Background Salvage radiotherapy (SRT) for prostate cancer (PCa) recurrence after prostatectomy offers long-term biochemical control in about 50–60% of patients. SRT is commonly initiated in patients ...with serum PSA levels < 1 ng/mL, a threshold at which standard-of-care imaging is insensitive for detecting recurrence. As such, SRT target volumes are usually drawn in the absence of radiographically visible disease. 68Ga-PSMA-11 (PSMA) PET/CT molecular imaging is highly sensitive and may offer anatomic localization of PCa biochemical recurrence. However, it is unclear if incorporation of PSMA PET/CT imaging into the planning of SRT could improve its likelihood of success. The purpose of this trial is to evaluate the success rate of SRT for recurrence of PCa after prostatectomy with and without planning based on PSMA PET/CT. Methods We will randomize 193 patients to proceed with standard SRT (control arm 1, n = 90) or undergo a PSMA PET/CT scan (free of charge for patients) prior to SRT planning (investigational arm 2, n = 103). The primary endpoint is the success rate of SRT measured as biochemical progression-free survival (BPFS) after initiation of SRT. Biochemical progression is defined by PSA ≥ 0.2 ng/mL and rising. The randomization ratio of 1:1.13 is based on the assumption that approximately 13% of subjects randomized to Arm 2 will not be treated with SRT because of PSMA-positive extra-pelvic metastases. These patients will not be included in the primary endpoint analysis but will still be followed. The choice of treating the prostate bed alone vs prostate bed and pelvic lymph nodes, with or without androgen deprivation therapy (ADT), is selected by the treating radiation oncologist. The radiation oncologist may change the radiation plan depending on the findings of the PSMA PET/CT scan. Any other imaging is allowed for SRT planning in both arms if done per routine care. Patients will be followed until either one of the following conditions occur: 5 years after the date of initiation of randomization, biochemical progression, diagnosis of metastatic disease, initiation of any additional salvage therapy, death. Discussion This is the first randomized phase 3 prospective trial designed to determine whether PSMA PET/CT molecular imaging can improve outcomes in patients with PCa early BCR following radical prostatectomy. Acronym PSMA-SRT Phase 3 trial. Clinical trial registration * ■ IND#130649 * ◦ Submission: 04.26.2016 * ◦ Safe-to-proceed letter issued by FDA: 05.25.2016 * ■ UCLA IRB #18–000484, * ■ First submission: 3.27.2018 * ■ Date of approval: 5.31.2018 * ■ UCLA JCCC Short Title NUC MED 18–000484 * ■ NCI Trial Identifier NCI-2018-01518 * ■ ClinicalTrials.gov Identifier NCT03582774 * ■ First Submitted: 06.19.2018 * ■ First Submitted that Met QC Criteria: 06.27.2018 * ■ First Posted: 07.11.2018 * ■ Last Update Submitted that Met QC Criteria: 07.17.2018 * ■ Last Update Posted: 07.19.2018 Trial status Current Trial Status Active as of 08/13/2018 Trial Start Date 09/01/2018-Actual Primary Completion Date 09/01/2023-Anticipated Trial Completion Date 09/01/2024-Anticipated
Management of locally recurrent prostate cancer after definitive radiotherapy remains controversial due to the perceived high rates of severe genitourinary (GU) and gastrointestinal (GI) toxicity ...associated with any local salvage modality.
To quantitatively compare the efficacy and toxicity of salvage radical prostatectomy (RP), high-intensity focused ultrasound (HIFU), cryotherapy, stereotactic body radiotherapy (SBRT), low–dose-rate (LDR) brachytherapy, and high-dose-rate (HDR) brachytherapy.
We performed a systematic review of PubMed, EMBASE, and MEDLINE. Two- and 5-yr recurrence-free survival (RFS) rates and crude incidences of severe GU and GI toxicity were extracted as endpoints of interest. Random-effect meta-analyses were conducted to characterize summary effect sizes and quantify heterogeneity. Estimates for each modality were then compared with RP after adjusting for individual study-level covariates using mixed-effect regression models, while allowing for differences in between-study variance across treatment modalities.
A total of 150 studies were included for analysis. There was significant heterogeneity between studies within each modality, and covariates differed between modalities, necessitating adjustment. Adjusted 5-yr RFS ranged from 50% after cryotherapy to 60% after HDR brachytherapy and SBRT, with no significant differences between any modality and RP. Severe GU toxicity was significantly lower with all three forms of radiotherapeutic salvage than with RP (adjusted rates of 20% after RP vs 5.6%, 9.6%, and 9.1% after SBRT, HDR brachytherapy, and LDR brachytherapy, respectively; p ≤ 0.001 for all). Severe GI toxicity was significantly lower with HDR salvage than with RP (adjusted rates 1.8% vs 0.0%, p < 0.01), with no other differences identified.
Large differences in 5-yr outcomes were not uncovered when comparing all salvage treatment modalities against RP. Reirradiation with SBRT, HDR brachytherapy, or LDR brachytherapy appears to result in less severe GU toxicity than RP, and reirradiation with HDR brachytherapy yields less severe GI toxicity than RP. Prospective studies of local salvage for radiorecurrent disease are warranted.
In a large study-level meta-analysis, we looked at treatment outcomes and toxicity for men treated with a number of salvage treatments for radiorecurrent prostate cancer. We conclude that relapse-free survival at 5 years is equivalent among salvage modalities, but reirradiation may lead to lower toxicity.
This meta-analysis provides pooled estimates of surgical and nonsurgical local salvage treatments for radiorecurrent prostate cancer. Five-year recurrence-free survival (RFS) was similar across modalities on meta-regression, although differences in severe genitourinary and gastrointestinal toxicity appear to favor reirradiation, particularly high-dose-rate brachytherapy. Pretreatment prostate-specific antigen emerged as a powerful predictor of 5-yr RFS. Additional prospective and randomized data are required to better define how to optimally select and treat patients with isolated local failures after definitive radiotherapy.
Radiotherapy and radical prostatectomy are the definitive treatment options for patients with localized prostate cancer. A rising level of prostate-specific antigen after radical prostatectomy ...indicates prostate cancer recurrence, and these patients may still be cured with salvage radiotherapy. To maximize chance for cure, the irradiated volumes should completely encompass the extent of disease. Therefore, accurate estimation of the location of disease is critical for radiotherapy planning in both the definitive and the salvage settings. Current first-line imaging for prostate cancer has limited sensitivity for detection of disease both at initial staging and at biochemical recurrence. Integration of PET into routine evaluation of prostate cancer patients may improve both staging accuracy and radiotherapy planning.
F-FDG PET/CT is now routinely used in radiation planning for several cancer types. However,
F-FDG PET/CT has low sensitivity for prostate cancer. Additional PET probes evaluated in prostate cancer include
F-sodium fluoride,
C-acetate,
C- or
F-choline,
F-fluciclovine, and
Ga- or
F-labeled ligands that bind prostate-specific membrane antigen (PSMA). PSMA ligands appear to be the most sensitive and specific but have not yet received Food and Drug Administration New Drug Application approval for use in the United States. Retrospective and prospective investigations suggest a potential major impact of PET/CT on prostate radiation treatment planning. Prospective trials randomizing patients to routine radiotherapy planning versus PET/CT-aided planning may show meaningful clinical outcomes. Prospective clinical trials evaluating the addition of
F-fluciclovine PET/CT for planning of salvage radiotherapy with clinical endpoints are under way. Prospective trials evaluating the clinical impact of PSMA PET/CT on prostate radiation planning are indicated.
Randomised trials have investigated various androgen deprivation therapy (ADT) intensification strategies in men receiving radiotherapy for the treatment of prostate cancer. This individual patient ...data meta-analysis of relevant randomised trials aimed to quantify the benefit of these interventions in aggregate and in clinically relevant subgroups.
For this meta-analysis, we performed a systematic literature search in MEDLINE, Embase, trial registries, the Web of Science, Scopus, and conference proceedings to identify trials with results published in English between Jan 1, 1962, and Dec 30, 2020. Multicentre randomised trials were eligible if they evaluated the use or prolongation of ADT (or both) in men with localised prostate cancer receiving definitive radiotherapy, reported or collected distant metastasis and survival data, and used ADT for a protocol-defined finite duration. The Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium was accessed to obtain individual patient data from randomised trials. The primary outcome was metastasis-free survival. Hazard ratios (HRs) were obtained through stratified Cox models for ADT use (radiotherapy alone vs radiotherapy plus ADT), neoadjuvant ADT extension (ie, extension of total ADT duration in the neoadjuvant setting from 3–4 months to 6–9 months), and adjuvant ADT prolongation (ie, prolongation of total ADT duration in the adjuvant setting from 4–6 months to 18–36 months). Formal interaction tests between interventions and metastasis-free survival were done for prespecified subgroups defined by age, National Comprehensive Cancer Network (NCCN) risk group, and radiotherapy dose. This meta-analysis is registered with PROSPERO, CRD42021236855.
Our search returned 12 eligible trials that provided individual patient data (10 853 patients) with a median follow-up of 11·4 years (IQR 9·0–15·0). The addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0·83 95% CI 0·77–0·89, p<0·0001), as did adjuvant ADT prolongation (0·84 0·78–0·91, p<0·0001), but neoadjuvant ADT extension did not (0·95 0·83–1·09, p=0·50). Treatment effects were similar irrespective of radiotherapy dose, patient age, or NCCN risk group.
Our findings provide the strongest level of evidence so far to the magnitude of the benefit of ADT treatment intensification with radiotherapy for men with localised prostate cancer. Adding ADT and prolonging the portion of ADT that follows radiotherapy is associated with improved metastasis-free survival in men, regardless of risk group, age, and radiotherapy dose delivered; however, the magnitude of the benefit could vary and shared decision making with patients is recommended.
University Hospitals Seidman Cancer Center, Prostate Cancer Foundation, and the American Society for Radiation Oncology.
Purpose
The application of automated image analyses could improve and facilitate standardization and consistency of quantification in
18
FDCFPyL (PSMA) PET/CT scans. In the current study, we ...analytically validated aPROMISE, a software as a medical device that segments organs in low-dose CT images with deep learning, and subsequently detects and quantifies potential pathological lesions in PSMA PET/CT.
Methods
To evaluate the deep learning algorithm, the automated segmentations of the low-dose CT component of PSMA PET/CT scans from 20 patients were compared to manual segmentations. Dice scores were used to quantify the similarities between the automated and manual segmentations. Next, the automated quantification of tracer uptake in the reference organs and detection and pre-segmentation of potential lesions were evaluated in 339 patients with prostate cancer, who were all enrolled in the phase II/III OSPREY study. Three nuclear medicine physicians performed the retrospective independent reads of OSPREY images with aPROMISE. Quantitative consistency was assessed by the pairwise Pearson correlations and standard deviation between the readers and aPROMISE. The sensitivity of detection and pre-segmentation of potential lesions was evaluated by determining the percent of manually selected abnormal lesions that were automatically detected by aPROMISE.
Results
The Dice scores for bone segmentations ranged from 0.88 to 0.95. The Dice scores of the PSMA PET/CT reference organs, thoracic aorta and liver, were 0.89 and 0.97, respectively. Dice scores of other visceral organs, including prostate, were observed to be above 0.79. The Pearson correlation for blood pool reference was higher between any manual reader and aPROMISE, than between any pair of manual readers. The standard deviations of reference organ uptake across all patients as determined by aPROMISE (SD = 0.21 blood pool and SD = 1.16 liver) were lower compared to those of the manual readers. Finally, the sensitivity of aPROMISE detection and pre-segmentation was 91.5% for regional lymph nodes, 90.6% for all lymph nodes, and 86.7% for bone in metastatic patients.
Conclusion
In this analytical study, we demonstrated the segmentation accuracy of the deep learning algorithm, the consistency in quantitative assessment across multiple readers, and the high sensitivity in detecting potential lesions. The study provides a foundational framework for clinical evaluation of aPROMISE in standardized reporting of PSMA PET/CT.
The LREX' prostate cancer model is resistant to the antiandrogen enzalutamide via activation of an alternative nuclear hormone receptor, glucocorticoid receptor (GR), which has similar DNA-binding ...specificity to the androgen receptor (AR). Small molecules that target DNA to interfere with protein-DNA interactions may retain activity against enzalutamide-resistant prostate cancers where ligand-binding domain antagonists are ineffective. We reported previously that a pyrrole-imidazole (Py-Im) polyamide designed to bind the consensus androgen response element half-site has antitumor activity against hormone-sensitive prostate cancer. In enzalutamide-resistant LREX' cells, Py-Im polyamide interfered with both AR- and GR-driven gene expression, whereas enzalutamide interfered with only that of AR. Genomic analyses indicated immediate interference with the AR transcriptional pathway. Long-term treatment with Py-Im polyamide demonstrated a global decrease in RNA levels consistent with inhibition of transcription. The polyamide was active against two enzalutamide-resistant xenografts with minimal toxicity. Overall, our results identify Py-Im polyamide as a promising therapeutic strategy in enzalutamide-resistant prostate cancer.
.
We provide the strongest evidence to date that local failure is an independent prognosticator of outcomes in high- and intermediate-risk prostate cancer patients treated with definitive radiation ...therapy. Distant metastasis predominantly develops from a clinical relapse-free state; however, a second wave of distant metastasis occurs subsequent to local failure, albeit less commonly.
The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear.
To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT.
A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states.
The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio HR 1.17, 95% confidence interval CI 1.06–1.30), PCSS (HR 2.02, 95% CI 1.75–2.33), and DMFS (HR 1.94, 95% CI 1.75–2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36–1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21–0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups.
Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a “second wave” of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis.
Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.
Androgen receptor (AR) is essential for the growth and progression of prostate cancer in both hormone-sensitive and hormone-refractory disease. A DNA-binding polyamide that targets the consensus ...androgen response element binds the prostate-specific antigen (PSA) promoter androgen response element, inhibits androgen-induced expression of PSA and several other AR-regulated genes in cultured prostate cancer cells, and reduces AR occupancy at the PSA promoter and enhancer. Down-regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide (Casodex) at the same concentration. Genome-wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide. Direct inhibition of the AR-DNA interface by sequence-specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity.
Abstract
Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) is a molecular and functional imaging modality with better restaging accuracy over ...conventional imaging for detecting prostate cancer in men suspected of lymph node (LN) progression after definitive therapy. However, the availability of PSMA PET/CT is limited in both low-resource settings and for repeating imaging surveillance. In contrast, CT is widely available, cost-effective, and routinely performed as part of patient follow-up or radiotherapy workflow. Compared with the molecular activities, the morphological and texture changes of subclinical LNs in CT are subtle, making manual detection of positive LNs infeasible. Instead, we harness the power of artificial intelligence for automated LN detection on CT. We examined
68
Ga-PSMA-11 PET/CT images from 88 patients (including 739 PSMA PET/CT-positive pelvic LNs) who experienced a biochemical recurrence after radical prostatectomy and presented for salvage radiotherapy with prostate-specific antigen < 1 ng/mL. Scans were divided into a training set (nPatient = 52, nNode = 400), a validation set (nPatient = 18, nNode = 143), and a test set (nPatient = 18, nNodes = 196). Using PSMA PET/CT as the ground truth and consensus pelvic LN clinical target volumes as search regions, a 2.5-dimensional (2.5D) Mask R-CNN based object detection framework was trained. The entire framework contained whole slice imaging pretraining, masked-out region fine-tuning, prediction post-processing, and “window bagging”. Following an additional preprocessing step—pelvic LN clinical target volume extraction, our pipeline located positive pelvic LNs solely based on CT scans. Our pipeline could achieve a sensitivity of 83.351%, specificity of 58.621% out of 196 positive pelvic LNs from 18 patients in the test set, of which most of the false positives can be post-removable by radiologists. Our tool may aid CT-based detection of pelvic LN metastasis and triage patients most unlikely to benefit from the PSMA PET/CT scan.
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