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Cardiac abnormalities among childhood cancer survivors
Photo by Bill Branson
A new study has provided additional insight into the development of cardiac abnormalities in adult survivors of childhood cancer.
Researchers analyzed more than 1800 cancer survivors who were exposed to cardiotoxic therapies as children.
The team said they found evidence of cardiac abnormalities in a substantial number of these subjects, many of whom were younger and did not exhibit symptoms of abnormalities.
Daniel A. Mulrooney, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Annals of Internal Medicine.
The team assessed cardiac outcomes among 1853 subjects who were 18 and older and had received cancer-related cardiotoxic therapy at least 10 years earlier.
The subjects were pretty evenly split along gender lines (52.3% male), their median age at cancer diagnosis was 8 (range, 0 to 24), and their median age at evaluation was 31 (range, 18 to 60).
At evaluation, 7.4% of subjects had cardiomyopathy (newly identified in 4.7%), 3.8% had coronary artery disease (newly identified in 2.2%), 28% had valvular regurgitation or stenosis (newly identified in 24.8%), and 4.4% had conduction or rhythm abnormalities (newly identified in 1.4%). All but 5 subjects were asymptomatic.
Multivariable analysis suggested the odds of developing cardiomyopathy were significantly associated with being male (odds ratio [OR]=1.9), receiving anthracycline doses of 250 mg/m2 or greater (OR=2.7), having cardiac radiation exposure greater than 1500 cGy (OR=1.9), and having hypertension (OR=3.0).
Being younger at diagnosis was associated with higher odds of valvular disease. The ORs were 1.5 for patients who were 0 to 4 years of age at diagnosis and 1.3 for patients who were 5 to 9 at diagnosis.
Receiving higher radiation doses was associated with higher odds of valvular disease as well. But associations between radiation and valvular disease varied according to a patient’s anthracycline exposure (interaction P<0.001). The highest odds were among survivors with the highest doses of radiation exposure and any anthracycline exposure (OR=4.5).
The researchers also noted a reduction in the OR for valvular disease among obese patients (OR=0.4) and those with dyslipidemia (OR=0.7).
The team said there were not enough cases of coronary artery disease and conduction or rhythm abnormalities to support a fully adjusted multivariable model. However, it seemed these outcomes were more common with older age (≥40 years) and among patients with cardiac radiation doses of 1500 cGy or greater.
The researchers said this study revealed “considerable cardiovascular disease” in a large cohort of adult survivors of childhood cancer, which suggests a substantial future healthcare burden.
The team believes their findings could guide stratification of risk factors, screening practices, health counseling, and potential therapeutic measures aimed at changing the disease trajectory in this young adult population. 
Photo by Bill Branson
A new study has provided additional insight into the development of cardiac abnormalities in adult survivors of childhood cancer.
Researchers analyzed more than 1800 cancer survivors who were exposed to cardiotoxic therapies as children.
The team said they found evidence of cardiac abnormalities in a substantial number of these subjects, many of whom were younger and did not exhibit symptoms of abnormalities.
Daniel A. Mulrooney, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Annals of Internal Medicine.
The team assessed cardiac outcomes among 1853 subjects who were 18 and older and had received cancer-related cardiotoxic therapy at least 10 years earlier.
The subjects were pretty evenly split along gender lines (52.3% male), their median age at cancer diagnosis was 8 (range, 0 to 24), and their median age at evaluation was 31 (range, 18 to 60).
At evaluation, 7.4% of subjects had cardiomyopathy (newly identified in 4.7%), 3.8% had coronary artery disease (newly identified in 2.2%), 28% had valvular regurgitation or stenosis (newly identified in 24.8%), and 4.4% had conduction or rhythm abnormalities (newly identified in 1.4%). All but 5 subjects were asymptomatic.
Multivariable analysis suggested the odds of developing cardiomyopathy were significantly associated with being male (odds ratio [OR]=1.9), receiving anthracycline doses of 250 mg/m2 or greater (OR=2.7), having cardiac radiation exposure greater than 1500 cGy (OR=1.9), and having hypertension (OR=3.0).
Being younger at diagnosis was associated with higher odds of valvular disease. The ORs were 1.5 for patients who were 0 to 4 years of age at diagnosis and 1.3 for patients who were 5 to 9 at diagnosis.
Receiving higher radiation doses was associated with higher odds of valvular disease as well. But associations between radiation and valvular disease varied according to a patient’s anthracycline exposure (interaction P<0.001). The highest odds were among survivors with the highest doses of radiation exposure and any anthracycline exposure (OR=4.5).
The researchers also noted a reduction in the OR for valvular disease among obese patients (OR=0.4) and those with dyslipidemia (OR=0.7).
The team said there were not enough cases of coronary artery disease and conduction or rhythm abnormalities to support a fully adjusted multivariable model. However, it seemed these outcomes were more common with older age (≥40 years) and among patients with cardiac radiation doses of 1500 cGy or greater.
The researchers said this study revealed “considerable cardiovascular disease” in a large cohort of adult survivors of childhood cancer, which suggests a substantial future healthcare burden.
The team believes their findings could guide stratification of risk factors, screening practices, health counseling, and potential therapeutic measures aimed at changing the disease trajectory in this young adult population.
Photo by Bill Branson
A new study has provided additional insight into the development of cardiac abnormalities in adult survivors of childhood cancer.
Researchers analyzed more than 1800 cancer survivors who were exposed to cardiotoxic therapies as children.
The team said they found evidence of cardiac abnormalities in a substantial number of these subjects, many of whom were younger and did not exhibit symptoms of abnormalities.
Daniel A. Mulrooney, MD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these findings in Annals of Internal Medicine.
The team assessed cardiac outcomes among 1853 subjects who were 18 and older and had received cancer-related cardiotoxic therapy at least 10 years earlier.
The subjects were pretty evenly split along gender lines (52.3% male), their median age at cancer diagnosis was 8 (range, 0 to 24), and their median age at evaluation was 31 (range, 18 to 60).
At evaluation, 7.4% of subjects had cardiomyopathy (newly identified in 4.7%), 3.8% had coronary artery disease (newly identified in 2.2%), 28% had valvular regurgitation or stenosis (newly identified in 24.8%), and 4.4% had conduction or rhythm abnormalities (newly identified in 1.4%). All but 5 subjects were asymptomatic.
Multivariable analysis suggested the odds of developing cardiomyopathy were significantly associated with being male (odds ratio [OR]=1.9), receiving anthracycline doses of 250 mg/m2 or greater (OR=2.7), having cardiac radiation exposure greater than 1500 cGy (OR=1.9), and having hypertension (OR=3.0).
Being younger at diagnosis was associated with higher odds of valvular disease. The ORs were 1.5 for patients who were 0 to 4 years of age at diagnosis and 1.3 for patients who were 5 to 9 at diagnosis.
Receiving higher radiation doses was associated with higher odds of valvular disease as well. But associations between radiation and valvular disease varied according to a patient’s anthracycline exposure (interaction P<0.001). The highest odds were among survivors with the highest doses of radiation exposure and any anthracycline exposure (OR=4.5).
The researchers also noted a reduction in the OR for valvular disease among obese patients (OR=0.4) and those with dyslipidemia (OR=0.7).
The team said there were not enough cases of coronary artery disease and conduction or rhythm abnormalities to support a fully adjusted multivariable model. However, it seemed these outcomes were more common with older age (≥40 years) and among patients with cardiac radiation doses of 1500 cGy or greater.
The researchers said this study revealed “considerable cardiovascular disease” in a large cohort of adult survivors of childhood cancer, which suggests a substantial future healthcare burden.
The team believes their findings could guide stratification of risk factors, screening practices, health counseling, and potential therapeutic measures aimed at changing the disease trajectory in this young adult population.
Paste may reduce radiation-induced fibrosis
woman for radiation
Photo by Rhoda Baer
A topical paste can reduce fibrosis caused by radiation therapy, according to preclinical research published in The FASEB Journal.
The study addressed a type of fibrosis called radiation dermatitis, in which radiation applied to the skin causes the buildup of fibrotic tissue and skin thickening.
To test their topical paste, researchers mimicked the development of radiation dermatitis in mice.
They exposed the mice’s skin to a single dose of 40 Gy, an amount of radiation similar to what patients undergoing anticancer radiation typically receive over 5 weeks.
Some of the irradiated animals were wild-type mice, while others were genetically engineered to lack the A2A receptor (A2AR). The researchers had previously shown that occupancy of A2AR induces collagen production.
The wild-type mice went on to receive placebo or daily treatment with ZM241385, a paste made with the research team’s patented A2AR blocker. The paste contains 2.5 milligrams of active ingredient per milliliter of 3% carboxymethyl cellulose, a gum “binder.”
A month after exposure, wild-type mice that received placebo had a nearly 2-fold increase in the amount of collagen and skin thickness. These mice also experienced epithelial hyperplasia.
On the other hand, mice treated with ZM241385 accumulated only 10% more skin-thickening collagen. ZM241385 treatment reduced the number of myofibroblasts, collagen fibrils, proliferating keratinocytes, and angiogenesis when compared to placebo. And the paste prevented epithelial hyperplasia.
Like ZM241385-treated mice, A2AR knockout mice did not have the excessive collagen production and skin thickening observed in placebo-treated wild-type mice. The knockout mice also exhibited reductions in myofibroblast content, angiogenesis, and epithelial hyperplasia.
The researchers noted that radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2AR knockout mice.
“Our latest study is the first to demonstrate that blocking or deleting the A2A receptor can be useful in reducing radiation-induced scarring in skin,” said study author Bruce Cronstein, MD, of New York University School of Medicine in New York, New York.
“The study also suggests that adenosine A2A receptor antagonists may have broad applications as drug therapies for preventing fibrosis and scarring, not just in the liver but also in the skin.”
If further experiments prove successful, Dr Cronstein said, clinicians treating early stage cancers with radiation could eventually prescribe an A2AR inhibitor paste to prevent fibrosis. He said his team next plans to study the mechanism underlying A2AR’s role in fibrosis.
woman for radiation
Photo by Rhoda Baer
A topical paste can reduce fibrosis caused by radiation therapy, according to preclinical research published in The FASEB Journal.
The study addressed a type of fibrosis called radiation dermatitis, in which radiation applied to the skin causes the buildup of fibrotic tissue and skin thickening.
To test their topical paste, researchers mimicked the development of radiation dermatitis in mice.
They exposed the mice’s skin to a single dose of 40 Gy, an amount of radiation similar to what patients undergoing anticancer radiation typically receive over 5 weeks.
Some of the irradiated animals were wild-type mice, while others were genetically engineered to lack the A2A receptor (A2AR). The researchers had previously shown that occupancy of A2AR induces collagen production.
The wild-type mice went on to receive placebo or daily treatment with ZM241385, a paste made with the research team’s patented A2AR blocker. The paste contains 2.5 milligrams of active ingredient per milliliter of 3% carboxymethyl cellulose, a gum “binder.”
A month after exposure, wild-type mice that received placebo had a nearly 2-fold increase in the amount of collagen and skin thickness. These mice also experienced epithelial hyperplasia.
On the other hand, mice treated with ZM241385 accumulated only 10% more skin-thickening collagen. ZM241385 treatment reduced the number of myofibroblasts, collagen fibrils, proliferating keratinocytes, and angiogenesis when compared to placebo. And the paste prevented epithelial hyperplasia.
Like ZM241385-treated mice, A2AR knockout mice did not have the excessive collagen production and skin thickening observed in placebo-treated wild-type mice. The knockout mice also exhibited reductions in myofibroblast content, angiogenesis, and epithelial hyperplasia.
The researchers noted that radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2AR knockout mice.
“Our latest study is the first to demonstrate that blocking or deleting the A2A receptor can be useful in reducing radiation-induced scarring in skin,” said study author Bruce Cronstein, MD, of New York University School of Medicine in New York, New York.
“The study also suggests that adenosine A2A receptor antagonists may have broad applications as drug therapies for preventing fibrosis and scarring, not just in the liver but also in the skin.”
If further experiments prove successful, Dr Cronstein said, clinicians treating early stage cancers with radiation could eventually prescribe an A2AR inhibitor paste to prevent fibrosis. He said his team next plans to study the mechanism underlying A2AR’s role in fibrosis.
woman for radiation
Photo by Rhoda Baer
A topical paste can reduce fibrosis caused by radiation therapy, according to preclinical research published in The FASEB Journal.
The study addressed a type of fibrosis called radiation dermatitis, in which radiation applied to the skin causes the buildup of fibrotic tissue and skin thickening.
To test their topical paste, researchers mimicked the development of radiation dermatitis in mice.
They exposed the mice’s skin to a single dose of 40 Gy, an amount of radiation similar to what patients undergoing anticancer radiation typically receive over 5 weeks.
Some of the irradiated animals were wild-type mice, while others were genetically engineered to lack the A2A receptor (A2AR). The researchers had previously shown that occupancy of A2AR induces collagen production.
The wild-type mice went on to receive placebo or daily treatment with ZM241385, a paste made with the research team’s patented A2AR blocker. The paste contains 2.5 milligrams of active ingredient per milliliter of 3% carboxymethyl cellulose, a gum “binder.”
A month after exposure, wild-type mice that received placebo had a nearly 2-fold increase in the amount of collagen and skin thickness. These mice also experienced epithelial hyperplasia.
On the other hand, mice treated with ZM241385 accumulated only 10% more skin-thickening collagen. ZM241385 treatment reduced the number of myofibroblasts, collagen fibrils, proliferating keratinocytes, and angiogenesis when compared to placebo. And the paste prevented epithelial hyperplasia.
Like ZM241385-treated mice, A2AR knockout mice did not have the excessive collagen production and skin thickening observed in placebo-treated wild-type mice. The knockout mice also exhibited reductions in myofibroblast content, angiogenesis, and epithelial hyperplasia.
The researchers noted that radiation-induced changes in the dermis and epidermis were accompanied by an infiltrate of T cells, which was prevented in both ZM241385-treated and A2AR knockout mice.
“Our latest study is the first to demonstrate that blocking or deleting the A2A receptor can be useful in reducing radiation-induced scarring in skin,” said study author Bruce Cronstein, MD, of New York University School of Medicine in New York, New York.
“The study also suggests that adenosine A2A receptor antagonists may have broad applications as drug therapies for preventing fibrosis and scarring, not just in the liver but also in the skin.”
If further experiments prove successful, Dr Cronstein said, clinicians treating early stage cancers with radiation could eventually prescribe an A2AR inhibitor paste to prevent fibrosis. He said his team next plans to study the mechanism underlying A2AR’s role in fibrosis.
Cancer drug discovery database goes 3D
Photo by Rhoda Baer
Researchers have updated the canSAR database, a tool designed to aid cancer drug discovery, by adding 3D structures of faulty proteins and maps of cancer’s communication networks.
The canSAR database brings together biological, chemical, and pharmacological data.
The goal of the database is to make these data accessible to researchers worldwide to help with hypothesis generation and support drug discovery decisions.
Users can search canSAR using text queries, protein/gene name searches, any keyword searches, chemical structure searches, and sequence similarity searches. Users can also explore and filter chemical compound sets, view experimental data, and produce summary plots.
The canSAR database was launched in 2011 with the goal of using Big Data approaches to build a detailed picture of how the majority of known human molecules behave.
The database has already collated billions of experimental measurements, mapping the actions of 1 million drugs and chemicals on human proteins, and it has combined these data with genetic information and results from clinical trials.
The updated version of canSAR uses artificial intelligence to identify nooks and crannies on the surface of faulty cancer-causing molecules as a key step in designing new drugs to block them. It also allows researchers to identify communication lines that can be intercepted within tumor cells, opening up potential new approaches for cancer treatment.
The growing database now holds the 3D structures of almost 3 million cavities on the surface of nearly 110,000 molecules.
“Our database is constantly growing with information and is the largest of its kind, with more than 140,000 users from over 175 countries,” said Bissan Al-Lazikani, PhD, of The Institute of Cancer Research in London, UK.
“And we regularly develop new artificial intelligence technologies that help scientists make predictions and design experiments. Our aim is that cancer scientists will be armed with the data they need to carry out life-saving research into the most exciting drugs of the future.”
“Scientists need to find all the information there is about a faulty gene or protein to understand whether a new drug might work. These data are vast and scattered, but the canSAR database brings them together and adds value by identifying hidden links and presenting the key information easily.”
Details on the updates to canSAR have been published in Nucleic Acid Research. The database is available online at https://cansar.icr.ac.uk/.
Photo by Rhoda Baer
Researchers have updated the canSAR database, a tool designed to aid cancer drug discovery, by adding 3D structures of faulty proteins and maps of cancer’s communication networks.
The canSAR database brings together biological, chemical, and pharmacological data.
The goal of the database is to make these data accessible to researchers worldwide to help with hypothesis generation and support drug discovery decisions.
Users can search canSAR using text queries, protein/gene name searches, any keyword searches, chemical structure searches, and sequence similarity searches. Users can also explore and filter chemical compound sets, view experimental data, and produce summary plots.
The canSAR database was launched in 2011 with the goal of using Big Data approaches to build a detailed picture of how the majority of known human molecules behave.
The database has already collated billions of experimental measurements, mapping the actions of 1 million drugs and chemicals on human proteins, and it has combined these data with genetic information and results from clinical trials.
The updated version of canSAR uses artificial intelligence to identify nooks and crannies on the surface of faulty cancer-causing molecules as a key step in designing new drugs to block them. It also allows researchers to identify communication lines that can be intercepted within tumor cells, opening up potential new approaches for cancer treatment.
The growing database now holds the 3D structures of almost 3 million cavities on the surface of nearly 110,000 molecules.
“Our database is constantly growing with information and is the largest of its kind, with more than 140,000 users from over 175 countries,” said Bissan Al-Lazikani, PhD, of The Institute of Cancer Research in London, UK.
“And we regularly develop new artificial intelligence technologies that help scientists make predictions and design experiments. Our aim is that cancer scientists will be armed with the data they need to carry out life-saving research into the most exciting drugs of the future.”
“Scientists need to find all the information there is about a faulty gene or protein to understand whether a new drug might work. These data are vast and scattered, but the canSAR database brings them together and adds value by identifying hidden links and presenting the key information easily.”
Details on the updates to canSAR have been published in Nucleic Acid Research. The database is available online at https://cansar.icr.ac.uk/.
Photo by Rhoda Baer
Researchers have updated the canSAR database, a tool designed to aid cancer drug discovery, by adding 3D structures of faulty proteins and maps of cancer’s communication networks.
The canSAR database brings together biological, chemical, and pharmacological data.
The goal of the database is to make these data accessible to researchers worldwide to help with hypothesis generation and support drug discovery decisions.
Users can search canSAR using text queries, protein/gene name searches, any keyword searches, chemical structure searches, and sequence similarity searches. Users can also explore and filter chemical compound sets, view experimental data, and produce summary plots.
The canSAR database was launched in 2011 with the goal of using Big Data approaches to build a detailed picture of how the majority of known human molecules behave.
The database has already collated billions of experimental measurements, mapping the actions of 1 million drugs and chemicals on human proteins, and it has combined these data with genetic information and results from clinical trials.
The updated version of canSAR uses artificial intelligence to identify nooks and crannies on the surface of faulty cancer-causing molecules as a key step in designing new drugs to block them. It also allows researchers to identify communication lines that can be intercepted within tumor cells, opening up potential new approaches for cancer treatment.
The growing database now holds the 3D structures of almost 3 million cavities on the surface of nearly 110,000 molecules.
“Our database is constantly growing with information and is the largest of its kind, with more than 140,000 users from over 175 countries,” said Bissan Al-Lazikani, PhD, of The Institute of Cancer Research in London, UK.
“And we regularly develop new artificial intelligence technologies that help scientists make predictions and design experiments. Our aim is that cancer scientists will be armed with the data they need to carry out life-saving research into the most exciting drugs of the future.”
“Scientists need to find all the information there is about a faulty gene or protein to understand whether a new drug might work. These data are vast and scattered, but the canSAR database brings them together and adds value by identifying hidden links and presenting the key information easily.”
Details on the updates to canSAR have been published in Nucleic Acid Research. The database is available online at https://cansar.icr.ac.uk/.
High-risk B-ALL subgroup has ‘outstanding outcomes’
Photo courtesy of ASH
ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.
Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.
The research suggested these patients will not benefit from further chemotherapy intensification.
Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).
She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.
Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).
At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.
Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.
Response and survival
Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.
Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.
For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).
Survival according to cytogenetics
Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).
And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.
For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).
For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).
For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).
For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).
Survival according to risk group and MRD
The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.
“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.
“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”
The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).
Standard-risk group
Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.
Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.
Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.
High-risk group
Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.
Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.
Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.
In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.
She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.
And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.
Photo courtesy of ASH
ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.
Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.
The research suggested these patients will not benefit from further chemotherapy intensification.
Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).
She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.
Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).
At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.
Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.
Response and survival
Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.
Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.
For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).
Survival according to cytogenetics
Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).
And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.
For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).
For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).
For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).
For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).
Survival according to risk group and MRD
The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.
“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.
“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”
The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).
Standard-risk group
Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.
Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.
Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.
High-risk group
Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.
Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.
Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.
In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.
She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.
And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.
Photo courtesy of ASH
ORLANDO, FL—A subgroup of young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) can have “outstanding outcomes” with contemporary therapy, according to researchers.
Results of a large study suggested that patients ages 1 to 30 who have high-risk B-ALL according to National Cancer Institute (NCI) classification can have high rates of event-free survival (EFS) and overall survival (OS) if they have favorable cytogenetic features, have no evidence of CNS disease, and have rapid minimal residual disease (MRD) responses.
The research suggested these patients will not benefit from further chemotherapy intensification.
Elizabeth Raetz, MD, of the University of Utah in Salt Lake City, presented these results at the 2015 ASH Annual Meeting (abstract 807).
She and her colleagues analyzed patients enrolled on the Children’s Oncology Group (COG) AALL03B1 classification study at the time of B-ALL diagnosis. From December 2003 to September 2011, there were 11,144 eligible patients enrolled on this trial.
Eighty-nine percent of these patients were also enrolled on a frontline ALL therapeutic trial, and 96% of these patients were evaluable for post-induction treatment assignment. Sixty-five percent of these patients were treated on a trial for NCI standard-risk B-ALL (COG-AALL0331), and 35% were treated on a trial for high-risk B-ALL (COG-AALL0232).
At the end of induction therapy, patients were classified into low-risk (29%), standard-risk (33%), high-risk (34%), and very-high-risk (4%) groups for further treatment allocation. The variables used for risk classification were age, initial white blood cell count, extramedullary disease status, blast cytogenetics, and early treatment response based on bone marrow morphology and day 29 MRD.
Patients with very-high-risk features (BCR-ABL1, hypodiploidy, induction failure, or poor response at day 43) did not continue on AALL0232/AALL0331 post-induction but did have outcome data captured for analysis.
Response and survival
Rapid early response was defined as M1 (<5% blasts) bone marrow by day 15 plus flow cytometry-based MRD <0.1% on day 29 of induction. Patients with either M2/M3 (≥5% blasts) day 15 marrow or MRD ≥0.1% at day 29 were deemed slow early responders.
Eighty-four percent of patients had a rapid early response to induction, and 16% had a slow early response.
For rapid early responders, the 5-year EFS was 89.3%, and the 5-year OS was 95.2%. For slow early responders, the EFS and OS rates were 67.9% and 84.3%, respectively (P<0.0001 for both EFS and OS comparisons).
Survival according to cytogenetics
Having favorable cytogenetic abnormalities (triple trisomies of chromosomes 4, 10, and 17 or ETV6-RUNX1 fusion) was associated with significantly better EFS and OS than having unfavorable cytogenetics (hypodiploidy [DNA index <0.81 or chromosomes < 44], MLL rearrangements, BCR-ABL1, or iAMP21).
And Dr Raetz pointed out that the 5-year OS exceeded 98% for patients with either standard- or high-risk disease who had favorable cytogenetics.
For patients who were ETV6-RUNX1-positive, the EFS was 93.2% and the OS was 98.3%. For patients who were ETV6-RUNX1 negative, the rates were 83.5% and 92%, respectively (P<0.0001).
For patients with triple trisomy, EFS was 94.7% and OS was 98.7%. For those without triple trisomy, the rates were 83.6% and 92.2%, respectively (P<0.0001).
For patients with MLL rearrangement, the EFS was 73.9% and the OS was 83.1%. For patients without MLL rearrangement, the rates were 85.9% and 93.6%, respectively (P<0.0001).
For patients who were positive for iAMP21, the EFS was 69.5% and the OS was 90.1%. For iAMP21-negative patients, the rates were 86.1% and 93.4%, respectively (P<0.0001 for PFS comparison and P=0.0026 for OS comparison).
Survival according to risk group and MRD
The researchers also assessed EFS and OS among patients with favorable cytogenetics according to NCI risk group and MRD at days 8 and 29.
“One thing to point out is that, regardless of having favorable cytogenetics, those individuals who had end-induction MRD values of greater than 0.01% had inferior outcomes, so that was still a prognostic marker,” Dr Raetz said.
“And one thing that we were pleasantly surprised to see was that, among the NCI high-risk patients, those who had very rapid MRD responses—so less than 1% at day 8 in the blood and less than 0.01% in the marrow on day 29—had a 94.9% 5-year event-free survival and 98.1% overall survival.”
The researchers also divided this group according to age—patients younger than 10 and those 10 years or older. There was no significant difference in EFS or OS between the age groups (P=0.126 and P=0.411).
Standard-risk group
Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 95.7% and the OS was 99.1%.
Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 91.7% and the OS was 99.4%.
Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 88.1% and the OS was 96.8%.
High-risk group
Among patients with <1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 94.9% and the OS was 98.1%.
Among patients with ≥1% MRD on day 8 and <0.01% MRD on day 29, the EFS was 93.6% and the OS was 95.5%.
Among patients with any MRD on day 8 and ≥0.01% MRD on day 29, the EFS was 75.4% and the OS was 90.4%.
In closing, Dr Raetz said this study showed that real‐time classification incorporating clinical features, blast cytogenetics, and early response was feasible in a large group of patients enrolled on COG ALL trials and identified patients with varying outcomes for risk‐based treatment allocation.
She noted that early response by marrow morphology was not prognostic when MRD response was used and is therefore no longer used in COG studies.
And although favorable cytogenetic features were not prognostic in NCI high-risk B‐ALL patients in prior COG studies, the current study indicates that these patients can have “excellent outcomes” if they have no evidence of CNS leukemia and are rapid MRD responders. So these patients will not benefit from further chemotherapy intensification.
Tool may provide new insight into pediatric cancers
and Xin Zhou, PhD
Photo by Peter Barta/St. Jude
Children’s Research Hospital
Researchers say they have developed a tool that may advance our understanding of the mutations that drive pediatric cancers.
The tool, called ProteinPaint, is a web application that allows the user to visualize genetic lesions and RNA expression in pediatric cancers.
ProteinPaint’s infographics let users see all mutations in individual genes and their corresponding proteins, including detailed information about mutation type, frequency in cancer subtype, and location in the protein domain.
That information provides clues about how a change might contribute to cancer’s start, progression, or relapse.
Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues described ProteinPaint in a letter to Nature Genetics.
ProteinPaint currently integrates information from 5 studies, but Dr Zhang and her colleagues said the data will be updated as new studies are published.
ProteinPaint now includes information on almost 27,500 mutations discovered in more than 1000 pediatric patients with 21 cancer subtypes. The application also includes RNA-sequencing data from 928 pediatric tumors belonging to 36 different subtypes.
Xin Zhou, PhD, also of St. Jude, developed ProteinPaint’s infographics to display the genomic information in an interactive format. A click of the mouse gives users additional details about the mutations listed, including the pediatric cancer subtype where the change has been validated and a link to the publication.
“ProteinPaint’s focus on pediatric cancer and presentation of mutations at the gene level complements existing cancer genome data portals,” Dr Zhang said. “For St. Jude, the application is the foundation for developing a global reference database for information about pediatric cancer.”
Dr Zhou added that the ProteinPaint software has the potential to help researchers studying other disorders, including sickle cell disease, that involve a mutation that affects protein function.
ProteinPaint is available at no cost to academic researchers who are free to use the tool to analyze their own data. The application also lets researchers compare information about pediatric and adult cancer genomes by providing a parallel view of data from COSMIC, the world’s largest database of somatic mutations, primarily from adult cancer.
ProteinPaint has already been used to study the role played by germline mutations in pediatric cancers. That research was published in NEJM in November.
More information about ProteinPaint is available on the St. Jude PeCan Data Portal.
and Xin Zhou, PhD
Photo by Peter Barta/St. Jude
Children’s Research Hospital
Researchers say they have developed a tool that may advance our understanding of the mutations that drive pediatric cancers.
The tool, called ProteinPaint, is a web application that allows the user to visualize genetic lesions and RNA expression in pediatric cancers.
ProteinPaint’s infographics let users see all mutations in individual genes and their corresponding proteins, including detailed information about mutation type, frequency in cancer subtype, and location in the protein domain.
That information provides clues about how a change might contribute to cancer’s start, progression, or relapse.
Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues described ProteinPaint in a letter to Nature Genetics.
ProteinPaint currently integrates information from 5 studies, but Dr Zhang and her colleagues said the data will be updated as new studies are published.
ProteinPaint now includes information on almost 27,500 mutations discovered in more than 1000 pediatric patients with 21 cancer subtypes. The application also includes RNA-sequencing data from 928 pediatric tumors belonging to 36 different subtypes.
Xin Zhou, PhD, also of St. Jude, developed ProteinPaint’s infographics to display the genomic information in an interactive format. A click of the mouse gives users additional details about the mutations listed, including the pediatric cancer subtype where the change has been validated and a link to the publication.
“ProteinPaint’s focus on pediatric cancer and presentation of mutations at the gene level complements existing cancer genome data portals,” Dr Zhang said. “For St. Jude, the application is the foundation for developing a global reference database for information about pediatric cancer.”
Dr Zhou added that the ProteinPaint software has the potential to help researchers studying other disorders, including sickle cell disease, that involve a mutation that affects protein function.
ProteinPaint is available at no cost to academic researchers who are free to use the tool to analyze their own data. The application also lets researchers compare information about pediatric and adult cancer genomes by providing a parallel view of data from COSMIC, the world’s largest database of somatic mutations, primarily from adult cancer.
ProteinPaint has already been used to study the role played by germline mutations in pediatric cancers. That research was published in NEJM in November.
More information about ProteinPaint is available on the St. Jude PeCan Data Portal.
and Xin Zhou, PhD
Photo by Peter Barta/St. Jude
Children’s Research Hospital
Researchers say they have developed a tool that may advance our understanding of the mutations that drive pediatric cancers.
The tool, called ProteinPaint, is a web application that allows the user to visualize genetic lesions and RNA expression in pediatric cancers.
ProteinPaint’s infographics let users see all mutations in individual genes and their corresponding proteins, including detailed information about mutation type, frequency in cancer subtype, and location in the protein domain.
That information provides clues about how a change might contribute to cancer’s start, progression, or relapse.
Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee, and her colleagues described ProteinPaint in a letter to Nature Genetics.
ProteinPaint currently integrates information from 5 studies, but Dr Zhang and her colleagues said the data will be updated as new studies are published.
ProteinPaint now includes information on almost 27,500 mutations discovered in more than 1000 pediatric patients with 21 cancer subtypes. The application also includes RNA-sequencing data from 928 pediatric tumors belonging to 36 different subtypes.
Xin Zhou, PhD, also of St. Jude, developed ProteinPaint’s infographics to display the genomic information in an interactive format. A click of the mouse gives users additional details about the mutations listed, including the pediatric cancer subtype where the change has been validated and a link to the publication.
“ProteinPaint’s focus on pediatric cancer and presentation of mutations at the gene level complements existing cancer genome data portals,” Dr Zhang said. “For St. Jude, the application is the foundation for developing a global reference database for information about pediatric cancer.”
Dr Zhou added that the ProteinPaint software has the potential to help researchers studying other disorders, including sickle cell disease, that involve a mutation that affects protein function.
ProteinPaint is available at no cost to academic researchers who are free to use the tool to analyze their own data. The application also lets researchers compare information about pediatric and adult cancer genomes by providing a parallel view of data from COSMIC, the world’s largest database of somatic mutations, primarily from adult cancer.
ProteinPaint has already been used to study the role played by germline mutations in pediatric cancers. That research was published in NEJM in November.
More information about ProteinPaint is available on the St. Jude PeCan Data Portal.
Factors predict low accrual in cancer clinical trials
for a clinical trial
Photo by Esther Dyson
Twelve factors may predict low patient accrual in cancer clinical trials, according to research published in JNCI.
Many studies have been conducted to investigate the perceived barriers to clinical trial accrual from the patient or provider perspective.
However, researchers have rarely taken a trial-level view and investigated why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants.
Caroline S. Bennette, PhD, of the University of Washington in Seattle, and her colleagues conducted their study to do just that.
They analyzed information on 787 phase 2/3 clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011.
After excluding trials that closed because of toxicity or interim results, the researchers found that 145 (18%) NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.
The team identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy.
The researchers then developed a multivariable prediction model of low accrual using 12 trial-level risk factors. The team said these factors had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.
Those 12 risk factors are:
- The number of competing trials per 10,000 eligible patients per year (odds ratio [OR]=1.88)
- Phase 3 vs phase 2 trial (OR=1.86)
- Enrollment as percentage of eligible population for targeted therapy (OR=0.57)
- Enrollment as percentage of eligible population for radiation therapy (OR=1.81)
- Annual incidence of clinical condition(s) per 10,000 (OR=0.99)
- Tissue sample required to assess eligibility (OR=1.26)
- Investigational new drug (OR=0.34)
- Metastatic setting (OR=1.46)
- Sample size per 100 (OR=0.95)
- More than one condition evaluated (OR=1.98)
- Common solid cancer (prostate, breast, lung, or colon) vs liquid or rare solid cancers (OR=2.32)
- Interaction term (phase 3 x investigational new drug, OR=2.47).
The researchers concluded that systematically considering the overall influence of these risk factors could aid in the design and prioritization of future clinical trials.
for a clinical trial
Photo by Esther Dyson
Twelve factors may predict low patient accrual in cancer clinical trials, according to research published in JNCI.
Many studies have been conducted to investigate the perceived barriers to clinical trial accrual from the patient or provider perspective.
However, researchers have rarely taken a trial-level view and investigated why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants.
Caroline S. Bennette, PhD, of the University of Washington in Seattle, and her colleagues conducted their study to do just that.
They analyzed information on 787 phase 2/3 clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011.
After excluding trials that closed because of toxicity or interim results, the researchers found that 145 (18%) NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.
The team identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy.
The researchers then developed a multivariable prediction model of low accrual using 12 trial-level risk factors. The team said these factors had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.
Those 12 risk factors are:
- The number of competing trials per 10,000 eligible patients per year (odds ratio [OR]=1.88)
- Phase 3 vs phase 2 trial (OR=1.86)
- Enrollment as percentage of eligible population for targeted therapy (OR=0.57)
- Enrollment as percentage of eligible population for radiation therapy (OR=1.81)
- Annual incidence of clinical condition(s) per 10,000 (OR=0.99)
- Tissue sample required to assess eligibility (OR=1.26)
- Investigational new drug (OR=0.34)
- Metastatic setting (OR=1.46)
- Sample size per 100 (OR=0.95)
- More than one condition evaluated (OR=1.98)
- Common solid cancer (prostate, breast, lung, or colon) vs liquid or rare solid cancers (OR=2.32)
- Interaction term (phase 3 x investigational new drug, OR=2.47).
The researchers concluded that systematically considering the overall influence of these risk factors could aid in the design and prioritization of future clinical trials.
for a clinical trial
Photo by Esther Dyson
Twelve factors may predict low patient accrual in cancer clinical trials, according to research published in JNCI.
Many studies have been conducted to investigate the perceived barriers to clinical trial accrual from the patient or provider perspective.
However, researchers have rarely taken a trial-level view and investigated why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants.
Caroline S. Bennette, PhD, of the University of Washington in Seattle, and her colleagues conducted their study to do just that.
They analyzed information on 787 phase 2/3 clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011.
After excluding trials that closed because of toxicity or interim results, the researchers found that 145 (18%) NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.
The team identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy.
The researchers then developed a multivariable prediction model of low accrual using 12 trial-level risk factors. The team said these factors had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.
Those 12 risk factors are:
- The number of competing trials per 10,000 eligible patients per year (odds ratio [OR]=1.88)
- Phase 3 vs phase 2 trial (OR=1.86)
- Enrollment as percentage of eligible population for targeted therapy (OR=0.57)
- Enrollment as percentage of eligible population for radiation therapy (OR=1.81)
- Annual incidence of clinical condition(s) per 10,000 (OR=0.99)
- Tissue sample required to assess eligibility (OR=1.26)
- Investigational new drug (OR=0.34)
- Metastatic setting (OR=1.46)
- Sample size per 100 (OR=0.95)
- More than one condition evaluated (OR=1.98)
- Common solid cancer (prostate, breast, lung, or colon) vs liquid or rare solid cancers (OR=2.32)
- Interaction term (phase 3 x investigational new drug, OR=2.47).
The researchers concluded that systematically considering the overall influence of these risk factors could aid in the design and prioritization of future clinical trials.
Cardiovascular risk assessment required with use of TKIs for CML
Treatment for chronic myeloid leukemia (CML) entails effective but mostly noncurative long-term use of tyrosine kinase inhibitors (TKIs) that require proactive, rational approaches to minimizing cardiovascular toxicities, according to a recent review.
Survival rates of patients with newly diagnosed CML are about 90%, and in those with a complete cytogenetic response, survival is comparable to that of age-matched controls. Although second-generation TKIs have increased efficacy, survival rates are similar to those of imatinib, possibly due in part to mortality from non-CML causes.
TKIs used in CML therapy target BCR-ABL1, but their potencies vary against other kinases, including receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). The relationship between off-target activities and adverse events (AEs) remains unclear, and AE management is largely empirical, said Dr. Javid Moslehi of Vanderbilt University Medical Center, Nashville, Tenn., and Dr. Michael Deininger, professor at the University of Utah Huntsman Cancer Institute, Salt Lake City.
“Reports of cardiovascular AEs with nilotinib, pulmonary arterial hypertension (PAH) on dasatinib, and frequent cardiovascular AEs with ponatinib have caused a reassessment of the situation,” they noted.
“Given the high population frequency of cardiovascular disease and the increased frequency of vascular events with nilotinib and ponatinib, cardiovascular risk assessment and, if necessary, treatment need to be integrated into the management of patients with CML on TKIs,” they wrote (J Clin Onc. 2015 Dec 10. doi: 10.1200/JCO.2015.62.4718).
Retrospective studies have indicated that imatinib may have favorable metabolic and vascular effects, but prospective controlled trials are lacking. Defining the cardiovascular baseline risk of the specific CML population under study will be crucial in future studies.
Dasatinib was approved for front-line CML treatment based on superior cytogenic response rates, compared with imatinib, but in 2011 the Food and Drug Administration warned against cardiopulmonary risks and recommended that patients be evaluated for signs and symptoms of cardiopulmonary disease before and during dasatinib treatment. Results of DASISION (Dasatinib Versus Imatinib Study in Treatment-Naive CML Patients) showed that, at 36 months of follow-up, PAH was reported in 3% of patients on dasatinib and 0% on imatinib.
Nilotinib has shown superior efficacy to imatinib and was FDA approved for first-line therapy, with recommendations for arrhythmia monitoring and avoidance of QT interval–prolonging medications. There have been no subsequent reports of ventricular arrhythmias with nilotinib, but 36% of patients on nilotinib experienced hyperglycemia in the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) study, compared with 20% on imatinib. Nilotinib also has been associated with hyperlipidemia and increased body mass. Recent results point to vascular toxicity with nilotinib. At the 6-year follow-up of the ENESTnd study, 10% of patients on nilotinib 300 mg twice per day and 16% on nilotinib 400 mg twice per day had cardiovascular events, compared with 2.5% of patients taking imatinib 400 mg once per day. The dose-dependent increased risk implicates a drug-dependent process.
Ponatinib is the only clinical TKI active against the BCR-ABL1T315I mutation. It is a potent inhibitor of numerous other kinases as well, including VEGF receptors. In the PACE (Ponatinib Ph-positive Acute Lymphoblastic Leukemia and CML Evaluation) study, 26% of patients on ponatinib developed hypertension, and traditional atherosclerosis risk factors (age, hypertension, and diabetes) predisposed patients to serious vascular AEs. Cardiovascular toxicity was shown to be dose dependent, and older patients with history of diabetes or ischemic events are the least tolerant of high dose intensity. A subset of patients will benefit from ponatinib, particularly those with BCR-ABL1T315I, but leukemia-related and cardiovascular risks must both be assessed.
Dr. Moslehi reported financial ties with Novartis, ARIAD, Takeda/Millennium, Bristol-Myers Squibb, and Acceleron Pharma. Dr. Deininger reported ties to Novartis, Bristol-Myers Squibb, Incyte, ARIAD, Pfizer, and Cellgene.
Treatment for chronic myeloid leukemia (CML) entails effective but mostly noncurative long-term use of tyrosine kinase inhibitors (TKIs) that require proactive, rational approaches to minimizing cardiovascular toxicities, according to a recent review.
Survival rates of patients with newly diagnosed CML are about 90%, and in those with a complete cytogenetic response, survival is comparable to that of age-matched controls. Although second-generation TKIs have increased efficacy, survival rates are similar to those of imatinib, possibly due in part to mortality from non-CML causes.
TKIs used in CML therapy target BCR-ABL1, but their potencies vary against other kinases, including receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). The relationship between off-target activities and adverse events (AEs) remains unclear, and AE management is largely empirical, said Dr. Javid Moslehi of Vanderbilt University Medical Center, Nashville, Tenn., and Dr. Michael Deininger, professor at the University of Utah Huntsman Cancer Institute, Salt Lake City.
“Reports of cardiovascular AEs with nilotinib, pulmonary arterial hypertension (PAH) on dasatinib, and frequent cardiovascular AEs with ponatinib have caused a reassessment of the situation,” they noted.
“Given the high population frequency of cardiovascular disease and the increased frequency of vascular events with nilotinib and ponatinib, cardiovascular risk assessment and, if necessary, treatment need to be integrated into the management of patients with CML on TKIs,” they wrote (J Clin Onc. 2015 Dec 10. doi: 10.1200/JCO.2015.62.4718).
Retrospective studies have indicated that imatinib may have favorable metabolic and vascular effects, but prospective controlled trials are lacking. Defining the cardiovascular baseline risk of the specific CML population under study will be crucial in future studies.
Dasatinib was approved for front-line CML treatment based on superior cytogenic response rates, compared with imatinib, but in 2011 the Food and Drug Administration warned against cardiopulmonary risks and recommended that patients be evaluated for signs and symptoms of cardiopulmonary disease before and during dasatinib treatment. Results of DASISION (Dasatinib Versus Imatinib Study in Treatment-Naive CML Patients) showed that, at 36 months of follow-up, PAH was reported in 3% of patients on dasatinib and 0% on imatinib.
Nilotinib has shown superior efficacy to imatinib and was FDA approved for first-line therapy, with recommendations for arrhythmia monitoring and avoidance of QT interval–prolonging medications. There have been no subsequent reports of ventricular arrhythmias with nilotinib, but 36% of patients on nilotinib experienced hyperglycemia in the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) study, compared with 20% on imatinib. Nilotinib also has been associated with hyperlipidemia and increased body mass. Recent results point to vascular toxicity with nilotinib. At the 6-year follow-up of the ENESTnd study, 10% of patients on nilotinib 300 mg twice per day and 16% on nilotinib 400 mg twice per day had cardiovascular events, compared with 2.5% of patients taking imatinib 400 mg once per day. The dose-dependent increased risk implicates a drug-dependent process.
Ponatinib is the only clinical TKI active against the BCR-ABL1T315I mutation. It is a potent inhibitor of numerous other kinases as well, including VEGF receptors. In the PACE (Ponatinib Ph-positive Acute Lymphoblastic Leukemia and CML Evaluation) study, 26% of patients on ponatinib developed hypertension, and traditional atherosclerosis risk factors (age, hypertension, and diabetes) predisposed patients to serious vascular AEs. Cardiovascular toxicity was shown to be dose dependent, and older patients with history of diabetes or ischemic events are the least tolerant of high dose intensity. A subset of patients will benefit from ponatinib, particularly those with BCR-ABL1T315I, but leukemia-related and cardiovascular risks must both be assessed.
Dr. Moslehi reported financial ties with Novartis, ARIAD, Takeda/Millennium, Bristol-Myers Squibb, and Acceleron Pharma. Dr. Deininger reported ties to Novartis, Bristol-Myers Squibb, Incyte, ARIAD, Pfizer, and Cellgene.
Treatment for chronic myeloid leukemia (CML) entails effective but mostly noncurative long-term use of tyrosine kinase inhibitors (TKIs) that require proactive, rational approaches to minimizing cardiovascular toxicities, according to a recent review.
Survival rates of patients with newly diagnosed CML are about 90%, and in those with a complete cytogenetic response, survival is comparable to that of age-matched controls. Although second-generation TKIs have increased efficacy, survival rates are similar to those of imatinib, possibly due in part to mortality from non-CML causes.
TKIs used in CML therapy target BCR-ABL1, but their potencies vary against other kinases, including receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). The relationship between off-target activities and adverse events (AEs) remains unclear, and AE management is largely empirical, said Dr. Javid Moslehi of Vanderbilt University Medical Center, Nashville, Tenn., and Dr. Michael Deininger, professor at the University of Utah Huntsman Cancer Institute, Salt Lake City.
“Reports of cardiovascular AEs with nilotinib, pulmonary arterial hypertension (PAH) on dasatinib, and frequent cardiovascular AEs with ponatinib have caused a reassessment of the situation,” they noted.
“Given the high population frequency of cardiovascular disease and the increased frequency of vascular events with nilotinib and ponatinib, cardiovascular risk assessment and, if necessary, treatment need to be integrated into the management of patients with CML on TKIs,” they wrote (J Clin Onc. 2015 Dec 10. doi: 10.1200/JCO.2015.62.4718).
Retrospective studies have indicated that imatinib may have favorable metabolic and vascular effects, but prospective controlled trials are lacking. Defining the cardiovascular baseline risk of the specific CML population under study will be crucial in future studies.
Dasatinib was approved for front-line CML treatment based on superior cytogenic response rates, compared with imatinib, but in 2011 the Food and Drug Administration warned against cardiopulmonary risks and recommended that patients be evaluated for signs and symptoms of cardiopulmonary disease before and during dasatinib treatment. Results of DASISION (Dasatinib Versus Imatinib Study in Treatment-Naive CML Patients) showed that, at 36 months of follow-up, PAH was reported in 3% of patients on dasatinib and 0% on imatinib.
Nilotinib has shown superior efficacy to imatinib and was FDA approved for first-line therapy, with recommendations for arrhythmia monitoring and avoidance of QT interval–prolonging medications. There have been no subsequent reports of ventricular arrhythmias with nilotinib, but 36% of patients on nilotinib experienced hyperglycemia in the ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients) study, compared with 20% on imatinib. Nilotinib also has been associated with hyperlipidemia and increased body mass. Recent results point to vascular toxicity with nilotinib. At the 6-year follow-up of the ENESTnd study, 10% of patients on nilotinib 300 mg twice per day and 16% on nilotinib 400 mg twice per day had cardiovascular events, compared with 2.5% of patients taking imatinib 400 mg once per day. The dose-dependent increased risk implicates a drug-dependent process.
Ponatinib is the only clinical TKI active against the BCR-ABL1T315I mutation. It is a potent inhibitor of numerous other kinases as well, including VEGF receptors. In the PACE (Ponatinib Ph-positive Acute Lymphoblastic Leukemia and CML Evaluation) study, 26% of patients on ponatinib developed hypertension, and traditional atherosclerosis risk factors (age, hypertension, and diabetes) predisposed patients to serious vascular AEs. Cardiovascular toxicity was shown to be dose dependent, and older patients with history of diabetes or ischemic events are the least tolerant of high dose intensity. A subset of patients will benefit from ponatinib, particularly those with BCR-ABL1T315I, but leukemia-related and cardiovascular risks must both be assessed.
Dr. Moslehi reported financial ties with Novartis, ARIAD, Takeda/Millennium, Bristol-Myers Squibb, and Acceleron Pharma. Dr. Deininger reported ties to Novartis, Bristol-Myers Squibb, Incyte, ARIAD, Pfizer, and Cellgene.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Most patients with chronic myeloid leukemia require long-term tyrosine kinase inhibitor (TKI) therapy, and cardiovascular effects are critical factors in treatment decisions.
Major finding: Second- and third-generation TKIs have been associated with more cardiovascular risk than first-generation imatinib.
Data source: Review of current literature on cardiovascular toxicity of BCR-ABL1 TKIs for treatment of chronic myeloid leukemia.
Disclosures: Dr. Moslehi reported financial ties with Novartis, ARIAD, Takeda/Millennium, Bristol-Myers Squibb, and Acceleron Pharma. Dr. Deininger reported ties to Novartis, Bristol-Myers Squibb, Incyte, ARIAD, Pfizer, and Cellgene.
Study reveals germline variants in AML, other cancers
A study published in Nature Communications has shed light on the hereditary elements of 12 cancer types.
Investigators looked for rare germline mutations in genes known to be associated with cancer and found the frequency of these mutations varied widely, from 4% in the acute myeloid leukemia (AML) cases studied to 19% in cases of ovarian cancer.
The team’s analysis also revealed an unexpected inherited component to stomach cancer and provided some clarity on the consequences of certain mutations in the BRCA1 and BRCA2 genes.
Li Ding, PhD, of Washington University School of Medicine in St Louis, Missouri, and her colleagues conducted this study, analyzing genetic information from more than 4000 cancer cases included in The Cancer Genome Atlas project.
“In general, we have known that ovarian and breast cancers have a significant inherited component, and others, such as acute myeloid leukemia and lung cancer, have a much smaller inherited genetic contribution,” Dr Ding said. “But this is the first time, on a large scale, that we’ve been able to pinpoint gene culprits or even the actual mutations responsible for cancer susceptibility.”
To help tease out cancer’s inherited components, Dr Ding and her colleagues looked for germline truncations in 114 genes known to be associated with cancer.
“We looked for germline mutations in the tumor, but it was not enough for the mutations simply to be present,” Dr Ding said. “They needed to be enriched in the tumor—present at higher frequency. If a mutation is present in the germline and amplified in the tumor, there is a high likelihood it is playing a role in the cancer.”
The investigators found germline truncations in all 12 cancer types analyzed, but the mutations occurred in varying frequencies depending on the cancer.
The percentage of tumors with truncations in the germline was 4% for AML and glioblastoma; 5% for kidney cancer; 7% for lung adenocarcinoma and endometrial cancer; 8% for head and neck cancer, glioma, lung squamous cell carcinoma, and prostate cancer; 9% for breast cancer; 11% for stomach cancer; and 19% for ovarian cancer.
“We also found a significant number of germline truncations in the BRCA1 and BRCA2 genes present in tumor types other than breast cancer, including stomach and prostate cancers, for example,” Dr Ding said. “This suggests we should pay attention to the potential involvement of these 2 genes in other cancer types.”
The investigators said they identified 13 cancer genes with significant enrichment of rare truncations. Some of these were associated with specific cancers—for example, RAD51C in AML, PALB2 in stomach cancer, and MSH6 in endometrial cancer.
And the team observed significant, tumor-specific loss of heterozygosity in 9 genes—ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2, and RAD51C/D.
Dr Ding said more research is needed to confirm these results before they can be used to advise patients making healthcare decisions.
“Our strategy of investigating germline-tumor interactions provides a good way to prioritize important mutations that we should focus on,” she said. “For the information to eventually be used in the clinic, we will need to perform this type of analysis on even larger numbers of patients.”
A study published in Nature Communications has shed light on the hereditary elements of 12 cancer types.
Investigators looked for rare germline mutations in genes known to be associated with cancer and found the frequency of these mutations varied widely, from 4% in the acute myeloid leukemia (AML) cases studied to 19% in cases of ovarian cancer.
The team’s analysis also revealed an unexpected inherited component to stomach cancer and provided some clarity on the consequences of certain mutations in the BRCA1 and BRCA2 genes.
Li Ding, PhD, of Washington University School of Medicine in St Louis, Missouri, and her colleagues conducted this study, analyzing genetic information from more than 4000 cancer cases included in The Cancer Genome Atlas project.
“In general, we have known that ovarian and breast cancers have a significant inherited component, and others, such as acute myeloid leukemia and lung cancer, have a much smaller inherited genetic contribution,” Dr Ding said. “But this is the first time, on a large scale, that we’ve been able to pinpoint gene culprits or even the actual mutations responsible for cancer susceptibility.”
To help tease out cancer’s inherited components, Dr Ding and her colleagues looked for germline truncations in 114 genes known to be associated with cancer.
“We looked for germline mutations in the tumor, but it was not enough for the mutations simply to be present,” Dr Ding said. “They needed to be enriched in the tumor—present at higher frequency. If a mutation is present in the germline and amplified in the tumor, there is a high likelihood it is playing a role in the cancer.”
The investigators found germline truncations in all 12 cancer types analyzed, but the mutations occurred in varying frequencies depending on the cancer.
The percentage of tumors with truncations in the germline was 4% for AML and glioblastoma; 5% for kidney cancer; 7% for lung adenocarcinoma and endometrial cancer; 8% for head and neck cancer, glioma, lung squamous cell carcinoma, and prostate cancer; 9% for breast cancer; 11% for stomach cancer; and 19% for ovarian cancer.
“We also found a significant number of germline truncations in the BRCA1 and BRCA2 genes present in tumor types other than breast cancer, including stomach and prostate cancers, for example,” Dr Ding said. “This suggests we should pay attention to the potential involvement of these 2 genes in other cancer types.”
The investigators said they identified 13 cancer genes with significant enrichment of rare truncations. Some of these were associated with specific cancers—for example, RAD51C in AML, PALB2 in stomach cancer, and MSH6 in endometrial cancer.
And the team observed significant, tumor-specific loss of heterozygosity in 9 genes—ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2, and RAD51C/D.
Dr Ding said more research is needed to confirm these results before they can be used to advise patients making healthcare decisions.
“Our strategy of investigating germline-tumor interactions provides a good way to prioritize important mutations that we should focus on,” she said. “For the information to eventually be used in the clinic, we will need to perform this type of analysis on even larger numbers of patients.”
A study published in Nature Communications has shed light on the hereditary elements of 12 cancer types.
Investigators looked for rare germline mutations in genes known to be associated with cancer and found the frequency of these mutations varied widely, from 4% in the acute myeloid leukemia (AML) cases studied to 19% in cases of ovarian cancer.
The team’s analysis also revealed an unexpected inherited component to stomach cancer and provided some clarity on the consequences of certain mutations in the BRCA1 and BRCA2 genes.
Li Ding, PhD, of Washington University School of Medicine in St Louis, Missouri, and her colleagues conducted this study, analyzing genetic information from more than 4000 cancer cases included in The Cancer Genome Atlas project.
“In general, we have known that ovarian and breast cancers have a significant inherited component, and others, such as acute myeloid leukemia and lung cancer, have a much smaller inherited genetic contribution,” Dr Ding said. “But this is the first time, on a large scale, that we’ve been able to pinpoint gene culprits or even the actual mutations responsible for cancer susceptibility.”
To help tease out cancer’s inherited components, Dr Ding and her colleagues looked for germline truncations in 114 genes known to be associated with cancer.
“We looked for germline mutations in the tumor, but it was not enough for the mutations simply to be present,” Dr Ding said. “They needed to be enriched in the tumor—present at higher frequency. If a mutation is present in the germline and amplified in the tumor, there is a high likelihood it is playing a role in the cancer.”
The investigators found germline truncations in all 12 cancer types analyzed, but the mutations occurred in varying frequencies depending on the cancer.
The percentage of tumors with truncations in the germline was 4% for AML and glioblastoma; 5% for kidney cancer; 7% for lung adenocarcinoma and endometrial cancer; 8% for head and neck cancer, glioma, lung squamous cell carcinoma, and prostate cancer; 9% for breast cancer; 11% for stomach cancer; and 19% for ovarian cancer.
“We also found a significant number of germline truncations in the BRCA1 and BRCA2 genes present in tumor types other than breast cancer, including stomach and prostate cancers, for example,” Dr Ding said. “This suggests we should pay attention to the potential involvement of these 2 genes in other cancer types.”
The investigators said they identified 13 cancer genes with significant enrichment of rare truncations. Some of these were associated with specific cancers—for example, RAD51C in AML, PALB2 in stomach cancer, and MSH6 in endometrial cancer.
And the team observed significant, tumor-specific loss of heterozygosity in 9 genes—ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2, and RAD51C/D.
Dr Ding said more research is needed to confirm these results before they can be used to advise patients making healthcare decisions.
“Our strategy of investigating germline-tumor interactions provides a good way to prioritize important mutations that we should focus on,” she said. “For the information to eventually be used in the clinic, we will need to perform this type of analysis on even larger numbers of patients.”
Education may increase clinical trial participation
Photo courtesy of NCI
and Matthews Media Group
A new study suggests that educating cancer patients about clinical trials—with either a general or patient-specific program—increases the likelihood that patients will enroll in such trials.
After completing either type of educational program, 21% of the cancer patients studied chose to enroll in clinical trials.
Traditionally, less than 5% of cancer patients decide to participate in trials, according to the American Cancer Society.
“Unfortunately, although clinical trials are critical for advancing cancer treatment and ultimately serve as the basis for new standards of care, very few patients participate,” said Neal J. Meropol, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio.
“We want to close the patient knowledge gap and positively affect their attitudes toward clinical trials.”
Dr Meropol and his colleagues described their effort to do just that in the Journal of Clinical Oncology.
The researchers compared a tailored video education program on clinical trials, PRE-ACT (Preparatory Education about Clinical Trials), to educational information delivered as written text.
PRE-ACT is an intervention in which patients access a website to take an online survey. The survey gauges the individual patient’s knowledge and attitudes about clinical trials, and then, based on that patient’s answers, video clips are presented addressing his or her specific concerns.
For example, patients may worry they will receive a placebo rather than active treatment, so one video clip explains how placebos are used ethically in cancer studies, and the fact that very few studies will include a placebo without any active treatment. The videos also help patients clarify their preferences in terms of quality of life or length of life.
Results
Dr Meropol and his colleagues enrolled 1255 cancer patients in the study. Half of them participated in the PRE-ACT program, and the other half received written information about clinical trials that was not specifically chosen based on their survey responses.
Both interventions improved patients’ knowledge and attitudes regarding clinical trials when compared with baseline (all P<0.001).
Patients in both arms said they felt more prepared to consider enrolling in a clinical trial after completing their assigned educational program (P<0.001), but there was a trend favoring the PRE-ACT arm (P<0.09).
Patients in the PRE-ACT arm also showed a significantly greater increase in knowledge (P<0.001) and a significantly greater decrease in attitudinal barriers (P<0.001) than patients in the text-only arm. And PRE-ACT was associated with greater patient satisfaction.
Financial concerns
During the course of this research, Dr Meropol and his colleagues made a surprising discovery. Video clips meant to address concerns about the costs of clinical trial treatment actually caused a spike in worries about the out-of-pocket costs of clinical trials.
These financial concerns generated yet another paper that appeared in the same edition of the Journal of Clinical Oncology.
“What was a surprise is that giving people information about costs in general terms made them more anxious,” Dr Meropol said. “It was not surprising to us that these concerns actually affect distress, add to decisional conflict, and interfere with decision-making.”
“This finding highlighted for us that communication about costs is both necessary and challenging. It indicates that we need to be sensitive to patients’ cost concerns as they navigate decisions about cancer care.”
The researchers are now planning to develop tools to assist patients with financial navigation. The team is also developing a web-based educational program for oncology nurses to help them discuss clinical trial participation with patients.
Photo courtesy of NCI
and Matthews Media Group
A new study suggests that educating cancer patients about clinical trials—with either a general or patient-specific program—increases the likelihood that patients will enroll in such trials.
After completing either type of educational program, 21% of the cancer patients studied chose to enroll in clinical trials.
Traditionally, less than 5% of cancer patients decide to participate in trials, according to the American Cancer Society.
“Unfortunately, although clinical trials are critical for advancing cancer treatment and ultimately serve as the basis for new standards of care, very few patients participate,” said Neal J. Meropol, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio.
“We want to close the patient knowledge gap and positively affect their attitudes toward clinical trials.”
Dr Meropol and his colleagues described their effort to do just that in the Journal of Clinical Oncology.
The researchers compared a tailored video education program on clinical trials, PRE-ACT (Preparatory Education about Clinical Trials), to educational information delivered as written text.
PRE-ACT is an intervention in which patients access a website to take an online survey. The survey gauges the individual patient’s knowledge and attitudes about clinical trials, and then, based on that patient’s answers, video clips are presented addressing his or her specific concerns.
For example, patients may worry they will receive a placebo rather than active treatment, so one video clip explains how placebos are used ethically in cancer studies, and the fact that very few studies will include a placebo without any active treatment. The videos also help patients clarify their preferences in terms of quality of life or length of life.
Results
Dr Meropol and his colleagues enrolled 1255 cancer patients in the study. Half of them participated in the PRE-ACT program, and the other half received written information about clinical trials that was not specifically chosen based on their survey responses.
Both interventions improved patients’ knowledge and attitudes regarding clinical trials when compared with baseline (all P<0.001).
Patients in both arms said they felt more prepared to consider enrolling in a clinical trial after completing their assigned educational program (P<0.001), but there was a trend favoring the PRE-ACT arm (P<0.09).
Patients in the PRE-ACT arm also showed a significantly greater increase in knowledge (P<0.001) and a significantly greater decrease in attitudinal barriers (P<0.001) than patients in the text-only arm. And PRE-ACT was associated with greater patient satisfaction.
Financial concerns
During the course of this research, Dr Meropol and his colleagues made a surprising discovery. Video clips meant to address concerns about the costs of clinical trial treatment actually caused a spike in worries about the out-of-pocket costs of clinical trials.
These financial concerns generated yet another paper that appeared in the same edition of the Journal of Clinical Oncology.
“What was a surprise is that giving people information about costs in general terms made them more anxious,” Dr Meropol said. “It was not surprising to us that these concerns actually affect distress, add to decisional conflict, and interfere with decision-making.”
“This finding highlighted for us that communication about costs is both necessary and challenging. It indicates that we need to be sensitive to patients’ cost concerns as they navigate decisions about cancer care.”
The researchers are now planning to develop tools to assist patients with financial navigation. The team is also developing a web-based educational program for oncology nurses to help them discuss clinical trial participation with patients.
Photo courtesy of NCI
and Matthews Media Group
A new study suggests that educating cancer patients about clinical trials—with either a general or patient-specific program—increases the likelihood that patients will enroll in such trials.
After completing either type of educational program, 21% of the cancer patients studied chose to enroll in clinical trials.
Traditionally, less than 5% of cancer patients decide to participate in trials, according to the American Cancer Society.
“Unfortunately, although clinical trials are critical for advancing cancer treatment and ultimately serve as the basis for new standards of care, very few patients participate,” said Neal J. Meropol, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio.
“We want to close the patient knowledge gap and positively affect their attitudes toward clinical trials.”
Dr Meropol and his colleagues described their effort to do just that in the Journal of Clinical Oncology.
The researchers compared a tailored video education program on clinical trials, PRE-ACT (Preparatory Education about Clinical Trials), to educational information delivered as written text.
PRE-ACT is an intervention in which patients access a website to take an online survey. The survey gauges the individual patient’s knowledge and attitudes about clinical trials, and then, based on that patient’s answers, video clips are presented addressing his or her specific concerns.
For example, patients may worry they will receive a placebo rather than active treatment, so one video clip explains how placebos are used ethically in cancer studies, and the fact that very few studies will include a placebo without any active treatment. The videos also help patients clarify their preferences in terms of quality of life or length of life.
Results
Dr Meropol and his colleagues enrolled 1255 cancer patients in the study. Half of them participated in the PRE-ACT program, and the other half received written information about clinical trials that was not specifically chosen based on their survey responses.
Both interventions improved patients’ knowledge and attitudes regarding clinical trials when compared with baseline (all P<0.001).
Patients in both arms said they felt more prepared to consider enrolling in a clinical trial after completing their assigned educational program (P<0.001), but there was a trend favoring the PRE-ACT arm (P<0.09).
Patients in the PRE-ACT arm also showed a significantly greater increase in knowledge (P<0.001) and a significantly greater decrease in attitudinal barriers (P<0.001) than patients in the text-only arm. And PRE-ACT was associated with greater patient satisfaction.
Financial concerns
During the course of this research, Dr Meropol and his colleagues made a surprising discovery. Video clips meant to address concerns about the costs of clinical trial treatment actually caused a spike in worries about the out-of-pocket costs of clinical trials.
These financial concerns generated yet another paper that appeared in the same edition of the Journal of Clinical Oncology.
“What was a surprise is that giving people information about costs in general terms made them more anxious,” Dr Meropol said. “It was not surprising to us that these concerns actually affect distress, add to decisional conflict, and interfere with decision-making.”
“This finding highlighted for us that communication about costs is both necessary and challenging. It indicates that we need to be sensitive to patients’ cost concerns as they navigate decisions about cancer care.”
The researchers are now planning to develop tools to assist patients with financial navigation. The team is also developing a web-based educational program for oncology nurses to help them discuss clinical trial participation with patients.
Protein discovery could have therapeutic implications
Photo courtesy of The
Scripps Research Institute
New research shows how NPM1—a protein implicated in non-Hodgkin lymphoma, acute myelogenous leukemia, and other cancers—twists and morphs into different structures.
This protein has many functions and, when mutated, has been shown to interfere with cells’ normal tumor suppressing ability.
Previous research showed that a section of NPM1, called the N-terminal domain, doesn’t have a defined, folded structure.
Instead, the protein morphs between 2 forms: a 1-subunit disordered monomer and a 5-subunit folded pentamer.
Until now, the mechanism behind this transformation was unknown, but researchers believed this monomer-pentamer equilibrium could be important for the protein’s location and functioning in the cell.
Ashok Deniz, PhD, of The Scripps Research Institute in La Jolla, California, and his colleagues conducted the current study to shed light on how this transformation occurs. They reported their findings in Angewandte Chemie.
The researchers used a combination of 3 techniques to analyze NPM1—single-molecule biophysics, fluorescence resonance energy transfer, and circular dichroism.
These techniques revealed that NPM1’s transformation can proceed through more than one pathway. In one pathway, the transformation begins when the cell sends signals to attach phosphoryl groups to NPM1.
This phosphorylation prompts the ordered pentamer to become disordered and likely causes NPM1 to shuttle outside the cell’s nucleus. A meeting with a binding partner can mediate the reverse transformation to a pentamer.
However, when NPM1 does become a pentamer again under these conditions, which likely causes it to move back to the nucleolus, it takes a different path instead of just retracing its earlier steps.
The study also revealed many intermediate states between monomer and pentamer structures. And it showed that these states can be manipulated or “tuned” by changing conditions such as salt levels, phosphorylation, and partner binding, which may explain how cells regulate NPM1’s multiple functions.
The researchers said future studies could shed more light on the biological functions of these different structures and how they might be used in future cancer therapies.
“We’re studying basic biophysics, but we believe the complexity and rules we uncover for the physics of protein disorder and folding could one day also be used for better designs of therapeutics,” Dr Deniz said.
He and his colleagues also believe that combining the 3 techniques used in this study, plus a novel protein-labeling technique for single-molecule fluorescence, could be a useful strategy for studying other unstructured, intrinsically disordered proteins.
Photo courtesy of The
Scripps Research Institute
New research shows how NPM1—a protein implicated in non-Hodgkin lymphoma, acute myelogenous leukemia, and other cancers—twists and morphs into different structures.
This protein has many functions and, when mutated, has been shown to interfere with cells’ normal tumor suppressing ability.
Previous research showed that a section of NPM1, called the N-terminal domain, doesn’t have a defined, folded structure.
Instead, the protein morphs between 2 forms: a 1-subunit disordered monomer and a 5-subunit folded pentamer.
Until now, the mechanism behind this transformation was unknown, but researchers believed this monomer-pentamer equilibrium could be important for the protein’s location and functioning in the cell.
Ashok Deniz, PhD, of The Scripps Research Institute in La Jolla, California, and his colleagues conducted the current study to shed light on how this transformation occurs. They reported their findings in Angewandte Chemie.
The researchers used a combination of 3 techniques to analyze NPM1—single-molecule biophysics, fluorescence resonance energy transfer, and circular dichroism.
These techniques revealed that NPM1’s transformation can proceed through more than one pathway. In one pathway, the transformation begins when the cell sends signals to attach phosphoryl groups to NPM1.
This phosphorylation prompts the ordered pentamer to become disordered and likely causes NPM1 to shuttle outside the cell’s nucleus. A meeting with a binding partner can mediate the reverse transformation to a pentamer.
However, when NPM1 does become a pentamer again under these conditions, which likely causes it to move back to the nucleolus, it takes a different path instead of just retracing its earlier steps.
The study also revealed many intermediate states between monomer and pentamer structures. And it showed that these states can be manipulated or “tuned” by changing conditions such as salt levels, phosphorylation, and partner binding, which may explain how cells regulate NPM1’s multiple functions.
The researchers said future studies could shed more light on the biological functions of these different structures and how they might be used in future cancer therapies.
“We’re studying basic biophysics, but we believe the complexity and rules we uncover for the physics of protein disorder and folding could one day also be used for better designs of therapeutics,” Dr Deniz said.
He and his colleagues also believe that combining the 3 techniques used in this study, plus a novel protein-labeling technique for single-molecule fluorescence, could be a useful strategy for studying other unstructured, intrinsically disordered proteins.
Photo courtesy of The
Scripps Research Institute
New research shows how NPM1—a protein implicated in non-Hodgkin lymphoma, acute myelogenous leukemia, and other cancers—twists and morphs into different structures.
This protein has many functions and, when mutated, has been shown to interfere with cells’ normal tumor suppressing ability.
Previous research showed that a section of NPM1, called the N-terminal domain, doesn’t have a defined, folded structure.
Instead, the protein morphs between 2 forms: a 1-subunit disordered monomer and a 5-subunit folded pentamer.
Until now, the mechanism behind this transformation was unknown, but researchers believed this monomer-pentamer equilibrium could be important for the protein’s location and functioning in the cell.
Ashok Deniz, PhD, of The Scripps Research Institute in La Jolla, California, and his colleagues conducted the current study to shed light on how this transformation occurs. They reported their findings in Angewandte Chemie.
The researchers used a combination of 3 techniques to analyze NPM1—single-molecule biophysics, fluorescence resonance energy transfer, and circular dichroism.
These techniques revealed that NPM1’s transformation can proceed through more than one pathway. In one pathway, the transformation begins when the cell sends signals to attach phosphoryl groups to NPM1.
This phosphorylation prompts the ordered pentamer to become disordered and likely causes NPM1 to shuttle outside the cell’s nucleus. A meeting with a binding partner can mediate the reverse transformation to a pentamer.
However, when NPM1 does become a pentamer again under these conditions, which likely causes it to move back to the nucleolus, it takes a different path instead of just retracing its earlier steps.
The study also revealed many intermediate states between monomer and pentamer structures. And it showed that these states can be manipulated or “tuned” by changing conditions such as salt levels, phosphorylation, and partner binding, which may explain how cells regulate NPM1’s multiple functions.
The researchers said future studies could shed more light on the biological functions of these different structures and how they might be used in future cancer therapies.
“We’re studying basic biophysics, but we believe the complexity and rules we uncover for the physics of protein disorder and folding could one day also be used for better designs of therapeutics,” Dr Deniz said.
He and his colleagues also believe that combining the 3 techniques used in this study, plus a novel protein-labeling technique for single-molecule fluorescence, could be a useful strategy for studying other unstructured, intrinsically disordered proteins.