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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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University of Miami Increases Neuro-Oncology Collaboration and Mentorship Through Innovative New Fellowship Program

By Brain Tumor, Tumor, Tumor SeriesNo Comments

Neurosurgery has a long history of mentorship through a trainee’s dedicated time under a more experienced surgeon’s tutelage. Surgical training has long been considered a more advanced form of apprenticeship, mastering a skill under a more experienced practitioner’s guidance. In this tradition, the Sylvester Comprehensive Cancer Center — part of the University of Miami Miller School of Medicine — has launched an International Neuro-oncology Scholars Program (INOSP) that allows neurosurgery trainees to join internationally renowned brain tumor experts in other countries to increase their experience.

The goal is to enhance education and facilitate multi-institutional collaboration. The INOSP program is made possible by a generous gift from a grateful donor family. The plan is to support four traveling rotations each year.

Charles Teo, MD, IFAANS, left, with neurosurgery fellow Daniel Eichberg, MD.

“INOSP represents a unique resource offered to our fellows to visit and learn from world-renowned experts in neurosurgical oncology,” said neurosurgeon Ricardo J. Komotar, MD, FAANS, FACS. He continued, “The goal of the program is to enhance further their neurosurgical training so that they may be able to translate these techniques to our patients. With this international collaboration, we ultimately hope to improve clinical outcomes and enhance surgical education.”

The inaugural recipient of INOSP was neurosurgery fellow Daniel Eichberg, MD, who spent two weeks in Sydney, Australia, learning from highly accomplished neurosurgeons Charles Teo, MD, IFAANS and Michael Sughrue, MD, at Prince of Wales Hospital in Randwick, Australia.

“The opportunity to learn minimally invasive keyhole approaches for complex brain and skull base tumors in one-on-one training sessions from two of the most experienced neurosurgeons in these techniques was a powerful experience and augmented my skillset for cranial neurosurgery,” said Dr. Eichberg.

Dr. Sughrue and Dr. Teo have developed the world’s most advanced technology for mapping the brain’s functional and structural connectivity, which may be markedly abnormal in patients with brain tumors. Providing a better understanding of an individual’s connectome — a map of the brain’s overall connectivity — may critically impact brain tumor surgical outcomes by minimizing postoperative deficits, predicting recovery and maximizing the amount of tumor that can safely be removed during surgery.

Furthermore, this brain mapping technology uses machine learning and artificial intelligence techniques to guide non-invasive transcranial magnetic stimulation (TMS)-based neuro-interventional rehabilitation to improve postoperative brain tumor patients’ strength and speech deficits.

As a result of the international collaboration fostered by INOSP, Sylvester and the University of Miami Department of Neurosurgery will partner with the Sydney team in the Glioma Connectome Project. This endeavor seeks to learn how gliomas cause the brain to reorganize its connectome and initiate a TMS Neuro-interventional Rehabilitation prospective clinical trial.

“Not only are we now able to give our neurosurgical fellows access to additional world-renowned brain tumor experts and each of their unique skills, but we are also seeing that these new international relationships lead to groundbreaking global collaborative research and enhanced clinical trials that will continue to allow us at Sylvester to be able to provide the most advanced and world-class brain tumor treatments possible to our patients,” said program co-director Michael E. Ivan MD, MBS, assistant professor of neurosurgery.

Ashish Shah, MD; Alexis Morell, MD; Ricardo J. Komotar, MD, FAANS, FACS and Christopher A. Sarkiss, MD

Additionally, in 2019, the AANS/CNS Tumor Section, in conjunction with the CNS Foundation, created the International Observership Program, which will allow an Argentinean neurosurgeon to participate as an observer for three months at the University of Miami in the division of surgical neuro-oncology. The rotation focuses on all central nervous system tumors, with participation in clinic, conferences, surgery, and consultations.

Editor’s Note: 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.

Ricardo J. Komotar, MD, FAANS, FACS
University of Miami Miller School of Medicine
Miami, Fla.

May 10, 2022
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Introduction to Tumor Focus Series: Bringing “Better” to Our Patients in Multiple Ways

By Tumor, Tumor SeriesNo Comments

Neurosurgery has historically been a uniquely wide-ranging and varied specialty. Unlike other specialties that focus on a particular organ system or body region, neurosurgery is quite literally a “head-to-toe” specialty dealing with the brain, spinal cord, peripheral nerves and the other organs intimately related to the nervous system. Neurosurgeons classically had to be experts in a wide variety of surgical procedures and disease processes. As medical knowledge and technology have advanced, neurosurgeons have evolved with medicine to become experts in particular disease processes, leading to a reorganization of neurosurgery into sub-specialty disciplines.

Over the years, the Neurosurgery Blog has partnered with various neurosurgery subspecialty sections to provide an update on the state of the subspecialty, highlight current issues, add to the conversation and portray their concerns to a non-specialized audience. Today’s neurosurgeon must be facile in many different areas — both medical and non-medical. As medical care and health care delivery have grown increasingly complex, neurosurgeons must wear several hats: surgeon, team-member in multi-disciplinary care teams, teacher, scientist and advocate.

We partnered with the AANS/CNS Joint Section on Tumors for the following series of blogs. Under the guidance of Tumor Section chair, Jason P. Sheehan, MD, PhD, FAANS, and AANS/CNS Washington Committee representative, Michael A. Vogelbaum, MD, PhD, FAANS, members of the section came together and produced a sweeping overview of ongoing topics:

  • Arnold B. Etame, MD, FAANS, leads us off with a piece about diversity in neurosurgical oncology. Isabelle M. Germano, MD, FAANS, FACS, then tackles disparities in access to care and outcomes in brain tumor patients.
  • Ricardo J. Komotar, MD, FAANS, FACS, reports on efforts in education and collaboration on an international scale. Edjah E. Nduom, MD, FAANS, speaks to brain tumor advocacy, providing an overview of the outward-looking direction of some of our efforts.
  • Michael Lim, MD, FAANS, and Nader Sanai, MD, FAANS, bring us two pieces highlighting the ability of neurosurgeons to translate discoveries from the lab into patient care and back again and how neurosurgeons contribute to drug development in the increasingly complex fight against brain tumors. These pieces are complemented by an article by Manish K. Aghi, MD, PhD, FAANS, updating the role of neurosurgeons in clinical trials and research in neurosurgical oncology.

Academic publishing, the Journal of Neuro-Oncology, and the dissemination of scientific results, particularly in the era of the COVID-19 pandemic, are at the center of a piece by Dr. Sheehan and Christopher P. Cifarelli, MD, PhD, MMM, FAANS, FACS. Dr. Vogelbaum presents “A Neurosurgical Perspective on Multidisciplinary Care for Patients with Brain Tumors,” emphasizing the team-based nature of neuro-oncology care today.

In the era of a worldwide pandemic and an increasingly complex care delivery environment, neurosurgeons are playing more and more roles in delivering better care to our patients. This is especially true in the field of neurooncology. We hope that these blogs inspire you to join the efforts of this important field. The amount of work that the members of the section and the authors, in particular, put into these issues outside of patient care is astonishing and deserves credit!

Editor’s Note: 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.

Clemens M. Schirmer, MD, PhD, FAANS, FAHA
Chair, AANS/CNS Communications and Public Relations Committee
Geisinger
Wilkes Barre, Pa.

January 20, 2022
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