Despite advances in neurosurgery, chemotherapy and radiotherapy, glioblastoma remains one of the most treatment-resistant CNS malignancies, and the tumour inevitably recurs. The majority of recurrences appear in or near the resection cavity, usually within the area that received the highest dose of radiation. Many new therapies focus on combatting these local recurrences by implementing treatments directly in or near the tumour bed. In this Review, we discuss the latest developments in local therapy for glioblastoma, focusing on recent preclinical and clinical trials. The approaches that we discuss include novel intraoperative techniques, various treatments of the surgical cavity, stereotactic injections directly into the tumour, and new developments in convection-enhanced delivery and intra-arterial treatments.
Glioblastoma almost always recurs at or near the resection cavity, within the radiotherapy field.
Local therapy provides a unique opportunity to deliver high doses of therapeutics to the area with the highest concentration of glioblastoma cells, with limited systemic adverse effects.
Many phase I and II trials experimenting with various forms of local therapy have been — and are being — conducted in glioblastoma, with many showing great potential for improving progression-free and overall survival.
Large randomized phase III trials comparing local therapies with standard of care have been hindered by high cost, labour intensity and challenges in patient recruitment.
Close collaboration between clinicians, researchers, companies and governmental institutions is needed to smooth the transition from laboratory to phase I and II trials to large-scale randomized controlled trials.
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The authors thank M. E. Haeflich for proofreading this manuscript for typographical and grammatical errors; skilled editorial assistance from S. McDavitt; and insights from X. Breakefield. M.L.D.B. is supported by grant NIH NCI R35 CA232103. T.S.v.S. is supported by grants from the Bontius Stichting, the Nijbakker-Morra Fund, Foundation Vrijvrouwe van Renswoude and the Bekker-la Bastide Fund. T.S.v.S. and E.A.C. are supported by NIH grant P01 CA069246.
E.A.C. is currently an advisor to Advantagene, Alcyone Biosciences, Insightec, DNAtrix, Immunomic Therapeutics, Seneca Therapeutics, GlaxoSmithKline and Voyager Therapeutics and has equity interest in DNAtrix, Immunomic Therapeutics and Seneca Therapeutics; he has also advised Oncorus, Merck, Tocagen, Ziopharm, Stemgen, NanoTx., Ziopharm Oncology, Cerebral Therapeutics, Genenta. Merck, Janssen, Karcinolysis, Shanghai Biotech and Sangamo Therapeutics. He has received research support from the NIH, the US Department of Defense, the American Brain Tumor Association, the National Brain Tumor Society, the Alliance for Cancer Gene Therapy, the Neurosurgical Research Education Foundation, Advantagene, NewLink Genetics and Amgen. He is also a named inventor on patents related to oncolytic HSV-1 and non-coding RNAs. The other authors declare no competing interests.
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In December 2020, we searched PubMed and Embase for studies utilizing any form of local therapy in glioblastoma. Keywords, Mesh terms and Emtree terms including “glioblastoma”, “glioma”, “local therapy”, “localized therapy”, “convection enhanced delivery”, “thermotherapy”, “wafer”, “brachytherapy”, “photodynamic therapy” and their synonyms were combined to form our search. Titles and abstracts were screened for relevant articles and studies. References from full-text articles were screened for additional studies. Articles had to be written in English and published within the past 20 years. Studies performed before implementation of the Stupp protocol were excluded, unless deemed relevant to current studies or patient care. Case reports were also excluded. Additional papers were recommended by all authors. For current clinical trials, ClinicalTrials.gov was searched for disease “glioblastoma” and “glioma”, and all trials with status ‘not yet recruiting’, ‘recruiting’, ‘enrolling by invitation’, ‘active, not recruiting’, or ‘available’.
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van Solinge, T.S., Nieland, L., Chiocca, E.A. et al. Advances in local therapy for glioblastoma — taking the fight to the tumour. Nat Rev Neurol 18, 221–236 (2022). https://doi.org/10.1038/s41582-022-00621-0
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