Interstitial photodynamic therapy for newly diagnosed glioblastoma

Adjuvant radiochemotherapy according to the EORTC/NCIC protocol has shown to improve the outcome of glioblastoma patients with a methylated MGMT-promoter status; however, overall survival remains limited [23]. Besides the incremental focus on biomarker profiling leading to more personalized treatment strategies, there remains an increasing need for the evaluation of more effective treatment concepts. One of these possible novel treatment concepts is iPDT for which this study provides a detailed outcome data analysis in comparison to the best available conventional treatment option. It is shown that iPDT, although requiring a careful planning procedure, is a feasible concept with an acceptable side effect profile for patients with untreated, small-sized, unresectable GBMs. A remarkable number of patients, in particular those with a methylated MGMT-promoter status, experienced long-term survival after iPDT. Furthermore, iPDT did not interfere with any further adjuvant treatment options.

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.

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 PFS and OS for a subgroup of iPDT patients. This favorable course of disease cannot be attributed to additional adjuvant treatment since all patients, with the exception of one case merely receiving radiotherapy, only underwent initial radiochemotherapy in analogy to the EORTC/NCIC protocol with up to nine cycles of TMZ at most. Thereafter, a treatment-free period up to the first sign of tumor recurrence was initiated in all patients. Thus, the burden of adjuvant treatment could be kept to a minimum for a good proportion of these iPDT patients in the initial stages of the disease. No exceptionally aggressive recurrence treatment was noted, either. In this patient series very promising PFS and OS rates one year and two years after iPDT treatment could be recorded. Most surprisingly, a significant proportion of seven patients (43.8%) experienced a PFS > 24.0 months not linked to very aggressive salvage treatment.

Two iPDT-treated patients harbored IDH-mutant tumors and would therefore, under the current WHO classification [24], be grouped as astrocytoma, IDH mutant, CNS WHO grade 4. Possibly, this molecular profile is in part responsible for the favorable outcome in these cases, although the value of iPDT for this subgroup is not clear. IDH mutant tumors were found in the reference group in comparable numbers. Another limitation of our study cohort is 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.

A methylated MGMT-promoter status was associated with improved outcome parameters in both treatment groups, as is also seen in other treatment settings [7, 25]. 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 [26]. 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 [11, 27]. In mouse models, following PDT, an immediate infiltration of the tumor tissue by neutrophil granulocytes, mast cells, monocytes, and macrophages has been observed [28]. Preliminary ex vivo studies also suggest that iPDT impacts the adaptive immune system by increasing the cytotoxic potential of human CD8 + T-cells by alterating the cells’ mRNA and protein expression profiles [29]. These findings point to a potential iPDT-related induction of so far unknown tumor-controlling processes possibly overcoming the limitations of other local treatment concepts.

Based on our experiences, we do 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.

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