Suppressive Effects of Eviprostat, a Phytotherapeutic Agent, on Lower Urinary Tract Symptoms in Prostate Cancer Patients Treated with Brachytherapy

Authors


Tomoaki Tanaka, MD, PhD, Department of Urology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abenoku, Osaka 545-8585, Japan. Tel: +81-6-6645-3857; Fax: +81-6-6647-4426. Email: tomoaki826@msic.med.osaka-cu.ac.jp

Abstract

Objectives: Eviprostat is an anti-oxidant, anti-inflammatory phytotherapeutic agent that is commonly used to treat lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia in Japan and Germany. Prostate cancer patients treated with brachytherapy generally have complaints of LUTS for several months postoperatively.

Methods: We investigated the protective effects of Eviprostat against the development of LUTS in 37 patients, who had received 125I prostate brachytherapy as monotherapy. These patients were divided into two groups, an Eviprostat-treated group (n = 18) and an untreated control (n = 19), whose background had no significant difference. The group treated with Eviprostat was prophylactically medicated from 3 weeks preoperatively until 3 months postoperatively. Symptom scores and quality of life for urination were evaluated according to the International Prostate Symptom Score (IPSS) and Expanded Prostate Cancer Index Composite (EPIC) on preoperative day 1, and postoperative months 1, 3 and 6.

Results: Both the scores of IPSS and the levels of quality of life in EPIC were significantly worse at 1 month postoperatively compared to the pretreatment baseline, and thereafter progressively improved in both groups. Eviprostat-treated patients showed significantly better recovery compared to Eviprostat-untreated control at 6 months postoperatively, with respect to urinary summary score, urinary function and urinary irritation/obstruction subscales in EPIC. Moreover, the feeling of incomplete emptying in IPSS and the urinary irritation/obstruction subscale in EPIC were significantly improved at 3 months postoperatively compared to the peak impairment at 1 month in the Eviprostat-treated group.

Conclusions: It is possible that Eviprostat has the potential to ameliorate postoperative LUTS caused by brachytherapy.

1. INTRODUCTION

125I brachytherapy for organ-confined prostate cancer, which is the low-risk group in the D’Amico risk classification, has until recently been the definitive treatment on the basis of no difference between radical prostatectomy and brachytherapy in terms of cancer control.1 However, it is obvious that brachytherapy is associated with temporary lower urinary tract symptoms (LUTS) caused by seed-implantation.2,3 Recent reports have revealed that α1-blockers may be effective in patients with radiation-induced LUTS.4

Eviprostat is a phytotherapeutic agent that has been used broadly for more than 40 years in the treatment of LUTS associated with benign prostatic hyperplasia (BPH) in Japan and Germany.5 Eviprostat consists of five components, four of which are extracted from the umbellate wintergreen Chimaphila umbellata, the aspen Populus tremula, the small pasque flower Pulsatilla pratensis and the field horsetail Equisetum arvense, and the fifth is germ oil from wheat (Tritium aestivum). In clinical settings, Eviprostat has been shown to improve International Prostate Symptom Score (IPSS), quality of life (QOL) scores, maximum and average urinary flow rates, decrease prostate volume, and reduce inflammation in prostate specimens resected from patients with BPH, without significant adverse events.6,7 In a rat model with hormone-associated nonbacterial prostatitis, Eviprostat treatment significantly suppressed oxidative stress and proinflammatory cytokines in the inflamed prostate.8 Therefore, Eviprostat, which has anti-oxidant and anti-inflammatory activity, may be useful for the amelioration of prostatic inflammation associated with BPH, chronic prostatitis/chronic pelvic pain syndrome, and radiation-induced LUTS.9–12

In the present study, we evaluated whether or not Eviprostat ameliorates both the grade of LUTS and the decrease in QOL, secondary to brachytherapy.

2. METHODS

We selected 37 patients for this study who had received brachytherapy as monotherapy between October 2008 and April 2010. These patients were divided into two groups: a control group (n = 19) and an Eviprostat-treated group (n = 18), whose background showed no significant difference. The group treated with Eviprostat had been medicated from 3 weeks preoperatively until 3 months postoperatively. Symptom scores and QOL for urination were evaluated according to the IPSS and Expanded Prostate Cancer Index Composite (EPIC) on preoperative day 1, and postoperative months 1, 3 and 6. Data from the returned questionnaires were entered to an Excel spreadsheet and were imported into a JMP 9 Statistical Discovery Software (SAS Institute, Cary, NC, USA) for analyses. Statistical analysis of differences in scores was performed by paired t-test or Mann–Whitney's U-test. P < 0.05 was considered to denote a statistically significant difference. The ethical review board of our institute approved the study, and informed consent was obtained from all patients.

3. RESULTS

As shown in Table 1, there were no differences between the Eviprostat-treated group and the control in patients' characteristic, including age, serum prostate-specific antigen level at diagnosis, pathological stage, Gleason score, pretreatment prostate volume, number of implanted seeds, each dosimetric parameter of brachytherapy, and proportions of neoadjuvant hormone therapy and use of an α1-blocker. The scores for summary (sum), storage symptoms, and voiding symptoms in IPSS were significantly increased at 1 month post-treatment compared to the pretreatment baseline in both the Eviprostat-treated group and the control group (Fig. 1). In the Eviprostat-treated group, the scores of both sum and storage symptoms were significantly decreased at 6 months compared to those at 1 month after the procedure. Particularly, the feeling of incomplete emptying, a domain of IPSS, had significantly declined at both 3 and 6 months after treatment compared to the worst scores at 1 month post-treatment in the Eviprostat-treated group. Next, the levels of QOL in urinary fractions of EPIC, including the sum and all the subscales, showed a maximum decrease at 1 month after brachytherapy and gradually improved over the following 5 months in both groups (Fig. 2). The arm treated with Eviprostat exhibited significant improvements in the sum of urinary fraction and the subscales of urinary function, urinary bother, and urinary irritation/obstruction in EPIC at 6 months post-treatment in comparison with the worst levels at 1 month after treatment. Moreover, the Eviprostat-treated group showed significantly enhanced ameliorations of the sum and the subscales of urinary function and urinary irritation/obstruction in EPIC compared to the control at 6 months.

Table 1.  Clinical characteristic of patients treated with or without Eviprostat
 Eviprostat-treated group (n = 18)Eviprostat-untreated group (n = 19)P-value*
  1. *P-values were assessed by

  2. unpaired t-test or

  3. Fisher's exact test. PSA, prostate-specific antigen.

Age67.4 ± 8.467.9 ± 6.10.836
PSA (ng/mL)7.82 ± 2.927.04 ± 2.300.372
Gleason score
 ≤5330.513
 61010 
 7 (3 + 4)56 
Prostate volume (cc)26.1 ± 7.624.6 ± 8.20.558
Number of implanted seeds65.1 ± 11.065.6 ± 15.30.906
Dosimetric parameters of brachytherapy (%)
 D30148.7 ± 24.7133.8 ± 19.90.053
 D90111.5 ± 6.3108.0 ± 7.30.117
 V10094.7 ± 2.293.1 ± 3.70.125
 V15060.0 ± 10.954.5 ± 13.40.177
Neoadjuvant hormone therapy
 Yes12100.385
 No69 
Administration of α1-blocker   
 Yes17140.180
 No15 
Figure 1.

Changes in evaluated items ((a)summary, (b) voiding symptom, (c) storage symptom and (d) feeling of incomplete emptying) of International Prostate Symptom Score (IPSS) from the baseline to 1, 3 and 6 months follow-up after brachytherapy. *P < 0.05 compared to pretreatment baseline (paired t-test). †P < 0.05 compared to scores at 1 month after the procedure.

Figure 2.

Changes in urinary components of Expanded Prostate Cancer Index Composite (EPIC) ((a) summary, (b) function, (c) bother, (d) incontinence and (e) irritation/obstruction) from baseline to 1, 3 and 6 months after treatment. *P < 0.05 compared to pretreatment baseline (paired t-test). †P < 0.05 compared to scores at 1 month after the procedure. ‡P < 0.05 between two groups at 6 months post-treatment (Mann–Whitney's U-test).

4. DISCUSSION

Urinary symptoms after 125I prostate brachytherapy commonly peak at 1 month after seed implantation and return to their baseline values within 1 year.3 In a previous study, prophylactic treatment with an α1-blocker was shown to significantly inhibit urinary morbidity compared to either its absence or therapeutic use on the appearance of symptoms.13 Furthermore, these observations were also confirmed in a prospective, double-blind, randomized trial; tamsulosin (0.8 mg, orally once a day) versus placebo, beginning 4 days before brachytherapy and continuing for 60 days.14 The use of an α1-blocker may also be effective for radiation-related LUTS, whose pathophysiology is similar to that of bladder outlet obstruction, so-called BPH, with the irritative voiding symptoms and bladder detrusor overactivity. There is evidence that Eviprostat, a phytotherapeutic agent, has valuable effects in the treatment of BPH.6,7,11 In animal models, Eviprostat has been shown to have effective anti-oxidant and anti-inflammatory activities in bladder outlet obstruction and chronic prostatitis/chronic pelvic pain syndrome.8,15 In this study, we confirmed the beneficial effects of prophylactic treatment with Eviprostat in alleviating acute LUTS caused by brachytherapy. Although treatment with Eviprostat did not improve the scores of LUTS-associated symptoms and QOL compared to the control group at 1 month after brachytherapy, the group treated with Eviprostat showed a significant decrease of several scores at 3 or 6 months post-treatment from those at 1 month post-treatment. Particularly, there were significant differences between the Eviprostat-treated group and the control in urinary sum, urinary function, and urinary irritation/obstruction fraction of EPIC at 6 months after implantation. On the basis of these observations, we speculate that earlier administration of Eviprostat before brachytherapy could also improve acute urinary symptoms during 3 months post-treatment. Further investigation is required to clarify this hypothesis. Moreover, administration of corticosteroids or non-steroidal anti-inflammatory drugs can also be used to reduce prostate edema derived from implantation.16,17 However, the compliance with these agents is low in older patients because of adverse events of gastrointestinal disorders and renal dysfunction. On the contrary, Eviprostat is available for long-term administration without serious side effects in patients with LUTS related to brachytherapy. For instance, prophylactic therapy combined with Eviprostat and an α1-blocker may be more effective in suppressing urinary morbidity after brachytherapy.

In conclusion, the results of this study demonstrated that prophylactic use of Eviprostat significantly reduced acute LUTS associated with 125I prostate brachytherapy during 6 months post-treatment.

Disclosure

The authors declare no conflict of interest.

Ancillary