Radiotherapy and Oncology最新文献

Background

The effectiveness and safety of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) in elderly patients with locoregionally advanced nasopharyngeal carcinomas (LANPCs) remain subjects of debate. This study evaluated the efficacy of IC+CCRT compared to CCRT alone in elderly LANPC patients.

Materials and methods

This retrospective, single-center study analyzed 335 elderly patients diagnosed with stage III or IVa NPC who received CCRT with or without IC between 2010 and 2016. Kaplan-Meier analysis and log-rank tests were used to estimate and compare survival rates. Multivariate analysis using Cox proportional hazards regression model was conducted to assess prognostic risk factors. Toxicities were compared using the χ² test.

Results

The median follow-up duration was 69.3 months (interquartile range: 42.7–72.6). Baseline clinical characteristics were well-balanced between groups. No significant differences were observed between IC+CCRT and CCRT for any survival-related endpoints, including overall survival (hazard ratio [HR] = 1.26, 95 % confidence interval [CI]: 0.89–1.77, p = 0.188), locoregional relapse-free survival (HR=1.03, 95 % CI: 0.56–1.91, p = 0.913), distant metastasis-free survival (HR=1.39, 95 % CI: 0.90–2.16, p = 0.139), and failure-free survival (HR = 1.25, 95 % CI: 0.85–1.83, p = 0.255). However, the incidence and severity of acute and late toxicities were significantly higher in the IC+CCRT group compared to the CCRT group.

Conclusion

In elderly LANPC patients, the addition of IC to CCRT did not improve survival outcomes, but was associated with significant toxicities.

Background

Electromagnetic Tracking (EMT) technology has been integrated in a prototype high-dose-rate brachytherapy (HDR-BT) afterloading device. Its potential for dwell position (DP) monitoring has earlier been demonstrated in prostate phantoms. However, its performance for prostate BT in the clinical setting remains to be assessed.

Aim

Assess the reliability and value of EMT measurements in transrectal ultrasound-based (TRUS-based) and computed tomography-based (CT-based) prostate HDR-BT.

Methods

EMT measurements were conducted on 20 patients undergoing dual-fraction prostate HDR-BT monotherapy. In each treatment fraction an individual TRUS-based or CT-based treatment plan was generated. The measurements were compared to DPs of manually reconstructed needles in those TRUS-based or CT-based treatment plans. An internal reference sensor was also placed in one needle to assess internal movement levels and its potential for movement correction.

Results

For TRUS-based treatments, median Euclidean distances (ED) of 1.00 mm were observed between EMT measurements and manual DP determination. Reference sensor movement was minimal at a median of 0.18 mm. For DPs measured in the CT-room and treatment room, median EDs of 1.60 mm and 2.24 mm compared to CT-based DP determination respectively were observed, indicating the system’s ability to detect changes in implant geometry over time and after patient repositioning. Median reference sensor movement of 0.97 mm was observed. Implementing reference sensor-based movement correction led to a significant but small decrease in ED for CT-based treatments.

Conclusion

EMT is suitable for TRUS-based prostate HDR-BT quality assurance and error detection. While EMT can identify changes in implant geometry in CT-based prostate HDR-BT treatments, it showed lower accuracy in this setting.

Background and purpose

Radiotherapy (RT) is an integral treatment part for patients with head and neck squamous cell carcinoma (HNSCC), but radioresistance remains a major issue. Here, we use MitoTam, a mitochondrially targeted analogue of tamoxifen, which we aim to stimulate ferroptotic cell death with, and sensitize radioresistant cells to RT.

Materials and methods

We assessed viability, reactive oxygen species (ROS) production, disruption of mitochondrial membrane potential, and lipid peroxidation in radiosensitive (UT-SCC-40) and radioresistant (UT-SCC-5) HNSCC cells following MitoTam treatment. To assess ferroptosis specificity, we used the ferroptosis inhibitor ferrostatin-1 (fer-1). Also, total antioxidant capacity and sensitivity to tert-butyl hydroperoxide were evaluated to assess ROS-responses. 53BP1 staining was used to assess radiosensitivity after MitoTam treatment.

Results

Our data revealed increased ROS, cell death, disruption of mitochondrial membrane potential, and lipid peroxidation following MitoTam treatment in both cell lines. Adverse effects of MitoTam on cell death, membrane potential and lipid peroxidation were prevented by fer-1, indicating induction of ferroptosis. Radioresistant HNSCC cells were less sensitive to the effects of MitoTam due to intrinsic higher antioxidant capacity. MitoTam treatment prior to RT led to superadditive residual DNA damage expressed by 53BP1 foci compared to RT or MitoTam alone.

Conclusion

MitoTam induced ferroptosis in HNSCC cells, which could be used to overcome the elevated antioxidant capacity of radioresistant cells and sensitize such cells to RT. Treatment with MitoTam followed by RT could therefore present a promising effective therapy of radioresistant cancers.

Statement of significance.

Radiotherapy is applied in the treatment of a majority of cancer patients. Radioresistance due to elevated antioxidant levels can be overcome by promoting ferroptotic cell death combining ROS-inducing drug MitoTam with radiotherapy.

Purpose

The aim of this study was to test the hypothesis that the levels of High Sensitive Troponin T (HS-TNT) and N-terminal Brain Natriuretic Peptide (NT-ProBNP) increase after radiation therapy in a dose dependent way and are predictive for clinical cardiac events.

Materials and Methods

Blood samples during and after radiotherapy of 87 esophageal cancer patients were analysed regarding the course of HS-TNT and NT-ProBNP levels and their relationship with clinical toxicity endpoints and radiation dose volume parameters.

Results

HS-TNT values at the end of treatment correlated with the mean heart dose (p = 0.02), whereas the rise of NT-ProBNP correlated with the mean lung dose (p = 0.01). Furthermore, the course of both HS-TNT (p < 0.001) and NT-ProBNP (p < 0.01) levels were significantly different for patients who developed new cardiac events as opposed to those without new cardiac events.

Conclusion

Significant correlations were found for both biomarkers with radiation dose and clinical toxicity endpoints after treatment. Therefore, these markers might be of additional value in NTCP models for cardiac events and might help us unravelling the mechanisms behind these toxicity endpoints.

Introduction

New radiotherapy machines such as Halcyon are capable of delivering dose-rate of 600 monitor-units per minute, allowing large numbers of patients treated per day. However, patient-specific quality assurance (QA) is still required, which dramatically decrease machine availability. Innovative artificial intelligence (AI) algorithms could predict QA result based on complexity metrics. However, no AI solution exists for Halcyon machines and the complexity metrics to be used have not been definitively determined. The aim of this study was to develop an AI solution capable of firstly determining the complexity indices to be obtained and secondly predicting patient-specific QA in a routine clinical setting.

Methods

Three hundred and eighteen beams from 56 patients with breast cancer were used. The seven complexity indices named Modulation-Complexity-Score (MCS), Small-Aperture-Score (SAS10), Beam-Area (BA), Beam-Irregularity (BI), Beam-Modulation (BM), Gantry and Collimator angles were used as input to the AI model. Machine learning (ML) and deep learning (DL) models using tensorflow were set up to predict DreamDose QA conformance.

Results

MCS, BI, gantry and collimator angle are not correlated with QA compliance. Therefore, ML and DL models were trained using SAS10, BA and BM complexity indices. ROC analyses enabled to find best predicted probability threshold to increase specificity and sensitivity. ML models did not show satisfactory performance with an area under-the-curve (AUC) of 0.75 and specificity and sensitivity of 0.88 and 0.86. However, optimised DL model showed better performance with an AUC of 0.95 and specificity and sensitivity of 0.98 and 0.97.

Conclusion

The DL model demonstrated a high degree of accuracy in its predictions of the quality assurance (QA) results. Our online predictive QA-platform offers significant time savings in terms of accelerator occupancy and working time.

Purpose

Currently there is no generally accepted standardized approach for the pathological evaluation of soft tissue sarcoma (STS) histology appearance after preoperative radiotherapy (PORT). This study aimed to investigate the prognostic value of pathological appearance after PORT for patients with high-grade limb/trunk STS.

Methods

A cohort of 116 patients with high-grade STS of the limb/trunk treated with PORT followed by resection were evaluated. Patient characteristics, imaging tumor morphology (size, volume), and histopathology (mitotic and necrosis rate, viable cell, hyalinization/fibrosis cytopathic effect) were reviewed and reassessed. Disease free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and the hazard ratio was derived from Cox proportional hazard models. Two predictive nomograms were calculated based on significant predictors identified.

Results

The 5-year DFS and OS were 52.9% and 70.3%, respectively. Tumor size before (HR:1.07, 95%CI: 1.01–1.14) and after PORT (HR:1.08, 95%CI: 1.01–1.14), tumor volume (HR:1.06, 95%CI: 1.01–1.12), mitotic rate after PORT (HR: 1.06, 95%CI: 1.02–1.11), mitotic rate change after PORT (HR:1.04, 95%CI:1.00–1.09) were independent risk factors for DFS. Tumor size before (HR:1.08, 95%CI: 1.03–1.14) and after PORT (HR:1.09, 95%CI: 1.04–1.15), tumor volume (HR:1.05, 95%CI: 1.01–1.09), mitotic rate after PORT (HR: 1.09, 95%CI: 1.04–1.13), mitotic rate change after PORT (HR:1.05, 95%CI:1.01–1.09) were independent risk factors for OS. The C-index of pathologic predictive nomogram based on mitotic rate for DFS and OS were 0.67 and 0.73, respectively. The C-index of morphology-pathology predictive nomogram for OS was 0.79.

Conclusion

Tumor size before and after PORT, tumor volume, mitotic rate after PORT, mitotic rate change after PORT were independent risk factors for DFS and OS in high-grade STS patients treated with PORT. The mitotic rate, independent of tumor morphology, showed its potential as a prognostic biomarker for pathologic evaluation in patients treated with PORT.

Introduction

Rib fracture is a known complication after stereotactic body radiotherapy (SBRT). Patient-related parameters are essential to provide patient-tailored risk estimation, however, their impact on rib fracture is less documented compared to dosimetric parameters. This study aimed to predict the risk of rib fractures in patients with localized non-small cell lung cancer (NSCLC) post-SBRT based on both patient-related and dosimetric parameters with death as a competing risk.

Materials and methods

In total, 602 patients with localized NSCLC treated with SBRT between 2010–2020 at Odense University Hospital, Denmark were included. All patients received SBRT with 45–66 Gray (Gy)/3 fractions. Rib fractures were identified in CT-scans using a word embedding model. The cumulative incidence function was based on cause-specific Cox hazard models with variable selection based on cross-validation model likelihood performed using 50 bootstraps.

Results

In total, 19 % of patients experienced a rib fracture. The cumulative risk of rib fracture increased rapidly from 6-54 months post-SBRT. Female gender, bone density, near max dose to the rib, V30 and V40 to the rib, gross tumor volume, and mean lung dose were significantly associated with rib fracture risk in univariable analysis. The final multi-variable model consisted of V20 and V30 to the rib and mean lung dose.

Conclusion

Female gender and low bone density in male patients are significant predictors of rib fracture risk. The final model predicting cumulative rib fracture risk of 19 % in patients with localized NSCLC treated with SBRT contained no patient-related parameters, suggesting that dosimetric parameters are the primary drivers.

Background

Cutaneous metastases (CMs) are a manifestation of advanced cancer and can be treated with oncolytic immunotherapy. Laboratory studies suggest radiotherapy (RT) may facilitate response to immunotherapy. We hypothesized that oncolytic immunotherapy with talimogene lapherparepvec (T-VEC, an oncolytic immunotherapy that expresses granulocyte–macrophage colony stimulating factor) and RT would produce response in non-targeted metastases.

Methods

A randomized phase 2 trial of T-VEC+/-RT was conducted. Eligible patients had ≥1 CM from a solid tumor amenable to T-VEC and RT and another measurable metastasis. Tumor and overall response was assessed using modified World Health Organization (mWHO) criteria. Adverse events (AEs) and quality of life (QOL) were characterized using CTCAE v4.0 and Skindex-16, respectively. Correlative analyses of tumor genomics and the immune system were performed.

Results

19 patients were randomized to receive T-VEC (n = 9) or T-VEC+RT (n = 10). One patient in each arm demonstrated complete response in the largest non-targeted metastasis. The trial was closed after the first stage of enrollment because of no overall mWHO responses, slow accrual and the COVID-19 pandemic. AEs were consistent with prior reports of T-VEC. Skin related QOL was poor before and after treatment. Median progression free survival was 1.2 and 2.5 months in the T-VEC and T-VEC+RT arms; median overall survival was 4.9 and 17.3 months in the T-VEC and T-VEC+RT arms. Analyses of peripheral blood cells and cytokines demonstrated responders exhibited several outlying lymphocyte and cytokine parameters.

Conclusions

Low overall response rate, slow accrual, and the COVID-19 pandemic led to closure of this trial. Responses in non-injected and non-irradiated metastases were infrequent.

Background and Purpose

Local radiotherapy (RT) exerts immunostimulatory effects by inducing immunogenic cell death. However, it remains unknown whether in vitro–irradiated tumor cells can elicit anti-tumor responses and enhance the efficacy of local RT and immune checkpoint inhibitors when injected in vivo.

Methods and Materials

We tested the “in vitro–irradiated cancer vaccine (ICV)”, wherein tumor cells killed by varying doses of irradiation and their supernatants are intravenously injected. We examined the efficacy of combining local RT (24 Gy in three fractions), PD-L1 blockade, and the ICV in a murine breast cancer model. The immune cell profiles were analyzed via flow cytometry and immunohistochemistry. The cytokine levels were measured by multiplex immunoassays.

Results

The ICV significantly increased the effector memory phenotype and interferon-γ production capacity in splenic CD8⁺ T cells. The in vitro–irradiated products contained immune response-related molecules. When combined with local RT and PD-L1 blockade, the ICV significantly delayed the growth of irradiated and non-irradiated tumors. The triple combination therapy increased the proportions of CD8⁺ T cells and effector memory CD8⁺ T cells while decreasing the proportion of CTLA-4⁺ exhausted CD8⁺ T cells within tumor microenvironment. Additionally, plasma level of interferon-γ and proliferation of effector T cells in the spleen and tumor-draining lymph nodes were significantly increased by the triple combination therapy.

Conclusions

The ICV enhanced the therapeutic efficacy of local RT and PD-L1 blockade by augmenting anti-tumor immune responses. Our findings suggest a therapeutic potential of in vitro–irradiation products of tumor cells.

Background and purpose

Chemoradiotherapy (CRT) for locally-advanced non-small cell lung cancer (LA-NSCLC) has undergone advances, including increased overall survival (OS) when combined with immune checkpoint blockade (ICB), and using cardiac-sparing techniques to reduce the radiotoxicity. This research investigated 1) how radiotherapy schedules can be optimised with CRT-ICB schemes, and 2) how cardiac-sparing might change the OS for concurrent CRT (cCRT).

Methods and materials

Survival data and dosimetric indices were sourced from published studies, with 2-year OS standardised and the hazard ratio of mean heart dose (MHD) against radiotoxicity tabulated in purpose. A published CRT dose–response model was selected, then modified with ICB and cardiac-sparing hypotheses. Models were maximum likelihood fitted, then visualised the prediction outcomes after bootstrapping.

Results

The modelled 2-year OS rate of cCRT-ICB reached 71 % (95 % confidence intervals, CI 62 %, 84 %) and 66 % (95 % CI: 53 %, 81 %) for stage IIIA and IIIB/C, respectively, given 60 Gy in 2 Gy-per-fraction. 60 Gy in 30 fractions remained the best schedule for cCRT-ICB, whereas modest dose de-escalation to 55 Gy only reduced the OS in 2 %. Sequential CRT (sCRT)-ICB provided 6 % OS increases versus the best OS rate achieved by sCRT alone. Photon MHD-sparing achieved a 5–10 % increase in modelled 2-year OS, with protons providing a further roughly 5–10 % increase.

Conclusion

Neither dose-escalation nor de-escalation relative to 60 Gy in 30 fractions influenced the survival with cCRT-ICB, while 5 Gy dose de-escalation might benefit patients with heavily irradiated organs at risk. Cardiac-sparing improved OS, and protons provided advantages for tumours anatomically overlapped or lay below the heart.