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In the reemergence of typhus, the challenge is early diagnosis
SAN DIEGO – Typhus in many forms, particularly scrub typhus, has reemerged worldwide, but none of these rickettsial infections poses a significant public health threat if promptly diagnosed, according to an update presented at an annual scientific meeting on infectious diseases.
Scrub typhus, which is spread by several species of trombiculid mites or chiggers, poses a large threat in regard to typhus epidemics, particularly in Asia, but sporadic cases of different types of typhus are being seen everywhere, including in the United States, according to George M. Varghese, MD, department of infectious diseases, Christian Medical College, Vellore, India.
“The typhus diseases are clinically similar but epidemiologically and etiologically distinct,” reported Dr. Varghese, “but doxycycline is the drug of choice for almost all of the rickettsial infections.”
The bacteria responsible for scrub typhus is Orientia tsutsugamushi, which is no longer included in the genus Rickettsia, but Dr. Varghese, who has published frequently on the epidemiology of scrub typhus, said that it is still appropriately grouped among rickettsial infections. It shares many features with the other rickettsioses, which were considered to be fading but are now resurging after the large epidemics that occurred prior to the introduction of antibiotics.
In the World Wars, Rickettsia prowazekii – which is carried and spread by body lice – was the most well known typhus threat. According to Dr. Varghese, this bacterium may have killed more soldiers in these conflicts than did firearms. Although R. prowazekii has not disappeared as a source of typhus outbreaks, particularly in South America and Africa, there are current epidemics produced from rickettsial infections carried by fleas, such as R. typhi, or ticks, like R. rickettsii, or mice, like R. felis.
For clinical detection of these forms of typhus, there are differences. Although all are associated with a rapid onset of fever, headache, and myalgia, subtle signs can be helpful in making a diagnosis while waiting for laboratory confirmation. For example, scrub typhus, unlike Rocky Mountain Fever, which is caused by tick bites, does not generally include a rash. Rather, eschars, which are small patches of necrotic skin, are far more characteristic.
“Serological tests are the most common diagnostic tool for typhus, but serology may not allow early diagnosis. You can obtain a false positive in the early stages of disease,” Dr. Varghese warned. To speed the diagnosis, he said that looking for the clinical clues characteristic of the suspected form of typhus, such as the scrub typhus-associated eschar, “is valuable.” However, he also emphasized that even with positive serology results, “good epidemiology and history is helpful for laboratory interpretation.”
A variety of serological tests can identify typhus pathogens, but ELISA is now the most widely used, according to Dr. Varghese, noting that this test offers a sensitivity of 93% and a specificity of 91%. Both are higher than those provided by alternatives. As a result of improved sensitivity of diagnostic tests, prevalence rates of some forms of typhus have proved to be unexpectedly high. For example, in a study undertaken in his region of India, the seroprevalence of scrub typhus was 31.8% (Trop Med Int Health. 2017;22:576-82. doi: 10.1111/tmi.12853).
Of unmet needs in the clinical management of typhus, Dr. Varghese listed better strategies for point-of-care diagnosis and treatment and better data on how to manage patients who are severely ill. Advanced disease, which is common to rural areas with limited access to health care, is the source of almost all typhus mortality, according to Dr. Varghese. He described a trial now being initiated in severe disease that will compare intravenous doxycycline to IV azithromycin and to a combination of both IV doxycycline and azithromycin.
Although Dr. Varghese cautioned that reports of resistant typhus infections, particularly in Thailand, might prove to be the next big clinical challenge in typhus, he said that progress is being made toward reducing the burden of this disease in his area of the world. In a disease associated with a mortality of 50% if left untreated, he attributes gains to earlier diagnosis and prompt treatment.
At his medical center, “we have been working with this disease for a decade and a half,” he said, referring to scrub typhus. “When we started off, the mortality was around 15% after diagnosis. Today, the mortality is about 5%-7%.”
Dr. Varghese reported that he has no financial relationships relevant to this topic. The event was the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
SAN DIEGO – Typhus in many forms, particularly scrub typhus, has reemerged worldwide, but none of these rickettsial infections poses a significant public health threat if promptly diagnosed, according to an update presented at an annual scientific meeting on infectious diseases.
Scrub typhus, which is spread by several species of trombiculid mites or chiggers, poses a large threat in regard to typhus epidemics, particularly in Asia, but sporadic cases of different types of typhus are being seen everywhere, including in the United States, according to George M. Varghese, MD, department of infectious diseases, Christian Medical College, Vellore, India.
“The typhus diseases are clinically similar but epidemiologically and etiologically distinct,” reported Dr. Varghese, “but doxycycline is the drug of choice for almost all of the rickettsial infections.”
The bacteria responsible for scrub typhus is Orientia tsutsugamushi, which is no longer included in the genus Rickettsia, but Dr. Varghese, who has published frequently on the epidemiology of scrub typhus, said that it is still appropriately grouped among rickettsial infections. It shares many features with the other rickettsioses, which were considered to be fading but are now resurging after the large epidemics that occurred prior to the introduction of antibiotics.
In the World Wars, Rickettsia prowazekii – which is carried and spread by body lice – was the most well known typhus threat. According to Dr. Varghese, this bacterium may have killed more soldiers in these conflicts than did firearms. Although R. prowazekii has not disappeared as a source of typhus outbreaks, particularly in South America and Africa, there are current epidemics produced from rickettsial infections carried by fleas, such as R. typhi, or ticks, like R. rickettsii, or mice, like R. felis.
For clinical detection of these forms of typhus, there are differences. Although all are associated with a rapid onset of fever, headache, and myalgia, subtle signs can be helpful in making a diagnosis while waiting for laboratory confirmation. For example, scrub typhus, unlike Rocky Mountain Fever, which is caused by tick bites, does not generally include a rash. Rather, eschars, which are small patches of necrotic skin, are far more characteristic.
“Serological tests are the most common diagnostic tool for typhus, but serology may not allow early diagnosis. You can obtain a false positive in the early stages of disease,” Dr. Varghese warned. To speed the diagnosis, he said that looking for the clinical clues characteristic of the suspected form of typhus, such as the scrub typhus-associated eschar, “is valuable.” However, he also emphasized that even with positive serology results, “good epidemiology and history is helpful for laboratory interpretation.”
A variety of serological tests can identify typhus pathogens, but ELISA is now the most widely used, according to Dr. Varghese, noting that this test offers a sensitivity of 93% and a specificity of 91%. Both are higher than those provided by alternatives. As a result of improved sensitivity of diagnostic tests, prevalence rates of some forms of typhus have proved to be unexpectedly high. For example, in a study undertaken in his region of India, the seroprevalence of scrub typhus was 31.8% (Trop Med Int Health. 2017;22:576-82. doi: 10.1111/tmi.12853).
Of unmet needs in the clinical management of typhus, Dr. Varghese listed better strategies for point-of-care diagnosis and treatment and better data on how to manage patients who are severely ill. Advanced disease, which is common to rural areas with limited access to health care, is the source of almost all typhus mortality, according to Dr. Varghese. He described a trial now being initiated in severe disease that will compare intravenous doxycycline to IV azithromycin and to a combination of both IV doxycycline and azithromycin.
Although Dr. Varghese cautioned that reports of resistant typhus infections, particularly in Thailand, might prove to be the next big clinical challenge in typhus, he said that progress is being made toward reducing the burden of this disease in his area of the world. In a disease associated with a mortality of 50% if left untreated, he attributes gains to earlier diagnosis and prompt treatment.
At his medical center, “we have been working with this disease for a decade and a half,” he said, referring to scrub typhus. “When we started off, the mortality was around 15% after diagnosis. Today, the mortality is about 5%-7%.”
Dr. Varghese reported that he has no financial relationships relevant to this topic. The event was the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
SAN DIEGO – Typhus in many forms, particularly scrub typhus, has reemerged worldwide, but none of these rickettsial infections poses a significant public health threat if promptly diagnosed, according to an update presented at an annual scientific meeting on infectious diseases.
Scrub typhus, which is spread by several species of trombiculid mites or chiggers, poses a large threat in regard to typhus epidemics, particularly in Asia, but sporadic cases of different types of typhus are being seen everywhere, including in the United States, according to George M. Varghese, MD, department of infectious diseases, Christian Medical College, Vellore, India.
“The typhus diseases are clinically similar but epidemiologically and etiologically distinct,” reported Dr. Varghese, “but doxycycline is the drug of choice for almost all of the rickettsial infections.”
The bacteria responsible for scrub typhus is Orientia tsutsugamushi, which is no longer included in the genus Rickettsia, but Dr. Varghese, who has published frequently on the epidemiology of scrub typhus, said that it is still appropriately grouped among rickettsial infections. It shares many features with the other rickettsioses, which were considered to be fading but are now resurging after the large epidemics that occurred prior to the introduction of antibiotics.
In the World Wars, Rickettsia prowazekii – which is carried and spread by body lice – was the most well known typhus threat. According to Dr. Varghese, this bacterium may have killed more soldiers in these conflicts than did firearms. Although R. prowazekii has not disappeared as a source of typhus outbreaks, particularly in South America and Africa, there are current epidemics produced from rickettsial infections carried by fleas, such as R. typhi, or ticks, like R. rickettsii, or mice, like R. felis.
For clinical detection of these forms of typhus, there are differences. Although all are associated with a rapid onset of fever, headache, and myalgia, subtle signs can be helpful in making a diagnosis while waiting for laboratory confirmation. For example, scrub typhus, unlike Rocky Mountain Fever, which is caused by tick bites, does not generally include a rash. Rather, eschars, which are small patches of necrotic skin, are far more characteristic.
“Serological tests are the most common diagnostic tool for typhus, but serology may not allow early diagnosis. You can obtain a false positive in the early stages of disease,” Dr. Varghese warned. To speed the diagnosis, he said that looking for the clinical clues characteristic of the suspected form of typhus, such as the scrub typhus-associated eschar, “is valuable.” However, he also emphasized that even with positive serology results, “good epidemiology and history is helpful for laboratory interpretation.”
A variety of serological tests can identify typhus pathogens, but ELISA is now the most widely used, according to Dr. Varghese, noting that this test offers a sensitivity of 93% and a specificity of 91%. Both are higher than those provided by alternatives. As a result of improved sensitivity of diagnostic tests, prevalence rates of some forms of typhus have proved to be unexpectedly high. For example, in a study undertaken in his region of India, the seroprevalence of scrub typhus was 31.8% (Trop Med Int Health. 2017;22:576-82. doi: 10.1111/tmi.12853).
Of unmet needs in the clinical management of typhus, Dr. Varghese listed better strategies for point-of-care diagnosis and treatment and better data on how to manage patients who are severely ill. Advanced disease, which is common to rural areas with limited access to health care, is the source of almost all typhus mortality, according to Dr. Varghese. He described a trial now being initiated in severe disease that will compare intravenous doxycycline to IV azithromycin and to a combination of both IV doxycycline and azithromycin.
Although Dr. Varghese cautioned that reports of resistant typhus infections, particularly in Thailand, might prove to be the next big clinical challenge in typhus, he said that progress is being made toward reducing the burden of this disease in his area of the world. In a disease associated with a mortality of 50% if left untreated, he attributes gains to earlier diagnosis and prompt treatment.
At his medical center, “we have been working with this disease for a decade and a half,” he said, referring to scrub typhus. “When we started off, the mortality was around 15% after diagnosis. Today, the mortality is about 5%-7%.”
Dr. Varghese reported that he has no financial relationships relevant to this topic. The event was the combined annual meetings of the Infectious Diseases Society of America, the Society for Healthcare Epidemiology of America, the HIV Medicine Association, and the Pediatric Infectious Diseases Society.
AT IDWEEK 2017
Key clinical point:
Major finding: Almost all of the estimated 15,000 annual global deaths attributed to rickettsial infections could be eliminated with prompt doxycycline therapy.
Data source: Topic review.
Disclosures: Dr. Varghese reported that he has no relevant conflicts to disclose.
Flotetuzumab for AML passes phase 1 test
MADRID – Flotetuzumab, a novel bispecific monoclonal antibody that employs a proprietary technology to redirect T lymphocytes to kill CD123-expressing cells, was safe and demonstrated efficacy in patients with acute myeloid leukemia in a phase 1 trial, based on data presented at the European Society for Medical Oncology (ESMO) Congress.
Flotetuzumab combines a portion of antibody recognizing CD3, which is an activating molecule expressed by T cells, and an arm that recognizes CD123 on the cancer cell, explained Norbert Vey, MD, PhD, Head, Leukemia Treatment Unit, Institut Paoli-Calmettes, Marseille, France. This bispecific quality, produced through a proprietary technology called Dual-Affinity ReTargeting, is considered promising because CD123 is expressed by more than 90% of AML cells and is highly expressed on stem cells involved in initiating myelodysplastic syndrome (MDS).
In this dose-ranging study (NCT02152956), 42 patients with AML and 5 patients with MDS were treated in the first cycle with infusions of flotetuzumab on either a continuous 7-day or a 4-days-on, 3-days-off schedule. For subsequent cycles, patients received the 4-days-on, 3-days-off schedule. Continuous infusion is employed due to the short half-life of flotetuzumab.
The most common adverse events were infusion-related reactions, which were observed in 76.6% of patients. Pyrexia, a potential sign of cytokine release syndrome (CRS), was observed in 23.4% of patients, who were given tocilizumab at the earliest sign of CRS. Two patients had grade 3 CRS, and one discontinued therapy. There was also one case of grade 3 myalgia. Dr. Vey characterized the overall level of adverse events as “acceptable.”
In addition to its relative safety, flotetuzumab was associated with “encouraging antileukemic activity,” Dr. Vey said. Six of 14 patients receiving doses that exceeded 500 ng/kg per day had objective responses and two of these patients had complete responses. Again, toxicity at these dose levels was considered manageable.
“This rate of clinical response is exciting,” commented Tim Somervaille, MD, Senior Group Leader, Leukemia Biology Laboratory, Cancer Research UK Institute, Manchester (England). An ESMO-invited discussant on this paper, Dr. Somervaille expressed enthusiasm in general about a growing role for bispecific T-cell engagers. Blinatumomab, the first of these agents, received regulatory approval for refractory AML in 2014.
“There are a number of these bispecific T cell antibodies that are in early-phase trials,” said Dr. Somervaille, citing several that also target CD123 within the context of a different partner antigen than that employed by flotetuzumab. He also mentioned ongoing efforts to develop bispecific natural killer cell engagers that target malignant cells through immune activation.
As for flotetuzumab, the phase 1 trial provided adequate data to encourage further development.
“A cohort expansion is now ongoing and enrolling patients at 11 sites in the United States and Europe,” Dr. Vey reported. “A clinical update on these results is expected by the end of the year.”
Dr. Vey reported financial relationships with Bristol-Myers Squibb, Novartis, and Servier.
MacroGenics retains full development and commercialization rights to flotetuzumab in the United States, Canada, Mexico, Japan, South Korea, and India. Servier participates in the development and has rights to flotetuzumab in all other countries. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the investigational treatment of AML, according to a press release from MacroGenics.
MADRID – Flotetuzumab, a novel bispecific monoclonal antibody that employs a proprietary technology to redirect T lymphocytes to kill CD123-expressing cells, was safe and demonstrated efficacy in patients with acute myeloid leukemia in a phase 1 trial, based on data presented at the European Society for Medical Oncology (ESMO) Congress.
Flotetuzumab combines a portion of antibody recognizing CD3, which is an activating molecule expressed by T cells, and an arm that recognizes CD123 on the cancer cell, explained Norbert Vey, MD, PhD, Head, Leukemia Treatment Unit, Institut Paoli-Calmettes, Marseille, France. This bispecific quality, produced through a proprietary technology called Dual-Affinity ReTargeting, is considered promising because CD123 is expressed by more than 90% of AML cells and is highly expressed on stem cells involved in initiating myelodysplastic syndrome (MDS).
In this dose-ranging study (NCT02152956), 42 patients with AML and 5 patients with MDS were treated in the first cycle with infusions of flotetuzumab on either a continuous 7-day or a 4-days-on, 3-days-off schedule. For subsequent cycles, patients received the 4-days-on, 3-days-off schedule. Continuous infusion is employed due to the short half-life of flotetuzumab.
The most common adverse events were infusion-related reactions, which were observed in 76.6% of patients. Pyrexia, a potential sign of cytokine release syndrome (CRS), was observed in 23.4% of patients, who were given tocilizumab at the earliest sign of CRS. Two patients had grade 3 CRS, and one discontinued therapy. There was also one case of grade 3 myalgia. Dr. Vey characterized the overall level of adverse events as “acceptable.”
In addition to its relative safety, flotetuzumab was associated with “encouraging antileukemic activity,” Dr. Vey said. Six of 14 patients receiving doses that exceeded 500 ng/kg per day had objective responses and two of these patients had complete responses. Again, toxicity at these dose levels was considered manageable.
“This rate of clinical response is exciting,” commented Tim Somervaille, MD, Senior Group Leader, Leukemia Biology Laboratory, Cancer Research UK Institute, Manchester (England). An ESMO-invited discussant on this paper, Dr. Somervaille expressed enthusiasm in general about a growing role for bispecific T-cell engagers. Blinatumomab, the first of these agents, received regulatory approval for refractory AML in 2014.
“There are a number of these bispecific T cell antibodies that are in early-phase trials,” said Dr. Somervaille, citing several that also target CD123 within the context of a different partner antigen than that employed by flotetuzumab. He also mentioned ongoing efforts to develop bispecific natural killer cell engagers that target malignant cells through immune activation.
As for flotetuzumab, the phase 1 trial provided adequate data to encourage further development.
“A cohort expansion is now ongoing and enrolling patients at 11 sites in the United States and Europe,” Dr. Vey reported. “A clinical update on these results is expected by the end of the year.”
Dr. Vey reported financial relationships with Bristol-Myers Squibb, Novartis, and Servier.
MacroGenics retains full development and commercialization rights to flotetuzumab in the United States, Canada, Mexico, Japan, South Korea, and India. Servier participates in the development and has rights to flotetuzumab in all other countries. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the investigational treatment of AML, according to a press release from MacroGenics.
MADRID – Flotetuzumab, a novel bispecific monoclonal antibody that employs a proprietary technology to redirect T lymphocytes to kill CD123-expressing cells, was safe and demonstrated efficacy in patients with acute myeloid leukemia in a phase 1 trial, based on data presented at the European Society for Medical Oncology (ESMO) Congress.
Flotetuzumab combines a portion of antibody recognizing CD3, which is an activating molecule expressed by T cells, and an arm that recognizes CD123 on the cancer cell, explained Norbert Vey, MD, PhD, Head, Leukemia Treatment Unit, Institut Paoli-Calmettes, Marseille, France. This bispecific quality, produced through a proprietary technology called Dual-Affinity ReTargeting, is considered promising because CD123 is expressed by more than 90% of AML cells and is highly expressed on stem cells involved in initiating myelodysplastic syndrome (MDS).
In this dose-ranging study (NCT02152956), 42 patients with AML and 5 patients with MDS were treated in the first cycle with infusions of flotetuzumab on either a continuous 7-day or a 4-days-on, 3-days-off schedule. For subsequent cycles, patients received the 4-days-on, 3-days-off schedule. Continuous infusion is employed due to the short half-life of flotetuzumab.
The most common adverse events were infusion-related reactions, which were observed in 76.6% of patients. Pyrexia, a potential sign of cytokine release syndrome (CRS), was observed in 23.4% of patients, who were given tocilizumab at the earliest sign of CRS. Two patients had grade 3 CRS, and one discontinued therapy. There was also one case of grade 3 myalgia. Dr. Vey characterized the overall level of adverse events as “acceptable.”
In addition to its relative safety, flotetuzumab was associated with “encouraging antileukemic activity,” Dr. Vey said. Six of 14 patients receiving doses that exceeded 500 ng/kg per day had objective responses and two of these patients had complete responses. Again, toxicity at these dose levels was considered manageable.
“This rate of clinical response is exciting,” commented Tim Somervaille, MD, Senior Group Leader, Leukemia Biology Laboratory, Cancer Research UK Institute, Manchester (England). An ESMO-invited discussant on this paper, Dr. Somervaille expressed enthusiasm in general about a growing role for bispecific T-cell engagers. Blinatumomab, the first of these agents, received regulatory approval for refractory AML in 2014.
“There are a number of these bispecific T cell antibodies that are in early-phase trials,” said Dr. Somervaille, citing several that also target CD123 within the context of a different partner antigen than that employed by flotetuzumab. He also mentioned ongoing efforts to develop bispecific natural killer cell engagers that target malignant cells through immune activation.
As for flotetuzumab, the phase 1 trial provided adequate data to encourage further development.
“A cohort expansion is now ongoing and enrolling patients at 11 sites in the United States and Europe,” Dr. Vey reported. “A clinical update on these results is expected by the end of the year.”
Dr. Vey reported financial relationships with Bristol-Myers Squibb, Novartis, and Servier.
MacroGenics retains full development and commercialization rights to flotetuzumab in the United States, Canada, Mexico, Japan, South Korea, and India. Servier participates in the development and has rights to flotetuzumab in all other countries. The U.S. Food and Drug Administration has granted orphan drug designation to flotetuzumab for the investigational treatment of AML, according to a press release from MacroGenics.
AT ESMO 2017
Key clinical point: The phase 1 trial provided adequate data to encourage further development of flotetuzumab for patients with acute myeloid leukemia.
Major finding: Six of 14 patients receiving doses that exceeded 500 ng/kg per day had objective responses and two of these patients had complete responses.
Data source: Phase 1 dose-escalation study in 42 patients with AML and 5 patients with MDS.
Disclosures: Dr. Vey reported financial relationships with Bristol-Myers Squibb, Novartis, and Servier.
New antibodies, drugs for refractory and relapsed myeloma are effective in patients over 65
MADRID – Patients with refractory/relapsed multiple myeloma had similar rates of progression-free survival (PFS) whether they were younger than age 65 or 65 years and older, based on the results of eight recent phase 3 trials in an analysis presented at the European Society for Medical Oncology Congress.
“The PFS benefit was significant in both younger and older patients with relapsed and refractory multiple myeloma with a cut off at 75 years,” reported Thierry Landre, PharmD, of the department of geriatric oncology, University of Paris 13, France. “Age, by itself, should not be a contraindication to the new myeloma drugs.”
In this meta-analysis, 5,421 patients were evaluated from the CASTOR and POLLUX trials, which evaluated daratumumab; the ELOQUENT-2 trial, which evaluated elotuzumab; the ASPIRE and ENDEAVOR trials, which evaluated carfilzomib; the TOURMALINE-MM trial, which evaluated ixazomib; the PANORAMA trial, which evaluated panobinostat; and the VANTAGE trial, which evaluated vorinostat.
For the analysis, patients were stratified by age younger than 65 years and age 65 years and older. Hazard ratios for benefit were calculated for the experimental and comparator arm for these two age groups. Though the number of patients over age 75 was small, hazard ratios were determined on an exploratory basis for that age group.
For the experimental arm relative to the comparator arm, all hazard ratios were statistically significant for patients less than age 65 with the exception of patients receiving elotuzumab in ELOQUENT-2. In that trial, the hazard ratio slightly exceeded the upward bound of the 95% confidence interval (95% CI, 0.55-1.02).
When the data were combined for the eight trials, the hazard ratio for PFS was 0.62 for newer agents relative to the comparator arms.
Similar results were seen for individual trial and aggregated trial data when the same calculations were done in patients aged 65-75. When the data for the eight trials were combined, the hazard ratio for PFS was 0.67 for newer agents relative to comparators.
The calculations for patients over age 75 were more limited because of the small numbers of trial participants in that age group. Of the hazard ratio estimates that were done, however, they were again of the same general magnitude seen in younger patients.
When PFS was broken down by type of therapy, the hazard ratios for patients younger than age 65 and those aged 65-75 were 0.57 and 0.52, respectively, for monoclonal antibodies. For combined data with the histone deacetylase inhibitors panobinostat and vorinostat, the respective hazard ratios were 0.67 and 0.78, respectively. For the second generation proteasome inhibitors carfilzomib and ixazomib, the respective hazard ratios were 0.61 and 0.70.
The ESMO-invited discussant for this presentation, Evangelos Terpos, MD, PhD, of the University of Athens, called the results reassuring. These data support treating relatively fit elderly patients with the newer agents.
“The data with the monoclonal antibodies suggest that these drugs actually provide their best results in elderly patients,” noted Dr. Terpos, pointing to the numerical advantage for the hazard ratio in older versus younger patients. The efficacy of monoclonal antibodies in older patients was further reinforced by the narrow confidence interval (95% CI, 0.42-0.61).
“There are many new drugs in the refractory setting [of multiple myeloma],” Dr. Terpos remarked. “It is helpful to have some data to show that these are also beneficial in the age group where this disease is most common.”
Dr. Landre agreed, noting that the median age at diagnosis of multiple myeloma is 69. This analysis helps to address the gap of “data available for evaluating efficacy in those older than 65 years and older than 75 years of age.”
MADRID – Patients with refractory/relapsed multiple myeloma had similar rates of progression-free survival (PFS) whether they were younger than age 65 or 65 years and older, based on the results of eight recent phase 3 trials in an analysis presented at the European Society for Medical Oncology Congress.
“The PFS benefit was significant in both younger and older patients with relapsed and refractory multiple myeloma with a cut off at 75 years,” reported Thierry Landre, PharmD, of the department of geriatric oncology, University of Paris 13, France. “Age, by itself, should not be a contraindication to the new myeloma drugs.”
In this meta-analysis, 5,421 patients were evaluated from the CASTOR and POLLUX trials, which evaluated daratumumab; the ELOQUENT-2 trial, which evaluated elotuzumab; the ASPIRE and ENDEAVOR trials, which evaluated carfilzomib; the TOURMALINE-MM trial, which evaluated ixazomib; the PANORAMA trial, which evaluated panobinostat; and the VANTAGE trial, which evaluated vorinostat.
For the analysis, patients were stratified by age younger than 65 years and age 65 years and older. Hazard ratios for benefit were calculated for the experimental and comparator arm for these two age groups. Though the number of patients over age 75 was small, hazard ratios were determined on an exploratory basis for that age group.
For the experimental arm relative to the comparator arm, all hazard ratios were statistically significant for patients less than age 65 with the exception of patients receiving elotuzumab in ELOQUENT-2. In that trial, the hazard ratio slightly exceeded the upward bound of the 95% confidence interval (95% CI, 0.55-1.02).
When the data were combined for the eight trials, the hazard ratio for PFS was 0.62 for newer agents relative to the comparator arms.
Similar results were seen for individual trial and aggregated trial data when the same calculations were done in patients aged 65-75. When the data for the eight trials were combined, the hazard ratio for PFS was 0.67 for newer agents relative to comparators.
The calculations for patients over age 75 were more limited because of the small numbers of trial participants in that age group. Of the hazard ratio estimates that were done, however, they were again of the same general magnitude seen in younger patients.
When PFS was broken down by type of therapy, the hazard ratios for patients younger than age 65 and those aged 65-75 were 0.57 and 0.52, respectively, for monoclonal antibodies. For combined data with the histone deacetylase inhibitors panobinostat and vorinostat, the respective hazard ratios were 0.67 and 0.78, respectively. For the second generation proteasome inhibitors carfilzomib and ixazomib, the respective hazard ratios were 0.61 and 0.70.
The ESMO-invited discussant for this presentation, Evangelos Terpos, MD, PhD, of the University of Athens, called the results reassuring. These data support treating relatively fit elderly patients with the newer agents.
“The data with the monoclonal antibodies suggest that these drugs actually provide their best results in elderly patients,” noted Dr. Terpos, pointing to the numerical advantage for the hazard ratio in older versus younger patients. The efficacy of monoclonal antibodies in older patients was further reinforced by the narrow confidence interval (95% CI, 0.42-0.61).
“There are many new drugs in the refractory setting [of multiple myeloma],” Dr. Terpos remarked. “It is helpful to have some data to show that these are also beneficial in the age group where this disease is most common.”
Dr. Landre agreed, noting that the median age at diagnosis of multiple myeloma is 69. This analysis helps to address the gap of “data available for evaluating efficacy in those older than 65 years and older than 75 years of age.”
MADRID – Patients with refractory/relapsed multiple myeloma had similar rates of progression-free survival (PFS) whether they were younger than age 65 or 65 years and older, based on the results of eight recent phase 3 trials in an analysis presented at the European Society for Medical Oncology Congress.
“The PFS benefit was significant in both younger and older patients with relapsed and refractory multiple myeloma with a cut off at 75 years,” reported Thierry Landre, PharmD, of the department of geriatric oncology, University of Paris 13, France. “Age, by itself, should not be a contraindication to the new myeloma drugs.”
In this meta-analysis, 5,421 patients were evaluated from the CASTOR and POLLUX trials, which evaluated daratumumab; the ELOQUENT-2 trial, which evaluated elotuzumab; the ASPIRE and ENDEAVOR trials, which evaluated carfilzomib; the TOURMALINE-MM trial, which evaluated ixazomib; the PANORAMA trial, which evaluated panobinostat; and the VANTAGE trial, which evaluated vorinostat.
For the analysis, patients were stratified by age younger than 65 years and age 65 years and older. Hazard ratios for benefit were calculated for the experimental and comparator arm for these two age groups. Though the number of patients over age 75 was small, hazard ratios were determined on an exploratory basis for that age group.
For the experimental arm relative to the comparator arm, all hazard ratios were statistically significant for patients less than age 65 with the exception of patients receiving elotuzumab in ELOQUENT-2. In that trial, the hazard ratio slightly exceeded the upward bound of the 95% confidence interval (95% CI, 0.55-1.02).
When the data were combined for the eight trials, the hazard ratio for PFS was 0.62 for newer agents relative to the comparator arms.
Similar results were seen for individual trial and aggregated trial data when the same calculations were done in patients aged 65-75. When the data for the eight trials were combined, the hazard ratio for PFS was 0.67 for newer agents relative to comparators.
The calculations for patients over age 75 were more limited because of the small numbers of trial participants in that age group. Of the hazard ratio estimates that were done, however, they were again of the same general magnitude seen in younger patients.
When PFS was broken down by type of therapy, the hazard ratios for patients younger than age 65 and those aged 65-75 were 0.57 and 0.52, respectively, for monoclonal antibodies. For combined data with the histone deacetylase inhibitors panobinostat and vorinostat, the respective hazard ratios were 0.67 and 0.78, respectively. For the second generation proteasome inhibitors carfilzomib and ixazomib, the respective hazard ratios were 0.61 and 0.70.
The ESMO-invited discussant for this presentation, Evangelos Terpos, MD, PhD, of the University of Athens, called the results reassuring. These data support treating relatively fit elderly patients with the newer agents.
“The data with the monoclonal antibodies suggest that these drugs actually provide their best results in elderly patients,” noted Dr. Terpos, pointing to the numerical advantage for the hazard ratio in older versus younger patients. The efficacy of monoclonal antibodies in older patients was further reinforced by the narrow confidence interval (95% CI, 0.42-0.61).
“There are many new drugs in the refractory setting [of multiple myeloma],” Dr. Terpos remarked. “It is helpful to have some data to show that these are also beneficial in the age group where this disease is most common.”
Dr. Landre agreed, noting that the median age at diagnosis of multiple myeloma is 69. This analysis helps to address the gap of “data available for evaluating efficacy in those older than 65 years and older than 75 years of age.”
AT ESMO 2017
Key clinical point: Recently approved monoclonal antibodies and drugs for treating refractory/relapsed multiple myeloma work well for patients aged 65-75 years.
Major finding: The hazard ratios for progression-free survival were largely similar for patients younger than age 65 years and patients aged 65 and older.
Data source: Meta-analysis of eight phase 3 randomized trials.
Disclosures: Dr. Landre reported having no financial conflicts of interest.
AML risk is doubled in low-risk thyroid cancer patients unnecessarily given radioactive iodine therapy
MADRID – Radioactive iodine treatment is associated with nearly twice the risk of developing acute myeloid leukemia (AML) in patients with well-differentiated thyroid cancer, based on data from the Surveillance Epidemiology and End Results (SEER) registry.
Up to 40% of patients in Europe and North America with well-differentiated thyroid cancer still receive radioactive iodine treatment “even though RAI has no proven benefit in this population,” Remco Molenaar, MD, PhD, of the University of Amsterdam reported at the European Society of Medical Oncology Congress.
Of 148,215 patients treated for well-differentiated thyroid cancer between 1973 and 2014, 55% had surgery only and 45% received surgery plus radioactive iodine treatment. After a median 4.3 years of follow-up, 44 patients developed AML. When cases in those exposed to RAI were cross-referenced to those who were not, the relative risk was increased more than fivefold. When the analysis controlled for an extensive list of potentially confounding variables, the hazard ratio of 1.79 remained statistically significant (P = .03).
“There is a nearly twofold increased risk even though radioactive iodine treatment is not indicated in this population,” Dr. Molenaar said. Moreover, AML following treatment for well-differentiated thyroid cancer was associated with a substantial reduction in expected overall survival, falling from a median 24.4 years to 7.5 years.
Compared with other AML patients, “those who develop AML after RAI also have a worse prognosis,” added Dr. Molenaar, noting the difference in overall survival is highly statistically significant (1.2 vs. 3.5 years; P = .004).
The ESMO-invited discussant, Tim Somervaille, MD, senior group leader of the Leukemia Biology Laboratory at the Cancer Research UK Manchester Institute, called this analysis “a more thorough and detailed study” than previous retrospective analyses, but he added a note of caution: Despite the almost twofold increase in risk, AML remains a rare iatrogenic event in thyroid cancer patients even if it is avoidable by withholding RAI therapy.
“These data do suggest that the risk is measurable and will further provide some downward pressure on the numbers of patients having unnecessary RAI therapy for well-differentiated thyroid cancer,” he said.
In the discussion that followed the presentation, one audience member suggested that telling patients they have a twofold increased risk of AML after RAI therapy is misleading. It was emphasized that a twofold increase of a very small number is still a very small number, but Dr. Molenaar suggested that this misses the point.
“I don’t think this is something that you need to discuss with patients, because you should not be giving RAI therapy to thyroid cancer patients with low- or intermediate-risk disease,” he said. Any AML case caused “by a therapy with no proven benefit is one too many,” especially since unnecessary RAI adds inconvenience and cost to treatment.
MADRID – Radioactive iodine treatment is associated with nearly twice the risk of developing acute myeloid leukemia (AML) in patients with well-differentiated thyroid cancer, based on data from the Surveillance Epidemiology and End Results (SEER) registry.
Up to 40% of patients in Europe and North America with well-differentiated thyroid cancer still receive radioactive iodine treatment “even though RAI has no proven benefit in this population,” Remco Molenaar, MD, PhD, of the University of Amsterdam reported at the European Society of Medical Oncology Congress.
Of 148,215 patients treated for well-differentiated thyroid cancer between 1973 and 2014, 55% had surgery only and 45% received surgery plus radioactive iodine treatment. After a median 4.3 years of follow-up, 44 patients developed AML. When cases in those exposed to RAI were cross-referenced to those who were not, the relative risk was increased more than fivefold. When the analysis controlled for an extensive list of potentially confounding variables, the hazard ratio of 1.79 remained statistically significant (P = .03).
“There is a nearly twofold increased risk even though radioactive iodine treatment is not indicated in this population,” Dr. Molenaar said. Moreover, AML following treatment for well-differentiated thyroid cancer was associated with a substantial reduction in expected overall survival, falling from a median 24.4 years to 7.5 years.
Compared with other AML patients, “those who develop AML after RAI also have a worse prognosis,” added Dr. Molenaar, noting the difference in overall survival is highly statistically significant (1.2 vs. 3.5 years; P = .004).
The ESMO-invited discussant, Tim Somervaille, MD, senior group leader of the Leukemia Biology Laboratory at the Cancer Research UK Manchester Institute, called this analysis “a more thorough and detailed study” than previous retrospective analyses, but he added a note of caution: Despite the almost twofold increase in risk, AML remains a rare iatrogenic event in thyroid cancer patients even if it is avoidable by withholding RAI therapy.
“These data do suggest that the risk is measurable and will further provide some downward pressure on the numbers of patients having unnecessary RAI therapy for well-differentiated thyroid cancer,” he said.
In the discussion that followed the presentation, one audience member suggested that telling patients they have a twofold increased risk of AML after RAI therapy is misleading. It was emphasized that a twofold increase of a very small number is still a very small number, but Dr. Molenaar suggested that this misses the point.
“I don’t think this is something that you need to discuss with patients, because you should not be giving RAI therapy to thyroid cancer patients with low- or intermediate-risk disease,” he said. Any AML case caused “by a therapy with no proven benefit is one too many,” especially since unnecessary RAI adds inconvenience and cost to treatment.
MADRID – Radioactive iodine treatment is associated with nearly twice the risk of developing acute myeloid leukemia (AML) in patients with well-differentiated thyroid cancer, based on data from the Surveillance Epidemiology and End Results (SEER) registry.
Up to 40% of patients in Europe and North America with well-differentiated thyroid cancer still receive radioactive iodine treatment “even though RAI has no proven benefit in this population,” Remco Molenaar, MD, PhD, of the University of Amsterdam reported at the European Society of Medical Oncology Congress.
Of 148,215 patients treated for well-differentiated thyroid cancer between 1973 and 2014, 55% had surgery only and 45% received surgery plus radioactive iodine treatment. After a median 4.3 years of follow-up, 44 patients developed AML. When cases in those exposed to RAI were cross-referenced to those who were not, the relative risk was increased more than fivefold. When the analysis controlled for an extensive list of potentially confounding variables, the hazard ratio of 1.79 remained statistically significant (P = .03).
“There is a nearly twofold increased risk even though radioactive iodine treatment is not indicated in this population,” Dr. Molenaar said. Moreover, AML following treatment for well-differentiated thyroid cancer was associated with a substantial reduction in expected overall survival, falling from a median 24.4 years to 7.5 years.
Compared with other AML patients, “those who develop AML after RAI also have a worse prognosis,” added Dr. Molenaar, noting the difference in overall survival is highly statistically significant (1.2 vs. 3.5 years; P = .004).
The ESMO-invited discussant, Tim Somervaille, MD, senior group leader of the Leukemia Biology Laboratory at the Cancer Research UK Manchester Institute, called this analysis “a more thorough and detailed study” than previous retrospective analyses, but he added a note of caution: Despite the almost twofold increase in risk, AML remains a rare iatrogenic event in thyroid cancer patients even if it is avoidable by withholding RAI therapy.
“These data do suggest that the risk is measurable and will further provide some downward pressure on the numbers of patients having unnecessary RAI therapy for well-differentiated thyroid cancer,” he said.
In the discussion that followed the presentation, one audience member suggested that telling patients they have a twofold increased risk of AML after RAI therapy is misleading. It was emphasized that a twofold increase of a very small number is still a very small number, but Dr. Molenaar suggested that this misses the point.
“I don’t think this is something that you need to discuss with patients, because you should not be giving RAI therapy to thyroid cancer patients with low- or intermediate-risk disease,” he said. Any AML case caused “by a therapy with no proven benefit is one too many,” especially since unnecessary RAI adds inconvenience and cost to treatment.
AT ESMO 2017
Key clinical point:
Major finding: The hazard ratio for AML after RAI therapy in well-differentiated thyroid cancer patients is almost doubled (HR = 1.79).
Data source: Population-based, retrospective study of 148,215 patients treated for well-differentiated thyroid cancer between 1973 and 2014.
Disclosures: Dr. Molenaar reported that he had no relevant financial relationships to disclose.
Most daratumumab infusion reactions occur in first infusion
MADRID – The high rate of infusion-related reactions at first daratumumab infusion may be related to treatment duration, based on data from the CASTOR and POLLUX studies presented at the European Society for Medical Oncology Congress.
Infusion-related reactions occur in half of relapsed or refractory multiple myeloma patients who receive daratumumab, but nearly all reactions are grade 2 or less and rarely lead to treatment discontinuation, reported Philippe Moreau, MD, of University Hospital, Nantes, France.
“In the two phase 3 trials, CASTOR and POLLUX, infusion-related reactions occurred in 45% and 48% of patients, respectively. Of these, 98% and 96%, respectively, occurred during the first infusion,” he said. Treatment duration was 7 hours for first infusion vs. 4 hours and 3 hours for the second and third infusions, respectively. Grade 3 infusion-related reactions occurred in 5.3% and 8.6% of patients in CASTOR and POLLUX, respectively. No grade 4 infusion-related reactions were observed in either trial.
(In CASTOR [NCT02136134], daratumumab was combined with bortezomib and dexamethasone. In POLLUX [NCT02076009], it was combined with lenalidomide and dexamethasone. Based on improvements in progression-free survival relative to the background drugs alone, daratumumab was approved for relapsed or refractory multiple myeloma.)
All patients in the trials received some form of preinfusion medications. These included 650-1,000 mg of paracetamol by intravenous or oral administration, 25-50 mg of diphenhydramine, 10 mg of montelukast, and 20 mg of dexamethasone. Patients thought to be at high risk of respiratory complications were candidates for postinfusion medications such as diphenhydramine or a short-acting beta agonist. However, only about 10% of high-risk patients received these therapies, so the impact of this potentially preventive approach is not clear, Dr. Moreau said.
In grade 1 reactions, Dr. Moreau recommended that infusions be paused at the first sign of an infusion-related reaction and then restarted at half the infusion rate when the condition is considered stable. Daratumumab treatment should be withdrawn in grade 2 or higher infusion-related reactions associated with laryngeal edema or grade 2 or higher bronchospasm that does not respond to systemic therapy and resolves within 6 hours of onset.
In grade 3 infusion-related reactions, the recommendation is to stop the daratumumab infusion and closely observe the patient. The infusion should be restarted only if the severity drops to grade 1. Again, the rate of infusion after the interruption should be half the rate provided prior to the infusion-related reaction. Therapy should be withdrawn if the infusion-related reaction recurs for a second time, according to Dr. Moreau.
Infusion-related reactions involving the upper respiratory tract – such as dyspnea, cough, bronchospasm, or throat irritation – may be related to the physiologic function of CD38, Dr. Moreau said. For this reason, grade 3 upper respiratory-related events deserve close attention and persisting symptoms warrant halting treatment.
The evidence is “reassuring” that the majority of infusion-related reactions are confined to the first infusion, said the ESMO-invited discussant, Evangelos Terpos, MD, PhD, of the University of Athens. He noted that the specific treatment recommendations outlined by Dr. Moreau could be helpful for minimizing nuisance infusion-related reactions as well as reducing the risk of more serious infusion-related reactions, particularly those involving respiratory events.
Prophylactic strategies for infusion-related reactions are particularly important in patients with risk factors for respiratory complications, Dr. Terpos added.
MADRID – The high rate of infusion-related reactions at first daratumumab infusion may be related to treatment duration, based on data from the CASTOR and POLLUX studies presented at the European Society for Medical Oncology Congress.
Infusion-related reactions occur in half of relapsed or refractory multiple myeloma patients who receive daratumumab, but nearly all reactions are grade 2 or less and rarely lead to treatment discontinuation, reported Philippe Moreau, MD, of University Hospital, Nantes, France.
“In the two phase 3 trials, CASTOR and POLLUX, infusion-related reactions occurred in 45% and 48% of patients, respectively. Of these, 98% and 96%, respectively, occurred during the first infusion,” he said. Treatment duration was 7 hours for first infusion vs. 4 hours and 3 hours for the second and third infusions, respectively. Grade 3 infusion-related reactions occurred in 5.3% and 8.6% of patients in CASTOR and POLLUX, respectively. No grade 4 infusion-related reactions were observed in either trial.
(In CASTOR [NCT02136134], daratumumab was combined with bortezomib and dexamethasone. In POLLUX [NCT02076009], it was combined with lenalidomide and dexamethasone. Based on improvements in progression-free survival relative to the background drugs alone, daratumumab was approved for relapsed or refractory multiple myeloma.)
All patients in the trials received some form of preinfusion medications. These included 650-1,000 mg of paracetamol by intravenous or oral administration, 25-50 mg of diphenhydramine, 10 mg of montelukast, and 20 mg of dexamethasone. Patients thought to be at high risk of respiratory complications were candidates for postinfusion medications such as diphenhydramine or a short-acting beta agonist. However, only about 10% of high-risk patients received these therapies, so the impact of this potentially preventive approach is not clear, Dr. Moreau said.
In grade 1 reactions, Dr. Moreau recommended that infusions be paused at the first sign of an infusion-related reaction and then restarted at half the infusion rate when the condition is considered stable. Daratumumab treatment should be withdrawn in grade 2 or higher infusion-related reactions associated with laryngeal edema or grade 2 or higher bronchospasm that does not respond to systemic therapy and resolves within 6 hours of onset.
In grade 3 infusion-related reactions, the recommendation is to stop the daratumumab infusion and closely observe the patient. The infusion should be restarted only if the severity drops to grade 1. Again, the rate of infusion after the interruption should be half the rate provided prior to the infusion-related reaction. Therapy should be withdrawn if the infusion-related reaction recurs for a second time, according to Dr. Moreau.
Infusion-related reactions involving the upper respiratory tract – such as dyspnea, cough, bronchospasm, or throat irritation – may be related to the physiologic function of CD38, Dr. Moreau said. For this reason, grade 3 upper respiratory-related events deserve close attention and persisting symptoms warrant halting treatment.
The evidence is “reassuring” that the majority of infusion-related reactions are confined to the first infusion, said the ESMO-invited discussant, Evangelos Terpos, MD, PhD, of the University of Athens. He noted that the specific treatment recommendations outlined by Dr. Moreau could be helpful for minimizing nuisance infusion-related reactions as well as reducing the risk of more serious infusion-related reactions, particularly those involving respiratory events.
Prophylactic strategies for infusion-related reactions are particularly important in patients with risk factors for respiratory complications, Dr. Terpos added.
MADRID – The high rate of infusion-related reactions at first daratumumab infusion may be related to treatment duration, based on data from the CASTOR and POLLUX studies presented at the European Society for Medical Oncology Congress.
Infusion-related reactions occur in half of relapsed or refractory multiple myeloma patients who receive daratumumab, but nearly all reactions are grade 2 or less and rarely lead to treatment discontinuation, reported Philippe Moreau, MD, of University Hospital, Nantes, France.
“In the two phase 3 trials, CASTOR and POLLUX, infusion-related reactions occurred in 45% and 48% of patients, respectively. Of these, 98% and 96%, respectively, occurred during the first infusion,” he said. Treatment duration was 7 hours for first infusion vs. 4 hours and 3 hours for the second and third infusions, respectively. Grade 3 infusion-related reactions occurred in 5.3% and 8.6% of patients in CASTOR and POLLUX, respectively. No grade 4 infusion-related reactions were observed in either trial.
(In CASTOR [NCT02136134], daratumumab was combined with bortezomib and dexamethasone. In POLLUX [NCT02076009], it was combined with lenalidomide and dexamethasone. Based on improvements in progression-free survival relative to the background drugs alone, daratumumab was approved for relapsed or refractory multiple myeloma.)
All patients in the trials received some form of preinfusion medications. These included 650-1,000 mg of paracetamol by intravenous or oral administration, 25-50 mg of diphenhydramine, 10 mg of montelukast, and 20 mg of dexamethasone. Patients thought to be at high risk of respiratory complications were candidates for postinfusion medications such as diphenhydramine or a short-acting beta agonist. However, only about 10% of high-risk patients received these therapies, so the impact of this potentially preventive approach is not clear, Dr. Moreau said.
In grade 1 reactions, Dr. Moreau recommended that infusions be paused at the first sign of an infusion-related reaction and then restarted at half the infusion rate when the condition is considered stable. Daratumumab treatment should be withdrawn in grade 2 or higher infusion-related reactions associated with laryngeal edema or grade 2 or higher bronchospasm that does not respond to systemic therapy and resolves within 6 hours of onset.
In grade 3 infusion-related reactions, the recommendation is to stop the daratumumab infusion and closely observe the patient. The infusion should be restarted only if the severity drops to grade 1. Again, the rate of infusion after the interruption should be half the rate provided prior to the infusion-related reaction. Therapy should be withdrawn if the infusion-related reaction recurs for a second time, according to Dr. Moreau.
Infusion-related reactions involving the upper respiratory tract – such as dyspnea, cough, bronchospasm, or throat irritation – may be related to the physiologic function of CD38, Dr. Moreau said. For this reason, grade 3 upper respiratory-related events deserve close attention and persisting symptoms warrant halting treatment.
The evidence is “reassuring” that the majority of infusion-related reactions are confined to the first infusion, said the ESMO-invited discussant, Evangelos Terpos, MD, PhD, of the University of Athens. He noted that the specific treatment recommendations outlined by Dr. Moreau could be helpful for minimizing nuisance infusion-related reactions as well as reducing the risk of more serious infusion-related reactions, particularly those involving respiratory events.
Prophylactic strategies for infusion-related reactions are particularly important in patients with risk factors for respiratory complications, Dr. Terpos added.
AT ESMO 2017
Key clinical point: In grade 1 infusion-related reactions, daratumumab infusion should be paused at the first sign of a reaction and then restarted at half the infusion rate when the condition is considered stable.
Major finding:
Data source: Post hoc analysis of the phase 3 trials, CASTOR and POLLUX.
Disclosures: Dr. Moreau reported financial relationships with Amgen, Celgene, Janssen, Novartis, and Takeda.
Biosimilar matches rituximab in large follicular lymphoma trial
MADRID – The biosimilar GP2013 met the criteria for therapeutic equivalence to rituximab in a large comparator trial of previously untreated patients with aggressive follicular lymphoma.
Based on results presented at the European Society for Medical Oncology Congress, “there is absolutely no difference in the objective response rates for GP2013 and rituximab,” the primary endpoint of the trial, reported Wojciech Jurczak, MD, PhD, head of lymphoma, department of hematology, Jagiellonian University, Krakow, Poland.
Dr. Jurczak characterized the double-blind, randomized phase 3 trial ASSIST_FL (NCT01419665) as the “largest biosimilar trial in hematology.” For the study, 629 patients with previously untreated, advanced-stage follicular lymphoma were randomized to GP2013 and the conventional regimen of cyclophosphamide, vincristine, and prednisone (G-CVP) or rituximab and the same three-agent regimen (R-CVP). Each regimen was given for eight cycles followed by maintenance monotherapy with the assigned monoclonal antibody for up to 2 years.
The primary endpoint, objective response rate (ORR), was 87.1% and 87.5% for G-CVP and R-CVP, respectively. There were no differences in ORR among the subgroups evaluated, which included patients aged 60 years and older vs. younger patients, presence or absence of bulky disease, high or low FLIPI (Follicular Lymphoma International Prognostic Index) score, gender, and the geographic region where treatment was given.
Safety was a secondary endpoint evaluated at the end of eight cycles and again after a year of maintenance therapy. The proportion of patients with any adverse event and the proportion with grade 3 or greater adverse events were not statistically different at any time point. There were also no significant differences in any of the other secondary endpoints evaluated, which included pharmacokinetic, pharmacodynamic, and immune measures.
The results are consistent with those of a related randomized bioequivalence trial comparing GP2013 and rituximab in 312 patients with rheumatoid arthritis (Ann Rheum Dis. 2017;76:1598-1602). The primary endpoint in that trial was area-under-the-curve serum concentration time.
The two studies are mutually reinforcing, and “the ASSIST_FL trial ends the story. We have the totality of evidence that GP2013 can be considered a biosimilar,” said Dr. Jurczak, who anticipates “major price differences” for this agent relative to rituximab.
“We may, based on the results of the follicular lymphoma trial, use the biosimilar in all registered indications for rituximab,” said Dr. Jurczak. This is also the conclusion of the European Medicine Agency, which approved this agent in June 2017 for all rituximab indications.
In explaining the process for approval of biosimilars, Dr. Jurczak emphasized that demonstrating bioequivalence is not the same as the approval process for a new therapeutic agent, for which regulatory agents require a demonstration of efficacy on a meaningful clinical endpoint, such as progression-free survival. For biosimilars, it is not necessary to show clinical benefits. Biosimilars must demonstrate the same biological activity, and ORR is considered an acceptable measure.
The ESMO-invited discussant, Michele Ghielmini, MD, PhD, medical director at the Oncology Institute of Southern Switzerland, Bellinzona, agreed. “We can reasonably speculate that (when rituximab and the biosimilar are associated with the same) response rate, they will lead to the same clinical benefits.”
MADRID – The biosimilar GP2013 met the criteria for therapeutic equivalence to rituximab in a large comparator trial of previously untreated patients with aggressive follicular lymphoma.
Based on results presented at the European Society for Medical Oncology Congress, “there is absolutely no difference in the objective response rates for GP2013 and rituximab,” the primary endpoint of the trial, reported Wojciech Jurczak, MD, PhD, head of lymphoma, department of hematology, Jagiellonian University, Krakow, Poland.
Dr. Jurczak characterized the double-blind, randomized phase 3 trial ASSIST_FL (NCT01419665) as the “largest biosimilar trial in hematology.” For the study, 629 patients with previously untreated, advanced-stage follicular lymphoma were randomized to GP2013 and the conventional regimen of cyclophosphamide, vincristine, and prednisone (G-CVP) or rituximab and the same three-agent regimen (R-CVP). Each regimen was given for eight cycles followed by maintenance monotherapy with the assigned monoclonal antibody for up to 2 years.
The primary endpoint, objective response rate (ORR), was 87.1% and 87.5% for G-CVP and R-CVP, respectively. There were no differences in ORR among the subgroups evaluated, which included patients aged 60 years and older vs. younger patients, presence or absence of bulky disease, high or low FLIPI (Follicular Lymphoma International Prognostic Index) score, gender, and the geographic region where treatment was given.
Safety was a secondary endpoint evaluated at the end of eight cycles and again after a year of maintenance therapy. The proportion of patients with any adverse event and the proportion with grade 3 or greater adverse events were not statistically different at any time point. There were also no significant differences in any of the other secondary endpoints evaluated, which included pharmacokinetic, pharmacodynamic, and immune measures.
The results are consistent with those of a related randomized bioequivalence trial comparing GP2013 and rituximab in 312 patients with rheumatoid arthritis (Ann Rheum Dis. 2017;76:1598-1602). The primary endpoint in that trial was area-under-the-curve serum concentration time.
The two studies are mutually reinforcing, and “the ASSIST_FL trial ends the story. We have the totality of evidence that GP2013 can be considered a biosimilar,” said Dr. Jurczak, who anticipates “major price differences” for this agent relative to rituximab.
“We may, based on the results of the follicular lymphoma trial, use the biosimilar in all registered indications for rituximab,” said Dr. Jurczak. This is also the conclusion of the European Medicine Agency, which approved this agent in June 2017 for all rituximab indications.
In explaining the process for approval of biosimilars, Dr. Jurczak emphasized that demonstrating bioequivalence is not the same as the approval process for a new therapeutic agent, for which regulatory agents require a demonstration of efficacy on a meaningful clinical endpoint, such as progression-free survival. For biosimilars, it is not necessary to show clinical benefits. Biosimilars must demonstrate the same biological activity, and ORR is considered an acceptable measure.
The ESMO-invited discussant, Michele Ghielmini, MD, PhD, medical director at the Oncology Institute of Southern Switzerland, Bellinzona, agreed. “We can reasonably speculate that (when rituximab and the biosimilar are associated with the same) response rate, they will lead to the same clinical benefits.”
MADRID – The biosimilar GP2013 met the criteria for therapeutic equivalence to rituximab in a large comparator trial of previously untreated patients with aggressive follicular lymphoma.
Based on results presented at the European Society for Medical Oncology Congress, “there is absolutely no difference in the objective response rates for GP2013 and rituximab,” the primary endpoint of the trial, reported Wojciech Jurczak, MD, PhD, head of lymphoma, department of hematology, Jagiellonian University, Krakow, Poland.
Dr. Jurczak characterized the double-blind, randomized phase 3 trial ASSIST_FL (NCT01419665) as the “largest biosimilar trial in hematology.” For the study, 629 patients with previously untreated, advanced-stage follicular lymphoma were randomized to GP2013 and the conventional regimen of cyclophosphamide, vincristine, and prednisone (G-CVP) or rituximab and the same three-agent regimen (R-CVP). Each regimen was given for eight cycles followed by maintenance monotherapy with the assigned monoclonal antibody for up to 2 years.
The primary endpoint, objective response rate (ORR), was 87.1% and 87.5% for G-CVP and R-CVP, respectively. There were no differences in ORR among the subgroups evaluated, which included patients aged 60 years and older vs. younger patients, presence or absence of bulky disease, high or low FLIPI (Follicular Lymphoma International Prognostic Index) score, gender, and the geographic region where treatment was given.
Safety was a secondary endpoint evaluated at the end of eight cycles and again after a year of maintenance therapy. The proportion of patients with any adverse event and the proportion with grade 3 or greater adverse events were not statistically different at any time point. There were also no significant differences in any of the other secondary endpoints evaluated, which included pharmacokinetic, pharmacodynamic, and immune measures.
The results are consistent with those of a related randomized bioequivalence trial comparing GP2013 and rituximab in 312 patients with rheumatoid arthritis (Ann Rheum Dis. 2017;76:1598-1602). The primary endpoint in that trial was area-under-the-curve serum concentration time.
The two studies are mutually reinforcing, and “the ASSIST_FL trial ends the story. We have the totality of evidence that GP2013 can be considered a biosimilar,” said Dr. Jurczak, who anticipates “major price differences” for this agent relative to rituximab.
“We may, based on the results of the follicular lymphoma trial, use the biosimilar in all registered indications for rituximab,” said Dr. Jurczak. This is also the conclusion of the European Medicine Agency, which approved this agent in June 2017 for all rituximab indications.
In explaining the process for approval of biosimilars, Dr. Jurczak emphasized that demonstrating bioequivalence is not the same as the approval process for a new therapeutic agent, for which regulatory agents require a demonstration of efficacy on a meaningful clinical endpoint, such as progression-free survival. For biosimilars, it is not necessary to show clinical benefits. Biosimilars must demonstrate the same biological activity, and ORR is considered an acceptable measure.
The ESMO-invited discussant, Michele Ghielmini, MD, PhD, medical director at the Oncology Institute of Southern Switzerland, Bellinzona, agreed. “We can reasonably speculate that (when rituximab and the biosimilar are associated with the same) response rate, they will lead to the same clinical benefits.”
AT ESMO 2017
Key clinical point:
Major finding: The objective response rates were 87.1% and 87.5% for G-CVP and R-CVP.
Data source: Double-blind, multicenter randomized trial of 629 patients with previously untreated, advanced-stage follicular lymphoma.
Disclosures: Dr. Jurczak reported financial relationships with Sandoz.
Alternating therapy in renal cell carcinoma fails to show an advantage
There was no efficacy or safety advantage for alternating everolimus with pazopanib over pazopanib alone in patients with metastatic or locally advanced clear cell renal cell carcinoma (ccRCC), according to a newly published randomized trial.
The study hypothesis was that alternating the two drugs would improve outcomes and reduce toxicity, but differences between arms for the major outcomes were not clinically significant, according to results of a multicenter trial led by Geert A. Cirkel, MD, of the department of medical oncology, University Medical Center, Utrecht, the Netherlands.
Investigators randomized 101 patients with histologically confirmed ccRCC to receive 8 weeks of pazopanib in a daily dose of 800 mg alternated with 8 weeks of everolimus in a daily dose of 10 mg or 800 mg per day of continuous pazopanib. Patients remained on either regimen until disease progression.
Median time until first progression or death was 7.4 months for the experimental alternating arm versus 9.4 months for the control arm of continuous single-agent pazopanib (P = .37), Dr. Cirkel and associates reported (JAMA Onc. 2017 Apr 1. doi: 10.1001/jamaoncol.2016.5202).
Progression-free survival after starting on a second-line therapy was 20.2 months for the alternating treatment vs. 14.5 months for the control, but the confidence intervals were wide, and the difference was not significant (P = .86).
There was no apparent toxicity or tolerability advantage from alternating therapy. Nearly 40% of patients in both arms required pazopanib dose reductions, while 14% in the alternating arm also required an everolimus dose reduction. The incidence of serious adverse events possibly related to treatment was comparable between arms.
Quality of life was measured with several tools, including the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), but no significant differences between treatment arms were observed in any measure.
Current guidelines recommend pazopanib, which is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, as a first-line therapy in ccRCC. Everolimus, an inhibitor of mammalian target of rapamycin, is recommended in the second-line setting. Noting that resistance to pazopanib has been shown to be reversible after a period of withdrawal in experimental studies, the authors had speculated an on-off strategy with everolimus might better preserve the efficacy of pazopanib, providing longer periods of disease control. They had also hypothesized that the cumulative adverse events might be less if the drugs were sequenced, allowing recovery from each set of drug-specific adverse events.
Several potential explanations were offered for the lack of improved efficacy from alternating everolimus with pazopanib. For one, the improved activity of pazopanib after withdrawal in experimental models was observed after drug-free periods. The authors questioned whether a period of tumor regrowth may be needed in order to overcome pazopanib resistance.
The study may still have supported the use of an alternating regimen if the alternating therapy had led to a significantly improved quality of life, but the authors found none, a outcome that they characterized as unexpected. They concluded that there are no apparent advantages for the alternating regimen of pazopanib and everolimus relative to pazopanib alone.
There was no efficacy or safety advantage for alternating everolimus with pazopanib over pazopanib alone in patients with metastatic or locally advanced clear cell renal cell carcinoma (ccRCC), according to a newly published randomized trial.
The study hypothesis was that alternating the two drugs would improve outcomes and reduce toxicity, but differences between arms for the major outcomes were not clinically significant, according to results of a multicenter trial led by Geert A. Cirkel, MD, of the department of medical oncology, University Medical Center, Utrecht, the Netherlands.
Investigators randomized 101 patients with histologically confirmed ccRCC to receive 8 weeks of pazopanib in a daily dose of 800 mg alternated with 8 weeks of everolimus in a daily dose of 10 mg or 800 mg per day of continuous pazopanib. Patients remained on either regimen until disease progression.
Median time until first progression or death was 7.4 months for the experimental alternating arm versus 9.4 months for the control arm of continuous single-agent pazopanib (P = .37), Dr. Cirkel and associates reported (JAMA Onc. 2017 Apr 1. doi: 10.1001/jamaoncol.2016.5202).
Progression-free survival after starting on a second-line therapy was 20.2 months for the alternating treatment vs. 14.5 months for the control, but the confidence intervals were wide, and the difference was not significant (P = .86).
There was no apparent toxicity or tolerability advantage from alternating therapy. Nearly 40% of patients in both arms required pazopanib dose reductions, while 14% in the alternating arm also required an everolimus dose reduction. The incidence of serious adverse events possibly related to treatment was comparable between arms.
Quality of life was measured with several tools, including the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), but no significant differences between treatment arms were observed in any measure.
Current guidelines recommend pazopanib, which is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, as a first-line therapy in ccRCC. Everolimus, an inhibitor of mammalian target of rapamycin, is recommended in the second-line setting. Noting that resistance to pazopanib has been shown to be reversible after a period of withdrawal in experimental studies, the authors had speculated an on-off strategy with everolimus might better preserve the efficacy of pazopanib, providing longer periods of disease control. They had also hypothesized that the cumulative adverse events might be less if the drugs were sequenced, allowing recovery from each set of drug-specific adverse events.
Several potential explanations were offered for the lack of improved efficacy from alternating everolimus with pazopanib. For one, the improved activity of pazopanib after withdrawal in experimental models was observed after drug-free periods. The authors questioned whether a period of tumor regrowth may be needed in order to overcome pazopanib resistance.
The study may still have supported the use of an alternating regimen if the alternating therapy had led to a significantly improved quality of life, but the authors found none, a outcome that they characterized as unexpected. They concluded that there are no apparent advantages for the alternating regimen of pazopanib and everolimus relative to pazopanib alone.
There was no efficacy or safety advantage for alternating everolimus with pazopanib over pazopanib alone in patients with metastatic or locally advanced clear cell renal cell carcinoma (ccRCC), according to a newly published randomized trial.
The study hypothesis was that alternating the two drugs would improve outcomes and reduce toxicity, but differences between arms for the major outcomes were not clinically significant, according to results of a multicenter trial led by Geert A. Cirkel, MD, of the department of medical oncology, University Medical Center, Utrecht, the Netherlands.
Investigators randomized 101 patients with histologically confirmed ccRCC to receive 8 weeks of pazopanib in a daily dose of 800 mg alternated with 8 weeks of everolimus in a daily dose of 10 mg or 800 mg per day of continuous pazopanib. Patients remained on either regimen until disease progression.
Median time until first progression or death was 7.4 months for the experimental alternating arm versus 9.4 months for the control arm of continuous single-agent pazopanib (P = .37), Dr. Cirkel and associates reported (JAMA Onc. 2017 Apr 1. doi: 10.1001/jamaoncol.2016.5202).
Progression-free survival after starting on a second-line therapy was 20.2 months for the alternating treatment vs. 14.5 months for the control, but the confidence intervals were wide, and the difference was not significant (P = .86).
There was no apparent toxicity or tolerability advantage from alternating therapy. Nearly 40% of patients in both arms required pazopanib dose reductions, while 14% in the alternating arm also required an everolimus dose reduction. The incidence of serious adverse events possibly related to treatment was comparable between arms.
Quality of life was measured with several tools, including the Functional Assessment of Cancer Therapy – Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS), but no significant differences between treatment arms were observed in any measure.
Current guidelines recommend pazopanib, which is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptor, as a first-line therapy in ccRCC. Everolimus, an inhibitor of mammalian target of rapamycin, is recommended in the second-line setting. Noting that resistance to pazopanib has been shown to be reversible after a period of withdrawal in experimental studies, the authors had speculated an on-off strategy with everolimus might better preserve the efficacy of pazopanib, providing longer periods of disease control. They had also hypothesized that the cumulative adverse events might be less if the drugs were sequenced, allowing recovery from each set of drug-specific adverse events.
Several potential explanations were offered for the lack of improved efficacy from alternating everolimus with pazopanib. For one, the improved activity of pazopanib after withdrawal in experimental models was observed after drug-free periods. The authors questioned whether a period of tumor regrowth may be needed in order to overcome pazopanib resistance.
The study may still have supported the use of an alternating regimen if the alternating therapy had led to a significantly improved quality of life, but the authors found none, a outcome that they characterized as unexpected. They concluded that there are no apparent advantages for the alternating regimen of pazopanib and everolimus relative to pazopanib alone.
FROM JAMA ONCOLOGY
Key clinical point:
Major finding: The median time to progression or death was 7.4 months for the combination versus 9.4 months for pazopanib alone (P = .37).
Data source: Randomized, multicenter controlled trial.
Disclosures: The principal investigator Dr. Cirkel reports travel expenses from Novartis, which, along with GlaxoSmithKline, provided funding for this study.
Genetic advances push personalization of cancer prevention
BOSTON – The avenues for identifying those individuals most likely to benefit from surveillance and chemoprevention of colorectal cancer (CRC) are multiplying, experts agreed at the 2017 AGA Tech Summit sponsored by the AGA Center for GI Innovation and Technology.
In a series of three consecutive presentations, the first updated efforts to improve germline genetic testing. The second identified biomarkers that appear likely to improve the risk-to-benefit ratio from aspirin in cancer prevention. The third cautioned about the potential pitfalls of genetic testing for cancer risk even though the overall effect was to highlight the value of this tool when performed appropriately.
Novel tools for germline testing
Dr. Syngal noted that the management of hereditary cancers differs from that of sporadic cancers in several ways – the surgical management of cancer, screening, and surveillance after the treatment of the primary cancer, surveillance for associated cancers, screening and surveillance of family members, and reproductive counseling.
In her talk, “Novel Tools to Accelerate Implementation of Germline Genetic Testing,” Dr. Syngal discussed the PREMM (Prediction Model for MLH1 and MSH2 gene mutations) risk assessment tool first developed in 2006. The web-based PREMM calculates a risk score based on personal and family histories, Dr. Syngal said. “If an individual scores above a certain threshold, they are referred to genetic counseling and possibly testing,” she noted.
A second-generation tool for identifying patients at increased genetic risk for CRC, called PREMM1,2,6, was based on a larger patient sample, and published in 2011. That model “is recommended by the National Comprehensive Cancer Network for testing for Lynch syndrome, so its use is already part of clinical practice in gastroenterology,” Dr. Syngal reported.
A third model, called PREMM5, was developed on the basis of an even larger patient sample, and it is now being tested in primary care practices with plans in the works to implement the model in general gastroenterology, oncology, and ob.gyn. settings, she added.
“There are probably about 1 million people in the United States who have Lynch syndrome and don’t know it,” according to Dr. Syngal, who noted that PREMM can be completed in only a minute or two by clinicians or patients once they collected information about CRC history among their blood relatives.
Ultimately, the same approaches can be applied to risk assessment for other GI cancers in which the goal is to first identify patients at an increased likelihood of having a genetic mutation that predicts cancer risk and then employing multigene panels to narrow down those who could benefit from specific surveillance strategies.
However, by itself, the work to develop better strategies to identify Lynch syndrome is important, according to Dr. Syngal. When a group of experts was recently convened under the Cancer Moonshot Program championed by former Vice President Joe Biden, “Lynch syndrome was identified as the top priority in terms of cancer prevention” over the coming 5-10 years.
Biomarkers for GI cancer chemoprevention
Citing a long list of studies and trials that have associated aspirin with protection against CRC, including a randomized controlled trial in Lynch syndrome, Dr. Chan characterized the evidence of a chemoprotective effect from ASA against GI cancer as “overwhelming.” However, not all individuals may derive a favorable risk-to-benefit ratio due to the antiplatelet effects of ASA that increase risk of bleeding events in the GI tract and elsewhere.
The best approach to providing a favorable risk-to-benefit ratio may involve identifying biomarkers that predict benefit. The progress in understanding how ASA inhibits pathways of tumor development has provided candidates, according to Dr. Chan, citing a series of studies, including those conducted at his center.
One proof of concept was derived from work in evaluating tumor expression of cyclooxygenase (COX), the enzyme that converts arachidonic acid to prostaglandins. Dr. Chan explained that prostaglandin are linked to many downstream cancer-promoting pathways. In a study that involved molecular analysis on tumor specimens from patients who participated in a cohort study, the presence of the COX-2 isoenzyme was a differentiator.
“When the evaluation was performed according to COX-2 status, we saw about a 30% reduction in risk for COX-2-positive tumors. In contrast, we did not see any appreciable reduction in risk in tumors that were COX-2-negative,” Dr. Chan reported.
Although Dr. Chan acknowledged that about 80% of CRC tumors are COX-2-positive, which may explain why CRC protection from ASA is observed in an unselected population, he reported that this study has supported pursuit of additional biomarkers, particularly those that might predict protection from ASA before or at the very earliest stages of the neoplastic process.
One such candidate is 15-prostaglandin dehydrogenase (15-PGDH) enzyme, which is known to catabolize or breakdown prostaglandin. When 15-PDGH levels were evaluated in normal tissue samples adjacent to CRC tumors, there was about a 50% reduction in risk of CRC in those with high 15-PGDH “but there was actually no reduction in risk among those with low 15-PGDH,” Dr. Chan reported.
Currently, ASA prophylaxis for preventing CRC is recommended by the U.S. Preventive Services Task Force in individuals who also have an increased risk of cardiovascular disease, but there is no accepted formula for weighing CRC risk against risk of bleeding. Biomarkers like 15-PGDH could be instrumental in guiding decisions for gastroenterologists.
“So you can imagine a strategy in which the endoscopist removes the polyp and also takes a biopsy of adjacent normal tissue to determine whether there are sufficient levels of 15-PGDH to potentially predict whether ASA will have a preventive effect,” Dr. Chan said.
There are other biomarkers also being pursued for their same potential to identify patients with a high likelihood to benefit from ASA, which Dr. Chan suggested could help clinicians determine when ASA is appropriate.
In clinical medicine, “we think a lot about biomarkers in respect to predicting who will benefit from cancer therapy, but we have thought less about whether we have the ability to use biomarkers to determine who would potentially be benefiting from a preventive intervention,” Dr. Chan said.
Genetic testing for GI cancer risk
“We have to be honest with ourselves about the limitations,” said Dr. Yurgelun, who expressed concern about how some of the commercially available multigene panels are being marketed and employed by both patients and physicians.
Despite the expectations of those without experience interpreting the results, “genetic testing often fails to give a black and white answer,” Dr. Yurgelun said in an interview. “Finding an inherited mutation in a cancer susceptibility gene carries plenty of uncertainty in many cases.”
One issue for interpretation of multigene panels involves variants of uncertain significance (VUS). These are germline genetic alterations that have been observed in individuals undergoing genetic testing but have not been confirmed as causative of inherited cancer risk.
“VUS are findings for which data are insufficient to classify them as either pathogenic or benign, and there’s significant concern about both patients and clinicians overinterpreting or misinterpreting their significance,” Dr. Yurgelun cautioned. In particular, aggressive intervention undertaken because of a VUS could introduce risk without benefit. He cited a recently published article that documented aggressive surgical management in the presence of VUS mutations “even though their genetic testing really should not have dictated that.”
Even when a mutation is present with a clear association with increased cancer risk, penetrance is another concept that may not be fully appreciated in gene panel interpretation. Penetrance expresses the proportion of patients with that mutation who will develop a cancer with which the gene mutation is associated.
“An inherited mutation in a cancer susceptibility gene influences their probability of developing cancer, but the odds are never zero and they are essentially never 100%,” Dr. Yurgelun explained. “Genetics is not necessarily destiny,” he added.
Genetic testing is important now, and its clinical value is improving, Dr. Yurgelun emphasized, but he cautioned that the “explosion in the availability of genetic testing” has the potential to cause unrealistic expectations and the potential for misuse of the information.
“Clinicians should expect to still encounter lots of uncertainty with genetic testing, which is why it’s so critically important that such testing be done with the guidance of professional genetic counselors who can help navigate many of these uncertainties. While our technology now allows for a tremendous breadth of genetic testing options, these options have hugely expanded the number of questions and the amount of uncertainty that can be generated,” he added.
Heidi Splete contributed to this report.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
BOSTON – The avenues for identifying those individuals most likely to benefit from surveillance and chemoprevention of colorectal cancer (CRC) are multiplying, experts agreed at the 2017 AGA Tech Summit sponsored by the AGA Center for GI Innovation and Technology.
In a series of three consecutive presentations, the first updated efforts to improve germline genetic testing. The second identified biomarkers that appear likely to improve the risk-to-benefit ratio from aspirin in cancer prevention. The third cautioned about the potential pitfalls of genetic testing for cancer risk even though the overall effect was to highlight the value of this tool when performed appropriately.
Novel tools for germline testing
Dr. Syngal noted that the management of hereditary cancers differs from that of sporadic cancers in several ways – the surgical management of cancer, screening, and surveillance after the treatment of the primary cancer, surveillance for associated cancers, screening and surveillance of family members, and reproductive counseling.
In her talk, “Novel Tools to Accelerate Implementation of Germline Genetic Testing,” Dr. Syngal discussed the PREMM (Prediction Model for MLH1 and MSH2 gene mutations) risk assessment tool first developed in 2006. The web-based PREMM calculates a risk score based on personal and family histories, Dr. Syngal said. “If an individual scores above a certain threshold, they are referred to genetic counseling and possibly testing,” she noted.
A second-generation tool for identifying patients at increased genetic risk for CRC, called PREMM1,2,6, was based on a larger patient sample, and published in 2011. That model “is recommended by the National Comprehensive Cancer Network for testing for Lynch syndrome, so its use is already part of clinical practice in gastroenterology,” Dr. Syngal reported.
A third model, called PREMM5, was developed on the basis of an even larger patient sample, and it is now being tested in primary care practices with plans in the works to implement the model in general gastroenterology, oncology, and ob.gyn. settings, she added.
“There are probably about 1 million people in the United States who have Lynch syndrome and don’t know it,” according to Dr. Syngal, who noted that PREMM can be completed in only a minute or two by clinicians or patients once they collected information about CRC history among their blood relatives.
Ultimately, the same approaches can be applied to risk assessment for other GI cancers in which the goal is to first identify patients at an increased likelihood of having a genetic mutation that predicts cancer risk and then employing multigene panels to narrow down those who could benefit from specific surveillance strategies.
However, by itself, the work to develop better strategies to identify Lynch syndrome is important, according to Dr. Syngal. When a group of experts was recently convened under the Cancer Moonshot Program championed by former Vice President Joe Biden, “Lynch syndrome was identified as the top priority in terms of cancer prevention” over the coming 5-10 years.
Biomarkers for GI cancer chemoprevention
Citing a long list of studies and trials that have associated aspirin with protection against CRC, including a randomized controlled trial in Lynch syndrome, Dr. Chan characterized the evidence of a chemoprotective effect from ASA against GI cancer as “overwhelming.” However, not all individuals may derive a favorable risk-to-benefit ratio due to the antiplatelet effects of ASA that increase risk of bleeding events in the GI tract and elsewhere.
The best approach to providing a favorable risk-to-benefit ratio may involve identifying biomarkers that predict benefit. The progress in understanding how ASA inhibits pathways of tumor development has provided candidates, according to Dr. Chan, citing a series of studies, including those conducted at his center.
One proof of concept was derived from work in evaluating tumor expression of cyclooxygenase (COX), the enzyme that converts arachidonic acid to prostaglandins. Dr. Chan explained that prostaglandin are linked to many downstream cancer-promoting pathways. In a study that involved molecular analysis on tumor specimens from patients who participated in a cohort study, the presence of the COX-2 isoenzyme was a differentiator.
“When the evaluation was performed according to COX-2 status, we saw about a 30% reduction in risk for COX-2-positive tumors. In contrast, we did not see any appreciable reduction in risk in tumors that were COX-2-negative,” Dr. Chan reported.
Although Dr. Chan acknowledged that about 80% of CRC tumors are COX-2-positive, which may explain why CRC protection from ASA is observed in an unselected population, he reported that this study has supported pursuit of additional biomarkers, particularly those that might predict protection from ASA before or at the very earliest stages of the neoplastic process.
One such candidate is 15-prostaglandin dehydrogenase (15-PGDH) enzyme, which is known to catabolize or breakdown prostaglandin. When 15-PDGH levels were evaluated in normal tissue samples adjacent to CRC tumors, there was about a 50% reduction in risk of CRC in those with high 15-PGDH “but there was actually no reduction in risk among those with low 15-PGDH,” Dr. Chan reported.
Currently, ASA prophylaxis for preventing CRC is recommended by the U.S. Preventive Services Task Force in individuals who also have an increased risk of cardiovascular disease, but there is no accepted formula for weighing CRC risk against risk of bleeding. Biomarkers like 15-PGDH could be instrumental in guiding decisions for gastroenterologists.
“So you can imagine a strategy in which the endoscopist removes the polyp and also takes a biopsy of adjacent normal tissue to determine whether there are sufficient levels of 15-PGDH to potentially predict whether ASA will have a preventive effect,” Dr. Chan said.
There are other biomarkers also being pursued for their same potential to identify patients with a high likelihood to benefit from ASA, which Dr. Chan suggested could help clinicians determine when ASA is appropriate.
In clinical medicine, “we think a lot about biomarkers in respect to predicting who will benefit from cancer therapy, but we have thought less about whether we have the ability to use biomarkers to determine who would potentially be benefiting from a preventive intervention,” Dr. Chan said.
Genetic testing for GI cancer risk
“We have to be honest with ourselves about the limitations,” said Dr. Yurgelun, who expressed concern about how some of the commercially available multigene panels are being marketed and employed by both patients and physicians.
Despite the expectations of those without experience interpreting the results, “genetic testing often fails to give a black and white answer,” Dr. Yurgelun said in an interview. “Finding an inherited mutation in a cancer susceptibility gene carries plenty of uncertainty in many cases.”
One issue for interpretation of multigene panels involves variants of uncertain significance (VUS). These are germline genetic alterations that have been observed in individuals undergoing genetic testing but have not been confirmed as causative of inherited cancer risk.
“VUS are findings for which data are insufficient to classify them as either pathogenic or benign, and there’s significant concern about both patients and clinicians overinterpreting or misinterpreting their significance,” Dr. Yurgelun cautioned. In particular, aggressive intervention undertaken because of a VUS could introduce risk without benefit. He cited a recently published article that documented aggressive surgical management in the presence of VUS mutations “even though their genetic testing really should not have dictated that.”
Even when a mutation is present with a clear association with increased cancer risk, penetrance is another concept that may not be fully appreciated in gene panel interpretation. Penetrance expresses the proportion of patients with that mutation who will develop a cancer with which the gene mutation is associated.
“An inherited mutation in a cancer susceptibility gene influences their probability of developing cancer, but the odds are never zero and they are essentially never 100%,” Dr. Yurgelun explained. “Genetics is not necessarily destiny,” he added.
Genetic testing is important now, and its clinical value is improving, Dr. Yurgelun emphasized, but he cautioned that the “explosion in the availability of genetic testing” has the potential to cause unrealistic expectations and the potential for misuse of the information.
“Clinicians should expect to still encounter lots of uncertainty with genetic testing, which is why it’s so critically important that such testing be done with the guidance of professional genetic counselors who can help navigate many of these uncertainties. While our technology now allows for a tremendous breadth of genetic testing options, these options have hugely expanded the number of questions and the amount of uncertainty that can be generated,” he added.
Heidi Splete contributed to this report.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
BOSTON – The avenues for identifying those individuals most likely to benefit from surveillance and chemoprevention of colorectal cancer (CRC) are multiplying, experts agreed at the 2017 AGA Tech Summit sponsored by the AGA Center for GI Innovation and Technology.
In a series of three consecutive presentations, the first updated efforts to improve germline genetic testing. The second identified biomarkers that appear likely to improve the risk-to-benefit ratio from aspirin in cancer prevention. The third cautioned about the potential pitfalls of genetic testing for cancer risk even though the overall effect was to highlight the value of this tool when performed appropriately.
Novel tools for germline testing
Dr. Syngal noted that the management of hereditary cancers differs from that of sporadic cancers in several ways – the surgical management of cancer, screening, and surveillance after the treatment of the primary cancer, surveillance for associated cancers, screening and surveillance of family members, and reproductive counseling.
In her talk, “Novel Tools to Accelerate Implementation of Germline Genetic Testing,” Dr. Syngal discussed the PREMM (Prediction Model for MLH1 and MSH2 gene mutations) risk assessment tool first developed in 2006. The web-based PREMM calculates a risk score based on personal and family histories, Dr. Syngal said. “If an individual scores above a certain threshold, they are referred to genetic counseling and possibly testing,” she noted.
A second-generation tool for identifying patients at increased genetic risk for CRC, called PREMM1,2,6, was based on a larger patient sample, and published in 2011. That model “is recommended by the National Comprehensive Cancer Network for testing for Lynch syndrome, so its use is already part of clinical practice in gastroenterology,” Dr. Syngal reported.
A third model, called PREMM5, was developed on the basis of an even larger patient sample, and it is now being tested in primary care practices with plans in the works to implement the model in general gastroenterology, oncology, and ob.gyn. settings, she added.
“There are probably about 1 million people in the United States who have Lynch syndrome and don’t know it,” according to Dr. Syngal, who noted that PREMM can be completed in only a minute or two by clinicians or patients once they collected information about CRC history among their blood relatives.
Ultimately, the same approaches can be applied to risk assessment for other GI cancers in which the goal is to first identify patients at an increased likelihood of having a genetic mutation that predicts cancer risk and then employing multigene panels to narrow down those who could benefit from specific surveillance strategies.
However, by itself, the work to develop better strategies to identify Lynch syndrome is important, according to Dr. Syngal. When a group of experts was recently convened under the Cancer Moonshot Program championed by former Vice President Joe Biden, “Lynch syndrome was identified as the top priority in terms of cancer prevention” over the coming 5-10 years.
Biomarkers for GI cancer chemoprevention
Citing a long list of studies and trials that have associated aspirin with protection against CRC, including a randomized controlled trial in Lynch syndrome, Dr. Chan characterized the evidence of a chemoprotective effect from ASA against GI cancer as “overwhelming.” However, not all individuals may derive a favorable risk-to-benefit ratio due to the antiplatelet effects of ASA that increase risk of bleeding events in the GI tract and elsewhere.
The best approach to providing a favorable risk-to-benefit ratio may involve identifying biomarkers that predict benefit. The progress in understanding how ASA inhibits pathways of tumor development has provided candidates, according to Dr. Chan, citing a series of studies, including those conducted at his center.
One proof of concept was derived from work in evaluating tumor expression of cyclooxygenase (COX), the enzyme that converts arachidonic acid to prostaglandins. Dr. Chan explained that prostaglandin are linked to many downstream cancer-promoting pathways. In a study that involved molecular analysis on tumor specimens from patients who participated in a cohort study, the presence of the COX-2 isoenzyme was a differentiator.
“When the evaluation was performed according to COX-2 status, we saw about a 30% reduction in risk for COX-2-positive tumors. In contrast, we did not see any appreciable reduction in risk in tumors that were COX-2-negative,” Dr. Chan reported.
Although Dr. Chan acknowledged that about 80% of CRC tumors are COX-2-positive, which may explain why CRC protection from ASA is observed in an unselected population, he reported that this study has supported pursuit of additional biomarkers, particularly those that might predict protection from ASA before or at the very earliest stages of the neoplastic process.
One such candidate is 15-prostaglandin dehydrogenase (15-PGDH) enzyme, which is known to catabolize or breakdown prostaglandin. When 15-PDGH levels were evaluated in normal tissue samples adjacent to CRC tumors, there was about a 50% reduction in risk of CRC in those with high 15-PGDH “but there was actually no reduction in risk among those with low 15-PGDH,” Dr. Chan reported.
Currently, ASA prophylaxis for preventing CRC is recommended by the U.S. Preventive Services Task Force in individuals who also have an increased risk of cardiovascular disease, but there is no accepted formula for weighing CRC risk against risk of bleeding. Biomarkers like 15-PGDH could be instrumental in guiding decisions for gastroenterologists.
“So you can imagine a strategy in which the endoscopist removes the polyp and also takes a biopsy of adjacent normal tissue to determine whether there are sufficient levels of 15-PGDH to potentially predict whether ASA will have a preventive effect,” Dr. Chan said.
There are other biomarkers also being pursued for their same potential to identify patients with a high likelihood to benefit from ASA, which Dr. Chan suggested could help clinicians determine when ASA is appropriate.
In clinical medicine, “we think a lot about biomarkers in respect to predicting who will benefit from cancer therapy, but we have thought less about whether we have the ability to use biomarkers to determine who would potentially be benefiting from a preventive intervention,” Dr. Chan said.
Genetic testing for GI cancer risk
“We have to be honest with ourselves about the limitations,” said Dr. Yurgelun, who expressed concern about how some of the commercially available multigene panels are being marketed and employed by both patients and physicians.
Despite the expectations of those without experience interpreting the results, “genetic testing often fails to give a black and white answer,” Dr. Yurgelun said in an interview. “Finding an inherited mutation in a cancer susceptibility gene carries plenty of uncertainty in many cases.”
One issue for interpretation of multigene panels involves variants of uncertain significance (VUS). These are germline genetic alterations that have been observed in individuals undergoing genetic testing but have not been confirmed as causative of inherited cancer risk.
“VUS are findings for which data are insufficient to classify them as either pathogenic or benign, and there’s significant concern about both patients and clinicians overinterpreting or misinterpreting their significance,” Dr. Yurgelun cautioned. In particular, aggressive intervention undertaken because of a VUS could introduce risk without benefit. He cited a recently published article that documented aggressive surgical management in the presence of VUS mutations “even though their genetic testing really should not have dictated that.”
Even when a mutation is present with a clear association with increased cancer risk, penetrance is another concept that may not be fully appreciated in gene panel interpretation. Penetrance expresses the proportion of patients with that mutation who will develop a cancer with which the gene mutation is associated.
“An inherited mutation in a cancer susceptibility gene influences their probability of developing cancer, but the odds are never zero and they are essentially never 100%,” Dr. Yurgelun explained. “Genetics is not necessarily destiny,” he added.
Genetic testing is important now, and its clinical value is improving, Dr. Yurgelun emphasized, but he cautioned that the “explosion in the availability of genetic testing” has the potential to cause unrealistic expectations and the potential for misuse of the information.
“Clinicians should expect to still encounter lots of uncertainty with genetic testing, which is why it’s so critically important that such testing be done with the guidance of professional genetic counselors who can help navigate many of these uncertainties. While our technology now allows for a tremendous breadth of genetic testing options, these options have hugely expanded the number of questions and the amount of uncertainty that can be generated,” he added.
Heidi Splete contributed to this report.
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 THE 2017 AGA TECH SUMMIT
Orbital, over rotational, atherectomy holds survival edge in elderly, obese
WASHINGTON – Orbital atherectomy (OA) was associated with a lower risk of in-hospital mortality than rotational atherectomy (RA) in female, obese, and elderly study groups, according to data from a prospective observational study.
Each procedure was employed to treat coronary artery calcifications (CAC) in the elderly and the obese prior to percutaneous interventions (PCI).
The data comparing OA with RA in these populations were drawn from the Clinical Outcomes of Atherectomy Prior to PCI (COAP) study, for which Perwaiz M. Meraj, MD, director of structural heart and peripheral vascular disease at the North Shore-LIJ Hospital, Manhasset, N.Y., served as the senior author.
Each set of data, as well as a third set of data comparing OA to RA in female patients, was presented separately at CRT 2017, sponsored by the Cardiovascular Research Institute at Washington Hospital Center.
In the comparison of OA to RA in the elderly, a substudy known as COAP-75, the focus was on patients 75 years of age or older who underwent either OA or RA to remove calcified coronary lesions within the context of PCI. As with the obese and female subgroups, the elderly patients in this study were drawn from 35,590 patients who underwent PCI at one of five tertiary care hospitals in a recent 5-year period.
Of the 310 elderly patients undergoing atherectomy, 117 were treated with OA and 193 with RA. The median lesion lengths and diameters were not significantly different between the two groups. Although OA was less likely to be performed through femoral access (53% vs. 68.9%; P = .005), no other measured differences in procedure were significant, with one exception: Fluoroscopy exposure was of shorter duration in the OA, versus the RA, arm (24.0 minutes vs. 29.4 minutes; P = .005).
On univariate analysis, the lower rate of in-hospital deaths for OA did not reach statistical significance (0% vs. 1.55%; P = .176), but the difference was significant on multivariate-adjusted analysis (P = .034).
There were also higher numerical rates of perforation, tamponade, heart failure, and red blood cell transfusion in the RA group, versus the OA group, but only the latter was significant (P = .002) on multivariate-adjusted analysis.
In contrast, there was a higher rate of MI among those treated with OA, rather than RA (17.1% vs. 13.5%), which was not significant on univariate analysis (P = .573) but did reach significance on adjusted-multivariate analysis (P = .008).
Overall, the authors suggested that both OA and RA are safe procedures, but the mortality reduction suggests a potential relative advantage for OA.
Similar conclusions were reached in the substudy of patients with obesity, called COAP-BMI. In that study, 222 patients were evaluated, of which 91 were treated with OA and 131 were treated with RA.
In-hospital mortality was 0% in the group treated with OA, compared with 3.05% in the group treated with RA (P = .004). The rate of in-hospital major adverse cardiovascular events was also significantly lower in the OA group (15.4% vs. 16.3%; P = .007).
“The rate of secondary outcomes for myocardial infarction and stroke were similar between groups, as were individual procedural safety endpoints, including dissection, perforation, tamponade, or heart failure,” reported Evan Shlofmitz, MD, a cardiology fellow at Northwell Health, Manhasset, N.Y., who collaborated with Dr. Meraj and presented the data at the meeting.
As with the study in the elderly, for which Dr. Shlofmitz was also a coauthor, the study in the obese is the first to compare OA and RA, he noted.
In a third substudy, called COAP-Female, OA and RA were compared in 247 women with CAC who were undergoing PCI.
Again, in-hospital mortality rates were higher in those treated with RA, compared with OA, but the difference was not significant (0.79% vs. 0%; P = .254). There were also no significant differences in any secondary outcomes, including MI, or in any procedural complications, such as rates of dissection, perforation, or major bleeding.
The only significant difference identified in the study was a lower fluoroscopy time in those treated with OA relative to RA (21.3 minutes vs. 27.6 minutes; P = .001).
Although fluoroscopy time was not a primary endpoint, “a reduction in radiation exposure has important ramifications for both patients and operators,” Dr. Shlofmitz noted. He suggested that objective data on outcomes in females is needed, because this group has been “severely underrepresented in atherectomy trials.”
Overall, the substudies reinforce a large body of evidence that atherectomy is safe and effective for achieving revascularization in patients undergoing PCI who have CAC, Dr. Shlofmitz concluded. However, the significant mortality advantage for OA relative to RA in the elderly and the obese suggests that the approaches may not be interchangeable.
Dr. Shlofmitz reported no financial relationships to disclose.
WASHINGTON – Orbital atherectomy (OA) was associated with a lower risk of in-hospital mortality than rotational atherectomy (RA) in female, obese, and elderly study groups, according to data from a prospective observational study.
Each procedure was employed to treat coronary artery calcifications (CAC) in the elderly and the obese prior to percutaneous interventions (PCI).
The data comparing OA with RA in these populations were drawn from the Clinical Outcomes of Atherectomy Prior to PCI (COAP) study, for which Perwaiz M. Meraj, MD, director of structural heart and peripheral vascular disease at the North Shore-LIJ Hospital, Manhasset, N.Y., served as the senior author.
Each set of data, as well as a third set of data comparing OA to RA in female patients, was presented separately at CRT 2017, sponsored by the Cardiovascular Research Institute at Washington Hospital Center.
In the comparison of OA to RA in the elderly, a substudy known as COAP-75, the focus was on patients 75 years of age or older who underwent either OA or RA to remove calcified coronary lesions within the context of PCI. As with the obese and female subgroups, the elderly patients in this study were drawn from 35,590 patients who underwent PCI at one of five tertiary care hospitals in a recent 5-year period.
Of the 310 elderly patients undergoing atherectomy, 117 were treated with OA and 193 with RA. The median lesion lengths and diameters were not significantly different between the two groups. Although OA was less likely to be performed through femoral access (53% vs. 68.9%; P = .005), no other measured differences in procedure were significant, with one exception: Fluoroscopy exposure was of shorter duration in the OA, versus the RA, arm (24.0 minutes vs. 29.4 minutes; P = .005).
On univariate analysis, the lower rate of in-hospital deaths for OA did not reach statistical significance (0% vs. 1.55%; P = .176), but the difference was significant on multivariate-adjusted analysis (P = .034).
There were also higher numerical rates of perforation, tamponade, heart failure, and red blood cell transfusion in the RA group, versus the OA group, but only the latter was significant (P = .002) on multivariate-adjusted analysis.
In contrast, there was a higher rate of MI among those treated with OA, rather than RA (17.1% vs. 13.5%), which was not significant on univariate analysis (P = .573) but did reach significance on adjusted-multivariate analysis (P = .008).
Overall, the authors suggested that both OA and RA are safe procedures, but the mortality reduction suggests a potential relative advantage for OA.
Similar conclusions were reached in the substudy of patients with obesity, called COAP-BMI. In that study, 222 patients were evaluated, of which 91 were treated with OA and 131 were treated with RA.
In-hospital mortality was 0% in the group treated with OA, compared with 3.05% in the group treated with RA (P = .004). The rate of in-hospital major adverse cardiovascular events was also significantly lower in the OA group (15.4% vs. 16.3%; P = .007).
“The rate of secondary outcomes for myocardial infarction and stroke were similar between groups, as were individual procedural safety endpoints, including dissection, perforation, tamponade, or heart failure,” reported Evan Shlofmitz, MD, a cardiology fellow at Northwell Health, Manhasset, N.Y., who collaborated with Dr. Meraj and presented the data at the meeting.
As with the study in the elderly, for which Dr. Shlofmitz was also a coauthor, the study in the obese is the first to compare OA and RA, he noted.
In a third substudy, called COAP-Female, OA and RA were compared in 247 women with CAC who were undergoing PCI.
Again, in-hospital mortality rates were higher in those treated with RA, compared with OA, but the difference was not significant (0.79% vs. 0%; P = .254). There were also no significant differences in any secondary outcomes, including MI, or in any procedural complications, such as rates of dissection, perforation, or major bleeding.
The only significant difference identified in the study was a lower fluoroscopy time in those treated with OA relative to RA (21.3 minutes vs. 27.6 minutes; P = .001).
Although fluoroscopy time was not a primary endpoint, “a reduction in radiation exposure has important ramifications for both patients and operators,” Dr. Shlofmitz noted. He suggested that objective data on outcomes in females is needed, because this group has been “severely underrepresented in atherectomy trials.”
Overall, the substudies reinforce a large body of evidence that atherectomy is safe and effective for achieving revascularization in patients undergoing PCI who have CAC, Dr. Shlofmitz concluded. However, the significant mortality advantage for OA relative to RA in the elderly and the obese suggests that the approaches may not be interchangeable.
Dr. Shlofmitz reported no financial relationships to disclose.
WASHINGTON – Orbital atherectomy (OA) was associated with a lower risk of in-hospital mortality than rotational atherectomy (RA) in female, obese, and elderly study groups, according to data from a prospective observational study.
Each procedure was employed to treat coronary artery calcifications (CAC) in the elderly and the obese prior to percutaneous interventions (PCI).
The data comparing OA with RA in these populations were drawn from the Clinical Outcomes of Atherectomy Prior to PCI (COAP) study, for which Perwaiz M. Meraj, MD, director of structural heart and peripheral vascular disease at the North Shore-LIJ Hospital, Manhasset, N.Y., served as the senior author.
Each set of data, as well as a third set of data comparing OA to RA in female patients, was presented separately at CRT 2017, sponsored by the Cardiovascular Research Institute at Washington Hospital Center.
In the comparison of OA to RA in the elderly, a substudy known as COAP-75, the focus was on patients 75 years of age or older who underwent either OA or RA to remove calcified coronary lesions within the context of PCI. As with the obese and female subgroups, the elderly patients in this study were drawn from 35,590 patients who underwent PCI at one of five tertiary care hospitals in a recent 5-year period.
Of the 310 elderly patients undergoing atherectomy, 117 were treated with OA and 193 with RA. The median lesion lengths and diameters were not significantly different between the two groups. Although OA was less likely to be performed through femoral access (53% vs. 68.9%; P = .005), no other measured differences in procedure were significant, with one exception: Fluoroscopy exposure was of shorter duration in the OA, versus the RA, arm (24.0 minutes vs. 29.4 minutes; P = .005).
On univariate analysis, the lower rate of in-hospital deaths for OA did not reach statistical significance (0% vs. 1.55%; P = .176), but the difference was significant on multivariate-adjusted analysis (P = .034).
There were also higher numerical rates of perforation, tamponade, heart failure, and red blood cell transfusion in the RA group, versus the OA group, but only the latter was significant (P = .002) on multivariate-adjusted analysis.
In contrast, there was a higher rate of MI among those treated with OA, rather than RA (17.1% vs. 13.5%), which was not significant on univariate analysis (P = .573) but did reach significance on adjusted-multivariate analysis (P = .008).
Overall, the authors suggested that both OA and RA are safe procedures, but the mortality reduction suggests a potential relative advantage for OA.
Similar conclusions were reached in the substudy of patients with obesity, called COAP-BMI. In that study, 222 patients were evaluated, of which 91 were treated with OA and 131 were treated with RA.
In-hospital mortality was 0% in the group treated with OA, compared with 3.05% in the group treated with RA (P = .004). The rate of in-hospital major adverse cardiovascular events was also significantly lower in the OA group (15.4% vs. 16.3%; P = .007).
“The rate of secondary outcomes for myocardial infarction and stroke were similar between groups, as were individual procedural safety endpoints, including dissection, perforation, tamponade, or heart failure,” reported Evan Shlofmitz, MD, a cardiology fellow at Northwell Health, Manhasset, N.Y., who collaborated with Dr. Meraj and presented the data at the meeting.
As with the study in the elderly, for which Dr. Shlofmitz was also a coauthor, the study in the obese is the first to compare OA and RA, he noted.
In a third substudy, called COAP-Female, OA and RA were compared in 247 women with CAC who were undergoing PCI.
Again, in-hospital mortality rates were higher in those treated with RA, compared with OA, but the difference was not significant (0.79% vs. 0%; P = .254). There were also no significant differences in any secondary outcomes, including MI, or in any procedural complications, such as rates of dissection, perforation, or major bleeding.
The only significant difference identified in the study was a lower fluoroscopy time in those treated with OA relative to RA (21.3 minutes vs. 27.6 minutes; P = .001).
Although fluoroscopy time was not a primary endpoint, “a reduction in radiation exposure has important ramifications for both patients and operators,” Dr. Shlofmitz noted. He suggested that objective data on outcomes in females is needed, because this group has been “severely underrepresented in atherectomy trials.”
Overall, the substudies reinforce a large body of evidence that atherectomy is safe and effective for achieving revascularization in patients undergoing PCI who have CAC, Dr. Shlofmitz concluded. However, the significant mortality advantage for OA relative to RA in the elderly and the obese suggests that the approaches may not be interchangeable.
Dr. Shlofmitz reported no financial relationships to disclose.
AT CRT 2017
Key clinical point: Orbital atherectomy was associated with better survival than rotational atherectomy in elderly and obese patients requiring percutaneous interventions.
Major finding: In-hospital mortality was significantly lower after orbital atherectomy, compared with rotational atherectomy, in both the elderly (0% vs. 1.55%; P = .034) and the obese (0% vs. 3.05%; P = .004).
Data source: A nonrandomized, prospective, multicenter study.
Disclosures: Dr. Shlofmitz reported no financial relationships to disclose.
Liver disease likely to become increasing indication for bariatric surgery
PHILADELPHIA – There is a long list of benefits from bariatric surgery in the morbidly obese, but prevention of end-stage liver disease and the need for a first or second liver transplant is likely to grow as an indication, according to an overview of weight loss surgery at Digestive Diseases: New Advances, held by Rutgers, the State University of New Jersey, and Global Academy for Medical Education.
“Bariatric surgery is associated with significant improvement not just in diabetes, dyslipidemia, hypertension, and other complications of metabolic disorders but for me more interestingly, it is effective for treating fatty liver disease where you can see a 90% improvement in steatosis,” reported Subhashini Ayloo, MD, chief of minimally invasive robotic hepato-pancreato-biliary surgery and liver transplantation at New Jersey Medical School, Newark.
Trained in both bariatric surgery and liver transplant, Dr. Ayloo predicts that these fields will become increasingly connected because of the obesity epidemic and the related rise in nonalcoholic fatty liver disease (NAFLD). Dr. Ayloo reported that bariatric surgery is already being used in her center to avoid a second liver transplant in obese patients who are unable to lose sufficient weight to prevent progressive NAFLD after a first transplant.
The emphasis Dr. Ayloo placed on the role of bariatric surgery in preventing progression of NAFLD to nonalcoholic steatohepatitis and the inflammatory process that leads to fibrosis, cirrhosis, and liver decompensation, was drawn from her interest in these two fields. However, she did not ignore the potential of protection from obesity control for other diseases.
“Obesity adversely affects every organ in the body,” Dr. Ayloo pointed out. As a result of weight loss achieved with bariatric surgery, there is now a large body of evidence supporting broad benefits, not just those related to fat deposited in hepatocytes.
“We have a couple of decades of experience that has been published [with bariatric surgery], and this has shown that it maintains weight loss long term, it improves all the obesity-associated comorbidities, and it is cost effective,” Dr. Ayloo said. Now with long-term follow-up, “all of the studies are showing that bariatric surgery improves survival.”
Although most of the survival data have been generated by retrospective cohort studies, Dr. Ayloo cited nine sets of data showing odds ratios associating bariatric surgery with up to a 90% reduction in death over periods of up to 10 years of follow-up. In a summary slide presented by Dr. Ayloo, the estimated mortality benefit over 5 years was listed as 85%. The same summary slide listed large improvements in relevant measures of morbidity for more than 10 organ systems, such as improvement or resolution of dyslipidemia and hypertension in the circulatory system, improvement or resolution of asthma and other diseases affecting the respiratory system, and resolution or improvement of gastroesophageal reflux disease and other diseases affecting the gastrointestinal system.
Specific to the liver, these benefits included a nearly 40% reduction in liver inflammation and 20% reduction in fibrosis. According to Dr. Ayloo, who noted that NAFLD is expected to overtake hepatitis C virus as the No. 1 cause of liver transplant within the next 5 years, these data are important for drawing attention to bariatric surgery as a strategy to control liver disease. She suggested that there is a need to create a tighter link between efforts to treat morbid obesity and advanced liver disease.
“There is an established literature showing that if somebody is morbidly obese, the rate of liver transplant is lower than when compared to patients with normal weight,” Dr. Ayloo said. “There is a call out in the transplant community that we need to address this and we cannot just be throwing this under the table.”
Because of the strong relationship between obesity and NAFLD, a systematic approach is needed to consider liver disease in obese patients and obesity in patients with liver disease, she said. The close relationship is relevant when planning interventions for either. Liver disease should be assessed prior to bariatric surgery regardless of the indication and then monitored closely as part of postoperative care, she said.
Dr. Ayloo identified weight control as an essential part of posttransplant care to prevent hepatic fat deposition that threatens transplant-free survival.
Global Academy and this news organization are owned by the same company. Dr. Ayloo reports no relevant financial relationships.
AGA Resource
The AGA Obesity Practice Guide provides tools for gastroenterologists to lead a multidisciplinary team of health-care professionals for the management of patients with obesity. Learn more at www.gastro.org/obesity.
PHILADELPHIA – There is a long list of benefits from bariatric surgery in the morbidly obese, but prevention of end-stage liver disease and the need for a first or second liver transplant is likely to grow as an indication, according to an overview of weight loss surgery at Digestive Diseases: New Advances, held by Rutgers, the State University of New Jersey, and Global Academy for Medical Education.
“Bariatric surgery is associated with significant improvement not just in diabetes, dyslipidemia, hypertension, and other complications of metabolic disorders but for me more interestingly, it is effective for treating fatty liver disease where you can see a 90% improvement in steatosis,” reported Subhashini Ayloo, MD, chief of minimally invasive robotic hepato-pancreato-biliary surgery and liver transplantation at New Jersey Medical School, Newark.
Trained in both bariatric surgery and liver transplant, Dr. Ayloo predicts that these fields will become increasingly connected because of the obesity epidemic and the related rise in nonalcoholic fatty liver disease (NAFLD). Dr. Ayloo reported that bariatric surgery is already being used in her center to avoid a second liver transplant in obese patients who are unable to lose sufficient weight to prevent progressive NAFLD after a first transplant.
The emphasis Dr. Ayloo placed on the role of bariatric surgery in preventing progression of NAFLD to nonalcoholic steatohepatitis and the inflammatory process that leads to fibrosis, cirrhosis, and liver decompensation, was drawn from her interest in these two fields. However, she did not ignore the potential of protection from obesity control for other diseases.
“Obesity adversely affects every organ in the body,” Dr. Ayloo pointed out. As a result of weight loss achieved with bariatric surgery, there is now a large body of evidence supporting broad benefits, not just those related to fat deposited in hepatocytes.
“We have a couple of decades of experience that has been published [with bariatric surgery], and this has shown that it maintains weight loss long term, it improves all the obesity-associated comorbidities, and it is cost effective,” Dr. Ayloo said. Now with long-term follow-up, “all of the studies are showing that bariatric surgery improves survival.”
Although most of the survival data have been generated by retrospective cohort studies, Dr. Ayloo cited nine sets of data showing odds ratios associating bariatric surgery with up to a 90% reduction in death over periods of up to 10 years of follow-up. In a summary slide presented by Dr. Ayloo, the estimated mortality benefit over 5 years was listed as 85%. The same summary slide listed large improvements in relevant measures of morbidity for more than 10 organ systems, such as improvement or resolution of dyslipidemia and hypertension in the circulatory system, improvement or resolution of asthma and other diseases affecting the respiratory system, and resolution or improvement of gastroesophageal reflux disease and other diseases affecting the gastrointestinal system.
Specific to the liver, these benefits included a nearly 40% reduction in liver inflammation and 20% reduction in fibrosis. According to Dr. Ayloo, who noted that NAFLD is expected to overtake hepatitis C virus as the No. 1 cause of liver transplant within the next 5 years, these data are important for drawing attention to bariatric surgery as a strategy to control liver disease. She suggested that there is a need to create a tighter link between efforts to treat morbid obesity and advanced liver disease.
“There is an established literature showing that if somebody is morbidly obese, the rate of liver transplant is lower than when compared to patients with normal weight,” Dr. Ayloo said. “There is a call out in the transplant community that we need to address this and we cannot just be throwing this under the table.”
Because of the strong relationship between obesity and NAFLD, a systematic approach is needed to consider liver disease in obese patients and obesity in patients with liver disease, she said. The close relationship is relevant when planning interventions for either. Liver disease should be assessed prior to bariatric surgery regardless of the indication and then monitored closely as part of postoperative care, she said.
Dr. Ayloo identified weight control as an essential part of posttransplant care to prevent hepatic fat deposition that threatens transplant-free survival.
Global Academy and this news organization are owned by the same company. Dr. Ayloo reports no relevant financial relationships.
AGA Resource
The AGA Obesity Practice Guide provides tools for gastroenterologists to lead a multidisciplinary team of health-care professionals for the management of patients with obesity. Learn more at www.gastro.org/obesity.
PHILADELPHIA – There is a long list of benefits from bariatric surgery in the morbidly obese, but prevention of end-stage liver disease and the need for a first or second liver transplant is likely to grow as an indication, according to an overview of weight loss surgery at Digestive Diseases: New Advances, held by Rutgers, the State University of New Jersey, and Global Academy for Medical Education.
“Bariatric surgery is associated with significant improvement not just in diabetes, dyslipidemia, hypertension, and other complications of metabolic disorders but for me more interestingly, it is effective for treating fatty liver disease where you can see a 90% improvement in steatosis,” reported Subhashini Ayloo, MD, chief of minimally invasive robotic hepato-pancreato-biliary surgery and liver transplantation at New Jersey Medical School, Newark.
Trained in both bariatric surgery and liver transplant, Dr. Ayloo predicts that these fields will become increasingly connected because of the obesity epidemic and the related rise in nonalcoholic fatty liver disease (NAFLD). Dr. Ayloo reported that bariatric surgery is already being used in her center to avoid a second liver transplant in obese patients who are unable to lose sufficient weight to prevent progressive NAFLD after a first transplant.
The emphasis Dr. Ayloo placed on the role of bariatric surgery in preventing progression of NAFLD to nonalcoholic steatohepatitis and the inflammatory process that leads to fibrosis, cirrhosis, and liver decompensation, was drawn from her interest in these two fields. However, she did not ignore the potential of protection from obesity control for other diseases.
“Obesity adversely affects every organ in the body,” Dr. Ayloo pointed out. As a result of weight loss achieved with bariatric surgery, there is now a large body of evidence supporting broad benefits, not just those related to fat deposited in hepatocytes.
“We have a couple of decades of experience that has been published [with bariatric surgery], and this has shown that it maintains weight loss long term, it improves all the obesity-associated comorbidities, and it is cost effective,” Dr. Ayloo said. Now with long-term follow-up, “all of the studies are showing that bariatric surgery improves survival.”
Although most of the survival data have been generated by retrospective cohort studies, Dr. Ayloo cited nine sets of data showing odds ratios associating bariatric surgery with up to a 90% reduction in death over periods of up to 10 years of follow-up. In a summary slide presented by Dr. Ayloo, the estimated mortality benefit over 5 years was listed as 85%. The same summary slide listed large improvements in relevant measures of morbidity for more than 10 organ systems, such as improvement or resolution of dyslipidemia and hypertension in the circulatory system, improvement or resolution of asthma and other diseases affecting the respiratory system, and resolution or improvement of gastroesophageal reflux disease and other diseases affecting the gastrointestinal system.
Specific to the liver, these benefits included a nearly 40% reduction in liver inflammation and 20% reduction in fibrosis. According to Dr. Ayloo, who noted that NAFLD is expected to overtake hepatitis C virus as the No. 1 cause of liver transplant within the next 5 years, these data are important for drawing attention to bariatric surgery as a strategy to control liver disease. She suggested that there is a need to create a tighter link between efforts to treat morbid obesity and advanced liver disease.
“There is an established literature showing that if somebody is morbidly obese, the rate of liver transplant is lower than when compared to patients with normal weight,” Dr. Ayloo said. “There is a call out in the transplant community that we need to address this and we cannot just be throwing this under the table.”
Because of the strong relationship between obesity and NAFLD, a systematic approach is needed to consider liver disease in obese patients and obesity in patients with liver disease, she said. The close relationship is relevant when planning interventions for either. Liver disease should be assessed prior to bariatric surgery regardless of the indication and then monitored closely as part of postoperative care, she said.
Dr. Ayloo identified weight control as an essential part of posttransplant care to prevent hepatic fat deposition that threatens transplant-free survival.
Global Academy and this news organization are owned by the same company. Dr. Ayloo reports no relevant financial relationships.
AGA Resource
The AGA Obesity Practice Guide provides tools for gastroenterologists to lead a multidisciplinary team of health-care professionals for the management of patients with obesity. Learn more at www.gastro.org/obesity.
AT DIGESTIVE DISEASES: NEW ADVANCES