Up to 1000-fold increased expression of PSMA in prostate cancer cells [9], has increased the use of PSMA-targeted imaging methods and made it an essential part of prostate cancer management in the recent 10 years. PSMA PET/CT is advantageous tool due to its on-site production and providing high quality imaging with low radiation dose thanks to its high emission rate. The diagnostic power of [68Ga]Ga-PSMA PET/CT agents in primary diagnosis, staging and biochemical recurrence of prostate adenocarcinoma was investigated by a lot of center and it was found superior to conventional imaging modalities with up to 90% of diagnostic rates [14]. However, limited data exist about the role of PSMA PET/CT in systemic therapy response assessment in the literature. It is still not clearly figured out that how androgen supressor agents and taxan-based chemotherapeuticals effect PSMA expression and uptake of [68Ga]Ga-PSMA agents in target cells and as a result how the changes of uptakes in target cells should be interpreted. PERCIST 1.0 criteria [15] which was published for therapy response of 2-fluorodeoxyglucose (2-[18F]FDG) PET/CT in 2009, is not entirely appropriate for PSMA PET/CT due to different uptake mechanisms and metabolic pathways of radiopharmaceuticals.
On February 2020, a panel was recruited by EAU and EANM with joining of intenational experts of prostate carcinoma in the fields of nuclear medicine, radiology and urology to make clear the utility, best timing for performing, criteria for treatment response, benefit to the patients and use of radiolabeled PSMA PET tracers [12]. According to the consensus criteria, PSMA PET/CT should be used prior and after all local/systemic treatments in metastatic disease to evaluate response. Besides, due to potential flare phenomenon of ADT and possibility of misinterpretation in early stage of therapy, the PSMA PET/CT should not be performed earlier than 3 months after initiation of ADT. The panelists also declared that the patients should be divided as responders to treatment (complete response, partial response and stable disease) and not responders (progressive disease). In responders to therapy, complete response can be considered as absence of PSMA uptake in target foci, more than 30% decrease in uptake and tumor volume in target foci can be considered as partial response and less than 30% decrease or increase in uptake and tumor volume in target foci can be considered as stable disease. Otherwise, more than 30% increase in uptake and/or ≥ 2 new lesion represents progression. Nevertheless, it is indicated that due to lack of sufficient data about PSMA behavior after therapy, the suspicion remains in therapy response assessment except in patients with complete response and obvious progression. Although the 30% of threshold value was determined for 2-[18F]FDG, due to not being a proved threshold value for PSMA and for the purpose of determining baseline value to further studies, 30% threshold value was chosen for PSMA as well. In this study, we evaluated comparatively 100 [68Ga]Ga-PSMA-11 PET/CT images of 50 patients in light of these response criteria. Then, the results of [68Ga]Ga-PSMA-11 PET/CT images were compared with serum PSA response. High concordance was found between PSMA PET/CT and serum PSA responses (Gamma coefficient: 0.84). In a study by Schmidkonz et al. [68Ga]Ga-PSMA-11 PET/CT that performed for biochemical recurrence and serum PSA values were compared and near to high concordance was found between total PSMA amount which equals the multiplication of total PSMA volume and SUVmean of each lesion and serum PSA changes (Cohen’s Kappa coefficient: 0.78) [16]. This value is similar to ours but in that study total PSMA amount was used for comparison with serum PSA values. Whereas we evaluated the therapy response categorically as progression, stable disease, partial or complete response.
In a study which has similar patient number and methodology to ours, Kuten et al. found a concordance between [68Ga]Ga-PSMA-11 PET/CT and serum PSA response with the rate of 65.4% which is close to ours (78%) [17]. Besides, the authors detected that most discordance occured in biochemical stable status (90.9%). In our study, five of 11 discordant situation were seen in biochemical stable patients. Serum PSA and PSMA PET/CT results of three of these patients whose further follow-up data could be obtained, became concordant at progressive status after a while. Because while serum PSA value represents cumulative active tumor cell amount of the body, the PSMA PET/CT results are obtained with lesion-based comparison in light of criteria. For instance, two new lymph node lesion in PSMA PET/CT is thought progression after therapy, but there may not be a significant difference in the number of active tumor cells between two assessment. On contrary, despite increasing number of active tumor cells with increased serum PSA, PSMA PET/CT may not be able to represent progressive results according to the criteria. It is possible to detect more clear relationships at following response assessments especially when they were evaluated with former PET/CT images and serum PSA values. That’s why serum PSA and PSMA PET/CT should be correlated during response assessment and therapy management process. Pathological studies and prospective randomized clinical trials are necessary to overcome that unclear situation.
Gupta et al. compared the molecular (EORTC and PERCIST) and morphological (RECIST and MDA) response criteria on biochemical progression and they found superior the molecular response criterias to morphologicals significantly [18]. They also pointed out that molecular criteria is more useful especially in bone lesions which are not easily diagnosed as sclerotic lesion or metastasis with morphological modalities. In our study, of the 19 patients whose PET/CT and PSA results are concordant as progression, 13 had progression due to sclerotic bone metastasis. It is very crucial to use molecular response criteria instead of morphological criteria especially in terms of bone metastases at follow-ups.
Despite wide use of PSMA PET/CT around the world, the question that how systemic antiandrogenic therapies effect PSMA expression still remains. It is known that antiandrogenic therapies increase PSMA expression of target cells via FOLH1 gene by suppressing androgen releasing hormones and androgen receptors [19, 20]. Increased PSMA expression in advanced stage and castration-resistant prostate carcinoma is also showed [21, 22]. In a study performed with cell culture that contains enzalutamide and abiraterone by Murga et al., it is showed that PSMA expression of target cells increases with antiandrogenic therapy and drops back to basal levels following cessation of therapy. Moreover, in the castration-sensitive cells, antiproliferative effect was seen in addition to increased PSMA expression while antiproliferative effect diminishes in the castration-resistant cells despite persisting increased PSMA expression [23]. Some clinical trials also showed that PSMA expression increases in early periods of ADT (< 6 weeks) and decreases at the later periods (> 3 months) [22, 24,25,26,27]. In a study which investigates the long period effects of ADT to PSMA expression by Afshar-Oromieh et al. ADT was initated to the patients and [68Ga]Ga-PSMA-11 PET/CT was performed after mean 229 ± 89 days to evaluate therapy response and changes in SUV values [26]. In the second PET/CT, 45% of lesions remain visible and SUVmean and SUVmax values decreased in 71% and 74.2% of lesions, respectively. Total lesion number, SUVmax and SUVmean values, tumor volume, SUV values/tumor volume and serum PSA values were also found statistically significantly lower at second PET/CT images. The authors concluded that the proportional decreasing of SUV values and tumor volume may be explained as that long-term ADT use causes decreased tumor cell clones following apoptosis. They also hypothesized that increase in SUVmean and SUVmax in the 12.9% and 19.4% of lesions could be compatible with the cell clones becoming resistant to castration. Due to presence of median 151 days between PET/CT images in our study, we assume that we are not be able to observe long-term effects of ADT. However, of the 17 patients who received ADT therapy, 14 (82.5%) had concordant results in PSMA PET/CT and serum PSA. There is a high concordance even it is not statistically significant. In a study which consists of non-metastatic 108 patients who received ADT median 2.9 months by Onal et al. a low but significant correlation was found between the changes of prostate gland SUVmax and serum PSA (Spearman coefficient: 0,367, p < 0,05) [28]. We found a low correlation between SUVmax and SUVmean of prostate gland and serum PSA changes (Spearman coefficient for SUVmax and SUVmean: 0.457 and 0.449, respectively) similar to that study. However, less patients with different received therapy agents exist in our study (50 vs. 108). We also compared the changes of serum PSA and SUVmax of lymph nodes and bones and significant correlation was found between them (Spearman coefficient for lymph nodes and bone: 0.657 and 0.707, respectively). When the results of Schmidkonz et al. which shows high concordance between total PSMA and serum PSA changes were taken under consideration [16], it may be concluded that serum PSA has higher concordance with PSMA PET/CT results in showing therapy response especially in metastatic patients according to the criteria.
A statistically significant difference was not found between patients with concordant and discordant results in terms of received therapies in our study. A study which is similar to ours in point of evaluating different therapy regimens was conducted with 43 patients who received 67 systemic therapies by Grubmüller et al. Serum PSA changes after therapy shows significant but low correlation both with changes of all PET parameters and response according to RECIST (Cohen’s Kappa: 0.2–0.3, p < 0.05) [29]. In our study, we found high concordance in PET/CT and serum PSA results regardless of received theapies (Gamma coefficient: 0.84). Gamma coefficent was used because it is more suitable for consecutive categorical data comparison.
Increased PSMA expression in the castration-resistant prostate cells was shown in the literature [21]. However, there is not a study which investigates the efficiacy of the hormone resistance status to response assessment to the best of our knowledge. When our patient group was divided as hormone sensitive and resistant, there was not a significant difference in terms of concordance between PSMA PET/CT and serum PSA results. Therefore, in our opinion, castration resistance status does not a restrictive factor in response assessment. The serum PSA and PSMA PET/CT findings should be evaluated together regardless whether the patient is castration sensitive or not.
There are some limitations of the study. First, limited number of patients who received different kinds of therapy were included. More homogenous patient groups in which patients who are at similar stage of disease and received same therapy agent were included, have to be created to get more accurate data about therapy response. Secondly, the long-term results of patients do not exist. The behavior of PSMA in target cells can be observed better at long-term results with correlation of PET/CT and serum PSA values. Thirdly, the study is retrospective. Multi-centered prospective studies with contribution of histopathological studies should be performed from the initiation of therapy so that the changes of PSMA uptake in target cells can be detected more clear.
