Interstitial Photodynamic Therapy for newly diagnosed Glioblastoma

Recent research published in Journal of Neuro Oncology has shown interstitial photodynamic therapy (iPDT) as a feasible treatment concept and might be associated with long-term improved functional scores in a subgroup of GBM patients, potentially via induction of so far unknown immunological tumor-controlling processes.

Glioblastoma (GBM) is the most common malignant brain tumor. Current treatment concepts comprise maximal safe resection followed by a combination of radiotherapy and chemotherapy with temozolomide, possibly augmented by tumor-treating fields. Despite this aggressive treatment regimen, median survival is limited to 15–20 months. Unfavorable outcome must be particularly expected if the tumor cannot be resected completely due to eloquent location, and/or if an unmethylated O6-methylguanin-DNA-methyltransferase (MGMT) promoter hampers response to chemotherapy. Thus, alternative treatment concepts need to be evaluated.

Photodynamic therapy (PDT) is a local treatment concept used for a variety of neoplastic and non-neoplastic conditions. It is based on the light-induced activation of a photosensitizer leading to the formation of reactive oxygen species and subsequent apoptosis and necrosis of the affected cells. The photosensitizer protoporphyrin IX is preferentially synthesized within malignant glioma cells after oral application of its precursor 5-aminolevulinic acid (5-ALA). This highly specific accumulation makes 5-ALA a well-suited photosensitizer predrug for PDT.. The good tumor-to-background-ratio of protoporphyrin IX synthesis is regularly exploited in fluorescence-guided resection. For tumors unamenable to safe complete resection, interstitial PDT (iPDT) has been explored as a minimally invasive procedure where treatment light is applied through stereotactically implanted optical fibers.

Quach et al found that, when assessing the resulting Kaplan-Meier survival curves for PFS and OS, the observed patterns for the iPDT patient cohort were found to reach a plateau indicating long-term function and survival for a subgroup of iPDT patients. Most surprisingly, they found a significant proportion of patients (43.8%) experienced a survival >24.0 months not linked to very aggressive salvage treatment.

The limitation of their study was that the selection of small tumor volumes, so as to minimize the risk of patient harm due to space-occupying increase in edema. “Whether this treatment may also benefit the many cases of larger tumors cannot be answered at this point. The patients’ excellent clinical status and prompt initiation of adjuvant therapy may have also contributed to the positive result”, say the authors.

One iPDT treated patient suffered a permanent treatment-associated morbidity. All other side effects were edema-associated and could be sufficiently treated by oral dexamethasone administration. Whenever possible, dexamethasone was waived so as to not impair potential immune-modulatory effects. No patient had to undergo long-term anti-edematous therapy and no delay of adjuvant treatment due to treatment-associated complications was recorded.

A methylated MGMT-promoter status was associated with improved outcome parameters in both treatment groups, as is also seen in other treatment settings. The remarkably large survival benefit of iPDT-treated patients with positive MGMT-promoter methylation status, however, can most likely not only be explained by the known increased chemosensitivity by itself. Patients with an unmethylated MGMT-promoter profile showed outcomes similar to resected patients. Meanwhile the subgroup with methylated MGMT-promoter responded even better than resected patients. This response might be mediated through an immune-modulatory effect. The observed outcome improvement may thus be seen as a surrogate marker of biologically different inflammatory/immunological re-sponses to iPDT.

The precise mechanisms of tumor inactivation by iPDT, reflected in the recorded favorable PFS rate, are not entirely understood yet. Ex vivo experimental data have shown that PDT does have the ability to induce ROS in glioma cell spheroids causing consecutive necrosis. It is now believed that through these events PDT does not only cause a local effect on the directly treated tumor volume but may also trigger a systemic immunological/inflammatory response which significantly contributes to the observed long-term tumor control.

The authors believe that iPDT is an appealing treatment concept for patients with newly diagnosed small-sized GBMs and deserves further evaluation in prospective clinical trials such as NCT03897491.

iPDT is a promising local treatment concept for patients with newly diagnosed small-sized GBMs. Notably, despite eloquent tumor localizations, a tolerable risk profile was seen. A considerable proportion of patients, especially those with methylated MGMT-promoter status, experienced long-term progression free survival after iPDT. Future clinical and experimental studies need to be performed to improve the understanding of the underlying cellular and serological mechanisms and, consequently, to help to identify the subset of patients most suitable for iPDT.

Reference: Quach, S., Schwartz, C., Aumiller, M. et al. Interstitial photodynamic therapy for newly diagnosed glioblastoma. J Neurooncol 162, 217–223 (2023). https://doi.org/10.1007/s11060-023-04284-9