treatment to use. That is more challenging,” said Dr. Klaus Pantel, a professor of oncology and director of tumor biology at the University of Hamburg, Germany.
“We can now say, by monitoring CTCs in blood, whether or not treatment is going in the right direction; and it is important to have an early indicator of treatment response, but the challenge is to get a good picture” of the tumor to guide drug selection, Dr. Pantel said in an interview. He has recently used a new approach to collect CTCs developed by Gilupi that employs a receptor-coated needle placed in a patient’s blood vessel and left there for 30 minutes, during which roughly a liter of blood passes by the needle, allowing for collection of many more CTCs than is possible from a 7.5-mL specimen.
Another question about CTCs is that collection works well in metastatic-stage disease, when CTCs are relatively plentiful, but can it also play a role in assessing mortality risk in patients with early-stage cancer? Dr. Pantel and his associates recently addressed this question by using the CellSearch assay in 2,026 patients with early-stage breast cancer prior to treatment with adjuvant chemotherapy, and 1,492 patients after chemotherapy. The results showed that the presence of CTCs was linked to worse prognosis, with the worst outcomes occurring in women with 5 or more CTCs in 30 mL of blood (J. Natl. Cancer Inst. 2014;106:dju066 [doi: 10.1093/jnci/dju066]). The findings are the first “to provide strong evidence for the prognostic relevance of CTCs in early breast cancer before and after adjuvant chemotherapy in a large patient cohort,” Dr. Pantel and his coauthors concluded. “Our data offer support for the clinical potential of CTCs to assess the individual risk of patients at the time of primary diagnosis.”
Coupling liquid biopsies with better treatments
One of the challenges of using liquid biopsies to improve cancer treatment is the inherent limitation researchers often encounter of having to rely on inadequate treatment regimens with limited efficacy, Dr. Ignatiadis noted. That limitation came into play in a recent report of a study that used CTCs to stratify risk in patients with metastatic breast cancer and randomize them to either of two different treatment regimens. The results confirmed the prognostic significance of CTC number but failed to show that changing treatment based on CTC number improved outcomes, likely because the alternative regimen applied offered no real advantages over the comparator, the researchers concluded (J. Clin. Oncol. 2014 June 2 [doi: 10.1200/JCO.2014.56.2561]).
Studies now in progress have been designed to specifically test the efficacy of new treatment approaches in cancer populations selected for their CTC or ctDNA profile, such as the TREAT CTC trial, which is evaluating the efficacy of trastuzumab for treating women with detectable CTCs and HER2-negative primary breast cancer. Another example is the DETECT III trial, which is investigating the efficacy of lapatinib in patients with metastatic breast cancer who have HER2-positive CTCs.
“Until now we have mostly had proof-of-principle studies. Now we need to see how CTCs and ctDNA work in real practice” and in coordination with new approaches to treatment, Dr. Pantel said.
Dr. Bardelli is a shareholder in Horizon Discovery and has been an adviser to Biocartis, Trovagene, and HD. Dr. Caldas had no disclosures. Dr. Prager has been an adviser and consultant to Bayer, Roche, Amgen, Merck Serono, and Sanofi-Aventis. Dr. Ignatiadis has received educational grants from Janssen Diagnostics and Roche. Dr. Pantel has been an adviser to Veridex/Janssen, Alere, and Gilupi.
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM ESMO 2014
VIDEO: Liquid tumor biopsies await prospective validation
MADRID – Assessing the genetic profile of tumor DNA circulating in a cancer patient’s blood is a potentially attractive way to track a tumor without the need for multiple tissue biopsies. The limitation of these liquid biopsies is that the clinical relevance of periodically assessing circulating tumor DNA has not yet been proven, Dr. Gerald Prager said during a video interview at the European Society for Medical Oncology Congress.
“We need to perform clinical trials to know what to do” with the information that comes from evaluating circulating tumor DNA, said Dr. Prager, an oncologist at the Medical University of Vienna.
“Should we change” a patient’s treatment based on genetic results “before we see disease progression? We have not answered that yet.”
Dr. Prager has been an adviser and consultant to Bayer, Roche, Amgen, Merck Serono, and Sanofi-Aventis.
On Twitter @mitchelzoler
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MADRID – Assessing the genetic profile of tumor DNA circulating in a cancer patient’s blood is a potentially attractive way to track a tumor without the need for multiple tissue biopsies. The limitation of these liquid biopsies is that the clinical relevance of periodically assessing circulating tumor DNA has not yet been proven, Dr. Gerald Prager said during a video interview at the European Society for Medical Oncology Congress.
“We need to perform clinical trials to know what to do” with the information that comes from evaluating circulating tumor DNA, said Dr. Prager, an oncologist at the Medical University of Vienna.
“Should we change” a patient’s treatment based on genetic results “before we see disease progression? We have not answered that yet.”
Dr. Prager has been an adviser and consultant to Bayer, Roche, Amgen, Merck Serono, and Sanofi-Aventis.
On Twitter @mitchelzoler
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MADRID – Assessing the genetic profile of tumor DNA circulating in a cancer patient’s blood is a potentially attractive way to track a tumor without the need for multiple tissue biopsies. The limitation of these liquid biopsies is that the clinical relevance of periodically assessing circulating tumor DNA has not yet been proven, Dr. Gerald Prager said during a video interview at the European Society for Medical Oncology Congress.
“We need to perform clinical trials to know what to do” with the information that comes from evaluating circulating tumor DNA, said Dr. Prager, an oncologist at the Medical University of Vienna.
“Should we change” a patient’s treatment based on genetic results “before we see disease progression? We have not answered that yet.”
Dr. Prager has been an adviser and consultant to Bayer, Roche, Amgen, Merck Serono, and Sanofi-Aventis.
On Twitter @mitchelzoler
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
EXPERT ANALYSIS FROM ESMO 2014
Biosimilars poised to make biologics more routine
The biosimilar age for rheumatology has arrived, and experts expect wider use of previously expensive biologic drugs as biosimilar competition drives prices down and makes biologics more affordable.
An infliximab biosimilar became the first such agent to arrive onto the European market in the second half of 2013, and by the start of 2014, it was already having an impact by, for example, dropping the cost of infliximab by a third in Norway. Norway may have received the biggest biosimilar effect so far because it runs an annual auction for the best prices on competing drugs from manufacturers and then mandates Norwegian clinicians to prescribe the lowest-price option when starting a new therapy.
A U.S. version of this scenario may soon follow. In August 2014, Celltrion and Hospira, the two companies jointly producing and marketing biosimilar forms of infliximab under the names Remsima and Inflectra (in parts of eastern Europe and elsewhere), announced they had submitted a marketing application to the Food and Drug Administration. In the announcement, Celltrion officials said they expected Food and Drug Administration approval within a year. If that were to happen, and if Celltrion mounts a successful patent challenge, the Remsima form of infliximab could become one of the first biosimilars on the U.S. market. (In July, Sandoz – a subsidiary of Novartis – announced it submitted an FDA application for Zarzio, a biosimilar version of filgrastim that until now has been only available as Neupogen, a granulocyte colony–stimulating factor. Biosimilar filgrastim seems like the only contender that could edge out Remsima as the first biosimilar on the U.S. market.)
At least two more biosimilars – a third form of infliximab, and a new form of etanercept – may come next, although rheumatologists following the field caution that additional studies are needed on top of what was reported for these two biosimilars last June at the annual European Congress of Rheumatology.
Lower cost broadens use
With one rheumatology biosimilar already on several global formularies and others nearing that status, the next challenge is convincing clinicians that cut-rate biologics are safe and effective and patients can switch from the brand-name form to a biosimilar without adverse effects. Meanwhile, payers and patients are pressing for biosimilars to cut the high cost of biologic treatment. By making biologic drugs more affordable for more patients, introduction of biosimilars will change patient care, experts said.
“A decrease in price will change how biologics are used in U.S. patients. In the United States today, about half of rheumatoid arthritis (RA) patients receive a biologic,” a rate substantially below where it should be, said Dr. Vibeke Strand, a biopharmaceutical consultant and rheumatologist at Stanford (Calif.) University. “Biosimilars will have a very big impact,” she predicted.
“Clinicians are under a lot of pressure from pharmacies, hospitals, and managed-care organization to avoid expensive medications when possible. Starting a biologic will become easier,” when prices start falling. And adherence may also improve. “Part of why patients don’t take their biologics for more than 1-2 years is they can’t afford the copay. That may change” if prices drop, Dr. Strand said in an interview.
Before biosimilars became available, “countries with low GDPs [gross domestic products] had less access to biologics and more restrictions; richer countries had better access,” noted Dr. Tore K. Kvien, a rheumatologist and professor of rheumatology at the University of Oslo.
Greater affordability and access to biologics is the sole factor driving the biosimilar movement. “Cost is the only reason why you have biosimilars,” noted Dr. Bruce N. Cronstein, a rheumatologist and professor of medicine, pathology, and pharmacology at New York University. Aside from cost, there are, by definition, no meaningful differences between a biosimilar and the reference brand-name formulation.
Biosimilars, Dr. Cronstein said, “will be cheaper, but it won’t be like the difference with generic and brand-name statins. You won’t see a 90% price drop. Maybe we’ll see a 30% or 40% price cut, which is considerable. The biologics are all very expensive drugs. But biosimilars will not lead to anything like the savings with small generic molecules.”
While Dr. Cronstein noted that there are no guarantees regarding the timing of price changes, the extent of price cuts, or how competition might affect pricing of the brand-name alternative, the experience in Norway showed a quick, one-third price cut when Remsima became an option, Dr. Kvien said in an interview. For years, Norway has negotiated 1-year contracts for setting drug costs with manufacturers. Norwegian officials invite competitors to submit bids in an annual auction. Celltrion won the auction to make Remsima the infliximab of choice in Norway during 2014 for all six European Medicines Agency (EMA)-approved infliximab indications: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn’s disease, and ulcerative colitis.
“My colleagues tell me that the one-third reduction in price [compared with Remicade's price in 2014] was larger than they expected,” Dr. Kvien said. A year of treatment for an RA patient receiving Remsima averages about 6,000 euro now, down from the roughly 9,000 euro current annual cost for Remicade.
Dr. Strand maintained that economic pressures play a role in how easily biosimilars gain regulatory approval. For example, EMA received pressure from Eastern European countries where biologics have been relatively unavailable because of their price, she said. In the United States, pressure on the FDA comes from payers and patients because biologic copays are so high. But despite pressure, Dr. Strand and others believe that EMA and the FDA have set reasonable approval standards for biosimilars that clinicians can rely on.
“I think for all intents and purposes if EMA decides something is a biosimilar then I definitely think it is,” Dr. Strand said. “There may be subtle differences, but nothing big.” In some cases reference, brand-name biologics themselves have undergone substantial changes from what they originally had been, as happened with Enbrel and Rituxan, she noted. “The FDA will not entertain even a small change in an amino acid sequence, and requires two immunogenicity studies.”
Concerns about safety
But biosimilars may be a special case, where even the regulatory stamp of approval may not fully convince some clinicians.
“There is still quite a bit of skepticism,” Dr. Strand said. “I think there will be less skepticism once more data show that biosimilars are safe. The biggest concern seems to be that if the FDA decides something is not just biosimilar but also equivalent then there might be substitutions by a pharmacist without knowledge of the health care provider. I think there is concern because people are still not sure what biosimilar means. It will take more data to convince some people.”
“I think that physicians will be convinced by the data showing these compounds act in a similar way. What physicians worry about is that while these drugs may look good in a trial there might be some subtle difference that increases drug resistance or anaphylaxis,” said Dr. Cronstein. “I think clinicians will accept biosimilars and use them, but worry that a safety signal may not be seen in clinical trials. I think the FDA is trying to figure out how to be sure that switching from one drug to another does not cause an adverse effect. That is the major potential downside people see.”
The safety of switching to a biosimilar was an important enough issue for the Norwegian government to sponsor a 2.5 million euro trial to address the question. The 500-patient study, slated to start in the fall of 2014, will randomize patients on stable Remicade treatment to either remain on Remicade or switch to Remsima. The NOR-SWITCH trial will include patients with any of the six indications for which Remsima received EMA approval.
Until trial results are available, anticipated to be in 2016, Norway does not sanction switching patients on a stable Remicade regimen to Remsima even though Remsima is the infliximab of choice for patients starting infliximab for the first time. Despite this, some Norwegian departments have already made the switch in some patients, said Dr. Kvien, who is lead investigator for NOR-SWITCH. “They say the scientific data available now are sufficient to show switching is safe, but I do not agree.” The willingness of some Norwegian clinicians to switch their patients now from infliximab to the biosimilar shows how eager they and patients in Norway are to save money with Remsima.
While biosimilars face challenges entering and gaining traction in the European and American markets, they also seem driven by an overwhelming inevitability.
“Biosimilars will absolutely be routine in 10-20 years. They will be accepted, but it will take time,” Dr. Cronstein predicted.
“Biosimilars are here, they are not going away, and as patents run out we’ll see more and more of them,” predicted Dr. Paul Emery, professor of rheumatology at Leeds (England) University, while speaking at the annual European Congress of Rheumatology last June in Paris.
“I expect biosimilars will be important. My hope is that their lower cost will improve access to these treatments and this will mean better treatment for more patients around the world,” Dr. Kvien said.
Dr. Strand has been a consultant to Hospira, Celltrion, Amgen, Pfizer, Epirus, Baxter, and Merck Serono. Dr. Kvien has been a consultant to AbbVie, Bristol-Myers Squibb, Hospira, Celltrion, Pfizer/Wyeth, Merck Serono, Merck Sharp & Dohme, Roche, UCB, Orion, and Takeda. Dr. Cronstein has been a consultant to Pfizer and Merck Serono. Dr. Emery has been a consultant to AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, and Takeda.
On Twitter @mitchelzoler
The biosimilar age for rheumatology has arrived, and experts expect wider use of previously expensive biologic drugs as biosimilar competition drives prices down and makes biologics more affordable.
An infliximab biosimilar became the first such agent to arrive onto the European market in the second half of 2013, and by the start of 2014, it was already having an impact by, for example, dropping the cost of infliximab by a third in Norway. Norway may have received the biggest biosimilar effect so far because it runs an annual auction for the best prices on competing drugs from manufacturers and then mandates Norwegian clinicians to prescribe the lowest-price option when starting a new therapy.
A U.S. version of this scenario may soon follow. In August 2014, Celltrion and Hospira, the two companies jointly producing and marketing biosimilar forms of infliximab under the names Remsima and Inflectra (in parts of eastern Europe and elsewhere), announced they had submitted a marketing application to the Food and Drug Administration. In the announcement, Celltrion officials said they expected Food and Drug Administration approval within a year. If that were to happen, and if Celltrion mounts a successful patent challenge, the Remsima form of infliximab could become one of the first biosimilars on the U.S. market. (In July, Sandoz – a subsidiary of Novartis – announced it submitted an FDA application for Zarzio, a biosimilar version of filgrastim that until now has been only available as Neupogen, a granulocyte colony–stimulating factor. Biosimilar filgrastim seems like the only contender that could edge out Remsima as the first biosimilar on the U.S. market.)
At least two more biosimilars – a third form of infliximab, and a new form of etanercept – may come next, although rheumatologists following the field caution that additional studies are needed on top of what was reported for these two biosimilars last June at the annual European Congress of Rheumatology.
Lower cost broadens use
With one rheumatology biosimilar already on several global formularies and others nearing that status, the next challenge is convincing clinicians that cut-rate biologics are safe and effective and patients can switch from the brand-name form to a biosimilar without adverse effects. Meanwhile, payers and patients are pressing for biosimilars to cut the high cost of biologic treatment. By making biologic drugs more affordable for more patients, introduction of biosimilars will change patient care, experts said.
“A decrease in price will change how biologics are used in U.S. patients. In the United States today, about half of rheumatoid arthritis (RA) patients receive a biologic,” a rate substantially below where it should be, said Dr. Vibeke Strand, a biopharmaceutical consultant and rheumatologist at Stanford (Calif.) University. “Biosimilars will have a very big impact,” she predicted.
“Clinicians are under a lot of pressure from pharmacies, hospitals, and managed-care organization to avoid expensive medications when possible. Starting a biologic will become easier,” when prices start falling. And adherence may also improve. “Part of why patients don’t take their biologics for more than 1-2 years is they can’t afford the copay. That may change” if prices drop, Dr. Strand said in an interview.
Before biosimilars became available, “countries with low GDPs [gross domestic products] had less access to biologics and more restrictions; richer countries had better access,” noted Dr. Tore K. Kvien, a rheumatologist and professor of rheumatology at the University of Oslo.
Greater affordability and access to biologics is the sole factor driving the biosimilar movement. “Cost is the only reason why you have biosimilars,” noted Dr. Bruce N. Cronstein, a rheumatologist and professor of medicine, pathology, and pharmacology at New York University. Aside from cost, there are, by definition, no meaningful differences between a biosimilar and the reference brand-name formulation.
Biosimilars, Dr. Cronstein said, “will be cheaper, but it won’t be like the difference with generic and brand-name statins. You won’t see a 90% price drop. Maybe we’ll see a 30% or 40% price cut, which is considerable. The biologics are all very expensive drugs. But biosimilars will not lead to anything like the savings with small generic molecules.”
While Dr. Cronstein noted that there are no guarantees regarding the timing of price changes, the extent of price cuts, or how competition might affect pricing of the brand-name alternative, the experience in Norway showed a quick, one-third price cut when Remsima became an option, Dr. Kvien said in an interview. For years, Norway has negotiated 1-year contracts for setting drug costs with manufacturers. Norwegian officials invite competitors to submit bids in an annual auction. Celltrion won the auction to make Remsima the infliximab of choice in Norway during 2014 for all six European Medicines Agency (EMA)-approved infliximab indications: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn’s disease, and ulcerative colitis.
“My colleagues tell me that the one-third reduction in price [compared with Remicade's price in 2014] was larger than they expected,” Dr. Kvien said. A year of treatment for an RA patient receiving Remsima averages about 6,000 euro now, down from the roughly 9,000 euro current annual cost for Remicade.
Dr. Strand maintained that economic pressures play a role in how easily biosimilars gain regulatory approval. For example, EMA received pressure from Eastern European countries where biologics have been relatively unavailable because of their price, she said. In the United States, pressure on the FDA comes from payers and patients because biologic copays are so high. But despite pressure, Dr. Strand and others believe that EMA and the FDA have set reasonable approval standards for biosimilars that clinicians can rely on.
“I think for all intents and purposes if EMA decides something is a biosimilar then I definitely think it is,” Dr. Strand said. “There may be subtle differences, but nothing big.” In some cases reference, brand-name biologics themselves have undergone substantial changes from what they originally had been, as happened with Enbrel and Rituxan, she noted. “The FDA will not entertain even a small change in an amino acid sequence, and requires two immunogenicity studies.”
Concerns about safety
But biosimilars may be a special case, where even the regulatory stamp of approval may not fully convince some clinicians.
“There is still quite a bit of skepticism,” Dr. Strand said. “I think there will be less skepticism once more data show that biosimilars are safe. The biggest concern seems to be that if the FDA decides something is not just biosimilar but also equivalent then there might be substitutions by a pharmacist without knowledge of the health care provider. I think there is concern because people are still not sure what biosimilar means. It will take more data to convince some people.”
“I think that physicians will be convinced by the data showing these compounds act in a similar way. What physicians worry about is that while these drugs may look good in a trial there might be some subtle difference that increases drug resistance or anaphylaxis,” said Dr. Cronstein. “I think clinicians will accept biosimilars and use them, but worry that a safety signal may not be seen in clinical trials. I think the FDA is trying to figure out how to be sure that switching from one drug to another does not cause an adverse effect. That is the major potential downside people see.”
The safety of switching to a biosimilar was an important enough issue for the Norwegian government to sponsor a 2.5 million euro trial to address the question. The 500-patient study, slated to start in the fall of 2014, will randomize patients on stable Remicade treatment to either remain on Remicade or switch to Remsima. The NOR-SWITCH trial will include patients with any of the six indications for which Remsima received EMA approval.
Until trial results are available, anticipated to be in 2016, Norway does not sanction switching patients on a stable Remicade regimen to Remsima even though Remsima is the infliximab of choice for patients starting infliximab for the first time. Despite this, some Norwegian departments have already made the switch in some patients, said Dr. Kvien, who is lead investigator for NOR-SWITCH. “They say the scientific data available now are sufficient to show switching is safe, but I do not agree.” The willingness of some Norwegian clinicians to switch their patients now from infliximab to the biosimilar shows how eager they and patients in Norway are to save money with Remsima.
While biosimilars face challenges entering and gaining traction in the European and American markets, they also seem driven by an overwhelming inevitability.
“Biosimilars will absolutely be routine in 10-20 years. They will be accepted, but it will take time,” Dr. Cronstein predicted.
“Biosimilars are here, they are not going away, and as patents run out we’ll see more and more of them,” predicted Dr. Paul Emery, professor of rheumatology at Leeds (England) University, while speaking at the annual European Congress of Rheumatology last June in Paris.
“I expect biosimilars will be important. My hope is that their lower cost will improve access to these treatments and this will mean better treatment for more patients around the world,” Dr. Kvien said.
Dr. Strand has been a consultant to Hospira, Celltrion, Amgen, Pfizer, Epirus, Baxter, and Merck Serono. Dr. Kvien has been a consultant to AbbVie, Bristol-Myers Squibb, Hospira, Celltrion, Pfizer/Wyeth, Merck Serono, Merck Sharp & Dohme, Roche, UCB, Orion, and Takeda. Dr. Cronstein has been a consultant to Pfizer and Merck Serono. Dr. Emery has been a consultant to AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, and Takeda.
On Twitter @mitchelzoler
The biosimilar age for rheumatology has arrived, and experts expect wider use of previously expensive biologic drugs as biosimilar competition drives prices down and makes biologics more affordable.
An infliximab biosimilar became the first such agent to arrive onto the European market in the second half of 2013, and by the start of 2014, it was already having an impact by, for example, dropping the cost of infliximab by a third in Norway. Norway may have received the biggest biosimilar effect so far because it runs an annual auction for the best prices on competing drugs from manufacturers and then mandates Norwegian clinicians to prescribe the lowest-price option when starting a new therapy.
A U.S. version of this scenario may soon follow. In August 2014, Celltrion and Hospira, the two companies jointly producing and marketing biosimilar forms of infliximab under the names Remsima and Inflectra (in parts of eastern Europe and elsewhere), announced they had submitted a marketing application to the Food and Drug Administration. In the announcement, Celltrion officials said they expected Food and Drug Administration approval within a year. If that were to happen, and if Celltrion mounts a successful patent challenge, the Remsima form of infliximab could become one of the first biosimilars on the U.S. market. (In July, Sandoz – a subsidiary of Novartis – announced it submitted an FDA application for Zarzio, a biosimilar version of filgrastim that until now has been only available as Neupogen, a granulocyte colony–stimulating factor. Biosimilar filgrastim seems like the only contender that could edge out Remsima as the first biosimilar on the U.S. market.)
At least two more biosimilars – a third form of infliximab, and a new form of etanercept – may come next, although rheumatologists following the field caution that additional studies are needed on top of what was reported for these two biosimilars last June at the annual European Congress of Rheumatology.
Lower cost broadens use
With one rheumatology biosimilar already on several global formularies and others nearing that status, the next challenge is convincing clinicians that cut-rate biologics are safe and effective and patients can switch from the brand-name form to a biosimilar without adverse effects. Meanwhile, payers and patients are pressing for biosimilars to cut the high cost of biologic treatment. By making biologic drugs more affordable for more patients, introduction of biosimilars will change patient care, experts said.
“A decrease in price will change how biologics are used in U.S. patients. In the United States today, about half of rheumatoid arthritis (RA) patients receive a biologic,” a rate substantially below where it should be, said Dr. Vibeke Strand, a biopharmaceutical consultant and rheumatologist at Stanford (Calif.) University. “Biosimilars will have a very big impact,” she predicted.
“Clinicians are under a lot of pressure from pharmacies, hospitals, and managed-care organization to avoid expensive medications when possible. Starting a biologic will become easier,” when prices start falling. And adherence may also improve. “Part of why patients don’t take their biologics for more than 1-2 years is they can’t afford the copay. That may change” if prices drop, Dr. Strand said in an interview.
Before biosimilars became available, “countries with low GDPs [gross domestic products] had less access to biologics and more restrictions; richer countries had better access,” noted Dr. Tore K. Kvien, a rheumatologist and professor of rheumatology at the University of Oslo.
Greater affordability and access to biologics is the sole factor driving the biosimilar movement. “Cost is the only reason why you have biosimilars,” noted Dr. Bruce N. Cronstein, a rheumatologist and professor of medicine, pathology, and pharmacology at New York University. Aside from cost, there are, by definition, no meaningful differences between a biosimilar and the reference brand-name formulation.
Biosimilars, Dr. Cronstein said, “will be cheaper, but it won’t be like the difference with generic and brand-name statins. You won’t see a 90% price drop. Maybe we’ll see a 30% or 40% price cut, which is considerable. The biologics are all very expensive drugs. But biosimilars will not lead to anything like the savings with small generic molecules.”
While Dr. Cronstein noted that there are no guarantees regarding the timing of price changes, the extent of price cuts, or how competition might affect pricing of the brand-name alternative, the experience in Norway showed a quick, one-third price cut when Remsima became an option, Dr. Kvien said in an interview. For years, Norway has negotiated 1-year contracts for setting drug costs with manufacturers. Norwegian officials invite competitors to submit bids in an annual auction. Celltrion won the auction to make Remsima the infliximab of choice in Norway during 2014 for all six European Medicines Agency (EMA)-approved infliximab indications: rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, Crohn’s disease, and ulcerative colitis.
“My colleagues tell me that the one-third reduction in price [compared with Remicade's price in 2014] was larger than they expected,” Dr. Kvien said. A year of treatment for an RA patient receiving Remsima averages about 6,000 euro now, down from the roughly 9,000 euro current annual cost for Remicade.
Dr. Strand maintained that economic pressures play a role in how easily biosimilars gain regulatory approval. For example, EMA received pressure from Eastern European countries where biologics have been relatively unavailable because of their price, she said. In the United States, pressure on the FDA comes from payers and patients because biologic copays are so high. But despite pressure, Dr. Strand and others believe that EMA and the FDA have set reasonable approval standards for biosimilars that clinicians can rely on.
“I think for all intents and purposes if EMA decides something is a biosimilar then I definitely think it is,” Dr. Strand said. “There may be subtle differences, but nothing big.” In some cases reference, brand-name biologics themselves have undergone substantial changes from what they originally had been, as happened with Enbrel and Rituxan, she noted. “The FDA will not entertain even a small change in an amino acid sequence, and requires two immunogenicity studies.”
Concerns about safety
But biosimilars may be a special case, where even the regulatory stamp of approval may not fully convince some clinicians.
“There is still quite a bit of skepticism,” Dr. Strand said. “I think there will be less skepticism once more data show that biosimilars are safe. The biggest concern seems to be that if the FDA decides something is not just biosimilar but also equivalent then there might be substitutions by a pharmacist without knowledge of the health care provider. I think there is concern because people are still not sure what biosimilar means. It will take more data to convince some people.”
“I think that physicians will be convinced by the data showing these compounds act in a similar way. What physicians worry about is that while these drugs may look good in a trial there might be some subtle difference that increases drug resistance or anaphylaxis,” said Dr. Cronstein. “I think clinicians will accept biosimilars and use them, but worry that a safety signal may not be seen in clinical trials. I think the FDA is trying to figure out how to be sure that switching from one drug to another does not cause an adverse effect. That is the major potential downside people see.”
The safety of switching to a biosimilar was an important enough issue for the Norwegian government to sponsor a 2.5 million euro trial to address the question. The 500-patient study, slated to start in the fall of 2014, will randomize patients on stable Remicade treatment to either remain on Remicade or switch to Remsima. The NOR-SWITCH trial will include patients with any of the six indications for which Remsima received EMA approval.
Until trial results are available, anticipated to be in 2016, Norway does not sanction switching patients on a stable Remicade regimen to Remsima even though Remsima is the infliximab of choice for patients starting infliximab for the first time. Despite this, some Norwegian departments have already made the switch in some patients, said Dr. Kvien, who is lead investigator for NOR-SWITCH. “They say the scientific data available now are sufficient to show switching is safe, but I do not agree.” The willingness of some Norwegian clinicians to switch their patients now from infliximab to the biosimilar shows how eager they and patients in Norway are to save money with Remsima.
While biosimilars face challenges entering and gaining traction in the European and American markets, they also seem driven by an overwhelming inevitability.
“Biosimilars will absolutely be routine in 10-20 years. They will be accepted, but it will take time,” Dr. Cronstein predicted.
“Biosimilars are here, they are not going away, and as patents run out we’ll see more and more of them,” predicted Dr. Paul Emery, professor of rheumatology at Leeds (England) University, while speaking at the annual European Congress of Rheumatology last June in Paris.
“I expect biosimilars will be important. My hope is that their lower cost will improve access to these treatments and this will mean better treatment for more patients around the world,” Dr. Kvien said.
Dr. Strand has been a consultant to Hospira, Celltrion, Amgen, Pfizer, Epirus, Baxter, and Merck Serono. Dr. Kvien has been a consultant to AbbVie, Bristol-Myers Squibb, Hospira, Celltrion, Pfizer/Wyeth, Merck Serono, Merck Sharp & Dohme, Roche, UCB, Orion, and Takeda. Dr. Cronstein has been a consultant to Pfizer and Merck Serono. Dr. Emery has been a consultant to AbbVie, Bristol-Myers Squibb, Merck, Pfizer, Roche, and Takeda.
On Twitter @mitchelzoler
VIDEO: New Drug Shows Efficacy in Metastatic CRC
MADRID – Results from a phase III trial of a new drug, TAS-102, that mimics the action of fluorouracil showed that it significantly boosted overall survival in heavily pretreated patients with metastatic colorectal cancer. This means that now two drugs, TAS-102 and regorafenib, have recently shown efficacy in this clinical setting, although the two drugs show notably different adverse-effect profiles, Dr. Christophe Tournigand said in an interview at the European Society for Medical Oncology Congress.
Another aspect when comparing these two new drugs is their ability to easily combine with other treatments. Regorafenib seems hard to combine. In contrast, the adverse-effect profile of TAS-102 suggests that it may be easier to use in combinations, said Dr. Tournigand, professor and head of medical oncology at Henri Mondor University Hospital in Créteil, France.
Dr. Tournigand has been an adviser to Roche, Sanofi, Merck, Amgen, and Bayer.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MADRID – Results from a phase III trial of a new drug, TAS-102, that mimics the action of fluorouracil showed that it significantly boosted overall survival in heavily pretreated patients with metastatic colorectal cancer. This means that now two drugs, TAS-102 and regorafenib, have recently shown efficacy in this clinical setting, although the two drugs show notably different adverse-effect profiles, Dr. Christophe Tournigand said in an interview at the European Society for Medical Oncology Congress.
Another aspect when comparing these two new drugs is their ability to easily combine with other treatments. Regorafenib seems hard to combine. In contrast, the adverse-effect profile of TAS-102 suggests that it may be easier to use in combinations, said Dr. Tournigand, professor and head of medical oncology at Henri Mondor University Hospital in Créteil, France.
Dr. Tournigand has been an adviser to Roche, Sanofi, Merck, Amgen, and Bayer.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MADRID – Results from a phase III trial of a new drug, TAS-102, that mimics the action of fluorouracil showed that it significantly boosted overall survival in heavily pretreated patients with metastatic colorectal cancer. This means that now two drugs, TAS-102 and regorafenib, have recently shown efficacy in this clinical setting, although the two drugs show notably different adverse-effect profiles, Dr. Christophe Tournigand said in an interview at the European Society for Medical Oncology Congress.
Another aspect when comparing these two new drugs is their ability to easily combine with other treatments. Regorafenib seems hard to combine. In contrast, the adverse-effect profile of TAS-102 suggests that it may be easier to use in combinations, said Dr. Tournigand, professor and head of medical oncology at Henri Mondor University Hospital in Créteil, France.
Dr. Tournigand has been an adviser to Roche, Sanofi, Merck, Amgen, and Bayer.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
EXPERT ANALYSIS FROM ESMO 2014
VIDEO: New drug shows efficacy in metastatic CRC
MADRID – Results from a phase III trial of a new drug, TAS-102, that mimics the action of fluorouracil showed that it significantly boosted overall survival in heavily pretreated patients with metastatic colorectal cancer. This means that now two drugs, TAS-102 and regorafenib, have recently shown efficacy in this clinical setting, although the two drugs show notably different adverse-effect profiles, Dr. Christophe Tournigand said in an interview at the European Society for Medical Oncology Congress.
Another aspect when comparing these two new drugs is their ability to easily combine with other treatments. Regorafenib seems hard to combine. In contrast, the adverse-effect profile of TAS-102 suggests that it may be easier to use in combinations, said Dr. Tournigand, professor and head of medical oncology at Henri Mondor University Hospital in Créteil, France.
Dr. Tournigand has been an adviser to Roche, Sanofi, Merck, Amgen, and Bayer.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @mitchelzoler
MADRID – Results from a phase III trial of a new drug, TAS-102, that mimics the action of fluorouracil showed that it significantly boosted overall survival in heavily pretreated patients with metastatic colorectal cancer. This means that now two drugs, TAS-102 and regorafenib, have recently shown efficacy in this clinical setting, although the two drugs show notably different adverse-effect profiles, Dr. Christophe Tournigand said in an interview at the European Society for Medical Oncology Congress.
Another aspect when comparing these two new drugs is their ability to easily combine with other treatments. Regorafenib seems hard to combine. In contrast, the adverse-effect profile of TAS-102 suggests that it may be easier to use in combinations, said Dr. Tournigand, professor and head of medical oncology at Henri Mondor University Hospital in Créteil, France.
Dr. Tournigand has been an adviser to Roche, Sanofi, Merck, Amgen, and Bayer.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
On Twitter @mitchelzoler
MADRID – Results from a phase III trial of a new drug, TAS-102, that mimics the action of fluorouracil showed that it significantly boosted overall survival in heavily pretreated patients with metastatic colorectal cancer. This means that now two drugs, TAS-102 and regorafenib, have recently shown efficacy in this clinical setting, although the two drugs show notably different adverse-effect profiles, Dr. Christophe Tournigand said in an interview at the European Society for Medical Oncology Congress.
Another aspect when comparing these two new drugs is their ability to easily combine with other treatments. Regorafenib seems hard to combine. In contrast, the adverse-effect profile of TAS-102 suggests that it may be easier to use in combinations, said Dr. Tournigand, professor and head of medical oncology at Henri Mondor University Hospital in Créteil, France.
Dr. Tournigand has been an adviser to Roche, Sanofi, Merck, Amgen, and Bayer.
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On Twitter @mitchelzoler
EXPERT ANALYSIS FROM ESMO 2014
VIDEO: Women with node-positive breast cancer benefit from dose-dense chemo
MADRID – Newly reported findings on the benefits from a dose-dense chemotherapy regimen for safely boosting the event-free survival rate in women with node-positive breast cancer help to better establish the dose-dense chemotherapy approach for these high-risk patients, Dr. Antonio Llombart-Cussac said in an interview during the European Society for Medical Oncology Congress.
Although the dose-dense strategy for administering epirubicin, paclitaxel, and cyclophosphamide has been widely adopted in the United States and Germany it has remained poorly used in most other European countries. The new German results, coupled with a similar report from Italian investigators last year, should help spark renewed interest in relying on the dose-dense approach for treating patients with early, node-positive breast cancer that is either triple negative or has the luminal B phenotype, said Dr. Llombart, head of medical oncology at Arnau de Vilanova Hospital in Valencia, Spain.
Dr. Llombart has received honoraria as a speaker for or advisor to Celgene, GlaxoSmithKline, Roche, AstraZeneca, Novartis, and Lilly.
On Twitter @mitchelzoler
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MADRID – Newly reported findings on the benefits from a dose-dense chemotherapy regimen for safely boosting the event-free survival rate in women with node-positive breast cancer help to better establish the dose-dense chemotherapy approach for these high-risk patients, Dr. Antonio Llombart-Cussac said in an interview during the European Society for Medical Oncology Congress.
Although the dose-dense strategy for administering epirubicin, paclitaxel, and cyclophosphamide has been widely adopted in the United States and Germany it has remained poorly used in most other European countries. The new German results, coupled with a similar report from Italian investigators last year, should help spark renewed interest in relying on the dose-dense approach for treating patients with early, node-positive breast cancer that is either triple negative or has the luminal B phenotype, said Dr. Llombart, head of medical oncology at Arnau de Vilanova Hospital in Valencia, Spain.
Dr. Llombart has received honoraria as a speaker for or advisor to Celgene, GlaxoSmithKline, Roche, AstraZeneca, Novartis, and Lilly.
On Twitter @mitchelzoler
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
MADRID – Newly reported findings on the benefits from a dose-dense chemotherapy regimen for safely boosting the event-free survival rate in women with node-positive breast cancer help to better establish the dose-dense chemotherapy approach for these high-risk patients, Dr. Antonio Llombart-Cussac said in an interview during the European Society for Medical Oncology Congress.
Although the dose-dense strategy for administering epirubicin, paclitaxel, and cyclophosphamide has been widely adopted in the United States and Germany it has remained poorly used in most other European countries. The new German results, coupled with a similar report from Italian investigators last year, should help spark renewed interest in relying on the dose-dense approach for treating patients with early, node-positive breast cancer that is either triple negative or has the luminal B phenotype, said Dr. Llombart, head of medical oncology at Arnau de Vilanova Hospital in Valencia, Spain.
Dr. Llombart has received honoraria as a speaker for or advisor to Celgene, GlaxoSmithKline, Roche, AstraZeneca, Novartis, and Lilly.
On Twitter @mitchelzoler
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
AT ESMO 2014
Dose-dense chemo aids high-risk breast cancer patients
MADRID – A dose-dense, third-generation chemotherapy regimen surpassed a more standard regimen for adjuvant therapy of high-risk breast cancer patients with positive nodes and either triple-negative tumors or aggressive, luminal B phenotypes in an analysis of about 1,600 patients treated in two German phase III trials.
Adding these results to those from two prior phase III studies with similar findings firmly establishes the intensified, dose-dense approach as the preferred way to deliver third-generation chemotherapy to patients with these breast-cancer presentations, Dr. Christoph Thomssen reported at the annual congress of the European Society for Medical Oncology.
“We suggest adding iddETC [intense dose-dense epirubicin, paclitaxel, cyclophosphamide] to the group of preferred regimens in current guidelines,” said Dr. Thomssen, professor and director of gynecology at the University Clinic in Halle, Germany. Dr. Thomssen noted that some existing guidelines for breast cancer chemotherapy, such as from the National Comprehensive Cancer Network, already recommend dose-dense adjuvant therapy for breast cancer patients with positive lymph nodes and either triple-negative disease or the luminal B phenotype,
But in other countries, such as in Spain, France, and Italy, adoption of a dose-dense approach has not caught on, said Dr. Antonio Llombart-Cussac, head of medical oncology at Arnau de Vilanova Hospital in Valencia, Spain. For example, fewer than 5% of women with breast cancer who fit one of these high-risk profiles and receive treatment at a Spanish hospital currently get a dose-dense regimen, he said in an interview. The new evidence reported by Dr. Thomssen as well as results from an Italian study reported last year should together help change the practice of physicians who have not yet adopted the dose-dense approach, Dr. Llombart said.
The first German study, known as AGO ETC compared a standard schedule for administering epirubicin, cyclophosphamide, and paclitaxel sequentially at 3-week intervals with an accelerated schedule in which patients received dosages every 2 weeks: three sequential doses of 150 mg epirubicin/m2 every 2 weeks, followed by three sequential doses of 225 mg/m2 paclitaxel every 2 weeks, and finally three sequential dosages of 2.5 g/m2 cyclophosphamide every 2 weeks. The study randomized 1,284 patients with at least four positive lymph nodes during 1998-2003. During an average 5-year follow-up, the rate of event-free survival was 70% among patients on the dose-dense regimen and 62% among those on the standard regimen (P less than .001), a 0.72 hazard ratio (95% confidence interval 0.59-0.87), Dr. Thomssen reported.
The second trial he presented, known as GAIN (German Adjuvant Intergroup Node-Positive study), randomized 3,023 patients to either the same dose-dense regimen tested in the first study (but with 2.0 g/m2 cyclophosphamide), or to a second, different dose-dense regimen that also included capecitabine. Five-year results in this second trial showed a virtually identical, 80% event-free survival rate in each of the two treatment arms.
Dr. Thomssen highlighted the similarity of this 80% rate seen in 1,498 patients who received a dose-dense regimen that was very similar to the one used in the first study with the 70% event-free survival rate seen in the dose-dense arm of the first study. He concluded that these results from the GAIN trial validated the results from the first trial. Among patients in GAIN with at least four positive lymph nodes, who most closely matched the patients enrolled in the first trial, the 5-year event-free survival rate was 75%.
Additional subgroup analyses of results from the first trial showed that the added benefit from the dose-dense regimen occurred consistently across all patient subgroups. The dose-dense regimen was also well tolerated, producing about a 7% rate of febrile neutropenia, and a cardiac failure rate of less than 1%. The most common adverse event was peripheral neuropathy, which occurred in 25%-55% of treated patients.
On Twitter @mitchelzoler
The results from these two German trials confirm that dose-dense chemotherapy regimens are extremely effective for adjuvant treatment of women with high-risk, node-positive early breast cancer of either the triple-negative type or with the luminal B phenotype.
U.S. researchers first reported similar findings in results published more than 10 years ago (J. Clin. Onc. 2003;21:1431-9), although concerns existed about the relevance of the treatment received by control patients in that study. Last year, Dr. Cognetti and other Italian researchers reported a significant benefit from a dose-dense regimen in a controlled study, but those results remain unpublished as of now. Further confirmation by these two German studies now clearly establishes dose-dense regimens as the standard of care for adjuvant treatment of these types of breast cancer patients. The intensified, dose-dense method is the preferred way to administer anthracyclines and taxanes for adjuvant treatment in these high-risk patients.
|
Dr. Antonio Llombart-Cussac |
In some countries, such as in the United States and Germany, dose-dense regimens are already standard, but not in other European countries including Spain, Italy, and France. One reason is that the dose-dense method costs more, as patients more often need support by treatment with granulocyte colony stimulating factor, an agent that can increase treatment costs three-fold. Some clinicians have also had lingering concern about the potential of the dose-dense method to boost episodes of secondary leukemia, So far, follow-up has shown no indication of increased hematologic malignancies in the German or Italian patients, but follow-up in these three trials has been brief, relative to the 10-20 years it could take for this adverse effect to appear. However, the immediate efficacy benefit from dose-dense treatment is important enough to justify using this approach even if we eventually see a small increased rate of late leukemias.
Dr. Antonio Llombart-Cussac is head of medical oncology at Arnau de Vilanova Hospital in Valencia, Spain. He has received honoraria as a speaker for or adviser to Celgene, GlaxoSmithKline, Roche, AstraZeneca, Novartis, and Lilly. He made these comments as a designated discussant for the reports and in an interview.
The results from these two German trials confirm that dose-dense chemotherapy regimens are extremely effective for adjuvant treatment of women with high-risk, node-positive early breast cancer of either the triple-negative type or with the luminal B phenotype.
U.S. researchers first reported similar findings in results published more than 10 years ago (J. Clin. Onc. 2003;21:1431-9), although concerns existed about the relevance of the treatment received by control patients in that study. Last year, Dr. Cognetti and other Italian researchers reported a significant benefit from a dose-dense regimen in a controlled study, but those results remain unpublished as of now. Further confirmation by these two German studies now clearly establishes dose-dense regimens as the standard of care for adjuvant treatment of these types of breast cancer patients. The intensified, dose-dense method is the preferred way to administer anthracyclines and taxanes for adjuvant treatment in these high-risk patients.
|
|
Dr. Antonio Llombart-Cussac |
In some countries, such as in the United States and Germany, dose-dense regimens are already standard, but not in other European countries including Spain, Italy, and France. One reason is that the dose-dense method costs more, as patients more often need support by treatment with granulocyte colony stimulating factor, an agent that can increase treatment costs three-fold. Some clinicians have also had lingering concern about the potential of the dose-dense method to boost episodes of secondary leukemia, So far, follow-up has shown no indication of increased hematologic malignancies in the German or Italian patients, but follow-up in these three trials has been brief, relative to the 10-20 years it could take for this adverse effect to appear. However, the immediate efficacy benefit from dose-dense treatment is important enough to justify using this approach even if we eventually see a small increased rate of late leukemias.
Dr. Antonio Llombart-Cussac is head of medical oncology at Arnau de Vilanova Hospital in Valencia, Spain. He has received honoraria as a speaker for or adviser to Celgene, GlaxoSmithKline, Roche, AstraZeneca, Novartis, and Lilly. He made these comments as a designated discussant for the reports and in an interview.
The results from these two German trials confirm that dose-dense chemotherapy regimens are extremely effective for adjuvant treatment of women with high-risk, node-positive early breast cancer of either the triple-negative type or with the luminal B phenotype.
U.S. researchers first reported similar findings in results published more than 10 years ago (J. Clin. Onc. 2003;21:1431-9), although concerns existed about the relevance of the treatment received by control patients in that study. Last year, Dr. Cognetti and other Italian researchers reported a significant benefit from a dose-dense regimen in a controlled study, but those results remain unpublished as of now. Further confirmation by these two German studies now clearly establishes dose-dense regimens as the standard of care for adjuvant treatment of these types of breast cancer patients. The intensified, dose-dense method is the preferred way to administer anthracyclines and taxanes for adjuvant treatment in these high-risk patients.
|
|
Dr. Antonio Llombart-Cussac |
In some countries, such as in the United States and Germany, dose-dense regimens are already standard, but not in other European countries including Spain, Italy, and France. One reason is that the dose-dense method costs more, as patients more often need support by treatment with granulocyte colony stimulating factor, an agent that can increase treatment costs three-fold. Some clinicians have also had lingering concern about the potential of the dose-dense method to boost episodes of secondary leukemia, So far, follow-up has shown no indication of increased hematologic malignancies in the German or Italian patients, but follow-up in these three trials has been brief, relative to the 10-20 years it could take for this adverse effect to appear. However, the immediate efficacy benefit from dose-dense treatment is important enough to justify using this approach even if we eventually see a small increased rate of late leukemias.
Dr. Antonio Llombart-Cussac is head of medical oncology at Arnau de Vilanova Hospital in Valencia, Spain. He has received honoraria as a speaker for or adviser to Celgene, GlaxoSmithKline, Roche, AstraZeneca, Novartis, and Lilly. He made these comments as a designated discussant for the reports and in an interview.
MADRID – A dose-dense, third-generation chemotherapy regimen surpassed a more standard regimen for adjuvant therapy of high-risk breast cancer patients with positive nodes and either triple-negative tumors or aggressive, luminal B phenotypes in an analysis of about 1,600 patients treated in two German phase III trials.
Adding these results to those from two prior phase III studies with similar findings firmly establishes the intensified, dose-dense approach as the preferred way to deliver third-generation chemotherapy to patients with these breast-cancer presentations, Dr. Christoph Thomssen reported at the annual congress of the European Society for Medical Oncology.
“We suggest adding iddETC [intense dose-dense epirubicin, paclitaxel, cyclophosphamide] to the group of preferred regimens in current guidelines,” said Dr. Thomssen, professor and director of gynecology at the University Clinic in Halle, Germany. Dr. Thomssen noted that some existing guidelines for breast cancer chemotherapy, such as from the National Comprehensive Cancer Network, already recommend dose-dense adjuvant therapy for breast cancer patients with positive lymph nodes and either triple-negative disease or the luminal B phenotype,
But in other countries, such as in Spain, France, and Italy, adoption of a dose-dense approach has not caught on, said Dr. Antonio Llombart-Cussac, head of medical oncology at Arnau de Vilanova Hospital in Valencia, Spain. For example, fewer than 5% of women with breast cancer who fit one of these high-risk profiles and receive treatment at a Spanish hospital currently get a dose-dense regimen, he said in an interview. The new evidence reported by Dr. Thomssen as well as results from an Italian study reported last year should together help change the practice of physicians who have not yet adopted the dose-dense approach, Dr. Llombart said.
The first German study, known as AGO ETC compared a standard schedule for administering epirubicin, cyclophosphamide, and paclitaxel sequentially at 3-week intervals with an accelerated schedule in which patients received dosages every 2 weeks: three sequential doses of 150 mg epirubicin/m2 every 2 weeks, followed by three sequential doses of 225 mg/m2 paclitaxel every 2 weeks, and finally three sequential dosages of 2.5 g/m2 cyclophosphamide every 2 weeks. The study randomized 1,284 patients with at least four positive lymph nodes during 1998-2003. During an average 5-year follow-up, the rate of event-free survival was 70% among patients on the dose-dense regimen and 62% among those on the standard regimen (P less than .001), a 0.72 hazard ratio (95% confidence interval 0.59-0.87), Dr. Thomssen reported.
The second trial he presented, known as GAIN (German Adjuvant Intergroup Node-Positive study), randomized 3,023 patients to either the same dose-dense regimen tested in the first study (but with 2.0 g/m2 cyclophosphamide), or to a second, different dose-dense regimen that also included capecitabine. Five-year results in this second trial showed a virtually identical, 80% event-free survival rate in each of the two treatment arms.
Dr. Thomssen highlighted the similarity of this 80% rate seen in 1,498 patients who received a dose-dense regimen that was very similar to the one used in the first study with the 70% event-free survival rate seen in the dose-dense arm of the first study. He concluded that these results from the GAIN trial validated the results from the first trial. Among patients in GAIN with at least four positive lymph nodes, who most closely matched the patients enrolled in the first trial, the 5-year event-free survival rate was 75%.
Additional subgroup analyses of results from the first trial showed that the added benefit from the dose-dense regimen occurred consistently across all patient subgroups. The dose-dense regimen was also well tolerated, producing about a 7% rate of febrile neutropenia, and a cardiac failure rate of less than 1%. The most common adverse event was peripheral neuropathy, which occurred in 25%-55% of treated patients.
On Twitter @mitchelzoler
MADRID – A dose-dense, third-generation chemotherapy regimen surpassed a more standard regimen for adjuvant therapy of high-risk breast cancer patients with positive nodes and either triple-negative tumors or aggressive, luminal B phenotypes in an analysis of about 1,600 patients treated in two German phase III trials.
Adding these results to those from two prior phase III studies with similar findings firmly establishes the intensified, dose-dense approach as the preferred way to deliver third-generation chemotherapy to patients with these breast-cancer presentations, Dr. Christoph Thomssen reported at the annual congress of the European Society for Medical Oncology.
“We suggest adding iddETC [intense dose-dense epirubicin, paclitaxel, cyclophosphamide] to the group of preferred regimens in current guidelines,” said Dr. Thomssen, professor and director of gynecology at the University Clinic in Halle, Germany. Dr. Thomssen noted that some existing guidelines for breast cancer chemotherapy, such as from the National Comprehensive Cancer Network, already recommend dose-dense adjuvant therapy for breast cancer patients with positive lymph nodes and either triple-negative disease or the luminal B phenotype,
But in other countries, such as in Spain, France, and Italy, adoption of a dose-dense approach has not caught on, said Dr. Antonio Llombart-Cussac, head of medical oncology at Arnau de Vilanova Hospital in Valencia, Spain. For example, fewer than 5% of women with breast cancer who fit one of these high-risk profiles and receive treatment at a Spanish hospital currently get a dose-dense regimen, he said in an interview. The new evidence reported by Dr. Thomssen as well as results from an Italian study reported last year should together help change the practice of physicians who have not yet adopted the dose-dense approach, Dr. Llombart said.
The first German study, known as AGO ETC compared a standard schedule for administering epirubicin, cyclophosphamide, and paclitaxel sequentially at 3-week intervals with an accelerated schedule in which patients received dosages every 2 weeks: three sequential doses of 150 mg epirubicin/m2 every 2 weeks, followed by three sequential doses of 225 mg/m2 paclitaxel every 2 weeks, and finally three sequential dosages of 2.5 g/m2 cyclophosphamide every 2 weeks. The study randomized 1,284 patients with at least four positive lymph nodes during 1998-2003. During an average 5-year follow-up, the rate of event-free survival was 70% among patients on the dose-dense regimen and 62% among those on the standard regimen (P less than .001), a 0.72 hazard ratio (95% confidence interval 0.59-0.87), Dr. Thomssen reported.
The second trial he presented, known as GAIN (German Adjuvant Intergroup Node-Positive study), randomized 3,023 patients to either the same dose-dense regimen tested in the first study (but with 2.0 g/m2 cyclophosphamide), or to a second, different dose-dense regimen that also included capecitabine. Five-year results in this second trial showed a virtually identical, 80% event-free survival rate in each of the two treatment arms.
Dr. Thomssen highlighted the similarity of this 80% rate seen in 1,498 patients who received a dose-dense regimen that was very similar to the one used in the first study with the 70% event-free survival rate seen in the dose-dense arm of the first study. He concluded that these results from the GAIN trial validated the results from the first trial. Among patients in GAIN with at least four positive lymph nodes, who most closely matched the patients enrolled in the first trial, the 5-year event-free survival rate was 75%.
Additional subgroup analyses of results from the first trial showed that the added benefit from the dose-dense regimen occurred consistently across all patient subgroups. The dose-dense regimen was also well tolerated, producing about a 7% rate of febrile neutropenia, and a cardiac failure rate of less than 1%. The most common adverse event was peripheral neuropathy, which occurred in 25%-55% of treated patients.
On Twitter @mitchelzoler
AT ESMO 2014
Key clinical point: A dose-dense chemotherapy regimen surpassed conventional dosing in high-risk breast-cancer patients.
Major finding: A dose-dense regimen produced 70% 5-year event-free survival, compared with a 62% rate with standard treatment.
Data source: AGO ETC and GAIN, two multicenter, controlled phase III German trials with a total of 2,141 patients receiving the dose-dense regimen.
Disclosures: The two investigator-initiated trials received grant support from Amgen, Bristol-Myers Squibb, Janssen-Cilag, and Roche. Dr. Thomssen has received honoraria as a speaker for Amgen, Celgene, Pfizer, Roche, Sanofi-Aventis, and TEVA.
