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Management of prostate cancer (PC) might be improved by combining external beam radiotherapy (EBRT) and prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with lutetium-177 ( 177 Lu)-labeled PSMA inhibitors. We hypothesized a higher efficacy of the combination due to augmentation of the radiation dose to the tumor and interactions of EBRT with PSMA expression potentially increasing radiopharmaceutical uptake. Therefore, this study analyzed the influence of radiation on PSMA expression levels in vitro . The results were translated to evaluate the efficacy of the combination of photon EBRT and [ 177 Lu]Lu-PSMA-617 in a murine PC xenograft model. Finally, a clinical case report on a combined elective field EBRT with RLT dose escalation illustrates a proof-of-concept. Methods: PSMA gene and protein expression were assessed in human PSMA-overexpressing LNCaP cells after irradiation using reverse transcription quantitative polymerase chain reaction (RT-qPCR), flow cytometry and On-Cell Western assays. In the in vivo therapy study, LNCaP tumor-bearing BALB/c nu/nu mice were irradiated once with 2 Gy X-ray EBRT and injected with 40 MBq [ 177 Lu]Lu-PSMA-617 after 4 h or received single or no treatment (n = 10 each). Tumor-absorbed doses by [ 177 Lu]Lu-PSMA-617 were calculated according to the Medical Internal Radiation Dosimetry (MIRD) formalism after deriving time-activity curves using a gamma probe. An exemplified patient case is demonstrated where fractionated EBRT (54 Gy to prostate; 45 Gy to pelvic lymphatics) and three cycles of [ 177 Lu]Lu-PSMA-617 (3.4-6.0 GBq per cycle) were sequentially combined under concurrent androgen deprivation for treating locally advanced PC. Results: At 4 h following irradiation with 2-8 Gy, LNCaP cells displayed a PSMA protein upregulation by around 18% relative to non-irradiated cells, and a stronger upregulation on mRNA level (up to 2.6-fold). This effect was reversed by 24 h when PSMA protein levels were downregulated by up to 22%. Mice treated with the combination therapy showed significantly improved outcomes regarding tumor control and median survival (p < 0.0001) as compared to single or no treatment. Relative to monotherapy with PSMA-RLT or EBRT, the tumor doubling time was prolonged 1.7- or 2.7-fold and the median survival was extended by 24% or 60% with the combination, respectively. Additionally, tumors treated with EBRT exhibited a 14% higher uptake of the radiopharmaceutical as evident from the calculated tumor-absorbed dose, albeit with high variability in the data. Concerning the patient case, the tri-modality treatment was well tolerated and the patient responded with a long-lasting complete biochemical remission for five years following end of PSMA-RLT. The patient then developed a biochemical relapse with oligo-recurrent disease on follow-up imaging. Conclusion: The present preclinical and clinical data demonstrate that the combination of EBRT with dose escalation by PSMA-RLT improves tumor control and potentially prolongs survival. This may pave the way for further clinical investigations of this approach to explore the curative potential of the combination therapy., Competing Interests: Competing Interests: This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - grant BA 6696/2-1 and DFG - grant 423813989/GRK2606. ME and ACE hold patent rights on PSMA-targeting inhibitors., (© The author(s).)

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies of men in the world. Due to a variety of treatment options in different risk groups, proper diagnostic and risk stratification is pivotal in treatment of PCa. The development of precise medical imaging procedures simultaneously to improvements in big data analysis has led to the establishment of radiomics - a computer-based method of extracting and analyzing image features quantitatively. This approach bears the potential to assess and improve PCa detection, tissue characterization and clinical outcome prediction. This article gives an overview on the current aspects of methodology and systematically reviews available literature on radiomics in PCa patients, showing its potential for personalized therapy approaches. The qualitative synthesis includes all imaging modalities and focuses on validated studies, putting forward future directions., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Purpose: 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 and methods: Patients with prostate cancer (PCa) who underwent [ 68 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. Results: 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. Conclusion: 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., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Purpose: The exact detection and delineation of the intraprostatic tumour burden is crucial for treatment planning in primary prostate cancer (PCa). We compared 68 Ga-HBED-CC-PSMA PET/CT with multiparametric MRI (mpMRI) for diagnosis and tumour delineation in patients with primary PCa based on slice by slice correlation with histopathological reference material., Methodology: Seven patients with histopathologically proven primary PCa underwent 68 Ga-HBED-CC-PSMA PET/CT and MRI followed by radical prostatectomy. Resected prostates were scanned by ex-vivo CT in a special localizer and prepared for histopathology. Invasive PCa was delineated on a HE stained histologic tissue slide and matched to ex-vivo CT to obtain gross tumor volume (GTV-)histo. Ex-vivo CT including GTV-histo and MRI data were matched to in-vivo CT(PET). Consensus contours based on MRI (GTV-MRI), PSMA PET (GTV-PET) or the combination of both (GTV-union/-intersection) were created. In each in-vivo CT slice the prostate was separated into 4 equal segments and sensitivity and specificity for PSMA PET and mpMRI were assessed by comparison with histological reference material. Furthermore, the spatial overlap between GTV-histo and GTV-PET/-MRI and the Sørensen-Dice coefficient (DSC) were calculated. In the case of multifocal PCa (4/7 patients), SUV values (PSMA PET) and ADC-values (diffusion weighted MRI) were obtained for each lesion., Results: PSMA PET and mpMRI detected PCa in all patients. GTV-histo was detected in 225 of 340 segments (66.2%). Sensitivity and specificity for GTV-PET, GTV-MRI, GTV-union and GTV-intersection were 75% and 87%, 70% and 82%, 82% and 67%, 55% and 99%, respectively. GTV-histo had on average the highest overlap with GTV-union (57±22%), which was significantly higher than overlap with GTV-MRI (p=0.016) and GTV-PET (p=0.016), respectively. The mean DSC for GTV-union, GTV-PET and GTV-MRI was 0.51 (±0.18), 0.45 (±0.17) and 0.48 (±0.19), respectively. In every patient with multifocal PCa there was one lesion which had both the highest SUV and the lowest ADC-value (mean and max)., Conclusion: In a slice by slice analysis with histopathology, 68 Ga-HBED-CC-PSMA PET/CT and mpMRI showed high sensitivity and specificity in detection of primary PCa. A combination of both methods performed even better in terms of sensitivity (GTV-union) and specificity (GTV-intersection). A moderate to good spatial overlap with GTV-histo was observed for PSMA PET/CT and mpMRI alone which was significantly improved by GTV-union. Further studies are warranted to analyse the impact of these preliminary findings for diagnostic (multimodal guided TRUS biopsy) and therapeutic (focal therapy) strategies in primary PCa., Competing Interests: Author PTM received research grants from Piramal and GE. Author MM received research grants from Philips Medical Systems. Author CZ declares that he has no conflict of interest. Author ALG declares that she has no conflict of interest. Author UW declares that he has no conflict of interest. Author TIB declares that she has no conflict of interest. Author HCR declares that he has no conflict of interest. Author VD declares that she has no conflict of interest. Author MW declares that he has no conflict of interest. Author CAJ declares that she has no conflict of interest. Author WSS declares that he has no conflict of interest. Author MW declares that he has no conflict of interest. Author FS declares that he has no conflict of interest. Author ML declares that he has no conflict of interest. Author MB declares that he has no conflict of interest. Author TK declares that he has no conflict of interest.

Purpose: We performed a voxel-wise comparison of (68)Ga-HBED-CC-PSMA PET/CT with prostate histopathology to evaluate the performance of (68)Ga-HBED-CC-PSMA for the detection and delineation of primary prostate cancer (PCa)., Methodology: Nine patients with histopathological proven primary PCa underwent (68)Ga-HBED-CC-PSMA PET/CT followed by radical prostatectomy. Resected prostates were scanned by ex-vivo CT in a special localizer and histopathologically prepared. Histopathological information was matched to ex-vivo CT. PCa volume (PCa-histo) and non-PCa tissue in the prostate (NPCa-histo) were processed to obtain a PCa-model, which was adjusted to PET-resolution (histo-PET). Each histo-PET was coregistered to in-vivo PSMA-PET/CT data., Results: Analysis of spatial overlap between histo-PET and PSMA PET revealed highly significant correlations (p < 10(-5)) in nine patients and moderate to high coefficients of determination (R²) from 42 to 82 % with an average of 60 ± 14 % in eight patients (in one patient R(2) = 7 %). Mean SUVmean in PCa-histo and NPCa-histo was 5.6 ± 6.1 and 3.3 ± 2.5 (p = 0.012). Voxel-wise receiver-operating characteristic (ROC) analyses comparing the prediction by PSMA-PET with the non-smoothed tumor distribution from histopathology yielded an average area under the curve of 0.83 ± 0.12. Absolute and relative SUV (normalized to SUVmax) thresholds for achieving at least 90 % sensitivity were 3.19 ± 3.35 and 0.28 ± 0.09, respectively., Conclusions: Voxel-wise analyses revealed good correlations of (68)Ga-HBED-CC-PSMA PET/CT and histopathology in eight out of nine patients. Thus, PSMA-PET allows a reliable detection and delineation of PCa as basis for PET-guided focal therapies.