In this prospective test-retest study we formally report the repeatability of 68Ga-PSMA in both relapsing and metastatic tumour. The main finding of this study is the relatively high day-to-day variability of tumour SUVmax with repeatability levels of agreement varying between +43% and -46% for all lesions taken together. For local recurrences values vary between +23% and -33%, for the smaller lymph node and bone metastases values are +40% to -49% and +56% to -47%, respectively. In addition to this, we show a significant correlation between lesion size and SUVmax repeatability levels of agreement.
With respect to our second aim no significant differences in repeatability between standard (OSEM+TOF+PSF) reconstruction and (TOF+PSF) + BPL reconstruction could be shown in this pilot study. There was a small difference in favour of the standard reconstruction. However, BPL reconstructions resulted in significantly higher SUVmax of tumour lesions as compared to standard reconstructions, with significantly higher relative increases in smaller lesions.
Pollard et al. reported on the repeatability of 68Ga-PSMA-HBED-CC (PSMA-11) SUVmax in relapsing prostate cancer (21). Repeatability levels of agreement were given for lymph node and bone metastases only and were lower than in our study: 30-40% versus 40-60%. Also for other radiotracers like 18F-DCFPyL, 18F-FDG and 18F-FLT values in the 30-40% range were reported for SUVmax (22,23). A possible explanation for the higher day-to-day variability in our study is the relative high number of small lesions. Our study hints at a negative correlation between lesion SUVmax variability and lesion size (Figure 2A). We believe the patient cohort of this pilot study to be representative for patients with relapsing prostate cancer showing relatively small tumour lesions in lymph nodes and bones. Pollard et al. did not find any relationship between lesion size and SUVmax variability (21). A possible explanation for this is that they only reported on relationships within classes, i.e. within typically smaller lymph node and bone metastases, where we report on all lesions including the larger relapses of the primary tumour in the prostate bed.
A larger day-to-day variability may have implications for lesion-specific response to treatment monitoring. With respect to treatment response monitoring using 18F-FDG Wahl et al. proposed a minimum of 30% SUVmax decrease for a true response in their PERCIST response criteria (24). A minimum of 30% response is probably not appropriate for the majority of the relatively small lesions that are typically found in (early) relapsing prostate cancer. Our study shows that a minimum response of 50% might be more appropriate in these cases, when using 68Ga-PSMA.
Measurements of SUVmax are known to be considerably subject to noise and thus to higher signal variability (25). In order to overcome the drawback of noisy SUVmax, SUVpeak was proposed using a 1 cm3 volume centered around the voxel with the highest SUV (i.e. SUVmax) thus being less subject to noise. Unfortunately SUVpeak seems to be appropriate for larger tumour volumes only, because a 1 cm3 volume would correspond to a sphere of at least 12 mm diameter. Most of the lymph node and bone metastases in our study had dimensions smaller than that. Thus SUVpeak was not used in our study. In addition, SUVmax is the SUV measurement that is widely used in the clinic.
When confronted with the relatively small tumour lesions in patients with (early) relapsing prostate cancer, partial volume effects have to be anticipated. This will be particularly the case when quantifying tracer expression in small lesions using tracers with high tumour-to-background ratios like 68Ga-PSMA, but is not always appreciated (26,27). For example, in a report on the effects of androgen deprivation therapy on 68Ga-PSMA SUVmax in primary prostate cancer, lymph node and bone metastases as recent as April 2020, possible impact of partial volume effects was not discussed at all (28).
The possible importance of partial volume effects can be illustrated by the BPL versus standard reconstructions, as applied in our study. Two factors that contribute to the partial volume effect (spill-in and spill-out) are the finite spatial resolution of the imaging system and image sampling on a voxel grid not exactly matching the actual contours of tracer distribution (17). Impact of partial volume effects is strongly dependent on lesion size and is coming into play when lesion size falls below 2 to 3 times the resolution of the system, i.e. below 10 to 15 mm for an average PET/CT scanner system (16). With respect to tracer SUVmax measurements, partial volume effect will generally result in lower SUVmax values. Correcting for the aforementioned factors (i.e. partial volume correction) is complex and not all factors can be controlled for from one imaging session to another, introducing possible biases. In addition, partial volume correction can be applied after image reconstruction but also during image reconstruction (18). The Bayesian penalized likelihood (BPL) reconstruction algorithm called Q.Clear can be regarded as an algorithm correcting for partial volume, because it has a component that is correcting at the voxel level during image reconstruction (16). The resulting higher uptake/expression values in small lesions (compared to standard reconstruction) have been reported for several radiotracers, including 18F-PSMA-1007 in prostate cancer patients (29). In the latter study SUVmax with BPL reconstruction has been compared to standard (OSEM+TOF+PSF) reconstruction, stratified for lesion size. A significant reported increase in SUVmax with BPL reconstruction for lesions smaller than 10 mm diameter only was reported. In our study we confirm these findings for the 68Ga-PSMA tracer, including the relationship with lesion size (table 1), thus highlighting the importance of partial volume effects and its correction.
We hypothesized that the BPL reconstruction algorithm Q.Clear has the ability to lower signal variability in the small lesions typically encountered in early relapse or early metastatic disease of prostate cancer. Our study did not confirm our hypothesis. In contrary, signal variability tended to be higher with BPL reconstruction compared to standard reconstruction. We speculate that the partial volume correction component of BPL reconstruction might be responsible for the higher signal variability. A possible explanation for this could be the ‘overshoot’ reported with BPL reconstruction for small spheres at high sphere-to-background ratios in a phantom study using 18F-FDG (30). The high sphere-to-background ratios in this study may correspond to the high tumour-to-background ratios typically encountered in 68Ga-PSMA avid prostate cancer lesions.
Limitations. This single site study has several limitations. The assignment of tumour lesions was only done by two experienced image readers, and inter-observer variability was not assessed. This was considered acceptable because the exact nature of the lesions was less important in light of the general aim of the study, i.e. assessment of signal variability. The same holds for the fact that for the majority of the lesions there has been no confirmation by histopathology.
With respect to the comparison of the BPL and standard reconstructions, the image reading was not blinded. This was deemed acceptable because the visual appearance of both reconstructions is different, precluding true blinded image reading.
No significant difference was found between BPL and standard reconstruction signal variability, probably because the study was underpowered. Being a pilot study, the results can be used for power calculations for a possible future study.