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Institute
- Klinik und Poliklinik für Strahlentherapie (14) (remove)
Background and Purpose
The standard treatment of glioblastoma patients consists of surgery followed by normofractionated radiotherapy (NFRT) with concomitant and adjuvant temozolomide chemotherapy. Whether accelerated hyperfractionated radiotherapy (HFRT) yields comparable results to NFRT in combination with temozolomide has only sparsely been investigated. The objective of this study was to compare NFRT with HFRT in a multicenter analysis.
Materials and Methods
A total of 484 glioblastoma patients from four centers were retrospectively pooled and analyzed. Three-hundred-ten and 174 patients had been treated with NFRT (30 × 1.8 Gy or 30 × 2 Gy) and HFRT (37 × 1.6 Gy or 30 × 1.8 Gy twice/day), respectively. The primary outcome of interest was overall survival (OS) which was correlated with patient-, tumor- and treatment-related variables via univariable and multivariable Cox frailty models. For multivariable modeling, missing covariates were imputed using multiple imputation by chained equations, and a sensitivity analysis was performed on the complete-cases-only dataset.
Results
After a median follow-up of 15.7 months (range 0.8-88.6 months), median OS was 16.9 months (15.0-18.7 months) in the NFRT group and 14.9 months (13.2-17.3 months) in the HFRT group (p = 0.26). In multivariable frailty regression, better performance status, gross-total versus not gross-total resection, MGMT hypermethylation, IDH mutation, smaller planning target volume and salvage therapy were significantly associated with longer OS (all p < 0.01). Treatment differences (HFRT versus NFRT) had no significant effect on OS in either univariable or multivariable analysis.
Conclusions
Since HFRT with temozolomide was not associated with worse OS, we assume HFRT to be a potential option for patients wishing to shorten their treatment time.
Background
Boluses are routinely used in radiotherapy to modify surface doses. Nevertheless, considerable dose discrepancies may occur in some cases due to fit inaccuracy of commercially available standard flat boluses. Moreover, due to the simple geometric design of conventional boluses, also surrounding healthy skin areas may be unintentionally covered, resulting in the unwanted dose buildup. With the fused deposition modeling (FDM) technique, there is a simple and possibly cost-effective way to solve these problems in routine clinical practice. This paper presents a procedure of self-manufacturing bespoke patient-specific silicone boluses and the evaluation of buildup and fit accuracy in comparison to standard rectangular commercially available silicone boluses.
Methods
3D-conformal silicone boluses were custom-built to cover the surgical scar region of 25 patients who received adjuvant radiotherapy of head and neck cancer at the University Hospital Würzburg. During a standard CT-based planning procedure, a 5-mm-thick 3D bolus contour was generated to cover the radiopaque marked surgical scar with an additional safety margin. From these digital contours, molds were 3D printed and poured with silicone. Dose measurements for both types of boluses were performed with radiochromic films (EBT3) at three points per patient—at least one aimed to be in the high-dose area (scar) and one in the lower-dose area (spared healthy skin). Surface–bolus distance, which ideally should not be present, was determined from cone-beam CT performed for positioning control. The dosimetric influence of surface–bolus distance was also determined on slab phantom for different field sizes. The trial was performed with hardware that may be routinely available in every radiotherapy department, with the exception of the 3D printer. The required number of patients was determined based on the results of preparatory measurements with the help of the statistical consultancy of the University of Würzburg. The number of measuring points represents the total number of patients.
Results
In the high-dose area of the scar, there was a significantly better intended dose buildup of 2.45% (95%CI 0.0014–0.0477, p = 0.038, N = 30) in favor of a 3D-conformal bolus. Median distances between the body surface and bolus differed significantly between 3D-conformal and commercially available boluses (3.5 vs. 7.9 mm, p = 0.001). The surface dose at the slab phantom did not differ between commercially available and 3D-conformal boluses. Increasing the surface–bolus distance from 5 to 10 mm decreased the surface dose by approximately 2% and 11% in the 6 × 6- and 3 × 3-cm2 fields, respectively. In comparison to the commercially available bolus, an unintended dose buildup in the healthy skin areas was reduced by 25.9% (95%CI 19.5–32.3, p < 0.01, N = 37) using the 3D-conformal bolus limited to the region surrounding the surgical scar.
Conclusions
Using 3D-conformal boluses allows a comparison to the commercially available boluses’ dose buildup in the covered areas. Smaller field size is prone to a larger surface–bolus distance effect. Higher conformity of 3D-conformal boluses reduces this effect. This may be especially relevant for volumetric modulated arc therapy (VMAT) and intensity-modulated radiotherapy (IMRT) techniques with a huge number of smaller fields. High conformity of 3D-conformal boluses reduces an unintended dose buildup in healthy skin. The limiting factor in the conformity of 3D-conformal boluses in our setting was the immobilization mask, which was produced primarily for the 3D boluses. The mask itself limited tight contact of subsequently produced 3D-conformal boluses to the mask-covered body areas. In this respect, bolus adjustment before mask fabrication will be done in the future setting.
Simple Summary
Prostate cancer often relapses after initial radical prostatectomy, and salvage radiotherapy offers a second chance of cure for relapsed patients. Modern imaging techniques, especially prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT), enable radiation oncologists to target radiotherapy at the involved sites of disease. In a group of patients, PSMA PET/CT imaging can detect a macroscopic local recurrence with or without locoregional lymph node metastasis. In these cases, an escalation of the radiotherapy dose is often considered for controlling the visible tumor mass. As the evidence for dose-escalated salvage radiotherapy for macroscopic recurrent prostate cancer after PSMA PET/CT imaging is still limited, we address this topic in the current analysis. We found that the outcome of patients with dose-escalated salvage radiotherapy for macroscopic prostate cancer recurrence is encouragingly favorable, while the toxicity is very limited.
Abstract
Background: The purpose of this study was to access the oncological outcome of prostate-specific membrane antigen positron emission tomography (PSMA PET/CT)-guided salvage radiotherapy (SRT) for localized macroscopic prostate cancer recurrence. Methods: Between February 2010 and June 2021, 367 patients received SRT after radical prostatectomy. Out of the 367 screened patients, 111 patients were staged by PSMA PET/CT before SRT. A total of 59 out of these 111 (53.2%) patients were treated for PSMA PET-positive macroscopic prostatic fossa recurrence. Dose-escalated SRT was applied with a simultaneous integrated boost at a median prescribed dose of 69.3 Gy (IQR 69.3–72.6 Gy). The oncological outcome was investigated using Kaplan-Meier and Cox regression analyses. The genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (version 5.0). Results: The median follow-up was 38.2 months. The three-year biochemical progression-free survival rate was 89.1% (95% CI: 81.1–97.8%) and the three-year metastasis-free survival rate reached 96.2% (95% CI: 91.2–100.0%). The cumulative three-year late grade 3 GU toxicity rate was 3.4%. No late grade 3 GI toxicity occurred. Conclusions: Dose-escalated PSMA PET/CT-guided salvage radiotherapy for macroscopic prostatic fossa recurrence resulted in favorable survival and toxicity rates.
This retrospective, single-institutional study investigated long-term outcome, toxicity and health-related quality of life (HRQoL) in meningioma patients after radiotherapy. We analyzed the data of 119 patients who received radiotherapy at our department from 1997 to 2014 for intracranial WHO grade I-III meningioma. Fractionated stereotactic radiotherapy (FSRT), intensity modulated radiotherapy (IMRT) or radiosurgery radiation was applied. The EORTC QLQ-C30 and QLQ-BN20 questionnaires were completed for assessment of HRQoL. Overall survival (OS) for the entire study group was 89.6% at 5 years and 75.9% at 10 years. Local control (LC) at 5 and 10 years was 82.4% and 73.4%, respectively. Local recurrence was observed in 22 patients (18.5%). Higher grade acute and chronic toxicities were observed in seven patients (5.9%) and five patients (4.2%), respectively. Global health status was rated with a mean of 59.9 points (SD 22.3) on QLQ-C30. In conclusion, radiotherapy resulted in very good long-term survival and tumor control rates with low rates of severe toxicities but with a deterioration of long-term HRQoL.
Background
Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy.
Results
We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model.
Conclusion
PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.
Differences in stem cell marker and osteopontin expression in primary and recurrent glioblastoma
(2022)
Background
Despite of a multimodal approach, recurrences can hardly be prevented in glioblastoma. This may be in part due to so called glioma stem cells. However, there is no established marker to identify these stem cells.
Methods
Paired samples from glioma patients were analyzed by immunohistochemistry for expression of the following stem cell markers: CD133, Musashi, Nanog, Nestin, octamer-binding transcription factor 4 (Oct4), and sex determining region Y-box 2 (Sox2). In addition, the expression of osteopontin (OPN) was investigated. The relative number of positively stained cells was determined. By means of Kaplan–Meier analysis, a possible association with overall survival by marker expression was investigated.
Results
Sixty tissue samples from 30 patients (17 male, 13 female) were available for analysis. For Nestin, Musashi and OPN a significant increase was seen. There was also an increase (not significant) for CD133 and Oct4. Patients with mutated Isocitrate Dehydrogenase-1/2 (IDH-1/2) status had a reduced expression for CD133 and Nestin in their recurrent tumors. Significant correlations were seen for CD133 and Nanog between OPN in the primary and recurrent tumor and between CD133 and Nestin in recurrent tumors. By confocal imaging we could demonstrate a co-expression of CD133 and Nestin within recurrent glioma cells. Patients with high CD133 expression had a worse prognosis (22.6 vs 41.1 months, p = 0.013). A similar trend was seen for elevated Nestin levels (24.9 vs 41.1 months, p = 0.08).
Conclusions
Most of the evaluated markers showed an increased expression in their recurrent tumor. CD133 and Nestin were associated with survival and are candidate markers for further clinical investigation.
Purpose: Any Linac will show geometric imprecisions, including non-ideal alignment of the gantry, collimator and couch axes, and gantry sag or wobble. Their angular dependence can be quantified and resulting changes of the dose distribution predicted (Wack, JACMP 20(5), 2020). We analyzed whether it is feasible to correct geometric shifts during treatment planning. The successful implementation of such a correction procedure was verified by measurements of different stereotactic treatment plans.
Methods: Isocentric shifts were quantified for two Elekta Synergy Agility Linacs using the QualiForMed ISO-CBCT+ module, yielding the shift between kV and MV isocenters, the gantry flex and wobble as well as the positions of couch and collimator rotation axes. Next, the position of each field's isocenter in the Pinnacle treatment planning system was adjusted accordingly using a script. Fifteen stereotactic treatment plans of cerebral metastases (0.34 to 26.53 cm3) comprising 9–11 beams were investigated; 54 gantry and couch combinations in total. Unmodified plans and corrected plans were measured using the Sun Nuclear SRS-MapCHECK with the Stereophan phantom and evaluated using gamma analysis.
Results: Geometric imprecisions, such as shifts of up to 0.8 mm between kV and MV isocenter, a couch rotation axis 0.9 mm off the kV isocente,r and gantry flex with an amplitude of 1.1 mm, were found. For eight, mostly small PTVs D98 values declined more than 5% by simulating these shifts. The average gamma (2%/2 mm, absolute, global, 20% threshold) was reduced from 0.53 to 0.31 (0.32 to 0.30) for Linac 1 (Linac 2) when including the isocentric corrections. Thus, Linac 1 reached the accuracy level of Linac 2 after correction.
Conclusion: Correcting for Linac geometric deviations during the planning process is feasible and was dosimetrically validated. The dosimetric impact of the geometric imperfections can vary between Linacs and should be assessed and corrected where necessary.
In locally advanced rectal cancer (LARC) neoadjuvant chemoradiotherapy is regarded as standard treatment. We assessed acute toxicities in patients receiving conventional 3D-conformal radiotherapy (3D-RT) and correlated them with dosimetric parameters after re-planning with volumetric modulated arc therapy (VMAT). Patients were randomized within the multicenter CAO/ARO/AIO-12 trial and received 50.4 Gy in 28 fractions and simultaneous chemotherapy with fluorouracil and oxaliplatin. Organs at risk (OAR) were contoured in a standardized approach. Acute toxicities and dose volume histogram parameters of 3D-RT plans were compared to retrospectively calculated VMAT plans. From 08/2015 to 01/2018, 35 patients with LARC were treated at one study center. Thirty-four patients were analyzed of whom 1 (3%) was UICC stage II and 33 (97%) patients were UICC stage III. Grade 3 acute toxicities occurred in 5 patients (15%). Patients with acute grade 1 cystitis (n = 9) had significantly higher D\(_{mean}\) values for bladder (29.4 Gy vs. 25.2 Gy, p < 0.01) compared to patients without bladder toxicities. Acute diarrhea was associated with small bowel volume (grade 2: 870.1 ccm vs. grade 0–1: 647.3 ccm; p < 0.01) and with the irradiated volumes V5 to V50. Using VMAT planning, we could reduce mean doses and irradiated volumes for all OAR: D\(_{mean}\) bladder (21.9 Gy vs. 26.3 Gy, p < 0.01), small bowel volumes V5–V45 (p < 0.01), D\(_{mean}\) anal sphincter (34.6 Gy vs. 35.6 Gy, p < 0.01) and D\(_{mean}\) femoral heads (right 11.4 Gy vs. 25.9 Gy, left 12.5 Gy vs. 26.6 Gy, p < 0.01). Acute small bowel and bladder toxicities were dose and volume dependent. Dose and volume sparing for all OAR could be achieved through VMAT planning and might result in less acute toxicities.
Background: There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer. Patient and Methods: The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3–4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated. Results: In the development cohort, 155 patients developed grade 3–4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (p < 0.001). Rates of toxicity (p = 0.001) and low treatment adherence (p = 0.007) remained significantly different in the validation cohort, whereas discrimination ability was not significantly worse (DeLong test 0.09). Conclusion: We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making.