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Entinostat doesn’t overcome endocrine resistance in advanced breast cancer
The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.
These results were reported at the 2020 San Antonio Breast Cancer Symposium.
“Clearly, we were very disappointed with these results after so many years of work,” said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.
“I think we’ve realized again the importance of phase 3 confirmation of promising phase 2 data,” she said, referring to results of the phase 2 ENCORE 301 trial.
“I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses,” Dr. Connolly said.
Why HDAC inhibitors in advanced breast cancer?
“Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem,” Dr. Connolly said.
One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.
Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.
Phase 3 trial details and results
The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.
The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.
A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.
“I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112,” Dr. Connolly said, observing that the study started in 2014 before the use of these drugs was really established.
Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).
The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).
The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.
Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).
There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.
Implications and next steps
“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.
“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.
Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”
When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”
Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.
“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”
The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.
The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.
These results were reported at the 2020 San Antonio Breast Cancer Symposium.
“Clearly, we were very disappointed with these results after so many years of work,” said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.
“I think we’ve realized again the importance of phase 3 confirmation of promising phase 2 data,” she said, referring to results of the phase 2 ENCORE 301 trial.
“I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses,” Dr. Connolly said.
Why HDAC inhibitors in advanced breast cancer?
“Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem,” Dr. Connolly said.
One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.
Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.
Phase 3 trial details and results
The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.
The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.
A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.
“I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112,” Dr. Connolly said, observing that the study started in 2014 before the use of these drugs was really established.
Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).
The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).
The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.
Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).
There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.
Implications and next steps
“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.
“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.
Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”
When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”
Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.
“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”
The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.
The study showed no difference in response, progression-free survival, or overall survival whether entinostat was added to exemestane or exemestane was given with placebo.
These results were reported at the 2020 San Antonio Breast Cancer Symposium.
“Clearly, we were very disappointed with these results after so many years of work,” said study investigator Roisin M. Connolly, MD, of University College Cork (Ireland) and Cork University Hospital in Wilton, Ireland.
“I think we’ve realized again the importance of phase 3 confirmation of promising phase 2 data,” she said, referring to results of the phase 2 ENCORE 301 trial.
“I think that the results speak for themselves. In this population of endocrine-resistant patients, the HDAC inhibitors clearly do not have a role unless we find something further on additional review of the correlative analyses,” Dr. Connolly said.
Why HDAC inhibitors in advanced breast cancer?
“Despite many advances in breast cancer in recent decades, resistance to endocrine therapy remains a significant clinical problem,” Dr. Connolly said.
One suggested approach to overcoming this resistance is to block the overacetylation of histones using HDAC inhibitors. This has been shown in preclinical studies with entinostat to inhibit growth factor signaling pathways and normalize the expression of the estrogen receptor, helping to overcome resistance to aromatase inhibitors in letrozole-resistant mouse models.
Results from the phase 2 ENCORE 301 trial, published in the Journal of Clinical Oncology, also suggested this approach could be effective. There was a 2-month improvement in progression-free survival and an 8.3-month improvement in overall survival when entinostat was added to exemestane.
Phase 3 trial details and results
The E2112 study enrolled 608 women with hormone receptor–positive, HER2-negative advanced breast cancer, 85% of whom had experienced progression after taking a nonsteroidal aromatase inhibitor in the metastatic setting.
The type of endocrine resistance, such as if ESR1 mutations were present, was not determined. Tissue samples and blood samples have been archived, so this might be a question that is investigated later on.
A quarter of patients had received one prior chemotherapy regimen for metastatic disease, around 30% had been treated with fulvestrant, and about a third of patients had received a CDK4/6 inhibitor.
“I think we had representation from both patients who did receive and did not receive a prior CDK4/6 inhibitor within E2112,” Dr. Connolly said, observing that the study started in 2014 before the use of these drugs was really established.
Patients were randomized to receive entinostat (5 mg daily) plus exemestane (25 mg daily) or exemestane plus placebo (at the same dose).
The median progression-free survival was 3.3 months in the entinostat arm and 3.1 months in the placebo arm (hazard ratio, 0.87; P = .30).
The median overall survival was 23.4 months with entinostat and 21.7 months with placebo (HR, 0.99; P = .94). The overall response rates were a respective 4.6% and 4.3%.
Grade 3/4 adverse events were more frequent in the entinostat arm. The most common were neutropenia (20% with entinostat vs. <1% with placebo), hypophosphatemia (14% vs. 1%), and anemia (8% vs. 2%).
There were three treatment-related deaths (heart failure, pneumonitis, and hepatic failure) in the entinostat arm and one (MI) in the placebo arm.
Implications and next steps
“The study is completely negative, with no benefit in progression-free or overall survival,” commented Hal Burstein, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, both in Boston, who was not involved in the study.
“It is unclear that this is a good clinical approach for further trials in advanced breast cancer, as correlative studies suggest the drug did hit the target,” he added.
Dr. Burstein’s takeaway was that “HDAC inhibition is stuck in a cul-de-sac, if not a complete dead end, for breast cancer.”
When asked if using a different aromatase inhibitor than exemestane might have affected the results, Dr. Connolly said that “it’s possible, but I think it’s unlikely.”
Exemestane was used in the phase 3 trial because it had been used in the ENCORE 301 study. Preclinical work had shown that both letrozole- and exemestane-resistant models benefited from the addition of an HDAC inhibitor.
“There is ongoing investigation of HDAC inhibitors in various combinations,” Dr. Connolly said. “HDAC inhibitors have been used with chemotherapies and other targeted therapies over the years but unfortunately have not broken into the solid tumor space. I think that ongoing work will be required to see where these may fit in the future.”
The E2122 study was coordinated by the ECOG-ACRIN Cancer Research Group with funding from the National Institutes of Health. Dr. Connolly disclosed relationships with Genentech, Merck, Novartis, Puma Biotechnology, Marcogenics, and Pfizer. Dr. Burstein had no relevant disclosures.
FROM SABCS 2020
Bedside EEG test aids prognosis in patients with brain injury
results of a new study suggest. The study showed that the use of a paradigm that measures the strength of responses to speech improved the accuracy of prognosis for these patients, compared with prognoses made solely on the basis of standard clinical characteristics.
“What we found is really compelling evidence” of the usefulness of the test, lead study author Rodika Sokoliuk, PhD, a postdoctoral researcher at the Center for Human Brain Health, University of Birmingham (England), said in an interview.
The passive measure of comprehension, which doesn’t require any other response from the patient, can reduce uncertainty at a critical phase of decision-making in the ICU, said Dr. Sokoliuk.
The study was published online Dec. 23, 2020, in Annals of Neurology.
Useful information at a time of ‘considerable prognostic uncertainty’
Accurate, early prognostication is vital for efficient stratification of patients after a TBI, the authors wrote. This can often be achieved from patient behavior and CT at admission, but some patients continue to fail to obey commands after washout of sedation.
These patients pose a significant challenge for neurologic prognostication, they noted. In these cases, clinicians and families must decide whether to “wait and see” or consider treatment withdrawal.
The authors noted that a lack of command following early in the postsedation period is associated with poor outcome, including vegetative state/unresponsive wakefulness syndrome (VS/UWS). This, they said, represents a “window of opportunity” for cessation of life-sustaining therapy at a time of considerable prognostic uncertainty.
Recent research shows that a significant proportion of unresponsive patients retain a level of cognition, and even consciousness, that isn’t evident from their external behavior – the so-called cognitive-motor dissociation.
The new study included 28 adult patients who had experienced a TBI and were admitted to the ICU of the Queen Elizabeth Hospital in Birmingham, England. The patients had a Glasgow Coma Scale motor score less than 6 (i.e., they were incapable of obeying commands). They had been sedation free for 2-7 days.
For the paradigm, researchers constructed 288 English words using the male voice of the Apple synthesizer. The words required the same amount of time to be generated (320 ms) and were monosyllabic, so the rhythms of the sounds were the same.
The words were presented in a specific order: an adjective, then a noun, then a verb, then a noun. Two words – for example, an adjective and noun – “would build a meaningful phrase,” and four words would build a sentence, said Dr. Sokoliuk.
The researchers built 72 of these four-word sentences. A trial comprised 12 of these sentences, resulting in a total of 864 four-word sentences.
Dr. Sokoliuk likened the paradigm to a rap song with a specific beat that is continually repeated. “Basically, we play 12 of these four-word sentences in a row, without any gaps,” she said.
Each sentence was played to patients, in random order, a minimum of eight and a maximum of nine times per patient throughout the experiment. The patients’ brain activity was recorded on EEG.
Dr. Sokoliuk noted that brain activity in healthy people synchronizes only with the rhythm of phrases and sentences when listeners consciously comprehend the speech. The researchers assessed the level of comprehension in the unresponsive patients by measuring the strength of this synchronicity or brain pattern.
After exclusions, 17 patients were available for outcome assessment 3 months post EEG, and 16 patients were available 6 months post EEG.
The analysis showed that outcome significantly correlated with the strength of patients’ acute cortical tracking of phrases and sentences (r > 0.6; P < .007), quantified by intertrial phase coherence.
Linear regressions revealed that the strength of this comprehension response (beta, 0.603; P = .006) significantly improved the accuracy of prognoses relative to clinical characteristics alone, such as the Glasgow Coma Scale or CT grade.
Previous studies showed that, if there is no understanding of the language used or if the subject is asleep, the brain doesn’t have the “signature” of tracking phrases and sentences, so it doesn’t have the synchronicity or the pattern of individuals with normal cognition, said Dr. Sokoliuk.
“You need a certain level of consciousness, and you need to understand the language, so your brain can actually track sentences or phrases,” she said.
Dr. Sokoliuk explained that the paradigm shows that patients are understanding the sentences and are not just hearing them.
“It’s not showing us that they only hear it, because there are no obvious gaps between the sentences; if there were gaps between sentences, it would probably only show that they hear it. It could be both, that they hear and understand it, but we wouldn’t know.”
A receiver operating characteristics analysis indicated 100% sensitivity and 80% specificity for a distinction between bad outcome (death, VS/UWS) and good outcome at 6 months.
“We could actually define a threshold of the tracking,” said Dr. Sokoliuk. “Patients who had phrases and sentences tracking below this threshold had worse outcome than those whose tracking value was above this threshold.”
The study illustrates that some posttraumatic patients who remain in an unresponsive state despite being sedation free may nevertheless comprehend speech.
The EEG paradigm approach, the authors said, may significantly reduce prognostic uncertainty in a critical phase of medical decision-making. It could also help clinicians make more appropriate decisions about whether or not to continue life-sustaining therapy and ensure more appropriate distribution of limited rehabilitation resources to patients most likely to benefit.
Dr. Sokoliuk stressed that the paradigm could be used at the bedside soon after a brain injury. “The critical thing is, we can actually use it during the acute phase, which is very important for clinical decisions about life-sustaining methods, therapy, and long-term care.”
A prognostic tool
The simple approach promises to be more accessible than fMRI, said Dr. Sokoliuk. “Putting an unresponsive coma patient in a scanner is very difficult and also much more expensive,” she said.
The next step, said Dr. Sokoliuk, is to repeat the study with a larger sample. “The number in the current study was quite small, and we can’t say if the sensitivity of the paradigm is strong enough to use it as a standard prognostic tool.”
To use it in clinical setting, “we really have to have robust measures,” she added.
She aims to conduct a collaborative study involving several institutions and more patients.
The research team plans to eventually build “an open-access toolbox” that would include the auditory streams to be played during EEG recordings and a program to analyze the data, said Dr. Sokoliuk. “Then, in the end, you would get a threshold or a value of tracking for phrases and sentences, and this could then classify a patient to be in a good-outcome or in bad-outcome group.”
She stressed this is a prognostic tool, not a diagnostic tool, and it should not be used in isolation. “It’s important to know that no clinician should only use this paradigm to prognosticate a patient; our paradigm should be part of a bigger battery of tests.”
But it could go a long way toward helping families as well as physicians. “If they know that the patient would be better in 3 months’ time, it’s easier for them to decide what should come next,” she said.
And it’s heartening to know that when families talk to their unresponsive loved one, the patient understands them, she added.
Promising basic research
Commenting on the study in an interview, Christine Blume, PhD, of the Center for Chronobiology, University of Basel (Switzerland), whose research interests include cognitive processing of patients with disorders of consciousness, described it as “very elegant and appealing” and the paradigm it used as “really promising.”
“However, we do, of course, not yet know about the prognostic value on a single-subject level, as the authors performed only group analyses,” said Dr. Blume. “This will require more extensive and perhaps even multicenter studies.”
It would also require developing a “solution” that “allows clinicians with limited time resources and perhaps lacking expert knowledge on the paradigm and the necessary analyses to apply the paradigm at bedside,” said Dr. Blume.
She agreed that a passive paradigm that helps determine whether a patient consciously understands speech, without the need for further processing, “has the potential to really improve the diagnostic process and uncover covert consciousness.”
One should bear in mind, though, that the paradigm “makes one essential assumption: that patients can understand speech,” said Dr. Blume. “For example, an aphasic patient might not understand but still be conscious.”
In this context, she added, “it’s essential to note that while the presence of a response suggests consciousness, the absence of a response does not suggest the absence of consciousness.”
Dr. Blume cautioned that the approach used in the study “is still at the stage of basic research.” Although the paradigm is promising, “I do not think it is ‘around the corner,’ ” she said.
The study was funded by the Medical Research Council. It was further supported by the National Institute for Health Research Surgical Reconstruction and Microbiology Research Center. Dr. Sokoliuk and Dr. Blume have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
results of a new study suggest. The study showed that the use of a paradigm that measures the strength of responses to speech improved the accuracy of prognosis for these patients, compared with prognoses made solely on the basis of standard clinical characteristics.
“What we found is really compelling evidence” of the usefulness of the test, lead study author Rodika Sokoliuk, PhD, a postdoctoral researcher at the Center for Human Brain Health, University of Birmingham (England), said in an interview.
The passive measure of comprehension, which doesn’t require any other response from the patient, can reduce uncertainty at a critical phase of decision-making in the ICU, said Dr. Sokoliuk.
The study was published online Dec. 23, 2020, in Annals of Neurology.
Useful information at a time of ‘considerable prognostic uncertainty’
Accurate, early prognostication is vital for efficient stratification of patients after a TBI, the authors wrote. This can often be achieved from patient behavior and CT at admission, but some patients continue to fail to obey commands after washout of sedation.
These patients pose a significant challenge for neurologic prognostication, they noted. In these cases, clinicians and families must decide whether to “wait and see” or consider treatment withdrawal.
The authors noted that a lack of command following early in the postsedation period is associated with poor outcome, including vegetative state/unresponsive wakefulness syndrome (VS/UWS). This, they said, represents a “window of opportunity” for cessation of life-sustaining therapy at a time of considerable prognostic uncertainty.
Recent research shows that a significant proportion of unresponsive patients retain a level of cognition, and even consciousness, that isn’t evident from their external behavior – the so-called cognitive-motor dissociation.
The new study included 28 adult patients who had experienced a TBI and were admitted to the ICU of the Queen Elizabeth Hospital in Birmingham, England. The patients had a Glasgow Coma Scale motor score less than 6 (i.e., they were incapable of obeying commands). They had been sedation free for 2-7 days.
For the paradigm, researchers constructed 288 English words using the male voice of the Apple synthesizer. The words required the same amount of time to be generated (320 ms) and were monosyllabic, so the rhythms of the sounds were the same.
The words were presented in a specific order: an adjective, then a noun, then a verb, then a noun. Two words – for example, an adjective and noun – “would build a meaningful phrase,” and four words would build a sentence, said Dr. Sokoliuk.
The researchers built 72 of these four-word sentences. A trial comprised 12 of these sentences, resulting in a total of 864 four-word sentences.
Dr. Sokoliuk likened the paradigm to a rap song with a specific beat that is continually repeated. “Basically, we play 12 of these four-word sentences in a row, without any gaps,” she said.
Each sentence was played to patients, in random order, a minimum of eight and a maximum of nine times per patient throughout the experiment. The patients’ brain activity was recorded on EEG.
Dr. Sokoliuk noted that brain activity in healthy people synchronizes only with the rhythm of phrases and sentences when listeners consciously comprehend the speech. The researchers assessed the level of comprehension in the unresponsive patients by measuring the strength of this synchronicity or brain pattern.
After exclusions, 17 patients were available for outcome assessment 3 months post EEG, and 16 patients were available 6 months post EEG.
The analysis showed that outcome significantly correlated with the strength of patients’ acute cortical tracking of phrases and sentences (r > 0.6; P < .007), quantified by intertrial phase coherence.
Linear regressions revealed that the strength of this comprehension response (beta, 0.603; P = .006) significantly improved the accuracy of prognoses relative to clinical characteristics alone, such as the Glasgow Coma Scale or CT grade.
Previous studies showed that, if there is no understanding of the language used or if the subject is asleep, the brain doesn’t have the “signature” of tracking phrases and sentences, so it doesn’t have the synchronicity or the pattern of individuals with normal cognition, said Dr. Sokoliuk.
“You need a certain level of consciousness, and you need to understand the language, so your brain can actually track sentences or phrases,” she said.
Dr. Sokoliuk explained that the paradigm shows that patients are understanding the sentences and are not just hearing them.
“It’s not showing us that they only hear it, because there are no obvious gaps between the sentences; if there were gaps between sentences, it would probably only show that they hear it. It could be both, that they hear and understand it, but we wouldn’t know.”
A receiver operating characteristics analysis indicated 100% sensitivity and 80% specificity for a distinction between bad outcome (death, VS/UWS) and good outcome at 6 months.
“We could actually define a threshold of the tracking,” said Dr. Sokoliuk. “Patients who had phrases and sentences tracking below this threshold had worse outcome than those whose tracking value was above this threshold.”
The study illustrates that some posttraumatic patients who remain in an unresponsive state despite being sedation free may nevertheless comprehend speech.
The EEG paradigm approach, the authors said, may significantly reduce prognostic uncertainty in a critical phase of medical decision-making. It could also help clinicians make more appropriate decisions about whether or not to continue life-sustaining therapy and ensure more appropriate distribution of limited rehabilitation resources to patients most likely to benefit.
Dr. Sokoliuk stressed that the paradigm could be used at the bedside soon after a brain injury. “The critical thing is, we can actually use it during the acute phase, which is very important for clinical decisions about life-sustaining methods, therapy, and long-term care.”
A prognostic tool
The simple approach promises to be more accessible than fMRI, said Dr. Sokoliuk. “Putting an unresponsive coma patient in a scanner is very difficult and also much more expensive,” she said.
The next step, said Dr. Sokoliuk, is to repeat the study with a larger sample. “The number in the current study was quite small, and we can’t say if the sensitivity of the paradigm is strong enough to use it as a standard prognostic tool.”
To use it in clinical setting, “we really have to have robust measures,” she added.
She aims to conduct a collaborative study involving several institutions and more patients.
The research team plans to eventually build “an open-access toolbox” that would include the auditory streams to be played during EEG recordings and a program to analyze the data, said Dr. Sokoliuk. “Then, in the end, you would get a threshold or a value of tracking for phrases and sentences, and this could then classify a patient to be in a good-outcome or in bad-outcome group.”
She stressed this is a prognostic tool, not a diagnostic tool, and it should not be used in isolation. “It’s important to know that no clinician should only use this paradigm to prognosticate a patient; our paradigm should be part of a bigger battery of tests.”
But it could go a long way toward helping families as well as physicians. “If they know that the patient would be better in 3 months’ time, it’s easier for them to decide what should come next,” she said.
And it’s heartening to know that when families talk to their unresponsive loved one, the patient understands them, she added.
Promising basic research
Commenting on the study in an interview, Christine Blume, PhD, of the Center for Chronobiology, University of Basel (Switzerland), whose research interests include cognitive processing of patients with disorders of consciousness, described it as “very elegant and appealing” and the paradigm it used as “really promising.”
“However, we do, of course, not yet know about the prognostic value on a single-subject level, as the authors performed only group analyses,” said Dr. Blume. “This will require more extensive and perhaps even multicenter studies.”
It would also require developing a “solution” that “allows clinicians with limited time resources and perhaps lacking expert knowledge on the paradigm and the necessary analyses to apply the paradigm at bedside,” said Dr. Blume.
She agreed that a passive paradigm that helps determine whether a patient consciously understands speech, without the need for further processing, “has the potential to really improve the diagnostic process and uncover covert consciousness.”
One should bear in mind, though, that the paradigm “makes one essential assumption: that patients can understand speech,” said Dr. Blume. “For example, an aphasic patient might not understand but still be conscious.”
In this context, she added, “it’s essential to note that while the presence of a response suggests consciousness, the absence of a response does not suggest the absence of consciousness.”
Dr. Blume cautioned that the approach used in the study “is still at the stage of basic research.” Although the paradigm is promising, “I do not think it is ‘around the corner,’ ” she said.
The study was funded by the Medical Research Council. It was further supported by the National Institute for Health Research Surgical Reconstruction and Microbiology Research Center. Dr. Sokoliuk and Dr. Blume have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
results of a new study suggest. The study showed that the use of a paradigm that measures the strength of responses to speech improved the accuracy of prognosis for these patients, compared with prognoses made solely on the basis of standard clinical characteristics.
“What we found is really compelling evidence” of the usefulness of the test, lead study author Rodika Sokoliuk, PhD, a postdoctoral researcher at the Center for Human Brain Health, University of Birmingham (England), said in an interview.
The passive measure of comprehension, which doesn’t require any other response from the patient, can reduce uncertainty at a critical phase of decision-making in the ICU, said Dr. Sokoliuk.
The study was published online Dec. 23, 2020, in Annals of Neurology.
Useful information at a time of ‘considerable prognostic uncertainty’
Accurate, early prognostication is vital for efficient stratification of patients after a TBI, the authors wrote. This can often be achieved from patient behavior and CT at admission, but some patients continue to fail to obey commands after washout of sedation.
These patients pose a significant challenge for neurologic prognostication, they noted. In these cases, clinicians and families must decide whether to “wait and see” or consider treatment withdrawal.
The authors noted that a lack of command following early in the postsedation period is associated with poor outcome, including vegetative state/unresponsive wakefulness syndrome (VS/UWS). This, they said, represents a “window of opportunity” for cessation of life-sustaining therapy at a time of considerable prognostic uncertainty.
Recent research shows that a significant proportion of unresponsive patients retain a level of cognition, and even consciousness, that isn’t evident from their external behavior – the so-called cognitive-motor dissociation.
The new study included 28 adult patients who had experienced a TBI and were admitted to the ICU of the Queen Elizabeth Hospital in Birmingham, England. The patients had a Glasgow Coma Scale motor score less than 6 (i.e., they were incapable of obeying commands). They had been sedation free for 2-7 days.
For the paradigm, researchers constructed 288 English words using the male voice of the Apple synthesizer. The words required the same amount of time to be generated (320 ms) and were monosyllabic, so the rhythms of the sounds were the same.
The words were presented in a specific order: an adjective, then a noun, then a verb, then a noun. Two words – for example, an adjective and noun – “would build a meaningful phrase,” and four words would build a sentence, said Dr. Sokoliuk.
The researchers built 72 of these four-word sentences. A trial comprised 12 of these sentences, resulting in a total of 864 four-word sentences.
Dr. Sokoliuk likened the paradigm to a rap song with a specific beat that is continually repeated. “Basically, we play 12 of these four-word sentences in a row, without any gaps,” she said.
Each sentence was played to patients, in random order, a minimum of eight and a maximum of nine times per patient throughout the experiment. The patients’ brain activity was recorded on EEG.
Dr. Sokoliuk noted that brain activity in healthy people synchronizes only with the rhythm of phrases and sentences when listeners consciously comprehend the speech. The researchers assessed the level of comprehension in the unresponsive patients by measuring the strength of this synchronicity or brain pattern.
After exclusions, 17 patients were available for outcome assessment 3 months post EEG, and 16 patients were available 6 months post EEG.
The analysis showed that outcome significantly correlated with the strength of patients’ acute cortical tracking of phrases and sentences (r > 0.6; P < .007), quantified by intertrial phase coherence.
Linear regressions revealed that the strength of this comprehension response (beta, 0.603; P = .006) significantly improved the accuracy of prognoses relative to clinical characteristics alone, such as the Glasgow Coma Scale or CT grade.
Previous studies showed that, if there is no understanding of the language used or if the subject is asleep, the brain doesn’t have the “signature” of tracking phrases and sentences, so it doesn’t have the synchronicity or the pattern of individuals with normal cognition, said Dr. Sokoliuk.
“You need a certain level of consciousness, and you need to understand the language, so your brain can actually track sentences or phrases,” she said.
Dr. Sokoliuk explained that the paradigm shows that patients are understanding the sentences and are not just hearing them.
“It’s not showing us that they only hear it, because there are no obvious gaps between the sentences; if there were gaps between sentences, it would probably only show that they hear it. It could be both, that they hear and understand it, but we wouldn’t know.”
A receiver operating characteristics analysis indicated 100% sensitivity and 80% specificity for a distinction between bad outcome (death, VS/UWS) and good outcome at 6 months.
“We could actually define a threshold of the tracking,” said Dr. Sokoliuk. “Patients who had phrases and sentences tracking below this threshold had worse outcome than those whose tracking value was above this threshold.”
The study illustrates that some posttraumatic patients who remain in an unresponsive state despite being sedation free may nevertheless comprehend speech.
The EEG paradigm approach, the authors said, may significantly reduce prognostic uncertainty in a critical phase of medical decision-making. It could also help clinicians make more appropriate decisions about whether or not to continue life-sustaining therapy and ensure more appropriate distribution of limited rehabilitation resources to patients most likely to benefit.
Dr. Sokoliuk stressed that the paradigm could be used at the bedside soon after a brain injury. “The critical thing is, we can actually use it during the acute phase, which is very important for clinical decisions about life-sustaining methods, therapy, and long-term care.”
A prognostic tool
The simple approach promises to be more accessible than fMRI, said Dr. Sokoliuk. “Putting an unresponsive coma patient in a scanner is very difficult and also much more expensive,” she said.
The next step, said Dr. Sokoliuk, is to repeat the study with a larger sample. “The number in the current study was quite small, and we can’t say if the sensitivity of the paradigm is strong enough to use it as a standard prognostic tool.”
To use it in clinical setting, “we really have to have robust measures,” she added.
She aims to conduct a collaborative study involving several institutions and more patients.
The research team plans to eventually build “an open-access toolbox” that would include the auditory streams to be played during EEG recordings and a program to analyze the data, said Dr. Sokoliuk. “Then, in the end, you would get a threshold or a value of tracking for phrases and sentences, and this could then classify a patient to be in a good-outcome or in bad-outcome group.”
She stressed this is a prognostic tool, not a diagnostic tool, and it should not be used in isolation. “It’s important to know that no clinician should only use this paradigm to prognosticate a patient; our paradigm should be part of a bigger battery of tests.”
But it could go a long way toward helping families as well as physicians. “If they know that the patient would be better in 3 months’ time, it’s easier for them to decide what should come next,” she said.
And it’s heartening to know that when families talk to their unresponsive loved one, the patient understands them, she added.
Promising basic research
Commenting on the study in an interview, Christine Blume, PhD, of the Center for Chronobiology, University of Basel (Switzerland), whose research interests include cognitive processing of patients with disorders of consciousness, described it as “very elegant and appealing” and the paradigm it used as “really promising.”
“However, we do, of course, not yet know about the prognostic value on a single-subject level, as the authors performed only group analyses,” said Dr. Blume. “This will require more extensive and perhaps even multicenter studies.”
It would also require developing a “solution” that “allows clinicians with limited time resources and perhaps lacking expert knowledge on the paradigm and the necessary analyses to apply the paradigm at bedside,” said Dr. Blume.
She agreed that a passive paradigm that helps determine whether a patient consciously understands speech, without the need for further processing, “has the potential to really improve the diagnostic process and uncover covert consciousness.”
One should bear in mind, though, that the paradigm “makes one essential assumption: that patients can understand speech,” said Dr. Blume. “For example, an aphasic patient might not understand but still be conscious.”
In this context, she added, “it’s essential to note that while the presence of a response suggests consciousness, the absence of a response does not suggest the absence of consciousness.”
Dr. Blume cautioned that the approach used in the study “is still at the stage of basic research.” Although the paradigm is promising, “I do not think it is ‘around the corner,’ ” she said.
The study was funded by the Medical Research Council. It was further supported by the National Institute for Health Research Surgical Reconstruction and Microbiology Research Center. Dr. Sokoliuk and Dr. Blume have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF NEUROLOGY
One-week radiotherapy course should be standard for early invasive breast cancer, experts say
The trial was designed to compare the standard regimen (40 Gy in 15 fractions over 3 weeks) with a higher-dose hypofractionated regimen (27 Gy in 5 fractions over 5 days) and a lower-dose hypofractionated regimen (26 Gy in 5 fractions over 5 days) in women who had undergone surgery for early invasive breast cancer.
The 5-year rate of ipsilateral breast tumor relapse was similar with all regimens – 2.1% with the 40-Gy regimen, 1.7% with the 27-Gy regimen, and 1.4% with the 26-Gy regimen. The 26-Gy regimen also had similar safety as the 40-Gy regimen.
These results were presented at the European Society for Radiology and Oncology 2020 Online Congress by Joanne S. Haviland, MSc, of the Institute of Cancer Research in London. Results were also published in The Lancet.
Ms. Haviland said that hypofractionated regimens are attractive because of their shorter overall treatment times, which translate to greater convenience and lower treatment costs.
The historic 5-week regimen (50 Gy in 25 fractions) has been replaced by a 3-week regimen (40 Gy in 15 fractions) in the United Kingdom and elsewhere, and ongoing efforts are exploring whether further hypofractionation can be achieved without compromising efficacy and safety.
“The FAST-Forward trial was the next step on from testing hypofractionated schedules evaluated in earlier trials, including the START trials in the early 2000s and the FAST trial, which published its 10-year results earlier this year,” Ms. Haviland explained.
FAST-Forward enrolled 4,096 women who had undergone breast-conserving surgery or mastectomy for early invasive breast cancer. The patients were randomized into the aforementioned groups for adjuvant whole-breast or chest-wall radiotherapy: 40 Gy in 15 fractions over 3 weeks, 27 Gy in 5 fractions over 5 days, or 26 Gy in 5 fractions over 5 days. Boosts were permitted for all regimens.
Relapse, safety, and patient reports
The median follow-up was 6 years. The 5-year rate of ipsilateral breast tumor relapse was 2.1% with the 40-Gy standard regimen, 1.7% with the 27-Gy hypofractionated regimen, and 1.4% with the 26-Gy hypofractionated regimen.
The upper bound of the 95% confidence interval for the difference comparing the hypofractionated regimens against the standard fell well within the 1.6% excess predefined for noninferiority for both the 27-Gy regimen and the 26-Gy regimen (0.9% and 0.3%, respectively).
The hazard ratio for ipsilateral breast tumor relapse, compared with the standard regimen, was 0.86 for the 27-Gy hypofractionated regimen and 0.67 for the 26-Gy hypofractionated regimen.
In terms of safety, the 5-year rate of late adverse effects of the breast or chest wall – distortion, shrinkage, induration, telangiectasia, or edema – rated as “moderate” or “marked” by clinicians was 10% with the standard regimen, 15% with the 27-Gy regimen (relative risk, 1.55 ; P < .001), and 12% with the 26-Gy regimen (RR, 1.19; P = .17).
Over the entire follow-up, women had significantly higher odds of all moderate or marked individual late adverse effects (except discomfort) with the 27-Gy regimen versus the standard regimen, whereas their odds were significantly higher only for induration and edema with the 26-Gy regimen.
However, absolute rates and risk differences between groups were small, Ms. Haviland pointed out. For example, the most common moderate or marked late adverse effect with the standard regimen was breast shrinkage, seen in 5% of patients, followed by discomfort, seen in 4%.
Patient-assessed change in breast appearance and shrinkage did not differ significantly across groups. But women in the 27-Gy group were more likely than peers in the standard regimen group to report a moderate or marked increase in breast hardness/firmness (21% vs. 14%; P = .008), and women in both the 27-Gy and 26-Gy groups were more likely to report moderate or marked breast swelling (5%; P = .007 and 4%; P = .02, respectively, vs. 2%).
A new standard
“We have shown noninferiority in terms of local tumor control for both 5-fraction schedules, compared with the control group of 40 Gy in 15 fractions,” Ms. Haviland summarized. “Late adverse effects in normal tissues were similar after 26 Gy in 5 fractions to 40 Gy in 15 fractions, and although rates were higher for the 27-Gy schedule, we noted that these are consistent with the historic standard of 50 Gy in 25 fractions.”
“There are obvious benefits to patients and health care systems of shorter radiotherapy treatments, particularly at the current time, and in fact, the COVID pandemic has accelerated uptake of the 26-Gy schedule around the world,” she added. “At a recent consensus meeting organized by the Royal College of Radiologists, the U.K. adopted the 26-Gy schedule as a new standard, also integrating this with partial breast irradiation, in close collaboration with the U.K. IMPORT Low trial.”
“This is very important work. I think this is one of the most important trials in the past few years. It has really changed practice,” commented session co-chair Ben Slotman, MD, PhD, of Vrije Universiteit Medical Center, Amsterdam, and AMC Amsterdam, who was not involved the trial.
Dr. Slotman wondered how extensive uptake of the new hypofractionated regimen has been. “I know it’s being used in the U.K. and the Netherlands, but do you have any idea about the rest of Europe? What do we need to make it the new standard?”
“I think there has been uptake in other countries in Europe and elsewhere around the world as well,” Ms. Haviland replied. But feedback suggests adoption has been tempered because of reservations related to the regimen’s safety in certain patient subgroups.
“We haven’t found any cause for concern in the subgroups, and also backed up by meta-analysis in the many patients randomized in the START trials,” she noted. “So I think there is very convincing evidence that it is safe as a new standard.”
FAST-Forward was sponsored by the Institute of Cancer Research and funded by the National Institute for Health Research Health Technology Assessment Programme. Ms. Haviland disclosed no conflicts of interest. Dr. Slotman has relationships with ViewRay and Varian Medical Systems.
SOURCE: Haviland J et al. ESTRO 2020, Abstract OC-0610.
The trial was designed to compare the standard regimen (40 Gy in 15 fractions over 3 weeks) with a higher-dose hypofractionated regimen (27 Gy in 5 fractions over 5 days) and a lower-dose hypofractionated regimen (26 Gy in 5 fractions over 5 days) in women who had undergone surgery for early invasive breast cancer.
The 5-year rate of ipsilateral breast tumor relapse was similar with all regimens – 2.1% with the 40-Gy regimen, 1.7% with the 27-Gy regimen, and 1.4% with the 26-Gy regimen. The 26-Gy regimen also had similar safety as the 40-Gy regimen.
These results were presented at the European Society for Radiology and Oncology 2020 Online Congress by Joanne S. Haviland, MSc, of the Institute of Cancer Research in London. Results were also published in The Lancet.
Ms. Haviland said that hypofractionated regimens are attractive because of their shorter overall treatment times, which translate to greater convenience and lower treatment costs.
The historic 5-week regimen (50 Gy in 25 fractions) has been replaced by a 3-week regimen (40 Gy in 15 fractions) in the United Kingdom and elsewhere, and ongoing efforts are exploring whether further hypofractionation can be achieved without compromising efficacy and safety.
“The FAST-Forward trial was the next step on from testing hypofractionated schedules evaluated in earlier trials, including the START trials in the early 2000s and the FAST trial, which published its 10-year results earlier this year,” Ms. Haviland explained.
FAST-Forward enrolled 4,096 women who had undergone breast-conserving surgery or mastectomy for early invasive breast cancer. The patients were randomized into the aforementioned groups for adjuvant whole-breast or chest-wall radiotherapy: 40 Gy in 15 fractions over 3 weeks, 27 Gy in 5 fractions over 5 days, or 26 Gy in 5 fractions over 5 days. Boosts were permitted for all regimens.
Relapse, safety, and patient reports
The median follow-up was 6 years. The 5-year rate of ipsilateral breast tumor relapse was 2.1% with the 40-Gy standard regimen, 1.7% with the 27-Gy hypofractionated regimen, and 1.4% with the 26-Gy hypofractionated regimen.
The upper bound of the 95% confidence interval for the difference comparing the hypofractionated regimens against the standard fell well within the 1.6% excess predefined for noninferiority for both the 27-Gy regimen and the 26-Gy regimen (0.9% and 0.3%, respectively).
The hazard ratio for ipsilateral breast tumor relapse, compared with the standard regimen, was 0.86 for the 27-Gy hypofractionated regimen and 0.67 for the 26-Gy hypofractionated regimen.
In terms of safety, the 5-year rate of late adverse effects of the breast or chest wall – distortion, shrinkage, induration, telangiectasia, or edema – rated as “moderate” or “marked” by clinicians was 10% with the standard regimen, 15% with the 27-Gy regimen (relative risk, 1.55 ; P < .001), and 12% with the 26-Gy regimen (RR, 1.19; P = .17).
Over the entire follow-up, women had significantly higher odds of all moderate or marked individual late adverse effects (except discomfort) with the 27-Gy regimen versus the standard regimen, whereas their odds were significantly higher only for induration and edema with the 26-Gy regimen.
However, absolute rates and risk differences between groups were small, Ms. Haviland pointed out. For example, the most common moderate or marked late adverse effect with the standard regimen was breast shrinkage, seen in 5% of patients, followed by discomfort, seen in 4%.
Patient-assessed change in breast appearance and shrinkage did not differ significantly across groups. But women in the 27-Gy group were more likely than peers in the standard regimen group to report a moderate or marked increase in breast hardness/firmness (21% vs. 14%; P = .008), and women in both the 27-Gy and 26-Gy groups were more likely to report moderate or marked breast swelling (5%; P = .007 and 4%; P = .02, respectively, vs. 2%).
A new standard
“We have shown noninferiority in terms of local tumor control for both 5-fraction schedules, compared with the control group of 40 Gy in 15 fractions,” Ms. Haviland summarized. “Late adverse effects in normal tissues were similar after 26 Gy in 5 fractions to 40 Gy in 15 fractions, and although rates were higher for the 27-Gy schedule, we noted that these are consistent with the historic standard of 50 Gy in 25 fractions.”
“There are obvious benefits to patients and health care systems of shorter radiotherapy treatments, particularly at the current time, and in fact, the COVID pandemic has accelerated uptake of the 26-Gy schedule around the world,” she added. “At a recent consensus meeting organized by the Royal College of Radiologists, the U.K. adopted the 26-Gy schedule as a new standard, also integrating this with partial breast irradiation, in close collaboration with the U.K. IMPORT Low trial.”
“This is very important work. I think this is one of the most important trials in the past few years. It has really changed practice,” commented session co-chair Ben Slotman, MD, PhD, of Vrije Universiteit Medical Center, Amsterdam, and AMC Amsterdam, who was not involved the trial.
Dr. Slotman wondered how extensive uptake of the new hypofractionated regimen has been. “I know it’s being used in the U.K. and the Netherlands, but do you have any idea about the rest of Europe? What do we need to make it the new standard?”
“I think there has been uptake in other countries in Europe and elsewhere around the world as well,” Ms. Haviland replied. But feedback suggests adoption has been tempered because of reservations related to the regimen’s safety in certain patient subgroups.
“We haven’t found any cause for concern in the subgroups, and also backed up by meta-analysis in the many patients randomized in the START trials,” she noted. “So I think there is very convincing evidence that it is safe as a new standard.”
FAST-Forward was sponsored by the Institute of Cancer Research and funded by the National Institute for Health Research Health Technology Assessment Programme. Ms. Haviland disclosed no conflicts of interest. Dr. Slotman has relationships with ViewRay and Varian Medical Systems.
SOURCE: Haviland J et al. ESTRO 2020, Abstract OC-0610.
The trial was designed to compare the standard regimen (40 Gy in 15 fractions over 3 weeks) with a higher-dose hypofractionated regimen (27 Gy in 5 fractions over 5 days) and a lower-dose hypofractionated regimen (26 Gy in 5 fractions over 5 days) in women who had undergone surgery for early invasive breast cancer.
The 5-year rate of ipsilateral breast tumor relapse was similar with all regimens – 2.1% with the 40-Gy regimen, 1.7% with the 27-Gy regimen, and 1.4% with the 26-Gy regimen. The 26-Gy regimen also had similar safety as the 40-Gy regimen.
These results were presented at the European Society for Radiology and Oncology 2020 Online Congress by Joanne S. Haviland, MSc, of the Institute of Cancer Research in London. Results were also published in The Lancet.
Ms. Haviland said that hypofractionated regimens are attractive because of their shorter overall treatment times, which translate to greater convenience and lower treatment costs.
The historic 5-week regimen (50 Gy in 25 fractions) has been replaced by a 3-week regimen (40 Gy in 15 fractions) in the United Kingdom and elsewhere, and ongoing efforts are exploring whether further hypofractionation can be achieved without compromising efficacy and safety.
“The FAST-Forward trial was the next step on from testing hypofractionated schedules evaluated in earlier trials, including the START trials in the early 2000s and the FAST trial, which published its 10-year results earlier this year,” Ms. Haviland explained.
FAST-Forward enrolled 4,096 women who had undergone breast-conserving surgery or mastectomy for early invasive breast cancer. The patients were randomized into the aforementioned groups for adjuvant whole-breast or chest-wall radiotherapy: 40 Gy in 15 fractions over 3 weeks, 27 Gy in 5 fractions over 5 days, or 26 Gy in 5 fractions over 5 days. Boosts were permitted for all regimens.
Relapse, safety, and patient reports
The median follow-up was 6 years. The 5-year rate of ipsilateral breast tumor relapse was 2.1% with the 40-Gy standard regimen, 1.7% with the 27-Gy hypofractionated regimen, and 1.4% with the 26-Gy hypofractionated regimen.
The upper bound of the 95% confidence interval for the difference comparing the hypofractionated regimens against the standard fell well within the 1.6% excess predefined for noninferiority for both the 27-Gy regimen and the 26-Gy regimen (0.9% and 0.3%, respectively).
The hazard ratio for ipsilateral breast tumor relapse, compared with the standard regimen, was 0.86 for the 27-Gy hypofractionated regimen and 0.67 for the 26-Gy hypofractionated regimen.
In terms of safety, the 5-year rate of late adverse effects of the breast or chest wall – distortion, shrinkage, induration, telangiectasia, or edema – rated as “moderate” or “marked” by clinicians was 10% with the standard regimen, 15% with the 27-Gy regimen (relative risk, 1.55 ; P < .001), and 12% with the 26-Gy regimen (RR, 1.19; P = .17).
Over the entire follow-up, women had significantly higher odds of all moderate or marked individual late adverse effects (except discomfort) with the 27-Gy regimen versus the standard regimen, whereas their odds were significantly higher only for induration and edema with the 26-Gy regimen.
However, absolute rates and risk differences between groups were small, Ms. Haviland pointed out. For example, the most common moderate or marked late adverse effect with the standard regimen was breast shrinkage, seen in 5% of patients, followed by discomfort, seen in 4%.
Patient-assessed change in breast appearance and shrinkage did not differ significantly across groups. But women in the 27-Gy group were more likely than peers in the standard regimen group to report a moderate or marked increase in breast hardness/firmness (21% vs. 14%; P = .008), and women in both the 27-Gy and 26-Gy groups were more likely to report moderate or marked breast swelling (5%; P = .007 and 4%; P = .02, respectively, vs. 2%).
A new standard
“We have shown noninferiority in terms of local tumor control for both 5-fraction schedules, compared with the control group of 40 Gy in 15 fractions,” Ms. Haviland summarized. “Late adverse effects in normal tissues were similar after 26 Gy in 5 fractions to 40 Gy in 15 fractions, and although rates were higher for the 27-Gy schedule, we noted that these are consistent with the historic standard of 50 Gy in 25 fractions.”
“There are obvious benefits to patients and health care systems of shorter radiotherapy treatments, particularly at the current time, and in fact, the COVID pandemic has accelerated uptake of the 26-Gy schedule around the world,” she added. “At a recent consensus meeting organized by the Royal College of Radiologists, the U.K. adopted the 26-Gy schedule as a new standard, also integrating this with partial breast irradiation, in close collaboration with the U.K. IMPORT Low trial.”
“This is very important work. I think this is one of the most important trials in the past few years. It has really changed practice,” commented session co-chair Ben Slotman, MD, PhD, of Vrije Universiteit Medical Center, Amsterdam, and AMC Amsterdam, who was not involved the trial.
Dr. Slotman wondered how extensive uptake of the new hypofractionated regimen has been. “I know it’s being used in the U.K. and the Netherlands, but do you have any idea about the rest of Europe? What do we need to make it the new standard?”
“I think there has been uptake in other countries in Europe and elsewhere around the world as well,” Ms. Haviland replied. But feedback suggests adoption has been tempered because of reservations related to the regimen’s safety in certain patient subgroups.
“We haven’t found any cause for concern in the subgroups, and also backed up by meta-analysis in the many patients randomized in the START trials,” she noted. “So I think there is very convincing evidence that it is safe as a new standard.”
FAST-Forward was sponsored by the Institute of Cancer Research and funded by the National Institute for Health Research Health Technology Assessment Programme. Ms. Haviland disclosed no conflicts of interest. Dr. Slotman has relationships with ViewRay and Varian Medical Systems.
SOURCE: Haviland J et al. ESTRO 2020, Abstract OC-0610.
FROM ESTRO 2020
Physicians react: Doctors worry about patients reading their clinical notes
Patients will soon be able to read the notes that physicians make during an episode of care, as well as information about diagnostic testing and imaging results, tests for STDs, fetal ultrasounds, and cancer biopsies. This open access is raising concerns among physicians.
As part of the 21st Century Cures Act, patients have the right to see their medical notes. Known as Open Notes, the policy will go into effect on April 5, 2021. The Department of Health & Human Services recently changed the original start date, which was to be Nov. 2, 2020.
The mandate has some physicians worrying about potential legal risks and possible violation of doctor-patient confidentiality. When asked to share their views on the new Open Notes mandate, many physicians expressed their concerns but also cited some of the positive effects that could come from this.
Potentially more legal woes for physicians?
A key concern raised by one physician commenter is that patients could misunderstand legitimate medical terminology or even put a physician in legal crosshairs. For example, a medical term such as “spontaneous abortion” could be misconstrued by patients. A physician might write notes with the idea that a patient is reading them and thus might alter those notes in a way that creates legal trouble.
“This layers another level of censorship and legal liability onto physicians, who in attempting to be [politically correct], may omit critical information or have to use euphemisms in order to avoid conflict,” one physician said.
She also questioned whether notes might now have to be run through legal counsel before being posted to avoid potential liability.
Another doctor questioned how physicians would be able to document patients suspected of faking injuries for pain medication, for example. Could such documentation lead to lawsuits for the doctor?
As one physician noted, some patients “are drug seekers. Some refuse to aid in their own care. Some are malingerers. Not documenting that is bad medicine.”
The possibility of violating doctor-patient confidentiality laws, particularly for teenagers, could be another negative effect of Open Notes, said one physician.
“Won’t this violate the statutes that teenagers have the right to confidential evaluations?” the commenter mused. “If charts are to be immediately available, then STDs and pregnancies they weren’t ready to talk about will now be suddenly known by their parents.”
One doctor has already faced this issue. “I already ran into this problem once,” he noted. “Now I warn those on their parents’ insurance before I start the visit. I have literally had a patient state, ‘well then we are done,’ and leave without being seen due to it.”
Another physician questioned the possibility of having to write notes differently than they do now, especially if the patients have lower reading comprehension abilities.
One physician who uses Open Notes said he receives patient requests for changes that have little to do with the actual diagnosis and relate to ancillary issues. He highlighted patients who “don’t want psych diagnosis in their chart or are concerned a diagnosis will raise their insurance premium, so they ask me to delete it.”
Will Open Notes erode patient communication?
One physician questioned whether it would lead to patients being less open and forthcoming about their medical concerns with doctors.
“The main problem I see is the patient not telling me the whole story, or worse, telling me the story, and then asking me not to document it (as many have done in the past) because they don’t want their spouse, family, etc. to read the notes and they have already given their permission for them to do so, for a variety of reasons,” he commented. “This includes topics of STDs, infidelity, depression, suicidal thoughts, and other symptoms the patient doesn’t want their family to read about.”
Some physicians envision positive developments
Many physicians are unconcerned by the new mandate. “I see some potential good in this, such as improving doctor-patient communication and more scrupulous charting,” one physician said.
A doctor working in the U.S. federal health care system noted that open access has been a part of that system for decades.
“Since health care providers work in this unveiled setting for their entire career, they usually know how to write appropriate clinical notes and what information needs to be included in them,” he wrote. “Now it’s time for the rest of the medical community to catch up to a reality that we have worked within for decades now.
“The world did not end, malpractice complaints did not increase, and physician/patient relationships were not damaged. Living in the information age, archaic practices like private notes were surely going to end at some point.”
One doctor who has been using Open Notes has had experiences in which the patient noted an error in the medical chart that needed correcting. “I have had one patient correct me on a timeline in the HPI which was helpful and I made the requested correction in that instance,” he said.
Another physician agreed. “I’ve had patients add or correct valuable information I’ve missed. Good probably outweighs the bad if we set limits on behaviors expressed by the personality disordered group. The majority of people don’t seem to care and still ask me ‘what would you do’ or ‘tell me what to do.’ It’s all about patient/physician trust.”
Another talked about how Open Notes should have little or no impact. “Here’s a novel concept – talking to our patients,” he commented. “There is nothing in every one of my chart notes that has not already been discussed with my patients and I dictate (speech to text) my findings and plan in front of them. So, if they are reviewing my office notes, it will only serve to reinforce what we have already discussed.”
“I don’t intend to change anything,” he added. “Chances are if they were to see a test result before I have a chance to discuss it with them, they will have already ‘Googled’ its meaning and we can have more meaningful interaction if they have a basic understanding of the test.”
“I understand that this is anxiety provoking, but in general I think it is appropriate for patients to have access to their notes,” said another physician. “If physicians write lousy notes that say they did things they didn’t do, that fail to actually state a diagnosis and a plan (and they often do), that is the doc’s problem, not the patient’s.”
A version of this article first appeared on Medscape.com.
Patients will soon be able to read the notes that physicians make during an episode of care, as well as information about diagnostic testing and imaging results, tests for STDs, fetal ultrasounds, and cancer biopsies. This open access is raising concerns among physicians.
As part of the 21st Century Cures Act, patients have the right to see their medical notes. Known as Open Notes, the policy will go into effect on April 5, 2021. The Department of Health & Human Services recently changed the original start date, which was to be Nov. 2, 2020.
The mandate has some physicians worrying about potential legal risks and possible violation of doctor-patient confidentiality. When asked to share their views on the new Open Notes mandate, many physicians expressed their concerns but also cited some of the positive effects that could come from this.
Potentially more legal woes for physicians?
A key concern raised by one physician commenter is that patients could misunderstand legitimate medical terminology or even put a physician in legal crosshairs. For example, a medical term such as “spontaneous abortion” could be misconstrued by patients. A physician might write notes with the idea that a patient is reading them and thus might alter those notes in a way that creates legal trouble.
“This layers another level of censorship and legal liability onto physicians, who in attempting to be [politically correct], may omit critical information or have to use euphemisms in order to avoid conflict,” one physician said.
She also questioned whether notes might now have to be run through legal counsel before being posted to avoid potential liability.
Another doctor questioned how physicians would be able to document patients suspected of faking injuries for pain medication, for example. Could such documentation lead to lawsuits for the doctor?
As one physician noted, some patients “are drug seekers. Some refuse to aid in their own care. Some are malingerers. Not documenting that is bad medicine.”
The possibility of violating doctor-patient confidentiality laws, particularly for teenagers, could be another negative effect of Open Notes, said one physician.
“Won’t this violate the statutes that teenagers have the right to confidential evaluations?” the commenter mused. “If charts are to be immediately available, then STDs and pregnancies they weren’t ready to talk about will now be suddenly known by their parents.”
One doctor has already faced this issue. “I already ran into this problem once,” he noted. “Now I warn those on their parents’ insurance before I start the visit. I have literally had a patient state, ‘well then we are done,’ and leave without being seen due to it.”
Another physician questioned the possibility of having to write notes differently than they do now, especially if the patients have lower reading comprehension abilities.
One physician who uses Open Notes said he receives patient requests for changes that have little to do with the actual diagnosis and relate to ancillary issues. He highlighted patients who “don’t want psych diagnosis in their chart or are concerned a diagnosis will raise their insurance premium, so they ask me to delete it.”
Will Open Notes erode patient communication?
One physician questioned whether it would lead to patients being less open and forthcoming about their medical concerns with doctors.
“The main problem I see is the patient not telling me the whole story, or worse, telling me the story, and then asking me not to document it (as many have done in the past) because they don’t want their spouse, family, etc. to read the notes and they have already given their permission for them to do so, for a variety of reasons,” he commented. “This includes topics of STDs, infidelity, depression, suicidal thoughts, and other symptoms the patient doesn’t want their family to read about.”
Some physicians envision positive developments
Many physicians are unconcerned by the new mandate. “I see some potential good in this, such as improving doctor-patient communication and more scrupulous charting,” one physician said.
A doctor working in the U.S. federal health care system noted that open access has been a part of that system for decades.
“Since health care providers work in this unveiled setting for their entire career, they usually know how to write appropriate clinical notes and what information needs to be included in them,” he wrote. “Now it’s time for the rest of the medical community to catch up to a reality that we have worked within for decades now.
“The world did not end, malpractice complaints did not increase, and physician/patient relationships were not damaged. Living in the information age, archaic practices like private notes were surely going to end at some point.”
One doctor who has been using Open Notes has had experiences in which the patient noted an error in the medical chart that needed correcting. “I have had one patient correct me on a timeline in the HPI which was helpful and I made the requested correction in that instance,” he said.
Another physician agreed. “I’ve had patients add or correct valuable information I’ve missed. Good probably outweighs the bad if we set limits on behaviors expressed by the personality disordered group. The majority of people don’t seem to care and still ask me ‘what would you do’ or ‘tell me what to do.’ It’s all about patient/physician trust.”
Another talked about how Open Notes should have little or no impact. “Here’s a novel concept – talking to our patients,” he commented. “There is nothing in every one of my chart notes that has not already been discussed with my patients and I dictate (speech to text) my findings and plan in front of them. So, if they are reviewing my office notes, it will only serve to reinforce what we have already discussed.”
“I don’t intend to change anything,” he added. “Chances are if they were to see a test result before I have a chance to discuss it with them, they will have already ‘Googled’ its meaning and we can have more meaningful interaction if they have a basic understanding of the test.”
“I understand that this is anxiety provoking, but in general I think it is appropriate for patients to have access to their notes,” said another physician. “If physicians write lousy notes that say they did things they didn’t do, that fail to actually state a diagnosis and a plan (and they often do), that is the doc’s problem, not the patient’s.”
A version of this article first appeared on Medscape.com.
Patients will soon be able to read the notes that physicians make during an episode of care, as well as information about diagnostic testing and imaging results, tests for STDs, fetal ultrasounds, and cancer biopsies. This open access is raising concerns among physicians.
As part of the 21st Century Cures Act, patients have the right to see their medical notes. Known as Open Notes, the policy will go into effect on April 5, 2021. The Department of Health & Human Services recently changed the original start date, which was to be Nov. 2, 2020.
The mandate has some physicians worrying about potential legal risks and possible violation of doctor-patient confidentiality. When asked to share their views on the new Open Notes mandate, many physicians expressed their concerns but also cited some of the positive effects that could come from this.
Potentially more legal woes for physicians?
A key concern raised by one physician commenter is that patients could misunderstand legitimate medical terminology or even put a physician in legal crosshairs. For example, a medical term such as “spontaneous abortion” could be misconstrued by patients. A physician might write notes with the idea that a patient is reading them and thus might alter those notes in a way that creates legal trouble.
“This layers another level of censorship and legal liability onto physicians, who in attempting to be [politically correct], may omit critical information or have to use euphemisms in order to avoid conflict,” one physician said.
She also questioned whether notes might now have to be run through legal counsel before being posted to avoid potential liability.
Another doctor questioned how physicians would be able to document patients suspected of faking injuries for pain medication, for example. Could such documentation lead to lawsuits for the doctor?
As one physician noted, some patients “are drug seekers. Some refuse to aid in their own care. Some are malingerers. Not documenting that is bad medicine.”
The possibility of violating doctor-patient confidentiality laws, particularly for teenagers, could be another negative effect of Open Notes, said one physician.
“Won’t this violate the statutes that teenagers have the right to confidential evaluations?” the commenter mused. “If charts are to be immediately available, then STDs and pregnancies they weren’t ready to talk about will now be suddenly known by their parents.”
One doctor has already faced this issue. “I already ran into this problem once,” he noted. “Now I warn those on their parents’ insurance before I start the visit. I have literally had a patient state, ‘well then we are done,’ and leave without being seen due to it.”
Another physician questioned the possibility of having to write notes differently than they do now, especially if the patients have lower reading comprehension abilities.
One physician who uses Open Notes said he receives patient requests for changes that have little to do with the actual diagnosis and relate to ancillary issues. He highlighted patients who “don’t want psych diagnosis in their chart or are concerned a diagnosis will raise their insurance premium, so they ask me to delete it.”
Will Open Notes erode patient communication?
One physician questioned whether it would lead to patients being less open and forthcoming about their medical concerns with doctors.
“The main problem I see is the patient not telling me the whole story, or worse, telling me the story, and then asking me not to document it (as many have done in the past) because they don’t want their spouse, family, etc. to read the notes and they have already given their permission for them to do so, for a variety of reasons,” he commented. “This includes topics of STDs, infidelity, depression, suicidal thoughts, and other symptoms the patient doesn’t want their family to read about.”
Some physicians envision positive developments
Many physicians are unconcerned by the new mandate. “I see some potential good in this, such as improving doctor-patient communication and more scrupulous charting,” one physician said.
A doctor working in the U.S. federal health care system noted that open access has been a part of that system for decades.
“Since health care providers work in this unveiled setting for their entire career, they usually know how to write appropriate clinical notes and what information needs to be included in them,” he wrote. “Now it’s time for the rest of the medical community to catch up to a reality that we have worked within for decades now.
“The world did not end, malpractice complaints did not increase, and physician/patient relationships were not damaged. Living in the information age, archaic practices like private notes were surely going to end at some point.”
One doctor who has been using Open Notes has had experiences in which the patient noted an error in the medical chart that needed correcting. “I have had one patient correct me on a timeline in the HPI which was helpful and I made the requested correction in that instance,” he said.
Another physician agreed. “I’ve had patients add or correct valuable information I’ve missed. Good probably outweighs the bad if we set limits on behaviors expressed by the personality disordered group. The majority of people don’t seem to care and still ask me ‘what would you do’ or ‘tell me what to do.’ It’s all about patient/physician trust.”
Another talked about how Open Notes should have little or no impact. “Here’s a novel concept – talking to our patients,” he commented. “There is nothing in every one of my chart notes that has not already been discussed with my patients and I dictate (speech to text) my findings and plan in front of them. So, if they are reviewing my office notes, it will only serve to reinforce what we have already discussed.”
“I don’t intend to change anything,” he added. “Chances are if they were to see a test result before I have a chance to discuss it with them, they will have already ‘Googled’ its meaning and we can have more meaningful interaction if they have a basic understanding of the test.”
“I understand that this is anxiety provoking, but in general I think it is appropriate for patients to have access to their notes,” said another physician. “If physicians write lousy notes that say they did things they didn’t do, that fail to actually state a diagnosis and a plan (and they often do), that is the doc’s problem, not the patient’s.”
A version of this article first appeared on Medscape.com.
After 48 years, NCI aims to track breast cancer recurrences
Change to SEER eventually planned.
Patients with breast cancer want accurate information on the risk of their cancer recurring once they have completed treatment.
“I would like to know the true stats of how many breast cancers come back no matter what the hell we do for treatment,” comments a typical post on a breast cancer patient bulletin board.
But those statistics have not been available from a robust population-based source.
Now, there is hope that they will – at last – be collected.
A new pilot project at the National Cancer Institute is setting out to collect that information, although the researchers say it is a “long-term goal” that will take a few years.
But it has already been a long time coming. The mother lode of all U.S. cancer data, the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program, started collecting cancer data in 1973.
“When they began to capture cancer data, the focus was primarily on the incidence of cancer, the different types of cancer, and survival,” explained Esmeralda Ramirez-Pena, PhD, MPH, cancer prevention fellow at the NCI.
“Later, SEER expanded to include subgroups of various cancers and different stages at diagnosis,” she added.
But this database has never included information on cancer recurrence.
In a 2017 press statement, the NCI commented: “Collecting recurrence data has been challenging for cancer registries because recurrence can be diagnosed through diverse methods and in a variety of locations.”
New project
The NCI now has a “long-term goal” to implement additional “data elements” into SEER that will allow calculation of breast cancer recurrences, said Dr. Ramirez-Pena.
The Breast Cancer Recurrence Project, a pilot program funded via an NCI–Department of Energy collaboration, “will take a couple of years,” she said.
She presented some details of the new project as a poster at the recent San Antonio Breast Cancer Symposium 2020.
“SEER has added data elements over time,” she said, and this latest move will – at last – include information on breast cancer recurrence.
Why the change now?
“There’s been so much interest [in breast cancer recurrence]. It’s a top cause of cancer death in the United States and globally. The urgent need is evident,” she explained.
Breast cancer advocates have long been calling for SEER to count recurrence, including metastatic recurrence.
Katherine O’Brien, a breast cancer “metser” from Chicago, is credited with especially turning the heat up on the NCI.
In 2015, Ms. O’Brien spearheaded the creation of an online petition on the website change.org, calling on the NCI’s SEER, the Centers for Disease Control and Prevention, and all state cancer registries to start counting all people living with metastatic breast cancer, including those whose early-stage disease progressed. The petition, which is now closed, collected nearly 12,000 signatures.
Tracking recurrences
In the new project, cancer recurrence is defined as a cancer that was treated, reduced to undetectable levels, and later returned either locally, regionally, or distantly.
Tracking recurrence is not a simple matter because posttreatment surveillance to detect it includes clinical exams, biomarker testing, pathologic studies, molecular testing, imaging, and patient-reported symptoms and because recurrence frequency varies by subtype of breast cancer and TNM classification. Additionally, recurrence may depend on age at diagnosis, a variety of risk factors, treatment type, and access to quality of care.
“It’s likely there are many elements that influence recurrence,” said Dr. Ramirez-Pena.
To get a handle on the complexity, the NCI needs to first identify which data are needed to tally recurrence and the frequency at which they are collected, explained Dr. Ramirez-Pena. To do so, she and her coinvestigators conducted a systematic review of phase 3 clinical trials of early-stage breast cancer.
On their own, such trials are not sufficient to provide recurrence estimates at the population level because they lack diversity, represent fewer than 5% of all cancer patients, and the study period may not be long enough to capture recurrences for long-latency breast cancers, such as estrogen receptor–positive malignancies.
Nonetheless, these clinical trials provide a starting place.
The investigators identified 444 early-stage clinical trials. They stratified participants by subtype and tumor characteristics, which will enable analysis of risk-group and treatment-dependent differences in recurrence.
The changing science of breast cancer makes this work a challenge, the investigators said. For example, in clinical trials from the early 1990s through the early 2000s, receptor status and subtyping was not commonly reported, and some treatment endpoints were added during the past few years.
“Our next step will be to extract recurrence rates from these trials so we can eventually provide individualized information about recurrence risk to survivors,” Dr. Ramirez-Pena said, describing the big-picture aims.
The Breast Cancer Recurrence Project is collaborating with external agencies, such as the International Agency for Research on Cancer and Public Health England, in fine-tuning data elements, because “recurrence is not captured well globally either,” said Dr. Ramirez-Pena.
The study was supported by NCI.
A version of this article first appeared on Medscape.com.
Change to SEER eventually planned.
Change to SEER eventually planned.
Patients with breast cancer want accurate information on the risk of their cancer recurring once they have completed treatment.
“I would like to know the true stats of how many breast cancers come back no matter what the hell we do for treatment,” comments a typical post on a breast cancer patient bulletin board.
But those statistics have not been available from a robust population-based source.
Now, there is hope that they will – at last – be collected.
A new pilot project at the National Cancer Institute is setting out to collect that information, although the researchers say it is a “long-term goal” that will take a few years.
But it has already been a long time coming. The mother lode of all U.S. cancer data, the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program, started collecting cancer data in 1973.
“When they began to capture cancer data, the focus was primarily on the incidence of cancer, the different types of cancer, and survival,” explained Esmeralda Ramirez-Pena, PhD, MPH, cancer prevention fellow at the NCI.
“Later, SEER expanded to include subgroups of various cancers and different stages at diagnosis,” she added.
But this database has never included information on cancer recurrence.
In a 2017 press statement, the NCI commented: “Collecting recurrence data has been challenging for cancer registries because recurrence can be diagnosed through diverse methods and in a variety of locations.”
New project
The NCI now has a “long-term goal” to implement additional “data elements” into SEER that will allow calculation of breast cancer recurrences, said Dr. Ramirez-Pena.
The Breast Cancer Recurrence Project, a pilot program funded via an NCI–Department of Energy collaboration, “will take a couple of years,” she said.
She presented some details of the new project as a poster at the recent San Antonio Breast Cancer Symposium 2020.
“SEER has added data elements over time,” she said, and this latest move will – at last – include information on breast cancer recurrence.
Why the change now?
“There’s been so much interest [in breast cancer recurrence]. It’s a top cause of cancer death in the United States and globally. The urgent need is evident,” she explained.
Breast cancer advocates have long been calling for SEER to count recurrence, including metastatic recurrence.
Katherine O’Brien, a breast cancer “metser” from Chicago, is credited with especially turning the heat up on the NCI.
In 2015, Ms. O’Brien spearheaded the creation of an online petition on the website change.org, calling on the NCI’s SEER, the Centers for Disease Control and Prevention, and all state cancer registries to start counting all people living with metastatic breast cancer, including those whose early-stage disease progressed. The petition, which is now closed, collected nearly 12,000 signatures.
Tracking recurrences
In the new project, cancer recurrence is defined as a cancer that was treated, reduced to undetectable levels, and later returned either locally, regionally, or distantly.
Tracking recurrence is not a simple matter because posttreatment surveillance to detect it includes clinical exams, biomarker testing, pathologic studies, molecular testing, imaging, and patient-reported symptoms and because recurrence frequency varies by subtype of breast cancer and TNM classification. Additionally, recurrence may depend on age at diagnosis, a variety of risk factors, treatment type, and access to quality of care.
“It’s likely there are many elements that influence recurrence,” said Dr. Ramirez-Pena.
To get a handle on the complexity, the NCI needs to first identify which data are needed to tally recurrence and the frequency at which they are collected, explained Dr. Ramirez-Pena. To do so, she and her coinvestigators conducted a systematic review of phase 3 clinical trials of early-stage breast cancer.
On their own, such trials are not sufficient to provide recurrence estimates at the population level because they lack diversity, represent fewer than 5% of all cancer patients, and the study period may not be long enough to capture recurrences for long-latency breast cancers, such as estrogen receptor–positive malignancies.
Nonetheless, these clinical trials provide a starting place.
The investigators identified 444 early-stage clinical trials. They stratified participants by subtype and tumor characteristics, which will enable analysis of risk-group and treatment-dependent differences in recurrence.
The changing science of breast cancer makes this work a challenge, the investigators said. For example, in clinical trials from the early 1990s through the early 2000s, receptor status and subtyping was not commonly reported, and some treatment endpoints were added during the past few years.
“Our next step will be to extract recurrence rates from these trials so we can eventually provide individualized information about recurrence risk to survivors,” Dr. Ramirez-Pena said, describing the big-picture aims.
The Breast Cancer Recurrence Project is collaborating with external agencies, such as the International Agency for Research on Cancer and Public Health England, in fine-tuning data elements, because “recurrence is not captured well globally either,” said Dr. Ramirez-Pena.
The study was supported by NCI.
A version of this article first appeared on Medscape.com.
Patients with breast cancer want accurate information on the risk of their cancer recurring once they have completed treatment.
“I would like to know the true stats of how many breast cancers come back no matter what the hell we do for treatment,” comments a typical post on a breast cancer patient bulletin board.
But those statistics have not been available from a robust population-based source.
Now, there is hope that they will – at last – be collected.
A new pilot project at the National Cancer Institute is setting out to collect that information, although the researchers say it is a “long-term goal” that will take a few years.
But it has already been a long time coming. The mother lode of all U.S. cancer data, the NCI’s Surveillance, Epidemiology, and End Results (SEER) Program, started collecting cancer data in 1973.
“When they began to capture cancer data, the focus was primarily on the incidence of cancer, the different types of cancer, and survival,” explained Esmeralda Ramirez-Pena, PhD, MPH, cancer prevention fellow at the NCI.
“Later, SEER expanded to include subgroups of various cancers and different stages at diagnosis,” she added.
But this database has never included information on cancer recurrence.
In a 2017 press statement, the NCI commented: “Collecting recurrence data has been challenging for cancer registries because recurrence can be diagnosed through diverse methods and in a variety of locations.”
New project
The NCI now has a “long-term goal” to implement additional “data elements” into SEER that will allow calculation of breast cancer recurrences, said Dr. Ramirez-Pena.
The Breast Cancer Recurrence Project, a pilot program funded via an NCI–Department of Energy collaboration, “will take a couple of years,” she said.
She presented some details of the new project as a poster at the recent San Antonio Breast Cancer Symposium 2020.
“SEER has added data elements over time,” she said, and this latest move will – at last – include information on breast cancer recurrence.
Why the change now?
“There’s been so much interest [in breast cancer recurrence]. It’s a top cause of cancer death in the United States and globally. The urgent need is evident,” she explained.
Breast cancer advocates have long been calling for SEER to count recurrence, including metastatic recurrence.
Katherine O’Brien, a breast cancer “metser” from Chicago, is credited with especially turning the heat up on the NCI.
In 2015, Ms. O’Brien spearheaded the creation of an online petition on the website change.org, calling on the NCI’s SEER, the Centers for Disease Control and Prevention, and all state cancer registries to start counting all people living with metastatic breast cancer, including those whose early-stage disease progressed. The petition, which is now closed, collected nearly 12,000 signatures.
Tracking recurrences
In the new project, cancer recurrence is defined as a cancer that was treated, reduced to undetectable levels, and later returned either locally, regionally, or distantly.
Tracking recurrence is not a simple matter because posttreatment surveillance to detect it includes clinical exams, biomarker testing, pathologic studies, molecular testing, imaging, and patient-reported symptoms and because recurrence frequency varies by subtype of breast cancer and TNM classification. Additionally, recurrence may depend on age at diagnosis, a variety of risk factors, treatment type, and access to quality of care.
“It’s likely there are many elements that influence recurrence,” said Dr. Ramirez-Pena.
To get a handle on the complexity, the NCI needs to first identify which data are needed to tally recurrence and the frequency at which they are collected, explained Dr. Ramirez-Pena. To do so, she and her coinvestigators conducted a systematic review of phase 3 clinical trials of early-stage breast cancer.
On their own, such trials are not sufficient to provide recurrence estimates at the population level because they lack diversity, represent fewer than 5% of all cancer patients, and the study period may not be long enough to capture recurrences for long-latency breast cancers, such as estrogen receptor–positive malignancies.
Nonetheless, these clinical trials provide a starting place.
The investigators identified 444 early-stage clinical trials. They stratified participants by subtype and tumor characteristics, which will enable analysis of risk-group and treatment-dependent differences in recurrence.
The changing science of breast cancer makes this work a challenge, the investigators said. For example, in clinical trials from the early 1990s through the early 2000s, receptor status and subtyping was not commonly reported, and some treatment endpoints were added during the past few years.
“Our next step will be to extract recurrence rates from these trials so we can eventually provide individualized information about recurrence risk to survivors,” Dr. Ramirez-Pena said, describing the big-picture aims.
The Breast Cancer Recurrence Project is collaborating with external agencies, such as the International Agency for Research on Cancer and Public Health England, in fine-tuning data elements, because “recurrence is not captured well globally either,” said Dr. Ramirez-Pena.
The study was supported by NCI.
A version of this article first appeared on Medscape.com.
Ultrasound ablation for Parkinson’s disease: Benefit limited by adverse effects
including dyskinesias and other neurologic complications, in a new randomized, sham-controlled trial.
“Longer-term and larger trials are needed to determine the role of focused ultrasound subthalamotomy in the management of Parkinson’s disease and its effect as compared with other available treatments, including deep-brain stimulation,” the authors concluded.
The trial was published online Dec.24, 2020, in the New England Journal of Medicine.
An accompanying editorial concluded that the high rate of adverse events and the lack of ability to modulate treatment over time to treat prominent tremor “raise questions about the appropriate implementation of focused ultrasound–produced lesions for the treatment of Parkinson’s disease.”
A scalpel-free alternative to brain surgery
The study authors, led by Raul Martinez-Fernandez, MD, PhD, University Hospital HM Puerta del Sur, Mostoles, Spain, explained that, in severe cases of refractory motor manifestations such as tremor and motor complications, a neurosurgical approach using deep-brain stimulation of the subthalamic nucleus can be used. But to avoid craniotomy and electrode penetration, MRI-guided focused ultrasound for the ablation of deep-brain structures, including the subthalamic nucleus, is being investigated as a treatment for Parkinson’s disease.
Patients are potential candidates for ultrasound ablation if they have prominently asymmetric parkinsonism, if they are not considered to be clinically suitable candidates for surgery because of contraindications, or if they are reluctant to undergo a brain operation or to have an implanted device.
The current trial involved 40 patients with markedly asymmetric Parkinson’s disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation surgery. They were randomly assigned in a 2:1 ratio to undergo focused ultrasound subthalamotomy on the side opposite their main motor signs or a sham procedure.
Results showed that the mean Movement Disorder Society–Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III) motor score for the more affected side – which was the primary endpoint – decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points); and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points). The between-group difference was 8.1 points (P < .001).
The change from baseline in the MDS-UPDRS III score for the more affected side in patients who underwent active treatment varied, ranging from 5% to 95%; the changes were qualitatively more evident for reduction of tremor and rigidity than for bradykinesia.
Adverse events in the active-treatment group were the following:
- Dyskinesia in the off-medication state in six patients and in the on-medication state in six, which persisted in three and one, respectively, at 4 months.
- Weakness on the treated side in five patients, which persisted in two at 4 months.
- Speech disturbance in 15 patients, which persisted in 3 at 4 months.
- Facial weakness in three patients, which persisted in one at 4 months.
- in 13 patients, which persisted in two at 4 months.
In six patients in the active-treatment group, some of these deficits were present at 12 months.
The researchers noted that an approach that has been suggested to reduce the risk of dyskinesias has been to extend ablations dorsal to the subthalamic nucleus in order to interrupt the pallidothalamic-projecting neurons.
The study also showed a greater reduction in the use of dopaminergic medication in the active-treatment group versus the control group, but the researchers noted that the 95% confidence intervals for this and other secondary outcomes were not adjusted for multiple comparisons, so no definite conclusions can be drawn from these data.
They also pointed out that subthalamotomy was performed in one hemisphere, and the natural evolution of Parkinson’s disease eventually leads to motor impairment on both sides of the body in most patients.
“The likely need for an increase in the daily dose of levodopa equivalent to maintain function on the untreated side of the body could lead to the development of dyskinesias on the treated side. However, the few open-label studies of long-term (≥36 months) follow-up of radiofrequency subthalamotomy performed in one hemisphere do not provide support for this concern,” they said.
An important step, but improvements are needed
In an accompanying editorial, Joel S. Perlmutter, MD, and Mwiza Ushe, MD, Washington University, St. Louis, noted that surgical deep brain stimulation of the left and right subthalamic nuclei has shown a reduction in the severity of motor signs of 40%-60% and a reduction in medication use of up to 50%. But this technique involves a small craniotomy with implantation of stimulating electrodes, which has a 1%-5% risk of major adverse events such as hemorrhage, stroke, or infection.
Less severe complications include dystonia, dysarthria, gait impairment, dyskinesia, swallowing dysfunction, or change in verbal fluency; however, modification of the device programming may alleviate these effects. Nevertheless, some patients are wary of the implantation surgery and hardware and therefore decline to undergo deep-brain stimulation, the editorialists explained.
“The development of alternative procedures to deep-brain stimulation is important to the field of Parkinson’s disease treatment. The current trial begins the path to that goal, and improvements in targeting may improve the risk-benefit ratio and permit the use of lesions in both hemispheres, which would widen the population of eligible patients,” Dr. Perlmutter and Dr. Ushe wrote.
They pointed out that limiting the treatment to one side of the brain by ultrasound-produced lesioning constrains the application, since most patients with Parkinson’s disease have progression of symptoms on both sides of the body.
“The potential advantages and limitations of focused ultrasound–produced lesioning should be discussed with patients. We hope that improved technique will reduce the associated risks and increase the applicability of this provocative procedure,” the editorialists concluded.
This study was supported by Insightec, the Focused Ultrasound Foundation, Fundacion MAPFRE, Fundacion Hospitales de Madrid, and the University of Virginia Center of Excellence. Dr. Martinez-Fernandez reported receiving for consultancy fees for Insightec. Dr. Ushe reported non-financial support for Abbott outside the submitted work. Dr. Perlmutter disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
including dyskinesias and other neurologic complications, in a new randomized, sham-controlled trial.
“Longer-term and larger trials are needed to determine the role of focused ultrasound subthalamotomy in the management of Parkinson’s disease and its effect as compared with other available treatments, including deep-brain stimulation,” the authors concluded.
The trial was published online Dec.24, 2020, in the New England Journal of Medicine.
An accompanying editorial concluded that the high rate of adverse events and the lack of ability to modulate treatment over time to treat prominent tremor “raise questions about the appropriate implementation of focused ultrasound–produced lesions for the treatment of Parkinson’s disease.”
A scalpel-free alternative to brain surgery
The study authors, led by Raul Martinez-Fernandez, MD, PhD, University Hospital HM Puerta del Sur, Mostoles, Spain, explained that, in severe cases of refractory motor manifestations such as tremor and motor complications, a neurosurgical approach using deep-brain stimulation of the subthalamic nucleus can be used. But to avoid craniotomy and electrode penetration, MRI-guided focused ultrasound for the ablation of deep-brain structures, including the subthalamic nucleus, is being investigated as a treatment for Parkinson’s disease.
Patients are potential candidates for ultrasound ablation if they have prominently asymmetric parkinsonism, if they are not considered to be clinically suitable candidates for surgery because of contraindications, or if they are reluctant to undergo a brain operation or to have an implanted device.
The current trial involved 40 patients with markedly asymmetric Parkinson’s disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation surgery. They were randomly assigned in a 2:1 ratio to undergo focused ultrasound subthalamotomy on the side opposite their main motor signs or a sham procedure.
Results showed that the mean Movement Disorder Society–Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III) motor score for the more affected side – which was the primary endpoint – decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points); and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points). The between-group difference was 8.1 points (P < .001).
The change from baseline in the MDS-UPDRS III score for the more affected side in patients who underwent active treatment varied, ranging from 5% to 95%; the changes were qualitatively more evident for reduction of tremor and rigidity than for bradykinesia.
Adverse events in the active-treatment group were the following:
- Dyskinesia in the off-medication state in six patients and in the on-medication state in six, which persisted in three and one, respectively, at 4 months.
- Weakness on the treated side in five patients, which persisted in two at 4 months.
- Speech disturbance in 15 patients, which persisted in 3 at 4 months.
- Facial weakness in three patients, which persisted in one at 4 months.
- in 13 patients, which persisted in two at 4 months.
In six patients in the active-treatment group, some of these deficits were present at 12 months.
The researchers noted that an approach that has been suggested to reduce the risk of dyskinesias has been to extend ablations dorsal to the subthalamic nucleus in order to interrupt the pallidothalamic-projecting neurons.
The study also showed a greater reduction in the use of dopaminergic medication in the active-treatment group versus the control group, but the researchers noted that the 95% confidence intervals for this and other secondary outcomes were not adjusted for multiple comparisons, so no definite conclusions can be drawn from these data.
They also pointed out that subthalamotomy was performed in one hemisphere, and the natural evolution of Parkinson’s disease eventually leads to motor impairment on both sides of the body in most patients.
“The likely need for an increase in the daily dose of levodopa equivalent to maintain function on the untreated side of the body could lead to the development of dyskinesias on the treated side. However, the few open-label studies of long-term (≥36 months) follow-up of radiofrequency subthalamotomy performed in one hemisphere do not provide support for this concern,” they said.
An important step, but improvements are needed
In an accompanying editorial, Joel S. Perlmutter, MD, and Mwiza Ushe, MD, Washington University, St. Louis, noted that surgical deep brain stimulation of the left and right subthalamic nuclei has shown a reduction in the severity of motor signs of 40%-60% and a reduction in medication use of up to 50%. But this technique involves a small craniotomy with implantation of stimulating electrodes, which has a 1%-5% risk of major adverse events such as hemorrhage, stroke, or infection.
Less severe complications include dystonia, dysarthria, gait impairment, dyskinesia, swallowing dysfunction, or change in verbal fluency; however, modification of the device programming may alleviate these effects. Nevertheless, some patients are wary of the implantation surgery and hardware and therefore decline to undergo deep-brain stimulation, the editorialists explained.
“The development of alternative procedures to deep-brain stimulation is important to the field of Parkinson’s disease treatment. The current trial begins the path to that goal, and improvements in targeting may improve the risk-benefit ratio and permit the use of lesions in both hemispheres, which would widen the population of eligible patients,” Dr. Perlmutter and Dr. Ushe wrote.
They pointed out that limiting the treatment to one side of the brain by ultrasound-produced lesioning constrains the application, since most patients with Parkinson’s disease have progression of symptoms on both sides of the body.
“The potential advantages and limitations of focused ultrasound–produced lesioning should be discussed with patients. We hope that improved technique will reduce the associated risks and increase the applicability of this provocative procedure,” the editorialists concluded.
This study was supported by Insightec, the Focused Ultrasound Foundation, Fundacion MAPFRE, Fundacion Hospitales de Madrid, and the University of Virginia Center of Excellence. Dr. Martinez-Fernandez reported receiving for consultancy fees for Insightec. Dr. Ushe reported non-financial support for Abbott outside the submitted work. Dr. Perlmutter disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
including dyskinesias and other neurologic complications, in a new randomized, sham-controlled trial.
“Longer-term and larger trials are needed to determine the role of focused ultrasound subthalamotomy in the management of Parkinson’s disease and its effect as compared with other available treatments, including deep-brain stimulation,” the authors concluded.
The trial was published online Dec.24, 2020, in the New England Journal of Medicine.
An accompanying editorial concluded that the high rate of adverse events and the lack of ability to modulate treatment over time to treat prominent tremor “raise questions about the appropriate implementation of focused ultrasound–produced lesions for the treatment of Parkinson’s disease.”
A scalpel-free alternative to brain surgery
The study authors, led by Raul Martinez-Fernandez, MD, PhD, University Hospital HM Puerta del Sur, Mostoles, Spain, explained that, in severe cases of refractory motor manifestations such as tremor and motor complications, a neurosurgical approach using deep-brain stimulation of the subthalamic nucleus can be used. But to avoid craniotomy and electrode penetration, MRI-guided focused ultrasound for the ablation of deep-brain structures, including the subthalamic nucleus, is being investigated as a treatment for Parkinson’s disease.
Patients are potential candidates for ultrasound ablation if they have prominently asymmetric parkinsonism, if they are not considered to be clinically suitable candidates for surgery because of contraindications, or if they are reluctant to undergo a brain operation or to have an implanted device.
The current trial involved 40 patients with markedly asymmetric Parkinson’s disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation surgery. They were randomly assigned in a 2:1 ratio to undergo focused ultrasound subthalamotomy on the side opposite their main motor signs or a sham procedure.
Results showed that the mean Movement Disorder Society–Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS III) motor score for the more affected side – which was the primary endpoint – decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points); and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points). The between-group difference was 8.1 points (P < .001).
The change from baseline in the MDS-UPDRS III score for the more affected side in patients who underwent active treatment varied, ranging from 5% to 95%; the changes were qualitatively more evident for reduction of tremor and rigidity than for bradykinesia.
Adverse events in the active-treatment group were the following:
- Dyskinesia in the off-medication state in six patients and in the on-medication state in six, which persisted in three and one, respectively, at 4 months.
- Weakness on the treated side in five patients, which persisted in two at 4 months.
- Speech disturbance in 15 patients, which persisted in 3 at 4 months.
- Facial weakness in three patients, which persisted in one at 4 months.
- in 13 patients, which persisted in two at 4 months.
In six patients in the active-treatment group, some of these deficits were present at 12 months.
The researchers noted that an approach that has been suggested to reduce the risk of dyskinesias has been to extend ablations dorsal to the subthalamic nucleus in order to interrupt the pallidothalamic-projecting neurons.
The study also showed a greater reduction in the use of dopaminergic medication in the active-treatment group versus the control group, but the researchers noted that the 95% confidence intervals for this and other secondary outcomes were not adjusted for multiple comparisons, so no definite conclusions can be drawn from these data.
They also pointed out that subthalamotomy was performed in one hemisphere, and the natural evolution of Parkinson’s disease eventually leads to motor impairment on both sides of the body in most patients.
“The likely need for an increase in the daily dose of levodopa equivalent to maintain function on the untreated side of the body could lead to the development of dyskinesias on the treated side. However, the few open-label studies of long-term (≥36 months) follow-up of radiofrequency subthalamotomy performed in one hemisphere do not provide support for this concern,” they said.
An important step, but improvements are needed
In an accompanying editorial, Joel S. Perlmutter, MD, and Mwiza Ushe, MD, Washington University, St. Louis, noted that surgical deep brain stimulation of the left and right subthalamic nuclei has shown a reduction in the severity of motor signs of 40%-60% and a reduction in medication use of up to 50%. But this technique involves a small craniotomy with implantation of stimulating electrodes, which has a 1%-5% risk of major adverse events such as hemorrhage, stroke, or infection.
Less severe complications include dystonia, dysarthria, gait impairment, dyskinesia, swallowing dysfunction, or change in verbal fluency; however, modification of the device programming may alleviate these effects. Nevertheless, some patients are wary of the implantation surgery and hardware and therefore decline to undergo deep-brain stimulation, the editorialists explained.
“The development of alternative procedures to deep-brain stimulation is important to the field of Parkinson’s disease treatment. The current trial begins the path to that goal, and improvements in targeting may improve the risk-benefit ratio and permit the use of lesions in both hemispheres, which would widen the population of eligible patients,” Dr. Perlmutter and Dr. Ushe wrote.
They pointed out that limiting the treatment to one side of the brain by ultrasound-produced lesioning constrains the application, since most patients with Parkinson’s disease have progression of symptoms on both sides of the body.
“The potential advantages and limitations of focused ultrasound–produced lesioning should be discussed with patients. We hope that improved technique will reduce the associated risks and increase the applicability of this provocative procedure,” the editorialists concluded.
This study was supported by Insightec, the Focused Ultrasound Foundation, Fundacion MAPFRE, Fundacion Hospitales de Madrid, and the University of Virginia Center of Excellence. Dr. Martinez-Fernandez reported receiving for consultancy fees for Insightec. Dr. Ushe reported non-financial support for Abbott outside the submitted work. Dr. Perlmutter disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Clinical Edge Commentary: Breast Cancer January 2021
Breast cancer patients treated with curative intent do not often experience symptoms related to the cancer itself, and treatment toxicities may impact adherence and subsequently prognosis. Mittendorf et al reported on patient reported outcomes (PROs) from the phase 3 IMpassion031 trial which showed pCR improvement with atezolizumab/chemotherapy compared to placebo/chemotherapy for neoadjuvant early-stage TNBC. Health-related quality of life items and treatment-related symptoms worsened similarly in both arms during neoadjuvant therapy, and recovered/stabilized in the adjuvant setting. Further exploration of immunotherapy PROs is warranted, as clinical benefit is seen with these agents and they do not appear to negatively impact functioning and patient experience with treatment long-term. Side effect profiles of immunotherapy and standard chemotherapy are different, and design of immunotherapy-specific PROs are desired.
The PRIME 2 10 year results evaluating the role of whole breast irradiation in women ≥65 years with early-stage HR-positive breast cancer receiving hormonal therapy showed RT reduced risk of local recurrence from 9.8% to 0.9% at 10 years (p=0.0008). Patients with low ER tumors had higher 10 year local recurrence rate compared to high ER tumors (18.8% versus 9.2% (p0.007)). Rates of overall survival (80.4% in no RT group vs 81.0% in RT group) and metastasis free survival were similar. A shared decision making approach is key, carefully weighing benefits and risks, considering pathologic features, patient preferences and co-morbidities that may influence endocrine therapy adherence. The impact of molecular subtypes and genomic assays is also being explored to help assess radiation benefit and guide treatment recommendations.
Breast cancer in young women presents unique challenges considering the lifetime period during which diagnosis occurs. Previous studies have supported the safety of pregnancy after breast cancer and guidelines recommend oncofertility counseling in young patients. Blondeaux et al found that breast cancer patients had a 60% lower chance of pregnancy after treatment and were more likely to have complications including low birth weight, small for gestational age, preterm delivery and cesarean section. Although increased risk of congenital abnormalities did not appear to be statistically significant, the HR was 1.63. Importantly, pregnancy after breast cancer did not negatively impact maternal outcomes. This study further supports the safety of pregnancy after breast cancer, highlights the need for close monitoring of pregnancies in these women, and emphasizes the importance of fertility and family planning discussion, which is most optimally provided in a multidisciplinary fashion.
References:
Dent R, Oliveira AM, Isakoff SJ, Im SA, Espié M, Blau S, Saura C, Wongchenko MJ, Xu N, Bradley D, Reilly SJ, Mani A, Kim SB. Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). Presented during 2020 ESMO breast cancer virtual meeting; May 23-24, 2020. Abstract 139O.
Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, Hall PS, Perren T, Stein RC, Mangel L, Ferrero JM, Phillips M, Conibear J, Cortes J, Foxley A, de Bruin EC, McEwen R, Stetson D, Dougherty B, Sarker SJ, Prendergast A, McLaughlin-Callan M, Burgess M, Lawrence C, Cartwright H, Mousa K, Turner NC. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38:423-433.
Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396:1090-1100.
King-Kallimanis BL, Howie LJ, Roydhouse JK, Singh H, Theoret MR, Blumenthal GM, Kluetz PG. Patient reported outcomes in anti-PD-1/PD-L1 inhibitor immunotherapy registration trials: FDA analysis of data submitted and future directions. Clin Trials. 2019;16:322-326.
Fodor A, Brombin C, Mangili P, Borroni F, Pasetti M, Tummineri R, Zerbetto F, Longobardi B, Perna L, Dell'Oca I, Deantoni CL, Deli AM, Chiara A, Broggi S, Castriconi R, Esposito PG, Slim N, Passoni P, Baroni S, Villa SL, Rancoita PMV, Fiorino C, Del Vecchio A, Bianchini G, Gentilini OD, Di Serio MS, Di Muzio NG. Impact of molecular subtype on 1325 early-stage breast cancer patients homogeneously treated with hypofractionated radiotherapy without boost: Should the indications for radiotherapy be more personalized? Breast. 2020;55:45-54.
Azim HA Jr, Santoro L, Pavlidis N, Gelber S, Kroman N, Azim H, Peccatori FA. Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies. Eur J Cancer. 2011;47:74-83.
Breast cancer patients treated with curative intent do not often experience symptoms related to the cancer itself, and treatment toxicities may impact adherence and subsequently prognosis. Mittendorf et al reported on patient reported outcomes (PROs) from the phase 3 IMpassion031 trial which showed pCR improvement with atezolizumab/chemotherapy compared to placebo/chemotherapy for neoadjuvant early-stage TNBC. Health-related quality of life items and treatment-related symptoms worsened similarly in both arms during neoadjuvant therapy, and recovered/stabilized in the adjuvant setting. Further exploration of immunotherapy PROs is warranted, as clinical benefit is seen with these agents and they do not appear to negatively impact functioning and patient experience with treatment long-term. Side effect profiles of immunotherapy and standard chemotherapy are different, and design of immunotherapy-specific PROs are desired.
The PRIME 2 10 year results evaluating the role of whole breast irradiation in women ≥65 years with early-stage HR-positive breast cancer receiving hormonal therapy showed RT reduced risk of local recurrence from 9.8% to 0.9% at 10 years (p=0.0008). Patients with low ER tumors had higher 10 year local recurrence rate compared to high ER tumors (18.8% versus 9.2% (p0.007)). Rates of overall survival (80.4% in no RT group vs 81.0% in RT group) and metastasis free survival were similar. A shared decision making approach is key, carefully weighing benefits and risks, considering pathologic features, patient preferences and co-morbidities that may influence endocrine therapy adherence. The impact of molecular subtypes and genomic assays is also being explored to help assess radiation benefit and guide treatment recommendations.
Breast cancer in young women presents unique challenges considering the lifetime period during which diagnosis occurs. Previous studies have supported the safety of pregnancy after breast cancer and guidelines recommend oncofertility counseling in young patients. Blondeaux et al found that breast cancer patients had a 60% lower chance of pregnancy after treatment and were more likely to have complications including low birth weight, small for gestational age, preterm delivery and cesarean section. Although increased risk of congenital abnormalities did not appear to be statistically significant, the HR was 1.63. Importantly, pregnancy after breast cancer did not negatively impact maternal outcomes. This study further supports the safety of pregnancy after breast cancer, highlights the need for close monitoring of pregnancies in these women, and emphasizes the importance of fertility and family planning discussion, which is most optimally provided in a multidisciplinary fashion.
References:
Dent R, Oliveira AM, Isakoff SJ, Im SA, Espié M, Blau S, Saura C, Wongchenko MJ, Xu N, Bradley D, Reilly SJ, Mani A, Kim SB. Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). Presented during 2020 ESMO breast cancer virtual meeting; May 23-24, 2020. Abstract 139O.
Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, Hall PS, Perren T, Stein RC, Mangel L, Ferrero JM, Phillips M, Conibear J, Cortes J, Foxley A, de Bruin EC, McEwen R, Stetson D, Dougherty B, Sarker SJ, Prendergast A, McLaughlin-Callan M, Burgess M, Lawrence C, Cartwright H, Mousa K, Turner NC. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38:423-433.
Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396:1090-1100.
King-Kallimanis BL, Howie LJ, Roydhouse JK, Singh H, Theoret MR, Blumenthal GM, Kluetz PG. Patient reported outcomes in anti-PD-1/PD-L1 inhibitor immunotherapy registration trials: FDA analysis of data submitted and future directions. Clin Trials. 2019;16:322-326.
Fodor A, Brombin C, Mangili P, Borroni F, Pasetti M, Tummineri R, Zerbetto F, Longobardi B, Perna L, Dell'Oca I, Deantoni CL, Deli AM, Chiara A, Broggi S, Castriconi R, Esposito PG, Slim N, Passoni P, Baroni S, Villa SL, Rancoita PMV, Fiorino C, Del Vecchio A, Bianchini G, Gentilini OD, Di Serio MS, Di Muzio NG. Impact of molecular subtype on 1325 early-stage breast cancer patients homogeneously treated with hypofractionated radiotherapy without boost: Should the indications for radiotherapy be more personalized? Breast. 2020;55:45-54.
Azim HA Jr, Santoro L, Pavlidis N, Gelber S, Kroman N, Azim H, Peccatori FA. Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies. Eur J Cancer. 2011;47:74-83.
Breast cancer patients treated with curative intent do not often experience symptoms related to the cancer itself, and treatment toxicities may impact adherence and subsequently prognosis. Mittendorf et al reported on patient reported outcomes (PROs) from the phase 3 IMpassion031 trial which showed pCR improvement with atezolizumab/chemotherapy compared to placebo/chemotherapy for neoadjuvant early-stage TNBC. Health-related quality of life items and treatment-related symptoms worsened similarly in both arms during neoadjuvant therapy, and recovered/stabilized in the adjuvant setting. Further exploration of immunotherapy PROs is warranted, as clinical benefit is seen with these agents and they do not appear to negatively impact functioning and patient experience with treatment long-term. Side effect profiles of immunotherapy and standard chemotherapy are different, and design of immunotherapy-specific PROs are desired.
The PRIME 2 10 year results evaluating the role of whole breast irradiation in women ≥65 years with early-stage HR-positive breast cancer receiving hormonal therapy showed RT reduced risk of local recurrence from 9.8% to 0.9% at 10 years (p=0.0008). Patients with low ER tumors had higher 10 year local recurrence rate compared to high ER tumors (18.8% versus 9.2% (p0.007)). Rates of overall survival (80.4% in no RT group vs 81.0% in RT group) and metastasis free survival were similar. A shared decision making approach is key, carefully weighing benefits and risks, considering pathologic features, patient preferences and co-morbidities that may influence endocrine therapy adherence. The impact of molecular subtypes and genomic assays is also being explored to help assess radiation benefit and guide treatment recommendations.
Breast cancer in young women presents unique challenges considering the lifetime period during which diagnosis occurs. Previous studies have supported the safety of pregnancy after breast cancer and guidelines recommend oncofertility counseling in young patients. Blondeaux et al found that breast cancer patients had a 60% lower chance of pregnancy after treatment and were more likely to have complications including low birth weight, small for gestational age, preterm delivery and cesarean section. Although increased risk of congenital abnormalities did not appear to be statistically significant, the HR was 1.63. Importantly, pregnancy after breast cancer did not negatively impact maternal outcomes. This study further supports the safety of pregnancy after breast cancer, highlights the need for close monitoring of pregnancies in these women, and emphasizes the importance of fertility and family planning discussion, which is most optimally provided in a multidisciplinary fashion.
References:
Dent R, Oliveira AM, Isakoff SJ, Im SA, Espié M, Blau S, Saura C, Wongchenko MJ, Xu N, Bradley D, Reilly SJ, Mani A, Kim SB. Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). Presented during 2020 ESMO breast cancer virtual meeting; May 23-24, 2020. Abstract 139O.
Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, Hall PS, Perren T, Stein RC, Mangel L, Ferrero JM, Phillips M, Conibear J, Cortes J, Foxley A, de Bruin EC, McEwen R, Stetson D, Dougherty B, Sarker SJ, Prendergast A, McLaughlin-Callan M, Burgess M, Lawrence C, Cartwright H, Mousa K, Turner NC. Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: the PAKT trial. J Clin Oncol. 2020;38:423-433.
Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020;396:1090-1100.
King-Kallimanis BL, Howie LJ, Roydhouse JK, Singh H, Theoret MR, Blumenthal GM, Kluetz PG. Patient reported outcomes in anti-PD-1/PD-L1 inhibitor immunotherapy registration trials: FDA analysis of data submitted and future directions. Clin Trials. 2019;16:322-326.
Fodor A, Brombin C, Mangili P, Borroni F, Pasetti M, Tummineri R, Zerbetto F, Longobardi B, Perna L, Dell'Oca I, Deantoni CL, Deli AM, Chiara A, Broggi S, Castriconi R, Esposito PG, Slim N, Passoni P, Baroni S, Villa SL, Rancoita PMV, Fiorino C, Del Vecchio A, Bianchini G, Gentilini OD, Di Serio MS, Di Muzio NG. Impact of molecular subtype on 1325 early-stage breast cancer patients homogeneously treated with hypofractionated radiotherapy without boost: Should the indications for radiotherapy be more personalized? Breast. 2020;55:45-54.
Azim HA Jr, Santoro L, Pavlidis N, Gelber S, Kroman N, Azim H, Peccatori FA. Safety of pregnancy following breast cancer diagnosis: a meta-analysis of 14 studies. Eur J Cancer. 2011;47:74-83.
Omitting postop radiotherapy doesn’t affect survival in older breast cancer patients
Key clinical point: Omitting adjuvant radiotherapy may be an option for some older women with low-risk, hormone receptor-positive breast cancer who are receiving appropriate endocrine treatment.
Major finding: The 10-year rate of ipsilateral recurrence was lower with radiotherapy than without (0.9% vs. 9.8%, P = .00008), but there was no significant between-arm difference in 10-year overall survival (81.0% and 80.4%, respectively; P = .68).
Study details: A phase 3, randomized trial of 1,326 women age 65 and older with hormone receptor–positive, low-risk early breast cancer undergoing breast-conserving surgery and receiving adjuvant endocrine therapy with or without whole breast irradiation (40-50 Gy in 15-25 fractions).
Disclosures: The study was funded by the Chief Scientist Office (Scottish Government) and the Breast Cancer Institute at the Western General Hospital in Edinburgh, Scotland. Dr. Kunkler did not have any disclosures.
Source: Kunkler IH J et al. SABCS 2020, Abstract GS2-03.
Key clinical point: Omitting adjuvant radiotherapy may be an option for some older women with low-risk, hormone receptor-positive breast cancer who are receiving appropriate endocrine treatment.
Major finding: The 10-year rate of ipsilateral recurrence was lower with radiotherapy than without (0.9% vs. 9.8%, P = .00008), but there was no significant between-arm difference in 10-year overall survival (81.0% and 80.4%, respectively; P = .68).
Study details: A phase 3, randomized trial of 1,326 women age 65 and older with hormone receptor–positive, low-risk early breast cancer undergoing breast-conserving surgery and receiving adjuvant endocrine therapy with or without whole breast irradiation (40-50 Gy in 15-25 fractions).
Disclosures: The study was funded by the Chief Scientist Office (Scottish Government) and the Breast Cancer Institute at the Western General Hospital in Edinburgh, Scotland. Dr. Kunkler did not have any disclosures.
Source: Kunkler IH J et al. SABCS 2020, Abstract GS2-03.
Key clinical point: Omitting adjuvant radiotherapy may be an option for some older women with low-risk, hormone receptor-positive breast cancer who are receiving appropriate endocrine treatment.
Major finding: The 10-year rate of ipsilateral recurrence was lower with radiotherapy than without (0.9% vs. 9.8%, P = .00008), but there was no significant between-arm difference in 10-year overall survival (81.0% and 80.4%, respectively; P = .68).
Study details: A phase 3, randomized trial of 1,326 women age 65 and older with hormone receptor–positive, low-risk early breast cancer undergoing breast-conserving surgery and receiving adjuvant endocrine therapy with or without whole breast irradiation (40-50 Gy in 15-25 fractions).
Disclosures: The study was funded by the Chief Scientist Office (Scottish Government) and the Breast Cancer Institute at the Western General Hospital in Edinburgh, Scotland. Dr. Kunkler did not have any disclosures.
Source: Kunkler IH J et al. SABCS 2020, Abstract GS2-03.
PENELOPE-B: Palbociclib disappoints in HR+, HER2– breast cancer
Key clinical point: One year of palbociclib added to endocrine therapy after neoadjuvant chemotherapy did not improve invasive disease-free survival when compared with placebo plus endocrine therapy in women with hormone receptor–positive, HER2-negative primary breast cancer.
Major finding: The 4-year invasive disease-free survival rate was 73.0% for palbociclib and 72.4% for placebo (hazard ratio, 0.93; P = .525).
Study details: A phase 3 trial of 1,250 women with hormone receptor–positive, HER2-negative primary breast cancer who were at high risk of relapse after neoadjuvant chemotherapy.
Disclosures: The trial was sponsored by the German Breast Group in collaboration with Pfizer, the AGO Study Group, NSABP Foundation, and the Breast International Group. Dr. Loibl disclosed grant and other support from Pfizer during the conduct of the study, relationships with other companies outside the submitted work, a pending patent for a method to predict response to anti-HER2–containing therapy and/or chemotherapy, and a relationship with Medscape, which is owned by the same company as MDedge.
Source: Loibl S et al. SABCS 2020, Abstract GS1-02.
Key clinical point: One year of palbociclib added to endocrine therapy after neoadjuvant chemotherapy did not improve invasive disease-free survival when compared with placebo plus endocrine therapy in women with hormone receptor–positive, HER2-negative primary breast cancer.
Major finding: The 4-year invasive disease-free survival rate was 73.0% for palbociclib and 72.4% for placebo (hazard ratio, 0.93; P = .525).
Study details: A phase 3 trial of 1,250 women with hormone receptor–positive, HER2-negative primary breast cancer who were at high risk of relapse after neoadjuvant chemotherapy.
Disclosures: The trial was sponsored by the German Breast Group in collaboration with Pfizer, the AGO Study Group, NSABP Foundation, and the Breast International Group. Dr. Loibl disclosed grant and other support from Pfizer during the conduct of the study, relationships with other companies outside the submitted work, a pending patent for a method to predict response to anti-HER2–containing therapy and/or chemotherapy, and a relationship with Medscape, which is owned by the same company as MDedge.
Source: Loibl S et al. SABCS 2020, Abstract GS1-02.
Key clinical point: One year of palbociclib added to endocrine therapy after neoadjuvant chemotherapy did not improve invasive disease-free survival when compared with placebo plus endocrine therapy in women with hormone receptor–positive, HER2-negative primary breast cancer.
Major finding: The 4-year invasive disease-free survival rate was 73.0% for palbociclib and 72.4% for placebo (hazard ratio, 0.93; P = .525).
Study details: A phase 3 trial of 1,250 women with hormone receptor–positive, HER2-negative primary breast cancer who were at high risk of relapse after neoadjuvant chemotherapy.
Disclosures: The trial was sponsored by the German Breast Group in collaboration with Pfizer, the AGO Study Group, NSABP Foundation, and the Breast International Group. Dr. Loibl disclosed grant and other support from Pfizer during the conduct of the study, relationships with other companies outside the submitted work, a pending patent for a method to predict response to anti-HER2–containing therapy and/or chemotherapy, and a relationship with Medscape, which is owned by the same company as MDedge.
Source: Loibl S et al. SABCS 2020, Abstract GS1-02.
Diabetes prevention diet may lower mortality risk in breast cancer
Key clinical point: Diet may influence breast cancer outcomes.
Major finding: Women who adhered to the healthiest diet had a 31% lower risk for all-cause mortality versus women in the lowest tier for dietary health.
Study details: A retrospective study of 8,320 women with breast cancer in the first and second Nurses’ Health Studies.
Disclosures: This research was supported, in part, by grants from the National Cancer Institute, Breast Cancer Research Foundations, and Susan G. Komen Breast Cancer Foundations. Dr. Wang reported no relevant conflicts of interest.
Source: Wang T et al. SABCS 2020, Abstract GS2-09.
Key clinical point: Diet may influence breast cancer outcomes.
Major finding: Women who adhered to the healthiest diet had a 31% lower risk for all-cause mortality versus women in the lowest tier for dietary health.
Study details: A retrospective study of 8,320 women with breast cancer in the first and second Nurses’ Health Studies.
Disclosures: This research was supported, in part, by grants from the National Cancer Institute, Breast Cancer Research Foundations, and Susan G. Komen Breast Cancer Foundations. Dr. Wang reported no relevant conflicts of interest.
Source: Wang T et al. SABCS 2020, Abstract GS2-09.
Key clinical point: Diet may influence breast cancer outcomes.
Major finding: Women who adhered to the healthiest diet had a 31% lower risk for all-cause mortality versus women in the lowest tier for dietary health.
Study details: A retrospective study of 8,320 women with breast cancer in the first and second Nurses’ Health Studies.
Disclosures: This research was supported, in part, by grants from the National Cancer Institute, Breast Cancer Research Foundations, and Susan G. Komen Breast Cancer Foundations. Dr. Wang reported no relevant conflicts of interest.
Source: Wang T et al. SABCS 2020, Abstract GS2-09.