Anterior Temporal Lobectomy in Temporal Glioblastoma

Official title

Randomized, Controlled Trial of Anterior Temporal Lobectomy Versus Gross Total Resection in Newly-diagnosed Temporal Glioblastoma (ATLAS/NOA-29)

Overview

The ATLAS/NOA-29 trial is a prospective, multicenter, phase III randomized controlled study evaluating whether anterior temporal lobectomy (ATL), a standardized resection technique adapted from epilepsy surgery, improves clinical outcomes in patients with newly diagnosed glioblastoma of the anterior temporal lobe compared to conventional gross-total resection (GTR). The rationale is based on the concept of glioblastoma as a diffusely connected tumor network, with infiltrative spread extending beyond MRI-detectable tumor margins. ATL offers a reproducible supramarginal resection approach within anatomical boundaries that are routinely respected in epilepsy surgery. Patients are randomized intraoperatively in a 1:1 ratio following histopathological confirmation via intraoperative frozen section procedure. The trial's primary objective is to demonstrate superiority of ATL in overall survival (OS), while confirming non-inferiority in health-related quality of life (QoL), measured by the global health status scale of the European Organisation for Research and Treatment of Cancer (EORTC) - Quality of Life Questionnaire Core 30 (QLQ-C30). Secondary outcomes include progression-free survival (PFS), seizure control, neurocognitive functioning, and longitudinal assessments of selected EORTC QLQ-C30 and BN20 domains. A total of 178 patients will be enrolled over three years, with a minimum follow-up of three years. An interim safety analysis after inclusion of 57 patients will assess functional outcome differences using the modified Rankin Scale (mRS) at 6 months postoperatively. The study is powered (\>80%) to detect a survival benefit assuming a median OS increase from 17 to 27.5 months. If proven superior to GTR, ATL could emerge as the preferred surgical strategy for isolated temporal lobe glioblastoma, offering robust evidence in favor of extending supramarginal resection principles to the broader context of glioblastoma care.

Interventions

• Procedure Anterior temporal lobectomy (ATL)
  Patients assigned to the experimental group will undergo an anterior temporal lobectomy (ATL) according to established protocols adapted from epilepsy surgery. ATL is a reproducible and anatomically well-defined procedure routinely performed in patients with pharmacoresistant temporal lobe epilepsy. On the non-dominant hemisphere, the neocortical resection typically extends 6.5 cm posteriorly from the temporal pole, while on the dominant side, the resection length is limited to 4.0 cm, both meas
• Procedure Gross Total Resection (GTR)
  Patients will be surgically treated with GTR in terms of removing 100% of the tumor tissue in gadolinium-enhanced MRI.

Primary outcome measures

• Overall survival [Time frame: From randomization until death or 36 months after recruitment of the last patient]
• Patient-reported Quality of Life [Time frame: From randomization until death or 36 months after recruitment of the last patient]

Secondary outcome measures (6)

• Progression-free survival [Time frame: PFS is measured from randomization at the day of surgery until progression or death. PFS will be assessed at the 12-week follow-up visit and at all subsequent visits scheduled at 12-week intervals up to three years.]
• Neurocognitive Outcome [Time frame: Cognitive performance across all domains will be quantitatively assessed at baseline (preoperatively), and at follow-up visits on day 90 (visit 8) and one year after surgery (visit 11).]
• Karnofsky Performance Scale [Time frame: KPS will be assessed at baseline, on postoperative day 1, and at follow-up visits on days 3, 14, 30, and 90, and subsequently at 12-week intervals.]
• Seizure outcome [Time frame: Seizure outcome will be assessed at the 12 weeks, the 6 months and all 12 week follow-up examination.]
• Modified Rankin Scale assessment (mRS) [Time frame: The mRS will be assessed at baseline, on postoperative day 1, and at follow-up visits on days 3, 14, 30, and 90, and subsequently at 12-week intervals.]
• Quality-of-life (QoL) [Time frame: QoL will be assessed at baseline, at follow-up visits on days 14, 30, and 90, and subsequently at 24-week intervals.]

Eligibility criteria

• Suspected glioblastoma with contrast-enhancement in preoperative MRI
• Diffuse high-grade glioma in frozen section procedure, newly-diagnosed
• Tumor localization (in gadolinium-enhanced MRI): solely temporal, non-dominant side (right hemisphere in right-handed patients, or left-handed patients after testing for dominance): within 6.5 cm from the temporal pole; dominant side (left hemisphere in right-handed patients, all left-handed patients unless additional testing for dominance performed): within 4.0 cm from the temporal pole, as determined dorsally along the Sylvian fissure.
• Macroscopic complete resection (no remaining contrast-enhancing tumoral lesion on early postoperative MRI) is achievable (decision of the treating neurosurgeon)
• In case further T1-contrast-enhancing and/or T2/FLAIR lesions are detected beyond the resection margins (6.5 cm on the non-dominant side and 4.0 cm on the dominant side), these lesions are not attributed to the tumor (except perifocal edema) but to other conditions according to the local treating neurosurgeon
• ≥ 18 and < 75 years of age
• KPS ≥ 70%
• Estimated life expectancy of at least 6 months
• Written informed consent
• Cognitive state to understand the rationale and necessity of the study therapy and procedures
• Patient compliance and geographic proximity that allow adequate follow-up
• For patients with childbearing potential: negative serum pregnancy test (beta-HCG) at baseline visit, patient's commitment to use an approved contraceptive method during the trial and for 3 months after (Pearl index < 1%)
• Adequate organ function at baseline visit that does not preclude alkylating chemotherapy and neurosurgical procedures (all criteria required):

• Adequate bone marrow reserve: white blood cell (WBC) count ≥ 3.000/µl; granulocyte count > 1.500/µl; platelets ≥ 100.000/µl; haemoglobin ≥ 10 g/dl
• Adequate liver function: bilirubin < 1.5 times above upper limit of normal range (ULN); alanine transaminase (ALT/SGPT) and aspartate transaminase (AST/ALAT) < 3 times ULN
• Adequate renal function: creatinine < 1.5 times ULN
• Adequate blood clotting: Partial Thromboplastin Time (PTT) not exceeding the upper limit of normal range and International Normalized Ratio (INR) <1.5; in case of intake of anticoagulant medication or platelet function inhibitors, the coagulation analysis must show no detectable effect in specific blood tests (as described below) at the time of surgery, and discontinuation of the anticoagulant medication must be justifiable for at least 1 week postoperatively

• Direct acting oral anticoagulants (e.g., rivaroxaban, apixaban, edoxaban, dabigatran): anti-Factor Xa (aFXa)-activity within the normal range (rivaroxaban, apixaban, edoxaban), TT/TCT (thrombin clotting time) or ecarin clotting time (ECT) not exceeding the upper limit of normal range (Dabigatran) or verification of subtherapeutic drug levels (apixaban, edoxaban, rivaroxaban, dabigatran)
• Vitamin K antagonists (coumarins): INR < 1.5
• Unfractionated heparin (UFH) and argatroban: activated Partial Thromboplastin Time (aPTT) not exceeding the upper limit of normal range
• Fractionated heparin/low-molecular-weight heparin (e.g., dalteparin, enoxaparin), heparinoid (e.g., fondaparinux, danaparoid): aFXa-activity within the normal range
• Antiplatelet agents (aspirin, clopidogrel, prasugrel, ticagrelor): platelet function analyzer (PFA) test not exceeding the upper limit of normal range (aspirin), whole blood aggregometry not below lower limits of normal range (clopidogrel, prasugrel, ticagrelor)

For details see study protocol.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Germany · 1 center

• University Hospital Bonn — Bonn

Publications

• Schneider M, Potthoff AL, Karpel-Massler G, Schuss P, Siegelin MD, Debatin KM, Duffau H, Vatter H, Herrlinger U, Westhoff MA. The Alcatraz-Strategy: a roadmap to break the connectivity barrier in malignant brain tumours. Mol Oncol. 2024 Dec;18(12):2890-2905. doi: 10.1002/1878-0261.13642. Epub 2024 Apr 3. PMID 38567664
• Schneider M, Potthoff AL, Ahmadipour Y, Borger V, Clusmann H, Combs SE, Czabanka M, Duhrsen L, Etminan N, Freiman TM, Gerlach R, Gessler F, Giordano FA, Gkika E, Goldbrunner R, Guresir E, Hamou H, Hau P, Ille S, Jagersberg M, Keric N, Khaleghi-Ghadiri M, Konig R, Konczalla J, Krenzlin H, Krieg S, McLean AL, Layer JP, Lehmberg J, Malinova V, Meyer B, Meyer HS, Miller D, Muller O, Musahl C, Pregler PMID 39979825
• Borger V, Hamed M, Ilic I, Potthoff AL, Racz A, Schafer N, Guresir E, Surges R, Herrlinger U, Vatter H, Schneider M, Schuss P. Seizure outcome in temporal glioblastoma surgery: lobectomy as a supratotal resection regime outclasses conventional gross-total resection. J Neurooncol. 2021 Apr;152(2):339-346. doi: 10.1007/s11060-021-03705-x. Epub 2021 Feb 7. PMID 33554293
• Schneider M, Potthoff AL, Keil VC, Guresir A, Weller J, Borger V, Hamed M, Waha A, Vatter H, Guresir E, Herrlinger U, Schuss P. Surgery for temporal glioblastoma: lobectomy outranks oncosurgical-based gross-total resection. J Neurooncol. 2019 Oct;145(1):143-150. doi: 10.1007/s11060-019-03281-1. Epub 2019 Sep 4. PMID 31485921
• Karschnia P, Young JS, Dono A, Hani L, Sciortino T, Bruno F, Juenger ST, Teske N, Morshed RA, Haddad AF, Zhang Y, Stoecklein S, Weller M, Vogelbaum MA, Beck J, Tandon N, Hervey-Jumper S, Molinaro AM, Ruda R, Bello L, Schnell O, Esquenazi Y, Ruge MI, Grau SJ, Berger MS, Chang SM, van den Bent M, Tonn JC. Prognostic validation of a new classification system for extent of resection in glioblastoma: A PMID 35961053
• Roh TH, Kang SG, Moon JH, Sung KS, Park HH, Kim SH, Kim EH, Hong CK, Suh CO, Chang JH. Survival benefit of lobectomy over gross-total resection without lobectomy in cases of glioblastoma in the noneloquent area: a retrospective study. J Neurosurg. 2019 Mar 1;132(3):895-901. doi: 10.3171/2018.12.JNS182558. Print 2020 Mar 1. PMID 30835701
• Schneider M, Ilic I, Potthoff AL, Hamed M, Schafer N, Velten M, Guresir E, Herrlinger U, Borger V, Vatter H, Schuss P. Safety metric profiling in surgery for temporal glioblastoma: lobectomy as a supra-total resection regime preserves perioperative standard quality rates. J Neurooncol. 2020 Sep;149(3):455-461. doi: 10.1007/s11060-020-03629-y. Epub 2020 Sep 29. PMID 32990861

Identifiers

NCT: NCT07021339 · 70114652 · 290/23

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗