Safety and Effectiveness of Neoadjuvant Luteinizing Hormone

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ORIGINAL ARTICLE Safety and effectiveness of neoadjuvant luteinizing hormone- releasing hormone agonist plus low-dose estramustine phosphate in high-risk prostate cancer: a prospective single-arm study

T Koie, C Ohyama, H Yamamoto, S Hatakeyama, T Yoneyama, Y Hashimoto and N Kamimura

BACKGROUND: Radical prostatectomy (RP) has limited cancer control potential for the patient with high-risk prostate cancer (Pca). We prospectively examined the efficacy and safety of neoadjuvant therapy with luteinizing hormone-releasing hormone (LHRH) agonist þ low-dose estramustine phosphate (EMP) (LHRH þ EMP) followed by RP. METHODS: High-risk Pca was defined by the D’Amico stratification system. A total of 142 patients with high-risk Pca were enrolled in this trial from September 2005 to March 2011. The LHRH þ EMP therapy included administration of LHRH agonist and 280 mg day--1 EMP for 6 months before RP. Pathological cancer-free (pT0) rate on the surgical specimen was the primary end point. Secondary end points were PSA-free survival and toxicity. RESULTS: The average patient age was 67.4 years (interquartile range (IQR) 72, 65) and the median initial PSA level was 14.80 ng ml--1 (IQR 26.22, 7.13). The median Gleason score was 9 (IQR 9, 7) and 97 patients (68.3%) had clinical stage T2c or T3. All patients completed 6 months of LHRH þ EMP neoadjuvant therapy with no delays in RP. Seven patients (4.9%) achieved pT0. Surgical margins were negative in 125 patients (87.0%). At a median follow-up period of 34.9 months, PSA-free survival was 84.3%. No serious adverse events were reported during the study and there were no toxicity- related deaths. CONCLUSIONS: Six months of LHRH þ EMP neoadjuvant therapy followed by RP is safe and oncological outcomes are acceptable. Although this study was a single-arm trial with a relatively short follow-up, this treatment may have a potential to improve PSA-free survival in high-risk Pca patients. Further clinical trials are warranted.

Prostate Cancer and Prostatic Diseases (2012) 15, 397--401; doi:10.1038/pcan.2012.29; published online 14 August 2012 Keywords: high-risk; neoadjuvant therapy; luteinizing hormone-releasing hormone agonist plus low-dose estramustine phosphate

INTRODUCTION may be applicable to neoadjuvant therapy for the patients with According to the D’Amico risk stratification, patients who have high-risk Pca. PSA levels of 20 ng ml--1 or greater, Gleason scores of 8 or higher, In this prospective study, we assessed the activity and safety of or clinical stage T2c/T3 are defined as high-risk localized or locally neoadjuvant LHRH plus low-dose EMP (LHRH þ EMP) before RP in advanced prostate cancer (Pca).1 In this group of patients, patients with high-risk Pca. reported rates of PSA-free survival after local therapy range from 30 to 50%.1,2 Neoadjuvant hormonal therapy alone before radical prostatect- MATERIALS AND METHODS omy (RP) reduces the rate of positive surgical margins and can Study population achieve a pathological complete response. However, neoadjuvant This was a prospective single-arm study carried out at a teaching hospital in androgen deprivation therapy has shown no benefits in patient Japan. All enrolled patients were Japanese. High-risk Pca was defined as outcomes, especially PSA-free survival, in randomized trials.3--6 clinical stage T2c or T3, and/or initial PSA levels of 20 ng ml--1 or greater, and/ Several studies have reported similar results with neoadjuvant or a biopsy Gleason sum score of 8 or higher according to the D’Amico risk docetaxel in high-risk Pca patients.7--10 Although various trials try to stratification system.1 Eligible patients had histologically confirmed high-risk achieve pT0 or prolonged PSA-free survival, the pT0 rate was ranged Pca without lymph node or distant metastasis, an Eastern Cooperative from 0 to 2.8%9--11 and the PSA-free survival rate was still low.8,12 Oncology Group (ECOG) performance status of 0--1, adequate bone marrow We thought that other combination with hormonal and function (absolute neutrophil count X1500 m--3 and platelet count cytotoxic agents may contribute to improve oncological outcome X100 000 m--3), adequate renal function (creatinine o2.0 mg dl--1 and/or of high-risk Pca. Estramustine phosphate (EMP) is a compound creatinine clearance 440 ml min--1), and adequate hepatic function (total of estrogen and nitrogen mustard, which deregulates microtubule bilirubin o1.5 mg dl--1). Patients who underwent prior radiation therapy for assembly.13,14 We have reported the active effect of luteinizing the prostate or pelvis, or had received chemotherapy or hormonal therapy hormone-releasing hormone (LHRH) plus EMP for the patients for Pca were not enrolled. The patients who administered finasteride or with advanced Pca.15,16 We expected that this combination dutasteride before surgery were excluded in this study.

Department of Urology, Hirosaki University, Graduate School of Medicine, Hirosaki, Japan. Correspondence: Professor C Ohyama, Department of Urology, Hirosaki University Graduate School of Medicine, 5 Zaifucho, Hirosaki 036-8562, Japan. E-mail: [email protected] Received 23 February 2012; revised 22 June 2012; accepted 24 June 2012; published online 14 August 2012 Neoadjuvant therapy for high-risk prostate cancer T Koie et al 398 Table 1. Clinical characteristics of patients administered neoadjuvant therapy with LHRH agonist plus estramustine phosphate

Initial PSA level (ng ml--1)(N,%) o20 84 (59.2) X20 58 (40.8) Median (IQR) 14.80 (7.13--26.23)

Clinical stage (N,%) T1c 20 (14.1) T2a 11 (7.7) T2b 14 (9.9) T2c 26 (18.3) T3 71 (50)

Biopsy Gleason score (N,%) Figure 1. Change in serum testosterone levels. The median serum testosterone level was 442 ng ml--1 at baseline. The nadir serum p6 4 (2.8) --1 7 43 (30.3) testosterone level was 10 ng ml (interquartile range 15, 5) at the X time of operation. The median serum testosterone levels 3 and 6 8 95 (66.9) --1 Number of positive biopsy cores (IQR) 4 (3--6) months after surgery were 225 and 338 ng ml , respectively. Abbreviations: IQR, interquartile rate; LHRH, luteinizing hormone-releasing hormone. Statistical analysis Data were analyzed using SPSS 18.0 statistical software (SPSS, Chicago, IL, USA). PSA-free survival was analyzed by the Kaplan--Meier method. The The present neoadjuvant therapy achieved 4.6% of pT0 at our 17 9 relationship between survival and subgroup classification was analyzed preliminary study. The highest pT0 rate ever reported was 2.8%. using the log-rank test. All P-values were two-sided, and the significance Therefore, we expected the highest pT0 rate for the neoadjuvant therapy level was set at Po0.05. The primary end point was the percentage of as around 5% in this study. patients showing pT0. The secondary end points were PSA-free survival All patients were informed about the treatment protocol, and and toxicity. provided written consent. The study protocol and informed consent documents were reviewed and approved by the Hirosaki University institutional review board. RESULTS Patient characteristics Treatment From September 2005 to March 2011, 142 patients with high-risk Pca were enrolled. The pre-treatment characteristics of these All treatments in this study were undertaken at our institution. All patients patients are listed in Table 1. The mean patient age was 67.4 years received LHRH agonist (leuprolide 11.25 mg or goserelin acetate 10.8 mg (interquartile range (IQR) 72, 65). All patients received neoadjuvant every 3 months) and EMP 280 mg day--1 for 6 months before RP. The use LHRH EMP according to the aforementioned protocol. of our retropubic retrograde technique with RP was previously described þ in detail.18 All patients in this study underwent the same lymphadenectomy procedure, which included removal of the bilateral obturator lymph Surgical outcomes node chains. All patients completed neoadjuvant therapy and underwent RP. Deep vein thrombosis or pulmonary embolism was not seen in our series. The median operative time for RP including bilateral Patient evaluation lymphadenectomy was 110 min (IQR 129, 94) and median Baseline evaluation included complete history and physical examination, estimated blood loss was 853 ml (IQR 1285, 610). The median assessment of ECOG performance status, serum testosterone and PSA number of removed lymph nodes was 8 (IQR 12, 4). levels, abdominal and pelvic computed tomography or magnetic We experienced one rectal injury (0.7%) with intraoperative resonance imaging, and chest X-ray or computed tomography. complication, which was successfully repaired. Leakage from the Toxicity was evaluated after neoadjuvant LHRH þ EMP every 3 months vesicourethral anastomosis, which is the most frequent periopera- and graded by the National Cancer Institute Common Terminology Criteria tive complication, occurred in 26 patients (18.3%), and surgical site for Adverse Events, version 3.0. infection occurred in 3 (2.1%). Prostatectomy specimens were evaluated by a single pathologist at our institution according to International Society of Urological Pathology Change in serum testosterone level 2005.19 The apex of the prostate was shaved perpendicular to the prostatic Chronological change in serum testosterone levels ±s.d. was urethra. The bladder neck margin was coned from the specimen and shown in Figure 1. The median serum testosterone level was sectioned perpendicularly. The remaining prostate was completely 442±133 ng ml--1 (IQR 516, 375) at baseline. Serum testosterone sectioned at 3 mm intervals in a plane perpendicular to the urethral axis. level had decreased to castration levels in all patients within 3 All tumors were staged by the 2002 American Joint Committee on Cancer months after starting neoadjuvant therapy and maintained staging manual.20 Absence of evidence of cancer in the prostate and 50 ng ml--1 until RP. Serum testosterone level became 20 ng lymph node specimens was classified as a pT0. o o ml--1 in 107 patients (75.3%). The nadir serum testosterone level was 10±10 ng ml--1 (IQR 15, 5) at the time of operation. The Follow-up schedule median serum testosterone levels 3 and 6 months after surgery were 225±78 and 338±125 ng ml--1, respectively. Following surgery, all patients were assessed by measuring serum PSA and testosterone at 3-month intervals. The date of disease recurrence or PSA failure was defined as when the serum PSA level exceeded 0.2 ng ml--1.If Pathological outcomes PSA did not decrease to o0.2 ng ml--1 after surgery, the date of RP was The estimated preoperative prostate volume on transrectal defined as date of disease recurrence. ultrasonography was 29.1 ml (IQR 37.9, 22.3). The median surgical

Prostate Cancer and Prostatic Diseases (2012), 397 -- 401 & 2012 Macmillan Publishers Limited Neoadjuvant therapy for high-risk prostate cancer T Koie et al 399 specimen weight was 19.8 g (IQR 25.0, 14.5). All patients were Oncological outcomes evaluated for pathological response. As to pathological T stage, The postoperative mean follow-up period was 34.9 months (IQR 4.9%, 56.3% and 38.7% of patients had pT0, pT2 and pT3, 51.6, 21.0). During follow-up, PSA relapse without clinical respectively. recurrence occurred in 21 patients (14.8%). Clinical recurrence Overall, 17 patients (13%) had positive surgical margins, occurred in two patients (1.4%). At 34.9 months, the PSA-free including 0% of those with pT0, 1.3% with pT2 and 29.1% with survival rate was 86.0% (95% conﬁdence interval (CI), 56.4--65.4) pT3 disease. Lymph node involvement was detected in 2 (1.4%) (Figure 2). The 3-year PSA-free survival rate was 96.9% for patients patients. in clinical stage T1c to T2b (95% CI, 33.5--36.6) and 78.5% for patients in clinical stage T2c or greater (95% CI, 53.2--63.9; P ¼ 0.035) (Figure 3a). The 3-year PSA-free survival rate was 91.5% in patients who achieved pathological T0 to T2 status (95% CI, 60.1--67.4) and 68.9% in those with T3 status (95% CI, 42.8--60.0; P ¼ 0.001) (Figure 3b). The 3-year PSA-free survival rate was 86.9% in patients with negative surgical margins (95% CI, 61.2--69.1) and 53.0% in those with positive surgical margins (95% CI, 23.3--45.7; Po0.0001) (Figure 3c).

Safety of neoadjuvant LHRH plus EMP No serious adverse events were reported during the study and there were no toxicity-related deaths. No grade 3 or 4 toxicities occurred (Table 2). The most common LHRH þ EMP-related adverse event was grade 1 gynecomastia (98.6%). All adverse events occurred within 3 months after administration of LHRH þ EMP.

DISCUSSION According to previous literatures, pT0 rate have been reported to range from 0 to 2.8%.9--11 To achieve better oncologic outcome of high-risk Pca is one of the major concerns in urological oncology.21 The results with phase II studies using docetaxel-based neoadjuvant therapy have been indicated Figure 2. Kaplan--Meier estimate of PSA-free survival. At 34.5 months, that pathological cancer-free status and acceptable PSA-free the PSA-free survival rate was 86.0%. survival can rarely be achieved although geﬁtinib was added on

Figure 3. Kaplan--Meier estimate of PSA-free survival. (a) Kaplan--Meier estimate of PSA-free survival according to clinical stage. The 3-year PSA-free survival rate was 96.9% for patients in clinical stages T1c to T2b and 78.5% for patients in clinical stage T2c or greater (P ¼ 0.035). (b) Kaplan--Meier estimate of PSA-free survival according to pathological stage. The 3-year PSA-free survival rate was 91.5% in patients who achieved pathological T0 or T2 status and 68.9% in those with T3 status (P ¼ 0.001). (c) Kaplan--Meier estimate of PSA-free survival according to surgical margin status. The 3-year PSA-free survival rate was 86.9% in patients with negative surgical margins and 53.0% in those with positive surgical margins (Po0.0001).

& 2012 Macmillan Publishers Limited Prostate Cancer and Prostatic Diseases (2012), 397 -- 401 Neoadjuvant therapy for high-risk prostate cancer T Koie et al 400 Table 2. Most common treatment-related toxicities CONFLICT OF INTEREST The authors declare no conﬂict of interest. No. (%)

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