TY  - JOUR
A1  - Kimpel, Otilia
A1  - Schindler, Paul
A1  - Schmidt-Pennington, Laura
A1  - Altieri, Barbara
A1  - Megerle, Felix
A1  - Haak, Harm
A1  - Pittaway, James
A1  - Dischinger, Ulrich
A1  - Quinkler, Marcus
A1  - Mai, Knut
A1  - Kroiss, Matthias
A1  - Polat, Bülent
A1  - Fassnacht, Martin
T1  - Efficacy and safety of radiation therapy in advanced adrenocortical carcinoma
JF  - British Journal of Cancer
N2  - Background
International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low.

Methods
We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. Primary endpoint: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses.

Results
In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50–60 Gy (n = 20) or 20–49 Gy (n = 69), stereotactic body RT of 35–50 Gy (SBRT) (n = 36), or brachytherapy of 12–25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0–148.6). In comparison to cRT\(_{20-49Gy}\), tTTP was significantly longer for cRT\(_{50-60Gy}\) (multivariate adjusted HR 0.10; 95% CI 0.03–0.33; p < 0.001) and SBRT (HR 0.31; 95% CI 0.12–0.80; p = 0.016), but not for BT (HR 0.66; 95% CI 0.22–1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established.

Conclusions
This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC.
KW  - adrenal tumours
KW  - adrenocortical carcinoma (ACC)
KW  - radiotherapy (RT)
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324411
VL  - 128
IS  - 4
ER  - 
TY  - JOUR
A1  - Klement, Rainer J.
A1  - Popp, Ilinca
A1  - Kaul, David
A1  - Ehret, Felix
A1  - Grosu, Anca L.
A1  - Polat, Bülent
A1  - Sweeney, Reinhart A.
A1  - Lewitzki, Victor
T1  - Accelerated hyper-versus normofractionated radiochemotherapy with temozolomide in patients with glioblastoma: a multicenter retrospective analysis
JF  - Journal of Neuro-Oncology
N2  - 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.
KW  - temozolomide
KW  - accelerated hyperfractionation
KW  - altered fractionation
KW  - glioblastoma
KW  - radiotherapy
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269806
SN  - 1573-7373
VL  - 156
IS  - 2
ER  - 
TY  - JOUR
A1  - Kraft, Johannes
A1  - Weick, Stefan
A1  - Breuer, Kathrin
A1  - Lutyj, Paul
A1  - Bratengeier, Klaus
A1  - Exner, Florian
A1  - Richter, Anne
A1  - Tamihardja, Jörg
A1  - Lisowski, Dominik
A1  - Polat, Bülent
A1  - Flentje, Michael
T1  - Treatment plan comparison for irradiation of multiple brain metastases with hippocampal avoidance whole brain radiotherapy and simultaneous integrated boost using the Varian Halcyon and the Elekta Synergy platforms
JF  - Radiation Oncology
N2  - No abstract available.
KW  - treatment plan
KW  - multiple brain metastases
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301221
VL  - 17
ER  - 
TY  - JOUR
A1  - Tamihardja, Jörg
A1  - Zehner, Leonie
A1  - Hartrampf, Philipp E.
A1  - Cirsi, Sinan
A1  - Wegener, Sonja
A1  - Buck, Andreas K.
A1  - Flentje, Michael
A1  - Polat, Bülent
T1  - Dose-escalated salvage radiotherapy for macroscopic local recurrence of prostate cancer in the prostate-specific membrane antigen positron emission tomography era
JF  - Cancers
N2  - 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.
KW  - prostate cancer
KW  - salvage radiotherapy
KW  - macroscopic recurrence
KW  - PSMA PET/CT
KW  - simultaneous integrated boost
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290302
SN  - 2072-6694
VL  - 14
IS  - 19
ER  - 
TY  - JOUR
A1  - Lisowski, Dominik
A1  - Trömel, Jannik
A1  - Lutyj, Paul
A1  - Lewitzki, Victor
A1  - Hartrampf, Philipp E.
A1  - Polat, Bülent
A1  - Flentje, Michael
A1  - Tamihardja, Jörg
T1  - Health-related quality of life and clinical outcome after radiotherapy of patients with intracranial meningioma
JF  - Scientific Reports
N2  - 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.
KW  - CNS cancer
KW  - outcomes research
KW  - radiotherapy
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301233
VL  - 12
ER  - 
TY  - JOUR
A1  - Fischer, Thomas
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Prieto-Garcia, Cristian
A1  - Klann, Kevin
A1  - Pahor, Nikolett
A1  - Schülein-Völk, Christina
A1  - Baluapuri, Apoorva
A1  - Polat, Bülent
A1  - Abazari, Arya
A1  - Gerhard-Hartmann, Elena
A1  - Kopp, Hans-Georg
A1  - Essmann, Frank
A1  - Rosenfeldt, Mathias
A1  - Münch, Christian
A1  - Flentje, Michael
A1  - Diefenbacher, Markus E.
T1  - PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy
JF  - Cell & Bioscience
N2  - 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.
KW  - PTEN
KW  - ATM
KW  - IR
KW  - NSCLC
KW  - radiotherapy
KW  - cancer
KW  - DNA-PK
KW  - PI3K
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299865
SN  - 2045-3701
VL  - 12
ER  - 
TY  - JOUR
A1  - Polat, Bülent
A1  - Wohlleben, Gisela
A1  - Kosmala, Rebekka
A1  - Lisowski, Dominik
A1  - Mantel, Frederick
A1  - Lewitzki, Victor
A1  - Löhr, Mario
A1  - Blum, Robert
A1  - Herud, Petra
A1  - Flentje, Michael
A1  - Monoranu, Camelia-Maria
T1  - Differences in stem cell marker and osteopontin expression in primary and recurrent glioblastoma
JF  - Cancer Cell International
N2  - 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.
KW  - Glioblastoma
KW  - Glioma stem cells
KW  - Osteopontin
KW  - CD133
KW  - Nestin
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301240
SN  - 1475-2867
VL  - 22
ER  - 
TY  - JOUR
A1  - Zimmermann, Marcus
A1  - Richter, Anne
A1  - Weick, Stefan
A1  - Exner, Florian
A1  - Mantel, Frederick
A1  - Diefenhardt, Markus
A1  - Fokas, Emmanouil
A1  - Kosmala, Rebekka
A1  - Flentje, Michael
A1  - Polat, Bülent
T1  - Acute toxicities of patients with locally advanced rectal cancer treated with intensified chemoradiotherapy within the CAO/ARO/AIO-12 trial: comparing conventional versus VMAT planning at a single center
JF  - Scientific Reports
N2  - 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.
KW  - radiotherapy
KW  - rectal cancer
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301255
VL  - 12
ER  - 
TY  - JOUR
A1  - Diefenhardt, Markus
A1  - Martin, Daniel
A1  - Ludmir, Ethan B.
A1  - Fleischmann, Maximilian
A1  - Hofheinz, Ralf-Dieter
A1  - Ghadimi, Michael
A1  - Kosmala, Rebekka
A1  - Polat, Bülent
A1  - Friede, Tim
A1  - Minsky, Bruce D.
A1  - Rödel, Claus
A1  - Fokas, Emmanouil
T1  - Development and validation of a predictive model for toxicity of neoadjuvant chemoradiotherapy in rectal cancer in the CAO/ARO/AIO-04 phase III trial
JF  - Cancers
N2  - 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.
KW  - rectal cancer
KW  - toxicity
KW  - neoadjuvant
KW  - chemoradiotherapy
KW  - risk score
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288081
SN  - 2072-6694
VL  - 14
IS  - 18
ER  - 
TY  - JOUR
A1  - Tamihardja, Jörg
A1  - Zehner, Leonie
A1  - Hartrampf, Philipp
A1  - Lisowski, Dominik
A1  - Kneitz, Susanne
A1  - Cirsi, Sinan
A1  - Razinskas, Gary
A1  - Flentje, Michael
A1  - Polat, Bülent
T1  - Salvage nodal radiotherapy as metastasis-directed therapy for oligorecurrent prostate cancer detected by positron emission tomography shows favorable outcome in long-term follow-up
JF  - Cancers
N2  - Simple Summary
Patients, who suffer from oligorecurrent prostate cancer with limited nodal involvement, may be offered positron emission tomography (PET)-directed salvage nodal radiotherapy to delay disease progression. This current analysis aimed to access salvage radiotherapy for nodal oligorecurrent prostate cancer with simultaneous integrated boost to PET-involved lymph nodes as metastasis-directed therapy. A long-term oncological outcome was favorable after salvage nodal radiotherapy and severe toxicity rates were low. Androgen deprivation therapy plays a major role in recurrent prostate cancer management and demonstrates a positive influence on the rate of biochemical progression in patients receiving salvage nodal radiotherapy. The present long-term analysis may help clinicians identify patients who would benefit from salvage nodal radiotherapy and androgen deprivation therapy, as a multimodal treatment strategy for oligorecurrent prostate cancer.
        
        
Abstract
Background: The study aimed to access the long-term outcome of salvage nodal radiotherapy (SNRT) in oligorecurrent prostate cancer. Methods: A total of 95 consecutive patients received SNRT for pelvic and/or extrapelvic nodal recurrence after prostate-specific membrane antigen (PSMA) or choline PET from 2010 to 2021. SNRT was applied as external beam radiotherapy with simultaneous integrated boost up to a median total dose of 62.9 Gy (EQD2\(_{1.5Gy}\)) to the recurrent lymph node metastases. The outcome was analyzed by cumulative incidence functions with death as the competing risk. Fine–Gray regression analyses were performed to estimate the relative hazards of the outcome parameters. Genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (v5.0). The results are as follows: the median follow-up was 47.1 months. The five-year biochemical progression rate (95% CI) was 50.1% (35.7–62.9%). Concomitant androgen deprivation therapy (ADT) was adminstered in 60.0% of the patients. The five-year biochemical progression rate was 75.0% (42.0–90.9%) without ADT versus 35.3% (19.6–51.4%) with ADT (p = 0.003). The cumulative five-year late grade 3 GU toxicity rate was 2.1%. No late grade 3 GI toxicity occured. Conclusions: Metastasis-directed therapy through SNRT for PET-staged oligorecurrent prostate cancer demonstrated a favorable long-term oncologic outcome. Omittance of ADT led to an increased biochemical progression.
KW  - metastasis-directed therapy
KW  - long-term outcome
KW  - oligorecurrence
KW  - prostate cancer
KW  - salvage radiotherapy
KW  - PSMA
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286064
SN  - 2072-6694
VL  - 14
IS  - 15
ER  -