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. 2026 Feb 20;10(1):6. doi: 10.1186/s41824-026-00289-5

The role of Choline-PET/CT in patients with recurrent prostate cancer and a negative PSMA-PET/CT

Nasir Gözlügöl 1,✉, Wolfram A Bosbach 1, Mohamed Shelan 2, Hasan Sari 1,3, Arion Bucher 4, Irene A Burger 5,6, Klaus Strobel 4, Ali Afshar-Oromieh 1
PMCID: PMC12920957  PMID: 41714514

Abstract

Aim

The sensitivity of PSMA-PET/CT for the detection of recurrent prostate cancer (rPC) is good at low PSA values and rapidly rises to > 80% in patients with PSA > 1.5 ng/mL. Currently, there are no general rules on how to manage PSMA-PET-negative patients with rPC and PSA levels at which a pathological PSMA-PET must be considered very likely. The aim of this evaluation was to assess the value of a choline-PET/CT in such a clinical context.

Materials and methods

We conducted a retrospective analysis incorporating data from 01/2017–09/2023 from two Swiss institutions. Eligible patients included those with rPC following radical prostatectomy (RP) who had a negative or equivocal [6 8 Ga]Ga-PSMA-11 or [1 8 F]F-PSMA-1007 PET/CT despite a PSA level ≥1.5 ng/mL, and were subsequently referred for [18F]F-Fluorocholine-PET/CT within two months. Two experienced nuclear medicine physicians reviewed both scans (choline and PSMA-PET/CTs) in a blinded consensus read.

Results

Eleven patients met all inclusion criteria. The median PSA level was 2.8 ng/mL (range: 1.7–16.0). Following [18F]F-Fluorocholine-PET/CT 6 out of 11 patients (54.5%) demonstrated pathologic choline positive findings indicative of rPC: 4 patients with local recurrence, 1 with distant metastasis only, and 1 with concomitant pelvic lymph node and distant metastases.

Conclusion

More than 50% of patients with a negative or equivocal PSMA-PET/CT showed pathologic [18F]F-Fluorocholine-PET/CT. These results indicate that [18F]F-Fluorocholine-PET/CT may serve as a valuable complementary imaging modality in patients with rPC after RP who present with a negative PSMA-PET/CT at PSA levels ≥1.5 ng/mL.

Keywords: Prostate cancer, [18F]F-PSMA-1007, [68Ga]Ga-PSMA-11, [18F]F-Fluorocholine, PET, Choline

Introduction

Prostate-specific membrane antigen (PSMA) PET/CT has largely replaced choline-based PET imaging in the evaluation of recurrent prostate cancer (rPC) owing to its superior sensitivity and specificity, particularly at low PSA levels (below 1 ng/mL), and its higher clinical impact on patient management decision (Alonso et al. 2018; Chevalme et al. 2021; Wang et al. 2021; Schwenck et al. 2020; Afshar-Oromieh et al. 2014).

Despite the superior sensitivity of PSMA-PET/CT, [18F]F-Fluorocholine-PET/CT may retain diagnostic value in selected clinical scenarios, particularly when PSMA imaging yields negative results and further characterization is required to guide subsequent management (Beheshti et al. 2025; Treglia et al. 2019). In cases of early biochemical recurrence, repeating PSMA-PET/CT after an initially negative scan may be reasonable. However, there also exists a subset of patients with sufficiently elevated PSA levels (above 1–2 ng/ml) after radical prostatectomy (RP) in whom PSMA-PET/CT remains negative (Bashir et al. 2019). The American Society of Clinical Oncology states that [18F]F-Fluorocholine-PET/CT can provide complementary information in men with rPC who have a negative PSMA-PET/CT scan, particularly when PSA is > 2 ng/mL, or in cases with aggressive disease features such as a primary Gleason score ≥7, PSA doubling time < 6 months, or PSA velocity > 2 ng/mL/year (Trabulsi et al. 2020). They justify this recommendation by noting that higher serum PSA levels during biochemical recurrence are associated with higher detectability on [18F]F-Fluorocholine-PET/CT, and that [18F]F-Fluorocholine-PET/CT has demonstrated pooled sensitivity and specificity of 80.9% and 84.1%, respectively, in this setting. At PSA levels below 1.0 ng/mL, the likelihood of a positive finding in [1 8 F]F-Fluorocholine-PET/CT varies considerably, influenced by factors such as the initial tumor stage and Gleason score, with reported detection rates ranging from approximately 10% to 40% (Evangelista et al. 2015).

In a study involving one of the largest cohorts of patients with rPC after RP (n = 2,533) who underwent PSMA-PET/CT, a PSA level of less than 0.2 ng/mL was associated with a 43% probability of a pathological PET/CT finding. This probability increased to > 80% at PSA levels between 1 and 2 ng/mL, but even at significantly higher PSA levels, it remained well below 100%. According to the authors, this is due to a subset of prostate cancers that do not sufficiently express PSMA (Afshar-Oromieh et al. 2021). This observation was in concordance with a retrospective analysis of PSMA expression based on immunohistochemistry of primary tumors in correlation with PSMA PET findings for biochemical recurrence, showing that lesions with more than 80% PSMA negative tumor on immunohistochemistry were negative on PSMA PET scans, regardless of PSA values (Ferraro et al. 2020). These results indicate that in patients with a non-pathological PSMA-PET/CT at PSA levels above 1–2 ng/mL, the likelihood of detecting the recurrent tumor in a subsequent PSMA-PET/CT does not significantly increase with higher PSA levels. Consequently, this raises the question of what role [1 8 F]F-Fluorocholine-PET plays in patients with a negative PSMA-PET/CT and PSA levels exceeding 1–2 ng/mL. Our evaluation was designed to address this question.

Material and methods

Imaging protocol

This retrospective study included patients with rPC after radical prostatectomy (RP) (n = 11) who underwent either [6 8 Ga]Ga-PSMA-11 (n = 3) or [1 8 F]F-PSMA-1007 PET/CT (n = 8) and [1 8 F]F-Fluorocholine-PET/CT (n = 11) between January 2017 and September 2023 at two academic nuclear medicine centers in Switzerland (University Hospital of Bern and Cantonal Hospital of Lucerne). Inclusion criteria were: patients with biochemical recurrence after radical prostatectomy, PSA ≥1.5 ng/mL at the time of PSMA-PET/CT, a negative or equivocal PSMA-PET/CT result, and a subsequent [1 8 F]F-Fluorocholine-PET/CT within 60 days. PSMA- and [1 8 F]F-Fluorocholine PET/CT scans were performed using Biograph mCT, Biograph Vision 128 edge, Biograph Vision 600, or Biograph Vision Quadra scanners (Siemens Healthineers, Knoxville, TN, USA) with standard protocols (Haupt et al. 2020; Alberts et al. 2021). The median administered activity was 212 MBq (range: 209–253 MBq) for [6 8 Ga]Ga-PSMA-11, 218 MBq (range: 195–376 MBq) for [1 8 F]F-PSMA-1007 and 218 MBq (range: 195–376 MBq) for [1 8 F]F-Fluorocholine PET, respectively. All scans included low-dose CT for attenuation correction and anatomical correlation. All three patients imaged with [6 8 Ga]Ga-PSMA-11 received pre-scan furosemide to reduce urinary activity and facilitate assessment of the prostate bed. A target dose of 3 MBq/kg body weight was administered (for all three tracers). Choline-PET/CT scans were conducted one hour post injection of [1 8 F]F-Fluorocholine (Massaro et al. 2012).

Image evaluation

Two experienced nuclear medicine physicians independently and retrospectively reviewed all PET/CT images in consensus (first and second author). Reviewers were blinded to clinical information and each other’s readings. Lesions were categorized as pathologic, equivocal, or negative based on tracer uptake intensity relative to surrounding background and known physiological biodistribution patterns. Semi-quantitative evaluation included SUVmean and SUVmax measurements, with SUVmean obtained from three-dimensional VOIs defined by a 40% isocontour of the SUVmax Lesion locations were recorded as prostatic fossa, pelvic lymph nodes, or distant sites. Pathological findings were correlated with follow-up data (e.g., MRI, PSA response to treatment, post treatment [1 8 F]F-Fluorocholine PET/CT, histopathology) when available.

The dataset included patients from both Bern and Lucerne. For cases from Lucerne, anonymized and coded data were transferred for centralized image analysis, which was performed entirely in Bern.

Statistical analysis

Descriptive statistics were used to summarize patient characteristics, PSA levels, and PET/CT findings. Continuous variables were reported as medians with ranges. Detection rates were calculated as proportions. No formal hypothesis testing was conducted due to the small sample size.

Results

A total of 11 patients (median age: 70.7 years; range: 54–80 years) with biochemical rPC met all inclusion criteria. The median PSA at the time of PSMA-PET/CT was 2.8 ng/mL (range: 1.7–16.0 ng/mL). Eight patients had a negative PSMA-PET/CT, and three scans were classified as equivocal(Table 1).

Table 1.

Patient characteristics (TNM: tumour stage; GSC: Gleason score; ADT: androgen deprivation therapy; RT: radiotherapy, a dash sign (-) indicates that no data are available)

Patient Age TNM GSC Previous treatments PSA at PSMA PET Tracer PET-Scanner PSMA PET result Site of pathologic lesion SUVmax PSMA PET Days between PSMA and Choline PET Choline PET Result Site of pathologic lesion SUVmax Choline PET Validation (method if available) Therapy after PET Follow up
1 83 pT3a pN1 cM0 3+4 Surgery 15.7 [68Ga]Ga-PSMA-11 Siemens Biograph mCT negative - - 26 pathologic Ductus deferens bilateral

7.8; resp.

10.4

 yes - MRI RT PSA ↓ Follow up Choline PET negative
2 59 pT2c pN0 cM0 R0 3+4 Surgery 5.6 [68Ga]Ga-PSMA-11 Siemens Biograph mCT negative - - 37 pathologic Prostate fossa 6.5 - - Unrelated death 2 years post- PET
3 75 pT2c pN0 cM0 3+4 Surgery, ADT 16 [68Ga]Ga-PSMA-11 Siemens Biograph Vision 600 equivocal Prostate fossa 16.4 23 pathologic Prostate fossa 5.9 yes RT PSA ↓
4 58 pT3b pN1 cM0 R0 3+4 Surgery, RT, ADT 2.8 [18F]F-PSMA-1007 Siemens Biograph Vision Quadra negative - - 31 negative - - - - PSMA-positive nodes at PSA 5.9 ng/mL (8 months later), treated with RT and ADT, PSA ↓
5 62 pT3a pN0 cM0 R1 3+4 Surgery 2.8 [18F]F-PSMA-1007 Siemens Biograph Vision 600 negative - - 31 negative - - - - MRI negative for local recurrence
6 78 cT3a pN0 cM0 4+4 Surgery, ADT 2.6 [18F]F-PSMA-1007 Siemens Biograph Vision Quadra equivocal 7thcervical vertebral body 7.1 45 pathologic 7thcervical vertebral body 10.3 yes RT PSA ↓ Follow up Choline PET negative
7 54 pT3b pN0 cM0 4+5 Surgery, RT, ADT 9.3 [18F]F-PSMA-1007 Siemens Biograph Vision Quadra negative - - 24 negative - - - - Choline PET negative
8 70 pT2 cN0 cM0 R0 4+3 Surgery, RT, ADT 6.8 [18F]F-PSMA-1007 Siemens Biograph Vision 128 Edge negative - - 23 pathologic lymph nodes: obturator left, pararectal left, infracarinal 6.7; 4.4; 12.7 yes – biopsy infracarinal lymph node - -
9 58 pT3b pN1 cM0 R1 4+3 Surgery 1.9 [18F]F-PSMA-1007 Siemens Biograph Vision 128 Edge equivocal Seminal vesicle left 1.8 9 pathologic Seminal vesical left 8.7 yes RT

PSA ↓

Follow up Choline PET negative
10 75 pT2c pN0 cM0 3+4 Surgery 1.7 [18F]F-PSMA-1007 Siemens Biograph Vision 128 Edge negative - - 24 negative - - - - Follow up Choline PET also negative
11 77 pT2c pN0 cM0 R1 3+4 Surgery 1.8 [18F]F-PSMA-1007 Siemens Biograph Vision 128 Edge negative - - 18 negative - - - - Patient refused all follow-up
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The median interval between PSMA-PET/CT and subsequent [1 8 F]F-Fluorocholine-PET/CT was 24 days (range: 9–45 days). Pathologic uptake on [1 8 F]F-Fluorocholine-PET/CT was observed in 6 of 11 patients (54.5%, exact 95% confidence interval [Clopper–Pearson], 23–83%). Among these, 9 lesions were identified, with a lesion-level SUVmax median of 7.8 (range 4.4–12.7). The most frequent sites of choline-avid lesions were the prostatic fossa (n = 4, exemplary case shown in Fig. 1) and pelvic lymph nodes (n = 3). Notably, two patients demonstrated [1 8 F]F-Fluorocholine uptake in distant locations, including a cervical vertebral lesion Fig. 2)and a biopsy proven mediastinal lymph node, indicative of distant metastasis.

Fig. 1.

Fig. 1

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Axial slice of [6 8 Ga]Ga-PSMA-11 PET/CT in a 57-year-old patient with prostate cancer (Gleason score 7) and a PSA level of 5.6 ng/mL at the time of imaging (patient #2) shows no pathological uptake in the prostatic fossa (A). The corresponding coronal maximum intensity projection (MIP) confirms the absence of PSMA-avidity (B). In contrast, the subsequent [1 8 F]F-Fluorocholine-PET/CT performed 37 days later reveals a focal area of intense uptake in the right prostatic fossa (yellow arrow) (C). The corresponding coronal MIP highlights the choline-avid lesion (red arrow), indicative of rPC

Fig. 2.

Fig. 2

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Equivocal PSMA uptake at the level of the 7th cervical vertebra (C7) in a 78- year-old patient with prostate cancer (Gleason score 8) and a PSA level of 2.6 ng/mL at the time of imaging with [18F]F-PSMA-1007 (patient #6). The axial PET/CT image (A) revealed a subtle, arc-shaped uptake at C7 (yellow arrow), suggestive of an equivocal lesion. This was accompanied by a heterogeneous tracer distribution in the cervical spine (B) on the corresponding maximum intensity projection (MIP) image (red arrow). The low-dose CT (C) identified a mixed lytic-sclerotic lesion at the same location (yellow arrow). In contrast, the axial1 8F]F-Fluorocholine PET/CT (D) demonstrated intense choline avidity at C7 (yellow arrow), clearly exceeding the uptake seen on PSMA imaging. The MIP image (E) confirmed focal tracer accumulation in C7 (red arrow), consistent with an intensely choline-avid osseous metastasis. Follow-up imaging 24 months post radiation treatment illustrates the [1 8 F]FFluorocholine PET/CT in the sagittal view (F), demonstrating no residual uptake at the level of the seventh cervical vertebral body (yellow arrow), consistent with treatment response

Follow-up data were available for a subset of patients. In four patients with positive [1 8 F]F-Fluorocholine scans, radiation therapy was initiated and led to a measurable PSA response. In another case, both PSMA- and [1 8 F]F-Fluorocholine-PET/CT performed at a PSA of 2.8 ng/mL revealed no evidence of tumor recurrence. However, eight months later, at a PSA of 5.9 ng/mL, repeated PSMA-PET/CT revealed metastasis-suspect locoregional lymph nodes, which were successfully (PSA-drop and negative follow-up PSMA-PET/CT) treated with radiotherapy and a 6-month course of ADT.

Four other patients (36.3%) had negative findings on both, PSMA-PET/CT and [1 8 F]F-Fluorocholine-PET/CT and remained under observation without specific treatments up to the time of manuscript submission.

Discussion

The integration of molecular imaging modalities such as PSMA PET/CT has significantly changed the landscape of PC management, particularly in the setting of biochemical recurrence. These advanced techniques have enhanced the detection of early locoregional and metastatic disease, enabling more precise and individualized treatment approaches. However, in cases where PSMA PET/CT is negative despite rising PSA levels, clinical decision-making remains challenging. To date, there is no established standard for managing PSMA-PET-negative patients with biochemical recurrence after RP and/or prior radiotherapy.

In the absence of prospective evidence, and based on retrospective series suggesting that PSMA-PET-negative patients may still derive benefit from local salvage RT (Adebahr et al. 2024; Scharl et al. 2023; Harsini et al. 2024; Solomonidou et al. 2023), current guidelines recommend delivering salvage RT to the prostate bed in cases of biochemical recurrence with a negative PSMA-PET/CT (Lowrance et al. 2023). However, accurately distinguishing between patients with true localized recurrence and those with emerging oligometastatic disease who may instead benefit from metastasis-directed therapy (MDT) remains a critical clinical need (Ost et al. 2025; Deek et al. 2022). This distinction is essential to inform appropriate treatment strategies and to avoid undertreatment or overtreatment and associated toxicities in this clinically heterogeneous patient population.

At PSA values higher than 1–2 ng/mL, the probability of a pathologic PSMA-PET/CT in patients with rPC after RP increases to over 80%, but even at significantly higher PSA levels, this probability remains well below 100% since a proportion of PC does not sufficiently express PSMA (Eiber et al. 2015).

While multiparametric MRI (mpMRI) offers high-resolution anatomical and functional imaging that is valuable for localizing intraprostatic or prostate bed recurrence, it may lack sensitivity in detecting microscopic or extraprostatic disease spread, particularly in cases of low PSA levels (Kim et al. 2022). In contrast, PSMA PET/CT provides superior whole-body sensitivity for detecting small-volume nodal and distant metastatic disease, often identifying lesions missed by MRI (Abramczyk et al. 2025). Therefore, the combination of mpMRI and PSMA PET/CT offers complementary diagnostic value: MRI enhances precise anatomical delineation critical for salvage radiotherapy planning (Buergy et al. 2018), while PSMA PET/CT broadens the field of view to detect occult oligometastatic disease (Calais et al. 2018; Schmidt-Hegemann et al. 2019). Relying on MRI alone may result in under-detection of early metastatic spread, leading to inappropriate local therapy in patients who may benefit more from MDT strategies (Wang et al. 2025).

Beyond imaging-related factors and potential interpretative pitfalls, biological mechanisms may also contribute to PSMA-negative/choline-positive discordance, including dedifferentiation or neuroendocrine differentiation with downregulation of PSMA, while choline uptake may persist due to increased membrane phospholipid turnover (Bakht et al. 2018). In clinically suspected aggressive or poorly differentiated disease, 1 8 F-FDG PET/CT may provide complementary information, as FDG+/PSMA− lesions can occur and may indicate more aggressive biology (Hartrampf et al. 2021). From a management perspective, additional lesion localization may help distinguish isolated local/locoregional recurrence amenable to salvage radiotherapy from metastatic disease.

Our evaluation has several limitations: aside from its retrospective nature, the number of included patients is very small despite an inclusion period spanning more than six years. This highlights the current lack of standardized approaches for further diagnostic evaluation in PSMA-negative patients. Another limitation of our analysis is that the recommendations apply exclusively to patients with biochemical recurrence following RP. We cannot draw any conclusions regarding the value of [1 8 F]F-Fluorocholine-PET/CT after negative PSMA-PET/CT in other clinical settings. Tracer-specific biodistribution may have also contributed to the classification of baseline PSMA scans as negative or equivocal. In particular, urinary excretion of [6 8 Ga]Ga-PSMA-11 can impair prostate bed assessment due to intense bladder activity and halo artifacts, and local recurrence after prostatectomy is at risk of being missed. All three patients imaged with [6 8 Ga]Ga-PSMA-11 in our cohort received pre-scan furosemide as part of a forced diuresis protocol, which has been shown to reduce bladder activity and the frequency of halo artifacts. Nevertheless, a masking effect cannot be completely excluded (Heußer et al. 2017; Afshar-Oromieh et al. 2017). In contrast, [1 8 F]F-PSMA-1007 is prone to unspecific skeletal uptake and non-specific bone lesions, which can lead to ‘’equivocal’’ interpretations independent of tumor biology. In addition, choline uptake is not fully tumor-specific and may also occur in benign or reparative bone processes, limiting definitive characterization of isolated skeletal foci in the absence of histologic confirmation (Grünig et al. 2021).

Additionally, this retrospective series may be subject to selection bias, as dual-tracer imaging was performed in a highly selected subgroup influenced by access and referral patterns, which may limit generalizability. In addition, examinations were acquired on different PET/CT system generations (analog Biograph mCT vs digital Biograph Vision/Quadra), which differ in sensitivity and spatial resolution and may therefore influence lesion detectability. However, within each patient, the subsequent [1 8 F]F-Fluorocholine PET/CT was performed on the same PET/CT system as the preceding PSMA PET/CT, which may reduce scanner-related confounding at the individual level.

The present preliminary findings encourage the conduct of further prospective studies with a larger number of patients to better explore the role of Choline PET/CT in this setting.

Conclusion

In this retrospective study, [1 8 F]F-Fluorocholine-PET/CT detected recurrent prostate cancer in more than 50% of selected post-prostatectomy patients with negative PSMA-PET/CT despite PSA levels ≥1.5 ng/mL. Performing an additional [1 8 F]F-Fluorocholine-PET/CT can therefore increase the likelihood of identifying recurrence and enable a more targeted treatment approach. Given the small sample size and the historically limited sensitivity of choline PET at low PSA values, our findings should not be extrapolated to early low-PSA biochemical recurrence.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Nasir Gözlügöl, Wolfram Bosbach, Hasan Sari and Arion Bucher. The first draft of the manuscript was written by Nasir Gözlügöl and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

The authors did not receive support from any organization for the submitted work.

Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

Declarations

Compliance with ethical standards

This retrospective study was approved by the Cantonal Ethics Committee of Bern (Req-2024-00783). Written informed consent for data evaluation was obtained from all participants. All procedures were carried out in accordance with the Declaration of Helsinki and applicable national regulations.

Competing interests

Ali Afshar-Oromieh is a member of the Editorial Board of European Journal of Nuclear Medicine and Molecular Imaging. Hasan Sari has part time employment with Siemens Healthineers. The other authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated during the current study are available from the corresponding author on reasonable request.

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