Background and Objective
Glioblastoma (GBM) is a malignant brain tumor with a median overall survival of approximately 15 months with the current standard of care (SOC). Although it is a rare neoplastic disease with low prevalence (0.3/10,000 persons), it remains the most frequent primary malignant brain tumor in adults. Currently, there is still no therapeutic option to prevent GBM recurrence and total resection is rarely feasible because of tumor cells infiltrating the surrounding brain. Thus, adjuvant therapies to improve local control are highly expected.
5-ALA photodynamic therapies have been reported with promising results. We present here an ongoing clinical trial (INDYGO) to evaluate 5-ALA PDT delivered intraoperatively to treat newly diagnosed GBM.
Materials and Methods
Our group has introduced a specific light applicator to deliver PDT in the surgical cavity early after maximal resection. 5-ALA PDT is delivered in combination with the SOC recommended by the current guidelines and enabling to simultaneously investigate the potential synergistic effects.
Results and Discussion
Between May 2017 and June 2018 ten patients have been enrolled. Currently, therapy has been delivered without significant toxicity or adverse event and are fulfilling the primary endpoint of this feasibility study. Secondary endpoints still being under investigation are progression-free survival, overall survival and patients' quality of life.
Conclusions
Finally, after the feasibility and the absence of adverse effects, multicentric, parallel-group, randomized controlled trial (RCT) is planned to assess the efficacy of 5-ALA PDT for the treatment of newly diagnosed GBM.
Background: Multimodal treatment associating surgery (pleurectomy/decortication, P/D) then IV adjuvant chemotherapy (platinum/pemetrexed) is an effective therapeutic option for some selected malignant pleural mesothelioma (MPM) patients. Intra-operative pleural photodynamic therapy (iPDT) has emerged as a promising option to improve this multimodal treatment outcome (Friedberg J, Ann Thorac Surg. 2017). The MesoPDT trial (NCT02662504) aimed at assessing the feasibility of such procedure outside the only two US expert centers performing multimodal treatment including iPDT to date. Methods: A single-center pilot clinical trial was designed to assess the feasibility of iPDT protocol in Lille University Hospital. A pool of maximum six patients was expected in order to apply the iPDT protocol, and to assess its applicability and safety outside US center expert. Results: In 2016-2017, four consecutive assessable patients were included and treated per protocol, reaching the study achievement cut-off. iPDT specific procedures have been applied and managed in partnership with US experts. The safety profile was favorable. The main and most specific adverse event was acute lung injury occurring within 72 hours after iPDT, which may lead to reversible respiratory distress, manageable with adequate intensive care. The 4 patients achieved the full scheduled protocol. Conclusion: The iPDT multimodal treatment for MPM is applicable and manageable in a European expert center, involving local skills and dedicated teams. The safety profile of the iPDT in Lille center was favorable, as validated by an external board. Median overall survival was promising (≈28 months), similar to previous US results. Our center is expected to join soon a large phase II randomized, multicentric US trial assessing MPM multimodal treatment (P/D, chemotherapy) ±iPDT (NCT02153229; UPENN, USA).
Whether preclinical studies either involve a cell or animal model, the distribution of light plays a determinant role in the reproducibility of results of photodynamic therapy (PDT) studies. Unfortunately, only few illumination devices dedicated to preclinical studies are available and are for the most, very expensive. Most research teams use home-made solutions that may not always be reproducible because of undefined light distribution, additive thermal emission, or unsuitable for shapes and volumes to illuminate. To address these issues, we developed illumination devices dedicated to our preclinical studies, which embed knitted light emitting fabrics (LEF) technology. LEF technology offers a homogeneous light distribution, without thermal emission and can be coupled with various light sources allowing investigation of several PDT modalities (irradiance, wavelength, illumination duration/mode). For in-vitro studies, we designed light plates, each allowing illumination of up to four 96-cells plates. For in-vivo studies, we designed mice boxes allowing three animals placement in prone position, equally surrounded by LEF and ensuring homogeneous extracorporeal illumination. Optical validation was performed and reproducibility of both preclinical systems were assessed. Both systems can deliver homogeneous light with an irradiance that can reach several mW/cm2, with varying durations and wavelengths. First results of preclinical studies demonstrate a high reproducibility, with an easy setup, and a great adaptability of illumination modalities with these devices based on light emitting fabrics.
A homogeneous and reproducible fluence rate delivery during clinical PDT plays a determinant role in preventing underor overtreatment. In Dermatology, topical PDT has been carried out with a wide variety of light sources delivering a broad range of light doses. However, these light sources do not deliver a uniform light distribution on the skin due to their structure and morphology and the complexities of the human anatomy. The development of a flexible light source able to generate uniform light on all its surface would considerably improve the homogeneity of light delivery. The integration of plastic optical fibers (POF) into textile structures offers an interesting alternative. The homogeneous light side-emission from the fabric is obtained by controlling the bending angles of POF inside the LEF due to specific architecture generated by knitting of textile structure. LEF of different surfaces can be easily manufactured (up to 500cm2 The LEF thickness is less than 1 mm. The mean irradiance is typically 2.5 mW.cm-2. W-1 with heterogeneity of 12.5% at any point of the LEF. The temperature elevation remains below 1°C. These LEF were evaluated in Dermatology for the treatment of Actinic Keratosis. Two clinical evaluation were performed. The first one was a monocentric, randomized, controlled, phase II clinical study (ClinicalTrials.gov Identifier: NCT03076918). Twenty five (25) patients with grade I-II actinic keratosis (AK) of the forehead and scalp were treated with methyl aminolevulinate photodynamic therapy in two symmetrical areas. One area was treated with the conventional LED panel (154 AK), whereas the other area was treated with the LEF device (156 AK). The second clinical was performed in 2 centers. This new LEF device was a more ergonomic and compact version of the original system developed for FLEXIPDT. In this clinical study (ClinicalTrials.gov Identifier: NCT03076892), the irradiance has been reduced from 12.3 mW/cm2 to 1.3 mW/cm2 and the light dose from 37 J/cm2 to 12 J/cm2 . Compared to Conventional PDT, the 2 protocols clearly shown that LEF are equivalent and even superior in terms of efficacy for treating AK of the forehead and scalp. However, the use of LEF resulted in much lower pain scores and fewer adverse effects. In conclusion, thanks to LEF, PDT of AK can be conducted in all weather conditions, in any geographic location, year-round and benefits from the optimal adaptability of the flexible, light-emitting, fabrics to the treatment area. At last, LEF can be easily can be easily manufactured in large series.
Glioblastoma is a malignant brain tumor with a poor prognosis. Currently, complete resection is rarely feasible, since tumor cells usually infiltrate the surrounding brain. Recently, the INDYGO clinical trial has been achieved to assess the toxicity of photodynamic therapy (PDT) delivered intraoperatively to treat newly diagnosed glioblastoma. Today, we believe that the PDT effect obtained in the INDYGO clinical trial can be improved by a higher light dose. The DOSINDYGO clinical trial aims to achieve a light-dose escalation increasing up to four times the initial light dose used in the INDYGO trial. An increase of both light power and treatment time should allow to treat deeper in the surrounding tissues (up to 8mm) and thus decrease the recurrence risk. First light dose will be reached by doubling the treatment time used in the INDYGO trial, the other one will be achieved by increasing light power only. This methodology was chosen in order to maintain an acceptable treatment time for anesthesia but also to prevent higher fluence rate that could induce a lower tolerance as observed in our preclinical results. Primary endpoint will be to determine the optimum light-dose regarding the ratio efficacy and tolerance of the treatment. Primary criterion is the assessment of the progression free survival within the bed border’s cavity. Finally, although no adverse effect has been noticed during the INDYGO trial, increasing light dose in this DOSINDYGO trial could result in other direct and indirect biological effects.
KEYWORDS: Photodynamic therapy, Brain, Medical devices, Surgery, Radiation oncology, Control systems, Luminescence, Light sources, Tissues, Light sources and illumination, Tumors, Laser therapeutics, System on a chip, Clinical trials, Liquids, Diffusers
Glioblastoma (GBM) is the most common primary brain tumor. Its incidence is estimated at 5 to 7 new cases
each year for 100 000 inhabitants. Despite reference treatment, including surgery, radiation oncology and
chemotherapy, GBM still has a very poor prognosis (median survival of 15 months). Because of a systematic
relapse of the tumor, the main challenge is to improve local control. In this context, PhotoDynamic Therapy
(PDT) may offer a new treatment modality.
GBM recurrence mainly occurs inside the surgical cavity borders. Thus, a new light applicator was designed for
delivering light during a PDT procedure on surgical cavity borders after Fluorescence Guided Resection. This
device combines an inflatable balloon and a light source.
Several experimentations (temperature and impermeability tests, homogeneity of the light distribution and ex-vivo
studies) were conducted to characterize the device. An abacus was created to determine illumination time
from the balloon volume in order to reach a therapeutic fluence value inside the borders of the surgical cavity.
According to our experience, cavity volumes usually observed in the neurosurgery department lead to an
acceptable average lighting duration, from 20 to 40 minutes. Thus, extra-time needed for PDT remains suitable
with anesthesia constraints. A pilot clinical trial is planned to start in 2017 in our institution. In view of the
encouraging results observed in preclinical or clinical, this intraoperative PDT treatment can be easily included
in the current standard of care.
The integration of optical fibers into flexible textile structures, by using knitting or weaving processes can allow the
development of flexible light sources. The paper aims to present a new technology: Light Emitting Fabrics (LEF), which
can be used for example for PDT of Actinic Keratosis in Dermatology.
The predetermined macro-bending of optical fibers, led to a homogeneous side emission of light over the entire surface
of the fabric. Tests showed that additional curvatures when applying the LEF on non-planar surfaces had no impact on
light delivery and proved that LEF can adapt to the human morphology.
The ability of the LEF, coupled with a 635nm LASER source, to deliver a homogeneous light to lesions is currently
assessed in a clinical trial for the treatment of AK of the scalp by PDT. The low irradiance and progressive activation of
the photosensitizer ensure a pain reduction, compared to discomfort levels experienced by patients during a conventional
PDT session.
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