Combination of ALA-induced fluorescence-guided resection and intraoperative open photodynamic therapy for recurrent glioblastoma: case series on a promising dual strategy for local tumor control

Schipmann, Stephanie; Müther, Michael; Stögbauer, Louise; Zimmer, Sebastian; Brokinkel, Benjamin; Holling, Markus; Grauer, Oliver; Suero Molina, Eric; Warneke, Nils; Stummer, Walter

doi:10.3171/2019.11.jns192443

Cited by 121Photodynamic Therapy Research StudiesGlioma Diagnosis and TreatmentNanoplatforms for cancer theranostics

Combination of ALA-induced fluorescence-guided resection and intraoperative open photodynamic therapy for recurrent glioblastoma: case series on a promising dual strategy for local tumor control

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Schipmann, Stephanie, Müther, Michael, Stögbauer, Louise, Zimmer, Sebastian, Brokinkel, Benjamin, Holling, Markus, Grauer, Oliver, Suero Molina, Eric +2 more·2021·Journal of Neurosurgery

DOI 10.3171/2019.11.jns192443

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Abstract

OBJECTIVE: High-grade glioma (HGG) prognosis remains dismal, with inevitable, mostly local recurrence. Regimens for improving local tumor control are therefore needed. Photodynamic therapy (PDT) using porfimer sodium has been investigated but was abandoned due to side effects and lack of survival benefits. Intracellular porphyrins induced by 5-aminolevulinic acid (5-ALA) are approved for fluorescence-guided resections (FGRs), but are also photosensitizers. Activated by light, they generate reactive oxygen species with resultant cytotoxicity. The authors present a combined approach of 5-ALA FGR and PDT. METHODS: After 5-ALA FGR in recurrent HGG, laser diffusors were strategically positioned inside the resection cavity. PDT was applied for 60 minutes (635 nm, 200 mW/cm diffusor, for 1 hour) under continuous irrigation for maintaining optical clarity and ventilation with 100% oxygen. MRI was performed at 24 hours, 14 days, and every 3 months after surgery, including diffusion tensor imaging and apparent diffusion coefficient maps. RESULTS: Twenty patients were treated. One surgical site infection after treatment was noted at 6 months as the only adverse event. MRI revealed cytotoxic edema along resection margins in 16 (80%) of 20 cases, mostly annular around the cavity, corresponding to prior laser diffusor locations (mean volume 3.3 cm 3 ). Edema appeared selective for infiltrated tissue or nonresected enhancing tumor. At the 14-day follow-up, enhancement developed in former regions of edema, in some cases vanishing after 4–5 months. Median progression-free survival (PFS) was 6 months (95% CI 4.8–7.2 months). CONCLUSIONS: Combined 5-ALA FGR and PDT provides an innovative and safe method of local tumor control resulting in promising PFS. Further prospective studies are warranted to evaluate long-term therapeutic effects.

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In a clinical trial, patients with recurrent glioblastoma underwent PpIX fluorescence-guided resection first followed immediately by PDT all after a single dose of ALA administration.
“The use of ALA-PpIX as a fluorescent theranostic agent is well illustrated in a clinical trial where patients with recurrent glioblastoma underwent PpIX fluorescence-guided resection first followed immediately by PDT all after a single dose of ALA administration [165].”
From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [165]
Selective ALA-induced PpIX disposition in tumors made it possible for maximum safe resection of glioblastoma as well as targeting infiltrating tumor cells and unresectable tumor tissues in eloquent regions by PDT, resulting in promising progression-free survival in a disease with dismal prognosis.
“Selective ALA-induced PpIX disposition in tumors made it possible for maximum safe resection of glioblastoma as well as targeting infiltrating tumor cells and unresectable tumor tissues in eloquent regions by PDT, resulting in promising progression-free survival in a disease with dismal prognosis.”
From 5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy (2023) · cites this paper as [165]

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Photodynamic Therapy Combined with Bcl-2/Bcl-xL Inhibition Increases the Noxa/Mcl-1 Ratio Independent of Usp9X and Synergistically Enhances Apoptosis in Glioblastoma
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Low-Level Laser Treatment Induces the Blood-Brain Barrier Opening and the Brain Drainage System Activation: Delivery of Liposomes into Mouse Glioblastoma
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Intraoperative photodynamic therapy in complex treatment of malignant gliomas
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A systematic review and meta-analysis of fluorescent-guided resection and therapy-based photodynamics on the survival of patients with glioma
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5-Aminolevulinic Acid False-Positive Rates in Newly Diagnosed and Recurrent Glioblastoma: Do Pseudoprogression and Radionecrosis Play a Role? A Meta-Analysis
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In-Vitro Use of Verteporfin for Photodynamic Therapy in Glioblastoma
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Comparison of Panitumumab-IRDye800CW and 5-Aminolevulinic Acid to Provide Optical Contrast in a Model of Glioblastoma Multiforme
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Laser-induced fluorescent visualization and photodynamic therapy in surgical treatment of glial brain tumors
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Dual Function Antibody Conjugates for Multimodal Imaging and Photoimmunotherapy of Cancer Cells
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Comparative analysis of 5-ALA and chlorin E6 fluorescence-guided navigation in malignant glioma surgery
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SIRIUS, Ultra-Scintillating Upconversion Breast Implant for Remote Orthotopic Photodynamic Therapy
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Unraveling the blue shift in porphyrin fluorescence in glioma: The 620 nm peak and its potential significance in tumor biology
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Feasibility of Photodynamic Therapy for Glioblastoma with the Mitochondria-Targeted Photosensitizer Tetramethylrhodamine Methyl Ester (TMRM)
Vasilev, A., Sofi, R., Smith, S. J., Rahman, R., Teschemacher, A. G., & Kasparov, S. (2021) · Biomedicines · doi:10.3390/biomedicines9101453 · Cited by 15 · see citing works
Combined Fluorescence-Guided Resection and Intracavitary Thermotherapy with Superparamagnetic Iron-Oxide Nanoparticles for Recurrent High-Grade Glioma: Case Series with Emphasis on Complication Management
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Photodynamic therapy in neurooncology
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Interrelation between Spectral Online Monitoring and Postoperative T1-Weighted MRI in Interstitial Photodynamic Therapy of Malignant Gliomas
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The Combined Use of 5-ALA and Chlorin e6 Photosensitizers for Fluorescence-Guided Resection and Photodynamic Therapy under Neurophysiological Control for Recurrent Glioblastoma in the Functional Motor Area after Ineffective Use of 5-ALA: Preliminary Results
Kozlikina, E. I., Трифонов, И. С., Sinkin, M. V., Krylov, V. V., & Loschenov, V. B. (2022) · Bioengineering · doi:10.3390/bioengineering9030104 · Cited by 15 · see citing works
Association of 5-aminolevulinic acid fluorescence guided resection with photodynamic therapy in recurrent glioblastoma: a matched cohort study
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Simulating photodynamic therapy for the treatment of glioblastoma using Monte Carlo radiative transport
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Towards Photodynamic Image-Guided Surgery of Head and Neck Tumors: Photodynamic Priming Improves Delivery and Diagnostic Accuracy of Cetuximab-IRDye800CW
Bhandari, C., Fakhry, J., Eroy, M., Song, J. J., Samkoe, K. S., Hasan, T. G., Hoyt, K., & Obaid, G. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.853660 · Cited by 13 · see citing works
Polymer theranostics with multiple stimuli-based activation of photodynamic therapy and tumor imaging
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Morphological evaluation of the effectiveness of fluorescence navigation with chlorin e6 in surgery for malignant gliomas
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Transcranial Photosensitizer-Free Laser Treatment of Glioblastoma in Rat Brain
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Increasing the Dye Payload of Cetuximab-IRDye800CW Enables Photodynamic Therapy
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Oral Delivery of Photoresponsive Milk-Derived Exosomes for the Local Therapy of Glioblastoma
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Sonodynamic Therapy Using 5-Aminolevulinic Acid for Malignant Gliomas: A Review
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5-aminolevulinic acid induced photodynamic reactions in diagnosis and therapy for female lower genital tract diseases
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Activatable Photosensitizers: From Fundamental Principles to Advanced Designs
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5-Aminolevulinic acid-mediated photodynamic therapy in combination with kinase inhibitor lapatinib enhances glioblastoma cell death
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Fluorescence guidance in skull base surgery: Applications and limitations – A systematic review
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Photodynamic therapy in glioblastoma: Detection of intraoperative inadvertent 5-ALA mediated photodynamic therapeutical effect after gross total resection
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Rapid (FLASH-FLIM) imaging of protoporphyrin IX in a lipid mixture using a CMOS based widefield fluorescence lifetime imaging camera in real time for margin demarcation applications
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Photodynamic therapy during second surgery for recurrent gliomas improves survival
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Agents for Fluorescence-Guided Glioblastoma Surgery
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A Warp-Knitted Light-Emitting Fabric-Based Device for In Vitro Photodynamic Therapy: Description, Characterization, and Application on Human Cancer Cell Lines
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5-Aminolevulinic acid as an emerging radiosensitizer for radiodynamic therapy in solid tumors: a systematic review of available data and clinical potential
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Robotic-assisted spine surgery: Application of preoperative and intraoperative imaging
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Stereotactic Photodynamic Therapy of Recurrent Malignant Gliomas
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Photodynamic therapy in glioma cell culture
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Application of 5-aminolevulinic acid in cancer radio-dynamic therapy: A systematic review
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5-Aminolevulinic Acid Imaging of Malignant Glioma
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Visualizing the Invisible: Dual Click Imaging of Ruthenium-Based Photoactivated Chemotherapy Agents and Their DNA Synthesis Inhibition in Fixed Cancer Cells
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5-Aminolevulinic acid-mediated protoporphyrin IX accumulation in the tumor microenvironment of glioma and its implications for 5-aminolevulinic acid-based local tumor therapies: A review of the literature
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Pharmaceutical equivalent 5-aminolevulinic acid fluorescence guided resection of central nervous system tumors: feasibility, safeness and cost-benefit considerations
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Predicting head and neck tumor nodule responses to TLD1433 photodynamic therapy using the image‐guided surgery probe ABY ‐029
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Novel Iron-Chelating Prodrug Significantly Enhanced Fluorescence-Mediated Detection of Glioma Cells Experimentally In Vitro
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Porphyrin–Camptothecin (CPT) Grafted Polyoxazoline Amphiphiles for Tumor Photodynamic–Chemotherapy Combination Treatment
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Hybrid laser activated phycocyanin/capecitabine treatment of cancerous MCF7 cells
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Single-Cell Sequencing Reveals Necroptosis-Related Prognostic Genes of Glioblastoma
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Efficacy and Low Toxicity of Normo-Fractionated Re-Irradiation with Combined Chemotherapy for Recurrent Glioblastoma—An Analysis of Treatment Response and Failure
Pepper, N. B., Prange, N. G., Troschel, F. M., Kroeger, K., Oertel, M., Kuhlmann, T., Müther, M., Grauer, O. M., Stummer, W., & Eich, H. T. (2024) · Cancers · doi:10.3390/cancers16213652 · Cited by 3 · see citing works
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RP11-552D4.1: a novel m6a-related LncRNA associated with immune status in glioblastoma
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Effects of photodynamic exposure using chlorine E6 on U251 glioblastoma cell line in vitro
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Photodynamic Therapy In Adult Intra-Axial Brain Tumours
Javed, Z., Aziz, H. F., & Shamim, M. S. (2024) · Journal of the Pakistan Medical Association · doi:10.47391/jpma.24-11 · Cited by 3 · see citing works
Cytodestructive Effects of Photodynamic Exposure in Primary Cultures of Malignant Glioma Cells
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Photodynamic therapy management of canine mammary gland tumour with wireless upconversion implant
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Dual‐Light‐Primed GSH‐Scavenging Lipid Hybrid Nanoplatform for Cascade‐Activated Photodynamic Therapy
Yoo, S., Kim, J., Lee, S. M., Lee, S., Kim, T., Kang, J., Pham, L. B. H., Lim, H., Kim, M., Lim, K., et al. (2026) · Small · doi:10.1002/smll.202512546 · Cited by 2 · see citing works
Photodynamic interstitial stereotactic therapy for recurrent malignant glioma
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Achievements and prospects for further development of photodynamic therapy technology in the treatment of cerebral tumors
Kukanov, K. K., Nechaeva, A., Ulitin, А. Y., Sklyar, S. S., Vershinin, A. E., Викторович, Д. М., Politova, А. О., Papayan, G. V., & Olyushin, V. E. (2024) · Russian Journal for Personalized Medicine · doi:10.18705/2782-3806-2024-4-1-44-57 · Cited by 2 · see citing works
Transcranial photosensitiser-free laser treatment of glioblastoma in rat brainPreprint
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Glioblastom hos voksne
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Noninvasive Ultra Low Intensity Light Photodynamic Treatment of Glioblastoma with Drug Augmentation: LoGlo PDT Regimen
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Method of photodynamic action in surgical treatment of local limited peritonitis in the experiment
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Contrastive learning and prior knowledge-induced feature extraction network for prediction of high-risk recurrence areas in Gliomas
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Sonodynamic therapy inhibition of invasive glioma cells from tumor spheroids
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Investigation of the impact of resveratrol on sublethal-dose ALA-PDT in glioblastoma cells
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Classification of Glioblastoma Associated with Immune Checkpoints and Tumor Microenvironment based on Immunogenomic Profiling
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Comparison of the effects of photodynamic exposure with the use of chlorine E6 on glioblastoma cells of the U251 line and human embryonic kidney cells of the HEK293 line in vitro
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Highly efficient lanthanide‐doped theranostic nanoplatform for real‐time monitoring of direct triplet‐sensitized photodynamic therapy
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Optimizing conditions for light delivery for intracranial photodynamic therapy for high grade gliomas: a 3D model study of light dosimetry
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Noninvasive, Drug Augmented, Ultra Low Intensity Transcranial Light Photodynamic Treatment of Glioblastoma: LIT-PDTPreprint
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Association of 5-aminolevulinic acid fluorescence guided resection with photodynamic therapy in recurrent glioblastoma: a matched cohort study
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Surgical resection and intraoperative open photodynamic therapy of recurrent glioblastoma – a promising strategy for local tumour control
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ALA and Malignant Glioma: Fluorescence-Guided Resection and Photodynamic Treatment
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Self-citation

Authors: Schipmann, S., Müther, M., Stögbauer, L., Zimmer, S., Brokinkel, B., Holling, M., Grauer, O., Suero Molina, E., Warneke, N., & Stummer, W.
Affiliations: Department of Neurosurgery,
Research Institute of Radiology (BY)
University Hospital Münster (DE)
Corresponding author: Schipmann, Stephanie
ORCID: Schipmann, Stephanie
Müther, Michael
Zimmer, Sebastian
Brokinkel, Benjamin
Holling, Markus
Grauer, Oliver
Stummer, Walter
Venue: Journal of Neurosurgery
Publisher: Journal of Neurosurgery Publishing Group (JNSPG)
Published: 2021-02
Volume: 134
Issue: 2
Pages: 426-436
ISSN: 0022-3085 (ISSN-L)
1933-0693
DOI: 10.3171/2019.11.jns192443
OpenAlex: W3001797168
Cited by: 121
References: 42
Citations by year: 2026: 10 · 2025: 18 · 2024: 29 · 2023: 20 · 2022: 22 · 2021: 15 · 2020: 7
FWCI: 9.03
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of neurosurgery (publishedVersion)
PubMed (publishedVersion)
Funders: Westfälische Wilhelms-Universität Münster
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Photodynamic Therapy Research Studies
Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
Keywords: recurrent glioblastoma, 5-aminolevulinic acid, fluorescence-guided resection, photodynamic therapy, porphyrins, local tumor control, cytotoxic edema, progression-free survival, high-grade glioma

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Combination of ALA-induced fluorescence-guided resection and intraoperative open photodynamic therapy for recurrent glioblastoma: case series on a promising dual strategy for local tumor control

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