Setting Of Biochemical Recurrence Research Articles

Role of PET imaging for biochemical recurrence following primary treatment for prostate cancer

Prostate cancer is one of the most common cancers in men worldwide, and primary prostate cancer is typically treated with surgery, radiation, androgen deprivation, or a combination of these therapeutic modalities. Despite technical advances, approximately 30% of men will experience biochemical recurrent within 10 years of definitive treatment. Upon detection of a rise in serum prostate specific antigen (PSA), there is great need to accurately stage these patients to help guide further therapy. As a result, there are considerable efforts underway to establish the role of positron emission tomography (PET) in the diagnostic algorithm of biochemically recurrent prostate cancer. This manuscript provides an overview of PET tracers used for the detection and localization of prostate cancer in the setting of biochemical recurrence with a focus on PET tracers that are currently being used in clinical practice in the United States.

Can free PSA be used as a biomarker in biochemical recurrence after surgery to predict castrate resistant prostate cancer?

177 Background: PSA produced from prostate cancer (PC) cells escapes proteolytic processing, resulting in a more complexed PSA and a lower %fPSA. Higher %fpsa correlates with lower PC risk. However, the role of fPSA in biochemical recurrence (BCR) after radical prostatectomy (RP) is unknown. Methods: All patients who had BCR after RP and at least one fPSA test, were included. Patients were stratified according to the %fPSA cut-off of 0.15. Multivariable logistic regression analysis was performed to predict covariates associated with a higher %fPSA. Results: A total of 81 men with BCR were found (Table 1). Interestingly, 20% (group 1) vs. 60% (groups 2) become castrate resistant (CRPC), p<0.0001 and the time to reach CRPC state was much shorter in group 2 (33.5 months) vs. group 1 (57.9 months), p=0.05. Additionally, 60% of group 2 patients vs. 32.5% of group 1 patients developed metastasis, p=0.014. Lastly, median survival of 193 months for group 2 patients with no median survival for group 1, Log Rank test p=0.023. Multivariable logistic regression analysis demonstrated that secondary Gleason score of 5 (compared to 3) and %fPSA>0.15 predicted CRPC status (OR 11.63, CI 95% 1.38-97.4, p=0.024, OR 7.99, CI 95% 2-31.95, p=0.003, respectively). Conclusions: %fPSA>0.15 in the setting of BCR confers a more aggressive disease, manifesting in a faster development of CRPC, metastasis and death. Our findings suggest a reversal in the significance of % fPSA values in BCR patients, and should be validated in larger cohorts. [Table: see text]

Multiparametric MRI for the detection of local recurrence of prostate cancer in the setting of biochemical recurrence after low dose rate brachytherapy.

Prostate multiparametric magnetic resonance imaging (mpMRI) has utility in detecting post-radiotherapy local recurrence. We conducted a multireader study to evaluate the diagnostic performance of mpMRI for local recurrence after low dose rate (LDR) brachytherapy. A total of 19 patients with biochemical recurrence after LDR brachytherapy underwent 3T endorectal coil mpMRI with T2-weighted imaging, dynamic contrast-enhanced imaging (DCE) and diffusion-weighted imaging (DWI) with pathologic confirmation. Prospective reads by an experienced prostate radiologist were compared with reads from 4 radiologists of varying experience. Readers identified suspicious lesions and rated each MRI detection parameter. MRI-detected lesions were considered true-positive with ipsilateral pathologic confirmation. Inferences for sensitivity, specificity, positive predictive value (PPV), kappa, and index of specific agreement were made with the use of bootstrap resampling. Pathologically confirmed recurrence was found in 15 of 19 patients. True positive recurrences identified by mpMRI were frequently located in the transition zone (46.7%) and seminal vesicles (30%). On patient-based analysis, average sensitivity of mpMRI was 88% (standard error [SE], 3.5%). For highly suspicious lesions, specificity of mpMRI was 75% (SE, 16.5%). On lesion-based analysis, the average PPV was 62% (SE, 6.7%) for all lesions and 78.7% (SE, 10.3%) for highly suspicious lesions. The average PPV for lesions invading the seminal vesicles was 88.8% (n=13). The average PPV was 66.6% (SE, 5.8%) for lesions identified with T2-weighted imaging, 64.9% (SE, 7.3%) for DCE, and 70% (SE, 7.3%) for DWI. This series provides evidence that mpMRI after LDR brachytherapy is feasible with a high patient-based cancer detection rate. Radiologists of varying experience demonstrated moderate agreement in detecting recurrence.

Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy.

The prostate-specific membrane antigen (PSMA) is highly expressed on most prostate cancer (PC) cells. Therefore, the targeting of PSMA has become increasingly important over the last decade. Glu-urea-based PSMA ligands used for both imaging and radioligand therapy are the mainstays of the current success. For PET imaging, both 68Ga- and 18F-labeled agents have been successfully translated to clinical applications. Mainly retrospective cohort studies have shown a high value in the setting of biochemical recurrence, with high detection rates even in the presence of low prostate-specific antigen levels. Preliminary data indicated that radioguided surgery with PSMA ligands may help to further improve patient outcomes because it facilitates the removal of small tumor deposits that are otherwise difficult to detect. For primary PC, PSMA ligand PET imaging has been shown to be superior to cross-sectional imaging for the detection of metastatic lymph nodes. In addition, it promises to also provide intraprostatic tumor localization, especially when used in combination with multiparametric MRI. Increasing numbers of studies have reported considerable changes in management resulting from PSMA ligand PET imaging for both biochemical recurrence and primary disease. The use of 177Lu-PSMA-based radioligand therapy has demonstrated a reasonable response, mainly as defined by a prostate-specific antigen response of more than 50%, comparable to other recently introduced agents. Especially given the high level of safety of 177Lu-PSMA radioligand therapy, with only minimal grade 3 and 4 toxicities reported so far, it has the potential to expand options for metastatic castration-resistant PC. This review is intended to provide a comprehensive overview of the current literature on low-molecular-weight PSMA ligands for both PET imaging and therapeutic approaches, with a focus on agents that have been clinically adopted.

Prostate cancer–specific PET radiotracers: A review on the clinical utility in recurrent disease

Prostate cancer–specific positron emission tomography (pcPET) has been shown to detect sites of disease recurrence at serum prostate-specific antigen (PSA) levels that are lower than those levels detected by conventional imaging. Commonly used pcPET radiotracers in the setting of biochemical recurrence are reviewed including carbon 11/fludeoxyglucose 18 (F-18) choline, gallium 68/F-18 prostate-specific membrane antigen (PSMA), and F-18 fluciclovine. Review of the literature generally favors PSMA-based agents for the detection of recurrence as a function of low PSA levels. Positive gallium 68/F-18 PSMA positron emission tomography/computed tomography scans detected potential sites of recurrence in a median 51.5% of patients when PSA level is <1.0 ng/mL, 74% of patients when PSA level is 1.0 to 2.0 ng/mL, and 90.5% of patients when PSA level is >2.0 ng/mL. Review of carbon 11/fludeoxyglucose 18 (F-18) choline and F-18 fluciclovine data commonly demonstrated lower detection rates for each respective PSA cohort, although with some important caveats, despite having similar operational characteristics to PSMA-based imaging. Sensitive pcPET imaging has provided new insight into the early patterns of disease spread, which has prompted judicious reconsideration of additional local therapy after either prostatectomy, definitive radiation therapy, or postprostatectomy radiation therapy. This review discusses the literature, clinical utility, availability, and fundamental understanding of pcPET imaging needed to improve clinical practice.

HSD3B1 genotype and response to androgen deprivation therapy for biochemical recurrence after radiotherapy for localized prostate cancer.

5050 Background: The enzyme encoded by the HSD3B1(1245C) variant allele has been shown to promote castration-resistant prostate cancer by increasing intratumoral dihydrotestosterone synthesis. In the setting of biochemical recurrence (BCR) following prostatectomy, inheritance of the variant allele has been associated with inferior clinical outcomes for men treated with androgen deprivation therapy (ADT). Whether the same is true in the context of BCR after radiotherapy (RT) is unknown. Methods: We determined HSD3B1 genotype retrospectively in men treated with ADT for post-RT BCR using an established biorepository at a large academic center. We analyzed time-to-progression (TTP), time-to-metastasis (TTM), and overall survival (OS) according to HSD3B1genotype using an additive genetic model with the log-rank trend test. Multivariable analyses (MVA) were performed to adjust for known prognostic factors with Cox regression. Results: We identified 218 men treated with ADT for BCR after RT, of whom 213 (98%) were successfully genotyped (46%, 45% and 9% carrying 0, 1, and 2 variant alleles, respectively). Median follow-up was 7.9 years (yrs). Demographic and treatment factors were similar across genotypes. Median TTP was 2.3 (95% CI: 1.6, 3.1) yrs in men who inherited 0 variant alleles, 2.3 (1.5, 3.3) yrs with 1 variant allele, and 1.4 (0.7, 3.3) yrs with 2 variant alleles (P = 0.683). Median TTM diminished with the number of variant alleles inherited (7.4 [6.7, 9.7], 5.8 [4.9, 6.5] and 4.4 [3.0, 5.7] yrs, respectively (P = 0.030). No difference in OS was detected (P = 0.305). On MVA with 0 variant alleles as the reference, the adjusted hazard ratio (HR) for metastasis was (1.19 [0.74, 1.92]; P = 0.480) for 1 allele and (2.01 [1.02, 3.97]; P = 0.045) for 2 alleles. MVA did not demonstrate significant differences in TTP or OS. Conclusions: The HSD3B1(1245C) allele that enhances dihydrotestosterone synthesis is associated with time-to-metastasis in men treated with ADT for BCR after RT for prostate cancer. Notably, 49% of men had received prior ADT as part of local therapy and 56% received an anti-androgen during ADT for BCR, which may blunt the effect of the variant allele.

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.

MP18-11 EXPLORING THE CLINICAL UPTAKE AND USE OF PSMA PET MRI HYBRID IMAGING IN PROSTATE CANCER PATIENTS AT AN ACADEMIC CENTER IN AUSTRALIA

You have accessJournal of UrologyImaging/Radiology: Uroradiology III1 Apr 2017MP18-11 EXPLORING THE CLINICAL UPTAKE AND USE OF PSMA PET MRI HYBRID IMAGING IN PROSTATE CANCER PATIENTS AT AN ACADEMIC CENTER IN AUSTRALIA Andre Joshi, Cheryl Nicholson, Handoo Rhee, Ian McKenzie, Janelle Munns, Greg Malone, Eric Chung, Malcolm Lawson, Peter Heathcote, John Preston, Simon Wood, Sonja Gustafson, Ken Miles, and Ian Vela Andre JoshiAndre Joshi More articles by this author , Cheryl NicholsonCheryl Nicholson More articles by this author , Handoo RheeHandoo Rhee More articles by this author , Ian McKenzieIan McKenzie More articles by this author , Janelle MunnsJanelle Munns More articles by this author , Greg MaloneGreg Malone More articles by this author , Eric ChungEric Chung More articles by this author , Malcolm LawsonMalcolm Lawson More articles by this author , Peter HeathcotePeter Heathcote More articles by this author , John PrestonJohn Preston More articles by this author , Simon WoodSimon Wood More articles by this author , Sonja GustafsonSonja Gustafson More articles by this author , Ken MilesKen Miles More articles by this author , and Ian VelaIan Vela More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.621AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Positron emission tomography (PET) using prostate specific membrane antigen (PSMA) detects prostate cancer lesions with a higher sensitivity and specificity when compared to standard imaging. Hybrid PET Magnetic Resonance Imaging (MRI) has now been introduced to provide potentially improved characterization of lesions with added PET avidity. We evaluate the utilization of this novel imaging modality at the Princess Alexandra Hospital (PAH) and assess our initial outcomes. METHODS A retrospective review of all PSMA PET MRI scans undertaken at the PAH since the introduction of the technology was performed. Imaging data was collected alongside baseline clinical data, PSA, previous histology, previous treatments, indication of scans, requesting clinicians and clinical outcomes. RESULTS A total of 187 PSMA PET MRI scans were performed at the PAH from April 2015 to October 2016. The median age of imaged patients was 68, with a median PSA of 6ng/ml and Gleason score of 7 at the time of scan. 153 scans were positive for PSMA avid disease (81.8%). Scans were requested in the setting of biochemical recurrence (n=94), preoperative staging (n=77), evaluation of treatment response (n=11) and diagnostic purposes (n=5). Urologists requested PSMA PET MRI most frequently with 111 scans, of which 58.6% requested for preoperative staging. Radiation oncologists requested 69 scans with 75.4% of these in the biochemical recurrence setting. Only 7 scans were requested by medical oncologists. Amongst patients with biochemical recurrence the lowest PSA of a positive scan was 0.02 ng/ml. In this group 43 patients had prior surgery with 19 positive scans (44%). 51 patients were treated with ADT and or EBRT and 46 had positive scans (90.2%). 29 patients had tissue samples to validate PSMA PET MRI. 26 patients (89.7%) had adenocarcinoma on histology correlating with avid lesions on PSMA PET. CONCLUSIONS PSMA PET MRI has had rapid uptake in use since introduction at the PAH. Urologists and radiation oncologists appear to utilize this imaging modality most; Urologists for a preoperative “one stop shop” staging study and radiation oncologists in biochemical recurrence. From this data is also appears that a positive PSMA PET/MRI is highly suggestive of prostate cancer, with a specificity of 89.7%. Hybrid PET/MRI may be used to stage men locally and systemically with one scan, with lower radiation and at PSA ≤1 ng/ml. This modality has the potential to significantly improve prostate cancer staging and allow early identification of recurrent disease. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e224 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Andre Joshi More articles by this author Cheryl Nicholson More articles by this author Handoo Rhee More articles by this author Ian McKenzie More articles by this author Janelle Munns More articles by this author Greg Malone More articles by this author Eric Chung More articles by this author Malcolm Lawson More articles by this author Peter Heathcote More articles by this author John Preston More articles by this author Simon Wood More articles by this author Sonja Gustafson More articles by this author Ken Miles More articles by this author Ian Vela More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

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.

Patterns of Local Failure following Radiation Therapy for Prostate Cancer

Little is known about patterns of local failure following radiation therapy for prostate cancer. We aimed to characterize post-radiation biopsy findings, including the treatment effect and the zonal distribution of recurrent disease after radiation therapy, in men experiencing biochemical recurrence. We identified patients who received post-radiation biopsy in the setting of biochemical recurrence following primary radiation for localized disease. Histological post-radiation biopsy results were categorized by the absence of tumor, demonstration of radiation treatment effect, failure (recurrent cancer) or a combination of treatment effect and failure. We described patterns of histological failure and compared them to the diagnostic biopsy findings. A total of 284 men underwent mapped post-radiation biopsy for biochemical recurrence. Mean age at initial diagnosis was 63 years and median prostate specific antigen was 8.2 ng/ml. Of the men 33%, 32% and 35% were classified at low, intermediate and high risk based on clinical CAPRA (Cancer of the Prostate Risk Assessment) categories. Median time to post-radiation biopsy was 61 months after treatment. Findings were negative in 4% of cases while we noted a treatment effect in 31%, failure in 45% and a combination in 20%. Failure rates were similar across sextants. Of 140 patients with mapped pretreatment and posttreatment biopsies 4% demonstrated cancer in a new location previously identified as negative. Gleason upgrading occurred in 43% of cases with 85% upgraded to 4 + 3 or higher. Men with rising prostate specific antigen after radiotherapy for prostate cancer most often experience recurrence in dominant tumor sites. Whether failure is due to inadequate targeting, dosing or intrinsic radiation resistance remains unknown to our knowledge. Further study is warranted.

Reply to M.R. Smith et al

Smith and Kantoff raise a question regarding the evaluation of changes in prostate-specific antigen (PSA) kinetics in our recent report of a phase I clinical trial of a DNA vaccine encoding prostatic acid phosphatase. They cite previous phase II clinical trials showing changes in PSA doubling time (PSA DT) in patients enrolled onto placebo control arms. They conclude that “post-treatment changes in PSA DT following vaccine treatment do not provide evidence of biologic activity. Additional studies are necessary to assess the relationship between PSA kinetics and clinical outcomes and to evaluate the utility of post-treatment PSA DT or PSA velocity in the development of new drugs.” We agree that the use of changes in PSA DT is not validated as an end point associated with known impact on clinical outcomes. We acknowledged this issue in the article, wherein we stated that “it should be highlighted that the clinical significance of changes in PSA DT from any treatment remains unknown and awaits the results of prospective randomized trials to determine whether changes are associated with changes in radiographic disease progression.” We would further highlight that our study was a phase I trial in which the primary end points were safety and immunologic effect in eliciting prostatic acid phosphatase– specific CD8 T cells. Consequently, our specified measure of biologic effect was an immunologic end point and not a change in PSA kinetics. We believe that our immunologic analyses do provide evidence of biologic activity. However, because PSA is the only measure of disease in the setting of biochemical recurrence of prostate cancer, it is important to collect and report these data, as has been recommended by a consensus panel on this topic. As such, our plan moving forward is to conduct a randomized phase II clinical trial with this DNA vaccine, using time to radiographic progression as the primary clinical end point.

Prostate Specific Antigen Working Group Guidelines on Prostate Specific Antigen Doubling Time

Prostate specific antigen is a glycoprotein found almost exclusively in normal and neoplastic prostate cells. Prostate specific antigen doubling time, or the change in prostate specific antigen over time, has emerged as a useful predictive marker for assessing disease outcome in patients with prostate cancer. It is important to agree on definitions and values for the calculation of prostate specific antigen doubling time, and to develop a common approach to outcome analysis and reporting. In September 2006 a conference was held at the National Cancer Institute in Bethesda, Maryland to define these parameters and develop guidelines for their use. The Prostate Specific Antigen Working Group defined criteria regarding prostate specific antigen doubling time including the calculation of prostate specific antigen doubling time, evidence to support prostate specific antigen doubling time as a predictive factor in the setting of biochemical recurrence and the use of prostate specific antigen doubling time as a stratification factor in clinical trials. We propose that investigators calculate prostate specific antigen doubling time before enrolling patients in clinical studies and calculate it as an additional measurement of therapeutic activity. We believe we have developed practical guidelines for the calculation of prostate specific antigen doubling time and its use as a measurement of prognosis and outcome. Furthermore, the use of common standards for prostate specific antigen doubling time in clinical trials is important as we determine which treatments should progress to randomized trials in which "hard" end points such as survival will be used.