Robert Tauber

Preliminary results for characterization of pelvic lymph nodes in patients with prostate cancer by diffusion-weighted MR-imaging.

Objectives:In this retrospective feasibility study diffusion-weighted magnetic resonance imaging (DWI) was evaluated as a potential tool for characterization of pelvic lymph nodes in patients with prostate cancer. Methods and Materials:Twenty-nine patients with prostate cancer underwent DWI of the pelvis at 1.5T by a non breath-hold SSEPI sequence using a body phased array coil with b values of 50, 300, and 600 s/mm2 and an additional T2-weighted sequence. A total of 118 lymph nodes (>6 mm short axis) were analyzed by measuring the ADC-value with a polygon region of interest. Feasibility for ADC-measurement was assessed by comparing the ADC-value from the automatically created ADC-map (ADCMR_unit) with a manually calculated ACD-value (ADCcalculated) and by using a linear-regression model for comparison with size and standard deviation of the ADC-value. Diagnostic performance was estimated by receiver operator characteristic analysis using histologic and/or clinical follow-up as standard of reference. Results:ADCMR_unit and ADCcalculated showed a high correlation (r = 0.8999) with a mean percentual deviation of 6.33%. There was a highly significant difference between the mean ADC-value (×10−3 mm2/s) of malignant (1.07 ± 0.23) versus benign (1.54 ± 0.25) lymph nodes, even in subgroup analysis for lymph nodes smaller versus larger than 10 mm. Receiver operator characteristic-analysis showed a good accuracy of the ADC-value (85.6% [101/118]; sensitivity: 86.0% [43/50]; specificity: 85.3% [53/68]) for differentiation of malignant and benign lymph nodes at a cutoff 1.30 × 10−3 mm2/s. This was superior to a size-based analysis at a cutoff of 8 mm (accuracy: 66.1% [78/118]; sensitivity: 82.0% [41/50]; specificity: 54.4% [37/68]; P < 0.01). Conclusions:DWI has the potential of being an accurate technique for analysis of pelvic lymph nodes. Moreover, our preliminary results suggest that the ADC-value might perform significantly superior to size criteria to discriminate between benign and malignant lymph nodes.

68Ga Prostate-Specific Membrane Antigen Uptake in Renal Cell Cancer Lymph Node Metastases.

Ga prostate-specific membrane antigen (PSMA)-HBED-CC PET/CT in a patient with a history of both prostate cancer (PC) and renal cell cancer (RCC) shows high PSMA expression in the residual right seminal vesicle suggestive of local recurrence of PC as well as suspected PSMA-positive mediastinal, retroperitoneal, and iliac lymph nodes. Regarding the latter, biopsy revealed lymph node metastases from RCC excluding PC metastases. This case exemplarily demonstrates that high PSMA expression in RCC metastases can potentially mimic PC metastases. Thus, for accurate interpretation of imaging results in PC patients with additional primary tumors, knowledge of PSMA expression of non-PC tissue is necessary.

Radiation dosimetry for 177Lu-PSMA-I&T in metastatic castration-resistant prostate cancer: Absorbed dose in normal organs and tumor lesions

Prostate-specific membrane antigen (PSMA)–targeted radioligand therapy is increasingly used in metastatic castration-resistant prostate cancer. We aimed to estimate the absorbed doses for normal organs and tumor lesions using 177Lu-PSMA I&T (I&T is imaging and therapy) in patients undergoing up to 4 cycles of radioligand therapy. Results were compared with pretherapeutic Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBEDCC)] (68Ga-PSMA-HBED-CC) PET. Methods: A total of 34 cycles in 18 patients were analyzed retrospectively. In 15 patients the first, in 9 the second, in 5 the third, and in 5 the fourth cycle was analyzed, respectively. Whole-body scintigraphy was performed at least between 30–120 min, 24 h, and 6–8 d after administration. Regions of interest covering the whole body, organs, and up to 4 tumor lesions were drawn. Organ and tumor masses were derived from pretherapeutic 68Ga-PSMA-HBED-CC PET/CT. Absorbed doses for individual cycles were calculated using OLINDA/EXM. SUVs from pretherapeutic PET were compared with absorbed doses and with change of SUV. Results: The mean whole-body effective dose for all cycles was 0.06 ± 0.03 Sv/GBq. The mean absorbed organ doses were 0.72 ± 0.21 Gy/GBq for the kidneys; 0.12 ± 0.06 Gy/GBq for the liver; and 0.55 ± 0.14 Gy/GBq for the parotid, 0.64 ± 0.40 Gy/GBq for the submandibular, and 3.8 ± 1.4 Gy/GBq for the lacrimal glands. Absorbed organ doses were relatively constant among the 4 different cycles. Tumor lesions received a mean absorbed dose per cycle of 3.2 ± 2.6 Gy/GBq (range, 0.22–12 Gy/GBq). Doses to tumor lesions gradually decreased, with 3.5 ± 2.9 Gy/GBq for the first, 3.3 ± 2.5 Gy/GBq for the second, 2.7 ± 2.3 Gy/GBq for the third, and 2.4 ± 2.2 Gy/GBq for the fourth cycle. SUVs of pretherapeutic PET moderately correlated with absorbed dose (r = 0.44, P < 0.001 for SUVmax; r = 0.43, P < 0.001 for SUVmean) and moderately correlated with the change of SUV (r = 0.478, P < 0.001 for SUVmax, and r = 0.50, P < 0.001 for SUVmean). Conclusion: Organ- and tumor-absorbed doses for 177Lu-PSMA I&T are comparable to recent reports and complement these with information on an excellent correlation between the 4 therapy cycles. With the kidneys representing the critical organ, a cumulative activity of 40 GBq of 177Lu-PSMA I&T appears to be safe and justifiable. The correlation between pretherapeutic SUV and absorbed tumor dose emphasizes the need for PSMA-ligand PET imaging for patient selection.

Chromogranin A and neurone‐specific enolase serum levels as predictors of treatment outcome in patients with metastatic castration‐resistant prostate cancer undergoing abiraterone therapy

To determine the impact of elevated neuroendocrine serum markers on treatment outcome in patients with metastatic castration‐resistant prostate cancer (mCRPC) undergoing treatment with abiraterone in a post‐chemotherapy setting.

AR-V7 in Peripheral Whole Blood of Patients with Castration-resistant Prostate Cancer: Association with Treatment-specific Outcome Under Abiraterone and Enzalutamide

BACKGROUND It has been demonstrated that androgen receptor splice variant 7 (AR-V7) expression in circulating tumor cells (CTCs) predicts poor treatment response in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone or enzalutamide. OBJECTIVE To develop a practical and robust liquid profiling approach for direct quantification of AR-V7 in peripheral whole blood without the need for CTC capture and to determine its potential for predicting treatment response in mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS Whole blood samples from a prospective biorepository of 85 mCRPC patients before treatment initiation with abiraterone (n=56) or enzalutamide (n=29) were analyzed via droplet digital polymerase chain reaction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The association of AR-V7 status with prostate-specific antigen (PSA) response defined by PSA decline ≥50% and with PSA-progression-free survival (PSA-PFS), clinical PFS, and overall survival (OS) was assessed. RESULTS AND LIMITATIONS High AR-V7 expression levels in whole blood were detectable in 18% (15/85) of patients. No patient with high AR-V7 expression achieved a PSA response, and AR-V7 status was an independent predictor of PSA response in multivariable logistic regression analysis (p=0.03). High AR-V7 expression was associated with shorter PSA-PFS (median 2.4 vs 3.7 mo; p<0.001), shorter clinical PFS (median 2.7 vs 5.5 mo; p<0.001), and shorter OS (median 4.0 vs. 13.9 mo; p<0.001). On multivariable Cox regression analysis, high AR-V7 expression remained an independent predictor of shorter PSA-PFS (hazard ratio [HR] 7.0, 95% confidence interval [CI] 2.3-20.7; p<0.001), shorter clinical PFS (HR 2.3, 95% CI 1.1-4.9; p=0.02), and shorter OS (HR 3.0, 95% CI 1.4-6.3; p=0.005). CONCLUSIONS Testing of AR-V7 mRNA levels in whole blood is a simple and promising approach to predict poor treatment outcome in mCRPC patients receiving abiraterone or enzalutamide. PATIENT SUMMARY We established a method for determining AR-V7 status in whole blood. This test predicted treatment resistance in patients with metastatic castration-resistant prostate cancer undergoing treatment with abiraterone or enzalutamide. Prospective validation is needed before application to clinical practice.

Exploring New Multimodal Quantitative Imaging Indices for the Assessment of Osseous Tumour Burden in Prostate Cancer using 68Ga-PSMA-PET/CT

PET combined with CT and prostate-specific membrane antigen (PSMA) ligands has gained significant interest for staging prostate cancer (PC). In this study, we propose 2 multimodal quantitative indices as imaging biomarkers for the assessment of osseous tumor burden using 68Ga-PSMA PET/CT and present preliminary clinical data. Methods: We defined 2 bone PET indices (BPIs) that incorporate anatomic information from CT and functional information from 68Ga-PSMA PET: BPIVOL is the percentage of bone volume affected by tumor and BPISUV additionally considers the level of PSMA expression. We describe a semiautomatic computation method based on segmentation of bones in CT and of lesions in PET. Data from 45 patients with castration-resistant PC and bone metastases during 223Ra-dichloride were retrospectively analyzed. We evaluated the computational stability and reproducibility of the proposed indices and explored their relation to the prostate-specific antigen blood value, the bone scan index (BSI), and disease classification using PERCIST. Results: On the technical side, BPIVOL and BPISUV showed an interobserver maximum difference of 3.5%, and their computation took only a few minutes. On the clinical side, BPIVOL and BPISUV showed significant correlations with BSI (r = 0.76 and 0.74, respectively, P < 0.001) and prostate-specific antigen values (r = 0.57 and 0.54, respectively, P < 0.01). When the proposed indices were compared against expert rating using PERCIST, BPIVOL and BPISUV showed better agreement than BSI, indicating their potential for objective response evaluation. Conclusion: We propose the evaluation of BPIVOL and BPISUV as imaging biomarkers for 68Ga-PSMA PET/CT in a prospective study exploring their potential for outcome prediction in patients with bone metastases from PC.

The Effect of Total Tumor Volume on the Biologically Effective Dose to Tumor and Kidneys for 177Lu-Labeled PSMA Peptides

The aim of this work was to simulate the effect of prostate-specific membrane antigen (PSMA)–positive total tumor volume (TTV) on the biologically effective doses (BEDs) to tumors and organs at risk in patients with metastatic castration-resistant prostate cancer who are undergoing 177Lu-PSMA radioligand therapy. Methods: A physiologically based pharmacokinetic model was fitted to the data of 13 patients treated with 177Lu-PSMA I&T (a PSMA inhibitor for imaging and therapy). The tumor, kidney, and salivary gland BEDs were simulated for TTVs of 0.1–10 L. The activity and peptide amounts leading to an optimal tumor-to-kidneys BED ratio were also investigated. Results: When the TTV was increased from 0.3 to 3 L, the simulated BEDs to tumors, kidneys, parotid glands, and submandibular glands decreased from 22 ± 15 to 11.0 ± 6.0 Gy1.49, 6.5 ± 2.3 to 3.7 ± 1.4 Gy2.5, 11.0 ± 2.7 to 6.4 ± 1.9 Gy4.5, and 10.9 ± 2.7 to 6.3 ± 1.9 Gy4.5, respectively (where the subscripts denote that an α/β of 1.49, 2.5, or 4.5 Gy was used to calculate the BED). The BED to the red marrow increased from 0.17 ± 0.05 to 0.32 ± 0.11 Gy15. For patients with a TTV of more than 0.3 L, the optimal amount of peptide was 273 ± 136 nmol and the optimal activity was 10.4 ± 4.4 GBq. Conclusion: This simulation study suggests that in patients with large PSMA-positive tumor volumes, higher activities and peptide amounts can be safely administered to maximize tumor BEDs without exceeding the tolerable BED to the organs at risk.

Modeling and predicting tumor response in radioligand therapy

The aim of this work was to develop a theranostic method that allows prediction of prostate-specific membrane antigen (PSMA)–positive tumor volume after radioligand therapy (RLT) based on a pretherapeutic PET/CT measurement and physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling at the example of RLT using 177Lu-labeled PSMA for imaging and therapy (PSMA I&T). Methods: A recently developed PBPK model for 177Lu-PSMA I&T RLT was extended to account for tumor (exponential) growth and reduction due to irradiation (linear quadratic model). Data from 13 patients with metastatic castration-resistant prostate cancer were retrospectively analyzed. Pharmacokinetic/pharmacodynamic parameters were simultaneously fitted in a Bayesian framework to PET/CT activity concentrations, planar scintigraphy data, and tumor volumes before and after (6 wk) therapy. The method was validated using the leave-one-out Jackknife method. The tumor volume after therapy was predicted on the basis of pretherapy PET/CT imaging and PBPK/PD modeling. Results: The relative deviation of the predicted and measured tumor volume for PSMA-positive tumor cells (6 wk after therapy) was 1% ± 40%, excluding 1 patient (prostate-specific antigen–negative) from the population. The radiosensitivity for the prostate-specific antigen–positive patients was determined to be 0.0172 ± 0.0084 Gy−1. Conclusion: To our knowledge, the proposed method is the first attempt to solely use PET/CT and modeling methods to predict the PSMA-positive tumor volume after RLT. Internal validation shows that this is feasible with an acceptable accuracy. Improvement of the method and external validation of the model is ongoing.

Stellenwert der Immunonkologie bei der Therapie des Urothelkarzinoms

Data published in November 2016 showed a significant survival benefit for the PD-1 antibody Pembrolizumab in the second-line treatment of metastatic urothelial cancer in comparison to standard chemotherapy. Other PD-1/PD-L1 antibodies are being tested in advanced clinical trials. This class of substances will become standard of care from the time of their approval which is expected for 2017 and will replace vinflunine, which is currently recommended in the German guideline. PD-1/PD-L1 directed substances are also being tested as a first line treatment of metastatic urothelial carcinoma. Monotherapy is evaluated as well as combination treatments with CTLA-4 inhibitors of conventional chemotherapy. First data are expected at the end of 2017.A new strategy is the application of PD-1/PD-L1 directed substances in the perioperative treatment of patients with a muscle-invasive urothelial carcinoma after complete surgical resection (cystectomy or nephroureterectomy). Two international phase III trials evaluate an adjuvant immunotherapy with nivolumab and atezolizumab. Recruitment will be completed in 2018.

Aktuelle Therapiemöglichkeiten individuell abwägen

ZusammenfassungFür Patienten mit metastasiertem, kastrationsresistentem Prostatakarzinom gibt es zwar keine — kurativen Behandlungsmöglichkeiten mehr. In den letzten Jahren sind allerdings einige neue Optionen hinzugekommen. Da eindeutige Daten zur optimalen Therapiesequenz noch ausstehen, gilt es bei der individuellen Therapieentscheidung, die Zulassungskriterien, das Nebenwirkungsprofil und natürlich die Patientenwünsche zu beachten.