Intra-therapeutic dosimetry of [177Lu]Lu-PSMA-617 in low-volume hormone-sensitive metastatic prostate cancer patients and correlation with treatment outcome.

INTRODUCTION: While [177Lu]Lu-PSMA radioligand therapy is currently only applied in end-stage metastatic castrate-resistant prostate cancer (mCRPC) patients, also low-volume hormone-sensitive metastatic prostate cancer (mHSPC) patients can benefit from it. However, there are toxicity concerns related to the sink effect in low-volume disease. This prospective study aims to determine the kinetics of [177Lu]Lu-PSMA in mHSPC patients, analyzing the doses to organs at risk (salivary glands, kidneys, liver, and bone marrow) and tumor lesions < 1 cm diameter. METHODS: Ten mHSPC patients underwent two cycles of [177Lu]Lu-PSMA therapy. Three-bed position SPECT/CT was performed at 5 time points after each therapy. Organ dosimetry and lesion dosimetry were performed using commercial software and a manual approach, respectively. Correlation between absorbed index lesion dose and treatment response (PSA drop of > 50% at the end of the study) was calculated and given as Spearman's r and p-values. RESULTS: Kinetics of [177Lu]Lu-PSMA in mHSPC patients are comparable to those in mCRPC patients. Lesion absorbed dose was high (3.25 ± 3.19 Gy/GBq) compared to organ absorbed dose (salivary glands: 0.39 ± 0.17 Gy/GBq, kidneys: 0.49 ± 0.11 Gy/GBq, liver: 0.09 ± 0.01 Gy/GBq, bone marrow: 0.017 ± 0.008 Gy/GBq). A statistically significant correlation was found between treatment response and absorbed index lesion dose (p = 0.047). CONCLUSIONS: We successfully performed small lesion dosimetry and showed that the tumor sink effect in mHSPC patients is of less concern than was expected. Tumor-to-organ ratio of absorbed dose was high and tumor uptake correlates with PSA response. Additional treatment cycles are legitimate in terms of organ toxicity and could lead to better tumor response.

Preparation of 177Lu-PSMA-617 in Hospital Radiopharmacy: Convenient Formulation of a Clinical Dose Using a Single-Vial Freeze-Dried PSMA-617 Kit Developed In-House.

OBJECTIVE: In the recent time, endoradionuclide therapy for metastatic castration-resistant prostate carcinoma employing 177Lu-PSMA-617 has yielded encouraging results and several clinical trials with the agent are currently ongoing. Routine preparation of 177Lu-PSMA-617 patient doses can be made simpler and convenient, if the ingredients essential for radiolabeling are made available in a ready-to-use lyophilized form. METHODS: PSMA-617 freeze-dried kit was formulated and used for the preparation of 177Lu-PSMA-617 clinical dose with high radiochemical purity using low/medium specific activity 177Lu. Detailed radiochemical studies were performed to determine the maximum activity and volume of 177LuCl3, which can be added in the kit for the formulation of 177Lu-PSMA-617. Studies were also performed to determine the shelf life of the kit to ensure its long-term usage. Studies were performed in buffer as well as human serum medium to determine the stability of the 177Lu-PSMA-617 complex after storing in respective media up to 7 days postpreparation. About ten patient doses of 177Lu-PSMA-617 were administered, and posttherapy scans were acquired. RESULTS: The formulated freeze-dried kit of PSMA-617 could be radiolabeled with an average percentage radiochemical purity > 98.53 ± 0.38. The freeze-dried kit was found suitable for tolerating up to 0.5 mL of 177LuCl3 (in 0.01 N HCl) and specific activity of 555 MBq/µg (15 mCi/µg) for the preparation of the patient dose of 177Lu-PSMA-617. The 177Lu-PSMA-617 complex prepared using the freeze-dried kit of PSMA-617 was observed to maintain % radiochemical purity (RCP) of 96.74 ± 0.87 and 94.81 ± 2.66, respectively, even after storing up to 7 days in buffer and human serum, respectively. 177Lu-PSMA-617 prepared using the in-house formulated freeze-dried kit of PSMA-617 exhibited accumulation in metastatic lesions picked up in a pretherapy PET scan. Reduction in number as well as size of lesions was observed in posttherapy scans acquired after two months of administering the first therapeutic dose of 177Lu-PSMA-617. CONCLUSIONS: The freeze-dried kit of PSMA-617 could be used for the preparation of 177Lu-PSMA-617 with high radiochemical purity (>98%) in a reproducible manner. 177Lu-PSMA-617 prepared using the developed kit was successfully evaluated in patients suffering from metastatic prostate cancer.

Evaluation of 177Lu and 47Sc Picaga-Linked, Prostate-Specific Membrane Antigen-Targeting Constructs for Their Radiotherapeutic Efficacy and Dosimetry.

Lu-177-based, targeted radiotherapeutics/endoradiotherapies are an emerging clinical tool for the management of various cancers. The chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) remains the workhorse for such applications but can limit apparent molar activity or efficient charge modulation, which can impact target binding and, as a consequence, target efficacy. Previously, our lab had developed the small, rare earth selective bifunctional chelator, picaga, as an efficient bifunctional chelator for scandium and lutetium isotopes. Here, we assess the performance of these constructs for therapy in prostate-specific membrane antigen (PSMA)-expressing tumor xenografts. To assess the viability of picaga conjugates in conjunction with long in vivo circulation, a picaga conjugate functionalized with a serum albumin binding moiety, 177Lu-picaga-Alb53-PSMA, was also synthesized. A directly comparative, low, single 3.7 MBq dose treatment study with Lu-PSMA-617 was conducted. Treatment with 177Lu-picaga-Alb53-PSMA resulted in tumor regression and lengthened median survival (54 days) when compared with the vehicle (16 days), 47Sc-picaga-DUPA-, 177Lu-picaga-DUPA-, and 177Lu-PSMA-617-treated cohorts (21, 23, and 21 days, respectively).

Detection Rate of 18F-Fluorethylcholine-PET/CT in relation to PSA Value in PCA Patients Referred with Biochemical Relapse.

Attempts to predict the likelihood of positive morphological imaging related with PSA value in patients referred with biochemical recurrence were the focus of many studies. Using nuclear medicine modalities, numerous studies likewise had been performed for the same purpose, however mostly using C-11-labeled choline. For this purpose, we selected 193 prostate cancer patients from our database between 2006 and 2010. They had been referred to our department to undergo 18F-fluorethylcholine (FECH)-PET/CT due to biochemical recurrence after potentially curative procedures. As a result, in 84 out of 193 patients, 18F-FECH-PET demonstrated positive findings with an overall detection rate of 44%. Statistically, there was a significant difference in PSA values in positive findings vs. negative findings (p < 0.001), and there was a linear correlation between the detection rate and PSA value (r = 0.91). Moreover, there was a relation between initial therapy and recurrence type. So, the local relapse was the most frequent recurrence (>70%) after radiation therapy alone. By contrast, patients after radical prostatectomy followed by salvage radiotherapy showed a low likelihood of local recurrence. In conclusion, PSA value was confirmed to have a determinant role in 18F-FECH-PET outcome. Moreover, there was a link between recurrence type and initial therapy, which-if prospectively confirmed-may play a guiding role in selecting the appropriate diagnostic methods.

Relación de las cinéticas del PSA en la detección de la recurrencia del cáncer de próstata post prostatectomía radical con la 18f-colina tomografía por emisión de positrones/tomografía computada [PET/TC colina (PETC)] / Kinetic Relation Between PSA and 18F-choline PET/ CT in the Detection of Recurrent Prostatic Cancer After Radical Prostatectomy

Resumen Objetivo: El objetivo de este estudio es evaluar la relación de las cinéticas del antígeno prostático específico (PSA por su sigla en inglés) con la positividad de la tomografía por emisión de positrones/tomografía computada [PET/TC colina (PETC)]en pacientes con una recaída de cáncer de próstata (RCP). Materiales y métodos: Se realizó un trabajo retrospectivo de 48 pacientes con RCP post prostatectomía radical (PR) evaluados con PETC. Resultados: La PETC negativa tuvo una mediana de 16,3 meses y la PETC positiva de 5,5 meses (p = < 0,001) para el tiempo de doblaje de PSA (PSADT por su sigla en inglés); la PETC fue positiva en el 96% de los pacientes con un PSADT< 12 meses. La PETC negativa tuvo una mediana de 0,03 ng/ml/año y la PETC positiva de 4,1 ng/ml/año (p = < 0,001) para la velocidad del PSA (PSAVpor su sigla en inglés); la PETC fue positiva en el 92% de los pacientes con un PSAV > 0,75 ng/ml/año. Las áreas bajo la curva ROC para PSAV fue de 0,984 con un punto de corte de mayor discriminación de 0.785 ng/ml/año, mostrando razones de verosimilitud (LR por su sigla en inglés) LR + = 25 y LR- = 0,1. Para PSADT el ROC fue de 0,992 con un punto de corte de mayor discriminación de 11 meses, mostrando LR + = 11 y LR- = 0. Discusión: El PSA es un indicador inespecífico de PETC positiva. Un estudio inicial demostró que los pacientes con una RCP con una PETC positiva tenían un menor PSADT y una mayor PSAV que los pacientes con una PETC negativa. Conclusión: La positividad de la PETC se vio influenciada por las cinéticas del PSA, observándose que a menor PSADT y que a mayor PSAV mayor fue la probabilidad de la positividad de la PETC.

Abstract Purpose: The aim of this study is to evaluate the relationship between Prostate-Specific Antigen (PSA) kinetics and the detection of Prostate Cancer Relapse (PCR) with Positron-Emission Tomography (PETC). Material and methods: A retrospective study of 48 patients with a PCR after a radical prostatectomy evaluated with PETC was performed. Results: PSA Doubling Time (PSADT), with negative PETC, had a median of 16.3 months and the positive PETC a median of 5.5 months (p = < 0.001); 96% of patients with a PSADT <12 months had positive PETC. PSA Velocity (PSAV), negative PETC, had a median of 0.03 ng/ml/year and positive PETC a median of 4.1 ng/ml/year (p = < 0.001); 92% of patients who had a PSAV > 0.75 ng/ml/year had positive PETC. The ROC for PSAV was 0.984 with a cut-off value of 0.785 ng/ml/year, Showing Likelihood Ratios (LR) LR + = 25 and LR- = 0.1. The ROC for PSADT was 0.992 with a cut off value of 11 months, showing LR + = 11 and LR- = 0. Discussion: PSA is a nonspecific indicator of positive PETC. An initial study demon-strated that patients with a PCR and positive PETC had lower PSADT and higher PSAV than patients with a negative PETC. Conclusion: The rate of detection of PCR with PETC was influenced by the kinetics of PSA, and it was observed that the lower the PSADT and the higher the PSAV, the greater the probability of the positivity of the PETC.

Design, Synthesis, Computational, and Preclinical Evaluation of natTi/45Ti-Labeled Urea-Based Glutamate PSMA Ligand.

Despite promising anti-cancer properties in vitro, all titanium-based pharmaceuticals have failed in vivo. Likewise, no target-specific positron emission tomography (PET) tracer based on the radionuclide 45Ti has been developed, notwithstanding its excellent PET imaging properties. In this contribution, we present liquid-liquid extraction (LLE) in flow-based recovery and the purification of 45Ti, computer-aided design, and the synthesis of a salan-natTi/45Ti-chelidamic acid (CA)-prostate-specific membrane antigen (PSMA) ligand containing the Glu-urea-Lys pharmacophore. The compound showed compromised serum stability, however, no visible PET signal from the PC3+ tumor was seen, while the ex vivo biodistribution measured the tumor accumulation at 1.1% ID/g. The in vivo instability was rationalized in terms of competitive citrate binding followed by Fe(III) transchelation. The strategy to improve the in vivo stability by implementing a unimolecular ligand design is presented.

Utilidad de la PET/TC con 18F-fluorocolina en la recidiva bioquímica del cáncer de próstata: relevancia de la cinética del PSA y la terapia hormonal / Usefulness of 18F-fluorocoline PET/CT in prostate cancer patients with biochemical recurrence: Influence of PSA kinetics and hormone therapy

Objetivo: Evaluar la capacidad de la 18F-fluorometilcolina (FCH) tomografía por emisión de positrones/tomografía computarizada (PET/TC) en la detección de la enfermedad en la recidiva bioquímica del cáncer de próstata, su correlación con la cinética del antígeno prostático específico (PSA) y la influencia de la terapia hormonal antiandrogénica. Pacientes y métodos: Estudio observacional y retrospectivo, que incluyó a pacientes con cáncer de próstata y criterios de recidiva bioquímica y/o resistencia a la castración, según la Asociación Europea de Urología. Los resultados de la FCH PET/TC se categorizaron en dos grupos (positivo vs. negativo) utilizando como gold estándar la anatomía patológica, otras pruebas de imagen y/o seguimiento clínico. Se estudió la relación entre la FCH PET/TC y la cinética del PSA (PSA en el momento de la exploración [trigger-PSA], tiempo de duplicación [PSAdt] y velocidad de ascenso [PSAva]) y se analizó la influencia de la terapia hormonal. Resultados: Se incluyeron 203 pacientes. La tasa de detección global de la FCH PET/TC fue del 43,3%. El grupo de pacientes con FCH PET/TC positiva mostró una cinética de PSA más agresiva (PSAdt: 7,5±7,5meses y PSAva 8,37±14,8ng/ml/a) que el grupo FCH PET/TC negativa (PSAdt: 14,5±7,6meses y PSAva: 1,8±3,7ng/ml/a). La tasa de detección de la FCH-PET/TC en el subgrupo con resistencia a la castración fue del 89,1%, significativamente mayor a la tasa del 29,9% del grupo con tratamiento curativo, p <0,001. Conclusiones: La FCH PET/TC es útil en la detección de la enfermedad en la recidiva bioquímica del cáncer de próstata, especialmente en los pacientes con terapia hormonal o cinética del PSA más agresiva

Purpose: To evaluate the capacity of 18f-fluorocholine positron emission tomography/computed tomography (FCH PET/CT) to detect biochemical recurrence of prostate cancer and to determine the correlation with PSA kinetics and influence of antiandrogen hormone therapy. Patients and methods: Observational and retrospective study, which included patients with prostate cancer and criteria for biochemical recurrence and/or resistance to castration, according to the European Association of Urology. FCH PET/CT results were classified as positive or negative, using as gold standard the pathology report, findings of other imaging test, and/or clinical follow-up results. The correlation between FCH PET/CT and PSA kinetics (PSA at the time of exploration [PSA-trigger], doubling time [PSAdt] and velocity [PSAva]) was studied and the influence of hormone therapy was analysed. Results: The study included 203 patients. The FCH PET/CT detection rate was 43.3%. The group of patients with FCH PET/CT positive showed more aggressive PSA kinetics (PSAdt: 7.5 months and PSAva 8.37±14.8ng/ml/a) than the FCH PET/CT negative group (PSAdt: 14.5±7.6 months and PSAva: 1.8±3.7ng/ml/a). The detection rate of FCH PET/CT in the subgroup with castration resistance was 89.1%, significantly higher than in the group with radical treatment at 29.9%, p<.001. Conclusions: FCH PET/CT is useful to detect biochemical recurrence of prostate cancer, especially in patients who receive hormone therapy or more aggressive PSA kinetics

Usefulness of 18F-fluorocoline PET/CT in prostate cancer patients with biochemical recurrence: Influence of PSA kinetics and hormone therapy. / Utilidad de la PET/TC con 18F-fluorocolina en la recidiva bioquímica del cáncer de próstata: relevancia de la cinética del PSA y la terapia hormonal.

PURPOSE: To evaluate the capacity of 18f-fluorocholine positron emission tomography/computed tomography (FCH PET/CT) to detect biochemical recurrence of prostate cancer and to determine the correlation with PSA kinetics and influence of antiandrogen hormone therapy. PATIENTS AND METHODS: Observational and retrospective study, which included patients with prostate cancer and criteria for biochemical recurrence and/or resistance to castration, according to the European Association of Urology. FCH PET/CT results were classified as positive or negative, using as gold standard the pathology report, findings of other imaging test, and/or clinical follow-up results. The correlation between FCH PET/CT and PSA kinetics (PSA at the time of exploration [PSA-trigger], doubling time [PSAdt] and velocity [PSAva]) was studied and the influence of hormone therapy was analysed. RESULTS: The study included 203 patients. The FCH PET/CT detection rate was 43.3%. The group of patients with FCH PET/CT positive showed more aggressive PSA kinetics (PSAdt: 7.5 months and PSAva 8.37±14.8ng/ml/a) than the FCH PET/CT negative group (PSAdt: 14.5±7.6 months and PSAva: 1.8±3.7ng/ml/a). The detection rate of FCH PET/CT in the subgroup with castration resistance was 89.1%, significantly higher than in the group with radical treatment at 29.9%, p<.001. CONCLUSIONS: FCH PET/CT is useful to detect biochemical recurrence of prostate cancer, especially in patients who receive hormone therapy or more aggressive PSA kinetics.

Biodistribution of [(68)Ga]PSMA-HBED-CC in Patients with Prostate Cancer: Characterization of Uptake in Normal Organs and Tumour Lesions.

PURPOSE: The aim of this study was to determine the physiological and pathophysiological biodistribution of [(68)Ga]PSMA-HBED-CC (PSMA-11) ([(68)Ga]PSMA) in patients with prostate cancer (PCA) to establish the range of normal uptake in relevant organs and primary prostate tumours, locally recurrent PCA, lymph and bone metastases and other metastatic lesions. Additionally, we aimed to determine a cut-off uptake value for differentiation of primary tumours from normal prostate tissue. PROCEDURES: Overall, [(68)Ga]PSMA positron emission tomography/x-ray computed tomography (PET/CT) of 101 patients (mean age 69.1 years) with PCA was analysed retrospectively. For assessment of tracer biodistribution, maximum standardized uptake values (SUVmax) were calculated for various normal organs, as well as for primary tumours (PT) and/or metastases. Results are presented as median, interquartile range (IQR; 25th quantil-75th quantil) and range (minimum-maximum). RESULTS: [(68)Ga]PSMA PET/CT was performed 50 min (range 30-126) after injection of 109 MBq (range 84-158). Regarding biodistribution, highest uptake (median/IQR/range) of the tracer was found in the kidneys (49.6/40.7-57.6/2.7-97.0) followed by the submandibular glands (17.3/13.7-21.2/7.5-30.4), parotid glands (16.1/12.2-19.8/5.5-30.9) and duodenum (13.8/10.5-17.2/5.8-26.9). The best cut-off value for differentiating physiological uptake in the primary tumour from that in the prostate was found to be an SUVmax of 3.2. The median SUVmax in the PT (n = 35), locally recurrent PCA (n = 8), lymph node (n = 166), bone (n = 157) and other metastases (n = 3) were 10.2, 5.9, 6.2, 7.4 and 3.8, respectively. The best cut-off values for differentiating non-pathological uptake in lymph nodes and bones from tumour uptake were found to be SUVmax of 3.2 and 1.9, respectively. Patients with PSA <2 had significantly lower SUVmax in bone metastases as compared to patients with PSA ≥2 (p < 0.01). CONCLUSIONS: This biodistribution study provided a broad range of uptake data of [(68)Ga]PSMA-11 for normal organs/tissues, primary prostate tumours and metastatic lesions based on a large patient cohort. Both PT and small metastatic lesions were detectable due to their high tracer uptake. Four-times-higher median uptake in PT in comparison to normal prostate stroma resulted in a high diagnostic accuracy that could potentially be used for multimodal image-guided biopsy with dedicated reconstruction software.

Gallium-68 PSMA uptake in adrenal adenoma.

Gallium-68 (Ga-68) labelled prostate-specific membrane antigen (PSMA) imaging by positron emission tomography (PET) has emerged as a promising tool for staging of prostate cancer and restaging of disease in recurrence or biochemical failure after definitive treatment of prostate cancer. Ga-68 PSMA PET produces high target-to-background images of prostate cancer and its metastases which are reflective of the significant overexpression of PSMA in these cells and greatly facilitates tumour detection. However, relatively little is known about the PSMA expression of benign neoplasms and non-prostate epithelial malignancies. This is a case report of PSMA uptake in an adrenal adenoma incidentally discovered on PET performed for restaging of biochemically suspected prostate cancer recurrence. With the increasing use of PSMA PET in the management of prostate cancer - and the not infrequent occurrence of adrenal adenomas - the appearance of low- to moderate-grade PSMA uptake in adrenal adenomas should be one with which reporting clinicians are familiar.

DNA vaccine coding for the rhesus prostate specific antigen delivered by intradermal electroporation in patients with relapsed prostate cancer.

We tested safety, clinical efficacy and immunogenicity of a DNA vaccine coding for rhesus prostate specific antigen (PSA) delivered by intradermal injection and skin electroporation. Fifteen patients with biochemical relapse of prostate cancer without macroscopic disease participated in this phase I study. Patients were started on a 1 month course of androgen deprivation therapy (ADT) prior to treatment. Vaccine doses ranged from 50 to 1,600 µg. Study subjects received five vaccinations at four week intervals. All patients have had at least one year of follow-up. No systemic toxicity was observed. Discomfort from electroporation did not require analgesia or topical anesthetic. No clinically significant changes in PSA kinetics were observed as all patients required antiandrogen therapy shortly after completion of the 5 months of vaccination due to rising PSA. Immunogenicity, as measured by T-cell reactivity to the modified PSA peptide and to a mix of overlapping PSA peptides representing the full length protein, was observed in some patients. All but one patient had pre-study PSA specific T-cell reactivity. ADT alone resulted in increases in T-cell reactivity in most patients. Intradermal vaccination with skin electroporation is easily performed with only minor discomfort for the patient. Patients with biochemical relapse of prostate cancer are a good model for testing immune therapies.

A critical assessment of post-prostatectomy prostate specific antigen doubling time acceleration--is it stable?

PURPOSE: We examined a retrospective cohort of patients with biochemical recurrence after prostatectomy to determine whether prostate specific antigen doubling time would remain stable with time. We also examined the relationship between other clinical parameters and the change in prostate specific antigen doubling time. MATERIALS AND METHODS: We retrospectively reviewed the prostate cancer database from 1989 to 2008 to identify patients treated with radical prostatectomy for prostate cancer who experienced prostate specific antigen recurrence. Of the 2,237 patients identified 329 had biochemical recurrence. Prostate specific antigen doubling time was calculated at each visit and linear regression of prostate specific antigen doubling time with time was fit. Rate of change in prostate specific antigen doubling time was defined as the slope of the least squares regression line. RESULTS: Median followup was 5 years (range 0.2 to 18). High Gleason score and local recurrence within 5 years were significantly associated with shorter 2-year prostate specific antigen doubling time and a decreased rate of change in doubling time (p = 0.0096, 0.0119, 0.0195 and 0.0258, respectively). Metastasis within 5 years was significantly associated with shorter 2 and 5-year doubling time (p = 0.0006 and 0.0014, respectively). Using all prostate specific antigen values within 5 years of initial biochemical recurrence yielded an overall median prostate specific antigen doubling time of 52.8 months (range 5.4 to 100.0). The median rate of change in doubling time was -1.05 (range -64.7 to 27.0). Median time to metastasis after biochemical recurrence was 12.9 years. CONCLUSIONS: Median prostate specific antigen doubling time decreases with time. This may influence the decision to offer secondary therapy to patients with biochemical recurrence sooner since initial prostate specific antigen doubling time is long and may not accurately reflect the biological nature of the disease.

Enzymatic triggered release of an HIV-1 entry inhibitor from prostate specific antigen degradable microparticles.

This paper describes the design, construction and characterization of the first anti-HIV drug delivery system that is triggered to release its contents in the presence of human semen. Microgel particles were synthesized with a crosslinker containing a peptide substrate for the seminal serine protease prostate specific antigen (PSA) and were loaded with the HIV-1 entry inhibitor sodium poly(styrene-4-sulfonate) (pSS). The particles were composed of N-2-hydroxyproplymethacrylamide and bis-methacrylamide functionalized peptides based on the PSA substrates GISSFYSSK and GISSQYSSK. Exposure to human seminal plasma (HSP) degraded the microgel network and triggered the release of the entrapped antiviral polymer. Particles with the crosslinker composed of the substrate GISSFYSSK showed 17 times faster degradation in seminal plasma than that of the crosslinker composed of GISSQYSSK. The microgel particles containing 1 mol% GISSFYSSK peptide crosslinker showed complete degradation in 30 h in the presence of HSP at 37°C and pSS released from the microgels within 30 min reached a concentration of 10 µg/mL, equivalent to the published IC(90) for pSS. The released pSS inactivated HIV-1 in the presence of HSP. The solid phase synthesis of the crosslinkers, preparation of the particles by inverse microemulsion polymerization, HSP-triggered release of pSS and inactivation of HIV-1 studies are described.

Prostate-specific antigen kinetics following external-beam radiotherapy and temporary (Ir-192) or permanent (I-125) brachytherapy for prostate cancer.

BACKGROUND AND PURPOSE: The aim of the study was the evaluation of PSA kinetics after different radiotherapy methods. MATERIALS AND METHODS: Two-hundred and ninety five patients received external-beam radiotherapy (EBRT; 70.2 Gy; n=135), Ir-192 brachytherapy as a boost to EBRT (HDR-BT; 18 Gy+50.4 Gy; n=66) or I-125 brachytherapy (LDR-BT; 145 Gy; n=94) as monotherapy. "PSA bounce" was defined as a PSA rise of > or = 0.2 ng/ml followed by spontaneous return to prebounce level or lower, biochemical failure as "nadir+2 ng/ml". RESULTS: Patients without biochemical failure reached a lower nadir after brachytherapy (median < or = 0.05 ng/ml after LDR- and HDR-BT without NHT) in comparison to EBRT (0.55 ng/ml without NHT; p<0.01). Not a single patient without NHT and a nadir <0.1 ng/ml failed biochemically (0% vs. 45% with a nadir > or = 0.1 ng/ml; p<0.01). PSA bounces were found predominantly in the LDR-BT group (42% vs. 23%/20% after HDR-BT/EBRT; p<0.01). In a multivariate Cox regression analysis, LDR-BT and HDR-BT were associated with a significantly lower biochemical failure rate in comparison to EBRT. CONCLUSIONS: PSA kinetics differ significantly following different radiotherapy methods. A lower nadir and a higher biochemical control rate suggest a higher radiobiological efficiency of brachytherapy in comparison to EBRT (with a dose of 70.2 Gy).

Prostate-specific antigen kinetics in clinical decision-making during active surveillance for early prostate cancer--a review.

CONTEXT: The kinetics of prostate specific antigen (PSA) are generally assumed to be indicative of tumour progression and are therefore used in clinical decision-making in men on active surveillance for early prostate cancer. OBJECTIVE: This review aims to provide support for exploiting PSA kinetics in an active surveillance setting. EVIDENCE ACQUISITION: We searched the Medline database and reviewed the evidence on both the relation between PSA kinetics before radical treatment for prostate cancer and outcome, as well as the role of PSA kinetics during active surveillance. Furthermore, the benefits and setbacks of different derivatives of PSA kinetics, minimum required time interval and number of measurements, practical recommendations, and pitfalls of their use in clinical practice are discussed. EVIDENCE SYNTHESIS: The evidence concerning the prognostic value of the PSA velocity (PSA-V) and PSA doubling time (PSA-DT) is sparse, especially in active surveillance. PSA kinetics should therefore be combined with other diagnostic measures as the trigger for deferred radical treatment or repeat prostate biopsies. There seems to be consensus among several reports on the unfavourable outcome relating to a PSA-DT <3-4 yr and on the favourable prognostic value of a PSA-DT >10 yr or a decreasing PSA level. Online tools provide help with calculations and insight on disease development. The best method of calculation, number of measurements, and time interval between measurements is unknown for now. CONCLUSIONS: Despite the current deficits in our understanding of the natural behaviour of early prostate cancer and its relation to serum PSA levels, and despite several secondary factors playing a role in PSA kinetics, PSA kinetics are a practical parameter we can offer men on active surveillance to assess the status of their disease.

Time to prostate-specific antigen nadir after androgen suppression therapy for postoperative or postradiation PSA failure and risk of prostate cancer-specific mortality.

OBJECTIVES: To examine whether the time to the prostate-specific antigen (PSA) nadir was associated with prostate cancer-specific mortality (PCSM) in men with PSA failure after radical prostatectomy or radiotherapy who do not achieve an undetectable PSA level (PSA level of 0.2 ng/mL or less) after 8 months of androgen suppression therapy (AST). METHODS: The cohort included 162 men with localized prostate cancer treated with AST for an increasing PSA level after radical prostatectomy or radiotherapy. Gray's analysis was used to evaluate for an association between the time to PSA nadir after 8 months of AST and the time to PCSM, adjusting for established prognostic factors. The median age and follow-up after 8 months of AST was 71.2 and 1.8 years, respectively. RESULTS: After adjusting for Gleason score, pre-AST PSA doubling time, PSA at AST, PSA nadir value, time to PSA failure, initial treatment, and age, the time to PSA nadir was significantly associated with PCSM (adjusted hazard ratio 2.53, 95% confidence interval 1.24 to 5.14, P = 0.01). Men with a PSA nadir greater than the median value of 0.9 ng/mL and the time to PSA nadir longer than the median of 4 months had significantly greater PCSM estimates (P <0.001) compared with men with a PSA nadir of 0.9 ng/mL or less. CONCLUSIONS: The time to PSA nadir, combined with the PSA nadir level, can be used to identify men who are at high risk of PCSM after a short course of AST for entry onto clinical trials using novel systemic agents with AST.

The top 13: what family physicians should know about prostate cancer.

OBJECTIVE: This article identifies 13 key factors of which family physicians should be aware in the ongoing care of men with prostate cancer. QUALITY OF EVIDENCE: PubMed was searched with the relevant search terms for each of the 13 topics discussed. Most of the studies described in this article provide level II or level III evidence. MAIN MESSAGE: Family physicians are increasingly involved in the care of men with prostate cancer. The 13 clinical pearls presented in this article will enhance family physicians' ability to care for these patients along the disease trajectory. CONCLUSION: Men with prostate cancer face unique challenges as they deal with their disease and its treatment. Family physicians can make a substantial contribution to improving the quality of life of their prostate cancer patients by applying the information in this paper.

Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer.

PURPOSE: To determine the maximum tolerated dose (MTD), toxicity, human anti-J591 response, pharmacokinetics (PK), organ dosimetry, targeting, and biologic activity of (177)Lutetium-labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 ((177)Lu-J591) in patients with androgen-independent prostate cancer (PC). PATIENTS AND METHODS: Thirty-five patients with progressing androgen-independent PC received (177)Lu-J591. All patients underwent (177)Lu-J591 imaging, PK, and biodistribution determinations. Patients were eligible for up to three retreatments. RESULTS: Thirty-five patients received (177)Lu-J591, of whom 16 received up to three doses. Myelosuppression was dose limiting at 75 mCi/m(2), and the 70-mCi/m(2) dose level was determined to be the single-dose MTD. Repeat dosing at 45 to 60 mCi/m(2) was associated with dose-limiting myelosuppression; however, up to three doses of 30 mCi/m(2) could be safely administered. Nonhematologic toxicity was not dose limiting. Targeting of all known sites of bone and soft tissue metastases was seen in all 30 patients with positive bone, computed tomography, or magnetic resonance images. No patient developed a human anti-J591 antibody response to deimmunized J591 regardless of number of doses. Biologic activity was seen with four patients experiencing >or= 50% declines in prostate-specific antigen (PSA) levels lasting from 3+ to 8 months. An additional 16 patients (46%) experienced PSA stabilization for a median of 60 days (range, 1 to 21+ months). CONCLUSION: The MTD of (177)Lu-J591 is 70 mCi/m(2). Multiple doses of 30 mCi/m(2) are well tolerated. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation.