Meta-analysis of non-tumour doses for radiation-induced cancer on the basis of dose-rate

Purpose:?Quantitative analysis of cancer risk of ionising radiation as a function of dose-rate.

Materials and methods:?Non-tumour dose, D_nt, defined as the highest dose of radiation at which no statistically significant tumour increase was observed above the control level, was analysed as a function of dose-rate of radiation.

Results:?An inverse correlation was found between D_nt and dose-rate of the radiation. D_nt increased 20-fold with decreasing dose-rate from 1–10^?8 Gy/min for whole body irradiation with low linear energy transfer (LET) radiation. Partial body radiation also showed a dose-rate dependence with a 5- to 10-fold larger D_nt as dose rate decreased. The dose-rate effect was also found for high LET radiation but at 10-fold lower D_nt levels.

Conclusions:?The cancer risk of ionising radiation varies 1000-fold depending on the dose-rate of radiation and exposure conditions. This analysis explains the discrepancy of cancer risk between A-bomb survivors and radium dial painters.     

低剂量率辐射生物效应的研究进展

辐射的剂量率能显著影响放射治疗的生物效应，降低剂量率就降低了生物效应。然而。当剂量率降低到一定阈值以下，DNA损伤不能激活细胞的探测器——共济失调毛细血管扩张症突变（ATM）基因以及ATM基因介导的损伤修复途径，因而出现细胞高的致死性，即“反剂量率效应”。在持续低剂量率照射下，主要有两条修复途径参与双链断裂（DSB）的修复，即非同源末端连接（NHEJ）修复和同源重组（HR）修复。这些修复系统在亚致死性损伤和产生剂量率效应中起重要作用。如果损伤得以完整和精确的修复，细胞的辐射敏感性就会发生改变；如果损伤不能被修复。则会诱导细胞凋亡。p53基因在低剂量率辐射引起的细胞周期阻滞和诱导细胞凋亡过程中起关键作用。     

Irradiated homozygous TGF- β 1 knockout fibroblasts show enhanced clonogenic survival as compared with TGF- β 1 wild-type fibroblasts

Purpose : To study the role of transforming growth factor β 1 (TGF- β 1) on cellular radiation sensitivity by analysing mouse lung fibroblasts of different TGF- β 1 genotypes. Materials and methods : Heterozygous TGF- β 1 knock-out mice were mated to produce offspring of different TGF- β 1 genotypes as confirmed by PCR-genotyping. Primary lung fibroblast populations were established from new-born animals of specific genotypes (TGF- β 1 +/+, TGF- β 1 +/-, TGF- β 1 -/-) . Production of TGF- β 1 was tested by ELISA. TGF- β 1 receptor-II mRNA expression was analysed by RT-PCR. Colony formation of untreated, TGF- β 1-treated and/or irradiated primary lung fibroblasts was determined under different medium conditions. Results : Plating efficiencies under different medium conditions were independent of TGF- β 1 genotype. Production of TGF- β 1 correlated with the genotype: heterozygous TGF- β 1 knock-out fibroblasts (TGF- β 1 +/-) produced 60-65% of wild-type (TGF- β 1 +/+ cells). As expected, homozygous TGF- β 1 knock-out fibroblasts (TGF- β 1 -/-) did not produce TGF- β 1. Radiation exposure significantly enhanced TGF- β 1 production in TGF- β 1 +/+ cells by a factor of 2. No such stimulation was observed in TGF- β 1 +/- cells. TGF- β 1 +/- and especially TGF- β 1 -/- cells were significantly more radioresistant than TGF- β 1 +/+ cells. TGF- β 1 treatment significantly reduced clonogenic survival for both TGF- β 1 +/+ and TGF- β 1 -/- cells. TGF- β 1 treatment of TGF- β 1 -/- cells resulted in an enhancement of radiation sensitivity. Conclusion : The data are the first direct evidence that TGF- β 1 is a major autocrine regulator of intrinsic radiation sensitivity of mouse lung fibroblasts.     

A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens

Quantitative methods for estimation of cancer risk have been developed for daily, lifetime human exposures. There are a variety of studies or methodologies available to address less-than-lifetime exposures. However, a common framework for evaluating risk from less-than-lifetime exposures (including short-term and/or intermittent exposures) does not exist, which could result in inconsistencies in risk assessment practice. To address this risk assessment need, a committee of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute conducted a multisector workshop in late 2009 to discuss available literature, different methodologies, and a proposed framework. The proposed framework provides a decision tree and guidance for cancer risk assessments for less-than-lifetime exposures based on current knowledge of mode of action and dose-response. Available data from rodent studies and epidemiological studies involving less-than-lifetime exposures are considered, in addition to statistical approaches described in the literature for evaluating the impact of changing the dose rate and exposure duration for exposure to carcinogens. The decision tree also provides for scenarios in which an assumption of potential carcinogenicity is appropriate (e.g., based on structural alerts or genotoxicity data), but bioassay or other data are lacking from which a chemical-specific cancer potency can be determined. This paper presents an overview of the rationale for the workshop, reviews historical background, describes the proposed framework for assessing less-than-lifetime exposures to potential human carcinogens, and suggests next steps.     

MRI-based low dose-rate brachytherapy experience in locally advanced cervical cancer patients initially treated by concomitant chemoradiotherapy

Purpose

To retrospectively assess the physics contributions and the clinical outcome with preliminary 3D MRI-guided low dose-rate (LDR) intracavitary brachytherapy (BT) experience in locally advanced cervical cancer patients.

Patients and methods

Eighty-four patients with primary locally advanced cervical carcinoma were analyzed. The median tumoral cervical volume was 48.0 cc (range 1-468 cc). Twenty-four patients (53%) had histological and/or radiological pelvic involvement. After pelvic ± paraaortic concomitant chemoradiation, a LDR BT boost was delivered to a 3D MRI-based clinical target volume taking into account dose volume constraints for critical organs and optimization of target volume coverage.

Results

With a median follow-up of 53 months (range 31-79 months), the 4-year overall survival and disease-free survival rates were 57 (95%CI, 43-69) and 52% (95%CI, 40-64), respectively. Adding EBRT and LDR using EQD2 model, the median D₁₀₀ and D₉₀ for the IR-CTV were 56.5 Gy_α/β10 (range 37-83 Gy_α/β10) and 69 Gy_α/β10 (range 52-113 Gy_α/β10), respectively. For HR-CTV, the median D₁₀₀ and D₉₀ were 67 Gy_α/β10 (range 47-119 Gy_α/β10) and 79 Gy_α/β10 (range 53-122 Gy_α/β10), respectively. Thirty-nine late complications were observed in 28 patients (33.3%): 13 bladder, 7 rectal, 5 small bowel, 4 urethral, 3 colic, 2 vaginal, 1 pelvic fibrosis, and 4 others. Four grade 3 delayed complications were observed and no grade 4 complication occurred.

Conclusions

Applying an individual treatment planning with 3D MRI-guided LDR brachytherapy appears to be feasible and efficient for patients with locally advanced cervical cancer in routine clinical practice.     

Risk of solid cancer in low dose-rate radiation epidemiological studies and the dose-rate effectiveness factor

Abstract

Purpose: Estimated radiation risks used for radiation protection purposes have been based primarily on the Life Span Study (LSS) of atomic bomb survivors who received brief exposures at high dose rates, many with high doses. Information is needed regarding radiation risks from low dose-rate (LDR) exposures to low linear-energy-transfer (low-LET) radiation. We conducted a meta-analysis of LDR epidemiologic studies that provide dose-response estimates of total solid cancer risk in adulthood in comparison to corresponding LSS risks, in order to estimate a dose rate effectiveness factor (DREF).

Materials and methods: We identified 22 LDR studies with dose-response risk estimates for solid cancer after minimizing information overlap. For each study, a parallel risk estimate was derived from the LSS risk model using matching values for sex, mean ages at first exposure and attained age, targeted cancer types, and accounting for type of dosimetric assessment. For each LDR study, a ratio of the excess relative risk per Gy (ERR Gy^?1) to the matching LSS ERR risk estimate (LDR/LSS) was calculated, and a meta-analysis of the risk ratios was conducted. The reciprocal of the resultant risk ratio provided an estimate of the DREF.

Results: The meta-analysis showed a LDR/LSS risk ratio of 0.36 (95% confidence interval [CI] 0.14, 0.57) for the 19 studies of solid cancer mortality and 0.33 (95% CI 0.13, 0.54) when three cohorts with only incidence data also were added, implying a DREF with values around 3, but statistically compatible with 2. However, the analyses were highly dominated by the Mayak worker study. When the Mayak study was excluded the LDR/LSS risk ratios increased: 1.12 (95% CI 0.40, 1.84) for mortality and 0.54 (95% CI 0.09, 0.99) for mortality?+?incidence, implying a lower DREF in the range of 1–2. Meta-analyses that included only cohorts in which the mean dose was <100 mGy yielded a risk ratio of 1.06 (95% CI 0.30, 1.83) for solid cancer mortality and 0.58 (95% CI 0.10, 1.06) for mortality?+?incidence data.

Conclusions: The interpretation of a best estimate for a value of the DREF depends on the appropriateness of including the Mayak study. This study indicates a range of uncertainty in the value of DREF between 1 and about 2 after protracted radiation exposure. The LDR data provide direct evidence regarding risk from exposures at low dose rates as an important complement to the LSS risk estimates used for radiation protection purposes.     

Diminished or inversed dose-rate effect on clonogenic ability in Ku-deficient rodent cells

The biological effects of ionizing radiation, especially those of sparsely ionizing radiations like X-ray and γ-ray, are generally reduced as the dose rate is reduced. This phenomenon is known as ‘the dose-rate effect’. The dose-rate effect is considered to be due to the repair of DNA damage during irradiation but the precise mechanisms for the dose-rate effect remain to be clarified. Ku70, Ku86 and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are thought to comprise the sensor for DNA double-strand break (DSB) repair through non-homologous end joining (NHEJ). In this study, we measured the clonogenic ability of Ku70-, Ku86- or DNA-PKcs-deficient rodent cells, in parallel with respective control cells, in response to high dose-rate (HDR) and low dose-rate (LDR) γ-ray radiation (~0.9 and ~1 mGy/min, respectively). Control cells and murine embryonic fibroblasts (MEF) from a severe combined immunodeficiency (scid) mouse, which is DNA-PKcs-deficient, showed higher cell survival after LDR irradiation than after HDR irradiation at the same dose. On the other hand, MEF from Ku70^−/− mice exhibited lower clonogenic cell survival after LDR irradiation than after HDR irradiation. XR-V15B and xrs-5 cells, which are Ku86-deficient, exhibited mostly identical clonogenic cell survival after LDR and HDR irradiation. Thus, the dose-rate effect in terms of clonogenic cell survival is diminished or even inversed in Ku-deficient rodent cells. These observations indicate the involvement of Ku in the dose-rate effect.     

Impact of dosimetric parameters on local control for patients treated with three-dimensional pulsed dose-rate brachytherapy for cervical cancer

PurposeTo investigate the impact of dose-volume histograms parameters on local control of three-dimensional (3D) image-based pulsed dose-rate brachytherapy (BT).Methods and MaterialsWithin a French multicentric prospective study, the data of the 110 patients treated for cervical cancer with external beam radiotherapy followed by 3D image-based and optimized pulsed dose-rate BT were analyzed. Delineation procedures were performed on magnetic resonance imaging in a minority of cases and on CT for the majority of cases, adapted from the Gynaecological Groupe Européen de Curiethérapie—European Society for Therapeutic Radiology and Oncology recommendations. Optimization procedure was left to the discretion of the treating center.ResultsAt 2 years, local control rate reached 78%. Dose to Point A, total reference air kerma, and intermediate-risk clinical target volume (IR-CTV) V₆₀ were predictive factors for local control (p = 0.001, p = 0.001, and p = 0.013, respectively). Patients with IR-CTV V₆₀ <75% had a relative risk of local recurrence of 3.8 (95% confidence interval, 1.4–11.1). There was no correlation found between the high-risk clinical target volume dosimetric parameters and local control.ConclusionsThis multicentric study has shown that 3D image-based BT provides a high local control rate for cervical cancer patients. The V₆₀ for IR-CTV was identified as an important predictive factor for local control.     

Cancer risks in a population with prolonged low dose-rate γ-radiation exposure in radiocontaminated buildings, 1983 – 2002

Purpose: To assess cancer risks in a population that received prolonged low dose-rate γ-irradiation for about 10 years as a result of occupying buildings containing ⁶⁰Co-contaminated steel in Taiwan.

Materials and methods: The cancer risks were compared with those populations with the same temporal and geographic characteristics in Taiwan by standardized incidence ratios (SIR), adjusted for age and gender. The association of cancer risks with excess cumulative exposure was further evaluated for their relative risks by the Poisson multiple regression analysis.

Result: A total of 7271 people were registered as the exposed population, with 101,560 person-years at risk. The average excess cumulative exposure was approximately 47.8 mSv (range < 1 – 2,363 mSv). A total of 141 exposed subjects with various cancers were observed, while 95 developed leukemia or solid cancers after more than 2 or 10 years initial residence in contaminated buildings respectively. The SIR were significantly higher for all leukemia except chronic lymphocytic leukemia (n = 6, SIR = 3.6, 95% confidence interval [CI] 1.2 – 7.4) in men, and marginally significant for thyroid cancers (n = 6, SIR = 2.6, 95% CI 1.0 – 5.7) in women. On the other hand, all cancers combined, all solid cancers combined were shown to exhibit significant exposure-dependent increased risks in individuals with the initial exposure before the age of 30, but not beyond this age.

Conclusions: The results suggest that prolonged low dose-rate radiation exposure appeared to increase risks of developing certain cancers in specific subgroups of this population in Taiwan.     

Curiethérapie du cancer de l’œsophage

The main indication of oesophageal brachytherapy is palliative: it can improve dysphagia in patients with a tumor not suitable for surgery or chemoradiotherapy. A randomized clinical trial showed that survival without dysphagia and quality of life was improved by endoluminal brachytherapy in comparison to self-expansible metallic stents. It also increases the duration of palliation after laser deobstruction. Its role as a curative treatment of locally advanced tumors is still discussed: in combination with external beam radiotherapy, it seems that brachytherapy increased the rate of severe toxicity (haemorrhages, fistula, stenosis). In superficial lesions, brachytherapy with or without external beam radiotherapy seems logical but large prospective studies are missing in this setting.