Urinary incontinence in prostate cancer patients treated with external beam radiotherapy

Radiotherapy and Oncology 74 (2005) 197–201 www.elsevier.com/locate/radonline

Urinary incontinence in prostate cancer patients treated with external beam radiotherapy Mitchell Liua,*, Tom Picklesb, Eric Bertheletc, Alexander Agranovicha, Winkle Kwana, Scott Tyldesleyb, Michael McKenzieb, Mira Keyesb, James Morrisb, Howard Paic, The Prostate Cohort Initiative a

Fraser Valley Centre, British Columbia Cancer Agency, 13750 96th Avenue, Surrey, BC, Canada V3V 1Z2 b Vancouver Centre, British Columbia Cancer Agency, Vancouver, BC, Canada c Vancouver Island Centre, British Columbia Cancer Agency, Vancouver, BC, Canada Received 4 February 2004; received in revised form 23 July 2004; accepted 28 September 2004 Available online 22 October 2004

Abstract Background and purpose: To describe the incidence of urinary incontinence among prostate cancer patients treated with external beam radiotherapy (RT) and to investigate associated risk factors. Patients and methods: One thousand and hundred ninety-two patients with R24 months follow-up were the subjects of this series. All patients received between 50 and 72 Gy in 20–37 fractions (median 66 Gy/33#). Post-RT urinary incontinence was scored by direct patient interviewing according to the modified RTOG/SOMA scale: Grade 1—occasional use of incontinence pads, Grade 2—intermittent use of incontinence pads, Grade 3—persistent use of incontinence pads, and Grade 4—permanent catheter. Risk-factors investigated were: age, diabetes, TURP prior to RT, elapsed time from TURP to RT, clinical stage, RT dose and presence of Grade R2 acute GU and GI toxicity. Non-parametric, actuarial univariate (Kaplan–Meier) and multivariate tests (MVA, Cox regression) were performed. Results: Median follow-up for the group is 52 months (24–109). Thirty-four patients (2.9%) had incontinence prior to RT, which was more common in TURP patients (7.8% vs 1.6% P!0.001). These are excluded from further analysis. Fifty-seven patients (4.9%) developed Grade 1 incontinence, 7 (0.6%) Grade 2, and 7 (0.6%) Grade 3. There was no Grade 4 incontinence. Actuarial rates for Grade R1 and R2 incontinence at 5 years are 7 and 1.7%, respectively. Risk factors on MVA associated with the development of Grade 1 or worse incontinence are pre-RT TURP (5-year rates 10% vs 6%, PZ0.026), presence of Grade R2 acute GU toxicity (5-year rates 11% vs 5%, PZ0.002). Age, diabetes, clinical stage, elapsed time from TURP to RT, RT dose or fraction size, acute GI toxicity were not significant. Patients who underwent post-RT TURP or dilatation for obstructive symptoms (4.3%), were more likely to develop Grade 2–3 incontinence (5-year rate 8 vs 1.5%, PZ0.0015). Conclusions: Grade 2 or greater urinary incontinence is rare among patients who have been treated with external beam radiotherapy. Associated risk factors are pre-RT TURP and the presence of increased acute GU toxicity. Post-radiation TURP increases the risk of incontinence five-fold. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Prostate neoplasms; Radiotherapy; Toxicity; Urinary incontinence

1. Introduction The risk of urinary incontinence can be a major consideration in men who are candidates for radical

* Corresponding author. 0167-8140/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2004.09.016

treatment for prostate cancer. Marks [11] in the Late Effects Consensus Conference reviewed that the incontinence rate can range from 0 to 10% after radiotherapy, depending on the definition used. A scoring system (LENT/SOMA) [11] was developed to better characterize GU toxicities including incontinence. Lee [7] reported their results using the above scoring system and noted an actuarial rate of 1.3%

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Grade 2–3 incontinence at 5 years, and there was no Grade 4 incontinence. They concluded that urinary incontinence is a rare event following external beam radiotherapy. Although incontinence can be an uncommon occurrence after radiotherapy, it is worthwhile to identify patients at higher risk of developing this unpleasant complication. Risk factors previously identified are: patients with previous TURP (transurethral resection of prostate) [3,7,11,14,15], especially in those who experience acute Grade 2 or above urinary toxicity during radiotherapy [15]. Jonler [6] also noted patients with T3 disease had higher rates of incontinence. In this study, we will describe the incontinence rate of patients treated at British Columbia Cancer Agency and report the risk factors identified. We will also look at the impact of post-radiotherapy TURP on the development of incontinence.

2. Methods and materials 2.1. Patients Between June 1994 and March 2000, 1880 patients with histologically confirmed, M0, prostate cancer who were treated at the British Columbia Cancer Agency with radical external beam radiation had relevant data stored in a prospective database. This represented approximately half of all radically treated patients during these years. A minimum clinical follow-up of 24 months was required for inclusion in this study, for a total patient accrual of 1192. The past medical history elicited from the patients including incontinence prior to radiotherapy, previous TURP, elapsed time from TURP to radiotherapy and presence of diabetes. 2.2. Radiotherapy Patients were treated to a median isocentric dose of 66 Gy (range: 50–72 Gy) with a median of 33 fractions (range: 20–37). In general, a box technique was used to

encompass the prostate only (72%), prostate and seminal vesicles (13%) or pelvic fields (10%). All patients underwent CT-planning. In the early 1990’s, 21/2 dimensional planning in conjunction with conventional simulation was performed, with 3-dimensional planning used since 1998. All patients received custom shielding to minimize irradiation of normal structures. Typical margins from clinical target volume (CTV) to the planning target volume (PTV, as defined by the 95% isodose) were 10–15 mm, except posteriorly where it was 1 cm. All patients were followed 6 monthly for the first 3 years and thereafter annually. Late toxicity was scored using a modified RTOG/SOMA grading system (Table 1). Specifically, the post-radiotherapy urinary incontinence was scored by direct patient interviewing as follows: Grade 1—occasional use (less frequent than weekly) of incontinence pads; Grade 2—intermittent use (less frequent than daily) of incontinence pads; Grade 3—persistent use (daily) of incontinence pads; Grade 4—permanent catheter. Potential risk factors analyzed were: age, presence of diabetes, TURP prior to radiotherapy, elapsed time from TURP to radiotherapy, T-stage, radiation dose, fraction size, development of acute GU or GI (Grade R2) toxicity. Univariate statistical tests were performed, and those covariates of possible significance significant (P!0.1) were subject to actuarial multivariate tests (Cox regression analysis).

3. Results The patients’ characteristics are described in Table 2. The median age is 72 years. Sixty-eight percent of patients had T1-2 disease with a median PSA of 9.4 ng/ml. Ten percent patients were diabetic and 20.6% patients had TURP prior to radiotherapy, with median elapsed time from TURP to radiotherapy of 18.5 months. Thirty-four patients (2.9%) had incontinence prior to RT, which was more common in TURP patients (7.8 vs 1.6%

Table 1 Modified RTOG/SOMA grading system for late GU toxicity Grade

1

2

3

4

GU

Occasional (less frequent than weekly) use of incontinence pads Nocturia twice baseline. Microscopic hematuria. Light mucosal atrophy and minor telangiectasia

Intermittent (less frequent than daily) use of incontinence pads Moderate frequency. Nocturia more than twice baseline. Generalized telangiectasia. Intermittent macroscopic hematuria. Two or fewer coagulations. Regular non-narcotic or occasional narcotic for pain

Persistent (daily) use of incontinence pads Severe frequency and dysuria. Nocturia more frequent than once every hour. Minor surgical procedure (e.g. TURP, dilatation). Reduction in bladder capacity (150 cc). Frequent hematuria requiring at least one transfusion. More than two coagulations for hematuria. Hyperbaric oxygen for bleeding/ulceration. Regular narcotic for pain

Permanent catheterization, urinary diversion and/or cystectomy Severe hemorrhagic cystitis or ulceration with requirement for urinary diversion and/or cystectomy

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Table 2 Patients characteristics Characteristics Patients Age (median) Follow-up (median) Pre-intervention PSA (median) Gleason 2–6:7:8–10 T1-2:T3-4 Past medical history Prior TURP Elapsed time from TURP to RT (median) Diabetes Radiotherapy Dose (median) RT dose !60 Gy:60 to !70 Gy:R70 Gy Number of fractions (median) Fraction size: %2 Gy:O2 Gy Presence of acute GU toxicity (Grade R2) Presence of acute GI toxicity (Grade R2) Total number of patients

72 Years 52 Months 9.4 ng/ml

(range: 46–86 years) (range: 24–109 months) (range: 0.24–250)

62:26:12% 68:32% 246 Patients 18.5 Months

(20.6%) (Range: 2–326 months)

122 Patients

(10.2%)

66 Gy 8.9:88:2.6%

(Range: 50–72 Gy)

33

(Range: 20–37)

90.7:9.3% 306 Patients

(25.7%)

624 Patients

(52.4%)

1192

P!0.001). These are excluded from further analysis, leaving a total of 1158 patients. Fifty-seven patients (4.9%) developed Grade 1 incontinence, 7 (0.6%) Grade 2, and 7 (0.6%) Grade 3. There was no Grade 4 incontinence. Actuarial rates for Grade R1 and R2 incontinence at 5 years are 7 and 1.7%, respectively, (Fig. 1). Risk factors on multivariate analysis associated with the development of Grade 1 or worse incontinence are pre-RT TURP (5-year rates 10 vs 6%, PZ0.026) (Fig. 2) and presence of Grade R2 acute GU toxicity (5-year rates 11 vs 5%, PZ0.002) (Fig. 3). Age, diabetes, clinical stage,

Fig. 1. Kaplan–Meier curves for Grade R1 or and Grade R2 urinary incontinence.

Fig. 2. Incontinence rate (Grade 1 or above) with and without pre-RT TURP.

elapsed time from TURP to RT, RT dose or fraction size, acute GI toxicity were not significant (Table 3). Patients who underwent post-RT TURP or dilatation (4.3%) for obstructive symptoms, were more likely to develop Grade 2–3 incontinence (5-year rate 8 vs 1.5%, PZ0.0015) (Fig. 4).

4. Discussion Incontinence is unusual in most radiotherapy series. Perez [14] reported that five of the 738 patients developed urinary incontinence following radiation therapy. The group also commented that prior TURP increased the risk of incontinence, although supporting data was not given. Shipley [18] reported an incontinence rate of 0.9% among more than 2500 patients treated with radiotherapy,

Fig. 3. Incontinence rate (Grade 1 or above) with and without presence of Grade 2 or above acute GU toxicity.

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Table 3 Risk factors associated with Grade R1 urinary incontinence, on mulitvariate analysis Risk factors

P value

Relative risk

Age T stage Co-existing GU disease (non-TURP) Prior TURP Elapsed time from TURP to RT Diabetes EBRT dose Fraction size Acute GU toxicity (Grade 2 or above) Acute GI toxicity (Grade 2 or above)

ns ns ns

– – –

0.026 ns

1.8 [1.07–3.04] –

ns ns ns 0.002

– – – 1.58 [1.19–2.09]

ns

–

while a separate analysis of 300 patients treated at two large academic institutions and within the RTOG revealed that the incontinence rate was only 0.4%. Depending on the definition of incontinence, the reported incontinence rate will differ. Vanuytsel [19] reported a 10% incontinence rate, but they included patients with fairly minor and transient symptoms (e.g. stress incontinence). Jonler [6] reported 11% of men using some type of pad for incontinence and that 13% leaked more than a few drops of urine daily. Urinary leakage prior to radiation therapy, however, was not evaluated. In our review, we used the LENT/SOMA scoring system [11] in attempt to better characterize urinary incontinence. Out of the 1192 patients we have reviewed, only seven had Grade 2 and seven had Grade 3 incontinence. No patients had Grade 4 incontinence. The actuarial rate for Grade 2 or above incontinence is 1.7% at 5 years. Risk factors in relations to incontinence are: previous TURP and presence of Grade 2 or above acute GU toxicity. Age, diabetes, stage,

Fig. 4. Grade 2–3 incontinence rate with and without post-RT TURP/dilatation.

elapsed time from TURP to radiotherapy, dose and fraction size were not significant. Our result is consistent with the data published by Lee [7]. Using the same scoring system, they reported an actuarial rate of 1.3% at 5 years among 758 patients. There were only three Grade 2 and one Grade 3 incontinence noted. The only risk factor identified was previous TURP, with Grade 2–3 incontinence of 2% with prior TURP vs 0.2% without TURP. The findings that patients with previous TURP are at higher risk of developing incontinence were previously reported [3,7,11,14,15], although the absolute rate of developing clinically significant incontinence is still small. Two percent reported from Fox Chase Cancer Centre [7]; 5.4% reported by Green [3], and in our series, the crude rate is 2.85% (seven of 246 patients with prior TURP had Grade 2–3 incontinence). The likely mechanism is related to the relative devascularization of the urethra after TURP and the decreased capability of the mucosa to repair sublethal damage after radiotherapy [17]. Patients who had radiotherapy and need TURP or dilatation for severe obstructive symptoms are also at higher risk of developing incontinence. In this current series, the rate of Grade 2–3 incontinence was increased from 1.5 to 8% at 5 years. The mechanism is also probably due to impaired healing secondary to previous radiotherapy. Gibbons [2] reported their series of 209 patients who had radiotherapy for stage C prostate cancer. Only one of 17 patients had post-radiotherapy TURP developed incontinence. Holzman [4] reviewed 121 patients with recurrence post-radiotherapy, 44 underwent TURP for subsequent obstruction and 12 of the 44 developed ‘total incontinence’. . Patel [13], on the other hand, reported a small series of seven patients who had TURP post-radiotherapy, none of them had developed incontinence. Locally advanced (T3-4) prostate cancer may increase the risk of incontinence post-radiotherapy. Jonler [6] has noted that T3 disease had higher rates of incontinence, although in our series, the effect of stage was not apparent. It is likely that the locally advanced cancer will compromise the sphincter control, the patients are also at higher risk of developing obstructive symptoms and require TURP, which may further affect continence. The development of Grade 2 or worse acute toxicity has been found by others as well as us, to increase the risk of late GU toxicity [9,16]. Sandhu [15] reported the group of patients with prior TURP, 18% of those developed RGrade 1 incontinence when they had RGrade 2 acute GU radiation toxicity vs 7% when they had only Grade 1 acute GU toxicity or no toxicity. In our series, the incontinence rate (Grade 1 or above) was 11 vs 5%, with or without Grade R2 GU, but not GI, acute radiation toxicity. In our series, although we did not use patient questionnaires, patients’ responses to standard questions posed at routine follow-up visits were prospectively recorded. Although this would be expected to underestimate the true

M. Liu et al. / Radiotherapy and Oncology 74 (2005) 197–201

rate of incontinence, it nonetheless serves as a valid reference in comparison with other studies using similar assessment methods. Additionally the risk factors that we have identified would be expected to be the same with different data collection methodologies. Incontinence rates reported using patient questionnaires are usually higher, due partly to more stringent definitions of incontinence, and also differences in perception of the problem between patients and physicians. The range of reported leakage is between 32 and 38% and incontinence using pads or other protective device is between 3 and 15% [1,8,10]. McCammon [12] reported in surgical patients, 62% claimed to leak urine but only 33.7% used pads, whereas in the radiation group, 29% claimed to leak urine but only 8.7% used pads. In comparison, in patients followed with deferred treatment, an incontinence rate of 27% was reported [5].

5. Conclusion Grade 2 or greater urinary incontinence is rare among patients who have been treated with external beam radiotherapy. Associated risk factors are pre-RT TURP and the presence of increased acute GU toxicity. Post-radiation TURP increases the risk of incontinence five-fold. Patients at risk of developing incontinence should be advised, although the overall chance of having significant incontinence is still small.

Acknowledgements Prostate Cohort Outcome Initiative (unless otherwise listed as an author) are: Drs Graeme Duncan; David Kim; Ed Kostashuk; Milton Po; Jane Wilson; Charmaine KimSing; Melanie Reed. The Prostate Cohort Outcomes Initiative is partly supported by an unrestricted educational grant from Abbott Laboratories Ltd.

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