Publications by authors named "Anca-Ligia Grosu"

150 Publications

Radiate Once More.

Int J Radiat Oncol Biol Phys 2021 Feb;109(2):314-315

Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1016/j.ijrobp.2019.05.068DOI Listing
February 2021

The Evolving Role of Radiation Therapy in the Treatment of Biliary Tract Cancer.

Front Oncol 2020 14;10:604387. Epub 2020 Dec 14.

Department of Radiation Oncology, University of Magdeburg, Magdeburg, Germany.

Biliary tract cancers (BTC) are a disease entity comprising diverse epithelial tumors, which are categorized according to their anatomical location as intrahepatic (iCCA), perihilar (pCCA), distal (dCCA) cholangiocarcinomas, and gallbladder carcinomas (GBC), with distinct epidemiology, biology, and prognosis. Complete surgical resection is the mainstay in operable BTC as it is the only potentially curative treatment option. Nevertheless, even after curative (R0) resection, the 5-year survival rate ranges between 20 and 40% and the disease free survival rates (DFS) is approximately 48-65% after one year and 23-35% after three years without adjuvant treatment. Improvements in adjuvant chemotherapy have improved the DFS, but the role of adjuvant radiotherapy is unclear. On the other hand, more than 50% of the patients present with unresectable disease at the time of diagnosis, which limits the prognosis to a few months without treatment. Herein, we review the role of radiotherapy in the treatment of cholangiocarcinoma in the curative and palliative setting.
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http://dx.doi.org/10.3389/fonc.2020.604387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768034PMC
December 2020

Treatment outcomes of elderly salivary gland cancer patients undergoing radiotherapy - Results from a large multicenter analysis.

Radiother Oncol 2020 Dec 24;156:266-274. Epub 2020 Dec 24.

Department of Radiation Oncology, University of Freiburg - Medical Center, Freiburg, Germany; German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), Heidelberg, Germany. Electronic address:

Background And Purpose: To evaluate oncological outcomes and treatment-related toxicities of elderly salivary gland cancer patients undergoing (chemo)radiotherapy.

Material And Methods: Local/locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) of elderly patients ≥ 65 years with primary salivary gland cancers undergoing (chemo)radiotherapy between 2005 and 2020 at three tertiary cancer centers were calculated. The impact of clinicopathological and treatment parameters on outcomes were analyzed, and acute and chronic toxicities were quantified.

Results: 288 elderly salivary gland cancer patients were included in this multicenter analysis, and their median LRC, PFS and OS amounted to 113, 39 and 75 months, respectively. Age, performance status, comorbidities, definitive vs. adjuvant (chemo)radiotherapy as well as locally/locoregionally advanced cancers and distant metastases correlated with reduced outcomes in elderly salivary gland patients. Patients receiving dose-escalated radiotherapy (total doses > 70 Gy) with carbon ion boost radiation resulted in improved LRC, but no improvements in PFS or OS. Concomitant chemoradiotherapy did not improve treatment outcomes in elderly salivary gland carcinoma patients. Radiotherapy of elderly salivary gland cancer patients resulted in moderate higher-grade toxicities despite dose escalation with 70 (24.3%) and 48 patients (16.7%) experiencing acute and chronic grade 3 toxicities, respectively. No grade 4/5 toxicities were observed in this patient cohort.

Conclusion: Data from the largest multicenter analysis of elderly salivary gland cancer patients undergoing (chemo)radiotherapy demonstrate favorable LRC and tolerable toxicity rates. Decision-making for these vulnerable patients should be based on patient performance rather than chronological patient age.
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http://dx.doi.org/10.1016/j.radonc.2020.12.024DOI Listing
December 2020

Evaluation of Prognostic Factors and Role of Participation in a Randomized Trial or a Prospective Registry in Pediatric and Adolescent Nonmetastatic Medulloblastoma - A Report From the HIT 2000 Trial.

Adv Radiat Oncol 2020 Nov-Dec;5(6):1158-1169. Epub 2020 Oct 7.

Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Purpose: We aimed to compare treatment results in and outside of a randomized trial and to confirm factors influencing outcome in a large retrospective cohort of nonmetastatic medulloblastoma treated in Austria, Switzerland and Germany.

Methods And Materials: Patients with nonmetastatic medulloblastoma (n = 382) aged 4 to 21 years and primary neurosurgical resection between 2001 and 2011 were assessed. Between 2001 and 2006, 176 of these patients (46.1%) were included in the randomized HIT SIOP PNET 4 trial. From 2001 to 2011 an additional 206 patients were registered to the HIT 2000 study center and underwent the identical central review program. Three different radiation therapy protocols were applied. Genetically defined tumor entity (former molecular subgroup) was available for 157 patients.

Results: Median follow-up time was 7.3 (range, 0.09-13.86) years. There was no difference between HIT SIOP PNET 4 trial patients and observational patients outside the randomized trial, with 7 years progression-free survival rates (PFS) of 79.5% ± 3.1% versus 78.7% ± 3.1% ( = .62). On univariate analysis, the time interval between surgery and irradiation (≤ 48 days vs ≥ 49 days) showed a strong trend to affect PFS (80.4% ± 2.2% vs 64.6% ± 9.1%; = .052). Furthermore, histologically and genetically defined tumor entities and the extent of postoperative residual tumor influenced PFS. On multivariate analyses, a genetically defined tumor entity wingless-related integration site-activated vs non-wingless-related integration site/non-SHH, group 3 hazard ratio, 5.49; = .014) and time interval between surgery and irradiation (hazard ratio, 2.2; = .018) were confirmed as independent risk factors.

Conclusions: Using a centralized review program and risk-stratified therapy for all patients registered to the study center, outcome was identical for patients with nonmetastatic medulloblastoma treated on and off the randomized HIT SIOP PNET 4 trial. The prognostic values of prolonged time to RT and genetically defined tumor entity were confirmed.
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http://dx.doi.org/10.1016/j.adro.2020.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718550PMC
October 2020

App-Controlled Treatment Monitoring and Support for Head and Neck Cancer Patients (APCOT): Protocol for a Prospective Randomized Controlled Trial.

JMIR Res Protoc 2020 Dec 9;9(12):e21693. Epub 2020 Dec 9.

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

Background: Head and neck cancers (HNCs) are among the most common malignancies, which often require multimodal treatment that includes radiation therapy and chemotherapy. Patients with HNC have a high burden of symptoms due to both the damaging effects of the tumor and the aggressive multimodal treatment. Close symptom monitoring over the course of the disease may help to identify patients in need of medical interventions.

Objective: This APCOT (App-Controlled Treatment Monitoring and Support for Head and Neck Cancer Patients) trial is designed to assess the feasibility of monitoring HNC patients during the course of (chemo)radiation therapy daily using a mobile app. Additionally, symptom patterns, patient satisfaction, and quality of life will be measured in app-monitored patients in comparison to a patient cohort receiving standard-of-care physician appointments, and health economy aspects of app monitoring will be analyzed.

Methods: This prospective randomized single-center trial will evaluate the feasibility of integrating electronic patient-reported outcome measures (ePROMs) into the treatment workflow of HNC patients. Patients undergoing definitive or adjuvant (chemo)radiation therapy as part of their HNC treatment at the Department of Radiation Oncology, University Medical Center Freiburg (Freiburg, Germany) will receive weekly physician appointments and additional appointments as requested to monitor and potentially treat symptoms during the course of treatment. Patients in the experimental arm will additionally be monitored daily using a dedicated app regarding their disease- and treatment-related symptoms, quality of life, and need for personal physician appointments. The feasibility of ePROM monitoring will be tested as the primary endpoint and will be defined if ≥80% of enrolled patients have answered ≥80% of their daily app-based questions. Quality of life will be assessed using the validated European Organisation for Research and Treatment of Cancer questionnaires, and patient satisfaction will be measured by the validated Patient Satisfaction Questionnaire Short Form at the initiation, in the middle, and at completion of radiation therapy, as well as at follow-up examinations. Additionally, the number and duration of physician appointments during the course of radiation therapy will be quantified for both ePROM-monitored and standard-of-care patients.

Results: This trial will enroll 100 patients who will be randomized (1:1) between the experimental arm with ePROM monitoring and the control arm with standard patient care. Recruitment will take 18 months, and trial completion is planned at 24 months after enrollment of the last patient.

Conclusions: This trial will establish the feasibility of close ePROM monitoring of HNC patients undergoing (chemo)radiation therapy. The results can form the basis for further trials investigating potential clinical benefits of detailed symptom monitoring and patient-centered care in HNC patients regarding oncologic outcomes and quality of life.

Trial Registration: German Clinical Trials Register DRKS00020491; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00020491.

International Registered Report Identifier (irrid): PRR1-10.2196/21693.
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http://dx.doi.org/10.2196/21693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758168PMC
December 2020

Development and validation of a novel prognostic score for elderly head-and-neck cancer patients undergoing radiotherapy or chemoradiation.

Radiother Oncol 2020 Nov 24;154:276-282. Epub 2020 Nov 24.

Department of Radiation Oncology, University of Freiburg - Medical Center, Germany; German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (dkfz), Heidelberg, Germany. Electronic address:

Background And Purpose: To establish a clinically feasible prognostic score and nomogram based on easily accessible clinical data that will aid decision-making in elderly head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiotherapy.

Material And Methods: 284 elderly HNSCC patients (≥65 years) undergoing curative (chemo)radiotherapy were included for the development of a score predicting overall survival (OS) based on the beta regression coefficients from significant parameters in a multivariate Cox regression analysis with p < 0.1 as inclusion criterion. A second, external cohort of 217 elderly HNSCC patients receiving (chemo)radiotherapy was used for validation. Using the aggregated data (n = 501), a nomogram was developed to predict 2- and 4-year OS.

Results: Karnofsky Performance Status (HR = 2.654; p < 0.001), Charlson Comorbidity Index (HR = 2.598; p < 0.001) and baseline C-reactive protein (CRP) level (HR = 1.634; p = 0.068) were prognostic for OS in the multivariate analysis. An OS score based on beta regression coefficients was created, in which reduced performance status, increased comorbidity burden and increased CRP levels were included, leading to 3 distinct survival groups. The median OS for the 3 groups amounted to 107, 28 and 6 months, respectively (p < 0.001). The developed score was able to significantly differentiate between a favorable (median OS = 130 months), intermediate (29 months) and unfavorable prognosis (9 months) also in the external validation cohort (p = 0.005).

Conclusion: We propose a novel, validated prognostic score based on easily accessible clinical data allowing stratification between prognostic groups of elderly HNSCC patients receiving (chemo)radiotherapy. The derived nomogram for the prediction of 2-year and 4-year OS may aid decision-making for this vulnerable population.
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http://dx.doi.org/10.1016/j.radonc.2020.11.023DOI Listing
November 2020

Uncovering the invisible-prevalence, characteristics, and radiomics feature-based detection of visually undetectable intraprostatic tumor lesions in GaPSMA-11 PET images of patients with primary prostate cancer.

Eur J Nucl Med Mol Imaging 2020 Nov 18. Epub 2020 Nov 18.

Department of Radiation Oncology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Robert-Koch Straße 3, 79106, Freiburg, Germany.

Introduction: Primary prostate cancer (PCa) can be visualized on prostate-specific membrane antigen positron emission tomography (PSMA-PET) with high accuracy. However, intraprostatic lesions may be missed by visual PSMA-PET interpretation. In this work, we quantified and characterized the intraprostatic lesions which have been missed by visual PSMA-PET image interpretation. In addition, we investigated whether PSMA-PET-derived radiomics features (RFs) could detect these lesions.

Methodology: This study consists of two cohorts of primary PCa patients: a prospective training cohort (n = 20) and an external validation cohort (n = 52). All patients underwent Ga-PSMA-11 PET/CT and histology sections were obtained after surgery. PCa lesions missed by visual PET image interpretation were counted and their International Society of Urological Pathology score (ISUP) was obtained. Finally, 154 RFs were derived from the PET images and the discriminative power to differentiate between prostates with or without visually undetectable lesions was assessed and areas under the receiver-operating curve (ROC-AUC) as well as sensitivities/specificities were calculated.

Results: In the training cohort, visual PET image interpretation missed 134 tumor lesions in 60% (12/20) of the patients, and of these patients, 75% had clinically significant (ISUP > 1) PCa. The median diameter of the missed lesions was 2.2 mm (range: 1-6). Standard clinical parameters like the NCCN risk group were equally distributed between patients with and without visually missed lesions (p < 0.05). Two RFs (local binary pattern (LBP) size-zone non-uniformality normalized and LBP small-area emphasis) were found to perform excellently in visually unknown PCa detection (Mann-Whitney U: p < 0.01, ROC-AUC: ≥ 0.93). In the validation cohort, PCa was missed in 50% (26/52) of the patients and 77% of these patients possessed clinically significant PCa. The sensitivities of both RFs in the validation cohort were ≥ 0.8.

Conclusion: Visual PSMA-PET image interpretation may miss small but clinically significant PCa in a relevant number of patients and RFs can be implemented to uncover them. This could be used for guiding personalized treatments.
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http://dx.doi.org/10.1007/s00259-020-05111-3DOI Listing
November 2020

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

Efficacy and Toxicity of Different Chemotherapy Protocols for Concurrent Chemoradiation in Non-Small Cell Lung Cancer-A Secondary Analysis of the PET Plan Trial.

Cancers (Basel) 2020 Nov 13;12(11). Epub 2020 Nov 13.

Department of Radiation Oncology, Medical Center-University of Freiburg, Robert-Koch-Str. 3, 79106 Freiburg, Germany.

(1) Background: The optimal chemotherapy (CHT) regimen for concurrent chemoradiation (cCRT) is not well defined. In this secondary analysis of the international randomized PET-Plan trial, we evaluate the efficacy of different CHT. (2) Methods: Patients with inoperable NSCLC were randomized at a 1:1 ratio regarding the target volume definition and received isotoxically dose-escalated cCRT using cisplatin 80 mg/m (day 1, 22) and vinorelbin 15 mg/m (day 1, 8, 22, 29) (P1) or cisplatin 20 mg/m (day 1-5, 29-33) and vinorelbin 12.5 mg/m (day 1, 8, 15, 29, 36, 43) (P2) or carboplatin AUC1 (day 1-5, 29-33) and vinorelbin 12.5 mg/m (day 1, 8, 15, 29, 36, 43) (P3) or other CHT at the treating physician's discretion. (3) Results: Between 05/2009 and 11/2016, 205 patients were randomized and 172 included in the per-protocol analysis. Patients treated in P1 or P2 had a better overall survival (OS) compared to P3 ( = 0.015, = 0.01, respectively). Patients treated with carboplatin had a worse OS compared to cisplatin (HR 1.78, = 0.03), but the difference did not remain significant after adjusting for age, ECOG, cardiac function creatinine and completeness of CHT. (4) Conclusions: Carboplatin doublets show no significant difference compared to cisplatin, after adjusting for possibly relevant factors, probably due to existing selection bias.
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http://dx.doi.org/10.3390/cancers12113359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697287PMC
November 2020

Prostate cancer tumour control probability modelling for external beam radiotherapy based on multi-parametric MRI-GTV definition.

Radiat Oncol 2020 Oct 20;15(1):242. Epub 2020 Oct 20.

Department of Radiation Oncology, Division of Medical Physics, Medical Centre, Faculty of Medicine, University of Freiburg, Robert-Koch-Str. 3, 79106, Freiburg, Germany.

Purpose: To evaluate the applicability and estimate the radiobiological parameters of linear-quadratic Poisson tumour control probability (TCP) model for primary prostate cancer patients for two relevant target structures (prostate gland and GTV). The TCP describes the dose-response of prostate after definitive radiotherapy (RT). Also, to analyse and identify possible significant correlations between clinical and treatment factors such as planned dose to prostate gland, dose to GTV, volume of prostate and mpMRI-GTV based on multivariate logistic regression model.

Methods: The study included 129 intermediate and high-risk prostate cancer patients (cN0 and cM0), who were treated with image-guided intensity modulated radiotherapy (IMRT) ± androgen deprivation therapy with a median follow-up period of 81.4 months (range 42.0-149.0) months. Tumour control was defined as biochemical relapse free survival according to the Phoenix definition (BRFS). MpMRI-GTV was delineated retrospectively based on a pre-treatment multi-parametric MR imaging (mpMRI), which was co-registered to the planning CT. The clinical treatment planning procedure was based on prostate gland, delineated on CT imaging modality. Furthermore, we also fitted the clinical data to TCP model for the two considered targets for the 5-year follow-up after radiation treatment, where our cohort was composed of a total number of 108 patients, of which 19 were biochemical relapse (BR) patients.

Results: For the median follow-up period of 81.4 months (range 42.0-149.0) months, our results indicated an appropriate α/β = 1.3 Gy for prostate gland and α/β = 2.9 Gy for mpMRI-GTV. Only for prostate gland, EQD2 and gEUD2Gy were significantly lower in the biochemical relapse (BR) group compared to the biochemical control (BC) group. Fitting results to the linear-quadratic Poisson TCP model for prostate gland and α/β = 1.3 Gy were D = 66.8 Gy with 95% CI [64.6 Gy, 69.0 Gy], and γ = 3.8 with 95% CI [2.6, 5.2]. For mpMRI-GTV and α/β = 2.9 Gy, D was 68.1 Gy with 95% CI [66.1 Gy, 70.0 Gy], and γ = 4.5 with 95% CI [3.0, 6.1]. Finally, for the 5-year follow-up after the radiation treatment, our results for the prostate gland were: D = 64.6 Gy [61.6 Gy, 67.4 Gy], γ = 3.1 [2.0, 4.4], α/β = 2.2 Gy (95% CI was undefined). For the mpMRI-GTV, the optimizer was unable to deliver any reasonable results for the expected clinical D and α/β. The results for the mpMRI-GTV were D = 50.1 Gy [44.6 Gy, 56.0 Gy], γ = 0.8 [0.5, 1.2], α/β = 0.0 Gy (95% CI was undefined). For a follow-up time of 5 years and a fixed α/β = 1.6 Gy, the TCP fitting results for prostate gland were D = 63.9 Gy [60.8 Gy, 67.0 Gy], γ = 2.9 [1.9, 4.1], and for mpMRI-GTV D = 56.3 Gy [51.6 Gy, 61.1 Gy], γ = 1.3 [0.8, 1.9].

Conclusion: The linear-quadratic Poisson TCP model was better fit when the prostate gland was considered as responsible target than with mpMRI-GTV. This is compatible with the results of the comparison of the dose distributions among BR and BC groups and with the results achieved with the multivariate logistic model regarding gEUD. Probably limitations of mpMRI in defining the GTV explain these results. Another explanation could be the relatively homogeneous dose prescription and the relatively low number of recurrences. The failure to identify any benefit for considering mpMRI-GTV as the target responsible for the clinical response is confirmed when considering a fixed α/β = 1.6 Gy, a fixed follow-up time for biochemical response at 5 years or Gleason score differentiation.
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http://dx.doi.org/10.1186/s13014-020-01683-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574270PMC
October 2020

Radiation-induced toxicities and outcomes after radiotherapy are independent of patient age in elderly salivary gland cancer patients: results from a matched-pair analysis of a rare disease.

Eur Arch Otorhinolaryngol 2020 Sep 30. Epub 2020 Sep 30.

Department of Radiation Oncology, University of Freiburg-Medical Center, Robert-Koch-Str. 3, 79106, Freiburg, Germany.

Purpose: This study analyzed survival and toxicity after (chemo)radiotherapy for primary salivary gland cancer patients aged ≥ 65 years and compared these results with younger patients using a matched-pair analysis.

Methods: Twenty-nine elderly patients with primary salivary gland carcinomas treated with (chemo)radiotherapy from 2008 to 2020 at University of Freiburg Medical Center were analyzed for oncological outcomes and therapy-associated toxicities. Local/locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and the influence of clinical parameters on patient outcomes was assessed. A matched-pair analysis was performed after matching with patients < 65 years.

Results: Nine patients (31.0%) received definitive (chemo)radiotherapy, and 20 patients (69.0%) were treated in the adjuvant setting. 2-year LRC, PFS and OS ranged at 82.4%, 53.7% and 71.8%, respectively. Smoking (HR 3.980, p = 0.020), reduced performance status (HR 3.735, p = 0.016) and higher comorbidity burden (HR 4.601, p = 0.005) correlated with inferior OS. Using a matched-pair analysis with younger patients, elderly patients exhibited a trend towards reduced OS (HR 3.015, p = 0.065), but not PFS (HR 1.474, p = 0.371) or LRC (HR 1.324, p = 0.633). Acute and chronic grade 3 toxicities occurred in 31.0% and 12.5% of elderly patients, respectively, and the matched-pair analysis revealed no significant differences between age groups regarding treatment-related toxicities.

Conclusion: Treatment-related toxicities as well as LRC and PFS were comparable for salivary gland cancer patients undergoing radiotherapy. Therefore, concerns for more pronounced toxicities or reduced local/locoregional response rates should not guide treatment decisions in affected elderly patients.
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http://dx.doi.org/10.1007/s00405-020-06393-xDOI Listing
September 2020

Characterization of health-related quality of life based on the EQ-5D-5L questionnaire in head-and-neck cancer patients undergoing modern radiotherapy.

Expert Rev Pharmacoecon Outcomes Res 2020 Dec 4;20(6):673-682. Epub 2020 Oct 4.

Department of Health Care Management, Albert-Ludwigs University of Freiburg , Freiburg, Germany.

: Patient-reported quality of life in cancer patients is becoming increasingly important, especially for head-and-neck (H&N) cancers, which are at risk of experiencing severe treatment-related toxicities. Therefore, we sought to characterize the peritherapeutic HRQOL of contemporary patients using the well-validated EQ-5D-5 L questionnaire. : All patients receiving radiotherapy for H&N cancers between July 2019 and November 2019 at the University of Freiburg Medical Center who completed the first two follow-ups were included. : All 49 patients completed the questionnaires at all time points of data collection, yielding 196 total questionnaires. The mean EQ-5D-5 L index score of the overall population before radiotherapy, after radiotherapy, and three and six months following radiotherapy was 0.837 (standard deviation, SD 0.17), 0.828 (SD 0.16), 0.855 (SD 0.15), and 0.856 (SD 0.14) respectively. The respective mean EQ VAS scores were 63.88 (SD 20.72), 63.67 (SD 21.81), 63.67 (SD 21.81), and 65.20 (SD 22.41) respectively. The respective changes of the HI and EQ VAS score over time for this cohort were not significant (Friedman test p = 0.273, p = 0.618). : Despite the known therapy-related toxicities, no significant permanent deterioration of HRQOL in this cohort was observed.
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http://dx.doi.org/10.1080/14737167.2020.1823220DOI Listing
December 2020

Hyperthermia Plus Re-Irradiation in the Management of Unresectable Locoregional Recurrence of Breast Cancer in Previously Irradiated Sites.

J Clin Oncol 2020 10 8;38(30):3576-3577. Epub 2020 Sep 8.

Andreas R. Thomsen MD; Peter Vaupel MD, PhD; and Anca-Ligia Grosu, MD, Department of Radiation Oncology, University Medical Center, University of Freiburg, Freiburg, Germany, and German Cancer Consortium (DKTK), Partner Site Freiburg, and German Cancer Research Center (DKFZ), Heidelberg, Germany; and Markus Notter, MD, Department of Radiation Oncology, Lindenhofspital Bern, Bern, Switzerland.

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http://dx.doi.org/10.1200/JCO.20.01857DOI Listing
October 2020

Convolutional neural networks for head and neck tumor segmentation on 7-channel multiparametric MRI: a leave-one-out analysis.

Radiat Oncol 2020 Jul 29;15(1):181. Epub 2020 Jul 29.

Department of Radiology, Medical Physics, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Automatic tumor segmentation based on Convolutional Neural Networks (CNNs) has shown to be a valuable tool in treatment planning and clinical decision making. We investigate the influence of 7 MRI input channels of a CNN with respect to the segmentation performance of head&neck cancer.

Methods: Head&neck cancer patients underwent multi-parametric MRI including T2w, pre- and post-contrast T1w, T2*, perfusion (k, v) and diffusion (ADC) measurements at 3 time points before and during radiochemotherapy. The 7 different MRI contrasts (input channels) and manually defined gross tumor volumes (primary tumor and lymph node metastases) were used to train CNNs for lesion segmentation. A reference CNN with all input channels was compared to individually trained CNNs where one of the input channels was left out to identify which MRI contrast contributes the most to the tumor segmentation task. A statistical analysis was employed to account for random fluctuations in the segmentation performance.

Results: The CNN segmentation performance scored up to a Dice similarity coefficient (DSC) of 0.65. The network trained without T2* data generally yielded the worst results, with ΔDSC = 5.7% for primary tumor and ΔDSC = 5.8% for lymph node metastases compared to the network containing all input channels. Overall, the ADC input channel showed the least impact on segmentation performance, with ΔDSC = 2.4% for primary tumor and ΔDSC = 2.2% respectively.

Conclusions: We developed a method to reduce overall scan times in MRI protocols by prioritizing those sequences that add most unique information for the task of automatic tumor segmentation. The optimized CNNs could be used to aid in the definition of the GTVs in radiotherapy planning, and the faster imaging protocols will reduce patient scan times which can increase patient compliance.

Trial Registration: The trial was registered retrospectively at the German Register for Clinical Studies (DRKS) under register number DRKS00003830 on August 20th, 2015.
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http://dx.doi.org/10.1186/s13014-020-01618-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392704PMC
July 2020

The Role of Palliative Radiotherapy in the Treatment of Spinal Bone Metastases from Head and Neck Tumors-A Multicenter Analysis of a Rare Event.

Cancers (Basel) 2020 Jul 18;12(7). Epub 2020 Jul 18.

Department of Radiation Oncology, University Hospital of Freiburg, Robert-Koch-Strasse 3, 79106 Freiburg, Germany.

This retrospective multi-center analysis aimed to assess the clinical response and stabilizing effects of palliative radiotherapy (RT) for spinal bone metastases (SBM) in head and neck cancer (HNC), and to establish potential predictive factors for stability and overall survival (OS). Patients included in this analysis were treated at the University Hospitals of Mainz, Freiburg, and Heidelberg between 2001 and 2019. Clinical information was taken from the medical records. The stability of affected vertebral bodies was assessed according to the validated spine instability neoplastic score (SINS) based on CT-imaging before RT, as well as 3 and 6 months after RT. OS was quantified as the time between the start of palliative RT and death from any cause or last follow-up. Potential predictive factors for stability and OS were analyzed using generalized estimating equations and Cox regression for time-varying covariates to take into account multiple observations per patient. The mean follow-up time of 66 included patients after the first palliative RT was 8.1 months (range 0.3-85.0 months). The majority of patients (70%; = 46) had squamous cell carcinomas (SCC) originating from the pharynx, larynx and oral cavity, while most of the remaining patients (26%; = 17) suffered from salivary glands tumors. A total of 95 target volumes including 178 SBM were evaluated that received a total of 81 irradiation series. In patients with more than one metastasis per irradiated region, only the most critical bone metastasis was analyzed according to the SINS system. Prior to RT, pain and neurologic deficits were present in 76% ( = 72) and 22% ( = 21) of irradiated lesions, respectively, and 68% of the irradiated lesions ( = 65) were assessed as unstable or potentially unstable prior to RT. SBM-related pain symptoms and neurologic deficits responded to RT in 63% and 47% of the treated lesions, respectively. Among patients still alive at 3 and 6 months after RT with potentially unstable or unstable SBM, a shift to a better stability class according to the SINS was observed in 20% and 33% of the irradiated SBM, respectively. Pathological fractures of SBM were frequently detected before the start of irradiation (43%; = 41), but after RT, new fractures or increasing vertebral body sintering within the irradiated region occurred rarely (8%; = 8). A pathological fracture before RT was negatively associated with stabilization 6 months after RT (OR 0.1, 95% CI 0.02-0.49, = 0.004), while a Karnofsky performance score (KPS) ≥ 70% was associated positively with a stabilization effect through irradiation (OR 6.09, 95% CI 1.68-22.05, = 0.006). Mean OS following first palliative RT was 10.7 months, and the KPS (≥70% vs. <70%) was shown to be a strong predictive factor for OS after RT (HR 0.197, 95% CI 0.11-0.35, < 0.001). There was no significant difference in OS between patients with SCC and non-SCC. Palliative RT in symptomatic SBM of HNC provides sufficient symptom relief in the majority of patients, while only about one third of initially unstable SBM show re-stabilization after RT. Since patients in our multi-center cohort exhibited very limited OS, fractionation schemes should be determined depending on the patients' performance status.
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http://dx.doi.org/10.3390/cancers12071950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409283PMC
July 2020

The Value of Laboratory Parameters for Anemia, Renal Function, Systemic Inflammation and Nutritional Status as Predictors for Outcome in Elderly Patients with Head-and-Neck Cancers.

Cancers (Basel) 2020 Jun 26;12(6). Epub 2020 Jun 26.

Department of Radiation Oncology, University of Freiburg-Medical Center, Robert-Koch-Str. 3, 79106 Freiburg, Germany.

The purpose of this study was to evaluate the value of routine blood markers regarding their predictive potential for treatment outcomes of elderly head-and-neck squamous cell carcinoma (HNSCC) patients. In total, 246 elderly HNSCC patients (≥65 years) undergoing (chemo)radiotherapy from 2010 to 2018 were analyzed for treatment outcomes, depending on their hemoglobin, glomerular filtration rate (GFR), C-reactive protein (CRP) and albumin values, representing anemia, kidney function, inflammation and nutrition status, respectively. Local/locoregional control, progression-free and overall survival (OS) were calculated using the Kaplan-Meier method. Cox analyses were performed to examine the influence of blood parameters on oncological outcomes. In the univariate Cox regression analysis, hemoglobin ≤ 12 g/dL (HR = 1.536, < 0.05), a GFR ≤ 60 mL/min/1.73 m (HR = 1.537, < 0.05), a CRP concentration > 5 mg/L (HR = 1.991, < 0.001) and albumin levels ≤ 4.2 g/dL (HR = 2.916, < 0.001) were significant risk factors for OS. In the multivariate analysis including clinical risk factors, only performance status (HR = 2.460, < 0.05) and baseline albumin (HR = 2.305, < 0.05) remained significant prognosticators. Additionally, baseline anemia correlated with the prevalence of higher-grade chronic toxicities. We could show for the first time that laboratory parameters for anemia (and at least partly, tumor oxygenation), decreased renal function, inflammation and reduced nutrition status are associated with impaired survival in elderly HNSCC patients undergoing (chemo)radiotherapy.
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http://dx.doi.org/10.3390/cancers12061698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352755PMC
June 2020

ERCC2 gene single-nucleotide polymorphism as a prognostic factor for locally advanced head and neck carcinomas after definitive cisplatin-based radiochemotherapy.

Pharmacogenomics J 2021 Feb 16;21(1):37-46. Epub 2020 Jun 16.

Department of Radiotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Identifying patients with locally advanced head and neck carcinoma on high risk of recurrence after definitive concurrent radiochemotherapy is of key importance for the selection for consolidation therapy and for individualized treatment intensification. In this multicenter study we analyzed recurrence-associated single-nucleotide polymorphisms (SNPs) in DNA repair genes in tumor DNA from 132 patients with locally advanced head and neck carcinoma (LadHnSCC). Patients were treated with definitive radiotherapy and simultaneous cisplatin-based chemotherapy at six partner sites of the German Cancer Consortium (DKTK) Radiation Oncology Group from 2005 to 2011. For validation, a group of 20 patients was available. Score selection method using proportional hazard analysis and leave-one-out cross-validation were performed to identify markers associated with outcome. The SNPs rs1799793 and rs13181 were associated with survival and the same SNPs and in addition rs17655 with freedom from loco-regional relapse (ffLRR) in the trainings datasets from all patients. The homozygote major rs1799793 genotype at the ERCC2 gene was associated with better (Hazard ratio (HR): 0.418 (0.234-0.744), p = 0.003) and the homozygote minor rs13181 genotype at ERCC2 with worse survival (HR: 2.074, 95% CI (1.177-3.658), p = 0.017) in comparison to the other genotypes. At the ffLRR endpoint, rs1799793 and rs13181 had comparable prognostic value. The rs1799793 and rs13181 genotypes passed the leave-one-out cross-validation procedure and associated with survival and ffLRR in patients with LadHnSCC treated with definitive radiochemotherapy. While findings were confirmed in a small validation dataset, further validation is underway within a prospective biomarker study of the DKTK.
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http://dx.doi.org/10.1038/s41397-020-0174-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840506PMC
February 2021

The utility of multiparametric MRI to characterize hypoxic tumor subvolumes in comparison to FMISO PET/CT. Consequences for diagnosis and chemoradiation treatment planning in head and neck cancer.

Radiother Oncol 2020 Sep 13;150:128-135. Epub 2020 Jun 13.

Department of Radiation Oncology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner site Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Background And Purpose: Hypoxia is an essential metabolic marker that determines chemo- and radiation resistance in head-and-neck squamous cell carcinoma (HNSCC) patients. Our exploratory analysis aimed to identify multiparametric MRI (mpMRI) parameters linked to hypoxia that might be used as surrogate for [F]FMISO-PET in diagnosis and chemoradiation treatment (CRT) of HNSCC.

Materials And Methods: 21 patients undergoing definitive CRT for HNSCC were prospectively imaged with serial [F]FMISO-PET and 3 Tesla mpMRI for T1- and T2-weighted and dynamic contrast-enhanced perfusion and diffusion-weighted measurements (k, v, k, ADC) in weeks 0, 2 and 5 and FDG-PET in week 0. [F]FMISO-PET-derived hypoxic subvolumes (HSV) and complementary non-hypoxic subvolumes (nonHSV) were created for tumor and lymph nodes and projected on the mpMRI scans after PET/MRI co-registration. MpMRI and [F]FMISO-PET parameters within HSVs and nonHSVs were statistically compared.

Results: FMISO-PET-based HSVs of the primary tumors on MRI were characterized by lower ADC at all time points (p = 0.012 at baseline; p = 0.015 in week 2) and reduced interstitial space volume fraction v and perfusion k at baseline (p = 0.006, p = 0.047) compared to nonHSVs. Hypoxic lymph nodes were characterized by significantly lower ADC values at baseline (p = 0.039), but not at later time points and a reduction in k-based perfusion at week 2 (p = 0.018).

Conclusion: MpMRI parameters differ significantly between hypoxic and non-hypoxic tumor regions, defined on FMISO-PET/CT as gold standard and might represent surrogate markers for tumor hypoxia. These findings suggest that mpMRI may be useful in the future as a surrogate modality for hypoxia imaging in order to personalize CRT.
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http://dx.doi.org/10.1016/j.radonc.2020.06.013DOI Listing
September 2020

Voxel-based comparison of [Ga]Ga-RM2-PET/CT and [Ga]Ga-PSMA-11-PET/CT with histopathology for diagnosis of primary prostate cancer.

EJNMMI Res 2020 Jun 12;10(1):62. Epub 2020 Jun 12.

Department of Nuclear Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Focal therapies or focally escalated therapies of primary prostate cancer are becoming more and more important. This increases the need to identify the exact extension of the intraprostatic tumor and possible dominant intraprostatic lesions by imaging techniques. While the prostate-specific membrane antigen (PSMA) is already a well-established target for imaging of prostate cancer cells, the gastrin-releasing peptide receptor (GRPR) seems to provide interesting additional information. Histopathology was used to examine the extent to which the single and combined image information of PET scans targeting GRPR and PSMA might lead to better tumor delineation.

Methods: Eight patients with histologically proven primary prostate cancer underwent two positron emission tomography with computer tomography scans, [Ga]Ga-RM2-PET/CT (RM2-PET) and [Ga]Ga-PSMA-11-PET/CT (PSMA-PET), prior to radical prostatectomy. RM2-PET data were correlated voxel-wise to a voxel-based model of the histopathologic tumor volume information. The results were compared to, correlated to, and combined with the correlation of PSMA-PET data analyzed analogously.

Results: In 4/8 patients, RM2-PET showed a higher signal in histologically proven tumor regions compared to PSMA. There were also tumor regions where PSMA-PET showed a higher signal than GRPR in 4/8 patients. A voxel-wise correlation of RM2-PET against histopathology yielded similar results compared to the correlation of PSMA-PET against histopathology, while PSMA-PET is the slightly better performing imaging technique. The combined information of both tracers yielded the best overall result, although this effect was not statistically significant compared to RM2-PET alone.

Conclusions: Qualitative and quantitative findings in this preliminary study with 8 patients indicate that RM2-PET and PSMA-PET partially show not only the same, but also distinct regions of prostate cancer. Patients with pPCa might profit from information given by tracers targeting GRPR and PSMA simultaneously, in terms of a better delineation of the gross tumor volume.
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http://dx.doi.org/10.1186/s13550-020-00652-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292851PMC
June 2020

Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging (HIPPORAD) - a phase II prospective randomized multicenter trial (NOA-14, ARO 2015-3, DKTK-ROG).

BMC Cancer 2020 Jun 8;20(1):532. Epub 2020 Jun 8.

Department of Radiation Oncology, Faculty of Medicine, Medical Center - University of Freiburg, Robert-Koch-Str. 3, 79106, Freiburg, Germany.

Background: Whole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB).

Methods: This is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter.

Discussion: This is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases.

Trial Registration: The HIPPORAD trial is registered with the German Clinical Trials Registry (DRKS00004598, registered 2 June 2016).
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http://dx.doi.org/10.1186/s12885-020-07011-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281918PMC
June 2020

Radiotherapy for nonagenarians: the value of biological versus chronological age.

Radiat Oncol 2020 May 19;15(1):113. Epub 2020 May 19.

Department of Radiation Oncology, University of Freiburg - Medical Center, Robert-Koch-Str. 3, 79106, Freiburg, Germany.

Background: The number of nonagenarian cancer patients (≥ 90 years) is continuously increasing, and radiotherapy is performed in a relevant proportion of patients, as surgery and chemotherapy are often not feasible for these patients. However, the evidence regarding the feasibility and treatment outcomes after radiotherapy for this patient group is very limited.

Methods: All nonagenarian patients receiving (chemo) radiotherapy between 2009 and 2019 at the University of Freiburg - Medical Center were analyzed for patterns of care, overall survival (OS) and therapy-associated toxicities according to the Common Terminology Criteria for Adverse Events. Uni- and multivariate Cox regression analyses were conducted to assess the influence of patient- and treatment-related factors on patient outcomes.

Results: One hundred nineteen patients with a total of 137 irradiated lesions were included in this analysis. After a median follow-up of 27 months, median OS was 10 months with a 3-year OS amounting to 11.1%. Univariate analyses demonstrated that a reduced performance status (HR = 1.56, 95% CI 1.00-2.45, p < 0.05), a higher burden of comorbidities (HR = 2.00, 95% CI 1.00-4.10, p < 0.05) and higher UICC tumor stages (HR = 2.21, 95% CI 1.14-4.26, p < 0.05) were associated with impaired survival rates. Split-course treatments (HR = 2.05, 95% CI 1.07-3.94, p < 0.05), non-completion of radiotherapy (HR = 7.17, 95% CI 3.88-13.26, p < 0.001) and palliative treatments (HR = 2.84, 95% CI 1.68-4.81, p < 0.05) were found to result in significantly reduced OS. In the multivariate analysis, split-course concepts (HR = 2.21, 95% CI 1.10-4.37, p < 0.05) and palliative treatments (HR = 3.19, 95% CI 1.77-5.75, p < 0.001) significantly deteriorated outcomes, while impaired ECOG status (HR = 1.49, 95% CI 0.91-2.43, p = 0.11) did not. The vast majority of patients reported either no (n = 40; 33.6%) or grade 1-2 acute toxicities (n = 66; 55.5%), and only very few higher-grade toxicities were observed in our study.

Conclusion: Radiotherapy for nonagenarian patients is generally feasible and associated with a low toxicity profile. Given the relatively poor OS rates and the importance of the quality of life for this patient group, individualized treatment regimens including hypofractionation concepts should be considered.
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http://dx.doi.org/10.1186/s13014-020-01563-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236131PMC
May 2020

Multipotent mesenchymal stromal cells are sensitive to thermic stress - potential implications for therapeutic hyperthermia.

Int J Hyperthermia 2020 ;37(1):430-441

Department of Radiation Oncology, Freiburg University Medical Center, Freiburg, Germany.

Hyperthermia demonstrated clinical efficacy in multimodal cancer treatment. Multipotent mesenchymal stromal cells (MSCs) as part of the tumor-supporting stroma modulate tumor response and tissue regeneration after hyperthermia. We aimed to investigate the effects of hyperthermia on the survival, stem cell characteristics and heat shock expression of human MSCs. Human MSCs and normal human dermal fibroblasts (NHDFs) were exposed to temperatures between 37 °C and 44 °C for 60 min, and hyperthermic sensitivity was examined by clonogenicity, proliferation and viability assays. The influence of 42 °C hyperthermia on the MSCs' adhesion potential, migratory capacity, surface marker expression and multi-lineage differentiation capability was investigated. Cell cycle distribution, apoptosis and senescence after 42 °C hyperthermia were determined by flow cytometry and β-galactosidase staining. Heat shock protein expression was determined by Western Blots. MSCs exhibited decreased clonogenic survival after 40 °C and 42 °C hyperthermia compared to NHDFs, while proliferative activity and viability were comparable after hyperthermia up to 44 °C. MSC adhesion was reduced after 42 °C hyperthermia, while the characteristic surface marker expression and the migratory ability remained unaffected in 42 °C hyperthermia-exposed MSCs. 42 °C hyperthermia diminished the adipogenic differential potential of all tested MSC samples. A pronounced G2/M arrest was found after 42 °C hyperthermia and was associated with increased apoptosis and senescence levels in MSCs. MSCs exhibited slightly lower heat shock protein levels compared to NHDFs. Human MSCs exhibit a thermosensitive phenotype which reduced the multipotent cells' regenerative abilities, resulting in impaired tissue regeneration after hyperthermia treatment or thermal injuries. On the other hand, tumor-associated MSCs may be efficiently targeted by hyperthermia treatment.
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http://dx.doi.org/10.1080/02656736.2020.1758350DOI Listing
November 2020

Deep abscopal response to radiotherapy and anti-PD-1 in an oligometastatic melanoma patient with unfavorable pretreatment immune signature.

Cancer Immunol Immunother 2020 Sep 29;69(9):1823-1832. Epub 2020 Apr 29.

Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Robert-Koch-Strasse 3, 79106, Freiburg, Germany.

Radiotherapy can elicit abscopal effects in non-irradiated metastases, particularly under immune checkpoint blockade (ICB). We report on two elderly patients with oligometastatic melanoma treated with anti-PD-1 and stereotactic body radiation therapy (SBRT). Before treatment, patient 1 showed strong tumor infiltration with exhausted CD8+ T cells and high expression of T cell-attracting chemokines. This patient rapidly mounted a complete response, now ongoing for more than 4.5 years. Patient 2 exhibited low CD8+ T cell infiltration and high expression of immunosuppressive arginase. After the first SBRT, his non-irradiated metastases did not regress and new metastases occurred although neoepitope-specific and differentiation antigen-specific CD8+ T cells were detected in the blood. A second SBRT after 10 months on anti-PD-1 induced a radiologic complete response correlating with an increase in activated PD-1-expressing CD8 T cells. Apart from a new lung lesion, which was also irradiated, this deep abscopal response lasted for more than 2.5 years. However, thereafter, his disease progressed and the activated PD-1-expressing CD8 T cells dropped. Our data suggest that oligometastatic patients, where a large proportion of the tumor mass can be irradiated, are good candidates to improve ICB responses by RT, even in the case of an unfavorable pretreatment immune signature, after progression on anti-PD-1, and despite advanced age. Besides repeated irradiation, T cell epitope-based immunotherapies (e.g., vaccination) may prolong antitumor responses even in patients with unfavorable pretreatment immune signature.
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http://dx.doi.org/10.1007/s00262-020-02587-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413872PMC
September 2020

[Intraoperative radiotherapy-Indications and options in visceral surgery].

Chirurg 2020 Sep;91(9):743-754

Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg, Hugstetterstraße 55, 79106, Freiburg, Deutschland.

Background: Intraoperative radiotherapy (IORT) enables a high precision through surgical exposure of the tumor and the tumor bed, which leads to a maximum radiation dose to the tumor while simultaneously protecting normal tissue from radiation as the dose-limiting factor. Therefore, IORT can be particularly advantageous if local tumor control decisively impacts on long-term survival and enables functional preservation.

Objective: This review summarizes the knowledge gained from a literature search to enable an evidence-based approach with respect to indications and treatment options of IORT for intra-abdominal tumors.

Results And Conclusion: Although the effectiveness of IORT cannot be finally assessed due to limited evidence, IORT is established in the clinical practice as a supplement to the multimodal treatment of (recurrent) rectal cancer and sarcomas. Gastric and pancreatic carcinomas are further indications but additional studies are necessary to clearly define the role of IORT in these tumor entities. An important factor to achieve a benefit with IORT seems to be patient selection in order to obtain good local control of local recurrences as well as overall survival rates for patients with primary or recurrent cancer.
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http://dx.doi.org/10.1007/s00104-020-01179-7DOI Listing
September 2020

Efficacy of PSMA ligand PET-based radiotherapy for recurrent prostate cancer after radical prostatectomy and salvage radiotherapy.

BMC Cancer 2020 Apr 29;20(1):362. Epub 2020 Apr 29.

Department of Radiotherapy and Special Oncology, Hannover Medical School, Carl-Neuberg-Str. 1, 30629, Hannover, Germany.

Background: A substantial number of patients will develop further biochemical progression after radical prostatectomy (RP) and salvage radiotherapy (sRT). Recently published data using prostate-specific membrane antigen ligand positron emission tomography (PSMA - PET) for re-staging suggest that those recurrences are often located outside the prostate fossa and most of the patients have a limited number of metastases, making them amenable to metastasis-directed treatment (MDT).

Methods: We analyzed 78 patients with biochemical progression after RP and sRT from a retrospective European multicenter database and assessed the biochemical recurrence-free survival (bRFS; PSA < nadir + 0.2 ng/ml or no PSA decline) as well as the androgen deprivation therapy- free survival (ADT-FS) using Kaplan-Meier curves. Log-rank test and multivariate analysis was performed to determine influencing factors.

Results: A total of 185 PSMA - PET positive metastases were detected and all lesions were treated with radiotherapy (RT). Concurrent ADT was prescribed in 16.7% (13/78) of patients. The median PSA level before RT was 1.90 ng/mL (range, 0.1-22.1) and decreased statistically significantly to a median PSA nadir level of 0.26 ng/mL (range, 0.0-12.25; p < 0.001). The median PSA level of 0.88 ng/mL (range, 0.0-25.8) at the last follow-up was also statistically significantly lower (p = 0.008) than the median PSA level of 1.9 ng/mL (range, 0.1-22.1) before RT. The median bRFS was 17.0 months (95% CI, 14.2-19.8). After 12 months, 55.3% of patients were free of biochemical progression. Multivariate analyses showed that concurrent ADT was the most important independent factor for bRFS (p = 0.01). The median ADT-FS was not reached and exploratory statistical analyses estimated a median ADT-FS of 34.0 months (95% CI, 16.3-51.7). Multivariate analyses revealed no significant parameters for ADT-FS.

Conclusions: RT as MDT based on PSMA - PET of all metastases of recurrent prostate cancer after RP and sRT represents a viable treatment option for well-informed and well-selected patients.
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http://dx.doi.org/10.1186/s12885-020-06883-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191762PMC
April 2020

Quality of life after pulmonary stereotactic fractionated radiotherapy (SBRT): Results of the phase II STRIPE trial.

Radiother Oncol 2020 Jul 6;148:82-88. Epub 2020 Apr 6.

Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Germany; German Cancer Consortium (DKTK) Partner Site Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background And Purpose: Preserving health related quality of life (HRQOL) plays an important role in considering stereotactic body fractionated radiotherapy (SBRT). The prospective monocenter phase II STRIPE trial investigated long-term HRQOL after SBRT, efficacy and toxicity.

Materials And Methods: Patients with ≤2 pulmonary lesions ≤5 cm were treated with 4DPET/CT-based SBRT (3 × 12.5 Gy or risk-adapted 5 × 7 Gy, to 60% isodose). Follow up (FU) was performed 2 and 7 weeks after SBRT, then 3-monthly for 2 years with assessment of response (primary endpoint: 2-year cumulative incidence of local progression (LP); secondary endpoints: local progression free survival (LPFS), overall survival (OS) and toxicity (CTCAE)). Impact of predefined patient and treatment related factors on HRQOL (EORTC QLQ-C30 and EORTC QLQ-LC13) was evaluated.

Results: Between 02/2011 and 11/2014, 100 patients were given SBRT for 56 NSCLC and 44 pulmonary metastases (M1). Long-term FU overall revealed stable Quality of Life (QoL)/Global health status (GHS), functions-scores and symptoms. For QoL/GHS, patients with low (
Conclusions: These prospective data on representative pulmonary SBRT patients confirm stable preservation of HRQOL after SBRT and demonstrate a QoL/GHS-benefit for patients with low initial QoL/GHS-scores, the regimen of 3 × 12.5 Gy SBRT being efficient and well tolerated. This result may inform shared decision making when discussing SBRT for frail patients.
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http://dx.doi.org/10.1016/j.radonc.2020.03.018DOI Listing
July 2020

The value of moderate dose escalation for re-irradiation of recurrent or second primary head-and-neck cancer.

Radiat Oncol 2020 Apr 16;15(1):81. Epub 2020 Apr 16.

Department of Radiation Oncology, University of Freiburg - Medical Center, Faculty of Medicine, Robert-Koch-Str. 3, 79106, Freiburg, Germany.

Background: Treatment for local and locoregional recurrence or second head-and-neck (H&N) cancers after previous radiotherapy is challenging, and re-irradiation carries a significantly increased risk for radiotherapy-related normal tissue toxicities and treatment failure due to a radioresistant tumor phenotype. Here, we analyzed re-irradiation management and outcomes in patients with recurrent or second primary H&N carcinoma using state-of-the-art diagnostic procedures and radiotherapy techniques.

Methods: Between 2010 and 2019, 48 patients with recurrent or second primary H&N carcinoma received re-radiotherapy at the University of Freiburg Medical Center and were included in this study. Overall survival (OS) and progression-free survival (PFS) were calculated with the Kaplan-Meier method, and univariate Cox-regression analyses were performed to assess the effects of clinico-pathological factors on treatment outcomes. Acute and chronic treatment-related toxicities were quantified using the Common Terminology Criteria for Adverse Events (CTCAE v4.03).

Results: Thirty-one patients (64.6%) received definitive and 17 (35.4%) adjuvant radiotherapy. Simultaneous chemotherapy was administered in 28 patients (58.3%) with cetuximab as the most commonly used systemic agent (n = 17, 60.7%). After a median time of 17 months (range 4 months to 176 months) between first and second radiotherapy, patients were re-irradiated with a median of 58.4 Gy and a treatment completion rate of 87.5% (n = 42). Median OS was 25 months with a 1-year OS amounting to 62.4%, and median PFS was 9 months with a 1-year PFS of 37.6%. Univariate analyses demonstrated that both a lower rT-status and a radiotherapy boost were associated with improved OS (p < 0.05). There was a trend towards superior OS for patients who received > 50 Gy (p = 0.091) and who completed the prescribed radiotherapy (p = 0.055). Five patients (10.4%) suffered from at least one grade 3 toxicities, while 9 patients (27.3%) experienced chronic higher-grade toxicities (≥ grade 3) with one (3.0%) grade 4 carotid blowout and one (3.0%) grade 4 osteoradionecrosis.

Conclusion: Re-irradiation of recurrent or second primary H&N cancer with modern radiation techniques such as intensity-modulated radiotherapy resulted in promising survival rates with acceptable toxicities compared to historical cohorts. Increased re-irradiation doses, utilization of a radiotherapy boost and completion of the re-irradiation treatment were found to result in improved survival.
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http://dx.doi.org/10.1186/s13014-020-01531-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164259PMC
April 2020

Radiotherapeutic management of cervical lymph node metastases from an unknown primary site - experiences from a large cohort treated with modern radiation techniques.

Radiat Oncol 2020 Apr 15;15(1):80. Epub 2020 Apr 15.

Department of Radiation Oncology, Medical Center, Faculty of Medicine, University of Freiburg, Robert-Koch-Str. 3, 79106, Freiburg, Germany.

Purpose: To analyze management and outcomes following (chemo)radiation therapy in patients with cervical lymph node metastases from an unknown primary site (CCUP) in a large single-center cohort.

Methods: Between 2008 and 2019, 58 patients with CCUP were treated with (chemo)radiation therapy at the University of Freiburg Medical Center and were included in this analysis. Overall survival (OS), locoregional progression-free survival (PFS) and distant metastasis-free survival (DMFS) were calculated using the Kaplan-Meier method. The use of diagnostic procedures and their impact on oncological outcomes was analyzed by Cox regression, and treatment-related toxicities were quantified.

Results: Median follow-up was 29.9 months (range 4.6-121.9). Twenty-one patients (36.2%) received definitive RT, 35 (60.3%) underwent adjuvant RT, and 2 (3.4%) were treated for oligometastatic disease. Concurrent chemotherapy was prescribed in 40 patients (69.0%). 89.6% of patients completed the prescribed RT, and 65.0% completed the prescribed simultaneous chemotherapy. Locoregional recurrence was observed in 7 patients (12.1%) and distant metastases in 13 cases (22.4%). OS was 81,1, 64.9% and 56,6% after 1, 3 and 5 years, respectively. Univariate analysis of age, gender, extracapsular spread, tumor grading, neck dissection, diagnostic utilization of F-fluorodeoxyglucose positron-emission tomography and concomitant chemotherapy showed no effect on OS (p > 0.05 for all), while smoking was significantly associated with decreased survival (p < 0.05). There was a trend towards impaired OS for patients with advanced nodal status (pN3) (p = 0.07). Three patients (5.2%) experienced grade 3 radiation dermatitis, and 12 (22.4%) developed grade 3 and 1 (1.7%) grade 4 mucositis.

Conclusions: RT of the panpharynx and cervical lymph nodes with concurrent chemotherapy in case of risk factors demonstrated good locoregional control, but the metachronous occurrence of distant metastases limited survival and must be further addressed.
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http://dx.doi.org/10.1186/s13014-020-01529-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158130PMC
April 2020

[Intraoperative radiotherapy in abdominal surgery-Own experiences].

Chirurg 2020 Nov;91(11):962-969

Klinik für Allgemein- und Viszeralchirurgie, Universitätsklinikum Freiburg, Hugstetter Str. 55, 79106, Freiburg, Deutschland.

Background: Intraoperative radiotherapy (IORT) can be applied for locally advanced tumors and expected or unavoidable R1 situations combined with surgical resection. The aim is to improve local tumor control and long-term survival. The indications are primary and recurrent intra-abdominal and retroperitoneal tumors. This study aimed to evaluate own data and experiences with IORT combined with surgical visceral resection.

Methods: Patients who underwent IORT combined with abdominal tumor resection in the Department of General and Visceral Surgery at the University Medical Center Freiburg between January 2008 and December 2018 were included in this study. The results were retrospectively evaluated regarding short-term and long-term outcomes.

Results: The most frequent indications for IORT were sarcoma followed by rectal and anal cancers. The median IORT dose used was 15 Gy (range 8-19 Gy). With a median comprehensive complication index (CCI) of 11.9, complications occurred in 24% of patients (Dindo-Clavien ≥ °III). The 90-day mortality was 0%. Especially in recurrent anal cancer the local control after 1 year was insufficient despite R0 resection.

Conclusion: In this cohort of patients IORT could be applied with acceptable morbidity. Nevertheless, the indications and patient selection are critical factors for carrying out the treatment. The effect of IORT to improve local tumor control and long-term survival should be evaluated in further studies.
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http://dx.doi.org/10.1007/s00104-020-01165-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581588PMC
November 2020