ABSTRACT
Alterations of the androgen receptor (AR) are associated with resistance to AR-directed therapy in prostate cancer. Thus, it is crucial to develop robust detection methods for AR alterations as predictive biomarkers to enable applicability in clinical practice. We designed and validated five multiplex droplet digital PCR assays for reliable detection of 12 AR targets including AR amplification, AR splice variant 7, and 10 AR hotspot mutations, as well as AR and KLK3 gene expression from plasma-derived cell-free DNA and cell-free RNA. The assays demonstrated excellent analytical sensitivity and specificity ranging from 95% to 100% (95% CI, 75% to 100%). Intrarun and interrun variation analyses revealed a high level of repeatability and reproducibility. The developed assays were applied further in peripheral blood samples from 77 patients with advanced prostate cancer to assess their feasibility in a real-world scenario. Optimizing the reverse transcription of RNA increased the yield of plasma-derived cell-free RNA by 30-fold. Among 23 patients with castration-resistant prostate cancer, 6 patients (26.1%) had one or a combination of several AR alterations, whereas only 2 of 54 patients (3.7%) in the hormone-sensitive stage showed AR alterations. These findings were consistent with other studies and suggest that implementation of comprehensive AR status detection in clinical practice is feasible and can support the treatment decision-making process.
Subject(s)
Receptors, Androgen , Humans , Receptors, Androgen/genetics , Male , Biomarkers, Tumor/genetics , Biomarkers, Tumor/blood , Aged , Prostatic Neoplasms/genetics , Prostatic Neoplasms/diagnosis , Reproducibility of Results , Mutation , Sensitivity and Specificity , Middle Aged , Cell-Free Nucleic Acids/genetics , Cell-Free Nucleic Acids/blood , Kallikreins/blood , Kallikreins/genetics , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/diagnosis , Prostatic Neoplasms, Castration-Resistant/blood , Multiplex Polymerase Chain Reaction/methodsABSTRACT
INTRODUCTION: Two randomized trials demonstrated a survival benefit of triplet therapy (androgen deprivation therapy [ADT]) plus androgen receptor pathway inhibitor [ARPI] plus docetaxel) over doublet therapy (ADT plus docetaxel), thus changing treatment strategies in metastatic hormonesensitive prostate cancer (mHSPC). PATIENTS AND METHODS: We conducted the first real-world analysis comprising 97 mHSPC patients from 16 Austrian medical centers, among them 79.4% of patients received abiraterone and 17.5% darolutamide treatment. Baseline characteristics and clinical parameters during triplet therapy were documented. Mann-Whitney U test for continuous or X²-test for categorical variables was used. Variables on progression were tested using logistic regression analysis and tabulated as hazard ratios (HR), 95% confidence interval (CI). RESULTS: Of 83.5% patients with synchronous and 16.5% with metachronous disease were included. 83.5% had high-volume disease diagnosed by conventional imaging (48.9%) or PSMA PET-CT (51.1%). While docetaxel and ARPI were administered consistent with pivotal trials, prednisolone, prophylactic gCSF and osteoprotective agents were not applied guideline conform in 32.5%, 37%, and 24.3% of patients, respectively. Importantly, a nonsimultaneous onset of chemotherapy and ARPI, performed in 44.3% of patients, was associated with significantly worse treatment response (P = .015, HR 0.245). Starting ARPI before chemotherapy was associated with significantly higher probability for progression (P = .023, HR 15.781) than vice versa. Strikingly, 15.6% (abiraterone) and 25.5% (darolutamide) low-volume patients as well as 14.4% (abiraterone) and 17.6% (darolutamide) metachronous patients received triplet therapy. Adverse events (AE) occurred in 61.9% with grade 3 to 5 in 15% of patient without age-related differences. All patients achieved a PSA decline of 99% and imaging response was confirmed in 88% of abiraterone and 75% of darolutamide patients. CONCLUSIONS: Triplet therapy arrived in clinical practice primarily for synchronous high-volume mHSPC. Regardless of selected therapy regimen, treatment is highly effective and tolerable. Preferably therapy should be administered simultaneously, however if not possible, chemotherapy should be started first.
Subject(s)
Prostatic Neoplasms , Humans , Male , Androgen Antagonists/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Austria , Docetaxel/therapeutic use , Hormones , Positron Emission Tomography Computed Tomography , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Randomized Controlled Trials as TopicABSTRACT
In recent years, new therapeutic options have brought improvements in the treatment of metastatic, castration-resistant prostate cancer. Targeted Hormone Therapy (THT) represents a novel therapeutic component for which recent studies have shown a maximum benefit in the time between failure of androgen deprivation therapy (patient is metastatic and still pain-free) and prior to chemotherapy. Prostate cancer experts of the Austrian Society of Urology and Andrology (ÖGU), the Working Group for Urologic Oncology as part of the ÖGU, and the Professional Association of Austrian Urologists (BvU) have developed recommendations for the treatment of patients with asymptomatic or mildly symptomatic metastatic, castration-resistant prostate cancer. The definition of failure of classical hormonal therapy has been based on the guidelines of the German Society of Urology (Deutsche Gesellschaft für Urologie, DGU) and the European Association of Urology (EAU). Criteria for the initiation of treatment with hormonal or chemotherapy include: Castration resistance with increase of prostate-specific antigen (PSA) Evidence of metastases in imaging No or mild symptoms Quality of Life Index of the Eastern Cooperative Oncology Group (ECOG) 0-1 (ECOG 2 requires individualized decision) [1]. Treatment should only be initiated when all of these four criteria are applicable, with the age of the patient being no exclusion criterion. First-line therapies for these patients include abiraterone, enzalutamide, and docetaxel as well as radium-223. The manuscript refers only to treatment regimens available in Austria.Selection of the initial treatment option-starting with THT or chemotherapy-should be determined based on the individual patient characteristics. When using abiraterone or enzalutamide, re-staging within 3-6 months is recommended.
Subject(s)
Androgen Antagonists/therapeutic use , Hormone Replacement Therapy/standards , Medical Oncology/standards , Molecular Targeted Therapy/standards , Practice Guidelines as Topic , Prostatic Neoplasms, Castration-Resistant/drug therapy , Androgen Antagonists/standards , Austria , Evidence-Based Medicine , Humans , Male , Treatment OutcomeABSTRACT
Within the last two years the therapy of castration resistant prostate cancer (CRPC) has made major advances. Both the COU-AA-301 phase III trial and the TROPIC trial showed a survival benefit for patients after docetaxel failure treated with abiraterone or cabazitaxel, respectively. With rising interest for chemotherapeutic options and novel drugs, our goal was to review within the context of a multidisciplinary team the available evidence and explore the standards for medical treatment of prostate cancer outside of clinical trials. From this background, we are carefully evaluating the current treatment recommendations, based on the available evidence, and highlight potential future treatment options but also discuss important clinical topics like treatment until progression versus the advantage of chemo holidays and definition of particular patient subgroups. Additionally, we focus on novel molecular entities, which will most likely be available in the near future, such as MDV3100 and Sipuleucel T. The role and importance of palliation with radiotherapy and proactive medical management of pain is also discussed, as well as new options for bone directed therapy. The multitude of treatment options for patients with advanced prostate cancer clearly asks for a close collaboration between urologists, medical oncologists and radiation therapists.
Subject(s)
Drug Therapy/standards , Practice Guidelines as Topic , Prostatic Neoplasms/therapy , Radiotherapy, Adjuvant/standards , Castration , Humans , Male , Treatment FailureABSTRACT
PURPOSE: To prospectively evaluate the potential value of fluorocholine (FCH) positron emission tomography (PET)/computed tomography (CT) in the preoperative staging of patients with prostate cancer who had intermediate or high risk of extracapsular disease. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. Overall, 132 patients with prostate cancer (mean age, 63 years +/- 7 [standard deviation]) were enrolled between October 2003 and June 2008. Two patients were subsequently excluded. In 111 patients, radical prostatectomy with extended pelvic lymph node (LN) dissection was performed. Patients were categorized into groups with intermediate (n = 47) or high (n = 83) risk of extracapsular extension on the basis of their Gleason scores and prostate specific antigen levels. Imaging was performed with an integrated PET/CT system after injection of 4.07 MBq FCH per kilogram of body weight with acquisition of dynamic images in the pelvis and whole-body images. Statistical analysis was performed on a per-patient basis. RESULTS: Significant correlation was found between sections with the highest FCH uptake and sextants with maximal tumor infiltration (r = 0.68; P = .0001). Overall, 912 LNs were histopathologically examined. A per-patient analysis revealed the sensitivity, specificity, and positive and negative predictive values of FCH PET/CT in the detection of malignant LNs were 45%, 96%, 82%, and 83%, respectively. For LN metastases greater than or equal to 5 mm in diameter, sensitivity, specificity, and positive and negative predictive values were 66%, 96%, 82%, and 92%, respectively. In 13 patients, 43 bone metastases were detected. Early bone marrow infiltration was detected with only FCH PET in two patients. FCH PET/CT led to a change in therapy in 15% of all patients and 20% of high-risk patients. CONCLUSION: FCH PET/CT could be useful in the evaluation of patients with prostate cancer who are at high risk for extracapsular disease, and it could be used to preoperatively exclude distant metastases. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.09090413/-/DC1.
Subject(s)
Choline/analogs & derivatives , Positron-Emission Tomography/methods , Prostatic Neoplasms/pathology , Radiopharmaceuticals , Tomography, X-Ray Computed/methods , Aged , Humans , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Metastasis , Neoplasm Staging , Predictive Value of Tests , Prospective Studies , Prostatectomy , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/surgery , Radiographic Image Interpretation, Computer-Assisted , Risk Factors , Sensitivity and SpecificityABSTRACT
PSA is without any doubt the most frequently used marker in urology due to its helpful information regarding various aspects of diagnosis, therapy and prognosis in men with prostate cancer. On the other hand, many controversies still exist about the various indications for PSA-determination. The following overview is aimed to analyse the current status of PSA in the management of men undergoing screening, therapy or follow-up of prostate cancer. Anyhow, a detailed knowledge of how to use and interpret PSA and PSA-kinetics is considered to play a crucial role in prostate cancer patients. Current strategies are aimed to start and stop PSA-use earlier.
Subject(s)
Biomarkers, Tumor/blood , Prostate-Specific Antigen/blood , Prostatic Neoplasms/blood , Prostatic Neoplasms/diagnosis , Aged , Algorithms , Biopsy , Early Diagnosis , Humans , Male , Mass Screening , Middle Aged , Neoplasm Staging , Predictive Value of Tests , Prognosis , Prostate/pathology , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathology , Survival RateABSTRACT
PURPOSE: The aim of this prospective study was to compare the potential value of (18)F fluorocholine (FCH) and (18)F fluoride positron emission tomography (PET)-CT scanning for the detection of bony metastases from prostate cancer. METHODS: Thirty-eight men (mean age, 69+/-8 years) with biopsy-proven prostate cancer underwent both imaging modalities within a maximum interval of 2 weeks. Seventeen patients were evaluated preoperatively, and 21 patients were referred for post-operative evaluation of suspected recurrence or progression based on clinical algorithms. The number, sites and morphological patterns of bone lesions on (18)F FCH and (18)F fluoride PET-CT were correlated: Concordant lesions between the two modalities with corresponding changes on CT were considered to be positive for malignancy; discordant lesions were verified by follow-up examinations. The mean follow-up interval was 9.1 months. RESULTS: Overall, 321 lesions were evaluated in this study. In a lesion-based analysis, a relatively close agreement was found between these two imaging modalities for detection of malignant bone lesions (kappa=0.57), as well as in a patient-based analysis (kappa=0.76). Sixteen malignant sclerotic lesions with a high density were negative in both (18)F FCH and (18)F fluoride PET-CT [mean Hounsfield unit (HU), 1,148+/-364]. There was also a significant correlation between tracer intensity by SUV and density of sclerotic lesions by HU both in (18)F FCH PET-CT (r= -0.28, p < 0.006) and (18)F fluoride PET-CT (r= -0.20, p<0.05). The sensitivity, specificity and accuracy of PET-CT in the detection of bone metastases in prostate cancer was 81%, 93% and 86% for (18)F fluoride, and 74% (p=0.12), 99% (p=0.01) and 85% for FCH, respectively. (18)F FCH PET-CT led to a change in the management in two out of 38 patients due to the early detection of bone marrow metastases. (18)F fluoride PET-CT identified more lesions in some patients when compared with (18)F FCH PET-CT but did not change patient management. CONCLUSION: FCH PET-CT may be superior for the early detection (i.e. bone marrow involvement) of metastatic bone disease. In patients with FCH-negative suspicious sclerotic lesions, a second bone-seeking agent (e.g. (18)F fluoride) is recommended. (18)F fluoride PET-CT demonstrated a higher sensitivity than (18)F FCH PET-CT, but the difference was not statistically significant. Furthermore, (18)F fluoride PET could be also negative in highly dense sclerotic lesions, which presumably reflects the effect of treatment. It will be important to clarify in future studies whether these lesions are clinically relevant when compared with metabolically active bone metastases.
Subject(s)
Bone Neoplasms/diagnosis , Bone Neoplasms/secondary , Choline/analogs & derivatives , Fluorine Radioisotopes , Positron-Emission Tomography/methods , Prostatic Neoplasms/diagnosis , Tomography, X-Ray Computed/methods , Adult , Humans , Male , Radiopharmaceuticals , Reproducibility of Results , Sensitivity and Specificity , Subtraction TechniqueABSTRACT
UNLABELLED: According to reports, re-staging of patients suffering from prostate cancer by positron emission tomography (PET) using C-11-choline has failed to produce positive findings at a PSA level of < 5 ng/ml. Hence, the purpose of our study has been to determine whether this is true also for PET/CT using F-18-fluorocholine (FCH PET/CT) or whether it is possible to obtain true positive results by FCH PET/CT even at lower PSA levels. METHODS: In 34 patients with prostate cancer who had undergone initial therapy (radical prostatectomy n = 31, radiotherapy n = 3), a PET/CT scan was performed using F-18-fluorocholine (FCH) during follow-up in case of demonstrable or rising PSA levels. Current PSA levels were determined in all patients at the time of examination. RESULTS: Median PSA in FCH positive patients was 6.1 ng/ml (mean PSA 17.1 ng/ml), median PSA in FCH negative patients was 2.3 ng/ml (mean PSA 3.4 ng/ml), respectively (p < 0.05). In eight of 17 examinations (47%) with PSA < 5 ng/ml, at least one FCH-positive focus was detected. So far the findings could be confirmed by correlating imaging methods (CT and/or MR), biopsy/histology and the course of the disease, respectively, in seven of the eight FCH-positive cases with PSA < 5 ng/ml, so that a true positive FCH PET/CT finding was obtained all in all in seven of 17 (41%) examinations with PSA < 5 ng/ml. In four of these seven FCH PET-positive patients with PSA < 5 ng/ml, adjuvant hormonal therapy was administered at the time of the examination or prior to the examination. CONCLUSION: In re-staging patients with prostate cancer, FCH PET/CT is able to yield true positive findings even at PSA < 5 ng/ml. Therefore, FCH PET/CT should not be restricted to patients with PSA > 5 ng/ml.
Subject(s)
Choline , Fluorine Radioisotopes , Positron-Emission Tomography , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Radiopharmaceuticals , Tomography, X-Ray Computed , Aged , Aged, 80 and over , Fluorine Radioisotopes/pharmacokinetics , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Staging , Prostate-Specific Antigen/blood , Prostatectomy , Prostatic Neoplasms/blood , Prostatic Neoplasms/radiotherapy , Prostatic Neoplasms/surgery , Radiopharmaceuticals/pharmacokinetics , Retrospective StudiesABSTRACT
PURPOSE: To define the clinical value of 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG PET) as a predictor for viable residual tumor in postchemotherapy seminoma residuals in a prospective multicentric trial. PATIENTS AND METHODS: FDG PET studies in patients with metastatic pure seminoma who had radiographically defined postchemotherapy residual masses were correlated with either the histology of the resected lesion or the clinical outcome documented by computer tomography (CT), tumor markers, and/or physical examination during follow-up. The size of the residual lesions on CT, either >3 cm or < or =3 cm, was correlated with the presence or absence of viable residual tumor. RESULTS: Fifty-six FDG PET scans of 51 patients were assessable. All 19 cases with residual lesions >3 cm and 35 (95%) of 37 with residual lesions < or =3 cm were correctly predicted by FDG PET. The specificity, sensitivity, positive predictive value, and negative predictive value of FDG PET were 100% (95% CI, 92% to 100%), 80% (95% CI, 44% to 95%), 100%, and 96%, respectively, versus 74% (95% CI, 58% to 85%), 70% (95% CI, 34% to 90%), 37%, and 92%, respectively, for CT discrimination of the residual tumor by size (>3 cm/< or =3 cm). CONCLUSION: This investigation confirms that FDG PET is the best predictor of viable residual tumor in postchemotherapy seminoma residuals and should be used as a standard tool for clinical decision making in this patient group.