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.
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.
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.
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 500cm<sup>2</sup> The LEF thickness is less than 1 mm. The mean irradiance is typically 2.5 mW.cm<sup>-2</sup>. 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/cm<sup>2</sup> to 1.3 mW/cm<sup>2</sup> and the light dose from 37 J/cm<sup>2</sup> to 12 J/cm<sup>2</sup> . 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.
Photodynamic therapy (PDT) is an established treatment for actinic keratosis (AK). The conventional approved PDT protocol in Europe (C-PDT) involves red-light photoactivation at irradiances higher than 60 mW/cm<sup>2</sup> , making the treatment painful. Several clinical studies have reported similar efficacy and better tolerability when using red-light photoactivation at lower irradiances. The aim of the study was to investigate whether there is a minimum irradiance threshold for red-light photoactivation above which there is no further improvement in efficacy. A photodiode sensor connected to a power meter was used to measure the irradiance delivered to 114 AKs on the scalp and forehead of 19 patients during C-PDT using the Aktilite CL 128 (Galderma SA, Switzerland). The widely ranging measured irradiances, resulting from the heterogeneous photoactivation over the treatment area provided by the Aktilite CL 128, were cross-referenced with the clinically evaluated complete responses (CR) at 3 months. The 66 AKs in CR at 3 months received an average irradiance of 30.9 mW/cm<sup>2</sup> (standard deviation: 16.7 mW/cm<sup>2</sup> ) compared to 33.3 mW/cm2 (standard deviation: 17.9 mW/cm<sup>2</sup> ) for the 48 AKs in incomplete response. No significant effect of the irradiance on the CR at 3 months was found (odds ratio for a 6 mW/cm<sup>2</sup> -unit change, 0.96; 95% confidence interval, 0.83 to 1.10; p=0.53). No minimum irradiance threshold could therefore be determined in the considered irradiance range. A red-light device enabling homogeneous irradiation at a lower irradiance than the Aktilite CL 128 may therefore provide similar efficacy and higher treatment tolerability than C-PDT.
Photodynamic therapy (PDT) for dermatological conditions relies on the photoactivation of the photosensitizer protoporphyrin IX (PpIX). Many light sources have been or are being investigated. The stronger the overlap of the spectral irradiance of the light source with the absorption spectrum of PpIX is, the more powerful to photoactivate PpIX is the light source. This overlap can be quantified using the PpIX-weighted irradiance, which results from the weighting of the spectral irradiance of the light source by the normalized PpIX absorption spectrum. We have previously developed a freely available website (http://www.oncothai.fr/light-efficiency-calculator/), which aims to compute the PpIX-weighted irradiance of any uploaded spectral irradiance. Through this website, we have assessed a variety of light sources proposed for use in dermatological PDT. The spectral irradiances of these light sources were collected by either extraction from the literature or request to manufacturers. Due to the variations in position, shape, and amplitude of the spectral irradiances with regard to the PpIX normalized absorption spectrum, a wide range of PpIX-weighted irradiances has been obtained. The maximal PpIX-weighted irradiance was achieved with daylight on a clear sunny day.
Primary Extramammary Paget’s disease (EMPD) is a rare cancer that mainly affects the genital region including vulvar and perianal areas. Without treatment, vulvar EMPD progresses and presents always more erythematous and pruritic plaques, which may become ulcerated and erosive. To control disease progression and symptoms usually experienced by patients, surgical excision is the mainstay of treatment. Unfortunately, even after large surgical excision with intra-operative margin control, recurrences are common . For recurrent patients which undergo multiple resections, severe functional and sexual alterations are described. Only few data are available on the efficacy of alternative conservative treatments, such as laser ablation, radiotherapy, topical chemotherapy and photodynamic therapy (PDT) . To date, none of them can be considered as a solid alternative to surgical excision yet . Nonetheless, multiple clinical cases suggest that PDT could provide the opportunity to treat subclinical lesions, and give some relief on patient’s symptoms of the disease [4-6]. Unfortunately, the benefits of using photodynamic therapy for vulvar EMPD remains a challenge to demonstrate, because of the inhomogeneous illumination of vulvar and perianal areas, and the extreme pain that patients usually experienced during the illumination procedure that may lead to premature end of treatment [7, 8]. Resulting from the knowledge of previous works on actinic keratosis of the scalp treatment with PDT, light emitting fabrics (LEF) technology could address both of the hereinbefore described issues [9-12]. A new medical device based on LEF named PAGETEX dedicated to illumination of vulvar and perianal areas has been developed. The device delivers a homogeneous red light (635 nm) with a low irradiance during 2h30, for a total fluence of 12 J/cm<sup>2</sup>. The PAGETEX device is being assessed in a clinical study (NCT03713203) which aims to establish PAGETEX- PDT efficacy and tolerability.
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