Low PSA Values Research Articles

68-Ga-PSMA-PET in lymph node staging in PSA recurrent prostate cancer-does the primary influence the result?

210 Background: Prostate cancer is the most common cancer in western countries. 68Ga PSMA-PET is the most accurate tool to detect lymph node metastases even at low PSA values. Salvage lymph node dissection prolongs biochemical recurrent free survival, whereas salvage radical prostatectomy has the potential to achieve long term tumor control at least in node negative disease. We compared the diagnostic value of 68Ga-PSMA PET in patients with biochemical recurrence after radical prostatectomy an salvage radiotherapy (Group1) and in patients with local recurrence after radiotherapy (Group2) to evaluate the influence of the primary. Methods: We retrospectively reviewed 57 and 31 patients in Group I and II respectively. In Group I a salvage lymph node dissection was performed on the side of the positive PSMA-staining. In Group II an extended pelvic lymph node dissection was performed in addiction to a salvage radical prostatectomy. Sensitivity, Specificity, posisive and negative predictive value as well as accuracy of PSMA-PET was calculated per lesion. Results: A total of 649 (2-32) and 515 (3-29) lymph nodes had been dissected. In 39 (68%) and 11(35,5%) at least one positive lymph node could be found. Mean diameter of the metastases was 0,81 (0,1-2,6)cm and 0,8(0,1-2) cm respectively. Sensitivity, Specificity, pos and neg. predicitve value as well as accuracy in Group I and two are 85, 96, 77, 98, 94,6 and 40, 100, 100, 98, 97,6%. Conclusions: In salvage surgeries in PCA good diagnostic tools to identify lymph node metastases are mandatory. With the primary in situ there is a significant reduced sensitivity of only 40% to identify positive nodes. The specific role of the primary tumor is not yet known.

104 Low PSA Level In Men Diagnosed With Prostate Cancer Predicts Testosterone Deficiency (TD)

PSA secretion is a testosterone (T) dependent process. There is published data suggesting that low serum total T level is an independent predictor of higher stage, higher grade prostate cancer. However, the link between men diagnosed with prostate cancer with low PSA values and T deficiency (TD) has not been explored before. All men diagnosed with prostate cancer since 2000 that had a record of pre-treatment early morning total T level measurement were included in the analysis. We analyzed demographic, clinical and pathological data. Patients were stratified according to pre-treatment PSA levels: 0-2; 2.1-4; >4 ng/ml. TD was defined as total T < 300 ng/dL. We evaluated the relationship between these PSA groups and TD. Age, diabetes, and hyperlipidemia were also included in both univariate and multivariable analyses. Mean age of 349 men was 64±8 years. The distribution by PSA group was: 5% (0-2), 16% (2.1-4), and 79% (>4). The mean T level across the entire cohort was 358±192 ng/dl. Overall, 38% had a T level < 300 ng/dl; 63% > 300 ng/dl. 9% had diabetes, 10% had hyperlipidemia. The mean T level by PSA group was: 265±168 (0-2); 328±210 (2.1-4); and 371±189 (>4), p=0.03. The percentage of men with TD by PSA group was: 53% (0-2); 49% (2.1-4); and 35% (>4), p=0.05. The percentage of men with extremely low T levels (<200) by PSA group was: 35% (0-2); 22% (2.1-4); and 13% (>4), p=0.01. Age, diabetes, and hyperlipidemia were not related to T level grouping on univariate analyses (p=0.35 to p=0.81). On multivariable analysis, PSA 0-2 compared to PSA >4: OR=2.1, 95% CI: 0.82-5.36, p=0.12; PSA 2.1-4 compared to PSA >4: OR=1.9, 95% CI: 1.02-3.34, p=0.04. PSA 0-2 compared to PSA >4 was not significant due to low sample size.

Innovations in imaging modalities for recurrent and metastatic prostate cancer: a systematic review.

The last decade has witnessed tremendous changes in the management of advanced and metastatic castration resistant prostate cancer. In the current systematic review, we analyze novel imaging techniques in the setting of recurrent and metastatic prostate cancer (PCa), exploring available data and highlighting future exams which could enter clinical practice in the upcoming years. The National Library of Medicine Database was searched for relevant articles published between January 2012 and August 2017. A wide search was performed including the combination of following words: "Prostate" AND "Cancer" AND ("Metastatic" OR "Recurrent") AND "imaging" AND ("MRI" OR "PET"). The selection procedure followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) principles and is presented using a PRISMA flow chart. Novel imaging techniques, as multiparametric magnetic resonance imaging (MRI), whole-body MRI and Choline and prostate-specific membrane antigen (PSMA) PET imaging techniques are currently revolutioning the treatment planning in patients with advanced and metastatic PCa, allowing a better characterization of the disease. Multiparametric MRI performs well in the detection of local recurrences, with sensitivity rates of 67-98% and overall diagnostic accuracy of 83-93%, depending on the type of magnetic field strength (1.5 vs. 3T). Whole body MRI instead shows a high specificity (>95%) for bone metastases. PET imaging, and in particular PSMA PET/CT, showed promising results in the detection of both local and distant recurrences, even for low PSA values (<0.5 ng/mL). Sensitivity varies from 77-98% depending on PSA value and PSA velocity. Whole body-MRI, NaF PET, Choline-PET/CT and PSMA PET/CT are flourishing techniques which find great application in the field of recurrent and metastatic PCa, in the effort to reduce treatment of "PSA only" and rather focus our therapies on clinical tumor entities. Standardization is urgently needed to allow adequate comparison of results and diffusion on a large scale.

68 Ga-PSMA PET/CT for the detection of bone metastases in prostate cancer: a systematic review of the published literature.

68 Ga-labelled prostate-specific membrane antigen (PSMA) is a promising PET ligand for the detection of prostate cancer. Little attention has been given to the ability of 68 Ga-PSMA PET/CT to detect malignant bone lesions and whether this approach is superior to existing bone imaging modalities. To review the existing data of 68 Ga-PSMA PET/CT for the diagnosis of bone metastases in prostate cancer. Systematic review of the peer-reviewed literature. Among 1858 papers in the original search, 37 papers were included in the analysis (six case reports and 31 case series). The vast majority of the studies were low-level evidence studies. Most studies presented data on detection rates without a reference standard. All but two studies were of a retrospective nature. Several cohort studies showed bone metastasis in 5-60% of patients with prostate cancer, including in patients with very low-PSA values. For primary staging, 68 Ga-PSMA PET/CT outperformed bone scans, while the superiority of 68 Ga-PSMA PET/CT compared with bone scans with respect to biochemical recurrence and metastatic castration-resistant prostate cancer (mCRPC) remains to be demonstrated. 68 Ga-PSMA PET/CT has shown to be a promising technique for use in prostate cancer. 68 Ga-PSMA PET/CT shows more lesions than bone scans, but data on diagnostic performance are very limited and indicate improved diagnostic performance in primary staging but not in mCRPC. Properly designed studies are needed to clarify the diagnostic performance of 68 Ga-PSMA PET/CT as well as its superiority over existing methods before 68 Ga-PSMA PET/CT can be routinely used for bone imaging.

Improving the Imaging Contrast of 68Ga-PSMA-11 by Targeted Linker Design: Charged Spacer Moieties Enhance the Pharmacokinetic Properties.

68Ga-Glu-urea-Lys-(Ahx)-HBED-CC (68Ga-PSMA-11) represents a successful radiopharmaceutical for PET/CT imaging of prostate cancer. Further optimization of the tumor-to-background contrast might significantly enhance the sensitivity of PET/CT imaging and the probability of detecting recurrent prostate cancer at low PSA values. This study describes the advantage of histidine (H)/glutamic acid (E) and tryptophan (W)/glutamic acid (E) containing linkers on the pharmacokinetic properties of 68Ga-PSMA-11. The tracers were obtained by a combination of standard Fmoc-based solid-phase synthesis and copper(I)-catalyzed azide-alkyne cycloaddition. Their 68Ga complexes were compared to the clinical reference 68Ga-PSMA-11 with respect to cell binding, effective internalization, and tumor targeting properties in LNCaP-bearing balb/c nu/nu mice. The introduction of (HE)i (i = 1-3) or (WE)i (i = 1-3) into PSMA-11 resulted in a significantly changed biodistribution profile. The uptake values in kidneys, spleen, liver, and other background organs were reduced for (HE)3 while the tumor uptake was not affected. For (HE)1 the tumor uptake was significantly increased. The introduction of tryptophan-containing linkers also modulated the organ distribution profile. The results clearly indicate that histidine is of essential impact in order to improve the tumor-to-organ contrast. Hence, the histidine/glutamic acid linker modifications considerably improved the pharmacokinetic properties of 68Ga-PSMA-11 leading to a reduced uptake in dose limiting organs and a significantly enhanced tumor-to-background contrast. Glu-urea-Lys-(HE)3-HBED-CC represents a promising 68Ga complex ligand for PET/CT-imaging of prostate cancer.

Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models.

Purpose: Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models.Experimental Design: Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups (n = 12-17) based on lesion grade and/or serum PSA level and administered radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology.Results: Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture, leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment, and PSA levels were significantly lower 72 hours after treatment, providing further evidence of the antitumor effects.Conclusions: Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathologic bone formation in tumor microenvironment of osseous CRPC growth in mice. Clin Cancer Res; 23(15); 4335-46. ©2017 AACR.

PET-CT and PET-MRI of the prostate : From 18F-FDG to 68Ga-PSMA

In the last few years nuclear medical diagnostics have experienced aunprecedented renaissance in the diagnostics of prostate cancer, due to the availability of hybrid imaging with positron emission tomography computed tomography (PET/CT), PET magnetic resonance imaging (PET/MRI) and single photon emission computed tomography (SPECT) CT as well as the development of prostate-specific radiopharmaceuticals. The use of fluorodeoxyglucose (FDG), which has been successfully implemented for many years in PET diagnostics, is only helpful in dedifferentiated tumors due to the biological characteristics of prostate cancer. New specific radiopharmaceuticals, such as choline-derivatives, which are incorporated into the prostate cancer cell and built into the cell membrane as well as the recently developed highly specific ligands for prostate-specific membrane antigen (PSMA) are revolutionizing prostate cancer imaging and (re-) staging. The 68 Ga-labeled PSMA ligands for PET-CT and PET-MRI are highly specific tracers for primary diagnostics and detection of metastases of prostate carcinoma. In risk patients, which includes patients with intermediate and high-risk tumors, they have largely replaced choline-based PET-CT, especially in the case of very low PSA values <0.5 ng/ml in the diagnostics of recurrence. The use in the primary diagnostics as PET-MRI, also in combination with multiparametric MRI (mpMRI), is promising with respect to early diagnostics and image fusion-assisted biopsy as well as surgery and irradiation planning.

Significance and Value of PSMA Ligands in Prostate Cancer

In recent years, PSMA-targeting PET tracers such as 68Ga-PSMA-11 have shown promising results, thus contributing to a better management of prostate cancer patients. At the present time, 68Ga-PSMA-11 is most frequently used for diagnostic evaluation in the setting of biochemical recurrence of prostate cancer. In this context, the 68Ga-PSMA-11 PET/CT delivers superior detection rates compared to conventional imaging, especially for the detection of small, unsuspicious lesions or lesions in the presence of low PSA values. Furthermore, 68Ga-PSMA PET imaging seems to be an encouraging alternative for the staging of high-risk patients, particularly in combination with multiparametric MRI. In addition to the increasing use of PSMA ligands in clinical diagnostics, some variants have also been successfully applied in therapy. Advanced metastasized prostate cancer patients showed a good response to PSMA radioligand therapy with tolerable side-effects after failure of guideline-compliant treatment.Due to recent developments, PSMA ligands will continue to play an important role in the management of prostate cancer patients and will be more widely used in the future.

The CHAPPP study: Changing care with PSMA-PET for prostate cancer—A retrospective study of the role of PSMA imaging in altering treatment pathways.

13 Background: The low sensitivity of standard imaging (SI) techniques in detecting metastases (Ms) may lead to unnecessary local treatment for patients (Pts) with newly diagnosed or recurrent prostate cancer (PC). Ga-68-PSMA (Prostate Specific Membrane Antigen)-PET-CT is a novel imaging technique with increased sensitivity in detection of PC especially at low PSA values and may change the decision to pursue primary local or salvage treatment. This study quantified changes in definitive local treatment secondary to occult Ms detected on Ga-68-PSMA not visualized on SI. Methods: A retrospective study was performed of 509 consecutive PSMA scans (and 481 Pts) at our tertiary cancer centre, the Royal Brisbane and Women’s Hospital between Sept 2014 and Dec 2015. PSMA imaging was compared with a CT scan and bone scan to determine whether PSMA results altered the decision to pursue local treatment. Results: 81 (16%) Pts had PSMA-PET-CT scan and no Ms on SI, 40 prior to definitive local treatment and 41 as work up for recurrence. 9/40 Pts (23%) undergoing primary work-up had PSMA-identified Ms not visible on SI and altered these patients treatment pathway (mean PSA 20.5 ng/mL). Because of PSMA-diagnosed Ms, 3 did not receive local treatment. 4 had pelvic nodal involvement and received definitive radiotherapy (RT) including nodal fields. 2 Pts proceeded to radical prostatectomy with the addition of lymph node dissection. 41 Pts investigated for recurrence following local treatment had SI for comparison, (mean PSA 4.7, range 0.11 – 35 ng/mL). 11/41 (27%) were found to have distant or nodal Ms not visualized on SI. 7/11 with prior surgery did not proceed to salvage RT and the remaining Pts who had Ms were referred for an earlier medical oncology opinion. In total 20/81 (25%) of Pts had a direct change in treatment due to the additional information conferred by PSMA imaging. Conclusions: PSMA is more sensitive in the detection of prostate cancer Ms for patients being evaluated for primary treatment or looking for recurrence following local treatment. These results show clinically meaningful changes in management with avoidance of local treatment because of enhanced detection of metastases.

Androgen deprivation with or without radiation therapy for clinically node-positive prostate cancer. Lin CC, Gray PJ, Jemal A, Efstathiou JA, Surveillance and Health Services Research Program, Intramural Research, American Cancer Society, Atlanta, GA (CCL, AJ); Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (PJG, JAE); e-mail: jefstathiou@partners.org. J Natl Cancer Inst. 2015 May 9;107(7). pii: djv119.

BackgroundClinically lymph node-positive (cN+) prostate cancer (PCa) is an often-fatal disease. Its optimal management remains largely undefined given a lack of prospective, randomized data to inform practice. We sought to describe modern practice patterns in the management of cN+PCa and assess the effect of adding radiation therapy (RT) to androgen deprivation therapy (ADT) on survival using the National Cancer Data Base. MethodsPatients with cN+PCa and without distant metastases diagnosed between 2004 and 2011 were included. Five-year overall survival for patients diagnosed between 2004 and 2006 and treated with ADT alone or ADT+RT were compared. Propensity score (PS) matching was used to balance baseline characteristics, and Cox multivariate regression analysis was used to estimate hazard ratios (HRs) for all-cause mortality. ResultsOf 3,540 total patients, 32.2% were treated with ADT alone and 51.4% received ADT+RT. Compared with ADT alone, patients treated with ADT+RT were younger and more likely to have private insurance, lower comorbidity scores, higher Gleason scores, and lower PSA values. After PS matching, 318 patients remained in each group. Compared with ADT alone, ADT+RT was associated with a 50% decreased risk of five-year all-cause mortality (HR = 0.50, 95% CI: 0.37–0.67, two-sided P<0.001; crude OS rate: 71.5% vs. 53.2%). ConclusionsUsing a large national database, we have identified a statistically significant survival benefit for patients with cN+PCa treated with ADT+RT. These data, if appropriately validated by randomized trials, suggest that a substantial proportion of such patients at high risk for prostate cancer death may be undertreated, warranting a reevaluation of current practice guidelines.

Significance of PSMA imaging in prostate cancer

Prostate cancer (PCa) is one of the most common malignancies of men in developed countries. To improve clinical diagnostics of PCa, 68Ga-PSMA-11 was recently introduced as anew PET tracer. 68Ga-PSMA-11 is able to specifically bind to the prostate-specific membrane antigen (PSMA), which is upregulated on the surface of prostate cancer cells in most patients. To analyse the current significance of 68Ga-PSMA-11 PET imaging in prostate cancer in relation to staging of men with initial diagnosis, biochemical recurrence and metastatic disease. Retrospective analysis of current literature (PubMed search) regarding 68Ga-PSMA-11 PET diagnostics in primary staging, in biochemical recurrence and in metastasized disease. Compared to conventional imaging, 68Ga-PSMA-11 PET/CT reaches ahigher sensitivity with an excellent specificity in the clinical diagnosis of primary staging as well as staging for recurrence and advanced, metastasized disease. In biochemical recurrence, 68Ga-PSMA-11 PET/CT shows significantly higher detection rates in comparison to choline PET/CT, especially in patients with low PSA values. In the clinical diagnosis of recurrent disease, therapy concepts were changed in more than aquarter of the patients due to the use of 68Ga-PSMA-11 PET/CT. The significance of staging with 68Ga-PSMA-11 PET/CT in advanced metastasized patients remains uncertain. Due to the excellent results of 68Ga-PSMA-11 PET imaging, even in patients with slightly elevated PSA levels, it will continue to play an important role in clinical diagnostics of prostate cancer and, thus, its clinical utilization will become more widely spread.

Rapidly changing landscape of PET/CT imaging in prostate cancer.

PET/CT imaging in men with prostate cancer (PCa) is rapidly growing as clinicians are becoming aware of its possible fundamental role in the diagnostic flow chart of these patients. As this technology becomes more available worldwide, a considerable number of scientific studies are focusing on specific clinical scenarios and novel PET radiopharmaceuticals that might assist improving early diagnosis and shifting to a truly tailored treatment for PCa. This review focuses on the most recent and important publications in PET/CT imaging of PCa. Choline, radiolabelled with either 11-C or 18-F, is now widely used and has shown good performance in detecting sites of disease compared with conventional imaging, especially in biochemical recurrence. However, its sensitivity and specificity when PSA values are low, and especially below 1.0 ng/ml, is insufficient. More recently, a number of new tracers have been proposed for clinical practice. Among them, 68-Ga Prostate-specific membrane antigen have shown so far the most promising results and is replacing choline PET in centres where it is available. It is particularly useful for detecting PCa relapse at low PSA values but may also be useful for staging of patients with intermediate or high risk prostate cancer. 18-F fluorodeoxyglucose PET/CT remains useful for a limited number of patients with PCa and may provide useful prognostic information. PET/CT is a reliable technique in the diagnostic work-up of patients with PCa, particularly in the setting of biochemical recurrence following previous definitive treatment. The landscape of available radiotracers is changing rapidly and includes fluorodeoxyglucose, sodium fluoride, choline, anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid, and prostate-specific membrane antigen. Of these, prostate-specific membrane antigen PET/CT appears the most likely to represent a new gold standard with evidence of clinical utility emerging in a variety of scenarios, including staging and biochemical recurrence.

Current use of PSMA-PET in prostate cancer management.

Currently, the findings of imaging procedures used for detection or staging of prostate cancer depend on morphology of lymph nodes or bone metabolism and do not always meet diagnostic needs. Prostate-specific membrane antigen (PSMA), a transmembrane protein that has considerable overexpression on most prostate cancer cells, has gained increasing interest as a target molecule for imaging. To date, several small compounds for labelling PSMA have been developed and are currently being investigated as imaging probes for PET with the (68)Ga-labelled PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC being the most widely studied agent. (68)Ga-PSMA-PET imaging in combination with multiparametric MRI (mpMRI) might provide additional molecular information on cancer localization within the prostate. In patients with primary prostate cancer of intermediate-risk to high-risk, PSMA-based imaging has been reported to improve detection of metastatic disease compared with CT or mpMRI, rendering additional cross-sectional imaging or bone scintigraphy unnecessary. Furthermore, in patients with biochemically recurrent prostate cancer, use of (68)Ga-PSMA-PET imaging has been shown to increase detection of metastatic sites, even at low serum PSA values, compared with conventional imaging or PET examination with different tracers. Thus, although current knowledge is still limited and derived mostly from retrospective series, PSMA-based imaging holds great promise to improve prostate cancer management.

(68)Ga-PSMA-11 dynamic PET/CT imaging in biochemical relapse of prostate cancer.

We aim to investigate the pharmacokinetics and distribution of the recently clinically introduced radioligand (68)Ga-PSMA-11 in men with recurrent prostate cancer (PC) by means of dynamic and whole-body PET/CT. The correlation between PSA levels and (68)Ga-PSMA-11 PET parameters is also investigated. 31 patients with biochemical failure after primary PC treatment with curative intent (median age 71.0years) were enrolled in the analysis. The median PSA value was 2.0ng/mL (range = 0.1 - 130.0ng/mL) and the median Gleason score was 7 (range = 5 - 9). 8/31 (25.8%) of the included patients had a PSA value < 0.5ng/ml. All patients underwent dynamic PET/CT (dPET/CT) scanning (60min) of the pelvis and lower abdomen as well as whole-body PET/CT with (68)Ga-PSMA-11. dPET/CT assessment was based on qualitative evaluation, SUV calculation, and quantitative analysis based on a two-tissue compartment model and a non-compartmental approach leading to the extraction of fractal dimension (FD). 22/31 patients (71.0%) were (68)Ga-PSMA-11-positive, while 9/31 (29.0%) patients were (68)Ga-PSMA-11-negative. The median PSA value in the (68)Ga-PSMA-11-positive group was significantly higher (median = 2.35ng/mL; range = 0.19 - 130.0ng/mL) than in the (68)Ga-PSMA-11-negative group (median value: 0.34ng/mL; range = 0.10 - 4.20ng/mL). A total of 76 lesions were semi-quantitatively evaluated. PC recurrence-associated lesions demonstrated a mean SUVaverage = 12.4 (median = 9.0; range = 2.2 - 84.5) and mean SUVmax = 18.8 (median = 14.1; range = 3.1 - 120.3). Dynamic PET/CT studies of the pelvis revealed the following mean values for the PC recurrence-suspicious lesions: K1 = 0.26, k3 = 0.30, influx = 0.14 and FD = 1.24. Time-activity curves derived from PC-recurrence indicative lesions revealed an increasing (68)Ga-PSMA-11 accumulation during dynamic PET acquisition. Correlation analysis revealed a moderate, but significant, correlation between PSA levels and the number of lesions detected on (68)Ga-PSMA-11 PET/CT (r = 0.54) and between PSA levels and SUVaverage (r = 0.48) or SUVmax (r = 0.44). Ga-PSMA-11 PET/CT demonstrated an overall detection rate of 71.0% 60min p.i. of the radiotracer in a mixed patient population with respect to PSA levels and including patients with very low PSA values. Higher PSA values were associated with a higher detection rate. The tracer uptake in PC-recurrence-indicative lesions is increasing during the 60minutes of dynamic PET acquisition.

Abstract A109: Radium-223 dichloride inhibits tumor growth and tumor-induced bone growth in osteoblastic prostate cancer models

Abstract Radium-223 dichloride (radium-223), an alpha particle-emitting calcium-mimetic, improves overall survival in prostate cancer patients with symptomatic bone metastases. We have defined radium-223 mode-of-action and efficacy in two clinically relevant prostate cancer xenograft models demonstrating PSA expression and osteoblastic growth upon intratibial inoculation of cancer cells. Immunocompromised male mice were inoculated with human LNCaP or patient-derived LuCaP 58 prostate cancer cells in the intratibial compartment and subsequently stratified into treatment groups based on lesion grade and/or serum PSA levels. Radium-223 (300 kBq/kg) or vehicle was administered intravenously, two times at 4-week intervals during the experiment. X-rays and serum samples were obtained biweekly and at sacrifice. Soft tissue tumors were examined macroscopically at sacrifice and tissue samples were collected and processed for γ-counter measurements, micro-CT, autoradiography and histology. Radium-223 treatment inhibited tumor-induced osteoblastic bone growth as indicated by reduced bone volume and surface in LNCaP and LuCaP 58 prostate cancer mouse models. In addition, radium-223 treatment suppressed metabolic activity in bone as evidenced by decreased number of osteoblasts and osteoclasts relative to bone surface and reduced levels of the bone formation marker PINP. Radium-223 resulted in lower PSA values as early as two weeks after the first dose, indicating constrained tumor growth following treatment. This phenomenon was further supported by reduced total bone lesion tissue and tumor area in LNCaP and LuCaP 58 models and increased percentage of necrotic tumor area in the LuCaP 58 model in radium-223-treated mice as compared to vehicle-treated mice. Moreover, DNA double-strand breaks were increased in cancer cells 24 hours post radium-223 treatment in the LuCaP 58 model providing further evidence of anti-tumor effects. Radium-223-treated mice exhibited less visceral metastases in the LuCaP 58 model (not significant). Based on autoradiography, radium-223 was deposited in the intratumoral bone matrix and in conjunction with osteoblasts in osteoblastic metastases. Our results demonstrate that radium-223 dichloride is successfully incorporated into the intratumoral bone matrix and inhibits tumor growth in both cell line- and patient-derived osteoblastic prostate cancer metastasis models. Given the α-particle range of 50-80 μm, potent radiation effects on the tumor microenvironment are evident whereas relevant effects on the more distant bone marrow are not expected. Taken together, radium-223 therapy exhibits a dual mode-of-action that impacts tumor growth and tumor-induced bone reaction, both important players in the destructive vicious cycle of osteoblastic bone metastasis in prostate cancer. Citation Format: Mari I. Suominen, Katja M. Fagerlund, Dominik Mumberg, Karl Ziegelbauer, Sanna-Maria Käkönen, Jussi M. Halleen, Robert L. Vessella, Arne Scholz. Radium-223 dichloride inhibits tumor growth and tumor-induced bone growth in osteoblastic prostate cancer models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A109.

Abstract 3447: Radium-223 dichloride exhibits dual mode-of-action inhibiting both tumor and tumor-induced bone growth in two osteoblastic prostate cancer models

Abstract Radium-223 dichloride (radium-223), an alpha particle-emitting calcium-mimetic, improves overall survival in prostate cancer patients with symptomatic bone metastases. Here, we define radium-223 mode-of-action and efficacy in two clinically relevant prostate cancer xenograft models demonstrating PSA expression and osteoblastic growth upon intratibial inoculation of cancer cells. Immunocompromized male mice were inoculated with human LNCaP or patient-derived LuCaP 58 prostate cancer cells in the intratibial compartment and subsequently stratified into treatment groups based on lesion grade and/or serum PSA levels. Radium-223 (300 kBq/kg) or vehicle was administered intravenously, two times at 4-week intervals during the experiment. X-rays and serum samples were obtained biweekly and at sacrifice. Soft tissue tumors were examined macroscopically at sacrifice and tissue samples were collected and processed for γ-counter measurements, micro-CT, autoradiography and histology. Radium-223 treatment inhibited tumor-induced osteoblastic bone growth as indicated by reduced bone volume and surface in LNCaP and LuCaP 58 prostate cancer mouse models. In addition, radium-223 treatment suppressed metabolic activity in bone as evidenced by decreased number of osteoblasts and osteoclasts relative to bone surface and reduced levels of the bone formation marker PINP. Radium-223 resulted in lower PSA values as early as two weeks after the first dose, indicating constrained tumor growth following treatment. This phenomenon was further supported by reduced total tissue and tumor area in tibia in LNCaP and LuCaP 58 models and increased percentage of necrotic tumor area in the LuCaP 58 model in radium-223-treated mice as compared to vehicle-treated mice. Moreover, DNA double-strand breaks were increased in cancer cells 24 hours post radium-223 treatment in the LuCaP 58 model providing further evidence of anti-tumor effects. Radium-223-treated mice exhibited less visceral metastases in the LuCaP 58 model (not significant). Based on autoradiography, radium-223 was deposited in the intratumoral bone matrix and in conjunction with osteoblasts in osteoblastic metastases. We demonstrate that radium-223 dichloride is successfully incorporated into the intratumoral bone matrix and inhibits tumor growth in both cell line- and patient-derived osteoblastic prostate cancer metastasis models. Given the α-particle range of 50-80 μm, potent radiation effects on the tumor microenvironment are evident whereas relevant effects on the more distant bone marrow are not expected. Taken together, radium-223 therapy exhibits a dual mode-of-action that impacts tumor growth and tumor-induced bone reaction, both important players in the destructive vicious cycle of osteoblastic bone metastasis in prostate cancer. Citation Format: Mari I. Suominen, Katja M. Fagerlund, Jukka P. Rissanen, Yvonne Konkol, Jukka Morko, Zhiqi Peng, Esa Alhoniemi, Dominik Mumberg, Karl Ziegelbauer, Sanna-Maria Käkönen, Jussi M. Halleen, Robert L. Vessella, Arne Scholz. Radium-223 dichloride exhibits dual mode-of-action inhibiting both tumor and tumor-induced bone growth in two osteoblastic prostate cancer models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3447. doi:10.1158/1538-7445.AM2015-3447

PET imaging with 68Gallium-labelled ligand of prostate-specific membrane antigen (68Ga-HBED-PSMA) for staging of biochemical recurrent prostate cancer after radical prostatectomy.

5023 Background: Staging of recurrent prostate cancer (PCa) after radical prostatectomy (RP) remains challenging especially at low PSA values. Prostate-specific membrane antigen (PSMA) shows increased expression on most PCa and might therefore be useful for detection of PCa lesions. Aim of this retrospective analysis of consecutive pts was to evaluate the detection rate of PET hybrid imaging using the PSMA inhibitor Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga(HBED-CC)] (68Ga-HBED-PSMA) in pts with biochemical recurrence (BCR) of PCa after RP. Methods: 332 consecutive pts with BCR of PCa after RP and a median PSA value of 1.7 ng/ml (range 0.2-63 ng/ml) were included in this analysis. After injection of 122±17 MBq 68Ga-HBED-PSMA-PET/CT or PET/MR was performed in 256 pts and 76 pts, respectively. One nuclear medicine physician and one radiologist reviewed imaging in consensus. Detection rates according to PSA value were determined. Results: In total, detection rates for 68Ga-HBED-PSMA-PET hybrid imaging were 96.0% (143/1...

Androgen deprivation with or without radiation therapy for clinically node-positive prostate cancer.

198 Background: Clinically lymph node positive (cN+) prostate cancer (PCa) is an often fatal disease. Its optimal management remains largely undefined given a lack of prospective, randomized data to inform practice. We sought to describe modern practice patterns in the management of cN+ PCa and assess the effect of adding radiation therapy (RT) to androgen deprivation therapy (ADT) on survival using the National Cancer Data Base. Methods: Patients with cN+ PCa with no distant metastases diagnosed between 2004-2011 were included. Five-year overall survival for patients diagnosed between 2004-2006 and treated with ADT alone or ADT+RT were compared. Propensity score (PS) matching was used to balance baseline characteristics and Cox multivariate regression analysis was used to estimate hazard ratios (HRs) for all-cause mortality. Results: 3,540 patients were included. 32.2% were treated with ADT alone and 51.4% received ADT+RT. Patients aged &lt;65, those with private insurance, lower comorbidity scores, higher Gleason scores, and lower PSA values were significantly more likely to receive ADT+RT (p&lt;.05). After PS matching, 318 patients remained in each group. Compared to ADT alone, ADT+RT was associated with a 50% decreased risk of five-year mortality (HR: 0.497, 95% CI: 0.37-0.67, p&lt;.001). Conclusions: Using data recorded in a large national database, we have identified a significant survival benefit for patients with cN+ PCa treated with ADT+RT. These data, if appropriately validated, suggest that a significant proportion of such patients at high risk for prostate cancer death may be undertreated warranting a re-evaluation of current practice guidelines.

Prostate-specific membrane antigen-based imaging in prostate cancer: impact on clinical decision making process.

There is an ongoing need for an accurate imaging modality which can be used for staging purposes, metastatic evaluation, predicting biologic aggresiveness and investigating recurrent disease in prostate cancer. Prostate specific membrane antigen, given its favorable molecular characteristics, holds a promise as an ideal target for prostate cancer-specific nuclear imaging. In this study, we evaluated our initial results of PSMA based PET/CT imaging in prostate cancer. A total of 22 patients with a median age and serum PSA level of 68 years and 4.15 ng/ml, respectively underwent Ga-68 PSMA PET/CT in our hospital between Februrary and August 2014. Their charts were retrospectively reviewed in order to document the clinical characteristics, the indications for and the results of PSMA based imaging and the impact of Ga-68 PSMA PET/CT findings on disease management. The most common indications were rising PSA after local ± adjuvant treatment followed by staging and metastatic evaluation before definitive or salvage treatment. All except 2 patients had prostatic ± extraprostatic PSMA positive lesions. For those who had a positive result; treatment strategies were tailored accordingly. Above the PSA level of 2 ng/ml, none of the PSMA based nuclear imaging studies revealed negative results. PSMA based nuclear imaging has significantly impacted our way of handling patients with prostate cancer. Its preliminary performance in different clinical scenarios and ability to detect lesions even in low PSA values seems fairly promising and deserves to be supplemented with further clinical studies.

English

Introduction: To examine the use of prostate magnetic resonance imaging (MRI) for staging after a new diagnosis of prostate cancer in our hospital system. There are no universally accepted recommendations to guide the use of MRI for staging purposes. In practice, prostate MRI is used to help distinguish T2 and T3 cancer. Prostate MRI is a modality that could aid in the triage of patients to radical prostatectomy or non-surgical treatments via accurate identification of organ-confined disease.Materials and Methods: We performed a retrospective review of prostate cancer patients who underwent staging MRI with 1.5T MRI with endorectal (ER) coil. We compared patient characteristics in patients who underwent surgery and those who did not, and used pathology reports from prostatectomy samples to calculate the negative predictive value (NPV) for extra-capsular extension (ECE) and seminal vesicle invasion (SVI).Results: We found that patients who underwent radical prostatectomy were younger, had lower Gleason scores, and had lower PSA values at diagnosis than patients who were not treated surgically. We calculated a NPV of 93.7% for SVI and 69.5% for ECE. We found variation in rates of accurate identification of T3 prostate cancer across the seven radiologists who interpreted MRI images in our study.Conclusions: 1.5T MRI with ER coil has a high NPV for SVI and a lower NPV for ECE. The utilization of 3TMRI may enable practitioners to more confidently rule out ECE. Future studies will be necessary to generate guidelines for use of MRI in prostate cancer staging.