Day-to-day variability of [⁶⁸Ga]Ga-PSMA-11 accumulation in primary prostate cancer: effects on tracer uptake and visual interpretation

Prostate cancer (PCa) is the second most common cancer amongst men in the world, as recorded in 2018 [1]. Molecular imaging of this malignancy either in primary or metastatic setting is presently dominated by the ligands directed to the prostate-specific membrane antigen (PSMA). This is a membrane-bound enzyme which is overexpressed in PCa cells compared to benign prostatic tissue by approximately 100- to 1000-fold [2, 3]. ⁶⁸Gallium-labeled PSMA compounds, such as [⁶⁸Ga]Ga-PSMA-11, is therefore considered a highly tumor-specific radiotracer for PCa. Since PSMA agents have an unprecedented accuracy in recurrent PCa, it has been rapidly adopted in the clinic over the last years [4, 5]. In staging of primary PCa, Hofman et al. recently published a prospective study, showing the higher diagnostic accuracy of [⁶⁸Ga]Ga-PSMA-11 PET/CT in men with high-risk primary prostate cancer, as compared to conventional imaging (CT and bone scan) [6], which is as well supported by retrospective studies [7‐9].

In many solid tumors, active surveillance and response monitoring with ¹⁸fluorine-fludeoxyglucose (2- [¹⁸F]FDG) PET/CT is quite common, and adopted in various guidelines [10]. Variations in [¹⁸F]FDG-accumulation can provide valuable information on the activity and efficacy of new cancer therapeutics. The Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) or European Organization for Research and Treatment of Cancer (EORTC) criteria are often used to quantify the response on therapy using [¹⁸F]FDG PET/CT. These criteria classify the disease status as ‘responder’, ‘progressed’, or ‘stable’ based on changes in the semiquantitative standard uptake values (SUV), corrected for lean body mass (SUL) [10]. However, [¹⁸F]FDG PET/CT is usually not suitable in PCa, as most tumors show limited FDG-accumulation, especially in hormone-sensitive setting.

Monitoring the response after therapy with [⁶⁸Ga]Ga-PSMA-11 PET/CT may be helpful in PCa, yet this approach is not validated yet [11]. As with FDG-accumulation, the extent and intensity of the PSMA-uptake can be compared between scans to quantify response, and when deemed necessary adjust therapy. However, not many papers are published about response monitoring or active surveillance using [⁶⁸Ga]Ga-PSMA-11 PET/CT [12]. One study by Gupta et al. [13] compared the functional criteria PERCIST 1.0 and EORTC in [⁶⁸Ga]Ga-PSMA-11 PET/CT with the morphological criteria according to RECIST V1.1 in patients with metastatic PCa and biochemical progression. According to this study, molecular imaging criteria performed best in detecting progression based on changes of ≥ 25% SUV_mean (EORTC) or ≥ 30% SUL_peak (PERCIST) after hormone treatment [13]. However, the study does not describe if the biological variation in [⁶⁸Ga]Ga-PSMA-11 uptake is comparable to that of [¹⁸F]FDG, and if the same cutoff values apply, while only changes that exceed the normal variability should be interpreted as treatment response or disease progression. Although two additional studies assessed this test–retest repeatability in metastatic prostate cancer using [⁶⁸Ga]Ga-PSMA-11 [14] and [¹⁸F]DCFPyL [15], no studies in the primary setting are performed to this day, as far as we are aware of. Therefore, the aim of this study was to assess the day-to-day variability of [⁶⁸Ga]Ga-PSMA-11 uptake and visual interpretation in patients with primary prostate cancer.

To our knowledge, repeatability of [⁶⁸Ga]Ga-PSMA-11 PET/CT scans in the primary PCa setting has not been investigated before. This information is essential to perform response monitoring based on PSMA PET/CT. Therefore, the aim of this study was to assess the repeatability of [⁶⁸Ga]Ga-PSMA-11 PET/CT scan in primary PCa patients in a 4-week interval.

The repeatability coefficient of SUL_peak in the prostate tumor was 18.1%, suggesting that below this value, the absolute difference between two scans in one patient (under the same circumstances) should fall within 95% probability. If the relative difference in SUL_peak is larger than ± 18%, then the difference is more likely to be explained by true changes and then by measurement errors. The absolute RC in the prostate tumor is probably less useful than the percentage, as there is a broad range in uptake between patients. The SUL_mean of normal tissue has a RC of 23.8% on average. In general, the RC of the SUL_max is higher than the RC of SUL_mean, since SUL_max is more susceptible to noa. The RC of the SUL_mean of the blood pool was 26%. However, due to the very low radiotracer activity in the bone and blood pool, small absolute differences in SUL_mean can already lead to a large percentage difference. Thus, in these organs, it is more informative to look at the repeatability coefficient of the absolute difference, which is 0.2 for the blood pool and 0.2 for bone.

The visual differences between the two scans were not considered clinically relevant by the expert readers, and were predominantly related to a variable urinary excretion or variances in noise levels. Particularly, in three patients the activity in the prostate was noisy; therefore, the primary tumor was difficult to distinguish from the background, probably explaining the initial inter-observer differences in visual assessment. Next, in one of the patients, the visual appearance of a lymph node was different, which might have been caused by a larger (22%) deviation in the injected dose between the two scan points in that particular case. Still, in this patient the tumor and other organs were not visually different.

The current study had quite a similar setup as previous studies described in the literature, but there are some relevant differences [14, 15]. Previous studies looked at metastatic patients or [¹⁸F]DCFPyL instead of [⁶⁸Ga]Ga-PSMA-11. Given the similar bio-distribution, findings for [⁶⁸Ga]Ga-PSMA-11 may probably be generalized to [¹⁸F]DCFPyL [22]. Noteworthy is that [¹⁸F]PSMA-1007 has a distinctly different bio-distribution than the latter radiotracers [23]. Also, most other studies quantified uptake with body-weight-corrected SUV instead of SUL, yet the RC of SUL_max and SUV_max within the same patient in a test–retest setting is comparable. The RC of SUL_max of the prostate lesion in our study was 21.9%. Pollard et al. reported 30.3% and Jansen et al. 31.0% SUV_max. The wCV of the prostate tumor in our study is 7.9% for SUL_max, compared to 10.9% for SUV_max reported in the study by Pollard et al. [24]. These studies investigated patients with metastatic lesions as opposed to the patients with primary prostate cancer in our study. Metastatic lesions have a larger variation in PSMA receptor expression and general expansion of disease between patients than primary PCa tumors, thus possibly resulting in a higher RC than ours. When comparing our TBR findings to Jansen et al. [15], the RC is within the same range (38.4% vs 37.3%). The RC of the SUL is smaller than the RC of the TBR (21.9% vs 38.4% SUL_max vs TBR_max), probably because TBR adds the SUL variation both the blood pool and the tumor. This was found by Jansen et al. as well [15]. In prior studies, a shorter window of not more than 7 days for repeatability was used. Due to the fact that prostate cancer is generally an indolent cancer, a 4-week interval was considered reliable, as shown in the present study.

In general, the SUL_max values of normal tissues found in the literature for PSMA PET/CT scans are comparable to ours [16, 25‐27]. The differences between the two scans are largest in the ureter and bladder, which can be explained by variations in urine volume and radiotracer activity in the bladder. Though patients were not allowed to receive furosemide according to study protocol study, two patients had a protocol violation and received furosemide before one acquisition, resulting in a clear difference in bladder radiotracer activity (i.e., 2.1 vs 9.6 SUL_mean). The differences between two scans are lowest in the liver, concordant to the findings of Li et al. [28]. The uptake variation of the parotid is on average repeatable (23.4%), although there is a large range, and comparable to the results of Pollard et al. (26.5%). However, comparing the SUL_mean to [¹⁸F]DCFPyL found by Li et al. [28], the parotid and kidney SUL_mean were lower than our findings. Still SUL_mean of the liver was equal.

The repeatability of [⁶⁸Ga]Ga-PSMA-11 uptake in prostatic lesions is not entirely comparable to previous findings of [¹⁸F]FDG uptake in malignancies [21]. However, [¹⁸F]FDG scans do require a more concise preparation and patients’ adherence to the protocol [29]. In the day-to-day clinical setting, patients are likely to have variation in, for instance, blood glucose levels or physical activity, thus directly resulting in a less reproducible [¹⁸F]FDG uptake. The advantage of [⁶⁸Ga]Ga-PSMA-11 PET/CT is that signal intensity depends primarily on the number of PSMA-expressing cells and expression density per cell [30]. In contrast to [¹⁸F]FDG, which accumulates to some extent in most tissues in the body, PSMA-ligands tend to accumulate only in specific tissues. Sahakyan et al. [31] found that variability in the liver and kidneys can be caused by intrapatient factors (i.e., time of day, recent meals, hydration status), and that interpatient factors (i.e., weight, height, body composition, medical comorbidities) can influence uptake in the salivary glands. Nonetheless, these influences were described in patients who underwent therapy, so it is difficult to distinguish between therapeutic effects and day-to-day physiological variations.

All these characteristics aid in repeatable quantitative [⁶⁸Ga]Ga-PSMA-11 uptake in PCa lesions, and so it should allow for stable follow-up monitoring of the disease. A change in PSMA uptake in the tumor more than 18% as mentioned before may indicate either disease progression or treatment response. In a preclinical setting, PSMA expression is already used for response monitoring in taxane-based chemotherapy [32]. Note that careful image interpretation is needed when describing an increase or decrease in PSMA uptake [33]. Androgen deprivation therapy can influence the PSMA expression, where up- or downregulation is not unambiguously affected by type and duration of medication [34‐36]. If PSMA PET/CT is used for response monitoring of radionuclide therapy, the tumor sink effect cannot be neglected [37].

[⁶⁸Ga]Ga-PSMA-11 PET/CT scans are repeatable in primary prostate cancer patients, with a repeatability coefficient of 18% SUL_peak in the primary prostate lesions within a 4-week time period. Variations found in the current study for normal tissues (liver, parotid) were comparable to those previously found in the metastatic setting. Based on these results, [⁶⁸Ga]Ga-PSMA-11 PET/CT scans may be used for accurate surveillance and therapy response monitoring. Still, repeatability and distribution is different from [¹⁸F]FDG-PET/CT, indicating that EORTC- or PERCIST-criteria for solid tumors may not be suitable in [⁶⁸Ga]Ga-PSMA-11 PET/CT.