Publications by authors named "Michael Mix"

69 Publications

FDG-PET Radiomics for Response Monitoring in Non-Small-Cell Lung Cancer Treated with Radiation Therapy.

Cancers (Basel) 2021 Feb 15;13(4). Epub 2021 Feb 15.

German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Freiburg of the German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

The aim of this study is to identify clinically relevant image feature (IF) changes during chemoradiation and evaluate their efficacy in predicting treatment response. Patients with non-small-cell lung cancer (NSCLC) were enrolled in two prospective trials (STRIPE, PET-Plan). We evaluated 48 patients who underwent static (3D) and retrospectively-respiratory-gated 4D PET/CT scans before treatment and a 3D scan during or after treatment. Our proposed method rejects IF changes due to intrinsic variability. The IF variability observed across 4D PET is employed as a patient individualized normalization factor to emphasize statistically relevant IF changes during treatment. Predictions of overall survival (OS), local recurrence (LR) and distant metastasis (DM) were evaluated. From 135 IFs, only 17 satisfied the required criteria of being normally distributed across 4D PET and robust between 3D and 4D images. Changes during treatment in the area-under-the-curve of the cumulative standard-uptake-value histogram (δ) within primary tumor discriminated (AUC = 0.87, Specificity = 0.78) patients with and without LR. The resulted prognostic model was validated with a different segmentation method (AUC = 0.83) and in a different patient cohort (AUC = 0.63). The quantification of tumor FDG heterogeneity by δ during chemoradiation correlated with the incidence of local recurrence and might be recommended for monitoring treatment response in patients with NSCLC.
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http://dx.doi.org/10.3390/cancers13040814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919471PMC
February 2021

Tc-labelled PSMA ligand for radio-guided surgery in nodal metastatic prostate cancer: proof of principle.

EJNMMI Res 2021 Mar 4;11(1):22. Epub 2021 Mar 4.

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

Purpose: Intraoperative identification of prostate cancer (PCa) lymph node (LN) metastases (LNM) detected by preoperative PSMA PET/CT may be facilitated by PSMA radio-guided surgery (RGS) with use of a γ-probe. Earlier we demonstrated excellent performance of the In-labelled PSMA ligand DKFZ-617 ([In]In-PSMA-617) in RGS for ex situ distinction of LN vs LNM at lymphadenectomy (LA) at a single LN level. In comparison with indium-111, technetium-99m has better physical properties for γ-probe measurements, better availability and lower radiation exposure for patients and medical personnel. Against this background, we evaluated the uptake of Tc-PSMA-I&S ligand at the level of single LN and its power to discriminate between unaffected LN and LNM.

Methods: Six patients with PCa with the suspicion of LNM on preoperative PSMA-PET/CT underwent [Tc]Tc-PSMA-I&S RGS (4 salvage LA, 2 primary LA) with intravenous injection of [Tc]Tc-PSMA-I&S 24 h prior to surgery. Resected samples were isolated manually aiming at the level of single LN. Uptake measurements were done ex situ with a high-purity germanium detector. Receiver operating characteristic (ROC) analysis was performed based on [Tc]Tc-PSMA-I&S uptake expressed as lean body mass standard uptake value (SUL).

Results: Separation of the tissue samples from 73 subregions resulted in 498 single samples. After final histopathology 356 LN, 160 LNM und 11 non-nodal PCa samples were identified. Median SUL of tumor-free samples (0.26) and samples with cancer (3.5) was significantly different (p < 0.0001). ROC analysis revealed an area under the curve (AUC) of 0.917 (95% CI 0.89-0.95). Using a SUL cutoff of 1.1, sensitivity, specificity, positive predictive value, and negative predictive values were 76.6%, 94.4%, 89.4% and 86.9%.

Conclusion: Ex situ analysis of [Tc]Tc-PSMA-I&S uptake at single LN level showed good diagnostic performance for the ex situ distinction of tumor-bearing vs tumor-free LN during RGS.
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http://dx.doi.org/10.1186/s13550-021-00762-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933311PMC
March 2021

FET-PET radiomics in recurrent glioblastoma: prognostic value for outcome after re-irradiation?

Radiat Oncol 2021 Mar 3;16(1):46. Epub 2021 Mar 3.

German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Partner Site Freiburg, Heidelberg, Germany.

Purpose: The value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-positron emission tomography (PET)-radiomics in the outcome assessment of patients with recurrent glioblastoma (rGBM) has not been evaluated until now. The aim of this study was to evaluate whether a prognostic model based on FET-PET radiomics features (RF) is feasible and can identify rGBM patients that would most benefit from re-irradiation.

Methods: We prospectively recruited rGBM patients who underwent FET-PET before re-irradiation (GLIAA-Pilot trial, DRKS00000633). Tumor volume was delineated using a semi-automatic method with a threshold of 1.8 times the standardized-uptake-value of the background. 135 FET-RF (histogram parameters, shape and texture features) were extracted. The analysis involved the characterization of tumor and non-tumor tissue with FET-RF and the evaluation of the prognostic value of FET-RF for time-to-progression (TTP), overall survival (OS) and recurrence location (RL).

Results: Thirty-two rGBM patients constituted our cohort. FET-RF discriminated significantly between tumor and non-tumor. The texture feature Small-Zone-Low-Gray-Level-Emphasis (SZLGE) showed the best performance for the prediction of TTP (p = 0.001, satisfying Bonferroni-multiple-test significance level). Additionally, two radiomics signatures could predict TTP (TTP-radiomics-signature, p = 0.001) and OS (OS-radiomics-signature, p = 0.038). SZLGE and the TTP-radiomics-signature additionally predicted RL. Specifically, high values for TTP-radiomics-signature and for SZLGE indicated not only earlier progression, but also a RL within the initial FET-PET active volume.

Conclusion: Our findings suggest that FET-PET radiomics could contribute to the prognostic assessment and selection of rGBM-patients benefiting from re-irradiation. Trial registration DRKS00000633. Registered on 8th of December in 2010. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00000633 .
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http://dx.doi.org/10.1186/s13014-020-01744-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931514PMC
March 2021

Follow-up Brain Imaging Within 30 Days of Gamma-Knife Surgery for New Symptoms: Retrospective Analysis.

World Neurosurg 2021 Feb 2. Epub 2021 Feb 2.

Department of Neurosurgery, Upstate Medical University, Syracuse, New York, USA. Electronic address:

Objective: Gamma Knife surgery is a complementary procedure to open microsurgery for several indications. However, posttreatment symptomatic complaints are common and often result in short-term follow-up imaging. Here we evaluate the efficacy of repeat brain imaging within 30 days of a Gamma Knife procedure by analyzing the frequency with which that imaging reveals addressable pathology.

Methods: All patients who underwent Gamma Knife treatments at our institution between January 2013 and August 2019 were retrospectively analyzed, and any patient who received imaging of the brain within 30 days for a symptomatic complaint was evaluated.

Results: Of the 956 Gamma Knife cases performed, 78 (8.2%) scans were performed within a 30-day time frame for symptomatic complaints. Of these, the most common complaint was headache (25%). Most images demonstrated no changes when compared with the treatment scan (68%) and there were no hemorrhages and only 1 stroke (<1%). Univariate analysis revealed that sex (P = 0.046), treatment volume (P < 0.001), and treatments for metastasis (P < 0.001) or glioma (P < 0.001) were associated with symptomatic complaints leading to imaging, but no factors were associated with higher rates of abnormal imaging.

Conclusions: Gamma Knife therapy remains a safe treatment for multiple indications, but it is not risk free and acute symptomatic complaints are common. However, our data suggest that the need for reimaging within 30 days for symptomatic complaints is likely overestimated as obtained imaging does not usually show any change and the rate of significant complication is exceedingly low.
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http://dx.doi.org/10.1016/j.wneu.2021.01.085DOI Listing
February 2021

A biologically effective dose threshold for stereotactic body radiation therapy-can we put the issue to BED?

Ann Transl Med 2020 Nov;8(22):1533

Department of Radiation Oncology, Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.

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http://dx.doi.org/10.21037/atm-20-3689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729357PMC
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

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

Intraprostatic Tumour Segmentation on PSMA-PET Images in Patients with Primary Prostate Cancer with a Convolutional Neural Network.

J Nucl Med 2020 Oct 30. Epub 2020 Oct 30.

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

Accurate delineation of the intraprostatic gross tumour volume (GTV) is a prerequisite for treatment approaches in patients with primary prostate cancer (PCa). Prostate-specific membrane antigen positron emission tomography (PSMA-PET) may outperform MRI in GTV detection. However, visual GTV delineation underlies interobserver heterogeneity and is time consuming. The aim of this study was to develop a convolutional neural network (CNN) for automated segmentation of intraprostatic tumour (GTV-CNN) in PSMA-PET. The CNN (3D U-Net) was trained on Ga-PSMA-PET images of 152 patients from two different institutions and the training labels were generated manually using a validated technique. The CNN was tested on two independent internal (cohort 1: Ga-PSMA-PET, = 18 and cohort 2: F-PSMA-PET, = 19) and one external (cohort 3: Ga-PSMA-PET, = 20) test-datasets. Accordance between manual contours and GTV-CNN was assessed with Dice-Sørensen coefficient (DSC). Sensitivity and specificity were calculated for the two internal test-datasets (cohort 1: = 18, cohort 2: = 11) by using whole-mount histology. Median DSCs for cohorts 1-3 were 0.84 (range: 0.32-0.95), 0.81 (range: 0.28-0.93) and 0.83 (range: 0.32-0.93), respectively. Sensitivities and specificities for GTV-CNN were comparable with manual expert contours: 0.98 and 0.76 (cohort 1) and 1 and 0.57 (cohort 2), respectively. Computation time was around 6 seconds for a standard dataset. The application of a CNN for automated contouring of intraprostatic GTV in Ga-PSMA- and F-PSMA-PET images resulted in a high concordance with expert contours and in high sensitivities and specificities in comparison with histology reference. This robust, accurate and fast technique may be implemented for treatment concepts in primary PCa. The trained model and the study's source code are available in an open source repository.
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http://dx.doi.org/10.2967/jnumed.120.254623DOI Listing
October 2020

Lymphocyte Infiltration Determines the Hypoxia-Dependent Response to Definitive Chemoradiation in Head-and-Neck Cancer: Results from a Prospective Imaging Trial.

J Nucl Med 2021 Apr 28;62(4):471-478. Epub 2020 Aug 28.

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

Tumor hypoxia in head-and-neck squamous cell carcinoma (HNSCC) leads to an immunosuppressive microenvironment and reduces the response to radiotherapy. In this prospective imaging trial, we investigated potential interactions between functional hypoxia imaging and infiltrating lymphocyte levels as a potential predictor for treatment response in HNSCC patients. In total, 49 patients receiving definitive chemoradiation for locally advanced HNSCCs underwent pretherapeutic biopsies and peritherapeutic hypoxia imaging using F-misonidazole PET at weeks 0, 2, and 5 during chemoradiation. Hematoxylin-eosin and immunohistochemical stainings for tumor-infiltrating lymphocytes, tissue-based hypoxia, and microvascular markers were analyzed and correlated with the longitudinal hypoxia dynamics and patient outcomes. High levels of tumor-infiltrating total lymphocytes correlated with superior locoregional control (LRC) (hazard ratio [HR], 0.279; = 0.011) and progression-free survival (PFS) (HR, 0.276; = 0.006). Similarly, early resolution of F-misonidazole PET-detected tumor hypoxia quantified by F-misonidazole dynamics between weeks 0 and 2 of chemoradiation was associated with improved LRC (HR, 0.321; = 0.015) and PFS (HR, 0.402; = 0.043). Outcomes in the favorable early hypoxia resolution subgroup significantly depended on infiltrating lymphocyte counts, with patients who showed both an early hypoxia response and high lymphocyte infiltration levels exhibiting significantly improved LRC (HR, 0.259; = 0.036) and PFS (HR, 0.242; = 0.017) compared with patients with an early hypoxia response but low lymphocyte counts. These patients exhibited oncologic results comparable to those of patients with no hypoxia response within the first 2 wk of chemoradiation. This analysis established a clinical hypoxia-immune score that predicted treatment responses and outcomes in HNSCC patients undergoing chemoradiation and may help to devise novel concepts for biology-driven personalization of chemoradiation.
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http://dx.doi.org/10.2967/jnumed.120.248633DOI Listing
April 2021

Hypoxia dynamics on FMISO-PET in combination with PD-1/PD-L1 expression has an impact on the clinical outcome of patients with Head-and-neck Squamous Cell Carcinoma undergoing Chemoradiation.

Theranostics 2020 23;10(20):9395-9406. Epub 2020 Jul 23.

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

Tumor-associated hypoxia influences the radiation response of head-and-neck cancer (HNSCC) patients, and a lack of early hypoxia resolution during treatment considerably deteriorates outcomes. As the detrimental effects of hypoxia are partly related to the induction of an immunosuppressive microenvironment, we investigated the interaction between tumor hypoxia dynamics and the PD-1/PD-L1 axis in HNSCC patients undergoing chemoradiation and its relevance for patient outcomes in a prospective trial. 49 patients treated with definitive chemoradiation for locally advanced HNSCC were enrolled in this trial and received longitudinal hypoxia PET imaging using fluorine-18 misonidazole ([F]FMISO) at weeks 0, 2 and 5 during treatment. Pre-therapeutic tumor biopsies were immunohistochemically analyzed regarding the PD-1/PD-L1 expression both on immune cells and on tumor cells, and potential correlations between the PD-1/PD-L1 axis and tumor hypoxia dynamics during chemoradiation were assessed using Spearman's rank correlations. Hypoxia dynamics during treatment were quantified by subtracting the standardized uptake value (SUV) index at baseline from the SUV values at weeks 2 or 5, whereby SUV index was defined as ratio of maximum tumor [F]FMISO SUV to mean SUV in the contralateral sternocleidomastoid muscle ( tumor-to-muscle ratio). The impact of the PD-1/PD-L1 expression alone and in combination with persistent tumor hypoxia on locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) was examined using log-rank tests and Cox proportional hazards models. Neither PD-L1 nor PD-1 expression levels on tumor-infiltrating immune cells influenced LRC (HR = 0.734; = 0.480 for PD-L1, HR = 0.991; = 0.989 for PD-1), PFS (HR = 0.813; = 0.597 for PD-L1, HR = 0.796; = 0.713 for PD-1) or OS (HR = 0.698; = 0.405 for PD-L1, HR = 0.315; = 0.265 for PD-1). However, patients with no hypoxia resolution between weeks 0 and 2 and PD-L1 expression on tumor cells, quantified by a tumor proportional score (TPS) of at least 1%, showed significantly worse LRC (HR = 3.374, = 0.022) and a trend towards reduced PFS (HR = 2.752, = 0.052). In the multivariate Cox regression analysis, the combination of absent tumor hypoxia resolution and high tumoral PD-L1 expression remained a significant prognosticator for impaired LRC (HR = 3.374, = 0.022). On the other side, tumoral PD-L1 expression did not compromise the outcomes of patients whose tumor-associated hypoxia declined between week 0 and 2 during chemoradiation (LRC: HR = 1.186, = 0.772, PFS: HR = 0.846, = 0.766). In this exploratory analysis, we showed for the first time that patients with both persistent tumor-associated hypoxia during treatment and PD-L1 expression on tumor cells exhibited a worse outcome, while the tumor cells' PD-L1 expression did not influence the outcomes of patients with early tumor hypoxia resolution. While the results have to be validated in an independent cohort, these findings form a foundation to investigate the combination of hypoxic modification and immune checkpoint inhibitors for the unfavorable subgroup, moving forward towards personalized radiation oncology treatment.
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http://dx.doi.org/10.7150/thno.48392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415814PMC
July 2020

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 09 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

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

Evaluation of radiation treatment volumes for unknown primaries of the head and neck in the era of FDG PET.

PLoS One 2020 10;15(4):e0231042. Epub 2020 Apr 10.

Roswell Park Comprehensive Cancer Center, Department of Radiation Medicine, Buffalo, NY, United States of America.

Objectives: Positron-emission tomography (PET) has improved identification of the primary tumor as well as occult nodal burden in cancer of the head and neck. Nevertheless, there are still patients where the primary tumor cannot be located. In these situations, the standard of care is comprehensive head and neck radiation therapy however it is unclear whether this is necessary. This study examines the effects of radiation treatment volume on outcomes among using data from two cancer centers in unknown primary carcinoma of the head and neck.

Methods: Patients received unilateral (n = 34), or bilateral radiation (n = 28). Patient factors such as age, gender, smoking history, and patterns of failure were compared using Mann Whitney U and Chi Square. Overall survival (OS) and disease free survival (DFS) trends were estimated using Kaplan-Meier survival curves. Effect of treatment volume on survival was examined using multivariate cox proportional hazard regression model.

Results: No significant differences were observed in the frequency of local (p = 0.32), regional (p = 0.50), or distant (p = 0.76) failures between unilateral and bilateral radiation therapy. By Kaplan-Meier estimates, OS (3-year OS bilateral = 71.67%, unilateral = 77.90%, p = 0.50) and DFS (3-year DFS bilateral = 77.92%, unilateral = 69.43%, p = 0.63) were similar between the two treatment approaches. Lastly, multivariate analysis did not demonstrate any significant differences in outcome by treatment volumes (OS: HR = 0.74, 95% CI: 0.31, 1.81, p = 0.51; DFS: HR: 0.68, 95% CI: 0.24, 1.93, p = 0.47).

Conclusions: Unilateral radiation therapy compared with bilateral produced similar survival.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231042PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147765PMC
July 2020

Prognostic risk classification for biochemical relapse-free survival in patients with oligorecurrent prostate cancer after [Ga]PSMA-PET-guided metastasis-directed therapy.

Eur J Nucl Med Mol Imaging 2020 09 16;47(10):2328-2338. Epub 2020 Mar 16.

Department of Radiation Oncology, Klinikum rechts der Isar, Technical University of Munich (TUM), Ismaninger Strasse 22, 81675, Munich, Germany.

Purpose: Since the success of prostate-specific membrane antigen-positron emission tomography (PSMA-PET) imaging for patients with oligorecurrent prostate cancer (ORPC), it is increasingly used for radiotherapy as metastasis-directed therapy (MDT). Therefore, we developed a prognostic risk classification for biochemical relapse-free survival (bRFS) for patients after PSMA-PET-guided MDT after radical prostatectomy.

Methods: We analyzed 292 patients with local recurrence (LR) and/or pelvic lymph node (LN) lesions and/or up to five distant LN, bone (BM), or visceral metastases (VM) detected with [Ga]PSMA-PET imaging. Median follow-up was 16 months (range 0-57). The primary endpoint was bRFS after MDT. Cox regression analysis for risk factors was incorporated into a recursive partitioning analysis (RPA) with classification and regression tree method.

Results: PSA at recurrence ≥ 0.8 ng/mL, BM, and VM was significantly associated with biochemical relapse. RPA showed five groups with tenfold cross-validation of 0.294 (SE 0.032). After building risk classes I to IV (p < 0.0001), mean bRFS was 36.3 months (95% CI 32.4-40.1) in class I (PSA < 0.8 ng/mL, no BM) and 25.8 months (95% CI 22.5-29.1) in class II (PSA ≥ 0.8 ng/mL, no BM, no VM). LR and/or pelvic LNs caused relapse in classes I and II. Mean bRFS was 16.0 months (95% CI 12.4-19.6) in class III (PSA irrelevant, present BM) and 5.7 months (95% CI 2.7-8.7) in class IV (PSA ≥ 0.8 ng/mL, no BM, present VM).

Conclusion: We developed and internally validated a risk classification for bRFS after PSMA-PET-guided MDT. Patients with PSA < 0.8 ng/mL and local relapse only (LR and/or pelvic LNs) had the most promising bRFS. PSA ≥ 0.8 ng/mL and local relapse only (LR and/or pelvic LNs) indicated intermediate risk for failure. Patients with BM were at higher risk regardless of the PSA. However, those patients still show satisfactory bRFS. In patients with VM, bRFS is heavily decreased. MDT in such cases should be discussed individually.
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http://dx.doi.org/10.1007/s00259-020-04760-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396407PMC
September 2020

Imaging-based target volume reduction in chemoradiotherapy for locally advanced non-small-cell lung cancer (PET-Plan): a multicentre, open-label, randomised, controlled trial.

Lancet Oncol 2020 04 12;21(4):581-592. Epub 2020 Mar 12.

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

Background: With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer.

Methods: We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing F-fluorodeoxyglucose (F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60-74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT00697333.

Findings: From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9-54), the risk of locoregional progression in the F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% [95% CI 5-21] vs 29% [17-38] at 1 year; HR 0·57 [95% CI 0·30-1·06]). The risk of locoregional progression in the F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% [95% CI 9-24] vs 30% [20-39] at 1 year; HR 0·64 [95% CI 0·37-1·10]). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the conventional target group vs 17 [16%] of 105 patients in the F-FDG PET-based target group); the most common late toxicities were lung-related (12 [12%] vs 11 [10%]). 20 deaths potentially related to study treatment were reported (seven vs 13).

Interpretation: F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours.

Funding: German Cancer Aid (Deutsche Krebshilfe).
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http://dx.doi.org/10.1016/S1470-2045(20)30013-9DOI Listing
April 2020

Results from extended lymphadenectomies with [In]PSMA-617 for intraoperative detection of PSMA-PET/CT-positive nodal metastatic prostate cancer.

EJNMMI Res 2020 Mar 6;10(1):17. Epub 2020 Mar 6.

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

Purpose: Identification of suspicious PSMA-PET/CT-positive lymph node (LN) metastases (LNM) from prostate cancer (PCa) during lymphadenectomy (LA) is challenging. We evaluated an In-labelled PSMA ligand (DKFZ-617, referred to as [In]PSMA-617) as a γ-emitting tracer for intraoperative γ-probe application for resected tissue samples in PCa patients. Forty-eight hours prior to LA, [In]PSMA-617 was administered intravenously in 23 patients with suspected LNM on PSMA-PET/CT (n = 21 with biochemical relapse, n = 2 at primary therapy). Resected tissue samples (LN, LNM and fibrofatty tissue) were measured ex situ by a γ-probe expressed as counts per second (CPS). [In]PSMA-617 tissue sample uptake was measured by a germanium detector for verification and calculated as %IA (percent injected activity per kilogram lean body mass at time of surgery). Based on a clinical requirement for a specificity > 95%, thresholds for both ex situ measurements were chosen accordingly. Correlation of the results from PET/CT, γ-probe and germanium detector with histopathology was done.

Results: Eight hundred sixty-four LNs (197 LNM) were removed from 275 subregions in 23 patients, on average 8.6 ± 14.9 LNM per patient. One hundred four of 275 tissue samples showed cancer. Median γ-probe and germanium detector results were significantly different between tumour-affected (33.5 CPS, 0.71 %IA) and tumour-free subregions (3.0 CPS, 0.03 %IA) (each p value < 0.0001). For the chosen γ-probe cut-off (CPS > 23) and germanium detector cut-off (%IA > 0.27), 64 and 74 true-positive and 158 true-negative samples for both measurements were identified. Thirty-nine and 30 false-negative and 6 and 5 false-positive tissue samples were identified by γ-probe and germanium detector measurements.

Conclusion: [In]PSMA-617 application for LA is feasible in terms of an intraoperative real-time measurement with a γ-probe for detection of tumour-affected tissue samples. γ-probe results can be confirmed by precise germanium detector measurements and were significantly different between tumour-affected and tumour-free samples.
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http://dx.doi.org/10.1186/s13550-020-0598-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060305PMC
March 2020

Outcomes Following Stereotactic Body Radiotherapy with Intensity-Modulated Therapy versus Three-Dimensional Conformal Radiotherapy in Early Stage Non-Small Cell Lung Cancer.

Lung Cancer (Auckl) 2019 20;10:151-159. Epub 2019 Dec 20.

Department of Radiation Oncology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

Introduction: The treatment techniques used for stereotactic body radiation therapy (SBRT) for early-stage lung cancer continue to evolve. In this study, clinical outcomes following SBRT were evaluated according to the use of either 3D conformal radiotherapy (3DCRT) or intensity-modulated radiation therapy (IMRT).

Patients And Methods: Patients with stage I NSCLC who received SBRT from 2007 to 2015 were retrospectively reviewed. Disease control and survival were assessed using Kaplan-Meier estimates. Dosimetric analyses for target dose heterogeneity and coverage were performed.

Results: A total of 297 patients with 351 lesions were included. 3DCRT was used in 52% and IMRT in 48%. IMRT was utilized at a higher rate in more recent years. The most common regimens were 48 Gy in 4 fractions and 54-60 Gy in 3 fractions. With a median follow up of 22.7 months, there were 17 local failures for a crude relapse rate of 5.7%. Local failure did not differ in patients treated with 3DCRT and IMRT (4.9% vs 6.5%, p=0.573). Mean dose to gross tumor volume (GTV) as a percent of prescription dose was higher with 3DCRT compared with IMRT (107.7% vs 103.6%, p < 0.0001). Tumor stage, histology, and SBRT regimen did not correlate with local tumor control. Overall survival for the entire population approximated 72% at 2 years. Treatment was well tolerated with 6 documented grade 3+ events.

Conclusion: In this single-institution cohort of SBRT for early-stage NSCLC, there was no discernible difference in clinical outcomes between those treated with 3DCRT and IMRT.
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http://dx.doi.org/10.2147/LCTT.S235713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929968PMC
December 2019

Correlative analyses between tissue-based hypoxia biomarkers and hypoxia PET imaging in head and neck cancer patients during radiochemotherapy-results from a prospective trial.

Eur J Nucl Med Mol Imaging 2020 05 7;47(5):1046-1055. Epub 2019 Dec 7.

German Cancer Consortium (DKTK), Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany.

Purpose: Tumor hypoxia impairs the response of head-and-neck cancer (HNSCC) patients to radiotherapy and can be detected both by tissue biomarkers and PET imaging. However, the value of hypoxia biomarkers and imaging for predicting HNSCC patient outcomes are incompletely understood, and potential correlations between tissue and PET data remain to be elucidated. Here, we performed exploratory analyses of potential correlations between tissue-based hypoxia biomarkers and longitudinal hypoxia imaging in a prospective trial of HNSCC patients.

Methods: Forty-nine patients undergoing chemoradiation for locally advanced HNSCCs were enrolled in this prospective trial. They underwent baseline biopsies and [F]FDG PET imaging and [F]FMISO PET at weeks 0, 2, and 5 during treatment. Immunohistochemical analyses for p16, Ki67, CD34, HIF1α, CAIX, Ku80, and CD44 were performed, and HPV status was assessed. Biomarker expression was correlated with biological imaging information and patient outcome data.

Results: High HIF1α tumor levels significantly correlated with increased tumor hypoxia at week 2 as assessed by the difference in the [F]FMISO tumor-to-background ratios, and high HIF1α and CAIX expressions were both associated with a deferred decrease in hypoxia between weeks 2 and 5. Loco-regional recurrence rates after radiotherapy were significantly higher in patients with high CAIX expression and also increased for high levels of the DNA repair factor Ku80. HPV status did not correlate with any of the tested hypoxia biomarkers, and HPV-positive patients showed higher loco-regional control rates and progression-free survival independent of their hypoxia dynamics.

Conclusion: In this exploratory trial, high expression of the tissue-based hypoxia biomarkers HIF1α and CAIX correlated with adverse hypoxia dynamics in HNSCCs during chemoradiation as assessed by PET imaging, and high CAIX levels were associated with increased loco-regional recurrence rates. Hence, hypoxia biomarkers warrant further investigations as potential predictors of hypoxia dynamics and hypoxia-associated radiation resistance.
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http://dx.doi.org/10.1007/s00259-019-04598-9DOI Listing
May 2020

Determination of whole-body tumour burden on [68Ga]PSMA-11 PET/CT for response assessment of [177Lu]PSMA-617 radioligand therapy: a retrospective analysis of serum PSA level and imaging derived parameters before and after two cycles of therapy.

Nuklearmedizin 2019 Dec 13;58(6):443-450. Epub 2019 Nov 13.

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

Aim:  In patients with metastasized castration-resistant prostate cancer a reliable imaging-based therapy response assessment in addition to PSA kinetics is desirable. Recently, measurements of whole-body tumour burden by [Ga]PSMA-11 PET/CT have been reported for response assessment in oligometastasic patients. The present study investigated the association of PSMA PET derived parameters and serum PSA level before and after [Lu]PSMA-617 radioligand therapy (RLT).

Methods:  This retrospective study assessed whole-body PSMA tumour volume (PSMA-TV) in 10 patients with multifocal to diffuse metastases before and after 2 cycles of RLT using volume of interest (VOI) analysis. A standardized uptake value (SUV) threshold-based approach was used to semi-automatically delineate all voxels with a SUV ≥ 2.0 g/ml using the software ROVER (ABX Radeberg, Germany). Voxels with physiological tracer uptake (e. g. kidneys) were excluded manually. Correlations between PSMA-TV and serum PSA level before and after two cycles of RLT as well as changes thereof (ΔPSMA-TV and ΔPSA, respectively) were calculated.

Results:  Changes of ΔPSMA-TV and ΔPSA were concordant in 7 of 10 patients. Whereas a good correlation was found between PSMA-TV and PSA before RLT (ρ = 0.81, p = 0.0049), this correlation was attenuated after RLT (ρ = 0.64, p = 0.0479). Consequently, no association was found between ΔPSMA-TV and ΔPSA (ρ = 0.39, p = 0.26).

Conclusion:  The attenuation of the correlation of PSA and PSMA-TV after RLT suggests that in patients with advanced disease the comparison of imaging based parameters such as PSMA-TV and PSA level might be useful for an adequate monitoring of treatment response.
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http://dx.doi.org/10.1055/a-1035-9052DOI Listing
December 2019

Prostate-specific Membrane Antigen Positron Emission Tomography-detected Oligorecurrent Prostate Cancer Treated with Metastases-directed Radiotherapy: Role of Addition and Duration of Androgen Deprivation.

Eur Urol Focus 2021 Mar 5;7(2):309-316. Epub 2019 Sep 5.

Department of Radiation Oncology, University Hospital Zürich, Zurich, Switzerland.

Background: Approximately 40-70% of biochemically recurrent prostate cancer (PCa) is oligorecurrent after prostate-specific membrane antigen (PSMA) positron emission tomography (PET) staging. Metastasis-directed radiotherapy (MDT) of PSMA-positive oligorecurrence is now frequently used, but the role of concurrent androgen deprivation therapy (ADT) remains unclear.

Objective: To determine the effect of concurrent ADT with PSMA PET-directed MDT on biochemical progression-free survival (bRFS).

Design, Setting, And Participants: This was a retrospective multicenter study of 305 patients with biochemical recurrence and PSMA PET-positive oligorecurrence following initial curative treatment between April 2013 and January 2018.

Intervention: MDT with fractionated or stereotactic body radiotherapy for all PSMA-positive metastatic sites; 37.8% received concurrent ADT.

Outcome Measurements And Statistical Analysis: The primary outcome was bRFS, which was measured using Kaplan-Meier curves and log-rank testing. Secondary outcomes were ADT-free survival, overall survival (OS), and toxicity was analyzed using the Common Terminology Criteria for Adverse Events v4.03. Univariate and multivariate analyses were performed to determine independent clinicopathological factors.

Results And Limitations: The median follow-up was 16 mo (interquartile range 9-27). Some 96% of the patients initially had high-risk PCa. A median of one (range 0-19) nodal metastases and one (range 0-5) distant metastases were treated. MDT+ADT significantly improved bRFS and remained an independent factor (hazard ratio 0.28, 95% confidence interval 0.16-0.51; p<0.0001). bRFS was not significantly different between MDT+≤6 mo of ADT and MDT alone (p=0.121). Patients receiving MDT had 1- and 2-yr ADT-free survival of 93% and 83%, respectively. New therapies, most frequently MDT (23%), were required more frequently after MDT (85% vs 29%; p<0.001). Grade ≥3 acute toxicity was observed in 0.9% of patients and late toxicity in 2.3%.

Conclusions: In this cohort of patients with oligorecurrent PCa, concurrent ADT with MDT improved bRFS significantly, but a large number of patients treated with MDT were spared from ADT for 2yr, although a greater need for other salvage therapies was observed.

Patient Summary: The role of concurrent androgen deprivation therapy (ADT) with radiotherapy for prostate cancer oligorecurrence identified on prostate-specific membrane antigen positron emission tomography was studied. We concluded that radiotherapy alone could prolong the time to start of ADT. However, the risk of disease progression and consequently the need for further treatments is higher after local radiotherapy alone without immediate ADT.
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http://dx.doi.org/10.1016/j.euf.2019.08.012DOI Listing
March 2021

Radiomic features from PSMA PET for non-invasive intraprostatic tumor discrimination and characterization in patients with intermediate- and high-risk prostate cancer - a comparison study with histology reference.

Theranostics 2019 13;9(9):2595-2605. Epub 2019 Apr 13.

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

To evaluate the performance of radiomic features (RF) derived from PSMA PET for intraprostatic tumor discrimination and non-invasive characterization of Gleason score (GS) and pelvic lymph node status. Patients with prostate cancer (PCa) who underwent [Ga]-PSMA-11 PET/CT followed by radical prostatectomy and pelvic lymph node dissection were prospectively enrolled (n=20). Coregistered histopathological gross tumor volume (GTV-Histo) in the prostate served as reference. 133 RF were derived from GTV-Histo and from manually created segmentations of the intraprostatic tumor volume (GTV-Exp). Spearman´s correlation coefficients (ρ) were assessed between RF derived from the different GTVs. We additionally analyzed the differences in RF values for PCa and non-PCa tissues. Furthermore, areas under receiver-operating characteristics curves (AUC) were calculated and uni- and multivariate analyses were performed to evaluate the RF based discrimination of GS 7 and ≥8 disease and of patients with nodal spread (pN1) and non-nodal spread (pN0) in surgical specimen. The results found in the latter analyses were validated by a retrospective cohort of 40 patients. Most RF from GTV-Exp showed strong correlations with RF from GTV-Histo (86% with ρ>0.7). 81% and 76% of RF from GTV-Exp and GTV-Histo significantly discriminated between PCa and non-PCa tissue. The texture feature QSZHGE discriminated between GS 7 and ≥8 considering GTV-Histo (AUC=0.93) and GTV-Exp (prospective cohort: AUC=0.91 / validation cohort: AUC=0.84). QSZHGE also discriminated between pN1 and pN0 disease considering GTV-Histo (AUC=0.85) and GTV-Exp (prospective cohort: AUC=0.87 / validation cohort: AUC=0.85). In uni- and multivariate analyses including patients of both cohorts QSZHGE was a statistically significant (p<0.01) predictor for PCa patients with GS ≥8 tumors and pN1 status. RF derived from PSMA PET discriminated between PCa and non-PCa tissue within the prostate. Additionally, the texture feature QSZHGE discriminated between GS 7 and GS ≥8 tumors and between patients with pN1 and pN0 disease. Our results support the role of RF in PSMA PET as a new tool for non-invasive PCa discrimination and characterization of its biological properties.
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http://dx.doi.org/10.7150/thno.32376DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525993PMC
May 2020

Limits for Reduction of Acquisition Time and Administered Activity in F-FDG PET Studies of Alzheimer Dementia and Frontotemporal Dementia.

J Nucl Med 2019 12 26;60(12):1764-1770. Epub 2019 Apr 26.

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

We evaluated the effect of a reduced acquisition time for F-FDG PET studies of Alzheimer dementia (AD) and frontotemporal dementia (FTD) to derive a limit for reductions of acquisition time (improving patient compliance) and administered activity (lowering the radiation dose) with uncompromised diagnostic outcome. We included patients with a clinical diagnosis of AD ( = 13) or FTD ( = 12) who were examined with F-FDG PET/CT after injection of 210 ± 9 MBq of F-FDG. List-mode data were reconstructed over various time intervals simulating reduced acquisition times or administered activities. Volume-of-interest-based and voxelwise statistical analyses including group contrasts were performed for 15 different acquisition times ranging from 10 min to 2 s. In addition, masked visual reads were obtained from 3 readers independently for 7 different acquisition times down to 30 s, providing a diagnosis of either AD or FTD and the individual diagnostic certainty. Regional mean uptake changed by less than 5% at a reduced acquisition time down to 1 min in all regions and patients except for the posterior cingulate cortex of 1 patient. Voxelwise group contrasts suggest a sufficient measurement time of only 2 min, for which the number of significant voxels decreased by merely 5% while maintaining their spatial pattern. In 450 visual reads at reduced times, no change in the original diagnosis was observed. The diagnostic certainty showed only a very slow and mild decline, with small effect sizes (Cohen's d) of 0.3, at acquisition times of 3 and 2 min compared with the original results at 10 min. Statistical results at a region and voxel level, as well as single-subject visual reads, reveal a considerable potential to reduce the typical 10-min acquisition time (by a factor of 4) without compromising diagnostic quality. Conversely, our data suggest that for a given acquisition time of 10 min and a similar effect size, the administered activity may be reduced to 50 MBq, resulting in an effective dose of less than 1 mSv for the PET examination.
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http://dx.doi.org/10.2967/jnumed.119.227132DOI Listing
December 2019

Accuracy of [Ga]Ga-RM2-PET/CT for diagnosis of primary prostate cancer compared to histopathology.

Nucl Med Biol 2019 03 29;70:32-38. Epub 2019 Jan 29.

Department of Urology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Introduction: Prostate cancer (PCa) often shows an overexpression of the gastrin-releasing peptide receptor (GRPr). Therefore, GRPr is a possible theragnostic target. An interesting antagonist GRPr-ligand is RM2 or BAY86-7548. This study examines the accuracy of positron emission tomography (PET) with [Ga]Ga-RM2 for diagnostic imaging of primary PCa (pPCa) compared to histopathology in patients undergoing radical prostatectomy (RP).

Methods: [Ga]Ga-RM2-PET examinations were performed in 15 patients before RP. All prostate specimens were histopathologically examined based on predefined spatial octants. Each prostate volume on PET was subdivided into octants, which were correlated to histopathology and evaluated according to presence of tumor by two experienced examiners. Additionally, PET data was evaluated by volume of interest (VOI) analyses in terms of maximum standardized uptake value (SUVmax) and normalized SUVmax relative to background activity (rSUVmax). Receiver operating characteristic (ROC) curves for SUVmax and rSUVmax were calculated.

Results: At least one focus of increased [Ga]Ga-RM2 uptake corresponding to a tumor manifestation on histology was found in 14 of 15 patients (93%). Spatial concordance of visual PET readings with histopathology was very variable. Intraindividual agreement reached from ≤2 octants in three, 3-5 octants in six to ≥6 octants in six patients, resulting in a relatively low correlation of visual PET readings with histopathology (accuracy = 0.63; p = 0.0018). Lesion-based analysis found a sensitivity of 69% and a positive predictive value of 73%. Concordantly, the octant-based ROC curves for SUVmax and rSUVmax indicated a relatively low diagnostic performance (area under the curve of 0.59 and 0.61, respectively).

Conclusions: [Ga]Ga-RM2-PET shows only a relatively low diagnostic accuracy for pPCa compared to histopathology on an octant basis, which may be explained to some extent by methodological weaknesses. Further studies need to explore, whether the observed high interindividual variability of agreement between [Ga]Ga-RM2-PET and histopathology can be explained by different tumor biologies or other coincident prostatic pathologies.
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http://dx.doi.org/10.1016/j.nucmedbio.2019.01.009DOI Listing
March 2019

Management of the Brain in Small Cell Lung Cancer: Are Patients Paying a Lot Now Instead of a Little Later?

J Thorac Oncol 2019 02;14(2):153-156

Department of Radiation Oncology, State University of New York Upstate Medical University, Syracuse, New York.

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http://dx.doi.org/10.1016/j.jtho.2018.11.008DOI Listing
February 2019

Clinical outcomes following advanced respiratory motion management (respiratory gating or dynamic tumor tracking) with stereotactic body radiation therapy for stage I non-small-cell lung cancer.

Lung Cancer (Auckl) 2018 5;9:103-110. Epub 2018 Nov 5.

Department of Radiation Oncology, SUNY Upstate Medical University, Syracuse, NY 13210, USA,

Purpose: To report the outcomes of stereotactic body radiation therapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) according to respiratory motion management method.

Methods: Patients with stage I NSCLC who received SBRT from 2007 to 2015 were reviewed. Computed tomography (CT) simulation with four-dimensional CT was performed for respiratory motion assessment. Tumor motion >1 cm in the craniocaudal direction was selectively treated with advanced respiratory management: either respiratory gating to a pre-specified portion of the respiratory cycle or dynamic tracking of an implanted fiducial marker. Comparisons were made with internal target volume approach, which treated all phases of respiratory motion.

Results: Of 297 patients treated with SBRT at our institution, 51 underwent advanced respiratory management (48 with respiratory gating and three with tumor tracking) and 246 underwent all-phase treatment. Groups were similarly balanced with regard to mean age (=0.242), tumor size (=0.315), and histology (=0.715). Tumor location in the lower lung lobes, as compared to middle or upper lobes, was more common in those treated with advanced respiratory management (78.4%) compared to all-phase treatment (25.6%, <.0001). There were 17 local recurrences in the treated lesions. Kaplan-Meier analyses showed that there were no differences with regard to mean time to local failure (91.5 vs 98.8 months, =0.56), mean time to any failure (73.2 vs 78.7 months, =0.73), or median overall survival (43.3 vs 45.5 months, =0.56) between patients who underwent advanced respiratory motion management and all-phase treatment.

Conclusion: SBRT with advanced respiratory management (the majority with respiratory gating) showed similar efficacy to all-phase treatment approach for stage I NSCLC.
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http://dx.doi.org/10.2147/LCTT.S175168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223331PMC
November 2018

Correction to: Effect of radiochemotherapy on T2* MRI in HNSCC and its relation to FMISO PET derived hypoxia and FDG PET.

Radiat Oncol 2018 09 21;13(1):183. Epub 2018 Sep 21.

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

Following the publication of this article [1], the authors noticed that figures 2, 3, 4 and 5 were in the incorrect order and thus had incorrect captions.
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http://dx.doi.org/10.1186/s13014-018-1134-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6148952PMC
September 2018

Diffusion-weighted MRI and ADC versus FET-PET and GdT1w-MRI for gross tumor volume (GTV) delineation in re-irradiation of recurrent glioblastoma.

Radiother Oncol 2019 01 12;130:121-131. Epub 2018 Sep 12.

Department of Radiation Oncology, Medical Center - University of Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, Germany.

Background And Purpose: GTV definition for re-irradiation treatment planning in recurrent glioblastoma (rGBM) is usually based on contrast-enhanced MRI (GdT1w-MRI) and, for an increased specificity, on amino acid PET. Diffusion-weighted (DWI) MRI and ADC maps can reveal regions of high cellularity as surrogate for active tumor. The objective of this study was to compare the localization and quality of diffusion restriction foci (GTV-ADClow) with FET-PET (GTV-PET) and GdT1w-MRI (GTV-GdT1w-MRI).

Material And Methods: We prospectively evaluated 41 patients, who received a fractionated stereotactic re-irradiation for rGBM. GTV-PET was generated automatically (tumor-to-background ratio 1.7-1.8) and manually customized. GTV-ADClow was manually defined based on DWI data (3D diffusion gradients, b = 0, 1000 s/mm) and parametric ADC maps. The localization of recurrence was correlated with initial GdT1w-MRI and PET data.

Results: In 30/41 patients, DWI-MRI showed areas with restricted diffusion (mean ADC-value 0.74 ± 0.22 mm/s). 66% of GTVs-ADClow were located outside the GdT1w-MRI volume and 76% outside increased FET uptake regions. Furthermore, GTVs-ADClow were only partially included in the high dose volume and received in mean 82% of the reference dose. An adjusted volume including GdT1w-MRI, PET-positive and restricted diffusion areas would imply a GTV increase of 48%. GTV-PET and GdT1w-MRI correlated better with the localization of re-recurrence in comparison to GTV-ADClow.

Conclusion: Unexpectedly, GTV-ADClow overlapped only partially with FET-PET and GdT1w-MRI in rGBM. Moreover, GTV-ADClow correlated poorly with later rGBM-recurrences. Seeing as a restricted diffusion is known to correlate with hypercellularity, this imaging discrepancy could only be further explained in histopathological studies.
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http://dx.doi.org/10.1016/j.radonc.2018.08.019DOI Listing
January 2019

Effect of radiochemotherapy on T2* MRI in HNSCC and its relation to FMISO PET derived hypoxia and FDG PET.

Radiat Oncol 2018 Aug 29;13(1):159. Epub 2018 Aug 29.

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

Background: To assess the effect of radiochemotherapy (RCT) on proposed tumour hypoxia marker transverse relaxation time (T2*) and to analyse the relation between T2* and F-misonidazole PET/CT (FMISO-PET) and F-fluorodeoxyglucose PET/CT (FDG-PET).

Methods: Ten patients undergoing definitive RCT for squamous cell head-and-neck cancer (HNSCC) received repeat FMISO- and 3 Tesla T2*-weighted MRI at weeks 0, 2 and 5 during treatment and FDG-PET at baseline. Gross tumour volumes (GTV) of tumour (T), lymph nodes (LN) and hypoxic subvolumes (HSV, based on FMISO-PET) and complementary non-hypoxic subvolumes (nonHSV) were generated. Mean values for T2* and SUVmean FDG were determined.

Results: During RCT, marked reduction of tumour hypoxia on FMISO-PET was observed (T, LN), while mean T2* did not change significantly. At baseline, mean T2* values within HSV-T (15 ± 5 ms) were smaller compared to nonHSV-T (18 ± 3 ms; p = 0.051), whereas FDG SUVmean (12 ± 6) was significantly higher for HSV-T (12 ± 6) than for nonHSV-T (6 ± 3; p = 0.026) and higher for HSV-LN (10 ± 4) than for nonHSV-LN (5 ± 2; p ≤ 0.011). Correlation between FMISO PET and FDG PET was higher than between FMSIO PET and T2* (R for GTV-T (FMISO/FDG) = 0.81, R for GTV-T (FMISO/T2*) = 0.32).

Conclusions: Marked reduction of tumour hypoxia between week 0, 2 and 5 found on FMISO PET was not accompanied by a significant T2*change within GTVs over time. These results suggest a relation between tumour oxygenation status and T2* at baseline, but no simple correlation over time. Therefore, caution is warranted when using T2* as a substitute for FMISO-PET to monitor tumour hypoxia during RCT in HNSCC patients.

Trial Registration: DRKS, DRKS00003830 . Registered 23.04.2012.
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http://dx.doi.org/10.1186/s13014-018-1103-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114038PMC
August 2018