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Cancer, infection, and heart disease are greater risk factors for death in kidney transplant recipients who die with a functional graft than organ rejection, a retrospective Mayo Clinic cohort study indicates.

“It’s important to have immunosuppression to protect people from rejection, but we wanted to be able to say, ‘What are the other causes of kidney failure that we might be able to identify that help improve longer-term outcomes’,” coauthor Andrew Bentall, MBChB, MD, a Mayo Clinic nephrologist, told this news organization.

“And I think the main thing we found is that we need to differentiate people into two groups,” he said, including younger, nondiabetic patients who develop graft failure due to alloimmunity and older often diabetic patients “who are less likely to have a rejection episode but who are still at high risk for death from a malignancy or infection so maybe we can modify their immunosuppression, for example, and reduce their mortality risk which could be very helpful.”

The study was published online Jan. 17 in Transplantation Direct.
 

Cohort study

The cohort was made up of 5,752 consecutive kidney transplant recipients treated at one of three Mayo Clinic sites. The mean age of recipients was 53.8 years and one-quarter were 65 years of age or older. “At the time of transplantation, 69.8% were on dialysis, and 10.3% had received a prior kidney,” of which half were from a deceased donor, the authors note.

Almost all patients received tacrolimus as part of their maintenance immunosuppressive regimen. At a median follow-up of 3.5 years, overall graft failure occurred in 21.6% of patients, including death with a functioning graft (DWFG) in 12% and graft failure in 9.6% of patients. The most common causes of DWFG included malignancy at 20.0%, followed closely by infection at 19.7%, investigators note.

Cardiac disease was the cause of DWFG in 12.6% of patients, and the cause was unknown in 37%. Of those patients who died with a functioning graft, 12.3% died within the first year of transplantation. Roughly 45% died between 1 and 5 years later, and 42% died more than 5 years after transplantation.

On multivariable analysis, independent predictors of DWFG included:

• Older age at transplantation (hazard ratio, 1.75; P < .001)
• Male sex (HR, 1.34; P < .001)
• Dialysis prior to transplant (HR, 1.49; P < .001)
• Diabetes as a cause of end-stage renal disease (ESRD) (HR, 1.88; P < .001)
• Prednisone use as maintenance therapy (HR, 1.34; P = .008)

Graft failure

Of patients who had graft failure, almost one-quarter occurred within the first year of transplantation, about 42% occurred 1 to 5 years later, and a third occurred more than 5 years later.

Most patients (39%) who went on to graft failure did so as a result of “alloimmunity”, a term investigators used to cover all types of rejection, with a smaller number of graft failures being caused by glomerular diseases, at 18.6%, and renal tubular injury, at 13.9%.

“In the first year after transplantation, surgical complications and primary nonfunction of the allograft caused 60.3% ... of graft losses,” the authors point out. Beyond the first year, alloimmunity accounted for approximately half of the cases of graft failure, investigators note.

In the multivariable analysis for overall graft failure, risk factors included:

• Young recipient age (HR, 0.80; P < .001)
• History of a previous kidney transplant (HR, 1.33; P = .042)
• Dialysis at time of transplantation (HR, 1.54; P < .001)
• Black recipient race (HR, 1.40; P = .006)
• Black donor race (HR, 1.35; P = .038)
• Diabetes as a cause of ESRD (HR, 1.40; P = .002)
• HLA mismatch (HR, 1.27; P < .001)
• Delayed graft function (HR, 2.20; P < .001)

“Over time, DWFG was more common than graft failure,” the authors note.
 

Modifiable risk factors

As Dr. Bentall acknowledged, not all risk factors contributing to DWFG or graft failure are modifiable. However, diabetes – which stood out as a risk factor for both DWFG and graft failure – is potentially modifiable before patients reach ESRD, as he suggested. Diabetes is currently a cause for up to 40% of all ESRD cases in the United States.

“We can’t necessarily always reverse the diabetes, but there are significant new medications that can be used along with weight loss strategies to improve diabetes control,” he noted.

Similarly, it’s well established that patients who come into transplantation with a body mass index in excess of 30 kg/m2 have more scarring and damage to the kidney 5- and 10-years post-transplantation than healthy weight patients, as Dr. Bentall observed. “Again, this is a key modifiable component, and it fits into diabetes intervention strategies as well,” he emphasized. The use of prednisone as maintenance immunosuppressive therapy similarly emerged as a risk factor for DWFG.

Transplant recipients who receive prednisone may well be a higher risk population to begin with, “but we are also using prednisone in our older patients because we try to use less induction immunosuppression at the time of transplantation. So if we can try and get people off prednisone, that may lessen their risk of infection and subsequent mortality,” Dr. Bentall noted.

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

Cancer, infection, and heart disease are greater risk factors for death in kidney transplant recipients who die with a functional graft than organ rejection, a retrospective Mayo Clinic cohort study indicates.

“It’s important to have immunosuppression to protect people from rejection, but we wanted to be able to say, ‘What are the other causes of kidney failure that we might be able to identify that help improve longer-term outcomes’,” coauthor Andrew Bentall, MBChB, MD, a Mayo Clinic nephrologist, told this news organization.

“And I think the main thing we found is that we need to differentiate people into two groups,” he said, including younger, nondiabetic patients who develop graft failure due to alloimmunity and older often diabetic patients “who are less likely to have a rejection episode but who are still at high risk for death from a malignancy or infection so maybe we can modify their immunosuppression, for example, and reduce their mortality risk which could be very helpful.”

The study was published online Jan. 17 in Transplantation Direct.
 

Cohort study

The cohort was made up of 5,752 consecutive kidney transplant recipients treated at one of three Mayo Clinic sites. The mean age of recipients was 53.8 years and one-quarter were 65 years of age or older. “At the time of transplantation, 69.8% were on dialysis, and 10.3% had received a prior kidney,” of which half were from a deceased donor, the authors note.

Almost all patients received tacrolimus as part of their maintenance immunosuppressive regimen. At a median follow-up of 3.5 years, overall graft failure occurred in 21.6% of patients, including death with a functioning graft (DWFG) in 12% and graft failure in 9.6% of patients. The most common causes of DWFG included malignancy at 20.0%, followed closely by infection at 19.7%, investigators note.

Cardiac disease was the cause of DWFG in 12.6% of patients, and the cause was unknown in 37%. Of those patients who died with a functioning graft, 12.3% died within the first year of transplantation. Roughly 45% died between 1 and 5 years later, and 42% died more than 5 years after transplantation.

On multivariable analysis, independent predictors of DWFG included:

• Older age at transplantation (hazard ratio, 1.75; P < .001)
• Male sex (HR, 1.34; P < .001)
• Dialysis prior to transplant (HR, 1.49; P < .001)
• Diabetes as a cause of end-stage renal disease (ESRD) (HR, 1.88; P < .001)
• Prednisone use as maintenance therapy (HR, 1.34; P = .008)

Graft failure

Of patients who had graft failure, almost one-quarter occurred within the first year of transplantation, about 42% occurred 1 to 5 years later, and a third occurred more than 5 years later.

Most patients (39%) who went on to graft failure did so as a result of “alloimmunity”, a term investigators used to cover all types of rejection, with a smaller number of graft failures being caused by glomerular diseases, at 18.6%, and renal tubular injury, at 13.9%.

“In the first year after transplantation, surgical complications and primary nonfunction of the allograft caused 60.3% ... of graft losses,” the authors point out. Beyond the first year, alloimmunity accounted for approximately half of the cases of graft failure, investigators note.

In the multivariable analysis for overall graft failure, risk factors included:

• Young recipient age (HR, 0.80; P < .001)
• History of a previous kidney transplant (HR, 1.33; P = .042)
• Dialysis at time of transplantation (HR, 1.54; P < .001)
• Black recipient race (HR, 1.40; P = .006)
• Black donor race (HR, 1.35; P = .038)
• Diabetes as a cause of ESRD (HR, 1.40; P = .002)
• HLA mismatch (HR, 1.27; P < .001)
• Delayed graft function (HR, 2.20; P < .001)

“Over time, DWFG was more common than graft failure,” the authors note.
 

Modifiable risk factors

As Dr. Bentall acknowledged, not all risk factors contributing to DWFG or graft failure are modifiable. However, diabetes – which stood out as a risk factor for both DWFG and graft failure – is potentially modifiable before patients reach ESRD, as he suggested. Diabetes is currently a cause for up to 40% of all ESRD cases in the United States.

“We can’t necessarily always reverse the diabetes, but there are significant new medications that can be used along with weight loss strategies to improve diabetes control,” he noted.

Similarly, it’s well established that patients who come into transplantation with a body mass index in excess of 30 kg/m2 have more scarring and damage to the kidney 5- and 10-years post-transplantation than healthy weight patients, as Dr. Bentall observed. “Again, this is a key modifiable component, and it fits into diabetes intervention strategies as well,” he emphasized. The use of prednisone as maintenance immunosuppressive therapy similarly emerged as a risk factor for DWFG.

Transplant recipients who receive prednisone may well be a higher risk population to begin with, “but we are also using prednisone in our older patients because we try to use less induction immunosuppression at the time of transplantation. So if we can try and get people off prednisone, that may lessen their risk of infection and subsequent mortality,” Dr. Bentall noted.

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

Cancer, infection, and heart disease are greater risk factors for death in kidney transplant recipients who die with a functional graft than organ rejection, a retrospective Mayo Clinic cohort study indicates.

“It’s important to have immunosuppression to protect people from rejection, but we wanted to be able to say, ‘What are the other causes of kidney failure that we might be able to identify that help improve longer-term outcomes’,” coauthor Andrew Bentall, MBChB, MD, a Mayo Clinic nephrologist, told this news organization.

“And I think the main thing we found is that we need to differentiate people into two groups,” he said, including younger, nondiabetic patients who develop graft failure due to alloimmunity and older often diabetic patients “who are less likely to have a rejection episode but who are still at high risk for death from a malignancy or infection so maybe we can modify their immunosuppression, for example, and reduce their mortality risk which could be very helpful.”

The study was published online Jan. 17 in Transplantation Direct.
 

Cohort study

The cohort was made up of 5,752 consecutive kidney transplant recipients treated at one of three Mayo Clinic sites. The mean age of recipients was 53.8 years and one-quarter were 65 years of age or older. “At the time of transplantation, 69.8% were on dialysis, and 10.3% had received a prior kidney,” of which half were from a deceased donor, the authors note.

Almost all patients received tacrolimus as part of their maintenance immunosuppressive regimen. At a median follow-up of 3.5 years, overall graft failure occurred in 21.6% of patients, including death with a functioning graft (DWFG) in 12% and graft failure in 9.6% of patients. The most common causes of DWFG included malignancy at 20.0%, followed closely by infection at 19.7%, investigators note.

Cardiac disease was the cause of DWFG in 12.6% of patients, and the cause was unknown in 37%. Of those patients who died with a functioning graft, 12.3% died within the first year of transplantation. Roughly 45% died between 1 and 5 years later, and 42% died more than 5 years after transplantation.

On multivariable analysis, independent predictors of DWFG included:

• Older age at transplantation (hazard ratio, 1.75; P < .001)
• Male sex (HR, 1.34; P < .001)
• Dialysis prior to transplant (HR, 1.49; P < .001)
• Diabetes as a cause of end-stage renal disease (ESRD) (HR, 1.88; P < .001)
• Prednisone use as maintenance therapy (HR, 1.34; P = .008)

Graft failure

Of patients who had graft failure, almost one-quarter occurred within the first year of transplantation, about 42% occurred 1 to 5 years later, and a third occurred more than 5 years later.

Most patients (39%) who went on to graft failure did so as a result of “alloimmunity”, a term investigators used to cover all types of rejection, with a smaller number of graft failures being caused by glomerular diseases, at 18.6%, and renal tubular injury, at 13.9%.

“In the first year after transplantation, surgical complications and primary nonfunction of the allograft caused 60.3% ... of graft losses,” the authors point out. Beyond the first year, alloimmunity accounted for approximately half of the cases of graft failure, investigators note.

In the multivariable analysis for overall graft failure, risk factors included:

• Young recipient age (HR, 0.80; P < .001)
• History of a previous kidney transplant (HR, 1.33; P = .042)
• Dialysis at time of transplantation (HR, 1.54; P < .001)
• Black recipient race (HR, 1.40; P = .006)
• Black donor race (HR, 1.35; P = .038)
• Diabetes as a cause of ESRD (HR, 1.40; P = .002)
• HLA mismatch (HR, 1.27; P < .001)
• Delayed graft function (HR, 2.20; P < .001)

“Over time, DWFG was more common than graft failure,” the authors note.
 

Modifiable risk factors

As Dr. Bentall acknowledged, not all risk factors contributing to DWFG or graft failure are modifiable. However, diabetes – which stood out as a risk factor for both DWFG and graft failure – is potentially modifiable before patients reach ESRD, as he suggested. Diabetes is currently a cause for up to 40% of all ESRD cases in the United States.

“We can’t necessarily always reverse the diabetes, but there are significant new medications that can be used along with weight loss strategies to improve diabetes control,” he noted.

Similarly, it’s well established that patients who come into transplantation with a body mass index in excess of 30 kg/m2 have more scarring and damage to the kidney 5- and 10-years post-transplantation than healthy weight patients, as Dr. Bentall observed. “Again, this is a key modifiable component, and it fits into diabetes intervention strategies as well,” he emphasized. The use of prednisone as maintenance immunosuppressive therapy similarly emerged as a risk factor for DWFG.

Transplant recipients who receive prednisone may well be a higher risk population to begin with, “but we are also using prednisone in our older patients because we try to use less induction immunosuppression at the time of transplantation. So if we can try and get people off prednisone, that may lessen their risk of infection and subsequent mortality,” Dr. Bentall noted.

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

Many patients with early breast cancer are being undertreated, concludes a novel study that examined the management of such patients across various geographical regions across the United States.

A standard treatment for early breast cancer is endocrine therapy (ET), with drugs such a tamoxifen and aromatase inhibitors.

But the study found that ET was not being used in about half of the eligible patients.

For example, only 13,115 of 26,255 eligible patients (48.8%) initiated ET within 1 year of diagnosis, and only 13,944 (52.1%) continued with ET.

“This is remarkable, considering that ET confers an impressive one-third reduction in the risk of death from breast cancer in the first 15 years after diagnosis,” comment authors Michael J. Hassett, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.

The findings were published online on Jan. 27 in JAMA Oncology.

This study provides an “important and disturbing” glimpse of the hidden barriers patients face when seeking quality, guideline-concordant care, says Kathy Miller, MD, the Ballve Lantero professor of oncology at Indiana University School of Medicine and associate director of clinical research at the IU Simon Comprehensive Cancer Center, Indianapolis, who was approached for comment.
 

Geographical variations

In their study, Dr. Hasset and colleagues set out determine the extent to which geospatial variations in early breast cancer care are attributable to health service area versus patient factors. They analyzed Surveillance, Epidemiology, and End Results (SEER) Medicare data for 31,571 patients with newly diagnosed with stage I-II nonmetastatic breast cancer between 2007 and 2013 who were followed for at least 3 years.

The patients had a median age of 71 years, and 61.4% had stage I disease at diagnosis.

Geospatial density maps (heat maps) in the paper highlight regional performance patterns. For initiation of ET within 1 year of diagnosis, the regions that appeared the worst (with less than 50% of patients getting this treatment) were parts of California, Utah, New Mexico, Louisiana, Georgia, Kentucky, Washington, and an isolated patch in Michigan.

In addition to the striking finding that nearly half of all women who are eligible for ET did not receive that therapy, the investigators found that 81.6% of 21,190 eligible patients received radiation therapy and 72.8% of 9,903 eligible patients received chemotherapy.

This also varied across the graphical regions, with the heat maps showing that the areas that were delivering radiation and chemotherapy to 70% to 80% of women were similar to the areas that were not initiating ET in about half of these women.

The authors found that the geographical region and health service area (HSA) explained more observed variation (24% to 48%) than patient factors (1% to 4%).

“While patient characteristics, such as race and ethnicity, were significantly associated with variation in breast cancer care, they explained a relatively small proportion of the total observed geospatial variance,” the authors comment.

“In fact, most of the total observed variance was owing to randomness or unexplained factors,” they add. The largest share of variation – 35% to 45% – was unexplained.

“The ET metrics demonstrated the largest total observed variance, the lowest absolute performance (only 49% of patients had an ET prescription within 1 year of diagnosis), and the strongest association with region/HSA,” they conclude.

Though limited by factors inherent in a retrospective review of SEER-Medicare data, the “unexplained nature of most geospatial variation in initial breast cancer care is not likely to change,” they comment.

Future quality improvement efforts should focus on reducing this unwarranted geospatial variation, particularly through the use of ET in eligible patients and with strategies that work across health care delivery systems, they suggest.

Approached for comment on the new findings, Dr. Miller posits that “many factors may be at play.”

“Unfortunately, the SEER database doesn’t allow us to sort out the impact of poverty/cost of care, distance to medical care, availability of specialty and subspecialty care, and payer/provider networks that may limit choices and options for second opinions,” Dr. Miller told this news organization.

She said that patients should be encouraged to consult reliable patient-focused information, such as that provided by the American Society of Clinical Oncology through its disease-specific sites, and to seek a second opinion from a university center. In many cases, major centers have become more accessible through virtual visits made available in the wake of the COVID-19 pandemic, she noted.

This study was supported by Dana-Farber Cancer Institute and the American Cancer Society. The authors and Dr. Miller have disclosed no relevant financial relationships. Dr. Miller is a regular contributor to Medscape with her Miller on Oncology column.

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

Many patients with early breast cancer are being undertreated, concludes a novel study that examined the management of such patients across various geographical regions across the United States.

A standard treatment for early breast cancer is endocrine therapy (ET), with drugs such a tamoxifen and aromatase inhibitors.

But the study found that ET was not being used in about half of the eligible patients.

For example, only 13,115 of 26,255 eligible patients (48.8%) initiated ET within 1 year of diagnosis, and only 13,944 (52.1%) continued with ET.

“This is remarkable, considering that ET confers an impressive one-third reduction in the risk of death from breast cancer in the first 15 years after diagnosis,” comment authors Michael J. Hassett, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.

The findings were published online on Jan. 27 in JAMA Oncology.

This study provides an “important and disturbing” glimpse of the hidden barriers patients face when seeking quality, guideline-concordant care, says Kathy Miller, MD, the Ballve Lantero professor of oncology at Indiana University School of Medicine and associate director of clinical research at the IU Simon Comprehensive Cancer Center, Indianapolis, who was approached for comment.
 

Geographical variations

In their study, Dr. Hasset and colleagues set out determine the extent to which geospatial variations in early breast cancer care are attributable to health service area versus patient factors. They analyzed Surveillance, Epidemiology, and End Results (SEER) Medicare data for 31,571 patients with newly diagnosed with stage I-II nonmetastatic breast cancer between 2007 and 2013 who were followed for at least 3 years.

The patients had a median age of 71 years, and 61.4% had stage I disease at diagnosis.

Geospatial density maps (heat maps) in the paper highlight regional performance patterns. For initiation of ET within 1 year of diagnosis, the regions that appeared the worst (with less than 50% of patients getting this treatment) were parts of California, Utah, New Mexico, Louisiana, Georgia, Kentucky, Washington, and an isolated patch in Michigan.

In addition to the striking finding that nearly half of all women who are eligible for ET did not receive that therapy, the investigators found that 81.6% of 21,190 eligible patients received radiation therapy and 72.8% of 9,903 eligible patients received chemotherapy.

This also varied across the graphical regions, with the heat maps showing that the areas that were delivering radiation and chemotherapy to 70% to 80% of women were similar to the areas that were not initiating ET in about half of these women.

The authors found that the geographical region and health service area (HSA) explained more observed variation (24% to 48%) than patient factors (1% to 4%).

“While patient characteristics, such as race and ethnicity, were significantly associated with variation in breast cancer care, they explained a relatively small proportion of the total observed geospatial variance,” the authors comment.

“In fact, most of the total observed variance was owing to randomness or unexplained factors,” they add. The largest share of variation – 35% to 45% – was unexplained.

“The ET metrics demonstrated the largest total observed variance, the lowest absolute performance (only 49% of patients had an ET prescription within 1 year of diagnosis), and the strongest association with region/HSA,” they conclude.

Though limited by factors inherent in a retrospective review of SEER-Medicare data, the “unexplained nature of most geospatial variation in initial breast cancer care is not likely to change,” they comment.

Future quality improvement efforts should focus on reducing this unwarranted geospatial variation, particularly through the use of ET in eligible patients and with strategies that work across health care delivery systems, they suggest.

Approached for comment on the new findings, Dr. Miller posits that “many factors may be at play.”

“Unfortunately, the SEER database doesn’t allow us to sort out the impact of poverty/cost of care, distance to medical care, availability of specialty and subspecialty care, and payer/provider networks that may limit choices and options for second opinions,” Dr. Miller told this news organization.

She said that patients should be encouraged to consult reliable patient-focused information, such as that provided by the American Society of Clinical Oncology through its disease-specific sites, and to seek a second opinion from a university center. In many cases, major centers have become more accessible through virtual visits made available in the wake of the COVID-19 pandemic, she noted.

This study was supported by Dana-Farber Cancer Institute and the American Cancer Society. The authors and Dr. Miller have disclosed no relevant financial relationships. Dr. Miller is a regular contributor to Medscape with her Miller on Oncology column.

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

Many patients with early breast cancer are being undertreated, concludes a novel study that examined the management of such patients across various geographical regions across the United States.

A standard treatment for early breast cancer is endocrine therapy (ET), with drugs such a tamoxifen and aromatase inhibitors.

But the study found that ET was not being used in about half of the eligible patients.

For example, only 13,115 of 26,255 eligible patients (48.8%) initiated ET within 1 year of diagnosis, and only 13,944 (52.1%) continued with ET.

“This is remarkable, considering that ET confers an impressive one-third reduction in the risk of death from breast cancer in the first 15 years after diagnosis,” comment authors Michael J. Hassett, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.

The findings were published online on Jan. 27 in JAMA Oncology.

This study provides an “important and disturbing” glimpse of the hidden barriers patients face when seeking quality, guideline-concordant care, says Kathy Miller, MD, the Ballve Lantero professor of oncology at Indiana University School of Medicine and associate director of clinical research at the IU Simon Comprehensive Cancer Center, Indianapolis, who was approached for comment.
 

Geographical variations

In their study, Dr. Hasset and colleagues set out determine the extent to which geospatial variations in early breast cancer care are attributable to health service area versus patient factors. They analyzed Surveillance, Epidemiology, and End Results (SEER) Medicare data for 31,571 patients with newly diagnosed with stage I-II nonmetastatic breast cancer between 2007 and 2013 who were followed for at least 3 years.

The patients had a median age of 71 years, and 61.4% had stage I disease at diagnosis.

Geospatial density maps (heat maps) in the paper highlight regional performance patterns. For initiation of ET within 1 year of diagnosis, the regions that appeared the worst (with less than 50% of patients getting this treatment) were parts of California, Utah, New Mexico, Louisiana, Georgia, Kentucky, Washington, and an isolated patch in Michigan.

In addition to the striking finding that nearly half of all women who are eligible for ET did not receive that therapy, the investigators found that 81.6% of 21,190 eligible patients received radiation therapy and 72.8% of 9,903 eligible patients received chemotherapy.

This also varied across the graphical regions, with the heat maps showing that the areas that were delivering radiation and chemotherapy to 70% to 80% of women were similar to the areas that were not initiating ET in about half of these women.

The authors found that the geographical region and health service area (HSA) explained more observed variation (24% to 48%) than patient factors (1% to 4%).

“While patient characteristics, such as race and ethnicity, were significantly associated with variation in breast cancer care, they explained a relatively small proportion of the total observed geospatial variance,” the authors comment.

“In fact, most of the total observed variance was owing to randomness or unexplained factors,” they add. The largest share of variation – 35% to 45% – was unexplained.

“The ET metrics demonstrated the largest total observed variance, the lowest absolute performance (only 49% of patients had an ET prescription within 1 year of diagnosis), and the strongest association with region/HSA,” they conclude.

Though limited by factors inherent in a retrospective review of SEER-Medicare data, the “unexplained nature of most geospatial variation in initial breast cancer care is not likely to change,” they comment.

Future quality improvement efforts should focus on reducing this unwarranted geospatial variation, particularly through the use of ET in eligible patients and with strategies that work across health care delivery systems, they suggest.

Approached for comment on the new findings, Dr. Miller posits that “many factors may be at play.”

“Unfortunately, the SEER database doesn’t allow us to sort out the impact of poverty/cost of care, distance to medical care, availability of specialty and subspecialty care, and payer/provider networks that may limit choices and options for second opinions,” Dr. Miller told this news organization.

She said that patients should be encouraged to consult reliable patient-focused information, such as that provided by the American Society of Clinical Oncology through its disease-specific sites, and to seek a second opinion from a university center. In many cases, major centers have become more accessible through virtual visits made available in the wake of the COVID-19 pandemic, she noted.

This study was supported by Dana-Farber Cancer Institute and the American Cancer Society. The authors and Dr. Miller have disclosed no relevant financial relationships. Dr. Miller is a regular contributor to Medscape with her Miller on Oncology column.

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

Immune checkpoint inhibitors (ICIs) are at least as effective in patients with advanced non–small cell lung cancer (NSCLC) and mild preexisting interstitial lung disease (ILD) as in those without ILD. However, the risk of checkpoint inhibitor pneumonitis (CIP) is higher in patients with the dual diagnoses and they need careful monitoring when introducing an ICI, a systematic review and meta-analysis indicated.

“Patients with preexisting ILD, especially symptomatic ILD, are frequently excluded from clinical trials so almost all the patients [we analyzed] were diagnosed with mild preexisting ILD,” said Yuan Cheng, MD, Peking University First Hospital, Beijing, China.

“At this stage, we think that mild ILD is not a contraindication to the use of anti-programmed death-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) treatment for patients with NSCLC but whether ICIs can be used in patients with moderate to severe ILD needs further study,” she added.

The study was published online Jan. 10 in the journal CHEST.
 

Ten studies

A total of 179 patients from 10 studies were included in the review and meta-analysis. Among these, six were retrospective case-control studies, one was a retrospective noncontrolled study and three were prospective, noncontrolled clinical trials. “All the included studies were from East Asian countries,” the authors noted.

Preexisting ILD was diagnosed by use of CT or high-resolution CT. The mean age of patients was 71 years (range, 33-85 years), 87% were male and 96% of the cohort had a history of smoking. Approximately one-quarter of patients with ILD had usual interstitial pneumonitis (UIP); about the same percentage had possible UIP; one-third were diagnosed with inconsistent UIP; 14% had nonspecific interstitial pneumonia (NSIP); and 6% had indeterminate UIP.

Patients received ICIs either as first-, second-, or third-line or higher therapy and all were treated with ICI monotherapy by way of either nivolumab (Opdivo), pembrolizumab (Keytruda), or atezolizumab (Tecentriq). About 10% of patients had a PD-L1 tumor proportion score (TPS) of less than 1%, one-quarter had a PD-L1 TPS of 1%-49%, and approximately two-thirds had a TPS of 50% or greater.
 

Objective response rates

Some 35% of patients with both NSCLC and preexisting ILD achieved an objective response rate (ORR) to ICI therapy and almost two-thirds of patients achieved disease control. However, there was considerable heterogeneity in ORRs between the studies where it ranged from 5.9% to 70%, the authors cautioned.

On meta-analysis, the pooled ORR was 34% (95% confidence interval, 20%-47%) but again, with significant heterogeneity (I2 = 75.9%). However, on meta-analysis of eligible studies, patients with NSCLC who had preexisting ILD were 99% more likely to achieve an ORR compared to those without ILD (odds ratio, 1.99; 95% CI, 1.31-3.00), the investigators pointed out.

The disease control rate (DCR) also varied considerably between studies from a low of 33.3% to a high of 100%, they added. On meta-analysis, the pooled DCR was 66% (95% CI, 56%-75%). “Meanwhile, in patients without preexisting ILD, the crude ORR and pooled ORR were 24.3% and 24% (95% CI, 17%-31%), respectively” – again with significant heterogeneity between studies (I2 = 87.4%).

In contrast to the ORR, there was no difference in the DCR between the two groups, with no evidence of heterogeneity. There were no significant differences between the two groups in either median progression-free survival (PFS) or overall survival (OS). In patients with NSCLC and preexisting ILD, median PFS ranged from 1.4 to 8 months whereas median OS ranged from 15.6 to 27.8 months.

For those without preexisting ILD, the median PFS ranged from 2.3 to 8.1 months while median OS ranged from 17.4 to 25.5 months.
 

ICI safety

In patients with NSCLC and preexisting ILD, the incidence of immune-related adverse events (irAes) of any grade was 56.7%, whereas the incidence of irAEs grade 3 and higher was 27.7%. “Among the 179 patients included in the studies, 45 developed any grade of CIP, corresponding to a crude incidence of 25.1%,” the authors noted – very similar to the pooled incidence of 27% on meta-analysis.

The pooled incidence of grade 3 and higher CIP in the same group of patients was 15%. The median time from initiation of ICIs to the development of CIP ranged from 31 to 74 days, but 88% of patients who developed CIP improved with appropriate treatment. In patients with NSCLC who did not have ILD, the pooled incidence of CIP was 10% (95% CI, 6%-13%), again with significant heterogeneity between studies (I2 = 78.8%). “Generally, CIP can be managed through ICI discontinuation with or without steroid administration,” the authors noted.

However, even if most CIP can be easily managed, “the incidence of severe CIP is higher [in NSCLC patients with preexisting ILD] than in other populations,” Dr. Chen observed. “So patients with preexisting ILD should be closely monitored during ICI therapy,” she added.

Indeed, compared with patients without preexisting ILD, grade 3 or higher CIP in patients with the dual diagnosis was significantly higher at an OR of 3.23 (95%, 2.06-5.06), the investigators emphasized.

A limitation to the review and systematic meta-analysis included the fact that none of the studies analyzed were randomized clinical trials and most of the studies were retrospective and had several other shortcomings.
 

Umbrella diagnosis

Asked to comment on the review, Karthik Suresh, MD, associate professor of medicine, Johns Hopkins University, Baltimore, pointed out that ILD is really an “umbrella” diagnosis that a few hundred diseases fit under, so the first question he and members of his multidisciplinary team ask is: What is the nature of the ILD in this patient? What is the actual underlying etiology?

It could, for example, be that the patient has undergone prior chemotherapy or radiation therapy and has developed ILD as a result, as Dr. Suresh and his coauthor, Jarushka Naidoo, MD, Sidney Kimmel Comprehensive Cancer Center, Baltimore, pointed out in their paper on how to approach patients with preexisting lung disease to avoid ICI toxicities. “We’ll go back to their prior CT scans and can see the ILD has been there for years – it’s stable and the patient’s lung function is not changing,” Dr. Suresh related to this news organization.

“That’s a very different story from a [patients] whom there are new interstitial changes, who are progressing and who are symptomatic,” he noted. Essentially, what Dr. Suresh and his team members want to know is: What is the specific subdiagnosis of this disease, how severe is it, and is it progressing? Then they need to take the tumor itself into consideration.

“Some tumors have high PD-L1 expression, others have low PD-L1 expression so response to immunotherapy is usually very different based on tumor histology,” Dr. Suresh pointed out. Thus, the next question that needs to be addressed is: What is the expected response of the tumor to ICI therapy? If a tumor is exquisitely sensitive to immunotherapy, “that changes the game,” Dr. Suresh said, “whereas with other tumors, the oncologist might say there may be some benefit but it won’t be dramatic.”

The third risk factor for ICI toxicity that needs to be evaluated is the patient’s general cardiopulmonary status – for example, if a patient has mild, even moderate, ILD but is still walking 3 miles a day, has no heart problems, and is doing fine. Another patient with the same severity of disease in turn may have mild heart failure, be relatively debilitated, and sedentary: “Performance status also plays a big role in determining treatment,” Dr. Suresh emphasized.

The presence of other pulmonary conditions such as chronic obstructive pulmonary disease – common in patients with NSCLC – has to be taken into account, too. Lastly, clinicians need to ask themselves if there are any alternative therapies that might work just as well if not better than ICI therapy for this particular patient. If the patient has had genomic testing, results might indicate that the tumor has a mutation that may respond well to targeted therapies. “We put all these factors out on the table,” Dr. Suresh said.

“And you obviously have to involve the patient, too, so they understand the risks of ICI therapy and together we decide, ‘Yes, this patient with ILD should get immunotherapy or no, they should not,’ “ he said.  

The study had no specific funding. The study authors and Dr. Suresh have disclosed no relevant financial relationships.

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

Immune checkpoint inhibitors (ICIs) are at least as effective in patients with advanced non–small cell lung cancer (NSCLC) and mild preexisting interstitial lung disease (ILD) as in those without ILD. However, the risk of checkpoint inhibitor pneumonitis (CIP) is higher in patients with the dual diagnoses and they need careful monitoring when introducing an ICI, a systematic review and meta-analysis indicated.

“Patients with preexisting ILD, especially symptomatic ILD, are frequently excluded from clinical trials so almost all the patients [we analyzed] were diagnosed with mild preexisting ILD,” said Yuan Cheng, MD, Peking University First Hospital, Beijing, China.

“At this stage, we think that mild ILD is not a contraindication to the use of anti-programmed death-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) treatment for patients with NSCLC but whether ICIs can be used in patients with moderate to severe ILD needs further study,” she added.

The study was published online Jan. 10 in the journal CHEST.
 

Ten studies

A total of 179 patients from 10 studies were included in the review and meta-analysis. Among these, six were retrospective case-control studies, one was a retrospective noncontrolled study and three were prospective, noncontrolled clinical trials. “All the included studies were from East Asian countries,” the authors noted.

Preexisting ILD was diagnosed by use of CT or high-resolution CT. The mean age of patients was 71 years (range, 33-85 years), 87% were male and 96% of the cohort had a history of smoking. Approximately one-quarter of patients with ILD had usual interstitial pneumonitis (UIP); about the same percentage had possible UIP; one-third were diagnosed with inconsistent UIP; 14% had nonspecific interstitial pneumonia (NSIP); and 6% had indeterminate UIP.

Patients received ICIs either as first-, second-, or third-line or higher therapy and all were treated with ICI monotherapy by way of either nivolumab (Opdivo), pembrolizumab (Keytruda), or atezolizumab (Tecentriq). About 10% of patients had a PD-L1 tumor proportion score (TPS) of less than 1%, one-quarter had a PD-L1 TPS of 1%-49%, and approximately two-thirds had a TPS of 50% or greater.
 

Objective response rates

Some 35% of patients with both NSCLC and preexisting ILD achieved an objective response rate (ORR) to ICI therapy and almost two-thirds of patients achieved disease control. However, there was considerable heterogeneity in ORRs between the studies where it ranged from 5.9% to 70%, the authors cautioned.

On meta-analysis, the pooled ORR was 34% (95% confidence interval, 20%-47%) but again, with significant heterogeneity (I2 = 75.9%). However, on meta-analysis of eligible studies, patients with NSCLC who had preexisting ILD were 99% more likely to achieve an ORR compared to those without ILD (odds ratio, 1.99; 95% CI, 1.31-3.00), the investigators pointed out.

The disease control rate (DCR) also varied considerably between studies from a low of 33.3% to a high of 100%, they added. On meta-analysis, the pooled DCR was 66% (95% CI, 56%-75%). “Meanwhile, in patients without preexisting ILD, the crude ORR and pooled ORR were 24.3% and 24% (95% CI, 17%-31%), respectively” – again with significant heterogeneity between studies (I2 = 87.4%).

In contrast to the ORR, there was no difference in the DCR between the two groups, with no evidence of heterogeneity. There were no significant differences between the two groups in either median progression-free survival (PFS) or overall survival (OS). In patients with NSCLC and preexisting ILD, median PFS ranged from 1.4 to 8 months whereas median OS ranged from 15.6 to 27.8 months.

For those without preexisting ILD, the median PFS ranged from 2.3 to 8.1 months while median OS ranged from 17.4 to 25.5 months.
 

ICI safety

In patients with NSCLC and preexisting ILD, the incidence of immune-related adverse events (irAes) of any grade was 56.7%, whereas the incidence of irAEs grade 3 and higher was 27.7%. “Among the 179 patients included in the studies, 45 developed any grade of CIP, corresponding to a crude incidence of 25.1%,” the authors noted – very similar to the pooled incidence of 27% on meta-analysis.

The pooled incidence of grade 3 and higher CIP in the same group of patients was 15%. The median time from initiation of ICIs to the development of CIP ranged from 31 to 74 days, but 88% of patients who developed CIP improved with appropriate treatment. In patients with NSCLC who did not have ILD, the pooled incidence of CIP was 10% (95% CI, 6%-13%), again with significant heterogeneity between studies (I2 = 78.8%). “Generally, CIP can be managed through ICI discontinuation with or without steroid administration,” the authors noted.

However, even if most CIP can be easily managed, “the incidence of severe CIP is higher [in NSCLC patients with preexisting ILD] than in other populations,” Dr. Chen observed. “So patients with preexisting ILD should be closely monitored during ICI therapy,” she added.

Indeed, compared with patients without preexisting ILD, grade 3 or higher CIP in patients with the dual diagnosis was significantly higher at an OR of 3.23 (95%, 2.06-5.06), the investigators emphasized.

A limitation to the review and systematic meta-analysis included the fact that none of the studies analyzed were randomized clinical trials and most of the studies were retrospective and had several other shortcomings.
 

Umbrella diagnosis

Asked to comment on the review, Karthik Suresh, MD, associate professor of medicine, Johns Hopkins University, Baltimore, pointed out that ILD is really an “umbrella” diagnosis that a few hundred diseases fit under, so the first question he and members of his multidisciplinary team ask is: What is the nature of the ILD in this patient? What is the actual underlying etiology?

It could, for example, be that the patient has undergone prior chemotherapy or radiation therapy and has developed ILD as a result, as Dr. Suresh and his coauthor, Jarushka Naidoo, MD, Sidney Kimmel Comprehensive Cancer Center, Baltimore, pointed out in their paper on how to approach patients with preexisting lung disease to avoid ICI toxicities. “We’ll go back to their prior CT scans and can see the ILD has been there for years – it’s stable and the patient’s lung function is not changing,” Dr. Suresh related to this news organization.

“That’s a very different story from a [patients] whom there are new interstitial changes, who are progressing and who are symptomatic,” he noted. Essentially, what Dr. Suresh and his team members want to know is: What is the specific subdiagnosis of this disease, how severe is it, and is it progressing? Then they need to take the tumor itself into consideration.

“Some tumors have high PD-L1 expression, others have low PD-L1 expression so response to immunotherapy is usually very different based on tumor histology,” Dr. Suresh pointed out. Thus, the next question that needs to be addressed is: What is the expected response of the tumor to ICI therapy? If a tumor is exquisitely sensitive to immunotherapy, “that changes the game,” Dr. Suresh said, “whereas with other tumors, the oncologist might say there may be some benefit but it won’t be dramatic.”

The third risk factor for ICI toxicity that needs to be evaluated is the patient’s general cardiopulmonary status – for example, if a patient has mild, even moderate, ILD but is still walking 3 miles a day, has no heart problems, and is doing fine. Another patient with the same severity of disease in turn may have mild heart failure, be relatively debilitated, and sedentary: “Performance status also plays a big role in determining treatment,” Dr. Suresh emphasized.

The presence of other pulmonary conditions such as chronic obstructive pulmonary disease – common in patients with NSCLC – has to be taken into account, too. Lastly, clinicians need to ask themselves if there are any alternative therapies that might work just as well if not better than ICI therapy for this particular patient. If the patient has had genomic testing, results might indicate that the tumor has a mutation that may respond well to targeted therapies. “We put all these factors out on the table,” Dr. Suresh said.

“And you obviously have to involve the patient, too, so they understand the risks of ICI therapy and together we decide, ‘Yes, this patient with ILD should get immunotherapy or no, they should not,’ “ he said.  

The study had no specific funding. The study authors and Dr. Suresh have disclosed no relevant financial relationships.

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

Immune checkpoint inhibitors (ICIs) are at least as effective in patients with advanced non–small cell lung cancer (NSCLC) and mild preexisting interstitial lung disease (ILD) as in those without ILD. However, the risk of checkpoint inhibitor pneumonitis (CIP) is higher in patients with the dual diagnoses and they need careful monitoring when introducing an ICI, a systematic review and meta-analysis indicated.

“Patients with preexisting ILD, especially symptomatic ILD, are frequently excluded from clinical trials so almost all the patients [we analyzed] were diagnosed with mild preexisting ILD,” said Yuan Cheng, MD, Peking University First Hospital, Beijing, China.

“At this stage, we think that mild ILD is not a contraindication to the use of anti-programmed death-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) treatment for patients with NSCLC but whether ICIs can be used in patients with moderate to severe ILD needs further study,” she added.

The study was published online Jan. 10 in the journal CHEST.
 

Ten studies

A total of 179 patients from 10 studies were included in the review and meta-analysis. Among these, six were retrospective case-control studies, one was a retrospective noncontrolled study and three were prospective, noncontrolled clinical trials. “All the included studies were from East Asian countries,” the authors noted.

Preexisting ILD was diagnosed by use of CT or high-resolution CT. The mean age of patients was 71 years (range, 33-85 years), 87% were male and 96% of the cohort had a history of smoking. Approximately one-quarter of patients with ILD had usual interstitial pneumonitis (UIP); about the same percentage had possible UIP; one-third were diagnosed with inconsistent UIP; 14% had nonspecific interstitial pneumonia (NSIP); and 6% had indeterminate UIP.

Patients received ICIs either as first-, second-, or third-line or higher therapy and all were treated with ICI monotherapy by way of either nivolumab (Opdivo), pembrolizumab (Keytruda), or atezolizumab (Tecentriq). About 10% of patients had a PD-L1 tumor proportion score (TPS) of less than 1%, one-quarter had a PD-L1 TPS of 1%-49%, and approximately two-thirds had a TPS of 50% or greater.
 

Objective response rates

Some 35% of patients with both NSCLC and preexisting ILD achieved an objective response rate (ORR) to ICI therapy and almost two-thirds of patients achieved disease control. However, there was considerable heterogeneity in ORRs between the studies where it ranged from 5.9% to 70%, the authors cautioned.

On meta-analysis, the pooled ORR was 34% (95% confidence interval, 20%-47%) but again, with significant heterogeneity (I2 = 75.9%). However, on meta-analysis of eligible studies, patients with NSCLC who had preexisting ILD were 99% more likely to achieve an ORR compared to those without ILD (odds ratio, 1.99; 95% CI, 1.31-3.00), the investigators pointed out.

The disease control rate (DCR) also varied considerably between studies from a low of 33.3% to a high of 100%, they added. On meta-analysis, the pooled DCR was 66% (95% CI, 56%-75%). “Meanwhile, in patients without preexisting ILD, the crude ORR and pooled ORR were 24.3% and 24% (95% CI, 17%-31%), respectively” – again with significant heterogeneity between studies (I2 = 87.4%).

In contrast to the ORR, there was no difference in the DCR between the two groups, with no evidence of heterogeneity. There were no significant differences between the two groups in either median progression-free survival (PFS) or overall survival (OS). In patients with NSCLC and preexisting ILD, median PFS ranged from 1.4 to 8 months whereas median OS ranged from 15.6 to 27.8 months.

For those without preexisting ILD, the median PFS ranged from 2.3 to 8.1 months while median OS ranged from 17.4 to 25.5 months.
 

ICI safety

In patients with NSCLC and preexisting ILD, the incidence of immune-related adverse events (irAes) of any grade was 56.7%, whereas the incidence of irAEs grade 3 and higher was 27.7%. “Among the 179 patients included in the studies, 45 developed any grade of CIP, corresponding to a crude incidence of 25.1%,” the authors noted – very similar to the pooled incidence of 27% on meta-analysis.

The pooled incidence of grade 3 and higher CIP in the same group of patients was 15%. The median time from initiation of ICIs to the development of CIP ranged from 31 to 74 days, but 88% of patients who developed CIP improved with appropriate treatment. In patients with NSCLC who did not have ILD, the pooled incidence of CIP was 10% (95% CI, 6%-13%), again with significant heterogeneity between studies (I2 = 78.8%). “Generally, CIP can be managed through ICI discontinuation with or without steroid administration,” the authors noted.

However, even if most CIP can be easily managed, “the incidence of severe CIP is higher [in NSCLC patients with preexisting ILD] than in other populations,” Dr. Chen observed. “So patients with preexisting ILD should be closely monitored during ICI therapy,” she added.

Indeed, compared with patients without preexisting ILD, grade 3 or higher CIP in patients with the dual diagnosis was significantly higher at an OR of 3.23 (95%, 2.06-5.06), the investigators emphasized.

A limitation to the review and systematic meta-analysis included the fact that none of the studies analyzed were randomized clinical trials and most of the studies were retrospective and had several other shortcomings.
 

Umbrella diagnosis

Asked to comment on the review, Karthik Suresh, MD, associate professor of medicine, Johns Hopkins University, Baltimore, pointed out that ILD is really an “umbrella” diagnosis that a few hundred diseases fit under, so the first question he and members of his multidisciplinary team ask is: What is the nature of the ILD in this patient? What is the actual underlying etiology?

It could, for example, be that the patient has undergone prior chemotherapy or radiation therapy and has developed ILD as a result, as Dr. Suresh and his coauthor, Jarushka Naidoo, MD, Sidney Kimmel Comprehensive Cancer Center, Baltimore, pointed out in their paper on how to approach patients with preexisting lung disease to avoid ICI toxicities. “We’ll go back to their prior CT scans and can see the ILD has been there for years – it’s stable and the patient’s lung function is not changing,” Dr. Suresh related to this news organization.

“That’s a very different story from a [patients] whom there are new interstitial changes, who are progressing and who are symptomatic,” he noted. Essentially, what Dr. Suresh and his team members want to know is: What is the specific subdiagnosis of this disease, how severe is it, and is it progressing? Then they need to take the tumor itself into consideration.

“Some tumors have high PD-L1 expression, others have low PD-L1 expression so response to immunotherapy is usually very different based on tumor histology,” Dr. Suresh pointed out. Thus, the next question that needs to be addressed is: What is the expected response of the tumor to ICI therapy? If a tumor is exquisitely sensitive to immunotherapy, “that changes the game,” Dr. Suresh said, “whereas with other tumors, the oncologist might say there may be some benefit but it won’t be dramatic.”

The third risk factor for ICI toxicity that needs to be evaluated is the patient’s general cardiopulmonary status – for example, if a patient has mild, even moderate, ILD but is still walking 3 miles a day, has no heart problems, and is doing fine. Another patient with the same severity of disease in turn may have mild heart failure, be relatively debilitated, and sedentary: “Performance status also plays a big role in determining treatment,” Dr. Suresh emphasized.

The presence of other pulmonary conditions such as chronic obstructive pulmonary disease – common in patients with NSCLC – has to be taken into account, too. Lastly, clinicians need to ask themselves if there are any alternative therapies that might work just as well if not better than ICI therapy for this particular patient. If the patient has had genomic testing, results might indicate that the tumor has a mutation that may respond well to targeted therapies. “We put all these factors out on the table,” Dr. Suresh said.

“And you obviously have to involve the patient, too, so they understand the risks of ICI therapy and together we decide, ‘Yes, this patient with ILD should get immunotherapy or no, they should not,’ “ he said.  

The study had no specific funding. The study authors and Dr. Suresh have disclosed no relevant financial relationships.

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

It is indisputable that patients with newly diagnosed advanced non–small cell lung cancer (NSCLC) bearing mutations in the epidermal growth factor receptor (EGFR) pathway may benefit from targeted therapy with a tyrosine kinase inhibitor (TKI) directed against EGFR.

What’s less clear is whether monotherapy with an EGFR TKI or combination therapy with a TKI and chemotherapy, immunotherapy, monoclonal antibodies or other targeted agents is the preferred frontline strategy.

NSCLC guidelines from the National Comprehensive Cancer Network, for example, recommend that patients with EFGR mutations such as exon 19 deletion, discovered prior to first-line systemic therapy, should preferably received osimertinib (Tagrisso) or another TKI, such as erlotinib (Tarceva), afatinib (Gilotrif), gefitinib (Iressa) or dacomitinib (Vizimpro), or erlotinib with a VEGF inhibitor. For patients with EGFR mutations identified during first-line systemic therapy, NCCN recommends complete systemic therapy or interrupting it, followed by osimertinib as the preferred agent, or another TKI with or without a VEGF inhibitors.

Similarly, guidelines from the American Society of Clinical Oncology and Ontario Health recommend osimertinib monotherapy as a preferred first-line option for patients with L858R/exon 19 deletion EGFR mutations. Alternatives for patients for whom osimertinib is not available include gefitinib plus platinum/pemetrexed chemotherapy with maintenance pemetrexed, monotherapy with dacomitinib, or other targeted agents with or without VEGF inhibitors.

Combination or go it alone?

The guidelines are largely mute on the question of chemotherapy in this population, primarily because they have not caught up to clinical trial evidence, said Paul Wheatley-Price, MBChB, FRCP, MD, from the University of Ottawa Hospital Research Institute.

“There is recent data that looks quite promising on combining EGFR inhibitors with either chemotherapy or antiangiogenic drugs, but it’s too soon, I think, and while the trials are promising, there are still too many question marks over it to make it into the guidelines,” he said in an interview.

The question of frontline combinations vs. monotherapy in patients with advanced EGFR-mutated NSCLC was the subject of a recent “controversies in thoracic oncology” feature in the Journal of Thoracic Oncology, with Dr. Wheatley-Price and University of Ottawa colleague Sara Moore, MD, FRCPC, arguing that combining EGFR TKIs with either cytotoxic chemotherapy or antiangiogenic monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) receptor has been shown consistently to improve progression-free survival (PFS) and in some cases overall survival (OS).

“There is a consistent drop-off in patients who receive second-line therapy, highlighting the importance of using combination therapy in the first-line setting to ensure patients will be exposed to multiple available therapies that may prolong survival. Chemotherapy-based combinations lead to improved response rates which may be especially helpful in patients with a significant burden of disease,” they wrote.

The authors noted that, compared with patients with wild-type EGFR, patients with EGFR-mutated NSCLC had a doubling of response rates to chemotherapy with a platinum-based doublet in the IPASS trial, suggesting that EGFR-mutated tumors may be more chemosensitive.
 

Promising trials, old drug

“Chemotherapy and EGFR TKIs may have a synergistic effect through combined reduction in vascular endothelial growth factor (VEGF)–mediated angiogenesis, and with EGFR TKIs counteracting chemotherapy-induced up-regulation of downstream EGFR signaling,” they wrote.

The authors cited two studies, one from Japan, and one from India, both of which showed significant improvements in response rates, PFS, and OS with the combination of gefitinib plus carboplatin and pemetrexed chemotherapy with pemetrexed maintenance vs. carboplatin alone,

“Now of course we don’t use gefitinib as our first-line treatment. In Canada and the United States, we use osimertinib, so certainly the chemotherapy/TKI combination, while it looks quite promising, was compared to an old control arm,” Dr. Wheatley-Price said.

He noted that the phase 3 FLAURA2 trial, currently underway, will address the question of whether adding osimertinib to a chemotherapy doublet with pemetrexed plus either carboplatin or cisplatin can improve PFS in patients with EGFR-positive locally advanced or metastatic NSCLC, compared with osimertinib alone.

The authors acknowledged that chemotherapy adds toxicities, compared with the use of TKI monotherapy, but added that, “even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”

VEGF plus EGFR

Adding a VEGF-targeted monoclonal antibody or TKI to and EGFR TKI has shown consistent PFS benefits in the NEJ026, ARTEMIS, RELAY, and ACTIVE trials, Dr. Moore and Dr. Wheatley-Price noted.

“In all four trials, resistance testing at the time of progression revealed similar rates of T790M mutation in both arms, highlighting the potential role of optimizing the sequence of therapy with use of second-line osimertinib among those with a T790M resistance mutation,” they wrote.

All four trials also showed higher rates of adverse events in the combination arms, but most, except for hypertension, were low grade, and in the RELAY trial the added toxicities did not significantly affect patient quality of life, they said.
 

Monotherapy advocated

Although in agreement that the combination of gefitinib and chemotherapy has both PFS and OS benefits compared with monotherapy alone, “these combinations are not applicable to real-life practice given their use of first-generation EGFR TKIs rather than third-generation EGFR TKI osimertinib,” wrote Sophie Stock-Martineau, MD, FRCPC from Hôpital Maisonneuve-Rosemont and the University of Montreal, and Frances A. Shepherd, MD, FRCPC from the Princess Margaret Cancer Centre in Toronto, in an article touting EGFR monotherapy.

They stated that until the results of FLAURA2 are available “osimertinib alone remains the current standard first-line therapy in metastatic EGFRm+ NSCLC.”

“The addition of an antiangiogenic agent to an EGFR TKI mildly prolongs PFS; however, it does not yet translate into survival benefit. Not only does it add more toxicity to patients, but it also adds cost, which is far from negligible,” they wrote.

Dr. Stock-Martineau and Dr. Shepherd also noted that two phase 2 trials comparing afatinib with the EGFR monoclonal antibody cetuximab (Erbitux) showed no PFS or OS benefits in patients with untreated EGFR-mutated NSCLC and were terminated for lack of efficacy.

In addition, clinical trials of combinations of EGFR TKIs with immune checkpoint inhibitors ­or MET inhibitors have failed to date to demonstrate survival benefits, the authors said.

“No trials have yet revealed PFS or OS benefit with osimertinib combinations. Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system. Combinations could potentially also worsen quality of life given their heightened toxicity profiles. Therefore, single-agent EGFR TKI, such as osimertinib, remains for now the standard of care in the first-line setting for advanced EGFRm+ NSCLC,” they concluded.

No funding sources for the articles were reported. All authors declared no conflicts of interest to disclose.

It is indisputable that patients with newly diagnosed advanced non–small cell lung cancer (NSCLC) bearing mutations in the epidermal growth factor receptor (EGFR) pathway may benefit from targeted therapy with a tyrosine kinase inhibitor (TKI) directed against EGFR.

What’s less clear is whether monotherapy with an EGFR TKI or combination therapy with a TKI and chemotherapy, immunotherapy, monoclonal antibodies or other targeted agents is the preferred frontline strategy.

NSCLC guidelines from the National Comprehensive Cancer Network, for example, recommend that patients with EFGR mutations such as exon 19 deletion, discovered prior to first-line systemic therapy, should preferably received osimertinib (Tagrisso) or another TKI, such as erlotinib (Tarceva), afatinib (Gilotrif), gefitinib (Iressa) or dacomitinib (Vizimpro), or erlotinib with a VEGF inhibitor. For patients with EGFR mutations identified during first-line systemic therapy, NCCN recommends complete systemic therapy or interrupting it, followed by osimertinib as the preferred agent, or another TKI with or without a VEGF inhibitors.

Similarly, guidelines from the American Society of Clinical Oncology and Ontario Health recommend osimertinib monotherapy as a preferred first-line option for patients with L858R/exon 19 deletion EGFR mutations. Alternatives for patients for whom osimertinib is not available include gefitinib plus platinum/pemetrexed chemotherapy with maintenance pemetrexed, monotherapy with dacomitinib, or other targeted agents with or without VEGF inhibitors.

Combination or go it alone?

The guidelines are largely mute on the question of chemotherapy in this population, primarily because they have not caught up to clinical trial evidence, said Paul Wheatley-Price, MBChB, FRCP, MD, from the University of Ottawa Hospital Research Institute.

“There is recent data that looks quite promising on combining EGFR inhibitors with either chemotherapy or antiangiogenic drugs, but it’s too soon, I think, and while the trials are promising, there are still too many question marks over it to make it into the guidelines,” he said in an interview.

The question of frontline combinations vs. monotherapy in patients with advanced EGFR-mutated NSCLC was the subject of a recent “controversies in thoracic oncology” feature in the Journal of Thoracic Oncology, with Dr. Wheatley-Price and University of Ottawa colleague Sara Moore, MD, FRCPC, arguing that combining EGFR TKIs with either cytotoxic chemotherapy or antiangiogenic monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) receptor has been shown consistently to improve progression-free survival (PFS) and in some cases overall survival (OS).

“There is a consistent drop-off in patients who receive second-line therapy, highlighting the importance of using combination therapy in the first-line setting to ensure patients will be exposed to multiple available therapies that may prolong survival. Chemotherapy-based combinations lead to improved response rates which may be especially helpful in patients with a significant burden of disease,” they wrote.

The authors noted that, compared with patients with wild-type EGFR, patients with EGFR-mutated NSCLC had a doubling of response rates to chemotherapy with a platinum-based doublet in the IPASS trial, suggesting that EGFR-mutated tumors may be more chemosensitive.
 

Promising trials, old drug

“Chemotherapy and EGFR TKIs may have a synergistic effect through combined reduction in vascular endothelial growth factor (VEGF)–mediated angiogenesis, and with EGFR TKIs counteracting chemotherapy-induced up-regulation of downstream EGFR signaling,” they wrote.

The authors cited two studies, one from Japan, and one from India, both of which showed significant improvements in response rates, PFS, and OS with the combination of gefitinib plus carboplatin and pemetrexed chemotherapy with pemetrexed maintenance vs. carboplatin alone,

“Now of course we don’t use gefitinib as our first-line treatment. In Canada and the United States, we use osimertinib, so certainly the chemotherapy/TKI combination, while it looks quite promising, was compared to an old control arm,” Dr. Wheatley-Price said.

He noted that the phase 3 FLAURA2 trial, currently underway, will address the question of whether adding osimertinib to a chemotherapy doublet with pemetrexed plus either carboplatin or cisplatin can improve PFS in patients with EGFR-positive locally advanced or metastatic NSCLC, compared with osimertinib alone.

The authors acknowledged that chemotherapy adds toxicities, compared with the use of TKI monotherapy, but added that, “even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”

VEGF plus EGFR

Adding a VEGF-targeted monoclonal antibody or TKI to and EGFR TKI has shown consistent PFS benefits in the NEJ026, ARTEMIS, RELAY, and ACTIVE trials, Dr. Moore and Dr. Wheatley-Price noted.

“In all four trials, resistance testing at the time of progression revealed similar rates of T790M mutation in both arms, highlighting the potential role of optimizing the sequence of therapy with use of second-line osimertinib among those with a T790M resistance mutation,” they wrote.

All four trials also showed higher rates of adverse events in the combination arms, but most, except for hypertension, were low grade, and in the RELAY trial the added toxicities did not significantly affect patient quality of life, they said.
 

Monotherapy advocated

Although in agreement that the combination of gefitinib and chemotherapy has both PFS and OS benefits compared with monotherapy alone, “these combinations are not applicable to real-life practice given their use of first-generation EGFR TKIs rather than third-generation EGFR TKI osimertinib,” wrote Sophie Stock-Martineau, MD, FRCPC from Hôpital Maisonneuve-Rosemont and the University of Montreal, and Frances A. Shepherd, MD, FRCPC from the Princess Margaret Cancer Centre in Toronto, in an article touting EGFR monotherapy.

They stated that until the results of FLAURA2 are available “osimertinib alone remains the current standard first-line therapy in metastatic EGFRm+ NSCLC.”

“The addition of an antiangiogenic agent to an EGFR TKI mildly prolongs PFS; however, it does not yet translate into survival benefit. Not only does it add more toxicity to patients, but it also adds cost, which is far from negligible,” they wrote.

Dr. Stock-Martineau and Dr. Shepherd also noted that two phase 2 trials comparing afatinib with the EGFR monoclonal antibody cetuximab (Erbitux) showed no PFS or OS benefits in patients with untreated EGFR-mutated NSCLC and were terminated for lack of efficacy.

In addition, clinical trials of combinations of EGFR TKIs with immune checkpoint inhibitors ­or MET inhibitors have failed to date to demonstrate survival benefits, the authors said.

“No trials have yet revealed PFS or OS benefit with osimertinib combinations. Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system. Combinations could potentially also worsen quality of life given their heightened toxicity profiles. Therefore, single-agent EGFR TKI, such as osimertinib, remains for now the standard of care in the first-line setting for advanced EGFRm+ NSCLC,” they concluded.

No funding sources for the articles were reported. All authors declared no conflicts of interest to disclose.

It is indisputable that patients with newly diagnosed advanced non–small cell lung cancer (NSCLC) bearing mutations in the epidermal growth factor receptor (EGFR) pathway may benefit from targeted therapy with a tyrosine kinase inhibitor (TKI) directed against EGFR.

What’s less clear is whether monotherapy with an EGFR TKI or combination therapy with a TKI and chemotherapy, immunotherapy, monoclonal antibodies or other targeted agents is the preferred frontline strategy.

NSCLC guidelines from the National Comprehensive Cancer Network, for example, recommend that patients with EFGR mutations such as exon 19 deletion, discovered prior to first-line systemic therapy, should preferably received osimertinib (Tagrisso) or another TKI, such as erlotinib (Tarceva), afatinib (Gilotrif), gefitinib (Iressa) or dacomitinib (Vizimpro), or erlotinib with a VEGF inhibitor. For patients with EGFR mutations identified during first-line systemic therapy, NCCN recommends complete systemic therapy or interrupting it, followed by osimertinib as the preferred agent, or another TKI with or without a VEGF inhibitors.

Similarly, guidelines from the American Society of Clinical Oncology and Ontario Health recommend osimertinib monotherapy as a preferred first-line option for patients with L858R/exon 19 deletion EGFR mutations. Alternatives for patients for whom osimertinib is not available include gefitinib plus platinum/pemetrexed chemotherapy with maintenance pemetrexed, monotherapy with dacomitinib, or other targeted agents with or without VEGF inhibitors.

Combination or go it alone?

The guidelines are largely mute on the question of chemotherapy in this population, primarily because they have not caught up to clinical trial evidence, said Paul Wheatley-Price, MBChB, FRCP, MD, from the University of Ottawa Hospital Research Institute.

“There is recent data that looks quite promising on combining EGFR inhibitors with either chemotherapy or antiangiogenic drugs, but it’s too soon, I think, and while the trials are promising, there are still too many question marks over it to make it into the guidelines,” he said in an interview.

The question of frontline combinations vs. monotherapy in patients with advanced EGFR-mutated NSCLC was the subject of a recent “controversies in thoracic oncology” feature in the Journal of Thoracic Oncology, with Dr. Wheatley-Price and University of Ottawa colleague Sara Moore, MD, FRCPC, arguing that combining EGFR TKIs with either cytotoxic chemotherapy or antiangiogenic monoclonal antibodies targeting the vascular endothelial growth factor (VEGF) receptor has been shown consistently to improve progression-free survival (PFS) and in some cases overall survival (OS).

“There is a consistent drop-off in patients who receive second-line therapy, highlighting the importance of using combination therapy in the first-line setting to ensure patients will be exposed to multiple available therapies that may prolong survival. Chemotherapy-based combinations lead to improved response rates which may be especially helpful in patients with a significant burden of disease,” they wrote.

The authors noted that, compared with patients with wild-type EGFR, patients with EGFR-mutated NSCLC had a doubling of response rates to chemotherapy with a platinum-based doublet in the IPASS trial, suggesting that EGFR-mutated tumors may be more chemosensitive.
 

Promising trials, old drug

“Chemotherapy and EGFR TKIs may have a synergistic effect through combined reduction in vascular endothelial growth factor (VEGF)–mediated angiogenesis, and with EGFR TKIs counteracting chemotherapy-induced up-regulation of downstream EGFR signaling,” they wrote.

The authors cited two studies, one from Japan, and one from India, both of which showed significant improvements in response rates, PFS, and OS with the combination of gefitinib plus carboplatin and pemetrexed chemotherapy with pemetrexed maintenance vs. carboplatin alone,

“Now of course we don’t use gefitinib as our first-line treatment. In Canada and the United States, we use osimertinib, so certainly the chemotherapy/TKI combination, while it looks quite promising, was compared to an old control arm,” Dr. Wheatley-Price said.

He noted that the phase 3 FLAURA2 trial, currently underway, will address the question of whether adding osimertinib to a chemotherapy doublet with pemetrexed plus either carboplatin or cisplatin can improve PFS in patients with EGFR-positive locally advanced or metastatic NSCLC, compared with osimertinib alone.

The authors acknowledged that chemotherapy adds toxicities, compared with the use of TKI monotherapy, but added that, “even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”

VEGF plus EGFR

Adding a VEGF-targeted monoclonal antibody or TKI to and EGFR TKI has shown consistent PFS benefits in the NEJ026, ARTEMIS, RELAY, and ACTIVE trials, Dr. Moore and Dr. Wheatley-Price noted.

“In all four trials, resistance testing at the time of progression revealed similar rates of T790M mutation in both arms, highlighting the potential role of optimizing the sequence of therapy with use of second-line osimertinib among those with a T790M resistance mutation,” they wrote.

All four trials also showed higher rates of adverse events in the combination arms, but most, except for hypertension, were low grade, and in the RELAY trial the added toxicities did not significantly affect patient quality of life, they said.
 

Monotherapy advocated

Although in agreement that the combination of gefitinib and chemotherapy has both PFS and OS benefits compared with monotherapy alone, “these combinations are not applicable to real-life practice given their use of first-generation EGFR TKIs rather than third-generation EGFR TKI osimertinib,” wrote Sophie Stock-Martineau, MD, FRCPC from Hôpital Maisonneuve-Rosemont and the University of Montreal, and Frances A. Shepherd, MD, FRCPC from the Princess Margaret Cancer Centre in Toronto, in an article touting EGFR monotherapy.

They stated that until the results of FLAURA2 are available “osimertinib alone remains the current standard first-line therapy in metastatic EGFRm+ NSCLC.”

“The addition of an antiangiogenic agent to an EGFR TKI mildly prolongs PFS; however, it does not yet translate into survival benefit. Not only does it add more toxicity to patients, but it also adds cost, which is far from negligible,” they wrote.

Dr. Stock-Martineau and Dr. Shepherd also noted that two phase 2 trials comparing afatinib with the EGFR monoclonal antibody cetuximab (Erbitux) showed no PFS or OS benefits in patients with untreated EGFR-mutated NSCLC and were terminated for lack of efficacy.

In addition, clinical trials of combinations of EGFR TKIs with immune checkpoint inhibitors ­or MET inhibitors have failed to date to demonstrate survival benefits, the authors said.

“No trials have yet revealed PFS or OS benefit with osimertinib combinations. Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system. Combinations could potentially also worsen quality of life given their heightened toxicity profiles. Therefore, single-agent EGFR TKI, such as osimertinib, remains for now the standard of care in the first-line setting for advanced EGFRm+ NSCLC,” they concluded.

No funding sources for the articles were reported. All authors declared no conflicts of interest to disclose.

Gender equality remains elusive for women in academic oncology, a survey of nearly 700 U.S. female oncologists suggests.

More than half of respondents in academic medicine said they believe their gender adversely affects their likelihood for promotion, and 1 in 5 said they were considering leaving academia in the next 5 years.

Given the percentage of female oncologists planning to exit academia, “gender inequality is at high risk of continuing if the culture is not addressed,” write the authors in their study, published online Dec. 30 in JAMA Network Open.

Although women currently outnumber men in U.S. medical schools – a shift that first occurred in 2019 – female representation in academic oncology dwindles at more senior levels. Women represent 45% of hematology and oncology residents, only about 36% of academic faculty, and an even smaller percentage of leadership positions in academic medicine. Women, for instance, occupy about 31% of the chair positions in medical oncology, 17.4% in radiation oncology, and 11% in surgical oncology.

A team of researchers led by Emily C. Merfeld, MD, of the University of Wisconsin Hospitals and Clinics, Madison, set out to understand the factors influencing female oncologists’ decisions to pursue academic versus nonacademic career paths.

Dr. Merfeld and colleagues analyzed survey responses from 667 female oncologists between August 1 and Oct. 31, 2020 – 422 (63.2%) in academic medicine and 245 (36.8%) in nonacademic practice.

Overall, 1 in 4 oncologists said their spouse or partner and family “extremely or moderately” affected their decision to pursue academic practice.

Almost 43% of academic oncologists perceived time spent with loved ones as the biggest sacrifice related to pursuing a career in academic medicine. Approximately the same percentage (41.6%) of nonacademic oncologists perceived the pressure to achieve academic promotion as the most significant sacrifice associated with academic oncology, whereas only 22.4% perceived less time with loved ones as the biggest sacrifice.

“Although work-life balance was a concern for academic oncologists and may be a factor in female oncologists leaving academia, survey data suggested that women in nonacademic practice faced similar challenges,” the authors write.

More specifically, women in academic oncology reported working 2 more hours on the weekends compared to women not in academic medicine; however, both groups worked a similar number of hours during the week.

On the hiring front, almost 24% of academic oncologists said their gender had a “negative or somewhat negative” impact on their ability to get a job, compared with 21% of nonacademic oncologists. Conversely, nearly 28% of academic oncologists said their gender had a “positive or somewhat positive” influence on whether they were hired compared with 41.2% of nonacademic oncologists.

Respondents, however, perceived that gender strongly influenced promotion opportunities. More than half of the respondents – 54.6% of academic oncologists and 50.6% of nonacademic oncologists – believed they were less likely to be promoted than their male colleagues.

This perception aligns with findings from prior studies, which “found women were less likely than men to be promoted to associate professor, full professor, or department chair positions,” the authors write.

Overall, most respondents in each group – 71.3% in academic medicine and 68.6% in nonacademic practice – said they would choose the same career path again. But almost 22% of those in academia said they were “likely or very likely” to leave academic oncology in the next 5 years. Of these women, 28.2% said they would switch to industry employment and 25% would move to community practice.

“Contrary to popular assumptions,” the researchers note, “a spouse or partner and/or family were not a major factor in female oncologists favoring nonacademic careers, because this factor was similarly important to both academic and nonacademic oncologists.”

However, they note, “the increased financial compensation in nonacademic oncology may play a large role in some women’s career decisions.”
 

Making headway on gender equality?

In 2013, oncologist Katherine Reeder-Hayes, MD, MBA, now an associate at the University of North Carolina, Chapel Hill, published a study on gender equality in oncology in which she concluded that despite “an increasingly significant presence in the oncology physician workforce” women remained “under-represented in leadership positions and at the senior levels of academic medicine.”

Since then, Dr. Reeder-Hayes says that she has seen progress but recognizes the need for more.

“To some extent, I think that representation is improving over time due to factors outside the workplace – women are entering medical school in large numbers and may have more supportive partners and more social support for pursuing a professional career in general, [compared with] a decade or two ago,” Dr. Reeder-Hayes told this news organization.

On a personal level, she noted, “I do see many midcareer women assuming key leadership roles in my own institution.” However, she added, “I think the translation of those good candidates into increased representation in leadership probably varies widely across different institutions.”

In a 2019 editorial, researchers highlighted this variation while calling attention to the “notable progress” made by the American Association for Cancer Research (AACR). Specifically, the editorialists reported that women represent 40% of AACR members, 45% of the AACR Board of Directors, and half of the last 10 association presidents.

Editorial coauthor Elizabeth Jaffee, MD, deputy director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, and former AACR president, told this news organization that she attributes this progress to “concrete measures to ensure equality throughout the organization,” which include gender balance on nominating and program committees as well as research meetings and providing opportunities for mentoring, leadership training, and networking.

Despite this positive change, the COVID-19 pandemic threatens to widen the gender imbalance. In a recent article, Julie Silver, MD, an expert in gender equity in medicine, told this news organization that she anticipates trouble ahead.

“There are many indications that women are leaving medicine in disproportionately high numbers,” said Dr. Silver, associate chair and director of cancer rehabilitation in the department of physical medicine and rehabilitation at Harvard Medical School, Boston. “A lack of fair pay and promotion opportunities that were present before COVID-19 are now combined with a host of pandemic-related challenges.”

In addition to salary and promotion disparities, the U.S. continues to suffer from “a chronic shortage of available, affordable, and high-quality childcare and a lack of federal-level policy initiatives or employer initiatives to broaden paid family leave and develop childcare infrastructure and workforce,” Dr. Reeder-Hayes said. Providing extended leave for new parents and on-site childcare could go a long way to improving this problem, she said.

However, Dr. Reeder-Hayes noted that perhaps the “leaky pipeline” problem in oncology highlights the fact that women “are making good decisions that reflect balanced life priorities, [and that] if we don’t structure job responsibilities, childcare, and pacing of promotion and tenure in ways that allow people to nurture other parts of their lives, employees will feel they’re being asked to sacrifice key things.”

In other words, she said, “it’s the workplace that needs to change if we’re going to convince [women], and many men with similar values, to stay.”

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

Gender equality remains elusive for women in academic oncology, a survey of nearly 700 U.S. female oncologists suggests.

More than half of respondents in academic medicine said they believe their gender adversely affects their likelihood for promotion, and 1 in 5 said they were considering leaving academia in the next 5 years.

Given the percentage of female oncologists planning to exit academia, “gender inequality is at high risk of continuing if the culture is not addressed,” write the authors in their study, published online Dec. 30 in JAMA Network Open.

Although women currently outnumber men in U.S. medical schools – a shift that first occurred in 2019 – female representation in academic oncology dwindles at more senior levels. Women represent 45% of hematology and oncology residents, only about 36% of academic faculty, and an even smaller percentage of leadership positions in academic medicine. Women, for instance, occupy about 31% of the chair positions in medical oncology, 17.4% in radiation oncology, and 11% in surgical oncology.

A team of researchers led by Emily C. Merfeld, MD, of the University of Wisconsin Hospitals and Clinics, Madison, set out to understand the factors influencing female oncologists’ decisions to pursue academic versus nonacademic career paths.

Dr. Merfeld and colleagues analyzed survey responses from 667 female oncologists between August 1 and Oct. 31, 2020 – 422 (63.2%) in academic medicine and 245 (36.8%) in nonacademic practice.

Overall, 1 in 4 oncologists said their spouse or partner and family “extremely or moderately” affected their decision to pursue academic practice.

Almost 43% of academic oncologists perceived time spent with loved ones as the biggest sacrifice related to pursuing a career in academic medicine. Approximately the same percentage (41.6%) of nonacademic oncologists perceived the pressure to achieve academic promotion as the most significant sacrifice associated with academic oncology, whereas only 22.4% perceived less time with loved ones as the biggest sacrifice.

“Although work-life balance was a concern for academic oncologists and may be a factor in female oncologists leaving academia, survey data suggested that women in nonacademic practice faced similar challenges,” the authors write.

More specifically, women in academic oncology reported working 2 more hours on the weekends compared to women not in academic medicine; however, both groups worked a similar number of hours during the week.

On the hiring front, almost 24% of academic oncologists said their gender had a “negative or somewhat negative” impact on their ability to get a job, compared with 21% of nonacademic oncologists. Conversely, nearly 28% of academic oncologists said their gender had a “positive or somewhat positive” influence on whether they were hired compared with 41.2% of nonacademic oncologists.

Respondents, however, perceived that gender strongly influenced promotion opportunities. More than half of the respondents – 54.6% of academic oncologists and 50.6% of nonacademic oncologists – believed they were less likely to be promoted than their male colleagues.

This perception aligns with findings from prior studies, which “found women were less likely than men to be promoted to associate professor, full professor, or department chair positions,” the authors write.

Overall, most respondents in each group – 71.3% in academic medicine and 68.6% in nonacademic practice – said they would choose the same career path again. But almost 22% of those in academia said they were “likely or very likely” to leave academic oncology in the next 5 years. Of these women, 28.2% said they would switch to industry employment and 25% would move to community practice.

“Contrary to popular assumptions,” the researchers note, “a spouse or partner and/or family were not a major factor in female oncologists favoring nonacademic careers, because this factor was similarly important to both academic and nonacademic oncologists.”

However, they note, “the increased financial compensation in nonacademic oncology may play a large role in some women’s career decisions.”
 

Making headway on gender equality?

In 2013, oncologist Katherine Reeder-Hayes, MD, MBA, now an associate at the University of North Carolina, Chapel Hill, published a study on gender equality in oncology in which she concluded that despite “an increasingly significant presence in the oncology physician workforce” women remained “under-represented in leadership positions and at the senior levels of academic medicine.”

Since then, Dr. Reeder-Hayes says that she has seen progress but recognizes the need for more.

“To some extent, I think that representation is improving over time due to factors outside the workplace – women are entering medical school in large numbers and may have more supportive partners and more social support for pursuing a professional career in general, [compared with] a decade or two ago,” Dr. Reeder-Hayes told this news organization.

On a personal level, she noted, “I do see many midcareer women assuming key leadership roles in my own institution.” However, she added, “I think the translation of those good candidates into increased representation in leadership probably varies widely across different institutions.”

In a 2019 editorial, researchers highlighted this variation while calling attention to the “notable progress” made by the American Association for Cancer Research (AACR). Specifically, the editorialists reported that women represent 40% of AACR members, 45% of the AACR Board of Directors, and half of the last 10 association presidents.

Editorial coauthor Elizabeth Jaffee, MD, deputy director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, and former AACR president, told this news organization that she attributes this progress to “concrete measures to ensure equality throughout the organization,” which include gender balance on nominating and program committees as well as research meetings and providing opportunities for mentoring, leadership training, and networking.

Despite this positive change, the COVID-19 pandemic threatens to widen the gender imbalance. In a recent article, Julie Silver, MD, an expert in gender equity in medicine, told this news organization that she anticipates trouble ahead.

“There are many indications that women are leaving medicine in disproportionately high numbers,” said Dr. Silver, associate chair and director of cancer rehabilitation in the department of physical medicine and rehabilitation at Harvard Medical School, Boston. “A lack of fair pay and promotion opportunities that were present before COVID-19 are now combined with a host of pandemic-related challenges.”

In addition to salary and promotion disparities, the U.S. continues to suffer from “a chronic shortage of available, affordable, and high-quality childcare and a lack of federal-level policy initiatives or employer initiatives to broaden paid family leave and develop childcare infrastructure and workforce,” Dr. Reeder-Hayes said. Providing extended leave for new parents and on-site childcare could go a long way to improving this problem, she said.

However, Dr. Reeder-Hayes noted that perhaps the “leaky pipeline” problem in oncology highlights the fact that women “are making good decisions that reflect balanced life priorities, [and that] if we don’t structure job responsibilities, childcare, and pacing of promotion and tenure in ways that allow people to nurture other parts of their lives, employees will feel they’re being asked to sacrifice key things.”

In other words, she said, “it’s the workplace that needs to change if we’re going to convince [women], and many men with similar values, to stay.”

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

Gender equality remains elusive for women in academic oncology, a survey of nearly 700 U.S. female oncologists suggests.

More than half of respondents in academic medicine said they believe their gender adversely affects their likelihood for promotion, and 1 in 5 said they were considering leaving academia in the next 5 years.

Given the percentage of female oncologists planning to exit academia, “gender inequality is at high risk of continuing if the culture is not addressed,” write the authors in their study, published online Dec. 30 in JAMA Network Open.

Although women currently outnumber men in U.S. medical schools – a shift that first occurred in 2019 – female representation in academic oncology dwindles at more senior levels. Women represent 45% of hematology and oncology residents, only about 36% of academic faculty, and an even smaller percentage of leadership positions in academic medicine. Women, for instance, occupy about 31% of the chair positions in medical oncology, 17.4% in radiation oncology, and 11% in surgical oncology.

A team of researchers led by Emily C. Merfeld, MD, of the University of Wisconsin Hospitals and Clinics, Madison, set out to understand the factors influencing female oncologists’ decisions to pursue academic versus nonacademic career paths.

Dr. Merfeld and colleagues analyzed survey responses from 667 female oncologists between August 1 and Oct. 31, 2020 – 422 (63.2%) in academic medicine and 245 (36.8%) in nonacademic practice.

Overall, 1 in 4 oncologists said their spouse or partner and family “extremely or moderately” affected their decision to pursue academic practice.

Almost 43% of academic oncologists perceived time spent with loved ones as the biggest sacrifice related to pursuing a career in academic medicine. Approximately the same percentage (41.6%) of nonacademic oncologists perceived the pressure to achieve academic promotion as the most significant sacrifice associated with academic oncology, whereas only 22.4% perceived less time with loved ones as the biggest sacrifice.

“Although work-life balance was a concern for academic oncologists and may be a factor in female oncologists leaving academia, survey data suggested that women in nonacademic practice faced similar challenges,” the authors write.

More specifically, women in academic oncology reported working 2 more hours on the weekends compared to women not in academic medicine; however, both groups worked a similar number of hours during the week.

On the hiring front, almost 24% of academic oncologists said their gender had a “negative or somewhat negative” impact on their ability to get a job, compared with 21% of nonacademic oncologists. Conversely, nearly 28% of academic oncologists said their gender had a “positive or somewhat positive” influence on whether they were hired compared with 41.2% of nonacademic oncologists.

Respondents, however, perceived that gender strongly influenced promotion opportunities. More than half of the respondents – 54.6% of academic oncologists and 50.6% of nonacademic oncologists – believed they were less likely to be promoted than their male colleagues.

This perception aligns with findings from prior studies, which “found women were less likely than men to be promoted to associate professor, full professor, or department chair positions,” the authors write.

Overall, most respondents in each group – 71.3% in academic medicine and 68.6% in nonacademic practice – said they would choose the same career path again. But almost 22% of those in academia said they were “likely or very likely” to leave academic oncology in the next 5 years. Of these women, 28.2% said they would switch to industry employment and 25% would move to community practice.

“Contrary to popular assumptions,” the researchers note, “a spouse or partner and/or family were not a major factor in female oncologists favoring nonacademic careers, because this factor was similarly important to both academic and nonacademic oncologists.”

However, they note, “the increased financial compensation in nonacademic oncology may play a large role in some women’s career decisions.”
 

Making headway on gender equality?

In 2013, oncologist Katherine Reeder-Hayes, MD, MBA, now an associate at the University of North Carolina, Chapel Hill, published a study on gender equality in oncology in which she concluded that despite “an increasingly significant presence in the oncology physician workforce” women remained “under-represented in leadership positions and at the senior levels of academic medicine.”

Since then, Dr. Reeder-Hayes says that she has seen progress but recognizes the need for more.

“To some extent, I think that representation is improving over time due to factors outside the workplace – women are entering medical school in large numbers and may have more supportive partners and more social support for pursuing a professional career in general, [compared with] a decade or two ago,” Dr. Reeder-Hayes told this news organization.

On a personal level, she noted, “I do see many midcareer women assuming key leadership roles in my own institution.” However, she added, “I think the translation of those good candidates into increased representation in leadership probably varies widely across different institutions.”

In a 2019 editorial, researchers highlighted this variation while calling attention to the “notable progress” made by the American Association for Cancer Research (AACR). Specifically, the editorialists reported that women represent 40% of AACR members, 45% of the AACR Board of Directors, and half of the last 10 association presidents.

Editorial coauthor Elizabeth Jaffee, MD, deputy director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, and former AACR president, told this news organization that she attributes this progress to “concrete measures to ensure equality throughout the organization,” which include gender balance on nominating and program committees as well as research meetings and providing opportunities for mentoring, leadership training, and networking.

Despite this positive change, the COVID-19 pandemic threatens to widen the gender imbalance. In a recent article, Julie Silver, MD, an expert in gender equity in medicine, told this news organization that she anticipates trouble ahead.

“There are many indications that women are leaving medicine in disproportionately high numbers,” said Dr. Silver, associate chair and director of cancer rehabilitation in the department of physical medicine and rehabilitation at Harvard Medical School, Boston. “A lack of fair pay and promotion opportunities that were present before COVID-19 are now combined with a host of pandemic-related challenges.”

In addition to salary and promotion disparities, the U.S. continues to suffer from “a chronic shortage of available, affordable, and high-quality childcare and a lack of federal-level policy initiatives or employer initiatives to broaden paid family leave and develop childcare infrastructure and workforce,” Dr. Reeder-Hayes said. Providing extended leave for new parents and on-site childcare could go a long way to improving this problem, she said.

However, Dr. Reeder-Hayes noted that perhaps the “leaky pipeline” problem in oncology highlights the fact that women “are making good decisions that reflect balanced life priorities, [and that] if we don’t structure job responsibilities, childcare, and pacing of promotion and tenure in ways that allow people to nurture other parts of their lives, employees will feel they’re being asked to sacrifice key things.”

In other words, she said, “it’s the workplace that needs to change if we’re going to convince [women], and many men with similar values, to stay.”

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

A new French study raises the possibility that immunotherapy can help some people with stomach cancer avoid surgery.

GERCOR NEONIPIGA was a phase 2 study with no comparator group and only 32 patients, but even so, after a 6-cycle course of nivolumab and ipilimumab, there was no sign of tumor in 17 of the 29 patients (59%) who had surgery specimens evaluable by pathology.

Indeed, two patients refused surgery after their preop endoscopic biopsies came back clear with no tumor cells. Surgery was called off in a third patient who developed metastases beforehand.

After a median of 12 months follow-up, there’s was no recurrence or progression in 30 patients (94%). The remaining two included the metastatic patient and one who died 3 days after surgery from cardiovascular complications.

If the findings pan out with additional research, the approach could be a boon for people who respond. “Avoiding surgery is a dream for these patients,” said lead investigator Thierry Andre, MD, a medical oncology professor at Sorbonne University, Paris, when he presented the findings at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The trial “raises the question whether surgery can be delayed or avoided in some patients with localized” disease. Given the findings, “it seems possible not for all but probably for half, maybe more.” As in the two subjects who opted out of surgery, preop endoscopic biopsies could be used to identify complete responders with active surveillance afterwards, he said.

The study included 16 patients with gastric cancer and 16 with esophagogastric adenocarcinoma. They were mismatch repair deficient, which Dr. Andre said predicts response to immunotherapy.

At baseline, 22 had stage T3 disease and four had stage T2 disease, and stage was not evaluable by echo-endoscopy in 6. Nodal status was unknown, but the patients had no metastases at baseline.

They underwent six nivolumab 240-mg infusions and two ipilimumab 1–mg/kg infusions over 12 weeks, followed by R0 resections a median of 5 weeks after the last nivolumab injection.

Surgical specimens from 17 patients (59%) showed a complete pathological response to neoadjuvant immunotherapy (Becker tumor regression grade (TRG) 1a, ypT0N0). TRG was 1b – less than 10% residual tumor in tumor bed in four patients. TRG was 2 in two patients with 10%-50% of residual tumor remaining, and six had a TRG of 3 with more than half of the tumor remaining after immunotherapy.

Based on tumor response, 25 patients had nine additional nivolumab infusions after surgery with 480 mg infused monthly.

Dr. Andre explained that people want to avoid surgery because of the substantial morbidity that was shown in the study, plus 54% of patients had complications, including anastomotic leaks, pancreatitis, pneumonia, and other problems.

There were no new safety signals with neoadjuvant therapy; 25% of patients had grade 3 or 4 events.

The study was conducted in 10 centers in France. About three-quarters of the subjects were men and the median age was 65 years.

Bristol Meyers Squibb supplied the nivolumab and ipilimumab and partially funded the work. Many of the investigators had ties to the company, including Dr. Andre, who is a consultant for BMS and reported payments from the company.

A new French study raises the possibility that immunotherapy can help some people with stomach cancer avoid surgery.

GERCOR NEONIPIGA was a phase 2 study with no comparator group and only 32 patients, but even so, after a 6-cycle course of nivolumab and ipilimumab, there was no sign of tumor in 17 of the 29 patients (59%) who had surgery specimens evaluable by pathology.

Indeed, two patients refused surgery after their preop endoscopic biopsies came back clear with no tumor cells. Surgery was called off in a third patient who developed metastases beforehand.

After a median of 12 months follow-up, there’s was no recurrence or progression in 30 patients (94%). The remaining two included the metastatic patient and one who died 3 days after surgery from cardiovascular complications.

If the findings pan out with additional research, the approach could be a boon for people who respond. “Avoiding surgery is a dream for these patients,” said lead investigator Thierry Andre, MD, a medical oncology professor at Sorbonne University, Paris, when he presented the findings at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The trial “raises the question whether surgery can be delayed or avoided in some patients with localized” disease. Given the findings, “it seems possible not for all but probably for half, maybe more.” As in the two subjects who opted out of surgery, preop endoscopic biopsies could be used to identify complete responders with active surveillance afterwards, he said.

The study included 16 patients with gastric cancer and 16 with esophagogastric adenocarcinoma. They were mismatch repair deficient, which Dr. Andre said predicts response to immunotherapy.

At baseline, 22 had stage T3 disease and four had stage T2 disease, and stage was not evaluable by echo-endoscopy in 6. Nodal status was unknown, but the patients had no metastases at baseline.

They underwent six nivolumab 240-mg infusions and two ipilimumab 1–mg/kg infusions over 12 weeks, followed by R0 resections a median of 5 weeks after the last nivolumab injection.

Surgical specimens from 17 patients (59%) showed a complete pathological response to neoadjuvant immunotherapy (Becker tumor regression grade (TRG) 1a, ypT0N0). TRG was 1b – less than 10% residual tumor in tumor bed in four patients. TRG was 2 in two patients with 10%-50% of residual tumor remaining, and six had a TRG of 3 with more than half of the tumor remaining after immunotherapy.

Based on tumor response, 25 patients had nine additional nivolumab infusions after surgery with 480 mg infused monthly.

Dr. Andre explained that people want to avoid surgery because of the substantial morbidity that was shown in the study, plus 54% of patients had complications, including anastomotic leaks, pancreatitis, pneumonia, and other problems.

There were no new safety signals with neoadjuvant therapy; 25% of patients had grade 3 or 4 events.

The study was conducted in 10 centers in France. About three-quarters of the subjects were men and the median age was 65 years.

Bristol Meyers Squibb supplied the nivolumab and ipilimumab and partially funded the work. Many of the investigators had ties to the company, including Dr. Andre, who is a consultant for BMS and reported payments from the company.

A new French study raises the possibility that immunotherapy can help some people with stomach cancer avoid surgery.

GERCOR NEONIPIGA was a phase 2 study with no comparator group and only 32 patients, but even so, after a 6-cycle course of nivolumab and ipilimumab, there was no sign of tumor in 17 of the 29 patients (59%) who had surgery specimens evaluable by pathology.

Indeed, two patients refused surgery after their preop endoscopic biopsies came back clear with no tumor cells. Surgery was called off in a third patient who developed metastases beforehand.

After a median of 12 months follow-up, there’s was no recurrence or progression in 30 patients (94%). The remaining two included the metastatic patient and one who died 3 days after surgery from cardiovascular complications.

If the findings pan out with additional research, the approach could be a boon for people who respond. “Avoiding surgery is a dream for these patients,” said lead investigator Thierry Andre, MD, a medical oncology professor at Sorbonne University, Paris, when he presented the findings at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The trial “raises the question whether surgery can be delayed or avoided in some patients with localized” disease. Given the findings, “it seems possible not for all but probably for half, maybe more.” As in the two subjects who opted out of surgery, preop endoscopic biopsies could be used to identify complete responders with active surveillance afterwards, he said.

The study included 16 patients with gastric cancer and 16 with esophagogastric adenocarcinoma. They were mismatch repair deficient, which Dr. Andre said predicts response to immunotherapy.

At baseline, 22 had stage T3 disease and four had stage T2 disease, and stage was not evaluable by echo-endoscopy in 6. Nodal status was unknown, but the patients had no metastases at baseline.

They underwent six nivolumab 240-mg infusions and two ipilimumab 1–mg/kg infusions over 12 weeks, followed by R0 resections a median of 5 weeks after the last nivolumab injection.

Surgical specimens from 17 patients (59%) showed a complete pathological response to neoadjuvant immunotherapy (Becker tumor regression grade (TRG) 1a, ypT0N0). TRG was 1b – less than 10% residual tumor in tumor bed in four patients. TRG was 2 in two patients with 10%-50% of residual tumor remaining, and six had a TRG of 3 with more than half of the tumor remaining after immunotherapy.

Based on tumor response, 25 patients had nine additional nivolumab infusions after surgery with 480 mg infused monthly.

Dr. Andre explained that people want to avoid surgery because of the substantial morbidity that was shown in the study, plus 54% of patients had complications, including anastomotic leaks, pancreatitis, pneumonia, and other problems.

There were no new safety signals with neoadjuvant therapy; 25% of patients had grade 3 or 4 events.

The study was conducted in 10 centers in France. About three-quarters of the subjects were men and the median age was 65 years.

Bristol Meyers Squibb supplied the nivolumab and ipilimumab and partially funded the work. Many of the investigators had ties to the company, including Dr. Andre, who is a consultant for BMS and reported payments from the company.

Patients with breast cancer treated with chemotherapy who also took a probiotics supplement had significantly fewer symptoms of chemotherapy-related cognitive impairment (CRCI) often referred to as “chemo brain,” compared with a control group taking placebo capsules, reports the first study of its kind.

“Our finding[s] provide a simple, inexpensive, and effective prevention strategy for chemotherapy-related side effects, including cognitive impairment,” senior author Jianbin Tong, MD, PhD, of the department of anesthesiology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China, said in an interview.

The research “is the first study showing that probiotics supplementation during chemotherapy can prevent chemotherapy-related brain impairment,” he noted.

The double-blind, randomized study was published in the European Journal of Cancer. It involved 159 patients in China with stage I-III breast cancer who required adjuvant chemotherapy between 2018 and 2019. These patients were randomized to receive a regimen of three capsules twice per day containing either probiotics (n = 80) or placebo (n = 79) during their chemotherapy.

The probiotic capsule (Bifico, Sine Pharmaceuticals) contained Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis (210 mg of each).

The reductions in symptoms seen with the supplementation “exceed our expectations,” Dr. Tong said in an interview.

He speculated that this may have longer-term effects, with the prevention of initial cognitive impairment potentially “changing the neurodegenerative trajectory of patients after chemotherapy.”

“Patients don’t need to take probiotics continuously, but it’s better to take probiotics intermittently,” he said.

Approached for comment, Melanie Sekeres, PhD, Canada Research Chair and assistant professor at the University of Ottawa, said the improvements, such as those seen in delayed recall, are especially of interest.

“This is particularly notable because one of the brain regions that is critically involved in long-term memory processing, the hippocampus, is known to be highly sensitive to chemotherapy-induced neurotoxicity,” she said in an interview.

“The finding that probiotic treatment given alongside chemotherapy is sufficient to, in part, protect against memory disturbances in these patients suggests that there may be some neuroprotection conferred by the probiotic treatment,” she said.

A key question is whether similar results would be seen with other chemotherapy regimens, Dr. Sekeres added. “To better understand the effectiveness of these probiotics in preventing CRCI, they should be tested using other classes of chemotherapies before any broad conclusions can be made.”
 

Measuring the effect on ‘chemo brain’

“Chemo brain” is commonly reported after chemotherapy, and some 35% of patients report having long-term effects. Key symptoms include deficits in memory, attention, and executive and processing speed skills.

In their study, Dr. Tong and colleagues assessed patients on their cognitive status with a number of validated neuropsychological battery tests 1 day prior to initiating chemotherapy and 21 days after the last cycle of chemotherapy. Tests included the Hopkins Verbal Learning Test–Revised for verbal memory, the Brief Visuospatial Memory Test–Revised for visuospatial memory, and various others.

The team reports that, after adjustment for confounding factors, the total incidence of CRCI was significantly lower in the probiotics group versus the placebo group 21 days post chemotherapy (35% vs. 81%; relative risk, 0.43).

Rates of mild cognitive impairment were also lower in the probiotics group (29% vs 52%; RR, 0.55), as were rates of moderate cognitive impairment (6% vs. 29%; RR, 0.22).

The improvements with probiotics were observed across most other neuropsychological domains, including instantaneous verbal memory and delayed visuospatial memory (for both, P = .003) and visuospatial interference and verbal fluency (for both, P < .001).

The greater improvements in the probiotics group were seen regardless of use of other medications or the type of chemotherapy regimen received, which could have included epirubicin or docetaxel and/or cyclophosphamide.

CRCI was more common in patients who were older and had lower education or a higher body mass index; however, the improvements in the probiotics group were observed regardless of those factors, the authors commented.

In addition to the reduction in cognitive impairment that was seen, the treatment with probiotics was also associated with lower blood glucose (mean, 4.96 vs. 5.30; P = .02) and lower LDL cholesterol (2.61 vs. 2.89; P = .03) versus placebo, while there were no significant differences between the groups prior to chemotherapy.

There were no reports of severe emesis or constipation (grade 3 or higher) in either group; however, the probiotics group did have a significantly lower incidence of both, the authors note.
 

How does it work?

The potential benefits with probiotics are theorized to result from stabilizing the colonic and bacterial disruptions that are caused by chemotherapy, potentially offsetting the neuroinflammation that is linked to the cancer treatment, the authors speculated.

A subanalysis of 78 stool samples from 20 patients in the study showed no differences in alpha diversity or beta diversity before or after chemotherapy; however, there were significant reductions in the abundance of Streptococcus and Tyzzerella (P = .023 and P = .033, respectively) in the probiotics group after chemotherapy.

Further analysis showed that probiotics supplement modulated the levels of nine plasma metabolites in patients with breast cancer, with the results suggesting that metabolites (including p-mentha-1,8-dien-7-ol) “may be modulators in preventing CRCI by probiotics,” the authors noted.
 

Benefits reported beyond breast cancer

A subsequent trial conducted by Dr. Tong and colleagues following the CRCI study further showed similar protective benefits with probiotics in the prevention of chemotherapy-related hand-foot syndrome and oral mucositis.

And in a recent study, the research team found evidence of probiotic supplements protecting against cognitive impairment in the elderly following surgery.

The study received support from the National Natural Science Foundation of China, Subproject of the National Key Research and Development Program Project of China, science and technology innovation platform and talent plan of Hunan province and Natural Science Foundation of Hunan Province.

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

Patients with breast cancer treated with chemotherapy who also took a probiotics supplement had significantly fewer symptoms of chemotherapy-related cognitive impairment (CRCI) often referred to as “chemo brain,” compared with a control group taking placebo capsules, reports the first study of its kind.

“Our finding[s] provide a simple, inexpensive, and effective prevention strategy for chemotherapy-related side effects, including cognitive impairment,” senior author Jianbin Tong, MD, PhD, of the department of anesthesiology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China, said in an interview.

The research “is the first study showing that probiotics supplementation during chemotherapy can prevent chemotherapy-related brain impairment,” he noted.

The double-blind, randomized study was published in the European Journal of Cancer. It involved 159 patients in China with stage I-III breast cancer who required adjuvant chemotherapy between 2018 and 2019. These patients were randomized to receive a regimen of three capsules twice per day containing either probiotics (n = 80) or placebo (n = 79) during their chemotherapy.

The probiotic capsule (Bifico, Sine Pharmaceuticals) contained Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis (210 mg of each).

The reductions in symptoms seen with the supplementation “exceed our expectations,” Dr. Tong said in an interview.

He speculated that this may have longer-term effects, with the prevention of initial cognitive impairment potentially “changing the neurodegenerative trajectory of patients after chemotherapy.”

“Patients don’t need to take probiotics continuously, but it’s better to take probiotics intermittently,” he said.

Approached for comment, Melanie Sekeres, PhD, Canada Research Chair and assistant professor at the University of Ottawa, said the improvements, such as those seen in delayed recall, are especially of interest.

“This is particularly notable because one of the brain regions that is critically involved in long-term memory processing, the hippocampus, is known to be highly sensitive to chemotherapy-induced neurotoxicity,” she said in an interview.

“The finding that probiotic treatment given alongside chemotherapy is sufficient to, in part, protect against memory disturbances in these patients suggests that there may be some neuroprotection conferred by the probiotic treatment,” she said.

A key question is whether similar results would be seen with other chemotherapy regimens, Dr. Sekeres added. “To better understand the effectiveness of these probiotics in preventing CRCI, they should be tested using other classes of chemotherapies before any broad conclusions can be made.”
 

Measuring the effect on ‘chemo brain’

“Chemo brain” is commonly reported after chemotherapy, and some 35% of patients report having long-term effects. Key symptoms include deficits in memory, attention, and executive and processing speed skills.

In their study, Dr. Tong and colleagues assessed patients on their cognitive status with a number of validated neuropsychological battery tests 1 day prior to initiating chemotherapy and 21 days after the last cycle of chemotherapy. Tests included the Hopkins Verbal Learning Test–Revised for verbal memory, the Brief Visuospatial Memory Test–Revised for visuospatial memory, and various others.

The team reports that, after adjustment for confounding factors, the total incidence of CRCI was significantly lower in the probiotics group versus the placebo group 21 days post chemotherapy (35% vs. 81%; relative risk, 0.43).

Rates of mild cognitive impairment were also lower in the probiotics group (29% vs 52%; RR, 0.55), as were rates of moderate cognitive impairment (6% vs. 29%; RR, 0.22).

The improvements with probiotics were observed across most other neuropsychological domains, including instantaneous verbal memory and delayed visuospatial memory (for both, P = .003) and visuospatial interference and verbal fluency (for both, P < .001).

The greater improvements in the probiotics group were seen regardless of use of other medications or the type of chemotherapy regimen received, which could have included epirubicin or docetaxel and/or cyclophosphamide.

CRCI was more common in patients who were older and had lower education or a higher body mass index; however, the improvements in the probiotics group were observed regardless of those factors, the authors commented.

In addition to the reduction in cognitive impairment that was seen, the treatment with probiotics was also associated with lower blood glucose (mean, 4.96 vs. 5.30; P = .02) and lower LDL cholesterol (2.61 vs. 2.89; P = .03) versus placebo, while there were no significant differences between the groups prior to chemotherapy.

There were no reports of severe emesis or constipation (grade 3 or higher) in either group; however, the probiotics group did have a significantly lower incidence of both, the authors note.
 

How does it work?

The potential benefits with probiotics are theorized to result from stabilizing the colonic and bacterial disruptions that are caused by chemotherapy, potentially offsetting the neuroinflammation that is linked to the cancer treatment, the authors speculated.

A subanalysis of 78 stool samples from 20 patients in the study showed no differences in alpha diversity or beta diversity before or after chemotherapy; however, there were significant reductions in the abundance of Streptococcus and Tyzzerella (P = .023 and P = .033, respectively) in the probiotics group after chemotherapy.

Further analysis showed that probiotics supplement modulated the levels of nine plasma metabolites in patients with breast cancer, with the results suggesting that metabolites (including p-mentha-1,8-dien-7-ol) “may be modulators in preventing CRCI by probiotics,” the authors noted.
 

Benefits reported beyond breast cancer

A subsequent trial conducted by Dr. Tong and colleagues following the CRCI study further showed similar protective benefits with probiotics in the prevention of chemotherapy-related hand-foot syndrome and oral mucositis.

And in a recent study, the research team found evidence of probiotic supplements protecting against cognitive impairment in the elderly following surgery.

The study received support from the National Natural Science Foundation of China, Subproject of the National Key Research and Development Program Project of China, science and technology innovation platform and talent plan of Hunan province and Natural Science Foundation of Hunan Province.

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

Patients with breast cancer treated with chemotherapy who also took a probiotics supplement had significantly fewer symptoms of chemotherapy-related cognitive impairment (CRCI) often referred to as “chemo brain,” compared with a control group taking placebo capsules, reports the first study of its kind.

“Our finding[s] provide a simple, inexpensive, and effective prevention strategy for chemotherapy-related side effects, including cognitive impairment,” senior author Jianbin Tong, MD, PhD, of the department of anesthesiology, Third Xiangya Hospital, Central South University, Changsha, Hunan, China, said in an interview.

The research “is the first study showing that probiotics supplementation during chemotherapy can prevent chemotherapy-related brain impairment,” he noted.

The double-blind, randomized study was published in the European Journal of Cancer. It involved 159 patients in China with stage I-III breast cancer who required adjuvant chemotherapy between 2018 and 2019. These patients were randomized to receive a regimen of three capsules twice per day containing either probiotics (n = 80) or placebo (n = 79) during their chemotherapy.

The probiotic capsule (Bifico, Sine Pharmaceuticals) contained Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis (210 mg of each).

The reductions in symptoms seen with the supplementation “exceed our expectations,” Dr. Tong said in an interview.

He speculated that this may have longer-term effects, with the prevention of initial cognitive impairment potentially “changing the neurodegenerative trajectory of patients after chemotherapy.”

“Patients don’t need to take probiotics continuously, but it’s better to take probiotics intermittently,” he said.

Approached for comment, Melanie Sekeres, PhD, Canada Research Chair and assistant professor at the University of Ottawa, said the improvements, such as those seen in delayed recall, are especially of interest.

“This is particularly notable because one of the brain regions that is critically involved in long-term memory processing, the hippocampus, is known to be highly sensitive to chemotherapy-induced neurotoxicity,” she said in an interview.

“The finding that probiotic treatment given alongside chemotherapy is sufficient to, in part, protect against memory disturbances in these patients suggests that there may be some neuroprotection conferred by the probiotic treatment,” she said.

A key question is whether similar results would be seen with other chemotherapy regimens, Dr. Sekeres added. “To better understand the effectiveness of these probiotics in preventing CRCI, they should be tested using other classes of chemotherapies before any broad conclusions can be made.”
 

Measuring the effect on ‘chemo brain’

“Chemo brain” is commonly reported after chemotherapy, and some 35% of patients report having long-term effects. Key symptoms include deficits in memory, attention, and executive and processing speed skills.

In their study, Dr. Tong and colleagues assessed patients on their cognitive status with a number of validated neuropsychological battery tests 1 day prior to initiating chemotherapy and 21 days after the last cycle of chemotherapy. Tests included the Hopkins Verbal Learning Test–Revised for verbal memory, the Brief Visuospatial Memory Test–Revised for visuospatial memory, and various others.

The team reports that, after adjustment for confounding factors, the total incidence of CRCI was significantly lower in the probiotics group versus the placebo group 21 days post chemotherapy (35% vs. 81%; relative risk, 0.43).

Rates of mild cognitive impairment were also lower in the probiotics group (29% vs 52%; RR, 0.55), as were rates of moderate cognitive impairment (6% vs. 29%; RR, 0.22).

The improvements with probiotics were observed across most other neuropsychological domains, including instantaneous verbal memory and delayed visuospatial memory (for both, P = .003) and visuospatial interference and verbal fluency (for both, P < .001).

The greater improvements in the probiotics group were seen regardless of use of other medications or the type of chemotherapy regimen received, which could have included epirubicin or docetaxel and/or cyclophosphamide.

CRCI was more common in patients who were older and had lower education or a higher body mass index; however, the improvements in the probiotics group were observed regardless of those factors, the authors commented.

In addition to the reduction in cognitive impairment that was seen, the treatment with probiotics was also associated with lower blood glucose (mean, 4.96 vs. 5.30; P = .02) and lower LDL cholesterol (2.61 vs. 2.89; P = .03) versus placebo, while there were no significant differences between the groups prior to chemotherapy.

There were no reports of severe emesis or constipation (grade 3 or higher) in either group; however, the probiotics group did have a significantly lower incidence of both, the authors note.
 

How does it work?

The potential benefits with probiotics are theorized to result from stabilizing the colonic and bacterial disruptions that are caused by chemotherapy, potentially offsetting the neuroinflammation that is linked to the cancer treatment, the authors speculated.

A subanalysis of 78 stool samples from 20 patients in the study showed no differences in alpha diversity or beta diversity before or after chemotherapy; however, there were significant reductions in the abundance of Streptococcus and Tyzzerella (P = .023 and P = .033, respectively) in the probiotics group after chemotherapy.

Further analysis showed that probiotics supplement modulated the levels of nine plasma metabolites in patients with breast cancer, with the results suggesting that metabolites (including p-mentha-1,8-dien-7-ol) “may be modulators in preventing CRCI by probiotics,” the authors noted.
 

Benefits reported beyond breast cancer

A subsequent trial conducted by Dr. Tong and colleagues following the CRCI study further showed similar protective benefits with probiotics in the prevention of chemotherapy-related hand-foot syndrome and oral mucositis.

And in a recent study, the research team found evidence of probiotic supplements protecting against cognitive impairment in the elderly following surgery.

The study received support from the National Natural Science Foundation of China, Subproject of the National Key Research and Development Program Project of China, science and technology innovation platform and talent plan of Hunan province and Natural Science Foundation of Hunan Province.

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

Two expert analyses appearing in the same issue of the Journal of Thoracic Oncology arrive at opposite conclusions regarding the value for metastatic non–small cell lung cancer (mNSCLC) of combining first-generation endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with either chemotherapy or vascular EGF (VEGF) monoclonal antibodies. One affirms single-agent EGFR TKI treatment, such as with osimertinib, as the current standard of care for first-line advanced metastatic EGFR-positive mNSCLC, and the other affirms clear benefits for first-generation EGFR TKIs combined with either chemotherapy or VEGF monoclonal antibodies.

In the analysis supporting combination therapy for mNSCLC, Sara Moore, MD, and Paul Wheatley-Price MD, wrote that while targeted therapy with EGFR TKIs is highly effective initially, resistance inevitably develops.

Recent data, they stated, have demonstrated that combination strategies can delay development of resistance and improve outcomes for mNSCLC populations. Combining first-generation EGFR TKIs with either chemotherapy or VEGF monoclonal antibodies has led to consistent improvement in progression-free survival (PFS) and overall survival (OS) in some cases. In the NEJ009 trial, the combination of chemotherapy (carboplatin and pemetrexed, with pemetrexed maintenance) plus gefitinib versus gefitinib alone improved response rate (84% vs. 67%, P < 0.001), PFS (median, 20.9 months vs. 11.2 months; P < .001), and OS (median, 50.9 months vs. 38.8 months; P = .021). An increase in adverse events in the chemotherapy arm led to a decrease in quality of life.

Another clinical trial (by Noronha and colleagues) conducted in India of the same combination found benefit for combination therapy in response rate (75% vs. 63%), PFS (median, 16 months vs. 8 months), and OS (not reached vs. 17 months). Grade 3 or higher adverse event rates were higher with the combination (51% vs. 25%) with quality of life was not yet reported.

While both trials have been criticized owing to a lack of standard T790M resistance testing and low use of osimertinib in subsequent lines of therapy, Dr. Moore and Dr. Wheatley-Price pointed out: “Even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”

The importance of using combination therapy in the first-line setting, they stated, is underscored by the consistent drop-off in patients who receive second-line combination therapy. In the phase 3 FLAURA trial of first-line osimertinib monotherapy, of the patients who discontinued osimertinib, the most common reason for not receiving subsequent therapy was death (60% went on to receive further systemic therapy). This highlights the need to use the most effective treatments up front, Dr. Moore and Dr. Wheatley-Price wrote.

The four large trials of VEGF-targeted therapy with either monoclonal antibodies or TKIs added to first-generation EGFR TKIs have consistently shown improved PFS. Increased toxicities led to discontinuation of VEGF-targeted therapy in 20%-30%.

In the RELAY trial, however, despite more toxicities, quality of life was not diminished. In general, the authors concluded that long-term detriments to quality of life have not been demonstrated. Ongoing studies of osimertinib in combination with VEGF inhibition include a phase 1/2 trial with bevacizumab in previously untreated patients showing an 80% response rate (median PFS, 18.4 months) with no unexpected toxicity.

Chemotherapy-based treatment for mNSCLC with third-generation EGFR TKIs, in appropriately selected patients, the authors concluded, “can offer an additional standard-of-care option as first-line treatment of EGFR-mutant lung cancer.”

Since the introduction of EGFR TKIs, Sophie Stock-Martineau, MD and Frances A. Shepherd, MD noted in their analysis, researchers have aimed to improve their efficacy through combining them with other agents. The authors review research on the addition of chemo- or immunotherapy and agents targeting major resistance mechanisms such as MET. Their review of the same NEJ009 trial focuses, however, on the 65.3% (EGFR TKI plus chemotherapy) versus 31.0% (gefitinib alone) grade 3 adverse event rate, and the 51% versus 25% grade 3 adverse event rate in a similar trial by Noronha and colleagues. The review by Dr. Stock-Martineau and Dr. Shepherd further found that, while adding antiangiogenic agents to an EGFR TKI “mildly” prolongs PFS, survival benefits have not been demonstrated. The added costs, not just in toxicity, were a “far from negligible” $120,000 above the cost of bevacizumab alone for 16 treatments. Data from trials of immune checkpoint inhibitors added to EGFR TKIs reveal heightened toxicities and limited efficacy. Trials of EGFR monoclonal antibodies with an EGFR TKI showed no PFS or OS benefit and were terminated early. Similarly, evidence to date shows no benefit beyond that shown for EGFR TKI monotherapy with the addition of a MET inhibitor.

“Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system,” Dr. Stock-Martineau and Dr. Shepherd concluded, further observing that combinations, given their heightened toxicity profiles, could potentially also worsen quality of life.

No conflicts of interest were reported by the authors of either study.

Two expert analyses appearing in the same issue of the Journal of Thoracic Oncology arrive at opposite conclusions regarding the value for metastatic non–small cell lung cancer (mNSCLC) of combining first-generation endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with either chemotherapy or vascular EGF (VEGF) monoclonal antibodies. One affirms single-agent EGFR TKI treatment, such as with osimertinib, as the current standard of care for first-line advanced metastatic EGFR-positive mNSCLC, and the other affirms clear benefits for first-generation EGFR TKIs combined with either chemotherapy or VEGF monoclonal antibodies.

In the analysis supporting combination therapy for mNSCLC, Sara Moore, MD, and Paul Wheatley-Price MD, wrote that while targeted therapy with EGFR TKIs is highly effective initially, resistance inevitably develops.

Recent data, they stated, have demonstrated that combination strategies can delay development of resistance and improve outcomes for mNSCLC populations. Combining first-generation EGFR TKIs with either chemotherapy or VEGF monoclonal antibodies has led to consistent improvement in progression-free survival (PFS) and overall survival (OS) in some cases. In the NEJ009 trial, the combination of chemotherapy (carboplatin and pemetrexed, with pemetrexed maintenance) plus gefitinib versus gefitinib alone improved response rate (84% vs. 67%, P < 0.001), PFS (median, 20.9 months vs. 11.2 months; P < .001), and OS (median, 50.9 months vs. 38.8 months; P = .021). An increase in adverse events in the chemotherapy arm led to a decrease in quality of life.

Another clinical trial (by Noronha and colleagues) conducted in India of the same combination found benefit for combination therapy in response rate (75% vs. 63%), PFS (median, 16 months vs. 8 months), and OS (not reached vs. 17 months). Grade 3 or higher adverse event rates were higher with the combination (51% vs. 25%) with quality of life was not yet reported.

While both trials have been criticized owing to a lack of standard T790M resistance testing and low use of osimertinib in subsequent lines of therapy, Dr. Moore and Dr. Wheatley-Price pointed out: “Even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”

The importance of using combination therapy in the first-line setting, they stated, is underscored by the consistent drop-off in patients who receive second-line combination therapy. In the phase 3 FLAURA trial of first-line osimertinib monotherapy, of the patients who discontinued osimertinib, the most common reason for not receiving subsequent therapy was death (60% went on to receive further systemic therapy). This highlights the need to use the most effective treatments up front, Dr. Moore and Dr. Wheatley-Price wrote.

The four large trials of VEGF-targeted therapy with either monoclonal antibodies or TKIs added to first-generation EGFR TKIs have consistently shown improved PFS. Increased toxicities led to discontinuation of VEGF-targeted therapy in 20%-30%.

In the RELAY trial, however, despite more toxicities, quality of life was not diminished. In general, the authors concluded that long-term detriments to quality of life have not been demonstrated. Ongoing studies of osimertinib in combination with VEGF inhibition include a phase 1/2 trial with bevacizumab in previously untreated patients showing an 80% response rate (median PFS, 18.4 months) with no unexpected toxicity.

Chemotherapy-based treatment for mNSCLC with third-generation EGFR TKIs, in appropriately selected patients, the authors concluded, “can offer an additional standard-of-care option as first-line treatment of EGFR-mutant lung cancer.”

Since the introduction of EGFR TKIs, Sophie Stock-Martineau, MD and Frances A. Shepherd, MD noted in their analysis, researchers have aimed to improve their efficacy through combining them with other agents. The authors review research on the addition of chemo- or immunotherapy and agents targeting major resistance mechanisms such as MET. Their review of the same NEJ009 trial focuses, however, on the 65.3% (EGFR TKI plus chemotherapy) versus 31.0% (gefitinib alone) grade 3 adverse event rate, and the 51% versus 25% grade 3 adverse event rate in a similar trial by Noronha and colleagues. The review by Dr. Stock-Martineau and Dr. Shepherd further found that, while adding antiangiogenic agents to an EGFR TKI “mildly” prolongs PFS, survival benefits have not been demonstrated. The added costs, not just in toxicity, were a “far from negligible” $120,000 above the cost of bevacizumab alone for 16 treatments. Data from trials of immune checkpoint inhibitors added to EGFR TKIs reveal heightened toxicities and limited efficacy. Trials of EGFR monoclonal antibodies with an EGFR TKI showed no PFS or OS benefit and were terminated early. Similarly, evidence to date shows no benefit beyond that shown for EGFR TKI monotherapy with the addition of a MET inhibitor.

“Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system,” Dr. Stock-Martineau and Dr. Shepherd concluded, further observing that combinations, given their heightened toxicity profiles, could potentially also worsen quality of life.

No conflicts of interest were reported by the authors of either study.

Two expert analyses appearing in the same issue of the Journal of Thoracic Oncology arrive at opposite conclusions regarding the value for metastatic non–small cell lung cancer (mNSCLC) of combining first-generation endothelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with either chemotherapy or vascular EGF (VEGF) monoclonal antibodies. One affirms single-agent EGFR TKI treatment, such as with osimertinib, as the current standard of care for first-line advanced metastatic EGFR-positive mNSCLC, and the other affirms clear benefits for first-generation EGFR TKIs combined with either chemotherapy or VEGF monoclonal antibodies.

In the analysis supporting combination therapy for mNSCLC, Sara Moore, MD, and Paul Wheatley-Price MD, wrote that while targeted therapy with EGFR TKIs is highly effective initially, resistance inevitably develops.

Recent data, they stated, have demonstrated that combination strategies can delay development of resistance and improve outcomes for mNSCLC populations. Combining first-generation EGFR TKIs with either chemotherapy or VEGF monoclonal antibodies has led to consistent improvement in progression-free survival (PFS) and overall survival (OS) in some cases. In the NEJ009 trial, the combination of chemotherapy (carboplatin and pemetrexed, with pemetrexed maintenance) plus gefitinib versus gefitinib alone improved response rate (84% vs. 67%, P < 0.001), PFS (median, 20.9 months vs. 11.2 months; P < .001), and OS (median, 50.9 months vs. 38.8 months; P = .021). An increase in adverse events in the chemotherapy arm led to a decrease in quality of life.

Another clinical trial (by Noronha and colleagues) conducted in India of the same combination found benefit for combination therapy in response rate (75% vs. 63%), PFS (median, 16 months vs. 8 months), and OS (not reached vs. 17 months). Grade 3 or higher adverse event rates were higher with the combination (51% vs. 25%) with quality of life was not yet reported.

While both trials have been criticized owing to a lack of standard T790M resistance testing and low use of osimertinib in subsequent lines of therapy, Dr. Moore and Dr. Wheatley-Price pointed out: “Even with the use of first-line osimertinib monotherapy, patients may still be exposed to chemotherapy with later lines of treatment. Therefore, combination therapy does not expose patients to new toxicity, it simply changes when they will be exposed to that toxicity during their treatment course.”

The importance of using combination therapy in the first-line setting, they stated, is underscored by the consistent drop-off in patients who receive second-line combination therapy. In the phase 3 FLAURA trial of first-line osimertinib monotherapy, of the patients who discontinued osimertinib, the most common reason for not receiving subsequent therapy was death (60% went on to receive further systemic therapy). This highlights the need to use the most effective treatments up front, Dr. Moore and Dr. Wheatley-Price wrote.

The four large trials of VEGF-targeted therapy with either monoclonal antibodies or TKIs added to first-generation EGFR TKIs have consistently shown improved PFS. Increased toxicities led to discontinuation of VEGF-targeted therapy in 20%-30%.

In the RELAY trial, however, despite more toxicities, quality of life was not diminished. In general, the authors concluded that long-term detriments to quality of life have not been demonstrated. Ongoing studies of osimertinib in combination with VEGF inhibition include a phase 1/2 trial with bevacizumab in previously untreated patients showing an 80% response rate (median PFS, 18.4 months) with no unexpected toxicity.

Chemotherapy-based treatment for mNSCLC with third-generation EGFR TKIs, in appropriately selected patients, the authors concluded, “can offer an additional standard-of-care option as first-line treatment of EGFR-mutant lung cancer.”

Since the introduction of EGFR TKIs, Sophie Stock-Martineau, MD and Frances A. Shepherd, MD noted in their analysis, researchers have aimed to improve their efficacy through combining them with other agents. The authors review research on the addition of chemo- or immunotherapy and agents targeting major resistance mechanisms such as MET. Their review of the same NEJ009 trial focuses, however, on the 65.3% (EGFR TKI plus chemotherapy) versus 31.0% (gefitinib alone) grade 3 adverse event rate, and the 51% versus 25% grade 3 adverse event rate in a similar trial by Noronha and colleagues. The review by Dr. Stock-Martineau and Dr. Shepherd further found that, while adding antiangiogenic agents to an EGFR TKI “mildly” prolongs PFS, survival benefits have not been demonstrated. The added costs, not just in toxicity, were a “far from negligible” $120,000 above the cost of bevacizumab alone for 16 treatments. Data from trials of immune checkpoint inhibitors added to EGFR TKIs reveal heightened toxicities and limited efficacy. Trials of EGFR monoclonal antibodies with an EGFR TKI showed no PFS or OS benefit and were terminated early. Similarly, evidence to date shows no benefit beyond that shown for EGFR TKI monotherapy with the addition of a MET inhibitor.

“Adding virtually all agents to EGFR TKIs has been associated with more toxicity to patients and a significant financial burden to the health care system,” Dr. Stock-Martineau and Dr. Shepherd concluded, further observing that combinations, given their heightened toxicity profiles, could potentially also worsen quality of life.

No conflicts of interest were reported by the authors of either study.

Abraxane, a chemotherapy treatment for advanced pancreatic cancer, advanced non–small cell lung cancer and metastatic breast cancer, is on allocation through early March because of manufacturing delays, forcing physicians to find alternatives for a drug once lauded for being easier to tolerate.

Abraxane (Bristol-Myers Squibb) is a paclitaxel albumin-bound injectable. It is different from alternative chemotherapy treatments like Taxol (paclitaxel) because it doesn’t use the solvents that can make Taxol difficult to tolerate. It was described as a “next-generation taxane” because it didn’t rely on solvents. It was approved in 2005 for metastatic breast cancer, then in 2012 for advanced non–small cell lung cancer, in 2013 for late-stage pancreatic cancer and in 2019 for people with PD-L1–positive metastatic triple-negative breast cancer.

The shortage, which was announced on Oct. 5, 2021, by the Food and Drug Administration, has led to some difficult decisions for patients and physicians. How long the shortage will last isn’t clear.

“I printed out [an] allotment sheet 2 days ago, and all it says [for Abraxane] is allocated,” said Kathy Oubre, MS, CEO of Pontchartrain Cancer Center, Hammond, La. “Everyone is keeping what they’ve got for their own patients, so there really isn’t anything available.”

The Pontchartrain Cancer Center sent two patients to the University of Texas MD Anderson Cancer Center, Houston, for continued treatment with Abraxane, but that option is costly and time consuming for patients. The two patients had the means to travel, but Ms. Oubre said that many others cannot afford to travel for treatment. “Everyone has patients who are living paycheck to paycheck who certainly couldn’t afford to do that. There are going to be patients across the nation that are not going to be able to have care as a result of these things.”

The supply problems are causing difficult decisions for physicians, who may have to switch a patient from an unavailable drug to an alternative that isn’t as effective, Ms. Oubre said. “I can’t imagine the stress and the sadness that the physicians have to feel when they have to go explain that to a patient. That runs counter to everything they are as physicians.”

Other strategies include chemo holidays and rounding down doses in patients with metastatic cancer, according to Camille Hill, PharmD, vice president of oncology pharmacy services, West Cancer Center, Germantown, Tenn.

Shortages and allocations are growing at an alarming rate, Ms. Oubre said. In her 15 years of working in the industry, “I don’t recall it ever being this challenging.” During a Zoom interview, she held up a lengthy list of drugs on allocation or unavailable that her pharmacy group purchasing organization sent her the previous week. “I don’t ever recall getting this kind of list. Every 3 days, I’m getting this. If it were just that one product, I can live with that. We figure it out. But it’s bigger than that.”

Worker shortages are exacerbating the issue. Ms. Oubre received a letter from a drug company describing its employee issues, which included chemists, plant workers, and loading dock staff. On top of that, delivery companies are experiencing staff shortages, which can result in more delays and complicate matters further. “It’s just compounding. These things can get really difficult very quickly. I don’t want to say we’re in crisis, and we’re not rationing care. We’re not in those buckets yet. But I would say that if these things don’t get better, it’s the first time in my work career that we are having those conversations of: ‘How we are going to plan for that it does come to that?’ ” she said.

“In general, with the pandemic, we have seen all sorts of just disruptions to the supply chain. So, I think you just do your best, you find alternatives for those patients that you can, and you come up with strategies. I don’t know that for Abraxane, or any other product, that I’d be particularly confident that we may not see another shortage,” Dr. Hill said.

Abraxane, a chemotherapy treatment for advanced pancreatic cancer, advanced non–small cell lung cancer and metastatic breast cancer, is on allocation through early March because of manufacturing delays, forcing physicians to find alternatives for a drug once lauded for being easier to tolerate.

Abraxane (Bristol-Myers Squibb) is a paclitaxel albumin-bound injectable. It is different from alternative chemotherapy treatments like Taxol (paclitaxel) because it doesn’t use the solvents that can make Taxol difficult to tolerate. It was described as a “next-generation taxane” because it didn’t rely on solvents. It was approved in 2005 for metastatic breast cancer, then in 2012 for advanced non–small cell lung cancer, in 2013 for late-stage pancreatic cancer and in 2019 for people with PD-L1–positive metastatic triple-negative breast cancer.

The shortage, which was announced on Oct. 5, 2021, by the Food and Drug Administration, has led to some difficult decisions for patients and physicians. How long the shortage will last isn’t clear.

“I printed out [an] allotment sheet 2 days ago, and all it says [for Abraxane] is allocated,” said Kathy Oubre, MS, CEO of Pontchartrain Cancer Center, Hammond, La. “Everyone is keeping what they’ve got for their own patients, so there really isn’t anything available.”

The Pontchartrain Cancer Center sent two patients to the University of Texas MD Anderson Cancer Center, Houston, for continued treatment with Abraxane, but that option is costly and time consuming for patients. The two patients had the means to travel, but Ms. Oubre said that many others cannot afford to travel for treatment. “Everyone has patients who are living paycheck to paycheck who certainly couldn’t afford to do that. There are going to be patients across the nation that are not going to be able to have care as a result of these things.”

The supply problems are causing difficult decisions for physicians, who may have to switch a patient from an unavailable drug to an alternative that isn’t as effective, Ms. Oubre said. “I can’t imagine the stress and the sadness that the physicians have to feel when they have to go explain that to a patient. That runs counter to everything they are as physicians.”

Other strategies include chemo holidays and rounding down doses in patients with metastatic cancer, according to Camille Hill, PharmD, vice president of oncology pharmacy services, West Cancer Center, Germantown, Tenn.

Shortages and allocations are growing at an alarming rate, Ms. Oubre said. In her 15 years of working in the industry, “I don’t recall it ever being this challenging.” During a Zoom interview, she held up a lengthy list of drugs on allocation or unavailable that her pharmacy group purchasing organization sent her the previous week. “I don’t ever recall getting this kind of list. Every 3 days, I’m getting this. If it were just that one product, I can live with that. We figure it out. But it’s bigger than that.”

Worker shortages are exacerbating the issue. Ms. Oubre received a letter from a drug company describing its employee issues, which included chemists, plant workers, and loading dock staff. On top of that, delivery companies are experiencing staff shortages, which can result in more delays and complicate matters further. “It’s just compounding. These things can get really difficult very quickly. I don’t want to say we’re in crisis, and we’re not rationing care. We’re not in those buckets yet. But I would say that if these things don’t get better, it’s the first time in my work career that we are having those conversations of: ‘How we are going to plan for that it does come to that?’ ” she said.

“In general, with the pandemic, we have seen all sorts of just disruptions to the supply chain. So, I think you just do your best, you find alternatives for those patients that you can, and you come up with strategies. I don’t know that for Abraxane, or any other product, that I’d be particularly confident that we may not see another shortage,” Dr. Hill said.

Abraxane, a chemotherapy treatment for advanced pancreatic cancer, advanced non–small cell lung cancer and metastatic breast cancer, is on allocation through early March because of manufacturing delays, forcing physicians to find alternatives for a drug once lauded for being easier to tolerate.

Abraxane (Bristol-Myers Squibb) is a paclitaxel albumin-bound injectable. It is different from alternative chemotherapy treatments like Taxol (paclitaxel) because it doesn’t use the solvents that can make Taxol difficult to tolerate. It was described as a “next-generation taxane” because it didn’t rely on solvents. It was approved in 2005 for metastatic breast cancer, then in 2012 for advanced non–small cell lung cancer, in 2013 for late-stage pancreatic cancer and in 2019 for people with PD-L1–positive metastatic triple-negative breast cancer.

The shortage, which was announced on Oct. 5, 2021, by the Food and Drug Administration, has led to some difficult decisions for patients and physicians. How long the shortage will last isn’t clear.

“I printed out [an] allotment sheet 2 days ago, and all it says [for Abraxane] is allocated,” said Kathy Oubre, MS, CEO of Pontchartrain Cancer Center, Hammond, La. “Everyone is keeping what they’ve got for their own patients, so there really isn’t anything available.”

The Pontchartrain Cancer Center sent two patients to the University of Texas MD Anderson Cancer Center, Houston, for continued treatment with Abraxane, but that option is costly and time consuming for patients. The two patients had the means to travel, but Ms. Oubre said that many others cannot afford to travel for treatment. “Everyone has patients who are living paycheck to paycheck who certainly couldn’t afford to do that. There are going to be patients across the nation that are not going to be able to have care as a result of these things.”

The supply problems are causing difficult decisions for physicians, who may have to switch a patient from an unavailable drug to an alternative that isn’t as effective, Ms. Oubre said. “I can’t imagine the stress and the sadness that the physicians have to feel when they have to go explain that to a patient. That runs counter to everything they are as physicians.”

Other strategies include chemo holidays and rounding down doses in patients with metastatic cancer, according to Camille Hill, PharmD, vice president of oncology pharmacy services, West Cancer Center, Germantown, Tenn.

Shortages and allocations are growing at an alarming rate, Ms. Oubre said. In her 15 years of working in the industry, “I don’t recall it ever being this challenging.” During a Zoom interview, she held up a lengthy list of drugs on allocation or unavailable that her pharmacy group purchasing organization sent her the previous week. “I don’t ever recall getting this kind of list. Every 3 days, I’m getting this. If it were just that one product, I can live with that. We figure it out. But it’s bigger than that.”

Worker shortages are exacerbating the issue. Ms. Oubre received a letter from a drug company describing its employee issues, which included chemists, plant workers, and loading dock staff. On top of that, delivery companies are experiencing staff shortages, which can result in more delays and complicate matters further. “It’s just compounding. These things can get really difficult very quickly. I don’t want to say we’re in crisis, and we’re not rationing care. We’re not in those buckets yet. But I would say that if these things don’t get better, it’s the first time in my work career that we are having those conversations of: ‘How we are going to plan for that it does come to that?’ ” she said.

“In general, with the pandemic, we have seen all sorts of just disruptions to the supply chain. So, I think you just do your best, you find alternatives for those patients that you can, and you come up with strategies. I don’t know that for Abraxane, or any other product, that I’d be particularly confident that we may not see another shortage,” Dr. Hill said.

Two close colleagues at New York’s Memorial Sloan Kettering Cancer Center, world leaders in hematopoietic stem cell transplantation (HSCT) who were both promoted days after COVID-19 locked down the city in 2020, were too busy battling the pandemic’s impact on patients in the summer of 2021 to notice their latest shared career milestone.

On July 29, 2021, Sergio Giralt, MD, deputy division head of the division of hematologic malignancies and Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at MSKCC, published their 100th peer-reviewed paper as coauthors. Listing hundreds of such articles on a CV is standard for top-tier physicians, but the pair had gone one better: 100 publications written together in 10 years.

Their centenary article hit scientific newsstands almost exactly a decade after their first joint paper, which appeared in September 2011, not long after they met.

Born in Cuba, Dr. Giralt grew up in Venezuela. From the age of 14, he knew that medicine was his path, and in 1984 he earned a medical degree from the Universidad Central de Venezuela, Caracas. Next came a research position at Harvard Medical School, a residency at the Good Samaritan Hospital, Cincinnati, and a fellowship at the University of Texas MD Anderson Cancer Center, Houston. Dr. Giralt arrived at MSKCC in 2010 as the new chief of the adult bone marrow transplant service. There he was introduced to a new colleague, Dr. Perales. They soon learned that in addition to expertise in hematology, they had second language in common: Spanish.

Dr. Giralt said: “We both have a Spanish background and in a certain sense, there was an affinity there. ... We both have shared experiences.”

Dr. Perales was brought up in Belgium, a European nation with three official languages: French, Dutch, and German. He speaks five tongues in all and learned Spanish from his father, who came from Spain.

Courtesy MSKCC

Fluency in Spanish enables both physicians to take care of the many New Yorkers who are more comfortable in that language – especially when navigating cancer treatment. However, both Dr. Giralt and Dr. Perales said that a second language is more than a professional tool. They described the enjoyable change of persona that happens when they switch to Spanish.

“People who are multilingual have different roles [as much as] different languages,” said Dr. Perales. “When I’m in Spanish, part of my brain is [thinking back to] summer vacations and hanging out with my cousins.”

When it comes to clinical science, however, English is the language of choice.
 

Global leaders in HSCT

Dr. Giralt and Dr. Perales are known worldwide in the field of allogeneic HSCT, a potentially curative treatment for an elongating list of both malignant and nonmalignant diseases.

In 1973, MSKCC conducted the first bone-marrow transplant from an unrelated donor. Fifty years on, medical oncologists in the United States conduct approximately 8,500 allogeneic transplants each year, 72% to treat acute leukemias or myelodysplastic syndrome (MDS).

However, stripping the immune system with intensive chemotherapy ‘conditioning,’ then rebuilding it with non-diseased donor hematopoietic cells is a hazardous undertaking. Older patients are less likely to survive the intensive conditioning, so historically have missed out. Also, even with a good human leukocyte antigen (HLA) match, the recipient needs often brutal immunosuppression.

Since Dr. Giralt and Dr. Perales began their partnership in 2010, the goals of their work have not changed: to develop safer, lower-intensity transplantation suitable for older, more vulnerable patients and reduce fearsome posttransplant sequelae such as graft-versus-host disease (GVHD).

Dr. Giralt’s publication list spans more than 600 peer-reviewed papers, articles and book chapters, almost exclusively on HSCT. Dr. Perales has more than 300 publication credits on the topic.

The two paired up on their first paper just months after Dr. Giralt arrived at MSKCC. That article, published in Biology of Blood and Marrow Transplantation, compared umbilical cord blood for HSCT with donor blood in 367 people with a variety of hematologic malignancies, including acute and chronic leukemias, MDS, and lymphoma.

Courtesy MSKCC

The MSKCC team found that transplant-related mortality in the first 180 days was higher for the cord blood (21%), but thereafter mortality and relapse were much lower than for donated blood, with the result that 2-year progression-free survival of 55% was similar. Dr. Perales, Dr. Giralt and their coauthors concluded that the data provided “strong support” for further work on cord blood as an alternative stem-cell source.

During their first decade of collaboration, Dr. Giralt and Dr. Perales worked on any promising avenue that could improve outcomes and the experience of HSCT recipients, including reduced-intensity conditioning regimens to allow older adults to benefit from curative HSCT and donor T-cell depletion by CD34 selection, to reduce graft-versus-host disease (GVHD).

The CD34 protein is typically found on the surface of early stage and highly active stem cell types. Selecting these cell types using a range of techniques can eliminate many other potentially interfering or inactive cells. This enriches the transplant population with the most effective cells and can lower the risk of GVHD.

The 100th paper on which Dr. Giralt and Dr. Perales were coauthors was published in Blood Advances on July 27, 2021. The retrospective study examined the fate of 58 MSKCC patients with a rare form of chronic lymphocytic leukemia, CLL with Richter’s transformation (CLL-RT). It was the largest such study to date of this rare disease.
M.D. Anderson Cancer Center had shown in 2006 that, despite chemotherapy, overall survival in patients with CLL-RT was approximately 8 months. HSCT improved survival dramatically (75% at 3 years; n = 7). However, with the advent of novel targeted drugs for CLL such as ibrutinib (Imbruvica), venetoclax (Venclexta), or idelalisib (Zydelig), the MSKCC team asked themselves: What was the role of reduced-intensive conditioning HSCT? Was it even safe? Among other findings, Dr. Giralt and Dr. Perales’ 100th paper showed that reduced-intensity HSCT remained a viable alternative after a CLL-RT patient progressed on a novel agent.

Impact of the pandemic

When COVID-19 hit, the team lost many research staff and developed a huge backlog, said Dr. Giralt. He and Dr. Perales realized that they needed to be “thoughtful and careful” about which studies to continue. “For example, the CD-34 selection trials we did not close because these are our workhorse trials,” Dr. Giralt said. “We have people we need to treat, and some of the patients that we need to treat can only be treated on trial.”

The team was also able to pivot some of their work into COVID 19 itself, and they collected crucial information on HSCT in recovered COVID-19 patients, as an example.

“We were living through a critical time, but that doesn’t mean we [aren’t] obligated to continue our mission, our research mission,” said Dr. Giralt. “It really is team science. The way we look at it ... there’s a common thread: We both like to do allogeneic transplant, and we both believe in trying to make CD-34 selection better. So we’re both very much [working on] how can we improve what we call ‘the Memorial way’ of doing transplants. Where we separate is, Miguel does primarily lymphoma. He doesn’t do myeloma [like me]. So in those two areas, we’re helping develop the junior faculty in a different way.”
 

Something more in common

Right from the start, Dr. Perales and Dr. Giralt also shared a commitment to mentoring. Since 2010, Dr. Perales has mentored 22 up-and-coming junior faculty, including 10 from Europe (8 from Spain) and 2 from Latin America.

“[It makes] the research enterprise much more productive but [these young scientists] really increase the visibility of the program,” said Dr. Giralt.

He cited Dr. Perales’ track record of mentoring as one of the reasons for his promotion to chief of the adult bone marrow transplant service. In March 2020, Dr. Perales seamlessly stepped into Dr. Giralt’s shoes, while Dr. Giralt moved on to his present role as deputy division head of the division of hematologic malignancies.

Dr. Perales said: “The key aspect [of these promotions] is the fantastic working relationship that we’ve had over the years. ... I consider Sergio my mentor, but also a good friend and colleague. And so I think it’s this ability that we’ve had to work together and that relationship of trust, which has been key.”

“Sergio is somebody who lifts people up,” Dr. Perales added. “Many people will tell you that Sergio has helped them in their career. ... And I think that’s a lesson I’ve learned from him: training the next generation. And [that’s] not just in the U.S., but outside. I think that’s a key role that we have. And our responsibility.”

Asked to comment on their 100th-paper milestone, Dr. Perales firmly turned the spotlight from himself and Dr. Giralt to the junior investigators who have passed through the doors of the bone-marrow transplant program: “This body of work represents not just our collaboration but also the many contributions of our team at MSK ... and beyond MSK.”

This article was updated 1/26/22.

Two close colleagues at New York’s Memorial Sloan Kettering Cancer Center, world leaders in hematopoietic stem cell transplantation (HSCT) who were both promoted days after COVID-19 locked down the city in 2020, were too busy battling the pandemic’s impact on patients in the summer of 2021 to notice their latest shared career milestone.

On July 29, 2021, Sergio Giralt, MD, deputy division head of the division of hematologic malignancies and Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at MSKCC, published their 100th peer-reviewed paper as coauthors. Listing hundreds of such articles on a CV is standard for top-tier physicians, but the pair had gone one better: 100 publications written together in 10 years.

Their centenary article hit scientific newsstands almost exactly a decade after their first joint paper, which appeared in September 2011, not long after they met.

Born in Cuba, Dr. Giralt grew up in Venezuela. From the age of 14, he knew that medicine was his path, and in 1984 he earned a medical degree from the Universidad Central de Venezuela, Caracas. Next came a research position at Harvard Medical School, a residency at the Good Samaritan Hospital, Cincinnati, and a fellowship at the University of Texas MD Anderson Cancer Center, Houston. Dr. Giralt arrived at MSKCC in 2010 as the new chief of the adult bone marrow transplant service. There he was introduced to a new colleague, Dr. Perales. They soon learned that in addition to expertise in hematology, they had second language in common: Spanish.

Dr. Giralt said: “We both have a Spanish background and in a certain sense, there was an affinity there. ... We both have shared experiences.”

Dr. Perales was brought up in Belgium, a European nation with three official languages: French, Dutch, and German. He speaks five tongues in all and learned Spanish from his father, who came from Spain.

Courtesy MSKCC

Fluency in Spanish enables both physicians to take care of the many New Yorkers who are more comfortable in that language – especially when navigating cancer treatment. However, both Dr. Giralt and Dr. Perales said that a second language is more than a professional tool. They described the enjoyable change of persona that happens when they switch to Spanish.

“People who are multilingual have different roles [as much as] different languages,” said Dr. Perales. “When I’m in Spanish, part of my brain is [thinking back to] summer vacations and hanging out with my cousins.”

When it comes to clinical science, however, English is the language of choice.
 

Global leaders in HSCT

Dr. Giralt and Dr. Perales are known worldwide in the field of allogeneic HSCT, a potentially curative treatment for an elongating list of both malignant and nonmalignant diseases.

In 1973, MSKCC conducted the first bone-marrow transplant from an unrelated donor. Fifty years on, medical oncologists in the United States conduct approximately 8,500 allogeneic transplants each year, 72% to treat acute leukemias or myelodysplastic syndrome (MDS).

However, stripping the immune system with intensive chemotherapy ‘conditioning,’ then rebuilding it with non-diseased donor hematopoietic cells is a hazardous undertaking. Older patients are less likely to survive the intensive conditioning, so historically have missed out. Also, even with a good human leukocyte antigen (HLA) match, the recipient needs often brutal immunosuppression.

Since Dr. Giralt and Dr. Perales began their partnership in 2010, the goals of their work have not changed: to develop safer, lower-intensity transplantation suitable for older, more vulnerable patients and reduce fearsome posttransplant sequelae such as graft-versus-host disease (GVHD).

Dr. Giralt’s publication list spans more than 600 peer-reviewed papers, articles and book chapters, almost exclusively on HSCT. Dr. Perales has more than 300 publication credits on the topic.

The two paired up on their first paper just months after Dr. Giralt arrived at MSKCC. That article, published in Biology of Blood and Marrow Transplantation, compared umbilical cord blood for HSCT with donor blood in 367 people with a variety of hematologic malignancies, including acute and chronic leukemias, MDS, and lymphoma.

Courtesy MSKCC

The MSKCC team found that transplant-related mortality in the first 180 days was higher for the cord blood (21%), but thereafter mortality and relapse were much lower than for donated blood, with the result that 2-year progression-free survival of 55% was similar. Dr. Perales, Dr. Giralt and their coauthors concluded that the data provided “strong support” for further work on cord blood as an alternative stem-cell source.

During their first decade of collaboration, Dr. Giralt and Dr. Perales worked on any promising avenue that could improve outcomes and the experience of HSCT recipients, including reduced-intensity conditioning regimens to allow older adults to benefit from curative HSCT and donor T-cell depletion by CD34 selection, to reduce graft-versus-host disease (GVHD).

The CD34 protein is typically found on the surface of early stage and highly active stem cell types. Selecting these cell types using a range of techniques can eliminate many other potentially interfering or inactive cells. This enriches the transplant population with the most effective cells and can lower the risk of GVHD.

The 100th paper on which Dr. Giralt and Dr. Perales were coauthors was published in Blood Advances on July 27, 2021. The retrospective study examined the fate of 58 MSKCC patients with a rare form of chronic lymphocytic leukemia, CLL with Richter’s transformation (CLL-RT). It was the largest such study to date of this rare disease.
M.D. Anderson Cancer Center had shown in 2006 that, despite chemotherapy, overall survival in patients with CLL-RT was approximately 8 months. HSCT improved survival dramatically (75% at 3 years; n = 7). However, with the advent of novel targeted drugs for CLL such as ibrutinib (Imbruvica), venetoclax (Venclexta), or idelalisib (Zydelig), the MSKCC team asked themselves: What was the role of reduced-intensive conditioning HSCT? Was it even safe? Among other findings, Dr. Giralt and Dr. Perales’ 100th paper showed that reduced-intensity HSCT remained a viable alternative after a CLL-RT patient progressed on a novel agent.

Impact of the pandemic

When COVID-19 hit, the team lost many research staff and developed a huge backlog, said Dr. Giralt. He and Dr. Perales realized that they needed to be “thoughtful and careful” about which studies to continue. “For example, the CD-34 selection trials we did not close because these are our workhorse trials,” Dr. Giralt said. “We have people we need to treat, and some of the patients that we need to treat can only be treated on trial.”

The team was also able to pivot some of their work into COVID 19 itself, and they collected crucial information on HSCT in recovered COVID-19 patients, as an example.

“We were living through a critical time, but that doesn’t mean we [aren’t] obligated to continue our mission, our research mission,” said Dr. Giralt. “It really is team science. The way we look at it ... there’s a common thread: We both like to do allogeneic transplant, and we both believe in trying to make CD-34 selection better. So we’re both very much [working on] how can we improve what we call ‘the Memorial way’ of doing transplants. Where we separate is, Miguel does primarily lymphoma. He doesn’t do myeloma [like me]. So in those two areas, we’re helping develop the junior faculty in a different way.”
 

Something more in common

Right from the start, Dr. Perales and Dr. Giralt also shared a commitment to mentoring. Since 2010, Dr. Perales has mentored 22 up-and-coming junior faculty, including 10 from Europe (8 from Spain) and 2 from Latin America.

“[It makes] the research enterprise much more productive but [these young scientists] really increase the visibility of the program,” said Dr. Giralt.

He cited Dr. Perales’ track record of mentoring as one of the reasons for his promotion to chief of the adult bone marrow transplant service. In March 2020, Dr. Perales seamlessly stepped into Dr. Giralt’s shoes, while Dr. Giralt moved on to his present role as deputy division head of the division of hematologic malignancies.

Dr. Perales said: “The key aspect [of these promotions] is the fantastic working relationship that we’ve had over the years. ... I consider Sergio my mentor, but also a good friend and colleague. And so I think it’s this ability that we’ve had to work together and that relationship of trust, which has been key.”

“Sergio is somebody who lifts people up,” Dr. Perales added. “Many people will tell you that Sergio has helped them in their career. ... And I think that’s a lesson I’ve learned from him: training the next generation. And [that’s] not just in the U.S., but outside. I think that’s a key role that we have. And our responsibility.”

Asked to comment on their 100th-paper milestone, Dr. Perales firmly turned the spotlight from himself and Dr. Giralt to the junior investigators who have passed through the doors of the bone-marrow transplant program: “This body of work represents not just our collaboration but also the many contributions of our team at MSK ... and beyond MSK.”

This article was updated 1/26/22.

Two close colleagues at New York’s Memorial Sloan Kettering Cancer Center, world leaders in hematopoietic stem cell transplantation (HSCT) who were both promoted days after COVID-19 locked down the city in 2020, were too busy battling the pandemic’s impact on patients in the summer of 2021 to notice their latest shared career milestone.

On July 29, 2021, Sergio Giralt, MD, deputy division head of the division of hematologic malignancies and Miguel-Angel Perales, MD, chief of the adult bone marrow transplant service at MSKCC, published their 100th peer-reviewed paper as coauthors. Listing hundreds of such articles on a CV is standard for top-tier physicians, but the pair had gone one better: 100 publications written together in 10 years.

Their centenary article hit scientific newsstands almost exactly a decade after their first joint paper, which appeared in September 2011, not long after they met.

Born in Cuba, Dr. Giralt grew up in Venezuela. From the age of 14, he knew that medicine was his path, and in 1984 he earned a medical degree from the Universidad Central de Venezuela, Caracas. Next came a research position at Harvard Medical School, a residency at the Good Samaritan Hospital, Cincinnati, and a fellowship at the University of Texas MD Anderson Cancer Center, Houston. Dr. Giralt arrived at MSKCC in 2010 as the new chief of the adult bone marrow transplant service. There he was introduced to a new colleague, Dr. Perales. They soon learned that in addition to expertise in hematology, they had second language in common: Spanish.

Dr. Giralt said: “We both have a Spanish background and in a certain sense, there was an affinity there. ... We both have shared experiences.”

Dr. Perales was brought up in Belgium, a European nation with three official languages: French, Dutch, and German. He speaks five tongues in all and learned Spanish from his father, who came from Spain.

Courtesy MSKCC

Fluency in Spanish enables both physicians to take care of the many New Yorkers who are more comfortable in that language – especially when navigating cancer treatment. However, both Dr. Giralt and Dr. Perales said that a second language is more than a professional tool. They described the enjoyable change of persona that happens when they switch to Spanish.

“People who are multilingual have different roles [as much as] different languages,” said Dr. Perales. “When I’m in Spanish, part of my brain is [thinking back to] summer vacations and hanging out with my cousins.”

When it comes to clinical science, however, English is the language of choice.
 

Global leaders in HSCT

Dr. Giralt and Dr. Perales are known worldwide in the field of allogeneic HSCT, a potentially curative treatment for an elongating list of both malignant and nonmalignant diseases.

In 1973, MSKCC conducted the first bone-marrow transplant from an unrelated donor. Fifty years on, medical oncologists in the United States conduct approximately 8,500 allogeneic transplants each year, 72% to treat acute leukemias or myelodysplastic syndrome (MDS).

However, stripping the immune system with intensive chemotherapy ‘conditioning,’ then rebuilding it with non-diseased donor hematopoietic cells is a hazardous undertaking. Older patients are less likely to survive the intensive conditioning, so historically have missed out. Also, even with a good human leukocyte antigen (HLA) match, the recipient needs often brutal immunosuppression.

Since Dr. Giralt and Dr. Perales began their partnership in 2010, the goals of their work have not changed: to develop safer, lower-intensity transplantation suitable for older, more vulnerable patients and reduce fearsome posttransplant sequelae such as graft-versus-host disease (GVHD).

Dr. Giralt’s publication list spans more than 600 peer-reviewed papers, articles and book chapters, almost exclusively on HSCT. Dr. Perales has more than 300 publication credits on the topic.

The two paired up on their first paper just months after Dr. Giralt arrived at MSKCC. That article, published in Biology of Blood and Marrow Transplantation, compared umbilical cord blood for HSCT with donor blood in 367 people with a variety of hematologic malignancies, including acute and chronic leukemias, MDS, and lymphoma.

Courtesy MSKCC

The MSKCC team found that transplant-related mortality in the first 180 days was higher for the cord blood (21%), but thereafter mortality and relapse were much lower than for donated blood, with the result that 2-year progression-free survival of 55% was similar. Dr. Perales, Dr. Giralt and their coauthors concluded that the data provided “strong support” for further work on cord blood as an alternative stem-cell source.

During their first decade of collaboration, Dr. Giralt and Dr. Perales worked on any promising avenue that could improve outcomes and the experience of HSCT recipients, including reduced-intensity conditioning regimens to allow older adults to benefit from curative HSCT and donor T-cell depletion by CD34 selection, to reduce graft-versus-host disease (GVHD).

The CD34 protein is typically found on the surface of early stage and highly active stem cell types. Selecting these cell types using a range of techniques can eliminate many other potentially interfering or inactive cells. This enriches the transplant population with the most effective cells and can lower the risk of GVHD.

The 100th paper on which Dr. Giralt and Dr. Perales were coauthors was published in Blood Advances on July 27, 2021. The retrospective study examined the fate of 58 MSKCC patients with a rare form of chronic lymphocytic leukemia, CLL with Richter’s transformation (CLL-RT). It was the largest such study to date of this rare disease.
M.D. Anderson Cancer Center had shown in 2006 that, despite chemotherapy, overall survival in patients with CLL-RT was approximately 8 months. HSCT improved survival dramatically (75% at 3 years; n = 7). However, with the advent of novel targeted drugs for CLL such as ibrutinib (Imbruvica), venetoclax (Venclexta), or idelalisib (Zydelig), the MSKCC team asked themselves: What was the role of reduced-intensive conditioning HSCT? Was it even safe? Among other findings, Dr. Giralt and Dr. Perales’ 100th paper showed that reduced-intensity HSCT remained a viable alternative after a CLL-RT patient progressed on a novel agent.

Impact of the pandemic

When COVID-19 hit, the team lost many research staff and developed a huge backlog, said Dr. Giralt. He and Dr. Perales realized that they needed to be “thoughtful and careful” about which studies to continue. “For example, the CD-34 selection trials we did not close because these are our workhorse trials,” Dr. Giralt said. “We have people we need to treat, and some of the patients that we need to treat can only be treated on trial.”

The team was also able to pivot some of their work into COVID 19 itself, and they collected crucial information on HSCT in recovered COVID-19 patients, as an example.

“We were living through a critical time, but that doesn’t mean we [aren’t] obligated to continue our mission, our research mission,” said Dr. Giralt. “It really is team science. The way we look at it ... there’s a common thread: We both like to do allogeneic transplant, and we both believe in trying to make CD-34 selection better. So we’re both very much [working on] how can we improve what we call ‘the Memorial way’ of doing transplants. Where we separate is, Miguel does primarily lymphoma. He doesn’t do myeloma [like me]. So in those two areas, we’re helping develop the junior faculty in a different way.”
 

Something more in common

Right from the start, Dr. Perales and Dr. Giralt also shared a commitment to mentoring. Since 2010, Dr. Perales has mentored 22 up-and-coming junior faculty, including 10 from Europe (8 from Spain) and 2 from Latin America.

“[It makes] the research enterprise much more productive but [these young scientists] really increase the visibility of the program,” said Dr. Giralt.

He cited Dr. Perales’ track record of mentoring as one of the reasons for his promotion to chief of the adult bone marrow transplant service. In March 2020, Dr. Perales seamlessly stepped into Dr. Giralt’s shoes, while Dr. Giralt moved on to his present role as deputy division head of the division of hematologic malignancies.

Dr. Perales said: “The key aspect [of these promotions] is the fantastic working relationship that we’ve had over the years. ... I consider Sergio my mentor, but also a good friend and colleague. And so I think it’s this ability that we’ve had to work together and that relationship of trust, which has been key.”

“Sergio is somebody who lifts people up,” Dr. Perales added. “Many people will tell you that Sergio has helped them in their career. ... And I think that’s a lesson I’ve learned from him: training the next generation. And [that’s] not just in the U.S., but outside. I think that’s a key role that we have. And our responsibility.”

Asked to comment on their 100th-paper milestone, Dr. Perales firmly turned the spotlight from himself and Dr. Giralt to the junior investigators who have passed through the doors of the bone-marrow transplant program: “This body of work represents not just our collaboration but also the many contributions of our team at MSK ... and beyond MSK.”

This article was updated 1/26/22.