Intraoperative Photodynamic Therapy Research Articles

Long term follow-up of patients with newly diagnosed glioblastoma treated by intraoperative photodynamic therapy: an update from the INDYGO trial (NCT03048240).

Glioblastoma remains incurable despite optimal multimodal management. The interim analysis of open label, single arm INDYGO pilot trial showed actuarial 12-months progression-free survival (PFS) of 60% (median 17.1months), actuarial 12-months overall survival (OS) of 80% (median 23.1months). We report updated, exploratory analyses of OS, PFS, and health-related quality of life (HRQOL) for patients receiving intraoperative photodynamic therapy (PDT) with 5-aminolevulinic acid hydrochloride (5-ALA HCl). Ten patients were included (May 2017 - April 2021) for standardized therapeutic approach including 5-ALA HCl fluorescence-guided surgery (FGS), followed by intraoperative PDT with a single 200J/cm2 dose of light. Postoperatively, patients received adjuvant therapy (Stupp protocol) then followed every 3months (clinical and cerebral MRI) and until disease progression and/or death. Procedure safety and toxicity occurring during the first four weeks after PDT were assessed. Data concerning relapse, HRQOL and survival were prospectively collected and analyzed. At the cut-off date (i.e., November 1st 2023), median follow-up was 23months (9,7-71,4). No unacceptable or unexpected toxicities and no treatment-related deaths occurred during the study. Kaplan-Meier estimated 23.4months median OS, actuarial 12-month PFS rate 60%, actuarial 12-month, 24-month, and 5-year OS rates 80%, 50% and 40%, respectively. Four patients were still alive (1 patient free of recurrence). At 5years-follow-up, intraoperative PDT with surgical maximal excision as initial therapy and standard adjuvant treatment suggests an increase of time to recurrence and overall survival in a high proportion of patients. Quality of life was maintained without any severe side effects. NCT03048240. EudraCT number: 2016-002706-39.

Dynamics of saliva cytokine levels during intraoperative photodynamic therapy in patients with locally advanced oral cancer

Dynamics of saliva cytokine levels during intraoperative photodynamic therapy in patients with locally advanced oral cancer

Association of 5-aminolevulinic acid fluorescence guided resection with photodynamic therapy in recurrent glioblastoma: a matched cohort study.

Glioblastoma is a malignant and aggressive brain tumour that, although there have been improvements in the first line treatment, there is still no consensus regarding the best standard of care (SOC) upon its inevitable recurrence. There are novel adjuvant therapies that aim to improve local disease control. Nowadays, the association of intraoperative photodynamic therapy (PDT) immediately after a 5-aminolevulinic acid (5-ALA) fluorescence-guided resection (FGR) in malignant gliomas surgery has emerged as a potential and feasible strategy to increase the extent of safe resection and destroy residual tumour in the surgical cavity borders, respectively. To assess the survival rates and safety of the association of intraoperative PDT with 5-ALA FGR, in comparison with a 5-ALA FGR alone, in patients with recurrent glioblastoma. This article describes a matched-pair cohort study with two groups of patients submitted to 5-ALA FGR for recurrent glioblastoma. Group 1 was a prospective series of 11 consecutive cases submitted to 5-ALA FGR plus intraoperative PDT; group 2 was a historical series of 11 consecutive cases submitted to 5-ALA FGR alone. Age, sex, Karnofsky performance scale (KPS), 5-ALA post-resection status, T1-contrast-enhanced extent of resection (EOR), previous and post pathology, IDH (Isocitrate dehydrogenase), Ki67, previous and post treatment, brain magnetic resonance imaging (MRI) controls and surgical complications were documented. The Mantel-Cox test showed a significant difference between the survival rates (p = 0.008) of both groups. 4 postoperative complications occurred (36.6%) in each group. As of the last follow-up (January 2024), 7/11 patients in group 1, and 0/11 patients in group 2 were still alive. 6- and 12-months post-treatment, a survival proportion of 71,59% and 57,27% is expected in group 1, versus 45,45% and 9,09% in group 2, respectively. 6months post-treatment, a progression free survival (PFS) of 61,36% and 18,18% is expected in group 1 and group 2, respectively. The association of PDT immediately after 5-ALA FGR for recurrent malignant glioma seems to be associated with better survival without additional or severe morbidity. Despite the need for larger, randomized series, the proposed treatment is a feasible and safe addition to the reoperation.

Achievements and prospects for further development of photodynamic therapy technology in the treatment of cerebral tumors

Literature review reflects the current status and development status of intraoperative photodynamic therapy in neurooncology and discusses the results of the most important studies on photodynamic therapy (PDT). We searched the Pubmed, EMBASE, Cochrane Library and eLibrary databases for publications published between January 2000 and December 2022. Found 204 publications in foreign sources and 59 publications in domestic editions, dealing with the issues of photodynamic therapy in neurooncology. An analysis of the literature has shown that intraoperative PDT in neurooncology is an important tool that contributes to increasing the radicality of the operation and local control. The basic rationale for the effectiveness of PDT lies in the study of the pathways leading to the complete devitalization of a malignant tumor, the study of the mechanisms of the local and systemic immune response. In addition, subcellular targets in PDT are determined by the properties of photosensitizers (PS). Second generation PSs have already been introduced into clinical practice. The effectiveness of PDT using photoditazine, 5-aminolevulinic acid has been demonstrated. The mechanisms of action and targets of these PS have been established. In Russia, a number of studies have repeatedly shown and proved the clinical effectiveness of PDT in groups of neurooncological patients with glial tumors and secondary metastatic tumors, but so far, the method has not been included in the clinical guidelines for the provision of high-tech neurosurgical care. There is certainly a need for further development of PTD techniques in neurooncology, especially in patients at high risk of recurrence and aggressive CNS tumors.

Simulating photodynamic therapy for the treatment of glioblastoma using Monte Carlo radiative transport.

Glioblastoma (GBM) is a rare but deadly form of brain tumor with a low median survival rate of 14.6 months, due to its resistance to treatment. An independent simulation of the INtraoperative photoDYnamic therapy for GliOblastoma (INDYGO) trial, a clinical trial aiming to treat the GBM resection cavity with photodynamic therapy (PDT) via a laser coupled balloon device, is demonstrated. To develop a framework providing increased understanding for the PDT treatment, its parameters, and their impact on the clinical outcome. We use Monte Carlo radiative transport techniques within a computational brain model containing a GBM to simulate light path and PDT effects. Treatment parameters (laser power, photosensitizer concentration, and irradiation time) are considered, as well as PDT's impact on brain tissue temperature. The simulation suggests that 39% of post-resection GBM cells are killed at the end of treatment when using the standard INDYGO trial protocol (light fluence = at balloon wall) and assuming an initial photosensitizer concentration of . Increases in treatment time and light power (light fluence = at balloon wall) result in further cell kill but increase brain cell temperature, which potentially affects treatment safety. Increasing the p hotosensitizer concentration produces the most significant increase in cell kill, with 61% of GBM cells killed when doubling concentration to and keeping the treatment time and power the same. According to these simulations, the standard trial protocol is reasonably well optimized with improvements in cell kill difficult to achieve without potentially dangerous increases in temperature. To improve treatment outcome, focus should be placed on improving the photosensitizer. With further development and optimization, the simulation could have potential clinical benefit and be used to help plan and optimize intraoperative PDT treatment for GBM.

Novel Iron-Chelating Prodrug Significantly Enhanced Fluorescence-Mediated Detection of Glioma Cells Experimentally In Vitro.

(1) Background: The protoporphyrin IX (PpIX)-mediated fluorescence-guided resection and interoperative photodynamic therapy (PDT) of remaining cells may be effective adjuvants to the resection of glioma. Both processes may be enhanced by increasing intracellular PpIX concentrations, which can be achieved through iron chelation. AP2-18 is a novel combinational drug, which ester-links a PpIX precursor (aminolaevulinic acid; ALA) to an iron-chelating agent (CP94). (2) Methods: Human glioma U-87 MG cells were cultured in 96-well plates for 24 h and incubated for 3 or 6 h with various test compound combinations: ALA (±) CP94, methyl aminolevulinate (MAL) (±) CP94 and AP2-18. PpIX fluorescence was measured at 0, 3 or 6 h with a Bio-tek Synergy HT plate reader, as well as immediately after irradiation with a 635 nm red light (Aktilite CL16 LED array), representing the PDT procedure. Cell viability post-irradiation was assessed using the neutral red assay. (3) Results: AP2-18 significantly increased PpIX fluorescence compared to all other test compounds. All treatment protocols effectively achieved PDT-induced cytotoxicity, with no significant difference between test compound combinations. (4) Conclusions: AP2-18 has potential to improve the efficacy of fluorescence-guided resection either with or without the subsequent intraoperative PDT of glioma. Future work should feature a more complex in vitro model of the glioma microenvironment.

Outcomes after intraoperative photodynamic therapy in the combined treatment of locally advanced colon cancer

Purpose. To study outcomes after the combined treatment of locally advanced colon cancer with intraoperative photodynamic therapy. Materials and methods. 35 patients with locally advanced colon cancer were included in the trial. Patients from the main group (n = 17) had intraoperative photodynamic therapy in combination with elective surgery. Patients from the control group (n = 18) had only surgical treatment. For photodynamic therapy, photosensitizer Photolon and “Lakhta-Milon” diode laser with wavelength 662 nm and power up to 2.5 W were used. Laser light was delivered via a quartz polymer fiber with diameter 600 microns. Results and discussion. Better positive immediate and long-term outcomes were registered in patients with locally advanced colon cancer from the main group, if to compare with the control group (length of hospital stay, number of remissions, relapses and mortality). Conclusion: Intraoperative photodynamic therapy improves outcomes after the combined treatment of patients with locally advanced colon cancer.

Photodynamic therapy in neurooncology

Literature review reflects the current status and development status of intraoperative photodynamic therapy in neurooncology and discusses the results of the most important studies on photodynamic therapy (PDT). We searched the Pubmed, EMBASE, Cochrane Library and eLibrary data-bases for publications published between January 2000 and December 2022. Found 204 publications in foreign sources and 59 publications in domestic editions, dealing with the issues of photodynamic therapy in neurooncology. An analysis of the literature has shown that intraoperative PDT in neurooncology is an important tool that contributes to increasing the radicality of the operation and local control. The basic rationale for the effectiveness of PDT lies in the study of the pathways leading to the complete devitalization of a malignant tumor, the study of the mechanisms of the local and systemic immune response. In addition, subcellular targets in PDT are determined by the properties of photosensitizers (PS). Second generation PSs have already been introduced into clinical practice. The effectiveness of PDT using photoditazine, 5-aminolevulinic acid has been demonstrated. The mechanisms of action and targets of these PS have been established. In Russia, a number of studies have repeatedly shown and proved the clinical effectiveness of PDT in groups of neurooncological patients with glial tumors and secondary metastatic tumors, but so far, the method has not been included in the clinical guidelines for the provision of high-tech neurosurgical care. There is certainly a need for further development of PTD techniques in neurooncology, especially in patients at high risk of recurrence and aggressive CNS tumors.

Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy.

Although mesothelioma is difficult to treat, we have shown that combining surgery with a form of radiation, photodynamic therapy, may help people with mesothelioma live longer. In this study, we demonstrate in mice that this regimen could be further improved by addressing the inflammation induced as a by-product of surgery.

Photosensitizers for Photodynamic Therapy of Brain Cancers-A Review.

On average, there are about 300,000 new cases of brain cancer each year. Studies have shown that brain and central nervous system tumors are among the top ten causes of death. Due to the extent of this problem and the percentage of patients suffering from brain tumors, innovative therapeutic treatment methods are constantly being sought. One such innovative therapeutic method is photodynamic therapy (PDT). Photodynamic therapy is an alternative and unique technique widely used in dermatology and other fields of medicine for the treatment of oncological and nononcological lesions. Photodynamic therapy consists of the destruction of cancer cells and inducing inflammatory changes by using laser light of a specific wavelength in combination with the application of a photosensitizer. The most commonly used photosensitizers include 5-aminolevulinic acid for the enzymatic generation of protoporphyrin IX, Temoporfin-THPC, Photofrin, Hypericin and Talaporfin. This paper reviews the photosensitizers commonly used in photodynamic therapy for brain tumors. An overview of all three generations of photosensitizers is presented. Along with an indication of the limitations of the treatment of brain tumors, intraoperative photodynamic therapy and its possibilities are described as an alternative therapeutic method.

Intraoperative photodynamic therapy in the combined treatment of soft tissue sarcoma

Soft tissue sarcoma is a rare malignant neoplasm. Despite the improvement of surgical techniques, the rate of relapses of the disease remains high. The search for alternative methods of treatment is relevant.Purpose. To evaluate safety and effectiveness of intraoperative photodynamic therapy of sarcoma in soft tissues.Material and methods. Forty-four patients with soft tissue sarcoma were included in the study. Patients were divided into three groups. Group 1 (n = 10): soft tissue sarcoma of stage T2-3N0M0G1, surgical treatment and intraoperative photodynamic therapy. Group 2 (n = 17): soft tissue sarcoma of stage T2-3N0M0G2-3, surgical treatment and intraoperative photodynamic therapy. Group 3 (n = 17): soft tissue sarcoma of stage T2-3N0M0-1G2-3, combined treatment – preoperative light therapy, surgical treatment, intraoperative photodynamic therapy, neoadjuvant and adjuvant chemotherapy. Fluorescence spectrometry was performed to determine the degree of photosensitizer accumulation in tumor tissue. Treatment methodology: photosensitizer was injected 2.5–3 hours before the surgery. The tumor was removed with resection of adjacent muscles and healthy tissues. Then, laser irradiation of the tumor bed was made using “Latus” device. Radiation power was up to 2,5 W, power density was up to 0,28 W/cm2, radiation dose was up to 100 J/cm2. Follow-up ranged from 14 to 44 months.Results. The spectrometry has revealed that photosensitizer was accumulated predominantly in tumor tissue. There were no reactions to photosensitizer injection, no changes in the tumor bed as well as no increase in wound healing period after intraoperative photodynamic therapy.Within the observation period, all patients stayed alive. Relapses of the disease were registered in 38.7 % of patients: in Group 1 – 30 %, in Group 2 – 35.3 %, in Group 3 – 53 %. Of the 20 patients with primary diagnosed neoplasms, relapses were seen in 30 %. Of the 24 patients with previously recurrent neoplasms, 45.8 % had repeated relapses.Conclusion. Intraoperative photodynamic therapy is a safe and effective technique for treating soft tissue sarcomas; it is also the promising direction for research. A small number of observations, a variety of histological forms and stages of the disease make it difficult to assess the effectiveness of the discussed approach. Further studies of intraoperative photodynamic therapy are required.

The Impact of Surgically Induced Inflammation on Outcomes Following Intraoperative Photodynamic Therapy in Patients with Thoracic Malignancies

The Impact of Surgically Induced Inflammation on Outcomes Following Intraoperative Photodynamic Therapy in Patients with Thoracic Malignancies

First Clinical Report of the Intraoperative Macro- and Micro-Photodiagnosis and Photodynamic Therapy Using Talaporfin Sodium for a Patient with Disseminated Lumbar Medulloblastoma.

Photodiagnosis (PD) and photodynamic therapy (PDT) using the second-generation photosensitizer talaporfin sodium together with an exciting laser for primary intracranial malignant tumors is well recognized in Japan, and many medical institutions are introducing this new therapeutic option. In particular, intraoperative PDT using talaporfin sodium for infiltrating tumor cells in the cavity walls after the resection of malignant glioma is now covered by health insurance after receiving governmental approvement, and this method has been recommended in therapeutic guidelines for primary malignant brain tumors in Japan. On the other hand, experimental and clinical studies on the development of novel therapeutic strategies for malignant spinal cord tumors have not been reported to date, although their histological features are almost identical to those of intracranial malignant tumors. Therefore, the clinical outcomes of malignant spinal cord tumors have been less favorable than those of malignant brain tumors. In this report, we performed the PD and PDT using talaporfin sodium on a patient with a metastatic lumbar lesion that was detected on magnetic resonance image (MRI) 50 months after the resection of cerebellar medulloblastoma who presented with lumbago and sciatica. We were able to detect the target lesion in the conus medullaris using a surgical microscope, and detected the disseminated medulloblastoma cells floating in the cerebrospinal fluid using a compact fluorescence microscope. Furthermore, we performed PDT to the resected lumbar lesion with the adjuvant platinum-based chemotherapy, and the patient survived a meaningful life for more than 2 years after the lumbar surgery. This report describes the first case of a human patient in whom the efficacy of PD and PDT was demonstrated for a malignant spinal cord tumor.

Intraoperative photodynamic therapy in complex treatment of malignant gliomas

To demonstrate the possibilities of chlorin e6-mediated photodynamic therapy for malignant glial tumors. There were 161 patients with malignant supratentorial glial tumors who were treated at the Polenov Russian Neurosurgery Institute between 2009 and 2016. Eighty patients comprised the main group (photodynamic therapy), 81 ones - control group (without photodynamic therapy). Photodynamic therapy in complex treatment of malignant brain gliomas significantly increases overall survival in patients with Grade III gliomas up to 39.1±5.5 months (control group - 22.8±3.3 months) and Grade IV gliomas up to 20.7±4.7 months (control group - 13.5±2.3 months) (p=0.0002). This method also increases relapse-free period in patients with Grade III gliomas up to 21.7±3.4 months (control group - 15.8±3.1 months) (p=0.0002) and Grade IV gliomas up to 11.1±2.1 months (control group - 8.0±2.3 months) (p=0.0001).

Use of intraoperative photodynamic therapy in the treatment of recurrent locally advanced scalp basal cell carcinoma

Use of intraoperative photodynamic therapy in the treatment of recurrent locally advanced scalp basal cell carcinoma

Results of using intraoperative photodynamic therapy for locally advanced head and neck skin cancer

Results of using intraoperative photodynamic therapy for locally advanced head and neck skin cancer

Definitive surgery and intraoperative photodynamic therapy for locally advanced non-small cell lung cancer: a case report

BackgroundThere are no guidelines for straightforwardly managing advanced lung cancer (T3 or T4). Although surgery has traditionally been regarded as the mainstay treatment and the only curative modality, it has limited relevance for patients with locally advanced non-small cell lung cancer (NSCLC). Photodynamic therapy (PDT) is a clinically approved cancer therapy; it is an established treatment modality with curative intent for early-stage and superficial endobronchial lesions. However, the efficacy of PDT in advanced lung cancer is controversial, and it has primarily been used in palliative care.Case presentationThis case report describes a 70-year-old male who had right upper lung cancer and an endobronchial lesion that extended into the distal trachea. A biopsy specimen was obtained upon bronchoscopy, and the result confirmed squamous cell carcinoma. We performed a definitive sleeve lobectomy and intraoperative PDT. Gross total resection of the tumor was achieved, but the presence of microscopic residual tumors was inevitable. Complete anatomical resection of the primary tumor by pneumonectomy was not possible due to poor lung function and endobronchial extension to the distal trachea. We decided to apply intraoperative PDT to the lumen and outer wall of the bronchi and distal trachea for local tumor control. The patient is alive with no evidence of disease after 13 months of follow-up.ConclusionsThis is the first report to describe the feasibility and efficacy of intraoperative PDT as part of multimodal therapy for locally advanced NSCLC.

Application of intraoperative photodynamic therapy in patients suspected of recurrence post radical surgery: A single center experience

BackgroundDifficult to resect tumors may be treated with a combination of radical surgery and photodynamic therapy to try to reduce recurrence. The aim of this single center study is to present results from a combined application of radical surgery with intraoperative PDT for patients with various cancers suspected of high risk for post-operative local recurrence. MethodsRadical surgery combined with intraoperative PDT was performed in each and every patient under study at different time points from June 2020 to July 2021, and the PDT irradiation time ranged from 10, 20, 25 and 30 min. Hematoporphyrin, as a photo synthesizer, was administered intravenously 48 h before surgery and during the operative period respectively, at a 3 mg/kg dose. In addition, the mean and median survival times for each of these patients were also evaluated. Patient's overall disease-Free Survival (DFS) and survival (OS) were immensely evaluated. Results12 patients (33.3% female and 66.7 % male) underwent radical surgery and PDT simultaneously. No photosensitivity events were reported in the included patients, except for one case with a moderate to severe erythema. Intraoperative PDT was tolerated in all included patients without serious liver and kidney damages. As from the time these patients underwent radical surgery and PDT, three mortalities were recorded and the remaining 9 patients had some remarkable outcomes with less or no recurrences. ConclusionsIntraoperative PDT is a potentially safe therapeutic strategy for various tumor patients who undergo operation. Intraoperative PDT combined with surgery may improve local tumor control but this needs to be tested in a larger patient population.

The Cost-Effectiveness Evaluation of the Intraoperative Additional Photodynamic Therapy for the Treatment of Newly Diagnosed Glioblastoma

The Cost-Effectiveness Evaluation of the Intraoperative Additional Photodynamic Therapy for the Treatment of Newly Diagnosed Glioblastoma

Theranostic PSMA ligands with optimized backbones for intraoperative multimodal imaging and photodynamic therapy of prostate cancer

IntroductionThe first generation ligands for prostate-specific membrane antigen (PSMA)–targeted radio- and fluorescence-guided surgery followed by adjuvant photodynamic therapy (PDT) have already shown the potential of this approach. Here, we developed three new photosensitizer-based dual-labeled PSMA ligands by crucial modification of existing PSMA ligand backbone structures (PSMA-1007/PSMA-617) for multimodal imaging and targeted PDT of PCa.MethodsVarious new PSMA ligands were synthesized using solid-phase chemistry and provided with a DOTA chelator for 111In labeling and the fluorophore/photosensitizer IRDye700DX. The performance of three new dual-labeled ligands was compared with a previously published first-generation ligand (PSMA-N064) and a control ligand with an incomplete PSMA-binding motif. PSMA specificity, affinity, and PDT efficacy of these ligands were determined in LS174T-PSMA cells and control LS174T wildtype cells. Tumor targeting properties were evaluated in BALB/c nude mice with subcutaneous LS174T-PSMA and LS174T wildtype tumors using µSPECT/CT imaging, fluorescence imaging, and biodistribution studies after dissection.ResultsIn order to synthesize the new dual-labeled ligands, we modified the PSMA peptide linker by substitution of a glutamic acid into a lysine residue, providing a handle for conjugation of multiple functional moieties. Ligand optimization showed that the new backbone structure leads to high-affinity PSMA ligands (all IC50 < 50 nM). Moreover, ligand-mediated PDT led to a PSMA-specific decrease in cell viability in vitro (P < 0.001). Linker modification significantly improved tumor targeting compared to the previously developed PSMA-N064 ligand (≥ 20 ± 3%ID/g vs 14 ± 2%ID/g, P < 0.01) and enabled specific visualization of PMSA-positive tumors using both radionuclide and fluorescence imaging in mice.ConclusionThe new high-affinity dual-labeled PSMA-targeting ligands with optimized backbone compositions showed increased tumor targeting and enabled multimodal image-guided PCa surgery combined with targeted photodynamic therapy.