Castration-resistant Prostate Carcinoma Research Articles

A randomized phase II trial of docetaxel plus carboplatin versus docetaxel in patients with castration-resistant prostate cancer who have progressed after response to prior docetaxel chemotherapy: The RECARDO trial.

166 Background: Docetaxel is the standard first-line chemotherapy for patients with castration resistant prostate carcinoma (CRPC). Docetaxel re-challenge has never been tested in a prospective randomized clinical trial. As some studies supported the addition of carboplatin to docetaxel in this setting, we performed a phase II trial investigating the combination of docetaxel plus carboplatin versus docetaxel monotherapy in docetaxel pre-treated CRPC patients. Methods: Patients with CRPC with a progression-free interval (PFI) of at least 3 months after initial treatment with docetaxel were randomized between docetaxel 75mg/m2 or docetaxel 60mg/m2 plus carboplatin AUC 4, both plus prednisone in a 3-weekly schedule. Treatment was continued until progressive disease, unacceptable toxicity or completion of 10 cycles. The primary endpoint is progression-free survival (PFS) (PSA and/or RECIST). Secondary objectives are overall survival, toxicity, PSA response and quality of life. Results: As a result of insufficient recruitment, the study was discontinued early after inclusion of 75 patients, instead of the targeted 150 patients. The median PFS was comparable between both groups (docetaxel 12.7 months versus combination therapy 11.7 months p = 0.99), and no difference in OS was found (median OS 18.5 months versus 18.9 months, p = 0.88). Rates of PSA response were comparable (response/stable PSA in 42.1%/39.4% of the patients in the monotherapy arm versus 35.1%/48.6% in the combination arm, NS). The incidence of grade 3-4 infections and gastro-intestinal (GI) side effects was higher in the docetaxel plus carboplatin arm (GI side effects 0% versus 13.9% p = 0.03; infection 2.7% versus 16.7% p = 0.056). The difference in febrile neutropenia (0% versus 11.1%) is not significant. Conclusions: For patients with CRPC and an initial good response to docetaxel, re-treatment with docetaxel monotherapy is a feasible, save and effective treatment. Addition of carboplatin resulted in more toxicity. Docetaxel re-challenge is a viable therapeutic option for selected patients. Clinical trial information: NTR3070.

P081 - Prospective, non-interventional study on the influence of adherence measures on the therapy with Abiraterone Acetate (AA) + Prednisone/prednisolone (P) in patients with metastatic, castration resistant prostate carcinoma

P081 - Prospective, non-interventional study on the influence of adherence measures on the therapy with Abiraterone Acetate (AA) + Prednisone/prednisolone (P) in patients with metastatic, castration resistant prostate carcinoma

Strategies for First-Line Treatment of mCRPC

At present, abiraterone acetate and enzalutamide are the most commonly used substances in the first-line treatment of asymptomatic or mildly symptomatic metastatic castration-resistant prostate carcinoma (mCRPC). Since the relevant pivotal trials have demonstrated comparable clinical efficacy for both substances, further factors should be considered for the choice of treatment. As mCRPC patients usually receive several lines of treatment, different adaptation and resistance mechanisms leading to treatment failure could be important. This is indicated by daily routine observations and some initial clinical studies on resistance and different sequences of therapy. However, until the clinical relevance has been confirmed, it is mostly adverse events and comorbidities that are taken into account for the choice of first-line therapy. Also potential interactions with comedications and patient preferences should be considered. In the first-line treatment of mCRPC, ongoing discussions not only centre around the choice of medication for first-line mCRPC therapy, but also around the point in time they are started. For abiraterone acetate, for example, there is confirmed evidence that patients may benefit from early use within the approved indication. If the clinical importance of the different resistance mechanisms and differences in efficacy of various sequences could be confirmed, this would be a strong argument for therapy decisions and should therefore be further analysed in prospective clinical studies.

Prospective, non-interventional study on the influence of adherence measures on the therapy with abiraterone acetate (AA) + prednisone/prednisolone (P) in patients with metastatic, castration resistant prostate carcinoma.

e16525Background: AA is a blocker of androgen biosynthesis, which is highly effective in men with mCRPC in prolonging PFS and OS. Oncology experiences an increase in oral cancer drugs treatments, f...

A feasibility study to determine T cell responses to neoantigens following treatment with ipilimumab in men with metastatic castration-resistant prostate carcinoma (mCRPC).

e14506Background: Ipilimumab (anti-CTLA-4) promotes durable antitumor responses in a subset of patients with mCRPC. We designed a clinical trial (NCT02113657) to test the hypothesis that the induct...

Implication of NPM1 phosphorylation and preclinical evaluation of the nucleoprotein antagonist N6L in prostate cancer.

Despite the advent of several new treatment options over the past years, advanced/metastatic prostate carcinoma (PCa) still remains incurable, which justifies the search for novel targets and therapeutic molecules. Nucleophosmin (NPM1) is a shuttling nucleoprotein involved in tumor growth and its targeting could be a potential approach for cancer therapy. We previously demonstrated that the multivalent pseudopeptide N6L binds to NPM1 potently affecting in vitro and in vivo tumor cell growth of various tumor types as well as angiogenesis. Furthermore, NPM1 binds to androgen receptor (AR) and modulate its activity. In this study, we first investigated the implication of the NPM1 and its Thr199 and Thr234/237 phosphorylated forms in PCa. We showed that phosphorylated forms of NPM1 interact with androgen receptor (AR) in nucleoplasm. N6L treatment of prostate tumor cells led to inhibition of NPM1 phosphorylation in conjunction with inhibition of AR activity. We also found that total and phosphorylated NPM1 were overexpressed in castration-resistant PCa. Assessment of the potential therapeutic role of N6L in PCa indicated that N6L inhibited tumor growth both in vitro and in vivo when used either alone or in combination with the standard-of-care first- (hormonotherapy) and second-line (docetaxel) treatments for advanced PCa. Our findings reveal the role of Thr199 and Thr234/237 phosphorylated NPM1 in PCa progression and define N6L as a new drug candidate for PCa therapy.

Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy.

BackgroundProstate-specific membrane antigen (PSMA) is a promising target for diagnostics and therapy of prostate carcinoma (PCa). Based on the hypothesis that PSMA expression can be modulated by variations in androgen deprivation therapy (ADT), we investigated the binding of a PSMA-directed radiopharmaceutical in vitro in order to get an insight of the interactions between altered premedication and PSMA expression before repetitive PSMA-directed PET/CT for therapy response and targeted therapy implementation.MethodsThe human castration-resistant PCa cell line VCaP (CRPC) was treated with either 1 nmol/L testosterone (T) over 20 passages yielding the androgen-sensitive cell line (revCRPC) or with 5 μmol/L abiraterone acetate (AA) generating the abiraterone-tolerant subtype CRPCAA. In these cell lines, T and AA were varied by either supply or withdrawal of T and AA. PSMA expression of the three cell culture models was detected by Western blot and immunohistochemical staining. For quantitative measurement of tracer uptake, 0.3 nmol/L 68Ga-labelled PSMA-HBED-CC peptide (100–300 kBq/ml) was added to different treated parallel cultures (n = 9 each). Time-dependent uptake per 106 cells of each culture was calculated and evaluated. PSMA mRNA expression was investigated by qPCR.ResultsPSMA expression increased dependently on intensified ADT in all three basic cell lines. 68Ga-PSMA-HBED-CC uptake almost doubled during 3 h in all cell lines (p < 0.01). Compared to the basic cells, pre-incubation with abiraterone for 48 h resulted in a significant increased uptake in CRPC (p < 0.001). In revCRPC, 48-h AA pre-incubation resulted in an eightfold higher uptake after 3 h (p < 0.001). Additional withdrawal of external testosterone increased the uptake up to tenfold (p < 0.01). The increase of PSMA expression upon ADT and AA treatments was confirmed by qPCR and Western blot data. Furthermore, in CRPCAA, 48-h AA withdrawal increased the uptake up to fivefold (p < 0.01).ConclusionsThe investigated three PCa cell culture subtypes represent a serial preclinical model of androgen deprivation therapy as a proxy for clinical situations with differing basal PSMA expression. The uptake of PSMA-binding tracers could be stimulated by therapeutic effective short-term variation in premedication in all stages of ADT response. These complex interactions have to be considered in the interpretation of diagnostic imaging using PSMA ligands as well as in the optimal timing of PSMA-based therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0145-8) contains supplementary material, which is available to authorized users.

Marine alkaloid Monanchocidin a overcomes drug resistance by induction of autophagy and lysosomal membrane permeabilization.

Monanchocidin A (MonA) is a novel alkaloid recently isolated from the marine sponge Monanchora pulchra. The compound reveals cytotoxic activity in genitourinary cancers including cisplatin-sensitive and -resistant germ cell tumor (GCT) cell lines, hormone-sensitive and castration-resistant prostate carcinoma cell lines and different bladder carcinoma cell lines. In contrast, non-malignant cells were significantly less sensitive. MonA is highly synergistic with cisplatin in GCT cells. Induction of autophagy at lower and lysosomal membrane permeabilization (LMP) at higher concentrations were identified as the dominating modes of action. Cytotoxicity and protein degradation could be inhibited by 3-methyladenine, an inhibitor of autophagy. LMP was confirmed by loss of acridine orange staining of lysosoms and by release of cathepsin B. In conclusion, MonA exerts cytotoxic activity by mechanisms different from "classical" apoptosis, and could be a promising new compound to overcome resistance to standard therapies in genitourinary malignancies.

Cabozantinib: a novel agent with a dual mechanism of action for castration-resistant prostate carcinoma

The landscape of castration-resistant prostate carcinoma has changed completely in the last few years, with the approval of four new agents with proven benefit in overall survival. Abiraterone, cabazitaxel, enzalutamide and radium-223 dichloride have been added to the armamentarium of available agents for the treatment of these patients. We still lack information about which agent works best in an individual patient and how to optimally use them in a sequential strategy. Cabozantinib, a targeted agent against MET and vascular endothelial growth factor receptor-2, has shown promising results and could become the first targeted therapy to be approved for castration-resistant prostate carcinoma. This paper reviews the clinical development of cabozantinib in prostate cancer and future research possibilities for this drug.

Comment on Afshar-Oromieh et al.: PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions

Dear Sir, It was with particular interest that we read the article by Afshar-Oromieh et al. [1]. The authors developed a novel 68Ga-labelled prostate-specific membrane antigen (PSMA)-binding small molecule, combining the well-known urea-based inhibitory motif glutamate-urea-lysine [2] with the lipophilic N,N′-bis[2-hydroxy-5-(carboxyethyl)-benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC) chelator for 68Ga [3]. The authors reasoned that the lipophilicity of HBED-CC might improve binding to PSMA and thus enable positron emission tomography (PET)/CT imaging of prostate carcinoma (PCa) [3]. Recognizing that PSMA targeting is one of the most exciting topics of molecular imaging and targeted therapy in prostate cancer at present, the authors are to be congratulated on offering the first larger patient series of 37 individuals with relapsing PCa, examined with a 68Ga-labelled PSMA inhibitor and PET/CT. Examination of the biodistribution of the novel tracer and capability to show presumed sites of metastatic involvement were major intents of the study. The authors described excellent lesion detection with impressive contrast of presumed sites of metastatic deposits of prostate cancer in 31 of their 37 patients (83.8 %) [1]. A detailed discussion of the many clinical and technical ambiguous aspects of the study is beyond the scope of this letter. However, we think that in a study comprising 37 patients a discussion of 42 patients in the text needs clarification. In addition, we cannot follow the assumption that a prostate involved with prostate cancer and treated with local radiation therapy and androgen deprivation therapy can be regarded as a ‘normal prostate’. Also, interpretation of the clinical state of patient 21 described in the legend of Fig. 7 as harbouring probably dedifferentiated prostate cancer because of positive pelvic nodes and a serum prostate-specific antigen (PSA) concentration of 0.01 ng/ml is confusing as this patient already had a Gleason score of 9 of his primary and bone as well as soft tissue metastases (Table 1) and therapy beyond prostatectomy is not discussed. Moreover, one of the two positive nodes in this patient is an inguinal node, a localization where positive nodes from PCa are very rare. Generally, a definition of assessment criteria of assumed prostate cancer deposits and verification by some reference standard in more than the six histologically controlled patients described would have been very welcome. Interestingly, the authors try to explain 68Ga-PSMA inhibitor biodistribution with rather high tracer uptake in lacrimal and salivary glands, nasal mucosa, liver, spleen, bowel, kidneys and bladder in the context of known PSMA tissue expression. A very similar biodistribution to that described by the authors was observed in a series of seven patients, examined with the PSMA inhibitor MIP-1072 ([(S)-2-(3-((S)-1-carboxy-5-(4-iodobenzylamino)pentyl)ureido) pentanedioic acid) and MIP-1095 ([(S)-2-(3-((S)-1-carboxy-5-(3-(4-iodophenyl)pentyl)ureido) pentanedioic acid) by Barrett et al. very recently [4]. Also in this study, lesions from PCa could be imaged with high contrast using single photon emission computed tomography (SPECT)/CT as the imaging technique [4]. Studying relapsing prostate cancer with another 68Ga-PSMA inhibitor, 68Ga-DOTA-DUPA-Pep (8,11-dibenzyl-2,7,10,13,22,27-hexaoxo-1-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraaza-cyclododecan-1-yl)-3,6,9,12,21,26,28-heptaazahentriacontane-25,29,31-tricarboxylic acid) we can confirm the very favourable imaging properties of PSMA targeting with urea-based inhibitors for showing metastatic disease with PET/CT (Fig. 1a), but we observed a remarkably different biodistribution (Fig. 1b) to that described by Afshar-Oromieh et al. [5]. We found predominant tracer uptake in kidneys, urinary tract, blood pool and lesions from PCa (Fig. 1a) and only very faint uptake in salivary glands and also in gynaecomastia (Fig. 1b). Interestingly, a current paper by Pomper’s group using the 18F-labelled PSMA inhibitor N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-L-cysteine (18F-DCFBC) described a strikingly similar biodistribution to that of 68Ga-DOTA-DUPA-Pep [6]. Thus, PSMA addressing through urea-based inhibitors with appropriate radiolabelled peptides seems to provide a very promising approach for targeting various stages of PCa in patients; however, factors governing extraprostatic tissue distribution need further careful analysis and consideration. Fig. 1 a A 70-year-old patient with a history of prostatectomy because of PCa 12 years before the examination, Gleason score 5 + 5, local radiation therapy and castration-resistant PCa at presentation, PSA 3 ng/ml. 11C-choline ...

Radium-223 Chloride

In the last few years, the treatment of castration-resistant prostate carcinoma (CRPC) has changed completely. The approval of docetaxel and subsequent investigation in this field have led to development of new agents that have demonstrated an improvement in overall survival in the post-docetaxel setting, such as cabazitaxel and abiraterone. Radium-223 chloride is a radioisotope that has recently shown efficacy after docetaxel and in patients unfit for docetaxel, with improvements in overall survival and the time to the first skeletal-related event, compared with placebo, without increasing toxicity. These findings have made this agent a new option for treatment of these patients in the near future.

Radium-223 Chloride

In the last few years, the treatment of castration-resistant prostate carcinoma (CRPC) has changed completely. The approval of docetaxel and subsequent investigation in this field have led to development of new agents that have demonstrated an improvement in overall survival in the post-docetaxel setting, such as cabazitaxel and abiraterone. Radium-223 chloride is a radioisotope that has recently shown efficacy after docetaxel and in patients unfit for docetaxel, with improvements in overall survival and the time to the first skeletal-related event, compared with placebo, without increasing toxicity. These findings have made this agent a new option for treatment of these patients in the near future.

Abiraterone acetate, an efficacy treatment option for metastatic castration-resistant prostate carcinoma (mCRPC) that improves functional status in elderly patients (EP)

only 7 patients (41.2%) received the full treatment initially planned. Grade III or IV toxicities were recorded in 5 patients (29.4%). Only 4 patients had a second line chemotherapy and only one patient (25%) could receive the planned treatment. At the time of data collection, 27 patients were in remission (52.9%; 27/51), 16 had progression disease (30.2%; 16/53), 16 were still under treatment (30.8%; 16/52), and 17 died (31.5%; 17/54). The mean time between diagnosis and death was 5.7±5.9 years. Conclusion: In the studied population, completion of surgical treatment and/or radiotherapy and/or hormone therapy was mainly possible, with no major toxicity. However, completion of chemotherapy was possible in less than 50% of cases.

Abiraterone acetate

Androgen-deprivation therapy is the mainstay of treatment for the management of advanced prostate carcinoma till transition to castration-resistant prostate carcinoma (CRPC). Recently, adrenal and intratumoral synthesis of androgens has been found to be the major cause for CRPC. Abiraterone acetate is an orally active, potent and selective inhibitor of 17 a hydroxylase and c 17, 20 lyase, which acts by decreasing the de novo production of androgens with no rise in steroids downstream. Multiple randomized trials have shown significant improvement of >50% decline in prostate-specific antigen (PSA) and time to PSA progression (TTPP) with abiraterone acetate 1000 mg per day in chemotherapy/ketoconazole treated and naive CRPC patients producing reversible and manageable adverse effects due to mineralocorticoid excess. This article reviews the available evidence on efficacy and safety of this drug in CRPC. Searches of Pubmed, Cochrane database, Medscape, Google and clinicaltrial.org were made for terms like CRPC and abiraterone.

NF-κB signaling in prostate cancer: A promising therapeutic target?

Prostate carcinoma (PCa) displays a wide variety of genetic alterations, versatile expression profiles as well as cell surface markers. Despite this heterogeneity, a common treatment for advanced PCa is androgen deprivation therapy (ADT). ADT targets the androgen receptor-a member of the nuclear receptor superfamily-which is required for development and function of the prostate and critical for PCa growth and survival. After an initial regression of the tumor during ADT, a large fraction of tumors progress to so-called castration-resistant prostate carcinoma (CRPca) which is highly resistant toward chemotherapy. The ensuing high mortality rates illustrate the importance of novel therapeutic targets for CRPCa. The transcription factor NF-κB was recently proposed as such a potential target for therapeutic intervention in CRPCa. Although NF-κB is essential for the regulation of innate and adaptive immunity recent data suggest a role of NF-κB in cancer initiation and progression. However, the exact function of NF-κB signaling in PCa is still a matter of debate. Here, we review known roles of NF-κB signaling in PCa and emphasize the crosstalk of NF-κB and androgen receptor signaling. Finally, we discuss potential therapeutic relevance of blocking NF-κB in PCa.

Use of speed and extent of PSA response during the first three cycles of docetaxel chemotherapy in metastatic castrate-resistant prostate cancer to predict overall survival.

48 Background: Docetaxel chemotherapy has an established role in the management of metastatic castrate-resistant prostate carcinoma (CRPC). With an overall survival benefit demonstrated with second line agents, identifying non-responders to docetaxel at an early stage would allow timely consideration of therapy change.We wished to assess PSA response rates to sequential cycles of docetaxel chemotherapy to determine after which cycle men should be considered nonresponders.We also wished to assess if previous therapy with diethylstilbestrol (DES) influenced subsequent response to docetaxel. Methods: Retrospective case review of all men with CRPC receiving docetaxel chemotherapy between January 2007 and April 2010 at our institution was performed. PSA immediately prior to cycle 1 (baseline) and subsequent cycles were noted and evaluated for response compared to baseline PSA. Results: 86 men with a median age of 65 years (47-81) received an average of 5 cycles (1-10) of docetaxel chemotherapy. 67 (77%) had a documented fall in PSA below baseline during chemotherapy with 56 (65%) and 43 (50%) having a PSA response of &gt;30% and &gt;50% respectively. A PSA level lower than baseline was seen in 54%, 63% and 72% of men after cycles 1, 2 and 3 respectively. Limited PSA falls below baseline were seen in 3 (3.4%) and 2 (2.3%) men after cycles 4 and 5 respectively. All PSA responses of &gt;50% had occurred by the start of cycle 4. Of the 14 men who had received DES prior to starting docetaxel, only 3 (21%) had &gt;50% reduction in PSA. The median overall survival for men achieving a PSA response &gt;50% below baseline was 20 mths and was significantly better than the median overall survival of 10mths for those with no PSA response &gt;50% (p&lt;0.0001). Site of metastatic disease also correlated with survival. Conclusions: In our population, men who fail to document a PSA response to the first 3 cycles of docetaxel chemotherapy are highly unlikely to do so after this time. Response defined as a fall below baseline and the extent of PSA decline below baseline are all correlated with survival. More modest PSA responses are seen in men pre-treated with DES than those who have not received DES. No significant financial relationships to disclose.

Tumor Regression and Growth Rates Determined in Five Intramural NCI Prostate Cancer Trials: The Growth Rate Constant as an Indicator of Therapeutic Efficacy

In solid tumors such as prostate cancer, novel paradigms are needed to assess therapeutic efficacy. We utilized a method estimating tumor growth and regression rate constants from serial PSA measurements, and assessed its potential in patients with metastatic castration resistant prostate carcinoma (mCRPC). Patients were enrolled in five phase II studies, including an experimental vaccine trial, representing the evolution of therapy in mCRPC. PSA measurements obtained before, and during, therapy were used. Data analysis using a two-phase mathematical equation yielded concomitant PSA growth and regression rate constants. Growth rate constants (g) can be estimated while patients receive therapy and in such patients g is superior to PSA-DT in predicting OS. Incremental reductions in growth rate constants were recorded in successive trials with a 10-fold slower g in the most recent combination therapy trial (log g = 10(-3.17)) relative to single-agent thalidomide (log g = 10(-2.08)) more than a decade earlier. Growth rate constants correlated with survival, except in patients receiving vaccine-based therapy where the evidence demonstrates prolonged survival presumably due to immunity developing subsequent to vaccine administration. Incremental reductions in tumor growth rate constants suggest increased efficacy in successive chemotherapy trials. The derived growth rate constant correlates with survival, and may be used to assess efficacy. The PSA-TRICOM vaccine appears to have provided marked benefit not apparent during vaccination, but consistent with subsequent development of a beneficial immune response. If validated as a surrogate for survival, growth rate constants would offer an important new efficacy endpoint for clinical trials.

Neuroendocrine prostate cancer xenografts with large‐cell and small‐cell features derived from a single patient's tumor: Morphological, immunohistochemical, and gene expression profiles

Small-cell carcinoma (SCC) of the prostate is an AR-negative variant of prostate cancer found at progression in 10-20% of castrate-resistant disease. Its finding predicts a distinct clinical course and a poor prognosis. Large-cell neuroendocrine carcinoma (LCNEC) is a much rarer variant that behaves similarly to SCC. The biological mechanisms that drive these disease variants are poorly understood. Eight tumor fragments from the salvage pelvic exenteration specimen of a patient with castrate-resistant prostate carcinoma were subcutaneously implanted into 6- to 8-week-old male CB17 SCID mice. Serial tissue sections and tissue microarrays of the resulting MDA PCa 144 xenograft lines were used for histopathologic and immunohistochemical characterization of the xenografts and their tissue of origin. RNA from two representative xenograft sublines was used for gene-expression profiling. All eight fragments formed tumors: four of the MDA PCa 144 xenograft sublines had morphologic characteristics of SCC and four, of LCNEC. All retained high fidelity to their parent tumor tissue, which remained stable through serial passages. Morphological transitions in the specimen of origin suggested LCNEC represents an intermediate step between adenocarcinoma and SCC. Over 2,500 genes were differentially expressed between the SCC (MDA PCa 144-13) and the LCNEC (MDA PCa 144-4) sublines and enriched in "Nervous System Development" Gene Ontology subtree. The eight xenograft models described represent the spectrum of neuroendocrine carcinomas in prostate cancer and will be valuable preclinical tools to study the pathogenesis of and therapy targets for this increasingly recognized subset of lethal prostate cancer.

18F-Fluoromethylcholine (FCH) PET imaging in patients with castration-resistant prostate cancer: prospective comparison with standard imaging

The aim of the study was to assess the utility of (18)F-fluorocholine (FCH), compared to standard imaging of bone scan (BS) and contrast-enhanced abdominopelvic computed tomography (CT), in patients with castration-resistant prostate carcinoma. FCH has shown promise as a metabolic imaging agent for prostate carcinoma. Twenty-six patients with castration-resistant prostate carcinoma had FCH, BS and CT imaging within a 2-month period. Individual FCH-positive lesions in bone were compared to the BS and soft tissue lesions were compared to CT. The lesions were then classified as concordant or discordant for the presence or absence of prostate cancer metastases. Discordant bone or soft tissue lesions were followed up with BS or CT, respectively, at 6-month intervals for up to 2 years or until a definitive diagnosis of the discordant lesion could be made. In 13 (50%) of the patients, all lesions identified were concordant; this included 5 patients in whom no lesions could be identified with any imaging modality. In 21 patients, 183 lesions were observed with 149 being concordant and 34 (19%) being discordant (13 patients). Based on follow-up, FCH correctly identified the presence or absence of disease in 27 of 34 lesions, and in 14 cases FCH-positive lesions, not identified on initial imaging, were confirmed as disease on follow-up. The sensitivity, specificity, accuracy, positive predictive and negative predictive values for lesion detection by FCH are 96% (92-98%), 96% (81-99%), 96% (93-97%), 99% (96-100%) and 81% (64-88%), respectively, with 95% confidence intervals shown in parentheses. In this patient cohort, FCH shows good initial concordance (81%) with BS and CT in the detection of metastatic prostate carcinoma. Follow-up of the cases where FCH was initially discordant with subsequent BS or CT shows that FCH was accurate in determining the presence or absence of prostate metastasis in 79% of lesions. While FCH imaging as compared to BS and CT in this patient group has a good sensitivity and specificity for the detection of lesions representing prostate metastasis, further prospective studies are needed to determine its role.

Neurology of the Visual System

<b>Background:</b> Metastatic prostate carcinoma over-expresses the prostate specific membrane antigen (PSMA) making this antigen a suitable target for radioligand therapy of the disease. Here we report on our experience in a series of 73 castrate resistant prostate carcinoma patients treated with ²²⁵Ac-PSMA-617, identifying variables predictive for overall and progression free survival following ²²⁵Ac-PSMA-617 treatment. <b>Methods:</b>²²⁵Ac-PSMA-617 was administered to patients with mCRPC who had exhausted available therapy options for their disease. Full blood count, glomerular filtration rate and liver function test were obtained at baseline and on follow-up for evaluation of toxicity. ⁶⁸Ga-PSMA PET/CT was obtained at baseline, prior to every treatment cycle and on follow-up for patients’ selection for treatment, to determine the activity of treatment agent to be adminsitered and for response assessment. Serial (prostate specific antigen) PSA was obatianed for PSA response assessment. <b>Results:</b> Seventy-three men (mean age=69 years, range:45-85) with mCRPC were treated with 210 cycles of ²²⁵Ac-PSMA-617. In 70% of patients, a PSA decline of ≥50% was obtained while 83% of patients had any PSA decline. In 29% of patients, all lesions on ⁶⁸Ga-PSMA-PET resolved in response to treatment. During follow-up, 23 patients experienced disease progression while 13 patients died from their disease. The estimated median progression free survival (PFS) and overall survival (OS) were 15.2 months (95% CI: 13.1 – 17.4) and 18 months (95% CI: 16.2 – 19.9) respectively. On univariate analyses factors such as baseline PSA, any PSA decline, PSA decline ≥50%, prior chemotherapy, prior radiation therapy, baseline hemoglobin level were associated with longer PFS and OS (all p&lt;0.05). On multivariate analyses, only prior Lu-PSMA therapy and a PSA decline ≥50% remained significant in their association with a longer PFS while only PSA decline ≥50% remained significantly associated with OS. Xerostomia was seen in 85% of patients, none was severe enough to warrant discontinuing treatment. Anaemia was seen in 27 patients, no patients with grade IV bone marrow toxicity was seen. Renal failure grade III-IV was seen in five patients with baseline renal impairement. <b>Conclusion:</b> In this study, a PSA decline of &gt; 50% proved significantly associated with OS and PFS in multivariate analysis following treatment with ²²⁵Ac-PSMA-617. Furthermore, previous ¹⁷⁷Lu-PSMA treatment was negatively associated with PFS in both uni- and multivariate analysis.