Articles

Platinum Priority – Prostate Cancer
Editorial by Matthew R. Cooperberg on pp. 53–54 of this issue

Prediction of Functional Outcomes After Nerve-Sparing Radical Prostatectomy: Results of Conditional Survival Analyses

By: Firas Abdollaha, Maxine Sunb, Nazareno Suardia, Andrea Gallinaa, Marco Bianchia b, Manuela Tutoloa, Niccolò Passonia, Zhe Tianb, Andrea Saloniaa, Renzo Colomboa, Patrizio Rigattia, Pierre I. Karakiewiczb, Francesco Montorsia and Alberto Brigantia lowast

European Urology, Volume 62 Issue 1, July 2012, Pages 42-52

Published online: 01 July 2012

Keywords: Erectile dysfunction, Urinary incontinence, Nerve-sparing radical prostatectomy, Prediction, Conditional survival

Abstract Full Text Full Text PDF (1,5 MB)

Abstract

Background

In prostate cancer (PCa) patients treated with radical prostatectomy (RP), the rate of urinary continence (UC) and erectile function (EF) recovery may change significantly depending on the time interval between surgery and patient assessment. This effect, known as conditional survival, has not yet been assessed.

Objective

Evaluate the conditional rates of UC and EF recovery after nerve-sparing RP (NSRP).

Design, setting, and participants

We included 1135 PCa patients treated between January 2000 and June 2011 at a single referral center.

Intervention

All patients underwent NSRP.

Outcome measurements and statistical analysis

The Kaplan-Meier method assessed the time to recovery of UC (defined as an International Consultation on Incontinence Questionnaire score <6) and of EF (defined as an International Index of Erectile Function-Erectile Function score ≥22). Cumulative survival estimates were used to generate conditional recovery rates assessed at a 6-mo interval. Multivariable Cox regression analyses were performed to predict functional outcomes recovery after accounting for confounders.

Results and limitations

UC recovery rates were 89.5%, 94.7%, and 97.0% at 6-, 24-, and 36-mo follow-up, respectively. Corresponding EF recovery rates were 53.6%, 65.0%, and 67.5%, respectively. In patients who were still incontinent at 1, 6, 12, 18, 24, 30, and 36 mo after surgery, UC recovery rates in the following 6-mo period significantly decreased as the time from surgery increased: 74.9%, 58.2%, 41.4%, 14.9%, 24.8%, 24.6%, and 13.3%, respectively. Similarly, in patients still impotent at the same time points, the 6-mo rate of sexual potency recovery was 36.9%, 26.8%, 17.8%, 8.2%, 3.1%, 4.0%, and 0%, respectively. Multivariable analyses confirmed these results. The study is limited by its retrospective design.

Conclusions

In incontinent and/or impotent patients, the period elapsed from surgery represents an important predictor of the recovery of subsequent functional outcomes. The highest increments in UC and EF recovery were observed during the first year after surgery; they were virtually null after 36 mo.

Take Home Message

The time interval elapsed from radical prostatectomy (RP) represents an important predictor of subsequent functional outcome. For impotent and/or incontinent patients, the probability of urinary continence and erectile function recovery at long term significantly decreases with increasing time from surgery. For these reasons, the postoperative interval between surgery and patient assessment should always be considered when counseling and considering the therapeutic approach for patients who have not yet regained functional outcomes at a certain point after RP.

Keywords: Erectile dysfunction, Urinary incontinence, Nerve-sparing radical prostatectomy, Prediction, Conditional survival.

1. Introduction

Radical prostatectomy (RP) represents one of the most commonly used first-line treatment modalities in patients with prostate cancer (PCa) [1] and [2], especially in men with clinically localized disease and a life expectancy of at least 10 yr [3] and [4]. Urinary incontinence and sexual dysfunction (hereafter referred to as functional outcomes) represent the most common long-term sequelae of RP and the most important determinants of postoperative quality of life [5] and [6].

Recent studies thoroughly addressed the rates of functional outcomes recovery after RP [7], [8], [9], and [10]. However, virtually all previous reports limited their estimates of functional outcomes recovery to either the immediate postoperative period or to a certain time point after surgery. But the recovery of functional outcomes represents a dynamic time-dependent process. For those men not recovering their urinary continence (UC) and/or erectile function (EF) at a certain point, the probability of functional recovery at longer follow-up might significantly change according to the duration of impaired functional status (hereafter referred to as the postoperative period).

This effect, otherwise known as conditional survival, has never been addressed in this setting. Such analyses may be of essential importance to achieve realistic estimates of functional outcomes recovery rates, allowing for improved patient counseling and individualized patient assessments. To address this point, we evaluated the conditional rates of functional recovery in PCa patients treated with nerve-sparing RP in a single tertiary care center cohort.

2. Methods

2.1. Patient population

We evaluated the data of all patients treated with nerve-sparing RP (NSRP) between 2000 and 2010 at our institution. Patients were excluded if they received any neoadjuvant, adjuvant, and/or salvage treatment for PCa. Excluded were also individuals who were incontinent preoperatively and/or those who did not provide a signed informed consent to participate in the study. These selection criteria yielded 1135 evaluable patients.

Surgical procedures were performed by nine surgeons using standardized techniques [11] and [12]. Preservation of neurovascular bundles was performed, whenever surgically and oncologically feasible, regardless of preoperative erectile status. An institutional review board approved this study.

2.2. Variable definitions

Complete preoperative data of all patients included age at surgery (years), comorbidity status evaluated using the Charlson Comorbidity Index (CCI), body mass index (BMI), prostate-specific antigen value (nanograms per milliliter), and EF assessed by the International Index of Erectile Function-Erectile Function (IIEF-EF) questionnaire and categorized according to the classification by Cappelleri et al. [13]. Surgical volume was defined as the number of procedures performed by the operating surgeon between the start of the study and the date of each specific RP for each individual patient [14], [15], and [16]. Perioperative data consisted of type of surgery: retropubic radical prostatectomy (RRP) versus robot-assisted laparoscopic radical prostatectomy (RALP), type of nerve sparing (unilateral vs bilateral), pathologic tumor stage (pT2 vs pT3), and pathologic Gleason score (≤6 vs 7 vs ≥8).

Patients were encouraged to attempt sexual intercourse as soon as possible following catheter removal and were stimulated to use either an on-demand phosphodiesterase type 5 inhibitor (PDE5-I) at the full dose or a daily low dose of PDE5-I for a period of 3–6 mo. The decision on the type of erectile dysfunction (ED) treatment followed surgeon and patient discussion about possible treatment options and expectations. However, none of the examined patients used intracavernosal injections or a vacuum device. All patients were assessed postoperatively every 3 mo and asked to complete the International Consultation on Incontinence Questionnaire (ICIQ) short form and the IIEF questionnaire during each visit. Postoperative continence recovery was defined as an ICIQ score <6 [17]. Postoperative sexual potency recovery was defined as an IIEF-EF domain score ≥22, regardless of the use of a PDE5-I [18] and [19].

2.3. Statistical analyses

Descriptive statistics of categorical variables focused on frequencies and proportions. Means, medians, and ranges were reported for continuously coded variables. The chi-square test and t test were used to compare the statistical significance of differences in proportions and means, respectively. We first estimated postoperative continence and sexual potency recovery rates using the Kaplan-Meier method. Then we calculated the conditional estimates of these events using the multiplicative law of probability, which states that knowledge of the probability of an event A and event B occurring, and the probability of event A occurring, allows the calculation of the conditional probability of event B occurring, given that event A has occurred: [probability A | B] = [probability of A and B]/[probability of A] [20]. Conditional estimates of continence recovery were stratified according to age categories (≤65 vs >65 yr). This age cut-off represented the highest tertile of age distribution in our cohort. Conditional estimates of sexual potency recovery were stratified according to previously published ED-risk groups [8]. These groups were classified as low risk (age ≤65 yr, preoperative IIEF-EF ≥26, CCI ≤1), intermediate risk (age 66–69 yr or preoperative IIEF-EF 11–25, CCI ≤1), and high risk (age ≥70 yr or IIEF-EF ≤10 or CCI ≥2).

Finally, Cox regression models were fitted to predict UC (ICIQ <6) according to age categories (≤65 vs >65 yr) and EF recovery according to ED-risk groups. Both models were adjusted for the appropriate available covariates. The hazard ratios (HRs) of these models were used to develop two conditional nomograms using a previously described methodology [21] and [22]. The accuracy of the conditional nomograms was quantified with Harrell's concordance index and the calibration plot method [23] and [24].

To examine the plausible conditional variation for continence and sexual potency recovery rates, separate multivariable Cox regression models were fitted in patients who did not achieve the end point (continence and/or sexual potency recovery) after 6, 12, 18, 24, 30, and 36 mo from RP. The HRs derived from these analyses were plotted against the postoperative period (months) and stratified according to age categories and ED-risk groups. All statistical analyses were performed using the R statistical package system (R Foundation for Statistical Computing, Vienna, Austria) and Prism Graph Pad software, v. 5.0 (San Diego, CA, USA). All statistical tests were two sided with a significance level set at <0.05.

3. Results

3.1. Descriptive characteristics

A total of 1135 assessable patients were included in the current study (Table 1). The average patient age was 62.0 yr (median: 62.1; range: 38.9–82.3). Average BMI was 25.8kg/m2 (median: 25.6; range: 17.3–39.1). Most patients had no comorbidity (69.1%). ED-risk group distribution was low, intermediate, and high in 32.0%, 37.4%, and 30.6% of patients, respectively. Roughly half of the patients received a RRP (50.7%); the remaining received a RALP (49.3%). Most patients received a bilateral nerve-sparing procedure (83.3%) and did use PDE5-I treatment after surgery (62.8%).

Table 1 Descriptive characteristics of 1135 patients with prostate cancer treated with nerve-sparing radical prostatectomy and pelvic lymph node dissection between 2000 and 2010 at a single tertiary referral center

Variables n (%)
Age, yr
Mean 62.0
Median 62.1
Range 38.9–82.3
Age categories, yr
≤65 752 (66.3)
>65 383 (33.7)
Body mass index, kg/m2
Mean 25.8
Median 25.6
Range 17.3–39.1
Body mass index categories, kg/m2
<25 444 (39.1)
25–30 606 (53.4)
>30 85 (7.5)
Charlson Comorbidity Index
0 784 (69.1)
1 288 (25.4)
≥2 63 (5.6)
Preoperative IIEF-EF
1–10 (severe ED) 222 (19.6)
11–17 (moderate ED) 69 (6.1)
18–21 (mild to moderate ED) 83 (7.3)
22–25 (mild ED) 246 (21.7)
≥26 (no ED) 515 (45.4)
Erectile dysfunction risk groups*
Low 363 (32)
Intermediate 425 (37.4)
High 347 (30.6)
Prostate-specific antigen, ng/ml
Mean 7.1
Median 6.0
Range 1.2–54.0
Pathologic stage
T2 943 (83.1)
T3 192 (16.9)
Pathologic Gleason score
≤6 511 (45)
7 555 (48.9)
≥8 69 (6.1)
Surgical volume
Mean 116.5
Median 89.0
Range 1.0–388.0
Surgery type
RRP 576 (50.7)
RALP 559 (49.3)
Nerve-sparing type
Unilateral 189 (16.7)
Bilateral 946 (83.3)
Postoperative phosphodiesterase type 5 inhibitor treatment
None 422 (37.2)
On demand 366 (32.2)
Daily 347 (30.6)

* Erectile dysfunction risk groups were defined as follows: low risk (age ≤65 yr, preoperative IIEF-EF ≥26, Charlson Comorbidity Index [CCI] ≤1), intermediate risk (age 66–69 yr or preoperative IIEF-EF 11-25, CCI ≤1), and high risk (age ≥70 yr or IIEF-EF ≤10 or CCI ≥2).

IIEF-EF=International Index of Erectile Function-Erectile Function; ED=erectile dysfunction; RRP=retropubic radical prostatectomy; RALP=robot-assisted laparoscopic radical prostatectomy.

3.2. Kaplan-Meier survival analyses

UC recovery rates at 12, 24, and 36 mo after NSRP were 89.5%, 94.7%, and 97.0%, respectively. In patients ≤65 yr of age, UC recovery rates were 90.9%, 95.8%, and 98.0% versus 86.7%, 92.7%, and 96.3% in patients >65 yr, respectively (p=0.01). EF recovery rates at 12, 24, and 36 mo after NSRP were 53.6%, 65.0%, and 67.5%, respectively. These rates were 70.6%, 83.6%, and 84.7% in patients with low ED risk versus 55.4%, 64.4%, and 65.9% in patients with intermediate ED risk versus 33.6%, 46.5%, and 51.9% in patients with high ED risk, respectively (p<0.001 for all comparisons).

3.3. Conditional survival estimates after radical prostatectomy

In patients still incontinent after 1, 6, 12, 18, 24, 30, and 36 mo from RP, UC recovery rates in the following 6-mo period were 74.9%, 58.2%, 41.4%, 14.9%, 24.8%, 24.6%, and 13.3%, respectively (Fig. 1A). Similar continence recovery trends were observed when patients were stratified according to age categories: ≤65 yr versus >65 yr (Fig. 1B).

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Fig. 1 Conditional 6-mo urinary continence recovery rates, accounting for the period elapsed from radical prostatectomy to patient assessment (postoperative period) in (A) the entire cohort, (B) after stratification to age categories: ≤65 versus >65 yr of age, and (C) after stratification to surgery type: retropubic radical prostatectomy (RRP) versus robot-assisted laparoscopic radical prostatectomy (RALP).

In patients who were still sexually impotent after 1, 6, 12, 18, 24, 30, and 36 mo from RP, the following 6-mo sexual potency recovery rates were 36.9%, 26.8%, 17.8%, 8.2%, 3.1%, 4.0%, and 0%, respectively (Fig. 2A). Similar sexual potency recovery trends were observed when patients were stratified according to ED risk: low versus intermediate versus high (Fig. 2B).

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Fig. 2 Conditional 6-mo erectile function recovery rates, accounting for the period elapsed from radical prostatectomy to patient assessment (postoperative period) (A) in the entire cohort, (B) after stratification to erectile dysfunction risk groups: low versus intermediate versus high, and (C) after stratification to surgery type: retropubic radical prostatectomy (RRP) versus robot-assisted laparoscopic radical prostatectomy (RALP).

In a sensitivity analysis, the conditional estimates of UC recovery and sexual potency recovery at 6 mo were stratified according to surgery type (RRP vs RALP) and are depicted in Figure 1C and 2C, respectively.

3.4. Proportional hazard Cox regression analyses

At baseline (1 mo after RP), patients ≤65 yr of age had a 1.4-fold (p=0.001) higher probability of UC recovery as compared with their counterparts >65 yr of age (Table 2). At the same time point, patients with low and intermediate ED risk had a 2.8- and 1.8-fold (both p<0.001), respectively, higher probability of sexual potency recovery compared with their counterparts with high ED risk (Table 3).

Table 2 Univariable and multivariable Cox regression analyses predicting post–radical prostatectomy urinary continence recovery*

Predictors Univariable analysis Multivariable analysis
HR (95% CI) p value HR (95% CI) p value
Age category
≤65 yr 1.00 (ref) 1.00 (ref)
≥65 yr 0.86 (0.76–0.98) 0.03 0.79 (0.69–0.91) 0.001
Body mass index, kg/m2 1.01 (0.98–1.03) 0.6 1.01 (0.98–1.03) 0.6
Charlson Comorbidity Index
0 1.00 (ref) 1.00 (ref)
1 1.07 (0.93–1.23) 0.3 1.08 (0.94–1.25) 0.2
≥2 0.93 (0.72–1.21) 0.5 0.97 (0.75–1.26) 0.8
Prostate-specific antigen value, ng/ml 0.99 (0.98–1.00) 0.2 0.99 (0.97–1.00) 0.09
Pathologic stage
pT2 1.00 (ref) 1.00 (ref)
pT3 1.06 (0.9–1.25) 0.4 1.07 (0.89–1.29) 0.4
Pathologic Gleason score
≤6 1.00 (ref) 1.00 (ref)
7 0.96 (0.85–1.08) 0.4 0.96 (0.84–1.09) 0.5
≤8 1.33 (1.03–1.72) 0.03 1.44 (1.08–1.92) 0.01
Type of RP
Open retropubic RP 1.00 (ref) 1.00 (ref)
Laparoscopic robot-assisted RP 1.54 (1.36–1.73) <0.001 1.67 (1.47–1.9) <0.001
Nerve-sparing technique
Unilateral 1.00 (ref) 1.00 (ref)
Bilateral 0.98 (0.84–1.16) 0.9 1.22 (1.02–1.46) 0.03
Surgical volume 1.00 (0.99–1.01) 0.4 1.00 (0.99–1.01) 0.5

* Defined as an International Consultation on Incontinence Questionnaire–short form score <6. The cohort consisted of 1135 patients with prostate cancer treated with nerve-sparing RP and pelvic lymph node dissection between 2000 and 2010 at a single tertiary referral center.

HR=hazard ratio; CI=confidence interval; RP=radical prostatectomy; ref=reference.

Table 3 Univariable and multivariable Cox regression analyses predicting post–radical prostatectomy erectile function recovery*

Predictors Univariable analysis Multivariable analysis
HR (95% CI) p value HR (95% CI) p value
Erectile dysfunction risk group
High 1.00 (ref) 1.00 (ref)
Intermediate 1.78 (1.44–2.21) <0.001 1.79 (1.44–2.22) <0.001
Low 2.84 (2.30–3.52) <0.001 2.78 (2.24–3.46) <0.001
Body mass index, kg/m2 0.97 (0.95–1.00) 0.06 0.98 (0.95–1.01) 0.2
Prostate-specific antigen value, ng/ml 0.97 (0.95–0.99) 0.003 0.98 (0.96–1.00) 0.07
Pathologic stage
pT2 1.00 (ref) 1.00 (ref)
pT3 0.56 (0.44–0.72) <0.001 0.71 (0.54–0.94) 0.02
Pathologic Gleason score
≤6 1.00 (ref) 1.00 (ref)
7 0.71 (0.60–0.83) <0.001 0.86 (0.73–1.03) 0.09
≤8 0.55 (0.38–0.82) 0.003 0.99 (0.65–1.53) 0.9
Type of RP
Open retropubic RP 1.00 (ref) 1.00 (ref)
Laparoscopic robot-assisted RP 1.37 (1.17–1.60) <0.001 1.7 (1.44–2.01) <.001
Nerve-sparing technique
Unilateral 1.00 (ref) 1.00 (ref)
Bilateral 1.68 (1.33–2.12) <0.001 1.68 (1.3–2.17) <0.001
Surgical volume 1.00 (0.99–1.01) 0.9 1.00 (0.99–1.01) 0.3
Phosphodiesterase type 5 inhibitor treatment
None 1.00 (ref) 1.00 (ref)
On demand 1.53 (1.26–1.86) <0.001 1.42 (1.17–1.74) 0.001
Daily 1.88 (1.55–2.29) <0.001 1.43 (1.17–1.75) 0.001

* Defined as an International Index of Erectile Function–Erectile Function domain score ≥22. The cohort consisted of 1135 patients with prostate cancer treated with nerve-sparing RP between 2000 and 2010 at a single tertiary referral center.

HR=hazard ratio; CI=confidence interval; RP=radical prostatectomy; ref=reference.

Relative to patients >65 yr of age, the HRs of continence recovery in patients ≤65 yr of age decreased to 1.3 in individuals who were still incontinent after 6 mo, and it further decreased to ≤1.0 in individuals who were still incontinent after 12 mo (Fig. 3A). Relative to patients with high ED risk, the HRs of sexual potency recovery in patients with low ED risk gradually decreased from 2.5 in individuals who were still impotent after 6 mo to 2.1 in individuals who were still impotent after 18 mo, and it dropped below 1.0 in individuals who were still impotent after 24 mo (Fig. 3B). Similarly, relative to patients with high ED risk, the HR of sexual potency recovery in patients with intermediate ED risk was 1.7 and 1.3 in patients who were still impotent after 6 and 12 mo, respectively, and it dropped below 1.0 in individuals who were still incontinent after 18 mo (Fig. 3B).

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Fig. 3 Proportional hazard ratios of multivariable Cox regression analyses for prediction of functional outcome recovery rate according to the period elapsed from radical prostatectomy to patient assessment in (A) patients ≤65 yr of age (reference category: patients >65 yr of age), (B) patients with low and intermediate erectile dysfunction (ED) risk (reference category: patients with high erectile dysfunction risk), and (C) in patients with a preoperative International Index of Erectile Function-Erectile Function (IIEF-EF) of 11–17, 18–21, 22–25, and ≥26 (reference category: patients with IIEF-EF of 1–10).

The HRs of the multivariable models were used to develop two nomograms predicting the probability of UC and sexual potency recovery at 6-, 12-, and 24-mo follow-up, respectively. The Harrell's concordance index of these models was favorable (Fig 4 and Fig 5).

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Fig. 4 (A) Nomogram, (B) calibration plot, and (C–E) conditional probability plots for prediction of the individual probability of urinary continence recovery after radical prostatectomy (RP). Nomogram instructions: Locate the patient's value for each individual predictor, and draw a line straight up to the point axis to determine how many points toward the probability of urinary continence recovery the patient receives for each predictor. Sum the points for each of the predictors. Locate the value corresponding to the sum on the total point axis (A). Subsequently, choose the time point of interest after RP (6, 12, or 24 mo) (C–E). Within the specific time point panel, draw a line straight up from the total point's axis. Then draw a horizontal line from a value on the y-axis that corresponds to the number of months without recovery of urinary continence that elapsed between RP and the current time. Use the intersection of both lines to identify a slanted line that crosses it or passes next to it. Follow the slanted line down to the x-axis to determine the probability of urinary continence recovery at the prespecified number of months.

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Fig. 5 (A) Nomogram, (B) calibration plot, and (C–E) conditional probability plots for prediction of the individual probability of sexual potency recovery after radical prostatectomy (RP). Nomogram instructions: Locate the patient's value for each individual predictor, and draw a line straight up to the point axis to determine how many points toward the probability of sexual potency recovery the patient receives for each predictor. Sum the points for each of the predictors. Locate the value corresponding to the sum on the total point axis (A). Subsequently, choose the time point of interest after RP (6, 12, or 24 mo) (C–E). Within the specific time point panel, draw a line straight up from the total point's axis. Then draw a horizontal line from a value on the y-axis that corresponds to the number of months without recovery of sexual potency that elapsed between RP and the current time. Use the intersection of both lines to identify a slanted line that crosses it or passes next to it. Follow the slanted line down to the x-axis to determine the probability of urinary continence recovery at the prespecified number of months.

In a sensitivity analysis, the three components of ED-risk classification (namely age, CCI, and preoperative IIEF-EF) were considered as separate covariates in multivariable analyses predicting sexual potency recovery. The conditional HRs of this analysis were stratified according to preoperative IIEF-EF and are depicted in Figure 3C.

4. Discussion

After RP, both continence and sexual potency recovery have a significant impact on postoperative quality of life [5] and [6]. It is well known that functional recovery after RP progressively increases with time after surgery. However, not all patients ultimately recover functional outcomes at long-term follow-up. The probability of long-term UC and EF recovery may differ according to the time between surgery and patient assessment. For instance, those patients not yet recovering functional outcomes at 1 yr after surgery are unlikely to ultimately recover their functional status. Conversely, those men not yet regaining either UC or EF at only 3 mo after surgery have an increased chance to reach their optimum function. Despite this intuitive clinical hypothesis, no objective data are available to evaluate this potential relationship. To address this void, we evaluated the conditional estimates of functional outcomes recovery in PCa patients treated with NSRP.

Our findings have several aspects. First, we confirm that the highest continence (41.1–74.9%) and sexual potency (36.9–17.8%) recovery rates are limited to the first 12 postoperative months. These rates gradually and progressively decrease with increasing time of impaired functional status after surgery. After 36 mo, the probability of subsequent UC recovery is low (13.3%), and the probability of potency recovery is null (0%). Second, the estimated functional outcome recovery rates at baseline were significantly different from the conditional estimates even considering the same time point after surgery. For example, the overall preoperative 12-mo UC recovery estimates were 89.5%. However, for those patients who were still incontinent at 6 mo after surgery, the probability of UC in the following 6 mo was only 58.2%. Similarly, although baseline 12-mo EF recovery estimates were 53.6%, these decreased to 26.5% for those patients who were still impotent at 6 mo after surgery. Similar trends were observed in subanalyses when patients were stratified according to age categories, ED-risk groups, and surgery type. It is noteworthy that patients treated with RALP had significantly higher UC and sexual potency recovery rates early after surgery as compared with RRP patients. Consequently, in RALP patients who did not recover functional outcomes within the first 6 mo, the probability of subsequent UC and sexual potency recovery was lower as compared with RRP patients (Fig. 1C and 2C).

These results were also confirmed at multivariable analyses, even after adjusting for potential confounders. At baseline, patients ≤65 yr of age had higher UC continence recovery rates as compared with their older counterparts (Table 2). This held true if UC recovery occurred during the first 12 mo. However, after that period, the UC recovery rates of patients ≤65 yr were not more favorable than UC recovery rates of those >65 yr (Fig. 3A). Similarly, at baseline, patients at low and intermediate ED risk had more favorable EF recovery rates as compared with men with high ED risk (Table 3). This held true if potency recovery occurred during the first 24 and 18 mo for patients with low and intermediate ED risk, respectively. After these time points, EF recovery rates for these patients were not more favorable than for those men with high ED risk. Similar findings were observed when postoperative EF recovery was stratified according to the preoperative IIEF-EF score (Fig. 3B and 3C). The impact of the postoperative period on the functional outcome recovery rates was further shown in the conditional nomograms. For example, in a patient with a sexual potency recovery nomogram score (total points) of 100, the 6-mo probability of IIEF-EF ≥22 is 70% at baseline, but it decreases to only 50% if the patient did not recover sexual potency within the first 3 postoperative months (Fig. 5).

It is noteworthy that surgical volume was not an independent predictor of functional outcomes. This might be attributed to the relatively high surgical volume of all the surgeons who participated in the study. The calculated surgical volume does not account for previous surgical experience, which might have already been significant. The latter may represent a limitation shared by virtually all previous studies that addressed a similar topic [3], [14], [15], [16], [25], and [26].

Our observations corroborate previous findings. For example, in a review of the literature in 2010, Coelho et al. [9] examined data from 14 open RP reports including 17 983 patients. They reported that the weighted mean of continence recovery rate at 6, 12, and ≥18 mo was 55.6%, 80.0%, and 88.2%, respectively. Eastham et al. [10] examined the data of 1577 PCa patients treated with RP between 2000 and 2006 at one tertiary care center. In their report, at 12 mo almost 80% and 40% of patients were continent and sexually potent, respectively. At 36 mo, these rates increased to almost 90% and 65%, respectively, and remained virtually the same thereafter. In a previous report, we examined EF recovery rates in 435 patients treated with NSRP between 2004 and 2008 at our center [8]. Our results showed that potency recovery rates may largely vary according to patient age, comorbidity, and preoperative erectile function. In patients with low, intermediate, and high ED risk, the 12-mo EF recovery rates were 83%, 55%, and 37%, respectively. These rates increased to 85%, 58%, and 39%, respectively, at 24 mo and remained virtually the same at 36 mo. All the reports just mentioned showed that most patients will achieve recovery of their functional status during the first 12 postoperative months. Conversely, small, if not null, rates of functional recovery are observed after 24–36 mo from RP. These observations are in line with our results. However, none of the previous reports examined the conditional estimates of functional outcome recovery rates after RP. Consequently, they were unable to provide the probability of recovery based on the postoperative period. Our study circumvented this limitation and demonstrated that the effect of “conditional survival” is highly applicable to functional outcomes after RP, even after adjusting for potential confounders such as age, comorbidity, and preoperative functional status.

Our findings also have several clinical implications. First, our results showed that the immediate postoperative functional outcome recovery estimates do not apply to patients who are still incontinent and/or impotent after a certain postoperative period. A simple immediate postoperative estimate is not sufficient. Patients should be informed and counseled about the change of functional recovery probabilities over time. In the same context, the follow-up visits, aimed at improving functional outcomes, can be planned based on the conditional estimates of functional outcomes recovery to achieve the most efficient trade-off between costs and benefits. Similarly, available predictive models [7] and [8] should account for postoperative time to provide more accurate estimates.

Second, any therapeutic approach should also be individualized according to postoperative period of nonfunctional status after surgery. For example, it may be appropriate to propose oral PDE5-I treatment to improve EF in the initial postoperative period. However, in patients still impotent after 12–24 mo, an alternative approach such as intracavernosal therapy might be proposed as first-line treatment.

Finally, patient classification according to preoperative characteristics into “risk groups” can be considered valid but only for a certain period after RP. For example, potency recovery rates of patients with a low ED risk who were still impotent at 24 mo from RP were not more favorable than those of patients with a preoperative high ED risk.

Despite these strengths, our study is not devoid of limitations. First, given the observational nature of our cohort, our findings must be interpreted with all the limitations applicable to observational, retrospective data. Second, the categorization of nerve sparing as unilateral versus bilateral might not be sufficient. The neurovascular bundle might be completely spared, completely excised, or partially spared. Unfortunately, no further information regarding this variable was available. This limitation is shared by several previous reports that addressed a similar end point [27] and [28]. Third, it may be argued that UC and sexual potency are not on/off phenomena and that they should rather be considered as continuous variables to account for the severity of the corresponding impairment. Unfortunately, the currently available methodology to test conditional survival does not allow for the assessment of linear end points. Finally, our cohort represents single-institution data. It remains to be tested whether our findings are applicable to other clinical settings. Therefore, a multicenter or a population-based analysis is warranted to confirm our results.

5. Conclusions

The time interval elapsed from RP represents an important predictor of the subsequent functional outcome. For impotent and/or incontinent patients, the probability of UC and EF recovery at long term significantly decreases with increasing time from surgery. The impact of patient characteristics such as preoperative functional status, age, and comorbidity profile on functional outcomes recovery also significantly decreases with time after RP. For all these reasons, the postoperative interval between surgery and patient assessment should always be considered when counseling and considering the therapeutic approach for patients who have not yet regained functional outcomes at a certain point after RP.

Author contributions: Alberto Briganti had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Briganti, Abdollah, Suardi, Gallina, Montorsi, Rigatti, Sun.

Acquisition of data: Gallina, Suardi, Tutolo, Bianchi, Passoni.

Analysis and interpretation of data: Briganti, Abdollah, Gallina, Sun.

Drafting of the manuscript: Briganti, Abdollah, Sun, Karakiewicz, Montorsi.

Critical revision of the manuscript for important intellectual content: Briganti, Karakiewicz, Sun, Abdollah, Salonia, Rigatti, Montorsi, Colombo.

Statistical analysis: Briganti, Abdollah.

Obtaining funding: None.

Administrative, technical, or material support: None.

Supervision: Karakiewicz, Montorsi, Rigatti.

Other (specify): None.

Financial disclosures: Alberto Briganti certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Pierre I. Karakiewicz is partially supported by the University of Montreal Health Centre Urology Specialists, Fonds de la Recherche en Santé du Québec, the University of Montreal Department of Surgery, and the University of Montreal Health Centre (CHUM) Foundation.

Funding/Support and role of the sponsor: None.

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Footnotes

a Department of Urology, Vita-Salute San Raffaele University, Milan, Italy

b Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre, Montreal, Canada

lowast Corresponding author. Department of Urology, San Raffaele Hospital, University Vita-Salute, Via Olgettina, 60, 20132 Milan, Italy. Tel. +39 02 2643 7286; Fax: +39 02 2643 7298.

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