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Delays in cancer referrals caused by the COVID-19 pandemic and the ensuing shutdown in cancer services will lead to thousands of additional deaths and tens of thousands of life-years lost, suggest two new modeling studies from the United Kingdom.

Clearing the backlog in cancer diagnoses will require a coordinated effort from the government and the National Health Service (NHS), say the authors, inasmuch as services were already running at “full capacity” before the pandemic.

Both studies were published in The Lancet Oncology on July 20.

When the UK-wide lockdown to combat the COVID-19 pandemic was implemented on March 23, cancer screening and routine outpatient referrals in the NHS were suspended, and treatment of cancer patients either halted or slowed down.

Moreover, because of physical distancing measures, which are expected to continue for up to a year, urgent 3-week referrals for suspected cancer cases have fallen by as much as 80%.

To estimate the potential impact on cancer deaths, Ajay Aggarwal, MD, from the London School of Hygiene and Tropical Medicine, United Kingdom, and colleagues conducted a population-based modeling study.

They collected data on 32,583 patients with breast cancer, 24,975 with colorectal cancer, 6744 with esophageal cancer, and 29,305 with lung cancer. Patients were diagnosed between 2010 and 2012 and were followed to 2015.

The investigators used that data to estimate the impact of diagnostic delays resulting from 12 months of physical distancing.

For breast cancer, this would lead to a 7.9%-9.6% increase in the number of cancer deaths within 5 years after diagnosis, or to 281-344 additional deaths.

For colorectal cancer, there would be a 15.3%-16.7% increase in mortality over 5 years, or an additional 1,445-1,563 deaths.

For lung cancer, there would a 4.8%-5.3% increase in mortality, or an additional 1235-1372 deaths.

For esophageal cancer, the mortality increase over 5 years would be 5.8%-6.0%, leading to 330-342 additional deaths.

Across the four tumor types, 59,204-63,229 life-years would be lost because of physical distancing compared to the prepandemic era.
 

Resources need to be increased

These additional deaths are not inevitable, the researchers suggest.

To prevent the increase in colorectal cancer deaths, for example, Aggarwal said, “It is vital that more resources are made urgently available for endoscopy and colonoscopy services, which are managing significant backlogs currently.

“Whilst currently attention is being focused on diagnostic pathways where cancer is suspected, the issue is that a significant number of cancers are diagnosed in patients awaiting investigation for symptoms not considered related to be cancer,” he added in a statement.

“Therefore we need a whole system approach to avoid the predicted excess deaths.”

Coauthor Bernard Rachet, PhD, also from the London School of Hygiene and Tropical Medicine, added that “to absorb the cancer patient backlog, the healthcare community also needs to establish clear criteria to prioritise patients on clinical grounds, in order to maintain equitability in care delivery.”

It will not be easy “to pin down the exact number of additional cancer deaths we expect to see over the coming years, but studies like this help us to understand the devastating long-term effect a pandemic like COVID-19 will have on the lives of thousands of cancer patients,” commented Michelle Mitchell, chief executive of Cancer Research UK.

Underlining the “enormous backlog” of cancer care that has built up during the pandemic, she said: “Diagnosing and treating people swiftly is vital to give people with cancer the greatest chances of survival.

“The government must work closely with the NHS to ensure it has sufficient staff and equipment to clear the backlog while giving patients the care that they need, quickly and safely,” Mitchell added.

Increasing resources will not be easy. In an accompanying editorial, William Hamilton, MD, PhD, University of Exeter, United Kingdom, warns that many NHS imaging departments, for example, were “working at full capacity before the COVID-19 pandemic.”

Consequently, they “might not be able to meet the increase in demand” resulting from the backlog in patients, especially as “the need to keep patients separate and to clean equipment has reduced their efficiency.

“The UK has had a long-term shortage of diagnostic capacity, although this shortage is not simply of equipment, but also of personnel, which is not so easily improved,” he cautions.
 

Another study, similar estimates

For the second study, Clare Turnbull, PhD, Institute of Cancer Research, London, and colleagues obtained age- and stage-stratified 10-year cancer survival estimates for patients in England diagnosed with 20 common tumor types between 2008 and 2017.

They also gathered data on cancer diagnoses made via urgent 2-week referrals between 2013 and 2016. They estimate that 6,281 patients were diagnosed with cancer of stages I-III per month.

Of those, 1,691 (27%) would die within 10 years of their diagnosis, they found.

They then calculated that delays in 2-week referrals during a 3-month lockdown would lead to an average delay in presentation of 2 months per patient.

A resulting 25% backlog in referrals would lead to 181 additional lives and 3,316 life-years lost. With a 75% backlog in referrals, an additional 276 lives and 5,075 life-years would be lost.

The team says that additional diagnostic delays spread over 3-8 months after the lockdown could increase the impact of a 25% backlog in referrals to 401 additional lives and 14,873 life-years lost.

For a 75% backlog in referrals, the additional lives lost would rise to 1,231, and the number of life-years lost would reach 22,635.

“Substantial additional deaths from diagnostic delays on top of those expected from delays in presentation – because many people are simply too afraid to visit their GP or hospital – are likely, especially if rapid provision of additional capacity, including technical provision and increased staffing, is not forthcoming,” Turnbull commented in a statement.

The study by Aggarwal and colleagues was funded by the U.K. Research and Innovation Economic and Social Research Council. Several of the researchers were supported by Cancer Research UK and Breast Cancer Now. Turnbull reports receiving support from the Movember Foundation.

This article first appeared on Medscape.com.

Delays in cancer referrals caused by the COVID-19 pandemic and the ensuing shutdown in cancer services will lead to thousands of additional deaths and tens of thousands of life-years lost, suggest two new modeling studies from the United Kingdom.

Clearing the backlog in cancer diagnoses will require a coordinated effort from the government and the National Health Service (NHS), say the authors, inasmuch as services were already running at “full capacity” before the pandemic.

Both studies were published in The Lancet Oncology on July 20.

When the UK-wide lockdown to combat the COVID-19 pandemic was implemented on March 23, cancer screening and routine outpatient referrals in the NHS were suspended, and treatment of cancer patients either halted or slowed down.

Moreover, because of physical distancing measures, which are expected to continue for up to a year, urgent 3-week referrals for suspected cancer cases have fallen by as much as 80%.

To estimate the potential impact on cancer deaths, Ajay Aggarwal, MD, from the London School of Hygiene and Tropical Medicine, United Kingdom, and colleagues conducted a population-based modeling study.

They collected data on 32,583 patients with breast cancer, 24,975 with colorectal cancer, 6744 with esophageal cancer, and 29,305 with lung cancer. Patients were diagnosed between 2010 and 2012 and were followed to 2015.

The investigators used that data to estimate the impact of diagnostic delays resulting from 12 months of physical distancing.

For breast cancer, this would lead to a 7.9%-9.6% increase in the number of cancer deaths within 5 years after diagnosis, or to 281-344 additional deaths.

For colorectal cancer, there would be a 15.3%-16.7% increase in mortality over 5 years, or an additional 1,445-1,563 deaths.

For lung cancer, there would a 4.8%-5.3% increase in mortality, or an additional 1235-1372 deaths.

For esophageal cancer, the mortality increase over 5 years would be 5.8%-6.0%, leading to 330-342 additional deaths.

Across the four tumor types, 59,204-63,229 life-years would be lost because of physical distancing compared to the prepandemic era.
 

Resources need to be increased

These additional deaths are not inevitable, the researchers suggest.

To prevent the increase in colorectal cancer deaths, for example, Aggarwal said, “It is vital that more resources are made urgently available for endoscopy and colonoscopy services, which are managing significant backlogs currently.

“Whilst currently attention is being focused on diagnostic pathways where cancer is suspected, the issue is that a significant number of cancers are diagnosed in patients awaiting investigation for symptoms not considered related to be cancer,” he added in a statement.

“Therefore we need a whole system approach to avoid the predicted excess deaths.”

Coauthor Bernard Rachet, PhD, also from the London School of Hygiene and Tropical Medicine, added that “to absorb the cancer patient backlog, the healthcare community also needs to establish clear criteria to prioritise patients on clinical grounds, in order to maintain equitability in care delivery.”

It will not be easy “to pin down the exact number of additional cancer deaths we expect to see over the coming years, but studies like this help us to understand the devastating long-term effect a pandemic like COVID-19 will have on the lives of thousands of cancer patients,” commented Michelle Mitchell, chief executive of Cancer Research UK.

Underlining the “enormous backlog” of cancer care that has built up during the pandemic, she said: “Diagnosing and treating people swiftly is vital to give people with cancer the greatest chances of survival.

“The government must work closely with the NHS to ensure it has sufficient staff and equipment to clear the backlog while giving patients the care that they need, quickly and safely,” Mitchell added.

Increasing resources will not be easy. In an accompanying editorial, William Hamilton, MD, PhD, University of Exeter, United Kingdom, warns that many NHS imaging departments, for example, were “working at full capacity before the COVID-19 pandemic.”

Consequently, they “might not be able to meet the increase in demand” resulting from the backlog in patients, especially as “the need to keep patients separate and to clean equipment has reduced their efficiency.

“The UK has had a long-term shortage of diagnostic capacity, although this shortage is not simply of equipment, but also of personnel, which is not so easily improved,” he cautions.
 

Another study, similar estimates

For the second study, Clare Turnbull, PhD, Institute of Cancer Research, London, and colleagues obtained age- and stage-stratified 10-year cancer survival estimates for patients in England diagnosed with 20 common tumor types between 2008 and 2017.

They also gathered data on cancer diagnoses made via urgent 2-week referrals between 2013 and 2016. They estimate that 6,281 patients were diagnosed with cancer of stages I-III per month.

Of those, 1,691 (27%) would die within 10 years of their diagnosis, they found.

They then calculated that delays in 2-week referrals during a 3-month lockdown would lead to an average delay in presentation of 2 months per patient.

A resulting 25% backlog in referrals would lead to 181 additional lives and 3,316 life-years lost. With a 75% backlog in referrals, an additional 276 lives and 5,075 life-years would be lost.

The team says that additional diagnostic delays spread over 3-8 months after the lockdown could increase the impact of a 25% backlog in referrals to 401 additional lives and 14,873 life-years lost.

For a 75% backlog in referrals, the additional lives lost would rise to 1,231, and the number of life-years lost would reach 22,635.

“Substantial additional deaths from diagnostic delays on top of those expected from delays in presentation – because many people are simply too afraid to visit their GP or hospital – are likely, especially if rapid provision of additional capacity, including technical provision and increased staffing, is not forthcoming,” Turnbull commented in a statement.

The study by Aggarwal and colleagues was funded by the U.K. Research and Innovation Economic and Social Research Council. Several of the researchers were supported by Cancer Research UK and Breast Cancer Now. Turnbull reports receiving support from the Movember Foundation.

This article first appeared on Medscape.com.

Delays in cancer referrals caused by the COVID-19 pandemic and the ensuing shutdown in cancer services will lead to thousands of additional deaths and tens of thousands of life-years lost, suggest two new modeling studies from the United Kingdom.

Clearing the backlog in cancer diagnoses will require a coordinated effort from the government and the National Health Service (NHS), say the authors, inasmuch as services were already running at “full capacity” before the pandemic.

Both studies were published in The Lancet Oncology on July 20.

When the UK-wide lockdown to combat the COVID-19 pandemic was implemented on March 23, cancer screening and routine outpatient referrals in the NHS were suspended, and treatment of cancer patients either halted or slowed down.

Moreover, because of physical distancing measures, which are expected to continue for up to a year, urgent 3-week referrals for suspected cancer cases have fallen by as much as 80%.

To estimate the potential impact on cancer deaths, Ajay Aggarwal, MD, from the London School of Hygiene and Tropical Medicine, United Kingdom, and colleagues conducted a population-based modeling study.

They collected data on 32,583 patients with breast cancer, 24,975 with colorectal cancer, 6744 with esophageal cancer, and 29,305 with lung cancer. Patients were diagnosed between 2010 and 2012 and were followed to 2015.

The investigators used that data to estimate the impact of diagnostic delays resulting from 12 months of physical distancing.

For breast cancer, this would lead to a 7.9%-9.6% increase in the number of cancer deaths within 5 years after diagnosis, or to 281-344 additional deaths.

For colorectal cancer, there would be a 15.3%-16.7% increase in mortality over 5 years, or an additional 1,445-1,563 deaths.

For lung cancer, there would a 4.8%-5.3% increase in mortality, or an additional 1235-1372 deaths.

For esophageal cancer, the mortality increase over 5 years would be 5.8%-6.0%, leading to 330-342 additional deaths.

Across the four tumor types, 59,204-63,229 life-years would be lost because of physical distancing compared to the prepandemic era.
 

Resources need to be increased

These additional deaths are not inevitable, the researchers suggest.

To prevent the increase in colorectal cancer deaths, for example, Aggarwal said, “It is vital that more resources are made urgently available for endoscopy and colonoscopy services, which are managing significant backlogs currently.

“Whilst currently attention is being focused on diagnostic pathways where cancer is suspected, the issue is that a significant number of cancers are diagnosed in patients awaiting investigation for symptoms not considered related to be cancer,” he added in a statement.

“Therefore we need a whole system approach to avoid the predicted excess deaths.”

Coauthor Bernard Rachet, PhD, also from the London School of Hygiene and Tropical Medicine, added that “to absorb the cancer patient backlog, the healthcare community also needs to establish clear criteria to prioritise patients on clinical grounds, in order to maintain equitability in care delivery.”

It will not be easy “to pin down the exact number of additional cancer deaths we expect to see over the coming years, but studies like this help us to understand the devastating long-term effect a pandemic like COVID-19 will have on the lives of thousands of cancer patients,” commented Michelle Mitchell, chief executive of Cancer Research UK.

Underlining the “enormous backlog” of cancer care that has built up during the pandemic, she said: “Diagnosing and treating people swiftly is vital to give people with cancer the greatest chances of survival.

“The government must work closely with the NHS to ensure it has sufficient staff and equipment to clear the backlog while giving patients the care that they need, quickly and safely,” Mitchell added.

Increasing resources will not be easy. In an accompanying editorial, William Hamilton, MD, PhD, University of Exeter, United Kingdom, warns that many NHS imaging departments, for example, were “working at full capacity before the COVID-19 pandemic.”

Consequently, they “might not be able to meet the increase in demand” resulting from the backlog in patients, especially as “the need to keep patients separate and to clean equipment has reduced their efficiency.

“The UK has had a long-term shortage of diagnostic capacity, although this shortage is not simply of equipment, but also of personnel, which is not so easily improved,” he cautions.
 

Another study, similar estimates

For the second study, Clare Turnbull, PhD, Institute of Cancer Research, London, and colleagues obtained age- and stage-stratified 10-year cancer survival estimates for patients in England diagnosed with 20 common tumor types between 2008 and 2017.

They also gathered data on cancer diagnoses made via urgent 2-week referrals between 2013 and 2016. They estimate that 6,281 patients were diagnosed with cancer of stages I-III per month.

Of those, 1,691 (27%) would die within 10 years of their diagnosis, they found.

They then calculated that delays in 2-week referrals during a 3-month lockdown would lead to an average delay in presentation of 2 months per patient.

A resulting 25% backlog in referrals would lead to 181 additional lives and 3,316 life-years lost. With a 75% backlog in referrals, an additional 276 lives and 5,075 life-years would be lost.

The team says that additional diagnostic delays spread over 3-8 months after the lockdown could increase the impact of a 25% backlog in referrals to 401 additional lives and 14,873 life-years lost.

For a 75% backlog in referrals, the additional lives lost would rise to 1,231, and the number of life-years lost would reach 22,635.

“Substantial additional deaths from diagnostic delays on top of those expected from delays in presentation – because many people are simply too afraid to visit their GP or hospital – are likely, especially if rapid provision of additional capacity, including technical provision and increased staffing, is not forthcoming,” Turnbull commented in a statement.

The study by Aggarwal and colleagues was funded by the U.K. Research and Innovation Economic and Social Research Council. Several of the researchers were supported by Cancer Research UK and Breast Cancer Now. Turnbull reports receiving support from the Movember Foundation.

This article first appeared on Medscape.com.

Starting breast cancer screening in young adulthood has the potential to sharply reduce deaths from the disease among women who have received chest radiation for childhood cancer, a modeling study suggests.

Two strategies – annual mammography with MRI and annual MRI alone – at least halved breast cancer mortality when started at the ages of 25 or 30 years.

Jennifer M. Yeh, PhD, of Harvard Medical School in Boston and colleagues reported these results in the Annals of Internal Medicine.

When cost was also considered, 30 years emerged as the preferred starting age, dropping the incremental cost-effectiveness ratio (ICER) below the generally accepted threshold of $100,000 per quality-adjusted life-year gained.

“Our findings underscore the importance of making sure that young women previously treated with chest radiation are informed about their elevated breast cancer risk and the benefits of routine screening. Both primary care providers and oncologists who care for survivors should discuss breast cancer screening with these patients,” Dr. Yeh and colleagues wrote.

“Screening guidelines should emphasize the importance of MRI screening (with or without mammography) among survivors,” the authors recommended. “Our findings also highlight the importance of ensuring that survivors have access to health insurance coverage for MRI screening.”
 

Implications for awareness, coverage

“My hope is that, by showing the significantly decreased risk of death associated with early breast cancer screening, with harm-benefit ratios considerably lower than benchmarks for average-risk women, this study will help health insurance companies see the benefit in covering early screening for at-risk survivors,” commented Karen E. Effinger, MD, of Emory University, Atlanta, and the Aflac Cancer & Blood Disorders Center at Children’s Healthcare of Atlanta.

“In many survivors, the cost of current screening [as recommended by] guidelines is prohibitive,” added Dr. Effinger, who was not involved in the current study.

The main concern regarding the study’s findings is generalizability to the contemporary era, given the use of a cohort diagnosed and treated decades ago and changes in radiation techniques and dosing since then, she noted in an interview. This limitation was addressed in a sensitivity analysis that halved the women’s base-case lifetime risk of breast cancer and still netted similar results.

“However, it will take many years to determine the true risk reduction of our current treatment strategies,” Dr. Effinger acknowledged.

“It is crucial that we improve our education of both survivors and our colleagues who care for these survivors, especially in regard to risk of subsequent malignancies and the benefits of screening,” Dr. Effinger maintained. “While many people are aware of the risk of breast cancer associated with BRCA mutations, the increased risk in survivors of childhood cancer is not as recognized by nononcologists. This study reinforces that increasing this awareness can save lives.”

In educating their patients about preventive care, health care providers must strike “a fine balance between discussing the risks and benefits of screening without provoking significant anxiety,” she concluded. “It is important for survivors to establish care with a primary care provider in order to develop trust and receive the guidance they need to decrease the risk of early mortality.”
 

Study details

Dr. Yeh and colleagues developed models to compare outcomes with various screening strategies among women aged 20 years who had received chest radiotherapy for childhood cancer during 1970-1986. The women had been diagnosed with Hodgkin lymphoma (55%), Wilms tumor (12%), non-Hodgkin lymphoma (8%), and other cancers.

The investigators conducted their analysis using data from the Childhood Cancer Survivor Study and other published sources, a lifetime time horizon, and a payer perspective.

The team assessed three strategies: no screening; digital mammography with MRI screening starting at 25 years of age (the current Children’s Oncology Group recommendation), 30 years, or 35 years and continuing to 74 years of age; and MRI only starting at age 25, 30, or 35 years and continuing to age 74 years.

The main study results showed that, without screening, women who had received chest radiation for childhood cancer had a 10%-11% lifetime risk of breast cancer mortality across models.

Relative to no screening, starting at age 25 years, the largest share of deaths was averted with the strategy of annual mammography with MRI – 56.3%-71.2% – or with the strategy of annual MRI alone – 55.7%-62.0%.

These two strategies also yielded the most screening tests, as well as the most false-positive test results and benign biopsy results.

For women who started screening at age 25, there were 4,188-4,879 false-positive test results per 1,000 women for mammography plus MRI and 3,283-3,764 false-positive results per 1,000 women for MRI alone.

For women who started screening at age 25, there were 1,340-1,561 benign biopsy results per 1,000 women for mammography plus MRI and 1,248-1,430 benign results per 1,000 women for MRI alone.

After cost was factored in, beginning screening at age 30 emerged as the preferred strategy to achieve an ICER threshold of less than $100,000 per quality-adjusted life-year gained.

When started at 30 years of age, annual mammography with MRI averted 54.7%-68.8% of breast cancer deaths, with an ICER of $25,400-$113,200 per quality-adjusted life-year gained. Annual MRI alone averted 54.0%-60.0% of breast cancer deaths, with an ICER of $21,800-$50,580 per quality-adjusted life-year gained.

This research was supported by grants from the National Cancer Institute, American Cancer Society, and American Lebanese Syrian Associated Charities. The authors disclosed relationships with GE Healthcare and Biovector. Dr. Effinger disclosed no relevant conflicts of interest.

SOURCE: Yeh JM et al. Ann Intern Med. 2020 Jul 7. doi: 10.7326/M19-3481.

Starting breast cancer screening in young adulthood has the potential to sharply reduce deaths from the disease among women who have received chest radiation for childhood cancer, a modeling study suggests.

Two strategies – annual mammography with MRI and annual MRI alone – at least halved breast cancer mortality when started at the ages of 25 or 30 years.

Jennifer M. Yeh, PhD, of Harvard Medical School in Boston and colleagues reported these results in the Annals of Internal Medicine.

When cost was also considered, 30 years emerged as the preferred starting age, dropping the incremental cost-effectiveness ratio (ICER) below the generally accepted threshold of $100,000 per quality-adjusted life-year gained.

“Our findings underscore the importance of making sure that young women previously treated with chest radiation are informed about their elevated breast cancer risk and the benefits of routine screening. Both primary care providers and oncologists who care for survivors should discuss breast cancer screening with these patients,” Dr. Yeh and colleagues wrote.

“Screening guidelines should emphasize the importance of MRI screening (with or without mammography) among survivors,” the authors recommended. “Our findings also highlight the importance of ensuring that survivors have access to health insurance coverage for MRI screening.”
 

Implications for awareness, coverage

“My hope is that, by showing the significantly decreased risk of death associated with early breast cancer screening, with harm-benefit ratios considerably lower than benchmarks for average-risk women, this study will help health insurance companies see the benefit in covering early screening for at-risk survivors,” commented Karen E. Effinger, MD, of Emory University, Atlanta, and the Aflac Cancer & Blood Disorders Center at Children’s Healthcare of Atlanta.

“In many survivors, the cost of current screening [as recommended by] guidelines is prohibitive,” added Dr. Effinger, who was not involved in the current study.

The main concern regarding the study’s findings is generalizability to the contemporary era, given the use of a cohort diagnosed and treated decades ago and changes in radiation techniques and dosing since then, she noted in an interview. This limitation was addressed in a sensitivity analysis that halved the women’s base-case lifetime risk of breast cancer and still netted similar results.

“However, it will take many years to determine the true risk reduction of our current treatment strategies,” Dr. Effinger acknowledged.

“It is crucial that we improve our education of both survivors and our colleagues who care for these survivors, especially in regard to risk of subsequent malignancies and the benefits of screening,” Dr. Effinger maintained. “While many people are aware of the risk of breast cancer associated with BRCA mutations, the increased risk in survivors of childhood cancer is not as recognized by nononcologists. This study reinforces that increasing this awareness can save lives.”

In educating their patients about preventive care, health care providers must strike “a fine balance between discussing the risks and benefits of screening without provoking significant anxiety,” she concluded. “It is important for survivors to establish care with a primary care provider in order to develop trust and receive the guidance they need to decrease the risk of early mortality.”
 

Study details

Dr. Yeh and colleagues developed models to compare outcomes with various screening strategies among women aged 20 years who had received chest radiotherapy for childhood cancer during 1970-1986. The women had been diagnosed with Hodgkin lymphoma (55%), Wilms tumor (12%), non-Hodgkin lymphoma (8%), and other cancers.

The investigators conducted their analysis using data from the Childhood Cancer Survivor Study and other published sources, a lifetime time horizon, and a payer perspective.

The team assessed three strategies: no screening; digital mammography with MRI screening starting at 25 years of age (the current Children’s Oncology Group recommendation), 30 years, or 35 years and continuing to 74 years of age; and MRI only starting at age 25, 30, or 35 years and continuing to age 74 years.

The main study results showed that, without screening, women who had received chest radiation for childhood cancer had a 10%-11% lifetime risk of breast cancer mortality across models.

Relative to no screening, starting at age 25 years, the largest share of deaths was averted with the strategy of annual mammography with MRI – 56.3%-71.2% – or with the strategy of annual MRI alone – 55.7%-62.0%.

These two strategies also yielded the most screening tests, as well as the most false-positive test results and benign biopsy results.

For women who started screening at age 25, there were 4,188-4,879 false-positive test results per 1,000 women for mammography plus MRI and 3,283-3,764 false-positive results per 1,000 women for MRI alone.

For women who started screening at age 25, there were 1,340-1,561 benign biopsy results per 1,000 women for mammography plus MRI and 1,248-1,430 benign results per 1,000 women for MRI alone.

After cost was factored in, beginning screening at age 30 emerged as the preferred strategy to achieve an ICER threshold of less than $100,000 per quality-adjusted life-year gained.

When started at 30 years of age, annual mammography with MRI averted 54.7%-68.8% of breast cancer deaths, with an ICER of $25,400-$113,200 per quality-adjusted life-year gained. Annual MRI alone averted 54.0%-60.0% of breast cancer deaths, with an ICER of $21,800-$50,580 per quality-adjusted life-year gained.

This research was supported by grants from the National Cancer Institute, American Cancer Society, and American Lebanese Syrian Associated Charities. The authors disclosed relationships with GE Healthcare and Biovector. Dr. Effinger disclosed no relevant conflicts of interest.

SOURCE: Yeh JM et al. Ann Intern Med. 2020 Jul 7. doi: 10.7326/M19-3481.

Starting breast cancer screening in young adulthood has the potential to sharply reduce deaths from the disease among women who have received chest radiation for childhood cancer, a modeling study suggests.

Two strategies – annual mammography with MRI and annual MRI alone – at least halved breast cancer mortality when started at the ages of 25 or 30 years.

Jennifer M. Yeh, PhD, of Harvard Medical School in Boston and colleagues reported these results in the Annals of Internal Medicine.

When cost was also considered, 30 years emerged as the preferred starting age, dropping the incremental cost-effectiveness ratio (ICER) below the generally accepted threshold of $100,000 per quality-adjusted life-year gained.

“Our findings underscore the importance of making sure that young women previously treated with chest radiation are informed about their elevated breast cancer risk and the benefits of routine screening. Both primary care providers and oncologists who care for survivors should discuss breast cancer screening with these patients,” Dr. Yeh and colleagues wrote.

“Screening guidelines should emphasize the importance of MRI screening (with or without mammography) among survivors,” the authors recommended. “Our findings also highlight the importance of ensuring that survivors have access to health insurance coverage for MRI screening.”
 

Implications for awareness, coverage

“My hope is that, by showing the significantly decreased risk of death associated with early breast cancer screening, with harm-benefit ratios considerably lower than benchmarks for average-risk women, this study will help health insurance companies see the benefit in covering early screening for at-risk survivors,” commented Karen E. Effinger, MD, of Emory University, Atlanta, and the Aflac Cancer & Blood Disorders Center at Children’s Healthcare of Atlanta.

“In many survivors, the cost of current screening [as recommended by] guidelines is prohibitive,” added Dr. Effinger, who was not involved in the current study.

The main concern regarding the study’s findings is generalizability to the contemporary era, given the use of a cohort diagnosed and treated decades ago and changes in radiation techniques and dosing since then, she noted in an interview. This limitation was addressed in a sensitivity analysis that halved the women’s base-case lifetime risk of breast cancer and still netted similar results.

“However, it will take many years to determine the true risk reduction of our current treatment strategies,” Dr. Effinger acknowledged.

“It is crucial that we improve our education of both survivors and our colleagues who care for these survivors, especially in regard to risk of subsequent malignancies and the benefits of screening,” Dr. Effinger maintained. “While many people are aware of the risk of breast cancer associated with BRCA mutations, the increased risk in survivors of childhood cancer is not as recognized by nononcologists. This study reinforces that increasing this awareness can save lives.”

In educating their patients about preventive care, health care providers must strike “a fine balance between discussing the risks and benefits of screening without provoking significant anxiety,” she concluded. “It is important for survivors to establish care with a primary care provider in order to develop trust and receive the guidance they need to decrease the risk of early mortality.”
 

Study details

Dr. Yeh and colleagues developed models to compare outcomes with various screening strategies among women aged 20 years who had received chest radiotherapy for childhood cancer during 1970-1986. The women had been diagnosed with Hodgkin lymphoma (55%), Wilms tumor (12%), non-Hodgkin lymphoma (8%), and other cancers.

The investigators conducted their analysis using data from the Childhood Cancer Survivor Study and other published sources, a lifetime time horizon, and a payer perspective.

The team assessed three strategies: no screening; digital mammography with MRI screening starting at 25 years of age (the current Children’s Oncology Group recommendation), 30 years, or 35 years and continuing to 74 years of age; and MRI only starting at age 25, 30, or 35 years and continuing to age 74 years.

The main study results showed that, without screening, women who had received chest radiation for childhood cancer had a 10%-11% lifetime risk of breast cancer mortality across models.

Relative to no screening, starting at age 25 years, the largest share of deaths was averted with the strategy of annual mammography with MRI – 56.3%-71.2% – or with the strategy of annual MRI alone – 55.7%-62.0%.

These two strategies also yielded the most screening tests, as well as the most false-positive test results and benign biopsy results.

For women who started screening at age 25, there were 4,188-4,879 false-positive test results per 1,000 women for mammography plus MRI and 3,283-3,764 false-positive results per 1,000 women for MRI alone.

For women who started screening at age 25, there were 1,340-1,561 benign biopsy results per 1,000 women for mammography plus MRI and 1,248-1,430 benign results per 1,000 women for MRI alone.

After cost was factored in, beginning screening at age 30 emerged as the preferred strategy to achieve an ICER threshold of less than $100,000 per quality-adjusted life-year gained.

When started at 30 years of age, annual mammography with MRI averted 54.7%-68.8% of breast cancer deaths, with an ICER of $25,400-$113,200 per quality-adjusted life-year gained. Annual MRI alone averted 54.0%-60.0% of breast cancer deaths, with an ICER of $21,800-$50,580 per quality-adjusted life-year gained.

This research was supported by grants from the National Cancer Institute, American Cancer Society, and American Lebanese Syrian Associated Charities. The authors disclosed relationships with GE Healthcare and Biovector. Dr. Effinger disclosed no relevant conflicts of interest.

SOURCE: Yeh JM et al. Ann Intern Med. 2020 Jul 7. doi: 10.7326/M19-3481.

The estimated one third of patients with acute promyelocytic leukemia (APL) who are older than 60 years now enjoy a notably better prognosis than in years past, thanks to the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, such patients still require special management considerations, and can only benefit from treatment advantages if properly identified.

In a recently published set of recommendations, the International Society of Geriatric Oncology Task Force outlined the latest information on the treatment of APL in older patients. Medscape spoke with the lead author of the article, Heidi Klepin, MD, MS, professor in the section on hematology and oncology at Wake Forest School of Medicine in Winston Salem, N.C., who highlighted the key points that clinicians need to know about this often highly treatable subtype of acute myeloid leukemia (AML). This interview has been edited for length and clarity.
 

Medscape: How do the potential benefits of therapy for APL compare with other AML subtypes in older persons?

Dr. Klepin: Potential benefits of therapy are dramatically better for APL, compared with other AML subtypes. The use of non–chemotherapy based regimens with ATRA and ATO has substantially changed options for APL management. ATRA+ATO are associated with high remission and cure rates. The chance of cure with less toxicity extends the clinical benefit to adults of advanced age and, to some extent, with comorbidities.

How has the management strategy for this subgroup of patients with APL changed in recent years?

Management options have changed dramatically with the advent of non–chemotherapy-based regimens. The majority of treated older adults could be expected to achieve remissions that are durable, with less risk of major side effects during treatment. Adults with comorbid conditions, at advanced age, and with some functional limitations could also still benefit from treatment.

Does that management strategy change based on whether patients are considered low-risk or high-risk?

Clinical trials are lacking to provide best evidence for the optimal treatment for adults over age 70 years. However, based on available data and experience, the expert consensus provided in this report recommends that older adults regardless of age with low-risk disease should be offered ATRA+ATO–based therapy if available.

The optimal approach for patients with high-risk disease is less clear based on available studies. For fit older adults without cardiac disease, the use of single-drug anthracycline chemotherapy with ATRA plus/minus ATO is appropriate. However, treatment with ATRA+ATO may also provide a good response with less side-effect risk. For older patients with high-risk disease and comorbidity or poor functional status, the use of non-chemotherapy regimen ATRA+ATO is preferred.
 

What role does frailty have in making treatment decisions in this population?

Although frail older adults have not been specifically studied in clinical trials, it is reasonable to offer treatment with a non–chemotherapy based regimen for many of these patients, particularly if frailty may in part be related to disease burden. Frailty is a dynamic state. Rapid initiation of therapy can improve function and symptoms, potentially reversing the phenotype of frailty if driven largely by disease burden.

What is the role of consolidation and maintenance therapy in older patients with APL?

Consolidation therapy is recommended with ATRA+ATO as a standard consideration for most patients when available, although protocol-based treatments may vary. For those older adults treated with chemotherapy+ATRA for high-risk disease, decreased anthracycline [chemotherapy] exposure during consolidation results in less mortality risk. Maintenance therapy is not needed when ATRA+ATO are used for induction and consolidation and after achieving a molecular remission.

What other patient factors should influence treatment decisions?

In practice, older age, concurrent comorbid conditions [particularly cardiac disease], and physical function may all influence treatment decisions. Regarding the disease itself, a high white blood cell count at diagnosis, which is classified as higher-risk disease, directs choice of therapy, particularly for fit older adults. Cardiac disease can limit certain treatment options because of risk of side effects. In particular, the use of anthracycline chemotherapy is contraindicated for people with heart failure, and the use of ATO can increase risk of arrhythmia and is not used with certain EKG findings.

Special considerations in older patients with APL

How would you characterize older individuals’ involvement in clinical trials?

Older adults are underrepresented on clinical trials, with very limited inclusion of those over age 75 years. Some APL trials have had upper age exclusions, which is something we have advocated to remove.

Are there unique challenges in diagnosing older adults with APL?

The presentation of APL with low blood counts can look similar to other types of AML or myelodysplastic syndrome when reviewing routine lab results. If additional testing is not done quickly, the diagnosis will be missed, as well as the opportunity for effective treatment. Rapid diagnosis is essential in this disease.

Are there age-related differences in the presentation of APL?

There are no available data to support more-aggressive APL biology in older adults.

How does age impact the outcomes of patients with APL?

Although the outcomes in APL have improved, the survival difference between age groups has not decreased in recent years and the magnitude of improvement in survival in older patients still lags behind younger patients. Older age is also associated with worse outcomes driven largely by increased early death, with greater rates of infection and multiorgan failure leading to a decreased overall survival.

How important is a geriatric assessment for older patients with APL? What role does it play in management?

There are no data on the use of a geriatric assessment specifically in APL, although a geriatric assessment is recommended for older adults starting new chemotherapy in general. A geriatric assessment may help determine who is fit enough to be treated like a younger patient, which has the greatest implications for those with high-risk disease where chemotherapy would be added.

A geriatric assessment can also play an important role in management by identifying vulnerabilities that could be addressed to minimize complications during treatment regardless of the type of treatment given. An example would be identifying and addressing polypharmacy (commonly defined as ≥5 medications). One challenge faced when treating older patients is the use of multiple concomitant medications. Polypharmacy is common among older patients with cancer. Among older adults, each new drug increases the risk of adverse drug events by 10%. Drugs commonly used for the treatment of APL, such as ATRA and ATO, have many potential drug interactions, which must be carefully assessed by a pharmacist prior to and during treatment. Active deprescribing of medications that are not critical during treatment for APL should be done to minimize risks. 
 

What is differentiation syndrome? What role does age appear to play in the risk of developing it and in strategies for managing it?

Differentiation syndrome is a serious side effect that may occur in patients with APL who have been treated with certain anticancer drugs. Differentiation syndrome usually occurs within a week or 2 of starting treatment. It is caused by a large, rapid release of cytokines [immune substances] from leukemia cells. The most common symptoms include fever; cough; shortness of breath; weight gain; swelling of the arms, legs, and neck; build-up of excess fluid around the heart and lungs; low blood pressure; and kidney failure. Differentiation syndrome can be life-threatening if not recognized and treated early.

Some evidence suggests older adults may be at a higher risk for developing differentiation syndrome and may be less likely to tolerate it. A risk factor is kidney dysfunction, which is more common in older adults.

It is not clear that management should differ by age, but vigilance is critical. The use of prophylactic steroids is considered for high-risk patients [high white cell count or kidney disease]. The treatment for differentiation syndrome involves rapid use of steroids.
 

Does the management of infections differ in older people with APL?

There is no clear data to support a different management of infection prevention for older adults, although preventive antibiotics can be considered as older adults are at a higher risk for infectious complications. However, drug interactions need to be carefully considered in this context.

Guiding clinicians toward better treatment of APL

Why did you decide to formulate these recommendations now?

It is particularly important to draw attention to the management of older adults with APL given the availability of effective non–chemotherapy based therapies and the large distinction between expected outcomes with APL vs. other types of acute leukemia in this population. This diagnosis should not be missed. Further, we highlight the importance of ensuring that older adults are included in trials to provide best evidence for both treatment choice and supportive care management.

How do you see these recommendations affecting clinical practice?

We want to emphasize that advanced age should not preclude treatment, which can have meaningful benefit with expectation of remission and quality time gained.

We hope that these recommendations provide a useful blueprint for guiding the management of older adults, particularly consolidating information to help inform treatment for those patients older than 75 years that can provide best estimates of side effects and benefits when making a decision with patients. We also hope that these recommendations will be used to educate providers on the importance of looking for this diagnosis in our older patients.

From a practical standpoint, it will be important that this information gets to those providers who are making the referrals to oncologists, which can include primary care physicians and emergency room providers, to ensure prompt diagnostic workup. Treatment decisions can only be made once a diagnosis has been recognized, and time is critical with this disease.

Dr. Klepin disclosed a consultancy for Genentech and Pfizer and is a contributor to UpToDate.

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

The estimated one third of patients with acute promyelocytic leukemia (APL) who are older than 60 years now enjoy a notably better prognosis than in years past, thanks to the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, such patients still require special management considerations, and can only benefit from treatment advantages if properly identified.

In a recently published set of recommendations, the International Society of Geriatric Oncology Task Force outlined the latest information on the treatment of APL in older patients. Medscape spoke with the lead author of the article, Heidi Klepin, MD, MS, professor in the section on hematology and oncology at Wake Forest School of Medicine in Winston Salem, N.C., who highlighted the key points that clinicians need to know about this often highly treatable subtype of acute myeloid leukemia (AML). This interview has been edited for length and clarity.
 

Medscape: How do the potential benefits of therapy for APL compare with other AML subtypes in older persons?

Dr. Klepin: Potential benefits of therapy are dramatically better for APL, compared with other AML subtypes. The use of non–chemotherapy based regimens with ATRA and ATO has substantially changed options for APL management. ATRA+ATO are associated with high remission and cure rates. The chance of cure with less toxicity extends the clinical benefit to adults of advanced age and, to some extent, with comorbidities.

How has the management strategy for this subgroup of patients with APL changed in recent years?

Management options have changed dramatically with the advent of non–chemotherapy-based regimens. The majority of treated older adults could be expected to achieve remissions that are durable, with less risk of major side effects during treatment. Adults with comorbid conditions, at advanced age, and with some functional limitations could also still benefit from treatment.

Does that management strategy change based on whether patients are considered low-risk or high-risk?

Clinical trials are lacking to provide best evidence for the optimal treatment for adults over age 70 years. However, based on available data and experience, the expert consensus provided in this report recommends that older adults regardless of age with low-risk disease should be offered ATRA+ATO–based therapy if available.

The optimal approach for patients with high-risk disease is less clear based on available studies. For fit older adults without cardiac disease, the use of single-drug anthracycline chemotherapy with ATRA plus/minus ATO is appropriate. However, treatment with ATRA+ATO may also provide a good response with less side-effect risk. For older patients with high-risk disease and comorbidity or poor functional status, the use of non-chemotherapy regimen ATRA+ATO is preferred.
 

What role does frailty have in making treatment decisions in this population?

Although frail older adults have not been specifically studied in clinical trials, it is reasonable to offer treatment with a non–chemotherapy based regimen for many of these patients, particularly if frailty may in part be related to disease burden. Frailty is a dynamic state. Rapid initiation of therapy can improve function and symptoms, potentially reversing the phenotype of frailty if driven largely by disease burden.

What is the role of consolidation and maintenance therapy in older patients with APL?

Consolidation therapy is recommended with ATRA+ATO as a standard consideration for most patients when available, although protocol-based treatments may vary. For those older adults treated with chemotherapy+ATRA for high-risk disease, decreased anthracycline [chemotherapy] exposure during consolidation results in less mortality risk. Maintenance therapy is not needed when ATRA+ATO are used for induction and consolidation and after achieving a molecular remission.

What other patient factors should influence treatment decisions?

In practice, older age, concurrent comorbid conditions [particularly cardiac disease], and physical function may all influence treatment decisions. Regarding the disease itself, a high white blood cell count at diagnosis, which is classified as higher-risk disease, directs choice of therapy, particularly for fit older adults. Cardiac disease can limit certain treatment options because of risk of side effects. In particular, the use of anthracycline chemotherapy is contraindicated for people with heart failure, and the use of ATO can increase risk of arrhythmia and is not used with certain EKG findings.

Special considerations in older patients with APL

How would you characterize older individuals’ involvement in clinical trials?

Older adults are underrepresented on clinical trials, with very limited inclusion of those over age 75 years. Some APL trials have had upper age exclusions, which is something we have advocated to remove.

Are there unique challenges in diagnosing older adults with APL?

The presentation of APL with low blood counts can look similar to other types of AML or myelodysplastic syndrome when reviewing routine lab results. If additional testing is not done quickly, the diagnosis will be missed, as well as the opportunity for effective treatment. Rapid diagnosis is essential in this disease.

Are there age-related differences in the presentation of APL?

There are no available data to support more-aggressive APL biology in older adults.

How does age impact the outcomes of patients with APL?

Although the outcomes in APL have improved, the survival difference between age groups has not decreased in recent years and the magnitude of improvement in survival in older patients still lags behind younger patients. Older age is also associated with worse outcomes driven largely by increased early death, with greater rates of infection and multiorgan failure leading to a decreased overall survival.

How important is a geriatric assessment for older patients with APL? What role does it play in management?

There are no data on the use of a geriatric assessment specifically in APL, although a geriatric assessment is recommended for older adults starting new chemotherapy in general. A geriatric assessment may help determine who is fit enough to be treated like a younger patient, which has the greatest implications for those with high-risk disease where chemotherapy would be added.

A geriatric assessment can also play an important role in management by identifying vulnerabilities that could be addressed to minimize complications during treatment regardless of the type of treatment given. An example would be identifying and addressing polypharmacy (commonly defined as ≥5 medications). One challenge faced when treating older patients is the use of multiple concomitant medications. Polypharmacy is common among older patients with cancer. Among older adults, each new drug increases the risk of adverse drug events by 10%. Drugs commonly used for the treatment of APL, such as ATRA and ATO, have many potential drug interactions, which must be carefully assessed by a pharmacist prior to and during treatment. Active deprescribing of medications that are not critical during treatment for APL should be done to minimize risks. 
 

What is differentiation syndrome? What role does age appear to play in the risk of developing it and in strategies for managing it?

Differentiation syndrome is a serious side effect that may occur in patients with APL who have been treated with certain anticancer drugs. Differentiation syndrome usually occurs within a week or 2 of starting treatment. It is caused by a large, rapid release of cytokines [immune substances] from leukemia cells. The most common symptoms include fever; cough; shortness of breath; weight gain; swelling of the arms, legs, and neck; build-up of excess fluid around the heart and lungs; low blood pressure; and kidney failure. Differentiation syndrome can be life-threatening if not recognized and treated early.

Some evidence suggests older adults may be at a higher risk for developing differentiation syndrome and may be less likely to tolerate it. A risk factor is kidney dysfunction, which is more common in older adults.

It is not clear that management should differ by age, but vigilance is critical. The use of prophylactic steroids is considered for high-risk patients [high white cell count or kidney disease]. The treatment for differentiation syndrome involves rapid use of steroids.
 

Does the management of infections differ in older people with APL?

There is no clear data to support a different management of infection prevention for older adults, although preventive antibiotics can be considered as older adults are at a higher risk for infectious complications. However, drug interactions need to be carefully considered in this context.

Guiding clinicians toward better treatment of APL

Why did you decide to formulate these recommendations now?

It is particularly important to draw attention to the management of older adults with APL given the availability of effective non–chemotherapy based therapies and the large distinction between expected outcomes with APL vs. other types of acute leukemia in this population. This diagnosis should not be missed. Further, we highlight the importance of ensuring that older adults are included in trials to provide best evidence for both treatment choice and supportive care management.

How do you see these recommendations affecting clinical practice?

We want to emphasize that advanced age should not preclude treatment, which can have meaningful benefit with expectation of remission and quality time gained.

We hope that these recommendations provide a useful blueprint for guiding the management of older adults, particularly consolidating information to help inform treatment for those patients older than 75 years that can provide best estimates of side effects and benefits when making a decision with patients. We also hope that these recommendations will be used to educate providers on the importance of looking for this diagnosis in our older patients.

From a practical standpoint, it will be important that this information gets to those providers who are making the referrals to oncologists, which can include primary care physicians and emergency room providers, to ensure prompt diagnostic workup. Treatment decisions can only be made once a diagnosis has been recognized, and time is critical with this disease.

Dr. Klepin disclosed a consultancy for Genentech and Pfizer and is a contributor to UpToDate.

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

The estimated one third of patients with acute promyelocytic leukemia (APL) who are older than 60 years now enjoy a notably better prognosis than in years past, thanks to the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, such patients still require special management considerations, and can only benefit from treatment advantages if properly identified.

In a recently published set of recommendations, the International Society of Geriatric Oncology Task Force outlined the latest information on the treatment of APL in older patients. Medscape spoke with the lead author of the article, Heidi Klepin, MD, MS, professor in the section on hematology and oncology at Wake Forest School of Medicine in Winston Salem, N.C., who highlighted the key points that clinicians need to know about this often highly treatable subtype of acute myeloid leukemia (AML). This interview has been edited for length and clarity.
 

Medscape: How do the potential benefits of therapy for APL compare with other AML subtypes in older persons?

Dr. Klepin: Potential benefits of therapy are dramatically better for APL, compared with other AML subtypes. The use of non–chemotherapy based regimens with ATRA and ATO has substantially changed options for APL management. ATRA+ATO are associated with high remission and cure rates. The chance of cure with less toxicity extends the clinical benefit to adults of advanced age and, to some extent, with comorbidities.

How has the management strategy for this subgroup of patients with APL changed in recent years?

Management options have changed dramatically with the advent of non–chemotherapy-based regimens. The majority of treated older adults could be expected to achieve remissions that are durable, with less risk of major side effects during treatment. Adults with comorbid conditions, at advanced age, and with some functional limitations could also still benefit from treatment.

Does that management strategy change based on whether patients are considered low-risk or high-risk?

Clinical trials are lacking to provide best evidence for the optimal treatment for adults over age 70 years. However, based on available data and experience, the expert consensus provided in this report recommends that older adults regardless of age with low-risk disease should be offered ATRA+ATO–based therapy if available.

The optimal approach for patients with high-risk disease is less clear based on available studies. For fit older adults without cardiac disease, the use of single-drug anthracycline chemotherapy with ATRA plus/minus ATO is appropriate. However, treatment with ATRA+ATO may also provide a good response with less side-effect risk. For older patients with high-risk disease and comorbidity or poor functional status, the use of non-chemotherapy regimen ATRA+ATO is preferred.
 

What role does frailty have in making treatment decisions in this population?

Although frail older adults have not been specifically studied in clinical trials, it is reasonable to offer treatment with a non–chemotherapy based regimen for many of these patients, particularly if frailty may in part be related to disease burden. Frailty is a dynamic state. Rapid initiation of therapy can improve function and symptoms, potentially reversing the phenotype of frailty if driven largely by disease burden.

What is the role of consolidation and maintenance therapy in older patients with APL?

Consolidation therapy is recommended with ATRA+ATO as a standard consideration for most patients when available, although protocol-based treatments may vary. For those older adults treated with chemotherapy+ATRA for high-risk disease, decreased anthracycline [chemotherapy] exposure during consolidation results in less mortality risk. Maintenance therapy is not needed when ATRA+ATO are used for induction and consolidation and after achieving a molecular remission.

What other patient factors should influence treatment decisions?

In practice, older age, concurrent comorbid conditions [particularly cardiac disease], and physical function may all influence treatment decisions. Regarding the disease itself, a high white blood cell count at diagnosis, which is classified as higher-risk disease, directs choice of therapy, particularly for fit older adults. Cardiac disease can limit certain treatment options because of risk of side effects. In particular, the use of anthracycline chemotherapy is contraindicated for people with heart failure, and the use of ATO can increase risk of arrhythmia and is not used with certain EKG findings.

Special considerations in older patients with APL

How would you characterize older individuals’ involvement in clinical trials?

Older adults are underrepresented on clinical trials, with very limited inclusion of those over age 75 years. Some APL trials have had upper age exclusions, which is something we have advocated to remove.

Are there unique challenges in diagnosing older adults with APL?

The presentation of APL with low blood counts can look similar to other types of AML or myelodysplastic syndrome when reviewing routine lab results. If additional testing is not done quickly, the diagnosis will be missed, as well as the opportunity for effective treatment. Rapid diagnosis is essential in this disease.

Are there age-related differences in the presentation of APL?

There are no available data to support more-aggressive APL biology in older adults.

How does age impact the outcomes of patients with APL?

Although the outcomes in APL have improved, the survival difference between age groups has not decreased in recent years and the magnitude of improvement in survival in older patients still lags behind younger patients. Older age is also associated with worse outcomes driven largely by increased early death, with greater rates of infection and multiorgan failure leading to a decreased overall survival.

How important is a geriatric assessment for older patients with APL? What role does it play in management?

There are no data on the use of a geriatric assessment specifically in APL, although a geriatric assessment is recommended for older adults starting new chemotherapy in general. A geriatric assessment may help determine who is fit enough to be treated like a younger patient, which has the greatest implications for those with high-risk disease where chemotherapy would be added.

A geriatric assessment can also play an important role in management by identifying vulnerabilities that could be addressed to minimize complications during treatment regardless of the type of treatment given. An example would be identifying and addressing polypharmacy (commonly defined as ≥5 medications). One challenge faced when treating older patients is the use of multiple concomitant medications. Polypharmacy is common among older patients with cancer. Among older adults, each new drug increases the risk of adverse drug events by 10%. Drugs commonly used for the treatment of APL, such as ATRA and ATO, have many potential drug interactions, which must be carefully assessed by a pharmacist prior to and during treatment. Active deprescribing of medications that are not critical during treatment for APL should be done to minimize risks. 
 

What is differentiation syndrome? What role does age appear to play in the risk of developing it and in strategies for managing it?

Differentiation syndrome is a serious side effect that may occur in patients with APL who have been treated with certain anticancer drugs. Differentiation syndrome usually occurs within a week or 2 of starting treatment. It is caused by a large, rapid release of cytokines [immune substances] from leukemia cells. The most common symptoms include fever; cough; shortness of breath; weight gain; swelling of the arms, legs, and neck; build-up of excess fluid around the heart and lungs; low blood pressure; and kidney failure. Differentiation syndrome can be life-threatening if not recognized and treated early.

Some evidence suggests older adults may be at a higher risk for developing differentiation syndrome and may be less likely to tolerate it. A risk factor is kidney dysfunction, which is more common in older adults.

It is not clear that management should differ by age, but vigilance is critical. The use of prophylactic steroids is considered for high-risk patients [high white cell count or kidney disease]. The treatment for differentiation syndrome involves rapid use of steroids.
 

Does the management of infections differ in older people with APL?

There is no clear data to support a different management of infection prevention for older adults, although preventive antibiotics can be considered as older adults are at a higher risk for infectious complications. However, drug interactions need to be carefully considered in this context.

Guiding clinicians toward better treatment of APL

Why did you decide to formulate these recommendations now?

It is particularly important to draw attention to the management of older adults with APL given the availability of effective non–chemotherapy based therapies and the large distinction between expected outcomes with APL vs. other types of acute leukemia in this population. This diagnosis should not be missed. Further, we highlight the importance of ensuring that older adults are included in trials to provide best evidence for both treatment choice and supportive care management.

How do you see these recommendations affecting clinical practice?

We want to emphasize that advanced age should not preclude treatment, which can have meaningful benefit with expectation of remission and quality time gained.

We hope that these recommendations provide a useful blueprint for guiding the management of older adults, particularly consolidating information to help inform treatment for those patients older than 75 years that can provide best estimates of side effects and benefits when making a decision with patients. We also hope that these recommendations will be used to educate providers on the importance of looking for this diagnosis in our older patients.

From a practical standpoint, it will be important that this information gets to those providers who are making the referrals to oncologists, which can include primary care physicians and emergency room providers, to ensure prompt diagnostic workup. Treatment decisions can only be made once a diagnosis has been recognized, and time is critical with this disease.

Dr. Klepin disclosed a consultancy for Genentech and Pfizer and is a contributor to UpToDate.

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

Ivosidenib may be effective against nonenhancing IDH1-mutated (mIDH1) advanced glioma, a phase 1 study suggests.

The median progression-free survival was 13.6 months for patients with nonenhancing tumors and 1.4 months for patients with enhancing tumors in a study of 66 adults with mIDH1 advanced glioma.

“On the basis of these data, additional clinical development of mIDH inhibitors for mIDH low-grade gliomas is warranted,” Ingo Mellinghoff, MD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues wrote in the Journal of Clinical Oncology.

“This is not a home run but is of interest to the community,” said Lawrence Recht, MD, of Stanford (Calif.) University, who was not involved in this study. “Other companies are also developing agents like this.”

Considering that the ivosidenib study “is uncontrolled, one cannot say for sure that this wasn’t just the natural history of the disease,” Dr. Recht continued. “This type of tumor can behave very indolently, and patients can survive years without treatment, so this is rather a short interval to make a long-time statement. I think the authors are a bit overenthusiastic.”

The authors tested ivosidenib in 66 adults with mIDH1 glioma – 35 with nonenhancing glioma and 31 with enhancing glioma. Tumors had recurred after, or did not respond to, initial surgery, radiation, or chemotherapy.

The patients’ median age was 41 years (range, 21-71 years), and 25 patients (37.9%) were women. The most common tumor type at screening was oligodendroglioma in 23 patients (34.8%).

Patients received ivosidenib at doses ranging from 100 mg twice a day to 900 mg once a day. A total of 50 patients received the phase 2 recommended dose – 500 mg once a day. There were no dose-limiting toxicities, and there was no maximum-tolerated dose.

Adverse events of grade 3 or higher occurred in 19.7% of patients and included headache, seizure, hyperglycemia, neutropenia, and hypophosphatemia. Grade 3 or higher treatment-related adverse events occurred in two patients.

A total of 30 patients with nonenhancing tumors (85.7%) and 14 with enhancing tumors (45.2%) had a best response of stable disease. There was one partial response in a nonenhancing patient on 500 mg/day. The rest of the subjects had a best response of progressive disease.

The median treatment duration was 18.4 months among patients with nonenhancing tumors and 1.9 months among those with enhancing tumors. Discontinuation was caused byo progression in all but one case.

Among patients with measurable disease, tumor measurements decreased from baseline in 22 nonenhancing tumors (66.7%) and in 9 enhancing tumors (33.3%).

“Despite the heterogeneous patient population in our trial, the nonrandomized design, and the lack of central pathology review, the data from our trial suggest that ivosidenib has greater activity against nonenhancing gliomas than against enhancing gliomas,” the investigators wrote. “This finding may seem surprising because the absence of contrast enhancement is typically associated with impaired drug delivery.

“We hypothesize that ivosidenib may be more effective in nonenhancing gliomas because these tumors represent an earlier disease stage with fewer genetic alterations, reminiscent of the greater antitumor activity of the BCR-ABL inhibitor imatinib in earlier stages of chronic myeloid leukemia,” the investigators wrote.

The team also noted that the median progression-free survival for patients with nonenhancing gliomas in the current study “compares favorably to that reported for temozolomide” in advanced mIDH1 low-grade glioma, which was approximately 7 months.

This research was funded by Agios Pharmaceuticals, the company developing ivosidenib. Dr. Mellinghoff receives travel compensation from and is an adviser to the company. Several other investigators are employees. Dr. Recht disclosed no conflicts of interest.

[email protected]

SOURCE: Mellinghoff I et al. J Clin Oncol. 2020 Jun 12. doi: 10.1200/JCO.19.03327

Ivosidenib may be effective against nonenhancing IDH1-mutated (mIDH1) advanced glioma, a phase 1 study suggests.

The median progression-free survival was 13.6 months for patients with nonenhancing tumors and 1.4 months for patients with enhancing tumors in a study of 66 adults with mIDH1 advanced glioma.

“On the basis of these data, additional clinical development of mIDH inhibitors for mIDH low-grade gliomas is warranted,” Ingo Mellinghoff, MD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues wrote in the Journal of Clinical Oncology.

“This is not a home run but is of interest to the community,” said Lawrence Recht, MD, of Stanford (Calif.) University, who was not involved in this study. “Other companies are also developing agents like this.”

Considering that the ivosidenib study “is uncontrolled, one cannot say for sure that this wasn’t just the natural history of the disease,” Dr. Recht continued. “This type of tumor can behave very indolently, and patients can survive years without treatment, so this is rather a short interval to make a long-time statement. I think the authors are a bit overenthusiastic.”

The authors tested ivosidenib in 66 adults with mIDH1 glioma – 35 with nonenhancing glioma and 31 with enhancing glioma. Tumors had recurred after, or did not respond to, initial surgery, radiation, or chemotherapy.

The patients’ median age was 41 years (range, 21-71 years), and 25 patients (37.9%) were women. The most common tumor type at screening was oligodendroglioma in 23 patients (34.8%).

Patients received ivosidenib at doses ranging from 100 mg twice a day to 900 mg once a day. A total of 50 patients received the phase 2 recommended dose – 500 mg once a day. There were no dose-limiting toxicities, and there was no maximum-tolerated dose.

Adverse events of grade 3 or higher occurred in 19.7% of patients and included headache, seizure, hyperglycemia, neutropenia, and hypophosphatemia. Grade 3 or higher treatment-related adverse events occurred in two patients.

A total of 30 patients with nonenhancing tumors (85.7%) and 14 with enhancing tumors (45.2%) had a best response of stable disease. There was one partial response in a nonenhancing patient on 500 mg/day. The rest of the subjects had a best response of progressive disease.

The median treatment duration was 18.4 months among patients with nonenhancing tumors and 1.9 months among those with enhancing tumors. Discontinuation was caused byo progression in all but one case.

Among patients with measurable disease, tumor measurements decreased from baseline in 22 nonenhancing tumors (66.7%) and in 9 enhancing tumors (33.3%).

“Despite the heterogeneous patient population in our trial, the nonrandomized design, and the lack of central pathology review, the data from our trial suggest that ivosidenib has greater activity against nonenhancing gliomas than against enhancing gliomas,” the investigators wrote. “This finding may seem surprising because the absence of contrast enhancement is typically associated with impaired drug delivery.

“We hypothesize that ivosidenib may be more effective in nonenhancing gliomas because these tumors represent an earlier disease stage with fewer genetic alterations, reminiscent of the greater antitumor activity of the BCR-ABL inhibitor imatinib in earlier stages of chronic myeloid leukemia,” the investigators wrote.

The team also noted that the median progression-free survival for patients with nonenhancing gliomas in the current study “compares favorably to that reported for temozolomide” in advanced mIDH1 low-grade glioma, which was approximately 7 months.

This research was funded by Agios Pharmaceuticals, the company developing ivosidenib. Dr. Mellinghoff receives travel compensation from and is an adviser to the company. Several other investigators are employees. Dr. Recht disclosed no conflicts of interest.

[email protected]

SOURCE: Mellinghoff I et al. J Clin Oncol. 2020 Jun 12. doi: 10.1200/JCO.19.03327

Ivosidenib may be effective against nonenhancing IDH1-mutated (mIDH1) advanced glioma, a phase 1 study suggests.

The median progression-free survival was 13.6 months for patients with nonenhancing tumors and 1.4 months for patients with enhancing tumors in a study of 66 adults with mIDH1 advanced glioma.

“On the basis of these data, additional clinical development of mIDH inhibitors for mIDH low-grade gliomas is warranted,” Ingo Mellinghoff, MD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues wrote in the Journal of Clinical Oncology.

“This is not a home run but is of interest to the community,” said Lawrence Recht, MD, of Stanford (Calif.) University, who was not involved in this study. “Other companies are also developing agents like this.”

Considering that the ivosidenib study “is uncontrolled, one cannot say for sure that this wasn’t just the natural history of the disease,” Dr. Recht continued. “This type of tumor can behave very indolently, and patients can survive years without treatment, so this is rather a short interval to make a long-time statement. I think the authors are a bit overenthusiastic.”

The authors tested ivosidenib in 66 adults with mIDH1 glioma – 35 with nonenhancing glioma and 31 with enhancing glioma. Tumors had recurred after, or did not respond to, initial surgery, radiation, or chemotherapy.

The patients’ median age was 41 years (range, 21-71 years), and 25 patients (37.9%) were women. The most common tumor type at screening was oligodendroglioma in 23 patients (34.8%).

Patients received ivosidenib at doses ranging from 100 mg twice a day to 900 mg once a day. A total of 50 patients received the phase 2 recommended dose – 500 mg once a day. There were no dose-limiting toxicities, and there was no maximum-tolerated dose.

Adverse events of grade 3 or higher occurred in 19.7% of patients and included headache, seizure, hyperglycemia, neutropenia, and hypophosphatemia. Grade 3 or higher treatment-related adverse events occurred in two patients.

A total of 30 patients with nonenhancing tumors (85.7%) and 14 with enhancing tumors (45.2%) had a best response of stable disease. There was one partial response in a nonenhancing patient on 500 mg/day. The rest of the subjects had a best response of progressive disease.

The median treatment duration was 18.4 months among patients with nonenhancing tumors and 1.9 months among those with enhancing tumors. Discontinuation was caused byo progression in all but one case.

Among patients with measurable disease, tumor measurements decreased from baseline in 22 nonenhancing tumors (66.7%) and in 9 enhancing tumors (33.3%).

“Despite the heterogeneous patient population in our trial, the nonrandomized design, and the lack of central pathology review, the data from our trial suggest that ivosidenib has greater activity against nonenhancing gliomas than against enhancing gliomas,” the investigators wrote. “This finding may seem surprising because the absence of contrast enhancement is typically associated with impaired drug delivery.

“We hypothesize that ivosidenib may be more effective in nonenhancing gliomas because these tumors represent an earlier disease stage with fewer genetic alterations, reminiscent of the greater antitumor activity of the BCR-ABL inhibitor imatinib in earlier stages of chronic myeloid leukemia,” the investigators wrote.

The team also noted that the median progression-free survival for patients with nonenhancing gliomas in the current study “compares favorably to that reported for temozolomide” in advanced mIDH1 low-grade glioma, which was approximately 7 months.

This research was funded by Agios Pharmaceuticals, the company developing ivosidenib. Dr. Mellinghoff receives travel compensation from and is an adviser to the company. Several other investigators are employees. Dr. Recht disclosed no conflicts of interest.

[email protected]

SOURCE: Mellinghoff I et al. J Clin Oncol. 2020 Jun 12. doi: 10.1200/JCO.19.03327

Patients with early onset cancers have an increased prevalence of germline pathogenic variants, suggesting that genetic testing would be worthwhile in this population, according to a presentation at the AACR virtual meeting II.

Investigators analyzed blood samples from 1,201 patients who were aged 18-39 years when diagnosed with a solid tumor malignancy.

In this group, there were 877 patients with early onset cancers, defined as cancers for which 39 years of age is greater than 1 standard deviation below the mean age of diagnosis for the cancer type.

The remaining 324 patients had young adult cancers, defined as cancers for which 39 years of age is less than 1 standard deviation below the mean age of diagnosis.

The most common early onset cancers were breast, colorectal, kidney, pancreas, and ovarian cancer.

The most common young adult cancers were sarcoma, brain cancer, and testicular cancer, as expected, said investigator Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Stadler and colleagues performed next-generation sequencing of the patient samples using a panel of up to 88 genes previously implicated in cancer predisposition. This revealed a significantly higher prevalence of germline mutations in patients with early onset cancers than in those with young adult cancers – 21% and 13%, respectively (P = .002).

In patients with only high- and moderate-risk cancer susceptibility genes, the prevalence was 15% in the early onset group and 10% in the young adult group (P = .01). “Among the early onset cancer group, pancreas, breast, and kidney cancer patients harbored the highest rates of germline mutations,” Dr. Stadler said, noting that the spectrum of mutated genes differed in early onset and young adult cancer patients.

“In early onset patients, the most commonly mutated genes were BRCA1 and BRCA2 [4.9%], Lynch syndrome genes [2.2%], ATM [1.6%], and CHECK2 [1.7%],” Dr. Stadler said. “On the other hand, in young adults, TP53 mutations [2.2%], and SDHA and SDHB mutations dominated [1.9%], with the majority of mutations occurring in sarcoma patients.”

These findings suggest the prevalence of inherited cancer susceptibility syndromes in young adults with cancer is not uniform.

“We found a very high prevalence of germline mutations in young patients with cancer types that typically present at later ages,” Dr. Stadler said, referring to the early onset patients.

Conversely, the young adult cancer patients had a prevalence and spectrum of mutations more similar to what is seen in pediatric cancer populations, she noted.

The findings are surprising, according to AACR past president Elaine R. Mardis, PhD, of The Ohio State University in Columbus.

Dr. Mardis said the results show that, in young adults with early onset cancers, “the germline prevalence of these mutations is significantly higher than we had previously thought.”

“Although representing only about 4% of all cancers, young adults with cancer ... face unique challenges,” Dr. Stadler said. “Identifying whether a young patient’s cancer occurred in the setting of an inherited cancer predisposition syndrome is especially important in this patient population.”

Such knowledge “can significantly impact the risk of second primary cancers and the need for increased surveillance measures or even risk-reducing surgeries,” Dr. Stadler explained. She added that it can also have implications for identifying at-risk family members, such as younger siblings or children who should pursue genetic testing and appropriate prevention measures.

“Our results suggest that, among patients with early onset cancer, the increased prevalence of germline mutations supports a role for genetic testing, irrespective of tumor type,” Dr. Stadler said.

This study was partially funded by the Precision, Interception and Prevention Program, the Robert and Katie Niehaus Center for Inherited Cancer Genomics, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, and a National Cancer Institute Cancer Center Core Grant. Dr. Stadler reported that an immediate family member serves as a consultant in ophthalmology for Allergan, Adverum Biotechnologies, Alimera Sciences, BioMarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Mardis disclosed relationships with Qiagen NV, Pact Pharma LLC, Moderna Inc., and Interpreta LLC.

[email protected]

SOURCE: Stadler Z et al. AACR 2020, Abstract 1122.

Patients with early onset cancers have an increased prevalence of germline pathogenic variants, suggesting that genetic testing would be worthwhile in this population, according to a presentation at the AACR virtual meeting II.

Investigators analyzed blood samples from 1,201 patients who were aged 18-39 years when diagnosed with a solid tumor malignancy.

In this group, there were 877 patients with early onset cancers, defined as cancers for which 39 years of age is greater than 1 standard deviation below the mean age of diagnosis for the cancer type.

The remaining 324 patients had young adult cancers, defined as cancers for which 39 years of age is less than 1 standard deviation below the mean age of diagnosis.

The most common early onset cancers were breast, colorectal, kidney, pancreas, and ovarian cancer.

The most common young adult cancers were sarcoma, brain cancer, and testicular cancer, as expected, said investigator Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Stadler and colleagues performed next-generation sequencing of the patient samples using a panel of up to 88 genes previously implicated in cancer predisposition. This revealed a significantly higher prevalence of germline mutations in patients with early onset cancers than in those with young adult cancers – 21% and 13%, respectively (P = .002).

In patients with only high- and moderate-risk cancer susceptibility genes, the prevalence was 15% in the early onset group and 10% in the young adult group (P = .01). “Among the early onset cancer group, pancreas, breast, and kidney cancer patients harbored the highest rates of germline mutations,” Dr. Stadler said, noting that the spectrum of mutated genes differed in early onset and young adult cancer patients.

“In early onset patients, the most commonly mutated genes were BRCA1 and BRCA2 [4.9%], Lynch syndrome genes [2.2%], ATM [1.6%], and CHECK2 [1.7%],” Dr. Stadler said. “On the other hand, in young adults, TP53 mutations [2.2%], and SDHA and SDHB mutations dominated [1.9%], with the majority of mutations occurring in sarcoma patients.”

These findings suggest the prevalence of inherited cancer susceptibility syndromes in young adults with cancer is not uniform.

“We found a very high prevalence of germline mutations in young patients with cancer types that typically present at later ages,” Dr. Stadler said, referring to the early onset patients.

Conversely, the young adult cancer patients had a prevalence and spectrum of mutations more similar to what is seen in pediatric cancer populations, she noted.

The findings are surprising, according to AACR past president Elaine R. Mardis, PhD, of The Ohio State University in Columbus.

Dr. Mardis said the results show that, in young adults with early onset cancers, “the germline prevalence of these mutations is significantly higher than we had previously thought.”

“Although representing only about 4% of all cancers, young adults with cancer ... face unique challenges,” Dr. Stadler said. “Identifying whether a young patient’s cancer occurred in the setting of an inherited cancer predisposition syndrome is especially important in this patient population.”

Such knowledge “can significantly impact the risk of second primary cancers and the need for increased surveillance measures or even risk-reducing surgeries,” Dr. Stadler explained. She added that it can also have implications for identifying at-risk family members, such as younger siblings or children who should pursue genetic testing and appropriate prevention measures.

“Our results suggest that, among patients with early onset cancer, the increased prevalence of germline mutations supports a role for genetic testing, irrespective of tumor type,” Dr. Stadler said.

This study was partially funded by the Precision, Interception and Prevention Program, the Robert and Katie Niehaus Center for Inherited Cancer Genomics, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, and a National Cancer Institute Cancer Center Core Grant. Dr. Stadler reported that an immediate family member serves as a consultant in ophthalmology for Allergan, Adverum Biotechnologies, Alimera Sciences, BioMarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Mardis disclosed relationships with Qiagen NV, Pact Pharma LLC, Moderna Inc., and Interpreta LLC.

[email protected]

SOURCE: Stadler Z et al. AACR 2020, Abstract 1122.

Patients with early onset cancers have an increased prevalence of germline pathogenic variants, suggesting that genetic testing would be worthwhile in this population, according to a presentation at the AACR virtual meeting II.

Investigators analyzed blood samples from 1,201 patients who were aged 18-39 years when diagnosed with a solid tumor malignancy.

In this group, there were 877 patients with early onset cancers, defined as cancers for which 39 years of age is greater than 1 standard deviation below the mean age of diagnosis for the cancer type.

The remaining 324 patients had young adult cancers, defined as cancers for which 39 years of age is less than 1 standard deviation below the mean age of diagnosis.

The most common early onset cancers were breast, colorectal, kidney, pancreas, and ovarian cancer.

The most common young adult cancers were sarcoma, brain cancer, and testicular cancer, as expected, said investigator Zsofia K. Stadler, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Stadler and colleagues performed next-generation sequencing of the patient samples using a panel of up to 88 genes previously implicated in cancer predisposition. This revealed a significantly higher prevalence of germline mutations in patients with early onset cancers than in those with young adult cancers – 21% and 13%, respectively (P = .002).

In patients with only high- and moderate-risk cancer susceptibility genes, the prevalence was 15% in the early onset group and 10% in the young adult group (P = .01). “Among the early onset cancer group, pancreas, breast, and kidney cancer patients harbored the highest rates of germline mutations,” Dr. Stadler said, noting that the spectrum of mutated genes differed in early onset and young adult cancer patients.

“In early onset patients, the most commonly mutated genes were BRCA1 and BRCA2 [4.9%], Lynch syndrome genes [2.2%], ATM [1.6%], and CHECK2 [1.7%],” Dr. Stadler said. “On the other hand, in young adults, TP53 mutations [2.2%], and SDHA and SDHB mutations dominated [1.9%], with the majority of mutations occurring in sarcoma patients.”

These findings suggest the prevalence of inherited cancer susceptibility syndromes in young adults with cancer is not uniform.

“We found a very high prevalence of germline mutations in young patients with cancer types that typically present at later ages,” Dr. Stadler said, referring to the early onset patients.

Conversely, the young adult cancer patients had a prevalence and spectrum of mutations more similar to what is seen in pediatric cancer populations, she noted.

The findings are surprising, according to AACR past president Elaine R. Mardis, PhD, of The Ohio State University in Columbus.

Dr. Mardis said the results show that, in young adults with early onset cancers, “the germline prevalence of these mutations is significantly higher than we had previously thought.”

“Although representing only about 4% of all cancers, young adults with cancer ... face unique challenges,” Dr. Stadler said. “Identifying whether a young patient’s cancer occurred in the setting of an inherited cancer predisposition syndrome is especially important in this patient population.”

Such knowledge “can significantly impact the risk of second primary cancers and the need for increased surveillance measures or even risk-reducing surgeries,” Dr. Stadler explained. She added that it can also have implications for identifying at-risk family members, such as younger siblings or children who should pursue genetic testing and appropriate prevention measures.

“Our results suggest that, among patients with early onset cancer, the increased prevalence of germline mutations supports a role for genetic testing, irrespective of tumor type,” Dr. Stadler said.

This study was partially funded by the Precision, Interception and Prevention Program, the Robert and Katie Niehaus Center for Inherited Cancer Genomics, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, and a National Cancer Institute Cancer Center Core Grant. Dr. Stadler reported that an immediate family member serves as a consultant in ophthalmology for Allergan, Adverum Biotechnologies, Alimera Sciences, BioMarin, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics. Dr. Mardis disclosed relationships with Qiagen NV, Pact Pharma LLC, Moderna Inc., and Interpreta LLC.

[email protected]

SOURCE: Stadler Z et al. AACR 2020, Abstract 1122.

Clearance of circulating tumor DNA (ctDNA) correlates with longer progression-free survival (PFS) in patients with EGFR-mutant, MET-amplified non–small cell lung cancer (NSCLC) treated with EGFR- and MET-targeted therapies, according to an analysis of data from the phase 1b TATTON study.

The median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for those without ctDNA clearance three to four cycles after starting treatment with osimertinib, an EGFR tyrosine kinase inhibitor (TKI), and savolitinib, a MET TKI (P = 0.0146).

“[O]ur findings indicate that EGFR-mutant ctDNA clearance may be predictive of longer PFS for patients with EGFR-mutant, MET-amplified non–small cell lung cancer and detectable ctDNA at baseline,” said investigator Ryan Hartmaier, PhD, of AstraZeneca in Boston, Mass.

Dr. Hartmaier presented these findings at the AACR virtual meeting II.
 

Prior results of TATTON

Interim results of the TATTON study were published earlier this year (Lancet Oncol. 2020 Mar;21[3]:373-386). The trial enrolled patients with locally advanced or metastatic EGFR-mutant, MET-amplified NSCLC who had progressed on a prior EGFR TKI. Results included patients enrolled in parts B and D.

Part B consisted of patients who had previously received a third-generation EGFR TKI and patients who had not received a third-generation EGFR TKI and were either Thr790Met negative or Thr790Met positive. There were 144 patients in part B. All received oral osimertinib at 80 mg, 138 received savolitinib at 600 mg, and 8 received savolitinib at 300 mg daily. Part D included 42 patients who had not received a third-generation EGFR TKI and were Thr790Met negative. In this cohort, patients received osimertinib at 80 mg and savolitinib at 300 mg daily.

The objective response rate (all partial responses) was 48% in part B and 64% in part D. The median PFS was 7.6 months and 9.1 months, respectively.

Alexander E. Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York said results of the TATTON study demonstrate that MET dependence is an actionable EGFR TKI resistance mechanism in EGFR-mutant lung cancers.

“We all would welcome the approval of an EGFR and MET TKI combination in the future,” Dr. Drilon said in a discussion of the study at the AACR meeting.

According to Dr. Hartmaier, MET-based resistance mechanisms are seen in up to 10% of patients with EGFR-mutated NSCLC following progression on first- and second-generation EGFR TKIs, and up to 25% of those progressing on osimertinib, a third-generation EGFR TKI.

“Nonclinical and clinical evidence suggests that combined treatment of a MET inhibitor and an EGFR TKI could overcome acquired MET-mediated resistance,” he said.
 

ctDNA analysis

Patients in the TATTON study had ctDNA samples collected at various time points from baseline through cycle five of treatment and until disease progression or treatment discontinuation.

Dr. Hartmaier’s analysis focused on ctDNA changes from baseline to day 1 of the third or fourth treatment cycle, time points at which the bulk of ctDNA could be observed, he said.

Among 34 evaluable patients in part B who received savolitinib at 600 mg, 22 had ctDNA clearance, and 12 had not. Among 16 evaluable patients in part D who received savolitinib at 300 mg, 13 had ctDNA clearance, and 3 had not.

Rates of ctDNA clearance were “remarkably similar” among the dosing groups, Dr. Hartmaier said.

In part B, the median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for patients without clearance (hazard ratio, 0.34; 95% confidence interval, 0.14-0.81; P = 0.0146).

Dr. Hartmaier did not present PFS results according to ctDNA clearance for patients in part D.

Dr. Drilon said serial ctDNA analyses can provide information on mechanisms of primary or acquired resistance, intra- and inter-tumoral heterogeneity, and the potential durability of benefit that can be achieved with combination targeted therapy. He acknowledged, however, that more work needs to be done in the field of MET-targeted therapy development.

“We need to work on standardizing diagnostic definitions of MET dependence, recognizing that loose definitions and poly-assay use make data challenging to interpret,” he said.

The TATTON study was supported by AstraZeneca. Dr. Hartmaier is an AstraZeneca employee and shareholder. Dr. Drilon disclosed relationships with AstraZeneca, Pfizer, Helsinn, Beigene, and other companies.

SOURCE: Hartmaier R, et al. AACR 2020, Abstract CT303.

Clearance of circulating tumor DNA (ctDNA) correlates with longer progression-free survival (PFS) in patients with EGFR-mutant, MET-amplified non–small cell lung cancer (NSCLC) treated with EGFR- and MET-targeted therapies, according to an analysis of data from the phase 1b TATTON study.

The median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for those without ctDNA clearance three to four cycles after starting treatment with osimertinib, an EGFR tyrosine kinase inhibitor (TKI), and savolitinib, a MET TKI (P = 0.0146).

“[O]ur findings indicate that EGFR-mutant ctDNA clearance may be predictive of longer PFS for patients with EGFR-mutant, MET-amplified non–small cell lung cancer and detectable ctDNA at baseline,” said investigator Ryan Hartmaier, PhD, of AstraZeneca in Boston, Mass.

Dr. Hartmaier presented these findings at the AACR virtual meeting II.
 

Prior results of TATTON

Interim results of the TATTON study were published earlier this year (Lancet Oncol. 2020 Mar;21[3]:373-386). The trial enrolled patients with locally advanced or metastatic EGFR-mutant, MET-amplified NSCLC who had progressed on a prior EGFR TKI. Results included patients enrolled in parts B and D.

Part B consisted of patients who had previously received a third-generation EGFR TKI and patients who had not received a third-generation EGFR TKI and were either Thr790Met negative or Thr790Met positive. There were 144 patients in part B. All received oral osimertinib at 80 mg, 138 received savolitinib at 600 mg, and 8 received savolitinib at 300 mg daily. Part D included 42 patients who had not received a third-generation EGFR TKI and were Thr790Met negative. In this cohort, patients received osimertinib at 80 mg and savolitinib at 300 mg daily.

The objective response rate (all partial responses) was 48% in part B and 64% in part D. The median PFS was 7.6 months and 9.1 months, respectively.

Alexander E. Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York said results of the TATTON study demonstrate that MET dependence is an actionable EGFR TKI resistance mechanism in EGFR-mutant lung cancers.

“We all would welcome the approval of an EGFR and MET TKI combination in the future,” Dr. Drilon said in a discussion of the study at the AACR meeting.

According to Dr. Hartmaier, MET-based resistance mechanisms are seen in up to 10% of patients with EGFR-mutated NSCLC following progression on first- and second-generation EGFR TKIs, and up to 25% of those progressing on osimertinib, a third-generation EGFR TKI.

“Nonclinical and clinical evidence suggests that combined treatment of a MET inhibitor and an EGFR TKI could overcome acquired MET-mediated resistance,” he said.
 

ctDNA analysis

Patients in the TATTON study had ctDNA samples collected at various time points from baseline through cycle five of treatment and until disease progression or treatment discontinuation.

Dr. Hartmaier’s analysis focused on ctDNA changes from baseline to day 1 of the third or fourth treatment cycle, time points at which the bulk of ctDNA could be observed, he said.

Among 34 evaluable patients in part B who received savolitinib at 600 mg, 22 had ctDNA clearance, and 12 had not. Among 16 evaluable patients in part D who received savolitinib at 300 mg, 13 had ctDNA clearance, and 3 had not.

Rates of ctDNA clearance were “remarkably similar” among the dosing groups, Dr. Hartmaier said.

In part B, the median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for patients without clearance (hazard ratio, 0.34; 95% confidence interval, 0.14-0.81; P = 0.0146).

Dr. Hartmaier did not present PFS results according to ctDNA clearance for patients in part D.

Dr. Drilon said serial ctDNA analyses can provide information on mechanisms of primary or acquired resistance, intra- and inter-tumoral heterogeneity, and the potential durability of benefit that can be achieved with combination targeted therapy. He acknowledged, however, that more work needs to be done in the field of MET-targeted therapy development.

“We need to work on standardizing diagnostic definitions of MET dependence, recognizing that loose definitions and poly-assay use make data challenging to interpret,” he said.

The TATTON study was supported by AstraZeneca. Dr. Hartmaier is an AstraZeneca employee and shareholder. Dr. Drilon disclosed relationships with AstraZeneca, Pfizer, Helsinn, Beigene, and other companies.

SOURCE: Hartmaier R, et al. AACR 2020, Abstract CT303.

Clearance of circulating tumor DNA (ctDNA) correlates with longer progression-free survival (PFS) in patients with EGFR-mutant, MET-amplified non–small cell lung cancer (NSCLC) treated with EGFR- and MET-targeted therapies, according to an analysis of data from the phase 1b TATTON study.

The median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for those without ctDNA clearance three to four cycles after starting treatment with osimertinib, an EGFR tyrosine kinase inhibitor (TKI), and savolitinib, a MET TKI (P = 0.0146).

“[O]ur findings indicate that EGFR-mutant ctDNA clearance may be predictive of longer PFS for patients with EGFR-mutant, MET-amplified non–small cell lung cancer and detectable ctDNA at baseline,” said investigator Ryan Hartmaier, PhD, of AstraZeneca in Boston, Mass.

Dr. Hartmaier presented these findings at the AACR virtual meeting II.
 

Prior results of TATTON

Interim results of the TATTON study were published earlier this year (Lancet Oncol. 2020 Mar;21[3]:373-386). The trial enrolled patients with locally advanced or metastatic EGFR-mutant, MET-amplified NSCLC who had progressed on a prior EGFR TKI. Results included patients enrolled in parts B and D.

Part B consisted of patients who had previously received a third-generation EGFR TKI and patients who had not received a third-generation EGFR TKI and were either Thr790Met negative or Thr790Met positive. There were 144 patients in part B. All received oral osimertinib at 80 mg, 138 received savolitinib at 600 mg, and 8 received savolitinib at 300 mg daily. Part D included 42 patients who had not received a third-generation EGFR TKI and were Thr790Met negative. In this cohort, patients received osimertinib at 80 mg and savolitinib at 300 mg daily.

The objective response rate (all partial responses) was 48% in part B and 64% in part D. The median PFS was 7.6 months and 9.1 months, respectively.

Alexander E. Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York said results of the TATTON study demonstrate that MET dependence is an actionable EGFR TKI resistance mechanism in EGFR-mutant lung cancers.

“We all would welcome the approval of an EGFR and MET TKI combination in the future,” Dr. Drilon said in a discussion of the study at the AACR meeting.

According to Dr. Hartmaier, MET-based resistance mechanisms are seen in up to 10% of patients with EGFR-mutated NSCLC following progression on first- and second-generation EGFR TKIs, and up to 25% of those progressing on osimertinib, a third-generation EGFR TKI.

“Nonclinical and clinical evidence suggests that combined treatment of a MET inhibitor and an EGFR TKI could overcome acquired MET-mediated resistance,” he said.
 

ctDNA analysis

Patients in the TATTON study had ctDNA samples collected at various time points from baseline through cycle five of treatment and until disease progression or treatment discontinuation.

Dr. Hartmaier’s analysis focused on ctDNA changes from baseline to day 1 of the third or fourth treatment cycle, time points at which the bulk of ctDNA could be observed, he said.

Among 34 evaluable patients in part B who received savolitinib at 600 mg, 22 had ctDNA clearance, and 12 had not. Among 16 evaluable patients in part D who received savolitinib at 300 mg, 13 had ctDNA clearance, and 3 had not.

Rates of ctDNA clearance were “remarkably similar” among the dosing groups, Dr. Hartmaier said.

In part B, the median PFS was 9.1 months for patients with ctDNA clearance and 3.9 months for patients without clearance (hazard ratio, 0.34; 95% confidence interval, 0.14-0.81; P = 0.0146).

Dr. Hartmaier did not present PFS results according to ctDNA clearance for patients in part D.

Dr. Drilon said serial ctDNA analyses can provide information on mechanisms of primary or acquired resistance, intra- and inter-tumoral heterogeneity, and the potential durability of benefit that can be achieved with combination targeted therapy. He acknowledged, however, that more work needs to be done in the field of MET-targeted therapy development.

“We need to work on standardizing diagnostic definitions of MET dependence, recognizing that loose definitions and poly-assay use make data challenging to interpret,” he said.

The TATTON study was supported by AstraZeneca. Dr. Hartmaier is an AstraZeneca employee and shareholder. Dr. Drilon disclosed relationships with AstraZeneca, Pfizer, Helsinn, Beigene, and other companies.

SOURCE: Hartmaier R, et al. AACR 2020, Abstract CT303.

BRCA carrier status alone should not influence screening recommendations for colorectal cancer or pancreatic ductal adenocarcinoma, according to an American Gastroenterological Association clinical practice update.

Relationships between BRCA carrier status and risks of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) remain unclear, reported lead author Sonia S. Kupfer, MD, AGAF, of the University of Chicago, and colleagues.

“Pathogenic variants in BRCA1 and BRCA2 have ... been associated with variable risk of GI cancer, including CRC, PDAC, biliary, and gastric cancers,” the investigators wrote in Gastroenterology. “However, the magnitude of GI cancer risks is not well established and there is minimal evidence or guidance on screening for GI cancers among BRCA1 and BRCA2 carriers.”

According to the investigators, personalized screening for CRC is well supported by evidence, as higher-risk individuals, such as those with a family history of CRC, have been shown to benefit from earlier and more frequent colonoscopies. Although the value of risk-based screening is less clear for other types of GI cancer, the investigators cited a growing body of evidence that supports screening individuals at high risk of PDAC.

Still, data illuminating the role of BRCA carrier status are relatively scarce, which has led to variability in clinical practice.

“Lack of accurate CRC and PDAC risk estimates in BRCA1 and BRCA2 leave physicians and patients without guidance, and result in a range of screening recommendations and practices in this population,” wrote Dr. Kupfer and colleagues.

To offer some clarity, they drafted the present clinical practice update on behalf of the AGA. The recommendations are framed within a discussion of relevant publications.

Data from multiple studies, for instance, suggest that BRCA pathogenic variants are found in 1.3% of patients with early-onset CRC, 0.2% of those with high-risk CRC, and 1.0% of those with any type of CRC, all of which are higher rates “than would be expected by chance.

“However,” the investigators added, “this association is not proof that the observed BRCA1 and BRCA2 pathogenic variants play a causative role in CRC.”

The investigators went on to discuss a 2018 meta-analysis by Oho et al., which included 14 studies evaluating risk of CRC among BRCA carriers. The analysis found that BRCA carriers had a 24% increased risk of CRC, which Dr. Kupfer and colleagues described as “small but statistically significant.” Subgroup analysis suggested that BRCA1 carriers drove this association, with a 49% increased risk of CRC, whereas no significant link was found with BRCA2.

Dr. Kupfer and colleagues described the 49% increase as “very modest,” and therefore insufficient to warrant more intensive screening, particularly when considered in the context of other risk factors, such as Lynch syndrome, which may entail a 1,600% increased risk of CRC. For PDAC, no such meta-analysis has been conducted; however, multiple studies have pointed to associations between BRCA and risk of PDAC.

For example, a 2018 case-control study by Hu et al. showed that BRCA1 and BRCA2 had relative prevalence rates of 0.59% and 1.95% among patients with PDAC. These rates translated to a 158% increased risk of PDAC for BRCA1, and a 520% increase risk for BRCA2; but Dr. Kupfer and colleagues noted that the BRCA2 carriers were from high-risk families, so the findings may not extend to the general population.

In light of these findings, the update recommends PDAC screening for BRCA carriers only if they have a family history of PDAC, with the caveat that the association between risk and degree of family involvement remains unknown.

Ultimately, for both CRC and PDAC, the investigators called for further BRCA research, based on the conclusion that “results from published studies provide inconsistent levels of evidence.”

The investigators reported no conflicts of interest.

SOURCE: Kupfer SS et al. Gastroenterology. 2020 Apr 23. doi: 10.1053/j.gastro.2020.03.086.

BRCA carrier status alone should not influence screening recommendations for colorectal cancer or pancreatic ductal adenocarcinoma, according to an American Gastroenterological Association clinical practice update.

Relationships between BRCA carrier status and risks of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) remain unclear, reported lead author Sonia S. Kupfer, MD, AGAF, of the University of Chicago, and colleagues.

“Pathogenic variants in BRCA1 and BRCA2 have ... been associated with variable risk of GI cancer, including CRC, PDAC, biliary, and gastric cancers,” the investigators wrote in Gastroenterology. “However, the magnitude of GI cancer risks is not well established and there is minimal evidence or guidance on screening for GI cancers among BRCA1 and BRCA2 carriers.”

According to the investigators, personalized screening for CRC is well supported by evidence, as higher-risk individuals, such as those with a family history of CRC, have been shown to benefit from earlier and more frequent colonoscopies. Although the value of risk-based screening is less clear for other types of GI cancer, the investigators cited a growing body of evidence that supports screening individuals at high risk of PDAC.

Still, data illuminating the role of BRCA carrier status are relatively scarce, which has led to variability in clinical practice.

“Lack of accurate CRC and PDAC risk estimates in BRCA1 and BRCA2 leave physicians and patients without guidance, and result in a range of screening recommendations and practices in this population,” wrote Dr. Kupfer and colleagues.

To offer some clarity, they drafted the present clinical practice update on behalf of the AGA. The recommendations are framed within a discussion of relevant publications.

Data from multiple studies, for instance, suggest that BRCA pathogenic variants are found in 1.3% of patients with early-onset CRC, 0.2% of those with high-risk CRC, and 1.0% of those with any type of CRC, all of which are higher rates “than would be expected by chance.

“However,” the investigators added, “this association is not proof that the observed BRCA1 and BRCA2 pathogenic variants play a causative role in CRC.”

The investigators went on to discuss a 2018 meta-analysis by Oho et al., which included 14 studies evaluating risk of CRC among BRCA carriers. The analysis found that BRCA carriers had a 24% increased risk of CRC, which Dr. Kupfer and colleagues described as “small but statistically significant.” Subgroup analysis suggested that BRCA1 carriers drove this association, with a 49% increased risk of CRC, whereas no significant link was found with BRCA2.

Dr. Kupfer and colleagues described the 49% increase as “very modest,” and therefore insufficient to warrant more intensive screening, particularly when considered in the context of other risk factors, such as Lynch syndrome, which may entail a 1,600% increased risk of CRC. For PDAC, no such meta-analysis has been conducted; however, multiple studies have pointed to associations between BRCA and risk of PDAC.

For example, a 2018 case-control study by Hu et al. showed that BRCA1 and BRCA2 had relative prevalence rates of 0.59% and 1.95% among patients with PDAC. These rates translated to a 158% increased risk of PDAC for BRCA1, and a 520% increase risk for BRCA2; but Dr. Kupfer and colleagues noted that the BRCA2 carriers were from high-risk families, so the findings may not extend to the general population.

In light of these findings, the update recommends PDAC screening for BRCA carriers only if they have a family history of PDAC, with the caveat that the association between risk and degree of family involvement remains unknown.

Ultimately, for both CRC and PDAC, the investigators called for further BRCA research, based on the conclusion that “results from published studies provide inconsistent levels of evidence.”

The investigators reported no conflicts of interest.

SOURCE: Kupfer SS et al. Gastroenterology. 2020 Apr 23. doi: 10.1053/j.gastro.2020.03.086.

BRCA carrier status alone should not influence screening recommendations for colorectal cancer or pancreatic ductal adenocarcinoma, according to an American Gastroenterological Association clinical practice update.

Relationships between BRCA carrier status and risks of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) remain unclear, reported lead author Sonia S. Kupfer, MD, AGAF, of the University of Chicago, and colleagues.

“Pathogenic variants in BRCA1 and BRCA2 have ... been associated with variable risk of GI cancer, including CRC, PDAC, biliary, and gastric cancers,” the investigators wrote in Gastroenterology. “However, the magnitude of GI cancer risks is not well established and there is minimal evidence or guidance on screening for GI cancers among BRCA1 and BRCA2 carriers.”

According to the investigators, personalized screening for CRC is well supported by evidence, as higher-risk individuals, such as those with a family history of CRC, have been shown to benefit from earlier and more frequent colonoscopies. Although the value of risk-based screening is less clear for other types of GI cancer, the investigators cited a growing body of evidence that supports screening individuals at high risk of PDAC.

Still, data illuminating the role of BRCA carrier status are relatively scarce, which has led to variability in clinical practice.

“Lack of accurate CRC and PDAC risk estimates in BRCA1 and BRCA2 leave physicians and patients without guidance, and result in a range of screening recommendations and practices in this population,” wrote Dr. Kupfer and colleagues.

To offer some clarity, they drafted the present clinical practice update on behalf of the AGA. The recommendations are framed within a discussion of relevant publications.

Data from multiple studies, for instance, suggest that BRCA pathogenic variants are found in 1.3% of patients with early-onset CRC, 0.2% of those with high-risk CRC, and 1.0% of those with any type of CRC, all of which are higher rates “than would be expected by chance.

“However,” the investigators added, “this association is not proof that the observed BRCA1 and BRCA2 pathogenic variants play a causative role in CRC.”

The investigators went on to discuss a 2018 meta-analysis by Oho et al., which included 14 studies evaluating risk of CRC among BRCA carriers. The analysis found that BRCA carriers had a 24% increased risk of CRC, which Dr. Kupfer and colleagues described as “small but statistically significant.” Subgroup analysis suggested that BRCA1 carriers drove this association, with a 49% increased risk of CRC, whereas no significant link was found with BRCA2.

Dr. Kupfer and colleagues described the 49% increase as “very modest,” and therefore insufficient to warrant more intensive screening, particularly when considered in the context of other risk factors, such as Lynch syndrome, which may entail a 1,600% increased risk of CRC. For PDAC, no such meta-analysis has been conducted; however, multiple studies have pointed to associations between BRCA and risk of PDAC.

For example, a 2018 case-control study by Hu et al. showed that BRCA1 and BRCA2 had relative prevalence rates of 0.59% and 1.95% among patients with PDAC. These rates translated to a 158% increased risk of PDAC for BRCA1, and a 520% increase risk for BRCA2; but Dr. Kupfer and colleagues noted that the BRCA2 carriers were from high-risk families, so the findings may not extend to the general population.

In light of these findings, the update recommends PDAC screening for BRCA carriers only if they have a family history of PDAC, with the caveat that the association between risk and degree of family involvement remains unknown.

Ultimately, for both CRC and PDAC, the investigators called for further BRCA research, based on the conclusion that “results from published studies provide inconsistent levels of evidence.”

The investigators reported no conflicts of interest.

SOURCE: Kupfer SS et al. Gastroenterology. 2020 Apr 23. doi: 10.1053/j.gastro.2020.03.086.

Hypercalcemia is found when the corrected serum calcium level is > 10.5 mg/dL.¹ Its symptoms are not specific and may include polyuria, dehydration, polydipsia, anorexia, nausea and/or vomiting, constipation, and other central nervous system manifestations, including confusion, delirium, cognitive impairment, muscle weakness, psychotic symptoms, and even coma.^1,2

Hypercalcemia has varied etiologies; however, malignancy-induced hypercalcemia is one of the most common causes. In the US, the most common causes of malignancy-induced hypercalcemia are primary tumors of the lung or breast, multiple myeloma (MM), squamous cell carcinoma of the head or neck, renal cancer, and ovarian cancer.¹

Men with prostate cancer and bone metastasis have relatively worse prognosis than do patient with no metastasis.³ In a recent meta-analysis of patients with bone-involved castration-resistant prostate cancer, the median survival was 21 months.³

Hypercalcemia is a rare manifestation of prostate cancer. In a retrospective study conducted between 2009 and 2013 using the Oncology Services Comprehensive Electronic Records (OSCER) warehouse of electronic health records (EHR), the rates of malignancy-induced hypercalcemia were the lowest among patients with prostate cancer, ranging from 1.4 to 2.1%.¹

We present this case to discuss different pathophysiologic mechanisms leading to hypercalcemia in a patient with prostate cancer with bone metastasis and to study the role of humoral and growth factors in the pathogenesis of the disease.

Case Presentation

An African American man aged 69 years presented to the emergency department (ED) with generalized weakness, fatigue, and lower extremities muscle weakness. He reported a 40-lb weight loss over the past 3 months, intermittent lower back pain, and a 50 pack-year smoking history. A physical examination suggested clinical signs of dehydration.

Laboratory test results indicated hypercalcemia, macrocytic anemia, and thrombocytopenia: calcium 15.8 mg/dL, serum albumin 4.1 mg/dL, alkaline phosphatase 139 μ/L, blood urea nitrogen 55 mg/dL, creatinine 3.4 mg/dL (baseline 1.4-1.5 mg/dL), hemoglobin 8 g/dL, mean corpuscular volume 99.6 fL, and platelets 100,000/μL. The patient was admitted for hypercalcemia. His intact parathyroid hormone (iPTH) was suppressed at 16 pg/mL, phosphorous was 3.8 mg/dL, parathyroid hormone-related peptide (PTHrP) was < 0.74 pmol/L, vitamin D (25 hydroxy cholecalciferol) was mildly decreased at 17.2 ng/mL, and 1,25 dihydroxy cholecalciferol (calcitriol) was < 5.0 (normal range 20-79.3 pg/mL).

A computed tomography (CT) scan of the chest and abdomen was taken due to the patient’s heavy smoking history, an incidentally detected right lung base nodule on chest X-ray, and hypercalcemia. The CT scan showed multiple right middle lobe lung nodules with and without calcifications and calcified right hilar lymph nodes (Figure 1).

To evaluate the pancytopenia, a bone marrow biopsy was done, which showed that 80 to 90% of the marrow space was replaced by fibrosis and metastatic malignancy. Trilinear hematopoiesis was not seen (Figure 2). The tumor cells were positive for prostate- specific membrane antigen (PSMA) and negative for cytokeratin 7 and 20 (CK7 and CK20).⁴ The former is a membrane protein expressed on prostate tissues, including cancer; the latter is a form of protein used to identify adenocarcinoma of unknown primary origin (CK7 usually found in primary/ metastatic lung adenocarcinoma and CK20 usually in primary and some metastatic diseases of colon adenocarcinoma).⁵ A prostatic specific antigen (PSA) test was markedly elevated: 335.94 ng/mL (1.46 ng/mL on a previous 2011 test).

Metastatic adenocarcinoma of the prostate was diagnosed without a prostate biopsy. To determine the extent of bone metastases, a technetium-99m-methylene diphosphonate (MDP) bone scintigraphy demonstrated a superscan with intense foci of increased radiotracer uptake involving the bilateral shoulders, sternoclavicular joints, and sternum with heterogeneous uptake involving bilateral anterior and posterior ribs; cervical, thoracic, and lumbar spines; sacrum, pelvis, and bilateral hips, including the femoral head/neck and intertrochanteric regions. Also noted were several foci of radiotracer uptake involving the mandible and bilateral skull in the region of the temporomandibular joints (Figure 3).

The patient was initially treated with IV isotonic saline, followed by calcitonin and then pamidronate after kidney function improved. His calcium level responded to the therapy, and a plan was made by medical oncology to start androgen deprivation therapy (ADT) prior to discharge.

He was initially treated with bicalutamide, while a luteinizing hormone-releasing hormone agonist (leuprolide) was added 1 week later. Bicalutamide was then discontinued and a combined androgen blockade consisting of leuprolide, ketoconazole, and hydrocortisone was started. This therapy resulted in remission, and PSA declined to 1.73 ng/ mL 3 months later. At that time the patient enrolled in a clinical trial with leuprolide and bicalutamide combined therapy. About 6 months after his diagnosis, patient’s cancer progressed and became hormone refractory disease. At that time, bicalutamide was discontinued, and his therapy was switched to combined leuprolide and enzalutamide. After 6 months of therapy with enzalutamide, the patient’s cancer progressed again. He was later treated with docetaxel chemotherapy but died 16 months after diagnosis.

showed improvement of hypercalcemia at the time of discharge, but 9 months later and toward the time of expiration, our patient developed secondary hyperparathyroidism, with calcium maintained in the normal range, while iPTH was significantly elevated, a finding likely explained by a decline in kidney function and a fall in glomerular filtration rate (Table).

Discussion

Hypercalcemia in the setting of prostate cancer is a rare complication with an uncertain pathophysiology.6 Several mechanisms have been proposed for hypercalcemia of malignancy, these comprise humoral hypercalcemia of malignancy mediated by increased PTHrP; local osteolytic hypercalcemia with secretion of other humoral factors; excess extrarenal activation of vitamin D (1,25[OH]2D); PTH secretion, ectopic or primary; and multiple concurrent etiologies.⁷

PTHrP is the predominant mediator for hypercalcemia of malignancy and is estimated to account for 80% of hypercalcemia in patients with cancer. This protein shares a substantial sequence homology with PTH; in fact, 8 of the first 13 amino acids at the N-terminal portion of PTH were identical.⁸ PTHrP has multiple isoforms (PTHrP 141, PTHrP 139, and PTHrP 173). Like PTH, it enhances renal tubular reabsorption of calcium while increasing urinary phosphorus excretion.⁷ The result is both hypercalcemia and hypophosphatemia. However, unlike PTH, PTHrP does not increase 1,25(OH)2D and thus does not increase intestinal absorption of calcium and phosphorus. PTHrP acts on osteoblasts, leading to enhanced synthesis of receptor activator of nuclear factor-κB ligand (RANKL).⁷

In one study, PTHrP was detected immunohistochemically in prostate cancer cells. Iwamura and colleagues used 33 radical prostatectomy specimens from patients with clinically localized carcinoma of the prostate.⁹ None of these patients demonstrated hypercalcemia prior to the surgery. Using a mouse monoclonal antibody to an amino acid fragment, all cases demonstrated some degree of immunoreactivity throughout the cytoplasm of the tumor cells, but immunostaining was absent from inflammatory and stromal cells.⁹Furthermore, the intensity of the staining appeared to directly correlate with increasing tumor grade.⁹

Another study by Iwamura and colleagues suggested that PTHrP may play a significant role in the growth of prostate cancer by acting locally in an autocrine fashion.¹⁰ In this study, all prostate cancer cell lines from different sources expressed PTHrP immunoreactivity as well as evidence of DNA synthesis, the latter being measured by thymidine incorporation assay. Moreover, when these cells were incubated with various concentrations of mouse monoclonal antibody directed to PTHrP fragment, PTHrP-induced DNA synthesis was inhibited in a dose-dependent manner and almost completely neutralized at a specific concentration. Interestingly, the study demonstrated that cancer cell line derived from bone metastatic lesions secreted significantly greater amounts of PTHrP than did the cell line derived from the metastasis in the brain or in the lymph node. These findings suggest that PTHrP production may confer some advantage on the ability of prostate cancer cells to grow in bone.¹⁰

Ando and colleagues reported that neuroendocrine dedifferentiated prostate cancer can develop as a result of long-term ADT even after several years of therapy and has the potential to worsen and develop severe hypercalcemia.⁸ Neuron-specific enolase was used as the specific marker for the neuroendocrine cell, which suggested that the prostate cancer cell derived from the neuroendocrine cell might synthesize PTHrP and be responsible for the observed hypercalcemia.⁸

Other mechanisms cited for hypercalcemia of malignancy include other humoral factors associated with increased remodeling and comprise interleukin 1, 3, 6 (IL-1, IL-3, IL-6); tumor necrosis factor α; transforming growth factor A and B observed in metastatic bone lesions in breast cancer; lymphotoxin; E series prostaglandins; and macrophage inflammatory protein 1α seen in MM.

Local osteolytic hypercalcemia accounts for about 20% of cases and is usually associated with extensive bone metastases. It is most commonly seen in MM and metastatic breast cancer and less commonly in leukemia. The proposed mechanism is thought to be because of the release of local cytokines from the tumor, resulting in excess osteoclast activation and enhanced bone resorption often through RANK/RANKL interaction.

Extrarenal production of 1,25(OH)2D by the tumor accounts for about 1% of cases of hypercalcemia in malignancy. 1,25(OH)2D causes increased intestinal absorption of calcium and enhances osteolytic bone resorption, resulting in increased serum calcium. This mechanism is most commonly seen with Hodgkin and non-Hodgkin lymphoma and had been reported in ovarian dysgerminoma.⁷

In our patient, bone imaging showed osteoblastic lesions, a finding that likely contrasts the local osteolytic bone destruction theory. PTHrP was not significantly elevated in the serum, and PTH levels ruled out any form of primary hyperparathyroidism. In addition, histopathology showed no evidence of mosaicism or neuroendocrine dedifferentiation.

Findings in aggregate tell us that an exact pathophysiologic mechanism leading to hypercalcemia in prostate cancer is still unclear and may involve an interplay between growth factors and possible osteolytic materials, yet it must be studied thoroughly.

Conclusions

Hypercalcemia in pure metastatic adenocarcinoma of prostate is a rare finding and is of uncertain significance. Some studies suggested a search for unusual histopathologies, including neuroendocrine cancer and neuroendocrine dedifferentiation.^8,11 However, in adenocarcinoma alone, it has an uncertain pathophysiology that needs to be further studied. Studies needed to investigate the role of PTHrP as a growth factor for both prostate cancer cells and development of hypercalcemia and possibly target-directed monoclonal antibody therapies may need to be extensively researched.

Hypercalcemia is found when the corrected serum calcium level is > 10.5 mg/dL.¹ Its symptoms are not specific and may include polyuria, dehydration, polydipsia, anorexia, nausea and/or vomiting, constipation, and other central nervous system manifestations, including confusion, delirium, cognitive impairment, muscle weakness, psychotic symptoms, and even coma.^1,2

Hypercalcemia has varied etiologies; however, malignancy-induced hypercalcemia is one of the most common causes. In the US, the most common causes of malignancy-induced hypercalcemia are primary tumors of the lung or breast, multiple myeloma (MM), squamous cell carcinoma of the head or neck, renal cancer, and ovarian cancer.¹

Men with prostate cancer and bone metastasis have relatively worse prognosis than do patient with no metastasis.³ In a recent meta-analysis of patients with bone-involved castration-resistant prostate cancer, the median survival was 21 months.³

Hypercalcemia is a rare manifestation of prostate cancer. In a retrospective study conducted between 2009 and 2013 using the Oncology Services Comprehensive Electronic Records (OSCER) warehouse of electronic health records (EHR), the rates of malignancy-induced hypercalcemia were the lowest among patients with prostate cancer, ranging from 1.4 to 2.1%.¹

We present this case to discuss different pathophysiologic mechanisms leading to hypercalcemia in a patient with prostate cancer with bone metastasis and to study the role of humoral and growth factors in the pathogenesis of the disease.

Case Presentation

An African American man aged 69 years presented to the emergency department (ED) with generalized weakness, fatigue, and lower extremities muscle weakness. He reported a 40-lb weight loss over the past 3 months, intermittent lower back pain, and a 50 pack-year smoking history. A physical examination suggested clinical signs of dehydration.

Laboratory test results indicated hypercalcemia, macrocytic anemia, and thrombocytopenia: calcium 15.8 mg/dL, serum albumin 4.1 mg/dL, alkaline phosphatase 139 μ/L, blood urea nitrogen 55 mg/dL, creatinine 3.4 mg/dL (baseline 1.4-1.5 mg/dL), hemoglobin 8 g/dL, mean corpuscular volume 99.6 fL, and platelets 100,000/μL. The patient was admitted for hypercalcemia. His intact parathyroid hormone (iPTH) was suppressed at 16 pg/mL, phosphorous was 3.8 mg/dL, parathyroid hormone-related peptide (PTHrP) was < 0.74 pmol/L, vitamin D (25 hydroxy cholecalciferol) was mildly decreased at 17.2 ng/mL, and 1,25 dihydroxy cholecalciferol (calcitriol) was < 5.0 (normal range 20-79.3 pg/mL).

A computed tomography (CT) scan of the chest and abdomen was taken due to the patient’s heavy smoking history, an incidentally detected right lung base nodule on chest X-ray, and hypercalcemia. The CT scan showed multiple right middle lobe lung nodules with and without calcifications and calcified right hilar lymph nodes (Figure 1).

To evaluate the pancytopenia, a bone marrow biopsy was done, which showed that 80 to 90% of the marrow space was replaced by fibrosis and metastatic malignancy. Trilinear hematopoiesis was not seen (Figure 2). The tumor cells were positive for prostate- specific membrane antigen (PSMA) and negative for cytokeratin 7 and 20 (CK7 and CK20).⁴ The former is a membrane protein expressed on prostate tissues, including cancer; the latter is a form of protein used to identify adenocarcinoma of unknown primary origin (CK7 usually found in primary/ metastatic lung adenocarcinoma and CK20 usually in primary and some metastatic diseases of colon adenocarcinoma).⁵ A prostatic specific antigen (PSA) test was markedly elevated: 335.94 ng/mL (1.46 ng/mL on a previous 2011 test).

Metastatic adenocarcinoma of the prostate was diagnosed without a prostate biopsy. To determine the extent of bone metastases, a technetium-99m-methylene diphosphonate (MDP) bone scintigraphy demonstrated a superscan with intense foci of increased radiotracer uptake involving the bilateral shoulders, sternoclavicular joints, and sternum with heterogeneous uptake involving bilateral anterior and posterior ribs; cervical, thoracic, and lumbar spines; sacrum, pelvis, and bilateral hips, including the femoral head/neck and intertrochanteric regions. Also noted were several foci of radiotracer uptake involving the mandible and bilateral skull in the region of the temporomandibular joints (Figure 3).

The patient was initially treated with IV isotonic saline, followed by calcitonin and then pamidronate after kidney function improved. His calcium level responded to the therapy, and a plan was made by medical oncology to start androgen deprivation therapy (ADT) prior to discharge.

He was initially treated with bicalutamide, while a luteinizing hormone-releasing hormone agonist (leuprolide) was added 1 week later. Bicalutamide was then discontinued and a combined androgen blockade consisting of leuprolide, ketoconazole, and hydrocortisone was started. This therapy resulted in remission, and PSA declined to 1.73 ng/ mL 3 months later. At that time the patient enrolled in a clinical trial with leuprolide and bicalutamide combined therapy. About 6 months after his diagnosis, patient’s cancer progressed and became hormone refractory disease. At that time, bicalutamide was discontinued, and his therapy was switched to combined leuprolide and enzalutamide. After 6 months of therapy with enzalutamide, the patient’s cancer progressed again. He was later treated with docetaxel chemotherapy but died 16 months after diagnosis.

showed improvement of hypercalcemia at the time of discharge, but 9 months later and toward the time of expiration, our patient developed secondary hyperparathyroidism, with calcium maintained in the normal range, while iPTH was significantly elevated, a finding likely explained by a decline in kidney function and a fall in glomerular filtration rate (Table).

Discussion

Hypercalcemia in the setting of prostate cancer is a rare complication with an uncertain pathophysiology.6 Several mechanisms have been proposed for hypercalcemia of malignancy, these comprise humoral hypercalcemia of malignancy mediated by increased PTHrP; local osteolytic hypercalcemia with secretion of other humoral factors; excess extrarenal activation of vitamin D (1,25[OH]2D); PTH secretion, ectopic or primary; and multiple concurrent etiologies.⁷

PTHrP is the predominant mediator for hypercalcemia of malignancy and is estimated to account for 80% of hypercalcemia in patients with cancer. This protein shares a substantial sequence homology with PTH; in fact, 8 of the first 13 amino acids at the N-terminal portion of PTH were identical.⁸ PTHrP has multiple isoforms (PTHrP 141, PTHrP 139, and PTHrP 173). Like PTH, it enhances renal tubular reabsorption of calcium while increasing urinary phosphorus excretion.⁷ The result is both hypercalcemia and hypophosphatemia. However, unlike PTH, PTHrP does not increase 1,25(OH)2D and thus does not increase intestinal absorption of calcium and phosphorus. PTHrP acts on osteoblasts, leading to enhanced synthesis of receptor activator of nuclear factor-κB ligand (RANKL).⁷

In one study, PTHrP was detected immunohistochemically in prostate cancer cells. Iwamura and colleagues used 33 radical prostatectomy specimens from patients with clinically localized carcinoma of the prostate.⁹ None of these patients demonstrated hypercalcemia prior to the surgery. Using a mouse monoclonal antibody to an amino acid fragment, all cases demonstrated some degree of immunoreactivity throughout the cytoplasm of the tumor cells, but immunostaining was absent from inflammatory and stromal cells.⁹Furthermore, the intensity of the staining appeared to directly correlate with increasing tumor grade.⁹

Another study by Iwamura and colleagues suggested that PTHrP may play a significant role in the growth of prostate cancer by acting locally in an autocrine fashion.¹⁰ In this study, all prostate cancer cell lines from different sources expressed PTHrP immunoreactivity as well as evidence of DNA synthesis, the latter being measured by thymidine incorporation assay. Moreover, when these cells were incubated with various concentrations of mouse monoclonal antibody directed to PTHrP fragment, PTHrP-induced DNA synthesis was inhibited in a dose-dependent manner and almost completely neutralized at a specific concentration. Interestingly, the study demonstrated that cancer cell line derived from bone metastatic lesions secreted significantly greater amounts of PTHrP than did the cell line derived from the metastasis in the brain or in the lymph node. These findings suggest that PTHrP production may confer some advantage on the ability of prostate cancer cells to grow in bone.¹⁰

Ando and colleagues reported that neuroendocrine dedifferentiated prostate cancer can develop as a result of long-term ADT even after several years of therapy and has the potential to worsen and develop severe hypercalcemia.⁸ Neuron-specific enolase was used as the specific marker for the neuroendocrine cell, which suggested that the prostate cancer cell derived from the neuroendocrine cell might synthesize PTHrP and be responsible for the observed hypercalcemia.⁸

Other mechanisms cited for hypercalcemia of malignancy include other humoral factors associated with increased remodeling and comprise interleukin 1, 3, 6 (IL-1, IL-3, IL-6); tumor necrosis factor α; transforming growth factor A and B observed in metastatic bone lesions in breast cancer; lymphotoxin; E series prostaglandins; and macrophage inflammatory protein 1α seen in MM.

Local osteolytic hypercalcemia accounts for about 20% of cases and is usually associated with extensive bone metastases. It is most commonly seen in MM and metastatic breast cancer and less commonly in leukemia. The proposed mechanism is thought to be because of the release of local cytokines from the tumor, resulting in excess osteoclast activation and enhanced bone resorption often through RANK/RANKL interaction.

Extrarenal production of 1,25(OH)2D by the tumor accounts for about 1% of cases of hypercalcemia in malignancy. 1,25(OH)2D causes increased intestinal absorption of calcium and enhances osteolytic bone resorption, resulting in increased serum calcium. This mechanism is most commonly seen with Hodgkin and non-Hodgkin lymphoma and had been reported in ovarian dysgerminoma.⁷

In our patient, bone imaging showed osteoblastic lesions, a finding that likely contrasts the local osteolytic bone destruction theory. PTHrP was not significantly elevated in the serum, and PTH levels ruled out any form of primary hyperparathyroidism. In addition, histopathology showed no evidence of mosaicism or neuroendocrine dedifferentiation.

Findings in aggregate tell us that an exact pathophysiologic mechanism leading to hypercalcemia in prostate cancer is still unclear and may involve an interplay between growth factors and possible osteolytic materials, yet it must be studied thoroughly.

Conclusions

Hypercalcemia in pure metastatic adenocarcinoma of prostate is a rare finding and is of uncertain significance. Some studies suggested a search for unusual histopathologies, including neuroendocrine cancer and neuroendocrine dedifferentiation.^8,11 However, in adenocarcinoma alone, it has an uncertain pathophysiology that needs to be further studied. Studies needed to investigate the role of PTHrP as a growth factor for both prostate cancer cells and development of hypercalcemia and possibly target-directed monoclonal antibody therapies may need to be extensively researched.

Hypercalcemia is found when the corrected serum calcium level is > 10.5 mg/dL.¹ Its symptoms are not specific and may include polyuria, dehydration, polydipsia, anorexia, nausea and/or vomiting, constipation, and other central nervous system manifestations, including confusion, delirium, cognitive impairment, muscle weakness, psychotic symptoms, and even coma.^1,2

Hypercalcemia has varied etiologies; however, malignancy-induced hypercalcemia is one of the most common causes. In the US, the most common causes of malignancy-induced hypercalcemia are primary tumors of the lung or breast, multiple myeloma (MM), squamous cell carcinoma of the head or neck, renal cancer, and ovarian cancer.¹

Men with prostate cancer and bone metastasis have relatively worse prognosis than do patient with no metastasis.³ In a recent meta-analysis of patients with bone-involved castration-resistant prostate cancer, the median survival was 21 months.³

Hypercalcemia is a rare manifestation of prostate cancer. In a retrospective study conducted between 2009 and 2013 using the Oncology Services Comprehensive Electronic Records (OSCER) warehouse of electronic health records (EHR), the rates of malignancy-induced hypercalcemia were the lowest among patients with prostate cancer, ranging from 1.4 to 2.1%.¹

We present this case to discuss different pathophysiologic mechanisms leading to hypercalcemia in a patient with prostate cancer with bone metastasis and to study the role of humoral and growth factors in the pathogenesis of the disease.

Case Presentation

An African American man aged 69 years presented to the emergency department (ED) with generalized weakness, fatigue, and lower extremities muscle weakness. He reported a 40-lb weight loss over the past 3 months, intermittent lower back pain, and a 50 pack-year smoking history. A physical examination suggested clinical signs of dehydration.

Laboratory test results indicated hypercalcemia, macrocytic anemia, and thrombocytopenia: calcium 15.8 mg/dL, serum albumin 4.1 mg/dL, alkaline phosphatase 139 μ/L, blood urea nitrogen 55 mg/dL, creatinine 3.4 mg/dL (baseline 1.4-1.5 mg/dL), hemoglobin 8 g/dL, mean corpuscular volume 99.6 fL, and platelets 100,000/μL. The patient was admitted for hypercalcemia. His intact parathyroid hormone (iPTH) was suppressed at 16 pg/mL, phosphorous was 3.8 mg/dL, parathyroid hormone-related peptide (PTHrP) was < 0.74 pmol/L, vitamin D (25 hydroxy cholecalciferol) was mildly decreased at 17.2 ng/mL, and 1,25 dihydroxy cholecalciferol (calcitriol) was < 5.0 (normal range 20-79.3 pg/mL).

A computed tomography (CT) scan of the chest and abdomen was taken due to the patient’s heavy smoking history, an incidentally detected right lung base nodule on chest X-ray, and hypercalcemia. The CT scan showed multiple right middle lobe lung nodules with and without calcifications and calcified right hilar lymph nodes (Figure 1).

To evaluate the pancytopenia, a bone marrow biopsy was done, which showed that 80 to 90% of the marrow space was replaced by fibrosis and metastatic malignancy. Trilinear hematopoiesis was not seen (Figure 2). The tumor cells were positive for prostate- specific membrane antigen (PSMA) and negative for cytokeratin 7 and 20 (CK7 and CK20).⁴ The former is a membrane protein expressed on prostate tissues, including cancer; the latter is a form of protein used to identify adenocarcinoma of unknown primary origin (CK7 usually found in primary/ metastatic lung adenocarcinoma and CK20 usually in primary and some metastatic diseases of colon adenocarcinoma).⁵ A prostatic specific antigen (PSA) test was markedly elevated: 335.94 ng/mL (1.46 ng/mL on a previous 2011 test).

Metastatic adenocarcinoma of the prostate was diagnosed without a prostate biopsy. To determine the extent of bone metastases, a technetium-99m-methylene diphosphonate (MDP) bone scintigraphy demonstrated a superscan with intense foci of increased radiotracer uptake involving the bilateral shoulders, sternoclavicular joints, and sternum with heterogeneous uptake involving bilateral anterior and posterior ribs; cervical, thoracic, and lumbar spines; sacrum, pelvis, and bilateral hips, including the femoral head/neck and intertrochanteric regions. Also noted were several foci of radiotracer uptake involving the mandible and bilateral skull in the region of the temporomandibular joints (Figure 3).

The patient was initially treated with IV isotonic saline, followed by calcitonin and then pamidronate after kidney function improved. His calcium level responded to the therapy, and a plan was made by medical oncology to start androgen deprivation therapy (ADT) prior to discharge.

He was initially treated with bicalutamide, while a luteinizing hormone-releasing hormone agonist (leuprolide) was added 1 week later. Bicalutamide was then discontinued and a combined androgen blockade consisting of leuprolide, ketoconazole, and hydrocortisone was started. This therapy resulted in remission, and PSA declined to 1.73 ng/ mL 3 months later. At that time the patient enrolled in a clinical trial with leuprolide and bicalutamide combined therapy. About 6 months after his diagnosis, patient’s cancer progressed and became hormone refractory disease. At that time, bicalutamide was discontinued, and his therapy was switched to combined leuprolide and enzalutamide. After 6 months of therapy with enzalutamide, the patient’s cancer progressed again. He was later treated with docetaxel chemotherapy but died 16 months after diagnosis.

showed improvement of hypercalcemia at the time of discharge, but 9 months later and toward the time of expiration, our patient developed secondary hyperparathyroidism, with calcium maintained in the normal range, while iPTH was significantly elevated, a finding likely explained by a decline in kidney function and a fall in glomerular filtration rate (Table).

Discussion

Hypercalcemia in the setting of prostate cancer is a rare complication with an uncertain pathophysiology.6 Several mechanisms have been proposed for hypercalcemia of malignancy, these comprise humoral hypercalcemia of malignancy mediated by increased PTHrP; local osteolytic hypercalcemia with secretion of other humoral factors; excess extrarenal activation of vitamin D (1,25[OH]2D); PTH secretion, ectopic or primary; and multiple concurrent etiologies.⁷

PTHrP is the predominant mediator for hypercalcemia of malignancy and is estimated to account for 80% of hypercalcemia in patients with cancer. This protein shares a substantial sequence homology with PTH; in fact, 8 of the first 13 amino acids at the N-terminal portion of PTH were identical.⁸ PTHrP has multiple isoforms (PTHrP 141, PTHrP 139, and PTHrP 173). Like PTH, it enhances renal tubular reabsorption of calcium while increasing urinary phosphorus excretion.⁷ The result is both hypercalcemia and hypophosphatemia. However, unlike PTH, PTHrP does not increase 1,25(OH)2D and thus does not increase intestinal absorption of calcium and phosphorus. PTHrP acts on osteoblasts, leading to enhanced synthesis of receptor activator of nuclear factor-κB ligand (RANKL).⁷

In one study, PTHrP was detected immunohistochemically in prostate cancer cells. Iwamura and colleagues used 33 radical prostatectomy specimens from patients with clinically localized carcinoma of the prostate.⁹ None of these patients demonstrated hypercalcemia prior to the surgery. Using a mouse monoclonal antibody to an amino acid fragment, all cases demonstrated some degree of immunoreactivity throughout the cytoplasm of the tumor cells, but immunostaining was absent from inflammatory and stromal cells.⁹Furthermore, the intensity of the staining appeared to directly correlate with increasing tumor grade.⁹

Another study by Iwamura and colleagues suggested that PTHrP may play a significant role in the growth of prostate cancer by acting locally in an autocrine fashion.¹⁰ In this study, all prostate cancer cell lines from different sources expressed PTHrP immunoreactivity as well as evidence of DNA synthesis, the latter being measured by thymidine incorporation assay. Moreover, when these cells were incubated with various concentrations of mouse monoclonal antibody directed to PTHrP fragment, PTHrP-induced DNA synthesis was inhibited in a dose-dependent manner and almost completely neutralized at a specific concentration. Interestingly, the study demonstrated that cancer cell line derived from bone metastatic lesions secreted significantly greater amounts of PTHrP than did the cell line derived from the metastasis in the brain or in the lymph node. These findings suggest that PTHrP production may confer some advantage on the ability of prostate cancer cells to grow in bone.¹⁰

Ando and colleagues reported that neuroendocrine dedifferentiated prostate cancer can develop as a result of long-term ADT even after several years of therapy and has the potential to worsen and develop severe hypercalcemia.⁸ Neuron-specific enolase was used as the specific marker for the neuroendocrine cell, which suggested that the prostate cancer cell derived from the neuroendocrine cell might synthesize PTHrP and be responsible for the observed hypercalcemia.⁸

Other mechanisms cited for hypercalcemia of malignancy include other humoral factors associated with increased remodeling and comprise interleukin 1, 3, 6 (IL-1, IL-3, IL-6); tumor necrosis factor α; transforming growth factor A and B observed in metastatic bone lesions in breast cancer; lymphotoxin; E series prostaglandins; and macrophage inflammatory protein 1α seen in MM.

Local osteolytic hypercalcemia accounts for about 20% of cases and is usually associated with extensive bone metastases. It is most commonly seen in MM and metastatic breast cancer and less commonly in leukemia. The proposed mechanism is thought to be because of the release of local cytokines from the tumor, resulting in excess osteoclast activation and enhanced bone resorption often through RANK/RANKL interaction.

Extrarenal production of 1,25(OH)2D by the tumor accounts for about 1% of cases of hypercalcemia in malignancy. 1,25(OH)2D causes increased intestinal absorption of calcium and enhances osteolytic bone resorption, resulting in increased serum calcium. This mechanism is most commonly seen with Hodgkin and non-Hodgkin lymphoma and had been reported in ovarian dysgerminoma.⁷

In our patient, bone imaging showed osteoblastic lesions, a finding that likely contrasts the local osteolytic bone destruction theory. PTHrP was not significantly elevated in the serum, and PTH levels ruled out any form of primary hyperparathyroidism. In addition, histopathology showed no evidence of mosaicism or neuroendocrine dedifferentiation.

Findings in aggregate tell us that an exact pathophysiologic mechanism leading to hypercalcemia in prostate cancer is still unclear and may involve an interplay between growth factors and possible osteolytic materials, yet it must be studied thoroughly.

Conclusions

Hypercalcemia in pure metastatic adenocarcinoma of prostate is a rare finding and is of uncertain significance. Some studies suggested a search for unusual histopathologies, including neuroendocrine cancer and neuroendocrine dedifferentiation.^8,11 However, in adenocarcinoma alone, it has an uncertain pathophysiology that needs to be further studied. Studies needed to investigate the role of PTHrP as a growth factor for both prostate cancer cells and development of hypercalcemia and possibly target-directed monoclonal antibody therapies may need to be extensively researched.

Transitioning from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone therapy increased proteasome inhibitor (PI)–based treatment adherence and duration, according to early results from a clinical trial designed to include patients representing the real-world U.S. multiple myeloma population.

The US MM-6 study was designed to evaluate a novel in-class therapy (iCT) transitioning approach from intravenous to oral treatment in the community-based setting with the aims of increasing PI-based treatment duration and adherence, maintaining health-related quality of life (HRQoL), and improving outcomes in a representative, real-world, community population of multiple myeloma patients, according to Sudhir Manda, MD, of Arizona Oncology/U.S. Oncology Research, Tucson, and colleagues.

Dr. Manda and colleagues reported on the early results of the US MM-6 trial (NCT03173092), which is a community-based, real-world, open-label, single-arm, phase 4 study of adult multiple myeloma patients who do not meet transplant-eligibility criteria, or for whom transplant would be delayed for 2 years or more, and who are receiving first-line bortezomib-based induction. All patients in the study had no evidence of progressive disease after three treatment cycles.

By the data cutoff for the reported analysis, 84 patients had been treated. The patients had a median age of 73 years; 49% were men; 15% black/African American; 10% Hispanic/Latino. A total of 62% of the patients remain on therapy, with a mean duration of total PI therapy of 10.1 months and of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) of 7.3 months.

The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after induction to all-oral ixazomib-Rd.

“The use of this novel iCT approach from parenteral bortezomib-based to oral ixazomib-based therapy facilitates long-term PI-based treatment that is well tolerated in real-world, nontransplant [newly diagnosed multiple myeloma] patients,” according to Dr. Manda and colleagues. In addition, “preliminary findings indicate that the iCT approach results in promising efficacy and high medication adherence, with no adverse impact on patients’ HRQoL or treatment satisfaction.”

The study was sponsored by Millennium Pharmaceuticals. Four of the authors are employees of Millennium Pharmaceuticals and several authors disclosed relationships with various pharmaceutical companies, including Millennium Pharmaceuticals.

[email protected]

SOURCE: Manda S et al. Clin Lymphoma Myeloma Leuk. 2020 Jun 30. doi: 10.1016/j.clml.2020.06.024.

Transitioning from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone therapy increased proteasome inhibitor (PI)–based treatment adherence and duration, according to early results from a clinical trial designed to include patients representing the real-world U.S. multiple myeloma population.

The US MM-6 study was designed to evaluate a novel in-class therapy (iCT) transitioning approach from intravenous to oral treatment in the community-based setting with the aims of increasing PI-based treatment duration and adherence, maintaining health-related quality of life (HRQoL), and improving outcomes in a representative, real-world, community population of multiple myeloma patients, according to Sudhir Manda, MD, of Arizona Oncology/U.S. Oncology Research, Tucson, and colleagues.

Dr. Manda and colleagues reported on the early results of the US MM-6 trial (NCT03173092), which is a community-based, real-world, open-label, single-arm, phase 4 study of adult multiple myeloma patients who do not meet transplant-eligibility criteria, or for whom transplant would be delayed for 2 years or more, and who are receiving first-line bortezomib-based induction. All patients in the study had no evidence of progressive disease after three treatment cycles.

By the data cutoff for the reported analysis, 84 patients had been treated. The patients had a median age of 73 years; 49% were men; 15% black/African American; 10% Hispanic/Latino. A total of 62% of the patients remain on therapy, with a mean duration of total PI therapy of 10.1 months and of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) of 7.3 months.

The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after induction to all-oral ixazomib-Rd.

“The use of this novel iCT approach from parenteral bortezomib-based to oral ixazomib-based therapy facilitates long-term PI-based treatment that is well tolerated in real-world, nontransplant [newly diagnosed multiple myeloma] patients,” according to Dr. Manda and colleagues. In addition, “preliminary findings indicate that the iCT approach results in promising efficacy and high medication adherence, with no adverse impact on patients’ HRQoL or treatment satisfaction.”

The study was sponsored by Millennium Pharmaceuticals. Four of the authors are employees of Millennium Pharmaceuticals and several authors disclosed relationships with various pharmaceutical companies, including Millennium Pharmaceuticals.

[email protected]

SOURCE: Manda S et al. Clin Lymphoma Myeloma Leuk. 2020 Jun 30. doi: 10.1016/j.clml.2020.06.024.

Transitioning from parenteral bortezomib-based induction to all-oral ixazomib-lenalidomide-dexamethasone therapy increased proteasome inhibitor (PI)–based treatment adherence and duration, according to early results from a clinical trial designed to include patients representing the real-world U.S. multiple myeloma population.

The US MM-6 study was designed to evaluate a novel in-class therapy (iCT) transitioning approach from intravenous to oral treatment in the community-based setting with the aims of increasing PI-based treatment duration and adherence, maintaining health-related quality of life (HRQoL), and improving outcomes in a representative, real-world, community population of multiple myeloma patients, according to Sudhir Manda, MD, of Arizona Oncology/U.S. Oncology Research, Tucson, and colleagues.

Dr. Manda and colleagues reported on the early results of the US MM-6 trial (NCT03173092), which is a community-based, real-world, open-label, single-arm, phase 4 study of adult multiple myeloma patients who do not meet transplant-eligibility criteria, or for whom transplant would be delayed for 2 years or more, and who are receiving first-line bortezomib-based induction. All patients in the study had no evidence of progressive disease after three treatment cycles.

By the data cutoff for the reported analysis, 84 patients had been treated. The patients had a median age of 73 years; 49% were men; 15% black/African American; 10% Hispanic/Latino. A total of 62% of the patients remain on therapy, with a mean duration of total PI therapy of 10.1 months and of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) of 7.3 months.

The overall response rate was 62% (complete response, 4%; very good partial response, 25%; partial response, 33%) after bortezomib-based induction and 70% (complete response, 26%; very good partial response, 29%; partial response, 15%) after induction to all-oral ixazomib-Rd.

“The use of this novel iCT approach from parenteral bortezomib-based to oral ixazomib-based therapy facilitates long-term PI-based treatment that is well tolerated in real-world, nontransplant [newly diagnosed multiple myeloma] patients,” according to Dr. Manda and colleagues. In addition, “preliminary findings indicate that the iCT approach results in promising efficacy and high medication adherence, with no adverse impact on patients’ HRQoL or treatment satisfaction.”

The study was sponsored by Millennium Pharmaceuticals. Four of the authors are employees of Millennium Pharmaceuticals and several authors disclosed relationships with various pharmaceutical companies, including Millennium Pharmaceuticals.

[email protected]

SOURCE: Manda S et al. Clin Lymphoma Myeloma Leuk. 2020 Jun 30. doi: 10.1016/j.clml.2020.06.024.

The incidence of colorectal cancer (CRC) in adults younger than 55 years has been increasing in recent years ― a “dramatic increase” was noted in the United States in 2017, and an increase in incidence has subsequently been seen in many other countries across Europe, as well as Australia, New Zealand, and Canada.

A new study has identified geographic hot spots across the United States, characterized by distinct patterns of early-onset CRC with worse survival among men. The hot spots primarily include counties in the lower Mississippi Delta, west-central Appalachia, and eastern Virginia/North Carolina.

In these hot spots, young adult non-Hispanic black men were specifically at risk and were more likely to die of the disease as compared to persons of other racial groups.

The study was published online on May 15 in the American Journal of Cancer Research.

These data can help to identify some of the risk factors associated with early-onset CRC/mortality, commented lead author Charles Rogers, PhD, MPH, a researcher at the Huntsman Cancer Institute and assistant professor of public health at the University of Utah, Salt Lake City.

“We noted potential explanations for the hot spots,” he told Medscape Medical News. “These include an enduring history of unique challenges, such as inadequate access to care, poor health literacy, and low educational attainment.”

Within hot-spot counties there were also higher rates of poverty, a lack of health insurance, and fewer primary care physicians.

“The disproportionate burden of early-onset colorectal cancer among non-Hispanic black men may result from distinctive stressors coupled with cultural and social expectations that impact screening and care behaviors,” said Rogers. “And while it’s estimated that approximately 14% of all US adults are current smokers, we observed that 24% of the adult population residing in hot-spot counties reported currently smoking and having smoked at least 100 cigarettes in their lifetime.”
 

Lifestyle and screening

Elements relating to the increase in early-onset CRC include environmental and geographical factors, as well as lifestyle factors, such as diet, obesity, and sedentary behaviors, Rogers commented.

“I think lifestyle factors are huge,” he said. “Consumption of high-fructose corn syrup and charred meat, for example, are worth considering and deserve more attention.”

He emphasized the importance of screening. Most health organizations in the United States recommend that screening start at age 50 years, but the American Cancer Society lowered this to 45 years, and the issue has been hotly debated. Rogers said that adults younger than 50 should be having conversations with their clinicians about screening for CRC. He noted that this is particularly important if they have any symptoms of CRC, have a family history of the disease, or reside in one of the hot spots that were identified in their study.

An expert who was approached for outside comment agreed. Chyke Doubeni, MBBS, MPH, director of the Center for Health Equity and Community Engagement Research at the Mayo Clinic in Rochester, Minnesota, said that anyone with health concerns should discuss preventive measures with their primary care physician.

“Screening for people younger than the age of 50 is currently controversial, as it is not recommended by some guidelines,” he said. “Recommendations for screening are different for people with a family history or certain genetic conditions.”

Such people include those younger than 50 years who have a family history of CRC or advanced adenomas. These patients should share that history with their primary care physician in order to determine when to begin screening and how often to be screened.

“People under the age of 50 who have symptoms such as unexplained rectal bleeding or iron deficiency anemia that may suggest the presence of colorectal cancer should be promptly evaluated for that possibility,” Doubeni added.
 

Hot spots versus other counties

The goal of the study was to identify mortality hot spots specific to men with early-onset CRC and to evaluate disparities while controlling for sex-specific differences. Rogers and colleagues identified counties with high early-onset CRC mortality rates using data from the Centers for Disease Control and Prevention (1999–2017) and linked them to data from the Surveillance, Epidemiology, and End Results (SEER) for men aged 15 to 49 years.

The team identified 232 US counties (7% of the total) as hot spots. The majority (214 of 232, 92%) were located in the South, and the remainder (18 of 232, 8%) were in the Midwest P < .01).

As compared to men living in other counties, those residing in hot-spot counties were more likely to be non-Hispanic blacks (30.82% vs 13.06%), less likely to be Hispanic (1.68% vs 16.65%; P < .01), and more likely to be diagnosed with metastatic disease (stage IV CRC) (2.58% vs 1.94%; P < .01).

Among men who lived in hot spots, CRC survival was poorer than was seen elsewhere (113.76 vs 129.04 months, respectively; P < .001). Among those with early-onset CRC, the risk for CRC-specific death was 24% higher (hazard ratio [HR], 1.24) than for men living outside of the hot-spot counties. However, that figure dropped to 12% after adjustment for county-level smoking (HR, 1.12).

With respect to racial/ethnic differences, non-Hispanic black (HR, 1.31) and Hispanic (HR, 1.12) patients had a 31% and 12% increased risk for CRC-specific death as compared to non-Hispanic white men (HR, 1.01) after adjusting for smoking status.

The authors note that among all determinants, “clinical stage explained the largest proportion of the variance” in early-onset CRC survival for men living in hot spots and other locations combined.

In the hot-spot counties, severe tumor grade was associated with greater CRC-specific mortality risk. Among patients with poorly differentiated tumors (HR, 1.87) and undifferentiated tumors (HR, 2.60), the mortality risk was nearly 2 times and 2.6 times greater, respectively, than those with well-differentiated tumors.

Compared to other counties, hot-spot counties were characterized by demographics that have been linked to poorer health outcomes, such as higher poverty rates (26.57% vs 16.77%), greater prevalence of adult obesity (34.94% vs 25.89%), higher adult smoking rates (23.97% vs 15.44%), higher uninsured rates (20.06% vs 17.91%), and fewer primary care physicians (58.28 vs 75.45 per 100,000 population).
 

Geographic distribution of CRC

Commenting to Medscape Medical News, Doubeni pointed out that the identified hot spots are similar to previously reported overall CRC hot spots.

“It shows the same patterns of geographic distribution of colorectal cancer in the United States,” he said. “These patterns tend to be associated with areas with high levels of poverty, as is the case with other chronic diseases, and may be related to clustering of risk factors and limited access to care in those areas.”

The research was supported by the National Cancer Institute of the National Institutes of Health, the Huntsman Cancer Foundation, and the Health Studies Fund of the Department of Family and Preventative Medicine at the University of Utah. The authors and Doubeni have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

The incidence of colorectal cancer (CRC) in adults younger than 55 years has been increasing in recent years ― a “dramatic increase” was noted in the United States in 2017, and an increase in incidence has subsequently been seen in many other countries across Europe, as well as Australia, New Zealand, and Canada.

A new study has identified geographic hot spots across the United States, characterized by distinct patterns of early-onset CRC with worse survival among men. The hot spots primarily include counties in the lower Mississippi Delta, west-central Appalachia, and eastern Virginia/North Carolina.

In these hot spots, young adult non-Hispanic black men were specifically at risk and were more likely to die of the disease as compared to persons of other racial groups.

The study was published online on May 15 in the American Journal of Cancer Research.

These data can help to identify some of the risk factors associated with early-onset CRC/mortality, commented lead author Charles Rogers, PhD, MPH, a researcher at the Huntsman Cancer Institute and assistant professor of public health at the University of Utah, Salt Lake City.

“We noted potential explanations for the hot spots,” he told Medscape Medical News. “These include an enduring history of unique challenges, such as inadequate access to care, poor health literacy, and low educational attainment.”

Within hot-spot counties there were also higher rates of poverty, a lack of health insurance, and fewer primary care physicians.

“The disproportionate burden of early-onset colorectal cancer among non-Hispanic black men may result from distinctive stressors coupled with cultural and social expectations that impact screening and care behaviors,” said Rogers. “And while it’s estimated that approximately 14% of all US adults are current smokers, we observed that 24% of the adult population residing in hot-spot counties reported currently smoking and having smoked at least 100 cigarettes in their lifetime.”
 

Lifestyle and screening

Elements relating to the increase in early-onset CRC include environmental and geographical factors, as well as lifestyle factors, such as diet, obesity, and sedentary behaviors, Rogers commented.

“I think lifestyle factors are huge,” he said. “Consumption of high-fructose corn syrup and charred meat, for example, are worth considering and deserve more attention.”

He emphasized the importance of screening. Most health organizations in the United States recommend that screening start at age 50 years, but the American Cancer Society lowered this to 45 years, and the issue has been hotly debated. Rogers said that adults younger than 50 should be having conversations with their clinicians about screening for CRC. He noted that this is particularly important if they have any symptoms of CRC, have a family history of the disease, or reside in one of the hot spots that were identified in their study.

An expert who was approached for outside comment agreed. Chyke Doubeni, MBBS, MPH, director of the Center for Health Equity and Community Engagement Research at the Mayo Clinic in Rochester, Minnesota, said that anyone with health concerns should discuss preventive measures with their primary care physician.

“Screening for people younger than the age of 50 is currently controversial, as it is not recommended by some guidelines,” he said. “Recommendations for screening are different for people with a family history or certain genetic conditions.”

Such people include those younger than 50 years who have a family history of CRC or advanced adenomas. These patients should share that history with their primary care physician in order to determine when to begin screening and how often to be screened.

“People under the age of 50 who have symptoms such as unexplained rectal bleeding or iron deficiency anemia that may suggest the presence of colorectal cancer should be promptly evaluated for that possibility,” Doubeni added.
 

Hot spots versus other counties

The goal of the study was to identify mortality hot spots specific to men with early-onset CRC and to evaluate disparities while controlling for sex-specific differences. Rogers and colleagues identified counties with high early-onset CRC mortality rates using data from the Centers for Disease Control and Prevention (1999–2017) and linked them to data from the Surveillance, Epidemiology, and End Results (SEER) for men aged 15 to 49 years.

The team identified 232 US counties (7% of the total) as hot spots. The majority (214 of 232, 92%) were located in the South, and the remainder (18 of 232, 8%) were in the Midwest P < .01).

As compared to men living in other counties, those residing in hot-spot counties were more likely to be non-Hispanic blacks (30.82% vs 13.06%), less likely to be Hispanic (1.68% vs 16.65%; P < .01), and more likely to be diagnosed with metastatic disease (stage IV CRC) (2.58% vs 1.94%; P < .01).

Among men who lived in hot spots, CRC survival was poorer than was seen elsewhere (113.76 vs 129.04 months, respectively; P < .001). Among those with early-onset CRC, the risk for CRC-specific death was 24% higher (hazard ratio [HR], 1.24) than for men living outside of the hot-spot counties. However, that figure dropped to 12% after adjustment for county-level smoking (HR, 1.12).

With respect to racial/ethnic differences, non-Hispanic black (HR, 1.31) and Hispanic (HR, 1.12) patients had a 31% and 12% increased risk for CRC-specific death as compared to non-Hispanic white men (HR, 1.01) after adjusting for smoking status.

The authors note that among all determinants, “clinical stage explained the largest proportion of the variance” in early-onset CRC survival for men living in hot spots and other locations combined.

In the hot-spot counties, severe tumor grade was associated with greater CRC-specific mortality risk. Among patients with poorly differentiated tumors (HR, 1.87) and undifferentiated tumors (HR, 2.60), the mortality risk was nearly 2 times and 2.6 times greater, respectively, than those with well-differentiated tumors.

Compared to other counties, hot-spot counties were characterized by demographics that have been linked to poorer health outcomes, such as higher poverty rates (26.57% vs 16.77%), greater prevalence of adult obesity (34.94% vs 25.89%), higher adult smoking rates (23.97% vs 15.44%), higher uninsured rates (20.06% vs 17.91%), and fewer primary care physicians (58.28 vs 75.45 per 100,000 population).
 

Geographic distribution of CRC

Commenting to Medscape Medical News, Doubeni pointed out that the identified hot spots are similar to previously reported overall CRC hot spots.

“It shows the same patterns of geographic distribution of colorectal cancer in the United States,” he said. “These patterns tend to be associated with areas with high levels of poverty, as is the case with other chronic diseases, and may be related to clustering of risk factors and limited access to care in those areas.”

The research was supported by the National Cancer Institute of the National Institutes of Health, the Huntsman Cancer Foundation, and the Health Studies Fund of the Department of Family and Preventative Medicine at the University of Utah. The authors and Doubeni have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.

The incidence of colorectal cancer (CRC) in adults younger than 55 years has been increasing in recent years ― a “dramatic increase” was noted in the United States in 2017, and an increase in incidence has subsequently been seen in many other countries across Europe, as well as Australia, New Zealand, and Canada.

A new study has identified geographic hot spots across the United States, characterized by distinct patterns of early-onset CRC with worse survival among men. The hot spots primarily include counties in the lower Mississippi Delta, west-central Appalachia, and eastern Virginia/North Carolina.

In these hot spots, young adult non-Hispanic black men were specifically at risk and were more likely to die of the disease as compared to persons of other racial groups.

The study was published online on May 15 in the American Journal of Cancer Research.

These data can help to identify some of the risk factors associated with early-onset CRC/mortality, commented lead author Charles Rogers, PhD, MPH, a researcher at the Huntsman Cancer Institute and assistant professor of public health at the University of Utah, Salt Lake City.

“We noted potential explanations for the hot spots,” he told Medscape Medical News. “These include an enduring history of unique challenges, such as inadequate access to care, poor health literacy, and low educational attainment.”

Within hot-spot counties there were also higher rates of poverty, a lack of health insurance, and fewer primary care physicians.

“The disproportionate burden of early-onset colorectal cancer among non-Hispanic black men may result from distinctive stressors coupled with cultural and social expectations that impact screening and care behaviors,” said Rogers. “And while it’s estimated that approximately 14% of all US adults are current smokers, we observed that 24% of the adult population residing in hot-spot counties reported currently smoking and having smoked at least 100 cigarettes in their lifetime.”
 

Lifestyle and screening

Elements relating to the increase in early-onset CRC include environmental and geographical factors, as well as lifestyle factors, such as diet, obesity, and sedentary behaviors, Rogers commented.

“I think lifestyle factors are huge,” he said. “Consumption of high-fructose corn syrup and charred meat, for example, are worth considering and deserve more attention.”

He emphasized the importance of screening. Most health organizations in the United States recommend that screening start at age 50 years, but the American Cancer Society lowered this to 45 years, and the issue has been hotly debated. Rogers said that adults younger than 50 should be having conversations with their clinicians about screening for CRC. He noted that this is particularly important if they have any symptoms of CRC, have a family history of the disease, or reside in one of the hot spots that were identified in their study.

An expert who was approached for outside comment agreed. Chyke Doubeni, MBBS, MPH, director of the Center for Health Equity and Community Engagement Research at the Mayo Clinic in Rochester, Minnesota, said that anyone with health concerns should discuss preventive measures with their primary care physician.

“Screening for people younger than the age of 50 is currently controversial, as it is not recommended by some guidelines,” he said. “Recommendations for screening are different for people with a family history or certain genetic conditions.”

Such people include those younger than 50 years who have a family history of CRC or advanced adenomas. These patients should share that history with their primary care physician in order to determine when to begin screening and how often to be screened.

“People under the age of 50 who have symptoms such as unexplained rectal bleeding or iron deficiency anemia that may suggest the presence of colorectal cancer should be promptly evaluated for that possibility,” Doubeni added.
 

Hot spots versus other counties

The goal of the study was to identify mortality hot spots specific to men with early-onset CRC and to evaluate disparities while controlling for sex-specific differences. Rogers and colleagues identified counties with high early-onset CRC mortality rates using data from the Centers for Disease Control and Prevention (1999–2017) and linked them to data from the Surveillance, Epidemiology, and End Results (SEER) for men aged 15 to 49 years.

The team identified 232 US counties (7% of the total) as hot spots. The majority (214 of 232, 92%) were located in the South, and the remainder (18 of 232, 8%) were in the Midwest P < .01).

As compared to men living in other counties, those residing in hot-spot counties were more likely to be non-Hispanic blacks (30.82% vs 13.06%), less likely to be Hispanic (1.68% vs 16.65%; P < .01), and more likely to be diagnosed with metastatic disease (stage IV CRC) (2.58% vs 1.94%; P < .01).

Among men who lived in hot spots, CRC survival was poorer than was seen elsewhere (113.76 vs 129.04 months, respectively; P < .001). Among those with early-onset CRC, the risk for CRC-specific death was 24% higher (hazard ratio [HR], 1.24) than for men living outside of the hot-spot counties. However, that figure dropped to 12% after adjustment for county-level smoking (HR, 1.12).

With respect to racial/ethnic differences, non-Hispanic black (HR, 1.31) and Hispanic (HR, 1.12) patients had a 31% and 12% increased risk for CRC-specific death as compared to non-Hispanic white men (HR, 1.01) after adjusting for smoking status.

The authors note that among all determinants, “clinical stage explained the largest proportion of the variance” in early-onset CRC survival for men living in hot spots and other locations combined.

In the hot-spot counties, severe tumor grade was associated with greater CRC-specific mortality risk. Among patients with poorly differentiated tumors (HR, 1.87) and undifferentiated tumors (HR, 2.60), the mortality risk was nearly 2 times and 2.6 times greater, respectively, than those with well-differentiated tumors.

Compared to other counties, hot-spot counties were characterized by demographics that have been linked to poorer health outcomes, such as higher poverty rates (26.57% vs 16.77%), greater prevalence of adult obesity (34.94% vs 25.89%), higher adult smoking rates (23.97% vs 15.44%), higher uninsured rates (20.06% vs 17.91%), and fewer primary care physicians (58.28 vs 75.45 per 100,000 population).
 

Geographic distribution of CRC

Commenting to Medscape Medical News, Doubeni pointed out that the identified hot spots are similar to previously reported overall CRC hot spots.

“It shows the same patterns of geographic distribution of colorectal cancer in the United States,” he said. “These patterns tend to be associated with areas with high levels of poverty, as is the case with other chronic diseases, and may be related to clustering of risk factors and limited access to care in those areas.”

The research was supported by the National Cancer Institute of the National Institutes of Health, the Huntsman Cancer Foundation, and the Health Studies Fund of the Department of Family and Preventative Medicine at the University of Utah. The authors and Doubeni have disclosed no relevant financial relationships.
 

This article first appeared on Medscape.com.