Predicting Severity of Radiation Induced Lymphopenia in Individual Proton Therapy Patients for Varying Dose Rate and Fractionation Using Dynamic 4-Dimensional Blood Flow Simulations

McCullum, Lucas; Shin, Jungwook; Xing, Stella; Beekman, Chris; Schuemann, Jan; Hong, Theodore S.; Duda, Dan G.; Mohan, Radhe; Lin, Steven H.; Correa-Alfonso, Camilo M; Domal, Sean; Withrow, Julia; Bolch, Wesley E.; Paganetti, Harald; Grassberger, Clemens

doi:10.1016/j.ijrobp.2023.01.054

Cited by 10 publications

(3 citation statements)

References 36 publications

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“…The results of this study demonstrate that lymphocyte‐sparing radiotherapy in PBS‐PBT can minimize the risk of severe radiation‐induced lymphopenia and enhance outcomes, particularly in maintenance immunotherapy. However, McCullum et al 8 . observed that among patients with hepatocellular carcinoma (HCC), those with highly sensitive lymphocytes benefited the most from decreasing dose rates, whereas those with slow lymphocyte recovery benefited the most from shorter fractionation regimens.…”

Section: The Effects Of Prt On the Immune Systemmentioning

confidence: 99%

Clinical application of high‐LET radiotherapy combined with immunotherapy in malignant tumors

Meng,

2024

Precision Radiation Oncology

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The superior physical and biological properties of high linear energy transfer (LET), as opposed to traditional low‐LET rays, underscore the advantage of proton therapy (PRT) and carbon ion radiotherapy (CIRT) are better than traditional photon radiotherapy (XRT). With the advancements in science, an increasing number of hospitals have introduced new technologies. However, radiotherapy is primarily used for local treatment, which means that if the tumor has metastasized to distant sites, it is often necessary to combine it with systemic therapies such as immunotherapy. In recent years, the combination of high‐LET radiotherapy and immunotherapy has emerged as a promising treatment option in oncology and many studies have confirmed its efficacy for both local and distant metastases. In this review, we summarize the effects of PRT and CIRT on the immune system in detail, followed by an introduction to preclinical and clinical studies of PRT and CIRT in combination with immune checkpoint inhibitor (ICIs) therapy. We also briefly introduce some preclinical studies on CIRT in combination with dendritic cells (DCs) and Treg inhibitor therapies.

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Section: The Effects Of Prt On the Immune Systemmentioning

confidence: 99%

Clinical application of high‐LET radiotherapy combined with immunotherapy in malignant tumors

Meng,

2024

Precision Radiation Oncology

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“…Similarly, for hepatocellular carcinoma the dose to circulating lymphocytes was estimated using a dynamic blood circulation model ( 23 ) and combined with the observed lymphocyte depletion in patients, empirically accounting for both cell death and lymphocyte replenishment. The in vivo derived patient-specific α had a median value of 0.58 Gy -1 (range 0.28 - 1.23 Gy -1 ) ( 109 ).…”

Section: Radiosensitivity Of Lymphocytesmentioning

confidence: 99%

A review on lymphocyte radiosensitivity and its impact on radiotherapy

Paganetti

2023

Front. Oncol.

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It is well known that radiation therapy causes lymphopenia in patients and that this is correlated with a negative outcome. The mechanism is not well understood because radiation can have both immunostimulatory and immunosuppressive effects. How tumor dose conformation, dose fractionation, and selective lymph node irradiation in radiation therapy does affect lymphopenia and immune response is an active area of research. In addition, understanding the impact of radiation on the immune system is important for the design and interpretation of clinical trials combining radiation with immune checkpoint inhibitors, both in terms of radiation dose and treatment schedules. Although only a few percent of the total lymphocyte population are circulating, it has been speculated that their increased radiosensitivity may contribute to, or even be the primary cause of, lymphopenia. This review summarizes published data on lymphocyte radiosensitivity based on human, small animal, and in vitro studies. The data indicate differences in radiosensitivity among lymphocyte subpopulations that affect their relative contribution and thus the dynamics of the immune response. In general, B cells appear to be more radiosensitive than T cells and NK cells appear to be the most resistant. However, the reported dose-response data suggest that in the context of lymphopenia in patients, aspects other than cell death must also be considered. Not only absolute lymphocyte counts, but also lymphocyte diversity and activity are likely to be affected by radiation. Taken together, the reviewed data suggest that it is unlikely that radiation-induced cell death in lymphocytes is the sole factor in radiation-induced lymphopenia.

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“…Specifically, radiation-induced lymphopenia (RIL), the depletion of the absolute number of circulating lymphocytes in the peripheral blood, has often been correlated with poor overall survival (Venkatesulu et al 2018, Damen et al 2021). While the precise mechanism causing this depletion remains elusive, it is often assumed that direct cell kill of circulating lymphocytes in the blood is a main contributor (Ellsworth et al 2022, McCullum et al 2023. This has led to the notion of blood as a dynamic organ at risk (OAR) in the context of RIL (Ladbury et al 2019).…”

Section: Introductionmentioning

confidence: 99%

A stochastic model of blood flow to calculate blood dose during radiotherapy

Beekman,

Withrow,

Correa Alfonso

et al. 2023

Phys. Med. Biol.

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Purpose: Lymphopenia is a common side effect in patients treated with radiotherapy, potentially caused by direct cell killing of circulating lymphocytes in the blood. To investigate this hypothesis, a method to assess dose to circulating lymphocytes is needed. Methods: A stochastic model to simulate systemic blood flow in the human body was developed based on a previously designed compartment model. Blood dose was obtained by superimposing the spatiotemporal distribution of blood particles with a time-varying dose rate field, and used as a surrogate for dose to circulating lymphocytes. We discuss relevant theory on compartmental modeling and how to combine it with models of explicit organ vasculature. Results: A general workflow was established which can be used for any anatomical site. Stochastic compartments can be replaced by explicit models of organ vasculatures for improved spatial resolution, and tumor compartments can be dynamically assigned. Generating a patient-specific blood flow distribution takes about one minute, fast enough to investigate the effect of varying treatment parameters such as the dose rate. Furthermore, the anatomical structures contributing most to the overall blood dose can be identified, which could potentially be used for lymphocyte-sparing treatment planning. Conclusion: The ability to report the blood dose distribution during radiotherapy is imperative to test and act upon the current paradigm that radiation-induced lymphopenia is caused by direct cell killing of lymphocytes in the blood. We have built a general model that can do so for various treatment sites. The presented framework is publicly available at https://github.com/mghro/hedos.

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Predicting Severity of Radiation Induced Lymphopenia in Individual Proton Therapy Patients for Varying Dose Rate and Fractionation Using Dynamic 4-Dimensional Blood Flow Simulations

Cited by 10 publications

References 36 publications

Clinical application of high‐LET radiotherapy combined with immunotherapy in malignant tumors

Clinical application of high‐LET radiotherapy combined with immunotherapy in malignant tumors

A review on lymphocyte radiosensitivity and its impact on radiotherapy

A stochastic model of blood flow to calculate blood dose during radiotherapy

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