Factors predicting biochemical response and survival benefits following radioligand therapy with [177Lu]Lu-PSMA in metastatic castrate-resistant prostate cancer: a review

Background Prostate cancer (PC) is one of the most common cancers in men. Although the overall prognosis is favorable, the management of metastatic castration-resistant prostate cancer (mCRPC) patients is challenging. Usually, mCRPC patients with progressive disease are considered for radioligand therapy (RLT) after exhaustion of other standard treatments. The prostate-specific membrane antigen (PSMA) labeled with Lutetium-177 ([177Lu]Lu-PSMA) has been widely used, showing favorable and successful results in reducing prostate-specific antigen (PSA) levels, increasing quality of life, and decreasing pain, in a multitude of studies. Nevertheless, approximately thirty percent of patients do not respond to [177Lu]Lu-PSMA RLT. Here, we only reviewed and reported the evaluated factors and their impact on survival or biochemical response to treatment to have an overview of the potentialprognostic parameters in [177Lu]Lu-PSMA RLT. Methods Studies were retrieved by searching MEDLINE/PubMed and GoogleScholar. The search keywords were as follows: {(“177Lu-PSMA”) AND (“radioligand”) AND (“prognosis”) OR (“predict”)}. Studies discussing one or more factors which may be prognostic or predictive of response to [177Lu]Lu-PSMA RLT, that is PSA response and survival parameters, were included. Results Several demographic, histological, biochemical, and imaging factors have been assessed as predictive parameters for the response to thistreatment; however, the evaluated factors were diverse, and the results mostly were divergent, except for the PSA level reduction after treatment, which unanimously predicted prolonged survival. Conclusion Several studies have investigated a multitude of factors to detect those predicting response to [177Lu]Lu-PSMA RLT. The results wereinconsistent regarding some factors, and some were evaluated in only a few studies. Future prospective randomized trials are required to detect theindependent prognostic factors, and to further determine the clinical and survival benefits of [177Lu]Lu-PSMA RLT.


Introduction
Prostate cancer (PC) is one of the most common cancers in men [1]. Although the prognosis is generally favorable [2], the treatment of PC is challenging in the cases of metastatic castration-resistant prostate cancer (mCRPC) [3]. The prostate-specific membrane antigen (PSMA) is a transmembrane protein and highly expressed in PC cells [1,4]. Radioligands targeting PSMA are promising agents for the imaging and treatment of PC patients [1,[5][6][7].
Although the phase III clinical trial is still ongoing, [ 177 Lu]Lu-PSMA RLT is widely accepted in countries where it is available and seems to be well-tolerated. It has been successfully employed reducing prostate-specific antigen (PSA) levels, increasing the quality of life, decreasing pain and analgesic intake, in a multitude of studies [4,[20][21][22][23][24][25][26][27]. [ 177 Lu]Lu-PSMA RLT seems safe even in patients at advanced stages of the disease [28]. A phase II trial demonstrated that 57% of patients achieve a biochemical response, described as ≥50% PSA reduction 12 weeks after therapy [21]. It should be emphasized that the response rate is reportedly variable [29]. The OS ranges between 7.5 and 15 months and progression-free survival (PFS) between 4.5 and 13.7 months [29].
Since approximately 30% of patients do not respond to this expensive treatment [22], it is still of concern to predict the outcome and individualize the treatment considering its potential benefits. Furthermore, [ 177 Lu]Lu-PSMA RLT is administered in almost all of the reviewed studies as a "last line" treatment. Most of the patients have already received chemotherapy, abiraterone, or enzalutamide, as well as [ 233 Ra]Radiumdichloride ([ 223 Ra]RaCl) or external radiation therapy, if they were not contraindicated. Hence, the moderate survival benefit in these heavily pre-treated patients would be of importance. So far, several demographic, histological, biochemical, and imaging factors have been assessed as predictive parameters for a response to [ 177 Lu]Lu-PSMA RLT. Here, we reviewed the evaluated factors and their impact on survival or biochemical response to treatment to have an overview of the potential prognostic parameters in [ 177 Lu]Lu-PSMA RLT.

Methods
In this narrative review, studies were retrieved by searching the following literature databases in September 2020: MEDLINE/PubMed and Google Scholar. No language or time limitation was applied in all the process of searching. Moreover, the references of the included and relevant systematic review studies were searched manually. The search keywords were as follows: {("177Lu-PSMA") AND ("radioligand") AND ("prognosis") OR ("predict")}. Studies discussing one or more factors which may be prognostic or predictive of response to [177Lu]Lu-PSMA RLT, that is, PSA response and survival parameters, were included. Since the 177Lu-PSMA is employed for the treatment of mCRPC patients less than a decade, we used the option of showing the results for every year, separately, to simplify the search.
Articles were excluded if they were a review, case report, letter, guideline, and articles on radiochemistry, preclinical studies, biodistribution, or dosimetry. Following retrieving the pertinent articles, two autonomous reviewers screened the title and abstract of all the included studies according to the inclusion criteria. In the next step, the full texts of included articles were reviewed in detail. Any disagreements were resolved by consensus. The following data were extracted from each included paper: title, first author, year of publication, sample size, age, initial PSA value, PSA doubling time, baseline PSA value, prior therapies, Gleason score, activity and number of [ 177 Lu]Lu-PSMA-RLT cycles, PSA decline, the intensity of uptake on PET/CT, visceral metastasis, bone metastasis, lymph node metastasis, level of alkaline phosphatase, level of lactate dehydrogenase, bone marrow status, level of other serum markers, performance status, and analgesic intake (Table 1).

Predictive factors
Initial PSA and PSA doubling time  [23]. In another investigation, Bräuer et al. assessed 59 mCRPC patients, who had been treated with at least one nextgeneration anti-hormonal drug as well as chemotherapy before [ 177 Lu]Lu-PSMA RLT, and depicted that initial PSA level (cut-off value of 350 ng/mL) and pre-treatment PSA doubling time (cut-off < 3 months) were not associated with PFS or OS [30]. Also, the findings of the study performed by Ferdinandus et al. revealed that PSA doubling time prior to the administration of [ 177 Lu]Lu-PSMA was deemed not prognostic for OS [31]. Therefore, the initial PSA level and its doubling time apparently have no significant impact on OS or PFS following [ 177 Lu]Lu-PSMA RLT warranting further confirmation.

PSA at the time of [ 177 Lu]Lu-PSMA RLT
Hypothetically, the higher baseline PSA may suggest a higher tumoral burden and possibly worse outcome. Studies evaluating the impact of baseline PSA level on patients' response to treatment or survival did not reach a consensus on this matter.
Yordanova et al. [32] outlined that baseline PSA level significantly correlates with survival following [ 177 Lu]Lu-PSMA RLT, as patients with PSA values lower than 47 ng/mL at baseline achieved a longer OS than patients with higher PSA levels (20 vs. 11 months). In another study, Gafita et al. [33] delineated that baseline PSA level significantly associates with OS in the multivariable analysis (HR: 1.63, P = 0.007) but not with the imaging-based PFS. Also, a retrospective analysis by Barber et al. [34] signified that baseline PSA of greater than 60 ng/mL is a significant determinant of inferior OS in taxane-pre-treated, taxane-naïve, and entire cohort ( [24]. The same results were reported by other authors who did not show any significant association between baseline PSA level and patients' OS after [ 177 Lu]Lu-PSMA RLT [31,32,35,36]. Gafita et al. [37] found no association between PSA level and either PFS or OS, in a cohort with the median PSA baseline of 126 ng/ml (IQR: 37-368). Moreover, Derlin et al. [38] found no  [39] or any PSA response [40]. In summary, the prognostic value of baseline PSA level has been controversially discussed, which warrants further investigations.

PSA decline
The decrease in PSA level after treatment is used as a surrogate marker for response in prostate cancer. Reviewing the literature, most authors have reported PSA decline ≥ 50% or any PSA decline 2 weeks to 3 months after the first or last cycle of [ 177 Lu]Lu-PSMA RLT, based on Prostate Cancer Clinical Trial Working Group criteria [21,41,42], and have correlated the data with survival and potentially predictive factors [4,20,21,30].
Recently, a repeated course of [ 177 Lu]Lu-PSMA RLT is being administered to some patients with a prior excellent response [44,45] and authors are investigating the prognostic factors [29]. They showed that rechallenge therapy is safe. Although patients with ≥ 50% PSA decline after the first cycle lived longer than those with an increase in PSA level, the difference was not statistically significant [29].
Although it may suggest that most of the patients showing PSA decline after the first cycle of therapy would have a better outcome, some studies reported that 30-50% of the patients with no PSA decline after the first cycle show the decrease in PSA level after second or third cycles [17,46]. On the other hand, the possibility of the flare phenomenon has been discussed after [ 177 Lu]Lu-PSMA RLT and the assumption that PSA increase may not always indicate disease progression [46]. However, Gafita et al. [33] recently demonstrated that the PSA flare is very uncommon after [ 177 Lu]Lu-PSMA RLT. Interestingly, while the decrease in PSA level predicted longer survival, the increase in PSA levels did not associate with worse outcome [20,26].
In summary, PSA decline after [ 177 Lu]Lu-PSMA RLT is a valuable factor to predict the outcome. Any PSA decline after the first treatment cycle is the most definite prognosticator of longer OS. Also, ≥ 50% PSA decline after the treatment conclusion appears as an important predictor of survival. The results regarding ≥ 50% PSA decline after the first cycle are controversial. In addition, it is of great importance to determine unified treatment protocols and endpoints of evaluating the therapy response. It should be also noted that although the PSA level is used for evaluation of the disease progression or response to therapy, there are patients having the radiologically progressive disease (e.g., osteoblastic bone metastases) without changes in PSA level. Thus, functional imaging (e.g., PET/CT) may play an important role, particularly in treatment assessment of such cases.  [47]. The impact of such prior therapies on survival or PSA response has been addressed in multiple studies showing controversial results.
In different studies, prior treatments, including antihormonal drugs, chemotherapy, or [ 223 Ra]RaCl, in advanced mCRPC patients did not correlate with PSA response, clinical PFS, or OS [20,24,28,40]. In detail, the results of the study performed by Rahbar et al. [23] did not show second-line chemotherapy or prior [ 223 Ra]RaCl to affect OS in the heavily pretreated advanced mCRPC patients. Bräuer et al. [30], in the same manner, depicted a lack of association between prior chemotherapy and OS following administration of [ 177 Lu]Lu-PSMA. Likewise, Ahmadzadehfar et al. [35] studied the influence of the history of chemotherapy on OS, in 100 mCRPC patients who had already received either abiraterone or enzalutamide prior to [ 177 Lu]Lu-PSMA RLT. They concluded that there is no significant difference in median OS between patients with the history of chemotherapy (approximately 14 months) and chemotherapy-naïve patients (approximately 15.5 months). Barber et al. [34] revealed an association between prior taxane chemotherapy and inferior OS and radiographic PFS in the univariate analysis (HR: 2.55 [P < 0.001], and HR: 1.71 [P = 0.003], respectively), none of which remained independent in the multivariable analysis. It should be kept in mind that this study was retrospective, and the patients that received chemotherapy were at higher risk of disease progression and had more adverse prognostic features. Hence, shorter OS would be expected for taxane-pre-treated patients, as it is evident in the multivariable analysis that factors other than the history of chemotherapy may influence the survival. This selection bias is plausible for all other studies with the retrospective nature.
Furthermore, according to the simple linear regression analysis by Derlin et al. [38], it has been demonstrated that previous treatments, including abiraterone, enzalutamide, chemotherapy, and external radiation therapy, do not have a significant association with change in PSA following [ 177 Lu]Lu-PSMA RLT. The use of abiraterone, steroid, or previous radiotherapy, as depicted by Suman et al. [48], did not stand as predictors of PFS or OS following [ 177 Lu]Lu-PSMA RLT. Also, the history of using abiraterone or enzalutamide or chemotherapy before [ 177 Lu]Lu-PSMA was not predictive of either any or ≥ 50% PSA decline following [ 177 Lu]Lu-PSMA RLT [26].
There are, on the other hand, some reports delineating a significant association between the existence or the number of received treatments with PSA response or OS following [ 177 Lu]Lu-PSMA RLT. Ahmadzadehfar [4]. The median OS in patients who had received one or two lines of chemotherapy with docetaxel or docetaxel followed by cabazitaxel was 10.9 and 8.9 months, respectively, which was significantly shorter than in patients without any prior chemotherapy (median OS of 14.6 months) [4]; however, no difference was noted in OS between patients who avoided to receive chemotherapy and patients for whom chemotherapy was contraindicated [4]. Other prior therapies, including antihormonal therapy and [ 223 Ra]RaCl, did not reveal any significant impact on OS [4]. As stated in Gafita et al.'s multivariate analysis [33], positive chemotherapy status prior to [ 177 Lu]Lu-PSMA RLT was significantly associated with imaging-based PFS (HR = 1.75, P = 0.04), but not with OS.
Gadot et al. [39] demonstrated that neither the number of total prior treatment lines for CRPC nor prior treatment with [ 223 Ra]RaCl was associated with PSA decline of more than 20%; nevertheless, there was a negative association between the number of previous chemotherapy lines (ranging from 0 to 2) and a PSA decline above 20% (P = 0.043).
Finally, Kulkarni et al. [49] categorized 224 mPC patients according to prior therapies, including chemotherapy (n = 110, second-line with cabazitaxel n = 20), androgen deprivation therapy (n = 206), newer anti-cancer agents (abiraterone [n = 91] and enzalutamide [n = 79]), [ 223 Ra]RaCl (n = 19), and no previous therapy (n = 18). They showed that the first-line [ 177 Lu]Lu-PSMA RLT was associated with the longest OS (median not reached at 55 months, since all patients were alive) [49]. The previous chemotherapy correlated with significantly shorter survival in comparison with chemotherapynaïve patients (19 vs. 38 months) [49]. Moreover, patients with the history of previous [ 223 Ra]RaCl had shorter OS, and those with the addition of abiraterone or enzalutamide had significantly prolonged survival [49]. Hence, previous first-or second-line chemotherapy and [ 223 Ra]RaCl were proposed as predictors of worse survival. In contrast, the addition of newer androgen receptor-targeted agents was suggested to have a synergistic effect in combination with [ 177 Lu]Lu-PSMA RLT [49].
Overall, it seems that except for chemotherapy, other prior therapies have no impact on outcome following [ 177 Lu]Lu-PSMA RLT. However, patients receiving chemotherapy usually have unfavorable characteristics, which might cause bias in the results of the published studies. Further researches and systematic reviews concerning each therapy, with particular attention to chemotherapy, are required to draw a definite conclusion. Also, early administration of [ 177 Lu]Lu-PSMA RLT is another interesting subject for future trails. Rahbar et al. [23] indicated that the cumulative injected activity of ≥ 18.8 GBq is a prognosticator of a longer OS in a total of 104 patients treated with 351 cycles of [ 177 Lu]Lu-PSMA RLT (median OS of 14.5 vs. 12.0 months in those receiving cumulative activity of ≥ 18.8 and < 18.8 GBq, respectively, HR: 0.53). However, as patients with longer survival had a higher chance of receiving higher cumulative activity, the inhomogeneous number of cycles in this study should be kept in mind. Furthermore, according to the multivariate analysis of 167 mCRPC who underwent [ 177 Lu]Lu-PSMA RLT, the cumulative administered activity of more than 16 GBq was found to be associated with inferior OS in both the taxane-pre-treated subgroup (HR = 0.37, P = 0.002) and the entire cohort (HR = 0.5, P = 0.005), but not in the taxane-naïve subgroup [34]. On the other hand, Ferdinandus et al. [24] evaluated 40 patients receiving one cycle of [ 177 Lu]Lu-PSMA with a mean dose of 6.0 GBq (range: 4.1-7.1 GBq) and a mean activity of 78.5 MBq/kg of body weight and demonstrated that PSA response was independent of these factors. Also, in other studies, the cumulative activity was not predictive of PSA response [28,50] or OS [48].
In another study of 145 mCRPC patients treated with 1-4 cycles (activity range: 2-8 GBq per cycle), Rahbar et al. [28] demonstrated that patients with a higher number of therapy cycles (≥ 3) had a higher rate of PSA response (odds ratio: 5.83, P = 0.02) in contrast to per cycle administered activity. The number of therapy cycles remained associated with the PSA response rate in the multivariate analysis (P ≤ 0.05) [28]. Likewise, Kesavan et al. [50] studied 20 progressive mCRPC patients with a mean prescribed activity of 5.5 GBq per patient. They showed that patients receiving three cycles of therapy were statistically more likely to experience ≥ 50% reduction in PSA compared to those treated with one, two, or four cycles (P < 0.0001) [50].
Additionally, Rathke et al. [51], although in a small patient group of 40 patients, demonstrated that four different treatment activities of [ 177 Lu]Lu-PSMA (4, 6, 7.4, and 9.3 GBq) did not influence the PSA response.
Overall, the studies concerning the impact of the administered activity, cumulative dose, and number of cycles on outcome following [ 177 Lu]Lu-PSMA RLT are inadequate, and results are controversial. Further trials would clarify the influence of these factors to help determine a standard protocol.
Intensity of uptake in positron emission tomography/computed tomography The intensity of uptake in [ 68 Ga]Ga-PSMA PET/CT represents the PSMA expression in prostate tumoral cells. Pretreatment imaging is used before [ 177 Lu]Lu-PSMA RLT to document the presence of PSMA-avid lesions. Although the exact amount of PSMA avidity required for treatment has not been established yet, some centers consider 1.5 as the least ratio of the mean standardized maximum value (SUVmean) of the lesion-to-liver [21]. It is hypothesized that the higher  [53]. Also, the change in SUVmax of the metastatic lesions may have an association with PSA response [54].
Heinzel et al. [56] correlated the decrease in SUVmean (≥ 30%) on [ 68 Ga]Ga-PSMA PET/CT, after at least 3 cycles of therapy, with PSA response (≥ 50% decline). The fitted receiver operating characteristic area was 0.70, and the difference in OS was not statistically significant between responders and non-responders (19.6 vs. 15.9, respectively) [56]. Also, the only [ 68 Ga]Ga-PSMA PET/CT-predictive parameter of longer OS was higher whole-body SUVmean (9.8 vs. 6.3 months) [31]. Additionally, higher pre-treatment total tumor volume (HR: 0.87) and SUVmean (HR: 0.94) predicted longer PSA PFS in a study by Gafita et al. [37]. However, Grubmüller et al. [36] assessed the changes in total tumor volume (from the pre-treatment to the post-treatment scan) and showed significant associations with PSA response and OS in contrast to changes in SUVmean [36].
In another study, Ferdinandus et al. [24] revealed no correlation between SUVmax of the metastatic lesions in different organs and response to therapy. Yadav et al. [26] showed that pre-treatment peak standardized uptake value corrected for lean body mass for different sites of metastases does not predict PSA response.
The impact of the intensity of [ 68 Ga]Ga-PSMA uptake is discussed controversially in the literature using inhomogeneous patient's population with different imaging protocols and quantitative approaches. Nevertheless, most studies were not able to predict response using tracer intensity alone. Hence, making the decision for [ 177 Lu]Lu-PSMA RLT should not be based on a predefined cut-off for [ 68 Ga]Ga-PSMA uptake in pre-treatment PET/CT.

Visceral metastasis
The prognostic value of the presence of visceral metastasis has been correlated with survival parameters or biochemical response after [ 177 Lu]Lu-PSMA RLT [20,28,33,55]. However, the results are inconsistent. Heck et al. [20] showed that visceral metastasis is independently associated with worse PSA response, clinical PFS (3.1 vs. 5.9 months) and OS (7.6 vs. 14.0 months). Also, in other studies, the multivariate analysis indicated the presence of visceral metastasis as an independent predictor of shorter OS [33,35,57]. Rahbar et al. [28] reported that the presence of visceral metastases independently lowers the biochemical response (odds ratio: 3.732 [95% CI, 1.412-9.864]). Also, Barber et al. [34] reported that the presence of visceral metastasis is associated with shorter imaging-based PFS (univariate analysis: HR: 1.90 [95% CI, 1.28-2.84], P = 0.002; multivariate analysis: P = 0.08) and OS (multivariate analysis: HR: 1.69 [95% CI, 1.02-2.80]). F u r t h e r m o r e , i n t h e r e c e n t m u l t i c e n t e r s t u d y , Ahmadzadehfar et al. [4] showed that liver metastasis worsens OS (HR: 2.394 [95% CI, 1.818-3.153]) while lung metastasis does not influence the survival [4]. However, they did not report the value of the presence of visceral (lung plus liver and other organs) metastases in cumulation. Also, the absence of visceral metastasis predicted longer PSA PFS (HR: 0.51) [37]. Contrarily, Ferdinandus et al. [24] and Derlin et al. [38] reported that liver metastasis does not influence the PSA response. Additionally, no correlation was demonstrated between visceral metastasis and PSA response [55] or OS [23,30,39], in other studies. However, Rahbar et al. [23] claimed that the presence of visceral metastasis showed poorer OS but did not reach the statistical significance.
The presence of visceral metastasis per se indicates an aggressive disease and shortens survival [47,58]. Hence, there is a higher probability that these patients fail to respond to standard treatments and receive [ 177 Lu]Lu-PSMA RLT. Additionally, the ratio of patients with visceral metastasis is relatively high and variable in the studies, which may have a negative impact on the statistical analysis justifying the absence of correlation between visceral metastasis and prognosis.

Bone metastasis
Bone metastasis is a common manifestation in prostate cancer [59,60] shortening overall survival [61]. It is the most common site of metastasis in prostate cancer [62]. Higher numbers of bone metastases indicate a high-risk disease [47]. However, the results regarding the impact of the presence of bone metastasis in response to [ 177 Lu]Lu-PSMA RLT are contradictory. In a large multicenter study, the presence of bone metastasis predicted worse OS (HR: 3.703 [95% CI, 1.900-7.214]; P < 0.0001) in the multivariate analysis [4]. Also, Barber et al. [34,63] showed that the presence of bone metastasis predicts shorter OS (HR: 5.90 [95% CI, 2. 15-16.19]) and imagingbased PFS (HR: 1.84 [95% CI, 1.10-3.07]) only in the univariate analysis. In another multicenter study, the absence of bone metastasis was predictive of longer PSA PFS [37]. Furthermore, the number of bone metastasis was predictive of shorter OS in the univariate analysis in one study [35]. Nevertheless, the presence [28,55] or number [24,26] of bone metastasis did not impact the biochemical response to [ 177 Lu]Lu-PSMA RLT nor did change OS [23,39], in other surveys. It may attribute to the fact that patients receiving [ 177 Lu]Lu-PSMA RLT are metastatic CRPC patients in an advanced state and most of them already have bone metastases, in almost all studies [4,23,24,28,55]. Hence, the low number of patients without bone involvement in these studies may cause bias in the statistical analysis. Additionally, studies have not separately investigated those patients with bone-only metastasis since concomitant metastasis in other organs may have an impact on the outcome. All in all, most of the eligible patients for [ 177 Lu]Lu-PSMA RLT have bone metastases; therefore, it would not impact the decision-making. However, the influence of the bone-only metastases and the extent of bone involvement on survival require further clarification.

Lymph node metastasis
The patients with advanced mCRPC rarely present with lymph node-only metastasis [58]. They have a better outcome than those with metastasis in other organs [58]. Multiple studies have reported that the presence of lymph node metastasis does not impact the outcome (including PSA response or survival) after [ 177 Lu]Lu-PSMA RLT [4,24,28,30,38,39,50,55]. Noteworthy, the studies rarely have evaluated the patients with lymph node-only metastasis [50]. Recently, Gafita et al. [33] reported that patients having concomitant bone and lymph node metastases have poorer OS following
Also, pre-treatment ALP level < 120 U/L and any change after the first cycle have been addressed in a study by Ahmadzadehfar et al. [32], which predicted longer survival. Additionally, Yordanova et al. [32] evaluated the Bonespecific Alkaline Phosphatase (BAP) and showed that the decreasing BAP after the treatment is predictive of longer OS. Nevertheless, Grubmüller et al. and Gafita et al. did not find a correlation between ALP and outcome following [ 177 Lu]Lu-PSMA RLT [33,36]. The patient population and the ratio of patients with distant metastases were similar to the other studies; however, they did not refer to the binary values (normal vs. abnormal) for analysis, in these two studies.
Overall, the increase in ALP levels suggests dysregulation in bone formation caused by metastases [65]; hence, abnormal ALP may indicate a higher burden of the disease with a poor prognosis. It seems that the abnormal level of ALP majorly impacts the survival, and it is a negative prognosticator of outcome following [ 177 Lu]Lu-PSMA RLT.

Lactate dehydrogenase
Lactate dehydrogenase (LDH) is considered a poor prognostic tumor marker in prostate cancer [66][67][68]. The prognostic value of LDH following [ 177 Lu]Lu-PSMA RLT has been reported in some studies [31]. Heck et al. [20] demonstrated that the rising LDH levels independently predict worse clinical PFS and OS. LDH ≥ 225 mg/L was prognostic of shorter OS in a study by Ahmadzadehfar et al., in the univariate analysis [35]. Also, the same research group reported that a baseline LDH level of < 248 mg/L and any change after the first cycle could predict better survival [32]. However, others did not find a correlation between higher LDH and response to therapy or OS [24,38,39,63]. Moreover, some authors showed that abnormal pre-treatment LDH has no prognostic value for predicting OS [23,33,36]. The results regarding LDH are controversial warranting further evaluations. Also, it is of importance to report the correlation using a unified endpoint, such as a normal cut-off value for future studies, as well.

Bone marrow status
Poor bone marrow function is an important determinant of exclusion of patients from [ 177 Lu]Lu-PSMA RLT. Patients should have acceptable parameters [69]. Lower levels of blood parameters may be caused by significant bone marrow infiltration with tumoral cells, prior toxic chemotherapies or radiation. Lower levels of hemoglobin (Hb) indicate poorer prognosis in mCRPC [68]. Barber et al. [63] showed that in mCRPC patients who underwent [ 177 Lu]Lu-PSMA RLT, the low level of pre-treatment Hb (<7.5 mmol/L [12.1 g/dl]) strongly and independently predicts worse OS in both groups of patients with a history of previous chemotherapy with taxane and taxane-naïve patients. Ahmadzadehfar et al. [35] and Gadot et al. reported the low Hb level (<10.4 and < 9.2 g/ dl, respectively) was a strong predictor of poor OS, in the multivariate analysis. In another multicenter survey including 267 patients by Gafita et al. [37], lower Hb level was predictive of shorter OS (HR: 1.53) and higher Hb level was correlated with longer PSA PFS (HR: 0.32).
Interestingly, Ferdinandus et al. [24] reported that the higher level of pre-treatment platelet level is the most significant predictor of poor response to therapy. The negative impact of thrombocytosis has been documented in other malignancies, as well [24]. It has been documented that some cytokines induce thrombocytosis [24]. Also, circulating tumoral cells use thrombocytes to protect themselves from the immune system [24] advocating the negative impact of high platelet levels.
Altogether, it can be inferred that patients with a low level of Hb have a poor prognosis and may show shorter survival after [ 177 Lu]Lu-PSMA RLT. Otherwise, white blood cells or platelet do not seem to impact the outcome.

Other serum markers
Factors mirroring renal and liver functions have been investigated to find a correlation with response to therapy. The higher level of gamma-glutamyl transferase (GGT), as a liver function test, showed a correlation in the univariate analysis, which was not confirmed on the multivariate assessment [24,35]. Also, the abnormal level of C-reactive protein (CRP) was predictive for outcome in the univariate analysis [24,35,36].
The level of albumin [24,39] and bilirubin was not predictive [24]. Additionally, aspartate aminotransferase (AST) and alanine transaminase (ALT) have shown no predictive value for the outcome [24,30,38]. However, in another study, lower albumin and higher AST levels were significant predictors of lower survival [35]. The hypothesis encouraging authors to investigate whether liver function tests predict survival might be related to the advanced disease status or liver metastases. However, these factors are assessed before the initiation of the therapy and patients with significant disturbed liver function do not meet the criteria to receive [ 177 Lu]Lu-PSMA RLT. Hence, the minimally disturbed liver function test, which is not clinically significant, may not alter the outcome after [ 177 Lu]Lu-PSMA RLT.
Moreover, Yordanova et al. [32] evaluated the prognostic value of neuroendocrine tumor markers. The presence of neuroendocrine features is proposed as a poor prognostic factor in PCa [32]. They showed that the decrease in pro-Gastrin-Releasing-Peptide and Chromogranin A levels after therapy predicts longer OS; however, the pre-treatment pro-Gastrin-Releasing-Peptide, Chromogranin A, and the change in the Chromogranin A level were not prognostic [32].
The results evaluating the liver function test is inconsistent. Also, the other biochemical parameters are sparsely evaluated in different surveys. Far more studies are required to detect the most predictive factors. Recent data proposed that other factors such as aggressive types of PC showing neuroendocrine differentiation or possessing somatic genomic alterations or specific germline mutations (BRCA2) may negatively influence the outcome, warranting future investigations [70].

Age
The age of patients has been evaluated as a prognostic factor for [ 177 Lu]Lu-PSMA RLT. Gadot et al. proposed older age as an independent predictor of longer OS after [ 177 Lu]Lu-PSMA [39]. Heck et al. [20] reported that younger patients have poorer clinical PFS and OS. However, the association with OS was not confirmed on the multivariate analysis [20]. Likewise, Ferdinandus et al. [24] showed that the response to treatment in younger patients is poorer in only univariate analysis. The correlation between age and outcome after [ 177 Lu]Lu-PSMA RLT was not confirmed in other studies [4,23,26,40,63]. The results are controversial regarding the age of the patients. Even though younger patients may reveal poorer response to [ 177 Lu]Lu-PSMA RLT, the impact should be confirmed in further trials and age by itself should not alter the decision of commencing or cessation of the treatment.

Performance status
The performance status of the patient is of importance to select patients for [ 177 Lu]Lu-PSMA RLT. Commonly, those with acceptable performance status are eligible to receive this therapy [69]. It is hypothesized that patients with poor performance are those with a more advanced and poor prognostic disease. It seems that the lower Eastern Cooperative Oncology Group (ECOG) score correlates with a better outcome [4,33,35]. In line with that, in a multicenter survey, the authors [4] confirmed that patients with ECOG 0 and 1 reveal significantly longer OS compared to those with score 2 (16.9 vs. 9.6 vs. 6.3, respectively). Likewise, a multivariate analysis [26] showed that patients with ECOG ≤ 2 have longer OS compared to those with a score of > 2. However, it was not correlated with PSA response [26]. Moreover, Karnofsky score ≤ 80% was independently correlated with shorter OS (HR: 1.83 [95% CI, 1.07-3.14]) [63]. On the other hand, no correlation was depicted between ECOG and response to therapy or OS in other studies [24,39,40]. In one study by Yadav et al. [26], visual analgesic score, analgesic score, and Karnofsky Performance Status scale were not predictive of PSA response. It is of note that the endpoints were different in these studies (OS vs. PSA response), as well as the performance status of the patients. Patients with ECOG 0-1 may be in earlier stages of the disease; therefore, they may show a better outcome. Further studies are demanded to confirm the results.

Analgesic intake
Bone pain is frequently seen in mCRPC patients, which may subside by [ 177 Lu]Lu-PSMA RLT [27]. Ferdinandus et al. [24] showed that regular need for analgesic medication is strongly associated with poor response to [ 177 Lu]Lu-PSMA RLT. Also, in two separate studies, Ahmadzadehfar et al. reported the inverse impact of regular need for analgesia or opioids with OS [35] and PSA response [40]. Patients with more advanced disease or higher disease burden may need more pain medication; therefore, the regular need for analgesia per se indicates more advanced disease.

Gleason score
A higher Gleason score indicates a higher risk of metastases [47]. Hence, several studies have tried to find its prognostic value. Ferdinandus et al. [24] revealed that a Gleason score of 10 had a negative impact on any PSA decline following [ 177 Lu]Lu-PSMA RLT in the univariate analysis; however, this did not keep its significance in the multivariate analysis. Likewise, Gadot et al.'s results [39] showed a lack of association between Gleason score and a PSA decline of 20% or more following [ 177 Lu]Lu-PSMA RLT. The findings were in line with the lack of association between Gleason score and either any PSA decline or ≥ 50% PSA decline following [ 177 Lu]Lu-PSMA RLT, reported by Yadav et al. [26]. Moreover, no significant association was identified between Gleason score [40,50] or Gleason grade [38] and PSA response to [ 177 Lu]Lu-PSMA RLT. Heck et al. [20] did not recognize the Gleason score (8-10 vs. 6-7) as a predictive factor of either maximum PSA decline of ≥50%, clinical PFS or OS. Furthermore, Gafita et al. [33] did not identify a Gleason score of 8 or more as a predictor of OS or imagingbased PFS, which was similar to findings of Suman et al.'s study [48], delineating Gleason score not to be predictive of either PFS or OS. It seems that the Gleason score has no significant impact on response rate or patients' survival following [ 177 Lu]Lu-PSMA RLT.

Conclusion
Radioligand therapy with [ 177 Lu]Lu-PSMA is demonstrating striking results in heavily treated mCRPC patients who have exhausted all standard treatments. The sequential images of two mCRPC patients are illustrated in Figs. 1 and 2  are needed to precisely define the prognostic value of other parameters, namely pre-treatment levels of Hb and LDH, performance status, analgesic intake, bone or lymph node metastases, the intensity of uptake in the pre-treatment PET/CT, and pre-treatment PSA level, as well as the dose and number of cycles of the therapy.
Noteworthy, there were limitations to our review. First, this article was a narrative review and we intentionally did not conduct a systematic review at this stage, to avoid any misleading reports; because the [ 177 Lu]Lu-PSMA RLT has been mainly performed in clinical practice in the last few years, and the authors believe that the current number of the publications may not reliably reflect the factors predicting treatment response. Moreover, there was not a unified treatment protocol throughout the studies. The number of administered cycles and the amount of administered activities were different. Moreover, an inhomogeneous patient population with a history of different prior treatments and performance status were included in the investigations. Additionally, studies have evaluated the response in different time points with inconsistent endpoints. Also, most of the studies were retrospective, and a significant subfraction of them was from Germany. Hence, the overlap of the patients' population was plausible. Finally, some factors were evaluated by only a few researchers. Importantly, the value of early administration of [ 177 Lu]Lu-PSMA RLT, which may show added survival benefits, was scarcely addressed. Therefore, future prospective randomized trials are required to detect the independent prognostic factors, and to further determine the clinical and survival benefits of [ 177 Lu]Lu-PSMA RLT.
Funding Open access funding provided by Paracelsus Medical University.

Declarations
Ethical approval This article does not contain any studies with human participants performed by any of the authors.

Conflict of interest The authors declare no competing interests.
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