AVAHO

A mechanistic link between red meat consumption and colorectal cancer (CRC) has been identified in the form of an alkylating mutational signature, according to investigators.

This is the first time a colorectal mutational signature has been associated with a component of diet, which demonstrates the value of large-scale molecular epidemiologic studies and suggests potential for early, precision dietary intervention, reported lead author Carino Gurjao, MSc, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, and colleagues.

“Red meat consumption has been consistently linked to the incidence of colorectal cancer,” the investigators wrote in Cancer Discovery. “The suggested mechanism is mutagenesis through alkylating damage induced by N-nitroso-compounds (NOCs), which are metabolic products of blood heme iron or meat nitrites/nitrates. Nevertheless, this mutational damage is yet to be observed directly in patients’ tumors.”

To this end, the investigators turned to three long-term, large-scale, prospective cohort studies: the Nurses’ Health Studies I and II, and the Health Professionals Follow-up Study. These databases include nearly 300,000 individuals with follow-up dating back as far as 1976. The investigators identified 900 cases of primary, untreated CRC with adequate tissue for analysis, then, for each case, performed whole exome sequencing on both tumor tissue and normal colorectal tissue.

This revealed an alkylating mutational signature previously undescribed in CRC that was significantly associated with consumption of red meat prior to diagnosis, but not other dietary or lifestyle factors. The signature occurred most frequently in tumors and normal crypts in the distal colon and rectum.

According to the investigators, the presence of the alkylating signature in normal colorectal crypts “suggests that mutational changes due to such damage may start to occur early in the path of colorectal carcinogenesis.”

Further analysis showed that tumors harboring common KRAS and PIK3CA driver mutations had the highest levels of alkylating damage, with higher levels predicting worse survival.

“These results ... further implicate the role of red meat in CRC initiation and progression,” the investigators concluded.
 

Early findings, important implications

Cosenior author Kana Wu, MD, PhD, principal research scientist in the department of nutrition at Harvard School of Public Health, Boston, noted that these are early findings, although they may pave the way toward new dietary recommendations and methods of food production.

“While more detailed analysis needs to be conducted, and our results need to be confirmed in other studies, this study is a promising first step to better understand the biological mechanisms underlying the role of red and processed meats in colorectal cancers,” Dr. Wu said in an interview. “It is important to gain more insight into the biological mechanisms so we can improve dietary guidelines for cancer prevention and guide food reformulation efforts to lower cancer risk.”

For now, Dr. Wu predicted that standing dietary recommendations will remain unchanged.

“This study will not alter current diet recommendations to limit intake of red and processed meats,” Dr. Wu said, referring to similar recommendations across several organizations, including the American Heart Association, the World Cancer Research Fund/American Institute for Cancer Research, and the American Cancer Society.

“For example,” Dr. Wu said, “the WCRF/AICR recommends limiting consumption of red and processed meat to ‘no more than moderate amounts [12-18 ounces per week] of red meat, such as beef, pork, and lamb, and [to] eat little, if any, processed meat.’”
 

Possible biomarker?

According to Patricia Thompson-Carino, PhD, deputy director of the Stony Brook (N.Y.) Cancer Center, the study provides convincing evidence linking red meat consumption with development of CRC.

“Higher frequency of the signature in the distal colon is compelling for its consistency with epidemiologic evidence,” Dr. Thompson-Carino said in an interview. “Combined with the observed worse survival in patients harboring the signature and association with oncogenic KRAS and PIK3CA driver mutations, this study significantly elevates the biological plausibility that red meat is a modifiable source of NOC mutagenicity and carcinogenesis in humans.”

The signature could be used as a biomarker to detect exposure to NOCs, and susceptibility to CRC, she added.

Still, Dr. Thompson-Carino suggested that more work is needed to fully elucidate underlying mechanisms of action, which are needed to accurately shape dietary guidance.

“Key to advancing red meat dietary recommendations will be understanding the relationships between the new mutation signature and the NOCs derived from red meat and their source, whether endogenous [for example, intestinal N-nitrosation] or exogenous [for example, chemical preservation or charring],” she said. The study was supported by the National Institutes of Health, the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (coadministered by the American Association for Cancer Research), the Project P Fund, and others. The investigators, Dr. Wu, and Dr. Thompson-Carino reported no conflicts of interest related to this study.

A mechanistic link between red meat consumption and colorectal cancer (CRC) has been identified in the form of an alkylating mutational signature, according to investigators.

This is the first time a colorectal mutational signature has been associated with a component of diet, which demonstrates the value of large-scale molecular epidemiologic studies and suggests potential for early, precision dietary intervention, reported lead author Carino Gurjao, MSc, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, and colleagues.

“Red meat consumption has been consistently linked to the incidence of colorectal cancer,” the investigators wrote in Cancer Discovery. “The suggested mechanism is mutagenesis through alkylating damage induced by N-nitroso-compounds (NOCs), which are metabolic products of blood heme iron or meat nitrites/nitrates. Nevertheless, this mutational damage is yet to be observed directly in patients’ tumors.”

To this end, the investigators turned to three long-term, large-scale, prospective cohort studies: the Nurses’ Health Studies I and II, and the Health Professionals Follow-up Study. These databases include nearly 300,000 individuals with follow-up dating back as far as 1976. The investigators identified 900 cases of primary, untreated CRC with adequate tissue for analysis, then, for each case, performed whole exome sequencing on both tumor tissue and normal colorectal tissue.

This revealed an alkylating mutational signature previously undescribed in CRC that was significantly associated with consumption of red meat prior to diagnosis, but not other dietary or lifestyle factors. The signature occurred most frequently in tumors and normal crypts in the distal colon and rectum.

According to the investigators, the presence of the alkylating signature in normal colorectal crypts “suggests that mutational changes due to such damage may start to occur early in the path of colorectal carcinogenesis.”

Further analysis showed that tumors harboring common KRAS and PIK3CA driver mutations had the highest levels of alkylating damage, with higher levels predicting worse survival.

“These results ... further implicate the role of red meat in CRC initiation and progression,” the investigators concluded.
 

Early findings, important implications

Cosenior author Kana Wu, MD, PhD, principal research scientist in the department of nutrition at Harvard School of Public Health, Boston, noted that these are early findings, although they may pave the way toward new dietary recommendations and methods of food production.

“While more detailed analysis needs to be conducted, and our results need to be confirmed in other studies, this study is a promising first step to better understand the biological mechanisms underlying the role of red and processed meats in colorectal cancers,” Dr. Wu said in an interview. “It is important to gain more insight into the biological mechanisms so we can improve dietary guidelines for cancer prevention and guide food reformulation efforts to lower cancer risk.”

For now, Dr. Wu predicted that standing dietary recommendations will remain unchanged.

“This study will not alter current diet recommendations to limit intake of red and processed meats,” Dr. Wu said, referring to similar recommendations across several organizations, including the American Heart Association, the World Cancer Research Fund/American Institute for Cancer Research, and the American Cancer Society.

“For example,” Dr. Wu said, “the WCRF/AICR recommends limiting consumption of red and processed meat to ‘no more than moderate amounts [12-18 ounces per week] of red meat, such as beef, pork, and lamb, and [to] eat little, if any, processed meat.’”
 

Possible biomarker?

According to Patricia Thompson-Carino, PhD, deputy director of the Stony Brook (N.Y.) Cancer Center, the study provides convincing evidence linking red meat consumption with development of CRC.

“Higher frequency of the signature in the distal colon is compelling for its consistency with epidemiologic evidence,” Dr. Thompson-Carino said in an interview. “Combined with the observed worse survival in patients harboring the signature and association with oncogenic KRAS and PIK3CA driver mutations, this study significantly elevates the biological plausibility that red meat is a modifiable source of NOC mutagenicity and carcinogenesis in humans.”

The signature could be used as a biomarker to detect exposure to NOCs, and susceptibility to CRC, she added.

Still, Dr. Thompson-Carino suggested that more work is needed to fully elucidate underlying mechanisms of action, which are needed to accurately shape dietary guidance.

“Key to advancing red meat dietary recommendations will be understanding the relationships between the new mutation signature and the NOCs derived from red meat and their source, whether endogenous [for example, intestinal N-nitrosation] or exogenous [for example, chemical preservation or charring],” she said. The study was supported by the National Institutes of Health, the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (coadministered by the American Association for Cancer Research), the Project P Fund, and others. The investigators, Dr. Wu, and Dr. Thompson-Carino reported no conflicts of interest related to this study.

A mechanistic link between red meat consumption and colorectal cancer (CRC) has been identified in the form of an alkylating mutational signature, according to investigators.

This is the first time a colorectal mutational signature has been associated with a component of diet, which demonstrates the value of large-scale molecular epidemiologic studies and suggests potential for early, precision dietary intervention, reported lead author Carino Gurjao, MSc, of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, and colleagues.

“Red meat consumption has been consistently linked to the incidence of colorectal cancer,” the investigators wrote in Cancer Discovery. “The suggested mechanism is mutagenesis through alkylating damage induced by N-nitroso-compounds (NOCs), which are metabolic products of blood heme iron or meat nitrites/nitrates. Nevertheless, this mutational damage is yet to be observed directly in patients’ tumors.”

To this end, the investigators turned to three long-term, large-scale, prospective cohort studies: the Nurses’ Health Studies I and II, and the Health Professionals Follow-up Study. These databases include nearly 300,000 individuals with follow-up dating back as far as 1976. The investigators identified 900 cases of primary, untreated CRC with adequate tissue for analysis, then, for each case, performed whole exome sequencing on both tumor tissue and normal colorectal tissue.

This revealed an alkylating mutational signature previously undescribed in CRC that was significantly associated with consumption of red meat prior to diagnosis, but not other dietary or lifestyle factors. The signature occurred most frequently in tumors and normal crypts in the distal colon and rectum.

According to the investigators, the presence of the alkylating signature in normal colorectal crypts “suggests that mutational changes due to such damage may start to occur early in the path of colorectal carcinogenesis.”

Further analysis showed that tumors harboring common KRAS and PIK3CA driver mutations had the highest levels of alkylating damage, with higher levels predicting worse survival.

“These results ... further implicate the role of red meat in CRC initiation and progression,” the investigators concluded.
 

Early findings, important implications

Cosenior author Kana Wu, MD, PhD, principal research scientist in the department of nutrition at Harvard School of Public Health, Boston, noted that these are early findings, although they may pave the way toward new dietary recommendations and methods of food production.

“While more detailed analysis needs to be conducted, and our results need to be confirmed in other studies, this study is a promising first step to better understand the biological mechanisms underlying the role of red and processed meats in colorectal cancers,” Dr. Wu said in an interview. “It is important to gain more insight into the biological mechanisms so we can improve dietary guidelines for cancer prevention and guide food reformulation efforts to lower cancer risk.”

For now, Dr. Wu predicted that standing dietary recommendations will remain unchanged.

“This study will not alter current diet recommendations to limit intake of red and processed meats,” Dr. Wu said, referring to similar recommendations across several organizations, including the American Heart Association, the World Cancer Research Fund/American Institute for Cancer Research, and the American Cancer Society.

“For example,” Dr. Wu said, “the WCRF/AICR recommends limiting consumption of red and processed meat to ‘no more than moderate amounts [12-18 ounces per week] of red meat, such as beef, pork, and lamb, and [to] eat little, if any, processed meat.’”
 

Possible biomarker?

According to Patricia Thompson-Carino, PhD, deputy director of the Stony Brook (N.Y.) Cancer Center, the study provides convincing evidence linking red meat consumption with development of CRC.

“Higher frequency of the signature in the distal colon is compelling for its consistency with epidemiologic evidence,” Dr. Thompson-Carino said in an interview. “Combined with the observed worse survival in patients harboring the signature and association with oncogenic KRAS and PIK3CA driver mutations, this study significantly elevates the biological plausibility that red meat is a modifiable source of NOC mutagenicity and carcinogenesis in humans.”

The signature could be used as a biomarker to detect exposure to NOCs, and susceptibility to CRC, she added.

Still, Dr. Thompson-Carino suggested that more work is needed to fully elucidate underlying mechanisms of action, which are needed to accurately shape dietary guidance.

“Key to advancing red meat dietary recommendations will be understanding the relationships between the new mutation signature and the NOCs derived from red meat and their source, whether endogenous [for example, intestinal N-nitrosation] or exogenous [for example, chemical preservation or charring],” she said. The study was supported by the National Institutes of Health, the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (coadministered by the American Association for Cancer Research), the Project P Fund, and others. The investigators, Dr. Wu, and Dr. Thompson-Carino reported no conflicts of interest related to this study.

Leading oncologist Professor Justin Stebbing has told a medical tribunal he provided “exceptional standards of care” to a cancer patient he’s accused of giving chemotherapy when there was no evidence it would bring any benefit.

Prof. Stebbing, a cancer medicine and oncology professor at Imperial College London with a private practice on Harley Street, claimed the patient would have died without the chemotherapy, and immunotherapy treatment led to him living for another 2 years.

He’s appearing before a Medical Practitioners Tribunal Service (MPTS) fitness-to-practice hearing and is accused of failing to provide good clinical care to 12 patients between March 2014 and March 2017.

In some cases, Prof. Stebbing is accused of inappropriately treating patients given their advanced cancer or poor prognosis, overstating life expectancy and the benefits of chemotherapy, and continuing to treat patients when it was futile, and they had just weeks to live.

The 36 charges – 21 of which he’s admitted – also include failing to keep proper records and failing to gain informed consent for treatment from patients.
 

Patient B

Prof. Stebbing’s international reputation for innovative treatments has led to wealthy, terminally ill cancer patients from around the world turning to him in the hope of extending their lives.

The tribunal heard about one lung cancer patient – known only as Patient B – from Spain he treated between May 2014 and October 2015.

Prof. Stebbing is accused of offering doublet chemotherapy to the patient beyond six cycles, despite evidence emerging that he was developing impaired renal function.

He’s also accused of continuing the treatment at a higher dose after 10 cycles despite a “lack of efficacy” and “evidence of harm emerging.”

It’s alleged the chemotherapy would have exposed the patient to risks “without any conceivable prospect of improving health.”

However, Prof. Stebbing defended his actions, saying he’d explained to the patient that if he stopped chemotherapy at any time, “his disease would progress rapidly and he would die.”

He said immunotherapy “typically took 3 months to work,” and because the patient’s lung cancer hadn’t progressed, it was evident that the chemotherapy had worked.

It was possible to provide chemotherapy in cases of renal failure, he said, and he’d only given it in small doses.

“This is one of two patients in the bundle who has an exceptional standard of care,” he said.

“If you look at the problem with his kidneys, this was the minimus in my terms.

“I think I made some very, very difficult decisions that other people may not have made, but I got them right and, as a result, he lived very happily for another 2 years.”
 

‘Guidelines are a guide’

But Sharon Beattie, for the General Medical Council (GMC), claimed he’d ignored guidelines, and there was no data to support the position he’d taken.

Prof. Stebbing replied: “The guidelines are a guide; they are helpful. They do not replace the skill of an individual doctor.”

“There were no guidelines for a patient like this. I’m absolutely amazed you’re saying, ‘You should have just let him die because there were no guidelines.’”

Ms. Beattie pointed out that Prof. Stebbing had accepted that he’d stopped the chemotherapy treatment in October 2015 because it was clear there was evidence of “toxicity and waning efficacy.”

But he claimed there were only “grade one” levels of toxicity and “mild” disease progression.

At that stage, he said, he realized he was approaching the “end of the line” with the treatment and he was “thinking out of the box” to get immunotherapy for the patient.

Earlier, Prof. Stebbing said the chemotherapy had been “a bridge” to the patient’s immunotherapy treatment, but it had “never been clear” it would be available.

He said: “The whole point of the extended duration chemotherapy was to try to get him to immunotherapy if it was available.”

“It was a very exciting, new possibility. I didn’t know if it was going to be available, but I wanted the patient to have every chance of it being available.”

“The longer he lived for with stable disease the more likelihood it had of becoming available.”

Prof. Stebbing denies failing to discuss the risks and benefits of chemotherapy with the patient and failing to maintain adequate records.

He told the tribunal that he had discussed both the chemotherapy and immunotherapy, but he accepted he’d had “problems” with documenting his decisions.

The tribunal continues.

A version of this article first appeared on Medscape.com.

Leading oncologist Professor Justin Stebbing has told a medical tribunal he provided “exceptional standards of care” to a cancer patient he’s accused of giving chemotherapy when there was no evidence it would bring any benefit.

Prof. Stebbing, a cancer medicine and oncology professor at Imperial College London with a private practice on Harley Street, claimed the patient would have died without the chemotherapy, and immunotherapy treatment led to him living for another 2 years.

He’s appearing before a Medical Practitioners Tribunal Service (MPTS) fitness-to-practice hearing and is accused of failing to provide good clinical care to 12 patients between March 2014 and March 2017.

In some cases, Prof. Stebbing is accused of inappropriately treating patients given their advanced cancer or poor prognosis, overstating life expectancy and the benefits of chemotherapy, and continuing to treat patients when it was futile, and they had just weeks to live.

The 36 charges – 21 of which he’s admitted – also include failing to keep proper records and failing to gain informed consent for treatment from patients.
 

Patient B

Prof. Stebbing’s international reputation for innovative treatments has led to wealthy, terminally ill cancer patients from around the world turning to him in the hope of extending their lives.

The tribunal heard about one lung cancer patient – known only as Patient B – from Spain he treated between May 2014 and October 2015.

Prof. Stebbing is accused of offering doublet chemotherapy to the patient beyond six cycles, despite evidence emerging that he was developing impaired renal function.

He’s also accused of continuing the treatment at a higher dose after 10 cycles despite a “lack of efficacy” and “evidence of harm emerging.”

It’s alleged the chemotherapy would have exposed the patient to risks “without any conceivable prospect of improving health.”

However, Prof. Stebbing defended his actions, saying he’d explained to the patient that if he stopped chemotherapy at any time, “his disease would progress rapidly and he would die.”

He said immunotherapy “typically took 3 months to work,” and because the patient’s lung cancer hadn’t progressed, it was evident that the chemotherapy had worked.

It was possible to provide chemotherapy in cases of renal failure, he said, and he’d only given it in small doses.

“This is one of two patients in the bundle who has an exceptional standard of care,” he said.

“If you look at the problem with his kidneys, this was the minimus in my terms.

“I think I made some very, very difficult decisions that other people may not have made, but I got them right and, as a result, he lived very happily for another 2 years.”
 

‘Guidelines are a guide’

But Sharon Beattie, for the General Medical Council (GMC), claimed he’d ignored guidelines, and there was no data to support the position he’d taken.

Prof. Stebbing replied: “The guidelines are a guide; they are helpful. They do not replace the skill of an individual doctor.”

“There were no guidelines for a patient like this. I’m absolutely amazed you’re saying, ‘You should have just let him die because there were no guidelines.’”

Ms. Beattie pointed out that Prof. Stebbing had accepted that he’d stopped the chemotherapy treatment in October 2015 because it was clear there was evidence of “toxicity and waning efficacy.”

But he claimed there were only “grade one” levels of toxicity and “mild” disease progression.

At that stage, he said, he realized he was approaching the “end of the line” with the treatment and he was “thinking out of the box” to get immunotherapy for the patient.

Earlier, Prof. Stebbing said the chemotherapy had been “a bridge” to the patient’s immunotherapy treatment, but it had “never been clear” it would be available.

He said: “The whole point of the extended duration chemotherapy was to try to get him to immunotherapy if it was available.”

“It was a very exciting, new possibility. I didn’t know if it was going to be available, but I wanted the patient to have every chance of it being available.”

“The longer he lived for with stable disease the more likelihood it had of becoming available.”

Prof. Stebbing denies failing to discuss the risks and benefits of chemotherapy with the patient and failing to maintain adequate records.

He told the tribunal that he had discussed both the chemotherapy and immunotherapy, but he accepted he’d had “problems” with documenting his decisions.

The tribunal continues.

A version of this article first appeared on Medscape.com.

Leading oncologist Professor Justin Stebbing has told a medical tribunal he provided “exceptional standards of care” to a cancer patient he’s accused of giving chemotherapy when there was no evidence it would bring any benefit.

Prof. Stebbing, a cancer medicine and oncology professor at Imperial College London with a private practice on Harley Street, claimed the patient would have died without the chemotherapy, and immunotherapy treatment led to him living for another 2 years.

He’s appearing before a Medical Practitioners Tribunal Service (MPTS) fitness-to-practice hearing and is accused of failing to provide good clinical care to 12 patients between March 2014 and March 2017.

In some cases, Prof. Stebbing is accused of inappropriately treating patients given their advanced cancer or poor prognosis, overstating life expectancy and the benefits of chemotherapy, and continuing to treat patients when it was futile, and they had just weeks to live.

The 36 charges – 21 of which he’s admitted – also include failing to keep proper records and failing to gain informed consent for treatment from patients.
 

Patient B

Prof. Stebbing’s international reputation for innovative treatments has led to wealthy, terminally ill cancer patients from around the world turning to him in the hope of extending their lives.

The tribunal heard about one lung cancer patient – known only as Patient B – from Spain he treated between May 2014 and October 2015.

Prof. Stebbing is accused of offering doublet chemotherapy to the patient beyond six cycles, despite evidence emerging that he was developing impaired renal function.

He’s also accused of continuing the treatment at a higher dose after 10 cycles despite a “lack of efficacy” and “evidence of harm emerging.”

It’s alleged the chemotherapy would have exposed the patient to risks “without any conceivable prospect of improving health.”

However, Prof. Stebbing defended his actions, saying he’d explained to the patient that if he stopped chemotherapy at any time, “his disease would progress rapidly and he would die.”

He said immunotherapy “typically took 3 months to work,” and because the patient’s lung cancer hadn’t progressed, it was evident that the chemotherapy had worked.

It was possible to provide chemotherapy in cases of renal failure, he said, and he’d only given it in small doses.

“This is one of two patients in the bundle who has an exceptional standard of care,” he said.

“If you look at the problem with his kidneys, this was the minimus in my terms.

“I think I made some very, very difficult decisions that other people may not have made, but I got them right and, as a result, he lived very happily for another 2 years.”
 

‘Guidelines are a guide’

But Sharon Beattie, for the General Medical Council (GMC), claimed he’d ignored guidelines, and there was no data to support the position he’d taken.

Prof. Stebbing replied: “The guidelines are a guide; they are helpful. They do not replace the skill of an individual doctor.”

“There were no guidelines for a patient like this. I’m absolutely amazed you’re saying, ‘You should have just let him die because there were no guidelines.’”

Ms. Beattie pointed out that Prof. Stebbing had accepted that he’d stopped the chemotherapy treatment in October 2015 because it was clear there was evidence of “toxicity and waning efficacy.”

But he claimed there were only “grade one” levels of toxicity and “mild” disease progression.

At that stage, he said, he realized he was approaching the “end of the line” with the treatment and he was “thinking out of the box” to get immunotherapy for the patient.

Earlier, Prof. Stebbing said the chemotherapy had been “a bridge” to the patient’s immunotherapy treatment, but it had “never been clear” it would be available.

He said: “The whole point of the extended duration chemotherapy was to try to get him to immunotherapy if it was available.”

“It was a very exciting, new possibility. I didn’t know if it was going to be available, but I wanted the patient to have every chance of it being available.”

“The longer he lived for with stable disease the more likelihood it had of becoming available.”

Prof. Stebbing denies failing to discuss the risks and benefits of chemotherapy with the patient and failing to maintain adequate records.

He told the tribunal that he had discussed both the chemotherapy and immunotherapy, but he accepted he’d had “problems” with documenting his decisions.

The tribunal continues.

A version of this article first appeared on Medscape.com.

Five years of treatment with bisphosphonates after chemotherapy for high-risk early breast cancer is too much, say researchers reporting new results from a phase 3 trial with almost 3,000 women.

Current guidelines call for 3-5 years of bisphosphonate therapy on the theory that these drugs might reduce breast cancer recurrence as well as treatment-related bone problems.

However, the new results show no difference in disease-free survival, distant disease-free survival, and overall survival – regardless of menopausal status – between the 1,540 women who received intravenous zoledronate over a 5-year period and 1,447 women who received such therapy over a 2-year period.

What they did find was a substantially higher risk for adverse events with prolonged bisphosphonate treatment, including risks for grade 3/4 events, bone pain, bone fractures, arthralgia, and jaw necrosis, a rare but well- recognized possibility with bisphosphonates.

Lead investigator Thomas Friedl, PhD, a statistician at University Hospital Ulm (Germany), and colleagues concluded that the current duration of treatment can be reduced and that, short of good reason to use bisphosphonates longer, such as decreased bone density, “treatment with zoledronate for 5 years should not be considered in patients with early breast cancer.”

The study was published online on June 24 in JAMA Oncology.

An accompanying editorial went even further, stating not only that “shorter duration of treatment is sufficient” but also that the whole idea of bisphosphonates for breast cancer is in doubt.

With “the modest outcomes of bisphosphonates, compared with no bone-targeted therapy, in historical trials” and the low rates of recurrence with modern treatment – less than 10% in the trial – “what, if any, is the benefit from adjuvant bisphosphonates? It’s time to reevaluate the guidelines,” said the editorialists, led by Alexandra Desnoyers, MD, a breast cancer fellow at the University of Toronto.

“We suggest that zoledronate or other amino-bisphosphonates should not be given as standard adjuvant therapy for unselected women with breast cancer,” they wrote.
 

Risk for necrosis with 5 years of zoledronate

The women in the trial had primary invasive breast cancer and were at high risk for recurrence. They had either positive nodes or high-risk features, including age (median, 53 years). They were treated at 250 centers in Germany.

The first part of the trial was to see whether use of gemcitabine improved outcomes when added to docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide adjuvant therapy following surgery. It did not, and the authors reported in 2020 that adjuvant gemcitabine should not be used in the treatment of high-risk early breast cancer.

The next phase of the trial involved zoledronate. Women were randomly assigned to receive zoledronate for 2 or 5 years after surgery and after undergoing chemotherapy. Dosing was 4 mg IV every 3 months for 2 years. The women in the 5-year group went on to receive 4 mg IV every 6 months for another 3 years.

At a mean of 5 years’ follow-up after the first zoledronate dose, there was no difference in any of the survival measures between the two dosage groups.

There was also no difference in rates of bone recurrence or in circulating tumor cells, which the bisphosphonates theory would have predicted. For instance, 10.5% of women in the 5-year group had one or more circulating tumor cells on follow-up versus 7.2% in the 2-year group.

Almost half of the women in the 5-year treatment group experienced adverse events with zoledronate – including 7.6% with grade 3/4 events – versus just over a quarter in the 2-year arm and only 5.1% with grade 3/4 events.

In the 5-year group, 8.3% of patients experienced bone pain and 5.1% experienced arthralgia versus 3.7% and 3.1%, respectively, in the 2-year arm.

Atypical fractures, such as femoral spiral fractures, are another concern with bisphosphonates. Although this trial did not report on fracture type, fractures were reported in 14 women in the 5-year group but in only 3 in the 2-year arm.

Jaw necrosis, another known adverse effect of bisphosphonates, was reported in 11 women in the 5-year group and in 5 in the 2-year group.

The study was funded by several pharmaceutical companies, including Novartis, the maker of zoledronate. The investigators have numerous industry ties. Dr. Friedl has received payments from Novartis.

A version of this article first appeared on Medscape.com.

Five years of treatment with bisphosphonates after chemotherapy for high-risk early breast cancer is too much, say researchers reporting new results from a phase 3 trial with almost 3,000 women.

Current guidelines call for 3-5 years of bisphosphonate therapy on the theory that these drugs might reduce breast cancer recurrence as well as treatment-related bone problems.

However, the new results show no difference in disease-free survival, distant disease-free survival, and overall survival – regardless of menopausal status – between the 1,540 women who received intravenous zoledronate over a 5-year period and 1,447 women who received such therapy over a 2-year period.

What they did find was a substantially higher risk for adverse events with prolonged bisphosphonate treatment, including risks for grade 3/4 events, bone pain, bone fractures, arthralgia, and jaw necrosis, a rare but well- recognized possibility with bisphosphonates.

Lead investigator Thomas Friedl, PhD, a statistician at University Hospital Ulm (Germany), and colleagues concluded that the current duration of treatment can be reduced and that, short of good reason to use bisphosphonates longer, such as decreased bone density, “treatment with zoledronate for 5 years should not be considered in patients with early breast cancer.”

The study was published online on June 24 in JAMA Oncology.

An accompanying editorial went even further, stating not only that “shorter duration of treatment is sufficient” but also that the whole idea of bisphosphonates for breast cancer is in doubt.

With “the modest outcomes of bisphosphonates, compared with no bone-targeted therapy, in historical trials” and the low rates of recurrence with modern treatment – less than 10% in the trial – “what, if any, is the benefit from adjuvant bisphosphonates? It’s time to reevaluate the guidelines,” said the editorialists, led by Alexandra Desnoyers, MD, a breast cancer fellow at the University of Toronto.

“We suggest that zoledronate or other amino-bisphosphonates should not be given as standard adjuvant therapy for unselected women with breast cancer,” they wrote.
 

Risk for necrosis with 5 years of zoledronate

The women in the trial had primary invasive breast cancer and were at high risk for recurrence. They had either positive nodes or high-risk features, including age (median, 53 years). They were treated at 250 centers in Germany.

The first part of the trial was to see whether use of gemcitabine improved outcomes when added to docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide adjuvant therapy following surgery. It did not, and the authors reported in 2020 that adjuvant gemcitabine should not be used in the treatment of high-risk early breast cancer.

The next phase of the trial involved zoledronate. Women were randomly assigned to receive zoledronate for 2 or 5 years after surgery and after undergoing chemotherapy. Dosing was 4 mg IV every 3 months for 2 years. The women in the 5-year group went on to receive 4 mg IV every 6 months for another 3 years.

At a mean of 5 years’ follow-up after the first zoledronate dose, there was no difference in any of the survival measures between the two dosage groups.

There was also no difference in rates of bone recurrence or in circulating tumor cells, which the bisphosphonates theory would have predicted. For instance, 10.5% of women in the 5-year group had one or more circulating tumor cells on follow-up versus 7.2% in the 2-year group.

Almost half of the women in the 5-year treatment group experienced adverse events with zoledronate – including 7.6% with grade 3/4 events – versus just over a quarter in the 2-year arm and only 5.1% with grade 3/4 events.

In the 5-year group, 8.3% of patients experienced bone pain and 5.1% experienced arthralgia versus 3.7% and 3.1%, respectively, in the 2-year arm.

Atypical fractures, such as femoral spiral fractures, are another concern with bisphosphonates. Although this trial did not report on fracture type, fractures were reported in 14 women in the 5-year group but in only 3 in the 2-year arm.

Jaw necrosis, another known adverse effect of bisphosphonates, was reported in 11 women in the 5-year group and in 5 in the 2-year group.

The study was funded by several pharmaceutical companies, including Novartis, the maker of zoledronate. The investigators have numerous industry ties. Dr. Friedl has received payments from Novartis.

A version of this article first appeared on Medscape.com.

Five years of treatment with bisphosphonates after chemotherapy for high-risk early breast cancer is too much, say researchers reporting new results from a phase 3 trial with almost 3,000 women.

Current guidelines call for 3-5 years of bisphosphonate therapy on the theory that these drugs might reduce breast cancer recurrence as well as treatment-related bone problems.

However, the new results show no difference in disease-free survival, distant disease-free survival, and overall survival – regardless of menopausal status – between the 1,540 women who received intravenous zoledronate over a 5-year period and 1,447 women who received such therapy over a 2-year period.

What they did find was a substantially higher risk for adverse events with prolonged bisphosphonate treatment, including risks for grade 3/4 events, bone pain, bone fractures, arthralgia, and jaw necrosis, a rare but well- recognized possibility with bisphosphonates.

Lead investigator Thomas Friedl, PhD, a statistician at University Hospital Ulm (Germany), and colleagues concluded that the current duration of treatment can be reduced and that, short of good reason to use bisphosphonates longer, such as decreased bone density, “treatment with zoledronate for 5 years should not be considered in patients with early breast cancer.”

The study was published online on June 24 in JAMA Oncology.

An accompanying editorial went even further, stating not only that “shorter duration of treatment is sufficient” but also that the whole idea of bisphosphonates for breast cancer is in doubt.

With “the modest outcomes of bisphosphonates, compared with no bone-targeted therapy, in historical trials” and the low rates of recurrence with modern treatment – less than 10% in the trial – “what, if any, is the benefit from adjuvant bisphosphonates? It’s time to reevaluate the guidelines,” said the editorialists, led by Alexandra Desnoyers, MD, a breast cancer fellow at the University of Toronto.

“We suggest that zoledronate or other amino-bisphosphonates should not be given as standard adjuvant therapy for unselected women with breast cancer,” they wrote.
 

Risk for necrosis with 5 years of zoledronate

The women in the trial had primary invasive breast cancer and were at high risk for recurrence. They had either positive nodes or high-risk features, including age (median, 53 years). They were treated at 250 centers in Germany.

The first part of the trial was to see whether use of gemcitabine improved outcomes when added to docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide adjuvant therapy following surgery. It did not, and the authors reported in 2020 that adjuvant gemcitabine should not be used in the treatment of high-risk early breast cancer.

The next phase of the trial involved zoledronate. Women were randomly assigned to receive zoledronate for 2 or 5 years after surgery and after undergoing chemotherapy. Dosing was 4 mg IV every 3 months for 2 years. The women in the 5-year group went on to receive 4 mg IV every 6 months for another 3 years.

At a mean of 5 years’ follow-up after the first zoledronate dose, there was no difference in any of the survival measures between the two dosage groups.

There was also no difference in rates of bone recurrence or in circulating tumor cells, which the bisphosphonates theory would have predicted. For instance, 10.5% of women in the 5-year group had one or more circulating tumor cells on follow-up versus 7.2% in the 2-year group.

Almost half of the women in the 5-year treatment group experienced adverse events with zoledronate – including 7.6% with grade 3/4 events – versus just over a quarter in the 2-year arm and only 5.1% with grade 3/4 events.

In the 5-year group, 8.3% of patients experienced bone pain and 5.1% experienced arthralgia versus 3.7% and 3.1%, respectively, in the 2-year arm.

Atypical fractures, such as femoral spiral fractures, are another concern with bisphosphonates. Although this trial did not report on fracture type, fractures were reported in 14 women in the 5-year group but in only 3 in the 2-year arm.

Jaw necrosis, another known adverse effect of bisphosphonates, was reported in 11 women in the 5-year group and in 5 in the 2-year group.

The study was funded by several pharmaceutical companies, including Novartis, the maker of zoledronate. The investigators have numerous industry ties. Dr. Friedl has received payments from Novartis.

A version of this article first appeared on Medscape.com.

Adults with sickle cell disease who experienced a vaso-occlusive crisis had substantially better outcomes when they were treated at specialty infusion centers than those treated in emergency departments (EDs), a prospective observational study shows.

At infusion centers, patients received pain medication an average of 70 minutes faster compared with patients treated in EDs (62 vs. 132 minutes), according to a study published online in the Annals of Internal Medicine. In addition, patients at infusion centers were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose. And they were 4 times more likely to be discharged home, the researchers found.

“It’s not that the emergency room doctors don’t want to do the right thing,” study author Sophie Lanzkron, MD, said in an interview. “They do, but they aren’t experts in sickle cell disease. They work in an emergency room, which is an incredibly busy, stressful place where they see trauma and heart attacks and strokes and all of these things that need emergency care. And so it just is not the right setting to treat people with sickle cell disease.”

To assess whether care at specialty infusion centers or EDs leads to better outcomes for patients with sickle cell disease with uncomplicated vaso-occlusive crises, Dr. Lanzkron, director of the Sickle Cell Center for Adults at the Johns Hopkins Hospital, Baltimore, and colleagues conducted the ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital) study.

The trial included 483 adults with sickle cell disease who lived within 60 miles of an infusion center in four U.S. cities: Baltimore, Maryland; Cleveland, Ohio; Milwaukee, Wisconsin; and Baton Rouge, Louisiana. Investigators recruited patients between April 2015 and December 2016 and followed them for 18 months after enrollment.

The present analysis focused on data from 269 participants who had infusion center visits or ED visits that occurred during weekdays when infusion centers were open. Two sites had infusion centers solely for adults with sickle cell disease (Baltimore and Milwaukee), and two infusion centers shared infusion space with other hematology-oncology patients. All four sites were in hospitals that also had EDs. 

Although participants may have received comprehensive care at one of the sites with an infusion center, those who lived farther from an infusion center were likely to receive care for acute pain at an ED closer to home, the authors explain in the article.

The investigators used propensity score methodology to balance patient characteristics in the study groups.
 

Quick, effective pain reduction is beneficial

The results suggest that infusion centers “are more likely to provide guideline-based care than EDs,” and this care “can improve overall outcomes,” the authors write. 

Although the specialty infusion centers the researchers studied used various models, similar outcomes were seen at all of them.

The study did not include patients who had complications of sickle cell disease in addition to vaso-occlusive crisis, the researchers note. 

“[Because] the magnitude of the treatment effects estimated in our study is large and we have captured most of the important potential confounders, an unmeasured confounder that can nullify the treatment effect is unlikely to exist,” the authors write. 

“Sickle cell disease is a complicated condition that affects multiple organs. Patients who present with acute pain will have better outcomes being treated under providers who know and understand the disease,” commented Julie Kanter, MD, director of the adult sickle cell disease program and codirector of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham. “Specialized infusion centers offer the opportunity to both improve outcomes and decrease the cost of care. Most importantly, it is better for the individual with sickle cell disease,” she said.

Dr. Kanter wrote an accompanying editorial about the ESCAPED findings. The editorialist notes that “opioid medications are the only option to reduce the pain caused by microvascular injury” in patients with sickle cell crisis, although these treatments do not reduce the underlying damage and have substantial side effects and risks. Nevertheless, “quick and effective reduction of pain can allow patients to more easily move, stretch, and breathe ... important to increase oxygenation and restore blood flow, which will eventually abate the crisis,” Dr. Kanter wrote. 

The study shows that the infusion center treatment approach can benefit patients across different settings, commented John J. Strouse, MD, PhD, medical director of the adult sickle cell program at Duke University Sickle Cell Center, Durham, N.C., who was not involved in the study. 

“They show that they can definitely get closer to the recommendations of guidelines for acute pain management and sickle cell disease” in a setting that is focused on one problem, he said. “The other piece that is really important is that people are much more likely to go home if you follow the guideline.”
 

Infusion centers are scarce

“These systems need to be built,” Dr. Lanzkron said. “In most places, patients don’t have access to the infusion center model for their care. And in some places, it is not going to be practical.” Still, there may be ways to establish infusion locations, such as at oncology centers. And while there are challenges to delivering sickle cell disease care in EDs, “emergency rooms need to try to meet the needs of this patient population as best as they can,” Dr. Lanzkron said.

“Structural racism has played a role in the quality of care delivered” to patients with sickle cell disease, Dr. Lanzkron said. “The big message is [that] there is a better way to do this.” 

The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Lanzkron’s disclosures included grants or contracts with government agencies and companies that are paid to her institution, as well as consulting fees from Bluebird Bio, Novo Nordisk, and Pfizer. Coauthors have disclosed working with sickle cell organizations and various medical companies. Dr. Kanter and Dr. Strouse have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adults with sickle cell disease who experienced a vaso-occlusive crisis had substantially better outcomes when they were treated at specialty infusion centers than those treated in emergency departments (EDs), a prospective observational study shows.

At infusion centers, patients received pain medication an average of 70 minutes faster compared with patients treated in EDs (62 vs. 132 minutes), according to a study published online in the Annals of Internal Medicine. In addition, patients at infusion centers were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose. And they were 4 times more likely to be discharged home, the researchers found.

“It’s not that the emergency room doctors don’t want to do the right thing,” study author Sophie Lanzkron, MD, said in an interview. “They do, but they aren’t experts in sickle cell disease. They work in an emergency room, which is an incredibly busy, stressful place where they see trauma and heart attacks and strokes and all of these things that need emergency care. And so it just is not the right setting to treat people with sickle cell disease.”

To assess whether care at specialty infusion centers or EDs leads to better outcomes for patients with sickle cell disease with uncomplicated vaso-occlusive crises, Dr. Lanzkron, director of the Sickle Cell Center for Adults at the Johns Hopkins Hospital, Baltimore, and colleagues conducted the ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital) study.

The trial included 483 adults with sickle cell disease who lived within 60 miles of an infusion center in four U.S. cities: Baltimore, Maryland; Cleveland, Ohio; Milwaukee, Wisconsin; and Baton Rouge, Louisiana. Investigators recruited patients between April 2015 and December 2016 and followed them for 18 months after enrollment.

The present analysis focused on data from 269 participants who had infusion center visits or ED visits that occurred during weekdays when infusion centers were open. Two sites had infusion centers solely for adults with sickle cell disease (Baltimore and Milwaukee), and two infusion centers shared infusion space with other hematology-oncology patients. All four sites were in hospitals that also had EDs. 

Although participants may have received comprehensive care at one of the sites with an infusion center, those who lived farther from an infusion center were likely to receive care for acute pain at an ED closer to home, the authors explain in the article.

The investigators used propensity score methodology to balance patient characteristics in the study groups.
 

Quick, effective pain reduction is beneficial

The results suggest that infusion centers “are more likely to provide guideline-based care than EDs,” and this care “can improve overall outcomes,” the authors write. 

Although the specialty infusion centers the researchers studied used various models, similar outcomes were seen at all of them.

The study did not include patients who had complications of sickle cell disease in addition to vaso-occlusive crisis, the researchers note. 

“[Because] the magnitude of the treatment effects estimated in our study is large and we have captured most of the important potential confounders, an unmeasured confounder that can nullify the treatment effect is unlikely to exist,” the authors write. 

“Sickle cell disease is a complicated condition that affects multiple organs. Patients who present with acute pain will have better outcomes being treated under providers who know and understand the disease,” commented Julie Kanter, MD, director of the adult sickle cell disease program and codirector of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham. “Specialized infusion centers offer the opportunity to both improve outcomes and decrease the cost of care. Most importantly, it is better for the individual with sickle cell disease,” she said.

Dr. Kanter wrote an accompanying editorial about the ESCAPED findings. The editorialist notes that “opioid medications are the only option to reduce the pain caused by microvascular injury” in patients with sickle cell crisis, although these treatments do not reduce the underlying damage and have substantial side effects and risks. Nevertheless, “quick and effective reduction of pain can allow patients to more easily move, stretch, and breathe ... important to increase oxygenation and restore blood flow, which will eventually abate the crisis,” Dr. Kanter wrote. 

The study shows that the infusion center treatment approach can benefit patients across different settings, commented John J. Strouse, MD, PhD, medical director of the adult sickle cell program at Duke University Sickle Cell Center, Durham, N.C., who was not involved in the study. 

“They show that they can definitely get closer to the recommendations of guidelines for acute pain management and sickle cell disease” in a setting that is focused on one problem, he said. “The other piece that is really important is that people are much more likely to go home if you follow the guideline.”
 

Infusion centers are scarce

“These systems need to be built,” Dr. Lanzkron said. “In most places, patients don’t have access to the infusion center model for their care. And in some places, it is not going to be practical.” Still, there may be ways to establish infusion locations, such as at oncology centers. And while there are challenges to delivering sickle cell disease care in EDs, “emergency rooms need to try to meet the needs of this patient population as best as they can,” Dr. Lanzkron said.

“Structural racism has played a role in the quality of care delivered” to patients with sickle cell disease, Dr. Lanzkron said. “The big message is [that] there is a better way to do this.” 

The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Lanzkron’s disclosures included grants or contracts with government agencies and companies that are paid to her institution, as well as consulting fees from Bluebird Bio, Novo Nordisk, and Pfizer. Coauthors have disclosed working with sickle cell organizations and various medical companies. Dr. Kanter and Dr. Strouse have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Adults with sickle cell disease who experienced a vaso-occlusive crisis had substantially better outcomes when they were treated at specialty infusion centers than those treated in emergency departments (EDs), a prospective observational study shows.

At infusion centers, patients received pain medication an average of 70 minutes faster compared with patients treated in EDs (62 vs. 132 minutes), according to a study published online in the Annals of Internal Medicine. In addition, patients at infusion centers were 3.8 times more likely to have their pain reassessed within 30 minutes of the first dose. And they were 4 times more likely to be discharged home, the researchers found.

“It’s not that the emergency room doctors don’t want to do the right thing,” study author Sophie Lanzkron, MD, said in an interview. “They do, but they aren’t experts in sickle cell disease. They work in an emergency room, which is an incredibly busy, stressful place where they see trauma and heart attacks and strokes and all of these things that need emergency care. And so it just is not the right setting to treat people with sickle cell disease.”

To assess whether care at specialty infusion centers or EDs leads to better outcomes for patients with sickle cell disease with uncomplicated vaso-occlusive crises, Dr. Lanzkron, director of the Sickle Cell Center for Adults at the Johns Hopkins Hospital, Baltimore, and colleagues conducted the ESCAPED (Examining Sickle Cell Acute Pain in the Emergency vs. Day Hospital) study.

The trial included 483 adults with sickle cell disease who lived within 60 miles of an infusion center in four U.S. cities: Baltimore, Maryland; Cleveland, Ohio; Milwaukee, Wisconsin; and Baton Rouge, Louisiana. Investigators recruited patients between April 2015 and December 2016 and followed them for 18 months after enrollment.

The present analysis focused on data from 269 participants who had infusion center visits or ED visits that occurred during weekdays when infusion centers were open. Two sites had infusion centers solely for adults with sickle cell disease (Baltimore and Milwaukee), and two infusion centers shared infusion space with other hematology-oncology patients. All four sites were in hospitals that also had EDs. 

Although participants may have received comprehensive care at one of the sites with an infusion center, those who lived farther from an infusion center were likely to receive care for acute pain at an ED closer to home, the authors explain in the article.

The investigators used propensity score methodology to balance patient characteristics in the study groups.
 

Quick, effective pain reduction is beneficial

The results suggest that infusion centers “are more likely to provide guideline-based care than EDs,” and this care “can improve overall outcomes,” the authors write. 

Although the specialty infusion centers the researchers studied used various models, similar outcomes were seen at all of them.

The study did not include patients who had complications of sickle cell disease in addition to vaso-occlusive crisis, the researchers note. 

“[Because] the magnitude of the treatment effects estimated in our study is large and we have captured most of the important potential confounders, an unmeasured confounder that can nullify the treatment effect is unlikely to exist,” the authors write. 

“Sickle cell disease is a complicated condition that affects multiple organs. Patients who present with acute pain will have better outcomes being treated under providers who know and understand the disease,” commented Julie Kanter, MD, director of the adult sickle cell disease program and codirector of the Comprehensive Sickle Cell Center at the University of Alabama at Birmingham. “Specialized infusion centers offer the opportunity to both improve outcomes and decrease the cost of care. Most importantly, it is better for the individual with sickle cell disease,” she said.

Dr. Kanter wrote an accompanying editorial about the ESCAPED findings. The editorialist notes that “opioid medications are the only option to reduce the pain caused by microvascular injury” in patients with sickle cell crisis, although these treatments do not reduce the underlying damage and have substantial side effects and risks. Nevertheless, “quick and effective reduction of pain can allow patients to more easily move, stretch, and breathe ... important to increase oxygenation and restore blood flow, which will eventually abate the crisis,” Dr. Kanter wrote. 

The study shows that the infusion center treatment approach can benefit patients across different settings, commented John J. Strouse, MD, PhD, medical director of the adult sickle cell program at Duke University Sickle Cell Center, Durham, N.C., who was not involved in the study. 

“They show that they can definitely get closer to the recommendations of guidelines for acute pain management and sickle cell disease” in a setting that is focused on one problem, he said. “The other piece that is really important is that people are much more likely to go home if you follow the guideline.”
 

Infusion centers are scarce

“These systems need to be built,” Dr. Lanzkron said. “In most places, patients don’t have access to the infusion center model for their care. And in some places, it is not going to be practical.” Still, there may be ways to establish infusion locations, such as at oncology centers. And while there are challenges to delivering sickle cell disease care in EDs, “emergency rooms need to try to meet the needs of this patient population as best as they can,” Dr. Lanzkron said.

“Structural racism has played a role in the quality of care delivered” to patients with sickle cell disease, Dr. Lanzkron said. “The big message is [that] there is a better way to do this.” 

The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Lanzkron’s disclosures included grants or contracts with government agencies and companies that are paid to her institution, as well as consulting fees from Bluebird Bio, Novo Nordisk, and Pfizer. Coauthors have disclosed working with sickle cell organizations and various medical companies. Dr. Kanter and Dr. Strouse have reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Breast and cervical cancer screenings declined sharply in the early months of the COVID-19 pandemic, particularly among certain racial and ethnic minority groups and rural populations, notes the U.S. Centers for Disease Control and Prevention.

The new data come from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), a program that provides cancer screening services to women with low income and inadequate health insurance.

The data show that the total number of screenings funded by the NBCCEDP declined by 87% for breast cancer screening and by 84% for cervical cancer screening in April 2020 in comparison with the previous 5-year averages for that month.

The declines in breast cancer screening varied from 84% among Hispanic women to 98% among American Indian/Alaskan Native women. The declines in cervical cancer screening varied from 82% among Black women to 92% among Asian Pacific Islander women.

In April 2020, breast cancer screening declined by 86% in metro areas, 88% in urban areas, and 89% in rural areas in comparison with respective 5-year averages. For cervical cancer screenings, the corresponding declines were 85%, 77%, and 82%.

The findings are consistent with those from studies conducted in insured populations, note the authors, led by the Amy DeGroff, PhD, MPH, of the CDC’s National Center for Chronic Disease Prevention and Health Promotion.

“Prolonged delays in screening related to the COVID-19 pandemic may lead to delayed diagnoses, poor health consequences, and an increase in cancer disparities among women already experiencing health inequities,” the CDC states in a press release.

Women from racial and ethnic minority groups already face a disproportionate burden of cervical and breast cancers in the United States: Black women and Hispanic women have the highest rates of cervical cancer incidence (8.3 and 8.9 per 100,000 women, respectively, vs. 7.3 per 100,000 among White women) and the highest rates of cervical cancer deaths. Black women have the highest rate of breast cancer death (26.9 per 100,000 women, vs. 19.4 per 100,000 among White women), the study authors explain.

Although the volume of screening began to recover in May 2020 – test volumes for breast and cervical cancer were 39% and 40% below the 5-year average by June 2020 – breast cancer screening in rural areas remained 52% below the 5-year average, they report.

The findings were published online June 30 in Preventive Medicine.

“This study highlights a decline in cancer screening among women of racial and ethnic minority groups with low incomes when their access to medical services decreased at the beginning of the pandemic,” Dr. DeGroff comments in the CDC press release.

The findings “reinforce the need to safely maintain routine health care services during the pandemic, especially when the health care environment meets COVID-19 safety guidelines,” she adds.

The investigators used NBCCEDP administrative and program data reported to the CDC by awardees – organizations that receive funding to implement the NBCCEDP – to assess the impact of COVID-19 on the number of breast and cervical cancer screening tests administered through the program and the effects of COVID-19 on the availability of screening services and NBCCEDP awardees’ capacity to support partner clinics.

A total of 630,264 breast and 594,566 cervical cancer screening tests were conducted during the review period of January-June 2015-2020.

Despite COVID-related challenges, “a large number of awardees reported flexibility and creative efforts to reach women and support clinics’ resumption of clinical care, including screening, during the COVID-19 pandemic,” the authors write.

“[The] CDC encourages health care professionals to help minimize delays in testing by continuing routine cancer screening for women having symptoms or at high risk for breast or cervical cancer,” Dr. DeGroff commented. “The Early Detection Program can help women overcome barriers to health equity by educating them about the importance of routine screening, addressing their concerns about COVID-19 transmission, and helping them to safely access screening through interventions like patient navigation.”

Future studies will examine the effect of the pandemic on screening during the second half of 2020, when surges of COVID-19 and their timing varied geographically, they note.

A version of this article first appeared on Medscape.com.

Breast and cervical cancer screenings declined sharply in the early months of the COVID-19 pandemic, particularly among certain racial and ethnic minority groups and rural populations, notes the U.S. Centers for Disease Control and Prevention.

The new data come from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), a program that provides cancer screening services to women with low income and inadequate health insurance.

The data show that the total number of screenings funded by the NBCCEDP declined by 87% for breast cancer screening and by 84% for cervical cancer screening in April 2020 in comparison with the previous 5-year averages for that month.

The declines in breast cancer screening varied from 84% among Hispanic women to 98% among American Indian/Alaskan Native women. The declines in cervical cancer screening varied from 82% among Black women to 92% among Asian Pacific Islander women.

In April 2020, breast cancer screening declined by 86% in metro areas, 88% in urban areas, and 89% in rural areas in comparison with respective 5-year averages. For cervical cancer screenings, the corresponding declines were 85%, 77%, and 82%.

The findings are consistent with those from studies conducted in insured populations, note the authors, led by the Amy DeGroff, PhD, MPH, of the CDC’s National Center for Chronic Disease Prevention and Health Promotion.

“Prolonged delays in screening related to the COVID-19 pandemic may lead to delayed diagnoses, poor health consequences, and an increase in cancer disparities among women already experiencing health inequities,” the CDC states in a press release.

Women from racial and ethnic minority groups already face a disproportionate burden of cervical and breast cancers in the United States: Black women and Hispanic women have the highest rates of cervical cancer incidence (8.3 and 8.9 per 100,000 women, respectively, vs. 7.3 per 100,000 among White women) and the highest rates of cervical cancer deaths. Black women have the highest rate of breast cancer death (26.9 per 100,000 women, vs. 19.4 per 100,000 among White women), the study authors explain.

Although the volume of screening began to recover in May 2020 – test volumes for breast and cervical cancer were 39% and 40% below the 5-year average by June 2020 – breast cancer screening in rural areas remained 52% below the 5-year average, they report.

The findings were published online June 30 in Preventive Medicine.

“This study highlights a decline in cancer screening among women of racial and ethnic minority groups with low incomes when their access to medical services decreased at the beginning of the pandemic,” Dr. DeGroff comments in the CDC press release.

The findings “reinforce the need to safely maintain routine health care services during the pandemic, especially when the health care environment meets COVID-19 safety guidelines,” she adds.

The investigators used NBCCEDP administrative and program data reported to the CDC by awardees – organizations that receive funding to implement the NBCCEDP – to assess the impact of COVID-19 on the number of breast and cervical cancer screening tests administered through the program and the effects of COVID-19 on the availability of screening services and NBCCEDP awardees’ capacity to support partner clinics.

A total of 630,264 breast and 594,566 cervical cancer screening tests were conducted during the review period of January-June 2015-2020.

Despite COVID-related challenges, “a large number of awardees reported flexibility and creative efforts to reach women and support clinics’ resumption of clinical care, including screening, during the COVID-19 pandemic,” the authors write.

“[The] CDC encourages health care professionals to help minimize delays in testing by continuing routine cancer screening for women having symptoms or at high risk for breast or cervical cancer,” Dr. DeGroff commented. “The Early Detection Program can help women overcome barriers to health equity by educating them about the importance of routine screening, addressing their concerns about COVID-19 transmission, and helping them to safely access screening through interventions like patient navigation.”

Future studies will examine the effect of the pandemic on screening during the second half of 2020, when surges of COVID-19 and their timing varied geographically, they note.

A version of this article first appeared on Medscape.com.

Breast and cervical cancer screenings declined sharply in the early months of the COVID-19 pandemic, particularly among certain racial and ethnic minority groups and rural populations, notes the U.S. Centers for Disease Control and Prevention.

The new data come from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP), a program that provides cancer screening services to women with low income and inadequate health insurance.

The data show that the total number of screenings funded by the NBCCEDP declined by 87% for breast cancer screening and by 84% for cervical cancer screening in April 2020 in comparison with the previous 5-year averages for that month.

The declines in breast cancer screening varied from 84% among Hispanic women to 98% among American Indian/Alaskan Native women. The declines in cervical cancer screening varied from 82% among Black women to 92% among Asian Pacific Islander women.

In April 2020, breast cancer screening declined by 86% in metro areas, 88% in urban areas, and 89% in rural areas in comparison with respective 5-year averages. For cervical cancer screenings, the corresponding declines were 85%, 77%, and 82%.

The findings are consistent with those from studies conducted in insured populations, note the authors, led by the Amy DeGroff, PhD, MPH, of the CDC’s National Center for Chronic Disease Prevention and Health Promotion.

“Prolonged delays in screening related to the COVID-19 pandemic may lead to delayed diagnoses, poor health consequences, and an increase in cancer disparities among women already experiencing health inequities,” the CDC states in a press release.

Women from racial and ethnic minority groups already face a disproportionate burden of cervical and breast cancers in the United States: Black women and Hispanic women have the highest rates of cervical cancer incidence (8.3 and 8.9 per 100,000 women, respectively, vs. 7.3 per 100,000 among White women) and the highest rates of cervical cancer deaths. Black women have the highest rate of breast cancer death (26.9 per 100,000 women, vs. 19.4 per 100,000 among White women), the study authors explain.

Although the volume of screening began to recover in May 2020 – test volumes for breast and cervical cancer were 39% and 40% below the 5-year average by June 2020 – breast cancer screening in rural areas remained 52% below the 5-year average, they report.

The findings were published online June 30 in Preventive Medicine.

“This study highlights a decline in cancer screening among women of racial and ethnic minority groups with low incomes when their access to medical services decreased at the beginning of the pandemic,” Dr. DeGroff comments in the CDC press release.

The findings “reinforce the need to safely maintain routine health care services during the pandemic, especially when the health care environment meets COVID-19 safety guidelines,” she adds.

The investigators used NBCCEDP administrative and program data reported to the CDC by awardees – organizations that receive funding to implement the NBCCEDP – to assess the impact of COVID-19 on the number of breast and cervical cancer screening tests administered through the program and the effects of COVID-19 on the availability of screening services and NBCCEDP awardees’ capacity to support partner clinics.

A total of 630,264 breast and 594,566 cervical cancer screening tests were conducted during the review period of January-June 2015-2020.

Despite COVID-related challenges, “a large number of awardees reported flexibility and creative efforts to reach women and support clinics’ resumption of clinical care, including screening, during the COVID-19 pandemic,” the authors write.

“[The] CDC encourages health care professionals to help minimize delays in testing by continuing routine cancer screening for women having symptoms or at high risk for breast or cervical cancer,” Dr. DeGroff commented. “The Early Detection Program can help women overcome barriers to health equity by educating them about the importance of routine screening, addressing their concerns about COVID-19 transmission, and helping them to safely access screening through interventions like patient navigation.”

Future studies will examine the effect of the pandemic on screening during the second half of 2020, when surges of COVID-19 and their timing varied geographically, they note.

A version of this article first appeared on Medscape.com.

No link between fertility treatment and an increase in the risk for breast cancer was found in the largest study of the issue to date.

This study “provides the evidence needed to reassure women and couples seeking fertility treatments,” commented senior author Sesh Sunkara, MD, a reproductive medicine specialist at King’s College London in a press release.

With an increasing number of women seeking help to become mothers, the question “is a matter of great importance” and a source of considerable concern among patients, the study authors comment.

This is the largest meta-analysis to date, involving 1.8 million women who were followed for an average of 27 years. The investigators found no link with the use of gonadotropins or clomiphene citrate to increase egg production in fertility cycles.

There has been concern over the years that fertility treatment could stimulate estrogen-sensitive precursor breast cancer cells.

More than 4,000 studies of this issue have been conducted since 1990, and results have been conflicting. The investigators analyzed results from the 20 strongest ones.

The new meta-analysis included nine retrospective studies, five case-control studies, five prospective studies, and one comparative study

The team cautioned that the quality of evidence in even these top 20 studies was “very low” but that such an approach is perhaps the best possible on this issue because a randomized trial among women seeking help to have children would be “ethically challenging.”

In the study, the team compared breast cancer incidence among women who underwent ovarian stimulation with the incidence in both age-matched unexposed women in the general population and unexposed infertile women.

There was no significant increase in the risk for breast cancer among women treated with any ovarian stimulation drug (pooled odds ratio, 1.03; 95% confidence interval, 0.86-1.23, but with substantial heterogeneity between study outcomes).

There was also no increased risk when the analysis was limited to the eight studies in which women were treated with both gonadotropins and clomiphene citrate (pooled OR, 0.92; 95% CI, 0.52-1.60, with substantial heterogeneity).

The authors noted that, among the many study limitations, no distinction was made between physiological dosing for anovulation and supraphysiological dosing for in vitro fertilization cycles. In addition, because the treated women were generally young, the follow-up period fell short of the age at which they’d be most at risk for breast cancer.

Individual patient data were also not available, but 14 studies did adjust for confounders, including weight, race, parity, age at first birth, age at menarche, and family history of breast cancer.

Although the findings are reassuring, “further long-term and detailed studies are now needed to confirm” them, Kotryna Temcinaite, PhD, senior research communications manager at the U.K. charity Breast Cancer Now, said in the press release.

A version of this article first appeared on Medscape.com.

No link between fertility treatment and an increase in the risk for breast cancer was found in the largest study of the issue to date.

This study “provides the evidence needed to reassure women and couples seeking fertility treatments,” commented senior author Sesh Sunkara, MD, a reproductive medicine specialist at King’s College London in a press release.

With an increasing number of women seeking help to become mothers, the question “is a matter of great importance” and a source of considerable concern among patients, the study authors comment.

This is the largest meta-analysis to date, involving 1.8 million women who were followed for an average of 27 years. The investigators found no link with the use of gonadotropins or clomiphene citrate to increase egg production in fertility cycles.

There has been concern over the years that fertility treatment could stimulate estrogen-sensitive precursor breast cancer cells.

More than 4,000 studies of this issue have been conducted since 1990, and results have been conflicting. The investigators analyzed results from the 20 strongest ones.

The new meta-analysis included nine retrospective studies, five case-control studies, five prospective studies, and one comparative study

The team cautioned that the quality of evidence in even these top 20 studies was “very low” but that such an approach is perhaps the best possible on this issue because a randomized trial among women seeking help to have children would be “ethically challenging.”

In the study, the team compared breast cancer incidence among women who underwent ovarian stimulation with the incidence in both age-matched unexposed women in the general population and unexposed infertile women.

There was no significant increase in the risk for breast cancer among women treated with any ovarian stimulation drug (pooled odds ratio, 1.03; 95% confidence interval, 0.86-1.23, but with substantial heterogeneity between study outcomes).

There was also no increased risk when the analysis was limited to the eight studies in which women were treated with both gonadotropins and clomiphene citrate (pooled OR, 0.92; 95% CI, 0.52-1.60, with substantial heterogeneity).

The authors noted that, among the many study limitations, no distinction was made between physiological dosing for anovulation and supraphysiological dosing for in vitro fertilization cycles. In addition, because the treated women were generally young, the follow-up period fell short of the age at which they’d be most at risk for breast cancer.

Individual patient data were also not available, but 14 studies did adjust for confounders, including weight, race, parity, age at first birth, age at menarche, and family history of breast cancer.

Although the findings are reassuring, “further long-term and detailed studies are now needed to confirm” them, Kotryna Temcinaite, PhD, senior research communications manager at the U.K. charity Breast Cancer Now, said in the press release.

A version of this article first appeared on Medscape.com.

No link between fertility treatment and an increase in the risk for breast cancer was found in the largest study of the issue to date.

This study “provides the evidence needed to reassure women and couples seeking fertility treatments,” commented senior author Sesh Sunkara, MD, a reproductive medicine specialist at King’s College London in a press release.

With an increasing number of women seeking help to become mothers, the question “is a matter of great importance” and a source of considerable concern among patients, the study authors comment.

This is the largest meta-analysis to date, involving 1.8 million women who were followed for an average of 27 years. The investigators found no link with the use of gonadotropins or clomiphene citrate to increase egg production in fertility cycles.

There has been concern over the years that fertility treatment could stimulate estrogen-sensitive precursor breast cancer cells.

More than 4,000 studies of this issue have been conducted since 1990, and results have been conflicting. The investigators analyzed results from the 20 strongest ones.

The new meta-analysis included nine retrospective studies, five case-control studies, five prospective studies, and one comparative study

The team cautioned that the quality of evidence in even these top 20 studies was “very low” but that such an approach is perhaps the best possible on this issue because a randomized trial among women seeking help to have children would be “ethically challenging.”

In the study, the team compared breast cancer incidence among women who underwent ovarian stimulation with the incidence in both age-matched unexposed women in the general population and unexposed infertile women.

There was no significant increase in the risk for breast cancer among women treated with any ovarian stimulation drug (pooled odds ratio, 1.03; 95% confidence interval, 0.86-1.23, but with substantial heterogeneity between study outcomes).

There was also no increased risk when the analysis was limited to the eight studies in which women were treated with both gonadotropins and clomiphene citrate (pooled OR, 0.92; 95% CI, 0.52-1.60, with substantial heterogeneity).

The authors noted that, among the many study limitations, no distinction was made between physiological dosing for anovulation and supraphysiological dosing for in vitro fertilization cycles. In addition, because the treated women were generally young, the follow-up period fell short of the age at which they’d be most at risk for breast cancer.

Individual patient data were also not available, but 14 studies did adjust for confounders, including weight, race, parity, age at first birth, age at menarche, and family history of breast cancer.

Although the findings are reassuring, “further long-term and detailed studies are now needed to confirm” them, Kotryna Temcinaite, PhD, senior research communications manager at the U.K. charity Breast Cancer Now, said in the press release.

A version of this article first appeared on Medscape.com.

Women who were Black, Latina, American Indian, or Alaska Native were significantly less likely than White women to receive guidelines-adherent treatment for endometrial cancer, based on data from more than 80,000 women.

The incidence of uterine cancer has increased across all ethnicities in recent decades, and adherence to the National Comprehensive Cancer Network treatment guidelines has been associated with improved survival, wrote Victoria A. Rodriguez, MSW, MPH, of the University of California, Irvine, and colleagues. “To date, however, there are few studies that have looked at endometrial cancer disparities with adherence to National Comprehensive Cancer Network treatment guidelines.”

In a retrospective study published in Obstetrics & Gynecology, the researchers used data from the SEER (Surveillance, Epidemiology, and End Results) database between Jan. 1, 2006, and Dec. 31, 2015. The study population included 83,883 women aged 18 years and older who were diagnosed with their first or only endometrial carcinoma. The primary dependent variable was adherence to the NCCN guidelines for the initial course of treatment, which included a combination of therapies based on cancer subtype and the extent of the disease, the researchers said.

The researchers combined the guidelines and the corresponding data from the SEER database to create “a binary variable representing adherence to [NCCN] guidelines (1 = adherent treatment, 0 = nonadherent treatment).”

Approximately 60% of the total patient population received guidelines-adherent treatment. In a multivariate analysis, Black women, Latina women, and American Indian or Alaska Native women were significantly less likely than White women to receive such treatment (odds ratios, 0.88, 0.92, and 0.82, respectively), controlling for factors including neighborhood socioeconomic status, age, and stage at diagnosis, year of diagnosis, histology, and disease grade. Asian women and Native Hawaiian/Pacific Islander women were significantly more likely to received guidelines-adherent treatment, compared with White women (OR, 1.14 and 1.19, respectively).

The researchers also found a significant gradient in guidelines-adherent treatment based on neighborhood socioeconomic status. Relative to the highest neighborhood socioeconomic status group, women in the lower groups had significantly lower odds of receiving guidelines-adherent treatment, with ORs of 0.89, 0.84, 0.80, and 0.73, respectively, for the high-middle neighborhood socioeconomic group, the middle group, the low-middle group, and the lowest group (P < .001 for all).

“Our study is novel in that it examines neighborhood socioeconomic disparities in the understudied context of treatment adherence for endometrial cancer,” the researchers noted.

The study findings were limited by several factors in including the retrospective design and potential for unmeasured confounding variables not included in SEER, such as hospital and physician characteristics, the researchers said. Also, the SEER data set was limited to only the first course of treatment, and did not include information on patient comorbidities that might affect treatment.

“Future research should qualitatively explore reasons for nonadherent treatment within endometrial cancer and other cancer sites among various racial-ethnic groups and socioeconomic status groups, with special attention to low-income women of color,” the researchers emphasized. More research on the impact of comorbidities on a patient’s ability to receive guidelines-based care should be used to inform whether comorbidities should be part of the NCCN guidelines.

However, the results were strengthened by the large sample size and diverse population, so the findings are generalizable to the overall U.S. population, the researchers said.

“Interventions are needed to ensure that equitable cancer treatment practices are available for all individuals regardless of their racial-ethnic or socioeconomic backgrounds,” they concluded.
 

Pursue optimal treatment to curb mortality

Even more concerning than the increase in the incidence of endometrial cancer in the United States is the increase in mortality from this disease, said Emma C. Rossi, MD, of the University of North Carolina at Chapel Hill, in an interview.

“Therefore, it is critical that we identify factors which might be contributing to the increasing lethality of this cancer,” she emphasized. “One such potential factor is race, as it has been observed that Black race is associated with an increased risk of death from endometrial cancer. Historically, this was attributed to the more aggressive subtypes of endometrial cancer (such as serous) which have a higher incidence among Black women. However, more recently, population-based studies have identified that this worse prognosis is independent of histologic cell type,” which suggests that something in our health care delivery is contributing to these worse outcomes.

“The present study helps to confirm these concerning associations, shedding some light on contributory factors, in this case, modifiable (adherence to recommended guidelines) and less modifiable (neighborhood socioeconomic environments) [ones],” Dr. Rossi noted. “The guidelines that are established by the NCCN are chosen after they have been shown to be associated with improved outcomes (including either survival or quality of life), and therefore lack of adherence to these outcomes may suggest inferior quality care is being delivered.”

Studies such as this are helpful in exposing the problem of treatment disparity to help identify sources of problems to develop solutions, she added.

The results should inspire clinicians “to feel agency in changing these outcomes, albeit by tackling very difficult social, political, and health system shortfalls,” she said.
 

Identify barriers to care

Barriers to greater adherence to guidelines-based care include varying definitions of such care, Dr. Rossi said.

“This is particularly true for surgical management of endometrial cancer, which remains controversial with respect to lymph node assessment. Lack of surgical staging with lymph node assessment was considered noncompliant care for this study; however, lymphadenectomy has not specifically, in and of itself, been associated with improved outcomes, and therefore some surgeons argue against performing it routinely,” she explained.

“Lack of access to sophisticated surgical tools and advanced surgical techniques may account for nonguidelines-based care in the patients with early-stage endometrial cancer; however, there are likely other differences in the ability to deliver guideline-concordant care (such as chemotherapy and radiation therapy) for advanced-stage cancers,” Dr. Rossi said. “Patient and provider positive attitudes toward adjuvant therapy, access to transportation, supportive home environments, paid sick leave, well-controlled or minimal comorbidities are all factors which promote the administration of complex adjuvant therapies such as chemotherapy and radiation. In low-resource neighborhoods and minority communities, barriers to these factors may be contributing to nonguidelines-concordant care.”

Dr. Rossi emphasized the need to “dive deeper into these data at individual health-system and provider levels.” For example, research is needed to compare the practice patterns and models of high-performing clinical practices with lower-performing practices in terms of factors such as tumor boards, journal review, peer review, dashboards, and metrics. By doing so, “we can ensure that we are understanding where and why variations in care are occurring,” Dr. Rossi said.

The study was supported in part by the Faculty Mentor Program Fellowship from the University of California, Irvine, graduate division. Ms. Rodriguez was supported in part by a grant from the National Cancer Institute. The researchers had no financial conflicts to disclose. Dr. Rossi had no financial conflicts to disclose.

Women who were Black, Latina, American Indian, or Alaska Native were significantly less likely than White women to receive guidelines-adherent treatment for endometrial cancer, based on data from more than 80,000 women.

The incidence of uterine cancer has increased across all ethnicities in recent decades, and adherence to the National Comprehensive Cancer Network treatment guidelines has been associated with improved survival, wrote Victoria A. Rodriguez, MSW, MPH, of the University of California, Irvine, and colleagues. “To date, however, there are few studies that have looked at endometrial cancer disparities with adherence to National Comprehensive Cancer Network treatment guidelines.”

In a retrospective study published in Obstetrics & Gynecology, the researchers used data from the SEER (Surveillance, Epidemiology, and End Results) database between Jan. 1, 2006, and Dec. 31, 2015. The study population included 83,883 women aged 18 years and older who were diagnosed with their first or only endometrial carcinoma. The primary dependent variable was adherence to the NCCN guidelines for the initial course of treatment, which included a combination of therapies based on cancer subtype and the extent of the disease, the researchers said.

The researchers combined the guidelines and the corresponding data from the SEER database to create “a binary variable representing adherence to [NCCN] guidelines (1 = adherent treatment, 0 = nonadherent treatment).”

Approximately 60% of the total patient population received guidelines-adherent treatment. In a multivariate analysis, Black women, Latina women, and American Indian or Alaska Native women were significantly less likely than White women to receive such treatment (odds ratios, 0.88, 0.92, and 0.82, respectively), controlling for factors including neighborhood socioeconomic status, age, and stage at diagnosis, year of diagnosis, histology, and disease grade. Asian women and Native Hawaiian/Pacific Islander women were significantly more likely to received guidelines-adherent treatment, compared with White women (OR, 1.14 and 1.19, respectively).

The researchers also found a significant gradient in guidelines-adherent treatment based on neighborhood socioeconomic status. Relative to the highest neighborhood socioeconomic status group, women in the lower groups had significantly lower odds of receiving guidelines-adherent treatment, with ORs of 0.89, 0.84, 0.80, and 0.73, respectively, for the high-middle neighborhood socioeconomic group, the middle group, the low-middle group, and the lowest group (P < .001 for all).

“Our study is novel in that it examines neighborhood socioeconomic disparities in the understudied context of treatment adherence for endometrial cancer,” the researchers noted.

The study findings were limited by several factors in including the retrospective design and potential for unmeasured confounding variables not included in SEER, such as hospital and physician characteristics, the researchers said. Also, the SEER data set was limited to only the first course of treatment, and did not include information on patient comorbidities that might affect treatment.

“Future research should qualitatively explore reasons for nonadherent treatment within endometrial cancer and other cancer sites among various racial-ethnic groups and socioeconomic status groups, with special attention to low-income women of color,” the researchers emphasized. More research on the impact of comorbidities on a patient’s ability to receive guidelines-based care should be used to inform whether comorbidities should be part of the NCCN guidelines.

However, the results were strengthened by the large sample size and diverse population, so the findings are generalizable to the overall U.S. population, the researchers said.

“Interventions are needed to ensure that equitable cancer treatment practices are available for all individuals regardless of their racial-ethnic or socioeconomic backgrounds,” they concluded.
 

Pursue optimal treatment to curb mortality

Even more concerning than the increase in the incidence of endometrial cancer in the United States is the increase in mortality from this disease, said Emma C. Rossi, MD, of the University of North Carolina at Chapel Hill, in an interview.

“Therefore, it is critical that we identify factors which might be contributing to the increasing lethality of this cancer,” she emphasized. “One such potential factor is race, as it has been observed that Black race is associated with an increased risk of death from endometrial cancer. Historically, this was attributed to the more aggressive subtypes of endometrial cancer (such as serous) which have a higher incidence among Black women. However, more recently, population-based studies have identified that this worse prognosis is independent of histologic cell type,” which suggests that something in our health care delivery is contributing to these worse outcomes.

“The present study helps to confirm these concerning associations, shedding some light on contributory factors, in this case, modifiable (adherence to recommended guidelines) and less modifiable (neighborhood socioeconomic environments) [ones],” Dr. Rossi noted. “The guidelines that are established by the NCCN are chosen after they have been shown to be associated with improved outcomes (including either survival or quality of life), and therefore lack of adherence to these outcomes may suggest inferior quality care is being delivered.”

Studies such as this are helpful in exposing the problem of treatment disparity to help identify sources of problems to develop solutions, she added.

The results should inspire clinicians “to feel agency in changing these outcomes, albeit by tackling very difficult social, political, and health system shortfalls,” she said.
 

Identify barriers to care

Barriers to greater adherence to guidelines-based care include varying definitions of such care, Dr. Rossi said.

“This is particularly true for surgical management of endometrial cancer, which remains controversial with respect to lymph node assessment. Lack of surgical staging with lymph node assessment was considered noncompliant care for this study; however, lymphadenectomy has not specifically, in and of itself, been associated with improved outcomes, and therefore some surgeons argue against performing it routinely,” she explained.

“Lack of access to sophisticated surgical tools and advanced surgical techniques may account for nonguidelines-based care in the patients with early-stage endometrial cancer; however, there are likely other differences in the ability to deliver guideline-concordant care (such as chemotherapy and radiation therapy) for advanced-stage cancers,” Dr. Rossi said. “Patient and provider positive attitudes toward adjuvant therapy, access to transportation, supportive home environments, paid sick leave, well-controlled or minimal comorbidities are all factors which promote the administration of complex adjuvant therapies such as chemotherapy and radiation. In low-resource neighborhoods and minority communities, barriers to these factors may be contributing to nonguidelines-concordant care.”

Dr. Rossi emphasized the need to “dive deeper into these data at individual health-system and provider levels.” For example, research is needed to compare the practice patterns and models of high-performing clinical practices with lower-performing practices in terms of factors such as tumor boards, journal review, peer review, dashboards, and metrics. By doing so, “we can ensure that we are understanding where and why variations in care are occurring,” Dr. Rossi said.

The study was supported in part by the Faculty Mentor Program Fellowship from the University of California, Irvine, graduate division. Ms. Rodriguez was supported in part by a grant from the National Cancer Institute. The researchers had no financial conflicts to disclose. Dr. Rossi had no financial conflicts to disclose.

Women who were Black, Latina, American Indian, or Alaska Native were significantly less likely than White women to receive guidelines-adherent treatment for endometrial cancer, based on data from more than 80,000 women.

The incidence of uterine cancer has increased across all ethnicities in recent decades, and adherence to the National Comprehensive Cancer Network treatment guidelines has been associated with improved survival, wrote Victoria A. Rodriguez, MSW, MPH, of the University of California, Irvine, and colleagues. “To date, however, there are few studies that have looked at endometrial cancer disparities with adherence to National Comprehensive Cancer Network treatment guidelines.”

In a retrospective study published in Obstetrics & Gynecology, the researchers used data from the SEER (Surveillance, Epidemiology, and End Results) database between Jan. 1, 2006, and Dec. 31, 2015. The study population included 83,883 women aged 18 years and older who were diagnosed with their first or only endometrial carcinoma. The primary dependent variable was adherence to the NCCN guidelines for the initial course of treatment, which included a combination of therapies based on cancer subtype and the extent of the disease, the researchers said.

The researchers combined the guidelines and the corresponding data from the SEER database to create “a binary variable representing adherence to [NCCN] guidelines (1 = adherent treatment, 0 = nonadherent treatment).”

Approximately 60% of the total patient population received guidelines-adherent treatment. In a multivariate analysis, Black women, Latina women, and American Indian or Alaska Native women were significantly less likely than White women to receive such treatment (odds ratios, 0.88, 0.92, and 0.82, respectively), controlling for factors including neighborhood socioeconomic status, age, and stage at diagnosis, year of diagnosis, histology, and disease grade. Asian women and Native Hawaiian/Pacific Islander women were significantly more likely to received guidelines-adherent treatment, compared with White women (OR, 1.14 and 1.19, respectively).

The researchers also found a significant gradient in guidelines-adherent treatment based on neighborhood socioeconomic status. Relative to the highest neighborhood socioeconomic status group, women in the lower groups had significantly lower odds of receiving guidelines-adherent treatment, with ORs of 0.89, 0.84, 0.80, and 0.73, respectively, for the high-middle neighborhood socioeconomic group, the middle group, the low-middle group, and the lowest group (P < .001 for all).

“Our study is novel in that it examines neighborhood socioeconomic disparities in the understudied context of treatment adherence for endometrial cancer,” the researchers noted.

The study findings were limited by several factors in including the retrospective design and potential for unmeasured confounding variables not included in SEER, such as hospital and physician characteristics, the researchers said. Also, the SEER data set was limited to only the first course of treatment, and did not include information on patient comorbidities that might affect treatment.

“Future research should qualitatively explore reasons for nonadherent treatment within endometrial cancer and other cancer sites among various racial-ethnic groups and socioeconomic status groups, with special attention to low-income women of color,” the researchers emphasized. More research on the impact of comorbidities on a patient’s ability to receive guidelines-based care should be used to inform whether comorbidities should be part of the NCCN guidelines.

However, the results were strengthened by the large sample size and diverse population, so the findings are generalizable to the overall U.S. population, the researchers said.

“Interventions are needed to ensure that equitable cancer treatment practices are available for all individuals regardless of their racial-ethnic or socioeconomic backgrounds,” they concluded.
 

Pursue optimal treatment to curb mortality

Even more concerning than the increase in the incidence of endometrial cancer in the United States is the increase in mortality from this disease, said Emma C. Rossi, MD, of the University of North Carolina at Chapel Hill, in an interview.

“Therefore, it is critical that we identify factors which might be contributing to the increasing lethality of this cancer,” she emphasized. “One such potential factor is race, as it has been observed that Black race is associated with an increased risk of death from endometrial cancer. Historically, this was attributed to the more aggressive subtypes of endometrial cancer (such as serous) which have a higher incidence among Black women. However, more recently, population-based studies have identified that this worse prognosis is independent of histologic cell type,” which suggests that something in our health care delivery is contributing to these worse outcomes.

“The present study helps to confirm these concerning associations, shedding some light on contributory factors, in this case, modifiable (adherence to recommended guidelines) and less modifiable (neighborhood socioeconomic environments) [ones],” Dr. Rossi noted. “The guidelines that are established by the NCCN are chosen after they have been shown to be associated with improved outcomes (including either survival or quality of life), and therefore lack of adherence to these outcomes may suggest inferior quality care is being delivered.”

Studies such as this are helpful in exposing the problem of treatment disparity to help identify sources of problems to develop solutions, she added.

The results should inspire clinicians “to feel agency in changing these outcomes, albeit by tackling very difficult social, political, and health system shortfalls,” she said.
 

Identify barriers to care

Barriers to greater adherence to guidelines-based care include varying definitions of such care, Dr. Rossi said.

“This is particularly true for surgical management of endometrial cancer, which remains controversial with respect to lymph node assessment. Lack of surgical staging with lymph node assessment was considered noncompliant care for this study; however, lymphadenectomy has not specifically, in and of itself, been associated with improved outcomes, and therefore some surgeons argue against performing it routinely,” she explained.

“Lack of access to sophisticated surgical tools and advanced surgical techniques may account for nonguidelines-based care in the patients with early-stage endometrial cancer; however, there are likely other differences in the ability to deliver guideline-concordant care (such as chemotherapy and radiation therapy) for advanced-stage cancers,” Dr. Rossi said. “Patient and provider positive attitudes toward adjuvant therapy, access to transportation, supportive home environments, paid sick leave, well-controlled or minimal comorbidities are all factors which promote the administration of complex adjuvant therapies such as chemotherapy and radiation. In low-resource neighborhoods and minority communities, barriers to these factors may be contributing to nonguidelines-concordant care.”

Dr. Rossi emphasized the need to “dive deeper into these data at individual health-system and provider levels.” For example, research is needed to compare the practice patterns and models of high-performing clinical practices with lower-performing practices in terms of factors such as tumor boards, journal review, peer review, dashboards, and metrics. By doing so, “we can ensure that we are understanding where and why variations in care are occurring,” Dr. Rossi said.

The study was supported in part by the Faculty Mentor Program Fellowship from the University of California, Irvine, graduate division. Ms. Rodriguez was supported in part by a grant from the National Cancer Institute. The researchers had no financial conflicts to disclose. Dr. Rossi had no financial conflicts to disclose.

Individuals diagnosed with primary colorectal cancer (CRC) at less than 50 years of age have better survival outcomes than individuals diagnosed at 51-55 years, based on data from more than 750,000 patients.

This finding emphasizes the importance of early CRC detection in younger individuals, reported lead author En Cheng, MD, PhD, of Yale University, New Haven, Conn., and colleagues.

“Early-onset CRC (i.e., CRC diagnosed at age less than 50 years) has been characterized by unique clinical, genetic, and epigenetic characteristics, and thus it may be associated with different survival from CRC diagnosed among individuals older than 50 years,” the investigators wrote in JAMA Network Open. Previous studies comparing survival times across age groups have yielded inconsistent results.

To gain a better understanding, the investigator conducted a retrospective study using data from the National Cancer Database. Excluding patients with primary CRC who had concomitant diagnosis, history of other malignant tumors, noninvasive adenocarcinoma, or missing data, the final dataset included 769,871 patients. Early-onset CRC was defined by age less than 50 years, whereas later-onset CRC was defined by ages 51-55 years.

“Individuals diagnosed at age 50 years were excluded to minimize an apparent screening detection bias at age 50 years in our population, given that these individuals disproportionately presented with earlier stages,” the investigators wrote.

Initial comparisons across groups revealed several significant differences. Individuals in the early-onset group were more often women (47.3% vs. 43.8%; P < .001), members of races in the “other” category (6.9% vs. 5.9%; P < .001), and Medicaid patients (12.3% vs. 10.3%; P < .001). They were also more likely to be diagnosed with stage IV cancer (27.8% vs 24.1%; P < .001) and have rectal tumors (29.3% vs. 28.7%; P = .004).

In the unadjusted Kaplan-Meier analysis, patients with early-onset CRC had a lower 10-year survival rate (53.6%; 95% CI, 53.2%-54.0% vs. 54.3%; 95% CI, 53.8%-54.8%; P < .001). The fully adjusted model revealed significantly higher survival for early-onset patients, compared with later-onset patients (adjusted hazard ratio, 0.95; 95% CI, 0.93-0.96; P < .001) . This disparity deepened when adjusting only for stage (HR, 0.89; 95% CI, 0.88-0.90; P < .001).

Survival was longest among patients 35-39 years (aHR, 0.88; 95% CI, 0.84-0.92; P < .001), compared with those aged 51-55, and among early-onset individuals with stage I disease (a HR, 0.87; 95% CI, 0.81-0.93; P < .001) or stage II disease (a HR, 0.86; 95% CI, 0.82-0.90; P < .001), compared with those having the same stages of later-onset CRC. No survival advantage was observed among patients diagnosed at age 25 or younger or those with stage III or IV disease.

“Interestingly, hereditary nonpolyposis colorectal cancer, owing to underlying mismatch repair deficiency, is associated with superior survival and is often diagnosed in individuals from ages 35-45 years,” the investigators noted. “In contrast, adenomatous polyposis coli syndrome is more common in individuals who are diagnosed with CRC at age younger than 20 years (10%), compared with those diagnosed at later ages (0.1%), and adenomatous polyposis coli syndrome is not associated with a survival advantage. These high penetrance syndromes could partly account for the relative heterogeneity in survival across ages among individuals with early-onset CRC.”
 

Cautious about interpretation

Dr. Cheng and colleagues concluded their publication with a disclaimer: “Our finding of a survival advantage associated with early-onset CRC among younger individuals should be interpreted cautiously, given that the advantage had a small magnitude and was heterogeneous by age and stage,” they wrote. “Further study is needed to understand the underlying heterogeneity of survival by age and stage among individuals with early-onset CRC.”

Kirbi L. Yelorda, MD, of Stanford (Calif.) University, and colleagues, had a similar interpretation.

“These results offer support for effectiveness of treatment in patients diagnosed with CRC at younger ages; however, they must be interpreted within the context of epidemiological and biological factors,” Dr. Yelorda and colleagues wrote in an accompanying editorial.

The findings also suggest that the recent reduction in recommended screening age by the U.S. Preventive Services Task Force – from 50 years to 45 years – is warranted, they added, but screening younger patients remains unnecessary.

“While these results do not suggest that screening should start for patients younger than 45 years, they do support the benefit of early detection in young patients,” Dr. Yelorda and colleagues wrote, noting a “fairly low incidence rate” among individuals younger than 45, which is insufficient to justify the risk-to-benefit ratio and increased costs associated with expanded screening.
 

Important but not surprising

It’s “not surprising” that early-onset patients typically have better survival than later-onset patients, according to Joseph C. Anderson, MD, associate professor at White River Junction Veterans Affairs Medical Center, Hartford, Vt.; Geisel School of Medicine at Dartmouth, Hanover, N.H.; and the University of Connecticut, Farmington.

“They’re younger, have less comorbidities, and can tolerate chemotherapy,” Dr. Anderson said in an interview. “It’s not surprising that people do poorly with later stages. Younger people are no exception.”

Dr. Anderson, who previously coauthored an editorial weighing the pros and cons of earlier screening, noted that earlier screening is needed because of the rising incidence of late-stage diagnoses among younger patients, which, as the study found, are associated with worse outcomes.

Beyond adherence to screening recommendations, Dr. Anderson urged clinicians to be aggressive when doing a workup of CRC symptoms in younger patients, among whom delayed diagnoses are more common.

“We can’t just say it’s something more benign, like hemorrhoids, like we used to,” Dr. Anderson said. “Somebody who’s 30 years old and having rectal bleeding needs to be evaluated promptly – there can’t be a delay.”

The study was supported by the National Institutes of Health and Stand Up To Cancer (grant administered by the American Association for Cancer Research). The investigators disclosed relationships with Evergrande Group, Janssen, Revolution Medicines, and others. One editorialist reported serving as a member of the USPSTF when the guideline for colorectal cancer was developed, and being a coauthor on the guideline. No other disclosures were reported among editorialists. Dr. Anderson reported no relevant conflicts of interest.

Individuals diagnosed with primary colorectal cancer (CRC) at less than 50 years of age have better survival outcomes than individuals diagnosed at 51-55 years, based on data from more than 750,000 patients.

This finding emphasizes the importance of early CRC detection in younger individuals, reported lead author En Cheng, MD, PhD, of Yale University, New Haven, Conn., and colleagues.

“Early-onset CRC (i.e., CRC diagnosed at age less than 50 years) has been characterized by unique clinical, genetic, and epigenetic characteristics, and thus it may be associated with different survival from CRC diagnosed among individuals older than 50 years,” the investigators wrote in JAMA Network Open. Previous studies comparing survival times across age groups have yielded inconsistent results.

To gain a better understanding, the investigator conducted a retrospective study using data from the National Cancer Database. Excluding patients with primary CRC who had concomitant diagnosis, history of other malignant tumors, noninvasive adenocarcinoma, or missing data, the final dataset included 769,871 patients. Early-onset CRC was defined by age less than 50 years, whereas later-onset CRC was defined by ages 51-55 years.

“Individuals diagnosed at age 50 years were excluded to minimize an apparent screening detection bias at age 50 years in our population, given that these individuals disproportionately presented with earlier stages,” the investigators wrote.

Initial comparisons across groups revealed several significant differences. Individuals in the early-onset group were more often women (47.3% vs. 43.8%; P < .001), members of races in the “other” category (6.9% vs. 5.9%; P < .001), and Medicaid patients (12.3% vs. 10.3%; P < .001). They were also more likely to be diagnosed with stage IV cancer (27.8% vs 24.1%; P < .001) and have rectal tumors (29.3% vs. 28.7%; P = .004).

In the unadjusted Kaplan-Meier analysis, patients with early-onset CRC had a lower 10-year survival rate (53.6%; 95% CI, 53.2%-54.0% vs. 54.3%; 95% CI, 53.8%-54.8%; P < .001). The fully adjusted model revealed significantly higher survival for early-onset patients, compared with later-onset patients (adjusted hazard ratio, 0.95; 95% CI, 0.93-0.96; P < .001) . This disparity deepened when adjusting only for stage (HR, 0.89; 95% CI, 0.88-0.90; P < .001).

Survival was longest among patients 35-39 years (aHR, 0.88; 95% CI, 0.84-0.92; P < .001), compared with those aged 51-55, and among early-onset individuals with stage I disease (a HR, 0.87; 95% CI, 0.81-0.93; P < .001) or stage II disease (a HR, 0.86; 95% CI, 0.82-0.90; P < .001), compared with those having the same stages of later-onset CRC. No survival advantage was observed among patients diagnosed at age 25 or younger or those with stage III or IV disease.

“Interestingly, hereditary nonpolyposis colorectal cancer, owing to underlying mismatch repair deficiency, is associated with superior survival and is often diagnosed in individuals from ages 35-45 years,” the investigators noted. “In contrast, adenomatous polyposis coli syndrome is more common in individuals who are diagnosed with CRC at age younger than 20 years (10%), compared with those diagnosed at later ages (0.1%), and adenomatous polyposis coli syndrome is not associated with a survival advantage. These high penetrance syndromes could partly account for the relative heterogeneity in survival across ages among individuals with early-onset CRC.”
 

Cautious about interpretation

Dr. Cheng and colleagues concluded their publication with a disclaimer: “Our finding of a survival advantage associated with early-onset CRC among younger individuals should be interpreted cautiously, given that the advantage had a small magnitude and was heterogeneous by age and stage,” they wrote. “Further study is needed to understand the underlying heterogeneity of survival by age and stage among individuals with early-onset CRC.”

Kirbi L. Yelorda, MD, of Stanford (Calif.) University, and colleagues, had a similar interpretation.

“These results offer support for effectiveness of treatment in patients diagnosed with CRC at younger ages; however, they must be interpreted within the context of epidemiological and biological factors,” Dr. Yelorda and colleagues wrote in an accompanying editorial.

The findings also suggest that the recent reduction in recommended screening age by the U.S. Preventive Services Task Force – from 50 years to 45 years – is warranted, they added, but screening younger patients remains unnecessary.

“While these results do not suggest that screening should start for patients younger than 45 years, they do support the benefit of early detection in young patients,” Dr. Yelorda and colleagues wrote, noting a “fairly low incidence rate” among individuals younger than 45, which is insufficient to justify the risk-to-benefit ratio and increased costs associated with expanded screening.
 

Important but not surprising

It’s “not surprising” that early-onset patients typically have better survival than later-onset patients, according to Joseph C. Anderson, MD, associate professor at White River Junction Veterans Affairs Medical Center, Hartford, Vt.; Geisel School of Medicine at Dartmouth, Hanover, N.H.; and the University of Connecticut, Farmington.

“They’re younger, have less comorbidities, and can tolerate chemotherapy,” Dr. Anderson said in an interview. “It’s not surprising that people do poorly with later stages. Younger people are no exception.”

Dr. Anderson, who previously coauthored an editorial weighing the pros and cons of earlier screening, noted that earlier screening is needed because of the rising incidence of late-stage diagnoses among younger patients, which, as the study found, are associated with worse outcomes.

Beyond adherence to screening recommendations, Dr. Anderson urged clinicians to be aggressive when doing a workup of CRC symptoms in younger patients, among whom delayed diagnoses are more common.

“We can’t just say it’s something more benign, like hemorrhoids, like we used to,” Dr. Anderson said. “Somebody who’s 30 years old and having rectal bleeding needs to be evaluated promptly – there can’t be a delay.”

The study was supported by the National Institutes of Health and Stand Up To Cancer (grant administered by the American Association for Cancer Research). The investigators disclosed relationships with Evergrande Group, Janssen, Revolution Medicines, and others. One editorialist reported serving as a member of the USPSTF when the guideline for colorectal cancer was developed, and being a coauthor on the guideline. No other disclosures were reported among editorialists. Dr. Anderson reported no relevant conflicts of interest.

Individuals diagnosed with primary colorectal cancer (CRC) at less than 50 years of age have better survival outcomes than individuals diagnosed at 51-55 years, based on data from more than 750,000 patients.

This finding emphasizes the importance of early CRC detection in younger individuals, reported lead author En Cheng, MD, PhD, of Yale University, New Haven, Conn., and colleagues.

“Early-onset CRC (i.e., CRC diagnosed at age less than 50 years) has been characterized by unique clinical, genetic, and epigenetic characteristics, and thus it may be associated with different survival from CRC diagnosed among individuals older than 50 years,” the investigators wrote in JAMA Network Open. Previous studies comparing survival times across age groups have yielded inconsistent results.

To gain a better understanding, the investigator conducted a retrospective study using data from the National Cancer Database. Excluding patients with primary CRC who had concomitant diagnosis, history of other malignant tumors, noninvasive adenocarcinoma, or missing data, the final dataset included 769,871 patients. Early-onset CRC was defined by age less than 50 years, whereas later-onset CRC was defined by ages 51-55 years.

“Individuals diagnosed at age 50 years were excluded to minimize an apparent screening detection bias at age 50 years in our population, given that these individuals disproportionately presented with earlier stages,” the investigators wrote.

Initial comparisons across groups revealed several significant differences. Individuals in the early-onset group were more often women (47.3% vs. 43.8%; P < .001), members of races in the “other” category (6.9% vs. 5.9%; P < .001), and Medicaid patients (12.3% vs. 10.3%; P < .001). They were also more likely to be diagnosed with stage IV cancer (27.8% vs 24.1%; P < .001) and have rectal tumors (29.3% vs. 28.7%; P = .004).

In the unadjusted Kaplan-Meier analysis, patients with early-onset CRC had a lower 10-year survival rate (53.6%; 95% CI, 53.2%-54.0% vs. 54.3%; 95% CI, 53.8%-54.8%; P < .001). The fully adjusted model revealed significantly higher survival for early-onset patients, compared with later-onset patients (adjusted hazard ratio, 0.95; 95% CI, 0.93-0.96; P < .001) . This disparity deepened when adjusting only for stage (HR, 0.89; 95% CI, 0.88-0.90; P < .001).

Survival was longest among patients 35-39 years (aHR, 0.88; 95% CI, 0.84-0.92; P < .001), compared with those aged 51-55, and among early-onset individuals with stage I disease (a HR, 0.87; 95% CI, 0.81-0.93; P < .001) or stage II disease (a HR, 0.86; 95% CI, 0.82-0.90; P < .001), compared with those having the same stages of later-onset CRC. No survival advantage was observed among patients diagnosed at age 25 or younger or those with stage III or IV disease.

“Interestingly, hereditary nonpolyposis colorectal cancer, owing to underlying mismatch repair deficiency, is associated with superior survival and is often diagnosed in individuals from ages 35-45 years,” the investigators noted. “In contrast, adenomatous polyposis coli syndrome is more common in individuals who are diagnosed with CRC at age younger than 20 years (10%), compared with those diagnosed at later ages (0.1%), and adenomatous polyposis coli syndrome is not associated with a survival advantage. These high penetrance syndromes could partly account for the relative heterogeneity in survival across ages among individuals with early-onset CRC.”
 

Cautious about interpretation

Dr. Cheng and colleagues concluded their publication with a disclaimer: “Our finding of a survival advantage associated with early-onset CRC among younger individuals should be interpreted cautiously, given that the advantage had a small magnitude and was heterogeneous by age and stage,” they wrote. “Further study is needed to understand the underlying heterogeneity of survival by age and stage among individuals with early-onset CRC.”

Kirbi L. Yelorda, MD, of Stanford (Calif.) University, and colleagues, had a similar interpretation.

“These results offer support for effectiveness of treatment in patients diagnosed with CRC at younger ages; however, they must be interpreted within the context of epidemiological and biological factors,” Dr. Yelorda and colleagues wrote in an accompanying editorial.

The findings also suggest that the recent reduction in recommended screening age by the U.S. Preventive Services Task Force – from 50 years to 45 years – is warranted, they added, but screening younger patients remains unnecessary.

“While these results do not suggest that screening should start for patients younger than 45 years, they do support the benefit of early detection in young patients,” Dr. Yelorda and colleagues wrote, noting a “fairly low incidence rate” among individuals younger than 45, which is insufficient to justify the risk-to-benefit ratio and increased costs associated with expanded screening.
 

Important but not surprising

It’s “not surprising” that early-onset patients typically have better survival than later-onset patients, according to Joseph C. Anderson, MD, associate professor at White River Junction Veterans Affairs Medical Center, Hartford, Vt.; Geisel School of Medicine at Dartmouth, Hanover, N.H.; and the University of Connecticut, Farmington.

“They’re younger, have less comorbidities, and can tolerate chemotherapy,” Dr. Anderson said in an interview. “It’s not surprising that people do poorly with later stages. Younger people are no exception.”

Dr. Anderson, who previously coauthored an editorial weighing the pros and cons of earlier screening, noted that earlier screening is needed because of the rising incidence of late-stage diagnoses among younger patients, which, as the study found, are associated with worse outcomes.

Beyond adherence to screening recommendations, Dr. Anderson urged clinicians to be aggressive when doing a workup of CRC symptoms in younger patients, among whom delayed diagnoses are more common.

“We can’t just say it’s something more benign, like hemorrhoids, like we used to,” Dr. Anderson said. “Somebody who’s 30 years old and having rectal bleeding needs to be evaluated promptly – there can’t be a delay.”

The study was supported by the National Institutes of Health and Stand Up To Cancer (grant administered by the American Association for Cancer Research). The investigators disclosed relationships with Evergrande Group, Janssen, Revolution Medicines, and others. One editorialist reported serving as a member of the USPSTF when the guideline for colorectal cancer was developed, and being a coauthor on the guideline. No other disclosures were reported among editorialists. Dr. Anderson reported no relevant conflicts of interest.

For adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL), frontline therapy with the chemotherapy-free combination of ponatinib (Iclusig) and blinatumomab (Blincyto) shows promise as an alternative to early hematopoietic stem cell transplantation (HSCT), investigators in a single-arm phase 2 study reported.

In an interim analysis of the combination in patients with newly diagnosed or relapsed/refractory Ph+ALL or lymphoid accelerated or blast phase chronic myeloid leukemia (CML), 20 patients who received it as frontline therapy had a rate of complete responses (CR) or complete responses with partial recovery of blood counts (CRp) of 100% and a complete molecular remission (CMR) rate of 85%, reported Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“This translated into an estimated 2-year overall survival of 93%, with no patients undergoing transplant in first remission, and none having relapse at last follow-up,” he said in an oral abstract presented during the European Hematology Association annual congress.

Among patients with relapsed/refractory Ph+ALL, the CR/CRp rate was 89%, the CMR rate was 88%, and the estimated 2-year overall survival rate was 53%, he said.
 

Transplants on hold

“The big selling point is the ability to avoid stem cell transplant, which is not always the first thing you do in Ph-positive ALL, but it’s always on your mind,” said Gwen Nichols, MD, chief medical officer of the Leukemia and Lymphoma Society, who was not involved in the study.

“It looks, albeit with very limited follow-up, that patients haven’t relapsed yet such that transplant would be necessary. Anything we can do to avoid people having long-term complications that go along with an allogeneic transplant is a step in the right direction,” she said in an interview.
 

One combination, three cohorts

Ph+ALL comprises about 25% of all adult ALL. The standard of care in newly diagnosed patients is chemotherapy plus a tyrosine kinase inhibitor (TKI) targeted against the BCR-ABL transcript.

Ponatinib is a pan-BCR-ABL TKI that has been shown to have activity against ALL with T315I mutations, which are present in about 75% of the cases of relapsed disease, Dr. Short said.

Blinatumomab is a bi-specific T-cell engager (BiTe) that has been shown to be effective as monotherapy against relapsed/refractory Ph+ALL as monotherapy and in combination with dasatinib.

Dr. Short and colleagues enrolled patients with newly diagnosed or relapsed/refractory Ph+ALL or lymphoid accelerated or blast phase CML. Patients in the frontline cohort could have received one or two prior lines of chemotherapy with or without a TKI.

The patients all had Eastern Cooperative Oncology Group performance status of 0-2, and adequate liver function.

Patients with clinically significant cardiovascular disease or central nervous system disease pathology were excluded, except that patients with CNS leukemia could be enrolled.

The induction phase consisted of 30 mg ponatinib daily plus blinatumomab standard dosing on a 4-week-on, 2-week-off schedule. Patients in CMR, defined for frontline patients as undetectable BCR-ABL transcripts by polymerase chain reaction, then received up to four consolidation cycles of the regimen with ponatinib at a 15-mg dose, followed by 5 years of ponatinib 15-mg maintenance. All patients also received CNS prophylaxis with 12 cycles of intrathecal chemotherapy with alternating administration of methotrexate and cytarabine.

Of the 35 patients treated to date with the combination, 20 with Ph+ALL received it as frontline therapy and 10 received it for relapsed/refractory disease; 5 patients with CML in lymphoid blast phase also were treated.
 

High CMR, CR rates

As noted before, the CMR rate, the primary endpoint among patients with newly diagnosed Ph+ALL, was 85%, with a CR/CRp rate of 100%. Six of the patients in the frontline group and one in the salvage therapy group had CRs but were positive for minimal residual disease (MRD) at study outset.

The CR/CRp rate for the entire cohort of 28 patients (excluding those with a CR at start) was 96%, with only 1 patient who had relapsed/refractory disease not having a CR. This patient had received ponatinib in a prior salvage regimen.

The CMR rate among the entire cohort was 79%, with 85% of patients in the frontline ALL cohort having a CMR, 88% in the relapsed/refractory cohort, and 40% in the CML cohort. There were no early deaths among any patients.

“After one cycle of ponatinib plus blinatumomab, 84% of frontline patients had achieved at least a major molecular response, and 58% had achieved a CMR. Among those with relapsed/refractory Ph+ALL, 75% achieved CMR after one cycle of therapy,” Dr. Short said.

Of the 20 frontline patients in CR, one patient experienced visual changes and possible stroke that were considered possibly related to the study medication. This patient was taken off study. During a later maintenance regimen this patient developed a non-ST elevation myocardial infarction and died from postprocedural bleeding and hypovolemic shock following a cardiac catheterization procedure.

The remainder of patients in the frontline cohort had ongoing responses without the need for HSCT at last follow-up. There were no relapses, with a median duration of CR of 6 months,

Among the 10 with relapsed/refractory Ph+ALL, one did not have a response, and the remaining 9 had CR/CRps.

Of the latter groups, four went on to allogeneic HSCT and three were still alive; one patient who underwent a transplant experienced a relapse and died. One additional patient was alive with relapsed disease with T315I and E255V mutations at the time of relapse, one patient in CR who went off study due to insurance issues died from an unknown cause, and the three remaining patients had ongoing responses without transplant.

Among the five patients with CML in lymphoid blast phase, two had relapses, but both are still alive and currently in remission, and three have ongoing responses without transplant.

After a median follow-up of 12 months the 1-year event-free survival (EFS) rate for the entire 35-patient group was 76%, and the 2-year EFS was 70%.

The 1-year overall survival rate was 93%, and the 2-year OS rate was 80%.

Among patients in the frontline group, the 1-year and 2-year EFS and OS rates were all 93%.

For the relapsed/refractory cohort, the estimated 2-year EFS was 41% and OS was 53%. For the CML cohort, the 2-year EFS was 60%, with all patients still alive at last follow-up.

There were no grade 4 adverse events on study. Grade 3 adverse events considered at least possibly related to study treatment were elevated lipase, fever/febrile neutropenia, increased alanine aminotransferase, cerebrovascular ischemia, hypertension, pancreatitis, deep vein thrombosis, and encephalopathy. There were no cases of grade 3 cytokine release syndrome or tremor.

The study was sponsored by MD Anderson Cancer Center with collaboration from the National Cancer Institute, Amgen, and Takeda. Dr. Short has disclosed relationships with Amgen and Takeda. Dr. Nichols reported having no conflicts of interest.

For adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL), frontline therapy with the chemotherapy-free combination of ponatinib (Iclusig) and blinatumomab (Blincyto) shows promise as an alternative to early hematopoietic stem cell transplantation (HSCT), investigators in a single-arm phase 2 study reported.

In an interim analysis of the combination in patients with newly diagnosed or relapsed/refractory Ph+ALL or lymphoid accelerated or blast phase chronic myeloid leukemia (CML), 20 patients who received it as frontline therapy had a rate of complete responses (CR) or complete responses with partial recovery of blood counts (CRp) of 100% and a complete molecular remission (CMR) rate of 85%, reported Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“This translated into an estimated 2-year overall survival of 93%, with no patients undergoing transplant in first remission, and none having relapse at last follow-up,” he said in an oral abstract presented during the European Hematology Association annual congress.

Among patients with relapsed/refractory Ph+ALL, the CR/CRp rate was 89%, the CMR rate was 88%, and the estimated 2-year overall survival rate was 53%, he said.
 

Transplants on hold

“The big selling point is the ability to avoid stem cell transplant, which is not always the first thing you do in Ph-positive ALL, but it’s always on your mind,” said Gwen Nichols, MD, chief medical officer of the Leukemia and Lymphoma Society, who was not involved in the study.

“It looks, albeit with very limited follow-up, that patients haven’t relapsed yet such that transplant would be necessary. Anything we can do to avoid people having long-term complications that go along with an allogeneic transplant is a step in the right direction,” she said in an interview.
 

One combination, three cohorts

Ph+ALL comprises about 25% of all adult ALL. The standard of care in newly diagnosed patients is chemotherapy plus a tyrosine kinase inhibitor (TKI) targeted against the BCR-ABL transcript.

Ponatinib is a pan-BCR-ABL TKI that has been shown to have activity against ALL with T315I mutations, which are present in about 75% of the cases of relapsed disease, Dr. Short said.

Blinatumomab is a bi-specific T-cell engager (BiTe) that has been shown to be effective as monotherapy against relapsed/refractory Ph+ALL as monotherapy and in combination with dasatinib.

Dr. Short and colleagues enrolled patients with newly diagnosed or relapsed/refractory Ph+ALL or lymphoid accelerated or blast phase CML. Patients in the frontline cohort could have received one or two prior lines of chemotherapy with or without a TKI.

The patients all had Eastern Cooperative Oncology Group performance status of 0-2, and adequate liver function.

Patients with clinically significant cardiovascular disease or central nervous system disease pathology were excluded, except that patients with CNS leukemia could be enrolled.

The induction phase consisted of 30 mg ponatinib daily plus blinatumomab standard dosing on a 4-week-on, 2-week-off schedule. Patients in CMR, defined for frontline patients as undetectable BCR-ABL transcripts by polymerase chain reaction, then received up to four consolidation cycles of the regimen with ponatinib at a 15-mg dose, followed by 5 years of ponatinib 15-mg maintenance. All patients also received CNS prophylaxis with 12 cycles of intrathecal chemotherapy with alternating administration of methotrexate and cytarabine.

Of the 35 patients treated to date with the combination, 20 with Ph+ALL received it as frontline therapy and 10 received it for relapsed/refractory disease; 5 patients with CML in lymphoid blast phase also were treated.
 

High CMR, CR rates

As noted before, the CMR rate, the primary endpoint among patients with newly diagnosed Ph+ALL, was 85%, with a CR/CRp rate of 100%. Six of the patients in the frontline group and one in the salvage therapy group had CRs but were positive for minimal residual disease (MRD) at study outset.

The CR/CRp rate for the entire cohort of 28 patients (excluding those with a CR at start) was 96%, with only 1 patient who had relapsed/refractory disease not having a CR. This patient had received ponatinib in a prior salvage regimen.

The CMR rate among the entire cohort was 79%, with 85% of patients in the frontline ALL cohort having a CMR, 88% in the relapsed/refractory cohort, and 40% in the CML cohort. There were no early deaths among any patients.

“After one cycle of ponatinib plus blinatumomab, 84% of frontline patients had achieved at least a major molecular response, and 58% had achieved a CMR. Among those with relapsed/refractory Ph+ALL, 75% achieved CMR after one cycle of therapy,” Dr. Short said.

Of the 20 frontline patients in CR, one patient experienced visual changes and possible stroke that were considered possibly related to the study medication. This patient was taken off study. During a later maintenance regimen this patient developed a non-ST elevation myocardial infarction and died from postprocedural bleeding and hypovolemic shock following a cardiac catheterization procedure.

The remainder of patients in the frontline cohort had ongoing responses without the need for HSCT at last follow-up. There were no relapses, with a median duration of CR of 6 months,

Among the 10 with relapsed/refractory Ph+ALL, one did not have a response, and the remaining 9 had CR/CRps.

Of the latter groups, four went on to allogeneic HSCT and three were still alive; one patient who underwent a transplant experienced a relapse and died. One additional patient was alive with relapsed disease with T315I and E255V mutations at the time of relapse, one patient in CR who went off study due to insurance issues died from an unknown cause, and the three remaining patients had ongoing responses without transplant.

Among the five patients with CML in lymphoid blast phase, two had relapses, but both are still alive and currently in remission, and three have ongoing responses without transplant.

After a median follow-up of 12 months the 1-year event-free survival (EFS) rate for the entire 35-patient group was 76%, and the 2-year EFS was 70%.

The 1-year overall survival rate was 93%, and the 2-year OS rate was 80%.

Among patients in the frontline group, the 1-year and 2-year EFS and OS rates were all 93%.

For the relapsed/refractory cohort, the estimated 2-year EFS was 41% and OS was 53%. For the CML cohort, the 2-year EFS was 60%, with all patients still alive at last follow-up.

There were no grade 4 adverse events on study. Grade 3 adverse events considered at least possibly related to study treatment were elevated lipase, fever/febrile neutropenia, increased alanine aminotransferase, cerebrovascular ischemia, hypertension, pancreatitis, deep vein thrombosis, and encephalopathy. There were no cases of grade 3 cytokine release syndrome or tremor.

The study was sponsored by MD Anderson Cancer Center with collaboration from the National Cancer Institute, Amgen, and Takeda. Dr. Short has disclosed relationships with Amgen and Takeda. Dr. Nichols reported having no conflicts of interest.

For adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ALL), frontline therapy with the chemotherapy-free combination of ponatinib (Iclusig) and blinatumomab (Blincyto) shows promise as an alternative to early hematopoietic stem cell transplantation (HSCT), investigators in a single-arm phase 2 study reported.

In an interim analysis of the combination in patients with newly diagnosed or relapsed/refractory Ph+ALL or lymphoid accelerated or blast phase chronic myeloid leukemia (CML), 20 patients who received it as frontline therapy had a rate of complete responses (CR) or complete responses with partial recovery of blood counts (CRp) of 100% and a complete molecular remission (CMR) rate of 85%, reported Nicholas Short, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“This translated into an estimated 2-year overall survival of 93%, with no patients undergoing transplant in first remission, and none having relapse at last follow-up,” he said in an oral abstract presented during the European Hematology Association annual congress.

Among patients with relapsed/refractory Ph+ALL, the CR/CRp rate was 89%, the CMR rate was 88%, and the estimated 2-year overall survival rate was 53%, he said.
 

Transplants on hold

“The big selling point is the ability to avoid stem cell transplant, which is not always the first thing you do in Ph-positive ALL, but it’s always on your mind,” said Gwen Nichols, MD, chief medical officer of the Leukemia and Lymphoma Society, who was not involved in the study.

“It looks, albeit with very limited follow-up, that patients haven’t relapsed yet such that transplant would be necessary. Anything we can do to avoid people having long-term complications that go along with an allogeneic transplant is a step in the right direction,” she said in an interview.
 

One combination, three cohorts

Ph+ALL comprises about 25% of all adult ALL. The standard of care in newly diagnosed patients is chemotherapy plus a tyrosine kinase inhibitor (TKI) targeted against the BCR-ABL transcript.

Ponatinib is a pan-BCR-ABL TKI that has been shown to have activity against ALL with T315I mutations, which are present in about 75% of the cases of relapsed disease, Dr. Short said.

Blinatumomab is a bi-specific T-cell engager (BiTe) that has been shown to be effective as monotherapy against relapsed/refractory Ph+ALL as monotherapy and in combination with dasatinib.

Dr. Short and colleagues enrolled patients with newly diagnosed or relapsed/refractory Ph+ALL or lymphoid accelerated or blast phase CML. Patients in the frontline cohort could have received one or two prior lines of chemotherapy with or without a TKI.

The patients all had Eastern Cooperative Oncology Group performance status of 0-2, and adequate liver function.

Patients with clinically significant cardiovascular disease or central nervous system disease pathology were excluded, except that patients with CNS leukemia could be enrolled.

The induction phase consisted of 30 mg ponatinib daily plus blinatumomab standard dosing on a 4-week-on, 2-week-off schedule. Patients in CMR, defined for frontline patients as undetectable BCR-ABL transcripts by polymerase chain reaction, then received up to four consolidation cycles of the regimen with ponatinib at a 15-mg dose, followed by 5 years of ponatinib 15-mg maintenance. All patients also received CNS prophylaxis with 12 cycles of intrathecal chemotherapy with alternating administration of methotrexate and cytarabine.

Of the 35 patients treated to date with the combination, 20 with Ph+ALL received it as frontline therapy and 10 received it for relapsed/refractory disease; 5 patients with CML in lymphoid blast phase also were treated.
 

High CMR, CR rates

As noted before, the CMR rate, the primary endpoint among patients with newly diagnosed Ph+ALL, was 85%, with a CR/CRp rate of 100%. Six of the patients in the frontline group and one in the salvage therapy group had CRs but were positive for minimal residual disease (MRD) at study outset.

The CR/CRp rate for the entire cohort of 28 patients (excluding those with a CR at start) was 96%, with only 1 patient who had relapsed/refractory disease not having a CR. This patient had received ponatinib in a prior salvage regimen.

The CMR rate among the entire cohort was 79%, with 85% of patients in the frontline ALL cohort having a CMR, 88% in the relapsed/refractory cohort, and 40% in the CML cohort. There were no early deaths among any patients.

“After one cycle of ponatinib plus blinatumomab, 84% of frontline patients had achieved at least a major molecular response, and 58% had achieved a CMR. Among those with relapsed/refractory Ph+ALL, 75% achieved CMR after one cycle of therapy,” Dr. Short said.

Of the 20 frontline patients in CR, one patient experienced visual changes and possible stroke that were considered possibly related to the study medication. This patient was taken off study. During a later maintenance regimen this patient developed a non-ST elevation myocardial infarction and died from postprocedural bleeding and hypovolemic shock following a cardiac catheterization procedure.

The remainder of patients in the frontline cohort had ongoing responses without the need for HSCT at last follow-up. There were no relapses, with a median duration of CR of 6 months,

Among the 10 with relapsed/refractory Ph+ALL, one did not have a response, and the remaining 9 had CR/CRps.

Of the latter groups, four went on to allogeneic HSCT and three were still alive; one patient who underwent a transplant experienced a relapse and died. One additional patient was alive with relapsed disease with T315I and E255V mutations at the time of relapse, one patient in CR who went off study due to insurance issues died from an unknown cause, and the three remaining patients had ongoing responses without transplant.

Among the five patients with CML in lymphoid blast phase, two had relapses, but both are still alive and currently in remission, and three have ongoing responses without transplant.

After a median follow-up of 12 months the 1-year event-free survival (EFS) rate for the entire 35-patient group was 76%, and the 2-year EFS was 70%.

The 1-year overall survival rate was 93%, and the 2-year OS rate was 80%.

Among patients in the frontline group, the 1-year and 2-year EFS and OS rates were all 93%.

For the relapsed/refractory cohort, the estimated 2-year EFS was 41% and OS was 53%. For the CML cohort, the 2-year EFS was 60%, with all patients still alive at last follow-up.

There were no grade 4 adverse events on study. Grade 3 adverse events considered at least possibly related to study treatment were elevated lipase, fever/febrile neutropenia, increased alanine aminotransferase, cerebrovascular ischemia, hypertension, pancreatitis, deep vein thrombosis, and encephalopathy. There were no cases of grade 3 cytokine release syndrome or tremor.

The study was sponsored by MD Anderson Cancer Center with collaboration from the National Cancer Institute, Amgen, and Takeda. Dr. Short has disclosed relationships with Amgen and Takeda. Dr. Nichols reported having no conflicts of interest.

A novel therapeutic approach using aptamers – short single strands of DNA or RNA designed to selectively bind to a target – shows promise for treating von Willebrand Disease (VWD), and other congenital bleed disorders such as hemophilia A, investigators say.

In a proof-of-concept study using healthy volunteers, the experimental anti–von Willebrand factor (VWF) molecule BT200 appeared to decrease clearance of VWF and resulted in a twofold increase in endogenous levels of VWF and factor VIII at low doses.

BT200 is currently being explored in a phase 2 trial in patients with hemophilia A and VWD type 2B, Katarina Kovacevic, MPharm, from the Medical University of Vienna, reported at the European Hematology Association annual congress.

“We expect to see a half-life increase of 2 to 4 times of factor VIII products, which will allow us to have a longer time between treatments,” she said in an oral abstract presentation (Abstract S302).
 

Lab-made nucleotide strings

Aptamers are sometimes call “chemical antibodies” because of their high affinity and high specificity for extracellular targets, Dr. Kovacevic said. Unlike conventional humanized or human-derived antibodies, however, they are nonimmunogenic and are less costly to manufacture.

In a previous study from her center, a different anti-VWF aptamer labeled ARC1779 increased plasma levels of VWF, factor VIII, and platelet counts in patients with VWD type 2B.

However, the drug was inconvenient to use, requiring 72-hour infusions, she noted.

In a study published in Feb. 4, 2021 in Scientific Reports, Dr. Kovacevic and colleagues reported that BT200 blocks VWF and platelet function in patients with ischemic strokes, even in the presence of high levels of VWF in patients with left carotid artery atherosclerotic strokes.

The ability of the molecule to block VWF platelet binding may explain how the anti-VWF agent actually results in higher circulating levels of VWF, which also carries factor VIII, said Veronica H. Flood, MD, a VWD specialist at Children’s Hospital of Wisconsin and associate professor at the Medical College of Wisconsin in Milwaukee.

“It might inhibit clearance of the von Willebrand factor, so it’s almost like this was an incidental side effect,” she said in an interview. “Incidentally, this happens to also give you higher levels of the von Willebrand factor and the factor VIII, and with a longer half-life than anything we currently have, so it’s a super-creative strategy,” she said.

Dr. Flood was not involved in the study.
 

Long half-life

BT200 is a third-generation peglyated anti-VWF aptamer that has been shown in preclinical studies to have a long half-life in nonhuman primates. It inhibits the A1 domain of VWF to prevent it from binding to platelet glycoprotein 1b (GP1b).

In the randomized, double-blind, placebo-controlled trial reported at the EHA congress, 88 healthy volunteers received single doses of BT200 ranging from 0.l8 mg to 48 mg by subcutaneous injection or intravenous infusion, 8 received multiple doses, 8 were evaluated for possible interactions with desmopressin, and 8 were evaluated for bioavailability of the aptamer.

The investigators observed a dose-related increase in BT200 concentrations, with a mean plasma terminal elimination half life of between 118 and 284 hours (about 5-12 days). There was also a dose-dependent increase in bioavailability of the agents, reaching 90% at the highest dose level.

The ability of BT200 to inhibit the A1 domains of VWF also was dose dependent, with the largest effect seen with doses of 12 mg and higher. The molecule decreased VWF activity and ristocetin-induced platelet aggregation, and prolonged collagen adenosine diphosphate closure time.

At the highest doses, BT200 caused complete inhibition of VWF (P < .001), and volunteers developed clinical signs of mild mucosal bleeding.

But the aptamer also increased in a dose-dependent fashion VWF antigen levels and factor VIII clotting activity more than fourfold (P <.001).

“This resulted in increased thrombogenicity as measured by thrombin generation and enhanced clotting. In the absence of an increase in VWF propeptide levels, this effect is considered due to decreased clearance of VWF,” the investigators wrote in the study abstract.

They noted that they saw a clinically meaningful twofold increase in both VWF and factor VIII at doses lower than 6 mg.
 

‘Super-exciting strategy’

“This trial identified a novel mechanism of action for BT200: It decreases the clearance of VWF/FVIII, which can be exploited for congenital bleeding disorders. This built a solid foundation for an ongoing basket trial in patients with von Willebrand disease or hemophilia A, which already confirms the expected effect sizes,” Dr. Kovacevic and colleagues wrote.

“I will be interested to see what the clinical side effects are, because there may be some off-target effects, but in reality it is a super-exciting strategy, and there is really a dire need for longer half-life products for these patients,” Dr. Flood said.

The study was sponsored by Band Therapeutics, a division of Guardian Therapeutics. Dr. Kovacevic and Dr. Flood reported having no conflicts of interest to disclose.

A novel therapeutic approach using aptamers – short single strands of DNA or RNA designed to selectively bind to a target – shows promise for treating von Willebrand Disease (VWD), and other congenital bleed disorders such as hemophilia A, investigators say.

In a proof-of-concept study using healthy volunteers, the experimental anti–von Willebrand factor (VWF) molecule BT200 appeared to decrease clearance of VWF and resulted in a twofold increase in endogenous levels of VWF and factor VIII at low doses.

BT200 is currently being explored in a phase 2 trial in patients with hemophilia A and VWD type 2B, Katarina Kovacevic, MPharm, from the Medical University of Vienna, reported at the European Hematology Association annual congress.

“We expect to see a half-life increase of 2 to 4 times of factor VIII products, which will allow us to have a longer time between treatments,” she said in an oral abstract presentation (Abstract S302).
 

Lab-made nucleotide strings

Aptamers are sometimes call “chemical antibodies” because of their high affinity and high specificity for extracellular targets, Dr. Kovacevic said. Unlike conventional humanized or human-derived antibodies, however, they are nonimmunogenic and are less costly to manufacture.

In a previous study from her center, a different anti-VWF aptamer labeled ARC1779 increased plasma levels of VWF, factor VIII, and platelet counts in patients with VWD type 2B.

However, the drug was inconvenient to use, requiring 72-hour infusions, she noted.

In a study published in Feb. 4, 2021 in Scientific Reports, Dr. Kovacevic and colleagues reported that BT200 blocks VWF and platelet function in patients with ischemic strokes, even in the presence of high levels of VWF in patients with left carotid artery atherosclerotic strokes.

The ability of the molecule to block VWF platelet binding may explain how the anti-VWF agent actually results in higher circulating levels of VWF, which also carries factor VIII, said Veronica H. Flood, MD, a VWD specialist at Children’s Hospital of Wisconsin and associate professor at the Medical College of Wisconsin in Milwaukee.

“It might inhibit clearance of the von Willebrand factor, so it’s almost like this was an incidental side effect,” she said in an interview. “Incidentally, this happens to also give you higher levels of the von Willebrand factor and the factor VIII, and with a longer half-life than anything we currently have, so it’s a super-creative strategy,” she said.

Dr. Flood was not involved in the study.
 

Long half-life

BT200 is a third-generation peglyated anti-VWF aptamer that has been shown in preclinical studies to have a long half-life in nonhuman primates. It inhibits the A1 domain of VWF to prevent it from binding to platelet glycoprotein 1b (GP1b).

In the randomized, double-blind, placebo-controlled trial reported at the EHA congress, 88 healthy volunteers received single doses of BT200 ranging from 0.l8 mg to 48 mg by subcutaneous injection or intravenous infusion, 8 received multiple doses, 8 were evaluated for possible interactions with desmopressin, and 8 were evaluated for bioavailability of the aptamer.

The investigators observed a dose-related increase in BT200 concentrations, with a mean plasma terminal elimination half life of between 118 and 284 hours (about 5-12 days). There was also a dose-dependent increase in bioavailability of the agents, reaching 90% at the highest dose level.

The ability of BT200 to inhibit the A1 domains of VWF also was dose dependent, with the largest effect seen with doses of 12 mg and higher. The molecule decreased VWF activity and ristocetin-induced platelet aggregation, and prolonged collagen adenosine diphosphate closure time.

At the highest doses, BT200 caused complete inhibition of VWF (P < .001), and volunteers developed clinical signs of mild mucosal bleeding.

But the aptamer also increased in a dose-dependent fashion VWF antigen levels and factor VIII clotting activity more than fourfold (P <.001).

“This resulted in increased thrombogenicity as measured by thrombin generation and enhanced clotting. In the absence of an increase in VWF propeptide levels, this effect is considered due to decreased clearance of VWF,” the investigators wrote in the study abstract.

They noted that they saw a clinically meaningful twofold increase in both VWF and factor VIII at doses lower than 6 mg.
 

‘Super-exciting strategy’

“This trial identified a novel mechanism of action for BT200: It decreases the clearance of VWF/FVIII, which can be exploited for congenital bleeding disorders. This built a solid foundation for an ongoing basket trial in patients with von Willebrand disease or hemophilia A, which already confirms the expected effect sizes,” Dr. Kovacevic and colleagues wrote.

“I will be interested to see what the clinical side effects are, because there may be some off-target effects, but in reality it is a super-exciting strategy, and there is really a dire need for longer half-life products for these patients,” Dr. Flood said.

The study was sponsored by Band Therapeutics, a division of Guardian Therapeutics. Dr. Kovacevic and Dr. Flood reported having no conflicts of interest to disclose.

A novel therapeutic approach using aptamers – short single strands of DNA or RNA designed to selectively bind to a target – shows promise for treating von Willebrand Disease (VWD), and other congenital bleed disorders such as hemophilia A, investigators say.

In a proof-of-concept study using healthy volunteers, the experimental anti–von Willebrand factor (VWF) molecule BT200 appeared to decrease clearance of VWF and resulted in a twofold increase in endogenous levels of VWF and factor VIII at low doses.

BT200 is currently being explored in a phase 2 trial in patients with hemophilia A and VWD type 2B, Katarina Kovacevic, MPharm, from the Medical University of Vienna, reported at the European Hematology Association annual congress.

“We expect to see a half-life increase of 2 to 4 times of factor VIII products, which will allow us to have a longer time between treatments,” she said in an oral abstract presentation (Abstract S302).
 

Lab-made nucleotide strings

Aptamers are sometimes call “chemical antibodies” because of their high affinity and high specificity for extracellular targets, Dr. Kovacevic said. Unlike conventional humanized or human-derived antibodies, however, they are nonimmunogenic and are less costly to manufacture.

In a previous study from her center, a different anti-VWF aptamer labeled ARC1779 increased plasma levels of VWF, factor VIII, and platelet counts in patients with VWD type 2B.

However, the drug was inconvenient to use, requiring 72-hour infusions, she noted.

In a study published in Feb. 4, 2021 in Scientific Reports, Dr. Kovacevic and colleagues reported that BT200 blocks VWF and platelet function in patients with ischemic strokes, even in the presence of high levels of VWF in patients with left carotid artery atherosclerotic strokes.

The ability of the molecule to block VWF platelet binding may explain how the anti-VWF agent actually results in higher circulating levels of VWF, which also carries factor VIII, said Veronica H. Flood, MD, a VWD specialist at Children’s Hospital of Wisconsin and associate professor at the Medical College of Wisconsin in Milwaukee.

“It might inhibit clearance of the von Willebrand factor, so it’s almost like this was an incidental side effect,” she said in an interview. “Incidentally, this happens to also give you higher levels of the von Willebrand factor and the factor VIII, and with a longer half-life than anything we currently have, so it’s a super-creative strategy,” she said.

Dr. Flood was not involved in the study.
 

Long half-life

BT200 is a third-generation peglyated anti-VWF aptamer that has been shown in preclinical studies to have a long half-life in nonhuman primates. It inhibits the A1 domain of VWF to prevent it from binding to platelet glycoprotein 1b (GP1b).

In the randomized, double-blind, placebo-controlled trial reported at the EHA congress, 88 healthy volunteers received single doses of BT200 ranging from 0.l8 mg to 48 mg by subcutaneous injection or intravenous infusion, 8 received multiple doses, 8 were evaluated for possible interactions with desmopressin, and 8 were evaluated for bioavailability of the aptamer.

The investigators observed a dose-related increase in BT200 concentrations, with a mean plasma terminal elimination half life of between 118 and 284 hours (about 5-12 days). There was also a dose-dependent increase in bioavailability of the agents, reaching 90% at the highest dose level.

The ability of BT200 to inhibit the A1 domains of VWF also was dose dependent, with the largest effect seen with doses of 12 mg and higher. The molecule decreased VWF activity and ristocetin-induced platelet aggregation, and prolonged collagen adenosine diphosphate closure time.

At the highest doses, BT200 caused complete inhibition of VWF (P < .001), and volunteers developed clinical signs of mild mucosal bleeding.

But the aptamer also increased in a dose-dependent fashion VWF antigen levels and factor VIII clotting activity more than fourfold (P <.001).

“This resulted in increased thrombogenicity as measured by thrombin generation and enhanced clotting. In the absence of an increase in VWF propeptide levels, this effect is considered due to decreased clearance of VWF,” the investigators wrote in the study abstract.

They noted that they saw a clinically meaningful twofold increase in both VWF and factor VIII at doses lower than 6 mg.
 

‘Super-exciting strategy’

“This trial identified a novel mechanism of action for BT200: It decreases the clearance of VWF/FVIII, which can be exploited for congenital bleeding disorders. This built a solid foundation for an ongoing basket trial in patients with von Willebrand disease or hemophilia A, which already confirms the expected effect sizes,” Dr. Kovacevic and colleagues wrote.

“I will be interested to see what the clinical side effects are, because there may be some off-target effects, but in reality it is a super-exciting strategy, and there is really a dire need for longer half-life products for these patients,” Dr. Flood said.

The study was sponsored by Band Therapeutics, a division of Guardian Therapeutics. Dr. Kovacevic and Dr. Flood reported having no conflicts of interest to disclose.