Patient-reported lower urinary tract symptoms, urinary incontinence, and quality of life after external beam radiotherapy for localized prostate cancer – 15 years’ follow-up. A comparison with age-matched controls

Abstract

Background. To prospectively examine the urinary toxicity and quality of life (QOL) in patients 15 years after external beam radiotherapy (EBRT) for localized prostate cancer (LPC) and compare the outcomes with results for age-matched controls. Material and methods. Urinary symptoms were assessed using the symptom-specific Prostate Cancer Symptom Scale (PCSS) questionnaire, and QOL was assessed with the European Organization for Research and Treatment of Cancer (EORTC)'s Quality of Life Questionnaire (QLQ-C30). Both questionnaires were sent to the surviving 41 patients (25%) and the PCSS questionnaire was sent to 69 age-matched controls for comparison. Results. The response rate was 71% in the patient group and 59% in the control group. Two patients and four controls were excluded due to other cancer diagnoses, resulting in a total of 27 patients and 37 controls for inclusion in the analyses. The mean age in both groups was 78 years. In the patient group, incontinence had increased between the 8-year (mean=0.6) and the 15-year follow-up (mean=2.1; p=0.038). No other differences in urinary problems were seen between these two follow-ups. Increased incontinence, stress incontinence, and pain while urinating were reported by the patients in comparison with the controls at 15 years. Role function was worse in the patient group (mean=67.3) compared with the controls (mean=82.4; p=0.046). The patients also reported more appetite loss, diarrhea, nausea/vomiting, and pain than the controls. Conclusion. EBRT for LPC has divergent effects on urinary symptoms and QOL in comparison with age-matched controls. In our patient population, urinary incontinence increased between 8 and 15 years of follow-up. Otherwise, no differences in urinary symptoms were seen between 4 and 15 years. Incontinence, stress incontinence, and pain while urinating were increased after EBRT in comparison with the controls. Conventional EBRT did not result in a major deterioration in QOL 15 years after treatment.

External beam radiotherapy (EBRT) is a common therapeutic option for localized prostate cancer (LPC), with high local control related to the delivered dose [1–4]. The treatment has undergone considerable technique development during the last decade, from conventional four-field box technique [5] to three-dimensional conformal technique with risk of rectal and bladder complications [6]. The recently developed intensity modulated radiotherapy (IMRT) technique has shown low rates of complications despite delivery of higher doses [7].

Previously, we reported on patient-reported toxicity, 4 and 8 years after EBRT in LPC patients treated with conventional four-field box EBRT technique, C:\GetARef\Refs\15 r bowel.ref #3;and an age-matched control population [8]. The present study presents a prospective evaluation of incontinence and lower urinary tract symptoms (LUTS) 15 years after primary EBRT in the same patients and also, a comparison with the followed control population.

To the best of our knowledge there is no other longitudinal study comparing treatment-related incontinence and LUTS with age-matched controls. The aim of the present study is therefore to address this important issue of very long evaluation of side effects after EBRT and also, to compare the toxicity with that in a normal population of prostate cancer (PC)-free men.

Materials and methods

Patient and control populations

Between 1986 and mid-1989, 284 LPC patients received EBRT to the pelvis with a curative intention at the Department of Oncology Radiotherapy Unit, Umeå, Sweden. From the primary group of 284 patients, we excluded 89 patients who, according to The Swedish Population Register, were dead at the date of administration of the first questionnaire (1991), patients with distant metastases, and patients who had received a total dose of <60 Gy (Table I). The first self-assessed questionnaire (4-year follow-up) was sent out in April 1991 (patient group) and November 1991 (controls), giving a mean follow-up time from the start of radiotherapy of 4 years (range 24–56 months) [5].

Table I.  Data collection from prostate cancer (PC) patients and controls at the 15-year follow-up.

	Patients	Controls
	n	n
4-year follow-up study^a	181	141
8-year follow-up study^b	88^d	98^e
15-year follow-up study
Dead after 8-year follow-up according to The Swedish population register (1 December 2002)	47	29
Questionnaires sent out	41	69
Questionnaires completed	29 (71%)	41 (59%)
Excluded from the analyze^c	2	4
Total	27	37

^aWidmark et al. Cancer, 1994; 74:2520–32.

^bFransson P et al.Cancer, 1999; 85:678–88.

^cTwo patients were excluded because of a former diagnose of bladder cancer. Four controls were excluded because diagnosed prostate cancer at the time for followup.

^dFive patients who were excluded from the 8-year followup due to castration are included in the present study.

^eThree controls who did not respond to the 8-year followup but respond to the present followup are included in the analyze.

The second questionnaire was sent out in May 1995 to the same patient group, giving a mean follow-up of 8 years from the start of radiotherapy (range 6–9 years). The questionnaire was sent to the control group at the same time [8].

The present study is a 15-year prospective follow-up of the same patient and control groups. The present questionnaires were sent out in December 2002, giving a mean follow-up of 15 years from the start of radiotherapy (Table II). The patient group was compared with the same age-matched control group as included in both the 4-year and the 8-year follow-ups, of men from the same region as the population of treated PC patients (Table I) [5], [8].

Table II.  Characteristics of the patients and controls.

	Patients	Controls
	n = 27	n = 37	p
Mean follow-up time (months)^a	176.8
Range	162.5–196.9
Age at time for 15-years follow-up (years)
Mean	78.1	77.3	0.376
Range	62–87	64–89
Tumor dose (Gy)
Mean	64.8
Range	62.0–67.8
T-classification^b
T1b	3
T2	21
T3	3

^aMean follow-up time since finished radiotherapy.

^bTumor classification at diagnosis according to UICC 1992.

Treatment technique

Computer tomography (CT)-planned EBRT, using conventional four-field box technique, was given 5 days a week, at 2 Gy per fraction, and with an average total dose of 64.8 Gy. The total dose of treatment was based on a CRE value of 18.5 (mean 18.3; range 18–19). The treatment was extended cranially to the sacral promontory, caudally to the ischial tuberosity, laterally to the medial walls of the pelvis, ventrally to the symphysis pubis, and dorsally to the sacrum including the whole rectum, resulting in an anterior–posterior field size of approximately 12×16 cm and a lateral field size of approximately 10×16 cm. Two treatment techniques were used: a shrinkage field technique (type A), and a technique in which a large treatment volume was given up to full dose (type B).

Type A was used for treatment of localized PC (mostly T0–T2), and involved a large treatment region receiving 50 Gy initially, and thereafter a reduction including the prostate only, with a 2 cm margin. The shrinkage field size was 9×9×9 cm (anterior–posterior–lateral).

Type B was used for treatment of locally advanced PC (mostly positive lymph nodes and/or T3 and T4 tumors, and all Grade 3), and consisted of a large treatment volume up to a full dose.

One patient had undergone a prostatectomy 3 months before EBRT, but was given type A treatment with a total dose of 65.3 Gy.

Instrument for evaluation of urinary symptoms

Urinary incontinence and LUTS were evaluated with the validated Prostate Cancer Symptom Scale (PCSS) self-assessment questionnaire [9].

The PCSS questionnaire uses a modified linear analog scale, with response boxes containing numerical values between 0 and 10, where 0 = “no problem/very good function” and 10 = “many problems/very bad function”. The patients were asked to evaluate their symptoms during the previous week. Additional questions request a written answer; these are not reported in the present study.

Instrument for evaluation of quality of life

The European Organization for Research and Treatment of Cancer (EORTC)-developed Quality of Life Questionnaire QLQ-C30, version 2, was used to assess quality of life (QOL) [10]. The questionnaire contains five functional scales: physical, role, emotional, cognitive, and social functioning. It also includes a global health status/QOL scale. Higher mean scores on these scales mean better functioning and better QOL. Three symptom scales were also included concerning nausea and vomiting, pain, and fatigue. Six single symptom items measured the levels of constipation, diarrhea, loss of appetite, sleep disturbance, dyspnea, and financial impact. Higher mean scores on the symptom and single items indicate more symptoms/problems.

Statistical methods

Mean values were calculated for all items. The non-parametric Mann-Whitney test was used to evaluate changes over time and differences between the patient and control groups. All patients included in the present follow-up answered the questionnaires at 4, 8, and 15 years. Three of the controls did not answer the 8-year follow-up questionnaire, but completed the 15-year follow-up questionnaire; these three controls were, however, included in the analyses in the present study. All hypothesis testing was two-sided, with a p-value <0.05 considered to be significant.

All analyses were performed using SPSS statistical software, version 14.0 (SPSS, Inc., Chicago, IL).

The study was approved by the Ethics Committee of the Faculty of Medicine at Umeå University, Sweden.

Results

Patients and controls

Forty-seven of 88 patients (53%), and 29 of 98 controls (30%) died between the 8-year and the 15-year follow-up (Table I). The response rate was 71% (n = 29 of 41 patients) in the patient group and 59% (n = 41 of 69 controls) in the age-matched control group (Table I).

Three of the patients had been diagnosed with another cancer before the diagnosis of PC, one with rectal cancer (diagnosed 2 years before the PC diagnosis) and two with bladder cancer (diagnosed 30 years and 2 years, respectively, before the PC diagnosis). The two patients with a prior diagnosis of bladder cancer have been excluded from the present study, resulting in a total patient number of 27 for the analyses (Table I).

Four men in the control group were diagnosed with PC between the 8- and the 15-year follow-up. These four controls were therefore excluded from the analyses, resulting in a total number of 37 controls for the analyses (Table I). Patient characteristics are given in Table II.

Urinary bother

No increase in urinary bother was measured over time from 4 to 15 years after completed EBRT (Table III). In comparison with the controls, no difference was detected at any time point (Table III).

Table III.  Urinary symptoms at 4, 8, and 15 years’ follow-up. A higher score indicates a severe symptom/problem. The scale ranges from 0 to 10.

		Followup time
		4-yr		8-yr		15-yr
Symptom/problem	Group	mean	SD	mean	SD	mean	SD
Urinary bother	Patients (n = 27)	2.4	2.9	1.9	2.4	2.9	3.1
	Controls (n = 37)	1.3	2.2	1.6	2.2	2.3	2.7
Limitation in daily activity	Patients (n = 27)	1.0	1.6	1.6	2.6	2.1	2.5
caused by urinary symptoms	Controls (n = 37)	0.4^a	0.7	0.3^ab	1.0	0.9^a	1.8
Incontinence	Patients (n = 27)	0.9	1.6	0.6	1.3	2.1^c	2.8
	Controls (n = 37)	0.3	0.5	0.3	0.6	0.5^a	1.5
Stress incontinence	Patients (n = 27)	^f		^f		1.8	2.5
	Controls (n = 37)	^f		^f		0.4^a	1.3
Urge incontinence	Patients (n = 27)	^f		^f		2.1	2.8
	Controls (n = 37)	^f		^f		1.1	2.1
Starting problems	Patients (n = 27)	1.9	2.4	0.8^b	1.1	1.5	1.9
	Controls (n = 37)	0.8^a	1.3	1.1	1.8	1.2	2.0
Urgency	Patients (n = 27)	2.1	2.9	1.6	2.0	1.6	2.4
	Controls (n = 37)	0.8^a	1.3	0.5^a	1.2	1.6	2.8
Urinary frequency (daily)	Patients (n = 27)	^e		5.5	1.9	5.4	2.4
	Controls (n = 37)	^e		4.9	1.4	5.6	2.1
Nocturia (frequency)	Patients (n = 27)	^e		1.3	1.0	1.7	1.2
	Controls (n = 37)	^e		1.1	1.0	1.8	1.8
Pain while urinating	Patients (n = 27)	^e		0.8	1.6	1.1	2.2
	Controls (n = 37)	^e		0.9^a	0.4	0.1^a	0.6
Emptying bladder	Patients (n = 27)	^f		^f		2.0	2.7
	Controls (n = 37)	^f		^f		1.8	2.5
Weak stream	Patients (n = 27)	^f		^f		3.0	2.6
	Controls (n = 37)	^f		^f		2.6	2.4

^ap < 0.05 when comparing patients with controls.

^bp < 0.05 when comparing 4-year with 8-year follow-up.

^cp < 0.05 when comparing 8-year with 15-year follow-up.

^dp < 0.05 when comparing 4-year with 15-year follow-up.

^eThis question was not included in the 4-year follow-up questionnaire.

^fThis question was not included in the 4-year or in the 8-year follow-up questionnaire. Data presented as mean±SD (standard deviation).

Neither did the “limitation in daily activities caused by urinary symptoms” differ between the 4-, 8-, and 15-year follow-ups in the patient group (Table III). However, increased limitation in daily activities was reported by the patients (mean = 2.1) in comparison with the controls at 15 years (mean = 0.9; p = 0.013; Table III) as well as at the 4-year and 8-year follow-ups (Table III).

Overall, none of the patients and 20% of the controls were “very content”, 29% and 32%, respectively, were “content”, 29% and 14% felt “satisfied”, while 25% vs. 17% had “mixed feelings”, 8% vs. 14% were “displeased”, and 8% and 0% felt “unhappy” about living the rest of their lives with their present bladder problems (n.s.).

Urinary incontinence

Urinary incontinence, defined as any involuntary loss during the previous week, included incontinence, stress incontinence, and urge incontinence. Incontinence had increased between the 8-year (mean = 0.6) and 15-year follow-up (mean = 2.1; p = 0.038; Table III). However, no increase was measured between 4 years and 8 years (p = 0.189; Table III). The patients reported more incontinence than the age-matched controls (p = 0.001; Table III).

Stress incontinence was only evaluated at 15 years. The patients had increased stress incontinence in comparison with the controls (Table III).

Urge incontinence was only evaluated at the 15-year follow-up. The patients had increased urge incontinence in comparison with the controls (Table III).

Three of the patients (11%) and one control (3%) reported urinary incontinence when “coughing, sneezing, or laughing”, four (15%) and three (8%) when “doing heavy lifting”, one (4%) and two (5%) when “standing from a sitting position”, three (11%) and none (0%) “without exertion (i.e., always)”, and four (15%) and three (8%) for “another reason” (n.s.).

Use of pads at 15 years’ follow-up was reported by seven patients (26%) and one of the controls (3%; p = 0.005). The mean number of pads/day was 3.8 in the patient group. The control who reported use of pads did not report the number of pads/day. There was no increase in use of pads over time (4 vs. 8 vs. 15 years).

Lower urinary tract symptoms

Weak urinary stream was the most frequently reported symptom in both the patient group and the controls (Table III). On the 10-point scale, the mean score for patients was 3.0 as compared with 2.6 in the control group (n.s.; Table III). This question was not included in the 4-year or the 8-year follow-ups. No difference in daily voiding was measured between the patients and controls at the 15-year follow-up and there was no difference between the 8-year and the 15-year follow-up (Table III).

The incidence of nocturia did not differ between the two groups at 15 years and was not increased over time (Table III). The only symptom that differed between the two groups was pain while urinating, where the patient group scored higher (mean = 1.1) than the controls (mean = 0.1; p = 0.012; Table III).

Comparison between treatment type A and B

The treatment type (A or B) did not have any impact on incontinence or LUTS.

Hormonal treatment

Fourteen of the 27 patients (52%) had received hormonal treatment by the time the 15-year follow-up took place. Eight of them had undergone surgical castration. There were no differences in incontinence or LUTS at 15 years after treatment between those who had and those who had not received hormonal treatment (Table IV). However, those with hormonal treatment (mean = 4.4) reported more urinary bother than those with no hormonal treatment (mean = 1.3; p = 0.023; Table IV).

Table IV.  Incontinence and lower urinary tract symptoms (LUTS) at the 15-year follow-up, stratified into hormonal or non-hormonal treatment, and treatment type. A higher score indicates a severe symptom/problem. The scale ranges from 0 to 10.

	Hormonal treatment^a
	“No”		“Yes”
	n = 14		n = 13
	mean	SD	mean	SD	p
PCSS urinary symptoms/problems^b
Urinary bother	1.3	1.7	4.4	3.5	0.023
Incontinence	1.9	2.7	2.4	3.0	0.583
Stress incontinence	2.0	2.8	1.4	2.2	0.615
Urge incontinence	2.5	3.0	1.6	2.6	0.464
Starting problems	1.2	2.0	1.7	1.9	0.352
Urgency	2.1	3.0	1.1	1.5	0.657
Pain while urinating	1.1	1.6	1.2	2.7	0.628
Emptying bladder	1.1	1.6	3.0	3.2	0.136
Weak stream	2.5	2.6	3.5	2.7	0.362
EORTC QLQ-C30 function^c
cognitive function	82.0	18.6	82.0	15.0	0.815
emotional function	76.9	27.2	79.4	18.8	0.867
physical function	73.8	17.1	77.3	23.7	0.758
global QOL	60.2	27.2	74.2	16.0	0.189
role function	67.9	36.9	66.7	31.0	0.717
social function	79.5	32.0	81.8	21.7	0.751
EORTC QLQ-C30 symptoms^d
appetite loss	7.7	14.6	5.6	13.0	0.695
constipation	11.1	21.7	12.1	16.8	0.674
diarrohea	19.4	30.0	15.1	22.9	0.803
dyspnea	15.4	29.2	24.2	15.6	0.088
fatigue	26.5	27.0	31.9	19.3	0.451
financial difficulties	10.2	28.5	5.6	19.2	0.596
nausea/womiting	6.4	14.5	2.8	6.5	0.639
pain	34.6	34.3	30.6	31.6	0.911
insomnia	25.0	35.2	30.5	36.1	0.680

^a Hormonal treatment. Fourteen of the 27 patients (52%) have received hormonal treatment, eight by surgical castration, at the time for the 15-years follow-up.Data presented as mean ±SD (standard deviation).

^bA higher score indicate severe symptom/problem. The scale ranges from “0” to “10”.

^cOn function and global quality of life scales, higher scores indicate better function or better QOL.

^dOn symptom scales higher scores indicate more severe symptoms.

Age

There was no difference in age between patients (mean = 78.1 years) and controls (mean = 77.3 years; p = 0.376; Table II) at the 15-year follow-up. The median age was 71.0 years. A stratification into two age groups, ≤71 years and >71 years, was performed to analyze the impact of age on incontinence or LUTS. Age had no significant impact on the reported incontinence or LUTS at the time of the 15-year follow-up in either the patient or the control groups.

Diabetes

Four of the patients (15%) and nine of the controls (24%) reported diabetes at the 15-year follow-up. The analysis of the individual LUTS problems showed a difference in weak stream between those four with diabetes (mean = 6.7) and the 23 without (mean = 2.4; p = 0.012) in the patient group (data not shown).

Quality of life

The role function scale was the only function scale that differed between the two groups at 15 years (Table V). Cognitive function was scored highest among the patients (mean = 82.0) while emotional (mean = 88.4) and social function (mean = 88.4) had the highest score among the controls (Table V).

Table V.  Results of EORTC QLQ-C30 questionnaire at the 15-year follow-up. On function and global quality of life (QOL) scales, higher scores indicate better function or better QOL. On the symptom scales, higher scores indicate more severe symptoms.

	Patients		Controls
	n = 27		n = 37
	mean	SD	mean	SD	p
EORTC QLQ-C30 function
cognitive function	82.0	16.6	82.3	15.0	0.966
emotional function	78.1	23.1	88.4	15.3	0.078
physical function	75.4	20.0	80.4	24.4	0.236
global QOL	66.7	23.4	71.3	25.1	0.437
role function	67.3	33.5	82.4	26.6	0.046
social function	80.6	27.2	88.4	19.3	0.315
EORTC QLQ-C30 symptoms
appetite loss	6.7	13.6	1.0	5.7	0.034
constipation	11.6	19.1	10.1	22.8	0.494
diarrohea	17.4	26.3	4.2	11.2	0.019
dyspnea	19.4	23.9	21.9	27.9	0.898
fatigue	29.1	23.3	22.9	20.1	0.333
financial difficulties	8.0	24.1	7.1	13.8	0.458
nausea/womiting	4.7	11.3	0.5	2.9	0.033
pain	32.7	32.4	12.7	25.0	0.004
insomnia	27.8	35.0	21.6	31.7	0.537

p, Mann-Whitney test.

Data presented as mean±SD (standard deviation).

On the single symptom scales, pain was scored as the most frequent symptom (mean = 32.7) among the patients in comparison with the controls (mean = 12.7; p = 0.004; Table V).

Six of the 27 patients (22%) compared with two controls (5%; p = 0.004) reported “quite a bit of/much” pain. However, in two of these six patients, the disease was progressing. Differences in symptoms were also measured in loss of appetite, diarrhea, and nausea and vomiting (Table V).

Hormonal treatment

Fourteen of the 27 patients (52%) had received hormonal treatment by the time the 15-year follow-up took place. Eight of them had undergone surgical castration. There were no differences in QOL functions or single symptoms scale at 15 years after treatment between those who had and those who had not received hormonal treatment (Table IV).

Age

Stratification into two age groups (≤71 years and >71 years) showed no significant difference between the groups in reported QOL at the time of the 15-year follow-up in the patient group. However, there was a clear difference in diarrhea between the ≤71-year (mean = 58.3) and the >71-year patient group (mean 8.7; p = 0.002) (data not shown).

In the control group, differences were seen in physical function, where those ≤71 years of age showed better physical function (mean = 100.0) in comparison with >71-year-olds (mean = 76.2; p = 0.013). The younger controls also reported more nausea/vomiting (mean 2.8) than the >71-year-old controls (mean = 0.0; p = 0.031), while older controls (>71 years) reported more dyspnea (mean = 26.4) than the younger controls (mean = 0.0; p = 0.020).

Diabetes

The analysis of the individual QOL functions and single symptom scales on the QLQ-C30 formula showed a difference in decreased cognitive function between those four with diabetes (mean = 62.5) and the 23 without (mean = 85.0; p = 0.015) in the patient group (data not shown). No differences were seen among the controls.

Missing case analysis

In order to verify the results, we compared the characteristics of the analyzed patients (n = 27) and controls (n = 37) with those of the non-respondents (n = 46) or those who were dead at the 15-year follow-up (n = 76; Table VI). Mean age differed between the analyzed groups, the non-respondents, and the dead in the control group (69 years, 74 years, and 82 years, respectively; p = 0.002). When comparing the 8-year profile of incontinence and LUTS of the analyzed patients and controls with that of the non-respondents or dead at the 15-year follow-up, no difference could be measured (Table VI).

Table VI.  Urinary symptoms and quality of life (QOL) at 8 years, stratified by respondents, non-respondents, and dead at the 15-year follow-up.

	Patients							Controls
	Analyzed		Non-respondents		Dead			Analyzed		Non-respondents		Dead
	n = 27		n = 14		n = 47			n = 37		n = 32		n = 29
	mean	SD	mean	SD	mean	SD	p	mean	SD	mean	SD	mean	SD	p
PCSS urinary symptoms/problems^a
Urinary bother	1.6	1.9	1.7	1.8	2.8	3.0	0.345	1.5	2.2	0.7	1.4	1.1	1.6	0.368
Incontinence	0.6	1.3	1.1	1.5	2.3	3.3	0.052	0.3	0.6	0.9	1.7	0.5	0.9	0.555
Starting problems	0.8	1.2	2.0	1.8	1.4	2.2	0.085	1.1	1.8	0.6	1.3	1.0	2.2	0.474
Urgency	1.3	1.8	1.8	2.9	1.9	2.2	0.682	0.5	1.1	0.5	1.0	1.2	1.9	0.120
Pain while urinating	0.9	1.7	0.9	1.1	0.6	1.5	0.263	0.1	0.4	0.1	0.4	0.0	0.0	0.412
EORTC QLQ-C30 function^b
cognitive function	86.3	10.6	83.3	12.3	79.5	21.2	0.613	85.9	13.9	86.8	18.6	83.3	22.6	0.764
emotional function	86.3	17.9	80.3	15.1	77.0	24.7	0.332	88.7	14.0	90.5	13.2	86.2	20.5	0.844
physical function	85.5	26.3	82.1	20.1	66.2	28.8	0.012	88.8	21.5	94.7	12.0	76.3	23.1	0.001
global QOL	70.6	27.5	77.1	18.8	55.9	24.4	0.009	76.0	27.3	80.7	24.5	67.7	24.1	0.089
role function	81.4	24.9	86.1	21.1	63.3	35.3	0.061	87.2	21.8	94.3	17.4	68.1	38.0	0.007
social function	82.4	29.7	87.9	18.4	73.3	31.5	0.242	89.3	17.3	90.8	17.6	79.9	31.5	0.427
EORTC QLQ-C30 symptoms^c
appetite loss	6.7	13.7	11.9	28.1	13.8	29.8	0.929	2.1	8.2	0.0	0.0	6.2	16.1	0.083
constipation	9.5	23.9	6.1	13.5	15.4	26.3	0.456	3.1	9.9	7.5	22.5	1.5	7.1	0.528
diarrohea	16.7	25.4	25.6	24.2	18.8	28.4	0.391	1.0	5.9	5.4	15.1	4.9	15.2	0.348
dyspnea	18.3	27.5	17.9	17.3	34.1	30.4	0.052	21.9	30.1	8.9	15.0	24.7	27.1	0.050
fatigue	19.0	22.8	27.0	22.5	37.6	26.4	0.017	17.4	17.2	8.4	10.1	28.0	25.9	0.008
financial difficulties	8.3	25.8	0.0	0.0	7.1	18.8	0.328	1.3	6.7	0.0	0.0	6.9	19.6	0.120
nausea/womiting	4.8	7.7	8.3	15.7	5.3	13.1	0.699	3.6	13.2	0.5	3.0	2.5	6.0	0.317
pain	13.5	22.1	15.4	19.8	28.2	26.2	0.034	22.9	28.6	5.4	11.7	21.6	29.9	0.017
insomnia	18.3	33.3	12.1	22.5	29.2	29.4	0.068	13.0	25.7	6.9	20.7	19.0	30.9	0.229

^aA higher score indicate severe symptom/problem. The scale ranges from “0” to “10”.

^bOn function and global quality of life scales, higher scores indicate better function or better QOL.

^cOn symptom scales higher scores indicate more severe symptoms.

Data presented as mean±SD (standard deviation).

Physical function and global QOL were decreased in the non-respondents and the dead compared with the analyzed patients (Table VI). In the control group physical and role function were decreased in the non-respondents and the dead in comparison with the analyzed controls (Table VI). Those patients and controls who were dead at the 15-year follow-up reported lower/worse physical function at 8-years follow-up compared with the analyzed patients and controls (Table VI).

Fatigue and pain were increased in both the non-respondent and dead patients compared with the analyzed patients (Table VI). Same findings were found when comparing analyzed, non-respondents, and dead controls (Table VI).

Discussion

The EBRT technique has undergone huge developments during the last decade, especially with an emerging focus on side effects and QOL [11]. Despite this fact, no previous longitudinal study of this type, with this very long follow-up time of 15 years, and including patient-reported treatment-related morbidity and a comparison with age-matched controls, has to our knowledge been published.

It is of major interest to evaluate the patients’ own perception of symptoms, especially when previous studies on morbidity with physician ratings have been shown to underestimate the toxicity [12].

The present study shows that incontinence and LUTS remained relatively stable in our patient population between 4 and 15 years after conventional four-field box EBRT. However, higher incontinence, stress incontinence, and pain while urinating were reported by patients compared with the controls.

The incontinence rate after radiotherapy is generally low. Elsewhere, incontinence rates of 0.6–0.9% in large patient series have been reported [13], [14]. Depending on the definition of incontinence and the method for evaluation of the incontinence, rates will differ. Jonler et al. [15] report that 13% of their patients leaked more than a few drops daily and Vanuytsel et al. [16] reported a 10% incontinence rate. In our population, 58% of the patients scored 0 (on the 10-graded scale), meaning no incontinence. This is a liberal definition of incontinence, but Talcott et al. [17] observed that 40% of interstitial brachytherapy patients reported some degree of urinary leakage.

In our study, 26% of patients used some form of pads on a daily basis. This is higher than previously reported rates of 11% by Jonler et al. [15] and 7% in the medicare population [18], but in agreement with the 20% recently reported by Ponholzer et al. [19].

Adolfsson et al. [20] report a relative risk for urinary leakage of 2.3 in patients after EBRT in comparison with age-matched controls. A comparison with our data may not be realistic, since we had different methods, including scales, for evaluating incontinence, but 81% of the controls in our study scored 0 on the 10-point scale, meaning no incontinence, in comparison with 58% of the patients.

Lower urinary tract symptoms were in fact not more frequently reported by the patients than by the controls. Nocturia, urgency, problems starting to urinate, and weak stream were almost identical within the patient and the control group at 15 years. Ponholzer et al. [19] report identical nocturia, defined as more than one void per night (48%), as we report for our EBRT patients (48%). In our study, the proportion of controls with nocturia was 46% (n.s.). In contrast to our findings, Schatzl et al. report that nocturia was almost doubled in PC patients after EBRT, as compared with untreated, healthy men [21].

We found that disease-specific QOL remains relatively stable during extended follow-up. Only role function was lower in the patients compared with the controls. However, specific symptoms (e.g., appetite loss, diarrhea, nausea/vomiting, and pain) were worse in the patients than in the controls. It has been reported in other studies that no difference in QOL was observed when comparing patients treated with EBRT [22] or radical prostectomy [23], with patients treated with watchful waiting.

In spite of the general findings in this study, several limitations need to be taken into consideration. This has become a study with a small number of patients (n = 27). Only 15% of 181 patients at first evaluation (4-year follow-up) are analyzed. The fact is that 99 of the 181 patients (55%) died between the 4-year and subsequent follow-ups (at 8 and 15 years) and were therefore not available for analysis. Thirty-two controls (23%) died during the same period.

The response rate was relatively low in both groups (71% and 59%), probably because of the advanced age of the subjects. In both groups, the respondents were 4–5 years younger than the non-respondents. However, when calculating the impact of age on incontinence or LUTS, we found no correlations.

There were some differences between the respondents and the non-respondents when evaluating the reported symptoms at 8 years. The decreased physical function, global QOL, and increased fatigue and pain may have had an impact on the patients’ ability to complete the filling in of the questionnaires and may therefore have given a lower response rate. It is easy to believe that the healthiest group of patients completed the evaluation.

Since we did not register any information from the controls other than that provided by the questions included in the questionnaire, this may also have been the case in the control group. No difference was measured regarding urinary incontinence, LUTS in the control group when comparing respondents with non-respondents. However, as in the patient group, decreased physical function and increased fatigue and pain were reported by the non-respondents.

Another important consideration is the given treatment technique and dose. All patients were treated with conventional four-field box technique, with a total dose of only 65 Gy, which is fairly uncommon today. However, due to the lack of studies on very long-term patient-reported side effects, the information we have gained is still valuable and important.

This report provides information from patients treated at a single institution in the northern part of Sweden. Regional, individual, and technical differences may have had an impact on the results; however, the control population was recruited from the same regional area. A longitudinal, multicenter trial would be the optimal study design with baseline (i.e., pretreatment) information to investigate treatment-related morbidity and QOL.

In summary, this study presents the first data from a 15-year-long follow-up of patient-reported outcome of urinary symptoms and QOL after EBRT and provides a comparison with age-matched controls.

Conclusion

In conclusion, patients treated with EBRT for LPC had divergent effects on urinary symptoms and QOL in comparison with age-matched controls. Urinary incontinence increased between the 8-year and the 15-year follow-up, but otherwise no urinary symptoms differed over time between 4 and 15 years. Incontinence, stress incontinence, and pain while urinating were higher in patients after EBRT than in the controls. Conventional EBRT did not result in a major deterioration in QOL 15 years after treatment.

Acknowledgements

This investigation was supported by grants from the Swedish Cancer Society and the Research Foundation of the Department of Oncology, University of Umeå.