Interstitial Photodynamic Therapy Using 5-ALA for Malignant Glioma Recurrences

Abstract

Interstitial photodynamic therapy (iPDT) using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) as a cytotoxic photosensitizer could be a feasible treatment option for malignant gliomas. In a monocentric cohort of consecutive patients treated between 2006 and 2018, a risk profile analysis of salvage iPDT for local malignant glioma recurrences and associated outcome measures are presented here. It was considered indicated in patients with circumscribed biopsy-proven malignant glioma recurrences after standard therapy, if not deemed eligible for safe complete resection. A 3D treatment-planning software was used to determine the number and suitable positions of the cylindrical diffusing fibers placed stereotactically to ensure optimal interstitial irradiation of the target volume. Outcome measurements included the risk profile of the procedure, estimated time-to-treatment-failure (TTF), post-recurrence survival (PRS) and prognostic factors. Forty-seven patients were treated, of which 44 (median age, 49.4 years, range, 33.4–87.0 years, 27 males) could be retrospectively evaluated. Recurrent gliomas included 37 glioblastomas (WHO grade IV) and 7 anaplastic astrocytomas (WHO grade III). Thirty (68.2%) tumors were O-6-methylguanine-DNA methyltransferase (MGMT)-methylated, 29 (65.9%)—isocitrate dehydrogenase (IDH)-wildtype. Twenty-six (59.1%) patients were treated for their first, 9 (20.5%)—for their second, 9 (20.5%)—for the third or further recurrence. The median iPDT target volume was 3.34 cm3 (range, 0.50–22.8 cm3). Severe neurologic deterioration lasted for more than six weeks in one patient only. The median TTF was 7.1 (95% confidence interval (CI), 4.4–9.8) months and the median PRS was 13.0 (95% CI, 9.2–16.8) months. The 2- and 5-year PRS rates were 25.0% and 4.5%, respectively. The treatment response was heterogeneous and not significantly associated with patient characteristics, treatment-related factors or molecular markers. The promising outcome and acceptable risk profile deserve further prospective evaluation particularly to identify mechanisms and prognostic factors of favorable treatment response.

Interstitial Photodynamic Therapy for Glioblastomas: A Standardized Procedure for Clinical Use

“…As a consequence, iPDT reduces the risk of morbidity. Lietke et al recently reported their clinical experience of over 44 patients who underwent iPDT for GBM recurrences [35]. In their series, only one patient (2%) reported a new neurological deficit still present 6 weeks after treatment.…”

“…It is of most interest to standardize and optimize the iPDT procedures for GBM. Available planning software on the market (e.g., Target, Brainlab, Munich, Germany) aims at defining a target volume and the optical fiber placement but does not provide the estimated treated volume with iPDT [35]. Our TPS is innovative in the sense that it calculates the estimated treated volume after the optical fiber placement.…”

“…Although our laboratory has strong experience and expertise in preclinical research [22,23], some limitations of in vivo testing can be reported in our case: (1) the difficulty of reproducing the complexity of the GBM patterns using cell lines in an animal model (e.g., U87 cells do not induce necrosis), (2) the small size of rodent brains that are currently used for such experiments, (3) the variation of the optical parameters between human and other species and (4) the ethical component, which must avoid all nonessential animal experimentation. Lastly, iPDT has been already performed in human clinical practice [35].…”

Perspectives on interstitial photodynamic therapy for malignant tumors

“…Currently, there are two ongoing clinical trials including GL-01, a pilot phase II trial examining efficacy of stereotactic IPDT (ClinicalTrials.gov #NCT03897491), and NOA-11, a multi-centre, randomized non-blinded trial of stereotactic IPDT for recurrent glioblastoma (ClinicalTrials.gov # NCT04469699). In addition, promising results have recently been published in regards to IPDT for recurrent malignant glioma treated with ALA. 52 Following surgery and during recovery, combining posttreatment sterilization with implantation of light emitting diodes (LEDs) could help in maintaining an immune-modulator effect through low-dose PDT that induces apoptosis. 53 Although not strictly IPDT in the classic sense of the term, the goal here is to combine some of the ideas of metronomic PDT 54 , 55 with the advances in dosimetry previously demonstrated by a number of research groups.…”

In Vivo Study of the Efficacy and Safety of 5-Aminolevulinic Radiodynamic Therapy for Glioblastoma Fractionated Radiotherapy

“…For glioma, interstitial PDT (a stereotactic phototherapy using fiber optics as a laser diffuser due to limited light transmission) or intraoperative PDT (which uses a lighting device placed inside the surgical cavity) have been developed [8][9][10]. Clinical studies and clinical trials of 5-ALA PDT for non-dermatologic cancer are ongoing [11,12]. The mechanism of 5-ALA-PDT is as follows: exogenous 5-ALA induces the accumulation of protoporphyrin IX (PpIX) in cancer cells, PpIX produces reactive oxygen species (ROS), mainly 1 O 2 , under laser light suitable for excitation of PpIX, which induces cellular damage and death [13,14].…”