Therapy resistance can arise within tumor cells because of genetic or phenotypic changes (intrinsic resistance), or it can be the result of an interaction with the tumor microenvironment (extrinsic ...resistance). Exosomes are membranous vesicles 40 to 100 nm in diameter constitutively released by almost all cell types, and mediate cell-to-cell communication by transferring mRNAs, miRNAs, DNAs and proteins causing extrinsic therapy resistance. They transfer therapy resistance by anti-apoptotic signalling, increased DNA-repair or delivering ABC transporters to drug sensitive cells. As functional mediators of tumor-stroma interaction and of epithelial to mesenchymal transition, exosomes also promote environment-mediated therapy resistance.Exosomes may be used in anticancer therapy exploiting their delivery function. They may effectively transfer anticancer drugs or RNAs in the context of gene therapy reducing immune stimulatory effects of these drugs and hydrophilic qualities facilitating crossing of cell membranes.
Resistance against radio(chemo)therapy-induced cell death is a major determinant of oncological treatment failure and remains a perpetual clinical challenge. The underlying mechanisms are manifold ...and demand for comprehensive, cancer entity- and subtype-specific examination. In the present study, resistance against radiotherapy was systematically assessed in a panel of human head-and-neck squamous cell carcinoma (HNSCC) cell lines and xenotransplants derived thereof with the overarching aim to extract master regulators and potential candidates for mechanism-based pharmacological targeting. Clonogenic survival data were integrated with molecular and functional data on DNA damage repair and different cell fate decisions. A positive correlation between radioresistance and early induction of HNSCC cell senescence accompanied by NF-κB-dependent production of distinct senescence-associated cytokines, particularly ligands of the CXCR2 chemokine receptor, was identified. Time-lapse microscopy and medium transfer experiments disclosed the non-cell autonomous, paracrine nature of these mechanisms, and pharmacological interference with senescence-associated cytokine production by the NF-κB inhibitor metformin significantly improved radiotherapeutic performance in vitro and in vivo. With regard to clinical relevance, retrospective analyses of TCGA HNSCC data and an in-house HNSCC cohort revealed that elevated expression of CXCR2 and/or its ligands are associated with impaired treatment outcome. Collectively, our study identifies radiation-induced tumor cell senescence and the NF-κB-dependent production of distinct senescence-associated cytokines as critical drivers of radioresistance in HNSCC whose therapeutic targeting in the context of multi-modality treatment approaches should be further examined and may be of particular interest for the subgroup of patients with elevated expression of the CXCR2/ligand axis.
Overall survival (OS) of patients with brain metastases treated with hypofractionated (HFSRT) or single-fraction (SRS) radiosurgery depends on several prognostic factors. The aim of this study was to ...investigate the potential of sex as an independent predictor of OS and evaluate the predictive accuracy of common prognostic scores. Retrospective analysis of 281 consecutive patients receiving radiosurgery of brain metastases was performed. Kaplan-Meier survival curves and Cox proportional hazards models were used to compare OS between SRS and HFSRT and by sex, before and after propensity-score matching (PSM) on key baseline prognostic covariates. Prognostic scores were evaluated using Harrell's concordance index. Median OS was 11 months after both SRS and HFSRT. After PSM, median OS was 12 months after SRS (95% CI: 7.5-16.5) and 9 months after HFSRT (95% CI: 5.0-13.0; p = 0.77). Independent prognostic factors were sex, primary tumor, KPI, and systemic disease status. Median OS was 16 months for women and 7 months for male patients (p < 0.001). After excluding sex specific tumors, PSM revealed a median OS of 16 months for women and 8 months for male patients (p < 0.01). Evaluation of prognostic indices showed BSBM to be the most accurate (Harrell's C = 0.68), followed by SIR (0.61), GPA (0.60), RPA (0.58), and Rades et al. (0.57). OS after HFSRT and SRS did not differ, although PSM revealed a non-significant advantage for SRS. Female sex was found to be a major independent positive prognostic factor for survival, and thus should be considered in the personalized decision-making of brain metastases treatment.
To evaluate safety and efficacy of stereotactic body radiotherapy (SBRT) for stage I non–small-cell lung cancer (NSCLC) in a patterns-of-care and patterns-of-outcome analysis.
The working group ...“Extracranial Stereotactic Radiotherapy” of the German Society for Radiation Oncology performed a retrospective multicenter analysis of practice and outcome after SBRT for stage I NSCLC. Sixteen German and Austrian centers with experience in pulmonary SBRT were asked to participate.
Data of 582 patients treated at 13 institutions between 1998 and 2011 were collected; all institutions, except one, were academic hospitals. A time trend to more advanced radiotherapy technologies and escalated irradiation doses was observed, but patient characteristics (age, performance status, pulmonary function) remained stable over time. Interinstitutional variability was substantial in all treatment characteristics but not in patient characteristics. After an average follow-up of 21 months, 3-year freedom from local progression (FFLP) and overall survival (OS) were 79.6% and 47.1%, respectively. The biological effective dose was the most significant factor influencing FFLP and OS: after more than 106 Gy biological effective dose as planning target volume encompassing dose (N = 164), 3-year FFLP and OS were 92.5% and 62.2%, respectively. No evidence of a learning curve or improvement of results with larger SBRT experience and implementation of new radiotherapy technologies was observed.
SBRT for stage I NSCLC was safe and effective in this multi-institutional, academic environment, despite considerable interinstitutional variability and time trends in SBRT practice. Radiotherapy dose was identified as a major treatment factor influencing local tumor control and OS.
Adaptive intensity-modulated photon and proton radiotherapy (IMRT and IMPT) of head and neck (H&N) cancer requires frequent three-dimensional (3D) dose calculation. We compared two approaches for ...dose recalculation on the basis of intensity-corrected cone-beam (CB) x-ray computed tomography (CT) images.
For nine H&N tumor patients, virtual CTs (vCT) were generated by deformable image registration of the planning CT (pCT) to the CBCT. The second intensity correction approach used population-based lookup tables for scaling CBCT intensities to the pCT HU range (CBCTLUT). IMRT and IMPT plans were generated with a commercial treatment planning system. Dose recalculations on vCT and CBCTLUT were analyzed using a (3%, 3 mm) gamma-index analysis and comparison of normal tissue and tumor dose/volume parameters. A replanning CT (rpCT) acquired within three days of the CBCT served as reference. Single field uniform dose (SFUD) proton plans were created and recalculated on vCT and CBCTLUT for proton range comparison.
Dose/volume parameters showed minor differences between rpCT, vCT and CBCTLUT in IMRT, but clinically relevant deviations between CBCTLUT and rpCT in the spinal cord for IMPT. Gamma-index pass-rates were found increased for vCT with respect to CBCTLUT in IMPT (by up to 21 percentage points) and IMRT (by up to 9 percentage points) for most cases. The SFUD-based proton range assessment showed improved agreement of vCT and rpCT, with 88-99% of the depth dose profiles in beam's eye view agreeing within 3 mm. For CBCTLUT, only 80-94% of the profiles fulfilled this criterion.
vCT and CBCTLUT are suitable options for dose recalculation in adaptive IMRT. In the scope of IMPT, the vCT approach is preferable.
Purpose:
Intensity modulated proton therapy (IMPT) of head and neck (H&N) cancer patients may be improved by plan adaptation. The decision to adapt the treatment plan based on a dose recalculation on ...the current anatomy requires a diagnostic quality computed tomography (CT) scan of the patient. As gantry‐mounted cone beam CT (CBCT) scanners are currently being offered by vendors, they may offer daily or weekly updates of patient anatomy. CBCT image quality may not be sufficient for accurate proton dose calculation and it is likely necessary to perform CBCT CT number correction. In this work, the authors investigated deformable image registration (dir) of the planning CT (pCT) to the CBCT to generate a virtual CT (vCT) to be used for proton dose recalculation.
Methods:
Datasets of six H&N cancer patients undergoing photon intensity modulated radiation therapy were used in this study to validate the vCT approach. Each dataset contained a CBCT acquired within 3 days of a replanning CT (rpCT), in addition to a pCT. The pCT and rpCT were delineated by a physician. A Morphons algorithm was employed in this work to perform dir of the pCT to CBCT following a rigid registration of the two images. The contours from the pCT were deformed using the vector field resulting from dir to yield a contoured vCT. The dir accuracy was evaluated with a scale invariant feature transform (SIFT) algorithm comparing automatically identified matching features between vCT and CBCT. The rpCT was used as reference for evaluation of the vCT. The vCT and rpCT CT numbers were converted to stopping power ratio and the water equivalent thickness (WET) was calculated. IMPT dose distributions from treatment plans optimized on the pCT were recalculated with a Monte Carlo algorithm on the rpCT and vCT for comparison in terms of gamma index, dose volume histogram (DVH) statistics as well as proton range. The dir generated contours on the vCT were compared to physician‐drawn contours on the rpCT.
Results:
The dir accuracy was better than 1.4 mm according to the SIFT evaluation. The mean WET differences between vCT (pCT) and rpCT were below 1 mm (2.6 mm). The amount of voxels passing 3%/3 mm gamma criteria were above 95% for the vCT vs rpCT. When using the rpCT contour set to derive DVH statistics from dose distributions calculated on the rpCT and vCT the differences, expressed in terms of 30 fractions of 2 Gy, were within −4, 2 Gy for parotid glands (Dmean), spinal cord (D2%), brainstem (D2%), and CTV (D95%). When using dir generated contours for the vCT, those differences ranged within −8, 11 Gy.
Conclusions:
In this work, the authors generated CBCT based stopping power distributions using dir of the pCT to a CBCT scan. dir accuracy was below 1.4 mm as evaluated by the SIFT algorithm. Dose distributions calculated on the vCT agreed well to those calculated on the rpCT when using gamma index evaluation as well as DVH statistics based on the same contours. The use of dir generated contours introduced variability in DVH statistics.
Purpose:
This work aims at investigating intensity corrected cone-beam x-ray computed tomography (CBCT) images for accurate dose calculation in adaptive intensity modulated proton therapy (IMPT) for ...prostate and head and neck (H&N) cancer. A deformable image registration (DIR)-based method and a scatter correction approach using the image data obtained from DIR as prior are characterized and compared on the basis of the same clinical patient cohort for the first time.
Methods:
Planning CT (pCT) and daily CBCT data (reconstructed images and measured projections) of four H&N and four prostate cancer patients have been considered in this study. A previously validated Morphons algorithm was used for DIR of the planning CT to the current CBCT image, yielding a so-called virtual CT (vCT). For the first time, this approach was translated from H&N to prostate cancer cases in the scope of proton therapy. The warped pCT images were also used as prior for scatter correction of the CBCT projections for both tumor sites. Single field uniform dose and IMPT (only for H&N cases) treatment plans have been generated with a research version of a commercial planning system. Dose calculations on vCT and scatter corrected CBCT (CBCTcor) were compared by means of the proton range and a gamma-index analysis. For the H&N cases, an additional diagnostic replanning CT (rpCT) acquired within three days of the CBCT served as additional reference. For the prostate patients, a comprehensive contour comparison of CBCT and vCT, using a trained physician’s delineation, was performed.
Results:
A high agreement of vCT and CBCTcor was found in terms of the proton range and gamma-index analysis. For all patients and indications between 95% and 100% of the proton dose profiles in beam’s eye view showed a range agreement of better than 3 mm. The pass rate in a (2%,2 mm) gamma-comparison was between 96% and 100%. For H&N patients, an equivalent agreement of vCT and CBCTcor to the reference rpCT was observed. However, for the prostate cases, an insufficient accuracy of the vCT contours retrieved from DIR was found, while the CBCTcor contours showed very high agreement to the contours delineated on the raw CBCT.
Conclusions:
For H&N patients, no considerable differences of vCT and CBCTcor were found. For prostate cases, despite the high dosimetric agreement, the DIR yields incorrect contours, probably due to the more pronounced anatomical changes in the abdomen and the reduced soft-tissue contrast in the CBCT. Using the vCT as prior, these inaccuracies can be overcome and images suitable for accurate delineation and dose calculation in CBCT-based adaptive IMPT can be retrieved from scatter correction of the CBCT projections.
The COVID-19 pandemic is challenging modern radiation oncology. At University Hospitals, we have a mandate to offer high-end treatments to all cancer patients. However, in times of crisis we must ...learn to prioritize resources, especially personnel. Compromising oncological outcome will blur all statistics, therefore all measures must be taken with great caution. Communication with our neighboring countries, within societies and between departments can help meet the challenge. Here, we report on our learning system and preparation measures to effectively tackle the COVID-19 challenge in University-Based Radiation Oncology Departments.
Despite a comparatively favorable prognosis relative to other malignancies, breast cancer continues to significantly impact women’s health globally, partly due to its high incidence rate. A critical ...factor in treatment failure is radiation resistance – the capacity of tumor cells to withstand high doses of ionizing radiation. Advancements in understanding the cellular and molecular mechanisms underlying radioresistance, coupled with enhanced characterization of radioresistant cell clones, are paving the way for the development of novel treatment modalities that hold potential for future clinical application. In the context of combating radioresistance in breast cancer, potential targets of interest include long non-coding RNAs (lncRNAs), micro RNAs (miRNAs), and their associated signaling pathways, along with other signal transduction routes amenable to pharmacological intervention. Furthermore, technical, and methodological innovations, such as the integration of hyperthermia or nanoparticles with radiotherapy, have the potential to enhance treatment responses in patients with radioresistant breast cancer. This review endeavors to provide a comprehensive survey of the current scientific landscape, focusing on novel therapeutic advancements specifically addressing radioresistant breast cancer.
Purpose
Nodal recurrent prostate cancer (PCa) represents a common state of disease, amenable to local therapy. PSMA-PET/CT detects PCa recurrence at low PSA levels. The aim of this study was to ...evaluate the outcome of PSMA-PET/CT-based salvage radiotherapy (sRT) for lymph node (LN) recurrence.
Methods
A total of 100 consecutive patients treated with PSMA-PET/CT-based salvage elective nodal radiotherapy (sENRT) for LN recurrence were retrospectively examined. Patients underwent PSMA-PET/CT scan due to biochemical persistence (bcP, 76%) or biochemical recurrence (bcR, 24%) after radical prostatectomy (RP). Biochemical recurrence-free survival (BRFS) defined as PSA < post-RT nadir + 0.2 ng/ml and distant metastasis-free survival (DMFS) were calculated using the Kaplan–Meier method and uni- and multivariate analysis was performed.
Results
Median follow-up was 37 months. Median PSA at PSMA-PET/CT was 1.7 ng/ml (range 0.1–40.1) in patients with bcP and 1.4 ng/ml (range 0.3–5.1) in patients with bcR. PSMA-PET/CT detected 1, 2, and 3 or more LN metastases in 35%, 23%, and 42%, respectively. Eighty-three percent had only pelvic, 2% had only paraaortic, and 15% had pelvic and paraaortic LN metastases. Cumulatively, a total dose converted to EQD2
1.5 Gy
of 66 Gy (60–70 Gy) was delivered to the prostatic fossa, 70 Gy (66–72 Gy) to the local recurrence, if present, 65.1 Gy (56–66 Gy) to PET-positive lymph nodes, and 47.5 Gy (42.4–50.9 Gy) to the lymphatic pathways. Concomitant androgen deprivation therapy (ADT) was administered in 83% of patients. One-, 2-, and 3-year BRFS was 80.7%, 71.6%, and 65.8%, respectively. One-, 2-, and 3-year DMFS was 91.6%, 79.1%, and 66.4%, respectively. In multivariate analysis, concomitant ADT, longer ADT duration (≥ 12 vs. < 12 months) and LN localization (pelvic vs. paraaortic) were associated with improved BRFS and concomitant ADT and lower PSA value before sRT (< 1 vs. > 1 ng/ml) with improved DMFS, respectively. No such association was seen for the number of affected lymph nodes.
Conclusions
Overall, the present analysis shows that the so far, unmatched sensitivity and specificity of PSMA-PET/CT translates in comparably high BRFS and DMFS after PSMA-PET/CT-based sENRT for patients with PCa LN recurrence. Concomitant ADT, duration of ADT, PSA value before sRT, and localization of LN metastases were significant factors for improved outcome.
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