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Influence of Target Location, Size, and Patient Age on Normal Tissue Sparing- Proton and Photon Therapy in Paediatric Brain Tumour Patient-Specific Approach.

ABSTRACT: BACKGROUND:Proton radiotherapy produces superior dose distributions compared to photon radiotherapy, reducing side effects. Differences between the two modalities are not fully quantified in paediatric patients for various intracranial tumour sites or age. Understanding these differences may help clinicians estimate the benefit and improve referral across available centres. Our aim was to compare intensity-modulated proton therapy (IMPT) and intensity-modulated photon radiotherapy (IMRT) radiation doses for select paediatric intracranial tumours. METHODS:IMPT and IMRT dose distributions for gender-matched paediatric cranial CT-datasets (ages 5, 9 and 13 years) were retrospectively calculated to simulate irradiation of supratentorial (ependymoma) and infratentorial (medulloblastoma) target volumes diameters (1-3 cm) and position (central and 1-2 cm shifts). RESULTS:Clinical dosimetric objectives were achieved for all 216 treatment plans. Whilst infratentorial IMPT plans achieved greater maximum dose sparing to optic structures (4.8-12.6 Gy optic chiasm), brainstem sparing was limited (~0.5 Gy). Mean dose difference for optic chiasm was associated with medulloblastoma target position (p < 0.0197). Supratentorial IMPT plans demonstrated greater dose reduction for the youngest patients (pituitary gland p < 0.001). CONCLUSIONS:Normal tissue sparing was achieved regardless of patient age for infratentorial tumours. However, for supratentorial tumours, there was a dosimetric advantage of IMPT across 9 vs. 13-year-old patients.

SUBMITTER: Dell'Oro M

PROVIDER: S-EPMC7563785 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Influence of Target Location, Size, and Patient Age on Normal Tissue Sparing- Proton and Photon Therapy in Paediatric Brain Tumour Patient-Specific Approach.

Dell'Oro Mikaela M Short Michala M Wilson Puthenparampil P Hua Chia-Ho CH Gargone Melissa M Merchant Thomas E TE Bezak Eva E

Cancers 20200910 9

<h4>Background</h4>Proton radiotherapy produces superior dose distributions compared to photon radiotherapy, reducing side effects. Differences between the two modalities are not fully quantified in paediatric patients for various intracranial tumour sites or age. Understanding these differences may help clinicians estimate the benefit and improve referral across available centres. Our aim was to compare intensity-modulated proton therapy (IMPT) and intensity-modulated photon radiotherapy (IMRT) ...[more]

PMID: 32927700

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Project description:Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RT with passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

Project description:Radiation-induced normal tissue toxicity often limits the curative treatment of cancer. Moreover, normal tissue relative biological effectiveness data for high-linear energy transfer particles are urgently needed. We propose a strategy based on transcriptome analysis of patient-derived human intestinal organoids (HIO) to determine molecular surrogates for radioresponse of gastrointestinal (GI) organs at risk in a personalized manner. HIO were generated from induced pluripotent stem cells (iPSC), which were derived from skin biopsies of three patients, including two patients with FANCA deficiency as a paradigm for enhanced radiosensitivity. For the two Fanconi anemia (FA) patients (HIO-104 and 106, previously published as FA-A#1 IND-iPS1 and FA-A#2 IND-iPS3), FANCA expression was reconstituted as a prerequisite for generation of HIO via lentiviral expression of a doxycycline inducible construct. For radiosensitivity analysis, FANCA deficient and FANCA rescued as well as wtHIO were sham treated or irradiated with 4Gy photon, proton or carbon ions at HIT, respectively. Immunofluorescence staining of HIO for 53BP1-foci was performed 1 h post IR and gene expression analyses was performed 12 and 48 h post IR. 53BP1-foci numbers and size correlated with the higher RBE of carbon ions. A FANCA dependent differential gene expression in response to radiation was found (p < 0.01, ANOVA; n = 1071 12 h; n = 1100 48 h). Pathways associated with FA and DNA-damage repair i.e., transcriptional coupled nucleotide excision repair, homology-directed repair and translational synthesis were found to be differentially regulated in FANCA deficient HIO. Next, differential regulated genes were investigated as a function of radiation quality (RQ, p < 0.05, ANOVA; n = 742 12 h; n = 553 48 h). Interestingly, a gradual increase or decrease of gene expression was found to correlate with the three main qualities, from photon to proton and carbon irradiation. Clustering separated high-linear energy transfer irradiation with carbons from proton and photon irradiation. Genes associated with dual incision steps of TC-NER were differentially regulated in photon vs. proton and carbon irradiation. Consequently, SUMO3, ALC1, POLE4, PCBP4, MUTYH expression correlated with the higher RBE of carbon ions. An interaction between the two studied parameters FA and RQ was identified (p < 0.01, 2-way ANOVA n = 476). A comparison of genes regulated as a function of FA, RQ and RBE suggest a role for p53 interacting genes BRD7, EWSR1, FBXO11, FBXW8, HMGB1, MAGED2, PCBP4, and RPS27 as modulators of FA in response to radiation. This proof of concept study demonstrates that patient tailored evaluation of GI response to radiation is feasible via generation of HIO and comparative transcriptome profiling. This methodology can now be further explored for a personalized assessment of GI radiosensitivity and RBE estimation.

Project description:BackgroundDespite their heterogeneity, the current standard preoperative radiotherapy regimen for localized high-grade soft tissue sarcoma (STS) follows a one fits all approach for all STS subtypes. Sarcoma patient-derived three-dimensional cell culture models represent an innovative tool to overcome challenges in clinical research enabling reproducible subtype-specific research on STS. In this pilot study, we present our methodology and preliminary results using STS patient-derived 3D cell cultures that were exposed to different doses of photon and proton radiation. Our aim was: (i) to establish a reproducible method for irradiation of STS patient-derived 3D cell cultures and (ii) to explore the differences in tumor cell viability of two different STS subtypes exposed to increasing doses of photon and proton radiation at different time points.MethodsTwo patient-derived cell cultures of untreated localized high-grade STS (an undifferentiated pleomorphic sarcoma (UPS) and a pleomorphic liposarcoma (PLS)) were exposed to a single fraction of photon or proton irradiation using doses of 0 Gy (sham irradiation), 2 Gy, 4 Gy, 8 Gy and 16 Gy. Cell viability was measured and compared to sham irradiation at two different time points (four and eight days after irradiation).ResultsThe proportion of viable tumor cells four days after photon irradiation for UPS vs. PLS were significantly different with 85% vs. 65% (4 Gy), 80% vs. 50% (8 Gy) and 70% vs. 35% (16 Gy). Proton irradiation led to similar diverging viability curves between UPS vs. PLS four days after irradiation with 90% vs. 75% (4 Gy), 85% vs. 45% (8 Gy) and 80% vs. 35% (16 Gy). Photon and proton radiation displayed only minor differences in cell-killing properties within each cell culture (UPS and PLS). The cell-killing effect of radiation sustained at eight days after irradiation in both cell cultures.ConclusionsPronounced differences in radiosensitivity are evident among UPS and PLS 3D patient-derived sarcoma cell cultures which may reflect the clinical heterogeneity. Photon and proton radiation showed similar dose-dependent cell-killing effectiveness in both 3D cell cultures. Patient-derived 3D STS cell cultures may represent a valuable tool to enable translational studies towards individualized subtype-specific radiotherapy in patients with STS.

Dataset Information

Influence of Target Location, Size, and Patient Age on Normal Tissue Sparing- Proton and Photon Therapy in Paediatric Brain Tumour Patient-Specific Approach.

Publications

Influence of Target Location, Size, and Patient Age on Normal Tissue Sparing- Proton and Photon Therapy in Paediatric Brain Tumour Patient-Specific Approach.

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