Comparisons of Quality of Life and Functional and Oncological Outcomes after Orthotopic Neobladder Reconstruction: Prostate-Sparing Cystectomy versus Conventional Radical Cystoprostatectomy

Objectives To compare health-related quality of life and oncological and functional outcomes on erectile function, continence, and voiding function among bladder patients who underwent orthotopic neobladder reconstruction after prostate-sparing cystectomy (PSC) and conventional radical cystoprostatectomy (CRC). Methods This is a retrospective cohort study from a single surgeon. During 2007 to 2015, we identified 25 of 186 male patients receiving radical cystectomies due to bladder cancer who underwent orthotopic neobladder reconstruction, 14 patients with PSC and the other 11 patients with CRC. International Index of Erectile Function-5 (IIEF-5), International Prostate Symptom Score (IPSS), European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Core 30-item questionnaire (EORTC-QLQ-C30), and self-catheterizations were used to evaluate functional outcomes in the baseline and 1 year after operation. Results There were better physical and social functioning scales, less fatigue symptoms, better IIEF (16 versus 3.7, p = 0.01), and less self-catheterization rate (33% versus 89%  p = 0.006) in the PSC group. The oncologic outcomes were the same between two groups. Conclusions For selected patients with bladder cancer who underwent neobladder reconstruction, prostate-sparing cystectomy provided better sexuality preservation, less daily self-catheterization, and better physical function and social function scales without compromising overall survival.


Introduction
Conventional radical cystoprostatectomy (CRC) has been the standard treatment for patients with muscle-invasive bladder cancer or refractory superficial urothelial carcinoma. There are several surgical options of following urinary diversion from ileal conduit and various pouches to orthotopic neobladder reconstruction. Under the emphasis on functional outcomes and quality of life in recent years, the comparisons of health-related quality of life (HR-QoL) were reported among different diversions. In current evidence, orthotopic ileal neobladder demonstrates better HR-QoL in recent studies [1,2]. For better functional outcomes, prostate-sparing cystectomy (PSC) with orthotopic neobladder reconstruction has been an alternative choice for selected patient groups without compromising oncological outcomes [3,4]. Although many studies have reported better functional outcomes of PSC, few of the studies had a control group. Furthermore, there is a paucity of comparative studies regarding the HR-QoL difference in patients who have undergone CRC and PSC. Our aim is to make a two-armed study to compare the HR-QoL, functional outcomes, and oncological outcomes between patients who underwent CRC and PSC.

Study Design.
The study proposal was approved by our Institutional Review Board (103-6330B) and this is a retrospective study of a single surgeon. We enrolled all the bladder cancer patients who received radical cystectomy 2 BioMed Research International A total of three measurements of IPSS score were recorded (before surgery, after surgery, and date of recent follow-up) for the evaluation of voiding function. The EORTC-QLQ-C30 contains 30 items and incorporates a global health status scale, 5 functional scales, 3 symptom scales, and a number of single items assessing additional symptoms. We standardized the scores from 0 to 100. Higher scores on "Global Quality of Life" and "Functional Scale" represent a better quality of life, whereas higher scores on the "Symptoms Scales" reflect more intense complaints.
For statistics, we used SPSS 21 for data analysis, Chisquare test, or Fisher's exact test for association between two categorical variables. For small sample size, Mann-Whitney test was used for comparison of medians of the age, BMI, and follow-up time between the patients in PSC and CRC groups. Kaplan-Meier survival estimates were obtained to compare the survival data and follow-up.

Participants and Baseline before Surgery.
There were 257 patients in total, with 186 males undergoing radical cystectomy in our hospital during 2007 to 2015 while 42 patients received orthotopic neobladder reconstruction. Among these patients, 6 patients underwent non-bladder cancer-related surgery and 9 patients underwent the surgery by other doctors. Besides, 2 patients were lost to follow-up from our department. Therefore, 25 patients were recorded in final statistics. The table lists the relevant patient characteristics (Table 1). There were no differences in age, BMI, pathological  stage (T < T2 or T ≧ T2), pathological grade, IIEF-5, and IPSS scores between the two groups. All the patients before surgery had total continence and most of the men had intact erectile function (7 in CRC group, 10 in PSC group, resp.). No single patient had required self-catheterization in daily life before surgery. The EORTC-QLQ-C30 of the patients before the surgery also showed no significant differences in functional scales and symptom scales between the two groups ( Table 2).

Functional Outcomes.
Our measurements of functional results included day and night continence, daily selfcatheterization, urethral stricture, IIEF-5 score, and IPSS score. As for continence function, 4 patients still need pad at day time one year after surgery (2 patients in each group). The remaining 21 patients revealed no significant differences in day or night continence (Table 4). In analysis of self-catheterization, 8 out of 9 patients (89%) needed selfcatheterization in their daily life in the CRC group compared to 4 out of 12 patients (33%) in the PSC group ( = 0.006). For patients needing CIC more than 3 times daily, PSC showed lower self-catheterization proportion (17%). Furthermore, there were 3 urethral stricture patients in the CRC group and none in the PSC group ( = 0.082). There were no significant differences of IPSS scores in both groups after surgery and 1 year after surgery.
In the measurement of IIEF-5 score, we excluded patients with moderate to severe erectile dysfunction (IIEF-5 less than 12) before surgery. Seventeen patients had intact erectile function before surgery. After surgery, IIEF-5 scores in CRC and PSC groups were 3.7 and 16.0, respectively ( = 0.014) ( Table 4).

Oncological Outcomes.
In total, 27 men received radical cystectomy with neobladder reconstruction during 2007 and 2015; all patients except 2 patients lost to follow-up were followed in our outpatient clinics until 2016 after the surgery. Five patients (2 in the CRC group and 3 in the PSC group) expired during follow-up. Kaplan-Meier analysis for overall survival between the two groups showed no statistically significant differences between the two groups ( Figure 1). Furthermore, 2 patients had distant brain metastasis (1 in each group). One patient in the PSC group revealed urothelial carcinoma following transurethral resection of the prostate due to urinary obstruction. Two specimens of radical cystoprostatectomy showed prostate invasion of urothelial carcinoma in the CRC group.

Oncological Outcomes and Functional
Outcomes. In a recent randomized controlled trial, prostate capsule-sparing and nerve-sparing radical cystectomy for bladder cancer reveal no differences of functional and oncologic outcomes [5]. However, total prostate-sparing including stroma still remains a controversial procedure for patients with muscleinvasive bladder cancer or refractory superficial urothelial carcinoma. Although it has been speculated that PSC preserves better sexual function and continence function, oncological outcome varies in different studies without consensus. Some studies disagreed with this operation due to inferior oncological outcomes [6][7][8][9]. Nevertheless, most of these studies did not reveal their own conventional radical cystoprostatectomy data compared to the PSC group. Furthermore, none of these had two-armed study designs. The only single matched-case control study showed better functional results without decreasing overall survival [10]. Some studies described invasive urothelial carcinoma or adenocarcinoma in the prostate specimens being found after radical cystoprostatectomy so that prostate-sparing surgery might not be performed in some circumstances [11,12]. Yang et al. even reported up to 53% incidental prostatic adenocarcinoma or urothelial carcinoma invasions in Chinese patients undergoing radical cystoprostatectomy [13].
We did not perform preoperation prostate biopsy routinely in PSC group, but we have took the effort to rule out the patients with prostate cancer by digital rectal examination and PSA level. Although the proportion of patients with prostate cancer within normal PSA is very low, the prostate biopsy may still be a useful procedure in clinical practice for the patients planning for prostate-sparing cystectomy. However, if prostate cancer was detected during follow-up, we still have many further treatments such as radiotherapy, cryotherapy, HIFU, and even radical prostatectomy. As for urothelial carcinoma invasion, we sent frozen sections of distal urethra and prostate urethra for all the patients during operation instead of performing a transurethral resection of the prostatic urethra and prostate before cystectomy. In our study, two of 11 patients (18%) of the CRC group revealed urothelial carcinoma invasion and no incidental prostate cancer in the CRC group. Therefore, the preoperative transurethral resection of the prostatic urethra and prostate may be necessary in prostate-sparing patients to confirm that no prostatic urethral or stromal involvement exists. This is not a randomized study. On the contrary, PSC was only performed in selected patients. All patients with tumors near to the bladder neck or suspicious of prostate cancer were excluded for PSC and it may illustrate this difference compared to previous studies.
In the largest prospective single-arm cohort study which involved 117 patients, better potency function without compromising oncological outcome was revealed [14]. Many reports have also shown no inferior cancer-specific outcome in the PSC group [3,10,15,16]. In the present study, there were no significant differences of overall survival between the two groups. In terms of functional outcomes, the PSC group provided better erectile function and less daily selfcatheterization.

EORTC-QLQ-C30.
There were no compared studies discussing HR-QoL between CRC and PSC groups but only discussing factors influencing ileal orthotopic neobladder reconstruction. Imbimbo et al. mentioned that age, urinary incontinence, length of follow-up, and comorbidity status may influence postoperative HR-QoL in neobladder patients [17]. In our study, PSC surgery not only provided better physical function but also social function and less fatigue symptoms. Patients in the PSC group showed the trend of less night incontinence and significant difference of lower self-catheterization rates. This might be the reason for better health-related quality of life and even getting back to their work after surgery in younger patients.

Strengths and Limitations of the Study
To the best of our knowledge, our study is the first twoarm retrospective cohort study in Asia population which uses EORTC-QLQ-C30 to aim at HR-QoL and functional and oncologic outcomes in CRC and PSC patients with neobladder reconstruction in the same literature. Besides, only 7.4% loss of follow-up rate took place in our cohort study. However, there are still limitations in our study. Firstly, our patient allocation was subjectively dependent on a single surgeon's evaluation and tumor location. Although it revealed no statistical differences in terms of results of pathological staging and pathological grading between groups, selection bias might still exist. Secondly, the case number was small, so external validity power was limited, and, owing to lack of patient numbers, we could not perform subgroup analysis of oncological outcomes. Thirdly, patients might have had recall bias when taking the questionnaire.
We expect that large number control trials and even randomized control trials may be undertaken in the future. Further investigation is warranted to confirm the quality of life and the oncological results in prostate-sparing cystectomy with neobladder reconstruction. We concluded that prostatesparing cystectomy can provide better functional outcomes and health-related quality of life without compromising survival in selected patients.