ML7710 for glioblastoma treatment

Customer case

Research by: University Hospital Münster provides cutting-edge medical treatments for patients all over the world. The department of neurosurgery provides full spectrum of neurosurgical care with interdisciplinary vascular and neuro-oncological specialization.

Modulight products: ML7710, ML7710i

Laser use: Randomized controlled PDT trials for both newly diagnosed and recurrent glioblastoma as well as compassionate care for terminal glioblastoma patients.

Link to the study:


Professor Walter Stummer, MD, PhD

Research topics: Professor Stummer is world leader in his research fields, which include vascular neurosurgery, microneurosurgery, fluorescence-based neurosurgical diagnostic methods as well as photodynamic therapy for brain tumors. He has developed now approved and widely used fluorescence-guided surgery with 5-ALA for high-grade gliomas and is currently evaluating the use of stereotactic PDT for small inoperable glioblastoma in two randomized controlled trials.

Background

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:

 
 

 

Objective

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.

Treatment protocol

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.

 

 

Results

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)

Kaplan-Meier survival curves created based on the data in the referred open access publication.

 

 

Conclusions:
The dual approach of combining 5-ALA FGR with intraoperative PDT was shown to be feasible and safe in patients with recurrent glioblastoma. This is first report of the use of a multiple-fiber PDT technique with intraoperative irrigation. A high-power laser provided enough power and distribution of light even in the complex resection cavities for efficient PDT without causing any harmful thermal effects. PDT enables creation of additional safety margin by killing the tumor cells that are not visible in FGR due to lower cell density. In addition, even nonresectable tumors in eloquent brain regions can be treated with PDT due to selectivity of 5-ALA. Despite promising results of this case series, further studies are needed concerning immune responses, synergies with adjuvant treatments, the number and position of light diffusers, light delivery protocols, and optimization of light dosimetry. A multicenter, controlled randomized trial is required to demonstrate long-term outcomes of this dual strategy regarding PFS and OS.

 

Related Modulight products and Services

 

Related Publications

Combination of ALA-induced fluorescence-guided resection and intraoperative open photodynamic therapy for recurrent glioblastoma: case series on a promising dual strategy for local tumor control
Stephanie Schipmann, Michael Müther, Louise Stögbauer, Sebastian Zimmer, Benjamin Brokinkel, Markus Holling, Oliver Grauer, Eric Suero Molina, Nils Warneke, Walter Stummer
J Neurosurg. 2020 Jan 24;1-11.

Configurable cloud based medical laser platform with real-time treatment monitoring
Visa Kaivosoja, Zoe Ylöniemi, Juha Lemmetti, Timo Tanila, Lasse Orsila, Petteri Uusimaa
SPIE BIOS 2021 Proceedings Volume 11628, Mechanisms and Techniques in Photodynamic Therapy and Photobiomodulation

Cloud-based medical laser platform for phototherapy and treatment monitoring for glioblastoma
Zoe Ylöniemi, Visa Kaivosoja, Juha Lemmetti, Timo Tanila, Eero Koivumäki, Lasse Orsila, Petteri Uusimaa
SPIE BIOS 2021 Proceedings Volume 11629, Optical Techniques in Neurosurgery, Neurophotonics, and Optogenetics

 

 

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