A Comprehensive Study of Reactive Oxygen Species Explicit Dosimetry for Pleural Photodynamic Therapy

Our plain-English summary of A Comprehensive Study of Reactive Oxygen Species Explicit Dosimetry for Pleural Photodynamic Therapy, by H. Sun, Y. Ong, M.M. Kim, et al (Antioxidants, 2024).

The study

• Authors: H. Sun, Y. Ong, M.M. Kim, A. Dimofte, S. Singhal, K.A. Cengel, A.G. Yodh, T.C. Zhu
• Journal: Antioxidants
• Published: 2024;13(12)
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Photodynamic therapy (PDT) relies on the interactions between light, photosensitizers, and tissue oxygen to produce cytotoxic reactive oxygen species (ROS), primarily singlet oxygen (1O2) through Type II photochemical reactions, along with superoxide anion radicals (O2•-), hydrogen peroxide (H2O2), and hydroxyl radicals (•OH) through Type I mechanisms. Accurate dosimetry, accounting for all three components, is crucial for predicting and optimizing PDT outcomes. Conventional dosimetry tracks only light fluence rate and photosensitizer concentration, neglecting the role of tissue oxygenation. Reactive oxygen species explicit dosimetry (ROSED) quantifies the reacted oxygen species concentration ([ROS]rx) by explicit measurements of light fluence (rate), photosensitizer concentration, and tissue oxygen concentration. Here we determine tissue oxygenation from non-invasive diffuse correlation spectroscopy (DCS) measurement of tumor blood flow using a conversion factor established preclinically. In this study, we have enrolled 24 pleural PDT patients into the study. Of these patients, we are able to obtain data on 20. Explicit dosimetry of light fluence, Photofrin concentration, and tissue oxygenation concentrations were integrated into the ROSED model to calculate [ROS]rx across multiple sites inside the pleural cavity and among different patients. Large inter- and intra-patient heterogeneities in [ROS]rx were observed, despite identical 60 J/cm2 light doses, with mean [ROS]rx,meas of 0.56 ± 0.26 mM for 13 patients with 21 sites, and [ROS]rx,calc1 of 0.48 ± 0.23 mM for 20 patients with 76 sites. This study presented the first comprehensive analysis of clinical ROSED in pleural mesothelioma patients, providing valuable data on future ROSED based pleural PDT that can potentially produce uniform ROS and thus improve the PDT efficacy for Photofrin-mediated pleural PDT.

In plain English

This study was part of an ongoing phase II trial at the University of Pennsylvania. It measured dose during photodynamic therapy (PDT), a light-activated drug treatment given during surgery for epithelioid pleural mesothelioma. Patients received Photofrin before surgery. After the tumor was removed as far as possible, laser light was delivered until detectors at monitored sites recorded the prescribed 60 J/cm2. The authors combined light, drug and oxygen data (oxygen estimated from blood flow, or modelled) to calculate reacted oxygen species, mainly singlet oxygen, which they call [ROS]rx. Of 24 enrolled patients, data were obtained on 20. Where oxygen was measured (13 patients, 21 sites), mean [ROS]rx was 0.56 plus or minus 0.26 mM (range 0.31 to 1.17 mM). Photofrin levels varied up to 9.2-fold between patients. An estimate using an average oxygen correction differed from measured values by 16 plus or minus 41% on average. The authors concluded that [ROS]rx varied substantially despite the same prescribed light dose. They noted the oxygen estimate relied on one conversion factor from preclinical studies. The article does not study asbestos exposure.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Clinical dosimetry measurement study carried out within an ongoing (randomized) phase II trial of surgery with intraoperative Photofrin-mediated pleural photodynamic therapy. The authors measured light, drug concentration and tissue oxygen (derived from diffuse correlation spectroscopy of blood flow) and fed them into a mathematical model.
• Who was studied: Patients with pathologically confirmed epithelioid malignant pleural mesothelioma treated with pleural PDT at the University of Pennsylvania. 24 were enrolled and data were obtained on 20. Measured oxygen data were available for 13 patients at 21 sites. The article does not give study dates.
• Exposure: The study did not examine asbestos exposure. The 'exposure' was the treatment. Patients received intravenous Photofrin at 2 mg/kg about 24 hours before PDT. After surgical tumor debulking to the maximal extent possible (extrapleural pneumonectomy or pleurectomy/decortication), 630 nm laser light was delivered into the pleural cavity to a prescribed surface fluence of 60 J/cm2, as measured by detectors sutured at monitored sites.
• Main results:
  • Measured [ROS]rx (based on directly measured oxygen) in 13 patients at 21 sites: mean 0.56 plus or minus 0.26 mM.
  • Measured [ROS]rx across those sites ranged from 0.31 mM to 1.17 mM. The authors describe this as a 3.8-fold variation despite delivery of the same prescribed light dose.
  • The largest difference in [ROS]rx between sites within a single patient was 2.6-fold.
  • [ROS]rx estimated by method 1 (average oxygen correction factor), across 20 patients: mean 0.48 plus or minus 0.23. The results section does not print a unit; the abstract gives mM.
  • [ROS]rx estimated by method 2 (modelled oxygen), across 20 patients (76 sites): mean 0.72 plus or minus 0.20 mM.
  • Compared with measured [ROS]rx, the average percentage difference was 16 plus or minus 41% for method 1 and 44 plus or minus 66% for method 2.
  • Photofrin concentration varied up to 9.2-fold between patients and up to 3.4-fold within a patient.
  • Across all treatment sites, mean Photofrin concentration was 4.98 µM and mean PDT dose was 493.2 µMJ/cm2.
  • In the 13 cases, mean PDT dose was 551.0 plus or minus 188.4 µM·J/cm2 when calculated by the model and 597.8 plus or minus 190.1 µM·J/cm2 when measured.
  • Light tracking in a representative patient showed that, although the prescribed dose was reached at monitored sites, the overall light distribution suggested regions of both over- and under-dosing.
  • Tissue oxygen was generally low at the start of light delivery, which the authors attributed to blood-flow disruption from the preceding surgery. Oxygen rose when high light levels were applied and fell back when the light moved elsewhere.
• The authors' conclusion: The authors concluded that [ROS]rx varied substantially across measurement sites, up to 3.8-fold between patients and 2.6-fold within a patient's pleural cavity, even though all patients received the same prescribed 60 J/cm2 light dose. They saw this as a limitation of conventional light-based dosimetry. They also concluded that the simpler average-correction method may be a viable alternative when oxygen cannot be measured directly.
• Limitations the authors state:
  • Blood flow was converted to an oxygen estimate using a single scaling factor taken from earlier preclinical studies. This factor could vary between tumor types and populations.
  • The calculations relied on macroscopic models that assume certain parameters stay constant.
  • The findings are specific to Photofrin-mediated PDT for pleural mesothelioma.
  • Measurements of drug concentration inside the body carry large uncertainty.
  • The model used a standardized starting oxygen level rather than patient-specific values.
  • Oxygen could not always be measured, because surgical conditions sometimes prevented use of the blood-flow probe.

Topics

Medical terms in this study, explained in our Lexicon: Reactive Oxygen Species (ROS), Superoxide, Hydroxyl Radical, Pleural Cavity, Pleural Mesothelioma.

Related studies

• A Comparison of Singlet Oxygen Explicit Dosimetry (SOED) and Singlet Oxygen Luminescence Dosimetry (SOLD) for Photofrin-Mediated Photodynamic Therapy — M.M. Kim, R. Penjweini, et al. (2016)
• Real-time light dosimetry for intra-cavity photodynamic therapy: Application for pleural mesothelioma treatment — N. Betrouni, C. Munck, et al. (2017)
• Illumination profile characterization of a light device for the dosimetry of intra-pleural photodynamic therapy for mesothelioma — C. Munck, S. Mordon, et al. (2016)
• Pulmonary oxidative stress, inflammation and cancer: respirable particulate matter, fibrous dusts and ozone as major causes of lung carcinogenesis through reactive oxygen species mechanisms — A. Valavanidis, T. Vlachogianni, et al. (2013)
• Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles — A. Valavanidis, T. Vlachogianni, et al. (2009)
• Reactive oxygen species, chromosome mutation, and cancer: possible role of clastogenic factors in carcinogenesis — I. Emerit (1994)

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