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Five “can’t miss” oncologic emergencies
SAN DIEGO – Acute promyelocytic leukemia is one of five “can’t miss” oncologic emergencies, Megan Boysen Osborn, MD, MHPE, told a standing-room-only crowd at the annual meeting of the American College of Emergency Physicians.
In our exclusive video interview, Dr. Osborn, vice chair of education and the residency program director in the department of emergency medicine at the University of California, Irvine, offered tips on how to recognize acute promyelocytic leukemia, leukostasis, neutropenic fever, tumor lysis syndrome, and disseminated intravascular coagulation.
“All patients with suspected leukemias should be admitted,” she said. “Time is of the essence.”
Dr. Osborn reported having no financial disclosures related to her presentation.
SAN DIEGO – Acute promyelocytic leukemia is one of five “can’t miss” oncologic emergencies, Megan Boysen Osborn, MD, MHPE, told a standing-room-only crowd at the annual meeting of the American College of Emergency Physicians.
In our exclusive video interview, Dr. Osborn, vice chair of education and the residency program director in the department of emergency medicine at the University of California, Irvine, offered tips on how to recognize acute promyelocytic leukemia, leukostasis, neutropenic fever, tumor lysis syndrome, and disseminated intravascular coagulation.
“All patients with suspected leukemias should be admitted,” she said. “Time is of the essence.”
Dr. Osborn reported having no financial disclosures related to her presentation.
SAN DIEGO – Acute promyelocytic leukemia is one of five “can’t miss” oncologic emergencies, Megan Boysen Osborn, MD, MHPE, told a standing-room-only crowd at the annual meeting of the American College of Emergency Physicians.
In our exclusive video interview, Dr. Osborn, vice chair of education and the residency program director in the department of emergency medicine at the University of California, Irvine, offered tips on how to recognize acute promyelocytic leukemia, leukostasis, neutropenic fever, tumor lysis syndrome, and disseminated intravascular coagulation.
“All patients with suspected leukemias should be admitted,” she said. “Time is of the essence.”
Dr. Osborn reported having no financial disclosures related to her presentation.
REPORTING FROM ACEP18
Checkpoint inhibitor linked to antiphospholipid syndrome in melanoma patient
A patient with melanoma experienced antiphospholipid syndrome following multiple infusions of the PD-1 inhibitor pembrolizumab, according to authors of a recent case report.
Presence of Raynaud phenomenon and high levels of antiphospholipid antibodies led to the diagnosis of antiphospholipid syndrome in the patient, who had stage IIIB unresectable melanoma.
This report provides additional evidence that this syndrome is an immune-related adverse event associated with checkpoint inhibitor therapy, said Alexandra Picard, MD, of Hôpital Archet, Nice, France, and coauthors.
“Due to the increased use of anti PD-1 therapies, clinicians should be aware of this new potential immune-mediated toxic effect that manifests as antiphospholipid syndrome,” the researchers wrote. The report is in JAMA Dermatology.
“Great caution” should be exercised when considering use of immune checkpoint inhibitors in patients with a history of antiphospholipid syndrome, the authors added.
The woman in this report was over 60 years of age and had first presented with superficial melanoma on her right calf, followed by recurrent lymph node metastases over the next few years, all of which were surgically treated.
Following a PET-CT scan showing a new metastatic lymph node, the woman started pembrolizumab 2 mg/kg every 3 weeks and had a partial response within 3 months, the investigators reported.
After the tenth infusion, however, the patient developed bilateral secondary Raynaud phenomenon that followed a typical discoloration sequence and resulted in a necrotic lesion at the tip of one finger.
The patient had no personal or family history of Raynaud phenomenon.
While beta2-glycoprotein 1 antibodies were not elevated, laboratory tests did show anticardiolipin antibodies and lupus anticoagulants at elevated levels, the investigators said, noting that repeat testing at 12 weeks confirmed positivity of antiphospholipid antibodies.
The Raynaud phenomenon disappeared and the necrotic lesion healed after pembrolizumab was stopped and prednisolone treatment was started, they added.
No recurrence of either was noted at the last follow-up.
Previous reports have described antiphospholipid syndrome in advanced melanoma patients treated with alfa-2b interferon alone or in combination with anti-interleukin 2, the authors said in their discussion of the case.
In addition, there has been another recent report of antiphospholipid syndrome associated with the CTLA4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab, they said. In that case, testing for antiphospholipid antibodies revealed elevated beta2-glycoprotein 1 antibody levels.
“We hypothesize that [antiphospholipid syndrome] is a kind of autoimmunity induced by anti–PD-1 due to the expansive expression of the immune system against tumor cells,” the researchers wrote.
Although a case of cancer-associated antiphospholipid syndrome could not be ruled out in the present report, the rapid and complete resolution of symptoms after treatment discontinuation suggested that pembrolizumab, a “known immunostimulant,” was the cause, they said.
While antibodies against PD-1 have improved melanoma prognosis, they are associated with a wide range of immune-related adverse effects in the skin, gastrointestinal tract, liver, and endocrine system, Dr. Picard and coauthors noted.
They reported having no conflicts of interest.
SOURCE: Sanchez A, et al. JAMA Derm. 2018 Sep 19. doi: 10.1001/jamadermatol.2018.2770.
A patient with melanoma experienced antiphospholipid syndrome following multiple infusions of the PD-1 inhibitor pembrolizumab, according to authors of a recent case report.
Presence of Raynaud phenomenon and high levels of antiphospholipid antibodies led to the diagnosis of antiphospholipid syndrome in the patient, who had stage IIIB unresectable melanoma.
This report provides additional evidence that this syndrome is an immune-related adverse event associated with checkpoint inhibitor therapy, said Alexandra Picard, MD, of Hôpital Archet, Nice, France, and coauthors.
“Due to the increased use of anti PD-1 therapies, clinicians should be aware of this new potential immune-mediated toxic effect that manifests as antiphospholipid syndrome,” the researchers wrote. The report is in JAMA Dermatology.
“Great caution” should be exercised when considering use of immune checkpoint inhibitors in patients with a history of antiphospholipid syndrome, the authors added.
The woman in this report was over 60 years of age and had first presented with superficial melanoma on her right calf, followed by recurrent lymph node metastases over the next few years, all of which were surgically treated.
Following a PET-CT scan showing a new metastatic lymph node, the woman started pembrolizumab 2 mg/kg every 3 weeks and had a partial response within 3 months, the investigators reported.
After the tenth infusion, however, the patient developed bilateral secondary Raynaud phenomenon that followed a typical discoloration sequence and resulted in a necrotic lesion at the tip of one finger.
The patient had no personal or family history of Raynaud phenomenon.
While beta2-glycoprotein 1 antibodies were not elevated, laboratory tests did show anticardiolipin antibodies and lupus anticoagulants at elevated levels, the investigators said, noting that repeat testing at 12 weeks confirmed positivity of antiphospholipid antibodies.
The Raynaud phenomenon disappeared and the necrotic lesion healed after pembrolizumab was stopped and prednisolone treatment was started, they added.
No recurrence of either was noted at the last follow-up.
Previous reports have described antiphospholipid syndrome in advanced melanoma patients treated with alfa-2b interferon alone or in combination with anti-interleukin 2, the authors said in their discussion of the case.
In addition, there has been another recent report of antiphospholipid syndrome associated with the CTLA4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab, they said. In that case, testing for antiphospholipid antibodies revealed elevated beta2-glycoprotein 1 antibody levels.
“We hypothesize that [antiphospholipid syndrome] is a kind of autoimmunity induced by anti–PD-1 due to the expansive expression of the immune system against tumor cells,” the researchers wrote.
Although a case of cancer-associated antiphospholipid syndrome could not be ruled out in the present report, the rapid and complete resolution of symptoms after treatment discontinuation suggested that pembrolizumab, a “known immunostimulant,” was the cause, they said.
While antibodies against PD-1 have improved melanoma prognosis, they are associated with a wide range of immune-related adverse effects in the skin, gastrointestinal tract, liver, and endocrine system, Dr. Picard and coauthors noted.
They reported having no conflicts of interest.
SOURCE: Sanchez A, et al. JAMA Derm. 2018 Sep 19. doi: 10.1001/jamadermatol.2018.2770.
A patient with melanoma experienced antiphospholipid syndrome following multiple infusions of the PD-1 inhibitor pembrolizumab, according to authors of a recent case report.
Presence of Raynaud phenomenon and high levels of antiphospholipid antibodies led to the diagnosis of antiphospholipid syndrome in the patient, who had stage IIIB unresectable melanoma.
This report provides additional evidence that this syndrome is an immune-related adverse event associated with checkpoint inhibitor therapy, said Alexandra Picard, MD, of Hôpital Archet, Nice, France, and coauthors.
“Due to the increased use of anti PD-1 therapies, clinicians should be aware of this new potential immune-mediated toxic effect that manifests as antiphospholipid syndrome,” the researchers wrote. The report is in JAMA Dermatology.
“Great caution” should be exercised when considering use of immune checkpoint inhibitors in patients with a history of antiphospholipid syndrome, the authors added.
The woman in this report was over 60 years of age and had first presented with superficial melanoma on her right calf, followed by recurrent lymph node metastases over the next few years, all of which were surgically treated.
Following a PET-CT scan showing a new metastatic lymph node, the woman started pembrolizumab 2 mg/kg every 3 weeks and had a partial response within 3 months, the investigators reported.
After the tenth infusion, however, the patient developed bilateral secondary Raynaud phenomenon that followed a typical discoloration sequence and resulted in a necrotic lesion at the tip of one finger.
The patient had no personal or family history of Raynaud phenomenon.
While beta2-glycoprotein 1 antibodies were not elevated, laboratory tests did show anticardiolipin antibodies and lupus anticoagulants at elevated levels, the investigators said, noting that repeat testing at 12 weeks confirmed positivity of antiphospholipid antibodies.
The Raynaud phenomenon disappeared and the necrotic lesion healed after pembrolizumab was stopped and prednisolone treatment was started, they added.
No recurrence of either was noted at the last follow-up.
Previous reports have described antiphospholipid syndrome in advanced melanoma patients treated with alfa-2b interferon alone or in combination with anti-interleukin 2, the authors said in their discussion of the case.
In addition, there has been another recent report of antiphospholipid syndrome associated with the CTLA4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab, they said. In that case, testing for antiphospholipid antibodies revealed elevated beta2-glycoprotein 1 antibody levels.
“We hypothesize that [antiphospholipid syndrome] is a kind of autoimmunity induced by anti–PD-1 due to the expansive expression of the immune system against tumor cells,” the researchers wrote.
Although a case of cancer-associated antiphospholipid syndrome could not be ruled out in the present report, the rapid and complete resolution of symptoms after treatment discontinuation suggested that pembrolizumab, a “known immunostimulant,” was the cause, they said.
While antibodies against PD-1 have improved melanoma prognosis, they are associated with a wide range of immune-related adverse effects in the skin, gastrointestinal tract, liver, and endocrine system, Dr. Picard and coauthors noted.
They reported having no conflicts of interest.
SOURCE: Sanchez A, et al. JAMA Derm. 2018 Sep 19. doi: 10.1001/jamadermatol.2018.2770.
FROM JAMA DERMATOLOGY
Key clinical point: Antiphospholipid syndrome appears to be an immune-related adverse event associated with anti-PD-1 therapy.
Major finding: A melanoma patient receiving pembrolizumab was diagnosed with antiphospholipid syndrome that resolved following discontinuation of that treatment.
Study details: Case report of a woman in her 60s with stage IIIB unresectable melanoma who was treated with pembrolizumab 2 mg/kg every 3 weeks.
Disclosures: The authors reported no conflicts of interest.
Source: Sanchez A et al. JAMA Derm. 2018 Sep 19. doi: 10.1001/jamadermatol.2018.2770.
The oncologist’s dilemma
The textbook answer would have been straightforward: No additional chemotherapy. Focus on palliative care.
But Max (not his real name) was not a textbook case. He was a person, and he was terrified of dying.
When I met him in clinic, four lines of chemotherapy had not slowed the spread of his rare cancer that was already metastatic at the time of diagnosis. His skin was yellow. His hair had fallen out in clumps. His legs were swollen to the point that he couldn’t walk. He had trouble transferring from his wheelchair on his own.
All this was offset by the college hoodie he wore, a disarming display of his youth. I had to look at the chart to remind myself. He was only 19 years old.
“Will Dr. D give Max chemotherapy?” his mother asked me, referring to the attending oncologist who had been caring for her son since the beginning. “I think he needs it right away,” she said. She was holding back tears.
Protected by the fact that I was a visiting fellow in her clinic for the day, and I was just meeting Max, I deferred the decision to Dr. D.
Dr. D and I reviewed Max’s case outside the room, scrolling through his PET scans showing spread of cancer in his liver, lungs, and bones in only 2 short months. We recounted the multiple lines of chemotherapy and immunotherapy he had tried and that had failed him.
Palliative care? I offered. She agreed.
But as we went back in together, it was harder. Max’s mother began to cry as Dr. D tried to broach the option. To her, palliative care meant death. That was not something she could swallow. Her questions turned back only to the next chemotherapy we would be giving.
I learned that Max’s father worked in a hospital. He knew how serious it was. “He calls me every day, crying,” my attending later told me solemnly. Begging her to do something. Pleading for more chemotherapy.
After some painful back and forth in the room, we didn’t come to a resolution. Dr. D would call them later, she said.
It was a busy clinic day, and we saw the rest of her patients.
“What are we going to do about Max?” I asked at the end of the day. I was writing the note in his chart. We still didn’t have a plan.
More chemotherapy, from any technical and data-based standpoint, was not the right choice. We had no evidence it would improve survival. We did have evidence that it could worsen the quality of life when time was limited. If we gave him more chemotherapy, it would be beyond guidelines, beyond evidence. We would be off the grid.
I thought about the conversations I’d been privy to about giving toxic therapies near the end of life. While a handful felt productive, others were uncomfortably strained. The latter involved a tension that manifests when the goals of the patient and the oncologist are misaligned. The words may be slightly different each time, but the theme is the same.
The oncologist says: “More chemotherapy is not going to work.”
The patient says: “But we don’t know. It’s better than doing nothing. Can’t we try?”
This can be excruciatingly challenging because both sides are correct. Both sides are logical, and yet they are talking past each other.
From the point of view of the person desperate to survive, anything is worth a try. Without trying some form of treatment, there’s a zero percent chance of surviving. Low odds of something working are still better than zero percent odds.
But it’s not an issue of logic. For people like Max’s parents, the questions come from a place of helplessness. The cognitive dissonance sets in because our job is to help and we struggle when we feel we cannot. We want to say yes. I wish we had a treatment to slow Max’s cancer, too. I wish more chemotherapy would help him.
What I’ve learned from these conversations is the importance of defining terms. Specifically, what do we mean when we say a treatment will or will not “work”? What are we trying to achieve? To prolong life by weeks? By months or years? To make your pain go away? To help you feel stronger? To allow you to spend time doing what you love?
The relevant question is not: Will this treatment work? It is: What are your goals, and will this treatment help you achieve them?
Defining terms in that way can mean the difference of a conversation where two sides are talking past one another to one that comes to a mutual understanding – even if the ultimate conclusion is painful for everyone.
Yet sometimes, even for the most skilled communicators, there may be compromise. There may be an agreement to trial Nth-line chemotherapy, even without evidence that it will achieve a person’s goals. It will require nuanced informed consent from both sides. And it will come from a place of compassion.
This is what I thought about as I signed chemotherapy orders for Max that evening. I felt for him, for his parents, and for his oncologist.
Because even though I suspected the treatment wouldn’t work the way they all hoped it would, I also wasn’t the one fielding daily phone calls from a father, begging his oncologist to do something, anything at all, to save his son’s life.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.
The textbook answer would have been straightforward: No additional chemotherapy. Focus on palliative care.
But Max (not his real name) was not a textbook case. He was a person, and he was terrified of dying.
When I met him in clinic, four lines of chemotherapy had not slowed the spread of his rare cancer that was already metastatic at the time of diagnosis. His skin was yellow. His hair had fallen out in clumps. His legs were swollen to the point that he couldn’t walk. He had trouble transferring from his wheelchair on his own.
All this was offset by the college hoodie he wore, a disarming display of his youth. I had to look at the chart to remind myself. He was only 19 years old.
“Will Dr. D give Max chemotherapy?” his mother asked me, referring to the attending oncologist who had been caring for her son since the beginning. “I think he needs it right away,” she said. She was holding back tears.
Protected by the fact that I was a visiting fellow in her clinic for the day, and I was just meeting Max, I deferred the decision to Dr. D.
Dr. D and I reviewed Max’s case outside the room, scrolling through his PET scans showing spread of cancer in his liver, lungs, and bones in only 2 short months. We recounted the multiple lines of chemotherapy and immunotherapy he had tried and that had failed him.
Palliative care? I offered. She agreed.
But as we went back in together, it was harder. Max’s mother began to cry as Dr. D tried to broach the option. To her, palliative care meant death. That was not something she could swallow. Her questions turned back only to the next chemotherapy we would be giving.
I learned that Max’s father worked in a hospital. He knew how serious it was. “He calls me every day, crying,” my attending later told me solemnly. Begging her to do something. Pleading for more chemotherapy.
After some painful back and forth in the room, we didn’t come to a resolution. Dr. D would call them later, she said.
It was a busy clinic day, and we saw the rest of her patients.
“What are we going to do about Max?” I asked at the end of the day. I was writing the note in his chart. We still didn’t have a plan.
More chemotherapy, from any technical and data-based standpoint, was not the right choice. We had no evidence it would improve survival. We did have evidence that it could worsen the quality of life when time was limited. If we gave him more chemotherapy, it would be beyond guidelines, beyond evidence. We would be off the grid.
I thought about the conversations I’d been privy to about giving toxic therapies near the end of life. While a handful felt productive, others were uncomfortably strained. The latter involved a tension that manifests when the goals of the patient and the oncologist are misaligned. The words may be slightly different each time, but the theme is the same.
The oncologist says: “More chemotherapy is not going to work.”
The patient says: “But we don’t know. It’s better than doing nothing. Can’t we try?”
This can be excruciatingly challenging because both sides are correct. Both sides are logical, and yet they are talking past each other.
From the point of view of the person desperate to survive, anything is worth a try. Without trying some form of treatment, there’s a zero percent chance of surviving. Low odds of something working are still better than zero percent odds.
But it’s not an issue of logic. For people like Max’s parents, the questions come from a place of helplessness. The cognitive dissonance sets in because our job is to help and we struggle when we feel we cannot. We want to say yes. I wish we had a treatment to slow Max’s cancer, too. I wish more chemotherapy would help him.
What I’ve learned from these conversations is the importance of defining terms. Specifically, what do we mean when we say a treatment will or will not “work”? What are we trying to achieve? To prolong life by weeks? By months or years? To make your pain go away? To help you feel stronger? To allow you to spend time doing what you love?
The relevant question is not: Will this treatment work? It is: What are your goals, and will this treatment help you achieve them?
Defining terms in that way can mean the difference of a conversation where two sides are talking past one another to one that comes to a mutual understanding – even if the ultimate conclusion is painful for everyone.
Yet sometimes, even for the most skilled communicators, there may be compromise. There may be an agreement to trial Nth-line chemotherapy, even without evidence that it will achieve a person’s goals. It will require nuanced informed consent from both sides. And it will come from a place of compassion.
This is what I thought about as I signed chemotherapy orders for Max that evening. I felt for him, for his parents, and for his oncologist.
Because even though I suspected the treatment wouldn’t work the way they all hoped it would, I also wasn’t the one fielding daily phone calls from a father, begging his oncologist to do something, anything at all, to save his son’s life.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.
The textbook answer would have been straightforward: No additional chemotherapy. Focus on palliative care.
But Max (not his real name) was not a textbook case. He was a person, and he was terrified of dying.
When I met him in clinic, four lines of chemotherapy had not slowed the spread of his rare cancer that was already metastatic at the time of diagnosis. His skin was yellow. His hair had fallen out in clumps. His legs were swollen to the point that he couldn’t walk. He had trouble transferring from his wheelchair on his own.
All this was offset by the college hoodie he wore, a disarming display of his youth. I had to look at the chart to remind myself. He was only 19 years old.
“Will Dr. D give Max chemotherapy?” his mother asked me, referring to the attending oncologist who had been caring for her son since the beginning. “I think he needs it right away,” she said. She was holding back tears.
Protected by the fact that I was a visiting fellow in her clinic for the day, and I was just meeting Max, I deferred the decision to Dr. D.
Dr. D and I reviewed Max’s case outside the room, scrolling through his PET scans showing spread of cancer in his liver, lungs, and bones in only 2 short months. We recounted the multiple lines of chemotherapy and immunotherapy he had tried and that had failed him.
Palliative care? I offered. She agreed.
But as we went back in together, it was harder. Max’s mother began to cry as Dr. D tried to broach the option. To her, palliative care meant death. That was not something she could swallow. Her questions turned back only to the next chemotherapy we would be giving.
I learned that Max’s father worked in a hospital. He knew how serious it was. “He calls me every day, crying,” my attending later told me solemnly. Begging her to do something. Pleading for more chemotherapy.
After some painful back and forth in the room, we didn’t come to a resolution. Dr. D would call them later, she said.
It was a busy clinic day, and we saw the rest of her patients.
“What are we going to do about Max?” I asked at the end of the day. I was writing the note in his chart. We still didn’t have a plan.
More chemotherapy, from any technical and data-based standpoint, was not the right choice. We had no evidence it would improve survival. We did have evidence that it could worsen the quality of life when time was limited. If we gave him more chemotherapy, it would be beyond guidelines, beyond evidence. We would be off the grid.
I thought about the conversations I’d been privy to about giving toxic therapies near the end of life. While a handful felt productive, others were uncomfortably strained. The latter involved a tension that manifests when the goals of the patient and the oncologist are misaligned. The words may be slightly different each time, but the theme is the same.
The oncologist says: “More chemotherapy is not going to work.”
The patient says: “But we don’t know. It’s better than doing nothing. Can’t we try?”
This can be excruciatingly challenging because both sides are correct. Both sides are logical, and yet they are talking past each other.
From the point of view of the person desperate to survive, anything is worth a try. Without trying some form of treatment, there’s a zero percent chance of surviving. Low odds of something working are still better than zero percent odds.
But it’s not an issue of logic. For people like Max’s parents, the questions come from a place of helplessness. The cognitive dissonance sets in because our job is to help and we struggle when we feel we cannot. We want to say yes. I wish we had a treatment to slow Max’s cancer, too. I wish more chemotherapy would help him.
What I’ve learned from these conversations is the importance of defining terms. Specifically, what do we mean when we say a treatment will or will not “work”? What are we trying to achieve? To prolong life by weeks? By months or years? To make your pain go away? To help you feel stronger? To allow you to spend time doing what you love?
The relevant question is not: Will this treatment work? It is: What are your goals, and will this treatment help you achieve them?
Defining terms in that way can mean the difference of a conversation where two sides are talking past one another to one that comes to a mutual understanding – even if the ultimate conclusion is painful for everyone.
Yet sometimes, even for the most skilled communicators, there may be compromise. There may be an agreement to trial Nth-line chemotherapy, even without evidence that it will achieve a person’s goals. It will require nuanced informed consent from both sides. And it will come from a place of compassion.
This is what I thought about as I signed chemotherapy orders for Max that evening. I felt for him, for his parents, and for his oncologist.
Because even though I suspected the treatment wouldn’t work the way they all hoped it would, I also wasn’t the one fielding daily phone calls from a father, begging his oncologist to do something, anything at all, to save his son’s life.
Dr. Yurkiewicz is a fellow in hematology and oncology at Stanford (Calif.) University. Follow her on Twitter @ilanayurkiewicz.
Advances in precision medicine help refine – and redefine – cancer care
Among the groundbreaking findings presented at this year’s annual meeting of the American Society of Clinical Oncology were those showing that most women with HR-positive, HER2-negative, early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy, and that upfront pembrolizumab for patients with NSCLC expressing PD-L1 on at least 1% of tumor cells can not only significantly improve overall survival, but do so with less toxicity than standard chemotherapy.
TAILORx marks major advance for precision medicine in breast cancer
Key clinical point The majority of women with HR-positive, HER2-negative, node-negative early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy. Major finding In women with an Oncotype DX Recurrence Score in the midrange (11-25), invasive DFS with endocrine therapy alone was not inferior to that with chemotherapy plus endocrine therapy (HR, 1.08; P = .26). Study details A phase 3 trial in 10,273 women with HR-positive, HER2-negative, node-negative, early-stage breast cancer, with a noninferiority randomized component in the 6,711 women with a midrange recurrence score (TAILORx trial). Funding This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and US Postal Service Breast Cancer Stamp. Disclosures Dr Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with MetaStat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. Source Sparano et al. ASCO 2018 Abstract LBA1: https://meetinglibrary.asco.org/record/161490/abstract
Use of the 21-tumor gene expression assay (Oncotype DX Recurrence Score) allows nearly 70% of women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer to safely forgo adjuvant chemotherapy, sparing them adverse effects and preventing overtreatment, TAILORx trial results show.
The findings, which were reported in the plenary session at the meeting and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2018; 379:111-121; [behind paywall]), mark a major advance in precision medicine.
“The rationale for the TAILORx precision medicine trial is that we are really trying to ‘thread the needle,’ “ lead study author Joseph A Sparano, MD, commented in a press briefing. Oncologists typically recommend adjuvant chemotherapy for the half of all breast cancers that are hormone receptor positive, HER2 negative, and node negative, even though its absolute benefit in reducing recurrences in this population is small. “This results in most patients being overtreated because endocrine therapy alone is adequate. But some are undertreated: They do not receive chemotherapy although they could have benefited from it,” he noted.
The recurrence score is known to be prognostic and predictive of benefit from adding chemotherapy to endocrine therapy, Dr Sparano said. “But there was a major gap: There was uncertain benefit for patients who had a midrange score, which is about two-thirds of all patients who are treated,” said Dr Sparano, the associate director for clinical research at Albert Einstein Cancer Center and Montefiore Health System in New York, and vice-chair of the ECOG-ACRIN Cancer Research Group.
The phase 3 TAILORx trial registered 10,273 women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer, making it the largest adjuvant breast cancer trial to date. Analyses focused on the 6,711 evaluable women with a midrange recurrence score (defined as 11 through 25 in the trial), who were randomized to receive endocrine therapy alone or adjuvant chemotherapy plus endocrine therapy, with a noninferiority design. Of note is that contemporary drugs and regimens were used.
Results at a median follow-up of 7.5 years showed that the trial met its primary endpoint: the risk of invasive disease-free survival (DFS) events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone compared with counterparts given chemotherapy plus endocrine therapy (hazard ratio [HR], 1.08; P = .26), Dr Sparano reported.
The groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, and overall survival (OS).
Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger and who had a recurrence score of 16-25 fared better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” Dr Sparano said. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”
In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes in women with a low recurrence score (0-10) who were given endocrine therapy alone, and at the other end of the spectrum, there was need for a more aggressive approach, including chemotherapy, in women with a high recurrence score (26-100).
Ultimately, application of the recurrence score allowed 69% of the trial population to skip chemotherapy: all of the women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).
An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but ihave node-positive disease.
Study details
All of the women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy. About 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% with a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.
Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr Sparano explained.
In the women with midrange scores who were randomized, the hazard ratio of 1.08 for invasive DFS with endocrine therapy alone compared with chemotherapy plus endocrine therapy fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive DFS was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.
The groups had similar rates of freedom from distant recurrence (94.5% vs 95.0%; HR, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs 92.9%; HR, 1.11; P = .33), and similar OSs (93.9% vs 93.8%; HR for death, 0.99; P = .89).
In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 years or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive DFS events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive DFS events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr Sparano said.
The 9-year rate of distant recurrence averaged 5% in women with midrange scores overall. It was 3% in those with a low recurrence score given endocrine therapy alone, but it was still 13% in those with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The latter finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.
Tailoring treatment: ‘not too much and not too little’
“These are important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all its side effects and potential benefits,” said ASCO expert Harold Burstein, MD, PhD, FASCO. “The data show that the majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”
The recurrence score has been used for a decade, but the trial was necessary because the score was originally developed in patients who were receiving older chemotherapy regimens and older endocrine therapies, and because there have been few data to guide decision making in the large group of patients with midrange scores, he said. “Now we can say with confidence ... that the patients got contemporary chemo regimens and still saw no benefit from chemotherapy.
“This is not so much about de-escalation ... the goal of this study was not to just use less treatment but to tailor treatment. The investigators chose the title very aptly,” said Dr Burstein, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine at the Harvard Medical School, Boston.
“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing well, and this test shows us how to tailor that management so that they get exactly the right amount of treatment – not too much and not too little.”
— Susan London
First-line immunotherapy boosts survival in NSCLC patients
Key clinical point Many patients with previously untreated NSCLC could benefit from first-line therapy with the checkpoint inhibitor pembrolizumab. Major finding In all patients with expression of PD-L1 on 1% or more of tumor cells, OS was 16.7 months with pembrolizumab, compared with 12.1 months for chemotherapy. Study details Randomized phase 3 trial of 1,274 patients with advanced or metastatic NSCLC. Funding Merck, the maker of the study drug, funded the study. Disclosures Dr Lopes disclosed institutional research funding from Merck Sharp & Dohme, EMD Serono, and AstraZeneca. Dr Heymach disclosed stock/ownership in Bio-Tree and Cardinal Spine, a consulting or advisory role for Abbvie, ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Genentech, Medivation, Novartis, Oncomed, and Synta, and institutional research funding from AstraZeneca. Dr Gandhi reported having no relevant disclosures. Source Lopes G et al. ASCO 2018, abstract LBA4. https://meetinglibrary.asco.org/record/165950/abstract
Pembrolizumab as first-line treatment of advanced non–small-cell lung cancer (NSCLC) offered longer OS with better tolerability compared with chemotherapy, results of the Keynote-042 phase 3 randomized trial show.
In 1,274 patients with advanced, previously untreated NSCLC with expression of the PD-L1 on 1% or more of tumor cells, median OS after a median follow-up of 12.8 months was 16.7 months for patients treated with pembrolizumab monotherapy, compared with 12.1 months for patients treated with either paclitaxel or pemetrexed plus carboplatin, reported lead author Gilberto Lopes, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami.
The survival benefit for immunotherapy was even greater for patients with higher levels of PD-L1 expression: 20 versus 12.2 months for patients with PD-L1 expression of 50% or greater, and 17.7 versus 13 months for patients with PD-L1 expression of 20% or greater, Dr Lopes noted.
For all 3 PD-L1 expression groups, the median duration of response was 20.2 months, compared with 10.8-8.3 months for patients in the chemotherapy arm.
“These are responses that are unlike anything that we have seen with chemotherapy in the past for non–small-cell lung cancer,” Dr Lopes said at a briefing before his presentation. “In addition to that, and probably more importantly, patients had fewer adverse events [with pembrolizumab]. Overall, about 60% had any treatment-related adverse event with pembrolizumab, versus 90% with chemotherapy,” he added.
‘A true milestone’
ASCO expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, said at the briefing that the study was “a true milestone for the field, because now, for the first time, we can say that in non–small-cell lung cancer patients receiving first-line therapy, the vast majority can receive immunotherapy with pembrolizumab instead of chemotherapy.”
He noted that an earlier study, Keynote-024, showed that pembrolizumab significantly improved progression-free survival in patients with tumors expressing PD-L1 on at least 50% of cells compared with standard platinum-based chemotherapy (10.3 vs 6 months).
“This more than doubles that population that can start immunotherapy as a first-line treatment, assuming the [Food and Drug Administration] modifies the label in accordance with this study,” he added.
The Keynote-042 investigators enrolled 1,274 patients with locally advanced or metastatic NSCLC, and randomly assigned them to receive either a maximum of 35 cycles of pembrolizumab 200 mg every 3 weeks, or the investigators’ choice of not more than 6 cycles of either paclitaxel–carboplatin or pemetrexed–carboplatin, with optional pemetrexed maintenance for patients with nonsquamous histologies only.
The randomization was stratified by region (Asia vs non-East Asia), Eastern Cooperative Oncology Group performance status 0 or 1, squamous versus nonsquamous histology, and PD-L1 expression, or TPS (tumor proportion score) greater than 50% versus 1%-49%.
As noted before, the primary endpoint of OS in all patients with a TPS of 1% or greater was met, with respective median OS in the pembrolizumab versus chemotherapy groups of 16.7 and 12.1 months, translating into an HR favoring pembrolizumab of 0.81 (P = .0018). Respective hazard ratios for the TPS 20% or greater and TPS 50% or greater groups were 0.77 (P = .0020) and 0.69 (P = .0003).
At 12.8 months of median follow-up, 13% of patients assigned to pembrolizumab were still on the drug, and 4.3% of patients were receiving maintenance pemetrexed.
Treatment-related adverse events of any grade occurred in 399 of 636 patients assigned to pembrolizumab (62.7%), compared with 553 of 615 patients assigned to chemotherapy (89.9%). Grade 3 or greater events occurred in 17.8% and 41% of patients, respectively. There were 13 deaths related to therapy in the pembrolizumab arm (2.0%), and 14 in the chemotherapy arm (2.3%). Adverse events leading to discontinuation were similar between the groups, at 9% and 9.4%, respectively.
There were more immune-mediated adverse events in the pembrolizumab arm than in the chemotherapy arm (27.8% vs 7.2%, respectively), and of those, grade 3 or higher events occurred in 8% and 1.5% of patients. There was 1 immune-mediated death, from pneumonitis, in the immunotherapy arm; there were no deaths related to immune-mediated side effects in the chemotherapy arm.
“I really view this as a ‘double whammy’ for patients,” Dr Heymach said at the briefing. “Often advances in survival for our lung cancer patients come at the cost of significant toxicities. Here, by contrast, not only are patients living longer and having a much higher likelihood of prolonged survival in years, often instead of months, but they’re also receiving a treatment that has substantially less toxicity across virtually all measures, and this really impacts the day-to-day life of these patients.”
Leena Gandhi, MD, PhD, of the Perlmutter Cancer Center at New York University, the invited discussant at the plenary, agreed that pembrolizumab improves survival, compared with chemotherapy patients with PD-L1 expression levels greater than 1%, but noted that most of the benefit – as also seen in Keynote-024 – was in those patients whose tumors had high levels of PD-L1 expression.
She emphasized that although PD-L1 is an imperfect biomarker, it should still be used to help select patients for therapy and it may be complementary with tumor mutational burden for more precise treatment selection.
“What we know, and what this study adds to, is that PD-L1 really does define a patient population that could receive benefit from pembrolizumab over chemotherapy. Patients with low or no PD-L1 expression likely should get some type of combination therapy,” she said. “This study extends what we’ve seen from other recent studies, which is that chemotherapy alone is no longer a first-line standard of care in non–small-cell lung cancer.”
— Neil Osterweil
Maintenance chemo improves survival in youth with rhabdomyosarcoma
Key clinical point 6 months of maintenance chemotherapy improves survival in youth with high-risk rhabdomyosarcoma. Major finding Patients given maintenance low-dose vinorelbine and cyclophosphamide had better 5-year OS compared with those not receiving any additional treatment (86.5% vs 73.7%; HR, 0.52). Study details A phase 3 randomized controlled trial in 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. Funding The study received funding from Fondazione Città della Speranza, Italy. Disclosures Dr Bisogno disclosed that he has a consulting or advisory role with Clinigen Group, and receives travel, accommodations, and/or expenses from Jazz Pharmaceuticals. Source Bisogno et al. ASCO 2018, Abstract LBA2. https://meetinglibrary.asco.org/record/161695/abstract
Six months of maintenance chemotherapy prolongs OS in youth with high-risk rhabdomyosarcoma, finds a phase 3 randomized controlled trial of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).
Rhabdomyosarcoma is a rare but highly aggressive tumor, lead study author Gianni Bisogno, MD, PhD, a professor at the University Hospital of Padova, Italy, and chair of the EpSSG, noted in a press briefing at the meeting, where the findings were reported. In pediatric patients who achieve complete response to standard therapy, “we know that after 1 or 2 years, one-third of these children relapse, and most of them die,” he said.
The EpSSG trial, which took about 10 years to conduct, enrolled 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. They were randomized evenly to stop treatment or to receive 6 months of maintenance treatment consisting of low-dose vinorelbine and cyclophosphamide.
Results reported in the meeting’s plenary session showed that giving maintenance chemotherapy improved the 5-year OS rate by an absolute 12.8%, which translated to a near halving of the risk of death. And the maintenance regimen used was generally well tolerated.
“At the end of this long, not-easy study, we concluded that maintenance chemotherapy is an effective and well tolerated treatment for children with high-risk rhabdomyosarcoma,” Dr Bisogno said.
There are three possibilities for its efficacy, he speculated. “It may be the duration, the type of drugs used, or the metronomic approach. Maybe altogether, these three different actions have a benefit to increase survival.
“Our group has decided this is the new standard treatment for patients. At least in Europe, we give standard intensive therapy and then we continue with 6 more months of low-dose chemotherapy,” Dr Bisogno concluded. “We think that this approach – a new way of using old drugs – can be of interest also for other pediatric tumors.”
The trial is noteworthy in that it shows “how to successfully conduct large and important trials in rare diseases,” said ASCO expert Warren Chow, MD.
The standard therapy for rhabdomyosarcomas is somewhat different in the United States, typically a regimen containing vincristine, actinomycin D, cyclophosphamide, and (more recently) irinotecan, he noted. “We have not been traditionally using maintenance chemo for any of the pediatric sarcomas, so this is a paradigm shift. These results will need to be tested with US-based protocols before becoming standard of care in the United States. Also, we will need to determine if these results are applicable to patients older than 21 years of age who are considered high risk based solely on their age.
“Even with these caveats, this is the first significant treatment advance in this rare cancer in more than 30 years,” concluded Dr Chow, a medical oncologist and clinical professor at City of Hope, Duarte, Calif. “No doubt, this trial was a home run.”
Study details
Patients enrolled in the EpSSG trial had had a complete response to the standard intensive therapy used in Europe: high-dose chemotherapy (ifosfamide, vincristine, and actinomycin D, with or without doxorubicin), radiation therapy, and surgery.
The maintenance chemotherapy consisted of a combination of low-dose intravenous vinorelbine given weekly and oral cyclophosphamide given daily. The 6-month duration was somewhat arbitrary, according to Dr Bisogno. “We had to start somewhere. So when we started, we decided to use 6 months because there was some evidence in the past for regimens that long. In our next European trial, we are going to test different kinds and durations of maintenance because this is very important.”
The maintenance regimen was well tolerated compared with the regimen given during standard intensive therapy, with, for example, lower rates of grade 3 and 4 anemia (8.9% vs 48.9%), neutropenia (80.6% vs 91.6%), and thrombocytopenia (0.6% vs 26.0%), which translated to less of a need for transfusions, and a lower rate of grade 3 or 4 infection (29.4% vs 56.4%), Dr Bisogno reported. There were no cases of grade 3 or 4 cardiac, hepatobiliary/pancreatic, or renal toxicity.
Relative to peers who stopped treatment after standard intensive therapy, patients who received maintenance treatment tended to have better DFS (77.6% vs 69.8%; HR, 0.68; P = .0613) and had significantly better OS (86.5% vs 73.7%; HR, 0.52; P = .0111).
— Susan London
Among the groundbreaking findings presented at this year’s annual meeting of the American Society of Clinical Oncology were those showing that most women with HR-positive, HER2-negative, early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy, and that upfront pembrolizumab for patients with NSCLC expressing PD-L1 on at least 1% of tumor cells can not only significantly improve overall survival, but do so with less toxicity than standard chemotherapy.
TAILORx marks major advance for precision medicine in breast cancer
Key clinical point The majority of women with HR-positive, HER2-negative, node-negative early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy. Major finding In women with an Oncotype DX Recurrence Score in the midrange (11-25), invasive DFS with endocrine therapy alone was not inferior to that with chemotherapy plus endocrine therapy (HR, 1.08; P = .26). Study details A phase 3 trial in 10,273 women with HR-positive, HER2-negative, node-negative, early-stage breast cancer, with a noninferiority randomized component in the 6,711 women with a midrange recurrence score (TAILORx trial). Funding This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and US Postal Service Breast Cancer Stamp. Disclosures Dr Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with MetaStat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. Source Sparano et al. ASCO 2018 Abstract LBA1: https://meetinglibrary.asco.org/record/161490/abstract
Use of the 21-tumor gene expression assay (Oncotype DX Recurrence Score) allows nearly 70% of women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer to safely forgo adjuvant chemotherapy, sparing them adverse effects and preventing overtreatment, TAILORx trial results show.
The findings, which were reported in the plenary session at the meeting and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2018; 379:111-121; [behind paywall]), mark a major advance in precision medicine.
“The rationale for the TAILORx precision medicine trial is that we are really trying to ‘thread the needle,’ “ lead study author Joseph A Sparano, MD, commented in a press briefing. Oncologists typically recommend adjuvant chemotherapy for the half of all breast cancers that are hormone receptor positive, HER2 negative, and node negative, even though its absolute benefit in reducing recurrences in this population is small. “This results in most patients being overtreated because endocrine therapy alone is adequate. But some are undertreated: They do not receive chemotherapy although they could have benefited from it,” he noted.
The recurrence score is known to be prognostic and predictive of benefit from adding chemotherapy to endocrine therapy, Dr Sparano said. “But there was a major gap: There was uncertain benefit for patients who had a midrange score, which is about two-thirds of all patients who are treated,” said Dr Sparano, the associate director for clinical research at Albert Einstein Cancer Center and Montefiore Health System in New York, and vice-chair of the ECOG-ACRIN Cancer Research Group.
The phase 3 TAILORx trial registered 10,273 women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer, making it the largest adjuvant breast cancer trial to date. Analyses focused on the 6,711 evaluable women with a midrange recurrence score (defined as 11 through 25 in the trial), who were randomized to receive endocrine therapy alone or adjuvant chemotherapy plus endocrine therapy, with a noninferiority design. Of note is that contemporary drugs and regimens were used.
Results at a median follow-up of 7.5 years showed that the trial met its primary endpoint: the risk of invasive disease-free survival (DFS) events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone compared with counterparts given chemotherapy plus endocrine therapy (hazard ratio [HR], 1.08; P = .26), Dr Sparano reported.
The groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, and overall survival (OS).
Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger and who had a recurrence score of 16-25 fared better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” Dr Sparano said. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”
In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes in women with a low recurrence score (0-10) who were given endocrine therapy alone, and at the other end of the spectrum, there was need for a more aggressive approach, including chemotherapy, in women with a high recurrence score (26-100).
Ultimately, application of the recurrence score allowed 69% of the trial population to skip chemotherapy: all of the women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).
An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but ihave node-positive disease.
Study details
All of the women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy. About 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% with a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.
Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr Sparano explained.
In the women with midrange scores who were randomized, the hazard ratio of 1.08 for invasive DFS with endocrine therapy alone compared with chemotherapy plus endocrine therapy fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive DFS was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.
The groups had similar rates of freedom from distant recurrence (94.5% vs 95.0%; HR, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs 92.9%; HR, 1.11; P = .33), and similar OSs (93.9% vs 93.8%; HR for death, 0.99; P = .89).
In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 years or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive DFS events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive DFS events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr Sparano said.
The 9-year rate of distant recurrence averaged 5% in women with midrange scores overall. It was 3% in those with a low recurrence score given endocrine therapy alone, but it was still 13% in those with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The latter finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.
Tailoring treatment: ‘not too much and not too little’
“These are important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all its side effects and potential benefits,” said ASCO expert Harold Burstein, MD, PhD, FASCO. “The data show that the majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”
The recurrence score has been used for a decade, but the trial was necessary because the score was originally developed in patients who were receiving older chemotherapy regimens and older endocrine therapies, and because there have been few data to guide decision making in the large group of patients with midrange scores, he said. “Now we can say with confidence ... that the patients got contemporary chemo regimens and still saw no benefit from chemotherapy.
“This is not so much about de-escalation ... the goal of this study was not to just use less treatment but to tailor treatment. The investigators chose the title very aptly,” said Dr Burstein, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine at the Harvard Medical School, Boston.
“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing well, and this test shows us how to tailor that management so that they get exactly the right amount of treatment – not too much and not too little.”
— Susan London
First-line immunotherapy boosts survival in NSCLC patients
Key clinical point Many patients with previously untreated NSCLC could benefit from first-line therapy with the checkpoint inhibitor pembrolizumab. Major finding In all patients with expression of PD-L1 on 1% or more of tumor cells, OS was 16.7 months with pembrolizumab, compared with 12.1 months for chemotherapy. Study details Randomized phase 3 trial of 1,274 patients with advanced or metastatic NSCLC. Funding Merck, the maker of the study drug, funded the study. Disclosures Dr Lopes disclosed institutional research funding from Merck Sharp & Dohme, EMD Serono, and AstraZeneca. Dr Heymach disclosed stock/ownership in Bio-Tree and Cardinal Spine, a consulting or advisory role for Abbvie, ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Genentech, Medivation, Novartis, Oncomed, and Synta, and institutional research funding from AstraZeneca. Dr Gandhi reported having no relevant disclosures. Source Lopes G et al. ASCO 2018, abstract LBA4. https://meetinglibrary.asco.org/record/165950/abstract
Pembrolizumab as first-line treatment of advanced non–small-cell lung cancer (NSCLC) offered longer OS with better tolerability compared with chemotherapy, results of the Keynote-042 phase 3 randomized trial show.
In 1,274 patients with advanced, previously untreated NSCLC with expression of the PD-L1 on 1% or more of tumor cells, median OS after a median follow-up of 12.8 months was 16.7 months for patients treated with pembrolizumab monotherapy, compared with 12.1 months for patients treated with either paclitaxel or pemetrexed plus carboplatin, reported lead author Gilberto Lopes, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami.
The survival benefit for immunotherapy was even greater for patients with higher levels of PD-L1 expression: 20 versus 12.2 months for patients with PD-L1 expression of 50% or greater, and 17.7 versus 13 months for patients with PD-L1 expression of 20% or greater, Dr Lopes noted.
For all 3 PD-L1 expression groups, the median duration of response was 20.2 months, compared with 10.8-8.3 months for patients in the chemotherapy arm.
“These are responses that are unlike anything that we have seen with chemotherapy in the past for non–small-cell lung cancer,” Dr Lopes said at a briefing before his presentation. “In addition to that, and probably more importantly, patients had fewer adverse events [with pembrolizumab]. Overall, about 60% had any treatment-related adverse event with pembrolizumab, versus 90% with chemotherapy,” he added.
‘A true milestone’
ASCO expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, said at the briefing that the study was “a true milestone for the field, because now, for the first time, we can say that in non–small-cell lung cancer patients receiving first-line therapy, the vast majority can receive immunotherapy with pembrolizumab instead of chemotherapy.”
He noted that an earlier study, Keynote-024, showed that pembrolizumab significantly improved progression-free survival in patients with tumors expressing PD-L1 on at least 50% of cells compared with standard platinum-based chemotherapy (10.3 vs 6 months).
“This more than doubles that population that can start immunotherapy as a first-line treatment, assuming the [Food and Drug Administration] modifies the label in accordance with this study,” he added.
The Keynote-042 investigators enrolled 1,274 patients with locally advanced or metastatic NSCLC, and randomly assigned them to receive either a maximum of 35 cycles of pembrolizumab 200 mg every 3 weeks, or the investigators’ choice of not more than 6 cycles of either paclitaxel–carboplatin or pemetrexed–carboplatin, with optional pemetrexed maintenance for patients with nonsquamous histologies only.
The randomization was stratified by region (Asia vs non-East Asia), Eastern Cooperative Oncology Group performance status 0 or 1, squamous versus nonsquamous histology, and PD-L1 expression, or TPS (tumor proportion score) greater than 50% versus 1%-49%.
As noted before, the primary endpoint of OS in all patients with a TPS of 1% or greater was met, with respective median OS in the pembrolizumab versus chemotherapy groups of 16.7 and 12.1 months, translating into an HR favoring pembrolizumab of 0.81 (P = .0018). Respective hazard ratios for the TPS 20% or greater and TPS 50% or greater groups were 0.77 (P = .0020) and 0.69 (P = .0003).
At 12.8 months of median follow-up, 13% of patients assigned to pembrolizumab were still on the drug, and 4.3% of patients were receiving maintenance pemetrexed.
Treatment-related adverse events of any grade occurred in 399 of 636 patients assigned to pembrolizumab (62.7%), compared with 553 of 615 patients assigned to chemotherapy (89.9%). Grade 3 or greater events occurred in 17.8% and 41% of patients, respectively. There were 13 deaths related to therapy in the pembrolizumab arm (2.0%), and 14 in the chemotherapy arm (2.3%). Adverse events leading to discontinuation were similar between the groups, at 9% and 9.4%, respectively.
There were more immune-mediated adverse events in the pembrolizumab arm than in the chemotherapy arm (27.8% vs 7.2%, respectively), and of those, grade 3 or higher events occurred in 8% and 1.5% of patients. There was 1 immune-mediated death, from pneumonitis, in the immunotherapy arm; there were no deaths related to immune-mediated side effects in the chemotherapy arm.
“I really view this as a ‘double whammy’ for patients,” Dr Heymach said at the briefing. “Often advances in survival for our lung cancer patients come at the cost of significant toxicities. Here, by contrast, not only are patients living longer and having a much higher likelihood of prolonged survival in years, often instead of months, but they’re also receiving a treatment that has substantially less toxicity across virtually all measures, and this really impacts the day-to-day life of these patients.”
Leena Gandhi, MD, PhD, of the Perlmutter Cancer Center at New York University, the invited discussant at the plenary, agreed that pembrolizumab improves survival, compared with chemotherapy patients with PD-L1 expression levels greater than 1%, but noted that most of the benefit – as also seen in Keynote-024 – was in those patients whose tumors had high levels of PD-L1 expression.
She emphasized that although PD-L1 is an imperfect biomarker, it should still be used to help select patients for therapy and it may be complementary with tumor mutational burden for more precise treatment selection.
“What we know, and what this study adds to, is that PD-L1 really does define a patient population that could receive benefit from pembrolizumab over chemotherapy. Patients with low or no PD-L1 expression likely should get some type of combination therapy,” she said. “This study extends what we’ve seen from other recent studies, which is that chemotherapy alone is no longer a first-line standard of care in non–small-cell lung cancer.”
— Neil Osterweil
Maintenance chemo improves survival in youth with rhabdomyosarcoma
Key clinical point 6 months of maintenance chemotherapy improves survival in youth with high-risk rhabdomyosarcoma. Major finding Patients given maintenance low-dose vinorelbine and cyclophosphamide had better 5-year OS compared with those not receiving any additional treatment (86.5% vs 73.7%; HR, 0.52). Study details A phase 3 randomized controlled trial in 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. Funding The study received funding from Fondazione Città della Speranza, Italy. Disclosures Dr Bisogno disclosed that he has a consulting or advisory role with Clinigen Group, and receives travel, accommodations, and/or expenses from Jazz Pharmaceuticals. Source Bisogno et al. ASCO 2018, Abstract LBA2. https://meetinglibrary.asco.org/record/161695/abstract
Six months of maintenance chemotherapy prolongs OS in youth with high-risk rhabdomyosarcoma, finds a phase 3 randomized controlled trial of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).
Rhabdomyosarcoma is a rare but highly aggressive tumor, lead study author Gianni Bisogno, MD, PhD, a professor at the University Hospital of Padova, Italy, and chair of the EpSSG, noted in a press briefing at the meeting, where the findings were reported. In pediatric patients who achieve complete response to standard therapy, “we know that after 1 or 2 years, one-third of these children relapse, and most of them die,” he said.
The EpSSG trial, which took about 10 years to conduct, enrolled 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. They were randomized evenly to stop treatment or to receive 6 months of maintenance treatment consisting of low-dose vinorelbine and cyclophosphamide.
Results reported in the meeting’s plenary session showed that giving maintenance chemotherapy improved the 5-year OS rate by an absolute 12.8%, which translated to a near halving of the risk of death. And the maintenance regimen used was generally well tolerated.
“At the end of this long, not-easy study, we concluded that maintenance chemotherapy is an effective and well tolerated treatment for children with high-risk rhabdomyosarcoma,” Dr Bisogno said.
There are three possibilities for its efficacy, he speculated. “It may be the duration, the type of drugs used, or the metronomic approach. Maybe altogether, these three different actions have a benefit to increase survival.
“Our group has decided this is the new standard treatment for patients. At least in Europe, we give standard intensive therapy and then we continue with 6 more months of low-dose chemotherapy,” Dr Bisogno concluded. “We think that this approach – a new way of using old drugs – can be of interest also for other pediatric tumors.”
The trial is noteworthy in that it shows “how to successfully conduct large and important trials in rare diseases,” said ASCO expert Warren Chow, MD.
The standard therapy for rhabdomyosarcomas is somewhat different in the United States, typically a regimen containing vincristine, actinomycin D, cyclophosphamide, and (more recently) irinotecan, he noted. “We have not been traditionally using maintenance chemo for any of the pediatric sarcomas, so this is a paradigm shift. These results will need to be tested with US-based protocols before becoming standard of care in the United States. Also, we will need to determine if these results are applicable to patients older than 21 years of age who are considered high risk based solely on their age.
“Even with these caveats, this is the first significant treatment advance in this rare cancer in more than 30 years,” concluded Dr Chow, a medical oncologist and clinical professor at City of Hope, Duarte, Calif. “No doubt, this trial was a home run.”
Study details
Patients enrolled in the EpSSG trial had had a complete response to the standard intensive therapy used in Europe: high-dose chemotherapy (ifosfamide, vincristine, and actinomycin D, with or without doxorubicin), radiation therapy, and surgery.
The maintenance chemotherapy consisted of a combination of low-dose intravenous vinorelbine given weekly and oral cyclophosphamide given daily. The 6-month duration was somewhat arbitrary, according to Dr Bisogno. “We had to start somewhere. So when we started, we decided to use 6 months because there was some evidence in the past for regimens that long. In our next European trial, we are going to test different kinds and durations of maintenance because this is very important.”
The maintenance regimen was well tolerated compared with the regimen given during standard intensive therapy, with, for example, lower rates of grade 3 and 4 anemia (8.9% vs 48.9%), neutropenia (80.6% vs 91.6%), and thrombocytopenia (0.6% vs 26.0%), which translated to less of a need for transfusions, and a lower rate of grade 3 or 4 infection (29.4% vs 56.4%), Dr Bisogno reported. There were no cases of grade 3 or 4 cardiac, hepatobiliary/pancreatic, or renal toxicity.
Relative to peers who stopped treatment after standard intensive therapy, patients who received maintenance treatment tended to have better DFS (77.6% vs 69.8%; HR, 0.68; P = .0613) and had significantly better OS (86.5% vs 73.7%; HR, 0.52; P = .0111).
— Susan London
Among the groundbreaking findings presented at this year’s annual meeting of the American Society of Clinical Oncology were those showing that most women with HR-positive, HER2-negative, early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy, and that upfront pembrolizumab for patients with NSCLC expressing PD-L1 on at least 1% of tumor cells can not only significantly improve overall survival, but do so with less toxicity than standard chemotherapy.
TAILORx marks major advance for precision medicine in breast cancer
Key clinical point The majority of women with HR-positive, HER2-negative, node-negative early-stage breast cancer who have an intermediate recurrence score can safely skip adjuvant chemotherapy. Major finding In women with an Oncotype DX Recurrence Score in the midrange (11-25), invasive DFS with endocrine therapy alone was not inferior to that with chemotherapy plus endocrine therapy (HR, 1.08; P = .26). Study details A phase 3 trial in 10,273 women with HR-positive, HER2-negative, node-negative, early-stage breast cancer, with a noninferiority randomized component in the 6,711 women with a midrange recurrence score (TAILORx trial). Funding This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and US Postal Service Breast Cancer Stamp. Disclosures Dr Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with MetaStat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. Source Sparano et al. ASCO 2018 Abstract LBA1: https://meetinglibrary.asco.org/record/161490/abstract
Use of the 21-tumor gene expression assay (Oncotype DX Recurrence Score) allows nearly 70% of women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer to safely forgo adjuvant chemotherapy, sparing them adverse effects and preventing overtreatment, TAILORx trial results show.
The findings, which were reported in the plenary session at the meeting and simultaneously published in the New England Journal of Medicine (N Engl J Med. 2018; 379:111-121; [behind paywall]), mark a major advance in precision medicine.
“The rationale for the TAILORx precision medicine trial is that we are really trying to ‘thread the needle,’ “ lead study author Joseph A Sparano, MD, commented in a press briefing. Oncologists typically recommend adjuvant chemotherapy for the half of all breast cancers that are hormone receptor positive, HER2 negative, and node negative, even though its absolute benefit in reducing recurrences in this population is small. “This results in most patients being overtreated because endocrine therapy alone is adequate. But some are undertreated: They do not receive chemotherapy although they could have benefited from it,” he noted.
The recurrence score is known to be prognostic and predictive of benefit from adding chemotherapy to endocrine therapy, Dr Sparano said. “But there was a major gap: There was uncertain benefit for patients who had a midrange score, which is about two-thirds of all patients who are treated,” said Dr Sparano, the associate director for clinical research at Albert Einstein Cancer Center and Montefiore Health System in New York, and vice-chair of the ECOG-ACRIN Cancer Research Group.
The phase 3 TAILORx trial registered 10,273 women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer, making it the largest adjuvant breast cancer trial to date. Analyses focused on the 6,711 evaluable women with a midrange recurrence score (defined as 11 through 25 in the trial), who were randomized to receive endocrine therapy alone or adjuvant chemotherapy plus endocrine therapy, with a noninferiority design. Of note is that contemporary drugs and regimens were used.
Results at a median follow-up of 7.5 years showed that the trial met its primary endpoint: the risk of invasive disease-free survival (DFS) events (invasive disease recurrence, second primary cancer, or death) was not inferior for women given endocrine therapy alone compared with counterparts given chemotherapy plus endocrine therapy (hazard ratio [HR], 1.08; P = .26), Dr Sparano reported.
The groups were also on par, with absolute differences of no more than 1% between rates, with respect to a variety of other efficacy outcomes: freedom from distant recurrence and any recurrence, and overall survival (OS).
Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger and who had a recurrence score of 16-25 fared better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” Dr Sparano said. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”
In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes in women with a low recurrence score (0-10) who were given endocrine therapy alone, and at the other end of the spectrum, there was need for a more aggressive approach, including chemotherapy, in women with a high recurrence score (26-100).
Ultimately, application of the recurrence score allowed 69% of the trial population to skip chemotherapy: all of the women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).
An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but ihave node-positive disease.
Study details
All of the women with hormone receptor-positive, HER2-negative, node-negative, early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy. About 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% with a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.
Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr Sparano explained.
In the women with midrange scores who were randomized, the hazard ratio of 1.08 for invasive DFS with endocrine therapy alone compared with chemotherapy plus endocrine therapy fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive DFS was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.
The groups had similar rates of freedom from distant recurrence (94.5% vs 95.0%; HR, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs 92.9%; HR, 1.11; P = .33), and similar OSs (93.9% vs 93.8%; HR for death, 0.99; P = .89).
In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 years or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive DFS events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive DFS events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr Sparano said.
The 9-year rate of distant recurrence averaged 5% in women with midrange scores overall. It was 3% in those with a low recurrence score given endocrine therapy alone, but it was still 13% in those with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The latter finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.
Tailoring treatment: ‘not too much and not too little’
“These are important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all its side effects and potential benefits,” said ASCO expert Harold Burstein, MD, PhD, FASCO. “The data show that the majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”
The recurrence score has been used for a decade, but the trial was necessary because the score was originally developed in patients who were receiving older chemotherapy regimens and older endocrine therapies, and because there have been few data to guide decision making in the large group of patients with midrange scores, he said. “Now we can say with confidence ... that the patients got contemporary chemo regimens and still saw no benefit from chemotherapy.
“This is not so much about de-escalation ... the goal of this study was not to just use less treatment but to tailor treatment. The investigators chose the title very aptly,” said Dr Burstein, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine at the Harvard Medical School, Boston.
“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing well, and this test shows us how to tailor that management so that they get exactly the right amount of treatment – not too much and not too little.”
— Susan London
First-line immunotherapy boosts survival in NSCLC patients
Key clinical point Many patients with previously untreated NSCLC could benefit from first-line therapy with the checkpoint inhibitor pembrolizumab. Major finding In all patients with expression of PD-L1 on 1% or more of tumor cells, OS was 16.7 months with pembrolizumab, compared with 12.1 months for chemotherapy. Study details Randomized phase 3 trial of 1,274 patients with advanced or metastatic NSCLC. Funding Merck, the maker of the study drug, funded the study. Disclosures Dr Lopes disclosed institutional research funding from Merck Sharp & Dohme, EMD Serono, and AstraZeneca. Dr Heymach disclosed stock/ownership in Bio-Tree and Cardinal Spine, a consulting or advisory role for Abbvie, ARIAD, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Calithera Biosciences, Genentech, Medivation, Novartis, Oncomed, and Synta, and institutional research funding from AstraZeneca. Dr Gandhi reported having no relevant disclosures. Source Lopes G et al. ASCO 2018, abstract LBA4. https://meetinglibrary.asco.org/record/165950/abstract
Pembrolizumab as first-line treatment of advanced non–small-cell lung cancer (NSCLC) offered longer OS with better tolerability compared with chemotherapy, results of the Keynote-042 phase 3 randomized trial show.
In 1,274 patients with advanced, previously untreated NSCLC with expression of the PD-L1 on 1% or more of tumor cells, median OS after a median follow-up of 12.8 months was 16.7 months for patients treated with pembrolizumab monotherapy, compared with 12.1 months for patients treated with either paclitaxel or pemetrexed plus carboplatin, reported lead author Gilberto Lopes, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami.
The survival benefit for immunotherapy was even greater for patients with higher levels of PD-L1 expression: 20 versus 12.2 months for patients with PD-L1 expression of 50% or greater, and 17.7 versus 13 months for patients with PD-L1 expression of 20% or greater, Dr Lopes noted.
For all 3 PD-L1 expression groups, the median duration of response was 20.2 months, compared with 10.8-8.3 months for patients in the chemotherapy arm.
“These are responses that are unlike anything that we have seen with chemotherapy in the past for non–small-cell lung cancer,” Dr Lopes said at a briefing before his presentation. “In addition to that, and probably more importantly, patients had fewer adverse events [with pembrolizumab]. Overall, about 60% had any treatment-related adverse event with pembrolizumab, versus 90% with chemotherapy,” he added.
‘A true milestone’
ASCO expert John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, said at the briefing that the study was “a true milestone for the field, because now, for the first time, we can say that in non–small-cell lung cancer patients receiving first-line therapy, the vast majority can receive immunotherapy with pembrolizumab instead of chemotherapy.”
He noted that an earlier study, Keynote-024, showed that pembrolizumab significantly improved progression-free survival in patients with tumors expressing PD-L1 on at least 50% of cells compared with standard platinum-based chemotherapy (10.3 vs 6 months).
“This more than doubles that population that can start immunotherapy as a first-line treatment, assuming the [Food and Drug Administration] modifies the label in accordance with this study,” he added.
The Keynote-042 investigators enrolled 1,274 patients with locally advanced or metastatic NSCLC, and randomly assigned them to receive either a maximum of 35 cycles of pembrolizumab 200 mg every 3 weeks, or the investigators’ choice of not more than 6 cycles of either paclitaxel–carboplatin or pemetrexed–carboplatin, with optional pemetrexed maintenance for patients with nonsquamous histologies only.
The randomization was stratified by region (Asia vs non-East Asia), Eastern Cooperative Oncology Group performance status 0 or 1, squamous versus nonsquamous histology, and PD-L1 expression, or TPS (tumor proportion score) greater than 50% versus 1%-49%.
As noted before, the primary endpoint of OS in all patients with a TPS of 1% or greater was met, with respective median OS in the pembrolizumab versus chemotherapy groups of 16.7 and 12.1 months, translating into an HR favoring pembrolizumab of 0.81 (P = .0018). Respective hazard ratios for the TPS 20% or greater and TPS 50% or greater groups were 0.77 (P = .0020) and 0.69 (P = .0003).
At 12.8 months of median follow-up, 13% of patients assigned to pembrolizumab were still on the drug, and 4.3% of patients were receiving maintenance pemetrexed.
Treatment-related adverse events of any grade occurred in 399 of 636 patients assigned to pembrolizumab (62.7%), compared with 553 of 615 patients assigned to chemotherapy (89.9%). Grade 3 or greater events occurred in 17.8% and 41% of patients, respectively. There were 13 deaths related to therapy in the pembrolizumab arm (2.0%), and 14 in the chemotherapy arm (2.3%). Adverse events leading to discontinuation were similar between the groups, at 9% and 9.4%, respectively.
There were more immune-mediated adverse events in the pembrolizumab arm than in the chemotherapy arm (27.8% vs 7.2%, respectively), and of those, grade 3 or higher events occurred in 8% and 1.5% of patients. There was 1 immune-mediated death, from pneumonitis, in the immunotherapy arm; there were no deaths related to immune-mediated side effects in the chemotherapy arm.
“I really view this as a ‘double whammy’ for patients,” Dr Heymach said at the briefing. “Often advances in survival for our lung cancer patients come at the cost of significant toxicities. Here, by contrast, not only are patients living longer and having a much higher likelihood of prolonged survival in years, often instead of months, but they’re also receiving a treatment that has substantially less toxicity across virtually all measures, and this really impacts the day-to-day life of these patients.”
Leena Gandhi, MD, PhD, of the Perlmutter Cancer Center at New York University, the invited discussant at the plenary, agreed that pembrolizumab improves survival, compared with chemotherapy patients with PD-L1 expression levels greater than 1%, but noted that most of the benefit – as also seen in Keynote-024 – was in those patients whose tumors had high levels of PD-L1 expression.
She emphasized that although PD-L1 is an imperfect biomarker, it should still be used to help select patients for therapy and it may be complementary with tumor mutational burden for more precise treatment selection.
“What we know, and what this study adds to, is that PD-L1 really does define a patient population that could receive benefit from pembrolizumab over chemotherapy. Patients with low or no PD-L1 expression likely should get some type of combination therapy,” she said. “This study extends what we’ve seen from other recent studies, which is that chemotherapy alone is no longer a first-line standard of care in non–small-cell lung cancer.”
— Neil Osterweil
Maintenance chemo improves survival in youth with rhabdomyosarcoma
Key clinical point 6 months of maintenance chemotherapy improves survival in youth with high-risk rhabdomyosarcoma. Major finding Patients given maintenance low-dose vinorelbine and cyclophosphamide had better 5-year OS compared with those not receiving any additional treatment (86.5% vs 73.7%; HR, 0.52). Study details A phase 3 randomized controlled trial in 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. Funding The study received funding from Fondazione Città della Speranza, Italy. Disclosures Dr Bisogno disclosed that he has a consulting or advisory role with Clinigen Group, and receives travel, accommodations, and/or expenses from Jazz Pharmaceuticals. Source Bisogno et al. ASCO 2018, Abstract LBA2. https://meetinglibrary.asco.org/record/161695/abstract
Six months of maintenance chemotherapy prolongs OS in youth with high-risk rhabdomyosarcoma, finds a phase 3 randomized controlled trial of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).
Rhabdomyosarcoma is a rare but highly aggressive tumor, lead study author Gianni Bisogno, MD, PhD, a professor at the University Hospital of Padova, Italy, and chair of the EpSSG, noted in a press briefing at the meeting, where the findings were reported. In pediatric patients who achieve complete response to standard therapy, “we know that after 1 or 2 years, one-third of these children relapse, and most of them die,” he said.
The EpSSG trial, which took about 10 years to conduct, enrolled 371 patients aged 0-21 years with high-risk rhabdomyosarcoma who had had a complete response to standard intensive therapy. They were randomized evenly to stop treatment or to receive 6 months of maintenance treatment consisting of low-dose vinorelbine and cyclophosphamide.
Results reported in the meeting’s plenary session showed that giving maintenance chemotherapy improved the 5-year OS rate by an absolute 12.8%, which translated to a near halving of the risk of death. And the maintenance regimen used was generally well tolerated.
“At the end of this long, not-easy study, we concluded that maintenance chemotherapy is an effective and well tolerated treatment for children with high-risk rhabdomyosarcoma,” Dr Bisogno said.
There are three possibilities for its efficacy, he speculated. “It may be the duration, the type of drugs used, or the metronomic approach. Maybe altogether, these three different actions have a benefit to increase survival.
“Our group has decided this is the new standard treatment for patients. At least in Europe, we give standard intensive therapy and then we continue with 6 more months of low-dose chemotherapy,” Dr Bisogno concluded. “We think that this approach – a new way of using old drugs – can be of interest also for other pediatric tumors.”
The trial is noteworthy in that it shows “how to successfully conduct large and important trials in rare diseases,” said ASCO expert Warren Chow, MD.
The standard therapy for rhabdomyosarcomas is somewhat different in the United States, typically a regimen containing vincristine, actinomycin D, cyclophosphamide, and (more recently) irinotecan, he noted. “We have not been traditionally using maintenance chemo for any of the pediatric sarcomas, so this is a paradigm shift. These results will need to be tested with US-based protocols before becoming standard of care in the United States. Also, we will need to determine if these results are applicable to patients older than 21 years of age who are considered high risk based solely on their age.
“Even with these caveats, this is the first significant treatment advance in this rare cancer in more than 30 years,” concluded Dr Chow, a medical oncologist and clinical professor at City of Hope, Duarte, Calif. “No doubt, this trial was a home run.”
Study details
Patients enrolled in the EpSSG trial had had a complete response to the standard intensive therapy used in Europe: high-dose chemotherapy (ifosfamide, vincristine, and actinomycin D, with or without doxorubicin), radiation therapy, and surgery.
The maintenance chemotherapy consisted of a combination of low-dose intravenous vinorelbine given weekly and oral cyclophosphamide given daily. The 6-month duration was somewhat arbitrary, according to Dr Bisogno. “We had to start somewhere. So when we started, we decided to use 6 months because there was some evidence in the past for regimens that long. In our next European trial, we are going to test different kinds and durations of maintenance because this is very important.”
The maintenance regimen was well tolerated compared with the regimen given during standard intensive therapy, with, for example, lower rates of grade 3 and 4 anemia (8.9% vs 48.9%), neutropenia (80.6% vs 91.6%), and thrombocytopenia (0.6% vs 26.0%), which translated to less of a need for transfusions, and a lower rate of grade 3 or 4 infection (29.4% vs 56.4%), Dr Bisogno reported. There were no cases of grade 3 or 4 cardiac, hepatobiliary/pancreatic, or renal toxicity.
Relative to peers who stopped treatment after standard intensive therapy, patients who received maintenance treatment tended to have better DFS (77.6% vs 69.8%; HR, 0.68; P = .0613) and had significantly better OS (86.5% vs 73.7%; HR, 0.52; P = .0111).
— Susan London
New guidelines frame treatment options for Castleman disease
The (MCD), although adjuvant chemotherapy can be critical in severe cases, according to the first-ever consensus treatment guidelines based on symptom severity.
Early intervention with combination chemotherapy may prevent a fatal outcome in patients with severe idiopathic MCD, according to the guidelines, which are based on input from 42 experts from 10 countries.
The guidelines should help clinicians select therapy, evaluate response, and thereby improve outcomes for this difficult-to-treat disease, according to guideline co-author David C. Fajgenbaum, MD, who is himself an idiopathic MCD patient. Frits van Rhee, MD, PhD, is the first author of the guidelines.*
“Right now we recommend siltuximab first line for everyone,” Dr. Fajgenbaum said in an interview, “but if we continue to dig deeper, it may be that there are clinical cases within idiopathic MCD that we think are even better candidates than others, and there may be alternative therapies for other patients.”
Experts reviewed published literature and a series of 344 clinical cases to develop the guidelines, which are published in the journal Blood.
Treating idiopathic MCD is challenging because of the rarity and heterogeneity of the disease, among other factors, said Dr. Fajgenbaum, of the division of translational medicine and human genetics at the University of Pennsylvania, Philadelphia.
Some 6,000-7,000 cases of Castleman disease are diagnosed yearly, and of those, only about 1,000 cases are idiopathic MCD, according to Dr. Fajgenbaum.
“Even within idiopathic MCD, there is some heterogeneity,” he said. “Some patients present in the intensive care unit with life-threatening multiple organ failure and will die within weeks of presentation, whereas others will have a slower presentation and certainly not nearly as aggressive presentation.”
Although the exact etiology of idiopathic MCD is unknown, human interleukin (IL)-6 is the most common pathological driver, experts said in the guidelines.
Siltuximab and tocilizumab are two IL-6–directed therapies used to treat multicentric Castleman disease, with siltuximab targeting IL-6 itself and tocilizumab targeting the IL-6 receptor. Siltuximab is recommended as the first choice because of rigorous data supporting its use, including randomized clinical trial data, while tocilizumab is recommended if siltuximab is not available.
However, clinicians need to carefully monitor laboratory results and clinical features for patients on these drugs because about 50% of idiopathic MCD patients don’t have a satisfactory response to first-line anti–IL-6 treatments, Dr. Fajgenbaum said.
“Once you get to second-line therapies, that’s really where the level of evidence is lower,” he said.
Second-line therapy should include rituximab, and immunomodulatory/immunosuppressive agents or steroids may be added, according to the guidelines.
Third line therapy is “less well defined,” according to the guidelines, and experts generally recommended immunomodulatory/immunosuppressive agents such as cyclosporine A, sirolimus, thalidomide, and lenalidomide.
Cytotoxic chemotherapy has a high response rate but also a high rate of relapse and significant toxicities, according to the data analysis conducted as part of the guideline development process. Based on that, the experts said to avoid it unless the patient progresses to severe idiopathic MCD.
“Patients who are literally dying in the intensive care unit, given the right combination chemotherapy, can improve within days to weeks and can even leave the hospital,” Dr. Fajgenbaum said. “It’s not necessarily going to be the answer long term, but it can be life saving in the short term. So we recommended a really quite aggressive approach for these patients.”
To bolster the evidence base, investigators in the Castleman Disease Collaborative Network (CDCN) set up an international registry to collect treatment and outcome data for 500 patients. After the first year and a half, 150 patients were enrolled, and the investigators have identified more than 30 drugs that have been used off label to treat idiopathic MCD, according to Dr. Fajgenbaum.
“Some of the drugs are demonstrating efficacy in small numbers,” he said. “With the goal of 500 patients total, we can certainly hope to see some trends.”
Dr. Fajgenbaum was diagnosed with idiopathic MCD as a medical student.
“That certainly served as a very strong personal motivator for me to get involved in the disease,” he said. “But as I’ve gotten more and more involved, I’ve obviously met a lot of other patients, and that really is a huge motivator for all members of the CDCN. We want more options for more patients more quickly so we can help as many people as possible.”
Dr. Fajgenbaum reported research funding from Janssen. Coauthors reported disclosures related to Janssen, Bristol-Myers Squibb, Genentech, Merck, Celgene, Incyte, Pfizer, Sequenom, and Foundation Medicine, among others.
SOURCE: van Rhee F et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-862334.
This story was updated 10/01/2018.
The (MCD), although adjuvant chemotherapy can be critical in severe cases, according to the first-ever consensus treatment guidelines based on symptom severity.
Early intervention with combination chemotherapy may prevent a fatal outcome in patients with severe idiopathic MCD, according to the guidelines, which are based on input from 42 experts from 10 countries.
The guidelines should help clinicians select therapy, evaluate response, and thereby improve outcomes for this difficult-to-treat disease, according to guideline co-author David C. Fajgenbaum, MD, who is himself an idiopathic MCD patient. Frits van Rhee, MD, PhD, is the first author of the guidelines.*
“Right now we recommend siltuximab first line for everyone,” Dr. Fajgenbaum said in an interview, “but if we continue to dig deeper, it may be that there are clinical cases within idiopathic MCD that we think are even better candidates than others, and there may be alternative therapies for other patients.”
Experts reviewed published literature and a series of 344 clinical cases to develop the guidelines, which are published in the journal Blood.
Treating idiopathic MCD is challenging because of the rarity and heterogeneity of the disease, among other factors, said Dr. Fajgenbaum, of the division of translational medicine and human genetics at the University of Pennsylvania, Philadelphia.
Some 6,000-7,000 cases of Castleman disease are diagnosed yearly, and of those, only about 1,000 cases are idiopathic MCD, according to Dr. Fajgenbaum.
“Even within idiopathic MCD, there is some heterogeneity,” he said. “Some patients present in the intensive care unit with life-threatening multiple organ failure and will die within weeks of presentation, whereas others will have a slower presentation and certainly not nearly as aggressive presentation.”
Although the exact etiology of idiopathic MCD is unknown, human interleukin (IL)-6 is the most common pathological driver, experts said in the guidelines.
Siltuximab and tocilizumab are two IL-6–directed therapies used to treat multicentric Castleman disease, with siltuximab targeting IL-6 itself and tocilizumab targeting the IL-6 receptor. Siltuximab is recommended as the first choice because of rigorous data supporting its use, including randomized clinical trial data, while tocilizumab is recommended if siltuximab is not available.
However, clinicians need to carefully monitor laboratory results and clinical features for patients on these drugs because about 50% of idiopathic MCD patients don’t have a satisfactory response to first-line anti–IL-6 treatments, Dr. Fajgenbaum said.
“Once you get to second-line therapies, that’s really where the level of evidence is lower,” he said.
Second-line therapy should include rituximab, and immunomodulatory/immunosuppressive agents or steroids may be added, according to the guidelines.
Third line therapy is “less well defined,” according to the guidelines, and experts generally recommended immunomodulatory/immunosuppressive agents such as cyclosporine A, sirolimus, thalidomide, and lenalidomide.
Cytotoxic chemotherapy has a high response rate but also a high rate of relapse and significant toxicities, according to the data analysis conducted as part of the guideline development process. Based on that, the experts said to avoid it unless the patient progresses to severe idiopathic MCD.
“Patients who are literally dying in the intensive care unit, given the right combination chemotherapy, can improve within days to weeks and can even leave the hospital,” Dr. Fajgenbaum said. “It’s not necessarily going to be the answer long term, but it can be life saving in the short term. So we recommended a really quite aggressive approach for these patients.”
To bolster the evidence base, investigators in the Castleman Disease Collaborative Network (CDCN) set up an international registry to collect treatment and outcome data for 500 patients. After the first year and a half, 150 patients were enrolled, and the investigators have identified more than 30 drugs that have been used off label to treat idiopathic MCD, according to Dr. Fajgenbaum.
“Some of the drugs are demonstrating efficacy in small numbers,” he said. “With the goal of 500 patients total, we can certainly hope to see some trends.”
Dr. Fajgenbaum was diagnosed with idiopathic MCD as a medical student.
“That certainly served as a very strong personal motivator for me to get involved in the disease,” he said. “But as I’ve gotten more and more involved, I’ve obviously met a lot of other patients, and that really is a huge motivator for all members of the CDCN. We want more options for more patients more quickly so we can help as many people as possible.”
Dr. Fajgenbaum reported research funding from Janssen. Coauthors reported disclosures related to Janssen, Bristol-Myers Squibb, Genentech, Merck, Celgene, Incyte, Pfizer, Sequenom, and Foundation Medicine, among others.
SOURCE: van Rhee F et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-862334.
This story was updated 10/01/2018.
The (MCD), although adjuvant chemotherapy can be critical in severe cases, according to the first-ever consensus treatment guidelines based on symptom severity.
Early intervention with combination chemotherapy may prevent a fatal outcome in patients with severe idiopathic MCD, according to the guidelines, which are based on input from 42 experts from 10 countries.
The guidelines should help clinicians select therapy, evaluate response, and thereby improve outcomes for this difficult-to-treat disease, according to guideline co-author David C. Fajgenbaum, MD, who is himself an idiopathic MCD patient. Frits van Rhee, MD, PhD, is the first author of the guidelines.*
“Right now we recommend siltuximab first line for everyone,” Dr. Fajgenbaum said in an interview, “but if we continue to dig deeper, it may be that there are clinical cases within idiopathic MCD that we think are even better candidates than others, and there may be alternative therapies for other patients.”
Experts reviewed published literature and a series of 344 clinical cases to develop the guidelines, which are published in the journal Blood.
Treating idiopathic MCD is challenging because of the rarity and heterogeneity of the disease, among other factors, said Dr. Fajgenbaum, of the division of translational medicine and human genetics at the University of Pennsylvania, Philadelphia.
Some 6,000-7,000 cases of Castleman disease are diagnosed yearly, and of those, only about 1,000 cases are idiopathic MCD, according to Dr. Fajgenbaum.
“Even within idiopathic MCD, there is some heterogeneity,” he said. “Some patients present in the intensive care unit with life-threatening multiple organ failure and will die within weeks of presentation, whereas others will have a slower presentation and certainly not nearly as aggressive presentation.”
Although the exact etiology of idiopathic MCD is unknown, human interleukin (IL)-6 is the most common pathological driver, experts said in the guidelines.
Siltuximab and tocilizumab are two IL-6–directed therapies used to treat multicentric Castleman disease, with siltuximab targeting IL-6 itself and tocilizumab targeting the IL-6 receptor. Siltuximab is recommended as the first choice because of rigorous data supporting its use, including randomized clinical trial data, while tocilizumab is recommended if siltuximab is not available.
However, clinicians need to carefully monitor laboratory results and clinical features for patients on these drugs because about 50% of idiopathic MCD patients don’t have a satisfactory response to first-line anti–IL-6 treatments, Dr. Fajgenbaum said.
“Once you get to second-line therapies, that’s really where the level of evidence is lower,” he said.
Second-line therapy should include rituximab, and immunomodulatory/immunosuppressive agents or steroids may be added, according to the guidelines.
Third line therapy is “less well defined,” according to the guidelines, and experts generally recommended immunomodulatory/immunosuppressive agents such as cyclosporine A, sirolimus, thalidomide, and lenalidomide.
Cytotoxic chemotherapy has a high response rate but also a high rate of relapse and significant toxicities, according to the data analysis conducted as part of the guideline development process. Based on that, the experts said to avoid it unless the patient progresses to severe idiopathic MCD.
“Patients who are literally dying in the intensive care unit, given the right combination chemotherapy, can improve within days to weeks and can even leave the hospital,” Dr. Fajgenbaum said. “It’s not necessarily going to be the answer long term, but it can be life saving in the short term. So we recommended a really quite aggressive approach for these patients.”
To bolster the evidence base, investigators in the Castleman Disease Collaborative Network (CDCN) set up an international registry to collect treatment and outcome data for 500 patients. After the first year and a half, 150 patients were enrolled, and the investigators have identified more than 30 drugs that have been used off label to treat idiopathic MCD, according to Dr. Fajgenbaum.
“Some of the drugs are demonstrating efficacy in small numbers,” he said. “With the goal of 500 patients total, we can certainly hope to see some trends.”
Dr. Fajgenbaum was diagnosed with idiopathic MCD as a medical student.
“That certainly served as a very strong personal motivator for me to get involved in the disease,” he said. “But as I’ve gotten more and more involved, I’ve obviously met a lot of other patients, and that really is a huge motivator for all members of the CDCN. We want more options for more patients more quickly so we can help as many people as possible.”
Dr. Fajgenbaum reported research funding from Janssen. Coauthors reported disclosures related to Janssen, Bristol-Myers Squibb, Genentech, Merck, Celgene, Incyte, Pfizer, Sequenom, and Foundation Medicine, among others.
SOURCE: van Rhee F et al. Blood. 2018 Sep 4. doi: 10.1182/blood-2018-07-862334.
This story was updated 10/01/2018.
FROM BLOOD
Autologous fecal transplant restores microbiota after allo-HSCT
For patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) with intensive antibiotics, a subsequent autologous fecal transplant (auto-FMT) can restore intestinal microbiota, a recent study found.
Loss of normal gut bacteria after allo-HSCT and antibiotics is a common occurrence and known risk factor for graft-versus-host disease (GVHD) and intestinal infection.
“Overall, patients who lose gut microbiota diversity at the time of hematopoietic stem cell engraftment have higher rates of transplant-related death,” reported Ying Taur, MD, of the Memorial Sloan Kettering Cancer Center in New York, and his colleagues. “We explored whether the microbiota could be restored in allo-HSCT patients through the use of auto-FMT.”
Allo-HSCT patients are immune suppressed for months after engraftment, so safety concerns led the investigators to use auto-FMT rather than a fecal transplant from another individual. The complex population of viruses, fungi, archaea, bacteria, and protozoa that inhabit the human gut remains poorly understood, as does the infectious potential of a heterologous fecal donor.
“Despite remarkable advances in recent years, current technologies are incapable of comprehensively determining fecal composition,” the authors wrote in Science Translational Medicine.
The study involved 25 patients undergoing allo-HSCT with intensive antibiotic therapy. Prior to engraftment, fecal samples were collected from all patients and analyzed for composition and diversity, measured by inverse Simpson index.
Samples were then frozen and stored. Fecal analysis also was performed after engraftment, and again after the auto-FMT time point. Auto-FMT was performed in 14 patients; 11 patients served as controls and did not receive treatment. Patients were followed for 1 year.
The investigators found that all of the patients who underwent auto-FMT recovered their pre–allo-HSCT microbiota composition and diversity, compared with none of the controls (P less than .0001). Further analysis showed that auto-FMT increased diversity (inverse Simpson index) by 64%, compared with 38% in controls.
“We have demonstrated the potential of auto-FMT as a clinical intervention to restore intestinal microbiota diversity to levels deemed safe in patients, thereby reversing the disruptive effects of broad-spectrum antibiotic treatment for patients undergoing allo-HSCT transplant,” the investigators concluded.
Study funding was provided by the Leonard Tow Foundation and the Memorial Sloan Kettering’s Center for Microbes, Inflammation, and Cancer. The authors reported financial relationships with Merck, AbbVie, Nektar Therapeutics, Novartis, and others.
SOURCE: Taur Y et al. Sci Transl Med. 2018 Sep 26. doi: 10.1126/scitranslmed.aap9489.
For patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) with intensive antibiotics, a subsequent autologous fecal transplant (auto-FMT) can restore intestinal microbiota, a recent study found.
Loss of normal gut bacteria after allo-HSCT and antibiotics is a common occurrence and known risk factor for graft-versus-host disease (GVHD) and intestinal infection.
“Overall, patients who lose gut microbiota diversity at the time of hematopoietic stem cell engraftment have higher rates of transplant-related death,” reported Ying Taur, MD, of the Memorial Sloan Kettering Cancer Center in New York, and his colleagues. “We explored whether the microbiota could be restored in allo-HSCT patients through the use of auto-FMT.”
Allo-HSCT patients are immune suppressed for months after engraftment, so safety concerns led the investigators to use auto-FMT rather than a fecal transplant from another individual. The complex population of viruses, fungi, archaea, bacteria, and protozoa that inhabit the human gut remains poorly understood, as does the infectious potential of a heterologous fecal donor.
“Despite remarkable advances in recent years, current technologies are incapable of comprehensively determining fecal composition,” the authors wrote in Science Translational Medicine.
The study involved 25 patients undergoing allo-HSCT with intensive antibiotic therapy. Prior to engraftment, fecal samples were collected from all patients and analyzed for composition and diversity, measured by inverse Simpson index.
Samples were then frozen and stored. Fecal analysis also was performed after engraftment, and again after the auto-FMT time point. Auto-FMT was performed in 14 patients; 11 patients served as controls and did not receive treatment. Patients were followed for 1 year.
The investigators found that all of the patients who underwent auto-FMT recovered their pre–allo-HSCT microbiota composition and diversity, compared with none of the controls (P less than .0001). Further analysis showed that auto-FMT increased diversity (inverse Simpson index) by 64%, compared with 38% in controls.
“We have demonstrated the potential of auto-FMT as a clinical intervention to restore intestinal microbiota diversity to levels deemed safe in patients, thereby reversing the disruptive effects of broad-spectrum antibiotic treatment for patients undergoing allo-HSCT transplant,” the investigators concluded.
Study funding was provided by the Leonard Tow Foundation and the Memorial Sloan Kettering’s Center for Microbes, Inflammation, and Cancer. The authors reported financial relationships with Merck, AbbVie, Nektar Therapeutics, Novartis, and others.
SOURCE: Taur Y et al. Sci Transl Med. 2018 Sep 26. doi: 10.1126/scitranslmed.aap9489.
For patients who undergo allogeneic hematopoietic stem cell transplant (allo-HSCT) with intensive antibiotics, a subsequent autologous fecal transplant (auto-FMT) can restore intestinal microbiota, a recent study found.
Loss of normal gut bacteria after allo-HSCT and antibiotics is a common occurrence and known risk factor for graft-versus-host disease (GVHD) and intestinal infection.
“Overall, patients who lose gut microbiota diversity at the time of hematopoietic stem cell engraftment have higher rates of transplant-related death,” reported Ying Taur, MD, of the Memorial Sloan Kettering Cancer Center in New York, and his colleagues. “We explored whether the microbiota could be restored in allo-HSCT patients through the use of auto-FMT.”
Allo-HSCT patients are immune suppressed for months after engraftment, so safety concerns led the investigators to use auto-FMT rather than a fecal transplant from another individual. The complex population of viruses, fungi, archaea, bacteria, and protozoa that inhabit the human gut remains poorly understood, as does the infectious potential of a heterologous fecal donor.
“Despite remarkable advances in recent years, current technologies are incapable of comprehensively determining fecal composition,” the authors wrote in Science Translational Medicine.
The study involved 25 patients undergoing allo-HSCT with intensive antibiotic therapy. Prior to engraftment, fecal samples were collected from all patients and analyzed for composition and diversity, measured by inverse Simpson index.
Samples were then frozen and stored. Fecal analysis also was performed after engraftment, and again after the auto-FMT time point. Auto-FMT was performed in 14 patients; 11 patients served as controls and did not receive treatment. Patients were followed for 1 year.
The investigators found that all of the patients who underwent auto-FMT recovered their pre–allo-HSCT microbiota composition and diversity, compared with none of the controls (P less than .0001). Further analysis showed that auto-FMT increased diversity (inverse Simpson index) by 64%, compared with 38% in controls.
“We have demonstrated the potential of auto-FMT as a clinical intervention to restore intestinal microbiota diversity to levels deemed safe in patients, thereby reversing the disruptive effects of broad-spectrum antibiotic treatment for patients undergoing allo-HSCT transplant,” the investigators concluded.
Study funding was provided by the Leonard Tow Foundation and the Memorial Sloan Kettering’s Center for Microbes, Inflammation, and Cancer. The authors reported financial relationships with Merck, AbbVie, Nektar Therapeutics, Novartis, and others.
SOURCE: Taur Y et al. Sci Transl Med. 2018 Sep 26. doi: 10.1126/scitranslmed.aap9489.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point:
Major finding: All patients who received auto-FMT regained pre–allo-HSCT microbiota composition and diversity (P less than .0001).
Study details: An open-label study involving 25 allo-HSCT patients that compared auto-FMT with no treatment.
Disclosures: Study funding was provided by the Leonard Tow Foundation and the Memorial Sloan Kettering’s Center for Microbes, Inflammation, and Cancer. The authors reported disclosures related Merck, AbbVie, Nektar Therapeutics, Novartis, and others.
Source: Taur Y et al. Sci Transl Med. 2018 Sep 26. doi: 10.1126/scitranslmed.aap9489.
Breast cancer patients getting unnecessary scans against recommendations
PHOENIX – Despite clear guidance on lack of benefit and potential harms, many patients with early-stage breast cancers at low metastasis risk have undergone imaging tests for staging, recent retrospective studies have shown.
Nearly one-third of early-stage breast cancer patients received the unnecessary and potentially harmful interventions in one of the two studies presented at a symposium on quality care sponsored by the American Society of Clinical Oncology (ASCO).
Low-risk patients in that study were more likely to undergo imaging if they were younger or had triple-negative disease, among other factors, said researcher Brett Barlow, of the University of Alabama at Birmingham.
Physicians should be further educated about the low-risk nature of early-stage breast cancer, even in subgroups that are perceived to be higher risk, Mr. Barlow said in an interview.
“I think we can reassure physicians that these patients will do well and that these guidelines are based on good data,” he said “There could potentially be an element of distrust in these guidelines in these higher-risk patients, and that may be what’s driving some of these extra tests.”
According to Mr. Barlow, imaging low-risk patients is inconsistent with guidance from Choosing Wisely, an initiative designed to promote discussions between clinicians and patients about medical tests or procedures that are unnecessary.
As part of that initiative, ASCO recommended that PET, CT, and radionuclide bone scans should not be performed for staging of early-stage breast cancer at low risk for metastasis.
There is a lack of evidence that demonstrates a benefit for those imaging modalities in patients with newly identified ductal carcinoma in situ (DCIS) or clinical stage I or II disease, the society said at the time.
Unnecessary imaging can result in unnecessary invasive procedures, overtreatment, radiation exposure, and misdiagnosis, the society said in the guidance, which was published in 2012.
Despite the guidance, 262 out of 872 patients with stage 0-II breast cancer (30%) seen during 2013-2015 underwent imaging, according to results of the single-center retrospective cohort study Mr. Barlow and his coauthors described in a poster presentation.
The median age of the patients who underwent unnecessary imaging was 55 years versus 60 years for patients who did not, according to the researchers.
Risk of inappropriate imaging was increased in younger patients, those with triple-negative disease versus those with any hormone receptor–positive disease, those with higher-stage breast cancer, and those without Medicare insurance, investigators found.
Although it’s unclear whether there were any formal, institution-level efforts to promote the ASCO recommendations during the 2013-2015 period, it was “definitely a topic of debate at the time,” Mr. Barlow said.
“Something we hope to evaluate further is whether we have improved,” he said. “It’s important to set a baseline and see how we did in this area. We look forward to reevaluating that in a few years to see.”
In a separate study, investigators reviewed records from Mount Sinai Health System in New York and found that unnecessary scans were performed in 19% of patients diagnosed with stage I-II breast cancer during 2014-2015.
No cases of metastatic disease were found in 733 patients included in the study, and 43% had false-positive findings, according to Ana I. Velazquez Manana, MD, MS, of Mount Sinai Beth Israel Foundation, New York, and her coinvestigators.
Imaging increased costs by $4,480 per patient, according to the investigators, who found in multivariate analysis that the unnecessary scans were associated with young age, presence of T2 tumor, positive lymph nodes, and triple-negative disease.
“Further educational efforts are needed to avoid unnecessary scans in patients with early-stage breast cancer,” the researchers wrote in an abstract describing the results.
Mr. Barlow reported no disclosures, while one coauthor reported disclosures related to Carevive Systems, Genentech/Roche, Medscape, Pack Health, and Pfizer. Dr. Velazquez Manana and her coauthors had no relationships to disclose, and their study was funded by the Medical Student Rotation for Underrepresented Populations.
SOURCE: Barlow B et al. Quality Care Symposium, Abstract 51. Velazquez Manana AI et al. Quality Care Symposium, Abstract 52.
PHOENIX – Despite clear guidance on lack of benefit and potential harms, many patients with early-stage breast cancers at low metastasis risk have undergone imaging tests for staging, recent retrospective studies have shown.
Nearly one-third of early-stage breast cancer patients received the unnecessary and potentially harmful interventions in one of the two studies presented at a symposium on quality care sponsored by the American Society of Clinical Oncology (ASCO).
Low-risk patients in that study were more likely to undergo imaging if they were younger or had triple-negative disease, among other factors, said researcher Brett Barlow, of the University of Alabama at Birmingham.
Physicians should be further educated about the low-risk nature of early-stage breast cancer, even in subgroups that are perceived to be higher risk, Mr. Barlow said in an interview.
“I think we can reassure physicians that these patients will do well and that these guidelines are based on good data,” he said “There could potentially be an element of distrust in these guidelines in these higher-risk patients, and that may be what’s driving some of these extra tests.”
According to Mr. Barlow, imaging low-risk patients is inconsistent with guidance from Choosing Wisely, an initiative designed to promote discussions between clinicians and patients about medical tests or procedures that are unnecessary.
As part of that initiative, ASCO recommended that PET, CT, and radionuclide bone scans should not be performed for staging of early-stage breast cancer at low risk for metastasis.
There is a lack of evidence that demonstrates a benefit for those imaging modalities in patients with newly identified ductal carcinoma in situ (DCIS) or clinical stage I or II disease, the society said at the time.
Unnecessary imaging can result in unnecessary invasive procedures, overtreatment, radiation exposure, and misdiagnosis, the society said in the guidance, which was published in 2012.
Despite the guidance, 262 out of 872 patients with stage 0-II breast cancer (30%) seen during 2013-2015 underwent imaging, according to results of the single-center retrospective cohort study Mr. Barlow and his coauthors described in a poster presentation.
The median age of the patients who underwent unnecessary imaging was 55 years versus 60 years for patients who did not, according to the researchers.
Risk of inappropriate imaging was increased in younger patients, those with triple-negative disease versus those with any hormone receptor–positive disease, those with higher-stage breast cancer, and those without Medicare insurance, investigators found.
Although it’s unclear whether there were any formal, institution-level efforts to promote the ASCO recommendations during the 2013-2015 period, it was “definitely a topic of debate at the time,” Mr. Barlow said.
“Something we hope to evaluate further is whether we have improved,” he said. “It’s important to set a baseline and see how we did in this area. We look forward to reevaluating that in a few years to see.”
In a separate study, investigators reviewed records from Mount Sinai Health System in New York and found that unnecessary scans were performed in 19% of patients diagnosed with stage I-II breast cancer during 2014-2015.
No cases of metastatic disease were found in 733 patients included in the study, and 43% had false-positive findings, according to Ana I. Velazquez Manana, MD, MS, of Mount Sinai Beth Israel Foundation, New York, and her coinvestigators.
Imaging increased costs by $4,480 per patient, according to the investigators, who found in multivariate analysis that the unnecessary scans were associated with young age, presence of T2 tumor, positive lymph nodes, and triple-negative disease.
“Further educational efforts are needed to avoid unnecessary scans in patients with early-stage breast cancer,” the researchers wrote in an abstract describing the results.
Mr. Barlow reported no disclosures, while one coauthor reported disclosures related to Carevive Systems, Genentech/Roche, Medscape, Pack Health, and Pfizer. Dr. Velazquez Manana and her coauthors had no relationships to disclose, and their study was funded by the Medical Student Rotation for Underrepresented Populations.
SOURCE: Barlow B et al. Quality Care Symposium, Abstract 51. Velazquez Manana AI et al. Quality Care Symposium, Abstract 52.
PHOENIX – Despite clear guidance on lack of benefit and potential harms, many patients with early-stage breast cancers at low metastasis risk have undergone imaging tests for staging, recent retrospective studies have shown.
Nearly one-third of early-stage breast cancer patients received the unnecessary and potentially harmful interventions in one of the two studies presented at a symposium on quality care sponsored by the American Society of Clinical Oncology (ASCO).
Low-risk patients in that study were more likely to undergo imaging if they were younger or had triple-negative disease, among other factors, said researcher Brett Barlow, of the University of Alabama at Birmingham.
Physicians should be further educated about the low-risk nature of early-stage breast cancer, even in subgroups that are perceived to be higher risk, Mr. Barlow said in an interview.
“I think we can reassure physicians that these patients will do well and that these guidelines are based on good data,” he said “There could potentially be an element of distrust in these guidelines in these higher-risk patients, and that may be what’s driving some of these extra tests.”
According to Mr. Barlow, imaging low-risk patients is inconsistent with guidance from Choosing Wisely, an initiative designed to promote discussions between clinicians and patients about medical tests or procedures that are unnecessary.
As part of that initiative, ASCO recommended that PET, CT, and radionuclide bone scans should not be performed for staging of early-stage breast cancer at low risk for metastasis.
There is a lack of evidence that demonstrates a benefit for those imaging modalities in patients with newly identified ductal carcinoma in situ (DCIS) or clinical stage I or II disease, the society said at the time.
Unnecessary imaging can result in unnecessary invasive procedures, overtreatment, radiation exposure, and misdiagnosis, the society said in the guidance, which was published in 2012.
Despite the guidance, 262 out of 872 patients with stage 0-II breast cancer (30%) seen during 2013-2015 underwent imaging, according to results of the single-center retrospective cohort study Mr. Barlow and his coauthors described in a poster presentation.
The median age of the patients who underwent unnecessary imaging was 55 years versus 60 years for patients who did not, according to the researchers.
Risk of inappropriate imaging was increased in younger patients, those with triple-negative disease versus those with any hormone receptor–positive disease, those with higher-stage breast cancer, and those without Medicare insurance, investigators found.
Although it’s unclear whether there were any formal, institution-level efforts to promote the ASCO recommendations during the 2013-2015 period, it was “definitely a topic of debate at the time,” Mr. Barlow said.
“Something we hope to evaluate further is whether we have improved,” he said. “It’s important to set a baseline and see how we did in this area. We look forward to reevaluating that in a few years to see.”
In a separate study, investigators reviewed records from Mount Sinai Health System in New York and found that unnecessary scans were performed in 19% of patients diagnosed with stage I-II breast cancer during 2014-2015.
No cases of metastatic disease were found in 733 patients included in the study, and 43% had false-positive findings, according to Ana I. Velazquez Manana, MD, MS, of Mount Sinai Beth Israel Foundation, New York, and her coinvestigators.
Imaging increased costs by $4,480 per patient, according to the investigators, who found in multivariate analysis that the unnecessary scans were associated with young age, presence of T2 tumor, positive lymph nodes, and triple-negative disease.
“Further educational efforts are needed to avoid unnecessary scans in patients with early-stage breast cancer,” the researchers wrote in an abstract describing the results.
Mr. Barlow reported no disclosures, while one coauthor reported disclosures related to Carevive Systems, Genentech/Roche, Medscape, Pack Health, and Pfizer. Dr. Velazquez Manana and her coauthors had no relationships to disclose, and their study was funded by the Medical Student Rotation for Underrepresented Populations.
SOURCE: Barlow B et al. Quality Care Symposium, Abstract 51. Velazquez Manana AI et al. Quality Care Symposium, Abstract 52.
REPORTING FROM THE QUALITY CARE SYMPOSIUM
Key clinical point: Many patients with early breast cancers at low metastasis risk received imaging tests for staging despite ASCO recommendations against such testing.
Major finding: In two studies, 30% and 19% of low-risk breast cancer patients underwent imaging for staging.
Study details: Two single-center, retrospective cohort studies that included 872 and 733 patients, respectively.
Disclosures: In one study, researchers reported disclosures related to Carevive Systems, Genentech/Roche, Medscape, Pack Health, and Pfizer. The second study was funded by the Medical Student Rotation for Underrepresented Populations.
Source: Barlow B et al. Quality Care Symposium, Abstract 51; Velazquez Manana AI et al. Quality Care Symposium, Abstract 52.
CGP guides cancer patient management, facilitates trial enrollment
TORONTO – according to findings from a retrospective study of 46 patients who were followed for 3 years after CGP.
A total of 263 genomic alterations were identified in the patients, leading to a change of therapy in 26% of cases and referral to a clinical trial in 13%, Kimberly Rohan, APN, reported at the World Conference on Lung Cancer.
The 13% referral rate was surprising, “because that’s way above the national average for enrollment in a clinical trial,” Ms. Rohan, of the Edward Cancer Center in Naperville, Ill., said during a press briefing at the meeting, sponsored by the International Association for the Study of Lung Cancer.
“Among those diagnosed with lung cancer, 6% were referred to clinical trials and 34% had a change of therapy,” she said, noting that all but one of the patients had non–small cell lung cancer, and the other had small cell lung cancer and many alterations.
Of note, three patients enrolled in hospice care based on the findings; sometimes, palliative care is the most appropriate option, and this information helps patients and their families make those decisions, Ms. Rohan said.
Patients were tested between 2014 and 2017, and the review looked at the number of genomic alterations identified in each, what treatments were associated with potential clinical trial benefits, what therapies were associated with lack of response, and the effects of the CGP findings on decision making.
An important next step is to work with payors to get them to pay for CGP testing, she said. “These tests are expensive so a lot of [insurance companies] don’t want to pay for them, but this data will help support the fact that [these tests] do allow better treatments for patients and allow patients to make better decisions for themselves in regard to treatment.”
Ms. Rohan is a speaker or advisory board member for Merck, Genentech, and AstraZeneca.
TORONTO – according to findings from a retrospective study of 46 patients who were followed for 3 years after CGP.
A total of 263 genomic alterations were identified in the patients, leading to a change of therapy in 26% of cases and referral to a clinical trial in 13%, Kimberly Rohan, APN, reported at the World Conference on Lung Cancer.
The 13% referral rate was surprising, “because that’s way above the national average for enrollment in a clinical trial,” Ms. Rohan, of the Edward Cancer Center in Naperville, Ill., said during a press briefing at the meeting, sponsored by the International Association for the Study of Lung Cancer.
“Among those diagnosed with lung cancer, 6% were referred to clinical trials and 34% had a change of therapy,” she said, noting that all but one of the patients had non–small cell lung cancer, and the other had small cell lung cancer and many alterations.
Of note, three patients enrolled in hospice care based on the findings; sometimes, palliative care is the most appropriate option, and this information helps patients and their families make those decisions, Ms. Rohan said.
Patients were tested between 2014 and 2017, and the review looked at the number of genomic alterations identified in each, what treatments were associated with potential clinical trial benefits, what therapies were associated with lack of response, and the effects of the CGP findings on decision making.
An important next step is to work with payors to get them to pay for CGP testing, she said. “These tests are expensive so a lot of [insurance companies] don’t want to pay for them, but this data will help support the fact that [these tests] do allow better treatments for patients and allow patients to make better decisions for themselves in regard to treatment.”
Ms. Rohan is a speaker or advisory board member for Merck, Genentech, and AstraZeneca.
TORONTO – according to findings from a retrospective study of 46 patients who were followed for 3 years after CGP.
A total of 263 genomic alterations were identified in the patients, leading to a change of therapy in 26% of cases and referral to a clinical trial in 13%, Kimberly Rohan, APN, reported at the World Conference on Lung Cancer.
The 13% referral rate was surprising, “because that’s way above the national average for enrollment in a clinical trial,” Ms. Rohan, of the Edward Cancer Center in Naperville, Ill., said during a press briefing at the meeting, sponsored by the International Association for the Study of Lung Cancer.
“Among those diagnosed with lung cancer, 6% were referred to clinical trials and 34% had a change of therapy,” she said, noting that all but one of the patients had non–small cell lung cancer, and the other had small cell lung cancer and many alterations.
Of note, three patients enrolled in hospice care based on the findings; sometimes, palliative care is the most appropriate option, and this information helps patients and their families make those decisions, Ms. Rohan said.
Patients were tested between 2014 and 2017, and the review looked at the number of genomic alterations identified in each, what treatments were associated with potential clinical trial benefits, what therapies were associated with lack of response, and the effects of the CGP findings on decision making.
An important next step is to work with payors to get them to pay for CGP testing, she said. “These tests are expensive so a lot of [insurance companies] don’t want to pay for them, but this data will help support the fact that [these tests] do allow better treatments for patients and allow patients to make better decisions for themselves in regard to treatment.”
Ms. Rohan is a speaker or advisory board member for Merck, Genentech, and AstraZeneca.
REPORTING FROM WCLC 2018
Key clinical point: Comprehensive genetic profiling (GCP) is useful for guiding the care of cancer patients.
Major finding: CGP led to a change of therapy in 26% of cases and referral to a clinical trial in 13% of cases.
Study details: A retrospective study of CGP for 46 cancer patients.
Disclosures: Ms. Rohan is a speaker or advisory board member for Merck, Genentech, and AstraZeneca.
AYA cancer: Bridging the divide
and older adult patients, a trend that has been going on for decades. But clinicians and researchers are getting serious about an important question: Why?
“This is a very heterogeneous group of disorders,” Rabi Hanna, MD, a pediatric hematologist and oncologist, and director of pediatric bone marrow transplantation at Cleveland Clinic Children’s Hospital, Ohio, said in an interview.
He is referring to the cancers that affect adolescents and young adults (AYAs), who are broadly defined as patients aged 15-39 years.
“A few cancers, such as [acute lymphoblastic leukemia], are more common in children, and others, such as breast cancer, are more common in adults; biology may be different in the adolescent and young adult patients, which may lead to different outcomes,” Dr. Hanna said.
In addition, the psychosocial needs in this age group differ vastly from those of other groups, he said.
“Many of these patients are in college or have just started their families, so we have to pay attention more to financial toxicities and fertility, for example,” he said.
Another factor that likely contributes to the disparities between AYAs and other populations with cancer is the relative lack of clinical trial involvement among AYAs. That’s a point on which Dr. Hanna and many other experts agree.
A recent series of articles published in Blood addressed these and other issues, including whether AYAs with ALL or aggressive B-cell non-Hodgkin lymphomas (NHLs) should be treated as children or adults, treatment strategies for those with acute myeloid leukemias, management of Hodgkin lymphoma, and psychosocial challenges and health-related quality of life (QOL) of AYAs with hematologic malignancies.
“Hematological malignancies occurring in AYAs represent a unique challenge because of their special biological features and distinctive therapeutic requirements, as well as the unique medical, social, and psychological characteristics of this patient population,” Jorge Cortes, MD, an assistant editor for Blood, wrote in an introduction to the series.
“Unfortunately, not much has been done to explore unique molecular and biological features of AYA hematologic malignancies. The discussion on the management of AYAs frequently centers on whether these patients should be treated in a pediatric setting or an adult setting, or with regimens designed for children or for adults. Clinical trials specifically designed for AYAs are scanty,” noted Dr. Cortes, who directs the chronic myeloid leukemia (CML) and acute myeloid leukemia programs (AML) at the University of Texas MD Anderson Cancer Center, Houston.
Treatment approach and setting
In the Blood article on ALL in AYAs, Nicolas Boissel, MD, and André Baruchel, MD, note that the use of “fully pediatric protocols” in patients aged 15-20 years is supported by numerous studies, and that in young adults, evidence increasingly supports “pediatric-inspired or even fully pediatric approaches” as they have been shown to dramatically improve outcomes, with long-term survival rates nearing 70% (2018;132:351-61).
Patients in these age groups require specific programs that take into account factors such as care access and trial access, increased risk of acute toxicities, and treatment adherence, which can be particularly problematic in AYAs, they concluded.
Kristen O’Dwyer, MD, and her colleagues, in their article on AML treatment in AYAs, argue that based on “the distinguishing characteristics of AYAs with AML,” neither the pediatric nor adult approaches are ideally suited for them.
Rather, AYA-specific approaches merit consideration, they concluded (Blood 2018;132:362-68).
Similarly, Kieron Dunleavy, MD, and Thomas G. Gross, MD, note in an article on managing aggressive B-cell NHLs in AYAs that a “remarkable divide” in the treatment of patients under age 18 years with lymphoma versus their young adult counterparts underscores the need for collaboration in developing consensus regarding treatment of AYAs (Blood 2018;132:369-75).
But recent findings from a study by Paul C. Nathan, MD, and his colleagues focuses more on where that treatment should take place (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy119).
The study provides new insights into the understanding of treatment differences for adolescents seen in pediatric vs. adult cancer facilities. And the findings suggest that the trade-off for improved outcomes among those treated in the pediatric setting – as emerging literature demonstrates – is higher resource use and cost, Helen M. Parsons, PhD, and her colleagues wrote in an accompanying editorial (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy123).
Among 1,356 patients aged 15-17 years who were diagnosed with cancer between 1996 and 2010, the cost of care was higher when treatment took place in a pediatric setting vs. an adult institution. This was driven in part by higher hospitalization rates and longer hospital stays, the investigators found.
“Additionally, adolescents treated in the pediatric setting tended to seek more [emergency department] care immediately before diagnosis and during the initial treatment phase; these adolescents also used more home care services during initial treatment and survivorship,” Dr. Parsons and her colleagues wrote.
This was true across different diagnoses, including leukemias, lymphomas, sarcomas, and germ cell tumors, but only during the initial treatment phase.
The findings of higher inpatient days in the pediatric setting is not surprising given that induction therapies for pediatric ALL are generally more complex and intensive than therapies commonly used in adults with ALL, and given that pediatric cancer hospitals tend to have a wider array of services, including psychosocial and family support services.
“What is less clear is why individuals seen in pediatric settings have higher rates of ED care directly before diagnosis and during the initial treatment phase ... more work on this topic is needed to more fully understand these patterns,” they wrote, adding that “the finding that adolescents treated in pediatric institutions had higher resource use across diagnostic groups demonstrates that resource utilization may be driven just as much by care setting as diagnosis.”
Disease and developmental biology
As Dr. Hanna noted, biological differences and changes over time suggest that different age groups need varying approaches to treatment and may have different outcomes with the same treatments.
For example, the biology of AML is known to change with age, Dr. Dwyer and her colleagues said, explaining that a recent European study showed that in 5,564 patients with de novo AML, the frequency of favorable cytogenetics was low in infants, increased in children and young adults, and decreased again in middle age and older age (Cancer. 2016 Dec 15;122[24]:3821-30).
“Normal karyotype increases in prevalence from 13.7% in infants to approximately 25% in children, 44% in AYAs, and 50% in adults. Most unfavorable cytogenetic abnormalities are rare across all age groups, though complex cytogenetics are relatively more frequent in infants, decrease in frequency in AYAs, and then increase in frequency beyond AYA,” Dr. Dwyer and her colleagues wrote, noting that it also is becoming more apparent that age influences the presence of AML-related molecular abnormalities.
The authors argue that recognition of age-related differences in disease biology “will provide the best opportunity to improve the clinical outcomes that have been static for decades.”
Dr. Boissel and Dr. Baruchel also note that the “black hole” of understanding of ALL biology in AYAs that characterized the last 15 years has been “nearly brought to light and revealed a continuum between childhood and adult ALL.”
One example of this involves data from the NOPHO-ALL-2008 trial, showing that the proportion of patients with intrachromosomal amplification of the long arm of chromosome 21 (iAMP21), which is a rare event occurring in about 2% of children with ALL, is more frequent in older children and adolescents and is associated with higher relapse risk that is only partially diminished by intensified treatment.
In NOPHO-2008, iAMP21 occurred in 1.5% of patients aged 1-9 years, 5.8% of those aged 10-17 years, and 12% of those aged 17-45 years. The authors provided numerous other examples of such age-related differences in disease biology and concluded that “risk stratification based on recent biology findings and sequential [minimum residual disease] evaluations should now be implemented, as well as new therapeutic options including immunotherapy and targeted therapies, at best within the setting of integrated pediatric and AYA protocols.”
Psychosocial factors
The “financial toxicity” mentioned by Dr. Hanna – the high cost of care, lost work time, and delays in reaching educational and career goals, for example – is a major factor that must be addressed in this population, but there are also many others.
“Cancer is a non-normative event for AYAs. It is extremely disruptive to them physically, psychologically, and vocationally ... and this poses significant challenges,” John M. Salsman, PhD, director of clinical research in AYA oncology at Wake Forest University, Winston-Salem, N.C., said in an interview.
These patients not only have 5-year survival rates that haven’t improved in tandem with those in pediatric and adult populations over the last 3 decades, but in addition to the financial toxicity and strain, they also have higher rates of depression and anxiety, including fear of recurrence, he added.
“Quality of life is incredibly important, and these things need to be addressed because of the developmental changes AYAs are navigating; there are issues of positive body image, family and career decisions ... These are challenging for anyone, and when you throw a cancer diagnosis into the mix they become disproportionately so,” he said.
In a 2014 study, he and his colleagues found that AYAs with cancer had poorer physical and emotional quality of life when compared with matched controls, but better social quality of life. The latter finding was surprising, and highlights the “critical importance” of the social dimension in AYAs’ lives.
“Patient after patient will say ‘I found out who my real friends are,’ ” Dr. Salsman said. “There’s this refinement and deepening of the social network among some posttreatment survivors.”
Dr. Salsman and his colleagues are using those findings to develop interventions that can maximize self care in posttreatment survivorship – a time when AYAs may feel they have a new lease on life and may be more motivated to adhere to recommendations and take care of themselves.
A randomized controlled pilot study incorporating social media apps and other technologies to build on the positive social components of their lives in promoting physical activity interventions, for example, is underway.
Another intervention targets emotional well-being via web-based tools to increase positive affect. A proof-of-concept study showed that the approach is feasible and well received, and efforts are underway to plan a larger-scale randomized controlled trial, he said.
Dr. Salsman also praised the PRISM (Promoting Resilience in Stress Management) tool developed by researchers at Seattle Children’s Hospital.
PRISM was created to help AYAs with cancer and other illnesses learn coping skills to manage stress after their diagnosis, and to boost quality of life beyond treatment. A digital app has also been developed to be used in conjunction with the program.
Trial enrollment
In his editorial introducing the Blood series on AYAs and cancer, Dr. Cortes noted a paucity of clinical trials specifically designed for this population.
“At the time of this writing, I could identify four therapeutic trials registered at www.clinicaltrials.gov that appeared to be somewhat specifically designed for AYAs (some included children also),” he wrote, adding that “enrollment of AYAs in clinical trials in cancer in general has been suboptimal at best.”
The dismal numbers with respect to enrollment of AYAs with cancer in clinical trials may be related in part to treatment setting, Dr. Salsman said.
Data suggest that the majority of AYAs with cancer are treated in community-based practices rather than comprehensive cancer centers, where the bulk of research is being done, he explained.
The bottom line is that more research involving AYAs is needed, as is greater understanding of why enrollment is so much lower among AYA patients, Dr. Hanna said, noting that in 2017, The American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FOCR) released a statement recommending that pediatric patients be considered for enrollment in later-phase trials for cancer types that span both adults and children.
Individuals aged 12 years and older should routinely be included in such trials as their drug metabolism is similar to that of adults, and inclusion of younger patients may also be appropriate if they are part of the population impacted by the disease, depending on specific disease biology, action of the drug, and available safety information, the organizations said.
Officials at the Food and Drug Administration are considering that possibility, Dr. Hanna said.
Attention to the disparities in survival improvements and trial involvement among AYAs with cancer, compared with other age groups, has definitely increased in recent years, Dr. Salsman added, noting that in addition to ASCO and FOCR, several other organizations are working to address the problem.
About 5 years ago, the National Clinical Trials Network formed a working group that developed a number of specific objectives for incorporating more AYAs into cancer trials and finding better ways to study this population; the Institute of Medicine held a forum on the care of AYAs with cancer; and the National Cancer Institute (NCI) held a state-of-the-science meeting that focused on identifying strategic priorities for AYA oncology, he noted.
An article in Cancer provides a summary of the progress toward the priorities identified during the NCI meeting, which convened five working groups to address various topics, including clinical trial enrollment (Cancer. 2016 Apr 1;122[7]:988-99).
Dr. Hanna added that groups such as the Southwest Oncology Group (SWOG) and Children’s Oncology Group (COG) also have AYA committees now.
“One of the success stories of working together between SWOG and COG was the intergroup study C10403 for patients with ALL. And now there are efforts for an intergroup AYA-AML task force to include representatives from each of the cooperative groups that historically coordinated myeloid disease clinical trials – COG, SWOG, Alliance, and ECOG-ACRIN,” he said.
In fact, all of the National Clinical Trials Network groups have some initiative in place to address AYA concerns, said Dr. Salsman, who chairs the ECOG-ACRIN AYA oncology subcommittee.
Despite these efforts, and many others, long-term survival improvements among AYAs with cancer still fall short, compared with those of other age groups.
What’s next?
Among the recommendations of the authors of the AYA series in Blood is a call for assessing AYA-specific therapy in future clinical trials, as well as improved collaboration between adult and pediatric teams with involvement of multidisciplinary teams.
Many centers are already working on models for collaborative care, Dr. Salsman said, citing the Fort Worth AYA Oncology Coalition led by medical director Karen Albritton, MD, as an example of a program that has been successful in “getting stakeholders on the same page, helping them have a shared vision, and working to maximize improvements in outcomes.”
Patients are also taking the lead in demanding better care and attention to their psychosocial needs, Dr. Hanna said. In the case of the community-powered advocacy organization Critical Mass, they succeeded in getting lawmakers to introduce a bill in the U.S. House of Representatives that would allow college students to defer loan payments while undergoing cancer treatment.
and older adult patients, a trend that has been going on for decades. But clinicians and researchers are getting serious about an important question: Why?
“This is a very heterogeneous group of disorders,” Rabi Hanna, MD, a pediatric hematologist and oncologist, and director of pediatric bone marrow transplantation at Cleveland Clinic Children’s Hospital, Ohio, said in an interview.
He is referring to the cancers that affect adolescents and young adults (AYAs), who are broadly defined as patients aged 15-39 years.
“A few cancers, such as [acute lymphoblastic leukemia], are more common in children, and others, such as breast cancer, are more common in adults; biology may be different in the adolescent and young adult patients, which may lead to different outcomes,” Dr. Hanna said.
In addition, the psychosocial needs in this age group differ vastly from those of other groups, he said.
“Many of these patients are in college or have just started their families, so we have to pay attention more to financial toxicities and fertility, for example,” he said.
Another factor that likely contributes to the disparities between AYAs and other populations with cancer is the relative lack of clinical trial involvement among AYAs. That’s a point on which Dr. Hanna and many other experts agree.
A recent series of articles published in Blood addressed these and other issues, including whether AYAs with ALL or aggressive B-cell non-Hodgkin lymphomas (NHLs) should be treated as children or adults, treatment strategies for those with acute myeloid leukemias, management of Hodgkin lymphoma, and psychosocial challenges and health-related quality of life (QOL) of AYAs with hematologic malignancies.
“Hematological malignancies occurring in AYAs represent a unique challenge because of their special biological features and distinctive therapeutic requirements, as well as the unique medical, social, and psychological characteristics of this patient population,” Jorge Cortes, MD, an assistant editor for Blood, wrote in an introduction to the series.
“Unfortunately, not much has been done to explore unique molecular and biological features of AYA hematologic malignancies. The discussion on the management of AYAs frequently centers on whether these patients should be treated in a pediatric setting or an adult setting, or with regimens designed for children or for adults. Clinical trials specifically designed for AYAs are scanty,” noted Dr. Cortes, who directs the chronic myeloid leukemia (CML) and acute myeloid leukemia programs (AML) at the University of Texas MD Anderson Cancer Center, Houston.
Treatment approach and setting
In the Blood article on ALL in AYAs, Nicolas Boissel, MD, and André Baruchel, MD, note that the use of “fully pediatric protocols” in patients aged 15-20 years is supported by numerous studies, and that in young adults, evidence increasingly supports “pediatric-inspired or even fully pediatric approaches” as they have been shown to dramatically improve outcomes, with long-term survival rates nearing 70% (2018;132:351-61).
Patients in these age groups require specific programs that take into account factors such as care access and trial access, increased risk of acute toxicities, and treatment adherence, which can be particularly problematic in AYAs, they concluded.
Kristen O’Dwyer, MD, and her colleagues, in their article on AML treatment in AYAs, argue that based on “the distinguishing characteristics of AYAs with AML,” neither the pediatric nor adult approaches are ideally suited for them.
Rather, AYA-specific approaches merit consideration, they concluded (Blood 2018;132:362-68).
Similarly, Kieron Dunleavy, MD, and Thomas G. Gross, MD, note in an article on managing aggressive B-cell NHLs in AYAs that a “remarkable divide” in the treatment of patients under age 18 years with lymphoma versus their young adult counterparts underscores the need for collaboration in developing consensus regarding treatment of AYAs (Blood 2018;132:369-75).
But recent findings from a study by Paul C. Nathan, MD, and his colleagues focuses more on where that treatment should take place (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy119).
The study provides new insights into the understanding of treatment differences for adolescents seen in pediatric vs. adult cancer facilities. And the findings suggest that the trade-off for improved outcomes among those treated in the pediatric setting – as emerging literature demonstrates – is higher resource use and cost, Helen M. Parsons, PhD, and her colleagues wrote in an accompanying editorial (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy123).
Among 1,356 patients aged 15-17 years who were diagnosed with cancer between 1996 and 2010, the cost of care was higher when treatment took place in a pediatric setting vs. an adult institution. This was driven in part by higher hospitalization rates and longer hospital stays, the investigators found.
“Additionally, adolescents treated in the pediatric setting tended to seek more [emergency department] care immediately before diagnosis and during the initial treatment phase; these adolescents also used more home care services during initial treatment and survivorship,” Dr. Parsons and her colleagues wrote.
This was true across different diagnoses, including leukemias, lymphomas, sarcomas, and germ cell tumors, but only during the initial treatment phase.
The findings of higher inpatient days in the pediatric setting is not surprising given that induction therapies for pediatric ALL are generally more complex and intensive than therapies commonly used in adults with ALL, and given that pediatric cancer hospitals tend to have a wider array of services, including psychosocial and family support services.
“What is less clear is why individuals seen in pediatric settings have higher rates of ED care directly before diagnosis and during the initial treatment phase ... more work on this topic is needed to more fully understand these patterns,” they wrote, adding that “the finding that adolescents treated in pediatric institutions had higher resource use across diagnostic groups demonstrates that resource utilization may be driven just as much by care setting as diagnosis.”
Disease and developmental biology
As Dr. Hanna noted, biological differences and changes over time suggest that different age groups need varying approaches to treatment and may have different outcomes with the same treatments.
For example, the biology of AML is known to change with age, Dr. Dwyer and her colleagues said, explaining that a recent European study showed that in 5,564 patients with de novo AML, the frequency of favorable cytogenetics was low in infants, increased in children and young adults, and decreased again in middle age and older age (Cancer. 2016 Dec 15;122[24]:3821-30).
“Normal karyotype increases in prevalence from 13.7% in infants to approximately 25% in children, 44% in AYAs, and 50% in adults. Most unfavorable cytogenetic abnormalities are rare across all age groups, though complex cytogenetics are relatively more frequent in infants, decrease in frequency in AYAs, and then increase in frequency beyond AYA,” Dr. Dwyer and her colleagues wrote, noting that it also is becoming more apparent that age influences the presence of AML-related molecular abnormalities.
The authors argue that recognition of age-related differences in disease biology “will provide the best opportunity to improve the clinical outcomes that have been static for decades.”
Dr. Boissel and Dr. Baruchel also note that the “black hole” of understanding of ALL biology in AYAs that characterized the last 15 years has been “nearly brought to light and revealed a continuum between childhood and adult ALL.”
One example of this involves data from the NOPHO-ALL-2008 trial, showing that the proportion of patients with intrachromosomal amplification of the long arm of chromosome 21 (iAMP21), which is a rare event occurring in about 2% of children with ALL, is more frequent in older children and adolescents and is associated with higher relapse risk that is only partially diminished by intensified treatment.
In NOPHO-2008, iAMP21 occurred in 1.5% of patients aged 1-9 years, 5.8% of those aged 10-17 years, and 12% of those aged 17-45 years. The authors provided numerous other examples of such age-related differences in disease biology and concluded that “risk stratification based on recent biology findings and sequential [minimum residual disease] evaluations should now be implemented, as well as new therapeutic options including immunotherapy and targeted therapies, at best within the setting of integrated pediatric and AYA protocols.”
Psychosocial factors
The “financial toxicity” mentioned by Dr. Hanna – the high cost of care, lost work time, and delays in reaching educational and career goals, for example – is a major factor that must be addressed in this population, but there are also many others.
“Cancer is a non-normative event for AYAs. It is extremely disruptive to them physically, psychologically, and vocationally ... and this poses significant challenges,” John M. Salsman, PhD, director of clinical research in AYA oncology at Wake Forest University, Winston-Salem, N.C., said in an interview.
These patients not only have 5-year survival rates that haven’t improved in tandem with those in pediatric and adult populations over the last 3 decades, but in addition to the financial toxicity and strain, they also have higher rates of depression and anxiety, including fear of recurrence, he added.
“Quality of life is incredibly important, and these things need to be addressed because of the developmental changes AYAs are navigating; there are issues of positive body image, family and career decisions ... These are challenging for anyone, and when you throw a cancer diagnosis into the mix they become disproportionately so,” he said.
In a 2014 study, he and his colleagues found that AYAs with cancer had poorer physical and emotional quality of life when compared with matched controls, but better social quality of life. The latter finding was surprising, and highlights the “critical importance” of the social dimension in AYAs’ lives.
“Patient after patient will say ‘I found out who my real friends are,’ ” Dr. Salsman said. “There’s this refinement and deepening of the social network among some posttreatment survivors.”
Dr. Salsman and his colleagues are using those findings to develop interventions that can maximize self care in posttreatment survivorship – a time when AYAs may feel they have a new lease on life and may be more motivated to adhere to recommendations and take care of themselves.
A randomized controlled pilot study incorporating social media apps and other technologies to build on the positive social components of their lives in promoting physical activity interventions, for example, is underway.
Another intervention targets emotional well-being via web-based tools to increase positive affect. A proof-of-concept study showed that the approach is feasible and well received, and efforts are underway to plan a larger-scale randomized controlled trial, he said.
Dr. Salsman also praised the PRISM (Promoting Resilience in Stress Management) tool developed by researchers at Seattle Children’s Hospital.
PRISM was created to help AYAs with cancer and other illnesses learn coping skills to manage stress after their diagnosis, and to boost quality of life beyond treatment. A digital app has also been developed to be used in conjunction with the program.
Trial enrollment
In his editorial introducing the Blood series on AYAs and cancer, Dr. Cortes noted a paucity of clinical trials specifically designed for this population.
“At the time of this writing, I could identify four therapeutic trials registered at www.clinicaltrials.gov that appeared to be somewhat specifically designed for AYAs (some included children also),” he wrote, adding that “enrollment of AYAs in clinical trials in cancer in general has been suboptimal at best.”
The dismal numbers with respect to enrollment of AYAs with cancer in clinical trials may be related in part to treatment setting, Dr. Salsman said.
Data suggest that the majority of AYAs with cancer are treated in community-based practices rather than comprehensive cancer centers, where the bulk of research is being done, he explained.
The bottom line is that more research involving AYAs is needed, as is greater understanding of why enrollment is so much lower among AYA patients, Dr. Hanna said, noting that in 2017, The American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FOCR) released a statement recommending that pediatric patients be considered for enrollment in later-phase trials for cancer types that span both adults and children.
Individuals aged 12 years and older should routinely be included in such trials as their drug metabolism is similar to that of adults, and inclusion of younger patients may also be appropriate if they are part of the population impacted by the disease, depending on specific disease biology, action of the drug, and available safety information, the organizations said.
Officials at the Food and Drug Administration are considering that possibility, Dr. Hanna said.
Attention to the disparities in survival improvements and trial involvement among AYAs with cancer, compared with other age groups, has definitely increased in recent years, Dr. Salsman added, noting that in addition to ASCO and FOCR, several other organizations are working to address the problem.
About 5 years ago, the National Clinical Trials Network formed a working group that developed a number of specific objectives for incorporating more AYAs into cancer trials and finding better ways to study this population; the Institute of Medicine held a forum on the care of AYAs with cancer; and the National Cancer Institute (NCI) held a state-of-the-science meeting that focused on identifying strategic priorities for AYA oncology, he noted.
An article in Cancer provides a summary of the progress toward the priorities identified during the NCI meeting, which convened five working groups to address various topics, including clinical trial enrollment (Cancer. 2016 Apr 1;122[7]:988-99).
Dr. Hanna added that groups such as the Southwest Oncology Group (SWOG) and Children’s Oncology Group (COG) also have AYA committees now.
“One of the success stories of working together between SWOG and COG was the intergroup study C10403 for patients with ALL. And now there are efforts for an intergroup AYA-AML task force to include representatives from each of the cooperative groups that historically coordinated myeloid disease clinical trials – COG, SWOG, Alliance, and ECOG-ACRIN,” he said.
In fact, all of the National Clinical Trials Network groups have some initiative in place to address AYA concerns, said Dr. Salsman, who chairs the ECOG-ACRIN AYA oncology subcommittee.
Despite these efforts, and many others, long-term survival improvements among AYAs with cancer still fall short, compared with those of other age groups.
What’s next?
Among the recommendations of the authors of the AYA series in Blood is a call for assessing AYA-specific therapy in future clinical trials, as well as improved collaboration between adult and pediatric teams with involvement of multidisciplinary teams.
Many centers are already working on models for collaborative care, Dr. Salsman said, citing the Fort Worth AYA Oncology Coalition led by medical director Karen Albritton, MD, as an example of a program that has been successful in “getting stakeholders on the same page, helping them have a shared vision, and working to maximize improvements in outcomes.”
Patients are also taking the lead in demanding better care and attention to their psychosocial needs, Dr. Hanna said. In the case of the community-powered advocacy organization Critical Mass, they succeeded in getting lawmakers to introduce a bill in the U.S. House of Representatives that would allow college students to defer loan payments while undergoing cancer treatment.
and older adult patients, a trend that has been going on for decades. But clinicians and researchers are getting serious about an important question: Why?
“This is a very heterogeneous group of disorders,” Rabi Hanna, MD, a pediatric hematologist and oncologist, and director of pediatric bone marrow transplantation at Cleveland Clinic Children’s Hospital, Ohio, said in an interview.
He is referring to the cancers that affect adolescents and young adults (AYAs), who are broadly defined as patients aged 15-39 years.
“A few cancers, such as [acute lymphoblastic leukemia], are more common in children, and others, such as breast cancer, are more common in adults; biology may be different in the adolescent and young adult patients, which may lead to different outcomes,” Dr. Hanna said.
In addition, the psychosocial needs in this age group differ vastly from those of other groups, he said.
“Many of these patients are in college or have just started their families, so we have to pay attention more to financial toxicities and fertility, for example,” he said.
Another factor that likely contributes to the disparities between AYAs and other populations with cancer is the relative lack of clinical trial involvement among AYAs. That’s a point on which Dr. Hanna and many other experts agree.
A recent series of articles published in Blood addressed these and other issues, including whether AYAs with ALL or aggressive B-cell non-Hodgkin lymphomas (NHLs) should be treated as children or adults, treatment strategies for those with acute myeloid leukemias, management of Hodgkin lymphoma, and psychosocial challenges and health-related quality of life (QOL) of AYAs with hematologic malignancies.
“Hematological malignancies occurring in AYAs represent a unique challenge because of their special biological features and distinctive therapeutic requirements, as well as the unique medical, social, and psychological characteristics of this patient population,” Jorge Cortes, MD, an assistant editor for Blood, wrote in an introduction to the series.
“Unfortunately, not much has been done to explore unique molecular and biological features of AYA hematologic malignancies. The discussion on the management of AYAs frequently centers on whether these patients should be treated in a pediatric setting or an adult setting, or with regimens designed for children or for adults. Clinical trials specifically designed for AYAs are scanty,” noted Dr. Cortes, who directs the chronic myeloid leukemia (CML) and acute myeloid leukemia programs (AML) at the University of Texas MD Anderson Cancer Center, Houston.
Treatment approach and setting
In the Blood article on ALL in AYAs, Nicolas Boissel, MD, and André Baruchel, MD, note that the use of “fully pediatric protocols” in patients aged 15-20 years is supported by numerous studies, and that in young adults, evidence increasingly supports “pediatric-inspired or even fully pediatric approaches” as they have been shown to dramatically improve outcomes, with long-term survival rates nearing 70% (2018;132:351-61).
Patients in these age groups require specific programs that take into account factors such as care access and trial access, increased risk of acute toxicities, and treatment adherence, which can be particularly problematic in AYAs, they concluded.
Kristen O’Dwyer, MD, and her colleagues, in their article on AML treatment in AYAs, argue that based on “the distinguishing characteristics of AYAs with AML,” neither the pediatric nor adult approaches are ideally suited for them.
Rather, AYA-specific approaches merit consideration, they concluded (Blood 2018;132:362-68).
Similarly, Kieron Dunleavy, MD, and Thomas G. Gross, MD, note in an article on managing aggressive B-cell NHLs in AYAs that a “remarkable divide” in the treatment of patients under age 18 years with lymphoma versus their young adult counterparts underscores the need for collaboration in developing consensus regarding treatment of AYAs (Blood 2018;132:369-75).
But recent findings from a study by Paul C. Nathan, MD, and his colleagues focuses more on where that treatment should take place (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy119).
The study provides new insights into the understanding of treatment differences for adolescents seen in pediatric vs. adult cancer facilities. And the findings suggest that the trade-off for improved outcomes among those treated in the pediatric setting – as emerging literature demonstrates – is higher resource use and cost, Helen M. Parsons, PhD, and her colleagues wrote in an accompanying editorial (J Natl Cancer Inst. 2018 Jul 19. doi: 10.1093/jnci/djy123).
Among 1,356 patients aged 15-17 years who were diagnosed with cancer between 1996 and 2010, the cost of care was higher when treatment took place in a pediatric setting vs. an adult institution. This was driven in part by higher hospitalization rates and longer hospital stays, the investigators found.
“Additionally, adolescents treated in the pediatric setting tended to seek more [emergency department] care immediately before diagnosis and during the initial treatment phase; these adolescents also used more home care services during initial treatment and survivorship,” Dr. Parsons and her colleagues wrote.
This was true across different diagnoses, including leukemias, lymphomas, sarcomas, and germ cell tumors, but only during the initial treatment phase.
The findings of higher inpatient days in the pediatric setting is not surprising given that induction therapies for pediatric ALL are generally more complex and intensive than therapies commonly used in adults with ALL, and given that pediatric cancer hospitals tend to have a wider array of services, including psychosocial and family support services.
“What is less clear is why individuals seen in pediatric settings have higher rates of ED care directly before diagnosis and during the initial treatment phase ... more work on this topic is needed to more fully understand these patterns,” they wrote, adding that “the finding that adolescents treated in pediatric institutions had higher resource use across diagnostic groups demonstrates that resource utilization may be driven just as much by care setting as diagnosis.”
Disease and developmental biology
As Dr. Hanna noted, biological differences and changes over time suggest that different age groups need varying approaches to treatment and may have different outcomes with the same treatments.
For example, the biology of AML is known to change with age, Dr. Dwyer and her colleagues said, explaining that a recent European study showed that in 5,564 patients with de novo AML, the frequency of favorable cytogenetics was low in infants, increased in children and young adults, and decreased again in middle age and older age (Cancer. 2016 Dec 15;122[24]:3821-30).
“Normal karyotype increases in prevalence from 13.7% in infants to approximately 25% in children, 44% in AYAs, and 50% in adults. Most unfavorable cytogenetic abnormalities are rare across all age groups, though complex cytogenetics are relatively more frequent in infants, decrease in frequency in AYAs, and then increase in frequency beyond AYA,” Dr. Dwyer and her colleagues wrote, noting that it also is becoming more apparent that age influences the presence of AML-related molecular abnormalities.
The authors argue that recognition of age-related differences in disease biology “will provide the best opportunity to improve the clinical outcomes that have been static for decades.”
Dr. Boissel and Dr. Baruchel also note that the “black hole” of understanding of ALL biology in AYAs that characterized the last 15 years has been “nearly brought to light and revealed a continuum between childhood and adult ALL.”
One example of this involves data from the NOPHO-ALL-2008 trial, showing that the proportion of patients with intrachromosomal amplification of the long arm of chromosome 21 (iAMP21), which is a rare event occurring in about 2% of children with ALL, is more frequent in older children and adolescents and is associated with higher relapse risk that is only partially diminished by intensified treatment.
In NOPHO-2008, iAMP21 occurred in 1.5% of patients aged 1-9 years, 5.8% of those aged 10-17 years, and 12% of those aged 17-45 years. The authors provided numerous other examples of such age-related differences in disease biology and concluded that “risk stratification based on recent biology findings and sequential [minimum residual disease] evaluations should now be implemented, as well as new therapeutic options including immunotherapy and targeted therapies, at best within the setting of integrated pediatric and AYA protocols.”
Psychosocial factors
The “financial toxicity” mentioned by Dr. Hanna – the high cost of care, lost work time, and delays in reaching educational and career goals, for example – is a major factor that must be addressed in this population, but there are also many others.
“Cancer is a non-normative event for AYAs. It is extremely disruptive to them physically, psychologically, and vocationally ... and this poses significant challenges,” John M. Salsman, PhD, director of clinical research in AYA oncology at Wake Forest University, Winston-Salem, N.C., said in an interview.
These patients not only have 5-year survival rates that haven’t improved in tandem with those in pediatric and adult populations over the last 3 decades, but in addition to the financial toxicity and strain, they also have higher rates of depression and anxiety, including fear of recurrence, he added.
“Quality of life is incredibly important, and these things need to be addressed because of the developmental changes AYAs are navigating; there are issues of positive body image, family and career decisions ... These are challenging for anyone, and when you throw a cancer diagnosis into the mix they become disproportionately so,” he said.
In a 2014 study, he and his colleagues found that AYAs with cancer had poorer physical and emotional quality of life when compared with matched controls, but better social quality of life. The latter finding was surprising, and highlights the “critical importance” of the social dimension in AYAs’ lives.
“Patient after patient will say ‘I found out who my real friends are,’ ” Dr. Salsman said. “There’s this refinement and deepening of the social network among some posttreatment survivors.”
Dr. Salsman and his colleagues are using those findings to develop interventions that can maximize self care in posttreatment survivorship – a time when AYAs may feel they have a new lease on life and may be more motivated to adhere to recommendations and take care of themselves.
A randomized controlled pilot study incorporating social media apps and other technologies to build on the positive social components of their lives in promoting physical activity interventions, for example, is underway.
Another intervention targets emotional well-being via web-based tools to increase positive affect. A proof-of-concept study showed that the approach is feasible and well received, and efforts are underway to plan a larger-scale randomized controlled trial, he said.
Dr. Salsman also praised the PRISM (Promoting Resilience in Stress Management) tool developed by researchers at Seattle Children’s Hospital.
PRISM was created to help AYAs with cancer and other illnesses learn coping skills to manage stress after their diagnosis, and to boost quality of life beyond treatment. A digital app has also been developed to be used in conjunction with the program.
Trial enrollment
In his editorial introducing the Blood series on AYAs and cancer, Dr. Cortes noted a paucity of clinical trials specifically designed for this population.
“At the time of this writing, I could identify four therapeutic trials registered at www.clinicaltrials.gov that appeared to be somewhat specifically designed for AYAs (some included children also),” he wrote, adding that “enrollment of AYAs in clinical trials in cancer in general has been suboptimal at best.”
The dismal numbers with respect to enrollment of AYAs with cancer in clinical trials may be related in part to treatment setting, Dr. Salsman said.
Data suggest that the majority of AYAs with cancer are treated in community-based practices rather than comprehensive cancer centers, where the bulk of research is being done, he explained.
The bottom line is that more research involving AYAs is needed, as is greater understanding of why enrollment is so much lower among AYA patients, Dr. Hanna said, noting that in 2017, The American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (FOCR) released a statement recommending that pediatric patients be considered for enrollment in later-phase trials for cancer types that span both adults and children.
Individuals aged 12 years and older should routinely be included in such trials as their drug metabolism is similar to that of adults, and inclusion of younger patients may also be appropriate if they are part of the population impacted by the disease, depending on specific disease biology, action of the drug, and available safety information, the organizations said.
Officials at the Food and Drug Administration are considering that possibility, Dr. Hanna said.
Attention to the disparities in survival improvements and trial involvement among AYAs with cancer, compared with other age groups, has definitely increased in recent years, Dr. Salsman added, noting that in addition to ASCO and FOCR, several other organizations are working to address the problem.
About 5 years ago, the National Clinical Trials Network formed a working group that developed a number of specific objectives for incorporating more AYAs into cancer trials and finding better ways to study this population; the Institute of Medicine held a forum on the care of AYAs with cancer; and the National Cancer Institute (NCI) held a state-of-the-science meeting that focused on identifying strategic priorities for AYA oncology, he noted.
An article in Cancer provides a summary of the progress toward the priorities identified during the NCI meeting, which convened five working groups to address various topics, including clinical trial enrollment (Cancer. 2016 Apr 1;122[7]:988-99).
Dr. Hanna added that groups such as the Southwest Oncology Group (SWOG) and Children’s Oncology Group (COG) also have AYA committees now.
“One of the success stories of working together between SWOG and COG was the intergroup study C10403 for patients with ALL. And now there are efforts for an intergroup AYA-AML task force to include representatives from each of the cooperative groups that historically coordinated myeloid disease clinical trials – COG, SWOG, Alliance, and ECOG-ACRIN,” he said.
In fact, all of the National Clinical Trials Network groups have some initiative in place to address AYA concerns, said Dr. Salsman, who chairs the ECOG-ACRIN AYA oncology subcommittee.
Despite these efforts, and many others, long-term survival improvements among AYAs with cancer still fall short, compared with those of other age groups.
What’s next?
Among the recommendations of the authors of the AYA series in Blood is a call for assessing AYA-specific therapy in future clinical trials, as well as improved collaboration between adult and pediatric teams with involvement of multidisciplinary teams.
Many centers are already working on models for collaborative care, Dr. Salsman said, citing the Fort Worth AYA Oncology Coalition led by medical director Karen Albritton, MD, as an example of a program that has been successful in “getting stakeholders on the same page, helping them have a shared vision, and working to maximize improvements in outcomes.”
Patients are also taking the lead in demanding better care and attention to their psychosocial needs, Dr. Hanna said. In the case of the community-powered advocacy organization Critical Mass, they succeeded in getting lawmakers to introduce a bill in the U.S. House of Representatives that would allow college students to defer loan payments while undergoing cancer treatment.
Bacteremic sepsis in ALL linked to later cognitive issues
Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.
Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.
Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.
“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.
The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.
Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.
As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.
Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.
Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.
This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.
Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.
Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.
The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.
SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.
Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.
Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.
Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.
“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.
The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.
Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.
As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.
Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.
Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.
This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.
Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.
Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.
The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.
SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.
Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.
Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.
Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.
“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.
The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.
Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.
As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.
Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.
Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.
This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.
Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.
Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.
The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.
SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.
FROM JAMA PEDIATRICS
Key clinical point:
Major finding: ALL survivors with a sepsis history performed worse than did those with no sepsis history on evaluations of spatial planning (difference, 0.78), verbal fluency (0.38), and attention (0.63).
Study details: Prospective cohort study of 212 ALL survivors who underwent neurocognitive testing at a median of nearly 8 years after diagnosis.
Disclosures: The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.
Source: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.