Visual Abstract
Keywords: PSMA PET/CT, biochemical recurrence, delayed pelvic imaging, diagnostic certainty
Abstract
The detection of biochemical recurrence (BCR) of prostate cancer remains challenging, as small-volume disease may fall below the sensitivity of standard imaging. Prostate-specific membrane antigen (PSMA) PET/CT is currently the most sensitive imaging modality for tumor detection at low prostate-specific antigen (PSA) levels, but recurrence continues to be difficult to detect. We evaluated whether routine delayed pelvic imaging at 90 min postinjection improves diagnosis of sites of recurrence in patients referred for BCR. Methods: We retrospectively analyzed 201 patients with prostate cancer undergoing dual-phase 68Ga-PSMA PET/CT for BCR of prostate cancer (median PSA, 0.52 ng/mL). Imaging of vertex to midthighs was acquired at approximately 60 min and delayed pelvic imaging at approximately 90 min postinjection. Two nuclear medicine physicians independently assessed whether delayed imaging improved diagnostic certainty or revealed additional 68Ga-PSMA–avid lesions. Results: Delayed pelvic imaging improved diagnostic certainty for 68 patients (34%) and revealed additional 68Ga-PSMA–avid lesions for 23 patients (11%). Of patients with additional lesions detected on delayed imaging, roughly one third—representing 3% of the total cohort—subsequently received focal radiation dose escalation during treatment planning. Improvements were primarily influenced by increased tracer uptake confirming subtle lesions, reduced bladder or ureteral interference, and differentiation of physiologic from pathologic uptake. All measurable lesions within the field of view of the delayed pelvic image were quantified. The median SUVmax for malignant lesions increased from 4.3 to 5.0, whereas benign lesions remained stable (median SUVmax of 2.7 on normal imaging and 2.6 on delayed imaging). Conclusion: Routine delayed pelvic imaging at 90 min postinjection enhanced lesion detection and diagnostic confidence in BCR of prostate cancer, particularly at low (<1 ng/mL) PSA levels. The addition of this additional acquisition into standard PSMA PET/CT protocols can improve staging accuracy and clinical decision-making.
Prostate cancer is the most frequently diagnosed cancer in men (1). Approximately one third of patients will experience recurrence within 10 y after definitive treatment with external beam radiation therapy (EBRT) or radical prostatectomy (RP). Continued surveillance of prostate-specific antigen (PSA) levels is therefore essential (2). Although PSA may reflect benign prostate tissue regrowth, such as after EBRT, it remains the target of choice for monitoring biochemical recurrence (BCR) and is associated with metastasis (3).
Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is highly overexpressed in prostate cancer cells (4). When a specifically radiolabeled small-molecule ligand binds to the extracellular domain of PSMA, PET can detect the positron emissions from PSMA-expressing cancer cells. This technique is currently the recommended modality for detecting low-volume disease, with a reported positive predictive value of 80%–90% (5).
The 2023 joint European Association of Nuclear Medicine/Society of Nuclear Medicine and Molecular Imaging guidelines for PSMA PET imaging recommend an uptake time of 60 min between the administration of 68Ga-PSMA and image acquisition (6). The guidelines indicate that when initial scans yield equivocal findings, particularly for lesions located near the ureter or bladder, a delayed scan beyond 120 min may be considered.
The objective of this study was to evaluate whether delayed pelvic imaging at 90 min postinjection, in addition to the standard whole-body scan at 60 min postinjection, can increase diagnostic certainty and detect new lesions in patients who are undergoing 68Ga-PSMA PET/CT for BCR of prostate cancer.
MATERIALS AND METHODS
Patient Population
This retrospective analysis of a prospectively maintained database at a single tertiary referral center reviewed data collected between January and October 2021. This study was reviewed by the institutional review board and categorized as a quality improvement project; thus, the requirements for institutional review board approval and patient consent were waived. Patients were referred for 68Ga-PSMA PET/CT for BCR of prostate cancer after primary treatment with curative intent. The final study cohort consisted of 201 consecutive patients who met the inclusion and exclusion criteria.
Eligible patients had a confirmed history (via histopathologic evaluation) of prostate adenocarcinoma and demonstrated BCR in accordance with Phoenix criteria after prior treatment with RP or EBRT. Patients were excluded if they were unable to comply with the imaging protocol or if a radioisotope other than 68Ga was used. Patients undergoing PET/CT for the indication of BCR per the referring oncologist were included in the study cohort. Technologists were requested to perform delayed pelvic imaging for all patients unless a patient showed multiple metastatic lesions on early maximal-intensity-projection images. Baseline characteristics of the study population are summarized in Table 1.
TABLE 1.
Baseline Patient Characteristics
| Parameter | Value |
|---|---|
| Age (y) | 68.9 ± 10.4 |
| Gleason score | |
| 6 | 6 (3.0) |
| 7 | 112 (55.7) |
| 8 | 25 (12.4) |
| 9 | 44 (21.9) |
| Initial treatment | |
| RP | 125 (62) |
| EBRT | 42 (21) |
| RP with EBRT | 34 (17) |
| PSA at time of PET/CT (ng/mL) | 0.52 (0.27–1.33) |
Qualitative data are expressed as number and percentage; continuous data are expressed as mean ± SD or median and interquartile range.
PET/CT Acquisition and Image Reconstruction
PET/CT imaging was performed using standardized institutional protocols. Early-phase imaging was performed from the skull vertex to midthigh in the supine position. Images were acquired in a caudal–cranial direction, with an acquisition time of 5 min per bed position. These noncontrast PET/CT scans were acquired at a mean of 64 ± 9.3 min after intravenous administration of 68Ga-PSMA-11 (mean injected activity, 222 ± 41 MBq). The bed position corresponding to the early pelvic image was acquired 10–15 min after initiation of the whole-body scan. Delayed pelvic imaging was obtained after the initial scan, bladder emptying, and patient repositioning. Delayed images were obtained at 96 ± 13.4 min after radiotracer injection. The mean time difference between early and delayed images was 32.4 ± 10.9 min. Imaging was conducted using either a Discovery 690 (143 scans) or Discovery 710 (58 scans) system (GE HealthCare).
Image Interpretation
The scans were interpreted by 2 board-certified nuclear medicine physicians with 5–10 y of experience and fellowships in oncologic body imaging. The final report constituted a consensus read. All measurable lesions within the field of view of the delayed pelvic images were assessed, and SUVmax was recorded for the early and delayed images. Lesions were categorized by 68Ga expression score, using PROMISE version 2 criteria, on the basis of relative SUVmax compared with that of reference tissues (i.e., blood pool, liver, and salivary glands). Readers also noted whether delayed pelvic imaging improved diagnostic certainty and categorized these improvements as stemming from increased uptake in a malignant lesion, decreased uptake in a benign lesion, differentiation of metastasis from urinary activity, or improved visualization of a lesion obscured by the bladder in early images.
Classification of Lesions and Follow-up of Additional Lesions Detected
Lesions were categorized as benign or malignant using a composite reference standard incorporating reader certainty on the current scan in conjunction with available clinical and imaging data, same-day cross-modality imaging (e.g., MRI), follow-up imaging, and biopsy results. Reader certainty exceeding 75% accounted for the classification of 60% of lesions. Of the remaining lesions, 27% were classified on the basis of findings from other imaging modalities, such as MRI or follow-up PET/CT demonstrating interval lesion growth, whereas 9% were classified as malignant on the basis of lesion response to treatment (e.g., radiation, systemic therapy) accompanied by a decline in PSA level. Biopsy confirmed malignancy in 2.4% of lesions, and 2.0% were excluded from the analysis (lost to follow-up or insufficient information to determine lesion status).
For all patients with additional lesions, retrospective chart review was performed with follow-up data collected for up to 4 y after the initial scan. In patients who subsequently underwent radiation therapy, treatment plans were reviewed to determine whether lesions identified exclusively on delayed imaging were specifically targeted during radiation planning; when this was the case, treatment was classified as “modified.”
Statistical Analysis
Numeric data were presented as the mean ± SD for normally distributed data or median with interquartile range (IQR) for nonnormally distributed data or data with extreme outliers. Normality was assessed using the Shapiro–Wilk test. The Mann–Whitney U test was used for continuous data. A 2-tailed P of less than 0.01 was considered statistically significant. Statistical analysis was performed using Real Statistics Resource Pack and RStudio (R version 2024.09.0 + 375; Posit Software).
RESULTS
In total, 201 patients with BCR of prostate cancer who underwent dual-phase 68Ga-PSMA PET/CT imaging were included in this study (mean age, 68.9 ± 10.4 y; range, 47–85 y). Initial treatments with curative intent included RP in 125 patients (62%), EBRT in 42 patients (21%), and RP followed by salvage EBRT in 34 patients (17%). The median PSA level at the time of imaging was 0.52 ng/mL (IQR, 0.27–1.32 ng/mL) (Table 1).
Of the 201 patients, 117 demonstrated suspicious pelvic lesions on delayed-phase imaging, whereas 84 showed no abnormal pelvic lesions. In 22 scans (10.9%), 1 additional 68Ga-PSMA–avid lesion not identified on early imaging was detected on delayed imaging. In 1 scan (0.5%), 2 additional 68Ga-PSMA–avid lesions were identified exclusively on delayed imaging. Most of these additional lesions were pelvic lymph nodes, including the external, internal, common iliac, and presacral nodes (n = 11), followed by lesions involving the seminal vesicles (n = 5) and prostate bed (n = 5) (Table 2). All scans were reread for the purposes of this study, and 2 of the 23 additional lesions identified on delayed imaging were not described in the original clinical reports. These patients were therefore excluded from the subset analysis evaluating the impact of delayed pelvic imaging on clinical management (Supplemental Table 1, available at http://jnm.snmjournals.org).
TABLE 2.
Additional Lesions Detected on Delayed Scans Only
| Parameter | No. scans |
|---|---|
| No. additional lesions | |
| 0 | 178 |
| 1 | 22 |
| 2 | 1 |
| Location of additional lesions | |
| Lymph nodes | 13 |
| Seminal vesicles | 5 |
| Prostate bed | 5 |
Radiation treatment plans were retrospectively reviewed to assess the clinical impact of lesions detected only on delayed imaging. Most of the newly detected lesions were located within standard pelvic salvage radiotherapy fields. In these cases, lesion identification did not alter the overall recommendation for salvage radiotherapy. However, in a subset of 6 patients, 3% of the total cohort, the newly detected lymph nodes were subsequently treated with focal radiation dose escalation, suggesting that delayed imaging may have influenced radiation treatment planning. Additionally, although clinical management was unchanged, 4 patients had no identifiable lesions on the early whole-body scan but demonstrated lesions on delayed imaging (Supplemental Table 1).
In 68 (34%) of 201 scans, readers indicated that the delayed pelvic images improved their diagnostic certainty when reading PSMA PET/CT scans. In cases where delayed imaging did not alter staging or overall interpretation, delayed imaging was not classified as improving diagnostic certainty (Table 3). For example, in 1 case, the SUVmax of already-suspicious left external iliac lymph node increased from 2.5 to 5.7 on delayed imaging; however, this finding did not meaningfully change the readers’ overall diagnostic confidence and was therefore not categorized as improving diagnostic certainty.
TABLE 3.
Improved Certainty with Delayed Scans
| Parameter | No. scans |
|---|---|
| Increased diagnostic certainty | 68 |
| Reasons for improved certainty | |
| Increased uptake | 42 |
| Decreased uptake | 7 |
| Ureteral troubleshooting | 24 |
| Bladder activity | 14 |
Increased uptake was the most common reason for improved diagnostic certainty, observed in 42 scans. Readers noted that increases in SUV between the whole-body images and delayed pelvic images strengthened their confidence that lesions represented true PSMA-avid disease rather than nonspecific activity, as shown in nodes and bones in Figures 1 and 2, respectively.
FIGURE 1.
Patient with prostate adenocarcinoma (Gleason score of 7 [4 + 3]) after RP presented with rising PSA level of 0.62 ng/mL. Left to right: whole-body maximum-intensity-projection image, fused PET/CT, CT, and PET-only images. (A) On early imaging, right pelvic sidewall node demonstrated low-level, equivocal uptake (SUVmax, 2.2). (B) On delayed imaging, lesion SUVmax was 3.7, consistent with metastatic involvement.
FIGURE 2.
Patient with prostate adenocarcinoma (Gleason score of 7 [4 + 3]) treated with EBRT and brachytherapy presented with rising PSA level of 1.54 ng/mL. (A) Sclerotic right L5 pedicle lesion with moderate uptake on early imaging (SUVmax, 4.2). (B) On delayed imaging, SUVmax was 5.2, increasing certainty of metastatic disease.
Decreased uptake in likely benign lesions improved diagnostic confidence in 7 scans. Readers found that the reduced PSMA avidity in delayed images helped avoid false-positive interpretations. Delayed imaging was especially helpful in addressing common pitfalls of 68Ga-PSMA PET/CT imaging, such as in the prostate bed where urinary activity may obscure lesions (Fig. 3). In 2 patients, bony lesions demonstrated decreased uptake on delayed imaging, consistent with hemangiomas, as confirmed by correlation with other imaging modalities and biopsy results (Fig. 4).
FIGURE 3.
Patient with prostate cancer (Gleason score of 9 [4 + 5]) treated with EBRT, brachytherapy, and androgen-deprivation therapy presented with BCR 6 y later (PSA, 0.33 ng/mL). (A) Early imaging shows focal uptake in right prostate gland (SUVmax, 4.0). (B) Delayed imaging shows decreased uptake (SUVmax, 2.4), favoring benign etiology rather than local recurrence. Subsequent MRI and 18F-piflufolastat PET/CT confirmed absence of recurrent disease.
FIGURE 4.
Patient with prostate adenocarcinoma (Gleason score of 7 [3 + 4]) treated with RP presented 1 y later with PSA level of 0.31 ng/mL. (A) Early imaging shows focal uptake in left sacrum (SUVmax, 3.0). (B) Delayed imaging shows SUVmax of 2.1. Biopsy confirmed lesion to be benign hemangioma.
Ureteral clearance helped improve interpretation in 24 scans. In a few cases, lesions initially suggestive of metastases were identified on delayed imaging as resulting from ureteral activity. Conversely, when lesions were adjacent to the ureter, delayed imaging helped identify persistent uptake after urinary activity had cleared, confirming that the focal uptake corresponded to a metastatic lesion (Fig. 5).
FIGURE 5.
Patient with prostate adenocarcinoma (Gleason score of 7 [4 + 3]) after RP and radiation to prostate bed had rising PSA level of 0.94 ng/dL. (A) Early imaging shows lesion was aligned with ureter. (B) Delayed pelvic imaging after washout of ureteric activity shows persistent PSMA-avid node.
Bladder activity affected diagnostic certainty in 14 scans, primarily because tracer accumulation in the bladder masked nearby lesions in early images. In these cases, delayed imaging after urinary clearance improved lesion visibility in areas such as the seminal vesicles (Fig. 6). Sites of lesions that were visualized only on delayed imaging in this cohort included the seminal vesicles, vesicourethral anastomosis, and prostate bed.
FIGURE 6.
Patient with prostate cancer (Gleason score of 6 [3 + 3]) with metastasis to left seminal vesicle. (A) Seminal vesicle not well-visualized on early whole-body scan because of bladder interference. (B) Recurrence in left seminal vesicle better seen on delayed imaging (SUV, 2.3).
All PSMA-avid lesions within the field of view of the delayed pelvic image acquisition were quantitatively assessed using SUVmax on early and delayed images. Across 110 patients, 209 measurable lesions could be classified as benign or malignant. The median SUVmax for the 36 lesions categorized as benign was 2.7 (IQR, 2.1–3.8) on early imaging and 2.6 (IQR, 2.1–3.2) on delayed imaging. Of the 173 malignant lesions measured, the median SUVmax was 4.3 (IQR, 2.5–8.9) on early whole-body imaging and 5.0 (IQR, 3.3–9.6) on delayed imaging (Fig. 7). The measured lesions were also categorized using PSMA expression scores. The percentage of benign lesions demonstrating PSMA uptake greater than the blood pool was 69% on early images and 72% on delayed images. In contrast, 83% of malignant lesions showed uptake greater than the blood pool on early imaging, increasing to 94% on delayed imaging (Supplemental Fig. 1).
FIGURE 7.
Absolute difference in SUVmax between benign and malignant lesions. Across 110 patients, 209 measurable lesions could be classified as benign (n = 36) or malignant (n = 173) with delayed imaging. Change in SUVmax between early and delayed images was calculated and displayed with IQRs (outliers not shown) (P < 0.01, Mann–Whitney U test).
DISCUSSION
Detecting BCR of prostate cancer at low PSA levels remains challenging, as recurrent disease is often low-volume with low radiotracer avidity. Although PSMA PET/CT is recommended as first-line imaging in this setting, its sensitivity drops substantially in patients with lower PSA values, with reported detection rates of only 30%–50% when the PSA value does not exceed 0.5 ng/mL (7,8). Therefore, the optimization of acquisition protocols to enhance detection in patients with a low disease burden and low PSA values is paramount in treatment planning.
In this cohort of 201 patients with BCR of prostate cancer (median PSA value, 0.52 ng/mL), a routine 90-min delayed pelvic acquisition improved interpretation in a meaningful proportion of cases. These findings are consistent with prior reports demonstrating improved lesion characterization with dual-time-point imaging, particularly in patients with PSA values of less than 1 ng/mL (9).
A review of radiation treatment records demonstrated that most additional lesions detected on delayed imaging were located within standard pelvic radiotherapy fields used for salvage treatment. However, in 3% of the total study cohort, additional lesions found on delayed imaging corresponded to lymph nodes that subsequently received focal radiation boosts during treatment planning. These findings suggest that delayed imaging may have contributed to dose escalation decisions at sites of gross disease.
Because treatment planning decisions were assessed retrospectively and documentation of dose escalation was not always explicit, it was not always possible to determine whether higher doses, such as escalation to the prostate bed, were specifically influenced by findings on delayed imaging. These cases were therefore categorized as having no change in management attributable to delayed pelvic imaging, and the true clinical impact of delayed imaging may be underestimated.
Several mechanisms contributed to the added value of delayed imaging. First, malignant lesions demonstrate higher tracer accumulation over time, whereas benign causes of radiotracer uptake tend to remain stable or decrease over time. In this study, malignant lesions showed an increase in median SUVmax between early and delayed imaging, whereas benign lesions showed no meaningful change. This divergence in kinetics supports the biologic rationale for delayed imaging acquisition. Stratification using the PSMA expression score further demonstrated a shift toward higher uptake on delayed imaging by malignant lesions, consistent with the expected kinetic behavior. This shift toward higher PSMA expression on delayed imaging also contributed to the increased lesion-to-background contrast over time.
Second, delayed imaging improved visualization in areas where physiologic urinary activity can obscure or mimic disease. Bladder clearance and ureteral washout clarified ambiguous findings in 24 scans, enabling differentiation of ureteral activity from true nodal uptake and improving assessment of the prostate bed and prostate and seminal vesicles. These pelvic structures are among the most common sites of early recurrence and among those most frequently obscured on standard whole-body acquisitions.
The benefit observed in this study was most pronounced in patients with PSA values of less than 1 ng/mL and low disease burden. This finding contrasts with studies that assessed patients with higher PSA levels, such as the delayed postdiuresis protocol evaluated by Bauckneht et al., where the incremental yield of delayed imaging was modest (10).
Compared with other studies, such as that by Kunikowska et al. who reported improved lesion detectability using a delayed imaging time point of 120–180 min postinjection (9), the interval between early and delayed pelvic image acquisition in our study was considerably shorter (mean, 32 min). Despite this shorter delay, we observed a reduction in equivocal findings and increased PSMA expression scores on delayed images, suggesting that even modest delays may improve lesion conspicuity.
The delayed acquisition time of 90 min for 68Ga-PSMA PET is largely constrained by the isotope’s 68-min half-life. This interval may be extended when using 18F-based PSMA tracers, which have a longer half-life (110 min). Notably, the currently recommended delayed imaging time point of 120 min approaches 2 half-lives of 68Ga, at which point tracer accumulation within a lesion may be attenuated by isotope decay. Prior pharmacokinetic studies have shown that malignant lesions typically reach a relatively stable SUV plateau between 60 and 120 min, whereas urinary clearance continues to improve pelvic contrast (11,12).
Although longer delays may further enhance lesion-to-background contrast, they may also be less practical in routine clinical workflows. In contrast, the shorter delay used in our protocol may represent a pragmatic approach that can be incorporated into standard imaging protocols. Additionally, factors such as bladder emptying, patient repositioning, and gravitational redistribution of urine between acquisitions also contributed to improved image interpretation.
Scanner variability and timing heterogeneity were considered in our analysis. Both scanners used in this study (Discovery 690 and 710) use similar detector and reconstruction technologies, and cross-calibration procedures were standardized, minimizing interscanner SUV variation (13,14). Although the delayed pelvic image was acquired 96 ± 13.4 min postinjection, this variation is unlikely to meaningfully affect diagnostic performance. This timing variation reflects real-world clinical practice, where patient throughput, scanner availability, and patient-specific factors (e.g., mobility, voiding capability) influence timing and scheduling.
Limitations to this retrospective, single-center study include potential selection biases, particularly in cases where delayed imaging was omitted for patients with widespread metastatic disease. Furthermore, lesion classification relied on clinical and imaging follow-up rather than systematic histopathologic confirmation. Results may differ across institutions using different scanners, tracers, or acquisition protocols. Potential limitations to assessment also exist because of the use of low-dose noncontrast CT for attenuation correction rather than contrast-enhanced diagnostic CT. The lack of contrast-enhanced CT may limit anatomic characterization of some pelvic findings. Additionally, scans were interpreted using a consensus read between 2 experienced nuclear medicine physicians without formal assessment of interobserver variability. The unquantified interobserver variability introduced a degree of subjectivity to the results and limits the generalizability of the data.
CONCLUSION
We demonstrated that routine delayed pelvic imaging at 90 min postinjection of 68Ga PSMA enhanced lesion detection and diagnostic confidence in interpreting scans for patients with BCR of prostate cancer. Given the substantial influence of 68Ga-PSMA PET/CT findings on patient management and salvage therapy planning, the addition of a delayed pelvic image acquisition into standard protocols may improve clinical decision-making in patients with BCR of prostate cancer and low PSA levels. Prospective multicenter studies are warranted to validate these results and to assess their impact on management pathways.
DISCLOSURE
This research was supported in part by NIH/NCI Cancer Center support grant P30 CA008748. No other potential conflict of interest relevant to this article was reported.
KEY POINTS
QUESTION: Does routine delayed pelvic imaging at 90 min postinjection improve lesion detection and diagnostic certainty on 68Ga-PSMA PET/CT in patients with BCR of prostate cancer?
PERTINENT FINDINGS: In this retrospective cohort study of 201 patients undergoing dual-phase 68Ga-PSMA PET/CT for BCR, delayed pelvic imaging increased diagnostic certainty in 34% of patients and identified additional PSMA-avid lesions not seen on standard whole-body imaging in 11% of patients. One third of the additional lesions found resulted in a focal radiation dose escalation, corresponding to 3% of the total patient cohort. Additional lesions were predominantly pelvic lymph nodes. Malignant lesions showed increased radiotracer uptake on delayed imaging, whereas benign lesions showed no meaningful change.
IMPLICATIONS FOR PATIENT CARE: Routine delayed pelvic imaging may enhance lesion detection and diagnostic confidence in patients with BCR of prostate cancer, particularly those with low PSA levels, with the potential to impact staging and treatment planning.
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