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. ¹⁸F-FDG PET/CT is now routinely used in radiation planning for several cancer types. However, ¹⁸F-FDG PET/CT has low sensitivity for prostate cancer. Additional PET probes evaluated in prostate cancer include ¹⁸F-sodium fluoride, ¹¹C-acetate, ¹¹C- or ¹⁸F-choline, ¹⁸F-fluciclovine, and ⁶⁸Ga- or ¹⁸F-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 ¹⁸F-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.

Rationale

Prostate cancer treatment response may be automatically quantified using a molecular imaging analysis platform targeting prostate-specific membrane antigen (PSMA).

Methods

A retrospective analysis of patients with castration-sensitive prostate cancer who underwent PSMA-targeted molecular imaging prior to and 3 months or more after treatment was conducted. Disease burden was analyzed with aPROMISE, an artificial intelligence imaging platform that automatically quantifies PSMA-positive lesions. The calculated PSMA scores for prostate/bed, nodal, and osseous disease sites were compared with prostate-specific antigen (PSA) values.

Results

Of 30 eligible patients, the median decline in prostate/bed, nodal, and osseous disease PSMA scores were 100% (range 52-100%), 100% (range - 87-100%), and 100% (range - 21-100%), respectively. PSMA score decline was significantly associated with PSA decline.

Conclusion

Changes in aPROMISE PSMA scores are associated with changes in PSA and may quantify treatment response.

Following publication of the original article [1], we have been notified that one of the author names was listed incorrectly.

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.

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 68Ga-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.

The purpose of this randomized trial is to evaluate the success rate of salvage radiation therapy for recurrence of prostate cancer after radical prostatectomy, with and without planning based on prostate-specific membrane antigen positron emission tomography/computed tomography. Enrollment has been completed and patients are being followed for 5yr.

Purpose

To determine the effect of daily shifts based on rigid registration to intraprostatic markers on coverage of boost doses delivered to gross nodal disease for prostate cancer.

Methods and materials

Seventy-five cone beam computed tomographies (CBCTs) from 15 patients treated with definitive radiation for clinically node-positive prostate cancer underwent fiducial-based and pelvic bony-based registration to the initial planning scans. Gross tumor volumes of nodal boost targets were contoured directly on each CBCT registration. The nodal displacement (3-dimensional translation from the node centroid on planning CT to node centroid on registered CBCT) and dose coverage (minimum dose [Dmin], mean dose [Dmean], dose delivered to 95% of the gross tumor volumes [D95]) were calculated for each registration on all nodal targets. All doses for each node were normalized to its intended prescription dose (dose covering 95% of a 3 mm planning target volume [PTV] expansion).

Results

Forty-one gross nodal targets were analyzed. Most boosted nodes (80.5%, 33/41) were treated with conventional fractionation using volumetric-arc radiation therapy, and 19.5% (8/41) underwent stereotactic body radiation therapy (SBRT). Dmin, Dmean, and D95 were all significantly lower with fiducial-based registration compared with bony-based registration (P < .0001). Nodal displacement was significantly higher for fiducial-based registrations (P < .0001). The 3-dimensional translation between the fiducial-based and bony-based registrations (bony-to-fiducial vector) was the most significant predictor of nodal displacement (P < .0001). On fiducial-based registrations, a 3 to 5 mm gross nodal PTV margin is sufficient in most directions; however, superior and posterior margins of 8 to 9 mm are required as a result of asymmetrical prostatic motion.

Conclusions

Large and anisotropic PTV margins are likely needed to adequately dose gross nodal targets when patient setup is based on rigid registration to intraprostatic markers. Alternative approaches such as adaptive replanning may be required to overcome these limitations.

Purpose

The application of automated image analyses could improve and facilitate standardization and consistency of quantification in [¹⁸F]DCFPyL (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.

Pyrrole-imidazole (Py-Im) polyamides are synthetic non-genotoxic minor groove-binding small molecules. We hypothesized that Py-Im polyamides can modulate the cellular response to ionizing radiation. Pre-treatment of cells with a Py-Im polyamide prior to exposure to ionizing radiation resulted in a delay in resolution of phosphorylated γ-H2AX foci, increase in XRCC1 foci, and reduced cellular replication potential. RNA-sequencing of cell lines exposed to the polyamide showed induction of genes related to the ultraviolet radiation response. We observed that the polyamide is almost 10-fold more toxic to a cell line deficient in DNA ligase 3 as compared to the parental cell line. Alkaline single cell gel electrophoresis reveals that the polyamide induces genomic fragmentation in the ligase 3 deficient cell line but not the corresponding parental line. The polyamide interferes directly with DNA ligation in vitro. We conclude that Py-Im polyamides may be further explored as sensitizers to genotoxic therapies.

Background

Definitive radiation therapy (dRT) is an effective initial treatment of intermediate-risk (IR) and high-risk (HR) prostate cancer (PCa). PSMA PET/CT is superior to standard of care imaging (CT, MRI, bone scan) for detecting regional and distant metastatic PCa. PSMA PET/CT thus has the potential to guide patient selection and the planning for dRT and improve patient outcomes.

Methods

This is a multicenter randomized phase 3 trial (NCT04457245). We will randomize 312 patients to proceed with standard dRT (control Arm, n = 150), or undergo a PSMA PET/CT scan at the study site (both 18F-DCFPyL and 68Ga-PSMA-11 can be used) prior to dRT planning (intervention arm, n = 162). dRT will be performed at the treating radiation oncologist facility. In the control arm, dRT will be performed as routinely planned. In the intervention arm, the treating radiation oncologist can incorporate PSMA PET/CT findings into the RT planning. Androgen deprivation therapy (ADT) is administered per discretion of the treating radiation oncologist and may be modified as a result of the PSMA PET/CT results. We assume that approximately 8% of subjects randomized to the PSMA PET arm will be found to have M1 disease and thus will be more appropriate candidates for long-term systemic or multimodal therapy, rather than curative intent dRT. PET M1 patients will thus not be included in the primary endpoint analysis. The primary endpoint is the success rate of patients with unfavorable IR and HR PCa after standard dRT versus PSMA PET-based dRT. Secondary Endpoints (whole cohort) include progression free survival (PFS), metastasis-free survival after initiation of RT, overall survival (OS), % of change in initial treatment intent and Safety.

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 who receive dRT. In this trial the incorporation of PSMA PET/CT may improve the success rate of curative intent radiotherapy in two ways: to optimize patient selection as a biomarker and to personalizes the radiotherapy plan.

Clinical trial registration

UCLA IND#147591 ○ Submission: 02.27.2020 ○ Safe-to-proceed letter issued by FDA: 04.01.2020 UCLA IRB #20-000378 ClinicalTrials.gov Identifier NCT04457245 . Date of Registry: 07.07.2020. Essen EudraCT 2020-003526-23.