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Surgically Based Clinical Trials for High-Grade Gliomas — Bringing the Laboratory to the Operating Room

By Tumor, Tumor SeriesNo Comments

For patients with aggressive, high-grade gliomas, clinical trials offer access to new experimental therapies studied for their effectiveness. Traditionally, clinical trials have been broken into three phases. Phase 1 clinical trials assess the safety of a new treatment. Phase 2 studies involve more patients and evaluate the efficacy of the treatment. Phase 3 studies are designed to compare the novel treatment to a proven treatment to validate its effectiveness further.

While most clinical trials for high-grade glioma patients study systemically administered chemotherapies managed by a neuro-oncologist, some high-grade glioma clinical trials are now surgically based. In these trials, tumor surgery plays more than its usual cytoreductive role. Examples of surgically based clinical trials include:

  • Trials in which biological information is obtained through the surgery;
  • Trials in which a therapy is derived from the surgical tissue; and
  • Trials in which the surgeon delivers a therapy at the time of the procedure.

The first example of obtaining biological information through the surgery consists of phase 0-like “window of opportunity” clinical trials, first in human studies in which a small number of patients are given a drug for a few days before surgery. Blood is drawn regularly before and during the surgery to obtain pharmacokinetic and pharmacodynamic information, which helps determine how quickly a steady-state concentration of the drug within the tumor is achieved under the prescribed dosing regimen. Cerebrospinal fluid is obtained during surgery to determine whether the agent’s intracranial penetration achieves a steady state after a similar time as occurs systemically. Tumor tissue is analyzed to measure drug levels in the enhancing versus non-enhancing tumor, with levels often 3-4 times higher in the former than the latter, underscoring the difficulty of treating the non-enhancing tumor with systemic chemotherapy. Tumor tissue can also be analyzed for levels of the drug’s target protein and its downstream mediators to determine whether the drug affects the intended target in tumor tissue.

The second example of surgically based clinical trials typically involves immunotherapies in which a vaccine is developed from tumor tissue. The vaccine can be peptide-based — in which an immunostimulatory peptide-like heat shock protein is combined with tumor peptides — or a cellular vaccine in which immune cells like dendritic cells taken from the patient are primed with tumor peptides and then returned to the patient to provide antitumor immunity.

The third example involves the surgical administration of cellular, viral or pharmacologic therapies. These can be delivered into craniotomy walls after resection or directly into the tumor without resection. The advantages of delivering the therapy into craniotomy walls include combining the benefit of cytoreductive surgery with the therapeutic injection. In contrast, the disadvantages of delivering the therapy into the craniotomy walls include the reflux of the agents back into the resection cavity. Needle delivery into the tumor avoids reflux into the resection cavity, but reflux up the injection tract or adjacent cavities from previous surgery must be accounted for. The lack of cytoreductive surgery means needle delivery may be best for smaller focal tumors. Needle delivery into the tumor can be accomplished via direct needle delivery or convection-enhanced delivery involving infusion through a catheter along a pressure gradient over hours or days.

Neurosurgeons play a critical role in designing and developing surgically based clinical trials for high-grade glioma patients. Many of these trials have developed from neurosurgeon-scientists’ basic science research in laboratories using preclinical animal models. There is hope that these trials will lead to discoveries that meaningfully impact the prognosis of patients diagnosed with high-grade gliomas in the future.

Editor’s Note: We hope you will share what you learn from our posts. We invite you to join the conversation on Twitter by following @Neurosurgery and @NSTumorSection and using the hashtag #TumorSeries.

Manish K. Aghi, MD, PhD, FAANS
UCSF Dept. of Neurological Surgery
San Francisco, Calif.

December 1, 2022
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Neurosurgeons Putting Patients First

By Access to Care, Faces of Neurosurgery, Health Reform, MedicareNo Comments

The Medicare physician payment system is on an unsustainable path that has failed to keep up with inflation over the years, threatening patient access to care. The American Association of Neurological Surgeons (AANS) and the Congress of Neurological Surgeons (CNS) are actively engaged in preventing steep Medicare payment cuts and preserving patient access to care through the Surgical Care Coalition. The coalition is in year three of its campaign to stop these cuts and implement lasting changes to the physician payment and quality improvement systems.

On Jan. 1, 2023, neurosurgeons face a minimum 8.5% Medicare payment cut, including a nearly 4.5% cut for all Medicare Physician Fee Schedule services and a 4% Statutory Pay-As-You-Go Act cut, triggered due to new federal spending. After successfully protecting patients’ timely access to quality surgical care in 2020 and 2021 by securing Congressional action to mitigate proposed cuts to Medicare, the coalition is fighting against similar cuts proposed for 2023. The AANS and the CNS are also working with Congress on long-term solutions to fix these broken systems. To that end, we submitted detailed comments in response to a Congressional request for information.

The people who the proposed cuts will most impact are our patients. Every day, neurosurgeons take care of some of the sickest patients who face painful and life-threatening neurologic conditions. Alexander A. Khalessi, MD, FAANS, John K. Ratliff, MD, FAANS and Maya A. Babu, MD, FAANS, share their experiences as neurosurgeons and how the cuts will impact neurosurgical practices and their patients. The videos are available as follows:

Patient Process

Why I Became a Surgeon

Earning a Patient’s Trust

Medicare Cuts are Back

Patients Deserve Timely, Quality Care

Editor’s Note: We hope you will share what you learn from our posts. We invite you to join the conversation on Twitter by following @Neurosurgery and @SurgeonsCare.

November 9, 2022
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Cross-Post: Why Is It Hard for Grandma To See Her Doctor?

By Cross Post, MedicareNo Comments

From time to time on Neurosurgery Blog, you will see us cross-posting or linking to items from other places that may be of interest to our readers. Today’s post originally appeared on AL.com on Nov. 1, titled “Why is it hard for grandma to see her doctor?” In the op-ed, Richard Menger, MD, MPA, assistant professor of neurosurgery and political science at the University of South Alabama in Mobile, Ala., discusses how steep Medicare physician payment cuts scheduled to go into effect on Jan. 1, 2023, are not a good prescription for a healthy physician workforce.

The average physician will receive 8.5% less for providing the same services they did last year. While adjusting for inflation, Medicare payments to physicians have declined 22% from 2001-2021. According to Dr. Menger, “The people most impacted by these cuts will be our Medicare patients. In the backdrop of inflation, practices will not be able to sustain themselves by treating Medicare patients.” Dr. Menger concludes by stating that this puts seniors at risk for reduced access to care.

Click here to read the full article.

Editor’s Note: We hope you will share what you learn from our posts. We invite you to join the conversation on Twitter by following @Neurosurgery.

November 3, 2022
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Cross-Post: It’s Never Too Late to Pivot From N.F.L. Safety to Neurosurgeon

By Career, Cross PostNo Comments

From time to time on Neurosurgery Blog, you will see us cross-posting or linking to items from other places that we believe will be of interest to our readers. Today’s post originally appeared in the New York Times on Oct. 11 as part of the “It’s Never Too Late” series. The article discusses how Myron Rolle, MD, a PGY-6 neurosurgery resident at Massachusetts General Hospital in Boston, Mass., transitioned from playing in the NFL to neurosurgery.

Dr. Rolle notes that he was inspired to become a neurosurgeon by the book “Gifted Hands” by Benjamin S. Carson, MD, FAANS (L) — a memoir that detailed how Dr. Carson went from being an inner-city youth with poor grades to the director of pediatric neurosurgery at Johns Hopkins University Hospital. Dr. Rolle’s long-term goal is to practice neurosurgery in the U.S. and spend a portion of the year in the Caribbean, developing neurosurgical services in the Bahamas and member states of CARICOM, an organization of Caribbean countries.

Editor’s Note: We hope you will share what you learn from our posts. We invite you to join the conversation on Twitter by following @Neurosurgery and @MyronRolle and using the hashtag #Neurosurgery.

October 28, 2022
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Increasing Patient Access to Stereotactic Radiosurgery through Innovation

By Brain Tumor, Tumor, Tumor SeriesNo Comments

Neurosurgery supports and welcomes transparent physician-industry interactions to foster healthy relations and spur innovative device development to benefit patients. Within the specialty of neurosurgery, there are numerous examples of just such benefits, including increased access to stereotactic radiosurgery (SRS). SRS is a treatment that delivers radiation to precise targets in the brain, such as tumors, while minimizing injury to adjacent areas.

As part of the ongoing Neurosurgery Blog Tumor Series, Deborah L. Benzil, MD, FAANS, FACS, interviewed Stefan Vilsmeier, the CEO and founder of Brainlab. Mr. Vilsmeier discusses why he founded the company and how his software and hardware have increased neurosurgical patient access to SRS. Mr. Vilsmeier observed that many institutions created homegrown radiosurgery systems, but there were no commercially available options.

Brainlab created an innovative software and hardware for performing SRS to provide greater treatment access through standardization. Taking it a step further, Brainlab offers the Novalis Circle, a user group to ensure quality, and Novalis Certified Accreditation Program to promote the delivery of radiosurgery at a level of efficacy and safety commensurate with the highest standards of clinical practice.

The interviews are available here and on Neurosurgery Blog’s YouTube channel.

Part I: What is stereotactic radiosurgery?

Part II: Dr. Benzil’s interview with Mr. Vilsmeier

Editor’s Note: Ethical interactions between industry and health care professionals are essential to strengthening patient trust in the health care system. The Open Payments system, also known as the Sunshine Act, is a federal program that collects information about the payments drug and device companies make to physicians and teaching hospitals. The data the Centers for Medicare & Medicaid Services collect is published annually.  

We hope that you will share what you learn from our posts. We invite you to join the conversation on Twitter by following @Neurosurgery and @NSTumorSection and using the hashtag #TumorSeries.

October 27, 2022
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Cross-Post: Neurosurgery Announces Global Neurosurgery ‘Moon Shot’ with New Editorial Board Section

By CNS Spotlight, Cross Post, Guest PostNo Comments

From time to time on Neurosurgery Blog, you will see us highlighting items from other places when we believe they hit the mark on an issue. To this end, we want to bring attention to the new Neurosurgery Editorial Board Section, “Global Neurosurgery,” highlighted by Section Editor Gail L. Rosseau, MD, FAANS, FACS, in the October issue of Neurosurgery.

As highlighted in a recent announcement about the new feature, “Despite rapid advancements in neurosurgical techniques and capabilities, much of the world’s population has limited or no access to modern care for brain and spinal trauma, stroke, tumors, and other neurological conditions.” To remedy this inequity, the Editor-in-Chief of Neurosurgery, Douglas S. Kondziolka, MD, FAANS, introduced this new section to help advance timely, safe and affordable neurosurgical care to all who need it. Comprised of experts from every generation and continent where neurosurgery is practiced, this new Neurosurgery feature is working to attract the highest-quality global neurosurgery manuscripts, emphasizing policies to assure equity in authorship, access and use of local data.

Dr. Rosseau likens the Global Neurosurgery initiative to President John F. Kennedy’s commitment to land American astronauts on the moon, “no specialty and no nation which expects to be a leader can expect to stay behind in the quest for highest quality health care for all people.”

To read the full Editorial in Neurosurgery, click here.

Editor’s Note: We hope you will share what you learn from our posts. We invite you to join the conversation on Twitter by following @Neurosurgery and @NeurosurgeryCNS.

October 19, 2022
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Myths and Truths: A Medical Student Perspective of Neurosurgery

By Career, Women in Neurosurgery, Work-Life BalanceNo Comments

Janine S. Hsu, MD

Diana Ghinda, MD, PhD

Neurosurgery is undeniably one of the most intriguing, challenging and rewarding specialties. It is also considered one of the most competitive specialties — as a result, many medical students self-exclude from neurosurgery based on preconceived notions of the field. This is especially true of female trainees, who see in neurosurgery a specialty dominated numerically by men. However, at the University of Ottawa, the Neurosurgery Medical Student Chapter is working to change these existing biases about the specialty. In terms of gender-based interest in neurosurgery, a third of the members of the neurosurgery interest group are female. In 2020, out of the 91 aforementioned students seeking surgical mentorship, four out of 13 who listed neurosurgery as their top choice were female. All of the club executives are female, as is our staff sponsor, Eve Tsai, MD PhD, FAANS, as well as our resident mentors, Diana Ghinda, MD, PhD, and Janine S. Hsu, MD. Having an all female organizing committee was not intentional. Perhaps some subconscious part of us gravitated towards seeking female mentors — a testament to the need for representation. Dr. Tsai, the only female staff neurosurgeon at the University of Ottawa, has provided us with this representation and serves as unspoken encouragement for other women to pursue a traditionally male dominated field such as neurosurgery.

Her leadership and mentorship have dispelled some of the most common myths we held about the specialty, as well as brought to light some of the important realities of being a female neurosurgeon.

Myths about neurosurgery

Adam Sachs, MD, MA

Myth #1: Having a family is difficult, especially as a female neurosurgeon

“It’s possible; you can have a family, that shouldn’t stop you. Dr. Tsai [female neurosurgeon] has done it, as have many others” according to Adam Sachs, MD, MA. The AANS Neurosurgeon has published articles on this topic, including The Challenges of Starting a Family During Neurosurgical Residency Training and Women in Neurosurgery: Walking the Balance Beam of Life.

 Myth #2: Your whole life must be about neurosurgery

Safraz Mohammed, MBBS, FRCSC

Many neurosurgeons have interests outside of their work that they are able to pursue: advocacy, sports and artistic endeavours. Read the six-article series Hustle, Think, Work, Play: Sports & Neurosurgery published in the AANS Neurosurgeon.

Myth #3: Poor patient outcomes

 “A lot of neurosurgical patients go on to live regular, normal lives, or even better lives than before. Patients often think that when they are referred to see a neurosurgeon that their prognosis is going to be grim, but this isn’t always the case. There is so much you can do as a neurosurgeon to help restore a patient’s quality of life” according to Safraz Mohammed, MBBS, FRCSC. A recent report from the Great Ormond Street Hospital for Children suggests that adverse events are a minority in neurosurgery.

Myth #4: I’ll be operating for hours on end on one case

One of the benefits of a career in neurosurgery is the variety of procedures one can perform. These procedures all vary in length and you can tailor your practice accordingly. Many neurosurgical procedures can be lengthy, but as the surgeon you are engrossed in the task at hand and time will fly.

Truths about neurosurgery

Truth #1: The hours are long, but it gets better

Residency is grueling and the hours are long. Neurosurgery is one of the busiest services at a hospital and thus requires a large time commitment. As you progress in your career, you gain the ability to tailor your schedule to your liking. You will always be busy, but there are ways to adapt and adjust.

Truth #2: You won’t be a trainee forever, but it will take time

Neurosurgery has one of the longest residency programs and many often go on to pursue fellowships. The length of the training required prepares you to be confident as a staff surgeon on call when confronted with a challenging case in the middle of the night.

Truth #3: Neurosurgery requires relentless dedication

Neurosurgery is demanding, like any specialty, and it requires continuous training, responding to urgent cases and dedication.

Truth #4: It is a physically, mentally and emotionally demanding career

It is true, but that’s why residency is a training program. You are trained to become a competent surgeon, which includes developing physical, mental and emotional resiliency.

Our mentors have helped us to better understand the myths and truths of a career in neurosurgery. The keys to dispelling myths are early exposure to neurosurgery, more hands-on opportunities in the form of workshops and demonstrations, mentorship programs pairing students with residents, fellows and staff and increased representation for women. For those who think that a career in neurosurgery is unattainable, there are ways to steer yourself toward the path — find a mentor and find out how they did it. Seek feedback from your mentor on how you can improve yourself as an applicant and person. Seek guidance from as many people in the field as you can. Spend time in the division learning about the specialty, finding out the myths and truths yourself. Get involved in research or service projects related to neurosurgery and the neurosciences. This AANS Medical Student Chapter at the University of Ottawa has been working in collaboration with the Division of Neurosurgery to offer as much early exposure as possible and hope to stimulate more interest in neurosurgery!

Editor’s note: We hope that you will share what you learn from our posts. September is Women in Medicine Month, which honors physicians who have offered their time and support to advance women with careers in medicine. We invite you to join the conversation on Twitter by following @Neurosurgery and @WINSNeurosurge1 and using the hashtag #WIMmonth.

Eve Tsai, MD, PhD, FAANS
Ottawa Hospital Research Institute
University of Ottawa
The Ottawa Hospital
Ottawa, Canada

 

Alexandra Beaudry-Richard, MD-PhD Candidate
University of Ottawa
Ottawa, Canada

 

 

Anahita Malvea, MD
University of Ottawa
Ottawa, Canada

 

 

September 29, 2022
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