Blood Flow Measurements Enable Optimization of Light Delivery for Personalized Photodynamic Therapy

Our plain-English summary of Blood Flow Measurements Enable Optimization of Light Delivery for Personalized Photodynamic Therapy, by Y.H. Ong, J. Miller, M. Yuan, et al (Cancers, 2020).

The study

• Authors: Y.H. Ong, J. Miller, M. Yuan, M. Chandra, M. El Khatib, S.A. Vinogradov, M.E. Putt, T.C. Zhu, K.A. Cengel, A.G. Yodh, T.M. Busch
• Journal: Cancers
• Published: 2020;12(6)
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Fluence rate is an effector of photodynamic therapy (PDT) outcome. Lower light fluence rates can conserve tumor perfusion during some illumination protocols for PDT, but then treatment times are proportionally longer to deliver equivalent fluence. Likewise, higher fluence rates can shorten treatment time but may compromise treatment efficacy by inducing blood flow stasis during illumination. We developed blood-flow-informed PDT (BFI-PDT) to balance these effects. BFI-PDT uses real-time noninvasive monitoring of tumor blood flow to inform selection of irradiance, i.e., incident fluence rate, on the treated surface. BFI-PDT thus aims to conserve tumor perfusion during PDT while minimizing treatment time. Pre-clinical studies in murine tumors of radiation-induced fibrosarcoma (RIF) and a mesothelioma cell line (AB12) show that BFI-PDT preserves tumor blood flow during illumination better than standard PDT with continuous light delivery at high irradiance. Compared to standard high irradiance PDT, BFI-PDT maintains better tumor oxygenation during illumination and increases direct tumor cell kill in a manner consistent with known oxygen dependencies in PDT-mediated cytotoxicity. BFI-PDT promotes vascular shutdown after PDT, thereby depriving remaining tumor cells of oxygen and nutrients. Collectively, these benefits of BFI-PDT produce a significantly better therapeutic outcome than standard high irradiance PDT. Moreover, BFI-PDT requires ~40% less time on average to achieve outcomes that are modestly better than those with standard low irradiance treatment. This contribution introduces BFI-PDT as a platform for personalized light delivery in PDT, documents the design of a clinically-relevant instrument, and establishes the benefits of BFI-PDT with respect to treatment outcome and duration.

In plain English

This was a laboratory study in mice, not of asbestos exposure or people. The authors tested a way of giving photodynamic therapy (light plus the drug Photofrin). A monitor tracked tumor blood flow, and the light was turned down or paused when flow fell quickly. They used two mouse tumor models: radiation-induced fibrosarcoma (RIF) and mouse mesothelioma (AB12). Each scheme was given to 10 to 12 mice. In RIF tumors, faster drops in blood flow during treatment were associated with faster regrowth. Compared with continuous high-intensity light, the blood-flow-guided schemes kept tumors better oxygenated, killed more tumor cells and delayed regrowth. In RIF tumors, median time to regrow to 400 cubic millimeters was 29 days with the guided-intensity scheme versus 11.0 days with high-intensity light. In AB12 tumors, complete response (no tumor at 90 days) occurred in 100% with the guided-intensity scheme (95% confidence interval 69 to 100%), 89% with continuous low-intensity light (52 to 100%) and 33% with continuous high-intensity light (7 to 71%). The authors concluded it gave results similar to low-intensity treatment in much less time.

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: Animal experiment (preclinical treatment study in mice) comparing three standard and two blood-flow-informed photodynamic therapy light-delivery schemes
• Who was studied: Mice with RIF tumors (C3H mice) or AB12 mouse mesothelioma tumors (BALB/c mice). Each illumination scheme was given to 10 to 12 mice. Groups of 6 to 7 mice were used for cell-survival assays and 5 mice for oxygen measurements. Work was done at the University of Pennsylvania.
• Exposure: No asbestos exposure was studied. The exposure was photodynamic therapy. Photofrin (5 mg/kg) was injected 20 to 24 hours before 630-nm laser light was given to a total of 135 J/cm2, either at 150 mW/cm2 (high irradiance), at 25 mW/cm2 (low irradiance), or switched between levels (including light-off) according to real-time blood-flow monitoring by diffuse correlation spectroscopy.
• Main results:
  • In RIF tumors given standard treatment, the median flow reduction rate was 9.3 %rBF per minute with continuous 25 mW/cm2 light. This was significantly smaller than 23 with continuous 150 mW/cm2 (p less than 0.001) and 25 with fractionated 150 mW/cm2 (p = 0.0016).
  • In RIF tumors given standard treatment, a Cox model found that the instantaneous 'risk' of regrowth to 400 mm3 rose by a factor of 2.1 (95% confidence interval 1.6, 2.7) per 10% increase in flow reduction rate.
  • In RIF tumors, median treatment length with blood-flow-informed irradiance (BFI-Irrad) was 53 min, about 59% of the 90 min needed for continuous 25 mW/cm2.
  • In RIF tumors, continuous 150 mW/cm2 did not reduce the number of surviving clonogenic tumor cells compared with controls (1.16 versus 1.06, in units of 10 to the 8th cells per gram). BFI-Irrad reduced it to 0.18 and BFI-Frac to 0.13, in the same units (p less than 0.001 for each).
  • In RIF tumors, mean tumor oxygen (baseline 32.8 mmHg) fell to 13.3 mmHg after continuous 150 mW/cm2. It fell only to 26.7 mmHg after BFI-Irrad and 25.5 mmHg after BFI-Frac.
  • In RIF tumors, median time to regrow to 400 mm3 was 11.0 days with continuous 150 mW/cm2, 19.6 days with continuous 25 mW/cm2 and 18 days with standard fractionated light. No animal given continuous 150 mW/cm2 had a complete response.
  • In RIF tumors, BFI-Irrad gave a median time to 400 mm3 of 29 days (p = 0.006 versus continuous 150 mW/cm2), and 40% (95% CI 12 to 74.5%) had a complete response. BFI-Frac gave 39 days, with 56% (95% CI 18 to 91%) complete response. Neither differed from continuous 25 mW/cm2 (p = 0.88 and p = 0.45).
  • Standard fractionated 150 mW/cm2 light caused high levels of edema, and 25% (95% CI 5 to 57%) of these RIF mice died within several days. With BFI-Frac, 10% (95% CI 0 to 45%) had a non-acute death more than 1 week after treatment.
  • In AB12 mouse mesothelioma tumors, complete response (defined as no tumor burden at 90 days after treatment) occurred in 33% (95% CI 7 to 71%) with continuous 150 mW/cm2, 89% (95% CI 52 to 100%) with continuous 25 mW/cm2 and 100% (95% CI 69 to 100%) with BFI-Irrad. Median survival time was 20 days for 150 mW/cm2 and exceeded 90 days for the other two. Survival did not differ significantly between 25 mW/cm2 and BFI-Irrad (p = 0.29).
• The authors' conclusion: The authors concluded that, in two mouse tumor models, blood-flow-informed irradiance gave a significantly better outcome than continuous high-irradiance treatment. They also concluded that it gave a response similar to low-irradiance treatment in a much shorter time.
• Limitations the authors state:
  • The authors stated that the blood-flow-informed fractionated scheme (BFI-Frac) does not appear practical clinically. A maximum treatment length cannot be set in advance, and treatment may not be completed if blood flow stays low.
  • The blood-flow measurement method is prone to motion artifacts from sudden movements. The authors smoothed the data to avoid false triggers.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma.

Related studies

• Measurement of blood flow and vascular permeability changes in response to 12-O-tetradecanoyl-phorbol-13-acetate and to asbestos fibers — J.A. Hamilton, P. Vadas, et al. (1981)
• Response of Photofrin-sensitised mesothelioma xenografts to photodynamic therapy with 514 nm light — T.H. Foster, S.L. Gibson, et al. (1996)
• 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)
• Surgical Inflammation Alters Immune Response to Intraoperative Photodynamic Therapy — R.W. Davis, A. Klampatsa, et al. (2023)
• A Novel Prospective Study Assessing the Combination of Photodynamic Therapy and Proton Radiation Therapy: Safety and Outcomes When Treating Malignant Pleural Mesothelioma — S.R. Rice, Y.R. Li, et al. (2019)

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