FLASH with carbon ions: Tumor control, normal tissue sparing, and distal metastasis in a mouse osteosarcoma model

Tinganelli, Walter; Weber, Uli; Puspitasari, Anggraeini; Simoniello, Palma; Abdollahi, Amir; Oppermann, Julius; Schuy, Christoph; Horst, Felix; Helm, Alexander; Fournier, Claudia; Durante, Marco

doi:10.1016/j.radonc.2022.05.003

Cited by 45 publications

(36 citation statements)

References 43 publications

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“…Moreover, a recent work of Tinganelli et al. ( 84 ) indicated a decrease in lung metastasis following FLASH with carbon ions, further suggesting a different immune modulation in FLASH radiations, which achieves abscopal effect and needs to be addressed in future works.…”

Section: Discussionmentioning

confidence: 97%

Practice-oriented solutions integrating intraoperative electron irradiation and personalized proton therapy for recurrent or unresectable cancers: Proof of concept and potential for dual FLASH effect

Ayestaran¹,

Serrano²,

Cambeiro³

et al. 2022

Front. Oncol.

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BackgroundOligo-recurrent disease has a consolidated evidence of long-term surviving patients due to the use of intense local cancer therapy. The latter combines real-time surgical exploration/resection with high-energy electron beam single dose of irradiation. This results in a very precise radiation dose deposit, which is an essential element of contemporary multidisciplinary individualized oncology.MethodsPatient candidates to proton therapy were evaluated in Multidisciplinary Tumor Board to consider improved treatment options based on the institutional resources and expertise. Proton therapy was delivered by a synchrotron-based pencil beam scanning technology with energy levels from 70.2 to 228.7 MeV, whereas intraoperative electrons were generated in a miniaturized linear accelerator with dose rates ranging from 22 to 36 Gy/min (at Dmax) and energies from 6 to 12 MeV.ResultsIn a period of 24 months, 327 patients were treated with proton therapy: 218 were adults, 97 had recurrent cancer, and 54 required re-irradiation. The specific radiation modalities selected in five cases included an integral strategy to optimize the local disease management by the combination of surgery, intraoperative electron boost, and external pencil beam proton therapy as components of the radiotherapy management. Recurrent cancer was present in four cases (cervix, sarcoma, melanoma, and rectum), and one patient had a primary unresectable locally advanced pancreatic adenocarcinoma. In re-irradiated patients (cervix and rectum), a tentative radical total dose was achieved by integrating beams of electrons (ranging from 10- to 20-Gy single dose) and protons (30 to 54-Gy Relative Biological Effectiveness (RBE), in 10–25 fractions).ConclusionsIndividual case solution strategies combining intraoperative electron radiation therapy and proton therapy for patients with oligo-recurrent or unresectable localized cancer are feasible. The potential of this combination can be clinically explored with electron and proton FLASH beams.

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Section: Discussionmentioning

confidence: 97%

Practice-oriented solutions integrating intraoperative electron irradiation and personalized proton therapy for recurrent or unresectable cancers: Proof of concept and potential for dual FLASH effect

Ayestaran¹,

Serrano²,

Cambeiro³

et al. 2022

Front. Oncol.

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“…For instance, a recent study found UHDR irradiations to be more effective for hypoxic tumors compared to CONV irradiations 30 . Another recent study found UHDR carbon ion irradiations to be more effective in a murine osteosarcoma model 31 . Such a behavior may be an additional asset for FLASH RT, which is not considered in this work and the current version of the formalism.…”

Section: Discussionmentioning

confidence: 95%

The minimal FLASH sparing effect needed to compensate the increase of radiobiological damage due to hypofractionation for late‐reacting tissues

et al. 2022

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Purpose Normal tissue (NT) sparing by ultra‐high dose rate (UHDR) irradiations compared to conventional dose rate (CONV) irradiations while being isotoxic to the tumor has been termed “FLASH effect” and has been observed when large doses per fraction (d ≳ 5 Gy) have been delivered. Since hypofractionated treatment schedules are known to increase toxicities of late‐reacting tissues compared to normofractionated schedules for many clinical scenarios at CONV dose rates, we developed a formalism based on the biologically effective dose (BED) to assess the minimum magnitude of the FLASH effect needed to compensate the loss of late‐reacting NT sparing when reducing the number of fractions compared to a normofractionated CONV treatment schedule while remaining isoeffective to the tumor. Methods By requiring the same BED for the tumor, we derived the “break‐even NT sparing weighting factor” WBE for the linear‐quadratic (LQ) and LQ‐linear (LQ‐L) models for an NT region irradiated at a relative dose r (relative to the prescribed dose per fraction d to the tumor). WBE was evaluated numerically for multiple values of d and r, and for different tumor and NT α/β‐ratios. WBE was compared against currently available experimental data on the magnitude of the NT sparing provided by the FLASH effect for single fraction doses. Results For many clinically relevant scenarios, WBE decreases steeply initially for d > 2 Gy for late‐reacting tissues with (α/β)NT ≈ 3 Gy, implying that a significant NT sparing by the FLASH effect (between 15% and 30%) is required to counteract the increased radiobiological damage experienced by late‐reacting NT for hypofractionated treatments with d < 10 Gy compared to normofractionated treatments that are equieffective to the tumor. When using the LQ model with generic α/β‐ratios for tumor and late‐reacting NT of (α/β)T = 10 Gy and (α/β)NT = 3 Gy, respectively, most currently available experimental evidence about the magnitude of NT sparing by the FLASH effect suggests no net NT sparing benefit for hypofractionated FLASH radiotherapy (RT) in the high‐dose region when compared with WBE. Instead, clinical indications with more similar α/β‐ratios of the tumor and dose‐limiting NT toxicities [i.e., (α/β)T ≈ (α/β)NT], such as prostate treatments, are generally less penalized by hypofractionated treatments and need consequently smaller magnitudes of NT sparing by the FLASH effect to achieve a net benefit. For strongly hypofractionated treatments (>10–15 Gy/fraction), the LQ‐L model predicts, unlike the LQ model, a larger WBE suggesting a possible benefit of strongly hypofractionated FLASH RT, even for generic α/β‐ratios of (α/β)T = 10 Gy and (α/β)NT = 3 Gy. However, knowledge on the isoeffect scaling for high doses per fraction (≳10 Gy/fraction) and its modeling is currently limited and impedes accurate and reliable predictions for such strongly hypofractionated treatments. Conclusions We developed a formalism that quantifies the minimal NT sparing by the FLASH effect needed to compensate for hypofracti...

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“…A promising modification of C-ion therapy is ultra-high dose rate (FLASH) irradiation, which is expected to reduce radiotoxicity. Pilot experiments using a mouse model of osteosarcoma and human fibroblasts support this assumption [76,77].…”

Section: Carbon Ionsmentioning

confidence: 93%

“…In murine models of osteosarcoma, C-ions showed promising results in combination with immune checkpoint blockade treatment using anti-PD-1 and anti-CTLA-4 antibodies [75,100]. In addition, C-ions used in ultra-high dose rate (FLASH) mode significantly reduced lung metastasis compared to the conventional dose rate irradiation and sham-irradiated animals [77]. Neutron irradiation has been also tested in mice; for instance, Jing et al demonstrated the dose-dependent anti-tumor effect of fast neutron beams in a pre-clinical model of cervical cancer.…”

Section: Molecular Responses To Particle Therapymentioning

confidence: 99%

Particle Therapy: Clinical Applications and Biological Effects

Kiseleva

Гордон

Vishnyakova

et al. 2022

Life

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Particle therapy is a developing area of radiotherapy, mostly involving the use of protons, neutrons and carbon ions for cancer treatment. The reduction of side effects on healthy tissues in the peritumoral area is an important advantage of particle therapy. In this review, we analyze state-of-the-art particle therapy, as compared to conventional photon therapy, to identify clinical benefits and specify the mechanisms of action on tumor cells. Systematization of published data on particle therapy confirms its successful application in a wide range of cancers and reveals a variety of biological effects which manifest at the molecular level and produce the particle therapy-specific molecular signatures. Given the rapid progress in the field, the use of particle therapy holds great promise for the near future.

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FLASH with carbon ions: Tumor control, normal tissue sparing, and distal metastasis in a mouse osteosarcoma model

Cited by 45 publications

References 43 publications

Practice-oriented solutions integrating intraoperative electron irradiation and personalized proton therapy for recurrent or unresectable cancers: Proof of concept and potential for dual FLASH effect

Practice-oriented solutions integrating intraoperative electron irradiation and personalized proton therapy for recurrent or unresectable cancers: Proof of concept and potential for dual FLASH effect

The minimal FLASH sparing effect needed to compensate the increase of radiobiological damage due to hypofractionation for late‐reacting tissues

Particle Therapy: Clinical Applications and Biological Effects

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