Interstitial photodynamic therapy for glioblastoma
Interstitial photodynamic therapy (PDT) is a promising approach for glioblastoma treatment, an aggressive and difficult-to-treat form of brain cancer. This therapy involves the use of photosensitizing agents and laser light to selectively target and destroy cancerous cells within the brain. Here's an overview of how interstitial PDT works for glioblastoma:
Photosensitizer Administration: A photosensitizing agent is introduced into the patient's body. This can be done through intravenous injection, oral administration, or direct placement at the tumor site. The photosensitizer is designed to accumulate preferentially in cancer cells.
Accumulation in Tumor: Over time, the photosensitizer accumulates in the glioblastoma tumor cells due to their increased vascularization and the disrupted blood-brain barrier often seen in these tumors. This process can take hours to days, depending on the specific photosensitizer used.
Light Delivery: Once a sufficient amount of the photosensitizer has accumulated within the tumor, a laser light of a specific wavelength is applied directly to the tumor site. The wavelength of the light is chosen to match the absorption peak of the photosensitizer.
Activation of Photosensitizer: When the laser light interacts with the photosensitizer, it activates the photosensitizer. This activation process generates highly reactive oxygen species (ROS), primarily singlet oxygen molecules, which can cause damage to nearby cancer cells.
Selective Destruction: The ROS generated during activation selectively damage the tumor cells while sparing normal brain tissue. This selectivity is a key advantage of PDT, as it minimizes collateral damage to healthy brain tissue.
Monitoring: During treatment, real-time monitoring techniques, such as MRI or fluorescence imaging, may be used to assess the extent of PDT-induced damage and ensure that the treatment is accurately targeting the tumor.
Repeat Treatments: In some cases, multiple PDT sessions may be required to effectively treat the entire tumor, as glioblastoma can be highly infiltrative and challenging to completely eradicate.
Post-Treatment Care: After PDT, patients typically undergo a period of recovery. Imaging studies are used to evaluate the response to treatment and the status of the tumor.
Interstitial PDT for glioblastoma has shown promise in preclinical studies and early-phase clinical trials. It offers several advantages, including its ability to target deep-seated brain tumors and its relatively low risk of systemic side effects compared to traditional chemotherapy. However, there are challenges and considerations associated with this therapy, such as optimizing the delivery of light to the tumor site and selecting the most effective photosensitizer.
It's important to note that interstitial PDT is still an area of active research, and its clinical use is evolving. The effectiveness of PDT for glioblastoma may vary from patient to patient, and its long-term outcomes are still being studied. As a result, it is typically considered as part of a multimodal treatment approach that may also include surgery, radiation therapy, and chemotherapy.
iPDT showed its potential as a treatment option for glioblastomas, with a large fraction of patients having prolonged OS. Parameters of prognostic relevance could be derived from the patient characteristics and MRI data, but they may partially need to be interpreted differently compared to the standard of care 1).
Sixteen patients (median age 65.8 years) with newly diagnosed, small-sized, not safely resectable supratentorial GBM underwent interstitial photodynamic therapy (iPDT) as upfront eradicating local therapy followed by standard chemoradiation. 5-aminolevulinic acid (5-ALA) induced protoporphyrin IX was used as the photosensitizer. The tumors were irradiated with light at 635 nm wavelength via stereotactically implanted cylindrical diffuser fibers. Outcome after iPDT was retrospectively compared with a positively selected in-house patient cohort (n = 110) who underwent complete tumor resection followed by chemoradiation.
Results: Median progression-free survival (PFS) was 16.4 months, and median overall survival (OS) was 28.0 months. Seven patients (43.8%) experienced long-term PFS > 24 months. Median follow-up was 113.9 months for the survivors. Univariate regression revealed MGMT-promoter methylation but not age as a prognostic factor for both OS (p = 0.04 and p = 0.07) and PFS (p = 0.04 and p = 0.67). Permanent iPDT-associated morbidity was seen in one iPDT patient (6.3%). Patients treated with iPDT experienced superior PFS and OS compared to patients who underwent complete tumor removal (p < 0.01 and p = 0.01, respectively). The rate of long-term PFS was higher in iPDT-treated patients (43.8% vs. 8.9%, p < 0.01).
iPDT is a feasible treatment concept and might be associated with long-term PFS in a subgroup of GBM patients, potentially via induction of so far unknown immunological tumor-controlling processes 2).
In the case of brain tumors, iPDT consists of introducing one or several optical fibers in the tumor area, without large craniotomy, to illuminate the photosensitized tumor cells. It induces necrosis and/or apoptosis of the tumor cells, and it can destruct the tumor vasculature and produces an acute inflammatory response that attracts leukocytes. Interstitial PDT has already been applied in the treatment of brain tumors with very promising results. However, no standardized procedure has emerged from previous studies. Leroy et al. proposed a standardized and reproducible workflow for the clinical application of iPDT to Glioblastoma. This workflow, which involves intraoperative imaging, a dedicated treatment planning system (TPS), and robotic assistance for the implantation of stereotactic optical fibers, represents a key step in the deployment of iPDT for glioblastoma treatment. This end-to-end procedure has been validated on a phantom in real operating room conditions. The thorough description of a fully integrated iPDT workflow is an essential step forward to a clinical trial to evaluate iPDT in the treatment of Glioblastoma. 3).
U87 glioblastoma cells were stereotactically engrafted into the brains of male fox1 rnu/rnu rats. Light delivery was studied after 5-ALA injection (100 mg/kg i.p.). 26J of 635 nm light was interstitially delivered to U87 tumor-bearing rats at a radiant power of either 30 mW (high fluence rate) or 4.8 mW (low fluence rate). In each group, half of the population received illumination in 2 fractions with a refractory interval of 120 s, whereas the other half received continuous illumination.
Twenty-two animals received 5-ALA-PDT, and the level of necrosis was scored. In the high-fluence-rate group, we observed a greater degree of tumor necrosis in rats receiving fractionated delivery than in rats receiving continuous illumination. Similar differences were not observed in the low-fluence-rate group, which exhibited only sparse necrosis. Higher morbidity and mortality rates were observed in the high-fluence-rate group.
We have developed a reproducible and reliable rodent model for interstitial 5-ALA PDT. We found that the effects of 5-ALA-PDT are dependent on light delivery conditions. Although the low-fluence-rate treatment was better tolerated, 5-ALA-PDT induced more necrosis using fractionated delivery at a high fluence rate. These results require confirmation with further studies involving larger populations and additional fractionation schemes 4).
Human U87 cells were grafted into the right putamen of 39 nude rats. After PS precursor intake (5-ALA), an optic fiber was introduced into the tumor. The rats were randomly divided into three groups: without light, with light split into 2 fractions and with light split into 5 fractions. Treatment effects were assessed using brain immunohistology.
Fractionated treatments induced intratumoral necrosis (P < 0.001) and peritumoral edema (P = 0.009) associated with a macrophagic infiltration (P = 0.006). The ratio of apoptotic cells was higher in the 5-fraction group than in either the sham (P = 0.024) or 2-fraction group (P = 0.01). Peripheral vascularization increased after treatment (P = 0.017), and these likely new vessels were more frequently observed in the 5-fraction group (P = 0.028).
Interstitial PDT with fractionated light resulted in specific tumoral lesions. The 5-fraction scheme induced more apoptosis but led to greater peripheral neovascularization 5).
Interstitial photodynamic therapy with 5-aminolevulinic acid for malignant brain tumor
Case series
2015
Patients diagnosed with primary brain tumors were treated with PDT. Treatment consisted in administration of the photosensitizer followed by craniotomy, surgical resection and laser illumination of the surgical bed. Primary brain tumors received also temozolomide-based chemotherapy and radiotherapy (RT).
From May 2000 to December 2010, 41 patients (27 male, 14 female) with a median age of 49 years (range 13 to 70) diagnosed of primary brain tumors were included in the study. In 7 patients PDT was repeated at the time of the relapse. In 22 episodes PDT was part of the initial treatment of primary brain tumors and in 26 episodes was part of the treatment at relapse.
PFS observed was 10 months for Glioblastoma (95% confidence interval 5.7-14.3), 26 months for AA (95% CI 4.5-47.5), and 43 months for OD (95% CI 4.5-47.5). Median OS was 9 months for Glioblastoma (95% CI 2.3-15.7), 20 months for AA (95% CI 0.0-59) and 50 months for OD (95% CI 32.5-67.5). The apparent discrepancy between PFS and OS data is due to patients not censored for PFS because they die from causes other than tumor progression. Median OS since first diagnosis was 17 months for Glioblastoma (95% CI 15.2-17.8), 66 months for AA (95% CI 2.9-129.1) and 122 months for OD (95% CI 116.1-127.8). Side effects were mild and manageable.
This study confirms that PDT can be considered as an adjunctive to surgery and/or RT and chemotherapy in the treatment of brain tumors, excluding those patients with thalamic or brain stem locations. It adds therapeutic effect without adding significant toxicity. In order to improve its contribution, it is essential to find new drugs with more penetration in order to destroy tumor cells more deeply at resection margins 6).