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Wenna Zhang,1– 3 Xin Cai,1– 3 Jiayao Sun,2– 4 Weiwei Wang,2– 4 Jingfang Zhao,2– 4 Qing Zhang,1– 3 Guoliang Jiang,1– 3,5 Zheng Wang1– 3,5 1Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Radiation Oncology (20dz2261000), Shanghai, People’s Republic of China; 3Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, People’s Republic of China; 4Department of Medical Physics, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of China; 5Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, People’s Republic of ChinaCorrespondence: Guoliang Jiang; Zheng Wang, Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, No. 4365 Kangxin Road, Pudong, Shanghai, 201315, People’s Republic of China, Email guoliang.jiang@sphic.org.cn; zheng.wang@sphic.org.cnPurpose: Carbon ion radiotherapy (CIRT) has emerged as a promising treatment modality for hepatocellular carcinoma (HCC). However, evidence of using the pencil beam scanning (PBS) technique to treat moving liver tumors remains lacking. The present study investigated the efficacy and toxicity of PBS CIRT in patients with HCC.Methods: Between January 2016 and October 2021, 90 consecutive HCC patients treated with definitive CIRT in our center were retrospectively analyzed. Fifty-eight patients received relative biological effectiveness-weighted doses of 50– 70 Gy in 10 fractions, and 32 received 60– 67.5 Gy in 15 fractions, which were determined by the tumor location and normal tissue constraints. Active motion-management techniques and necessary strategies were adopted to mitigate interplay effects efficiently. Oncologic outcomes and toxicities were evaluated.Results: The median follow-up time was 28.6 months (range 5.7– 74.6 months). The objective response rate was 75.0% for all 90 patients with 100 treated lesions. The overall survival rates at 1-, 2- and 3-years were 97.8%, 83.3% and 75.4%, respectively. The local control rates at 1-, 2- and 3-years were 96.4%, 96.4% and 93.1%, respectively. Radiation-induced liver disease was not documented, and 4 patients (4.4%) had their Child–Pugh score elevated by 1 point after CIRT. No grade 3 or higher acute non-hematological toxicities were observed. Six patients (6.7%) experienced grade 3 or higher late toxicities.Conclusion: The active scanning technique was clinically feasible to treat HCC by applying necessary mitigation measures for interplay effects. The desirable oncologic outcomes as well as favorable toxicity profiles presented in this study will be a valuable reference for other carbon-ion centers using the PBS technique and local effect model-based system, and add to a growing body of evidence about the role of CIRT in the management of HCC.Keywords: hepatocellular carcinoma, carbon ion radiotherapy, pencil beam scanning, local effect model

Abstract Background Gadolinium-based nanoparticles (GdNPs) are clinically used agents to increase the radiosensitivity of tumor cells. However, studies on the mechanisms and biological modeling of GdNP radio-enhancement are still preliminary. This study aims to investigate the mechanism of radio-enhancement of GdNPs for kilovoltage photons using Monte Carlo (MC) simulations, and to establish local effect model (LEM)-based biological model of GdNP radiosensitization. Methods The spectrum and yield of secondary electrons and dose enhancement around a single GdNP and clustered GdNPs were calculated in a water cube phantom by MC track-structure simulations using TOPAS code. We constructed a partial shell-like cell geometry model of pancreatic cancer cell based on transmission electron microscope (TEM) observations. LEM-based biological modeling of GdNP radiosensitization was established based on the MC-calculated nano-scale dose distributions in the cell model to predict the cell surviving fractions after irradiation. Results The yield of secondary electrons for GdNP was 0.16% of the yield for gold nanoparticle (GNP), whereas the average electron energy was 12% higher. The majority of the dose enhancement came from the contribution of Auger electrons. GdNP clusters had a larger range and extent of dose enhancement than single GdNPs, although GdNP clustering reduced radial dose per interacting photon significantly. For the dose range between 0 and 8 Gy, the surviving fraction predicted using LEM-based biological model laid within one standard deviation of the published experimental results, and the deviations between them were all within 25%. Conclusions The mechanism of radio-enhancement of GdNPs for kilovoltage photons was investigated using MC simulations. The prediction results of the established LEM-based biological model for GdNP radiosensitization showed good agreement with published experimental results, although the deviation of simulation parameters can lead to large disparity in the results. To our knowledge, this was the first LEM-based biological model for GdNP radiosensitization.

Background: Gadolinium-based nanoparticles (GdNPs) are clinically used agents to increase the radiosensitivity of tumor cells. However, studies on the mechanisms and biological modeling of GdNP radio-enhancement are still preliminary. This study aims to investigate the mechanism of radio-enhancement of GdNPs for kilovoltage photons using Monte Carlo (MC) simulations, and to establish local effect model (LEM)-based biological model of GdNP radiosensitization. Methods: The spectrum and yield of secondary electrons and dose enhancement around a single GdNP and clustered GdNPs were calculated in a water cube phantom by MC track-structure simulations using TOPAS code. We constructed a partial shell-like cell geometry model of pancreatic cancer cell based on transmission electron microscope (TEM) observations. LEM-based biological modeling of GdNP radiosensitization was established based on the MC-calculated nano-scale dose distributions in the cell model to predict the cell surviving fractions after irradiation. Results: The yield of secondary electrons for GdNP was 0.16% of the yield for gold nanoparticle (GNP), whereas the average electron energy was 12% higher. The majority of the dose enhancement came from the contribution of Auger electrons. GdNP clusters had a larger range and extent of dose enhancement than single GdNPs, although GdNP clustering reduced radial dose per interacting photon significantly. For the dose range between 0 and 8 Gy, the surviving fraction predicted using LEM-based biological model laid within one standard deviation of the published experimental results, and the deviations between them were all within 25%. Conclusions: The mechanism of radio-enhancement of GdNPs for kilovoltage photons was investigated using MC simulations. The prediction results of the established LEM-based biological model for GdNP radiosensitization showed good agreement with published experimental results, although the deviation of simulation parameters can lead to large disparity in the results. To our knowledge, this was the first LEM-based biological model for GdNP radiosensitization. [ABSTRACT FROM AUTHOR]

Active targeting gold nanoparticles (AuNPs) are a very promising avenue for cancer treatment with many publications on AuNP mediated radiosensitization at kilovoltage (kV) photon energies. However, uncertainty on the effectiveness of AuNPs under clinically relevant megavoltage (MV) radiation energies hinders the clinical translation of AuNP-assisted radiation therapy (RT) paradigm. The aim of this study was to investigate radiosensitization mediated by PSMA-targeted AuNPs irradiated by a 6 MV radiation beam at different depths to explore feasibility of AuNP-assisted prostate cancer RT under clinically relevant conditions. PSMA-targeted AuNPs (PSMA-AuNPs) were synthesized by conjugating PSMA antibodies onto PEGylated AuNPs through EDC/NHS chemistry. Confocal fluorescence microscopy was used to verify the active targeting of the developed PSMA-AuNPs. Transmission electron microscopy (TEM) was used to demonstrate the intracellular biodistribution of PSMA-AuNPs. LNCaP prostate cancer cells treated with PSMA-AuNPs were irradiated on a Varian 6 MV LINAC under varying depths (2.5 cm, 10 cm, 20 cm, 30 cm) of solid water. Clonogenic assays were carried out to determine the in vitro cell survival fractions. A Monte Carlo (MC) model developed on TOPAS platform was then employed to determine the nano-scale radial dose distribution around AuNPs, which was subsequently used to predict the radiation dose response of LNCaP cells treated with AuNPs. Two different cell models, with AuNPs located within the whole cell or only in the cytoplasm, were used to assess how the intracellular PSMA-AuNP biodistribution impacts the prostate cancer radiosensitization. Then, MC-based microdosimetry was combined with the local effect model (LEM) to calculate cell survival fraction, which was benchmarked against the in vitro clonogenic assays at different depths. In vitro clonogenic assay of LNCaP cells demonstrated the depth dependence of AuNP radiosensitization under clinical megavoltage beams, with sensitization enhancement ratio (SER) of 1.14 ± 0.03 and 1.55 ± 0.05 at 2.5 cm depth and 30 cm depth, respectively. The MC microdosimetry model showed the elevated percent of low-energy photons in the MV beams at greater depth, consequently resulting in increased dose enhancement ratio (DER) of AuNPs with depth. The AuNP-induced DER reached ~5.7 and ~8.1 at depths of 2.5 cm and 30 cm, respectively. Microdosimetry based LEM accurately predicted the cell survival under 6 MV beams at different depths, for the cell model with AuNPs placed only in the cell cytoplasm. TEM results demonstrated the distribution of PSMA-AuNPs in the cytoplasm, confirming the accuracy of MC microdosimetry based LEM with modelled AuNPs distributed within the cytoplasm. We conclude that AuNP radiosensitization can be achieved under megavoltage clinical radiotherapy energies with a dependence on tumor depth. Furthermore, the combination of Monte Carlo microdosimetry and LEM will be a valuable tool to assist with developing AuNP-aided radiotherapy paradigm and drive clinical translation. [ABSTRACT FROM AUTHOR]

Purpose: As local recurrence remains a challenge and the advantages of the simultaneous integrated boost (SIB) technique have been validated in photon radiotherapy, we applied the SIB technique to CIRT. The aim was to investigate the metabolomic changes of the CIRT with concurrent androgen deprivation therapy (ADT) in localized prostate cancer (PCa) and the unique metabolic effect of the SIB technique. Material and methods: This study enrolled 24 pathologically confirmed PCa patients. All patients went through CIRT with concurrent ADT. The gross target volume (GTV) boost was defined as positive lesions on both 68Ga-PSMA PET/CT and mpMRI images. Urine samples collected before and after CIRT were analyzed by the Q-TOF UPLC-MS/MS system. R platform and MetDNA were used for peak detection and identification. Statistical analysis and metabolic pathway analysis were performed on Metaboanalyst. Results: The metabolite profiles were significantly altered after CIRT. The most significantly altered metabolic pathway is PSMA participated alanine, aspartate and glutamate metabolism. Metabolites in this pathway showed a trend to be better suppressed in the SIB group. A total of 11 identified metabolites were significantly discriminative between two groups and all of them were better down-regulated in the SIB group. Meanwhile, among these metabolites, three metabolites in DNA damage and repair related purine metabolism were down-regulated to a greater extent in the SIB group. Conclusion: Metabolic dysfunction was one of the typical characteristics of PCa. CIRT with ADT showed a powerful inhibition of PCa metabolism, especially in PSMA participated metabolic pathway. The SIB CIRT showed even better performance on down-regulation of most metabolism than uniform-dose-distribution CIRT. Meanwhile, the SIB CIRT also showed its unique superiority to inhibit purine metabolism. PSMA PET/CT guided SIB CIRT showed its potentials to further benefit PCa patients. [ABSTRACT FROM AUTHOR]

BackgroundWe aimed at determining the safety and feasibility of spot-scanning carbon ion radiotherapy (CIRT) for patients with localized prostate cancer.MethodsWe enrolled 118 patients with localized prostate cancer who underwent treatment with spot-scanning CIRT at the Shanghai Proton and Heavy Ion Center (SPHIC) from January 2016 to December 2020. The dose was gradually increased from relative biological effectiveness (RBE)-weighted dose (DRBE) = 59.2–65.6 Gy in 16 fractions. The primary endpoint was the occurrence of acute and late toxicities, while the secondary endpoints were biochemical relapse-free survival (bRFS), distant metastasis-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS).ResultsThe median follow-up time was 30.2 months (4.8–62.7 months). Acute grade 1 and 2 genitourinary (GU) toxicities were 15.3% and 18.6%, while acute grade 1 and 2 gastrointestinal (GI) toxicities were 2.5% and 0%, respectively. Late grade 1 and 2 GU toxicities were 4.2% and 1.7%, respectively. No late GI toxicity was observed. Moreover, there were no cases of severe acute or late toxicity (≥ grade 3). No significant association were observed between the factors and the acute GU toxicities, except for clinical target volume (CTV) (p = 0.031) on multivariate analysis. The 2-year bRFS, DMFS, PCSS, and OS were 100%, 100%, 100%, and 98.8%, respectively.ConclusionThe 2-year outcomes were encouraging, providing additional and useful information on the feasibility and safety of spot-scanning CIRT for treating prostate cancer. Thus, we recommend long-term follow-up and prospective multicentered studies to reinforce the role of CIRT in the management of localized prostate cancer.

Background: We aimed at determining the safety and feasibility of spot-scanning carbon ion radiotherapy (CIRT) for patients with localized prostate cancer. Methods: We enrolled 118 patients with localized prostate cancer who underwent treatment with spot-scanning CIRT at the Shanghai Proton and Heavy Ion Center (SPHIC) from January 2016 to December 2020. The dose was gradually increased from relative biological effectiveness (RBE)-weighted dose (DRBE) = 59.2–65.6 Gy in 16 fractions. The primary endpoint was the occurrence of acute and late toxicities, while the secondary endpoints were biochemical relapse-free survival (bRFS), distant metastasis-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Results: The median follow-up time was 30.2 months (4.8–62.7 months). Acute grade 1 and 2 genitourinary (GU) toxicities were 15.3% and 18.6%, while acute grade 1 and 2 gastrointestinal (GI) toxicities were 2.5% and 0%, respectively. Late grade 1 and 2 GU toxicities were 4.2% and 1.7%, respectively. No late GI toxicity was observed. Moreover, there were no cases of severe acute or late toxicity (≥ grade 3). No significant association were observed between the factors and the acute GU toxicities, except for clinical target volume (CTV) (p = 0.031) on multivariate analysis. The 2-year bRFS, DMFS, PCSS, and OS were 100%, 100%, 100%, and 98.8%, respectively. Conclusion: The 2-year outcomes were encouraging, providing additional and useful information on the feasibility and safety of spot-scanning CIRT for treating prostate cancer. Thus, we recommend long-term follow-up and prospective multicentered studies to reinforce the role of CIRT in the management of localized prostate cancer. [ABSTRACT FROM AUTHOR]