Radiothérapie flash à très haut débit de dose : point sur les avancées récentes

In the last decade, major advances in high precision treatment delivery and multimodal imaging allowed radiotherapy to be more efficient and better tolerated. However, the technology of the accelerators used to generate X-ray beams is outdated and does not allow to explore the tolerance to novel approaches in terms of dose-rate. We have been the first to propose a completely novel modality of irradiation, named Flash radiotherapy, in which the dose per pulse and the instant dose-rate during the pulses is 10³ to 10⁴ higher than those used in conventional facilities. Flash has been shown to spare mouse lung from radio-induced fibrosis, whilst leaving unchanged the antitumor potential. Other teams have shown that the advantage of Flash in terms of reduced complications extends to normal brain and intestinal crypts. The goal of this paper is to review the progress of studies dealing with very high dose-rate “Flash” irradiation, describe the theoretical models proposed to explain the underlying mechanisms, and discuss the prospects for clinical applications of this emerging technique.     

A modelled comparison of prostate cancer control rates after high-dose-rate brachytherapy (3145 multicentre patients) combined with,or in contrast to,external-beam radiotherapy

Background and purpose

To analyse biochemical relapse-free-survival results for prostate cancer patients receiving combined external beam and high-dose-rate brachytherapy, in comparison with expected results using projections based on dose/fractionation/response parameter values deduced from a previous external-beam-alone 5969-patient multicentre dataset.

Material and methods

Results on a total of 3145 prostate cancer patients receiving brachytherapy (BT) as part or all of their treatment were collected from 10 institutions, and subjected to linear-quadratic (LQ) modelling of dose response and fractionation parameters.

Results

Treatments with BT components of less than 25 Gy, 3–4 BT fractions, doses per BT fraction up to 6 Gy, and treatment times of 3–7 weeks, all gave outcomes expected from LQ projections of the external-beam-alone data (α/β = 1.42 Gy). However, BT doses higher than 30 Gy, 1–2 fractions, 9 fractions (BT alone), doses per fraction of 9–15 Gy, and treatment in only 1 week (one example), gave local control levels lower than the expected levels by up to ∼35%.

Conclusions

There are various potential causes of the lower-than-projected control levels for some schedules of brachytherapy: it seems plausible that cold spots in the brachytherapy dose distribution may be contributory, and the applicability of the LQ model at high doses per fraction remains somewhat uncertain. The results of further trials may help elucidate the true benefit of hypofractionated high-dose-rate brachytherapy.     

Intracavitary Irradiation of Prostatic Carcinoma by a High Dose-Rate Afterloading Technique

A high dose-rate (⁶⁰Co) afterloading technique was evaluated in a series of 73 patients with prostatic carcinoma stages I-IV. The intraurethral irradiation was combined with external pelvic radiotherapy. A minimum total dose of 78 Gy was delivered to the target volume. in a subgroup of patients estramustine (Estracyt) was given as adjuvant chemohormonal therapy during irradiation. The median follow-up for the whole group was 63 months. The crude 5-year survival rate was 60% and the corrected survival rate 90%. Survival was related to the tumor grade. Local pelvic recurrences were recorded in 17.8%. 'Viable cells' in posttherapy aspiration biopsy were not associated with tumor recurrences or survival. Four patients (5%) had grade 3 late radiation reactions with urethral stricture or bladder fibrosis. Urinary tract infections and prior transurethral resections were not associated with a higher frequency of reactions. Concurrent estramustine therapy seemed to increase the frequency of both acute and chronic radiation reactions. Local control, recurrence, and survival were not affected by chemohormonal therapy. The use of tomography, magnetic resonance, and ultrasound as aids to computerized dosimetry may improve local dose distribution and reduce the irradiated volume.     

Acoustic Dose and Acoustic Dose-Rate

Acoustic dose is defined as the energy deposited by absorption of an acoustic wave per unit mass of the medium supporting the wave. Expressions for acoustic dose and acoustic dose-rate are given for plane-wave conditions, including temporal and frequency dependencies of energy deposition. The relationship between the acoustic dose-rate and the resulting temperature increase is explored, as is the relationship between acoustic dose-rate and radiation force. Energy transfer from the wave to the medium by means of acoustic cavitation is considered, and an approach is proposed in principle that could allow cavitation to be included within the proposed definitions of acoustic dose and acoustic dose-rate. (E-mail: f.duck@bath.ac.uk)     

The biological effect of pentoxifylline on the survival of human head and neck cancer cells treated with continuous low and high dose-rate irradiation

Aim The aim of this study was to compare the radiosensitivity effect of the G₂/M arrest-abrogating substance, pentoxifylline (PTX), with high dose-rate irradiation (HDRI) and low dose-rate irradiation (LDRI), during which DNA repair and cell proliferation occur.Methods Three squamous cell carcinoma cell lines, FaDu, RPMI 2650 and SCC-61, with differences in genomic imbalance and intrinsic radiosensitivity, were irradiated with 140 cGy/min (HDRI) and 0.7 cGy/min (LDRI) in the presence and absence of 2.0 mM PTX. The surviving fraction at 2.0 Gy (SF2) and cell-cycle phase distribution were assessed by DNA flow cytometry analysis and bromodeoxyuridine incorporation.Results With HDRI and LDRI the SF2 of FaDu cells decreased by 38.5% and 27.6%, respectively, while the corresponding figures for RPMI 2650 were 28.5% and 48.5%, and for SCC-61 were 44.2% and 28.6%. Increases in G₂ populations were evident after both HDRI and LDRI of all cell lines.Conclusions The enhancement in the cytotoxic effect of PTX was statistically significant after HDRI as well as after LDRI in all three cell lines. We therefore conclude that PTX in combination with LDRI is worth further study, both in vitro, for disclosing underlying mechanisms, and in vivo, to confirm the findings.This work was supported by grants from the King Gustav V Jubilee Clinical Cancer Research Foundation in Gothenburg, Sweden, and also by the Berit and Carl Johan Wettergrens Foundation for Cancer Research in Sweden.     

低剂量率电离辐射对淋巴细胞活存和超微结构的研究

本文报道⁶⁰Coγ线小剂量低剂率对狗血淋巴细胞的活存效立。实验结果表明:淋巴细胞活存效应与所用的剂量率呈负相关;淋巴细胞经小剂量低剂量率γ线辐照而引起的死亡,可能是因质膜受损和细胞溶解所致。这种现象在较低的剂量率较为明显。     

低剂量率γ线连续照射后造血损伤与恢复的长期观察

小鼠经低剂量率(70拉德/天)γ线连续照射25天后,造血干细胞和造血祖细胞数量大幅度减少。在连续观察的一年期间,虽然骨髓有核细胞数和晚红系祖细胞(CFU-E)很快恢复到了正常水平,但造血干细胞(CFU-S)、祖细胞(BFU-E、CFU-GM)却始终处于低下状态,其水平相当于向年龄正常动物的50～70%.骨髓造血微环境也同时受到不同程度的破坏,停止照射詹半年其CFU-F只恢复至正常的70%.这些结果表明,小鼠经低剂量率γ线连续照射后,造血组织中存在着潜在的损伤,它是产生一系列辐射远后效应的重要原因。     

Mechanisms of the elimination of low dose hyper-radiosensitivity in T-47D cells by low dose-rate priming

Purpose:?To investigate the mechanisms of elimination of low-dose hyper-radiosensitivity (HRS) in T-47D cells induced by 0.3?Gy low dose-rate (LDR) priming.

Materials and methods:?The mitotic ratio was measured using mitotic marker histone H3 phosphorylation in LDR primed as well as untreated T-47D cells. The HRS response in unprimed cells receiving medium which was irradiated after being harvested from unprimed cells was measured with or without serum present during cell conditioning. 4,6-benzylidene-D-glucose (BG) was used to inhibit protein synthesis during LDR priming.

Results:?LDR primed T-47D cells were HRS-deficient and showed a decrease in mitotic ratio with increasing dose while unprimed, i.e., HRS-competent T-47D cells, showed no decrease in mitotic ratio for doses in the HRS-range. HRS was eliminated in LDR primed cells, in cells receiving medium transfer from LDR primed cells, and in cells receiving LDR irradiated medium harvested from unprimed cells. The efficacy of the transferred medium depended on the presence of serum during cell conditioning. LDR priming eliminated HRS even in the presence of protein synthesis inhibitor BG.

Conclusions:?LDR priming of T-47D cells as well as LDR priming of medium conditioned on T-47D cells induce a factor in the medium which cause the early G₂-checkpoint to be activated in recipient cells by doses normally in the HRS dose-range.     

The involvement of serum serotonin levels producing radiation-induced bystander effects for an in vivo assay with fractionated high dose-rate (HDR) brachytherapy

Abstract

Purpose: The primary goal of this investigation was to observe whether measurable levels of bystander factor(s) can be detected in esophageal carcinoma patients’ urine samples taken after undergoing high dose rate (HDR) intraluminal brachytherapy (ILBT). However, a small pilot study was developed to evaluate whether serotonin [5-Hydroxytryptamine (5-HT)] serum levels play an active role in the mechanisms of radiation-induced bystander effects (RIBE) at high doses.

Materials and methods: In the present study, a colony-forming in vivo assay was developed and used for the detection of non-targeted effects. Samples of urine were collected from five esophageal carcinoma patients undergoing fractionated HDR-ILBT. To observe whether 5-HT modulates the bystander effect at higher doses, different batches of foetal bovine serum (FBS) and 5-HT were tested on the same urine samples before and after brachytherapy.

Results: Some of our data suggests statistically significant evidence for serotonin playing an active role as a signalling molecule at higher doses when patients underwent HDR-ILBT.

Conclusion: However, a more thorough investigation, with a larger sample size, is warranted before serotonin can be known to play a role in bystander effects at this particular dose range and treatment regime.