Glioblastoma is the most aggressive brain cancer with extremely poor prognosis. Many novel therapies have been tried for glioblastoma with disappointing results. Despite the best currently available treatment involving maximal safe resection followed by adjuvant radiation and chemotherapy, the recurrence is inevitable and typically happens within 2 cm of the initial tumor margin due to infiltrative nature of the glioblastoma. 5-aminolevulinic acid (5-ALA) is approved for fluorescence-guided resection (FGR) to help improve the extent of resection, but even with this modality all residual tumor cells cannot be removed to prevent the recurrence. Thus, there is high, unmet need for methods that could selectively kill tumor cells at the infiltrating margins of the resection cavity.
Photodynamic therapy (PDT) is a clinically approved two-stage treatment where laser light is used to activate photosensitizer to produce cytotoxic reactive oxygen species (ROS) locally within tumor tissue. PDT has been investigated for glioblastoma using Photofrin but was abandoned due to side effects and lack of tumor specificity. Newer photosensitizer 5-ALA has potential to act as a highly tumor-selective agent for glioblastoma PDT. Modulight has developed a tailored medical laser for glioblastoma PDT which can be equipped with up to eight channels on 635 nm. System can be configured based on desired illumination approach and has also capacity to perform interstitial measurements for treatment monitoring purposes and collected data can be viewed from Modulight cloud.
Professor Stummer on glioblastoma surgeries and iPDT:
The objective of the study is to combine FGR with PDT as a compassionate care of recurrent glioblastoma patients. PDT has potential as a selective cytotoxic therapy to improve local tumor control in the infiltrating tumor margins. Even in cases when complete resection in FGR is achieved, cell density lower than 12% contributes to residual tumor burden. Hence, target tissue for PDT is both the visible but nonresectable fluorescent tumor tissue as well as these residual non-fluorescent infiltrating tumor cells that are the main cause of recurrences. A major advantage of this treatment strategy is that it can be conveniently integrated into standard of care, since FGR and PDT are performed in a same operation and 5-ALA can function as both a fluorescent agent in FGR and a photosensitizer in PDT, without need for any additional agents or doses of 5-ALA for PDT.
20 patients were treated. 5-ALA (Gliolan) was administered at a dosage of 20 mg/kg body weight 4 hours before anesthesia. Craniotomy was performed using FGR, with aim of maximal safe resection of the fluorescent tumor. Once there was no visible fluorescence or only tumor-infiltrated fluorescence in the eloquent areas left, PDT was performed. 1-4 cylindrical diffuser were strategically inserted depending on the size and architecture of the resection cavity and fixed to a retractor system. Laser illumination was applied for 1 hour (635 nm, 200 mW/cm diffuser) using high-power, multi-port Modulight ML7710 laser. During the illumination, the resection cavity was continuously irrigated with fluid to prevent formation of blood clots and debris that could interfere with laser light transmission, as well as ventilated with 100% oxygen since high oxygen levels are important for the efficacy of PDT. Most patients received concomitant radio- and chemotherapy after PDT. Patients were monitored with MRI at 24 hours, 14 days, and every 3 months after surgery.
20 mg/kg body weight 5-ALA
State-of-the-art fluorescence-guided microsurgical resection
Open photodynamic therapy of resection cavity
Fibers placed into the tumor cavity.
OR staff performing a PDT treatment for a glioblastoma patient.
Modulight’s tailored ML7710 high-power medical laser with 8 ports allows efficient interstitial illumination for PDT even in complex resection cavities.
Effect from PDT was seen in postoperative MRI in 16 (80%) of treated patients, who showed cytotoxic edema in the resection margins. Edema corresponded to the location of laser diffusers with a mean volume of 3.3 cm2 and appeared to be selective for infiltrative or nonresectable residual tumor. Median PFS was 6 months (95% CI 4.8–7.2 months) and overall survival 75% during the follow-up, with 4 tumor-related deaths registered. No adverse events or post-therapeutic neurological deficits were observed. One patient developed surgical site infection requiring surgical revision, although it developed only 6 months after initial surgery and may be related to second-line anti-angiogenic treatment.
Progression-free survival (PFS)
Overall survival (OS)
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