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Platinum Priority – Reconstructive Urology
Editorial by Aaron A. Laviana and Jim C. Hu on pp. 281–282 of this issue

Propensity-weighted Long-term Risk of Urinary Adverse Events After Prostate Cancer Surgery, Radiation, or Both

By: Stephanie L. Jarosek a lowast , Beth A. Virnig b , Haitao Chu c and Sean P. Elliott a

European Urology, Volume 67 Issue 2, February 2015, Pages 273-280

Published online: 01 February 2015

Keywords: Outcomes research, Prostate cancer, Reconstructive urology, SEER-Medicare, Urinary adverse effects

Abstract Full Text Full Text PDF (572 KB) Patient Summary

Abstract

Background

Prostate cancer is the second most common cancer in men and has high survivorship, yet little is known about the long-term risk of urinary adverse events (UAEs) after treatment.

Objective

To compare the long-term UAE incidence across treatment and control groups.

Design, setting, and participants

Using a matched-cohort design, we identified elderly men treated with external-beam radiotherapy (EBRT;n = 44 318), brachytherapy (BT;n = 14 259), EBRT+BT (n = 11 835), radical prostatectomy (RP;n = 26 970), RP+EBRT (n = 1557), or cryotherapy (n = 2115) for non-metastatic prostate cancer and 144 816 non-cancer control individuals from the population-based Surveillance, Epidemiology, and End Results-Medicare linked data from 1992–2007 with follow-up through 2009.

Outcome measures and statistical analysis

The incidence of treated UAEs and time from cancer treatment to first UAE were analyzed in terms of propensity-weighted survival.

Results

Median follow-up was 4.14 yr. At 10 yr, all treatment groups experienced higher propensity-weighted cumulative UAE incidence than the control group (16.1%; hazard risk [HR] 1.0), with the highest incidence for RP+EBRT (37.8%; HR 3.19, 95% confidence interval [CI] 2.79–3.66), followed by BT+EBRT (28.4%; HR 1.97, CI 1.85–2.10), RP (26.6%; HR 2.44, CI 2.34–2.55), cryotherapy (23.4%; HR 1.56, CI 1.30–1.87), BT (19.8%; HR 1.43, CI 1.33–1.53), and EBRT (19.7%; HR 1.11, CI 1.07–1.16). Bladder outlet obstruction was the most common event.

Conclusions

Men undergoing RP, RP+EBRT, and BT+EBRT experienced the highest UAE risk at 10 yr, although UAEs accrued differently over extended follow-up. The significant background UAE rate among non-cancer control individuals yields a risk attributable to prostate cancer treatment that is 17% lower than prior estimates.

Patient summary

We show that treatment for prostate cancer, especially combinations of two treatments such as radiation and surgery, carries a significant risk of urinary adverse events such as urethral stricture. This risk increases with time since treatment, emphasizing that treatments have long-term effects.

Take Home Message

Urinary adverse events (UAEs) are not unusual in elderly men, but treatment for prostate cancer, especially combination therapy, increases the risk. UAEs accrue differently among treatment groups, making a long time horizon essential for understanding UAEs due to treatment.

Keywords: Outcomes research, Prostate cancer, Reconstructive urology, SEER-Medicare, Urinary adverse effects.

1. Introduction

Prostate cancer is the most common non-dermatologic cancer [1] and is usually treated with radiation or surgery with high long-term survival. This yields a large cohort of cancer survivors (approx. 2 778 630 in the USA in 2014 [2] ) who are at risk of urinary adverse events (UAEs) after cancer treatment.

Surgical UAEs manifest as urethral stricture (inclusive of bladder neck contracture, BNC) and urinary incontinence; radiation UAEs include urethral stricture, cystitis, and incontinence. Surgical UAEs are due to intraoperative injury and present soon after surgery. For example, urethral strictures occur in 7% of patients in the first year after radical prostatectomy (RP) but new cases are rare after 1 yr [3] . By contrast, radiation UAEs accrue over the long term[3] and [4]. Combination therapy (radiation plus surgery or two forms of radiation) is known to increase the UAE risk[5], [6], [7], and [8].

The long-term risk of UAEs is central to any discussion about the comparative effectiveness of radiation and surgery. Furthermore, given an expected background rate of urinary events, framing any discussion about the risks after cancer treatment around a comparison with the experience of the non-cancer population is important. An efficient mechanism for such a comparison exists in the Surveillance, Epidemiology and End Results (SEER)-Medicare database. This database provides data for large numbers of patients with long-term follow-up for UAEs likely to be present in billing claims, whereas most randomized trials and cohort series have follow-up of less than 10 yr or small populations [9] . Thus, we compared the long-term risks of severe UAEs (those managed with surgery or a procedure) among local prostate cancer treatments and non-cancer control individuals using propensity-weighted methods to adjust for selection bias.

2. Patients and methods

2.1. Study subjects

This research was approved by the University of Minnesota Institutional Review Board.

The SEER data include cancer registry information for 25% of the US population and describe patient demographics, tumor characteristics, and primary treatment. Medicare claim data can be linked to SEER data to provide long-term follow-up data for elderly beneficiaries [10] .

We identified 322 472 men aged ≥66 yr diagnosed with non-metastatic prostate cancer in 1992–2007 who received local treatment for prostate cancer and were continuously enrolled in fee-for-service Medicare Parts A and B from 1 yr before diagnosis until death or the end of the observation period in December 2009 ( Fig. 1 A). Exclusion criteria included diagnosis at autopsy, a death certificate or residence in a nursing home, previous pelvic cancer diagnosis, diagnosis in Louisiana in 2005 (hurricane Katrina caused disrupted registry ascertainment), and residence in zip codes without census information for income and education, leaving a final cohort of 100 874.

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Fig. 1 Cohort criteria for (A) prostate cancer patients and (B) the non-cancer control group. HMO = health maintenance organization; RP = radical prostatectomy; EBRT = external beam radiotherapy; BT = brachytherapy; AST = androgen suppression therapy; SEER = Surveillance, Epidemiology, and End Results.

The control individuals were drawn from 193 150 elderly men without cancer in the 5% sample of Medicare beneficiaries residing in the SEER areas between 1992 and 2007 ( Fig. 1 B). Pseudo-diagnosis dates were assigned to control subjects by determining the proportion of cases in each diagnosis month and randomly assigning the appropriate number of control subjects to that diagnosis month for individuals who had at least 12 mo of continuous Medicare enrollment before the pseudo-diagnosis date (to calculate the Charlson comorbidity score) [11] . Men not residing in a SEER area at pseudo-diagnosis (n = 4340, 2.8%) or in a zip code with linked census information (n = 5541, 3.7%) were excluded.

2.2. Covariates

Covariates included the presence of baseline UAEs, Charlson comorbidity score [11] , patient age, race, quartiles for zip-code–level median household income and educational status, clinical tumor stage and WHO grade (cases only), and tumor registry of residence.

2.3. Treatment identification

From claims data we identified local treatments received within 12 mo of diagnosis: RP, external beam radiotherapy (EBRT; intensity-modulated, conformal, and proton beam radiotherapy), brachytherapy (BT; high- and low-dose rate), and cryotherapy. These data were used to create six treatment groups for comparison (RP, RP+EBRT, BT, EBRT, BT+EBRT, and cryotherapy).

2.4. UAE identification

We defined severe UAEs as grade 3 or 4 events according to the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute [12] ; thus, we required both a UAE diagnosis code and correlating procedure code on one claim to count an adverse event. Events of interest were procedures for bladder spasm, cystitis, hematuria, incontinence, urinary fistula, ureteral obstruction, benign prostatic hypertrophy (BPH), and urethral stricture/BNC (Supplementary Table 1). Procedures performed ostensibly for BPH after prostate radiation are likely to represent obstruction secondary to radiation[13] and [14]; therefore, we present BPH and urethral stricture or BNC separately and combined as bladder outlet obstruction (BOO). Bladder spasms, cystitis, and hematuria are grouped because of symptom and procedure overlap; all were considered to represent variations of radiation cystitis.

Procedures for conditions that would otherwise qualify as severe UAEs but occurred in the 12 mo before prostate cancer treatment (or pseudo-treatment in the control group) were considered to be pre-existing conditions, termed baseline UAEs. We adjusted for the presence of baseline UAEs in our weighting and multivariate models.

2.5. Propensity weighting

Patients in each treatment group and the control group differed by patient and tumor characteristics ( Table 1 ). Ideally, we would compare the experience after treatment of men with similar characteristics. To approximate this, we assigned each man a stabilized inverse probability of treatment weight (IPTW)[15] and [16]. We first modeled the propensity of a diagnosis of prostate cancer using age, race, comorbidity, zip code income and education, SEER registry, year of treatment (or pseudo-treatment), and presence of baseline UAEs. Then we modeled the propensity of receiving treatment for each cancer case in a generalized logit model using those covariates, clinical T stage, and grade. The IPTW was equal to the inverse of the probability of cancer diagnosis for control subjects, and the product of the inverse of the probability of cancer diagnosis and of receiving their treatment for cases. The stabilized weights were truncated at the 99th percentile to reduce potential data sparsity [17] . Men who are least like others in their treatment group have higher weights, balancing the covariates across treatment groups ( Table 1 ).

Table 1 Unweighted demographic characteristics of non-cancer control group and prostate cancer cohort stratified by treatment group

  Treatment group
Control EBRT BT BT+EBRT RP RP+EBRT Cryotherapy
Number 144 816 44 318 14 259 11 835 26 790 1557 2,115
Age at treatment (%)
 65-69 36.74 17.55 25.91 25.29 51.00 51.12 22.30
 70-74 30.83 37.21 40.26 40.56 40.37 39.82 34.06
 75-79 19.18 32.64 26.54 27.02 7.97 b 29.90
 80-84 13.25 12.59 7.29 7.13 0.66 b 13.75
Race (%)
 White 83.33 83.10 88.70 84.36 86.70 84.59 82.95
 Black 6.62 9.99 6.67 9.51 6.55 6.23 10.54
 Hispanic 2.50 1.78 1.02 1.61 1.95 2.44 2.35
 Asian 3.95 2.99 2.03 2.57 2.28 4.11 2.26
 Other unknown 3.60 2.13 1.59 1.94 2.52 2.63 1.90
Median income (%)
 Q1 27.08 22.53 20.54 17.92 19.38 18.43 28.00
 Q2 25.82 24.22 21.97 20.23 25.30 26.72 24.69
 Q3 24.16 25.44 26.99 28.07 26.75 26.91 25.10
 Q4 22.94 27.81 30.50 33.78 28.56 27.94 22.21
High school completion (%)
 Q1 27.36 23.50 21.01 20.81 18.30 20.36 27.23
 Q2 25.54 25.05 23.70 22.61 22.55 21.77 24.88
 Q3 24.58 25.83 26.32 26.13 26.47 27.17 25.64
 Q4 22.52 25.63 28.97 30.44 32.69 30.70 22.25
Charlson score (%)
 0 69.11 62.11 65.57 62.92 68.28 65.19 54.50
 1 19.68 24.36 23.68 25.56 23.45 25.05 29.13
 2 6.85 8.43 7.21 7.72 5.98 7.19 10.36
 3+ 4.35 5.09 3.55 3.80 2.29 2.57 6.02
Clinical T stage (%)
 1 N/A 37.85 50.89 38.85 37.11 31.28 42.20
 2x a N/A 16.83 17.15 16.89 15.01 13.55 14.88
 2y N/A 11.32 5.91 13.38 10.40 12.14 9.14
 2z N/A 25.85 23.78 25.40 28.31 23.96 28.22
 3 or 4 N/A 5.10 0.36 3.77 7.27 17.53 2.89
 Unknown N/A 3.05 1.91 1.71 1.90 1.54 2.67
WHO grade (%)
 1 N/A 4.92 3.45 2.18 4.45 2.12 1.09
 2 N/A 57.81 80.01 52.49 63.85 40.98 52.92
 3 N/A 34.37 14.03 43.05 30.54 55.81 43.10
 Unknown N/A 2.90 2.51 2.28 1.16 1.09 2.89

a T2x, y, z are roughly equivalent to T2a, T2b, T2NOS, allowing for changes in definition and Surveillance, Epidemiology, and End Results (SEER) reporting over time; chi-square p < 0.0001 for all variables.

b Cell masked for n < 11, per National Cancer Institute guidelines.

RP = radical prostatectomy; EBRT = external beam radiotherapy; Q = quartile; BT = brachytherapy; N/A = not applicable.

2.6. Survival analysis

Median follow-up for each treatment group was obtained using the reverse Kaplan-Meier method, treating events as censoring events [18] . Time to the first UAE or censoring event was measured in days elapsed from the first treatment claim date. We generated unweighted Kaplan-Meier survival curves for incidence of the first UAE, stratified by treatment group. Patients were censored on enrollment in a health maintenance organization, on death, or at the end of the observation period. Patients were also censored on possible disease progression (first chemotherapy use, cancer treatment after 12 mo, or androgen suppression therapy outside of 36 mo for men receiving concurrent radiotherapy as a primary treatment) and subsequent pelvic cancer diagnosis. Competing risks estimates of the unweighted data were also generated because mortality was associated with the type of treatment[19] and [20].

Propensity-weighted Cox proportional hazard models estimated the hazard ratio of severe UAEs in general, and BOO in particular, for men with each treatment versus control subjects. To control for effects of covariates on the outcome apart from their impact on treatment selection, we also estimated a weighted model, adjusting for age, comorbidity, and baseline UAE. We then tested the impact of baseline BOO on subsequent BOO for each treated group using an interaction term in a Cox proportional hazards model.

All statistical analyses were performed using SAS v9.3 (SAS Institute, Inc., Cary, NC, USA). Allpvalues reported are two-sided, andp < 0.05 was considered to be statistically significant.

3. Results

Radiotherapy was twice as common as surgery. RP-treated men were younger, resided in higher income/education areas, had lower comorbidity scores, and were less likely to have baseline UAEs. RP+EBRT in the first year after cancer diagnosis was uncommon, but these patients tended to have higher clinical T stage and higher grade disease than those receiving RP alone. Among patients managed with radiotherapy, patients treated with BT alone were more likely to be non-Hispanic white, have lower T stage, grade, and Charlson score, and were more likely to reside in the highest income/education areas. Cryotherapy was uncommon but had the greatest proportion of older patients, higher comorbidity scores, and the highest rate of baseline UAEs. The non-cancer control subjects resided in areas with lower socioeconomic status than the cancer cases and had lower Charlson comorbidity and baseline UAE rates. After propensity weighting, the covariates were balanced across groups; given the large sample size, statistically significant differences persisted but were clinically nonsignificant ( Table 1 ).

The median potential follow-up was as follows: control subjects, 3.5 yr; EBRT group, 4.6 yr; BT group, 5.0 yr; BT+EBRT group, 5.3 yr; RP group, 6.2 yr; RP+EBRT group, 5.4 yr; and cryotherapy group, 3.5 yr.

Before propensity weighting, the 10-yr cumulative UAE incidence was highest in the RP+EBRT group, followed by BT+EBRT and then RP ( Table 2 ). After weighting, the RP+EBRT group had the highest cumulative UAE incidence (36.4% at 10 yr; Fig. 2 ). UAE accumulation after RP declined after the first year, leading to a relative plateau for the cumulative incidence (27.2% at 10 yr); other groups experienced a more constant rate. BT+EBRT patients experienced a similar rate of UAEs at 10 yr (27.4%) to patients managed with RP and a higher rate than patients managed with either therapy alone (BT 20.0%, EBRT 17.6%). Although the control group experienced the fewest events, cumulative incidence was 17.0% at 10 yr and was largely due to BPH or urethral stricture ( Table 3 ). The competing risks analysis of unweighted events yielded similar relative results (results not shown).

Table 2 Unweighted and propensity-weighted risk of any urinary adverse effect and bladder outlet obstruction

Control EBRT BT BT+EBRT RP RP+EBRT Cryotherapy
Subjects (n) 144 816 44 318 14 259 11 835 26 790 1557 2115
Any UAE (unweighted)
 Event rate (n per 100 person-yr) 1.78 2.40 2.70 3.91 4.02 6.08 3.71
 KM 10-yr cumulative incidence (%) 16.1 19.7 19.8 28.4 26.6 37.8 23.4
Any UAE (propensity-weighted)
 KM 10-yr cumulative incidence (%) 17.0 17.6 20.0 27.4 27.2 36.4 19.4
 HR a 1 1.114 1.428 1.969 2.442 3.194 1.56
 (95% CI)   (1.07–1.16) (1.33–1.53) (1.85–2.10) (2.34–2.55) (2.79–3.66) (1.30–1.87)
BOO (unweighted)
 Event rate (n per 100 person-yr) 1.56 1.80 2.13 3.14 2.99 4.61 3.14
 KM 10-yr cumulative incidence (%) 14.3 15.1 15.6 23.5 20.3 29.5 19.3
BOO (propensity-weighted)
 KM 10-yr cumulative incidence (%) 15.0 13.3 15.7 23.3 20.4 27.0 15.0
 HR a 1 0.955 1.322 1.878 2.091 2.765 1.55
 (95% CI)   (0.91–0.99) (1.22–1.43) (1.75–2.01) (1.99–2.19) (2.38–3.22) (1.27–1.89)
Treatment × baseline BOO interaction
 Frequency of baseline BOO (%) 1.9 8.9 7.4 8.0 5.1 4.6 9.0
 Adjusted HR for baseline BOO vs. no BOO b N/A 4.143 3.008 2.88 1.956 1.631 2.403
 (95% CI)   (3.81–4.51) (2.43–3.72) (2.36–3.52) (1.66–2.31) (0.96–2.78) (1.17–4.93)

a Cox proportional hazard model adjusted using the inverse probability of treatment weight, age, Charlson score, and year of treatment.

b Cox proportional hazard model adjusted using the inverse probability of treatment weight, including covariates for treatment group, year of treatment, baseline BOO, and interaction between treatment group and BOO.

EBRT = external beam radiotherapy; BT = brachytherapy; RP = radical prostatectomy; UAE = urinary adverse event; KM = Kaplan-Meier; HR = hazard ratio; CI = confidence interval; BOO = bladder outlet obstruction; N/A = not applicable.

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Fig. 2 Unadjusted cumulative incidence (1–Kaplan-Meier estimate) of any urinary adverse event by treatment group. RP = radical prostatectomy, EBRT = external beam radiotherapy, BT = brachytherapy.

Table 3 The 10-yr propensity-weighted cumulative incidence of specific urinary adverse events stratified by prostate cancer treatment group

  10-yr propensity-weighted cumulative incidence, % (95% confidence interval)
Control EBRT BT BT+EBRT RP RP+EBRT Cryotherapy
Spasm/cystitis/hematuria 2.24 4.95 4.83 6.9 3.21 8.8 4.22
  (2.1–2.38) (4.61–5.31) (4.26–5.48) (6.2–7.67) (2.9–3.55) (6.78–11.39) (3.01–5.91)
Incontinence 0.14 0.28 0.61 0.95 6.24 7.11 2.44
  (0.11–0.18) (0.21–0.38) (0.45–0.84) (0.7–1.29) (5.88–6.62) (5.48–9.22) (1.23–4.82)
Ureteral stricture 1.21 2.22 1.78 1.86 1.72 2.7 1.05
  (1.11–1.31) (1.99–2.48) (1.37–2.31) (1.51–2.29) (1.52–1.95) (1.6–4.53) (0.63–1.74)
Fistula 0.06 0.11 0.14 0.28 0.33 0 a
  (0.04–0.09) (0.07–0.16) (0.06–0.3) (0.18–0.43) (0.26–0.42) (0–0)  
Urethral stricture/BNC 6.78 9.56 11.94 19.39 19.34 25.86 10.27
  (6.56–7.01) (9.1–10.04) (11–12.95) (18.23–20.62) (18.74–19.96) (22.82–29.22) (8.14–12.91)
BPH 12.32 5.79 7.44 8.83 1.27 2.34 6.5
  (12.02–12.63) (5.42–6.19) (6.66–8.31) (7.98–9.77) (1.11–1.46) (1.54–3.55) (4.72–8.91)
BOO b 15.08 13.29 15.68 23.26 20.35 27.03 15.03
  (14.75–15.41) (12.7–-13.85) (14.83–16.57) (22.18–24.39) (19.71–20.99) (23.73–30.68) (13.52–16.69)

a Cell masked for n < 11 in accordance with National Cancer Institute guidelines.

b BOO includes both urethral stricture/BNC and BPH.

EBRT = external beam radiotherapy; BT = brachytherapy; RP = radical prostatectomy; BNC = bladder neck contracture; BPH = benign prostatic hypertrophy; BOO = bladder outlet obstruction.

BOO events were the most common events in men with prostate cancer and control subjects; the RP+EBRT group had the highest weighted cumulative incidence at 10 yr (36.4%; Table 2 ). Patients managed with EBRT alone or in combination with RP exhibited higher rates of ureteral stricture than other groups ( Table 3 ), and those undergoing RP or RP+EBRT had higher rates of incontinence. Patients managed with radiotherapy in any form had higher rates of spasm/cystitis/hematuria than RP-treated men.

A propensity-weighted Cox proportional hazards model predicting time to first UAE showed an increased risk of UAEs among all treatments groups versus control subjects. Patients with RP+EBRT had the highest risk (hazard ratio [HR] 3.19, 95% confidence interval [CI] 2.79–3.66), followed by patients receiving RP (HR 2.44, 95% CI 2.34–2.55). The lowest increase in risk was found after EBRT alone (HR 1.11, 95% CI 1.07–1.16). Running the model without adjustment for age, year of treatment, Charlson comorbidity score, and baseline UAE did not change the findings (results not shown).

In a propensity-weighted Cox proportional hazards model predicting time to first BOO event, EBRT-treated men had a significant 4% decrease in hazard (HR 0.96, 95% CI 0.91–0.99) compared to control subjects, whereas the risk was doubled for the RP (HR 2.09, 95% CI 1.99–2.19) and RP+EBRT (HR 2.77, 95% CI 2.38–3.22) groups. Running the model without adjustment for age, Charlson comorbidity score, and baseline UAE did not change the findings (results not shown).

The rates of baseline BOO varied among the groups, from lows of 1.9%, 4.6%, and 5.1% in the control, RP+EBRT, and RP groups, respectively, to a high of 9.0% after cryotherapy. The EBRT group experienced the greatest increase in the likelihood of BOO after treatment in the presence of baseline BOO (vs without baseline BOO; HR 4.14, 95% CI 3.81–4.51), and patients with RP experienced the smallest increase in risk (HR 1.96, 95% CI 1.66–2.31); the risk for patients with RP+EBRT with baseline BOO did not significantly differ compared to those without.

4. Discussion

Elderly men commonly undergo procedures or surgeries for urinary complaints: 17.0% of non-cancer control subjects in our cohort underwent procedures for some type of severe UAE. Understanding this background rate of intervention is important when measuring the impact of prostate cancer treatment on urinary health. Demographic and cancer characteristics confound measurement of UAEs after prostate cancer therapy because they impact cancer treatment selection and the subsequent development of or treatment for UAEs. In this study we accounted for the background rate of events in non-cancer control subjects and balance the characteristics of the population with propensity weighting.

Compared to the adjusted background 10-yr incidence of severe UAEs of 17.0%, the UAE incidence after prostate cancer treatment was 17.6–36.4%; the BT and EBRT groups had the lowest incidence, and the RP, RP+EBRT, and BT+EBRT groups had the highest incidence in this analysis. The weighted model adjusted for patient characteristics yielded similar results to the unadjusted model, suggesting that the differences in outcomes observed are indeed secondary to cancer treatment rather than to patient characteristics.

The type of UAE differed by treatment type. Intervention for spasm/cystitis/hematuria occurred more often in men with prior radiotherapy (5.0–6.9%) than in men with prior RP (3.2%). Surgery for urinary incontinence occurred in 6.2% of men after RP and 7.1% after RP+EBRT, accounting for approximately a quarter of UAEs after surgery. Surgery for urinary incontinence was rare among radiotherapy-treated men. Although all events reported here were consistent with the CTCAE and bothersome enough to warrant corrective procedures, some UAEs are more correctable and others have a greater impact on quality of life, and we cannot detect this with the current analysis [21] .

BOO, the most common UAE, occurred in 13–16% of men treated with BT or EBRT at 10 yr and in 23.3% after BT+EBRT at 10 yr. Although the 10-yr cumulative incidence of BOO among control subjects is similar to that after BT or EBRT (15%), the type was different: predominantly BPH in control subject versus urethral stricture after radiation. BOO after RP was chiefly urethral stricture or BNC and occurred in 20.4% of cases, similar to the BT+EBRT group. Like other reports, most cases of incident urethral stricture or BNC after RP occur in the first year[3] and [14]; after that, the incidence appears to be similar to the background event rate in control subjects ( Fig. 2 ). We also find, like others, that adjuvant RT after RP significantly increases the risk of urethral stricture or BNC (27.5%)[6] and [7]. The adjusted HRs paralleled these findings.

In patients treated with radiation, where the prostate remains in situ, prior BPH surgery may impact the future BOO risk[14], [22], and [23]. We found that BOO surgery (usually a transurethral resection, TURP) was performed in 7.4–9.0% of men in the 12 mo before treatment with radiation or cryotherapy and elevates the likelihood of subsequent BOO surgery by 4.1-fold in the EBRT group and approximately 2.7-fold in the cryotherapy, BT, and BT+EBRT groups.

Our analysis differs from that of others in that we focus on an elderly population and only urinary symptoms managed with a procedure. Our results are not comparable to survey reports of urinary symptoms (eg, incontinence requiring pads); however, our measures have good specificity for symptoms bothersome enough to indicate a procedure p24–26]. In addition, our 10-yr incidence of grade 3–4 UAEs in the RP group (27.2%) and the RP+EBRT group (36.4%) differ from those reported by Bolla et al. [7] for a randomized trial of adjuvant EBRT versus observation in men with locally advanced prostate cancer after RP, with 10-yr incidence rates of grade 3 UAE of 5.3% and 2.5% after RP and RP+EBRT, respectively. However, our findings are in line with those reported for other community-based observational cohorts[3], [13], and [14]; this may reflect differences in patient population (younger, healthier patients in clinical trials) or may better represent the treatment quality provided in community-based settings compared to clinical trial sites. Interestingly, when we consider the background rate of events (17.0% in control subjects), the risk attributable r to treatment is reduced such that it is more similar to the results seen in randomized trials. Nevertheless, it is important to note that the predominant procedure performed in control subjects was TURP for BPH, whereas among cancer patients it was treatment of a urethral stricture; we should not pretend to equate these events, as they differ in success rate and effect on quality of life.

Certain limitations deserve mention. Radiation proctitis and erectile dysfunction are important adverse effects of prostate cancer therapy not examined in this study because we elected to focus on urinary adverse events only. Second, the validity of claims data for detecting UAEs is central to the interpretation of these findings. Claims for surgeries or procedures have good positive predictive value[24], [25], and [26]; however, bias may be present in our estimate if the likelihood of actually undergoing surgical correction of a severe UAE differs by cancer treatment type. Third, our study population is only generalizable to elderly men. Fourth, the elderly population and inclusion of large registries that began reporting cases after 1999 resulted in relatively short median follow-up; however, our large cohort provided adequate sample size to report the 10-yr incidence. In addition, radiologic improvements have resulted in increasingly smaller fields, which reduce damage to surrounding tissues, although these improvements may reduce gastrointestinal more than genitourinary effects [27] . Finally, despite the use of propensity weighting, unmeasured confounders may still bias our outcomes.

5. Conclusion

Decision-making for prostate cancer treatment is complex. The disease often progresses slowly, local treatment options have similar oncologic outcomes [9] , and watchful waiting is a viable approach. In a population-based database with long-term follow-up, we used propensity weighting to account for differences among treatment groups. Men treated with RP, RP+EBRT, or BT+EBRT were at the highest risk of UAEs. Information on differences in the time course of UAE development and the specific UAE by prostate cancer treatment type, along with the non-negligible rate of UAEs in the control population, is valuable for counseling patients about treatment.

Author contributions:Stephanie L. Jarosek 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:Elliott, Virnig, Chu.

Acquisition of data:Elliott, Virnig, Jarosek.

Analysis and interpretation of data:Elliott, Virnig, Chu, Jarosek.

Drafting of the manuscript:Elliott, Jarosek.

Critical revision of the manuscript for important intellectual content:Elliott, Virnig, Chu.

Statistical analysis:Chu, Virnig.

Obtaining funding:Elliott, Virnig, Chu.

Administrative, technical, or material support:Jarosek.

Supervision:Elliott, Virnig.

Other(specify):None.

Financial disclosures:Stephanie L. Jarosek 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: None.

Funding/Support and role of the sponsor:This study was supported by the American Cancer Society. The sponsor was involved in the design and conduct of the study.

Acknowledgment statement:This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the Applied Research Program, NCI; the Office of Research, Development, and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database. This study was funded by the American Cancer Society.

Appendix A. Supplementary data

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Footnotes

a Department of Urology, Medical School, University of Minnesota, Minneapolis, USA

b Division of Health Policy and Management, School of Public Health, University of Minnesota, Minneapolis, USA

c Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, USA

lowast Corresponding author. Department of Urology, University of Minnesota Medical School, MMC 394 Mayo, 420 Delaware Street SE, Minneapolis, MN 55455, USA. Tel. +612-626-0601.

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