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ORIGINAL ARTICLE
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11C-choline positron emission tomography/computed tomography for detection of disease relapse in patients with history of biochemically recurrent prostate cancer and prostate-specific antigen ≤0.1 ng/ml


1 Department of Radiology, Mayo Clinic, Rochester, MN, USA
2 Department of Urology, Mayo Clinic, Rochester, MN, USA
3 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
4 Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA

Date of Submission29-May-2019
Date of Decision05-Aug-2019
Date of Acceptance12-Sep-2019
Date of Web Publication10-Sep-2020

Correspondence Address:
Ajit H Goenka,
Department of Radiology, Mayo Clinic, 200 First St Sw, Charlton 1, Rochester, MN 55905
USA
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_373_19

PMID: 33063697

 > Abstract 


Objectives: The objective was to evaluate the diagnostic performance of surveillance11 C-choline positron emission tomography/computed tomography (PET/CT) for the detection of disease relapse in patients with a history of biochemically recurrent (BCR) prostate cancer (PCa) and prostate-specific antigen (PSA) ≤0.1 ng/ml.
Materials and Methods: We included patients who had been treated for BCR PCa and had a surveillance11 C-choline PET/CT at serum PSA ≤0.1 ng/ml. Positive surveillance PET/CT was defined as a study that identified a new tracer-avid lesion or new tracer uptake in a previously treated lesion or both. Findings were confirmed against a composite radiologic-pathologic gold standard. Time to recurrence association analyses were performed for disease relapse risk with the use of Cox proportional hazards regression.
Results: In total, 13 (12.1%) of the 107 patients had positive surveillance PET/CT scans, confirmed on pathologic assessment (n = 5) and subsequent imaging (n = 8). Among these 13 patients, ten had distant metastases, two had local recurrence, and one had both. Nine of the ten patients with metastases had oligometastatic disease defined as the presence of ≤3 metastases. Serum PSA became detectable again in only seven patients with positive surveillance PET/CT, after a mean interval from surveillance PET/CT of 292 days (range: 105–543 days). We identified an association of N stage with increased risk of recurrence (hazard ratio = 3.85; P = 0.036) although this was not significant after accounting for multiple testing.
Conclusions: Surveillance11 C-choline PET/CT can detect early disease relapse at serum PSA ≤0.1 ng/ml in patients with a history of BCR PCa.

Keywords: 11C-Choline, castration resistant, positron emission tomography/computed tomography, prostate cancer, urology



How to cite this URL:
Garg I, Nathan MA, Packard AT, Kwon ED, Larson NB, Lowe V, Davis BJ, Haloi R, Mahon ML, Goenka AH. 11C-choline positron emission tomography/computed tomography for detection of disease relapse in patients with history of biochemically recurrent prostate cancer and prostate-specific antigen ≤0.1 ng/ml. J Can Res Ther [Epub ahead of print] [cited 2020 Oct 28]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=294670




 > Introduction Top


Radical prostatectomy (RP) or radiotherapeutic management is offered with curative intent to patients with prostate cancer (PCa) with clinically localized disease. However, ≥20% of patients who undergo primary treatment have biochemically recurrent (BCR) disease within 10 years of treatment.[1],[2],[3],[4] Among patients with BCR PCa, metabolic imaging with different positron-emitting radiotracers has been shown to identify the relapse site earlier and with better accuracy than conventional imaging.[5],[6] In particular, positron emission tomography (PET) with carbon-11-labeled choline (11 C-choline) has shown high sensitivity and specificity for the detection of metastases in BCR PCa.[7],[8],[9],[10],[11]

Numerous studies have suggested that the positive detection rate of11 C-choline PET/computed tomography (PET/CT) in general is linearly dependent on levels of prostate-specific antigen (PSA).[12] Therefore, imaging evaluation of patients with BCR PCa including PET/CT is primarily guided by serial PSA measurements. A PSA >1.0 ng/ml is generally accepted as a reasonable indication for PET/CT with radiolabeled choline.[13] However, uncertainty exists about the yield of11 C-choline PET/CT at very low PSA levels in the early BCR PCa as well as about its utility in patients who have received multiple lines of treatment for late-stage BCR PCa. The disease in the latter group of patients tends to be phenotypically diverse and evolves through multiple clinical courses. In practice, the PSA level is the most widely used and often the only parameter for disease monitoring in these patients despite the fact that this approach has not been adequately tested. The utility of imaging in monitoring of these patients, if any, is not known partly because the utility of early detection of disease relapse is contingent on the availability of therapeutic agents that can be used to act on that information in a way that is beneficial to the patients.[14]

We hypothesize that patients who have been treated for their BCR PCa and have consequently achieved an undetectable PSA level (PSA ≤0.1 ng/ml) may exhibit disease relapse during subsequent surveillance imaging with11 C-choline PET/CT even at undetectable PSA levels. The purpose of this study was to evaluate the yield of surveillance11 C-choline PET/CT for detection of disease relapse in patients with PSA ≤0.1 ng/ml and history of BCR PCa. A secondary aim was to identify factors that could predict the risk of disease relapse in these patients with PSA ≤0.1 ng/ml.


 > Materials and Methods Top


Ethics

The Institutional Review Board (IRB) approved our study, which was compliant with the Health Insurance Portability and Accountability Act. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. A waiver of informed consent was obtained from our IRB for this retrospective study.

Study design

Patient population

Inclusion criteria for this single-center retrospective study were patients who had been treated for BCR PCa and had serum PSA ≤0.1 ng/ml at the time of11 C-choline PET/CT (<30 days). For this study, surveillance PET/CT scans were defined as the second and subsequent PET/CT scans after one prior negative baseline PET/CT performed at an undetectable PSA level. Patients were excluded if they did not have a surveillance PET/CT at serum PSA ≤0.1 ng/ml or did not have clinical or imaging follow-up, or both, of ≥6 months (mo) since their surveillance PET/CT [Figure 1].
Figure 1: Study scheme of the retrospective analyses. BCR indicates biochemically recurrent; PCa, prostate cancer; PET/CT = Positron emission tomography/computed tomography, PSA = Prostate-specific antigen, Treat = Treatment

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The following parameters were recorded for each patient: age; follow-up time since surveillance PET/CT; primary tumor characteristics (Gleason score, tumor DNA ploidy, and tumor stage); form of primary treatment (RP or external beam radiation therapy); resection margins for patients who had undergone surgery; PSA level (ng/ml) at the time of diagnosis of primary tumor; PSA peak (ng/ml) after last BCR and rate of PSA decline (mo) from peak PSA to undetectable PSA; chromogranin level (ng/ml); testosterone level (ng/dl); and presence or absence of ongoing androgen deprivation therapy (ADT) at the time of surveillance PET/CT.

Positron emission tomography/computed tomography imaging protocol

11 C-choline PET/CT was performed on an integrated PET/CT scanner (Discovery LS, RX, 690, or 710, GE Healthcare) with the use of11 C-choline produced at our on-site cyclotron facility. A CT scout scan was performed to define the body axial range to be imaged. Next, the patient received a single-dose, intravenous bolus injection of 555–740 MBq11 C-choline. Low-dose helical CT images were then obtained with the patient doing shallow breathing for attenuation correction and anatomic localization (detector row configuration, 16 mm × 0.625 mm; pitch, 1.75; gantry rotation time, 0.5 s; slice thickness, 3.75 mm; 140 kVp; and range, 60–120 mA with the use of automatic current modulation) followed by PET acquisition initiated at approximately 5 min after injection. PET images were acquired from midthigh to the orbits (in three dimensions, with a 128 × 128 matrices and at a rate of 3–4 min/bed position depending on body mass index). PET images were reconstructed with a three-dimensional ordered subsets expectation maximization algorithm (28 subsets, two iterations).

Image analyses

Images were reviewed with MIM Software (MIM Software Inc., Cleveland, USA) and a picture archiving and communication system workstation (Centricity; GE Healthcare, Milwaukee, USA). A positive surveillance PET/CT was defined as a PET/CT study that identified a new tracer-avid lesion (focal tracer uptake greater than the surrounding blood pool), or new tracer uptake in a treated lesion that had become metabolically quiescent or nontracer avid on the prior baseline PET/CT study, or both. Maximum standardized uptake value (SUVmax) was calculated and considered, but an absolute cutoff value was not used for diagnosis. For patients with multiple lesions, SUVmax was calculated from the lesion that showed the most intense tracer uptake on qualitative evaluation. Longest bidimensional size of the tracer-avid component was calculated for lesions that had well-circumscribed margins. Oligometastatic disease was defined as the presence of one to three metastatic lesions outside the prostate or prostate bed. Initial screening of all images and imaging reports was performed by a nuclear radiology trainee physician (ATP). All studies deemed positive on this first review were rereviewed in consensus by two board-certified staff nuclear radiologists (AHG and MAN). In addition, a percentage (20%) of randomly selected studies that were deemed negative on the review by the nuclear radiology trainee physician were rereviewed by each of the two nuclear radiologists as a quality control measure.

Statistical analyses

Patient baseline characteristics were summarized as mean and standard deviation for continuous predictors and number (percentage) for ordinal and nominal predictors. For continuous predictors that showed nonnormality, values were presented instead by median and interquartile range. For measurements with a lower limit of detection (e.g., PSA level), values below that limit were set to zero for summarization and modeling purposes.

Time to recurrence association analyses were performed for the risk of disease relapse with the use of Cox proportional hazards regression, and time-dependent covariates were used for predictors collected at each successive scan. The index date was defined as the date of PSA measurement ≤0.1 ng/ml around the time of the baseline PET/CT. Follow-up time to a positive PET/CT study was recorded in days and right censored at the time of the last recorded scan. Linearity for continuous-valued predictors was assessed graphically through the examination of Martingale residuals; the proportional hazards' assumption was evaluated through analysis of the Schoenfeld residuals. Transformations were considered for highly skewed predictors. For instances of quasiseparability in modeling categorical predictors, a Firth correction was applied to the model fit. Reported P values were based on likelihood ratio tests, and all P values were declared statistically significant at a Bonferroni-corrected α of 0.05 to account for multiple testing.

The predictors such as PSA at diagnosis, posttreatment PSA, and PSA rate of decline were modeled using a log (X + 1) transformation, and Gleason score was modeled as a continuous predictor. Association analysis of the surgical margin was restricted to the patients who underwent RP. Ploidy and chromogranin were excluded from analyses because of high rates of unavailable values.


 > Results Top


Our institutional11 C-choline PET/CT database includes ≥10,000 PET/CT studies performed for ≥3500 patients with BCR PCa. Among these studies, 358 PET/CTs in 107 patients fulfilled the study criteria [Table 1].
Table 1: Characteristics of patients in study cohorta

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Of these patients, 13 (12.1%) had a positive surveillance PET/CT. The diagnosis of disease relapse was confirmed by image-guided biopsy (n = 5) and follow-up imaging (n = 8). False-positive or false-negative results were not observed. Mean follow-up duration from the time of surveillance PET/CT was 3 years (range: 1–5 years) [Table 2].
Table 2: Characteristics of patients with positive surveillance11C-choline positron emission tomography/computed tomography

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Among the 13 patients, two had local recurrence in the prostate bed and ten had distant metastases; one patient had both [Figure 2]. Most patients with distant metastases (9/10) had oligometastatic disease, with the most common sites being bones and lymph nodes [Figure 3] and [Figure 4]. The lesions tended to be moderately to intensely tracer avid (mean value of SUVmax: 6.1; range: 2.9–13.8) with various sizes (ranging from a cluster of multiple subcentimeter lymph nodes to osseous metastases up to 3.9 cm) [Table 2].
Figure 2:11C-choline positron emission tomography/computed tomography (a and b) showed pelvic lymph nodes (white arrows in a) and prostate bed mass (white arrow in b) at prostate-specific antigen <0.1 ng/ml. Diagnosis was confirmed on biopsy. Postchemotherapy positron emission tomography/computed tomography (c and d) showed complete metabolic response

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Figure 3:11C-choline positron emission tomography/computed tomography (a and b) showed supraclavicular (white arrow in a) and retrocrural lymph node (white arrow in b) at prostate-specific antigen <0.1 ng/ml. Diagnosis was confirmed on biopsy. Postchemotherapy positron emission tomography/computed tomography (c and d, white arrow in each) showed favorable treatment response

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Figure 4:11C-choline positron emission tomography/computed tomography (a and b) showed iliac bone (white arrow in a) and rib metastases (white arrow in b). Diagnosis was confirmed on biopsy. Postradiation positron emission tomography/computed tomography (c and d, white arrow in each) showed complete metabolic response

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Of the five patients with biopsy-proven metastases on PET/CT, three had histologic findings of small cell carcinoma and one had histologic evidence of adenocarcinoma with neuroendocrine differentiation. Serum chromogranin was raised (264 ng/ml) in one patient with small cell carcinoma characteristics. The level also was raised in two other patients who had metastases proven on subsequent imaging follow-up [Table 2]. Of note, the original tumor histologic finding of these patients was adenocarcinoma without small cell or neuroendocrine differentiation.

Serum PSA became detectable again for seven patients with positive surveillance PET/CT after a mean interval of 292 days (range: 105–543 days) from surveillance PET/CT. PSA ranged from 0.11 to 0.54 ng/ml. By comparison, the other six patients did not have detectable serum PSA at last follow-up.

We identified one association with a nominal P < 0.05 – N stage was associated increased risk of disease relapse (hazard ratio [95% confidence interval]: 3.85 [1.08–13.68]; P = 0.04) [Table 3]. However, no result met the overall level of significance after accounting for multiple testing (α = 0.05/12 features ≈ 0.0042).
Table 3: Association analyses for risk of relapse

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 > Discussion Top


We present a series of patients with a history of BCR PCa who underwent surveillance imaging with11 C-choline-PET/CT when they had an undetectable PSA level (≤0.1 ng/ml). In our study, surveillance11 C-choline-PET/CT detected disease relapse at an undetectable PSA in 12.1% (13/107) patients. Of note, the serum PSA became detectable again in only seven patients with positive surveillance PET/CT, after a mean interval from surveillance PET/CT of 292 days (range: 105–543 days). Thus, our cohort had disease relapse detected much earlier than what would have occurred on the basis of PSA alone. Of the ten patients with distant metastases, nine had oligometastatic disease on surveillance PET/CT.

Serum PSA level and PSA kinetics are considered strong predictors of metastases detection on a PET/CT study of patients with BCR PCa. In general, the correlation is linear between these predictive factors and rate of detection of metastases on PET/CT.[12] The low rate of detection of metastases, which was in the range of 14%–20.5% in recent studies, at low PSA levels (between 0.2 and 1.0 ng/ml) is considered a relative limitation of11 C-choline PET/CT.[10],[15],[16] This PSA range is considered to be a window of opportunity when salvage therapies are likely to be most efficacious.[12],[17] Moreover, positive11 C-choline PET/CT can predict PCa-specific survival in this low PSA range, and a normal11 C-choline PET/CT can be associated with a very low rate of recurrence at 30 months.[15],[16] Yet, a PSA level >1.0 ng/ml is generally accepted as a reasonable indication for PET/CT with radiolabeled11 C-choline. The European Association of Urology endorses this practice.[13] Our results should not be taken as running contrary to this generally accepted practice. These guidelines specifically apply to patients with early biochemical relapse after curative therapies. On the other hand, the patients in our study had late-stage disease that had evolved through multiple clinical courses. Therefore, our findings at best show a proof of concept that in a selected group of patients that have previously received multiple treatment regimens for BCR PCa,11 C-choline PET/CT has the potential to detect disease relapse at an undetectable PSA level.

The underlying pathophysiologic factors of disease relapses at an undetectable PSA are not entirely evident. Small cell histology or neuroendocrine differentiation, seen in four of the five patients in our cohort who had histopathologic confirmation of their metastases, is clearly one potential factor. Small cell histology, in particular, is known to be associated with undetectable PSA related to tumor burden.[18] Second, radiographic progression of the disease with nonincreasing PSA levels can be seen in patients receiving ADT.[14] A European expert consensus panel recommends early imaging in patients with metastatic castration-resistant PCa who receives androgen receptor pathway inhibitors independently of PSA response because of the discordance between PSA progression and radiographic progression.[14],[19] However, in the present study, almost all patients received some form of ADT or had known castrate levels of testosterone, or both. We surmise that prolonged chemohormonal therapy may result in selective outgrowth of non-PSA-producing disease in some patients. Surrogate end points based on serum PSA levels are increasingly being used for assessment of oncology agents in clinical trials and for the US Food and Drug Administration approval[20] despite the fact that overall survival and radiologic progression-free survival are the recommended primary end points for such clinical trials.[19] Based on results of the present study, we also believe that investigation is needed to identify alternative biomarkers of early disease relapse or progression in PCa patients who have received multiple treatment regimens for their BCR PCa.

In patients with BCR PCa, there is heterogeneity of relationship between the volume of metastatic disease and a given PSA level. Unlike at higher PSA levels, the detection of subtle or low-volume local recurrence in the prostate bed at low PSA levels is considered a limitation of11 C-choline PET/CT.[12],[21] The inferior detection rate for local recurrence is postulated to be due to an intrinsic dependence of11 C-choline PET/CT on a critical volume of disease. Moreover, urinary excretion of the radiotracer can sometimes confound detection of local recurrence in and around the prostate bed. Therefore, possibly, the detection rate of disease relapse at undetectable PSA levels that we observed in the present study may be underestimated slightly. We also used a relatively stringent definition of a true-positive PET/CT scan. The determination of a positive PET/CT was not based on original radiology reports but on joint review by two experienced nuclear radiologists. Finally, all patients with negative surveillance PET/CT scans were monitored for at least 6 months to minimize the possibility of a false-negative result.

We aimed to identify prognostic factors that could help predict the risk of disease relapse among patients with undetectable PSA. However, few events occurred in our relatively small study cohort, and the data were underpowered to identify even large effect sizes. This implies that we do not know the clinical or laboratory variables that may allow us to identify at-risk patients with treated BCR PCa who may benefit from surveillance11 C-choline PET/CT at undetectable PSA levels. Prospective studies are warranted to further evaluate this question given the paucity of surveillance and follow-up imaging guidelines for patients with BCR PCa after they achieve an undetectable PSA level.

In the near future, prostate-specific membrane antigen (PSMA)-based PET radiotracers are likely to become the mainstay of molecular imaging in BCR PCa patients.68 Ga-PSMA PET tends to have a high diagnostic yield for the detection of metastases in patients with BCR PCa even at low PSA levels.[22],[23],[24],[25] Second, metastatic lesions tend to have higher contrast on68 Ga-PSMA PET than on PET with choline-based radiotracers. However, PSMA-based radiotracers have not been evaluated for the detection of disease relapse specifically at undetectable PSA in patients with history of BCR PCa. Therefore, it would be interesting to know the rate of detection of metastases with PSMA-based PET radiotracers in this challenging cohort of patients. The results of our study can serve as a baseline for future studies that may perform this evaluation of PSMA-based radiotracers.

Our retrospective study has limitations. Despite interrogation of a large database with ≥10,000 studies, our study cohort of 107 patients was relatively small albeit the largest series reported in the literature. Important considerations beyond the scope of our study were evaluation of (1) the impact of detection of disease relapse at undetectable PSA levels on patient outcomes and (2) the frequency of surveillance PET/CT and the economic implications of PET/CT as a surveillance modality in patients with late-stage BCR PCa and undetectable PSA levels. Another limitation is the lack of histopathologic confirmation in all patients with positive surveillance11 C-choline PET/CT. This limitation has been acknowledged by other investigators who had similar aims.[6],[26] The decision to biopsy is at the discretion of the referring provider and often is decided after taking into consideration of various clinical circumstances.


 > Conclusion Top


Surveillance11 C-choline PET/CT has the potential for detection of early disease relapse in patients with history of BCR PCa at serum PSA ≤0.1 ng/ml. Our results suggest that further research is necessary to investigate additional biomarkers beyond PSA that can identify early disease relapse or disease progression in late-stage BCR PCa patients with undetectable PSA levels. Moreover, prospective studies are needed to evaluate the impact of early disease detection on the outcomes of these patients.

Acknowledgments

We are grateful to Colleen M. Sauber, MEd, ELS, Instructor in Biomedical Communications, Section of Scientific Publications, Mayo Clinic for her help with editing the manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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