Accelerated hypofractionated radiation for elderly or frail patients with a newly diagnosed glioblastoma: A pooled analysis of patient-level data from 4 prospective trials.

BACKGROUND: The standard of care for elderly or frail patients with glioblastoma (GBM) is 40 Gy in 15 fractions of radiotherapy. However, this regimen has a lower biological effective dose (BED) compared with the Stupp regimen of 60 Gy in 30 fractions. It is hypothesized that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) is safe and efficacious. METHODS: Elderly or frail patients with GBM treated with 52.5 Gy in 15 fractions were pooled from 3 phase 1/2 studies and a prospective observational study. Overall survival (OS) and progression-free survival (PFS) were defined time elapsing between surgery/biopsy and death from any cause or progression of disease. RESULTS: Sixty-two newly diagnosed patients were eligible for this pooled analysis of individual patient data. The majority (66%) had a Karnofsky performance status (KPS) score <70. The median age was 73 years. The median OS and PFS were 10.3 and 6.9 months, respectively. Patients with KPS scores ≥70 and <70 had a median OS of 15.3 and 9.5 months, respectively. Concurrent chemotherapy was an independent prognostic factor for improved PFS and OS. Grade 3 neurologic toxicity was seen in 2 patients (3.2%). There was no grade 4/5 toxicity. CONCLUSIONS: This is the only analysis of elderly/frail patients with GBM prospectively treated with a hypofractionated radiation regimen that is isoeffective to the Stupp regimen. Treatment was well tolerated and demonstrated excellent OS and PFS compared with historical studies. This regimen gives the elderly/frail population an alternative to regimens with a lower BED. Randomized trials are needed to validate these results.

Dose-escalated accelerated hypofractionation for elderly or frail patients with a newly diagnosed glioblastoma.

BACKGROUND: The standard of care for elderly glioblastoma patients is 40 Gy in 15 fraction radiotherapy with temozolomide (TMZ). However, this regimen has a lower biologic equivalent dose (BED) compared to the Stupp regimen of 60 Gy in 30 fractions. We hypothesize that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) will have superior survival compared to 40 Gy in 15 fractions. METHODS: Elderly patients (≥ 65 years old) who received hypofractionated radiation with TMZ from 2010 to 2020 were included in this analysis. Overall survival (OS) and progression free survival were defined as the time elapsed between surgery/biopsy and death from any cause or progression. Baseline characteristics were compared between patients who received 40 and 52.5 Gy. Univariable and multivariable analyses were performed. RESULTS: Sixty-six newly diagnosed patients were eligible for analysis. Thirty-nine patients were treated with 40 Gy in 15 fractions while twenty-seven were treated with 52.5 Gy in 15 fractions. Patients had no significant differences in age, sex, methylation status, or performance status. OS was superior in the 52.5 Gy group (14.1 months) when compared to the 40 Gy group (7.9 months, p = 0.011). Isoeffective dosing to 52.5 Gy was shown to be an independent prognostic factor for improved OS on multivariable analysis. CONCLUSIONS: Isoeffective dosing to 52.5 Gy in 15 fractions was associated with superior OS compared to standard of care 40 Gy in 15 fractions. These hypothesis generating data support accelerated hypofractionation in future prospective trials.

Surgical management of craniopharyngiomas in adult patients: a systematic review and consensus statement on behalf of the EANS skull base section.

BACKGROUND AND OBJECTIVE: Craniopharyngiomas are locally aggressive neuroepithelial tumors infiltrating nearby critical neurovascular structures. The majority of published surgical series deal with childhood-onset craniopharyngiomas, while the optimal surgical management for adult-onset tumors remains unclear. The aim of this paper is to summarize the main principles defining the surgical strategy for the management of craniopharyngiomas in adult patients through an extensive systematic literature review in order to formulate a series of recommendations. MATERIAL AND METHODS: The MEDLINE database was systematically reviewed (January 1970-February 2019) to identify pertinent articles dealing with the surgical management of adult-onset craniopharyngiomas. A summary of literature evidence was proposed after discussion within the EANS skull base section. RESULTS: The EANS task force formulated 13 recommendations and 4 suggestions. Treatment of these patients should be performed in tertiary referral centers. The endonasal approach is presently recommended for midline craniopharyngiomas because of the improved GTR and superior endocrinological and visual outcomes. The rate of CSF leak has strongly diminished with the use of the multilayer reconstruction technique. Transcranial approaches are recommended for tumors presenting lateral extensions or purely intraventricular. Independent of the technique, a maximal but hypothalamic-sparing resection should be performed to limit the occurrence of postoperative hypothalamic syndromes and metabolic complications. Similar principles should also be applied for tumor recurrences. Radiotherapy or intracystic agents are alternative treatments when no further surgery is possible. A multidisciplinary long-term follow-up is necessary.

Fabrication and characterization of implantable flushable electrodes for electric field-mediated drug delivery in a brain tissue-mimic agarose gel.

Every forty minutes, one person dies in the USA due to glioblastoma multiforme; a deadly form of brain cancer with an average five-year survival rate less than 3%. The current standard of care for treatment involves surgical resection of the accessible tumor followed by radiation therapy and concomitant chemotherapy. Despite their potency, delivering chemotherapeutic agents to the brain is limited by the highly selective blood-brain barrier, which prevents molecules >500 Da from reaching the brain. Other techniques, such as convection-enhanced delivery, controlled release by drug-loaded wafers or intracerebroventricular infusion have limited clinical utility due to unpredictable targeting and volume of drug distribution. We introduce a novel drug delivery technique that can use direct current electric fields to deliver charged chemotherapeutics to the site of brain parenchyma after tumor resection. We fabricate and characterize an implantable drug delivery system using flushable electrodes to deliver the charged chemotherapeutic or doxorubicin (+1) in a brain tissue-mimic agarose gel (0.2% w/v) model by electrophoresis. The optimized capillary-embedded electrode system exhibited a sustained movement of charged doxorubicin through nearly 3.5 mm in four hours, a distance for achieving effective intratumoral concentrations.

Quantitative evaluation of different far lateral approaches to the cranio-vertebral junction using the microscope and the endoscope: a cadaveric study using a tumor model.

BACKGROUND: Several far lateral approaches have been proposed to deal with cranio-vertebral junction (CVJ) tumors including the basic, transcondylar, and supracondylar far lateral approaches (B-FLA, T-FLA, and S-FLA). However, the indications on when to use one versus the other are not well systematized yet. Our purpose is to evaluate in an experimental cadaveric setting which approach is best suited to remove tumors of different sizes. METHODS: We implanted at the CVJ, using a transoral approach, tumor models of different sizes (five 1-cm3 and five 3-cm3 tumors) in ten embalmed cadaveric heads. The artificial tumors were exposed via the three approaches using endoscopic-assisted microneurosurgical technique and neuronavigation. The skull base area exposed and the maneuverability linked to each approach were evaluated using neuronavigation. RESULTS: In 1-cm3 tumors, the T-FLA and the S-FLA exposed a significantly larger skull base area than the B-FLA both using the microscope and the endoscope (P < 0.05); the T-FLA executed with the microscope provided wider vertical and horizontal maneuverability than the B-FLA (P = 0.030 and 0.017, respectively); the S-FLA executed with the endoscope provided wider vertical maneuverability than the T-FLA (P = 0.031). The S-FLA executed using the microscope and the endoscope provided wider vertical maneuverability than the B-FLA both in 1 and 3-cm3 tumors (P < 0.05). CONCLUSIONS: In 1-cm3 tumors, the S-FLA and the T-FLA expose a wider skull base area than the B-FLA. In larger tumors, the exposure is similar for all three approaches. Use of the endoscope in an assistive mode may further increase the surgical exposure and maneuverability.

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

Quantitative analysis of surgical exposure and surgical freedom to the anterosuperior pons: comparison of pterional transtentorial, orbitozygomatic, and anterior petrosal approaches.

Surgical approaches to the pons lump together different areas of the pons, such as the anterosuperior and the anteroinferior pons. These areas are topographically different, and different approaches may be best suited for one or the other area. We evaluated the exposure of the anterosuperior pons using different surgical approaches. We quantify the surgical exposure and surgical freedom to the anterosuperior pons afforded by the pterional transtentorial (PT), the orbitozygomatic with anterior clinoidectomy (OZ), and the anterior petrosal (AP) approaches. Five embalmed cadaver heads were used. The three approaches were executed on each side, for a total of 30 approaches. The area of maximal exposure of the anterosuperior pons was measured with the aid of neuronavigation. We also evaluated the feasible angles of approach in the vertical and horizontal planes. We were able to successfully expose the anterosuperior pons using all the selected approaches. In the PT and OZ approaches, mobilization of the sphenoparietal sinus can prevent over-retraction of the temporal bridging veins, while use of the endoscope can help in preserving the integrity of the fourth nerve while cutting the tentorium. The mean exposure area was largest for the AP and smallest for the PT; the surgical freedom was similar among all the approaches. However, there was no statistically significant difference among all the approaches in the exposure area or in the surgical freedom. There is no significant difference among the three evaluated approaches in exposure of the anterosuperior pons.

Petroclival tumor model--technical note and educational implications.

Petroclival area lesions are rare, and their surgery is challenging due to the deep location and to the complex relationships between the tumor and the neurovascular structures. The objective is to present a petroclival tumor model simulating the distorted anatomy of a real petroclival lesion and propose its use to practice microsurgical removal while preserving neurovascular structures. Four embalmed cadaver heads were used in this study. An endoscopic endonasal transclival approach was used to access the dura in front of the trigeminal nerve; a pediatric Foley was inserted above the trigeminal nerve and was gradually inflated (one-balloon technique). If a larger tumor model was desired, an additional balloon was placed below the trigeminal nerve (two-balloon technique). A pre-mixed tumor polymer was injected into the petroclival space and allowed to harden to create an implanted tumor. A post-implant CT scan was done to evaluate the location and volume of the implanted artificial tumor. Tumors were subsequently excised via retrosigmoid and anterior petrosal approaches. Six petroclival tumors were successfully developed: three were small (9.41-10.36 ml) and three large (21.05-23.99 ml). During dissection, distorted anatomy created by the tumor model mimicked that of real surgery. We have established a petroclival tumor model with adjustable size which offers opportunities to study the distorted anatomy of the area and that is able to be used as a training tool to practice microsurgical removal of petroclival lesions. The practice dissection of this tumor model can be a bridge between a normal anatomic dissection and real surgery.

Central Nervous System Cancers, Version 1.2015.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Central Nervous System (CNS) Cancers provide interdisciplinary recommendations for managing adult CNS cancers. Primary and metastatic brain tumors are a heterogeneous group of neoplasms with varied outcomes and management strategies. These NCCN Guidelines Insights summarize the NCCN CNS Cancers Panel's discussion and highlight notable changes in the 2015 update. This article outlines the data and provides insight into panel decisions regarding adjuvant radiation and chemotherapy treatment options for high-risk newly diagnosed low-grade gliomas and glioblastomas. Additionally, it describes the panel's assessment of new data and the ongoing debate regarding the use of alternating electric field therapy for high-grade gliomas.

Image-guided, microsurgical topographic anatomy of the endolymphatic sac and vestibular aqueduct via a suboccipital retrosigmoid approach.

The endolymphatic sac (ES) and the vestibular aqueduct (VA) are often in the surgical field when posterior fossa lesions are targeted using retrosigmoid approaches. The purpose of this work is to validate neuronavigator accuracy in predicting VA location as well as to give guidelines to preserve the ES and VA. A retrosigmoid approach was performed bilaterally in six specimens in the semisitting position. Preoperatively, we registered in the CT scans the position of the VA genu (virtual genu). After the approach execution, ES and VA genu topographic relationships with evident posterolateral cranial base structures were measured using neuronavigation. Next, we exposed the VA genu: its position coincided with the virtual VA genu in all the specimens. On the average, the ES was 17.93 mm posterosuperolateral to the XI nerve in the jugular foramen, 12.26 mm posterolateral to the internal acoustic meatus, 20.13 mm anteromedial to the petro-sigmoid intersection at a point 13.30 mm inferior to the petrous ridge. The VA genu was located 7.23 mm posterolateral to the internal acoustic meatus, 18.11 mm superolateral to the XI nerve in the jugular foramen, 10.27 mm inferior to the petrous ridge, and 6.28 mm anterolateral to the endolymphatic ledge at a depth of 3.46 mm from the posterior pyramidal wall. Our study demonstrates that is possible to use neuronavigation to reliably predict the location of the VA genu. In addition, neuronavigation may be effectively used to create a topographical framework that may help maintaining the integrity of the ES/VA during retrosigmoid approaches.

Central nervous system cancers, version 2.2014. Featured updates to the NCCN Guidelines.

The NCCN Guidelines for Central Nervous System Cancers provide multidisciplinary recommendations for the clinical management of patients with cancers of the central nervous system. These NCCN Guidelines Insights highlight recent updates regarding the management of metastatic brain tumors using radiation therapy. Use of stereotactic radiosurgery (SRS) is no longer limited to patients with 3 or fewer lesions, because data suggest that total disease burden, rather than number of lesions, is predictive of survival benefits associated with the technique. SRS is increasingly becoming an integral part of management of patients with controlled, low-volume brain metastases.

Optic nerve surface temperature during intradural anterior clinoidectomy: a comparison between high-speed diamond burr and ultrasonic bone curette.

Ultrasonic bone curettes are increasingly used in cranial base surgery. The heat generated by these devices during anterior clinoidectomy has not been evaluated. The purpose of this study was to compare the optic nerve surface temperature during intradural anterior clinoidectomy using the drill and ultrasonic bone curette. Ten fresh cadaver heads were used. During intradural clinoidectomy and optic nerve unroofing with either a 2-mm diamond burr drill or ultrasonic bone curette, temperature was measured along the medial cisternal and proximal intracanalicular segments of the optic nerve. Additional experiments were performed to determine optimal ultrasonic bone curette settings for anterior clinoidectomy. At the lateral cisternal segment, peak and mean temperature were significantly higher with the ultrasonic bone curette (peak 38.8 vs 29.3 °C, p = 0.03, mean 29.5 vs 22.6 °C, p = 0.003). At the proximal intracanalicular segment, only peak temperature was significantly higher with the ultrasonic bone curette (peak 32.0 vs 23.5 °C, p = 0.02, mean 26.9 vs 22.4 °C, p = 0.07). Using standard company settings, room temperature irrigation fluid was heated by the oscillating tip to peak temperature 36.1 °C without drilling. In order to maintain emitted irrigation fluid at room temperature, optimal settings were power 70 %, cool irrigation (5 °C) at 40 mL/min. Using these settings, the ultrasonic bone curette generated optic nerve surface temperature measurements similar to the drill. Further work is necessary to translate these findings into the operating room.

An endoscopic-assisted technique for retrosellar access during the extended retrosigmoid approach: a cadaveric feasibility study and quantitative analysis of retrosellar working area.

The retrosigmoid approach has been advocated for certain petroclival tumors but provides limited access to any retrosellar extension of tumor, necessitating a two-stage operation. Our purpose was to demonstrate preliminary feasibility of an endoscopic-assisted technique to provide retrosellar access during the extended retrosigmoid approach and compare microscopic and endoscopic retrosellar working area. Standard retrosigmoid craniectomy and partial petrosectomy respecting inner ear structures were performed on six embalmed cadaveric heads. Two balloons were inflated to simulate a 15 mm petroclival tumor. Retrosellar clival and brainstem working area and ipsilateral oculomotor nerve and posterior cerebral artery (PCA) working distance were measured using the endoscope and microscope. Artificial tumors were implanted and resected using the endoscopic-assisted technique to assess feasibility. The endoscope provided significantly greater mean working area/distance on the clivus (201.6 vs 114.8 mm(2), p < 0.01), brainstem (223.5 vs 121.2 mm(2), p < 0.01), ipsilateral oculomotor nerve (10.8 vs 6.4 mm, p < 0.01), and ipsilateral PCA (13.7 vs 8.9 mm, p = 0.01). Petrous dissection to create a 10 × 10 mm working channel and artificial tumor resection was feasible in all dissections. The superior petrosal vein required ligation in 9 (75%) cases. Air cells were exposed in 1 (8%) case. The described endoscopic-assisted technique can provide retrosellar access during the extended retrosigmoid approach to access petroclival tumors with retrosellar extension. Risks include superior petrosal vein sacrifice, bleeding that can impair visualization, injury to the trigeminal nerve during endoscopic insertion/manipulation or injury to the brainstem while working in the medial limits of exposure. Further work is necessary to determine clinical feasibility, safety, and efficacy.

Short-term outcome of endoscopic versus microscopic pituitary adenoma surgery: a systematic review and meta-analysis.

Endoscopic transsphenoidal pituitary surgery has become increasingly more popular for the removal of pituitary adenomas. It is also widely recognised that transsphenoidal microscopic removal of pituitary adenomas is a well-established procedure with good outcomes. Our objective was to meta-analyse the short-term results of endoscopic and microscopic pituitary adenoma surgery. We undertook a systematic review of the English literature on results of transsphenoidal surgery, both microscopic and endoscopic from 1990 to 2011. Series with less than 10 patients were excluded. Pooled data were analysed using meta-analysis techniques to obtain estimate of death, complication rates and extent of tumour removal. Complications evaluated included cerebrospinal fluid leak, meningitis, vascular complications, visual complications, diabetes insipidus, hypopituitarism and cranial nerve injury. Data were also analysed for tumour size and sex. 38 studies met the inclusion criteria yielding 24 endoscopic and 22 microscopic datasets (eight studies included both endoscopic and microscopic series). Meta-analysis of the available literature showed that the endoscopic transsphenoidal technique was associated with a higher incidence of vascular complications (p<0.0001). No difference was found between the two techniques in all other variables examined. Meta-analysis of the available literature reveals that endoscopic removal of pituitary adenoma, in the short term, does not seem to confer any advantages over the microscopic technique and the incidence of reported vascular complications was higher with endoscopic than with microscopic removal of pituitary adenomas. While we recognise the limitations of meta-analysis, our study suggests that a multicentre, randomised, comparative effectiveness study of the microscopic and endoscopic transsphenoidal techniques may be a reasonable approach towards establishing a true valuation of these techniques.

Central nervous system cancers.

Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.

Placement of thoracolumbar pedicle screws using O-arm-based navigation: technical note on controlling the operational accuracy of the navigation system.

Suboptimal placements of pedicle screws may lead to neurological and vascular complications. Computer-assisted image guidance has been shown to improve accuracy in spinal instrumentation. Checking the accuracy of the navigation system during pedicle screw placement is fundamental. We describe a novel technique of using continuous accuracy check of the navigation system during O-arm-based neuronavigation to instrument the thoracolumbar region. Forty thoracic and 42 lumbar screws were inserted in 12 patients. The Mirza evaluation system was used to evaluate the accuracy of the inserted screws. There was no neurological injury and no need to reposition any screw. The accuracy of the screws placement was excellent. Our technique of continuous at will operational accuracy check of the neuronavigation system is associated with extreme accuracy of screw placement, no need to bring a patient back to the operating room to reposition a pedicle screw, and with excellent outcome.