Publications by authors named "Claus Belka"

366 Publications

Comparison of liver exposure in CT-guided high-dose rate (HDR) interstitial brachytherapy versus SBRT in hepatocellular carcinoma.

Radiat Oncol 2021 May 6;16(1):86. Epub 2021 May 6.

Department of Radiation Oncology, University Hospital, LMU Munich, 81377, Munich, Germany.

Background: In unresectable hepatocellular carcinoma several local ablative treatments are available. Among others, radiation based treatments such as stereotactic body radiotherapy (SBRT) and high-dose rate interstitial brachytherapy (HDR BT) have shown good local control rates.

Methods: We conducted a dose comparison between actually performed HDR BT versus virtually planned SBRT to evaluate the respective clinically relevant radiation exposure to uninvolved liver tissue. Moreover, dose coverage and conformity indices were assessed.

Results: Overall, 46 treatment sessions (71 lesions, 38 patients) were evaluated. HDR BT was applied in a single fraction with a dose prescription of 1 × 15 Gy. D98 was 17.9 ± 1.3 Gy, D50 was 41.8 ± 8.1 Gy. The SBRT was planned with a prescribed dose of 3 × 12.5 Gy (65%-Isodose), D98 was 50.7 ± 3.1 Gy, D2 was 57.0 ± 2.3 Gy, and D50 was 55.2 ± 2.3 Gy. Regarding liver exposure Vliver10Gy was compared to Vliver15.9Gy, Vliver16.2Gy (EQD2 equivalent doses), and Vliver20Gy (clinically relevant dose), all results showed significant differences (p < .001). In a case by case analysis Vliver10Gy was smaller than Vliver20Gy in 38/46 cases (83%). Dmean of the liver was significantly smaller in BT compared to SBRT (p < .001). GTV volume was correlated to the liver exposure and showed an advantage of HDR BT over SBRT in comparison of clinically relevant doses, and for EQD2 equivalent doses. The advantage was more pronounced for greater liver lesions The Conformity Index (CI) was significantly better for BT, while Healthy Tissue Conformity Index (HTCI) and Conformation Number (CN) showed an advantage for SBRT (p < .001).

Conclusion: HDR BT can be advantageous in respect of sparing of normal liver tissue as compared to SBRT, while providing excellent target conformity.
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http://dx.doi.org/10.1186/s13014-021-01812-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103624PMC
May 2021

Simultaneous stereotactic radiosurgery of multiple brain metastases using single-isocenter dynamic conformal arc therapy: a prospective monocentric registry trial.

Strahlenther Onkol 2021 Apr 21. Epub 2021 Apr 21.

Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistraße 15, 81377, Munich, Germany.

Background: Single-isocenter dynamic conformal arc (SIDCA) therapy is a technically efficient way of delivering stereotactic radiosurgery (SRS) to multiple metastases simultaneously. This study reports on the safety and feasibility of linear accelerator (LINAC) based SRS with SIDCA for patients with multiple brain metastases.

Methods: All patients who received SRS with this technique between November 2017 and June 2019 within a prospective registry trial were included. The patients were irradiated with a dedicated planning tool for multiple brain metastases using a LINAC with a 5 mm multileaf collimator. Follow-up was performed every 3 months, including clinical and radiological examination with cranial magnetic resonance imaging (MRI). These early data were analyzed using descriptive statistics and the Kaplan-Meier method.

Results: A total of 65 patients with 254 lesions (range 2-12) were included in this analysis. Median beam-on time was 23 min. The median follow-up at the time of analysis was 13 months (95% CI 11.1-14.9). Median overall survival and median intracranial progression-free survival was 15 months (95% CI 7.7-22.3) and 7 months (95% CI 3.9-10.0), respectively. Intracranial and local control after 1 year was 64.6 and 97.5%, respectively. During follow-up, CTCAE grade I adverse effects (AE) were experienced by 29 patients (44.6%; 18 of them therapy related, 27.7%), CTCAE grade II AEs by four patients (6.2%; one of them therapy related, 1.5%), and CTCAE grade III by three patients (4.6%; none of them therapy related). Two lesions (0.8%) in two patients (3.1%) were histopathologically proven to be radiation necrosis.

Conclusion: Simultaneous SRS using SIDCA seems to be a feasible and safe treatment for patients with multiple brain metastases.
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http://dx.doi.org/10.1007/s00066-021-01773-6DOI Listing
April 2021

Current status and recent advances in resection cavity irradiation of brain metastases.

Radiat Oncol 2021 Apr 15;16(1):73. Epub 2021 Apr 15.

Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.

Despite complete surgical resection brain metastases are at significant risk of local recurrence without additional radiation therapy. Traditionally, the addition of postoperative whole brain radiotherapy (WBRT) has been considered the standard of care on the basis of randomized studies demonstrating its efficacy in reducing the risk of recurrence in the surgical bed as well as the incidence of new distant metastases. More recently, postoperative stereotactic radiosurgery (SRS) to the surgical bed has emerged as an effective and safe treatment option for resected brain metastases. Published randomized trials have demonstrated that postoperative SRS to the resection cavity provides superior local control compared to surgery alone, and significantly decreases the risk of neurocognitive decline compared to WBRT, without detrimental effects on survival. While studies support the use of postoperative SRS to the resection cavity as the standard of care after surgery, there are several issues that need to be investigated further with the aim of improving local control and reducing the risk of leptomeningeal disease and radiation necrosis, including the optimal dose prescription/fractionation, the timing of postoperative SRS treatment, and surgical cavity target delineation. We provide a clinical overview on current status and recent advances in resection cavity irradiation of brain metastases, focusing on relevant strategies that can improve local control and minimize the risk of radiation-induced toxicity.
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http://dx.doi.org/10.1186/s13014-021-01802-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051036PMC
April 2021

Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond.

Front Oncol 2021 17;11:612354. Epub 2021 Mar 17.

Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.

Radiotherapy is an essential component of multi-modality treatment of glioblastoma (GBM). However, treatment failure and recurrence are frequent and give rise to the dismal prognosis of this aggressive type of primary brain tumor. A high level of inherent treatment resistance is considered to be the major underlying reason, stemming from constantly activated DNA damage response (DDR) mechanisms as a consequence of oncogene overexpression, persistent replicative stress, and other so far unknown reasons. The molecular chaperone heat shock protein 90 (HSP90) plays an important role in the establishment and maintenance of treatment resistance, since it crucially assists the folding and stabilization of various DDR regulators. Accordingly, inhibition of HSP90 represents a multi-target strategy to interfere with DDR function and to sensitize cancer cells to radiotherapy. Using NW457, a pochoxime-based HSP90 inhibitor with favorable brain pharmacokinetic profile, we show here that HSP90 inhibition at low concentrations with limited cytotoxicity leads to downregulation of various DNA damage response factors on the protein level, distinct transcriptomic alterations, impaired DNA damage repair, and reduced clonogenic survival in response to ionizing irradiation in glioblastoma cells . , HSP90 inhibition by NW457 improved the therapeutic outcome of fractionated CBCT-based irradiation in an orthotopic, syngeneic GBM mouse model, both in terms of tumor progression and survival. Nevertheless, in view of the promising results the efficacy was not as strong as expected, although apart from the radiosensitizing effects HSP90 inhibition also reduced irradiation-induced GBM cell migration and tumor invasiveness. Hence, our findings identify the combination of HSP90 inhibition and radiotherapy in principle as a promising strategy for GBM treatment whose performance needs to be further optimized by improved inhibitor substances, better formulations and/or administration routes, and fine-tuned treatment sequences.
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http://dx.doi.org/10.3389/fonc.2021.612354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011354PMC
March 2021

Feasibility and Early Clinical Experience of Online Adaptive MR-Guided Radiotherapy of Liver Tumors.

Cancers (Basel) 2021 Mar 26;13(7). Epub 2021 Mar 26.

Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistr 15, 81377 Munich, Germany.

Purpose: To assess the feasibility and early results of online adaptive MR-guided radiotherapy (oMRgRT) of liver tumors.

Methods: We retrospectively examined consecutive patients with primary or secondary liver lesions treated at our institution using a 0.35T hybrid MR-Linac (Viewray Inc., Mountain View, CA, USA). Online-adaptive treatment planning was used to account for interfractional anatomical changes, and real-time intrafractional motion management using online 2D cine MRI was performed using a respiratory gating approach. Treatment response and toxicity were assessed during follow-up.

Results: Eleven patients and a total of 15 lesions were evaluated. Histologies included cholangiocarcinomas and metastases of neuroendocrine tumors, colorectal carcinomas, sarcomas and a gastrointestinal stroma tumor. The median BED of the PTV prescription doses was 84.4 Gy (range 59.5-112.5 Gy) applied in 3-5 fractions and the mean GTV BED was in median 147.9 Gy (range 71.7-200.5 Gy). Online plan adaptation was performed in 98% of fractions. The median overall treatment duration was 53 min. The treatment was feasible and successfully completed in all patients. After a median follow-up of five months, no local failure occurred and no ≥ grade two toxicity was observed. OMRgRT resulted in better PTV coverage and fewer OAR constraint violations.

Conclusion: Early results of MR-linac based oMRgRT for the primary and secondary liver tumors are promising. The treatment was feasible in all cases and well tolerated with minimal toxicity. The technique should be compared to conventional SBRT in further studies to assess the advantages of the technique.
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http://dx.doi.org/10.3390/cancers13071523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037065PMC
March 2021

Durvalumab after Chemoradiotherapy for PD-L1 Expressing Inoperable Stage III NSCLC Leads to Significant Improvement of Local-Regional Control and Overall Survival in the Real-World Setting.

Cancers (Basel) 2021 Mar 31;13(7). Epub 2021 Mar 31.

Department of Radiation Oncology, University Hospital, LMU Munich, 81377 Munich, Germany.

Concurrent chemoradiotherapy (CRT) followed by maintenance treatment with the PD-L1 inhibitor durvalumab is a new standard of care for inoperable stage III NSCLC. The present study compares the oncological outcome of patients treated with CRT to those treated with CRT and durvalumab (CRT-IO) in the real-world setting. The analysis was performed based on the retro- and prospectively collected data of 144 consecutive inoperable stage III NSCLC patients treated between 2011-2020. Local-regional-progression-free-survival (LRPFS-defined as progression in the mediastinum, hilum and/or supraclavicular region at both sites and the involved lung), progression-free survival (PFS), and overall survival (OS) were evaluated from the last day of thoracic radiotherapy (TRT). Median follow-up for the entire cohort was 33.1 months (range: 6.3-111.8) and median overall survival was 27.2 (95% CI: 19.5-34.9) months. In the CRT-IO cohort after a median follow-up of 20.9 (range: 6.3-27.4) months, median PFS was not reached, LRPFS ( = 0.002), PFS ( = 0.018), and OS ( = 0.005) were significantly improved vs. the historical cohort of conventional CRT patients. After propensity-score matching (PSM) analysis with age, gender, histology, tumor volume, and treatment mode, and exact matching for T-and N-stage, 22 CRT-IO patients were matched 1:2 to 44 CRT patients. Twelve-month LRPFS, PFS, and OS rates in the CRT-IO vs. CRT cohort were 78.9 vs. 45.5% ( = 0.002), 60.0 vs. 31.8% ( = 0.007), and 100 vs. 70.5% ( = 0.003), respectively. This real-world analysis demonstrated that durvalumab after CRT led to significant improvement of local-regional control, PFS, and OS in PD-L1 expressing inoperable stage III NSCLC patients compared to a historical cohort.
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http://dx.doi.org/10.3390/cancers13071613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037429PMC
March 2021

Neoadjuvant Chemoradiation Combined with Regional Hyperthermia in Locally Advanced or Recurrent Rectal Cancer.

Cancers (Basel) 2021 Mar 13;13(6). Epub 2021 Mar 13.

Department of Radiation Oncology, Universitätsklinikum Erlangen, 91054 Erlangen, Germany.

Background: To prospectively analyze feasibility and pathological complete response (pCR) rates of neoadjuvant chemoradiotherapy combined with regional hyperthermia (RHT) in patients with locally advanced (LARC) or recurrent (LRRC) rectal cancer.

Methods: between 2012 and 2018, 111 patients with UICC stage IIB-IV or any locally recurrent rectal cancer were included (HyRec-Trial, ClinicalTrials.gov Identifier: NCT01716949). Patients received radiotherapy with concurrent 5-Fluororuracil (5-FU)/Capecitabine and Oxaliplatin, and RHT. Stage 1 feasibility analysis evaluated dose-limiting toxicities (DLT) after 19 patients, stage 2 after 59 evaluable patients. Analysis of the pCR rate was based on histopathological reports.

Results: the feasibility rates for stages 1 and 2 were 90% (17/19) and 73% (43/59), respectively. In the intention-to-treat population the pCR rate was 19% (20/105; 90% confidence interval (CI) 13.0-26.5). In the per-protocol-analysis, complete tumor regression was seen in 28% (18/64) and 38% (3/8) of the patients with LARC and LRRC, respectively. Complete resection rates (R0) among patients with LARC and LRRC who received surgery were 99% (78/84) and 67% (8/12).

Conclusions: the intensified neoadjuvant and multimodality treatment schedule was feasible and led to comparable early toxicity rates as described by other trials that used the similar chemoradiation protocol. The presented treatment regimen resulted in a very high pCR rate and appears as a promising option for patients with LRRC.
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http://dx.doi.org/10.3390/cancers13061279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001688PMC
March 2021

ESTRO-ACROP recommendations on the clinical implementation of hybrid MR-linac systems in radiation oncology.

Radiother Oncol 2021 Mar 26;159:146-154. Epub 2021 Mar 26.

Department of Radiation Oncology, University Hospital, LMU Munich, Germany.

Online magnetic resonance-guided radiotherapy (oMRgRT) represents one of the most innovative applications of current image-guided radiation therapy (IGRT). The revolutionary concept of oMRgRT systems is the ability to acquire MR images for adaptive treatment planning and also online imaging during treatment delivery. The daily adaptive planning strategies allow to improve targeting accuracy while avoiding critical structures. This ESTRO-ACROP recommendation aims to provide an overview of available systems and guidance for best practice in the implementation phase of hybrid MR-linac systems. Unlike the implementation of other radiotherapy techniques, oMRgRT adds the MR environment to the daily practice of radiotherapy, which might be a new experience for many centers. New issues and challenges that need to be thoroughly explored before starting clinical treatments will be highlighted.
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http://dx.doi.org/10.1016/j.radonc.2021.03.025DOI Listing
March 2021

PET/CT imaging for evaluation of multimodal treatment efficacy and toxicity in advanced NSCLC-current state and future directions.

Eur J Nucl Med Mol Imaging 2021 Mar 24. Epub 2021 Mar 24.

Department of Nuclear Medicine, University Hospital, LMU Munich, Munich, Germany.

Purpose: The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced NSCLC, leading to a string of approvals in recent years. Herein, a narrative review on the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in the ever-evolving treatment landscape of advanced NSCLC is presented.

Methods: This comprehensive review will begin with an introduction into current treatment paradigms incorporating ICIs; the evolution of CT-based criteria; moving onto novel phenomena observed with ICIs and the current state of hybrid imaging for diagnosis, treatment planning, evaluation of treatment efficacy and toxicity in advanced NSCLC, also taking into consideration its limitations and future directions.

Conclusions: The advent of ICIs marks the dawn of a new era bringing forth new challenges particularly vis-à-vis treatment response assessment and observation of novel phenomena accompanied by novel systemic side effects. While FDG PET/CT is widely adopted for tumor volume delineation in locally advanced disease, response assessment to immunotherapy based on current criteria is of high clinical value but has its inherent limitations. In recent years, modifications of established (PET)/CT criteria have been proposed to provide more refined approaches towards response evaluation. Not only a comprehensive inclusion of PET-based response criteria in prospective randomized controlled trials, but also a general harmonization within the variety of PET-based response criteria is pertinent to strengthen clinical implementation and widespread use of hybrid imaging for response assessment in NSCLC.
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http://dx.doi.org/10.1007/s00259-021-05211-8DOI Listing
March 2021

Identification and validation of hypoxia-derived gene signatures to predict clinical outcomes and therapeutic responses in stage I lung adenocarcinoma patients.

Theranostics 2021 5;11(10):5061-5076. Epub 2021 Mar 5.

Department of Radiation Oncology, University Hospital, LMU Munich, Munich D-81377, Germany.

The current tumour-node-metastasis (TNM) staging system is insufficient for precise treatment decision-making and accurate survival prediction for patients with stage I lung adenocarcinoma (LUAD). Therefore, more reliable biomarkers are urgently needed to identify the high-risk subset in stage I patients to guide adjuvant therapy. This study retrospectively analysed the transcriptome profiles and clinical parameters of 1,400 stage I LUAD patients from 14 public datasets, including 13 microarray datasets from different platforms and 1 RNA-Seq dataset from The Cancer Genome Atlas (TCGA). A series of bioinformatic and machine learning approaches were combined to establish hypoxia-derived signatures to predict overall survival (OS) and immune checkpoint blockade (ICB) therapy response in stage I patients. In addition, enriched pathways, genomic and copy number alterations were analysed in different risk subgroups and compared to each other. Among various hallmarks of cancer, hypoxia was identified as a dominant risk factor for overall survival in stage I LUAD patients. The hypoxia-related prognostic risk score (HPRS) exhibited more powerful capacity of survival prediction compared to traditional clinicopathological features, and the hypoxia-related immunotherapeutic response score (HIRS) outperformed conventional biomarkers for ICB therapy. An integrated decision tree and nomogram were generated to optimize risk stratification and quantify risk assessment. In summary, the proposed hypoxia-derived signatures are promising biomarkers to predict clinical outcomes and therapeutic responses in stage I LUAD patients.
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http://dx.doi.org/10.7150/thno.56202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978303PMC
March 2021

Radiotherapy of oligometastatic prostate cancer: a systematic review.

Radiat Oncol 2021 Mar 9;16(1):50. Epub 2021 Mar 9.

Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.

Background: Due to improved imaging sensitivity, the term "oligometastatic" prostate cancer disease is diagnosed more often, leading to an increasing interest in metastasis-directed therapy (MDT). There are two types of radiation based MDT applied when treating oligometastatic disease: (1) stereotactic body radiation therapy (SBRT) generally used for bone metastases; or (2) SBRT for isolated nodal oligometastases combined with prophylactic elective nodal radiotherapy. This review aims to summarize current evidence data, which may shed light on the optimal management of this heterogeneous group of patients.

Methods: A systematic review of the Medline database through PubMed was performed according to PRISMA guidelines. All relevant studies published up to November 2020 were identified and screened. Fifty-six titles were included. Besides outcome parameters, different prognostic and predictive factors were assessed, including site of metastases, time between primary treatment and MDT, use of systemic therapies, hormone sensitivity, as well as pattern of recurrence.

Findings: Evidence consists largely of retrospective case series and no consistent precise definition of oligometastasis exists, however, most investigators seem to acknowledge the need to distinguish between patients presenting with what is frequently called "synchronous" versus "metachronous" oligometastatic disease. Available data on radiotherapy as MDT demonstrate high local control rates and a small but relevant proportion of patients without progressive disease after 2 years. This holds true for both hormone sensitive and castration resistant prostate cancer diseases. The use of Ga-PSMA PET/CT for staging increased dramatically. Radiation doses and field sizes varied considerably among the studies. The search for relevant prognostic and predictive factors is ongoing.

Conclusions: To our best knowledge this review on oligometastatic prostate cancer included the largest number of original articles. It demonstrates the therapeutic potential and challenges of MDT for oligometastatic prostate cancer. Prospective studies are under way and will provide further high-level evidence.
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http://dx.doi.org/10.1186/s13014-021-01776-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941976PMC
March 2021

Distant metastasis time to event analysis with CNNs in independent head and neck cancer cohorts.

Sci Rep 2021 Mar 19;11(1):6418. Epub 2021 Mar 19.

Department of Radiation Oncology, University Hospital, LMU Munich, Munich, 81377, Germany.

Deep learning models based on medical images play an increasingly important role for cancer outcome prediction. The standard approach involves usage of convolutional neural networks (CNNs) to automatically extract relevant features from the patient's image and perform a binary classification of the occurrence of a given clinical endpoint. In this work, a 2D-CNN and a 3D-CNN for the binary classification of distant metastasis (DM) occurrence in head and neck cancer patients were extended to perform time-to-event analysis. The newly built CNNs incorporate censoring information and output DM-free probability curves as a function of time for every patient. In total, 1037 patients were used to build and assess the performance of the time-to-event model. Training and validation was based on 294 patients also used in a previous benchmark classification study while for testing 743 patients from three independent cohorts were used. The best network could reproduce the good results from 3-fold cross validation [Harrell's concordance indices (HCIs) of 0.78, 0.74 and 0.80] in two out of three testing cohorts (HCIs of 0.88, 0.67 and 0.77). Additionally, the capability of the models for patient stratification into high and low-risk groups was investigated, the CNNs being able to significantly stratify all three testing cohorts. Results suggest that image-based deep learning models show good reliability for DM time-to-event analysis and could be used for treatment personalisation.
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http://dx.doi.org/10.1038/s41598-021-85671-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979766PMC
March 2021

Real-world prospective analysis of treatment patterns in durvalumab maintenance after chemoradiotherapy in unresectable, locally advanced NSCLC patients.

Invest New Drugs 2021 Mar 11. Epub 2021 Mar 11.

Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistrasse 15, 81377, Munich, Germany.

The aim of this prospective study is to evaluate the clinical use and real-world efficacy of durvalumab maintenance treatment after chemoradiotherapy (CRT) in unresectable stage, locally advanced non-small cell lung cancer (NSCLC). All consecutive patients with unresectable, locally advanced NSCLC and PD-L1 expression (≥1%) treated after October 2018 were included. Regular follow up, including physical examination, PET/CT and/or contrast-enhanced CT-Thorax/Abdomen were performed every three months after CRT. Descriptive treatment pattern analyses, including reasons of discontinuation and salvage treatment, were undertaken. Statistics were calculated from the last day of thoracic irradiation (TRT). Twenty-six patients were included. Median follow up achieved 20.6 months (range: 1.9-30.6). Durvalumab was initiated after a median of 25 (range: 13-103) days after completion of CRT. In median 14 (range: 2-24) cycles of durvalumab were applied within 6.4 (range 1-12.7) months. Six patients (23%) are still in treatment and seven (27%) have completed treatment with 24 cycles. Maintenance treatment was discontinued in 13 (50%) patients: 4 (15%) patients developed grade 3 pneumonitis according to CTCAE v5 after a median of 3.9 (range: 0.5-11.6) months and 7 (range: 2-17) cycles of durvalumab. Four (15%) patients developed grade 2 skin toxicity. One (4%) patient has discontinued treatment due to incompliance. Six and 12- month progression-free survival (PFS) rates were 82% and 62%, median PFS was not reached. No case of hyperprogression was documented. Eight (31%) patients have relapsed during maintenance treatment after a median of 4.8 (range: 2.2-11.3) months and 11 (range: 6-17) durvalumab cycles. Two patients (9%) developed a local-regional recurrence after 14 and 17 cycles of durvalumab. Extracranial distant metastases and brain metastases as first site of failure were detected in 4 (15%) and 2 (8%) patients, respectively. Three (13%) patients presented with symptomatic relapse. Our prospective study confirmed a favourable safety profile of durvalumab maintenance treatment after completion of CRT in unresectable stage, locally advanced NSCLC in a real-world setting. In a median follow-up time of 20.6 months, durvalumab was discontinued in 27% of all patients due to progressive disease. All patients with progressive disease were eligible for second-line treatment.
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http://dx.doi.org/10.1007/s10637-021-01091-9DOI Listing
March 2021

Radiation necrosis after a combination of external beam radiotherapy and iodine-125 brachytherapy in gliomas.

Radiat Oncol 2021 Feb 23;16(1):40. Epub 2021 Feb 23.

Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.

Purpose: Frequency and risk profile of radiation necrosis (RN) in patients with glioma undergoing either upfront stereotactic brachytherapy (SBT) and additional salvage external beam radiotherapy (EBRT) after tumor recurrence or vice versa remains unknown.

Methods: Patients with glioma treated with low-activity temporary iodine-125 SBT at the University of Munich between 1999 and 2016 who had either additional upfront or salvage EBRT were included. Biologically effective doses (BED) were calculated. RN was diagnosed using stereotactic biopsy and/or metabolic imaging. The rate of RN was estimated with the Kaplan Meier method. Risk factors were obtained from logistic regression models.

Results: Eighty-six patients (49 male, 37 female, median age 47 years) were included. 38 patients suffered from low-grade and 48 from high-grade glioma. Median follow-up was 15 months after second treatment. Fifty-eight patients received upfront EBRT (median total dose: 60 Gy), and 28 upfront SBT (median reference dose: 54 Gy, median dose rate: 10.0 cGy/h). Median time interval between treatments was 19 months. RN was diagnosed in 8/75 patients. The 1- and 2-year risk of RN was 5.1% and 11.7%, respectively. Tumor volume and irradiation time of SBT, number of implanted seeds, and salvage EBRT were risk factors for RN. Neither of the BED values nor the time interval between both treatments gained prognostic influence.

Conclusion: The combination of upfront EBRT and salvage SBT or vice versa is feasible for glioma patients. The risk of RN is mainly determined by the treatment volume but not by the interval between therapies.
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http://dx.doi.org/10.1186/s13014-021-01762-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903688PMC
February 2021

Current status and recent advances in reirradiation of glioblastoma.

Radiat Oncol 2021 Feb 18;16(1):36. Epub 2021 Feb 18.

Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.

Despite aggressive management consisting of maximal safe surgical resection followed by external beam radiation therapy (60 Gy/30 fractions) with concomitant and adjuvant temozolomide, approximately 90% of WHO grade IV gliomas (glioblastomas, GBM) will recur locally within 2 years. For patients with recurrent GBM, no standard of care exists. Thanks to the continuous improvement in radiation science and technology, reirradiation has emerged as feasible approach for patients with brain tumors. Using stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT), either hypofractionated or conventionally fractionated schedules, several studies have suggested survival benefits following reirradiation of patients with recurrent GBM; however, there are still questions to be answered about the efficacy and toxicity associated with a second course of radiation. We provide a clinical overview on current status and recent advances in reirradiation of GBM, addressing relevant clinical questions such as the appropriate patient selection and radiation technique, optimal dose fractionation, reirradiation tolerance of the brain and the risk of radiation necrosis.
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http://dx.doi.org/10.1186/s13014-021-01767-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890828PMC
February 2021

X-change symposium: status and future of modern radiation oncology-from technology to biology.

Radiat Oncol 2021 Feb 4;16(1):27. Epub 2021 Feb 4.

Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.

Future radiation oncology encompasses a broad spectrum of topics ranging from modern clinical trial design to treatment and imaging technology and biology. In more detail, the application of hybrid MRI devices in modern image-guided radiotherapy; the emerging field of radiomics; the role of molecular imaging using positron emission tomography and its integration into clinical routine; radiation biology with its future perspectives, the role of molecular signatures in prognostic modelling; as well as special treatment modalities such as brachytherapy or proton beam therapy are areas of rapid development. More clinically, radiation oncology will certainly find an important role in the management of oligometastasis. The treatment spectrum will also be widened by the rational integration of modern systemic targeted or immune therapies into multimodal treatment strategies. All these developments will require a concise rethinking of clinical trial design. This article reviews the current status and the potential developments in the field of radiation oncology as discussed by a panel of European and international experts sharing their vision during the "X-Change" symposium, held in July 2019 in Munich (Germany).
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http://dx.doi.org/10.1186/s13014-021-01758-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863262PMC
February 2021

A Privacy-Preserving Log-Rank Test for the Kaplan-Meier Estimator With Secure Multiparty Computation: Algorithm Development and Validation.

JMIR Med Inform 2021 Jan 18;9(1):e22158. Epub 2021 Jan 18.

Chair of Network Architectures and Services, Department of Informatics, Technical University of Munich, TUM, Garching, Germany.

Background: Patient data is considered particularly sensitive personal data. Privacy regulations strictly govern the use of patient data and restrict their exchange. However, medical research can benefit from multicentric studies in which patient data from different institutions are pooled and evaluated together. Thus, the goals of data utilization and data protection are in conflict. Secure multiparty computation (SMPC) solves this conflict because it allows direct computation on distributed proprietary data-held by different data owners-in a secure way without exchanging private data.

Objective: The objective of this work was to provide a proof-of-principle of secure and privacy-preserving multicentric computation by SMPC with real-patient data over the free internet. A privacy-preserving log-rank test for the Kaplan-Meier estimator was implemented and tested in both an experimental setting and a real-world setting between two university hospitals.

Methods: The domain of survival analysis is particularly relevant in clinical research. For the Kaplan-Meier estimator, we provided a secure version of the log-rank test. It was based on the SMPC realization SPDZ and implemented via the FRESCO framework in Java. The complexity of the algorithm was explored both for synthetic data and for real-patient data in a proof-of-principle over the internet between two clinical institutions located in Munich and Berlin, Germany.

Results: We obtained a functional realization of an SMPC-based log-rank evaluation. This implementation was assessed with respect to performance and scaling behavior. We showed that network latency strongly influences execution time of our solution. Furthermore, we identified a lower bound of 2 Mbit/s for the transmission rate that has to be fulfilled for unimpeded communication. In contrast, performance of the participating parties have comparatively low influence on execution speed, since the peer-side processing is parallelized and the computational time only constitutes 30% to 50% even with optimal network settings. In the real-world setting, our computation between three parties over the internet, processing 100 items each, took approximately 20 minutes.

Conclusions: We showed that SMPC is applicable in the medical domain. A secure version of commonly used evaluation methods for clinical studies is possible with current implementations of SMPC. Furthermore, we infer that its application is practically feasible in terms of execution time.
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http://dx.doi.org/10.2196/22158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850908PMC
January 2021

Radiation to the Primary Tumor in Metastatic Anaplastic Thyroid Cancer.

In Vivo 2021 Jan-Feb;35(1):461-465

Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany;

Background/aim: Metastatic anaplastic thyroid cancer is associated with a dismal prognosis. We evaluated outcome and prognostic factors in patients receiving radiation to the primary tumor in metastatic anaplastic thyroid cancer (ATC).

Patients And Methods: All consecutive patients with metastatic ATC (n=20) undergoing irradiation between 2009 and 2019 for anaplastic thyroid cancer were investigated.

Results: Median survival time and median progression-free survival were 2 (range=1-22) and 2 (1-20) months. In univariate analyses, surgery, concurrent or sequential chemotherapy and higher radiation dose escalation (>39 Gy) were correlated with longer overall survival (p=0.005, p=0.018 and p=0.038), respectively. Karnofsky performance status >70% showed a trend of longer survival time (p=0.062). Limited metastatic disease, surgery and concurrent/sequential chemotherapy are correlated with longer progression-free survival times (p=0.043, p=0.024 and p=0.039), respectively.

Conclusion: Radiation to the primary tumor in metastatic anaplastic thyroid cancer is safe and offers durable local control. Treatment intensification including concurrent or sequential chemotherapy and radiation dose escalation were associated with longer survival rates and should be considered in selected patients with metastatic disease.
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http://dx.doi.org/10.21873/invivo.12279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880735PMC
November 2020

Digital scoring of EpCAM and slug expression as prognostic markers in head and neck squamous cell carcinomas.

Mol Oncol 2021 Apr 29;15(4):1040-1053. Epub 2020 Dec 29.

Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-University Munich, Germany.

Head and neck squamous cell carcinomas (HNSCCs) have poor clinical outcome owing to therapy resistance and frequent recurrences that are among others attributable to tumor cells in partial epithelial-to-mesenchymal transition (pEMT). We compared side-by-side software-based and visual quantification of immunohistochemistry (IHC) staining of epithelial marker EpCAM and EMT regulator Slug in n = 102 primary HNSCC to assess optimal analysis protocols. IHC scores incorporated expression levels and percentages of positive cells. Digital and visual evaluation of membrane-associated EpCAM yielded correlating scorings, whereas visual evaluation of nuclear Slug resulted in significantly higher overall scores. Multivariable Cox proportional hazard analysis defined the median EpCAM expression levels resulting from visual quantification as an independent prognostic factor of overall survival. Slug expression levels resulting from digital quantification were an independent prognostic factor of recurrence-free survival, locoregional recurrence-free survival, and disease-specific survival. Hence, we propose to use visual assessment for the membrane-associated EpCAM protein, whereas nuclear protein Slug assessment was more accurate following digital measurement.
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http://dx.doi.org/10.1002/1878-0261.12886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024715PMC
April 2021

ESTRO ACROP guideline for target volume delineation of skull base tumors.

Radiother Oncol 2021 03 10;156:80-94. Epub 2020 Dec 10.

Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy; IRCCS Neuromed, Pozzilli, Italy. Electronic address:

Background And Purpose: For skull base tumors, target definition is the key to safe high-dose treatments because surrounding normal tissues are very sensitive to radiation. In the present work we established a joint ESTRO ACROP guideline for the target volume definition of skull base tumors.

Material And Methods: A comprehensive literature search was conducted in PubMed using various combinations of the following medical subjects headings (MeSH) and free-text words: "radiation therapy" or "stereotactic radiosurgery" or "proton therapy" or "particle beam therapy" and "skull base neoplasms" "pituitary neoplasms", "meningioma", "craniopharyngioma", "chordoma", "chondrosarcoma", "acoustic neuroma/vestibular schwannoma", "organs at risk", "gross tumor volume", "clinical tumor volume", "planning tumor volume", "target volume", "target delineation", "dose constraints". The ACROP committee identified sixteen European experts in close interaction with the ESTRO clinical committee who analyzed and discussed the body of evidence concerning target delineation.

Results: All experts agree that magnetic resonance (MR) images with high three-dimensional spatial accuracy and tissue-contrast definition, both T2-weighted and volumetric T1-weighted sequences, are required to improve target delineation. In detail, several key issues were identified and discussed: i) radiation techniques and immobilization, ii) imaging techniques and target delineation, and iii) technical aspects of radiation treatments including planning techniques and dose-fractionation schedules. Specific target delineation issues with regard to different skull base tumors, including pituitary adenomas, meningiomas, craniopharyngiomas, acoustic neuromas, chordomas and chondrosarcomas are presented.

Conclusions: This ESTRO ACROP guideline achieved detailed recommendations on target volume definition for skull base tumors, as well as comprehensive advice about imaging modalities and radiation techniques.
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http://dx.doi.org/10.1016/j.radonc.2020.11.014DOI Listing
March 2021

Improved risk stratification in younger wild-type glioblastoma patients by combining a 4-miRNA signature with promoter methylation status.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa137. Epub 2020 Oct 15.

Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.

Background: The potential benefit of risk stratification using a 4-miRNA signature in combination with promoter methylation in wild-type glioblastoma patients was assessed.

Methods: Primary tumors from 102 patients with comparable treatment from the LMU Munich ( = 37), the University Hospital Düsseldorf ( = 33), and The Cancer Genome Atlas ( = 32) were included. Risk groups were built using expressions of hsa-let-7a-5p, hsa-let-7b-5p, hsa-miR-615-5p, and hsa-miR-125a-5p to assess prognostic performance in overall survival (OS). promoter methylation and age were considered as cofactors. Integrated miRNA, DNA methylome, and transcriptome analysis were used to explore the functional impact of signature miRNAs.

Results: The 4-miRNA signature defined high-risk ( = 46, median OS: 15.8 months) and low-risk patients ( = 56, median OS: 20.7 months; univariable Cox proportional hazard analysis: hazard ratio [HR]: 1.8, 95% confidence interval [CI]: 1.14-2.83, = .01). The multivariable Cox proportional hazard model including the 4-miRNA signature ( = .161), promoter methylation ( < .001), and age ( = .034) significantly predicted OS (Log-rank < .0001). Likewise to clinical routine, analysis was performed for younger (≤60 years, = 50, median OS: 20.2 months) and older patients (>60 years, = 52, median OS: 15.8) separately. In younger patients, the 4-miRNA signature had prognostic value (HR: 1.92, 95% CI: 0.93-3.93, = .076). Particularly, younger, methylated, 4-miRNA signature low-risk patients ( = 18, median OS: 37.4 months) showed significantly improved survival, compared to other younger patients ( = 32, OS 18.5 months; HR: 0.33, 95% CI: 0.15-0.71, = .003). Integrated data analysis revealed 4-miRNA signature-associated genes and pathways.

Conclusion: The prognostic 4-miRNA signature in combination with promoter methylation improved risk stratification with the potential for therapeutic substratification, especially of younger patients.
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http://dx.doi.org/10.1093/noajnl/vdaa137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712804PMC
October 2020

Long-term outcome of stereotactic brachytherapy with temporary Iodine-125 seeds in patients with WHO grade II gliomas.

Radiat Oncol 2020 Dec 9;15(1):275. Epub 2020 Dec 9.

Department of Radiation Oncology, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.

Background: This long-term retrospective analysis aimed to investigate the outcome and toxicity profile of stereotactic brachytherapy (SBT) in selected low-grade gliomas WHO grade II (LGGII) in a large patient series.

Methods: This analysis comprised 106 consecutive patients who received SBT with temporary Iodine-125 seeds for histologically verified LGGII at the University of Munich between March 1997 and July 2011. Investigation included clinical characteristics, technical aspects of SBT, the application of other treatments, outcome analyses including malignization rates, and prognostic factors with special focus on molecular biomarkers.

Results: For the entire study population, the 5- and 10-years overall survival (OS) rates were 79% and 62%, respectively, with a median follow-up of 115.9 months. No prognostic factors could be identified. Interstitial radiotherapy was applied in 51 cases as first-line treatment with a median number of two seeds (range 1-5), and a median total implanted activity of 21.8 mCi (range 4.2-43.4). The reference dose average was 54.0 Gy. Five- and ten-years OS and progression-free survival rates after SBT were 72% and 43%, and 40% and 23%, respectively, with a median follow-up of 86.7 months. The procedure-related mortality rate was zero, although an overall complication rate of 16% was registered. Patients with complications had a significantly larger tumor volume (p = 0.029).

Conclusion: SBT is a minimally invasive treatment modality with a favorable outcome and toxicity profile. It is both an alternative primary treatment method as well as an adjunct to open tumor resection in selected low-grade gliomas.
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http://dx.doi.org/10.1186/s13014-020-01719-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724805PMC
December 2020

Anthropomorphic lung phantom based validation of in-room proton therapy 4D-CBCT image correction for dose calculation.

Z Med Phys 2020 Nov 25. Epub 2020 Nov 25.

Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany; Department of Medical Physics, Faculty of Physics, Ludwig-Maximilians-Universität München (LMU Munich), Garching, Germany. Electronic address:

Purpose: Ventilation-induced tumour motion remains a challenge for the accuracy of proton therapy treatments in lung patients. We investigated the feasibility of using a 4D virtual CT (4D-vCT) approach based on deformable image registration (DIR) and motion-aware 4D CBCT reconstruction (MA-ROOSTER) to enable accurate daily proton dose calculation using a gantry-mounted CBCT scanner tailored to proton therapy.

Methods: Ventilation correlated data of 10 breathing phases were acquired from a porcine ex-vivo functional lung phantom using CT and CBCT. 4D-vCTs were generated by (1) DIR of the mid-position 4D-CT to the mid-position 4D-CBCT (reconstructed with the MA-ROOSTER) using a diffeomorphic Morphons algorithm and (2) subsequent propagation of the obtained mid-position vCT to the individual 4D-CBCT phases. Proton therapy treatment planning was performed to evaluate dose calculation accuracy of the 4D-vCTs. A robust treatment plan delivering a nominal dose of 60Gy was generated on the average intensity image of the 4D-CT for an approximated internal target volume (ITV). Dose distributions were then recalculated on individual phases of the 4D-CT and the 4D-vCT based on the optimized plan. Dose accumulation was performed for 4D-vCT and 4D-CT using DIR of each phase to the mid position, which was chosen as reference. Dose based on the 4D-vCT was then evaluated against the dose calculated on 4D-CT both, phase-by-phase as well as accumulated, by comparing dose volume histogram (DVH) values (D, D, D, D) for the ITV, and by a 3D-gamma index analysis (global, 3%/3mm, 5Gy, 20Gy and 30Gy dose thresholds).

Results: Good agreement was found between the 4D-CT and 4D-vCT-based ITV-DVH curves. The relative differences ((CT-vCT)/CT) between accumulated values of ITV D, D, D and D for the 4D-CT and 4D-vCT-based dose distributions were -0.2%, 0.0%, -0.1% and -0.1%, respectively. Phase specific values varied between -0.5% and 0.2%, -0.2% and 0.5%, -3.5% and 1.5%, and -5.7% and 2.3%. The relative difference of accumulated D over the lungs was 2.3% and D for the phases varied between -5.4% and 5.8%. The gamma pass-rates with 5Gy, 20Gy and 30Gy thresholds for the accumulated doses were 96.7%, 99.6% and 99.9%, respectively. Phase-by-phase comparison yielded pass-rates between 86% and 97%, 88% and 98%, and 94% and 100%.

Conclusions: Feasibility of the suggested 4D-vCT workflow using proton therapy specific imaging equipment was shown. Results indicate the potential of the method to be applied for daily 4D proton dose estimation.
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http://dx.doi.org/10.1016/j.zemedi.2020.09.004DOI Listing
November 2020

Variance-based sensitivity analysis for uncertainties in proton therapy: A framework to assess the effect of simultaneous uncertainties in range, positioning, and RBE model predictions on RBE-weighted dose distributions.

Med Phys 2021 Feb 18;48(2):805-818. Epub 2020 Dec 18.

Department of Radiation Oncology, University Hospital, LMU Munich, Munich, 81377, Germany.

Purpose: Treatment plans in proton therapy are more sensitive to uncertainties than in conventional photon therapy. In addition to setup uncertainties, proton therapy is affected by uncertainties in proton range and relative biological effectiveness (RBE). While to date a constant RBE of 1.1 is commonly assumed, the actual RBE is known to increase toward the distal end of the spread-out Bragg peak. Several models for variable RBE predictions exist. We present a framework to evaluate the combined impact and interactions of setup, range, and RBE uncertainties in a comprehensive, variance-based sensitivity analysis (SA).

Material And Methods: The variance-based SA requires a large number (10 -10 ) of RBE-weighted dose (RWD) calculations. Based on a particle therapy extension of the research treatment planning system CERR we implemented a fast, graphics processing unit (GPU) accelerated pencil beam modeling of patient and range shifts. For RBE predictions, two biological models were included: The mechanistic repair-misrepair-fixation (RMF) model and the phenomenological Wedenberg model. All input parameters (patient position, proton range, RBE model parameters) are sampled simultaneously within their assumed probability distributions. Statistical formalisms rank the input parameters according to their influence on the overall uncertainty of RBE-weighted dose-volume histogram (RW-DVH) quantiles and the RWD in every voxel, resulting in relative, normalized sensitivity indices (S = 0: noninfluential input, S = 1: only influential input). Results are visualized as RW-DVHs with error bars and sensitivity maps.

Results And Conclusions: The approach is demonstrated for two representative brain tumor cases and a prostate case. The full SA including RWD calculations took 39, 11, and 55 min, respectively. Range uncertainty was an important contribution to overall uncertainty at the distal end of the target, while the relatively smaller uncertainty inside the target was governed by biological uncertainties. Consequently, the uncertainty of the RW-DVH quantile D for the target was governed by range uncertainty while the uncertainty of the mean target dose was dominated by the biological parameters. The SA framework is a powerful and flexible tool to evaluate uncertainty in RWD distributions and DVH quantiles, taking into account physical and RBE uncertainties and their interactions. The additional information might help to prioritize research efforts to reduce physical and RBE uncertainties and could also have implications for future approaches to biologically robust planning and optimization.
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http://dx.doi.org/10.1002/mp.14596DOI Listing
February 2021

Outcome After 68Ga-PSMA-11 versus Choline PET-Based Salvage Radiotherapy in Patients with Biochemical Recurrence of Prostate Cancer: A Matched-Pair Analysis.

Cancers (Basel) 2020 Nov 16;12(11). Epub 2020 Nov 16.

Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

The purpose of this analysis was primarily to analyze biochemical-recurrence free survival (BRFS) after positron emission tomography (PET)-guided salvage radiotherapy (sRT) in a large cohort, and to further compare BRFS after PSMA vs. choline PET/ computer tomography (CT)-based sRT. This retrospective analysis is based on 421 patients referred for PSMA or choline PET/CT after radical prostatectomy due to biochemically recurrent or persistent disease. BRFS (PSA: 0.2 ng/mL) was defined as the study endpoint. Cox regression analyses were performed to assess the impact of different clinical parameters on BRFS. Additionally, propensity score matching was performed to adjust patient cohorts (PSMA vs. choline PET/CT-based sRT). The median follow-up time was 30 months. BRFS at three years after sRT was 58%. In the multivariate analysis, only PSA before PET imaging and PSA before sRT were significantly associated with BRFS ( < 0.05). After propensity score matching, 272 patients were further analyzed; there was no significant difference in three-year BRFS between patients with PSMA PET-based vs. choline PET-based sRT (55% vs. 63%, = 0.197). The present analysis confirmed the overall high BRFS rates after PET-based sRT and the strong prognostic effect of PSA level prior to sRT. PSMA PET-based sRT did not have superior BRFS rates when compared with choline PET-based sRT.
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http://dx.doi.org/10.3390/cancers12113395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698293PMC
November 2020

Porcine lung phantom-based validation of estimated 4D-MRI using orthogonal cine imaging for low-field MR-Linacs.

Phys Med Biol 2021 Feb 16;66(5):055006. Epub 2021 Feb 16.

Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.

Real-time motion monitoring of lung tumors with low-field magnetic resonance imaging-guided linear accelerators (MR-Linacs) is currently limited to sagittal 2D cine magnetic resonance imaging (MRI). To provide input data for improved intrafractional and interfractional adaptive radiotherapy, the 4D anatomy has to be inferred from data with lower dimensionality. The purpose of this study was to experimentally validate a previously proposed propagation method that provides continuous time-resolved estimated 4D-MRI based on orthogonal cine MRI for a low-field MR-Linac. Ex vivo porcine lungs were injected with artificial nodules and mounted in a dedicated phantom that allows for the simulation of periodic and reproducible breathing motion. The phantom was scanned with a research version of a commercial 0.35 T MR-Linac. Respiratory-correlated 4D-MRI were reconstructed and served as ground truth images. Series of interleaved orthogonal slices in sagittal and coronal orientation, intersecting the injected targets, were acquired at 7.3 Hz. Estimated 4D-MRI at 3.65 Hz were created in post-processing using the propagation method and compared to the ground truth 4D-MRI. Eight datasets at different breathing frequencies and motion amplitudes were acquired for three porcine lungs. The overall median (95[Formula: see text] percentile) deviation between ground truth and estimated deformation vector fields was 2.3 mm (5.7 mm), corresponding to 0.7 (1.6) times the in-plane imaging resolution (3.5 × 3.5 mm). Median (95[Formula: see text] percentile) estimated nodule position errors were 1.5 mm (3.8 mm) for nodules intersected by orthogonal slices and 2.1 mm (7.1 mm) for nodules located more than 2 cm away from either of the orthogonal slices. The estimation error depended on the breathing phase, the motion amplitude and the location of the estimated position with respect to the orthogonal slices. By using the propagation method, the 4D motion within the porcine lung phantom could be accurately and robustly estimated. The method could provide valuable information for treatment planning, real-time motion monitoring, treatment adaptation, and post-treatment evaluation of MR-guided radiotherapy treatments.
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http://dx.doi.org/10.1088/1361-6560/abc937DOI Listing
February 2021

Accounting for prompt gamma emission and detection for range verification in proton therapy treatment planning.

Phys Med Biol 2021 Feb 16;66(5):055005. Epub 2021 Feb 16.

Ludwig-Maximilians-Universität München, Department of Medical Physics, Munich, Germany. These authors have contributed to this work equally.

Prompt gamma (PG) imaging is widely investigated as one of the most promising methods for proton range verification in proton therapy. The performance of this technique is affected by several factors like tissue heterogeneity, number of protons in the considered pencil beam and the detection device. Our previous work proposed a new treatment planning concept which boosts the number of protons of a few PG monitoring-friendly pencil beams (PBs), selected on the basis of two proposed indicators quantifying the conformity between the dose and PG at the emission level, above the desired detectability threshold. To further explore this method at the detection level, in this work we investigated the response of a knife-edge slit PG camera which was deployed in the first clinical application of PG to proton therapy monitoring. The REGistration Graphical User Interface (REGGUI) is employed to simulate the PG emission, PG detection as well as the corresponding dose distribution. As the PG signal detected by this kind of PG camera is sensitive to the relative position of the camera and PG signal falloff, we optimized our PB selection method for this camera by introducing a new camera position indicator identifying whether the expected falloff of the PG signal is centered in the field of view of the camera or not. Our camera-adapted PB selection method is investigated using computed tomography (CT) scans at two different treatment time points of a head and neck, and a prostate cancer patient under scenarios considering different statistics level. The results show that a precision of 0.8 mm for PG falloff identification can be achieved when a PB has more than 2 × 10 primary protons. Except for one case due to unpredictable and comparably large anatomical changes, the PG signals of most of the PBs recommended by all our indicators are observed to be reliable for proton range verification with deviations between the inter-fractional shift of proton range (as deduced from the PB dose distribution) and the detected PG signal within 2.0 mm. In contrast, a shift difference up to 9.6 mm has been observed for the rejected PBs. The magnitude of the proton range shift due to the inter-fractional anatomical changes is observed to be up to 23 mm. The proposed indicators are shown to be valuable for identifying and recommending reliable PBs to create new PG monitoring-friendly TPs. Comparison between our PB boosting method and the alternative PB aggregation, which combines the signal of nearby PBs to reach the desired counting statistics, is also discussed.
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http://dx.doi.org/10.1088/1361-6560/abc939DOI Listing
February 2021

Dosimetric impact of geometric distortions in an MRI-only proton therapy workflow for lung, liver and pancreas.

Z Med Phys 2020 Nov 6. Epub 2020 Nov 6.

Department of Medical Physics, Faculty of Physics, Ludwig-Maximilians-Universität München, Am Coulombwall 1, 85748 Garching bei München, Germany. Electronic address:

In a radiation therapy workflow based on Magnetic Resonance Imaging (MRI), dosimetric errors may arise due to geometric distortions introduced by MRI. The aim of this study was to quantify the dosimetric effect of system-dependent geometric distortions in an MRI-only workflow for proton therapy applied at extra-cranial sites. An approach was developed, in which computed tomography (CT) images were distorted using an MRI displacement map, which represented the MR distortions in a spoiled gradient-echo sequence due to gradient nonlinearities and static magnetic field inhomogeneities. A retrospective study was conducted on 4DCT/MRI digital phantoms and 18 4DCT clinical datasets of the thoraco-abdominal site. The treatment plans were designed and separately optimized for each beam in a beam specific Planning Target Volume on the distorted CT, and the final dose distribution was obtained as the average. The dose was then recalculated in undistorted CT using the same beam geometry and beam weights. The analysis was performed in terms of Dose Volume Histogram (DVH) parameters. No clinically relevant dosimetric impact was observed on organs at risk, whereas in the target structure, geometric distortions caused statistically significant variations in the planned dose DVH parameters and dose homogeneity index (DHI). The dosimetric variations in the target structure were smaller in abdominal cases (ΔD, ΔD, and ΔD all below 0.1% and ΔDHI below 0.003) compared to the lung cases. Indeed, lung patients with tumors isolated inside lung parenchyma exhibited higher dosimetric variations (ΔD≥0.3%, ΔD≥15.9%, ΔD≥3.3% and ΔDHI≥0.102) than lung patients with tumor close to soft tissue (ΔD≤0.4%, ΔD≤5.6%, ΔD≤0.9% and ΔDHI≤0.027) potentially due to higher density variations along the beam path. Results suggest the potential applicability of MRI-only proton therapy, provided that specific analysis is applied for isolated lung tumors.
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http://dx.doi.org/10.1016/j.zemedi.2020.10.002DOI Listing
November 2020

[F18] FDG-PET/CT for manual or semiautomated GTV delineation of the primary tumor for radiation therapy planning in patients with esophageal cancer: is it useful?

Strahlenther Onkol 2020 Oct 26. Epub 2020 Oct 26.

Department of Radiotherapy and Radiation Oncology, Paracelsus Medical University (PMU), Landeskrankenhaus, Salzburg, Austria.

Background: Target volume definition of the primary tumor in esophageal cancer is usually based on computed tomography (CT) supported by endoscopy and/or endoscopic ultrasound and can be difficult given the low soft-tissue contrast of CT resulting in large interobserver variability. We evaluated the value of a dedicated planning [F18] FDG-Positron emission tomography/computer tomography (PET/CT) for harmonization of gross tumor volume (GTV) delineation and the feasibility of semiautomated structures for planning purposes in a large cohort.

Methods: Patients receiving a dedicated planning [F18] FDG-PET/CT (06/2011-03/2016) were included. GTV was delineated on CT and on PET/CT (GTV and GTV, respectively) by three independent radiation oncologists. Interobserver variability was evaluated by comparison of mean GTV and mean tumor lengths, and via Sørensen-Dice coefficients (DSC) for spatial overlap. Semiautomated volumes were constructed based on PET/CT using fixed standardized uptake values (SUV) thresholds (SUV30, 35, and 40) or background- and metabolically corrected PERCIST-TLG and Schaefer algorithms, and compared to manually delineated volumes.

Results: 45 cases were evaluated. Mean GTV and GTV were 59.2/58.0 ml, 65.4/64.1 ml, and 60.4/59.2 ml for observers A-C. No significant difference between CT- and PET/CT-based delineation was found comparing the mean volumes or lengths. Mean Dice coefficients on CT and PET/CT were 0.79/0.77, 0.81/0.78, and 0.8/0.78 for observer pairs AB, AC, and BC, respectively, with no significant differences. Mean GTV volumes delineated semiautomatically with SUV30/SUV35/SUV40/Schaefer's and PERCIST-TLG threshold were 69.1/23.9/18.8/18.6 and 70.9 ml. The best concordance of a semiautomatically delineated structure with the manually delineated GTV/GTV was observed for PERCIST-TLG.

Conclusion: We were not able to show that the integration of PET/CT for GTV delineation of the primary tumor resulted in reduced interobserver variability. The PERCIST-TLG algorithm seemed most promising compared to other thresholds for further evaluation of semiautomated delineation of esophageal cancer.
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http://dx.doi.org/10.1007/s00066-020-01701-0DOI Listing
October 2020

Comprehensive Analysis of Tumour Sub-Volumes for Radiomic Risk Modelling in Locally Advanced HNSCC.

Cancers (Basel) 2020 Oct 19;12(10). Epub 2020 Oct 19.

OncoRay-National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01307 Dresden, Germany.

Imaging features for radiomic analyses are commonly calculated from the entire gross tumour volume (GTV ). However, tumours are biologically complex and the consideration of different tumour regions in radiomic models may lead to an improved outcome prediction. Therefore, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma. The GTV  was cropped by different margins to define the rim and the corresponding core sub-volumes of the tumour. Subsequently, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. Radiomic risk models were developed and validated using a retrospective cohort consisting of 291 patients in one of the six Partner Sites of the German Cancer Consortium Radiation Oncology Group treated between 2005 and 2013. The validation concordance index (C-index) averaged over all applied learning algorithms and feature selection methods using the GTVentire achieved a moderate prognostic performance for loco-regional tumour control (C-index: 0.61 ± 0.04 (mean ± std)). The models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed higher median performances (C-index: 0.65 ± 0.02 and 0.64 ± 0.05, respectively), while models based on the corresponding tumour core volumes performed less (C-index: 0.59 ± 0.01). The difference in C-index between the 5 mm tumour rim and the corresponding core volume showed a statistical trend ( = 0.10). After additional prospective validation, the consideration of tumour sub-volumes may be a promising way to improve prognostic radiomic risk models.
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http://dx.doi.org/10.3390/cancers12103047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589463PMC
October 2020