AVAHO

Two patients with chronic lymphocytic leukemia (CLL) who 10 years ago were among the first to receive groundbreaking chimeric antigen receptor T-cell therapy were still in remission a decade later, and they continued to show detectable levels of CAR T cells.

“We can now conclude that CAR T cells can actually cure patients with leukemia based on these results,” said senior author Carl H. June, MD, in a press briefing on the study published in Nature.

“The major finding from this paper is that, 10 years down the road, you can find these [CAR T] cells,” Dr. June, director of the Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, added. “The cells have evolved, and that was a big surprise ... but they are still able to kill leukemia cells 10 years after infusion.”

CAR T-cell therapy, in which patients’ own T cells are removed, reprogrammed in a lab to recognize and attack cancer cells, and then infused back into the patients, has transformed treatment of various blood cancers and shows often-remarkable results in achieving remissions.

While the treatment has become a routine therapy for certain leukemias, long-term results on the fate and function of the cells over time has been highly anticipated.

In the first published observations of a 10-year follow-up of patients treated with CAR T cells, Dr. June and colleagues described the findings for two patients, both with CLL, who back in 2010 were among the first to be treated with this groundbreaking therapy at the University of Pennsylvania.

A decade later, the CAR T cells are found to have remained detectable in both patients, who achieved complete remission in their first year of treatment, and both have sustained that remission.

Notably, the cells have evolved over the years – from initially being dominated by killer T cells to being dominated primarily by proliferative CD4-positive CAR T cells – with one of the patients exclusively having CD4-positive cells at year 9.3.

“The killer T cells did the initial heavy lifting of eliminating the tumor, “ first author J. Joseph Melenhorst, PhD, said in an interview.

“Once their job was done, those cells went down to very low levels, but the CD4-positive population persisted,” said Dr. Melenhorst, who established the lab at the University of Pennsylvania to follow patients treated with CAR T-cell therapy. “[This] delayed phase of immune response against cancer is a novel insight, and we were surprised to see it.”

Dr. Melenhorst noted that the clonal makeup of the CD4-positive cells importantly stabilized and became dominated by a small number of clones, suggesting further sustainability.

When one of the two patients, Doug Olson, who participated in the press conference, donated his cells back to the center after 9.3 years, the researchers found that his cells were still capable of destroying leukemia cells in the lab.

“Ten years [post infusion], we can’t find any of the leukemia cells and we still have the CAR T cells that are on patrol and on surveillance for residual leukemia,” Dr. June said.

One challenge of the otherwise desirable elimination of leukemia cells is that some aspects of sustaining CAR T-cell activity become problematic.

“The aspect of how the remission is maintained [is] very hard to study in a patient when there is no leukemia at all,” Dr. June explained. “It could be the last cell was gone within 3 weeks [of treatment], or it could be that the [cancer cells] are coming up like whack-a-moles, and they are killed because these CAR T cells are on patrol.”

Sadly, the other CLL patient, Bill Ludwig, who was first to receive the CAR T-cell treatment, died in 2021 from COVID-19.
 

Effects in other blood diseases similar?

CAR T-cell therapy is currently approved in the United States for several blood cancers, and whether similar long-term patterns of the cells may be observed in other patient and cancer types remains to be seen, Dr. Melenhorst said.

“I think in CLL we will see something similar, but in other diseases, we have yet to learn,” he said. “It may depend on issues including which domain has been engineered into the CAR.”

While the prospect of some patients being “cured” is exciting, responses to the therapy have generally been mixed. In CLL, for instance, full remissions have been observed to be maintained in about a quarter of patients, with higher rates observed in some lymphomas and pediatric ALL patients, Dr. Melenhorst explained.

The effects of CAR T-cell therapy in solid cancers have so far been more disappointing, with no research centers reproducing the kinds of results that have been seen with blood cancers.

“There appear to be a number of reasons, including that the [solid] tumor is more complex, and these solid cancers have ways to evade the immune system that need to be overcome,” Dr. June explained.

And despite the more encouraging findings in blood cancers, even with those, “the biggest disappointment is that CAR T-cell therapy doesn’t work all the time. It doesn’t work in every patient,” coauthor David Porter, MD, the University of Pennsylvania oncologist who treated the two patients, said in the press briefing.

“I think the importance of the Nature study is that we are starting to learn the mechanisms of why and how this works, so that we can start to get at how to make it work for more people,” Dr. Porter added. “But what we do see is that, when it works, it really is beyond what we expected 10 or 11 years ago.”

Speaking in the press briefing, Mr. Olson described how several weeks after his treatment in 2010, he became very ill with what has become known as the common, short-term side effect of cytokine release syndrome.

However, after Mr. Olson recovered a few days later, Dr. Porter gave him the remarkable news that “we cannot find a single cancer cell. You appear completely free of CLL.”

Mr. Olson reported that he has since lived a “full life,” kept working, and has even run some half-marathons.

Dr. June confided that the current 10-year results far exceed the team’s early expectations for CAR T-cell therapy. “After Doug [initially] signed his informed consent document for this, we thought that the cells would all be gone within a month or 2. The fact that they have survived for 10 years was a major surprise – and a happy one at that.”

Dr. June, Dr. Melenhorst, and Dr. Porter reported holding patents related to CAR T-cell manufacturing and biomarker discovery.

Two patients with chronic lymphocytic leukemia (CLL) who 10 years ago were among the first to receive groundbreaking chimeric antigen receptor T-cell therapy were still in remission a decade later, and they continued to show detectable levels of CAR T cells.

“We can now conclude that CAR T cells can actually cure patients with leukemia based on these results,” said senior author Carl H. June, MD, in a press briefing on the study published in Nature.

“The major finding from this paper is that, 10 years down the road, you can find these [CAR T] cells,” Dr. June, director of the Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, added. “The cells have evolved, and that was a big surprise ... but they are still able to kill leukemia cells 10 years after infusion.”

CAR T-cell therapy, in which patients’ own T cells are removed, reprogrammed in a lab to recognize and attack cancer cells, and then infused back into the patients, has transformed treatment of various blood cancers and shows often-remarkable results in achieving remissions.

While the treatment has become a routine therapy for certain leukemias, long-term results on the fate and function of the cells over time has been highly anticipated.

In the first published observations of a 10-year follow-up of patients treated with CAR T cells, Dr. June and colleagues described the findings for two patients, both with CLL, who back in 2010 were among the first to be treated with this groundbreaking therapy at the University of Pennsylvania.

A decade later, the CAR T cells are found to have remained detectable in both patients, who achieved complete remission in their first year of treatment, and both have sustained that remission.

Notably, the cells have evolved over the years – from initially being dominated by killer T cells to being dominated primarily by proliferative CD4-positive CAR T cells – with one of the patients exclusively having CD4-positive cells at year 9.3.

“The killer T cells did the initial heavy lifting of eliminating the tumor, “ first author J. Joseph Melenhorst, PhD, said in an interview.

“Once their job was done, those cells went down to very low levels, but the CD4-positive population persisted,” said Dr. Melenhorst, who established the lab at the University of Pennsylvania to follow patients treated with CAR T-cell therapy. “[This] delayed phase of immune response against cancer is a novel insight, and we were surprised to see it.”

Dr. Melenhorst noted that the clonal makeup of the CD4-positive cells importantly stabilized and became dominated by a small number of clones, suggesting further sustainability.

When one of the two patients, Doug Olson, who participated in the press conference, donated his cells back to the center after 9.3 years, the researchers found that his cells were still capable of destroying leukemia cells in the lab.

“Ten years [post infusion], we can’t find any of the leukemia cells and we still have the CAR T cells that are on patrol and on surveillance for residual leukemia,” Dr. June said.

One challenge of the otherwise desirable elimination of leukemia cells is that some aspects of sustaining CAR T-cell activity become problematic.

“The aspect of how the remission is maintained [is] very hard to study in a patient when there is no leukemia at all,” Dr. June explained. “It could be the last cell was gone within 3 weeks [of treatment], or it could be that the [cancer cells] are coming up like whack-a-moles, and they are killed because these CAR T cells are on patrol.”

Sadly, the other CLL patient, Bill Ludwig, who was first to receive the CAR T-cell treatment, died in 2021 from COVID-19.
 

Effects in other blood diseases similar?

CAR T-cell therapy is currently approved in the United States for several blood cancers, and whether similar long-term patterns of the cells may be observed in other patient and cancer types remains to be seen, Dr. Melenhorst said.

“I think in CLL we will see something similar, but in other diseases, we have yet to learn,” he said. “It may depend on issues including which domain has been engineered into the CAR.”

While the prospect of some patients being “cured” is exciting, responses to the therapy have generally been mixed. In CLL, for instance, full remissions have been observed to be maintained in about a quarter of patients, with higher rates observed in some lymphomas and pediatric ALL patients, Dr. Melenhorst explained.

The effects of CAR T-cell therapy in solid cancers have so far been more disappointing, with no research centers reproducing the kinds of results that have been seen with blood cancers.

“There appear to be a number of reasons, including that the [solid] tumor is more complex, and these solid cancers have ways to evade the immune system that need to be overcome,” Dr. June explained.

And despite the more encouraging findings in blood cancers, even with those, “the biggest disappointment is that CAR T-cell therapy doesn’t work all the time. It doesn’t work in every patient,” coauthor David Porter, MD, the University of Pennsylvania oncologist who treated the two patients, said in the press briefing.

“I think the importance of the Nature study is that we are starting to learn the mechanisms of why and how this works, so that we can start to get at how to make it work for more people,” Dr. Porter added. “But what we do see is that, when it works, it really is beyond what we expected 10 or 11 years ago.”

Speaking in the press briefing, Mr. Olson described how several weeks after his treatment in 2010, he became very ill with what has become known as the common, short-term side effect of cytokine release syndrome.

However, after Mr. Olson recovered a few days later, Dr. Porter gave him the remarkable news that “we cannot find a single cancer cell. You appear completely free of CLL.”

Mr. Olson reported that he has since lived a “full life,” kept working, and has even run some half-marathons.

Dr. June confided that the current 10-year results far exceed the team’s early expectations for CAR T-cell therapy. “After Doug [initially] signed his informed consent document for this, we thought that the cells would all be gone within a month or 2. The fact that they have survived for 10 years was a major surprise – and a happy one at that.”

Dr. June, Dr. Melenhorst, and Dr. Porter reported holding patents related to CAR T-cell manufacturing and biomarker discovery.

Two patients with chronic lymphocytic leukemia (CLL) who 10 years ago were among the first to receive groundbreaking chimeric antigen receptor T-cell therapy were still in remission a decade later, and they continued to show detectable levels of CAR T cells.

“We can now conclude that CAR T cells can actually cure patients with leukemia based on these results,” said senior author Carl H. June, MD, in a press briefing on the study published in Nature.

“The major finding from this paper is that, 10 years down the road, you can find these [CAR T] cells,” Dr. June, director of the Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, added. “The cells have evolved, and that was a big surprise ... but they are still able to kill leukemia cells 10 years after infusion.”

CAR T-cell therapy, in which patients’ own T cells are removed, reprogrammed in a lab to recognize and attack cancer cells, and then infused back into the patients, has transformed treatment of various blood cancers and shows often-remarkable results in achieving remissions.

While the treatment has become a routine therapy for certain leukemias, long-term results on the fate and function of the cells over time has been highly anticipated.

In the first published observations of a 10-year follow-up of patients treated with CAR T cells, Dr. June and colleagues described the findings for two patients, both with CLL, who back in 2010 were among the first to be treated with this groundbreaking therapy at the University of Pennsylvania.

A decade later, the CAR T cells are found to have remained detectable in both patients, who achieved complete remission in their first year of treatment, and both have sustained that remission.

Notably, the cells have evolved over the years – from initially being dominated by killer T cells to being dominated primarily by proliferative CD4-positive CAR T cells – with one of the patients exclusively having CD4-positive cells at year 9.3.

“The killer T cells did the initial heavy lifting of eliminating the tumor, “ first author J. Joseph Melenhorst, PhD, said in an interview.

“Once their job was done, those cells went down to very low levels, but the CD4-positive population persisted,” said Dr. Melenhorst, who established the lab at the University of Pennsylvania to follow patients treated with CAR T-cell therapy. “[This] delayed phase of immune response against cancer is a novel insight, and we were surprised to see it.”

Dr. Melenhorst noted that the clonal makeup of the CD4-positive cells importantly stabilized and became dominated by a small number of clones, suggesting further sustainability.

When one of the two patients, Doug Olson, who participated in the press conference, donated his cells back to the center after 9.3 years, the researchers found that his cells were still capable of destroying leukemia cells in the lab.

“Ten years [post infusion], we can’t find any of the leukemia cells and we still have the CAR T cells that are on patrol and on surveillance for residual leukemia,” Dr. June said.

One challenge of the otherwise desirable elimination of leukemia cells is that some aspects of sustaining CAR T-cell activity become problematic.

“The aspect of how the remission is maintained [is] very hard to study in a patient when there is no leukemia at all,” Dr. June explained. “It could be the last cell was gone within 3 weeks [of treatment], or it could be that the [cancer cells] are coming up like whack-a-moles, and they are killed because these CAR T cells are on patrol.”

Sadly, the other CLL patient, Bill Ludwig, who was first to receive the CAR T-cell treatment, died in 2021 from COVID-19.
 

Effects in other blood diseases similar?

CAR T-cell therapy is currently approved in the United States for several blood cancers, and whether similar long-term patterns of the cells may be observed in other patient and cancer types remains to be seen, Dr. Melenhorst said.

“I think in CLL we will see something similar, but in other diseases, we have yet to learn,” he said. “It may depend on issues including which domain has been engineered into the CAR.”

While the prospect of some patients being “cured” is exciting, responses to the therapy have generally been mixed. In CLL, for instance, full remissions have been observed to be maintained in about a quarter of patients, with higher rates observed in some lymphomas and pediatric ALL patients, Dr. Melenhorst explained.

The effects of CAR T-cell therapy in solid cancers have so far been more disappointing, with no research centers reproducing the kinds of results that have been seen with blood cancers.

“There appear to be a number of reasons, including that the [solid] tumor is more complex, and these solid cancers have ways to evade the immune system that need to be overcome,” Dr. June explained.

And despite the more encouraging findings in blood cancers, even with those, “the biggest disappointment is that CAR T-cell therapy doesn’t work all the time. It doesn’t work in every patient,” coauthor David Porter, MD, the University of Pennsylvania oncologist who treated the two patients, said in the press briefing.

“I think the importance of the Nature study is that we are starting to learn the mechanisms of why and how this works, so that we can start to get at how to make it work for more people,” Dr. Porter added. “But what we do see is that, when it works, it really is beyond what we expected 10 or 11 years ago.”

Speaking in the press briefing, Mr. Olson described how several weeks after his treatment in 2010, he became very ill with what has become known as the common, short-term side effect of cytokine release syndrome.

However, after Mr. Olson recovered a few days later, Dr. Porter gave him the remarkable news that “we cannot find a single cancer cell. You appear completely free of CLL.”

Mr. Olson reported that he has since lived a “full life,” kept working, and has even run some half-marathons.

Dr. June confided that the current 10-year results far exceed the team’s early expectations for CAR T-cell therapy. “After Doug [initially] signed his informed consent document for this, we thought that the cells would all be gone within a month or 2. The fact that they have survived for 10 years was a major surprise – and a happy one at that.”

Dr. June, Dr. Melenhorst, and Dr. Porter reported holding patents related to CAR T-cell manufacturing and biomarker discovery.

The names of health care professionals and patients cited within the dialogue text have been changed to protect their privacy.

Early in my career, before I had any notion that years later I would be doing palliative care consults in a cancer center, I heard a senior physician refer to palliative care as “the most misunderstood” medical specialty. I wasn’t sure what she meant at that time, but over the years I have come to realize that she was right – most people, including many within health care, don’t have a good appreciation of what palliative care is or how it can help patients and health care teams.

A recent national survey about cancer-related health information found that of more than 1,000 surveyed Americans, less than 30% professed any knowledge of palliative care. Of those who had some knowledge of palliative care, around 30% believed palliative care was synonymous with hospice.¹ Another 15% believed that a patient would have to give up cancer-directed treatments to receive palliative care.¹

It’s not giving up

This persistent belief that palliative care is equivalent to hospice, or is tantamount to “giving up,” is one of the most commonly held myths I encounter in everyday practice.

I knock on the exam door and walk in.
A small, trim woman in her late 50s is sitting in a chair, arms folded across her chest, face drawn in.

“Hi,” I start. “I’m Sarah, the palliative care nurse practitioner who works in this clinic. I work closely with Dr. Smith.”
Dr. Smith is the patient’s oncologist.

“I really didn’t want to meet you,” she says in a quiet voice, her eyes large with concern.

I don’t take it personally. Few patients really want to be in the position of needing to meet the palliative care team.

“I looked up palliative care on Google and saw the word hospice.”

“Yeah,” I say. “I hear that a lot. Well, I can reassure you that this isn’t hospice.
In this clinic, our focus is on your cancer symptoms, your treatment side effects, and your quality of life.”

She looks visibly relieved. “Quality of life,” she echoes. “I need more of that.”
“OK,” I say. “So, tell me what you’re struggling with the most right now.”

That’s how many palliative care visits start. I actually prefer if patients haven’t heard of palliative care because it allows me to frame it for them, rather than having to start by addressing a myth or a prior negative experience. Even when patients haven’t had a negative experience with palliative care per se, typically, if they’ve interacted with palliative care in the past, it’s usually because someone they loved died in a hospital setting and it is the memory of that terrible loss that becomes synonymous with their recollection of palliative care.

Many patients I meet have never seen another outpatient palliative care practitioner – and this makes sense – we are still too few and far between. Most established palliative care teams are hospital based and many patients seen in the community do not have easy access to palliative care teams where they receive oncologic care.² As an embedded practitioner, I see patients in the same exam rooms and infusion centers where they receive their cancer therapies, so I’m effectively woven into the fabric of their oncology experience. Just being there in the cancer center allows me to be in the right place at the right time for the right patients and their care teams.
 

More than pain management

Another myth I tend to dispel a lot is that palliative care is just a euphemism for “pain management.” I have seen this less lately, but still occasionally in the chart I’ll see documented in a note, “patient is seeing palliative/pain management,” when a patient is seeing me or one of my colleagues. Unfortunately, when providers have limited or outdated views of what palliative care is or the value it brings to patient-centered cancer care, referrals to palliative care tend to be delayed.³

“I really think Ms. Lopez could benefit from seeing palliative care,” an oncology nurse practitioner says to an oncologist.
I’m standing nearby, about to see another patient in one of the exam rooms in our clinic.
“But I don’t think she’s ready. And besides, she doesn’t have any pain,” he says.
He turns to me quizzically. “What do you think?”

“Tell me about the patient,” I ask, taking a few steps in their direction.

“Well, she’s a 64-year-old woman with metastatic cancer.
She has a really poor appetite and is losing some weight.
Seems a bit down, kind of pessimistic about things.
Her scan showed some new growth, so guess I’m not surprised by that.”

“I might be able to help her with the appetite and the mood changes. 
I can at least talk with her and see where she’s at,” I offer.

“Alright,” he says. “We’ll put the palliative referral in.”
He hesitates. “But are you sure you want to see her? 
She doesn’t have any pain.” He sounds skeptical.

“Yeah, I mean, it sounds like she has symptoms that are bothering her, so I’d be happy to see her. She sounds completely appropriate for palliative care.”

I hear this assumption a lot – that palliative care is somehow equivalent to pain management and that unless a patient’s pain is severe, it’s not worth referring the patient to palliative care. Don’t get me wrong – we do a lot of pain management, but at its heart, palliative care is an interdisciplinary specialty focused on improving or maintaining quality of life for people with serious illness. Because the goal is so broad, care can take many shapes.⁴

In addition to pain, palliative care clinicians commonly treat nausea, shortness of breath, constipation or diarrhea, poor appetite, fatigue, anxiety, depression, and insomnia.
 

Palliative care is more than medical or nursing care

A related misconception about palliative care held by many lay people and health care workers alike is that palliative care is primarily medical or nursing care focused mostly on alleviating physical symptoms such as pain or nausea. This couldn’t be further from the truth.

We’ve been talking for a while.
Ms. Lopez tells me about her struggles to maintain her weight while undergoing chemotherapy. She has low-grade nausea that is impacting her ability and desire to eat more and didn’t think that her weight loss was severe enough to warrant taking medication.
We talk about how she may be able to use antinausea medication sparingly to alleviate nausea while also limiting side effects from the medications—which was a big concern for her.

I ask her what else is bothering her.

She tells me that she has always been a strong Catholic and even when life has gotten tough, her faith was never shaken – until now.
She is struggling to understand why she ended up with metastatic cancer at such a relatively young age—why would God do this to her?
She had plans for retirement that have since evaporated in the face of a foreshortened life.
Why did this happen to her of all people? She was completely healthy until her diagnosis.
Her face is wet with tears.

We talk a little about how a diagnosis like this can change so much of a person’s life and identity. I try to validate her experience. She’s clearly suffering from a sense that her life is not what she expected, and she is struggling to integrate how her future looks at this point.

I ask her what conversations with her priest have been like.

At this point you may be wondering where this conversation is going. Why are we talking about Ms. Lopez’s religion? Palliative care is best delivered through high functioning interdisciplinary teams that can include other supportive people in a patient’s life. We work in concert to try to bring comfort to a patient and their family.⁴ That support network can include nurses, physicians, social workers, and chaplains. In this case, Ms. Lopez had not yet reached out to her priest. She hasn’t had the time or energy to contact her priest given her symptoms.
 

“Can I contact your priest for you?
Maybe he can visit or call and chat with you?”
She nods and wipes tears away.
“That would be really nice,” she says. “I’d love it if he could pray with me.”

A few hours after the visit, I call Ms. Lopez’s priest.
I ask him to reach out to her and about her request for prayer.
He says he’s been thinking about her and that her presence has been missed at weekly Mass. He thanks me for the call and says he’ll call her tomorrow.

I say my own small prayer for Ms. Lopez and head home, the day’s work completed.

Sarah D'Ambruoso was born and raised in Maine. She completed her undergraduate and graduate nursing education at New York University and UCLA, respectively, and currently works as a palliative care nurse practitioner in an oncology clinic in Los Angeles. 

References

1. Cheng BT et al. Patterns of palliative care beliefs among adults in the U.S.: Analysis of a National Cancer Database. J Pain Symptom Manage. 2019 Aug 10. doi: 10.1016/j.jpainsymman.2019.07.030.

2. Finlay E et al. Filling the gap: Creating an outpatient palliative care program in your institution. Am Soc Clin Oncol Educ Book. 2018 May 23. doi: 10.1200/EDBK_200775.

3. Von Roenn JH et al. Barriers and approaches to the successful integration of palliative care and oncology practice. J Natl Compr Canc Netw. 2013 Mar. doi: 10.6004/jnccn.2013.0209.

4. Ferrell BR et al. Integration of palliative care into standard oncology care: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2016 Oct 31. doi: 10.1200/JCO.2016.70.1474.

The names of health care professionals and patients cited within the dialogue text have been changed to protect their privacy.

Early in my career, before I had any notion that years later I would be doing palliative care consults in a cancer center, I heard a senior physician refer to palliative care as “the most misunderstood” medical specialty. I wasn’t sure what she meant at that time, but over the years I have come to realize that she was right – most people, including many within health care, don’t have a good appreciation of what palliative care is or how it can help patients and health care teams.

A recent national survey about cancer-related health information found that of more than 1,000 surveyed Americans, less than 30% professed any knowledge of palliative care. Of those who had some knowledge of palliative care, around 30% believed palliative care was synonymous with hospice.¹ Another 15% believed that a patient would have to give up cancer-directed treatments to receive palliative care.¹

It’s not giving up

This persistent belief that palliative care is equivalent to hospice, or is tantamount to “giving up,” is one of the most commonly held myths I encounter in everyday practice.

I knock on the exam door and walk in.
A small, trim woman in her late 50s is sitting in a chair, arms folded across her chest, face drawn in.

“Hi,” I start. “I’m Sarah, the palliative care nurse practitioner who works in this clinic. I work closely with Dr. Smith.”
Dr. Smith is the patient’s oncologist.

“I really didn’t want to meet you,” she says in a quiet voice, her eyes large with concern.

I don’t take it personally. Few patients really want to be in the position of needing to meet the palliative care team.

“I looked up palliative care on Google and saw the word hospice.”

“Yeah,” I say. “I hear that a lot. Well, I can reassure you that this isn’t hospice.
In this clinic, our focus is on your cancer symptoms, your treatment side effects, and your quality of life.”

She looks visibly relieved. “Quality of life,” she echoes. “I need more of that.”
“OK,” I say. “So, tell me what you’re struggling with the most right now.”

That’s how many palliative care visits start. I actually prefer if patients haven’t heard of palliative care because it allows me to frame it for them, rather than having to start by addressing a myth or a prior negative experience. Even when patients haven’t had a negative experience with palliative care per se, typically, if they’ve interacted with palliative care in the past, it’s usually because someone they loved died in a hospital setting and it is the memory of that terrible loss that becomes synonymous with their recollection of palliative care.

Many patients I meet have never seen another outpatient palliative care practitioner – and this makes sense – we are still too few and far between. Most established palliative care teams are hospital based and many patients seen in the community do not have easy access to palliative care teams where they receive oncologic care.² As an embedded practitioner, I see patients in the same exam rooms and infusion centers where they receive their cancer therapies, so I’m effectively woven into the fabric of their oncology experience. Just being there in the cancer center allows me to be in the right place at the right time for the right patients and their care teams.
 

More than pain management

Another myth I tend to dispel a lot is that palliative care is just a euphemism for “pain management.” I have seen this less lately, but still occasionally in the chart I’ll see documented in a note, “patient is seeing palliative/pain management,” when a patient is seeing me or one of my colleagues. Unfortunately, when providers have limited or outdated views of what palliative care is or the value it brings to patient-centered cancer care, referrals to palliative care tend to be delayed.³

“I really think Ms. Lopez could benefit from seeing palliative care,” an oncology nurse practitioner says to an oncologist.
I’m standing nearby, about to see another patient in one of the exam rooms in our clinic.
“But I don’t think she’s ready. And besides, she doesn’t have any pain,” he says.
He turns to me quizzically. “What do you think?”

“Tell me about the patient,” I ask, taking a few steps in their direction.

“Well, she’s a 64-year-old woman with metastatic cancer.
She has a really poor appetite and is losing some weight.
Seems a bit down, kind of pessimistic about things.
Her scan showed some new growth, so guess I’m not surprised by that.”

“I might be able to help her with the appetite and the mood changes. 
I can at least talk with her and see where she’s at,” I offer.

“Alright,” he says. “We’ll put the palliative referral in.”
He hesitates. “But are you sure you want to see her? 
She doesn’t have any pain.” He sounds skeptical.

“Yeah, I mean, it sounds like she has symptoms that are bothering her, so I’d be happy to see her. She sounds completely appropriate for palliative care.”

I hear this assumption a lot – that palliative care is somehow equivalent to pain management and that unless a patient’s pain is severe, it’s not worth referring the patient to palliative care. Don’t get me wrong – we do a lot of pain management, but at its heart, palliative care is an interdisciplinary specialty focused on improving or maintaining quality of life for people with serious illness. Because the goal is so broad, care can take many shapes.⁴

In addition to pain, palliative care clinicians commonly treat nausea, shortness of breath, constipation or diarrhea, poor appetite, fatigue, anxiety, depression, and insomnia.
 

Palliative care is more than medical or nursing care

A related misconception about palliative care held by many lay people and health care workers alike is that palliative care is primarily medical or nursing care focused mostly on alleviating physical symptoms such as pain or nausea. This couldn’t be further from the truth.

We’ve been talking for a while.
Ms. Lopez tells me about her struggles to maintain her weight while undergoing chemotherapy. She has low-grade nausea that is impacting her ability and desire to eat more and didn’t think that her weight loss was severe enough to warrant taking medication.
We talk about how she may be able to use antinausea medication sparingly to alleviate nausea while also limiting side effects from the medications—which was a big concern for her.

I ask her what else is bothering her.

She tells me that she has always been a strong Catholic and even when life has gotten tough, her faith was never shaken – until now.
She is struggling to understand why she ended up with metastatic cancer at such a relatively young age—why would God do this to her?
She had plans for retirement that have since evaporated in the face of a foreshortened life.
Why did this happen to her of all people? She was completely healthy until her diagnosis.
Her face is wet with tears.

We talk a little about how a diagnosis like this can change so much of a person’s life and identity. I try to validate her experience. She’s clearly suffering from a sense that her life is not what she expected, and she is struggling to integrate how her future looks at this point.

I ask her what conversations with her priest have been like.

At this point you may be wondering where this conversation is going. Why are we talking about Ms. Lopez’s religion? Palliative care is best delivered through high functioning interdisciplinary teams that can include other supportive people in a patient’s life. We work in concert to try to bring comfort to a patient and their family.⁴ That support network can include nurses, physicians, social workers, and chaplains. In this case, Ms. Lopez had not yet reached out to her priest. She hasn’t had the time or energy to contact her priest given her symptoms.
 

“Can I contact your priest for you?
Maybe he can visit or call and chat with you?”
She nods and wipes tears away.
“That would be really nice,” she says. “I’d love it if he could pray with me.”

A few hours after the visit, I call Ms. Lopez’s priest.
I ask him to reach out to her and about her request for prayer.
He says he’s been thinking about her and that her presence has been missed at weekly Mass. He thanks me for the call and says he’ll call her tomorrow.

I say my own small prayer for Ms. Lopez and head home, the day’s work completed.

Sarah D'Ambruoso was born and raised in Maine. She completed her undergraduate and graduate nursing education at New York University and UCLA, respectively, and currently works as a palliative care nurse practitioner in an oncology clinic in Los Angeles. 

References

1. Cheng BT et al. Patterns of palliative care beliefs among adults in the U.S.: Analysis of a National Cancer Database. J Pain Symptom Manage. 2019 Aug 10. doi: 10.1016/j.jpainsymman.2019.07.030.

2. Finlay E et al. Filling the gap: Creating an outpatient palliative care program in your institution. Am Soc Clin Oncol Educ Book. 2018 May 23. doi: 10.1200/EDBK_200775.

3. Von Roenn JH et al. Barriers and approaches to the successful integration of palliative care and oncology practice. J Natl Compr Canc Netw. 2013 Mar. doi: 10.6004/jnccn.2013.0209.

4. Ferrell BR et al. Integration of palliative care into standard oncology care: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2016 Oct 31. doi: 10.1200/JCO.2016.70.1474.

The names of health care professionals and patients cited within the dialogue text have been changed to protect their privacy.

Early in my career, before I had any notion that years later I would be doing palliative care consults in a cancer center, I heard a senior physician refer to palliative care as “the most misunderstood” medical specialty. I wasn’t sure what she meant at that time, but over the years I have come to realize that she was right – most people, including many within health care, don’t have a good appreciation of what palliative care is or how it can help patients and health care teams.

A recent national survey about cancer-related health information found that of more than 1,000 surveyed Americans, less than 30% professed any knowledge of palliative care. Of those who had some knowledge of palliative care, around 30% believed palliative care was synonymous with hospice.¹ Another 15% believed that a patient would have to give up cancer-directed treatments to receive palliative care.¹

It’s not giving up

This persistent belief that palliative care is equivalent to hospice, or is tantamount to “giving up,” is one of the most commonly held myths I encounter in everyday practice.

I knock on the exam door and walk in.
A small, trim woman in her late 50s is sitting in a chair, arms folded across her chest, face drawn in.

“Hi,” I start. “I’m Sarah, the palliative care nurse practitioner who works in this clinic. I work closely with Dr. Smith.”
Dr. Smith is the patient’s oncologist.

“I really didn’t want to meet you,” she says in a quiet voice, her eyes large with concern.

I don’t take it personally. Few patients really want to be in the position of needing to meet the palliative care team.

“I looked up palliative care on Google and saw the word hospice.”

“Yeah,” I say. “I hear that a lot. Well, I can reassure you that this isn’t hospice.
In this clinic, our focus is on your cancer symptoms, your treatment side effects, and your quality of life.”

She looks visibly relieved. “Quality of life,” she echoes. “I need more of that.”
“OK,” I say. “So, tell me what you’re struggling with the most right now.”

That’s how many palliative care visits start. I actually prefer if patients haven’t heard of palliative care because it allows me to frame it for them, rather than having to start by addressing a myth or a prior negative experience. Even when patients haven’t had a negative experience with palliative care per se, typically, if they’ve interacted with palliative care in the past, it’s usually because someone they loved died in a hospital setting and it is the memory of that terrible loss that becomes synonymous with their recollection of palliative care.

Many patients I meet have never seen another outpatient palliative care practitioner – and this makes sense – we are still too few and far between. Most established palliative care teams are hospital based and many patients seen in the community do not have easy access to palliative care teams where they receive oncologic care.² As an embedded practitioner, I see patients in the same exam rooms and infusion centers where they receive their cancer therapies, so I’m effectively woven into the fabric of their oncology experience. Just being there in the cancer center allows me to be in the right place at the right time for the right patients and their care teams.
 

More than pain management

Another myth I tend to dispel a lot is that palliative care is just a euphemism for “pain management.” I have seen this less lately, but still occasionally in the chart I’ll see documented in a note, “patient is seeing palliative/pain management,” when a patient is seeing me or one of my colleagues. Unfortunately, when providers have limited or outdated views of what palliative care is or the value it brings to patient-centered cancer care, referrals to palliative care tend to be delayed.³

“I really think Ms. Lopez could benefit from seeing palliative care,” an oncology nurse practitioner says to an oncologist.
I’m standing nearby, about to see another patient in one of the exam rooms in our clinic.
“But I don’t think she’s ready. And besides, she doesn’t have any pain,” he says.
He turns to me quizzically. “What do you think?”

“Tell me about the patient,” I ask, taking a few steps in their direction.

“Well, she’s a 64-year-old woman with metastatic cancer.
She has a really poor appetite and is losing some weight.
Seems a bit down, kind of pessimistic about things.
Her scan showed some new growth, so guess I’m not surprised by that.”

“I might be able to help her with the appetite and the mood changes. 
I can at least talk with her and see where she’s at,” I offer.

“Alright,” he says. “We’ll put the palliative referral in.”
He hesitates. “But are you sure you want to see her? 
She doesn’t have any pain.” He sounds skeptical.

“Yeah, I mean, it sounds like she has symptoms that are bothering her, so I’d be happy to see her. She sounds completely appropriate for palliative care.”

I hear this assumption a lot – that palliative care is somehow equivalent to pain management and that unless a patient’s pain is severe, it’s not worth referring the patient to palliative care. Don’t get me wrong – we do a lot of pain management, but at its heart, palliative care is an interdisciplinary specialty focused on improving or maintaining quality of life for people with serious illness. Because the goal is so broad, care can take many shapes.⁴

In addition to pain, palliative care clinicians commonly treat nausea, shortness of breath, constipation or diarrhea, poor appetite, fatigue, anxiety, depression, and insomnia.
 

Palliative care is more than medical or nursing care

A related misconception about palliative care held by many lay people and health care workers alike is that palliative care is primarily medical or nursing care focused mostly on alleviating physical symptoms such as pain or nausea. This couldn’t be further from the truth.

We’ve been talking for a while.
Ms. Lopez tells me about her struggles to maintain her weight while undergoing chemotherapy. She has low-grade nausea that is impacting her ability and desire to eat more and didn’t think that her weight loss was severe enough to warrant taking medication.
We talk about how she may be able to use antinausea medication sparingly to alleviate nausea while also limiting side effects from the medications—which was a big concern for her.

I ask her what else is bothering her.

She tells me that she has always been a strong Catholic and even when life has gotten tough, her faith was never shaken – until now.
She is struggling to understand why she ended up with metastatic cancer at such a relatively young age—why would God do this to her?
She had plans for retirement that have since evaporated in the face of a foreshortened life.
Why did this happen to her of all people? She was completely healthy until her diagnosis.
Her face is wet with tears.

We talk a little about how a diagnosis like this can change so much of a person’s life and identity. I try to validate her experience. She’s clearly suffering from a sense that her life is not what she expected, and she is struggling to integrate how her future looks at this point.

I ask her what conversations with her priest have been like.

At this point you may be wondering where this conversation is going. Why are we talking about Ms. Lopez’s religion? Palliative care is best delivered through high functioning interdisciplinary teams that can include other supportive people in a patient’s life. We work in concert to try to bring comfort to a patient and their family.⁴ That support network can include nurses, physicians, social workers, and chaplains. In this case, Ms. Lopez had not yet reached out to her priest. She hasn’t had the time or energy to contact her priest given her symptoms.
 

“Can I contact your priest for you?
Maybe he can visit or call and chat with you?”
She nods and wipes tears away.
“That would be really nice,” she says. “I’d love it if he could pray with me.”

A few hours after the visit, I call Ms. Lopez’s priest.
I ask him to reach out to her and about her request for prayer.
He says he’s been thinking about her and that her presence has been missed at weekly Mass. He thanks me for the call and says he’ll call her tomorrow.

I say my own small prayer for Ms. Lopez and head home, the day’s work completed.

Sarah D'Ambruoso was born and raised in Maine. She completed her undergraduate and graduate nursing education at New York University and UCLA, respectively, and currently works as a palliative care nurse practitioner in an oncology clinic in Los Angeles. 

References

1. Cheng BT et al. Patterns of palliative care beliefs among adults in the U.S.: Analysis of a National Cancer Database. J Pain Symptom Manage. 2019 Aug 10. doi: 10.1016/j.jpainsymman.2019.07.030.

2. Finlay E et al. Filling the gap: Creating an outpatient palliative care program in your institution. Am Soc Clin Oncol Educ Book. 2018 May 23. doi: 10.1200/EDBK_200775.

3. Von Roenn JH et al. Barriers and approaches to the successful integration of palliative care and oncology practice. J Natl Compr Canc Netw. 2013 Mar. doi: 10.6004/jnccn.2013.0209.

4. Ferrell BR et al. Integration of palliative care into standard oncology care: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2016 Oct 31. doi: 10.1200/JCO.2016.70.1474.

Pembrolizumab (Keytruda) plus chemotherapy should be considered the new first-line standard of care in advanced esophageal cancer, according to the final results of a large phase 3 study.

An interim analysis of the KEYNOTE-590 study, published in 2020, found that the combination of pembrolizumab and chemotherapy in the first-line setting proved superior to chemotherapy alone in all outcome measures.

The updated analysis, which adds 12 months of follow-up data, shows “first-line pembrolizumab plus chemotherapy continued to provide clinically meaningful benefits in all patients with locally advanced and metastatic esophageal cancer, including [gastroesophageal junction] adenocarcinoma,” said lead author Jean-Philippe Metges, MD, of the CHU Brest-Institut de Cancerologie et d’Hematologie ARPEGO Network, Brest, France.

Similar quality of life and safety data were also observed with pembrolizumab plus chemotherapy versus chemotherapy alone, Dr. Metges added.

“These longer-term data further support first-line pembrolizumab plus chemotherapy as a new standard of care in patients with locally advanced and metastatic esophageal cancer,” he said.

The updated analysis was presented at the 2022 Gastrointestinal Cancers Symposium.
 

Pembro for esophageal cancer

Pembrolizumab first received regulatory approval in 2019 as monotherapy in the second-line setting to treat recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus in tumors with programmed death–ligand 1 (PD-L1) expression.

In response to the interim KEYNOTE-590 data, the FDA expanded the indication in 2021, granting accelerated approval for pembrolizumab in combination with platinum and fluoropyrimidine-based chemotherapy in the first-line setting for patients who were not candidates for surgical resection or definitive chemoradiotherapy.

The updated KEYNOTE-590 data lend greater weight for the use of pembrolizumab plus chemotherapy as first-line standard of care in advanced esophageal cancer.

In the analysis, a total of 749 eligible patients with previously untreated locally advanced, unresectable, or metastatic esophageal squamous cell carcinoma (ESCC), adenocarcinoma, or Siewert type 1 esophagogastric junction adenocarcinoma, regardless of PD-L1 status, were randomly assigned (1:1) to pembrolizumab 200 mg or placebo plus 5-fluorouracil and cisplatin once every 3 weeks for up to 35 cycles.

The authors evaluated overall survival in all patients as well as subgroups including those with ESCC, ESCC PD-L1 combined positive score ≥10 tumors, and PD-L1 CPS ≥10 tumors. The research team also looked at progression-free survival in most groups and overall response rate, duration of response, safety, and health-related quality of life.

Treatment continued until progression, unacceptable toxicity, withdrawal, or until 2 years, with no crossover permitted.

At the median follow-up of 34.8 months, median overall survival was longer for all patients receiving the combination therapy (hazard ratio, 0.73) as well as patients with ESCC (HR, 0.73), ESCC CPS ≥10 (HR, 0.59), CPS ≥10 (HR, 0.64), and adenocarcinoma (HR, 0.73).

For progression-free survival, pembrolizumab plus chemotherapy was superior in all patients (HR, 0.64), the ESCC group (HR, 0.65), as well as the PD-L1 CPS ≥10 tumor group (HR, 0.51).

The 24-month overall survival in all patients was also notably higher for those receiving the combination therapy – 26.3% versus 16.1% – as was 24-month progression-free survival – 11.6% versus 3.3%.

The overall response rate was 45.0% in the combination group, with 25 complete responses (6.7%), versus 29.3% in the control group, with 9 complete responses (2.4%). The median duration of response was 8.3 months in the combination group versus 6.0 months in the chemotherapy group. About 20% of patients in the combination group had a response rate lasting 24 months or longer, compared with 6% who received chemotherapy alone.

As for safety, grade 3-5 drug-related adverse events were similar in both arms – 72% for the combination versus 68% for chemotherapy alone. However, more patients in the combination group discontinued treatment because of drug-related adverse events – 21% versus 12%.

No additional or surprise adverse events occurred with the longer follow-up, plus quality of life was comparable between groups, Dr. Metges noted.

Stefano Cascinu, MD, Università Vita-Salute, San Raffaele Hospital, Milan, who was not involved in the analysis, reiterated that this update confirms the findings from earlier analyses and shows a benefit across all subgroups.

“One of the most relevant findings was that 20% of patients were responding for more than 24 months,” he said. “It is also important that a similar quality of life was maintained.”

Although Dr. Cascinu emphasized that this is a landmark trial in advanced esophageal and gastric cancers, he indicated to several points that remain to be investigated. These include the reproducibility of the findings in common clinical situations – such as a patient with impaired performance status, malnutrition, or peritoneal involvement – as well as the role of PD-L1.

The efficacy of the combination therapy across all subgroups led to a wide FDA approval, though the European Medicines Agency limited its approval to patients with PD-L1 CPS ≥10 tumors.

“Even though all subgroups did well, patients with [PD-L1] CPS ≥10 did better,” said Dr. Cascinu. “[And] in reality, the benefit may only be driven by a specific subpopulation.”

Dr. Cascinu added: “PD-L1 may be a negative biomarker and may be informative about the magnitude of benefit. This may be useful to discuss with patients regarding the expected benefit [of this therapeutic option].”

The study was supported by Merck & Co. Dr. Metges reported receiving payment for travel, accommodations, expenses from Amgen, LEO Pharma, and MSD Oncology, and receiving honoraria from Bristol-Myers Squibb, Lilly, Novartis, Sanofi, and Syncore. Dr. Cascinu has disclosed honoraria from BMS, Lilly, MSD Oncology, and others, as well as a consulting or advisory role for many of these same manufacturers and serving on the speakers’ bureau of Lilly and SERVIER. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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

Pembrolizumab (Keytruda) plus chemotherapy should be considered the new first-line standard of care in advanced esophageal cancer, according to the final results of a large phase 3 study.

An interim analysis of the KEYNOTE-590 study, published in 2020, found that the combination of pembrolizumab and chemotherapy in the first-line setting proved superior to chemotherapy alone in all outcome measures.

The updated analysis, which adds 12 months of follow-up data, shows “first-line pembrolizumab plus chemotherapy continued to provide clinically meaningful benefits in all patients with locally advanced and metastatic esophageal cancer, including [gastroesophageal junction] adenocarcinoma,” said lead author Jean-Philippe Metges, MD, of the CHU Brest-Institut de Cancerologie et d’Hematologie ARPEGO Network, Brest, France.

Similar quality of life and safety data were also observed with pembrolizumab plus chemotherapy versus chemotherapy alone, Dr. Metges added.

“These longer-term data further support first-line pembrolizumab plus chemotherapy as a new standard of care in patients with locally advanced and metastatic esophageal cancer,” he said.

The updated analysis was presented at the 2022 Gastrointestinal Cancers Symposium.
 

Pembro for esophageal cancer

Pembrolizumab first received regulatory approval in 2019 as monotherapy in the second-line setting to treat recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus in tumors with programmed death–ligand 1 (PD-L1) expression.

In response to the interim KEYNOTE-590 data, the FDA expanded the indication in 2021, granting accelerated approval for pembrolizumab in combination with platinum and fluoropyrimidine-based chemotherapy in the first-line setting for patients who were not candidates for surgical resection or definitive chemoradiotherapy.

The updated KEYNOTE-590 data lend greater weight for the use of pembrolizumab plus chemotherapy as first-line standard of care in advanced esophageal cancer.

In the analysis, a total of 749 eligible patients with previously untreated locally advanced, unresectable, or metastatic esophageal squamous cell carcinoma (ESCC), adenocarcinoma, or Siewert type 1 esophagogastric junction adenocarcinoma, regardless of PD-L1 status, were randomly assigned (1:1) to pembrolizumab 200 mg or placebo plus 5-fluorouracil and cisplatin once every 3 weeks for up to 35 cycles.

The authors evaluated overall survival in all patients as well as subgroups including those with ESCC, ESCC PD-L1 combined positive score ≥10 tumors, and PD-L1 CPS ≥10 tumors. The research team also looked at progression-free survival in most groups and overall response rate, duration of response, safety, and health-related quality of life.

Treatment continued until progression, unacceptable toxicity, withdrawal, or until 2 years, with no crossover permitted.

At the median follow-up of 34.8 months, median overall survival was longer for all patients receiving the combination therapy (hazard ratio, 0.73) as well as patients with ESCC (HR, 0.73), ESCC CPS ≥10 (HR, 0.59), CPS ≥10 (HR, 0.64), and adenocarcinoma (HR, 0.73).

For progression-free survival, pembrolizumab plus chemotherapy was superior in all patients (HR, 0.64), the ESCC group (HR, 0.65), as well as the PD-L1 CPS ≥10 tumor group (HR, 0.51).

The 24-month overall survival in all patients was also notably higher for those receiving the combination therapy – 26.3% versus 16.1% – as was 24-month progression-free survival – 11.6% versus 3.3%.

The overall response rate was 45.0% in the combination group, with 25 complete responses (6.7%), versus 29.3% in the control group, with 9 complete responses (2.4%). The median duration of response was 8.3 months in the combination group versus 6.0 months in the chemotherapy group. About 20% of patients in the combination group had a response rate lasting 24 months or longer, compared with 6% who received chemotherapy alone.

As for safety, grade 3-5 drug-related adverse events were similar in both arms – 72% for the combination versus 68% for chemotherapy alone. However, more patients in the combination group discontinued treatment because of drug-related adverse events – 21% versus 12%.

No additional or surprise adverse events occurred with the longer follow-up, plus quality of life was comparable between groups, Dr. Metges noted.

Stefano Cascinu, MD, Università Vita-Salute, San Raffaele Hospital, Milan, who was not involved in the analysis, reiterated that this update confirms the findings from earlier analyses and shows a benefit across all subgroups.

“One of the most relevant findings was that 20% of patients were responding for more than 24 months,” he said. “It is also important that a similar quality of life was maintained.”

Although Dr. Cascinu emphasized that this is a landmark trial in advanced esophageal and gastric cancers, he indicated to several points that remain to be investigated. These include the reproducibility of the findings in common clinical situations – such as a patient with impaired performance status, malnutrition, or peritoneal involvement – as well as the role of PD-L1.

The efficacy of the combination therapy across all subgroups led to a wide FDA approval, though the European Medicines Agency limited its approval to patients with PD-L1 CPS ≥10 tumors.

“Even though all subgroups did well, patients with [PD-L1] CPS ≥10 did better,” said Dr. Cascinu. “[And] in reality, the benefit may only be driven by a specific subpopulation.”

Dr. Cascinu added: “PD-L1 may be a negative biomarker and may be informative about the magnitude of benefit. This may be useful to discuss with patients regarding the expected benefit [of this therapeutic option].”

The study was supported by Merck & Co. Dr. Metges reported receiving payment for travel, accommodations, expenses from Amgen, LEO Pharma, and MSD Oncology, and receiving honoraria from Bristol-Myers Squibb, Lilly, Novartis, Sanofi, and Syncore. Dr. Cascinu has disclosed honoraria from BMS, Lilly, MSD Oncology, and others, as well as a consulting or advisory role for many of these same manufacturers and serving on the speakers’ bureau of Lilly and SERVIER. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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

Pembrolizumab (Keytruda) plus chemotherapy should be considered the new first-line standard of care in advanced esophageal cancer, according to the final results of a large phase 3 study.

An interim analysis of the KEYNOTE-590 study, published in 2020, found that the combination of pembrolizumab and chemotherapy in the first-line setting proved superior to chemotherapy alone in all outcome measures.

The updated analysis, which adds 12 months of follow-up data, shows “first-line pembrolizumab plus chemotherapy continued to provide clinically meaningful benefits in all patients with locally advanced and metastatic esophageal cancer, including [gastroesophageal junction] adenocarcinoma,” said lead author Jean-Philippe Metges, MD, of the CHU Brest-Institut de Cancerologie et d’Hematologie ARPEGO Network, Brest, France.

Similar quality of life and safety data were also observed with pembrolizumab plus chemotherapy versus chemotherapy alone, Dr. Metges added.

“These longer-term data further support first-line pembrolizumab plus chemotherapy as a new standard of care in patients with locally advanced and metastatic esophageal cancer,” he said.

The updated analysis was presented at the 2022 Gastrointestinal Cancers Symposium.
 

Pembro for esophageal cancer

Pembrolizumab first received regulatory approval in 2019 as monotherapy in the second-line setting to treat recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus in tumors with programmed death–ligand 1 (PD-L1) expression.

In response to the interim KEYNOTE-590 data, the FDA expanded the indication in 2021, granting accelerated approval for pembrolizumab in combination with platinum and fluoropyrimidine-based chemotherapy in the first-line setting for patients who were not candidates for surgical resection or definitive chemoradiotherapy.

The updated KEYNOTE-590 data lend greater weight for the use of pembrolizumab plus chemotherapy as first-line standard of care in advanced esophageal cancer.

In the analysis, a total of 749 eligible patients with previously untreated locally advanced, unresectable, or metastatic esophageal squamous cell carcinoma (ESCC), adenocarcinoma, or Siewert type 1 esophagogastric junction adenocarcinoma, regardless of PD-L1 status, were randomly assigned (1:1) to pembrolizumab 200 mg or placebo plus 5-fluorouracil and cisplatin once every 3 weeks for up to 35 cycles.

The authors evaluated overall survival in all patients as well as subgroups including those with ESCC, ESCC PD-L1 combined positive score ≥10 tumors, and PD-L1 CPS ≥10 tumors. The research team also looked at progression-free survival in most groups and overall response rate, duration of response, safety, and health-related quality of life.

Treatment continued until progression, unacceptable toxicity, withdrawal, or until 2 years, with no crossover permitted.

At the median follow-up of 34.8 months, median overall survival was longer for all patients receiving the combination therapy (hazard ratio, 0.73) as well as patients with ESCC (HR, 0.73), ESCC CPS ≥10 (HR, 0.59), CPS ≥10 (HR, 0.64), and adenocarcinoma (HR, 0.73).

For progression-free survival, pembrolizumab plus chemotherapy was superior in all patients (HR, 0.64), the ESCC group (HR, 0.65), as well as the PD-L1 CPS ≥10 tumor group (HR, 0.51).

The 24-month overall survival in all patients was also notably higher for those receiving the combination therapy – 26.3% versus 16.1% – as was 24-month progression-free survival – 11.6% versus 3.3%.

The overall response rate was 45.0% in the combination group, with 25 complete responses (6.7%), versus 29.3% in the control group, with 9 complete responses (2.4%). The median duration of response was 8.3 months in the combination group versus 6.0 months in the chemotherapy group. About 20% of patients in the combination group had a response rate lasting 24 months or longer, compared with 6% who received chemotherapy alone.

As for safety, grade 3-5 drug-related adverse events were similar in both arms – 72% for the combination versus 68% for chemotherapy alone. However, more patients in the combination group discontinued treatment because of drug-related adverse events – 21% versus 12%.

No additional or surprise adverse events occurred with the longer follow-up, plus quality of life was comparable between groups, Dr. Metges noted.

Stefano Cascinu, MD, Università Vita-Salute, San Raffaele Hospital, Milan, who was not involved in the analysis, reiterated that this update confirms the findings from earlier analyses and shows a benefit across all subgroups.

“One of the most relevant findings was that 20% of patients were responding for more than 24 months,” he said. “It is also important that a similar quality of life was maintained.”

Although Dr. Cascinu emphasized that this is a landmark trial in advanced esophageal and gastric cancers, he indicated to several points that remain to be investigated. These include the reproducibility of the findings in common clinical situations – such as a patient with impaired performance status, malnutrition, or peritoneal involvement – as well as the role of PD-L1.

The efficacy of the combination therapy across all subgroups led to a wide FDA approval, though the European Medicines Agency limited its approval to patients with PD-L1 CPS ≥10 tumors.

“Even though all subgroups did well, patients with [PD-L1] CPS ≥10 did better,” said Dr. Cascinu. “[And] in reality, the benefit may only be driven by a specific subpopulation.”

Dr. Cascinu added: “PD-L1 may be a negative biomarker and may be informative about the magnitude of benefit. This may be useful to discuss with patients regarding the expected benefit [of this therapeutic option].”

The study was supported by Merck & Co. Dr. Metges reported receiving payment for travel, accommodations, expenses from Amgen, LEO Pharma, and MSD Oncology, and receiving honoraria from Bristol-Myers Squibb, Lilly, Novartis, Sanofi, and Syncore. Dr. Cascinu has disclosed honoraria from BMS, Lilly, MSD Oncology, and others, as well as a consulting or advisory role for many of these same manufacturers and serving on the speakers’ bureau of Lilly and SERVIER. The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

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.

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.