The influence of fractionated radiotherapy on the stability of spinal bone metastases: a retrospective analysis from 1047 cases

Background: The effect of radiotherapy, in particular the application of different multi-fraction schedules in the management of unstable spinal bone metastases (SBM), is incompletely understood. This study aims to compare the radiological response regarding various dose and fractionation schedules of radiotherapy in the palliative treatment of SBM. Methods: We retrospectively assessed 1047 patients with osteolytic SBM, treated with palliative radiotherapy at our department between 2000 and 2015. Lung cancer (40.2%), breast (16.7%) and renal cancer (15.2%) were the most common solid tumors in this study. Different common multi-fraction regimen (5x4Gy, 10x3Gy, 14 × 2.5Gy and 20x2Gy) were compared with regard to radiological response and recalcification at 3 and 6 months after radiotherapy. The Taneichi score was used for classification of osteolytic SBM. Results: Median follow up was 6.3 months. The median overall survival (OS) in the short-course radiotherapy (SCR) group using less than 10 treatment fractions was 5.5 months vs. 9.5 months in the long-course radiotherapy (LCR) group using in excess of 10 fractions (log rank p < .0001). Overall survival (OS) in the SCR group after 3 and 6 months was 66.8 and 49.1%, respectively vs 80.9 and 61.5%, respectively in the LCR group. 17.6% (n = 54/306) and 31.1% (n = 89/286) of unstable SBM were classified as stable in the SCR group at 3 and 6 months post radiotherapy, respectively (p < .001 for both). In the LCR group, 24.1% (n = 28/116) and 34.2% (n = 38/111) of unstable SBM were stabilized after 3 and 6 months, respectively (p < .001 for both). Conclusions: Our study shows no significant difference in stabilization achieving recalcification rates between multi-fraction schedules (SCR vs. LCR) in the palliative management of unstable SBM. Both groups with multi-fraction regimen demonstrate a stabilizing effect following 3 and 6 months after radiotherapy

Linear accelerator-based stereotactic fractionated photon radiotherapy as an eye-conserving treatment for uveal melanoma

Background: The purpose of this retrospective analysis is to analyze clinical outcome, visual acuity and enucleation rates after linear accelerator-based stereotactic fractionated photon radiotherapy for primary uveal melanoma. Methods: Twenty-four patients with primary uveal melanoma treated at the Department of Radiation and Oncology of the University Hospital Heidelberg between 1991 and 2015 were analyzed regarding survival and treatment-related toxicity including eye- and sight-preservation. Results: Photon radiotherapy (RT) offered good overall local control rates with a local progression-free survival (LPFS) of 82% after 5 years and a median LPFS of 5.5 years at a median follow-up time of 5.2 years. Gender had a significant impact on LPFS yielding a mean LPFS of 8.1 years for women and 8.7 years for men (p = 0.04). Of all local progressions, 80% occurred within the first 5 years after RT. In one case, enucleation as final therapy option was necessary. Enucleation-free survival (EFS) was related to the radiotherapy dose (p < 0.0001). Thus, higher prescribed doses led to a significantly higher enucleation rate. T-stage had no significant impact on EFS, but affected the enucleation rate (p = 0.01). The overall survival (OS) rate was 100% after 2 years and 70% after 5 years with a median OS of 5.75 years. Age (p = 0.046), T stage (p = 0.019), local control rate (p = 0.041) and the time between diagnosis and the first radiation session (p = 0.01) had a significant effect on OS. Applied biologically effective dose (BED) did not significantly influence OS or PFS. A 2-year sight preservation rate of 75% could be achieved. In all patients, irradiation could be applied safely without any interruptions due to side effects. Six significant late toxicities with consequential blindness could be observed, making a secondary enucleation necessary in four patients. An impairment of visual acuity due to chronic optic nerve atrophy was identified in five patients within 2 years after treatment. Conclusions: Linear accelerator-based stereotactic fractionated photon radiotherapy is an effective method in the treatment of uveal melanoma with excellent local control rates and a 2-year vision retention rate comparable to brachytherapy (BRT) or proton beam radiotherapy, even available in small centers and easy to implement. Interdisciplinary decision making is necessary to guarantee best treatment for every patient

In vivo demonstration of a tumor pretargeting approach with peptide nucleic acids as complementary system

A novel, promising strategy for cancer diagnosis and therapy is the use of a pretargeting approach. For this purpose, the non-natural DNA/RNA analogues Peptide Nucleic Acids (PNAs) are ideal candidates as in vivo recognition units due to their high metabolic stability and lack of unspecific accumulation. In the pretargeting approach, an unlabeled, highly specific antibody–PNA conjugate has sufficient time to target a tumor before administration of a small fast-clearing radiolabeled complementary PNA that hybridizes with the antibody–PNA conjugate at the tumor site. Herein, we report the first successful application of this multistep process using a PNA-modified epidermal growth factor receptor (EGFR) specific antibody (cetuximab) and a complementary 99mTc-labeled PNA. In vivo studies on tumor bearing mice demonstrated a rapid and efficient in vivo hybridization of the radiolabeled PNA with the antibody–PNA conjugate. Decisively, a high specific tumor accumulation was observed with a tumor-to-muscle ratio of >8, resulting in a clear visualization of the tumor by single photon emission computed tomography (SPECT

Survival and stability of patients with urothelial cancer and spinal bone metastases after palliative radiotherapy

The aim of the study was to analyze survival and stability of patients with urothelial cell cancer and spinal bone metastases (SBM) after radiotherapy (RT). Furthermore, to assess the effects of RT on bone mineral density (BMD) as a local response in SBM after RT

Percutaneous parametrial dose escalation in women with advanced cervical cancer: feasibility and efficacy in relation to long-term quality of life

We analyzed long-term quality of life (QoL) and prognostic factors for QoL as well as clinical outcome in patients with advanced cervical cancer (ACC) treated with primary radiochemotherapy (RChT) consisting of external beam radiotherapy (EBRT) with or without sequential or simultaneous integrated boost (SIB) to the parametria, intracavitary brachytherapy and concomitant chemotherapy (ChT)

Percutaneous parametrial dose escalation in women with advanced cervical cancer: feasibility and efficacy in relation to long-term quality of life

Background We analyzed long-term quality of life (QoL) and prognostic factors for QoL as well as clinical outcome in patients with advanced cervical cancer (ACC) treated with primary radiochemotherapy (RChT) consisting of external beam radiotherapy (EBRT) with or without sequential or simultaneous integrated boost (SIB) to the parametria, intracavitary brachytherapy and concomitant chemotherapy (ChT). Patients and methods Eighty-three women were treated with primary RChT between 2008 and 2014. Survival of all patients was calculated and prognostic factors for survival were assessed in univariate and multivariate analysis. In 31 patients QoL was assessed in median 3 years (range 2-8 years) after treatment. QoL was compared to published normative data and the influence of age, tumour stage, treatment and observed acute toxicities was analyzed. Results Thirty-six patients (43.4%) died, 18 (21.7%) had a local recurrence and 24 (28.9%) had a distant progression. Parametrial boost (p = 0.027) and ChT (p = 0.041) were independent prognostic factors for overall survival in multivariate analysis. Specifically, a parametrial equivalent doses in 2-Gy fractions (EQD2) > 50 Gy was associated with an improved overall survival (OS) (p = 0.020), but an EQD2 > 53 Gy did not further improve OS (p = 0.194). Tumour size was the only independent prognostic factor for local control (p = 0.034). Lymph node status (p = 0.038) and distant metastases other than in paraaortic lymph nodes (p = 0.002) were independent prognostic factors for distant progressionfree survival. QoL was generally inferior to the reference population. Age only correlated with menopausal symptoms (p = 0.003). The degree of acute gastrointestinal (p = 0.038) and genitourinary (p = 0.041) toxicities correlated with the extent of chronic symptom experience. Sexual/vaginal functioning was reduced in patients with larger tumours (p = 0.012). Parametrial EQD2 > 53 Gy correlated with reduced sexual/vaginal functioning (p = 0.009) and increased sexual worry (p = 0.009). Whether parametrial dose escalation was achieved by sequential boost or SIB, did not affect survival or QoL. Conclusions Primary RChT is an effective treatment, but long-term QoL is reduced. The degree of acute side effects of RChT correlates with the extent of chronic symptoms. Patients benefit from parametrial SIB or sequential boost, but an EQD2 > 53 Gy does not further improve survival and negatively affects QoL

The impact of vaginal dilator use on vaginal stenosis and sexual quality of life in women treated with adjuvant radiotherapy for endometrial cancer

BACKGROUND: Despite a lack of evidence and low compliance, current guidelines recommend the use of a vaginal dilator (VD) after pelvic radiotherapy (RT). We analyzed the effect of VD on vaginal stenosis (VS) and its influence on sexual quality of life (QoL) in women treated with adjuvant RT for endometrial cancer (EC). METHODS: Between 2014 and 2015, 56 consecutive patients were instructed to use a VD after completion of treatment. The maximum diameter of the comfortably introducible VD was measured before and at 1 year after treatment. The degree of VS was evaluated clinically, and sexual QoL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) sexual functioning items before RT, during RT, at 6 weeks, and at 1 year after RT. RESULTS: One year after RT, mean VD diameter had decreased by 2.7 ± 3.2 mm (p < 0.001) and 36 patients (64.3%) had clinical VS (grade I-III). A larger decrease in VD diameter correlated with a higher degree of clinical VS (p < 0.001). VD use (p = 0.81), RT modality (p = 0.68), and adjuvant ChT (p = 0.87) had no influence on VD diameter. Sexual activity decreased during RT and increased beyond pre-RT values 1 year after RT (p < 0.001). Sexual enjoyment decreased continuously during and after completion of RT (p = 0.013) and was influenced negatively by a higher degree of clinical VS (p = 0.01). CONCLUSION: Almost two thirds of patients developed clinical VS 1 year after adjuvant RT for EC, and sexual enjoyment was substantially reduced by VS. The use of a VD after RT may not serve to prevent sexual impairments and VS

Neurodevelopmental toxicity assessment of flame retardants using a human DNT in vitro testing battery

Due to their neurodevelopmental toxicity, flame retardants (FRs) like polybrominated diphenyl ethers are banned from the market and replaced by alternative FRs, like organophosphorus FRs, that have mostly unknown toxicological profiles. To study their neurodevelopmental toxicity, we evaluated the hazard of several FRs including phased-out polybrominated FRs and organophosphorus FRs: 2,2′,4,4′-tetrabromodiphenylether (BDE-47), 2,2′,4,4′,5-pentabromodiphenylether (BDE-99), tetrabromobisphenol A, triphenyl phosphate, tris(2-butoxyethyl) phosphate and its metabolite bis-(2-butoxyethyl) phosphate, isodecyl diphenyl phosphate, triphenyl isopropylated phosphate, tricresyl phosphate, tris(1,3-dichloro-2-propyl) phosphate, tert-butylphenyl diphenyl phosphate, 2-ethylhexyl diphenyl phosphate, tris(1-chloroisopropyl) phosphate, and tris(2-chloroethyl) phosphate. Therefore, we used a human cell–based developmental neurotoxicity (DNT) in vitro battery covering a large variety of neurodevelopmental endpoints. Potency according to the respective most sensitive benchmark concentration (BMC) across the battery ranked from 10 μM range (3 FRs). Evaluation of the data with the ToxPi tool revealed a distinct ranking (a) than with the BMC and (b) compared to the ToxCast data, suggesting that DNT hazard of these FRs is not well predicted by ToxCast assays. Extrapolating the DNT in vitro battery BMCs to human FR exposure via breast milk suggests low risk for individual compounds. However, it raises a potential concern for real-life mixture exposure, especially when different compounds converge through diverse modes-of-action on common endpoints, like oligodendrocyte differentiation in this study. This case study using FRs suggests that human cell–based DNT in vitro battery is a promising approach for neurodevelopmental hazard assessment and compound prioritization in risk assessment. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10565-021-09603-2