Effet du traitement par alpha-bloquant avant la biopsie de la prostate sur les fonctions vesicale, les scores de douleur et les résultats de qualité de vie liés à la santé: un essai prospectif randomisé

25 mars 2020

Auteurs : E. Sefik, A. Eker, B. Gunlusoy, S. Celik, I.H. Bozkurt, I. Basmaci, S. Polat, T. Degirmenci, Y. Ceylan
Référence : Prog Urol, 2020, 4, 30, 198-204




 




Introduction


Transrectal ultrasound-guided biopsy of the prostate (TRUS-Bx) is considered as a standard of care for diagnosis of prostate cancer. Many doubts about the biopsy process related with morbidity and harmful effects of biopsy are known. In some patients, bothersome post biopsy symptoms can lead to increased anxiety, distinct from distress related to diagnosis of prostate cancer [1]. Problems related to TRUS-Bx may cause further limitation and acts against its wide use as a main diagnostic tool due to major levels of anxiety or depression. The major side effects are local pain, hematuria, hematospermia, dysuria and fever [2, 3].


In addition to these undesirable side effects, the effect of TRUS-Bx on the effect of voiding dysfunction is a matter of curiosity. Mild or moderate lower urinary tract symptoms (LUTS) inpatients may exacerbate after biopsy or 0.2-2.6% of patients will develop acute urinary retention (AUR) [4, 5, 6]. The pathophysiology that causes biopsy-related voiding dysfunction is a matter of fact [7]. Traumatic instrumentation of the prostate may be responsible for voiding impairment by increasing the bladder outlet resistance [8]. Alpha-blocker treatment beginning before the biopsy procedure can relieve bladder resistance by relaxing the bladder neck outlet and preventing voiding impairment in this group of patients [9]. In this prospective randomized trial, we evaluated the effect of alpha-blocker treatment prior to prostate biopsy on voiding functions, pain scores and health-related quality-of-life outcomes.


Materials and methods


After ethical approval of the local ethics committee and written informed consent from all patients, between January 2018 and April 2019, patients who underwent TRUS-Bx due to elevated PSA (greater than 3ng/mL) or/and positive rectal examination findings were prospectively evaluated. After the power analysis, eligible patients for the study were randomized into two groups. Randomization was made by flipping a coin. Group 1 consisted of patients with no alpha blocker treatment prior to biopsy and Group 2 consisted of patients who received tamsulosin 0.4mg once a day for one week before biopsy continuing for one week after biopsy. Primary endpoint was the difference between 7th day IPSS and baseline IPSS (Δ1IPSS), secondary endpoints were Qmax, pain scores and health related quality of life outcomes. Exclusion criteria were as follows; patients who had prior prostate biopsy, receiving medical therapy for benign prostatic hyperplasia (BPH), with a history of surgical treatment for prostate, severe diabetes mellitus, severe coagulation disorders, rectal disease such as anal fissure, anal fistula or hemorrhoid, patients with concomitant malignancies and neurological diseases.


Voiding function was evaluated three times using the validated IPSS and uroflowmetry (maximal Qmax and PVR): before Tamsulosin treatment, at the end of the postoperative 1st week and postoperative 1st month. Δ1 was defined as the difference between 7th day and baseline voiding results and Δ2 was defined as the difference between 1st month and baseline voiding results.


The Turkish version of the Medical Outcomes Study Short Form 36-item Questionnaire (SF-36) was used to assess health-related quality of life [10]. All patients completed the SF-36 form two times: before Tamsulosin treatment and postoperative 1st month.


Biopsy was performed in patients with negative urine culture. All patients used oral ciprofloxacin 500mg for antibiotic prophylaxis one day before biopsy and three days thereafter. All patients underwent periprostatic nerve blockade with 10mL of 2% prilocaine prior to biopsy. Standardized 12 core biopsy was performed with an 18 G needle.


Patients' pain scores were rated according to the Visual Analogue Scale (VAS) just after the biopsy procedure.


Histopathological results and biopsy related complications were recorded. Two groups were compared according to the patient characteristics, voiding functions, pain scores and health related quality of life outcomes.


Statistical analysis


The sample size was calculated according to the power analysis (with 80% power and 5% type I error rate) of the previous studies' results; the minimum number of samples for each group was found to be 29 patients for Δ1Qmax and 37 patients for Δ1IPSS. Therefore, we have randomized a total of 112 patients into two groups as no treatment (Group 1) and Tamsulosin (Group 2) groups. The power of this study was found to be 0.996 (P <0.001) using the variance analysis. These two groups were compared with Chi-square test, Fisher's exact test and independent sample t test. Statistical analyses were performed with the Statistical Package of Social Sciences (SPSS, Chicago, IL) version 21. Categorical variables were presented as numbers. Continuous variables were presented as means and standard deviations of mean. Statistical significance was set at a p value of 0.05.


Results


A total of 112 patients who met the inclusion criteria were included in this study. One of the patients in Group 1 was excluded from the study because of missing data. There were 56 patients in Group 1 and 55 patients in Group 2 (Figure 1). The two groups were similar according to patient characteristics such as age, PSA and prostate volume. No statistical significance was found between the groups in terms of baseline voiding functions (IPSS, Qmax and PVR) (Table 1). Mean VAS score was 2.7±2.3 for the Tamsulosin group and 4.2±2.2 for control group (P =0.001).


Figure 1
Figure 1. 

CONSORT diagram of the study.




Post-biopsy day 7 IPSS was 15.5±5.2 for Group 1 and 11.7±4.2 for Group 2 (P <0.001) and Δ1 IPSS was significantly in favor of Group 2 (P <0.001). Mean Qmax on the post-biopsy day 7 was 12.1±5.5ml/sec and 15.1±4.3ml/sec for Group 1 and 2 respectively (p=0.004) and Δ1 Qmax was also significantly in favor of Group 2 (P <0.001). Although post-biopsy day 7 PVR was similar between the groups, Δ1 PVR was significantly in favor of Group 2 (P =0.004). Voiding functions in the post-biopsy 1st month were also similar between the groups like the baseline values. The most common side effect after biopsy was hematuria in both groups. Other side effects were urinary tract infection, dysuria, hematuria, hematospermia and rectal bleeding. AUR occurred in one patient in the control group after the procedure. The rates of benign and malignant pathology were not different between the groups (Table 2). Health related Quality of Life results are given in Table 3. There was no significant difference between the two groups according to baseline and postoperative 1st month SF-36 scores.


Discussion


Benign prostatic hyperplasia (BPH) is a major public health issue because of its high prevalence, progressive nature, voiding symptoms such as dysuria but also storage symptoms such as urinary frequency, urgency, nocturia and associated economic costs [11]. While the disease is treated in patients presenting with symptoms, biopsy is needed for the diagnosis of cancer in suspected cases. In addition to the familiar side effects such as pain, hematuria, hematospermia, infection, and sepsis, TRUS-Bx can cause voiding dysfunction in some patients after the procedure. Zisman et al. first investigated the voiding functions after TRUS-Bx [12]. Several other studies supported the alterations in voiding functions after TRUS-Bx [12, 13, 14]. After the negative effect of biopsy on voiding functions was shown, pharmacological treatment before biopsy was introduced in order to reduce these negative effects. 5-alpha-reductase inhibitors which act by reducing the prostate microvessel density and decreasing the rate of hemorrhagic symptoms after prostate biopsy, and alpha-blockers which reduce the sympathetic tone of blood vessels resulting in decreased vascular resistance and minimized local hemorrhagic adverse effects are common drugs that are used for this purpose [9, 15]. In this study, we investigated the effect of alpha-blocker treatment on voiding dysfunction after biopsy, as well as its effect on pain occurring during biopsy. We also examined health-related quality-of-life outcomes in the 2 groups. The exact mechanism of biopsy-related voiding impairment has not been clearly defined [6]. In two studies exploring causative factors for biopsy-related voiding impairment, an increased transitional zone volume was reported as a risk factor for urinary retention [12, 13]. The rate of difficult voiding after TRUS-guided biopsy was found to be between 0.8-40% in different studies [12, 13, 14]. In another comparative study, Chung et al. presented their results after TRUS-Bx and reported that the PVR was increased and Qmax was decreased on postbiopsy day 7 in the control, compared with their baselines [7]. In the tamsulosin group this was entirely the opposite. They found that post-biopsy AUR developed in none of the patients (0%) in tamsulosin group, but AUR occurred in two patients (4.5%) in the control, after 8-core TRUS-Bx [7]. These results were supported by Bozlu et al. in which IPSS was significantly decreased on postbiopsy days 7 and 30 compared with the baseline value, and Qmax was significantly elevated on postbiopsy day 30 in the tamsulosin group [6]. AUR after the biopsy procedure developed in 1 patient in the tamsulosin group and 3 patients in the control group [6]. BorboroÄŸlu et al. reported high incidence of AUR (10%) after biopsy with an average of 22.5 cores. This high rate can be attributed to the sampled core number and biopsy technique [8]. In the current study, there was a significant difference in IPSS scores on post-biopsy 7 day between patients without any medication and the tamsulosin group (IPSS was 15.5±5.2 for Group 1 and 11.7±4.2 for Group 2 (P <0.001) and Δ1 IPSS was significantly in favor of Group 2 (P <0.001)). Δ1 Qmax was significantly in favor of Group 2 (P <0.001) and Δ1 PVR on the 7th day was significantly in favor of Group 2 (P =0.004). While AUR occurred in one patient in the control group after the procedure, none of our patients in the tamsulosin group experienced AUR.


TRUS-Bx is associated with significant pain and discomfort in a proportion of men [16]. Predictors of pain include young age, anxiety level, anorectal compliance, prostate volume and number of biopsy cores; while pain seems not to be affected by using 16- versus18-gauge needles. One study showed that more than 50% of patients reported moderate to intolerable pain even with intrarectal lidocaine application before the procedure [17]. Hence, effective analgesia before TRUS-Bx is considered mandatory according to current consensus [18]. All patients in our study group underwent periprostatic nerve blockade with 10mL of 2% prilocaine prior to biopsy. Standardized 12 core biopsy was performed with 18 G needle. Another important issue in the current study was to find the effect of alpha-blocker therapy on pain during the procedure. To obtain these results, we used VAS scoring just after the biopsy procedure. There was statistical significance between the 2 groups according to VAS scores. Alpha-blocker treatment seems to be effective in reducing pain during the procedure in patients undergoing biopsy. Alpha-blockers causes relaxation on the prostate and bladder neck, and therefore they can affect potential side effects due to prostate biopsy. There are a limited number of studies examining the effect of alpha blockers on pain during and after prostate biopsy. Consistent with our study, although not statistically significant, Zamuner et al. found that alpha-blocker therapy before the biopsy prevented pain after TRUS-BX. However, they evaluated the pain 24hours after TRUS-Bx [9].


The most common side effect of the procedure was hematuria in both groups. The second most common side effect was dysuria and no major complication was observed. There was no difference between the two groups according to complications.


Interestingly, there was no significant difference between the two groups according to baseline and postoperative 1st month SF-36 scores. This can be a result of the similarity in complications between the groups and evaluating the quality of life at the end of the 1st month.


The current study has some limitations. Our analyses stratified by biopsy result were based on small numbers because of the strict inclusion criteria and, for that reason, should be considered exploratory. Because of the small number of patients in the current study, randomization by flipping a coin can be considered as a limitation of the study. Block randomization would be better method for studies with a small number of patients, like our study. Also the lack of a placebo use and open label arm is a limitation of this study. A meta-analysis by Eredics et al. showed a placebo effect on IPSS and Qmax, but this improvement was statistically lower than the improvement in alpha blocker use [19]. In the current study, the effect of Tamsulosin use on voiding functions and pain after TRUS-Bx was evaluated and Tamsulosin use was found to be effective to reduce post-biopsy symptoms and pain.


Conclusions


In conclusion, preoperative Tamsulosin treatment resulted in statistically significant improvements in IPSS, Qmax and pain scores. Although, a protocol change cannot be made with the results of the current study, we think that preoperative Tamsulosin may be beneficial especially in patients with high pre-biopsy symptom scores. Larger placebo controlled randomized studies are needed to support our findings.


Disclosure of interest


The authors declare that they have no competing interest.



Acknowledgements


None.




Table 1 - Patients' characteristics, pain scores and voiding functions of Group 1 and 2.
Data  Group 1 (n =56)  Group 2 (n =55)  P  
Age (yr), mean±SD (min-max)  63.6±6.4 (50-76)  63.6±6.4 (46-75)  0.979 
PSA (ng/ml) mean±SD (min-max)  8.2±6.7 (3.1-35)  10.1±6.7 (3.4-47)  0.224 
Prostate volume (cm3), mean±SD (min-max)  50.3±17.5 (20-100)  56.8±22.6 (20-130)  0.126 
VAS, mean±SD (min-max)  4.2±2.2 (0-8)  2.7±2.3 (0-10)  0.001 
Voiding functions       
IPSS, mean±SD (min-max)       
Baseline IPSS  12.8±5.2 (3-25)  13.1±4.9 (3-25)  0.758 
7th day IPSS  15.5±5.2 (3-26)  11.7±4.2 (4-22)  <0.001 
Δ1 IPSS  2.7±2.3 (−2±8)  −1.4±2.8 (−8±6)  <0.001 
1st month IPSS  15.6±5.7 (5-26)  13.6±6.5 (3-35)  0.087 
Δ2 IPSS  3.1±3.5 (−8±10)  0.4±4.4 (−9±13)  0.002 
Qmax (mL/s), mean±SD (min-max)       
Baseline Qmax  13.8±5.2 (6.3-34)  14.3±4.4 (5.6-23)  0.598 
7th day Qmax  12.1±5.5 (3-30)  15.1±4.3 (7-25)  0.004 
Δ1 Qmax  −1.7±2.8 (−11±2.9)  0.8±1.5 (−2±6.8)  <0.001 
1st month Qmax  13.2±4 (6-27)  14.3±4.8 (7-32)  0.267 
Δ2 Qmax  −0.4±3.3 (−8.8±8.7)  −0.1±3.5 (−9.6±9)  0.592 
PVR (ml), mean±SD (min-max)       
Baseline PVR  25±28.1 (0-110)  36.3±30.3 (0-110)  0.064 
7th day PVR  40.4±63 (0-400)  21.3±22.9 (0-80)  0.053 
Δ1 PVR  15.5±65.2 (−55±350)  −15.1±29.4 (−80±60)  0.004 
1st month PVR  19.8±23.8 (0-100)  20.8±23 (0-100)  0.826 
Δ2 PVR  −4.2±34.9 (−110±60)  −15.5±30 (−80±50)  0.099 



Légende :
Δ1: the difference between 7th day and baseline results; Δ2: the difference between 1st month and baseline results; PSA: Prostate specific Antigen; IPSS: International Prostate Symptom Score; PVR: Post-voiding Residue; Qmax: Maximal flow rate; VAS: Visual Analogue Scale. T -test and Chi2 test analysis were used between Group 1 and 2.



Table 2 - Side effects and pathological results after TRUS-Bx.
Data  Group 1 (n =56)  Group 2 (n =55)  P  
Pathological result       
Benign  43 (76.8)  40 (72.7)  0.680 
Malignant  13 (23.2)  15 (27.3)   
Side effect       
Negative  26 (46.4)  27 (49.1)  0.751 
Positive  30 (53.6)  28 (50.9)   
Urinar tract infection, n (%)  3 (5.6)  2 (3.6)  0.492 
Disuria, n (%)  10  0.393 
Hematuria, n (%)  17  16  0.769 
Hematospermia, n (%)  0.148 
Rectal bleeding, n (%)  0.975 
AUR, n (%) 



Légende :
AUR: Acute urinary retention. Chi2 test analysis and Fisher's exact test were used between Group 1 and 2.



Table 3 - Comparison of Health related Quality of Life results between the groups.
Data  Group 1 (n =56)  Group 2 (n =55)  P  
SF-36 (Baseline)       
Physical functioning, mean±SD (min-max)  74.2±20.8 (10-100)  73.8±25.8 (0-100)  0.933 
Physical role limitations, mean±SD (min-max)  79.3±30.3 (0-100)  72.2±37.3 (0-100)  0.319 
Emotional role limitation, mean±SD (min-max)  71.2±36.2 (0-100)  75.2±38.3 (0-100)  0.612 
Vitality, mean±SD (min-max)  58.5±23.8 (0-100)  66.5±24.6 (0-100)  0.114 
Emotional well-being, mean±SD (min-max)  66.9±18.9 (28-100)  69.7±20.1 (20-100)  0.496 
Social functioning, mean ±SD (min-max)  78.9±23.3 (0-100)  73.5±22.3 (25-100)  0.252 
Pain, mean±SD (min-max)  78.8±24.2 (0-100)  75.5±25.2 (0-100)  0.512 
General health, mean±SD (min-max)  61.8±17.3 (32-100)  62.3±21.9 (10-100)  0.9 
SF-36 (postoperative 1st month)       
Physical functioning, mean±SD (min-max)  77.5±17.8 (30-100)  75.7±23.1 (5-100)  0.683 
Physical role limitations, mean±SD (min-max)  76.6±28.9 (0-100)  77.1±25.3 (0-100)  0.927 
Emotional role limitation, mean±SD (min-max)  68.7±36.7 (0-100)  74.7±37.1 (0-100)  0.431 
Vitality, mean ±SD (min-max)  64±22.5 (10-100)  70.6±23.4 (0-100)  0.168 
Emotional well-being, mean±SD (min-max)  74.7±19.9 (31-100)  73.5±19.4 (36-100)  0.776 
Social functioning, mean±SD (min-max)  79.3±23 (0-100)  79.5±17.6 (35-100)  0.961 
Pain, mean±SD (min-max)  70.3±17.8 (30-100)  74.1±18.7 (30-100)  0.317 
General health, mean±SD (min-max)  61.9±19.2 (25-100)  68±19.3 (26-100)  0.129 



Légende :
T -test analysis was used between Group 1 and 2.


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