Research ArticleTheranostics

Predictors of Response to Radioligand Therapy of Metastatic Castrate-Resistant Prostate Cancer with 177Lu-PSMA-617

Justin Ferdinandus, Elisabeth Eppard, Florian C. Gaertner, Stefan Kürpig, Rolf Fimmers, Anna Yordanova, Stefan Hauser, Georg Feldmann, Markus Essler and Hojjat Ahmadzadehfar
Journal of Nuclear Medicine February 2017, 58 (2) 312-319; DOI: https://doi.org/10.2967/jnumed.116.178228

Abstract

Radioligand therapy (RLT) with 177Lu-PSMA-617 (PSMA is prostate-specific membrane antigen) is a novel targeted therapy for metastatic prostate cancer. In this study, we evaluated the effect of different pretherapeutic parameters on the therapeutic response measured by prostate-specific antigen (PSA) 2 mo after RLT. Methods: RLT was performed in 40 hormone-refractory patients with distant metastases and progressive disease (mean age, 71.4 y). 68Ga-PSMA-11 PET/CT was performed in all patients 1–2 wk before RLT. All patients were treated with a mean of 6 GBq. The SUVmax of tumor lesions was determined using region-of-interest analysis. Complete blood counts, renal and liver function assessments, previous therapies, pain medication, and SUVs were included in the analysis. PSA was assessed 2 mo after RLT. Results: In the univariate analysis, younger age, higher levels of γ-glutamyl transferase, lower pretherapeutic hemoglobin, a higher Gleason score, a higher number of platelets, higher C-reactive protein, regular need for pain medication, and higher lactate dehydrogenase had a negative impact on the therapeutic response; however, the multivariate analysis revealed that the most significant independent factors were the number of platelets and regular need for pain medication. The response was independent of the amount of PSMA uptake as well as previous therapies and other measured factors. Conclusion: A PSA decline of more than 50% was observed significantly more in patients without a regular need for analgesics.

Prostate-specific membrane antigen (PSMA) is an attractive target for the diagnosis and therapy of metastasized prostate cancer (PC) (1,2). All of the recently published papers about radioligand therapy (RLT) with 177Lu-PSMA-617 have indicated that this therapy is safe and has a low toxicity profile (3–8). The first results showed a positive effect on the prolongation of overall survival as well (6). Although, at the moment, RLT is performed for hormone-refractory patients in an advanced stage of disease with continuously increasing prostate-specific antigen (PSA), a decline in PSA has been detected in about 60%–70% of patients (3–8). However, it is still unclear as to whether any of the pretherapeutic parameters, such as the level of PSMA expression in 68Ga-PSMA-11 PET or prior therapies, may affect the treatment response according to PSA changes. In the current study, we retrospectively evaluated the effect of different pretherapeutic parameters and prior therapies on the therapeutic response measured by PSA 2 mo after the first cycle of RLT.

MATERIALS AND METHODS

Patients

Forty consecutive hormone-refractory PC patients with distant metastases and progressive disease according to the PSA level were treated with 177Lu-PSMA-617. The data regarding the treatment response and toxicity as well as treatment tolerability of the included patients in this study have been published together with the data from 3 other centers as a multicenter study (7). The prior therapies are listed in Table 1. All patients had an extensive metastatic disease, which is demonstrated in Table 1. PSMA PET was performed for all patients 1–2 wk before therapy to evaluate the PSMA expression status of the metastases. The local ethics committee approved this retrospective study, and all subjects signed a written informed consent form.

View this table:
TABLE 1

Patient Characteristics

Treatment Planning

68Ga-PSMA-11 PET/CT

68Ga-PSMA-11 was applied via slow intravenous injection (30–60 s) using a weight-adapted dose of 2 MBq/kg of body weight in a total volume of 5–10 mL (diluted with 0.9% sterile sodium chloride solution), followed by 20 mL of sterile 0.9% sodium chloride. The average injected dose was 140 MBq. PET/CT was performed on a Biograph 2 PET/CT scanner (Siemens Medical Solutions). PET emission data were acquired from the pelvis to the head using 6–8 bed positions (3-dimensional mode); the emission time was 4 min per bed position. PET images were reconstructed iteratively. After reconstruction, images were smoothed by a 5-mm gaussian filter. Attenuation correction was performed using CT data. The SUVmax was determined by a region of interest applied in the transaxial attenuation-corrected PET slice with the highest PSMA uptake. The SUVmax was recorded for up to 5 bone and lymph node metastases as well as for liver and spleen for the calculation of target/nontarget. Thus, the following parameters were calculated: mean SUVmax of the bone lesions (SUVmaxBn = SUVmaxBn1+…..SUVmaxBnx/x), mean SUVmax of the lymph node metastases (SUVmaxLn = SUVmaxLn1+…..SUVmaxLnx/x), SUVmaxBn/SUVmaxLiver, SUVmaxBn/SUVmaxspleen, SUVmaxLn/SUVmaxliver, SUVmaxLn/SUVmaxspleen.

Laboratory Tests

One day before therapy, the hematologic and renal status, liver function tests, tumor marker PSA, alkaline phosphatase, and blood biochemistry were evaluated in all patients (Tables 2 and 3).

View this table:
TABLE 2

Blood, Renal, and Hepatic Parameters Before First Cycle

View this table:
TABLE 3

Tumor Parameters

RLT

PSMA ligand (PSMA-617) was obtained from ABX GmbH. The preparation of 177Lu-PSMA-617 was explained in detail in a previous publication (3).

The treatment solution was administered by slow intravenous injection over 1 min followed by 1,000 mL of NaCl or Ringer’s. All patients were discharged 48 h after therapy according to the rules of the Federal Office for Radiation Protection in Germany (BfS).

Tumor Response Evaluation

The tumor marker PSA was used as the main marker for the response evaluation. We classified the changes in PSA level as a decrease of more than 50% and any decline. Any increase in PSA was considered as disease progression.

Evaluated Parameters for Evaluation of Predictive Factors of Response

All of the patients' parameters and laboratory tests are shown in Tables 1–4, including the extent of bone and lymph node metastases, the existence of liver metastases, age, the need for pain medication, the Eastern Cooperative Oncology Group (ECOG) score, SUV, SUVmaxBn, SUVmaxLn, SUVmaxBN/liver, SUVmaxBN/spleen, SUVmaxLn/liver; SUVmaxLn/spleen, injected dose of 177Lu-PSMA-617, and injected dose/kg of body weight.

Statistical Analysis

The baseline characteristics of the study were analyzed with regard to their correlation to quantitative PSA changes. For this, a linear regression was used. Two qualitative assessments of PSA decline (any PSA decline and PSA decline > 50%) were analyzed with uni- and multivariate logistic regression. Multivariate models were derived by stepwise regression analysis primarily including parameters selected depending on the results of the unifactoral logistic regression.

RESULTS

Forty cycles of 177Lu-PSMA-617 were performed in 40 consecutive hormone-refractory patients with a mean age of 71.4 y (age range, 43–87 y). Each patient received a mean of 6.0 GBq (range, 4.1–7.1 GBq; median, 6.1 GBq) of 177Lu-PSMA-617. According to the patient’s weight, each patient received a mean activity of 78.5 MBq/kg of body weight. The mean and median time between diagnosis of PC and RLT was 6.9 and 5.5 y (range, 0.8–20 y), respectively. The median Gleason score was 9 (range, 6–10). The extent of disease in these patients and their prior and ongoing therapies are shown in Table 1. The mean and median PSA levels before therapy were 495.1 and 325.5 ng/mL (range, 4.73–2,360 ng/mL), respectively (Table 3).

Twenty-six patients exhibited good ECOG scores (0 or 1). Thirteen patients exhibited an ECOG score of 2, and 1 an ECOG score of 3. The blood and renal parameters before the first cycle are shown in Table 2. Seven patients had received blood transfusion before therapy because of grade 3 tumor anemia 10–180 d before 177Lu-PSMA-617 therapy (median, 21 d). The tumor parameters are listed in Table 3. The SUVs of bone and lymph node metastases are shown in Table 4. Eight weeks after RLT, 27 of 40 patients (67.5%) experienced a PSA decline, of whom 13 showed a PSA decline of more than 50% (32.5%). Thirteen patients showed progressive disease according to an increasing PSA level (Supplemental Fig. 1; supplemental materials are available at http://jnm.snmjournals.org).

View this table:
TABLE 4

SUVs of 40 Patients Before 177Lu-PSMA Therapy

Impact of Pretherapeutic Parameters on Percentage PSA Changes

The linear regression analysis of different parameters showed that a higher platelets count, high C-reactive protein (CRP) level, younger age, higher Gleason score, and a regular need for pain medication have a negative impact on the PSA response according to percentage PSA changes (Table 5). Figure 1 shows the significant correlation between age and better PSA response (r2 = 0.149; P = 0.013), and Figure 2 shows the significant correlation between the platelet count and worse PSA response (r2 = 0.274; P = 0.0005).

View this table:
TABLE 5

Linear Regression Analysis of Different Pretherapeutic Parameters and Their Impact on PSA Change

FIGURE 1.
FIGURE 1.

Correlation between age and percentage PSA changes (R2 = 0.149).

FIGURE 2.
FIGURE 2.

Correlation between platelet counts and percentage PSA changes (R2 = 0.274).

Impact of Pretherapeutic Parameters on Any PSA Decline

The univariate analysis showed that higher levels of γ-glutamyl transferase (GGT) (>100U/L; P = 0.001), platelet counts (>300 G/L; P = 0.001), high CRP (>20 mg/L; P = 0.006), a Gleason score of 10, younger age (cutoff, 65 y; P = 0.001), high lactate dehydrogenase, lower pretherapeutic hemoglobin, and regular need for pain medication had a negative impact on any PSA decline. The other factors, including SUVs, did not have any significant impact on PSA (Table 6). In the multivariate analysis, only a high platelet count and regular need for pain medication kept their significance (Table 5).

View this table:
TABLE 6

Univariate and Multivariate Analyses of Different Pretherapeutic Parameters Regarding Any PSA Decline

Impact of Pretherapeutic Parameters on PSA Decline of More Than 50%

The univariate analysis showed that only a Gleason score of 10 and regular need for pain medication had a negative impact on PSA decline of more than 50%. No patient with a Gleason score of 10 showed a PSA decline, and only 2 from 15 patients (13.3%), who had a regular need for analgesics, showed a PSA decline of more than 50%. Again, the regular need for pain medication kept its significance in the multivariate analysis (Table 7).

View this table:
TABLE 7

Univariate and Multivariate Analysis of Different Pretherapeutic Parameters Regarding PSA Decline of More Than 50%

DISCUSSION

In addition to docetaxel, which until 2010 was the only drug with a positive effect on overall survival, in recent years, 5 new drugs (abiraterone, enzalutamide, sipuleucel-T, cabazitaxel, and 223Ra) have shown efficacy in prolonging survival in castration-resistant PC patients (9–14). However, despite all of these new and effective therapies, patients with hormone-refractory metastatic PC still reach an endpoint at which no approved therapy is effective or indicated.

According to retrospective studies, RLT with 177Lu-PSMA-617 has been shown to be effective, inducing PSA decline in almost 70% of patients who were in a salvage situation, with a favorable toxicity profile and mild side effects (3–8).

In our recently published study (8), we demonstrated the treatment response and side effects of 177Lu-PSMA-617 therapy in 24 patients, who were treated with up to 2 cycles. In this small group of patients, we found that the only pretherapeutic factor that had a negative impact on PSA decline was the regular use of opioids. No other pretherapeutic factors, inclusive of prior therapies, had any impact on the treatment response according to PSA decline.

We also showed the reliability of PSA for treatment follow-up. There was a significant correlation between the treatment response according to PSMA PET/CT imaging and PSA changes, which shows the value of PSA changes for the follow-up of patients on PSMA therapy. In the current study, we evaluated more parameters in a greater number of patients after the first cycle. The data regarding the treatment response and toxicity as well as treatment tolerability of the included patients in this study have been published together with the data from 3 other centers as a multicenter study (7). In the current study, we first tried to determine whether there was a correlation between the percentage of PSA change and any of the pretherapeutic factors (Table 5). One of the first issues for the treatment planning is the influence of prior therapies on the treatment response. Although all of our patients had received different treatments before 177Lu-PSMA-617, in this patient collective, these therapies did not have any influence on the treatment response; however, the influence of prior therapies in combination with RLT on toxicity should be evaluated. It is still unclear whether the treatment response could be better using 177Lu-PSMA-617 as first- or second-line therapy.

In theranostics, 2 issues should be clarified using diagnostic scans before planning radionuclide therapy: first, whether there is any tracer uptake in the tumor, and second, the amount of the uptake.

Concerning the first point, in the case of thyroid cancer or neuroendocrine tumors without any tracer uptake, 131I diagnostic scanning or somatostatin receptor imaging, respectively, is generally excluded from 131I or 177Lu-DOTATATE therapy. This also applies to 177Lu-PSMA-617 therapy. Moreover, only metastases that show PSMA expression can be treated with PSMA therapy.

The second point implies that the amount of tracer uptake is also of considerable importance, because higher radioiodine uptake predicts a better treatment response. In the case of neuroendocrine tumors, there is a positive correlation between the degree of somatostatin receptor expression and the treatment response as well as prognosis (15,16); however, in the current study, the SUVmax of 68Ga-PSMA-11 did not significantly influence the treatment response. One explanation for this difference between somatostatin receptor imaging and PSMA imaging may be the physiopathologic mechanism of tracer uptake. There is an inverse association between somatostatin receptor type 2A (SSTR2A) with the Ki-67 index, and SSTR2A is highly expressed in G1 and G2 neuroendocrine tumors but is significantly less abundant in neuroendocrine carcinomas (G3) (17); thus, higher expression of SSTR2A is correlated with lower grade of the neuroendocrine tumor. In contrast, the amount of PSMA expression is directly correlated with metastases, androgen independence, and progression of PC (18). More aggressive tumors may express higher PSMA levels, but despite better uptake of 177Lu-PSMA-617, because of the rapid growth of metastases, the response rate does not correlate with uptake. Another explanation could be the different washout times of 177Lu-PSMA-617 in the respective metastases. These should both be confirmed in studies with more patients.

Compared with prior therapies and the SUV of PSMA-11, there were some parameters shown to have a negative impact on the treatment response. A higher platelet count, high CRP level, younger age, higher Gleason score, and a regular need for pain medication had a negative impact on the PSA response according to percentage PSA changes. In our study, 8 patients were younger than 65 y, of whom 4 had PC with a Gleason score of 10 and the others a Gleason score of 8 or greater, which could explain the worse response in these patients.

Bensalah et al. (19) reported the prognostic value of thrombocytosis in 774 patients with renal cell carcinoma. They reported that platelet count was strongly correlated with T stage, Fuhrman grade, tumor size, nodal invasion, and the presence of distant metastasis. Thrombocytosis had an impact on prognosis in localized and metastatic disease. In their study on patients with a platelet count of less than 450,000/mm3, the 5-y survival rate was 70%, compared with 38% when the platelet count was 450,000/mm3 or greater. The negative impact of thrombocytosis on prognosis has been also reported in other cancer types, such as bladder cancer (20), gynecologic malignancies (21–23), and gastrointestinal cancers (24), as well as in early and advanced breast cancer (25,26). According to different published studies, cytokines, in particular IL-6, play an important role in the development of thrombopoiesis and thrombocytosis (22–24). Circulating tumor cells may use platelets as a protective shield against attack by the immune system and as facilitators for attachment to endothelial cells at metastatic sites (27,28). Antiplatelet agents and anticoagulants have potent inhibitory effects on tumor cell platelet interactions and can prevent metastases in experimental settings in various malignancies (27,29–32).

In our study, there was also a significant correlation between the number of platelets and the negative percentage change in PSA (Fig. 2). In the univariate analysis of different pretherapeutic factors regarding any PSA decline, a platelet count of more than 300 G/L also had a negative impact on the therapeutic response in addition to high GGT (>100U/L), high CRP (>20 mg/L), and a Gleason score of 10, younger age (cutoff: 65 y), lower pretherapeutic hemoglobin, and regular need for pain medication; however, in the multivariate analysis, only the platelet count and regular need for pain medication retained their significance.

Regarding a PSA decline of more than 50%, only a Gleason score of 10 and regular need for pain medication had a negative impact on the therapeutic response in the univariate analysis; in the multivariate analysis, only the regular need for pain medication was significant. Patients with advanced disease and high tumor load often suffer from pain, which affects their quality of life. A regular need for pain medication is an indirect sign of advanced disease, which explains its negative impact on the treatment response.

CONCLUSION

According to the results of this study, a favorable response rate (PSA decline > 50%) may be observed significantly more in patients without a regular need for analgesics. The results of the current study should be confirmed by prospective trials especially in respect to the effect of these parameters on survival.

DISCLOSURE

No potential conflict of interest relevant to this article was reported.

Acknowledgments

We are grateful to the nursing staff of the treatment ward in our department. We give special thanks to our study nurse, Ulrike Kuhn-Seifer (Department of Nuclear Medicine Bonn).

Footnotes

  • Published online Sep. 1, 2016.

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  • Received for publication May 16, 2016.
  • Accepted for publication August 10, 2016.
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