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Many pandemic-driven changes to cancer clinical trials should remain
Many of the changes to cancer clinical trials forced through by the COVID-19 pandemic should remain, as they have made trials “more patient centered and efficient,” according to a group of thought leaders in oncology.
Among the potential improvements were more efficient study enrollment through secure electronic platforms, direct shipment of oral drugs to patients, remote assessment of adverse events, and streamlined data collection.
These changes should be implemented on a permanent basis, the group argues in a commentary published online July 21, 2021, in Cancer Discovery, a journal of the American Association for Cancer Research.
“The ability to distribute oral investigational drugs by mail to patients at their home has probably been the single most impactful change to clinical trial conduct, linked with virtual visits with patients to assess side effects and symptoms,” commented lead author Keith Flaherty, MD, who is director of clinical research at Massachusetts General Hospital, a professor at Harvard Medical School, Boston, and a member of the AACR board of directors.
“This has made it more feasible for patients for whom participation in clinical trials poses a disruption of their ability to work or provide care for family members to participate in trials,” he added in a press statement issued by the AACR.
Pandemic halted many clinical trials
A survey of cancer programs in early 2020 showed that nearly 60% halted screening and/or enrollment for at least some trials because of COVID-19.
“In the spring of 2020, clinical trial conduct halted and then restarted focusing on the bare minimum procedures that first allowed patients continued access to their experimental therapies, and then allowed clinical trial sites and sponsors to collect information on the effects of the therapies,” the authors said.
“The COVID-19–induced changes to clinical trials were a big challenge, probably the largest change in clinical trial conduct since the start of modern oncology clinical testing,” they commented.
“But it also represents an opportunity to rethink the key aspects of clinical trial conduct that are strictly necessary to reach the goal of testing the effectiveness of cancer therapies, and which others are dispensable or provide only minor additional contributions,” they added.
As previously reported at the time by this news organization, efforts to find alternative approaches to conducting trials amid the pandemic led to the emergence of a few “silver linings.”
Key adaptations made to clinical trials and highlighted by the authors include:
- Uptake of remote consenting and telemedicine
- Use of alternative laboratories and imaging centers
- Delivery or administration of investigational drugs at patients’ homes or local clinics
- Commercial attainment of study drugs already approved for other indications
Indeed, the restrictions encountered during the pandemic underscore the importance of designing patient-centered trials versus study site–centered trials, added Antoni Ribas, MD, commentary coauthor and immediate past president of the AACR.
Many of the changes implemented during the pandemic could help increase access for patients living in underserved communities who are underrepresented in clinical trials, he explained.
Harnessing the lessons learned
The authors also recommended the following additional adaptations, which they believe will enhance efficiency and further expand access to clinical trials:
- Incorporating patient-reported outcomes and alternative endpoints in efficacy assessments
- Aiming for 100% remote drug infusions and monitoring
- Increasing funding for clinical trials conducted in underserved communities
- Expanding clinical trial eligibility to include patients with a wide range of comorbidities
- Reducing collection of low-grade adverse events and allowing minor protocol deviations
The group’s recommendations are based on discussions by the AACR COVID-19 and Cancer Task Force, in which they participated.
The American Society of Clinical Oncology is also working to leverage pandemic-related lessons to streamline care and trial planning.
ASCO’s “Road to Recovery” recommendations, published in December 2020, aim to “ensure lessons learned from the COVID-19 experience are used to craft a more equitable, accessible, and efficient clinical research system that protects patient safety, ensures scientific integrity, and maintains data quality,” the authors explained.
Dr. Flaherty and colleagues further underscore the importance of focusing on improvements going forward.
“Guided by lessons learned, many of the remote assessments and trial efficiencies deployed during the pandemic can be preserved and improved upon. We strongly encourage use of these streamlined procedures where appropriate in future prospectively designed cancer clinical trials,” they wrote.
Dr. Flaherty reported receiving personal fees from numerous pharmaceutical companies. Dr. Ribas reported receiving grants from Agilent and Bristol Myers Squibb.
A version of this article first appeared on Medscape.com.
Many of the changes to cancer clinical trials forced through by the COVID-19 pandemic should remain, as they have made trials “more patient centered and efficient,” according to a group of thought leaders in oncology.
Among the potential improvements were more efficient study enrollment through secure electronic platforms, direct shipment of oral drugs to patients, remote assessment of adverse events, and streamlined data collection.
These changes should be implemented on a permanent basis, the group argues in a commentary published online July 21, 2021, in Cancer Discovery, a journal of the American Association for Cancer Research.
“The ability to distribute oral investigational drugs by mail to patients at their home has probably been the single most impactful change to clinical trial conduct, linked with virtual visits with patients to assess side effects and symptoms,” commented lead author Keith Flaherty, MD, who is director of clinical research at Massachusetts General Hospital, a professor at Harvard Medical School, Boston, and a member of the AACR board of directors.
“This has made it more feasible for patients for whom participation in clinical trials poses a disruption of their ability to work or provide care for family members to participate in trials,” he added in a press statement issued by the AACR.
Pandemic halted many clinical trials
A survey of cancer programs in early 2020 showed that nearly 60% halted screening and/or enrollment for at least some trials because of COVID-19.
“In the spring of 2020, clinical trial conduct halted and then restarted focusing on the bare minimum procedures that first allowed patients continued access to their experimental therapies, and then allowed clinical trial sites and sponsors to collect information on the effects of the therapies,” the authors said.
“The COVID-19–induced changes to clinical trials were a big challenge, probably the largest change in clinical trial conduct since the start of modern oncology clinical testing,” they commented.
“But it also represents an opportunity to rethink the key aspects of clinical trial conduct that are strictly necessary to reach the goal of testing the effectiveness of cancer therapies, and which others are dispensable or provide only minor additional contributions,” they added.
As previously reported at the time by this news organization, efforts to find alternative approaches to conducting trials amid the pandemic led to the emergence of a few “silver linings.”
Key adaptations made to clinical trials and highlighted by the authors include:
- Uptake of remote consenting and telemedicine
- Use of alternative laboratories and imaging centers
- Delivery or administration of investigational drugs at patients’ homes or local clinics
- Commercial attainment of study drugs already approved for other indications
Indeed, the restrictions encountered during the pandemic underscore the importance of designing patient-centered trials versus study site–centered trials, added Antoni Ribas, MD, commentary coauthor and immediate past president of the AACR.
Many of the changes implemented during the pandemic could help increase access for patients living in underserved communities who are underrepresented in clinical trials, he explained.
Harnessing the lessons learned
The authors also recommended the following additional adaptations, which they believe will enhance efficiency and further expand access to clinical trials:
- Incorporating patient-reported outcomes and alternative endpoints in efficacy assessments
- Aiming for 100% remote drug infusions and monitoring
- Increasing funding for clinical trials conducted in underserved communities
- Expanding clinical trial eligibility to include patients with a wide range of comorbidities
- Reducing collection of low-grade adverse events and allowing minor protocol deviations
The group’s recommendations are based on discussions by the AACR COVID-19 and Cancer Task Force, in which they participated.
The American Society of Clinical Oncology is also working to leverage pandemic-related lessons to streamline care and trial planning.
ASCO’s “Road to Recovery” recommendations, published in December 2020, aim to “ensure lessons learned from the COVID-19 experience are used to craft a more equitable, accessible, and efficient clinical research system that protects patient safety, ensures scientific integrity, and maintains data quality,” the authors explained.
Dr. Flaherty and colleagues further underscore the importance of focusing on improvements going forward.
“Guided by lessons learned, many of the remote assessments and trial efficiencies deployed during the pandemic can be preserved and improved upon. We strongly encourage use of these streamlined procedures where appropriate in future prospectively designed cancer clinical trials,” they wrote.
Dr. Flaherty reported receiving personal fees from numerous pharmaceutical companies. Dr. Ribas reported receiving grants from Agilent and Bristol Myers Squibb.
A version of this article first appeared on Medscape.com.
Many of the changes to cancer clinical trials forced through by the COVID-19 pandemic should remain, as they have made trials “more patient centered and efficient,” according to a group of thought leaders in oncology.
Among the potential improvements were more efficient study enrollment through secure electronic platforms, direct shipment of oral drugs to patients, remote assessment of adverse events, and streamlined data collection.
These changes should be implemented on a permanent basis, the group argues in a commentary published online July 21, 2021, in Cancer Discovery, a journal of the American Association for Cancer Research.
“The ability to distribute oral investigational drugs by mail to patients at their home has probably been the single most impactful change to clinical trial conduct, linked with virtual visits with patients to assess side effects and symptoms,” commented lead author Keith Flaherty, MD, who is director of clinical research at Massachusetts General Hospital, a professor at Harvard Medical School, Boston, and a member of the AACR board of directors.
“This has made it more feasible for patients for whom participation in clinical trials poses a disruption of their ability to work or provide care for family members to participate in trials,” he added in a press statement issued by the AACR.
Pandemic halted many clinical trials
A survey of cancer programs in early 2020 showed that nearly 60% halted screening and/or enrollment for at least some trials because of COVID-19.
“In the spring of 2020, clinical trial conduct halted and then restarted focusing on the bare minimum procedures that first allowed patients continued access to their experimental therapies, and then allowed clinical trial sites and sponsors to collect information on the effects of the therapies,” the authors said.
“The COVID-19–induced changes to clinical trials were a big challenge, probably the largest change in clinical trial conduct since the start of modern oncology clinical testing,” they commented.
“But it also represents an opportunity to rethink the key aspects of clinical trial conduct that are strictly necessary to reach the goal of testing the effectiveness of cancer therapies, and which others are dispensable or provide only minor additional contributions,” they added.
As previously reported at the time by this news organization, efforts to find alternative approaches to conducting trials amid the pandemic led to the emergence of a few “silver linings.”
Key adaptations made to clinical trials and highlighted by the authors include:
- Uptake of remote consenting and telemedicine
- Use of alternative laboratories and imaging centers
- Delivery or administration of investigational drugs at patients’ homes or local clinics
- Commercial attainment of study drugs already approved for other indications
Indeed, the restrictions encountered during the pandemic underscore the importance of designing patient-centered trials versus study site–centered trials, added Antoni Ribas, MD, commentary coauthor and immediate past president of the AACR.
Many of the changes implemented during the pandemic could help increase access for patients living in underserved communities who are underrepresented in clinical trials, he explained.
Harnessing the lessons learned
The authors also recommended the following additional adaptations, which they believe will enhance efficiency and further expand access to clinical trials:
- Incorporating patient-reported outcomes and alternative endpoints in efficacy assessments
- Aiming for 100% remote drug infusions and monitoring
- Increasing funding for clinical trials conducted in underserved communities
- Expanding clinical trial eligibility to include patients with a wide range of comorbidities
- Reducing collection of low-grade adverse events and allowing minor protocol deviations
The group’s recommendations are based on discussions by the AACR COVID-19 and Cancer Task Force, in which they participated.
The American Society of Clinical Oncology is also working to leverage pandemic-related lessons to streamline care and trial planning.
ASCO’s “Road to Recovery” recommendations, published in December 2020, aim to “ensure lessons learned from the COVID-19 experience are used to craft a more equitable, accessible, and efficient clinical research system that protects patient safety, ensures scientific integrity, and maintains data quality,” the authors explained.
Dr. Flaherty and colleagues further underscore the importance of focusing on improvements going forward.
“Guided by lessons learned, many of the remote assessments and trial efficiencies deployed during the pandemic can be preserved and improved upon. We strongly encourage use of these streamlined procedures where appropriate in future prospectively designed cancer clinical trials,” they wrote.
Dr. Flaherty reported receiving personal fees from numerous pharmaceutical companies. Dr. Ribas reported receiving grants from Agilent and Bristol Myers Squibb.
A version of this article first appeared on Medscape.com.
AGA News
AGA journals’ reach record-high Impact Factors
AGA is proud to announce that its journals have maintained their exceptional standing in the field of gastroenterology and hepatology, based on Impact Factor. The Impact Factor is a measure of the frequency with which articles published in the previous 2 years are cited and is commonly used to rank the significance of journals within their fields.
Gastroenterology, AGA’s flagship journal, received a record-high Impact Factor of 22.682, a substantial increase from its 2019 Impact Factor of 17.37. Gastroenterology maintains its position among an elite group of journals focused on publishing original research, spanning basic to clinical, in our field. Co–Editors in Chief (EICs) Richard M. Peek Jr., MD, and Douglas A. Corley, MD, PhD, remarked, “We would like to thank our entire board of editors and reviewers, as well as the incredible AGA editorial staff, for their exceptional work in this challenging pandemic year as we continue to publish articles and reviews of outstanding quality that are widely used by our readership. It is an honor to be part of such a remarkable team.”
Clinical Gastroenterology and Hepatology (CGH), AGA’s clinically focused journal, also reached a record high with an Impact Factor of 11.382, pulling ahead as the field’s top exclusively clinically oriented journal. This puts CGH at a rank of 8th among 92 journals in the field. Fasiha Kanwal, MD, MSHS, EIC of CGH, noted, “We are delighted that CGH remains in a strong position in the top 10 GI journals in terms of Impact Factor. On behalf of the CGH board of editors, I want to extend a warm and most heartfelt thanks to our authors, reviewers, and readers! We would not have been able to achieve this milestone without your support, contributions, and the faith that you place in us.”
To round things out, Cellular and Molecular Gastroenterology and Hepatology (CMGH), AGA’s basic and translational open-access journal also reached a record high with an Impact Factor of 9.225, placing it 13th, and second among nonclinical journals in that topic area. EICs Klaus Kaestner, PhD, and Michael Pack, MD, stated, “As co-EICs of CMGH, we send congratulations to the journal’s board of editors, editorial board, reviewers, and superb editorial staff on this year’s Impact Factor. We are honored to work with these outstanding colleagues and to provide our readership with highly impactful and cutting-edge research and review articles.”
In its online announcement, AGA congratulates and thanks the boards of all three journals for their editorial leadership. We also thank our authors, readers, and reviewers for their continued support of AGA’s journals. We look forward to continuing to push the envelope in scientific publishing in the upcoming year.
AGA journals select new editorial fellows
The AGA journals Gastroenterology, Clinical Gastroenterology and Hepatology (CGH), Cellular and Molecular Gastroenterology and Hepatology (CMGH), and Techniques and Innovations in Gastrointestinal Endoscopy (TIGE) recently selected the recipients of their editorial fellowships, which will run from July 2021 through June 2022. The AGA editorial fellowship program is in its 4th year.
- Amisha Ahuja, MD (Gastroenterology)
- Helenie Kefalalkes, MD (Gastroenterology)
- Katherine Falloon, MD (CGH)
- Judy Trieu, MD, MPH (CGH)
- Lindsey Kennedy, PhD (CMGH)
- Vivian Ortiz, MD (CMGH)
- Sagarika Satyavada, MD (TIGE)
- Eric Swei, MD (TIGE)
Gain perspectives, insights, and experience in diagnostic and therapeutic GI care
Accurately diagnosing and treating GI disorders such as irritable bowel syndrome, inflammatory bowel disease, or eosinophilic esophagitis are challenging for any health care practitioners. Why not be the advanced practice provider (APP) in your practice that others look to for providing the best course of action for patients? The all-virtual 2021 Principles of GI for the NP and PA, Aug. 14-15, 2021, explores these GI conditions in detail, as well as colorectal cancer and disorders of the liver and pancreas, to give you a foundation in which to provide superlative patient care.
The virtual format also offers a safe and affordable forum for learning from your home or office as the impact of the COVID-19 pandemic continues to be felt throughout 2021. You’ll also benefit from on-demand access for 2 years after the live course so you can reference and refresh what you learned.
Take the opportunity to refine your skills and improve your patient care outcomes.
Honor your peers with an AGA Recognition Award
When you think about outstanding GI educators, clinicians, investigators, and mentors, who comes to mind?
Share your appreciation by nominating your colleagues for a prestigious 2022 AGA Recognition Award!
Make your nominee stand out by sharing specific examples of how they have devoted themselves to eradicating the world of digestive disease, demonstrated innovation in bettering our community, and made a lasting impact, all of which exemplifies an outstanding AGA member.
Need some inspiration? Read about our 2021 winners before submitting your nomination.
AGA journals’ reach record-high Impact Factors
AGA is proud to announce that its journals have maintained their exceptional standing in the field of gastroenterology and hepatology, based on Impact Factor. The Impact Factor is a measure of the frequency with which articles published in the previous 2 years are cited and is commonly used to rank the significance of journals within their fields.
Gastroenterology, AGA’s flagship journal, received a record-high Impact Factor of 22.682, a substantial increase from its 2019 Impact Factor of 17.37. Gastroenterology maintains its position among an elite group of journals focused on publishing original research, spanning basic to clinical, in our field. Co–Editors in Chief (EICs) Richard M. Peek Jr., MD, and Douglas A. Corley, MD, PhD, remarked, “We would like to thank our entire board of editors and reviewers, as well as the incredible AGA editorial staff, for their exceptional work in this challenging pandemic year as we continue to publish articles and reviews of outstanding quality that are widely used by our readership. It is an honor to be part of such a remarkable team.”
Clinical Gastroenterology and Hepatology (CGH), AGA’s clinically focused journal, also reached a record high with an Impact Factor of 11.382, pulling ahead as the field’s top exclusively clinically oriented journal. This puts CGH at a rank of 8th among 92 journals in the field. Fasiha Kanwal, MD, MSHS, EIC of CGH, noted, “We are delighted that CGH remains in a strong position in the top 10 GI journals in terms of Impact Factor. On behalf of the CGH board of editors, I want to extend a warm and most heartfelt thanks to our authors, reviewers, and readers! We would not have been able to achieve this milestone without your support, contributions, and the faith that you place in us.”
To round things out, Cellular and Molecular Gastroenterology and Hepatology (CMGH), AGA’s basic and translational open-access journal also reached a record high with an Impact Factor of 9.225, placing it 13th, and second among nonclinical journals in that topic area. EICs Klaus Kaestner, PhD, and Michael Pack, MD, stated, “As co-EICs of CMGH, we send congratulations to the journal’s board of editors, editorial board, reviewers, and superb editorial staff on this year’s Impact Factor. We are honored to work with these outstanding colleagues and to provide our readership with highly impactful and cutting-edge research and review articles.”
In its online announcement, AGA congratulates and thanks the boards of all three journals for their editorial leadership. We also thank our authors, readers, and reviewers for their continued support of AGA’s journals. We look forward to continuing to push the envelope in scientific publishing in the upcoming year.
AGA journals select new editorial fellows
The AGA journals Gastroenterology, Clinical Gastroenterology and Hepatology (CGH), Cellular and Molecular Gastroenterology and Hepatology (CMGH), and Techniques and Innovations in Gastrointestinal Endoscopy (TIGE) recently selected the recipients of their editorial fellowships, which will run from July 2021 through June 2022. The AGA editorial fellowship program is in its 4th year.
- Amisha Ahuja, MD (Gastroenterology)
- Helenie Kefalalkes, MD (Gastroenterology)
- Katherine Falloon, MD (CGH)
- Judy Trieu, MD, MPH (CGH)
- Lindsey Kennedy, PhD (CMGH)
- Vivian Ortiz, MD (CMGH)
- Sagarika Satyavada, MD (TIGE)
- Eric Swei, MD (TIGE)
Gain perspectives, insights, and experience in diagnostic and therapeutic GI care
Accurately diagnosing and treating GI disorders such as irritable bowel syndrome, inflammatory bowel disease, or eosinophilic esophagitis are challenging for any health care practitioners. Why not be the advanced practice provider (APP) in your practice that others look to for providing the best course of action for patients? The all-virtual 2021 Principles of GI for the NP and PA, Aug. 14-15, 2021, explores these GI conditions in detail, as well as colorectal cancer and disorders of the liver and pancreas, to give you a foundation in which to provide superlative patient care.
The virtual format also offers a safe and affordable forum for learning from your home or office as the impact of the COVID-19 pandemic continues to be felt throughout 2021. You’ll also benefit from on-demand access for 2 years after the live course so you can reference and refresh what you learned.
Take the opportunity to refine your skills and improve your patient care outcomes.
Honor your peers with an AGA Recognition Award
When you think about outstanding GI educators, clinicians, investigators, and mentors, who comes to mind?
Share your appreciation by nominating your colleagues for a prestigious 2022 AGA Recognition Award!
Make your nominee stand out by sharing specific examples of how they have devoted themselves to eradicating the world of digestive disease, demonstrated innovation in bettering our community, and made a lasting impact, all of which exemplifies an outstanding AGA member.
Need some inspiration? Read about our 2021 winners before submitting your nomination.
AGA journals’ reach record-high Impact Factors
AGA is proud to announce that its journals have maintained their exceptional standing in the field of gastroenterology and hepatology, based on Impact Factor. The Impact Factor is a measure of the frequency with which articles published in the previous 2 years are cited and is commonly used to rank the significance of journals within their fields.
Gastroenterology, AGA’s flagship journal, received a record-high Impact Factor of 22.682, a substantial increase from its 2019 Impact Factor of 17.37. Gastroenterology maintains its position among an elite group of journals focused on publishing original research, spanning basic to clinical, in our field. Co–Editors in Chief (EICs) Richard M. Peek Jr., MD, and Douglas A. Corley, MD, PhD, remarked, “We would like to thank our entire board of editors and reviewers, as well as the incredible AGA editorial staff, for their exceptional work in this challenging pandemic year as we continue to publish articles and reviews of outstanding quality that are widely used by our readership. It is an honor to be part of such a remarkable team.”
Clinical Gastroenterology and Hepatology (CGH), AGA’s clinically focused journal, also reached a record high with an Impact Factor of 11.382, pulling ahead as the field’s top exclusively clinically oriented journal. This puts CGH at a rank of 8th among 92 journals in the field. Fasiha Kanwal, MD, MSHS, EIC of CGH, noted, “We are delighted that CGH remains in a strong position in the top 10 GI journals in terms of Impact Factor. On behalf of the CGH board of editors, I want to extend a warm and most heartfelt thanks to our authors, reviewers, and readers! We would not have been able to achieve this milestone without your support, contributions, and the faith that you place in us.”
To round things out, Cellular and Molecular Gastroenterology and Hepatology (CMGH), AGA’s basic and translational open-access journal also reached a record high with an Impact Factor of 9.225, placing it 13th, and second among nonclinical journals in that topic area. EICs Klaus Kaestner, PhD, and Michael Pack, MD, stated, “As co-EICs of CMGH, we send congratulations to the journal’s board of editors, editorial board, reviewers, and superb editorial staff on this year’s Impact Factor. We are honored to work with these outstanding colleagues and to provide our readership with highly impactful and cutting-edge research and review articles.”
In its online announcement, AGA congratulates and thanks the boards of all three journals for their editorial leadership. We also thank our authors, readers, and reviewers for their continued support of AGA’s journals. We look forward to continuing to push the envelope in scientific publishing in the upcoming year.
AGA journals select new editorial fellows
The AGA journals Gastroenterology, Clinical Gastroenterology and Hepatology (CGH), Cellular and Molecular Gastroenterology and Hepatology (CMGH), and Techniques and Innovations in Gastrointestinal Endoscopy (TIGE) recently selected the recipients of their editorial fellowships, which will run from July 2021 through June 2022. The AGA editorial fellowship program is in its 4th year.
- Amisha Ahuja, MD (Gastroenterology)
- Helenie Kefalalkes, MD (Gastroenterology)
- Katherine Falloon, MD (CGH)
- Judy Trieu, MD, MPH (CGH)
- Lindsey Kennedy, PhD (CMGH)
- Vivian Ortiz, MD (CMGH)
- Sagarika Satyavada, MD (TIGE)
- Eric Swei, MD (TIGE)
Gain perspectives, insights, and experience in diagnostic and therapeutic GI care
Accurately diagnosing and treating GI disorders such as irritable bowel syndrome, inflammatory bowel disease, or eosinophilic esophagitis are challenging for any health care practitioners. Why not be the advanced practice provider (APP) in your practice that others look to for providing the best course of action for patients? The all-virtual 2021 Principles of GI for the NP and PA, Aug. 14-15, 2021, explores these GI conditions in detail, as well as colorectal cancer and disorders of the liver and pancreas, to give you a foundation in which to provide superlative patient care.
The virtual format also offers a safe and affordable forum for learning from your home or office as the impact of the COVID-19 pandemic continues to be felt throughout 2021. You’ll also benefit from on-demand access for 2 years after the live course so you can reference and refresh what you learned.
Take the opportunity to refine your skills and improve your patient care outcomes.
Honor your peers with an AGA Recognition Award
When you think about outstanding GI educators, clinicians, investigators, and mentors, who comes to mind?
Share your appreciation by nominating your colleagues for a prestigious 2022 AGA Recognition Award!
Make your nominee stand out by sharing specific examples of how they have devoted themselves to eradicating the world of digestive disease, demonstrated innovation in bettering our community, and made a lasting impact, all of which exemplifies an outstanding AGA member.
Need some inspiration? Read about our 2021 winners before submitting your nomination.
No prehydration prior to contrast-enhanced CT in patients with stage 3 CKD
Background: Postcontrast acute kidney injury (PC-AKI) is known to have a mild, often self-limiting, clinical course. Despite this, preventative measures are advised by international guidelines in high-risk patients.
Study design: The Kompas trial was a multicenter, open-label, noninferiority randomized clinical trial in which 523 patients with stage 3 CKD were randomized to receive no hydration or prehydration with 250 mL of 1.4% sodium bicarbonate in a 1-hour infusion before undergoing elective contrast-enhanced CT. The primary endpoint was the mean relative increase in serum creatinine 2-5 days after contrast administration, compared with baseline.
Setting: Six hospitals in the Netherlands during April 2013–September 2016.
Synopsis: Of the 523 patients, (median age, 74 years), the mean relative increase in creatinine level 2-5 days after contrast administration compared with baseline was 3.0% in the no-prehydration group vs. 3.5% in the prehydration group. This demonstrates that withholding prehydration is noninferior to administrating prehydration. PC-AKI occurred in 7 of 262 patients in the no-prehydration group and 4 of 261 patients in the prehydration group and no patients required dialysis or developed heart failure. These results reassure us that prehydration with sodium bicarbonate can be safely omitted in patients with stage 3 CKD who undergo contrast-enhanced CT.
Bottom line: Prehydration with sodium bicarbonate is not needed to prevent additional renal injury in patients with CKD stage 3 undergoing contrast-enhanced CT imaging.
Citation: Timal RJ et al. Effect of no prehydration vs sodium bicarbonate prehydration prior to contrast-enhanced computed tomography in the prevention of postcontrast acute kidney injury in adults with chronic kidney disease: The Kompas Randomized Clinical Trial. JAMA Intern Med. 2020 Feb 17. doi: 10.1001/jamainternmed.2019.7428.
Dr. Moulder is assistant professor of medicine, section of hospital medicine, at the University of Virginia School of Medicine, Charlottesville.
Background: Postcontrast acute kidney injury (PC-AKI) is known to have a mild, often self-limiting, clinical course. Despite this, preventative measures are advised by international guidelines in high-risk patients.
Study design: The Kompas trial was a multicenter, open-label, noninferiority randomized clinical trial in which 523 patients with stage 3 CKD were randomized to receive no hydration or prehydration with 250 mL of 1.4% sodium bicarbonate in a 1-hour infusion before undergoing elective contrast-enhanced CT. The primary endpoint was the mean relative increase in serum creatinine 2-5 days after contrast administration, compared with baseline.
Setting: Six hospitals in the Netherlands during April 2013–September 2016.
Synopsis: Of the 523 patients, (median age, 74 years), the mean relative increase in creatinine level 2-5 days after contrast administration compared with baseline was 3.0% in the no-prehydration group vs. 3.5% in the prehydration group. This demonstrates that withholding prehydration is noninferior to administrating prehydration. PC-AKI occurred in 7 of 262 patients in the no-prehydration group and 4 of 261 patients in the prehydration group and no patients required dialysis or developed heart failure. These results reassure us that prehydration with sodium bicarbonate can be safely omitted in patients with stage 3 CKD who undergo contrast-enhanced CT.
Bottom line: Prehydration with sodium bicarbonate is not needed to prevent additional renal injury in patients with CKD stage 3 undergoing contrast-enhanced CT imaging.
Citation: Timal RJ et al. Effect of no prehydration vs sodium bicarbonate prehydration prior to contrast-enhanced computed tomography in the prevention of postcontrast acute kidney injury in adults with chronic kidney disease: The Kompas Randomized Clinical Trial. JAMA Intern Med. 2020 Feb 17. doi: 10.1001/jamainternmed.2019.7428.
Dr. Moulder is assistant professor of medicine, section of hospital medicine, at the University of Virginia School of Medicine, Charlottesville.
Background: Postcontrast acute kidney injury (PC-AKI) is known to have a mild, often self-limiting, clinical course. Despite this, preventative measures are advised by international guidelines in high-risk patients.
Study design: The Kompas trial was a multicenter, open-label, noninferiority randomized clinical trial in which 523 patients with stage 3 CKD were randomized to receive no hydration or prehydration with 250 mL of 1.4% sodium bicarbonate in a 1-hour infusion before undergoing elective contrast-enhanced CT. The primary endpoint was the mean relative increase in serum creatinine 2-5 days after contrast administration, compared with baseline.
Setting: Six hospitals in the Netherlands during April 2013–September 2016.
Synopsis: Of the 523 patients, (median age, 74 years), the mean relative increase in creatinine level 2-5 days after contrast administration compared with baseline was 3.0% in the no-prehydration group vs. 3.5% in the prehydration group. This demonstrates that withholding prehydration is noninferior to administrating prehydration. PC-AKI occurred in 7 of 262 patients in the no-prehydration group and 4 of 261 patients in the prehydration group and no patients required dialysis or developed heart failure. These results reassure us that prehydration with sodium bicarbonate can be safely omitted in patients with stage 3 CKD who undergo contrast-enhanced CT.
Bottom line: Prehydration with sodium bicarbonate is not needed to prevent additional renal injury in patients with CKD stage 3 undergoing contrast-enhanced CT imaging.
Citation: Timal RJ et al. Effect of no prehydration vs sodium bicarbonate prehydration prior to contrast-enhanced computed tomography in the prevention of postcontrast acute kidney injury in adults with chronic kidney disease: The Kompas Randomized Clinical Trial. JAMA Intern Med. 2020 Feb 17. doi: 10.1001/jamainternmed.2019.7428.
Dr. Moulder is assistant professor of medicine, section of hospital medicine, at the University of Virginia School of Medicine, Charlottesville.
When is MRI useful in the management of congenital melanocytic nevi?
When used for appropriate patients, results from a small multi-institutional study showed.
“The majority of congenital nevi are considered low risk for cutaneous and/or systemic complications,” Holly Neale said at the annual meeting of the Society for Pediatric Dermatology. “However, a subset of children born with higher-risk congenital nevi require close monitoring, as some features of congenital nevi have been associated with cutaneous melanoma, central nervous system melanoma, melanin in the brain or spine, and structural irregularities in the brain or spine. It’s important to understand which congenital nevi are considered higher risk in order to guide management and counseling decisions.”
One major management decision is to do a screening magnetic resonance image of the CNS to evaluate for neurologic involvement, said Ms. Neale, a fourth-year medical student at the University of Massachusetts, Worcester. Prior studies have shown that congenital nevi that are bigger than 20 cm, posterior axial location, and having more than one congenital nevus may predict CNS abnormalities, while recent guidelines from experts in the field suggest that any child with more than one congenital nevus at birth undergo screening MRI.
“However, guidelines are evolving, and more data is required to better understand the CNS abnormalities and patient outcomes for children with congenital nevi,” said Ms. Neale, who spent the past year as a pediatric dermatology research fellow at Massachusetts General Hospital, Boston.
To address this knowledge gap, she and colleagues at the University of Massachusetts, Massachusetts General Hospital, and Boston Children’s Hospital performed a retrospective chart review between Jan. 1, 2009, and Dec. 31, 2019, of individuals ages 18 and younger who had an MRI of the brain or spine with at least one dermatologist-diagnosed nevus as identified via key words in the medical record. Of the 909 patients screened, 46 met inclusion criteria, evenly split between males and females.
The most common location of the largest nevus was the trunk (in 41% of patients), followed by lesions that spanned multiple regions. More than one-third of patients had giant nevi (greater than 40 cm).
“The majority of images were considered nonconcerning, which includes normal, benign, or other findings such as trauma related, infectious, or orthopedic, which we did not classify as abnormal as it did not guide our study question,” Ms. Neale said. Specifically, 8% of spine images and 27% of brain images were considered “concerning,” defined as any finding that prompted further workup or monitoring, which includes findings concerning for melanin.
The most common brain finding was melanin (in eight children), and one child with brain melanin also had findings suggestive of melanin in the thoracic spine. The most common finding in spine MRIs was fatty filum (in four children), requiring intervention for tethering in only one individual. No cases of cutaneous melanoma developed during the study period, and only one patient with abnormal imaging had CNS melanoma, which was fatal.
All patients with findings suggestive of CNS melanin had more than four nevi present at birth, which is in line with current imaging screening guidelines. In addition, children with concerning imaging had higher rates of death, neurodevelopmental problems, seizures, and neurosurgery, compared with their counterparts with unremarkable imaging findings. Describing preliminary analyses, Ms. Neale said that a chi square analysis was performed to test statistical significance of these differences, “and neurosurgery was the only variable that children with concerning imaging were significantly more likely to experience, although sample size limits detection for the other variables.”
The authors concluded that MRI is a helpful tool when used in the appropriate clinical context for the management of congenital nevi. “As more children undergo imaging, we may discover more nonmelanin abnormalities,” she said.
Joseph M. Lam, MD, who was asked to comment on the study, said that the increased risk of CNS melanin in patients with larger lesions and in those with multiple lesions confirms previous reports.
“It is interesting to note that some patients with nonconcerning imaging results still had neurodevelopmental problems and seizures, albeit at a lower rate than those with concerning imaging results,” said Dr. Lam, a pediatric dermatologist at British Columbia Children’s Hospital, Vancouver. “The lack of a control group for comparison of rates of neurological sequelae, such as NDP, seizures and nonmelanin structural anomalies, limits the generalizability of the findings. However, this is a nice study that helps us understand better the CNS anomalies in CMN.”
Ms. Neale acknowledged certain limitations of the study, including the lack of a control group without CMN, the small number of patients, the potential for referral bias, and its retrospective design. Also, the proximity of the study period does not allow for chronic follow-up and detection of the development of melanoma or other problems in the future.
Ms. Neale and associates reported having no relevant financial disclosures. Dr. Lam disclosed that he has received speaker fees from Pierre Fabre.
When used for appropriate patients, results from a small multi-institutional study showed.
“The majority of congenital nevi are considered low risk for cutaneous and/or systemic complications,” Holly Neale said at the annual meeting of the Society for Pediatric Dermatology. “However, a subset of children born with higher-risk congenital nevi require close monitoring, as some features of congenital nevi have been associated with cutaneous melanoma, central nervous system melanoma, melanin in the brain or spine, and structural irregularities in the brain or spine. It’s important to understand which congenital nevi are considered higher risk in order to guide management and counseling decisions.”
One major management decision is to do a screening magnetic resonance image of the CNS to evaluate for neurologic involvement, said Ms. Neale, a fourth-year medical student at the University of Massachusetts, Worcester. Prior studies have shown that congenital nevi that are bigger than 20 cm, posterior axial location, and having more than one congenital nevus may predict CNS abnormalities, while recent guidelines from experts in the field suggest that any child with more than one congenital nevus at birth undergo screening MRI.
“However, guidelines are evolving, and more data is required to better understand the CNS abnormalities and patient outcomes for children with congenital nevi,” said Ms. Neale, who spent the past year as a pediatric dermatology research fellow at Massachusetts General Hospital, Boston.
To address this knowledge gap, she and colleagues at the University of Massachusetts, Massachusetts General Hospital, and Boston Children’s Hospital performed a retrospective chart review between Jan. 1, 2009, and Dec. 31, 2019, of individuals ages 18 and younger who had an MRI of the brain or spine with at least one dermatologist-diagnosed nevus as identified via key words in the medical record. Of the 909 patients screened, 46 met inclusion criteria, evenly split between males and females.
The most common location of the largest nevus was the trunk (in 41% of patients), followed by lesions that spanned multiple regions. More than one-third of patients had giant nevi (greater than 40 cm).
“The majority of images were considered nonconcerning, which includes normal, benign, or other findings such as trauma related, infectious, or orthopedic, which we did not classify as abnormal as it did not guide our study question,” Ms. Neale said. Specifically, 8% of spine images and 27% of brain images were considered “concerning,” defined as any finding that prompted further workup or monitoring, which includes findings concerning for melanin.
The most common brain finding was melanin (in eight children), and one child with brain melanin also had findings suggestive of melanin in the thoracic spine. The most common finding in spine MRIs was fatty filum (in four children), requiring intervention for tethering in only one individual. No cases of cutaneous melanoma developed during the study period, and only one patient with abnormal imaging had CNS melanoma, which was fatal.
All patients with findings suggestive of CNS melanin had more than four nevi present at birth, which is in line with current imaging screening guidelines. In addition, children with concerning imaging had higher rates of death, neurodevelopmental problems, seizures, and neurosurgery, compared with their counterparts with unremarkable imaging findings. Describing preliminary analyses, Ms. Neale said that a chi square analysis was performed to test statistical significance of these differences, “and neurosurgery was the only variable that children with concerning imaging were significantly more likely to experience, although sample size limits detection for the other variables.”
The authors concluded that MRI is a helpful tool when used in the appropriate clinical context for the management of congenital nevi. “As more children undergo imaging, we may discover more nonmelanin abnormalities,” she said.
Joseph M. Lam, MD, who was asked to comment on the study, said that the increased risk of CNS melanin in patients with larger lesions and in those with multiple lesions confirms previous reports.
“It is interesting to note that some patients with nonconcerning imaging results still had neurodevelopmental problems and seizures, albeit at a lower rate than those with concerning imaging results,” said Dr. Lam, a pediatric dermatologist at British Columbia Children’s Hospital, Vancouver. “The lack of a control group for comparison of rates of neurological sequelae, such as NDP, seizures and nonmelanin structural anomalies, limits the generalizability of the findings. However, this is a nice study that helps us understand better the CNS anomalies in CMN.”
Ms. Neale acknowledged certain limitations of the study, including the lack of a control group without CMN, the small number of patients, the potential for referral bias, and its retrospective design. Also, the proximity of the study period does not allow for chronic follow-up and detection of the development of melanoma or other problems in the future.
Ms. Neale and associates reported having no relevant financial disclosures. Dr. Lam disclosed that he has received speaker fees from Pierre Fabre.
When used for appropriate patients, results from a small multi-institutional study showed.
“The majority of congenital nevi are considered low risk for cutaneous and/or systemic complications,” Holly Neale said at the annual meeting of the Society for Pediatric Dermatology. “However, a subset of children born with higher-risk congenital nevi require close monitoring, as some features of congenital nevi have been associated with cutaneous melanoma, central nervous system melanoma, melanin in the brain or spine, and structural irregularities in the brain or spine. It’s important to understand which congenital nevi are considered higher risk in order to guide management and counseling decisions.”
One major management decision is to do a screening magnetic resonance image of the CNS to evaluate for neurologic involvement, said Ms. Neale, a fourth-year medical student at the University of Massachusetts, Worcester. Prior studies have shown that congenital nevi that are bigger than 20 cm, posterior axial location, and having more than one congenital nevus may predict CNS abnormalities, while recent guidelines from experts in the field suggest that any child with more than one congenital nevus at birth undergo screening MRI.
“However, guidelines are evolving, and more data is required to better understand the CNS abnormalities and patient outcomes for children with congenital nevi,” said Ms. Neale, who spent the past year as a pediatric dermatology research fellow at Massachusetts General Hospital, Boston.
To address this knowledge gap, she and colleagues at the University of Massachusetts, Massachusetts General Hospital, and Boston Children’s Hospital performed a retrospective chart review between Jan. 1, 2009, and Dec. 31, 2019, of individuals ages 18 and younger who had an MRI of the brain or spine with at least one dermatologist-diagnosed nevus as identified via key words in the medical record. Of the 909 patients screened, 46 met inclusion criteria, evenly split between males and females.
The most common location of the largest nevus was the trunk (in 41% of patients), followed by lesions that spanned multiple regions. More than one-third of patients had giant nevi (greater than 40 cm).
“The majority of images were considered nonconcerning, which includes normal, benign, or other findings such as trauma related, infectious, or orthopedic, which we did not classify as abnormal as it did not guide our study question,” Ms. Neale said. Specifically, 8% of spine images and 27% of brain images were considered “concerning,” defined as any finding that prompted further workup or monitoring, which includes findings concerning for melanin.
The most common brain finding was melanin (in eight children), and one child with brain melanin also had findings suggestive of melanin in the thoracic spine. The most common finding in spine MRIs was fatty filum (in four children), requiring intervention for tethering in only one individual. No cases of cutaneous melanoma developed during the study period, and only one patient with abnormal imaging had CNS melanoma, which was fatal.
All patients with findings suggestive of CNS melanin had more than four nevi present at birth, which is in line with current imaging screening guidelines. In addition, children with concerning imaging had higher rates of death, neurodevelopmental problems, seizures, and neurosurgery, compared with their counterparts with unremarkable imaging findings. Describing preliminary analyses, Ms. Neale said that a chi square analysis was performed to test statistical significance of these differences, “and neurosurgery was the only variable that children with concerning imaging were significantly more likely to experience, although sample size limits detection for the other variables.”
The authors concluded that MRI is a helpful tool when used in the appropriate clinical context for the management of congenital nevi. “As more children undergo imaging, we may discover more nonmelanin abnormalities,” she said.
Joseph M. Lam, MD, who was asked to comment on the study, said that the increased risk of CNS melanin in patients with larger lesions and in those with multiple lesions confirms previous reports.
“It is interesting to note that some patients with nonconcerning imaging results still had neurodevelopmental problems and seizures, albeit at a lower rate than those with concerning imaging results,” said Dr. Lam, a pediatric dermatologist at British Columbia Children’s Hospital, Vancouver. “The lack of a control group for comparison of rates of neurological sequelae, such as NDP, seizures and nonmelanin structural anomalies, limits the generalizability of the findings. However, this is a nice study that helps us understand better the CNS anomalies in CMN.”
Ms. Neale acknowledged certain limitations of the study, including the lack of a control group without CMN, the small number of patients, the potential for referral bias, and its retrospective design. Also, the proximity of the study period does not allow for chronic follow-up and detection of the development of melanoma or other problems in the future.
Ms. Neale and associates reported having no relevant financial disclosures. Dr. Lam disclosed that he has received speaker fees from Pierre Fabre.
FROM SPD 2021
ADHD: Treatment
The robot comes to mastectomy, but cancer outcomes data not attached
The FDA warning was issued in February 2019 to both the public and physicians. The FDA cautioned that the safety and effectiveness of robotic surgical devices for mastectomy “have not been established” and robots are not approved for the prevention or treatment of breast cancer.
The agency also noted that “diminished long-term survival” was associated with robotic surgery in another women’s cancer, that of hysterectomy for cervical cancer.
The FDA also made a surprising statement. The agency typically approves the robot for surgical use based on 30-day complication rates (compared with standards of care). But it said that going forward it “anticipates” that any evaluation of new use of robots in cancer “would be supported” by cancer outcomes such as progression-free survival and overall survival, which require much longer follow-up.
In short, the FDA hinted that it would change how it regulated medical devices, or at least robots used in women’s cancers. “The FDA takes women’s health very seriously,” said the organization.
Fast forward to 2021, and there are several prospective clinical trials of robot-assisted nipple-sparing mastectomy underway in the United States, including a five-center study sponsored by Intuitive Surgical, the maker of da Vinci robots, the dominant machine on the market. There are also single-center studies at Ohio State and University of Texas Southwestern Medical Center.
However, in each case, the study design either excludes cancer outcomes or does not primarily focus on those measures.
Instead, the primary outcomes are relatively short term and include safety and efficacy measures such as en bloc (in one piece) removal of the breast tissue, conversions to open mastectomy, and the incidence of adverse events during surgery and up to 6 weeks after surgery.
Importantly, none of the studies is a randomized trial; all have single arms.
That’s not what is needed, says breast surgeon Julie A. Margenthaler, MD of Washington University in St. Louis.
“I firmly believe that robotic-assisted mastectomy should only be considered in the context of a well-designed, randomized trial evaluating patient selection, patient safety, surgical complications, and oncologic outcomes with a concomitant cost analysis,” Dr. Margenthaler wrote in an essay published last year in JAMA Surgery.
As with the FDA warning, she cites worse survival with commonly used minimally invasive radical hysterectomy for cervical cancer, saying it “is a stark reminder that the marketing of robotic surgery has its roots in cosmesis and convenience rather than oncologic outcomes.”
In addition, robotic surgery is prohibitively expensive, said Dr. Margenthaler. In fact, cost is her “main criticism regarding robotic-assisted mastectomy.” It costs an additional $6,000 for robot use per procedure, according to a study conducted at a center in Taiwan. “I simply cannot be convinced that this will ever achieve cost-effective or even cost-neutral status,” Dr. Margenthaler wrote.
Not looking at the right outcomes
“They’re not looking at the right outcomes,” said Hooman Noorchashm, MD, PhD, about the current trials in the United States. He is a former surgeon and faculty member at the University of Pennsylvania in Philadelphia, and is now a patient advocate after his wife, Amy Reed, MD, died of uterine cancer in 2017 following a laparoscopic hysterectomy performed with a power morcellator that resulted in the upstaging of an undetected gynecologic cancer.
“You have to look at oncologic outcomes and do randomized, noninferiority trials to demonstrate that those cancer outcomes are at least equivalent to standard of care,” he said in an interview.
The current U.S. trials are “totally inappropriate,” he said.
Are randomized trials forthcoming after this initial set of single-arm trials? This news organization reached out to Intuitive Surgical, maker of the market leader da Vinci robotic surgical equipment to find out.
“Any plans for use of da Vinci Xi surgical system in nipple-sparing mastectomy will be based on these [single-arm] study results as well as other data and evidence,” said a company spokesperson, who did not confirm use of a randomized trial.
What about the FDA? Will the agency change its current approach to approving robots in surgeries for women’s cancers and require – not just anticipate – cancer-related outcomes data? At press time, the FDA did not respond to a request for comment.
Not having a randomized trial with cancer outcomes in any eventual FDA review opens the door for robotic mastectomy to be cleared for use in some mastectomies with short-term, nononcologic data, said Dr. Noorchashm.
Safety concerns with robotic mastectomy
Proponents of robot-assisted nipple-sparing mastectomy, which is coupled with reconstruction to preserve the shape of both the breast and nipple-areola area, suggest that improved patient cosmesis is a significant advantage with the high-tech intervention, said Dr. Margenthaler.
That’s because most robotic mastectomies performed to date (almost exclusively in Europe and Asia) have employed a 3- to 5-cm vertical incision located behind the lateral breast fold, allowing the scar to be hidden under the patient’s arm.
But therein also lies a safety concern, she asserted.
The “oncologic integrity” of the specimen on extraction is in question in some cases, she wrote, because of “such a small opening.”
Dr. Noorchashm agreed: “It all comes down to trying to get a large specimen out of a small incision.”
Traditional open mastectomy optimally yields the en bloc removal of a tumor – in one whole piece – to avoid fragmenting the cancerous tissue and possibly leaving residual disease behind. These undesirable events are associated with a higher risk for recurrence and treatment failure, he explained.
Thus, there is a need for a randomized trial with longer-term oncologic outcomes that compares the new approach with traditional open mastectomy, argued both Dr. Margenthaler and Dr. Noorchashm.
In defense of single-arm trials
“Oncologic safety is what we are concerned about and what we would like to study,” said Ko Un (Clara) Park, MD, a breast surgeon at The Ohio State University in Columbus.
Dr. Park is leading a single-center, single-arm pilot study of robotic nipple-sparing mastectomy enrolling up to 20 women with early-stage breast cancer or inherited genetic risk factors (but no cancer diagnosis). The trial, sponsored by a Pelotonia Idea Grant and Ohio State, recently enrolled its first patient.
The study’s primary outcomes include the feasibility of removal of the breast tissue en bloc; however, none of the outcomes are classic oncologic metrics such as progression-free survival.
The en bloc removal outcome is in direct response to the FDA’s concerns about minimally invasive cancer surgeries in women, Dr. Park said in an interview. The pilot trial has an investigational device exemption (IDE) granted by the FDA.
“The reason why we can’t just open a randomized controlled study (of robot versus open) and measure oncologic outcomes like recurrence-free survival is because, before we get to that point, we have to make sure” basic safety issues are addressed and established, she explained.
But Dr. Noorchashm said that argument is missing the larger, more important point: “They are still doing an oncologic procedure – you are still obliged to do noninferiority [randomized] testing with respect to cancer outcomes.”
Dr. Park sounded a different note: “We are doing it as safely as we can do it.”
Prophylactic use is also a cancer surgery
Intuitive’s five-center trial does not include en bloc removal of the breast gland as a primary outcome. Instead, the two primary outcomes are conversions to open mastectomy (efficacy measure) and the incidence of adverse events during surgery to 42 days after surgery (safety measure).
The company’s trial does not include any women with breast cancer, but is limited to women at increased risk for breast cancer and seeking prophylactic nipple-sparing mastectomy surgery.
Enrollment in the 145-patient single-arm trial began in the last few months and has a primary completion date of December 2022. It also has an IDE from the FDA.
“I do think that things like this need to be done with caution,” said Katherine Kopkash, MD, an investigator in the Intuitive trial and a breast surgeon at NorthShore University HealthSystem in Evanston, Ill., referring to the trial’s FDA exemption.
Dr. Kopkash said in an interview that the researchers in the multisite, single-arm Intuitive trial will also track oncologic outcomes, but the trial description at clinicaltrials.gov does not indicate that.
Both Dr. Kopkash and Dr. Park cited the high-profile missteps that took place in 2018 at Monmouth County Medical Center in Long Branch, N.J., during what was described as the first-ever use of robotic nipple-sparing mastectomy for invasive cancer in the United States, as reported by Medscape Medical News. However, neither the center or surgeon, Stephen Chagares, MD, requested or received an IDE from the FDA, and use of robotic mastectomy was halted after two cases.
It’s conceivable that Intuitive will seek out FDA clearance for use of its da Vinci system in robotic nipple-sparing mastectomy with data in a prophylactic setting and then expand the pool of patients, argued Dr. Noorchashm.
“Even if you introduce a new technology ... for a narrow subset of patients, the application of it eventually occurs on a ‘sliding scale,’ ” he said.
The former surgeon gave an example: The first device used in gastric bypass surgery was cleared for use in 2001 by the FDA for adults who were “severely morbidly obese.” But by the late 2000s, the operation was also being performed on people with lower body mass indexes who hadn’t exhausted traditional weight loss procedures. “It was very lucrative,” Dr. Noorchashm said about the surgery.
Surgeons only get one body
Intuitive has been hugely successful in developing and marketing its da Vinci system around the world for general and oncologic surgeries, with more than 1 million surgeries in 2018, a greater than sevenfold increase in 10 years, according to the authors of a new essay published in the June issue of the Annals of Surgery. The authors include breast surgeon Rosa F. Hwang, MD, of MD Anderson Cancer Center in Houston, who is also an investigator for the Intuitive trial.
However, robotic mastectomy is still a new surgery – only about 150 patients have been treated in the world, mostly in Italy, France, Taiwan, and Korea, the authors noted.
Despite such small numbers, “there’s a lot of interest in bringing this to the United States,” said Dr. Park.
One of the arguments in favor of robotic mastectomy for nipple-sparing procedures has nothing to do with patients. Instead, it is improved ergonomics – the robot makes a tough surgery easier on the surgeon.
Even stalwart robot critic Dr. Margenthaler conceded that this was possibly a winning feature.
“Nipple-sparing mastectomy is a very physically demanding procedure for the surgeon, resulting in higher rates of neck and back pain and fatigue compared with a standard skin-sparing approach,” she noted. She suggested, however, that practitioners of traditional mastectomy ought to first experiment with changes to patient positioning and incision placement to alleviate stress before looking to the robot for change.
When this news organization interviewed NorthShore University’s Dr. Kopkash, she had conducted four nipple-sparing mastectomies in the previous week. “It’s a difficult procedure on our bodies. I just turned 40 and I’m considered young for a surgeon. We get one body for our career and we have to figure out ways to make it work and protect it.”
Intuitive Surgical is funding the five-center clinical trial of robot-assisted nipple-sparing mastectomy, and UT Southwestern is funding its own trial. The Ohio State trial is funded by the university and a Pelotonia Idea Grant. Dr. Noorchashm and Dr. Margenthaler have no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
The FDA warning was issued in February 2019 to both the public and physicians. The FDA cautioned that the safety and effectiveness of robotic surgical devices for mastectomy “have not been established” and robots are not approved for the prevention or treatment of breast cancer.
The agency also noted that “diminished long-term survival” was associated with robotic surgery in another women’s cancer, that of hysterectomy for cervical cancer.
The FDA also made a surprising statement. The agency typically approves the robot for surgical use based on 30-day complication rates (compared with standards of care). But it said that going forward it “anticipates” that any evaluation of new use of robots in cancer “would be supported” by cancer outcomes such as progression-free survival and overall survival, which require much longer follow-up.
In short, the FDA hinted that it would change how it regulated medical devices, or at least robots used in women’s cancers. “The FDA takes women’s health very seriously,” said the organization.
Fast forward to 2021, and there are several prospective clinical trials of robot-assisted nipple-sparing mastectomy underway in the United States, including a five-center study sponsored by Intuitive Surgical, the maker of da Vinci robots, the dominant machine on the market. There are also single-center studies at Ohio State and University of Texas Southwestern Medical Center.
However, in each case, the study design either excludes cancer outcomes or does not primarily focus on those measures.
Instead, the primary outcomes are relatively short term and include safety and efficacy measures such as en bloc (in one piece) removal of the breast tissue, conversions to open mastectomy, and the incidence of adverse events during surgery and up to 6 weeks after surgery.
Importantly, none of the studies is a randomized trial; all have single arms.
That’s not what is needed, says breast surgeon Julie A. Margenthaler, MD of Washington University in St. Louis.
“I firmly believe that robotic-assisted mastectomy should only be considered in the context of a well-designed, randomized trial evaluating patient selection, patient safety, surgical complications, and oncologic outcomes with a concomitant cost analysis,” Dr. Margenthaler wrote in an essay published last year in JAMA Surgery.
As with the FDA warning, she cites worse survival with commonly used minimally invasive radical hysterectomy for cervical cancer, saying it “is a stark reminder that the marketing of robotic surgery has its roots in cosmesis and convenience rather than oncologic outcomes.”
In addition, robotic surgery is prohibitively expensive, said Dr. Margenthaler. In fact, cost is her “main criticism regarding robotic-assisted mastectomy.” It costs an additional $6,000 for robot use per procedure, according to a study conducted at a center in Taiwan. “I simply cannot be convinced that this will ever achieve cost-effective or even cost-neutral status,” Dr. Margenthaler wrote.
Not looking at the right outcomes
“They’re not looking at the right outcomes,” said Hooman Noorchashm, MD, PhD, about the current trials in the United States. He is a former surgeon and faculty member at the University of Pennsylvania in Philadelphia, and is now a patient advocate after his wife, Amy Reed, MD, died of uterine cancer in 2017 following a laparoscopic hysterectomy performed with a power morcellator that resulted in the upstaging of an undetected gynecologic cancer.
“You have to look at oncologic outcomes and do randomized, noninferiority trials to demonstrate that those cancer outcomes are at least equivalent to standard of care,” he said in an interview.
The current U.S. trials are “totally inappropriate,” he said.
Are randomized trials forthcoming after this initial set of single-arm trials? This news organization reached out to Intuitive Surgical, maker of the market leader da Vinci robotic surgical equipment to find out.
“Any plans for use of da Vinci Xi surgical system in nipple-sparing mastectomy will be based on these [single-arm] study results as well as other data and evidence,” said a company spokesperson, who did not confirm use of a randomized trial.
What about the FDA? Will the agency change its current approach to approving robots in surgeries for women’s cancers and require – not just anticipate – cancer-related outcomes data? At press time, the FDA did not respond to a request for comment.
Not having a randomized trial with cancer outcomes in any eventual FDA review opens the door for robotic mastectomy to be cleared for use in some mastectomies with short-term, nononcologic data, said Dr. Noorchashm.
Safety concerns with robotic mastectomy
Proponents of robot-assisted nipple-sparing mastectomy, which is coupled with reconstruction to preserve the shape of both the breast and nipple-areola area, suggest that improved patient cosmesis is a significant advantage with the high-tech intervention, said Dr. Margenthaler.
That’s because most robotic mastectomies performed to date (almost exclusively in Europe and Asia) have employed a 3- to 5-cm vertical incision located behind the lateral breast fold, allowing the scar to be hidden under the patient’s arm.
But therein also lies a safety concern, she asserted.
The “oncologic integrity” of the specimen on extraction is in question in some cases, she wrote, because of “such a small opening.”
Dr. Noorchashm agreed: “It all comes down to trying to get a large specimen out of a small incision.”
Traditional open mastectomy optimally yields the en bloc removal of a tumor – in one whole piece – to avoid fragmenting the cancerous tissue and possibly leaving residual disease behind. These undesirable events are associated with a higher risk for recurrence and treatment failure, he explained.
Thus, there is a need for a randomized trial with longer-term oncologic outcomes that compares the new approach with traditional open mastectomy, argued both Dr. Margenthaler and Dr. Noorchashm.
In defense of single-arm trials
“Oncologic safety is what we are concerned about and what we would like to study,” said Ko Un (Clara) Park, MD, a breast surgeon at The Ohio State University in Columbus.
Dr. Park is leading a single-center, single-arm pilot study of robotic nipple-sparing mastectomy enrolling up to 20 women with early-stage breast cancer or inherited genetic risk factors (but no cancer diagnosis). The trial, sponsored by a Pelotonia Idea Grant and Ohio State, recently enrolled its first patient.
The study’s primary outcomes include the feasibility of removal of the breast tissue en bloc; however, none of the outcomes are classic oncologic metrics such as progression-free survival.
The en bloc removal outcome is in direct response to the FDA’s concerns about minimally invasive cancer surgeries in women, Dr. Park said in an interview. The pilot trial has an investigational device exemption (IDE) granted by the FDA.
“The reason why we can’t just open a randomized controlled study (of robot versus open) and measure oncologic outcomes like recurrence-free survival is because, before we get to that point, we have to make sure” basic safety issues are addressed and established, she explained.
But Dr. Noorchashm said that argument is missing the larger, more important point: “They are still doing an oncologic procedure – you are still obliged to do noninferiority [randomized] testing with respect to cancer outcomes.”
Dr. Park sounded a different note: “We are doing it as safely as we can do it.”
Prophylactic use is also a cancer surgery
Intuitive’s five-center trial does not include en bloc removal of the breast gland as a primary outcome. Instead, the two primary outcomes are conversions to open mastectomy (efficacy measure) and the incidence of adverse events during surgery to 42 days after surgery (safety measure).
The company’s trial does not include any women with breast cancer, but is limited to women at increased risk for breast cancer and seeking prophylactic nipple-sparing mastectomy surgery.
Enrollment in the 145-patient single-arm trial began in the last few months and has a primary completion date of December 2022. It also has an IDE from the FDA.
“I do think that things like this need to be done with caution,” said Katherine Kopkash, MD, an investigator in the Intuitive trial and a breast surgeon at NorthShore University HealthSystem in Evanston, Ill., referring to the trial’s FDA exemption.
Dr. Kopkash said in an interview that the researchers in the multisite, single-arm Intuitive trial will also track oncologic outcomes, but the trial description at clinicaltrials.gov does not indicate that.
Both Dr. Kopkash and Dr. Park cited the high-profile missteps that took place in 2018 at Monmouth County Medical Center in Long Branch, N.J., during what was described as the first-ever use of robotic nipple-sparing mastectomy for invasive cancer in the United States, as reported by Medscape Medical News. However, neither the center or surgeon, Stephen Chagares, MD, requested or received an IDE from the FDA, and use of robotic mastectomy was halted after two cases.
It’s conceivable that Intuitive will seek out FDA clearance for use of its da Vinci system in robotic nipple-sparing mastectomy with data in a prophylactic setting and then expand the pool of patients, argued Dr. Noorchashm.
“Even if you introduce a new technology ... for a narrow subset of patients, the application of it eventually occurs on a ‘sliding scale,’ ” he said.
The former surgeon gave an example: The first device used in gastric bypass surgery was cleared for use in 2001 by the FDA for adults who were “severely morbidly obese.” But by the late 2000s, the operation was also being performed on people with lower body mass indexes who hadn’t exhausted traditional weight loss procedures. “It was very lucrative,” Dr. Noorchashm said about the surgery.
Surgeons only get one body
Intuitive has been hugely successful in developing and marketing its da Vinci system around the world for general and oncologic surgeries, with more than 1 million surgeries in 2018, a greater than sevenfold increase in 10 years, according to the authors of a new essay published in the June issue of the Annals of Surgery. The authors include breast surgeon Rosa F. Hwang, MD, of MD Anderson Cancer Center in Houston, who is also an investigator for the Intuitive trial.
However, robotic mastectomy is still a new surgery – only about 150 patients have been treated in the world, mostly in Italy, France, Taiwan, and Korea, the authors noted.
Despite such small numbers, “there’s a lot of interest in bringing this to the United States,” said Dr. Park.
One of the arguments in favor of robotic mastectomy for nipple-sparing procedures has nothing to do with patients. Instead, it is improved ergonomics – the robot makes a tough surgery easier on the surgeon.
Even stalwart robot critic Dr. Margenthaler conceded that this was possibly a winning feature.
“Nipple-sparing mastectomy is a very physically demanding procedure for the surgeon, resulting in higher rates of neck and back pain and fatigue compared with a standard skin-sparing approach,” she noted. She suggested, however, that practitioners of traditional mastectomy ought to first experiment with changes to patient positioning and incision placement to alleviate stress before looking to the robot for change.
When this news organization interviewed NorthShore University’s Dr. Kopkash, she had conducted four nipple-sparing mastectomies in the previous week. “It’s a difficult procedure on our bodies. I just turned 40 and I’m considered young for a surgeon. We get one body for our career and we have to figure out ways to make it work and protect it.”
Intuitive Surgical is funding the five-center clinical trial of robot-assisted nipple-sparing mastectomy, and UT Southwestern is funding its own trial. The Ohio State trial is funded by the university and a Pelotonia Idea Grant. Dr. Noorchashm and Dr. Margenthaler have no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
The FDA warning was issued in February 2019 to both the public and physicians. The FDA cautioned that the safety and effectiveness of robotic surgical devices for mastectomy “have not been established” and robots are not approved for the prevention or treatment of breast cancer.
The agency also noted that “diminished long-term survival” was associated with robotic surgery in another women’s cancer, that of hysterectomy for cervical cancer.
The FDA also made a surprising statement. The agency typically approves the robot for surgical use based on 30-day complication rates (compared with standards of care). But it said that going forward it “anticipates” that any evaluation of new use of robots in cancer “would be supported” by cancer outcomes such as progression-free survival and overall survival, which require much longer follow-up.
In short, the FDA hinted that it would change how it regulated medical devices, or at least robots used in women’s cancers. “The FDA takes women’s health very seriously,” said the organization.
Fast forward to 2021, and there are several prospective clinical trials of robot-assisted nipple-sparing mastectomy underway in the United States, including a five-center study sponsored by Intuitive Surgical, the maker of da Vinci robots, the dominant machine on the market. There are also single-center studies at Ohio State and University of Texas Southwestern Medical Center.
However, in each case, the study design either excludes cancer outcomes or does not primarily focus on those measures.
Instead, the primary outcomes are relatively short term and include safety and efficacy measures such as en bloc (in one piece) removal of the breast tissue, conversions to open mastectomy, and the incidence of adverse events during surgery and up to 6 weeks after surgery.
Importantly, none of the studies is a randomized trial; all have single arms.
That’s not what is needed, says breast surgeon Julie A. Margenthaler, MD of Washington University in St. Louis.
“I firmly believe that robotic-assisted mastectomy should only be considered in the context of a well-designed, randomized trial evaluating patient selection, patient safety, surgical complications, and oncologic outcomes with a concomitant cost analysis,” Dr. Margenthaler wrote in an essay published last year in JAMA Surgery.
As with the FDA warning, she cites worse survival with commonly used minimally invasive radical hysterectomy for cervical cancer, saying it “is a stark reminder that the marketing of robotic surgery has its roots in cosmesis and convenience rather than oncologic outcomes.”
In addition, robotic surgery is prohibitively expensive, said Dr. Margenthaler. In fact, cost is her “main criticism regarding robotic-assisted mastectomy.” It costs an additional $6,000 for robot use per procedure, according to a study conducted at a center in Taiwan. “I simply cannot be convinced that this will ever achieve cost-effective or even cost-neutral status,” Dr. Margenthaler wrote.
Not looking at the right outcomes
“They’re not looking at the right outcomes,” said Hooman Noorchashm, MD, PhD, about the current trials in the United States. He is a former surgeon and faculty member at the University of Pennsylvania in Philadelphia, and is now a patient advocate after his wife, Amy Reed, MD, died of uterine cancer in 2017 following a laparoscopic hysterectomy performed with a power morcellator that resulted in the upstaging of an undetected gynecologic cancer.
“You have to look at oncologic outcomes and do randomized, noninferiority trials to demonstrate that those cancer outcomes are at least equivalent to standard of care,” he said in an interview.
The current U.S. trials are “totally inappropriate,” he said.
Are randomized trials forthcoming after this initial set of single-arm trials? This news organization reached out to Intuitive Surgical, maker of the market leader da Vinci robotic surgical equipment to find out.
“Any plans for use of da Vinci Xi surgical system in nipple-sparing mastectomy will be based on these [single-arm] study results as well as other data and evidence,” said a company spokesperson, who did not confirm use of a randomized trial.
What about the FDA? Will the agency change its current approach to approving robots in surgeries for women’s cancers and require – not just anticipate – cancer-related outcomes data? At press time, the FDA did not respond to a request for comment.
Not having a randomized trial with cancer outcomes in any eventual FDA review opens the door for robotic mastectomy to be cleared for use in some mastectomies with short-term, nononcologic data, said Dr. Noorchashm.
Safety concerns with robotic mastectomy
Proponents of robot-assisted nipple-sparing mastectomy, which is coupled with reconstruction to preserve the shape of both the breast and nipple-areola area, suggest that improved patient cosmesis is a significant advantage with the high-tech intervention, said Dr. Margenthaler.
That’s because most robotic mastectomies performed to date (almost exclusively in Europe and Asia) have employed a 3- to 5-cm vertical incision located behind the lateral breast fold, allowing the scar to be hidden under the patient’s arm.
But therein also lies a safety concern, she asserted.
The “oncologic integrity” of the specimen on extraction is in question in some cases, she wrote, because of “such a small opening.”
Dr. Noorchashm agreed: “It all comes down to trying to get a large specimen out of a small incision.”
Traditional open mastectomy optimally yields the en bloc removal of a tumor – in one whole piece – to avoid fragmenting the cancerous tissue and possibly leaving residual disease behind. These undesirable events are associated with a higher risk for recurrence and treatment failure, he explained.
Thus, there is a need for a randomized trial with longer-term oncologic outcomes that compares the new approach with traditional open mastectomy, argued both Dr. Margenthaler and Dr. Noorchashm.
In defense of single-arm trials
“Oncologic safety is what we are concerned about and what we would like to study,” said Ko Un (Clara) Park, MD, a breast surgeon at The Ohio State University in Columbus.
Dr. Park is leading a single-center, single-arm pilot study of robotic nipple-sparing mastectomy enrolling up to 20 women with early-stage breast cancer or inherited genetic risk factors (but no cancer diagnosis). The trial, sponsored by a Pelotonia Idea Grant and Ohio State, recently enrolled its first patient.
The study’s primary outcomes include the feasibility of removal of the breast tissue en bloc; however, none of the outcomes are classic oncologic metrics such as progression-free survival.
The en bloc removal outcome is in direct response to the FDA’s concerns about minimally invasive cancer surgeries in women, Dr. Park said in an interview. The pilot trial has an investigational device exemption (IDE) granted by the FDA.
“The reason why we can’t just open a randomized controlled study (of robot versus open) and measure oncologic outcomes like recurrence-free survival is because, before we get to that point, we have to make sure” basic safety issues are addressed and established, she explained.
But Dr. Noorchashm said that argument is missing the larger, more important point: “They are still doing an oncologic procedure – you are still obliged to do noninferiority [randomized] testing with respect to cancer outcomes.”
Dr. Park sounded a different note: “We are doing it as safely as we can do it.”
Prophylactic use is also a cancer surgery
Intuitive’s five-center trial does not include en bloc removal of the breast gland as a primary outcome. Instead, the two primary outcomes are conversions to open mastectomy (efficacy measure) and the incidence of adverse events during surgery to 42 days after surgery (safety measure).
The company’s trial does not include any women with breast cancer, but is limited to women at increased risk for breast cancer and seeking prophylactic nipple-sparing mastectomy surgery.
Enrollment in the 145-patient single-arm trial began in the last few months and has a primary completion date of December 2022. It also has an IDE from the FDA.
“I do think that things like this need to be done with caution,” said Katherine Kopkash, MD, an investigator in the Intuitive trial and a breast surgeon at NorthShore University HealthSystem in Evanston, Ill., referring to the trial’s FDA exemption.
Dr. Kopkash said in an interview that the researchers in the multisite, single-arm Intuitive trial will also track oncologic outcomes, but the trial description at clinicaltrials.gov does not indicate that.
Both Dr. Kopkash and Dr. Park cited the high-profile missteps that took place in 2018 at Monmouth County Medical Center in Long Branch, N.J., during what was described as the first-ever use of robotic nipple-sparing mastectomy for invasive cancer in the United States, as reported by Medscape Medical News. However, neither the center or surgeon, Stephen Chagares, MD, requested or received an IDE from the FDA, and use of robotic mastectomy was halted after two cases.
It’s conceivable that Intuitive will seek out FDA clearance for use of its da Vinci system in robotic nipple-sparing mastectomy with data in a prophylactic setting and then expand the pool of patients, argued Dr. Noorchashm.
“Even if you introduce a new technology ... for a narrow subset of patients, the application of it eventually occurs on a ‘sliding scale,’ ” he said.
The former surgeon gave an example: The first device used in gastric bypass surgery was cleared for use in 2001 by the FDA for adults who were “severely morbidly obese.” But by the late 2000s, the operation was also being performed on people with lower body mass indexes who hadn’t exhausted traditional weight loss procedures. “It was very lucrative,” Dr. Noorchashm said about the surgery.
Surgeons only get one body
Intuitive has been hugely successful in developing and marketing its da Vinci system around the world for general and oncologic surgeries, with more than 1 million surgeries in 2018, a greater than sevenfold increase in 10 years, according to the authors of a new essay published in the June issue of the Annals of Surgery. The authors include breast surgeon Rosa F. Hwang, MD, of MD Anderson Cancer Center in Houston, who is also an investigator for the Intuitive trial.
However, robotic mastectomy is still a new surgery – only about 150 patients have been treated in the world, mostly in Italy, France, Taiwan, and Korea, the authors noted.
Despite such small numbers, “there’s a lot of interest in bringing this to the United States,” said Dr. Park.
One of the arguments in favor of robotic mastectomy for nipple-sparing procedures has nothing to do with patients. Instead, it is improved ergonomics – the robot makes a tough surgery easier on the surgeon.
Even stalwart robot critic Dr. Margenthaler conceded that this was possibly a winning feature.
“Nipple-sparing mastectomy is a very physically demanding procedure for the surgeon, resulting in higher rates of neck and back pain and fatigue compared with a standard skin-sparing approach,” she noted. She suggested, however, that practitioners of traditional mastectomy ought to first experiment with changes to patient positioning and incision placement to alleviate stress before looking to the robot for change.
When this news organization interviewed NorthShore University’s Dr. Kopkash, she had conducted four nipple-sparing mastectomies in the previous week. “It’s a difficult procedure on our bodies. I just turned 40 and I’m considered young for a surgeon. We get one body for our career and we have to figure out ways to make it work and protect it.”
Intuitive Surgical is funding the five-center clinical trial of robot-assisted nipple-sparing mastectomy, and UT Southwestern is funding its own trial. The Ohio State trial is funded by the university and a Pelotonia Idea Grant. Dr. Noorchashm and Dr. Margenthaler have no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
More children with high-risk brain cancer now surviving
A practice-changing study that used molecular testing to distinguish between subtypes of medulloblastoma has shown a significant improvement in survival for children with high-risk disease who underwent treatment intensification with carboplatin.
“Each of the four subgroups of medulloblastoma has a different prognosis, but for this particular subgroup, 20 fewer children out of every 100 would have survived prior to this study,” James Olson, MD, professor of medicine, French Hutchinson Cancer Research Center, University of Washington, Seattle, said in an interview.
“This is the reason for celebration – for now and forevermore, we can expect 20 more children with high-risk, group 3 medulloblastoma to survive,” he said.
“We recommend that all children with high-risk, group 3 medulloblastoma receive carboplatin and all children in the other subgroups do not, because we don’t want them to experience the toxicity without benefit,” Dr. Olson said.
The study was published online July 22, 2021, in JAMA Oncology.
Hematologic toxicity was more pronounced in the carboplatin arm in the induction phase of the protocol, and toxicity persisted into the first cycles of maintenance therapy. On the other hand, “there weren’t enough additional side effects to recommend children not get carboplatin if they would benefit from it,” Dr. Olson noted.
At least 75% of children with newly diagnosed medulloblastoma survive, although those with high-risk, group 3 disease have a substantially poorer prognosis than those with other molecular subtypes.
However, if a child with medulloblastoma experiences relapse, “the likelihood of survival is near zero, so it’s important to get it right the first time,” Dr. Olson said.
One of the patients who took part in this trial, Sammy Loch of Seattle, is now 27 years old and has been cancer free for 11 years.
She was diagnosed with medulloblastoma when in high school. At the time of her diagnosis, she was asked by her pediatric oncologist at Seattle Children’s Hospital about taking part in the study. After careful consideration, she agreed.
“Participating in research was my way to give back and pay it forward,” Ms. Loch said in a statement. “It’s really exciting to know more people will survive because of the research I was involved in,” she added. She continues to pay her debt forward, serving as a therapist for people with chronic health conditions and raising funds for pediatric cancer research.
Patients had high-risk features
The study involved 261 evaluable patients (median age, 8.6 years). All patients had high-risk features, including metastatic disease (72.4% of the group), diffuse anaplastic histologic characteristics (22.2%), and incomplete surgical resection (5.4%), defined as residual tumor greater than 1.5 cm2.
“All patients received 36 Gy craniospinal radiotherapy with boost to the posterior fossa of 55.8 Gy cumulative dose with conventional fractionation of 1.8 Gy/d,” Dr. Olson and colleagues explain. Patients also received six doses of vincristine 1.5 mg/m2 weekly during radiotherapy and were randomly assigned to receive carboplatin 35 mg/m2 for a total of 30 doses given daily prior to radiotherapy or placebo.
This regimen was followed by maintenance therapy, which consisted of six 28-day cycles of the combination of cisplatin 75 mg/m2 on day 1; cyclophosphamide 1,000 mg/m2 on days 2 and 3; and vincristine 1.5 mg/m2 on days 1 and 8.
Patients were originally assigned to receive an additional 12 cycles of isotretinoin or placebo, to be given during and after maintenance therapy. However, randomization to isotretinoin was discontinued early because of futility.
The study was initially powered to evaluate medulloblastoma as a single disease. However, as a result of biologic insights gained after the study was conceived, it was amended to include a molecular subgroup analysis to better distinguish patients who might truly benefit from intensified therapy, the authors explained.
Study results
The World Health Organization categorizes tumors of the central nervous system into four groups. The authors followed this system of categorization for their patients with medulloblastoma. The four groups are WNT, in which WNT signaling pathway is activated; SHH, in which the SHH signaling pathway is activated; with or without TP53 mutation (provisionally designated group 3); and non-WNT/non-SHH (provisionally designed group 4)
The primary endpoint of the trial was event-free survival (EFS). In the patient population overall, there was no significant difference regarding this endpoint among those who received carboplatin and those who did not (EFS at 5 years, 66.4% vs. 59.2%).
However, there was a significant improvement among the patients in subgroup 3. Among those patients, EFS at 5 years was 73.2% with carboplatin versus 53.7% without (P = .047).
Similarly, in the overall group, there was no significant improvement in overall survival (OS) at 5 years from the addition of carboplatin (77.6% vs. 68.8% without carboplatin). However, the OS at 5 years varied widely between the different subtypes. There was again a significant improvement in OS at 5 years among the patients in subgroup 3 (82% with carboplation vs 63.7% without).
The beneficial effects from the addition of carboplatin on both endpoints were seen exclusively in patients in group 3, the authors emphasized.
“The WNT group does really well with less therapy, so if we treated all children the same, we would likely be overtreating WNT children and undertreating group 3 children,” Dr. Olson observed. “Genetic analysis is essential.”
In an earlier study, Dr. Olson and colleagues found that 70% of children with primitive neuroectodermal tumor of the CNS and pineoblastoma had been misdiagnosed even by outstanding children’s oncology centers because clinicians were relying on microscopic diagnosis.
“With molecular diagnosis, we were able to learn that many of these children had completely different diseases that require complexly different treatments, so doing diagnosis by molecular classification is absolutely essential,” he reemphasized.
“Glimmers of hope”
This study provides clinicians with “glimmers of hope” that children with high-risk, group 3 medulloblastoma will experience improvements in survival, wrote Allison Martin, MD, Albert Einstein College of Medicine, New York, and Sadhana Jackson, MD, National Institutes of Health, Bethesda, M.d., in an accompanying editorial.
The editorialists hope that “the treatment paradigm for all patients with high-risk disease can be improved through incorporation of detailed molecular analyses.”
However, they pointed out that DNA methylation and other advanced testing methods used to distinguish subgroups 3 and 4 in this study are not widely available, even at most Children’s Oncology Group member institutions. (Dr. Olson countered that, even if these sophisticated tests are not available at all pediatric oncology centers, tests will be performed if clinicians send tissue to the few sites that are equipped to conduct them.)
The editorialists also noted that therapy intensification with carboplatin is associated with an increased risk for adverse effects – “underscoring the importance of correctly identifying patients who could benefit from this intervention and avoid unnecessary toxic effects.”
The study was funded by the National Cancer Institute. Dr. Olson has disclosed no relevant financial relationships. Dr. Martin reported that she previously owed shares in Celgene, which she has subsequently sold.
A version of this article first appeared on Medscape.com.
A practice-changing study that used molecular testing to distinguish between subtypes of medulloblastoma has shown a significant improvement in survival for children with high-risk disease who underwent treatment intensification with carboplatin.
“Each of the four subgroups of medulloblastoma has a different prognosis, but for this particular subgroup, 20 fewer children out of every 100 would have survived prior to this study,” James Olson, MD, professor of medicine, French Hutchinson Cancer Research Center, University of Washington, Seattle, said in an interview.
“This is the reason for celebration – for now and forevermore, we can expect 20 more children with high-risk, group 3 medulloblastoma to survive,” he said.
“We recommend that all children with high-risk, group 3 medulloblastoma receive carboplatin and all children in the other subgroups do not, because we don’t want them to experience the toxicity without benefit,” Dr. Olson said.
The study was published online July 22, 2021, in JAMA Oncology.
Hematologic toxicity was more pronounced in the carboplatin arm in the induction phase of the protocol, and toxicity persisted into the first cycles of maintenance therapy. On the other hand, “there weren’t enough additional side effects to recommend children not get carboplatin if they would benefit from it,” Dr. Olson noted.
At least 75% of children with newly diagnosed medulloblastoma survive, although those with high-risk, group 3 disease have a substantially poorer prognosis than those with other molecular subtypes.
However, if a child with medulloblastoma experiences relapse, “the likelihood of survival is near zero, so it’s important to get it right the first time,” Dr. Olson said.
One of the patients who took part in this trial, Sammy Loch of Seattle, is now 27 years old and has been cancer free for 11 years.
She was diagnosed with medulloblastoma when in high school. At the time of her diagnosis, she was asked by her pediatric oncologist at Seattle Children’s Hospital about taking part in the study. After careful consideration, she agreed.
“Participating in research was my way to give back and pay it forward,” Ms. Loch said in a statement. “It’s really exciting to know more people will survive because of the research I was involved in,” she added. She continues to pay her debt forward, serving as a therapist for people with chronic health conditions and raising funds for pediatric cancer research.
Patients had high-risk features
The study involved 261 evaluable patients (median age, 8.6 years). All patients had high-risk features, including metastatic disease (72.4% of the group), diffuse anaplastic histologic characteristics (22.2%), and incomplete surgical resection (5.4%), defined as residual tumor greater than 1.5 cm2.
“All patients received 36 Gy craniospinal radiotherapy with boost to the posterior fossa of 55.8 Gy cumulative dose with conventional fractionation of 1.8 Gy/d,” Dr. Olson and colleagues explain. Patients also received six doses of vincristine 1.5 mg/m2 weekly during radiotherapy and were randomly assigned to receive carboplatin 35 mg/m2 for a total of 30 doses given daily prior to radiotherapy or placebo.
This regimen was followed by maintenance therapy, which consisted of six 28-day cycles of the combination of cisplatin 75 mg/m2 on day 1; cyclophosphamide 1,000 mg/m2 on days 2 and 3; and vincristine 1.5 mg/m2 on days 1 and 8.
Patients were originally assigned to receive an additional 12 cycles of isotretinoin or placebo, to be given during and after maintenance therapy. However, randomization to isotretinoin was discontinued early because of futility.
The study was initially powered to evaluate medulloblastoma as a single disease. However, as a result of biologic insights gained after the study was conceived, it was amended to include a molecular subgroup analysis to better distinguish patients who might truly benefit from intensified therapy, the authors explained.
Study results
The World Health Organization categorizes tumors of the central nervous system into four groups. The authors followed this system of categorization for their patients with medulloblastoma. The four groups are WNT, in which WNT signaling pathway is activated; SHH, in which the SHH signaling pathway is activated; with or without TP53 mutation (provisionally designated group 3); and non-WNT/non-SHH (provisionally designed group 4)
The primary endpoint of the trial was event-free survival (EFS). In the patient population overall, there was no significant difference regarding this endpoint among those who received carboplatin and those who did not (EFS at 5 years, 66.4% vs. 59.2%).
However, there was a significant improvement among the patients in subgroup 3. Among those patients, EFS at 5 years was 73.2% with carboplatin versus 53.7% without (P = .047).
Similarly, in the overall group, there was no significant improvement in overall survival (OS) at 5 years from the addition of carboplatin (77.6% vs. 68.8% without carboplatin). However, the OS at 5 years varied widely between the different subtypes. There was again a significant improvement in OS at 5 years among the patients in subgroup 3 (82% with carboplation vs 63.7% without).
The beneficial effects from the addition of carboplatin on both endpoints were seen exclusively in patients in group 3, the authors emphasized.
“The WNT group does really well with less therapy, so if we treated all children the same, we would likely be overtreating WNT children and undertreating group 3 children,” Dr. Olson observed. “Genetic analysis is essential.”
In an earlier study, Dr. Olson and colleagues found that 70% of children with primitive neuroectodermal tumor of the CNS and pineoblastoma had been misdiagnosed even by outstanding children’s oncology centers because clinicians were relying on microscopic diagnosis.
“With molecular diagnosis, we were able to learn that many of these children had completely different diseases that require complexly different treatments, so doing diagnosis by molecular classification is absolutely essential,” he reemphasized.
“Glimmers of hope”
This study provides clinicians with “glimmers of hope” that children with high-risk, group 3 medulloblastoma will experience improvements in survival, wrote Allison Martin, MD, Albert Einstein College of Medicine, New York, and Sadhana Jackson, MD, National Institutes of Health, Bethesda, M.d., in an accompanying editorial.
The editorialists hope that “the treatment paradigm for all patients with high-risk disease can be improved through incorporation of detailed molecular analyses.”
However, they pointed out that DNA methylation and other advanced testing methods used to distinguish subgroups 3 and 4 in this study are not widely available, even at most Children’s Oncology Group member institutions. (Dr. Olson countered that, even if these sophisticated tests are not available at all pediatric oncology centers, tests will be performed if clinicians send tissue to the few sites that are equipped to conduct them.)
The editorialists also noted that therapy intensification with carboplatin is associated with an increased risk for adverse effects – “underscoring the importance of correctly identifying patients who could benefit from this intervention and avoid unnecessary toxic effects.”
The study was funded by the National Cancer Institute. Dr. Olson has disclosed no relevant financial relationships. Dr. Martin reported that she previously owed shares in Celgene, which she has subsequently sold.
A version of this article first appeared on Medscape.com.
A practice-changing study that used molecular testing to distinguish between subtypes of medulloblastoma has shown a significant improvement in survival for children with high-risk disease who underwent treatment intensification with carboplatin.
“Each of the four subgroups of medulloblastoma has a different prognosis, but for this particular subgroup, 20 fewer children out of every 100 would have survived prior to this study,” James Olson, MD, professor of medicine, French Hutchinson Cancer Research Center, University of Washington, Seattle, said in an interview.
“This is the reason for celebration – for now and forevermore, we can expect 20 more children with high-risk, group 3 medulloblastoma to survive,” he said.
“We recommend that all children with high-risk, group 3 medulloblastoma receive carboplatin and all children in the other subgroups do not, because we don’t want them to experience the toxicity without benefit,” Dr. Olson said.
The study was published online July 22, 2021, in JAMA Oncology.
Hematologic toxicity was more pronounced in the carboplatin arm in the induction phase of the protocol, and toxicity persisted into the first cycles of maintenance therapy. On the other hand, “there weren’t enough additional side effects to recommend children not get carboplatin if they would benefit from it,” Dr. Olson noted.
At least 75% of children with newly diagnosed medulloblastoma survive, although those with high-risk, group 3 disease have a substantially poorer prognosis than those with other molecular subtypes.
However, if a child with medulloblastoma experiences relapse, “the likelihood of survival is near zero, so it’s important to get it right the first time,” Dr. Olson said.
One of the patients who took part in this trial, Sammy Loch of Seattle, is now 27 years old and has been cancer free for 11 years.
She was diagnosed with medulloblastoma when in high school. At the time of her diagnosis, she was asked by her pediatric oncologist at Seattle Children’s Hospital about taking part in the study. After careful consideration, she agreed.
“Participating in research was my way to give back and pay it forward,” Ms. Loch said in a statement. “It’s really exciting to know more people will survive because of the research I was involved in,” she added. She continues to pay her debt forward, serving as a therapist for people with chronic health conditions and raising funds for pediatric cancer research.
Patients had high-risk features
The study involved 261 evaluable patients (median age, 8.6 years). All patients had high-risk features, including metastatic disease (72.4% of the group), diffuse anaplastic histologic characteristics (22.2%), and incomplete surgical resection (5.4%), defined as residual tumor greater than 1.5 cm2.
“All patients received 36 Gy craniospinal radiotherapy with boost to the posterior fossa of 55.8 Gy cumulative dose with conventional fractionation of 1.8 Gy/d,” Dr. Olson and colleagues explain. Patients also received six doses of vincristine 1.5 mg/m2 weekly during radiotherapy and were randomly assigned to receive carboplatin 35 mg/m2 for a total of 30 doses given daily prior to radiotherapy or placebo.
This regimen was followed by maintenance therapy, which consisted of six 28-day cycles of the combination of cisplatin 75 mg/m2 on day 1; cyclophosphamide 1,000 mg/m2 on days 2 and 3; and vincristine 1.5 mg/m2 on days 1 and 8.
Patients were originally assigned to receive an additional 12 cycles of isotretinoin or placebo, to be given during and after maintenance therapy. However, randomization to isotretinoin was discontinued early because of futility.
The study was initially powered to evaluate medulloblastoma as a single disease. However, as a result of biologic insights gained after the study was conceived, it was amended to include a molecular subgroup analysis to better distinguish patients who might truly benefit from intensified therapy, the authors explained.
Study results
The World Health Organization categorizes tumors of the central nervous system into four groups. The authors followed this system of categorization for their patients with medulloblastoma. The four groups are WNT, in which WNT signaling pathway is activated; SHH, in which the SHH signaling pathway is activated; with or without TP53 mutation (provisionally designated group 3); and non-WNT/non-SHH (provisionally designed group 4)
The primary endpoint of the trial was event-free survival (EFS). In the patient population overall, there was no significant difference regarding this endpoint among those who received carboplatin and those who did not (EFS at 5 years, 66.4% vs. 59.2%).
However, there was a significant improvement among the patients in subgroup 3. Among those patients, EFS at 5 years was 73.2% with carboplatin versus 53.7% without (P = .047).
Similarly, in the overall group, there was no significant improvement in overall survival (OS) at 5 years from the addition of carboplatin (77.6% vs. 68.8% without carboplatin). However, the OS at 5 years varied widely between the different subtypes. There was again a significant improvement in OS at 5 years among the patients in subgroup 3 (82% with carboplation vs 63.7% without).
The beneficial effects from the addition of carboplatin on both endpoints were seen exclusively in patients in group 3, the authors emphasized.
“The WNT group does really well with less therapy, so if we treated all children the same, we would likely be overtreating WNT children and undertreating group 3 children,” Dr. Olson observed. “Genetic analysis is essential.”
In an earlier study, Dr. Olson and colleagues found that 70% of children with primitive neuroectodermal tumor of the CNS and pineoblastoma had been misdiagnosed even by outstanding children’s oncology centers because clinicians were relying on microscopic diagnosis.
“With molecular diagnosis, we were able to learn that many of these children had completely different diseases that require complexly different treatments, so doing diagnosis by molecular classification is absolutely essential,” he reemphasized.
“Glimmers of hope”
This study provides clinicians with “glimmers of hope” that children with high-risk, group 3 medulloblastoma will experience improvements in survival, wrote Allison Martin, MD, Albert Einstein College of Medicine, New York, and Sadhana Jackson, MD, National Institutes of Health, Bethesda, M.d., in an accompanying editorial.
The editorialists hope that “the treatment paradigm for all patients with high-risk disease can be improved through incorporation of detailed molecular analyses.”
However, they pointed out that DNA methylation and other advanced testing methods used to distinguish subgroups 3 and 4 in this study are not widely available, even at most Children’s Oncology Group member institutions. (Dr. Olson countered that, even if these sophisticated tests are not available at all pediatric oncology centers, tests will be performed if clinicians send tissue to the few sites that are equipped to conduct them.)
The editorialists also noted that therapy intensification with carboplatin is associated with an increased risk for adverse effects – “underscoring the importance of correctly identifying patients who could benefit from this intervention and avoid unnecessary toxic effects.”
The study was funded by the National Cancer Institute. Dr. Olson has disclosed no relevant financial relationships. Dr. Martin reported that she previously owed shares in Celgene, which she has subsequently sold.
A version of this article first appeared on Medscape.com.
Prostate Cancer: Small Cell Prostate Carcinoma-Pathology
Occipital nerve stimulation offers relief for patients with intractable chronic cluster headache
Occipital nerve stimulation may help safely prevent attacks of medically intractable chronic cluster headache, according to a new study.
Medically intractable chronic cluster headaches are unilateral headaches that cause excruciating pain during attacks, which may happen as frequently as eight times per day. They are refractory to, or intolerant of, preventive medications typically used in chronic cluster headaches.
“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting medically intractable chronic cluster headache, both at high and low intensity,” Leopoldine A. Wilbrink, MD, of Leiden (the Netherlands) University Medical Centre, and coauthors wrote in their paper.
The findings were published online.
The multicenter, randomized, double-blind, phase 3 clinical trial was carried out at seven hospitals in the Netherlands, Belgium, Germany, and Hungary. A total of 150 patients with suspected medically intractable chronic cluster headache were enrolled between October 2010 and December 2017, and observed for 12 weeks at baseline. Of those initially enrolled, 131 patients with at least four medically intractable chronic cluster headache attacks per week and a history of nonresponsiveness to at least three standard preventive medications were randomly allocated to one of two groups: Sixty-five patients received 24 weeks of ONS at high intensity (100% intensity, or the intensity 10% below the threshold of discomfort as reported by the patient) while 66 received low-intensity (30%) ONS. At 25-48 weeks, the patients received open-label ONS.
Safe and well tolerated
“Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy,” wrote Dr. Wilbrink and colleagues.
From baseline to weeks 21-24, the median weekly mean attack frequencies decreased to 7.38 (95% confidence interval [CI]: 2.5-18.5, P < .0001). A median decrease in 5.21 attacks per week (–11.18 to –0.19, P < .0001) was observed.
The 100% ONS group saw a decrease in mean attack frequency from 17.58 at baseline (range, 9.83-29.33) to 9.5 (3-21.25) at 21-24 weeks with a median change of –4.08 (–11.92 to –0.25). In the 30% ONS group, the mean attack frequency decreased from 15 (9.25 to 22.33) to 6.75 (1.5-16.5) with a median change of –6.5 (–10.83 to –0.08).
At weeks 21-24, the difference in median weekly mean attack frequency between the groups was –2.42 (–5.17 to 3.33).
The authors stated that, in both groups, ONS was “safe and well tolerated.” A total of 129 adverse events were reported in the 100% ONS group and 95 in the 30% ONS group, of which 17 and 9 were considered serious, respectively. The serious adverse events required a short hospital stay to resolve minor hardware issues. The adverse events most frequently observed were local pain, impaired wound healing, neck stiffness, and hardware damage.
Low intensity stimulation may be best
“The main limitation of the study comes from the difficulty in defining the electrical dose, which was not constant across patients within each group, but individually adjusted depending on the perception of the ONS-induced paraesthesia,” Denys Fontaine, MD, and Michel Lanteri-Minet, MD, both from Université Cote D’Azur in France, wrote in an accompanying editorial.
Given that the primary outcome did not differ significantly between the treatment groups, the editorialists stated that “the lowest stimulation intensity that induces paraesthesia is sufficient to obtain an effect in the patients who respond. Increasing the electrical dose or intensity does not seem to bring better efficacy and might even induce discomfort (painful paraesthesia or shock-like sensations) that might substantially reduce the tolerance of this approach.”
While the trial did not provide convincing evidence of high intensity ONS in medically intractable chronic cluster headache, the editorialists are otherwise optimistic about the findings: “… considering the significant difference between baseline and the end of the randomised stimulation phase in both groups (about half of the patients showed a 50% decrease in attack frequency), the findings of this study support the favourable results of previous real-world studies, and indicate that a substantial proportion of patients with intractable chronic cluster headache, although not all, could have their condition substantially improved by ONS.” Dr. Fontaine and Dr. Lanteri-Minet added that they hope that “these data will help health authorities to recognise the efficacy of ONS and consider its approval for use in patients with intractable chronic cluster headache.”
Priorities for future research in this area should “focus on optimising stimulation protocols and disentangling the underlying mechanism of action,” Dr. Wilbrink and colleagues wrote.
The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium, the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement program for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to Dr. Ferrari.
Occipital nerve stimulation may help safely prevent attacks of medically intractable chronic cluster headache, according to a new study.
Medically intractable chronic cluster headaches are unilateral headaches that cause excruciating pain during attacks, which may happen as frequently as eight times per day. They are refractory to, or intolerant of, preventive medications typically used in chronic cluster headaches.
“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting medically intractable chronic cluster headache, both at high and low intensity,” Leopoldine A. Wilbrink, MD, of Leiden (the Netherlands) University Medical Centre, and coauthors wrote in their paper.
The findings were published online.
The multicenter, randomized, double-blind, phase 3 clinical trial was carried out at seven hospitals in the Netherlands, Belgium, Germany, and Hungary. A total of 150 patients with suspected medically intractable chronic cluster headache were enrolled between October 2010 and December 2017, and observed for 12 weeks at baseline. Of those initially enrolled, 131 patients with at least four medically intractable chronic cluster headache attacks per week and a history of nonresponsiveness to at least three standard preventive medications were randomly allocated to one of two groups: Sixty-five patients received 24 weeks of ONS at high intensity (100% intensity, or the intensity 10% below the threshold of discomfort as reported by the patient) while 66 received low-intensity (30%) ONS. At 25-48 weeks, the patients received open-label ONS.
Safe and well tolerated
“Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy,” wrote Dr. Wilbrink and colleagues.
From baseline to weeks 21-24, the median weekly mean attack frequencies decreased to 7.38 (95% confidence interval [CI]: 2.5-18.5, P < .0001). A median decrease in 5.21 attacks per week (–11.18 to –0.19, P < .0001) was observed.
The 100% ONS group saw a decrease in mean attack frequency from 17.58 at baseline (range, 9.83-29.33) to 9.5 (3-21.25) at 21-24 weeks with a median change of –4.08 (–11.92 to –0.25). In the 30% ONS group, the mean attack frequency decreased from 15 (9.25 to 22.33) to 6.75 (1.5-16.5) with a median change of –6.5 (–10.83 to –0.08).
At weeks 21-24, the difference in median weekly mean attack frequency between the groups was –2.42 (–5.17 to 3.33).
The authors stated that, in both groups, ONS was “safe and well tolerated.” A total of 129 adverse events were reported in the 100% ONS group and 95 in the 30% ONS group, of which 17 and 9 were considered serious, respectively. The serious adverse events required a short hospital stay to resolve minor hardware issues. The adverse events most frequently observed were local pain, impaired wound healing, neck stiffness, and hardware damage.
Low intensity stimulation may be best
“The main limitation of the study comes from the difficulty in defining the electrical dose, which was not constant across patients within each group, but individually adjusted depending on the perception of the ONS-induced paraesthesia,” Denys Fontaine, MD, and Michel Lanteri-Minet, MD, both from Université Cote D’Azur in France, wrote in an accompanying editorial.
Given that the primary outcome did not differ significantly between the treatment groups, the editorialists stated that “the lowest stimulation intensity that induces paraesthesia is sufficient to obtain an effect in the patients who respond. Increasing the electrical dose or intensity does not seem to bring better efficacy and might even induce discomfort (painful paraesthesia or shock-like sensations) that might substantially reduce the tolerance of this approach.”
While the trial did not provide convincing evidence of high intensity ONS in medically intractable chronic cluster headache, the editorialists are otherwise optimistic about the findings: “… considering the significant difference between baseline and the end of the randomised stimulation phase in both groups (about half of the patients showed a 50% decrease in attack frequency), the findings of this study support the favourable results of previous real-world studies, and indicate that a substantial proportion of patients with intractable chronic cluster headache, although not all, could have their condition substantially improved by ONS.” Dr. Fontaine and Dr. Lanteri-Minet added that they hope that “these data will help health authorities to recognise the efficacy of ONS and consider its approval for use in patients with intractable chronic cluster headache.”
Priorities for future research in this area should “focus on optimising stimulation protocols and disentangling the underlying mechanism of action,” Dr. Wilbrink and colleagues wrote.
The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium, the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement program for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to Dr. Ferrari.
Occipital nerve stimulation may help safely prevent attacks of medically intractable chronic cluster headache, according to a new study.
Medically intractable chronic cluster headaches are unilateral headaches that cause excruciating pain during attacks, which may happen as frequently as eight times per day. They are refractory to, or intolerant of, preventive medications typically used in chronic cluster headaches.
“ONS was associated with a major, rapid, and sustained improvement of severe and long-lasting medically intractable chronic cluster headache, both at high and low intensity,” Leopoldine A. Wilbrink, MD, of Leiden (the Netherlands) University Medical Centre, and coauthors wrote in their paper.
The findings were published online.
The multicenter, randomized, double-blind, phase 3 clinical trial was carried out at seven hospitals in the Netherlands, Belgium, Germany, and Hungary. A total of 150 patients with suspected medically intractable chronic cluster headache were enrolled between October 2010 and December 2017, and observed for 12 weeks at baseline. Of those initially enrolled, 131 patients with at least four medically intractable chronic cluster headache attacks per week and a history of nonresponsiveness to at least three standard preventive medications were randomly allocated to one of two groups: Sixty-five patients received 24 weeks of ONS at high intensity (100% intensity, or the intensity 10% below the threshold of discomfort as reported by the patient) while 66 received low-intensity (30%) ONS. At 25-48 weeks, the patients received open-label ONS.
Safe and well tolerated
“Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy,” wrote Dr. Wilbrink and colleagues.
From baseline to weeks 21-24, the median weekly mean attack frequencies decreased to 7.38 (95% confidence interval [CI]: 2.5-18.5, P < .0001). A median decrease in 5.21 attacks per week (–11.18 to –0.19, P < .0001) was observed.
The 100% ONS group saw a decrease in mean attack frequency from 17.58 at baseline (range, 9.83-29.33) to 9.5 (3-21.25) at 21-24 weeks with a median change of –4.08 (–11.92 to –0.25). In the 30% ONS group, the mean attack frequency decreased from 15 (9.25 to 22.33) to 6.75 (1.5-16.5) with a median change of –6.5 (–10.83 to –0.08).
At weeks 21-24, the difference in median weekly mean attack frequency between the groups was –2.42 (–5.17 to 3.33).
The authors stated that, in both groups, ONS was “safe and well tolerated.” A total of 129 adverse events were reported in the 100% ONS group and 95 in the 30% ONS group, of which 17 and 9 were considered serious, respectively. The serious adverse events required a short hospital stay to resolve minor hardware issues. The adverse events most frequently observed were local pain, impaired wound healing, neck stiffness, and hardware damage.
Low intensity stimulation may be best
“The main limitation of the study comes from the difficulty in defining the electrical dose, which was not constant across patients within each group, but individually adjusted depending on the perception of the ONS-induced paraesthesia,” Denys Fontaine, MD, and Michel Lanteri-Minet, MD, both from Université Cote D’Azur in France, wrote in an accompanying editorial.
Given that the primary outcome did not differ significantly between the treatment groups, the editorialists stated that “the lowest stimulation intensity that induces paraesthesia is sufficient to obtain an effect in the patients who respond. Increasing the electrical dose or intensity does not seem to bring better efficacy and might even induce discomfort (painful paraesthesia or shock-like sensations) that might substantially reduce the tolerance of this approach.”
While the trial did not provide convincing evidence of high intensity ONS in medically intractable chronic cluster headache, the editorialists are otherwise optimistic about the findings: “… considering the significant difference between baseline and the end of the randomised stimulation phase in both groups (about half of the patients showed a 50% decrease in attack frequency), the findings of this study support the favourable results of previous real-world studies, and indicate that a substantial proportion of patients with intractable chronic cluster headache, although not all, could have their condition substantially improved by ONS.” Dr. Fontaine and Dr. Lanteri-Minet added that they hope that “these data will help health authorities to recognise the efficacy of ONS and consider its approval for use in patients with intractable chronic cluster headache.”
Priorities for future research in this area should “focus on optimising stimulation protocols and disentangling the underlying mechanism of action,” Dr. Wilbrink and colleagues wrote.
The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium, the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement program for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to Dr. Ferrari.
FROM LANCET NEUROLOGY