Usefulness of combined androgen blockade therapy with gonadotropin-releasing hormone antagonist for bone metastatic prostate cancer with pretreatment prostate-specific antigen level ≥ 50 ng/mL

Usefulness of combined androgen blockade therapy with gonadotropin-releasing hormone antagonist... Background: This study was performed to examine the usefulness of combined androgen blockade (CAB) therapy with a gonadotropin-releasing hormone (GnRH) antagonist (CAB-antagonist therapy), instead of CAB therapy with GnRH agonist (CAB-agonist therapy) against very high-risk prostate cancer (Pca). Methods: We retrospectively studied 84 Pca patients with pretreatment prostate-specific antigen (PSA) level ≥ 50 ng/mL, who were pathologically diagnosed between January 2007 and December 2016. GnRH antagonist was administered to 34 patients and GnRH agonist was administered to 50 patients. All patients received concurrent antiandrogen treatment. The primary end point was PSA progression-free survival (PSA-PFS). Results: PSA-PFS was significantly longer for the CAB-antagonist group compared to the CAB-agonist group (log-rank test, P < 0.01) in Pca patients with more than six bone metastases (the extent of disease [EOD] grade 2–4). On multivariate analysis, CAB-antagonist therapy was shown to be a possible prognostic factor for PSA-PFS (adjusted hazard ratio: 0.41, 95% confidence interval: 0.16–0.90, P =0.03). Conclusions: CAB-antagonist therapy may be a useful option in bone metastatic Pca patients with EOD grade 2–4. Keywords: Bone metastasis, Combined androgen blockade, Gonadotropin-releasing hormone receptor antagonist, Prostate cancer Background of diagnosis [1]. In 2014, 14% of patients were found to Japan had 92,600 patients with prostate cancer (Pca) in have suffered from metastatic Pca in Japan. Japan’s 2016, making it the most common form of cancer Clinical Practice Guidelines recommended combined among men in the country, and both the incidence and androgen blockade (CAB) as the standard therapy for number of deaths from Pca are increasing. The 5- and metastatic Pca. CAB therapy, which involves concurrent 10-year survival rates of non-metastatic Pca are close to use of a gonadotropin-releasing hormone (GnRH) agon- 100%. However, metastatic Pca shows 5- and 10-year ist and non-steroidal antiandrogen (CAB-agonist), is survival rates of 62 and 49%, respectively, and many pa- more effective than androgen deprivation therapy (ADT) tients that died of Pca had advanced cancer at the time alone and is recommended as the standard treatment for high-risk Pca in Japan. Patients on primary ADT in * Correspondence: kashiwabara.takeshi@sakuhp.or.jp Japan were reported to have an adjusted prostate Department of Urology, Saku Central Hospital, 197 Usuda, Saku, Nagano cancer-specific mortality rate less than half those in the 384-0393, Japan © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 2 of 11 USA. The adverse event of CAB is tolerable and the cost recurrence was defined as the day on which the PSA of CAB is acceptable for patients. Although these guide- level increased by ≥ 25% and ≥ 2.0 ng/mL from the nadir lines take into account that there is no clear evidence of level. If PSA did not decrease from the baseline, PSA the efficacy of CAB in metastatic Pca, CAB-agonist recurrence was confirmed in the 12th week from the day therapy is widely used in treatment of advanced or meta- on which treatment was started. static Pca throughout Japan [2]. However, it remains The primary end point was PSA-PFS, whereas the difficult to improve the prognosis of metastatic Pca, and secondary end point was OS. an improved therapeutic modality is required. The chi-square test was used for comparison of the Recently, next-generation CAB therapy, abiraterone rates between the two groups and Wilcoxon’s rank sum with ADT, was reported to significantly prolong overall test was used for comparison of the median values survival (OS) and progression-free survival (PFS) in between the two groups. Kaplan–Meier analysis was metastatic and hormone-sensitive Pca (HSPC) compared used to estimate the differences in time to events be- to ADT alone. Most of the metastatic Pca patients in tween the CAB-antagonist group and the CAB-agonist these studies received GnRH agonist as ADT [3, 4]. group using the log-rank test. Prognostic factors con- Unlike GnRH agonists, the GnRH antagonist, degarelix, sisted of age at the time of diagnosis, bone metastasis, neither induces a transient rise in testosterone nor Gleason score (GS), and application of CAB-antagonist aggravates the symptoms. Antiandrogen was adminis- therapy, and multivariate analyses were performed with tered concurrently in 83% of patients treated with Cox’s proportional hazard models. Statistical analyses degarelix in Japan. It is of interest to determine whether were performed using SAS JMP, Version 13, and P<0.05 there are differences in efficacy between GnRH antagon- was taken to indicate statistical significance. ist and GnRH agonist in CAB therapy. This study was approved by the Institutional Review Sixty-five percent of Pca patients with prostate-specific Board of Saku Central Hospital. antigen (PSA) level > 50 ng/mL have metastatic disease, and optimal management for these patients is controver- Results sial [5]. Patients with PSA level > 50 ng/mL were The study population consisted of 34 patients in the reported to have higher risk of PSA recurrence than CAB-antagonist group and 50 in the CAB-agonist group. those with PSA level 20–50 ng/mL [6]. The baseline Their clinical characteristics and observation periods are serum alkaline phosphatase (ALP) in patients with PSA shown in Table 1. Pathologically, there were 24 cases level > 50 ng/mL is four times higher than in those with (71%) in the CAB-antagonist group and 40 (80%) in the PSA level < 50 ng/mL, and high serum ALP indicated CAB-agonist group with GS ≥ 8. The difference between metastatic disease in patients with PSA level > 50 ng/mL the two groups was not significant (P = 0.19). In the total [7]. PSA control after treatment was reported to be asso- population, Seventy patients (83%) had primary tumor ciated with improved OS. GnRH antagonist monother- category ≥ T3, 57 patients (69%) had metastatic Pca, 44 apy was shown to be associated with improved PSA-PFS (54%) had bone metastasis, and 46 (56%) had lymph compared with CAB-agonist therapy [8]. Patients with node metastasis. Thirty-two patients (40%) had concur- PSA level ≥ 50 ng/mL were suitable for inclusion in our rent bone metastasis and lymph node metastasis, 11 retrospective patient cohort study. Here, we compared (14%) had bone metastasis alone, and 13 (17%) had only the therapeutic effects of CAB using concurrent GnRH lymph node metastasis. Among the cases with bone antagonist (CAB-antagonist) and CAB-agonist therapy metastasis, 13 (72%) in the CAB-antagonist group and in treatment of high-risk Pca with PSA level ≥ 50 ng/mL. 19 (73%) in the CAB-agonist group were treated with denosumab or zoledronic acid, respectively; the difference Methods between the two groups was not significant. Thirty-five We identified 103 patients with a pathological diagnosis (69%) of 52 patients with PSA level > 100 ng/mL and nine of Pca with PSA level ≥ 50 ng/mL at our hospital (28%) of 32 patients with PSA level 50–100 ng/mL had between January 2007 and December 2016 (Fig. 1). All bone metastases in the present study. The number of cases were followed up for more than 12 weeks. GnRH bone metastatic Pca patients with PSA level > 100 ng/mL antagonist (degarelix) or GnRH agonist (leuprorelin in was significantly greater than that of patients with PSA 13 cases and goserelin in 37 cases) was administered as level 50–100 ng/mL (P <0.01). ADT. Oral non-steroidal antiandrogen (bicalutamide, There were no significant differences between the two 80 mg/daily) was begun before or concomitant with the groups in terms of age at the time of diagnosis, bone start of ADT. metastasis, lymph node metastasis, GS, or pretreatment Diagnosis during the clinical phase was performed by PSA level. The two groups were not mismatched with bone scintigraphy, magnetic resonance imaging (MRI), regard to patient characteristics, but there were differ- and computed tomography (CT). The timing of PSA ences in observation period between the groups. No Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 3 of 11 Fig. 1 Selection and outcome of patients pathologically diagnosed with pretreatment PSA level ≥ 50 ng/mL patients in either group suffered from cardiovascular dis- Among cases with bone metastasis, there were signifi- ease during the observation period. cant differences in PSA-PFS (Fig. 3a) and OS (Fig. 3b) PSA recurrence within 1 year was observed in five between the two groups. Patients with PSA level ≥ 50 ng/ patients (15%) in the CAB-antagonist group, and one mL without metastasis between both groups showed no patient died from Pca during the observation period. differences in PSA-PFS (Fig. 4a)orOS (Fig. 4b). Eight of PSA recurred within 1 year in 22 patients (44%) in the 27 patients without metastasis received adjuvant radiation CAB-agonist group. Twenty-one patients died from Pca therapy, three patients were in the CAB-antagonist group among those patients with PSA recurrence in the and five were in the CAB-agonist group. CAB-agonist group during the observation period (Fig. 1). The CAB-antagonist group with high volume disease, All patients with PSA recurrence had bone or lymph node defined as more than six bone metastases (the extent of metastasis at the time of diagnosis. disease (EOD) grade 2–4), was associated with signifi- PSA-PFS (Fig. 2a) and OS (Fig. 2b) of patients with cantly greater improvement of PSA-PFS (Fig. 5b) in the PSA level ≥ 50 ng/mL were significantly different be- Kaplan–Meier estimate compared to the CAB-agonist tween the two groups in the Kaplan–Meier estimate. group [9, 10]. The two groups with low volume disease, Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 4 of 11 Table 1 Patient characteristics CAB with GnRH antagonist CAB with GnRH agonist n =34 n =50 P-value Median age at diagnosis years (range) 75(50–88) 74 (55–85) 0.09† ≥ 75 years old (%) 19 (56) 22 (44) 0.28‡ Median pretreatment PSA level ng/mL (range) 176.4 (51.5–5076) 136.4 (51.9–5827) 0.82† Pathological diagnosis Gleason score 6 1 2 0.78‡ Gleason score 7 9 8 Gleason score 8 11 21 Gleason score 9 11 16 Gleason score10 2 3 No of Gleason score 8–10 (%) 24(70) 40(80) 0.19‡ T category T2 4 9 0.60‡ T3 24 33 T4 6 7 Unknown 0 1 Bone metastasis EOD0 16 22 0.72‡ EOD1 7 9 EOD2 8 10 EOD3 3 6 EOD4 0 1 Unknown 0 2 Lymph node metastasis (%) Positive 21 (62) 25 (50) 0.58‡ Negative 13 (38) 23 (46) Unknown 0 2 When to use bicalutamide Concurrently 15 12 Before 19 38 Median observation period days (range) 761 (212–1529) 1141(175–3419) < 0.01* †: Wilcoxon’s rank sum test, ‡: Chi-square test, *: Log-rank test CAB combined androgen blockade, EOD the extent of disease, GnRH gonadotropin-releasing hormone, PSA prostate-specific antigen EOD stratification EOD grade 0; normal and benign bone disease EOD grade 1; number of bone metastases < 6 EOD grade 2; number of bone metastases 6–20 EOD grade 3; number of bone metastases > 20 but less than “super scan” EOD grade 4; super scan defined as less than six bone metastases (EOD grade 1), CAB therapy to block adrenal gland-derived testoster- showed no differences in PSA-PFS (Fig. 5a). Median one was first reported in 1979. There have since been a PSA levels during treatment in the two groups are number of reports that CAB therapy has a greater effect shown in Fig. 6a. There was a significant difference in in improving survival rate than castration alone, but it PSA elevation > 4 ng/mL after commencement of CAB has not been adopted as a standard therapy around the therapy between the two groups (Fig. 6b). On multivari- world [12, 13]. ate analysis, CAB-antagonist therapy was shown to be a CAB therapy, in which a nonsteroidal antiandrogen is significant prognostic factor for PSA-PFS (Table 2)in used along with GnRH agonist, has been used in 59% of Pca patients with pretreatment PSA level ≥ 50 ng/mL. patients with advanced Pca in Japan. CAB therapy is increasingly used with increasing Gleason score and clinical stage [14, 15]. In Japan, CAB therapy has been Discussion adopted as a standard treatment modality for advanced ADT has become the primary treatment option in cases Pca. However, CAB-agonist therapy does not sufficiently of advanced Pca since Huggins et al. first reported the improve prognosis in cases of bone metastatic Pca. Re- clinical efficacy of orchiectomy in such patients [11]. cently, next-generation CAB therapy with abiraterone Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 5 of 11 Fig. 2 Kaplan–Meier curves of prostate-specific antigen progression-free survival (PSA-PFS) (a) and overall survival (OS) (b) showed significantly better results in the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone antagonist (CAB-antagonist therapy) than the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone agonist (CAB-agonist therapy) among prostate cancer patients with pretreatment PSA level ≥ 50 ng/mL and ADT was shown to significantly prolong OS and hormone (FSH) secretion from the pituitary gland. progression-free survival in metastatic Pca and HSPC GnRH antagonists do not lead to a transient rise in compared to ADT alone. GnRH agonists as ADT testosterone (testosterone surge) as seen with GnRH were used for most metastatic Pca patients in these agonists. After 1 month of treatment, 59% of patients studies [3, 4]. The present study examined therapeutic treated with the GnRH antagonist, degarelix, reached a effects of CAB therapy with GnRH antagonist and PSA level of ≤ 4 ng/mL, suggesting a faster pace of GnRH agonist concurrently using the conventional decrease in PSA level compared to patients treated with antiandrogen, bicalutamide in Pca patients with PSA leuprorelin [6]. In the present study, the PSA level from level > 50 ng/mL. baseline decreased rapidly in the two groups, however there GnRH antagonists competitively inhibit GnRH from was a significant difference in PSA elevation > 4 ng/mL the hypothalamus. These interactions result in suppres- after commencement of CAB therapy between the two sion of luteinizing hormone (LH) and follicle-stimulating groups. Metastatic Pca patients with PSA level > 4 ng/mL Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 6 of 11 Fig. 3 Kaplan–Meier curves for prostate-specific antigen progression-free survival (PSA-PFS) (a) and overall survival (OS) (b) showed significantly better results in the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone antagonist (CAB-antagonist therapy, n = 18) than the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone agonist (CAB-agonist therapy, n = 26) among patients with bone metastatic prostate cancer at 7 months after commencement of therapy could be early within 1 and 2 years, respectively. The PSA recurrence treatment failure and PSA levels rarely decreased further rate increased rapidly, particularly with PSA ≥ 50 ng/mL after 6 months [16]. PSA–PFS was associated with OS. at the time of diagnosis. Particularly for clinical cases [17]. PSA elevation > 4 ng/ml was clinically important to with pretreatment PSA ≥ 50 ng/mL, the PSA recurrence detect treatment failure at an early time point after rate within 1 year decreased to 29% for the degarelix commencement of primary CAB therapy. These findings group, in comparison to 40% for the leuprorelin group indicated the efficacy of CAB-antagonist therapy for [6]. In the present study, the PSA recurrence rates within metastatic Pca. 1 year were 15% for the CAB-antagonist group and 44% In metastatic Pca, PSA recurrence was reported 18– for the CAB-agonist group. Thus, CAB-antagonist group 24 months after the start of ADT. In the present study, showed a significantly reduced PSA recurrence rate, PSA recurrence was observed at rates of 79 and 91% suggesting that the PSA recurrence rate using Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 7 of 11 Fig. 4 Kaplan–Meier curves for prostate-specific antigen progression-free survival (PSA-PFS) (a) and overall survival (OS) (b) showed no difference between the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone antagonist (CAB-antagonist therapy, n = 11) and the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone agonist (CAB-agonist therapy, n = 16) in patients without metastatic prostate cancer CAB-antagonist may be lower than that with GnRH significantly improved OS in cases with lymph node antagonist alone. metastasis. In contrast, CAB-agonist therapy did not The results of the present study indicated that improve OS in cases with bone metastasis. To improve CAB-antagonist therapy improved PSA-PFS to a signifi- the prognosis of advanced Pca, it is necessary to improve cantly greater extent than CAB-agonist therapy. This the prognosis of bone metastatic Pca. Our findings indi- suggests that CAB therapy using both GnRH antagonist cated that CAB-antagonist therapy prolonged PSA-PFS and nonsteroidal antiandrogen agent may prevent PSA to a greater extent than CAB-agonist therapy in Kaplan– recurrence and further improve PSA-PFS. In advanced Meier estimate. The greater improvement of PSA-PFS Pca, the retention of PSA at a low level by initial-phase by CAB-antagonist therapy may be clinically significant endocrine therapy improves the prognosis [16]. It was for metastatic Pca. reported that GnRH antagonist significantly prolonged Currently abiraterone or docetaxel with ADT have PSA-PFS compared to treatment with GnRH agonist been reported to be beneficial in cases of high-volume [18]. In cases of metastatic Pca, CAB-agonist therapy disease stratified according to visceral metastasis or the Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 8 of 11 Fig. 5 Kaplan–Meier curves for prostate-specific antigen progression-free survival (PSA-PFS) showed significantly better results in the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone antagonist (CAB-antagonist therapy, n = 11) than the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone agonist (CAB-agonist therapy, n = 17) in prostate cancer patients with more than six bone metastases (b). There were no differences between the two groups in prostate cancer patients with less than six bone metastases (a) number of bone metastases [3, 4, 10]. In the present phenomenon. However, it has been reported that the tes- study, CAB-antagonist therapy with more than six bone tosterone surge occurs in 74% of patients even with anti- metastases (EOD grade 2–4) was associated with greater androgen administration [20]. In cases with pretreatment improvement in PSA-PFS than CAB-agonist therapy. PSA ≥ 50 ng/mL, PSA-PFS showed a more significant im- Multivariate analysis indicated that CAB-antagonist provement in the group treated with degarelix alone than therapy was a possible prognostic factor for PSA-PFS. in the group given GnRH agonist, in which antiandrogens Although the reasons for the above observations are not were administered to prevent the flare phenomenon [8]. yet clear, there are a number of possible underlying Therefore, degarelix, which is not associated with a testos- mechanisms. One mechanism may involve the lack of tes- terone surge, may improve the prognosis of metastatic Pca. tosterone surge when degarelix is used, as the flare Another mechanism involves the administration of phenomenon defined as aggravation of Pca is stimulated degarelix to inhibit FSH secretion. In recent years, atten- by the testosterone surge, resulting in death in some cases tion has focused on the influence of FSH in Pca, which [19]. In cases with advanced and metastatic Pca, including is as significant as that of testosterone [21]. Degarelix those with pretreatment PSA ≥ 50 ng/mL, antiandrogen was reported to be capable of maintaining FSH at a low therapy is used before GnRH agonist to prevent the flare level during the period of treatment [20]. Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 9 of 11 Fig. 6 a Prostate-specific antigen (PSA) level during treatment in the two groupsThe black line shows the median PSA level in combined androgen blockade (CAB) therapy with concurrent gonadotropin-releasing hormone (GnRH) antagonist (CAB-antagonist therapy) and the black-dotted line shows the median PSA level in CAB therapy with concurrent GnRH agonist (CAB-agonist therapy). The box plot indicates upper whisker (+ 1.5 interquartile range), upper quartile, median, lower quartile, and lower whisker (− 1.5 interquartile range), respectively, with outlier marks. b The probability of PSA elevation > 4 ng/mL was significantly lower in CAB-antagonist therapy than CAB-agonist therapy in prostate cancer patients with PSA level > 50 ng/ml Table 2 Multivariate analysis for PSA-PFS Univariate analysis Multivariate analysis HR 95% CI P-value HR 95% CI P-value ≥ 75 years old at diagnosis 1.09 0.55–2.16 0.79 1.17 0.59–2.35 0.65 CAB therapy with GnRH antagonist 0.40 0.16–0.87 0.02 0.41 0.16–0.90 0.03 Bone metastasis positive 4.12 1.93–9.79 < 0.01 3.60 1.66–8.74 < 0.01 Gleason score ≥ 8 3.38 1.21–14.07 0.02 1.94 0.66–8.34 0.25 CAB combined androgen blockade, CI confidential interval, HR hazard ratio, PFS progression-free survival, PSA prostate-specific antigen Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 10 of 11 FSH is considered important for bone metabolism as it would represent an important source of bias. Therefore, regulates the control of bone resorption and the forma- the present study may not have allowed adequate assess- tion of osteoblasts and osteoclasts. Degarelix maintains ment of the effects of CAB-antagonist therapy for bone alkaline phosphatase (ALP), a marker of bone metasta- metastatic prostate cancer. Despite these limitations, our sis, at a low level during the period of treatment. ALP findings could help to improve the prognosis of bone level rose in the GnRH agonist group 10 months after metastatic prostate cancer patients. Further large-scale commencement of treatment [7]. The delayed ALP rise prospective studies with well-matched groups of patients after commencement of GnRH agonist administration are required to confirm our findings. may represent a therapeutic failure for advanced Pca. This phenomenon suggests that the impacts of the Conclusions testosterone surge and the transient rise in FSH in the In cases of bone metastatic Pca with pretreatment PSA initial phase of GnRH agonist treatment remain intact level ≥ 50 ng/mL, CAB-antagonist therapy as the primary even after inhibition of testosterone. The lack of a ADT could be associated with greater prolongation of delayed increase in ALP after commencement of degare- PSA-PFS than CAB-agonist therapy. CAB-antagonist ther- lix treatment suggests that the aggravation of bone apy may be a useful therapeutically option for treatment metastasis is inhibited. FSH receptor expression has of bone metastatic Pca patients with EOD grade 2–4. been confirmed in cases of castration-resistant prostate cancer (CRPC). Lower FSH level is associated with Abbreviations longer period of progression from HSPC to CRPC [22]. ADT: Androgen deprivation therapy; ALP: Alkaline phosphatase; The observations with degarelix treatment suggested CAB: Combined androgen blockade; CAB-agonist: Combined androgen blockade with concurrent use of gonadotropin-releasing hormone agonist; that delayed transition to CRPC may be related to CAB-antagonist: Combined androgen blockade with concurrent use of improved prognosis of bone metastatic Pca. gonadotropin-releasing hormone antagonist; CI: Confidence interval; There have been few reports regarding the effective- CRPC: Castration-resistant prostate cancer; EOD: The extent of disease; FSH: Follicle-stimulating hormone; GnRH: Gonadotropin-releasing hormone; ness of CAB-antagonist therapy as the initial-phase GS: Gleason score; HR: Hazard ratio; HSPC: Hormone-sensitive prostate endocrine therapy in metastatic Pca. The results of the cancer; LH: Luteinizing hormone; OS: Overall survival; PFS: Progression-free present study suggest that CAB-antagonist therapy may survival; PSA: Prostate-specific antigen; PSA-PFS: Prostate-specific antigen progression-free survival reduce PSA recurrence and prolong PSA-PFS in bone metastatic Pca. Thus, the present study suggested that Acknowledgements CAB-antagonist therapy may improve the prognosis of Thanks are due to Mr. Shin-Ichirou Yoshimoto for his linguistic advice. bone metastatic Pca with EOD grade 2–4. The survival of Pca patients is related to several risk Availability of data and materials factors, including the extent of the tumor, pathological The datasets analyzed during the present study are available from the grade, patient’s age, and pretreatment PSA level [23–26]. corresponding author on reasonable request. Individual patient data cannot be made available. Patients with lymph node metastases were reported to have better outcome than those with bone metastases Authors’ contributions [26]. Pretreatment PSA levels could be associated with TK conceived of the study and wrote the draft. SS revised the draft. TK and bone metastases in the present study. Prognostic factors SS contributed to data collection and analysis. Both authors read and consisting of patient’s age at the time of diagnosis, bone approved the final manuscript. metastasis, GS, and application of CAB-antagonist therapy would be suitable for the present multivariate Authors’ information TK and SS are urologists. analysis of PSA-PFS. CAB-antagonist therapy was found to be a possible prognostic factor for PSA-PFS; however, Ethics approval and consent to participate the frequency of PSA recurrence and number of deaths The present study was approved by the Institutional Review Board (IRB) of were so small that there may have been confounding fac- Saku Central Hospital (Reference number: R201510–04). Consent was obtained tors or bias that were not addressed in the present study. from all participants included in the study through the opt-out method in accordance with the national regulations and the ethical guidelines for clinical The limitations of the present study include the small studies in Japan. The IRB waived the requirement for written informed consent number of the two groups, the study was performed in a due to the retrospective nature of the present analysis. single institute, its retrospective nature, concern regard- ing matching between the two groups in terms of the Competing interests patient population with Gleason score 8–10. Risk of bias The authors declare that they have no competing interests. resulting from differences in number at risk in each year on the Kaplan–Meier curve for PSA-PFS must be taken Publisher’sNote into consideration, because the observation periods be- Springer Nature remains neutral with regard to jurisdictional claims in tween the two groups were significantly different and published maps and institutional affiliations. Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 11 of 11 Received: 1 October 2017 Accepted: 21 May 2018 20. Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, et al. 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Thompson IM. Flare associated with GnRH-agonist therapy. Rev Urol. 2014; 3(Suppl 3):10–4. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Cancer Springer Journals

Usefulness of combined androgen blockade therapy with gonadotropin-releasing hormone antagonist for bone metastatic prostate cancer with pretreatment prostate-specific antigen level ≥ 50 ng/mL

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Copyright © 2018 by The Author(s).
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Biomedicine; Cancer Research; Oncology; Surgical Oncology; Health Promotion and Disease Prevention; Biomedicine, general; Medicine/Public Health, general
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Abstract

Background: This study was performed to examine the usefulness of combined androgen blockade (CAB) therapy with a gonadotropin-releasing hormone (GnRH) antagonist (CAB-antagonist therapy), instead of CAB therapy with GnRH agonist (CAB-agonist therapy) against very high-risk prostate cancer (Pca). Methods: We retrospectively studied 84 Pca patients with pretreatment prostate-specific antigen (PSA) level ≥ 50 ng/mL, who were pathologically diagnosed between January 2007 and December 2016. GnRH antagonist was administered to 34 patients and GnRH agonist was administered to 50 patients. All patients received concurrent antiandrogen treatment. The primary end point was PSA progression-free survival (PSA-PFS). Results: PSA-PFS was significantly longer for the CAB-antagonist group compared to the CAB-agonist group (log-rank test, P < 0.01) in Pca patients with more than six bone metastases (the extent of disease [EOD] grade 2–4). On multivariate analysis, CAB-antagonist therapy was shown to be a possible prognostic factor for PSA-PFS (adjusted hazard ratio: 0.41, 95% confidence interval: 0.16–0.90, P =0.03). Conclusions: CAB-antagonist therapy may be a useful option in bone metastatic Pca patients with EOD grade 2–4. Keywords: Bone metastasis, Combined androgen blockade, Gonadotropin-releasing hormone receptor antagonist, Prostate cancer Background of diagnosis [1]. In 2014, 14% of patients were found to Japan had 92,600 patients with prostate cancer (Pca) in have suffered from metastatic Pca in Japan. Japan’s 2016, making it the most common form of cancer Clinical Practice Guidelines recommended combined among men in the country, and both the incidence and androgen blockade (CAB) as the standard therapy for number of deaths from Pca are increasing. The 5- and metastatic Pca. CAB therapy, which involves concurrent 10-year survival rates of non-metastatic Pca are close to use of a gonadotropin-releasing hormone (GnRH) agon- 100%. However, metastatic Pca shows 5- and 10-year ist and non-steroidal antiandrogen (CAB-agonist), is survival rates of 62 and 49%, respectively, and many pa- more effective than androgen deprivation therapy (ADT) tients that died of Pca had advanced cancer at the time alone and is recommended as the standard treatment for high-risk Pca in Japan. Patients on primary ADT in * Correspondence: kashiwabara.takeshi@sakuhp.or.jp Japan were reported to have an adjusted prostate Department of Urology, Saku Central Hospital, 197 Usuda, Saku, Nagano cancer-specific mortality rate less than half those in the 384-0393, Japan © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 2 of 11 USA. The adverse event of CAB is tolerable and the cost recurrence was defined as the day on which the PSA of CAB is acceptable for patients. Although these guide- level increased by ≥ 25% and ≥ 2.0 ng/mL from the nadir lines take into account that there is no clear evidence of level. If PSA did not decrease from the baseline, PSA the efficacy of CAB in metastatic Pca, CAB-agonist recurrence was confirmed in the 12th week from the day therapy is widely used in treatment of advanced or meta- on which treatment was started. static Pca throughout Japan [2]. However, it remains The primary end point was PSA-PFS, whereas the difficult to improve the prognosis of metastatic Pca, and secondary end point was OS. an improved therapeutic modality is required. The chi-square test was used for comparison of the Recently, next-generation CAB therapy, abiraterone rates between the two groups and Wilcoxon’s rank sum with ADT, was reported to significantly prolong overall test was used for comparison of the median values survival (OS) and progression-free survival (PFS) in between the two groups. Kaplan–Meier analysis was metastatic and hormone-sensitive Pca (HSPC) compared used to estimate the differences in time to events be- to ADT alone. Most of the metastatic Pca patients in tween the CAB-antagonist group and the CAB-agonist these studies received GnRH agonist as ADT [3, 4]. group using the log-rank test. Prognostic factors con- Unlike GnRH agonists, the GnRH antagonist, degarelix, sisted of age at the time of diagnosis, bone metastasis, neither induces a transient rise in testosterone nor Gleason score (GS), and application of CAB-antagonist aggravates the symptoms. Antiandrogen was adminis- therapy, and multivariate analyses were performed with tered concurrently in 83% of patients treated with Cox’s proportional hazard models. Statistical analyses degarelix in Japan. It is of interest to determine whether were performed using SAS JMP, Version 13, and P<0.05 there are differences in efficacy between GnRH antagon- was taken to indicate statistical significance. ist and GnRH agonist in CAB therapy. This study was approved by the Institutional Review Sixty-five percent of Pca patients with prostate-specific Board of Saku Central Hospital. antigen (PSA) level > 50 ng/mL have metastatic disease, and optimal management for these patients is controver- Results sial [5]. Patients with PSA level > 50 ng/mL were The study population consisted of 34 patients in the reported to have higher risk of PSA recurrence than CAB-antagonist group and 50 in the CAB-agonist group. those with PSA level 20–50 ng/mL [6]. The baseline Their clinical characteristics and observation periods are serum alkaline phosphatase (ALP) in patients with PSA shown in Table 1. Pathologically, there were 24 cases level > 50 ng/mL is four times higher than in those with (71%) in the CAB-antagonist group and 40 (80%) in the PSA level < 50 ng/mL, and high serum ALP indicated CAB-agonist group with GS ≥ 8. The difference between metastatic disease in patients with PSA level > 50 ng/mL the two groups was not significant (P = 0.19). In the total [7]. PSA control after treatment was reported to be asso- population, Seventy patients (83%) had primary tumor ciated with improved OS. GnRH antagonist monother- category ≥ T3, 57 patients (69%) had metastatic Pca, 44 apy was shown to be associated with improved PSA-PFS (54%) had bone metastasis, and 46 (56%) had lymph compared with CAB-agonist therapy [8]. Patients with node metastasis. Thirty-two patients (40%) had concur- PSA level ≥ 50 ng/mL were suitable for inclusion in our rent bone metastasis and lymph node metastasis, 11 retrospective patient cohort study. Here, we compared (14%) had bone metastasis alone, and 13 (17%) had only the therapeutic effects of CAB using concurrent GnRH lymph node metastasis. Among the cases with bone antagonist (CAB-antagonist) and CAB-agonist therapy metastasis, 13 (72%) in the CAB-antagonist group and in treatment of high-risk Pca with PSA level ≥ 50 ng/mL. 19 (73%) in the CAB-agonist group were treated with denosumab or zoledronic acid, respectively; the difference Methods between the two groups was not significant. Thirty-five We identified 103 patients with a pathological diagnosis (69%) of 52 patients with PSA level > 100 ng/mL and nine of Pca with PSA level ≥ 50 ng/mL at our hospital (28%) of 32 patients with PSA level 50–100 ng/mL had between January 2007 and December 2016 (Fig. 1). All bone metastases in the present study. The number of cases were followed up for more than 12 weeks. GnRH bone metastatic Pca patients with PSA level > 100 ng/mL antagonist (degarelix) or GnRH agonist (leuprorelin in was significantly greater than that of patients with PSA 13 cases and goserelin in 37 cases) was administered as level 50–100 ng/mL (P <0.01). ADT. Oral non-steroidal antiandrogen (bicalutamide, There were no significant differences between the two 80 mg/daily) was begun before or concomitant with the groups in terms of age at the time of diagnosis, bone start of ADT. metastasis, lymph node metastasis, GS, or pretreatment Diagnosis during the clinical phase was performed by PSA level. The two groups were not mismatched with bone scintigraphy, magnetic resonance imaging (MRI), regard to patient characteristics, but there were differ- and computed tomography (CT). The timing of PSA ences in observation period between the groups. No Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 3 of 11 Fig. 1 Selection and outcome of patients pathologically diagnosed with pretreatment PSA level ≥ 50 ng/mL patients in either group suffered from cardiovascular dis- Among cases with bone metastasis, there were signifi- ease during the observation period. cant differences in PSA-PFS (Fig. 3a) and OS (Fig. 3b) PSA recurrence within 1 year was observed in five between the two groups. Patients with PSA level ≥ 50 ng/ patients (15%) in the CAB-antagonist group, and one mL without metastasis between both groups showed no patient died from Pca during the observation period. differences in PSA-PFS (Fig. 4a)orOS (Fig. 4b). Eight of PSA recurred within 1 year in 22 patients (44%) in the 27 patients without metastasis received adjuvant radiation CAB-agonist group. Twenty-one patients died from Pca therapy, three patients were in the CAB-antagonist group among those patients with PSA recurrence in the and five were in the CAB-agonist group. CAB-agonist group during the observation period (Fig. 1). The CAB-antagonist group with high volume disease, All patients with PSA recurrence had bone or lymph node defined as more than six bone metastases (the extent of metastasis at the time of diagnosis. disease (EOD) grade 2–4), was associated with signifi- PSA-PFS (Fig. 2a) and OS (Fig. 2b) of patients with cantly greater improvement of PSA-PFS (Fig. 5b) in the PSA level ≥ 50 ng/mL were significantly different be- Kaplan–Meier estimate compared to the CAB-agonist tween the two groups in the Kaplan–Meier estimate. group [9, 10]. The two groups with low volume disease, Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 4 of 11 Table 1 Patient characteristics CAB with GnRH antagonist CAB with GnRH agonist n =34 n =50 P-value Median age at diagnosis years (range) 75(50–88) 74 (55–85) 0.09† ≥ 75 years old (%) 19 (56) 22 (44) 0.28‡ Median pretreatment PSA level ng/mL (range) 176.4 (51.5–5076) 136.4 (51.9–5827) 0.82† Pathological diagnosis Gleason score 6 1 2 0.78‡ Gleason score 7 9 8 Gleason score 8 11 21 Gleason score 9 11 16 Gleason score10 2 3 No of Gleason score 8–10 (%) 24(70) 40(80) 0.19‡ T category T2 4 9 0.60‡ T3 24 33 T4 6 7 Unknown 0 1 Bone metastasis EOD0 16 22 0.72‡ EOD1 7 9 EOD2 8 10 EOD3 3 6 EOD4 0 1 Unknown 0 2 Lymph node metastasis (%) Positive 21 (62) 25 (50) 0.58‡ Negative 13 (38) 23 (46) Unknown 0 2 When to use bicalutamide Concurrently 15 12 Before 19 38 Median observation period days (range) 761 (212–1529) 1141(175–3419) < 0.01* †: Wilcoxon’s rank sum test, ‡: Chi-square test, *: Log-rank test CAB combined androgen blockade, EOD the extent of disease, GnRH gonadotropin-releasing hormone, PSA prostate-specific antigen EOD stratification EOD grade 0; normal and benign bone disease EOD grade 1; number of bone metastases < 6 EOD grade 2; number of bone metastases 6–20 EOD grade 3; number of bone metastases > 20 but less than “super scan” EOD grade 4; super scan defined as less than six bone metastases (EOD grade 1), CAB therapy to block adrenal gland-derived testoster- showed no differences in PSA-PFS (Fig. 5a). Median one was first reported in 1979. There have since been a PSA levels during treatment in the two groups are number of reports that CAB therapy has a greater effect shown in Fig. 6a. There was a significant difference in in improving survival rate than castration alone, but it PSA elevation > 4 ng/mL after commencement of CAB has not been adopted as a standard therapy around the therapy between the two groups (Fig. 6b). On multivari- world [12, 13]. ate analysis, CAB-antagonist therapy was shown to be a CAB therapy, in which a nonsteroidal antiandrogen is significant prognostic factor for PSA-PFS (Table 2)in used along with GnRH agonist, has been used in 59% of Pca patients with pretreatment PSA level ≥ 50 ng/mL. patients with advanced Pca in Japan. CAB therapy is increasingly used with increasing Gleason score and clinical stage [14, 15]. In Japan, CAB therapy has been Discussion adopted as a standard treatment modality for advanced ADT has become the primary treatment option in cases Pca. However, CAB-agonist therapy does not sufficiently of advanced Pca since Huggins et al. first reported the improve prognosis in cases of bone metastatic Pca. Re- clinical efficacy of orchiectomy in such patients [11]. cently, next-generation CAB therapy with abiraterone Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 5 of 11 Fig. 2 Kaplan–Meier curves of prostate-specific antigen progression-free survival (PSA-PFS) (a) and overall survival (OS) (b) showed significantly better results in the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone antagonist (CAB-antagonist therapy) than the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone agonist (CAB-agonist therapy) among prostate cancer patients with pretreatment PSA level ≥ 50 ng/mL and ADT was shown to significantly prolong OS and hormone (FSH) secretion from the pituitary gland. progression-free survival in metastatic Pca and HSPC GnRH antagonists do not lead to a transient rise in compared to ADT alone. GnRH agonists as ADT testosterone (testosterone surge) as seen with GnRH were used for most metastatic Pca patients in these agonists. After 1 month of treatment, 59% of patients studies [3, 4]. The present study examined therapeutic treated with the GnRH antagonist, degarelix, reached a effects of CAB therapy with GnRH antagonist and PSA level of ≤ 4 ng/mL, suggesting a faster pace of GnRH agonist concurrently using the conventional decrease in PSA level compared to patients treated with antiandrogen, bicalutamide in Pca patients with PSA leuprorelin [6]. In the present study, the PSA level from level > 50 ng/mL. baseline decreased rapidly in the two groups, however there GnRH antagonists competitively inhibit GnRH from was a significant difference in PSA elevation > 4 ng/mL the hypothalamus. These interactions result in suppres- after commencement of CAB therapy between the two sion of luteinizing hormone (LH) and follicle-stimulating groups. Metastatic Pca patients with PSA level > 4 ng/mL Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 6 of 11 Fig. 3 Kaplan–Meier curves for prostate-specific antigen progression-free survival (PSA-PFS) (a) and overall survival (OS) (b) showed significantly better results in the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone antagonist (CAB-antagonist therapy, n = 18) than the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone agonist (CAB-agonist therapy, n = 26) among patients with bone metastatic prostate cancer at 7 months after commencement of therapy could be early within 1 and 2 years, respectively. The PSA recurrence treatment failure and PSA levels rarely decreased further rate increased rapidly, particularly with PSA ≥ 50 ng/mL after 6 months [16]. PSA–PFS was associated with OS. at the time of diagnosis. Particularly for clinical cases [17]. PSA elevation > 4 ng/ml was clinically important to with pretreatment PSA ≥ 50 ng/mL, the PSA recurrence detect treatment failure at an early time point after rate within 1 year decreased to 29% for the degarelix commencement of primary CAB therapy. These findings group, in comparison to 40% for the leuprorelin group indicated the efficacy of CAB-antagonist therapy for [6]. In the present study, the PSA recurrence rates within metastatic Pca. 1 year were 15% for the CAB-antagonist group and 44% In metastatic Pca, PSA recurrence was reported 18– for the CAB-agonist group. Thus, CAB-antagonist group 24 months after the start of ADT. In the present study, showed a significantly reduced PSA recurrence rate, PSA recurrence was observed at rates of 79 and 91% suggesting that the PSA recurrence rate using Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 7 of 11 Fig. 4 Kaplan–Meier curves for prostate-specific antigen progression-free survival (PSA-PFS) (a) and overall survival (OS) (b) showed no difference between the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone antagonist (CAB-antagonist therapy, n = 11) and the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone agonist (CAB-agonist therapy, n = 16) in patients without metastatic prostate cancer CAB-antagonist may be lower than that with GnRH significantly improved OS in cases with lymph node antagonist alone. metastasis. In contrast, CAB-agonist therapy did not The results of the present study indicated that improve OS in cases with bone metastasis. To improve CAB-antagonist therapy improved PSA-PFS to a signifi- the prognosis of advanced Pca, it is necessary to improve cantly greater extent than CAB-agonist therapy. This the prognosis of bone metastatic Pca. Our findings indi- suggests that CAB therapy using both GnRH antagonist cated that CAB-antagonist therapy prolonged PSA-PFS and nonsteroidal antiandrogen agent may prevent PSA to a greater extent than CAB-agonist therapy in Kaplan– recurrence and further improve PSA-PFS. In advanced Meier estimate. The greater improvement of PSA-PFS Pca, the retention of PSA at a low level by initial-phase by CAB-antagonist therapy may be clinically significant endocrine therapy improves the prognosis [16]. It was for metastatic Pca. reported that GnRH antagonist significantly prolonged Currently abiraterone or docetaxel with ADT have PSA-PFS compared to treatment with GnRH agonist been reported to be beneficial in cases of high-volume [18]. In cases of metastatic Pca, CAB-agonist therapy disease stratified according to visceral metastasis or the Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 8 of 11 Fig. 5 Kaplan–Meier curves for prostate-specific antigen progression-free survival (PSA-PFS) showed significantly better results in the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone antagonist (CAB-antagonist therapy, n = 11) than the group undergoing combined androgen blockade therapy with concurrent gonadotropin-releasing hormone agonist (CAB-agonist therapy, n = 17) in prostate cancer patients with more than six bone metastases (b). There were no differences between the two groups in prostate cancer patients with less than six bone metastases (a) number of bone metastases [3, 4, 10]. In the present phenomenon. However, it has been reported that the tes- study, CAB-antagonist therapy with more than six bone tosterone surge occurs in 74% of patients even with anti- metastases (EOD grade 2–4) was associated with greater androgen administration [20]. In cases with pretreatment improvement in PSA-PFS than CAB-agonist therapy. PSA ≥ 50 ng/mL, PSA-PFS showed a more significant im- Multivariate analysis indicated that CAB-antagonist provement in the group treated with degarelix alone than therapy was a possible prognostic factor for PSA-PFS. in the group given GnRH agonist, in which antiandrogens Although the reasons for the above observations are not were administered to prevent the flare phenomenon [8]. yet clear, there are a number of possible underlying Therefore, degarelix, which is not associated with a testos- mechanisms. One mechanism may involve the lack of tes- terone surge, may improve the prognosis of metastatic Pca. tosterone surge when degarelix is used, as the flare Another mechanism involves the administration of phenomenon defined as aggravation of Pca is stimulated degarelix to inhibit FSH secretion. In recent years, atten- by the testosterone surge, resulting in death in some cases tion has focused on the influence of FSH in Pca, which [19]. In cases with advanced and metastatic Pca, including is as significant as that of testosterone [21]. Degarelix those with pretreatment PSA ≥ 50 ng/mL, antiandrogen was reported to be capable of maintaining FSH at a low therapy is used before GnRH agonist to prevent the flare level during the period of treatment [20]. Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 9 of 11 Fig. 6 a Prostate-specific antigen (PSA) level during treatment in the two groupsThe black line shows the median PSA level in combined androgen blockade (CAB) therapy with concurrent gonadotropin-releasing hormone (GnRH) antagonist (CAB-antagonist therapy) and the black-dotted line shows the median PSA level in CAB therapy with concurrent GnRH agonist (CAB-agonist therapy). The box plot indicates upper whisker (+ 1.5 interquartile range), upper quartile, median, lower quartile, and lower whisker (− 1.5 interquartile range), respectively, with outlier marks. b The probability of PSA elevation > 4 ng/mL was significantly lower in CAB-antagonist therapy than CAB-agonist therapy in prostate cancer patients with PSA level > 50 ng/ml Table 2 Multivariate analysis for PSA-PFS Univariate analysis Multivariate analysis HR 95% CI P-value HR 95% CI P-value ≥ 75 years old at diagnosis 1.09 0.55–2.16 0.79 1.17 0.59–2.35 0.65 CAB therapy with GnRH antagonist 0.40 0.16–0.87 0.02 0.41 0.16–0.90 0.03 Bone metastasis positive 4.12 1.93–9.79 < 0.01 3.60 1.66–8.74 < 0.01 Gleason score ≥ 8 3.38 1.21–14.07 0.02 1.94 0.66–8.34 0.25 CAB combined androgen blockade, CI confidential interval, HR hazard ratio, PFS progression-free survival, PSA prostate-specific antigen Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 10 of 11 FSH is considered important for bone metabolism as it would represent an important source of bias. Therefore, regulates the control of bone resorption and the forma- the present study may not have allowed adequate assess- tion of osteoblasts and osteoclasts. Degarelix maintains ment of the effects of CAB-antagonist therapy for bone alkaline phosphatase (ALP), a marker of bone metasta- metastatic prostate cancer. Despite these limitations, our sis, at a low level during the period of treatment. ALP findings could help to improve the prognosis of bone level rose in the GnRH agonist group 10 months after metastatic prostate cancer patients. Further large-scale commencement of treatment [7]. The delayed ALP rise prospective studies with well-matched groups of patients after commencement of GnRH agonist administration are required to confirm our findings. may represent a therapeutic failure for advanced Pca. This phenomenon suggests that the impacts of the Conclusions testosterone surge and the transient rise in FSH in the In cases of bone metastatic Pca with pretreatment PSA initial phase of GnRH agonist treatment remain intact level ≥ 50 ng/mL, CAB-antagonist therapy as the primary even after inhibition of testosterone. The lack of a ADT could be associated with greater prolongation of delayed increase in ALP after commencement of degare- PSA-PFS than CAB-agonist therapy. CAB-antagonist ther- lix treatment suggests that the aggravation of bone apy may be a useful therapeutically option for treatment metastasis is inhibited. FSH receptor expression has of bone metastatic Pca patients with EOD grade 2–4. been confirmed in cases of castration-resistant prostate cancer (CRPC). Lower FSH level is associated with Abbreviations longer period of progression from HSPC to CRPC [22]. ADT: Androgen deprivation therapy; ALP: Alkaline phosphatase; The observations with degarelix treatment suggested CAB: Combined androgen blockade; CAB-agonist: Combined androgen blockade with concurrent use of gonadotropin-releasing hormone agonist; that delayed transition to CRPC may be related to CAB-antagonist: Combined androgen blockade with concurrent use of improved prognosis of bone metastatic Pca. gonadotropin-releasing hormone antagonist; CI: Confidence interval; There have been few reports regarding the effective- CRPC: Castration-resistant prostate cancer; EOD: The extent of disease; FSH: Follicle-stimulating hormone; GnRH: Gonadotropin-releasing hormone; ness of CAB-antagonist therapy as the initial-phase GS: Gleason score; HR: Hazard ratio; HSPC: Hormone-sensitive prostate endocrine therapy in metastatic Pca. The results of the cancer; LH: Luteinizing hormone; OS: Overall survival; PFS: Progression-free present study suggest that CAB-antagonist therapy may survival; PSA: Prostate-specific antigen; PSA-PFS: Prostate-specific antigen progression-free survival reduce PSA recurrence and prolong PSA-PFS in bone metastatic Pca. Thus, the present study suggested that Acknowledgements CAB-antagonist therapy may improve the prognosis of Thanks are due to Mr. Shin-Ichirou Yoshimoto for his linguistic advice. bone metastatic Pca with EOD grade 2–4. The survival of Pca patients is related to several risk Availability of data and materials factors, including the extent of the tumor, pathological The datasets analyzed during the present study are available from the grade, patient’s age, and pretreatment PSA level [23–26]. corresponding author on reasonable request. Individual patient data cannot be made available. Patients with lymph node metastases were reported to have better outcome than those with bone metastases Authors’ contributions [26]. Pretreatment PSA levels could be associated with TK conceived of the study and wrote the draft. SS revised the draft. TK and bone metastases in the present study. Prognostic factors SS contributed to data collection and analysis. Both authors read and consisting of patient’s age at the time of diagnosis, bone approved the final manuscript. metastasis, GS, and application of CAB-antagonist therapy would be suitable for the present multivariate Authors’ information TK and SS are urologists. analysis of PSA-PFS. CAB-antagonist therapy was found to be a possible prognostic factor for PSA-PFS; however, Ethics approval and consent to participate the frequency of PSA recurrence and number of deaths The present study was approved by the Institutional Review Board (IRB) of were so small that there may have been confounding fac- Saku Central Hospital (Reference number: R201510–04). Consent was obtained tors or bias that were not addressed in the present study. from all participants included in the study through the opt-out method in accordance with the national regulations and the ethical guidelines for clinical The limitations of the present study include the small studies in Japan. The IRB waived the requirement for written informed consent number of the two groups, the study was performed in a due to the retrospective nature of the present analysis. single institute, its retrospective nature, concern regard- ing matching between the two groups in terms of the Competing interests patient population with Gleason score 8–10. Risk of bias The authors declare that they have no competing interests. resulting from differences in number at risk in each year on the Kaplan–Meier curve for PSA-PFS must be taken Publisher’sNote into consideration, because the observation periods be- Springer Nature remains neutral with regard to jurisdictional claims in tween the two groups were significantly different and published maps and institutional affiliations. Kashiwabara and Suda BMC Cancer (2018) 18:619 Page 11 of 11 Received: 1 October 2017 Accepted: 21 May 2018 20. Klotz L, Boccon-Gibod L, Shore ND, Andreou C, Persson BE, Cantor P, et al. 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Journal

BMC CancerSpringer Journals

Published: May 31, 2018

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