Although permanent prostate brachytherapy with or without

ORIGINAL ARTICLE Long-Term Rectal Function After Permanent Prostate Brachytherapy Gregory S. Merrick, MD,* Wayne M. Butler, PhD,* Kent E. Wallner, MD...
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ORIGINAL ARTICLE

Long-Term Rectal Function After Permanent Prostate Brachytherapy Gregory S. Merrick, MD,* Wayne M. Butler, PhD,* Kent E. Wallner, MD,† Robert W. Galbreath, PhD,*‡ Zachariah A. Allen, MS,* Sarah Gutman, BS,* and Jonathan Lief, PhD*

Purpose: To evaluate the effect of prostate brachytherapy with or without supplemental therapies on long-term rectal function by means of a patient-administered quality-of-life instrument. Materials and Methods: As part of an ongoing prospective evaluation, 164 of an initial 209 patients who remain alive were mailed the Rectal Function Assessment Score (R-FAS) with a prestamped return envelope. R-FAS range from 0 to 27 with lower scores being indicative of better bowel function. Of the 162 eligible patients, 161 (99.4%) returned the survey. Median follow-up was 9.0 years (range 8.2–11.2 years). Clinical, treatment, and dosimetric parameters evaluated for bowel function included patient age, diabetes, hypertension, tobacco consumption, clinical T stage, elapsed time since brachytherapy, ultrasound volume, planning target volume, androgen deprivation therapy, supplemental external beam radiation, isotope, rectal dose, prostate D100/D150/D200, and prostate D90. Results: For the entire cohort, the current R-FAS was 3.59, which represented a nonstatistical improvement from prior surveys in 1999 (4.29) and 2002 (3.92) (P ⫽ 0.134). Only 16 patients (9.9%) reported bowel function to be worse after brachytherapy. Of the clinical, treatment, and dosimetric parameters evaluated, only the number of preimplant bowel movements, tobacco use, and diabetes correlated with R-FAS. Despite lower rectal doses with 103Pd, isotope did not predict for bowel function. Consistent with prior surveys, patient perception of overall rectal quality of life was inversely related to supplemental external beam radiation (P ⫽ 0.027). Conclusion: Prostate brachytherapy adversely affects bowel function. However, in most patients the changes are minimal and slowly resolve with time. Overall rectal quality of life is inversely related to supplemental external beam radiation. Key Words: prostate, brachytherapy, rectal function, quality of life. (Cancer J 2007;13: 95–104)

From the *Schiffler Cancer Center, Wheeling Jesuit University, Wheeling, WV; †Puget Sound Healthcare Corporation, Group Health Cooperative, Seattle, WA; and ‡Ohio University Eastern, St. Clairsville, OH. Reprints: Gregory S. Merrick, MD, Schiffler Cancer Center, Wheeling Hospital, 1 Medical Park, Wheeling, WV 26003-6300. E-mail: [email protected]. Copyright © 2007 by Lippincott Williams & Wilkins ISSN: 1528-9117/07/1302-0095

The Cancer Journal • Volume 13, Number 2, March/April 2007

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lthough permanent prostate brachytherapy with or without supplemental therapies results in high rates of biochemical control and acceptable morbidity profiles, the availability of multiple competing modalities has resulted in a lack of consensus regarding the optimal management of clinically localized prostate cancer.1– 4 Because of a high probability of long-term survival in patients with early-stage prostate cancer, the late effects of therapeutic intervention are being increasingly scrutinized with health-related quality-of-life (HRQOL) issues assuming greater importance with physicians and patients.4,5 Unfortunately, physicians’ perceptions of patient’s symptoms do not fully correlate with the patient’s self-assessment of HRQOL, necessitating the use of patientadministered instruments.6 In addition, substantial differences exist between instruments regarding the ability to discern subtle changes in bodily function.6 Bowel function can be adversely affected by all definitive prostate cancer treatment approaches.7–12 However, even in men without prostate cancer, bowel function deteriorates with age.13 Litwin13 reported that one third of healthy men without a history of prostate cancer experienced rectal dysfunction including urgency, loose or liquid bowel movements or crampy abdominal pain. After brachytherapy, investigators have consistently reported a 4% to -12% incidence of mild self-limited proctitis with ⬍1% progression to ulceration and/or fistula formation.1,14 –16 Substantial rectal bleeding, fecal incontinence, and/or rectal fistulas have also been reported after external beam radiation therapy, radical prostatectomy, and cryotherapy.9 –12 In an effort to quantitate the late effects of prostate brachytherapy on rectal HRQOL we have prospectively evaluated a consecutive cohort of brachytherapy patients using the Rectal Function Assessment Score (R-FAS).7,8 Our initial 2 publications demonstrated minor bowel function changes with most patients denying deterioration in bowel function.7,8 In the current study, we update our brachytherapy-related bowel function series by evaluating the same consecutive cohort of previously reported patients.

MATERIALS AND METHODS Between April 1995 and February 1998, 219 consecutive patients underwent prostate brachytherapy using either 103 Pd or 125I for clinical T1c–T3a prostate cancer. In our 1999 study, 7 of the 219 patients had died with 209 (98.6%) of the

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remaining 212 patients completing the R-FAS instrument (Table 1).7 In a 2002 update, of the initial 212 respondents, 21 had died and an additional 2 patients were institutionalized with Alzheimer disease.8 Of the remaining 189 patients, 187 (98.4%) completed and returned the R-FAS instrument. In April 2006, 164 patients remained alive. These 164 patients were mailed a self-addressed R-FAS questionnaire with a prestamped envelope. Of the 164 patients, one had undergone an abdominoperitoneal resection for rectal cancer and another was institutionalized with Alzheimer disease. Of the remaining 162 patients able to complete the survey, 161 (99.4%) returned the questionnaire. The one patient who declined to complete the questionnaire remains biochemically free of disease without known urinary or bowel dysfunction. R-FAS consists of 9 questions (each scored on a 0 –3 scale with a range of 0 –27) with lower scores indicative of better bowel function plus an overall summary score. At the time of initial consultation, patients were clinically staged by medical history, physical examination, and serum prostate-specific antigen determinations. Bone scans and computed tomography of the pelvis and prostatic acid phosphatase levels were obtained at the discretion of the

referring physician or the brachytherapist. Table 2 details the clinical and treatment parameters of the 2006 survey respondents. The brachytherapy target volume consisted of the prostate with a periprostatic margin with a resultant planning volume approximately 1.75 ⫻ the ultrasound determined volume.17 The minimum peripheral dose was prescribed to the target volume with margin. Planned treatment margins were ⬎5 mm in all dimensions, whereas executed margins were ⬎5 mm in all dimensions except posteriorly (approximately 3– 4 mm) and at the bladder neck (small negative margin).17–19 Calculation algorithms and seed parameters used in planning and postoperative dosimetry were those recommended by the American Association of Physicists in Medicine Task Group No. 43.20 Of the 161 patients, 94 (58.4%) received supplemental external beam radiation therapy (XRT). For patients with ⬍10% to 15% of pelvic lymph node involvement, the XRT target volume consisted of the prostate gland, seminal vesicles, and first echelon lymph nodes. For patients with a pelvic lymph node risk ⬎10% to 15%, the pelvic nodes were

TABLE 1. Schiffler Cancer Center Rectal Function Assessment Score (R-FAS) 1. 䡺 䡺 䡺 䡺 2. 䡺 䡺 䡺 䡺 3. 䡺 䡺 䡺 䡺 4. 䡺 䡺 䡺 䡺 5. 䡺 䡺 䡺 䡺 6. 䡺 䡺 䡺 䡺

96

Number of bowel movements (BMs) per day: 0–1 BM per day 2 BMs per day 3 BMs per day 4 or more BMs per day Consistency of stools: All stools formed Stools formed and loose Stools loose Watery stools Urgency of stools: No urgency Somewhat urgent Urgent Very urgent Abdominal discomfort: No discomfort Mild to moderate discomfort Somewhat severe discomfort Very severe discomfort Hemorrhoidal discomfort: No discomfort Requires mild treatment (ie, tucks, sitz baths) Requires topical medication (ie, Prep H, etc.) Requires oral analgesics or narcotics for relief Rectal bleeding: No rectal bleeding Blood on toilet paper: 1 time per week 2–3 times per week ⱖ4 times per week

7. 䡺 䡺 䡺 䡺 䡺 䡺 8. 䡺 䡺 䡺 䡺 䡺 䡺 9. 䡺 䡺 䡺 䡺 10. 䡺 䡺 䡺

Continence: Normal continence; able to control stool movements at all times Gas incontinence only; able to control stool movements but not gas Minor spotting or leakage of stool (up to coin size) about once per week Minor spotting or leakage of stool (up to coin size) more than once per week Significant leakage of stool (larger than coin size) about once per week Significant leakage of stool (larger than coin size) more than once per week Nighttime bowel movements (total number of nights in last week that you had to get up from bed to have a bowel movement): 0 1 2 3 4 More than 4 Completeness of evacuation: Complete evacuation (requires one movement to completely empty bowel or feel you’re ⬙all done⬙) Occasional multiple evacuations (about once a week feel like you’re not ⬙all done⬙ or it takes more than one movement to finish) Frequent multiple evacuations (more than once a week feel like you’re not ⬙all done⬙ or it takes more than one movement to finish) Requires enema to obtain complete emptying My bowel movements after the implant are: Better Worse Same

© 2007 Lippincott Williams & Wilkins

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TABLE 2. Clinical, Treatment, and Dosimetric Parameters of Brachytherapy Patients Evaluated Most Recent Survey (2006), n ⴝ 161 Variable

Mean ⴞ SD

Median

Age (yr) Follow-up (yr) Gleason score PSA (ng/mL) Bowel movement/day preimplant Prostate volume (cm3) ADT (mo)* V100 (% volume) V150 (% volume) V200 (% volume) D90 (% mPD) Total activity (mCi) 125 I monotherapy 125 I boost 103 Pd monotherapy 103 Pd boost Average rectal dose (% mPD) 125 I 103 Pd Median rectal dose (% mPD) 125 I 103 Pd Maximum rectal dose (% mPD) 125 I 103 Pd

65.6 ⫾ 6.9 9.2 ⫾ 0.9 6.5 ⫾ 1.0 9.8 ⫾ 7.4 1.5 ⫾ 0.6 37.9 ⫾ 10.2 6.5 ⫾ 8.2 89.7 ⫾ 8.8 43.5 ⫾ 12.7 17.9 ⫾ 7.5 99.8 ⫾ 13.4

67.0 9.0 7.0 8.0 1.3 37.6 4.0 92.1 42.9 17.0 100.9

45.7 ⫾ 5.9 35.2 ⫾ 4.5 203.2 ⫾ 11.2 140.8 ⫾ 19.9

45.7 34.8 203.2 142.6

85.9 ⫾ 10.7 67.6 ⫾ 18.2

86.0 66.4

85.9 ⫾ 10.71 67.6 ⫾ 18.2

86.2 66.4

P (t test)

⬍0.001

⬍0.001

0.013 124.4 ⫾ 23.9 107.2 ⫾ 40.8

116.8 94.7 1-

Supplemental external beam: Yes No ADT Yes No Supplemental beam and ADT Yes No

No. patient 94 67 36 125 19 142

ADT, androgen deprivation therapy; mPD, minimum peripheral dose. *Only those who had ADT were included (n ⫽ 36).

included in the target volume. XRT was delivered via a four-field technique with custom treatment devices. Supplemental XRT was delivered before brachytherapy. Typically, patients received 45 Gy prescribed to the 97% isodose line using 15 to 18 MV photons. Thirty-six patients (22.4%) received androgen deprivation therapy (ADT). ADT consisted of a luteinizing hormonereleasing hormone agonist and an antiandrogen. ADT was initiated 3 months before brachytherapy. The mean and median durations were 6.5 ⫾ 8.2 and 4.0 months, respectively (range 3–36 months). Within 2 hours of implantation, a computed tomography scan was obtained for postoperative dosimetric evaluation. All prostate, urethral, and rectal volumes were determined by a single brachytherapist (GSM). Dose distributions © 2007 Lippincott Williams & Wilkins

to the prostate, urethra, and rectum were generated using a dedicated treatment planning computer (VariSeed, Charlottesville, VA). During the time period 1995–1998, rectal doses were calculated as the maximal point dose along the anterior rectal wall.21 Clinical, treatment, and dosimetric parameters evaluated for bowel function included patient age, diabetes, hypertension, tobacco consumption, clinical T stage, elapsed time since implant, prostate ultrasound volume, planning target volume, ADT, supplemental XRT, isotope, rectal doses (average, median, and maximum), total implanted seed strength, and the percentage of the target volume receiving 100%, 150% and 200% of the prescribed dose (V100/V150/V200) and minimum percentage of the dose covering 90% of the target volume (D90).

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The analysis for this study was developed from the 161 patients who completed all 3 surveys (1999, 2002, and 2006). Responses to each of the first 9 questions were scored from 0 to 3 with weighted values applied to questions with other than 4 responses (questions 7 and 8). Clinical, treatment, and dosimetric variables were used to determine correlations to each survey question and to the total score at each time period. The response to each question was compared across time using a repeated measures analysis of variance. Differences in mean, median, and maximal rectal doses were determined between isotopes using an independent t test. All data were analyzed using the Statistical Package for Social Sciences software (version 14, SPSS, Inc., Chicago, IL). Statistical significance was set at P ⱕ 0.05 for all analyses.

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20

15

10

5

RESULTS

0 0

2

4

6

8

10

12

14

16

18

14

16

18

14

16

18

Total RFA Score

30

2002 Survey

N o . o f P a ti e n ts

25

20

15

10

5

0 0

2

4

6

8

10

12

Total RFA Score 30

2006 Survey

25

N o . o f P a ti e n ts

Table 2 summarizes the clinical, treatment, and dosimetric parameters of the brachytherapy cohort evaluated. The mean and median follow-up times were was 9.2 ⫾ 0.9 and 9.0 years, respectively (range 8.2–11.2 years). The mean, median, and maximal rectal doses were statistically higher in the 125I cohort. Consistent with the previous surveys, none of these patients developed ulceration or fistulas or required hematologic support. To date, of the initial 219 patients, 8 have had colorectal cancer after brachytherapy and 2 have died of metastatic disease. Figure 1 illustrates the skewed right distribution of R-FAS in all 3 surveys with the 2006 survey being most heavily weighted with lower scores. In the 1999, 2002, and 2006 surveys, 71.4% (115 patients), 71.4% (115 patients), and 75.8% (122 patients) had R-FAS ⱕ5. Patients with R-FAS ⬎10 comprised 3.1% (5 patients), 2.5% (4 patients), and 2.5% (4 patients) in the 1999, 2002, and 2006 surveys, respectively. The percent of patients who answered a question with a score in the upper half of the discomfort range (responses 4, 5, or 6 on questions 7 and 8 or responses 3 or 4 in all other questions) are illustrated in Figure 2. The percent of patients with scores in the upper half of the discomfort range changed by no more than 7% points between the maximum and minimum of any of the survey dates, and in the current survey by no more than 5% between the 2002 and 2006 studies. Specifically, in terms of rectal bleeding (question 6), 78.3% of patients in the 2006 survey reported no rectal bleeding and only 1.2% reported blood on the toilet paper 4 or more times per week, whereas in the 1999 survey 73.9% of the patients reported no rectal bleeding and 3.1% reported blood on the toilet paper at least 4 times per week. Table 3 summarizes the means of the individual questions stratified by the number of patients in each survey and then by the 161 patients who completed all 3 surveys. The current 161 patient cohort had lower mean R-FAS in 1999 and 2002 than the full original populations of 209 and 187 patients, respectively, for those years— 4.00 versus 4.29 in 1999 and 3.85 versus 3.92 in 2002. Within the current cohort, a statistically significant improvement in frequency and consistency was reported over time, and nonsignificant improvements were reported for rectal bleeding, continence, and

1999 Survey

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N o o f P a ti e n t s

Merrick et al

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15

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5

0 0

2

4

6

8

10

12

Total RFA Score

FIGURE 1. Histograms of total questionnaire score per patient in the 1999, 2002, and 2006 surveys using the same 161 patients for all figures. The maximum total score on the questionnaire is 27. © 2007 Lippincott Williams & Wilkins

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100 90 80

1999

2002

2006

P a ti e n ts ( % )

70 60 50 40 30 20 10 0 1

2

3

4

5

6

7

8

9

RFAS Question Number

FIGURE 2. Bar graph of the percentage of patients (n ⫽ 161) who answered a given question with a score in the upper onehalf of the 0 to 3 discomfort range. 1999 and 2002 answers that were previously reported by patients who are now deceased were not included in the 1999 and 2002 bars.

completeness of evacuation. No substantial differences were discerned in urgency, abdominal discomfort, hemorrhoidal discomfort, continence, or nighttime bowel movements. Overall, for the 161 patients participating in all 3 surveys, a trend for improvement in mean R-FAS was identified (4.00 in 1999, 3.85 in 2002, and 3.59 in 2006; P ⫽ 0.134). Of the evaluated clinical, treatment, and dosimetric parameters, the number of pretreatment daily bowel movements consistently correlated with the total R-FAS (Table 4). Diabetes correlated with the total R-FAS in 2002 and 2006, whereas tobacco use correlated only with the latest total

R-FAS. The incidence of former and current smokers remained constant throughout the 3 surveys (17.5%, 17.1%, and 15.5% of patients were current smokers in the 1999, 2002, and 2006 surveys, whereas 53.9%, 51.3%, and 52.8% of respondents in the 3 respective surveys were former smokers). It is notable in Table 4 that correlations for the current patient cohort were seen in only 3 of 9 categories in 1999, but that correlations were found in 7 of 9 categories in 2002 and in 8 of 9 in 2006. Also, the number of clinical, implant, and dosimetric parameters serving as

TABLE 3. Mean survey responses of all patients in the 1999 and 2002 surveys compared with the mean responses of the 161 patients who completed both of those surveys and the 2006 survey No. 1 2 3 4 5 6 7 8 9

Item Frequency Consistency Urgency Abdominal discomfort Hemorrhoidal discomfort Rectal bleeding Continence Nighttime bowel movement Completeness Total score

1999 survey (n ⴝ 209)

2002 survey (n ⴝ 187)

1999 survey (n ⴝ 161)

2002 survey (n ⴝ 161)

2006 survey (n ⴝ 161)

0.75 ⫾ 0.84 0.69 ⫾ 0.73 0.70 ⫾ 0.79 0.29 ⫾ 0.53 0.36 ⫾ 0.71 0.34 ⫾ 0.66 0.44 ⫾ 0.69 0.08 ⫾ 0.31 0.60 ⫾ 0.70 4.29 ⫾ 3.50

0.81 ⫾ 0.76 0.59 ⫾ 0.52 0.66 ⫾ 0.71 0.27 ⫾ 0.50 0.28 ⫾ 0.61 0.29 ⫾ 0.62 0.45 ⫾ 0.64 0.04 ⫾ 0.14 0.54 ⫾ 0.63 3.92 ⫾ 2.84

0.73 ⫾ 0.78 0.66 ⫾ 0.69 0.66 ⫾ 0.74 0.26 ⫾ 0.52 0.32 ⫾ 0.67 0.34 ⫾ 0.67 0.38 ⫾ 0.58 0.08 ⫾ 0.32 0.57 ⫾ 0.67 4.00 ⫾ 3.14

0.81 ⫾ 0.75 0.58 ⫾ 0.51 0.66 ⫾ 0.74 0.24 ⫾ 0.44 0.27 ⫾ 0.61 0.30 ⫾ 0.61 0.43 ⫾ 0.63 0.03 ⫾ 0.14 0.52 ⫾ 0.63 3.85 ⫾ 2.79

0.58 ⫾ 0.71 0.50 ⫾ 0.58 0.67 ⫾ 0.71 0.27 ⫾ 0.56 0.33 ⫾ 0.70 0.26 ⫾ 0.55 0.40 ⫾ 0.56 0.07 ⫾ 0.25 0.49 ⫾ 0.64 3.59 ⫾ 2.83

P ⬍0.001† 0.011‡ 0.979 0.751 0.539 0.285 0.636 0.179 0.342 0.134

Data are means ⫾ SD. *A one-way repeated-measures analysis of variance was used to compare the means of the 161 patients who completed the survey all 3 times. †Survey means for each year were significantly different from each other. ‡The survey mean for the 1999 survey was significantly greater than that for the 2006 survey.

© 2007 Lippincott Williams & Wilkins

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TABLE 4. Statistically significant correlations of clinical and implant parameters with survey questions over time with the current patient cohort 1999 Survey (n ⴝ 161) Questions

Parameter

Correlation*

2002 Survey (n ⴝ 161) P

⬍0.01 Preimplant BM — Preimplant BM

1. Frequency 2. Consistency

Preimplant BM —

0.58 —

3. Urgency







4. Abdominal discomfort 5. Hemorrhoidal bleeding

— —

— —

— —

6. Rectal bleeding

Time to survey

⫺0.18

7. Continence 8. Nighttime BM

— Avg. rectal dose Max. rectal dose Age — Preimplant BM

— 0.24 0.24 0.16 — 0.21

9. Completeness Total score

Parameter

Correlation* 0.57 0.27

Preimplant BM

0.21

— PSA Tobacco use† Age 0.03 Time to survey

— ⫺0.25 0.19 ⫺0.17 ⫺0.20

— 0.02 0.02 ⬍0.05 — ⬍0.01

Preimplant BM —

0.27 —

Preimplant BM Preimplant BM Diabetes†

0.17 0.33 ⫺0.17

2006 Survey (n ⴝ 161) P

Parameter

Correlation*

P

⬍0.01 Preimplant BM ⬍0.01 Avg. rectal dose Med. rectal dose Max. rectal dose ⬍0.01 Avg. rectal dose Med. rectal dose Diabetes† Time to survey — Tobacco use† ⬍0.01 PSA 0.02 Tobacco use† 0.04 Max. rectal dose 0.01 Max. rectal dose Hypertension† ⬍0.01 — — Hypertension†

0.46 0.23 0.25 0.22 0.26 0.29 ⫺0.20 ⫺0.22 0.17 ⫺0.19 0.18 ⫺0.25 ⫺0.22 ⫺0.16 — 0.20

⬍0.01 0.02 0.01 0.03 0.01 0.01 0.01 0.01 0.03 0.01 0.03 0.01 0.04 0.04 — 0.01

0.03 Preimplant BM ⬍0.01 Preimplant BM 0.03 Diabetes† Tobacco use†

0.19 0.24 ⫺0.17 0.18

0.01 ⬍0.01 0.03 0.02

BM, bowel movement; Avg., average; Med., medium; Max., maximal; PSA, prostate-specific antigen; dashes (—), not statistically significant. *Spearman’s ␳ nonparametric correlation coefficient. †Categorical variable.

predictors of question responses increased with time. Variants of rectal dose were predictors of 4 categories in 2006. In contrast, rectal dose was predictive of only 1 category in 1999 and did not predict for any categories in 2002. This result may provide a hint of long-term dosimetric effects that are not yet reflected in correlations with the total R-FAS. Dosimetric parameters determined at the time of

brachytherapy are fixed in time, whereas clinical parameters such as tobacco use, diabetes, and hypertension are labile. Such clinical predictors recorded at the time of implant are therefore expected to become less reliable with time because quality-of-life responses may be more dependent on the patient’s current activities and behaviors than on those of the past.

TABLE 5. Comparison of Survey Responses of Patients in the 1999, 2002, and 2006 Surveys Stratified by External Beam Treatment 1999 survey (n ⴝ 161) No. 1 2 3 4 5 6 7 8 9

100

Item Frequency Consistency Urgency Abdominal discomfort Hemorrhoidal discomfort Rectal bleeding Continence Nighttime bowel movement Completeness Total score

2002 survey (n ⴝ 161)

2006 survey (n ⴝ 161)

P

Monotherapy

XRT

Monotherapy

XRT

Monotherapy

XRT

Within factor (time)

Between factor (therapy)

0.66 0.60 0.63 0.24 0.27 0.21 0.44 0.08 0.57 3.68

0.79 0.70 0.69 0.28 0.35 0.44 0.34 0.08 0.57 4.23

0.78 0.55 0.58 0.24 0.27 0.27 0.51 0.04 0.55 3.79

0.84 0.60 0.71 0.23 0.28 0.33 0.38 0.03 0.50 3.90

0.54 0.48 0.64 0.18 0.27 0.22 0.32 0.07 0.52 3.24

0.62 0.52 0.69 0.33 0.37 0.29 0.46 0.07 0.47 3.82

⬍0.001 0.016 0.951 0.873 0.642 0.420 0.484 0.189 0.405 0.130

0.365 0.392 0.382 0.334 0.451 0.134 0.644 0.847 0.683 0.307

© 2007 Lippincott Williams & Wilkins

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Rectal Function After Prostate Brachytherapy

TABLE 6. Comparison of Survey Responses of the Same Patients in the 1999, 2002, and 2006 Surveys Stratified by Tobacco Smoking 1999 survey (n ⴝ 161) No.

Item

1 2 3 4 5 6 7 8 9

2002 survey (n ⴝ 161)

2006 survey (n ⴝ 161)

Never Former Present Never Former Present Never Former Present

Frequency Consistency Urgency Abdominal discomfort Hemorrhoidal discomfort Rectal bleeding Continence Nighttime bowel movement Completeness Total score

0.80 0.55 0.55 0.22 0.22 0.29 0.3.2 0.06 0.69 3.69

0.75 0.72 0.74 0.31 0.34 0.36 0.41 0.10 0.53 4.26

0.52 0.68 0.64 0.20 0.44 0.36 0.41 0.05 0.48 3.78

0.90 0.53 0.69 0.16 0.12 0.24 0.39 0.02 0.49 3.53

0.84 0.61 0.67 0.31 0.33 0.29 0.46 0.05 0.55 4.11

Table 5 stratifies bowel function by supplemental XRT status. In the 2006 survey, the total R-FAS was 3.24 versus 3.82 for patients without and with supplemental XRT. For each survey, patients receiving monotherapy had a lower mean total R-FAS than patients treated with XRT, but the differences were not significant either for total score or scores for individual questions. There was also a temporal trend for a lower total R-FAS regardless of supplemental XRT status. As per the results in Table 3, this temporal trend was significant only for the questionnaire categories of frequency and consistency. Table 6 summarizes R-FAS when stratified by tobacco status at the time of brachytherapy. Figure 3 illustrates a nonstatistical trend for lower R-FAS in patients who never smoked but, surprisingly, the highest R-FAS was in former smokers. Neither the total score nor any individual question revealed any significant difference in terms of tobacco use, and the only significant temporal trend was restricted to bowel frequency. The R-FAS continues to improve slightly as a function of time since implantation (Fig. 4). Although there remains significant scatter in the current study, the absolute maximum

0.56 0.56 0.56 0.16 0.40 0.48 0.43 0.00 0.48 3.63

0.69 0.45 0.63 0.24 0.16 0.18 0.29 0.06 0.45 3.16

0.54 0.52 0.75 0.33 0.37 0.26 0.45 0.09 0.52 3.85

0.52 0.56 0.48 0.12 0.48 0.44 0.48 0.00 0.48 3.56

P Within factor Between factor (time) (therapy) 0.014 0.056 0.936 0.796 0.565 0.651 0.7.42 0.296 0.404 0.268

0.229 0.430 0.388 0.121 0.053 0.278 0.367 0.203 0.872 0.358

score has decreased from 17 in the first study to 12 in the current study. Figure 5 illustrates the results for summary question 10. Over time, the percentage of patients reporting deterioration in bowel function continues to decrease. In the 1999, 2002, and 2006 surveys, 17.4%, 11.2%, and 9.9% of the patients reported deterioration in bowel function. In contrast, an increasing proportion of patients in the 3 surveys (82.6%, 88.8%, and 90.1%, respectively), reported bowel habits to be the same or better. Of the 9 survey questions, question 2 (consistency of stools) and question 5 (hemorrhoidal discomfort) were significantly correlated with the summary evaluation question. Of the clinical, treatment, and dosimetric parameters evaluated, only supplemental XRT correlated with the summary question (P ⫽ 0.027)

DISCUSSION Because of a high probability of long-term survival after definitive local therapy for early stage prostate cancer,

5

Never

4.26 4

Current

4.11 3.78

3.69

Former

3.85

3.63

3.53

3.56

Me a n R F A S

3.16 3

2

1

0 1999

2002

Survey Year

© 2007 Lippincott Williams & Wilkins

2006

FIGURE 3. Effect of preimplant smoking status on mean total RFA-S for the 161 patient study population over time. The maximum total score on the questionnaire is 27.

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2002

2006

T o ta l R F A S c o r e

15

12

9

6

3

0 12

24

36

48

60

72

84

Months Since Implant

the late effects of therapeutic intervention are being increasingly scrutinized.4,5,7,8,21 Detailed information regarding long-term bowel function after all local treatments has begun to accumulate. Although rare, serious bowel complications including profuse rectal bleeding necessitating hematologic support, fecal incontinence, ulcerations, and rectal fistulas can occur after local therapy.9 –12,14 –16 Brachytherapy-related HRQOL has been evaluated with patient-administered instruments and physician interview with the conclusion that severe long-term bowel dysfunction is relatively uncommon.7,8,22,23 After permanent prostate brachytherapy, the ability to discern subtle changes in rectal function is dependent on the sensitivity of the survey instrument used.6 We have used a multifactorial instrument (R-FAS) to assess and report changes in various components of bowel function. R-FAS has been demonstrated to be more sensitive than the modified Radiation Therapy Oncology Group (RTOG) toxicity scale.6 Significant adverse bowel dysfunction such as incontinence, urgency, abdominal discomfort, hemorrhoidal discomfort, nighttime bowel movements, and completeness of evacuation are not addressed by modified RTOG morbidity criteria.6 Previously, we had detailed rectal function after prostate brachytherapy using R-FAS, with some patients having minor bowel changes secondary to brachytherapy and a vast majority of patients having no deterioration in bowel function.7,8 In addition, R-FAS has improved with time (Table 3), the number of patients reporting deterioration in bowel function has decreased (Fig. 5), and the percentage of patients scoring in the upper half of the discomfort range remains low and relatively constant (Fig. 2). There has also been a slight

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FIGURE 4. Scatter plot of total individual RFA-S versus elapsed time in months since implant. E, 1999 survey, Œ, 2002 survey; 〫, 2006 survey. Only those who completed all three surveys (n ⫽ 161) were included. The solid line is the linear regression best fit and shows a slight improvement in scores over time.

increase in the percentage of patients without rectal bleeding (73.9% versus 78.3% in 1999 and 2006, respectively) and the number of patients with substantial rectal bleeding (blood on the toilet paper 4 or more times per week) has decreased from 3.1% in 1999 to 1.2% in 2006. Consistent with our findings, Miller et al24 (over a 4-year period) reported significant improvement in bowel function using the patient-administered expanded Prostate Cancer Index Composite. In our earlier studies, total R-FAS correlated statistically with the number of preimplant bowel movements, tobacco use, and median rectal dose.6,7 In the current study, median rectal dose was no longer statistically significant, whereas diabetes joined tobacco use and the number of preimplant bowel movements as the strongest predictors for total R-FAS (Table 4). In addition, ADT, either as a categorical or continuous variable based on duration of use, did not adversely impact brachytherapy-related bowel function.25 Consistent with our prior publications, patient-perceived changes in bowel function correlated with the use of supplemental XRT (P ⫽ 0.027). The prolonged adverse effect of supplemental XRT is consistent with the radiobiologic model of Jani et al26, showing that increasing the external beam component of treatment relative to the brachytherapy portion resulted in higher biologically delivered doses to the rectum and thus would predict for greater bowel morbidity. Although tobacco use was strongly correlated with adverse bowel function in an earlier analysis,8 the current study failed to discern such a relationship. We initially thought that the absence of tobacco as a predictor for poor function was probably the result of right-censored data due to an increased rate of death in current and former smok© 2007 Lippincott Williams & Wilkins

The Cancer Journal • Volume 13, Number 2, March/April 2007

100

1999

2002

Rectal Function After Prostate Brachytherapy

2006

90 80

71.4

73.9

78.3

P a ti e n ts ( % )

70 60 50 40 30 20

11.2

14.9

17.4 11.8

11.2

10

9.9

0 Better

Same

FIGURE 5. Perceived changes in bowel function over time. Only those who completed all three surveys (n ⫽ 161) were included.

Worse

Perceived change in bowel function

ers. However, the percentage of former and current smokers in all 3 surveys remained surprisingly constant (53.9%, 51.3%, and 52.8% in the 1999, 2002, and 2006 surveys, respectively). To the best of our knowledge, this cohort of patients possesses the longest median follow-up of any prostate cancer–related HRQOL study. It is probable that with extended follow-up, the statistical significance of clinical variables changes as a result of the effects of aging, changes in nutrition and exercise regimens, and the onset of competing chronic illnesses. In addition, rectal dose was no longer statistically significant in the overall score but remained a predictor for 4 of the 9 questions including rectal bleeding. With time, the number of men with rectal bleeding has decreased, indicating some extent of late repair and thus negating the impact of the rectal dose. The continued prospective follow-up of this cohort of patients will provide valuable information about the impact of brachytherapy on colorectal health.

10.

CONCLUSION

15.

Prostate brachytherapy adversely affects bowel function. However, in most patients, the changes are small and slowly resolve with time. Overall rectal quality of life is inversely related to use of supplemental XRT.

16.

REFERENCES

18.

1. Merrick GS, Wallner KE, Butler WM. Permanent interstitial brachytherapy for the management of carcinoma of the prostate gland. J Urol. 2003;169:1643–1652. 2. Potters L, Morganstern C, Calugaru E, et al. 12-year outcomes following permanent prostate brachytherapy in patients with clinically localized prostate cancer. J Urol. 2005;173:1562–1566. 3. Merrick GS, Wallner KE, Butler WM. Minimizing prostate brachytherapy-related morbidity. Urology. 2003;62:786 –792. 4. Merrick GS, Butler WM, Wallner KE, et al. Androgen deprivation therapy does not impact cause-specific or overall survival following permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys. 2006;65:669 – 677. 5. Gutman S, Merrick GS, Butler WM, et al. Temporal relationship between prostate brachytherapy and the diagnosis of colorectal cancer. Int J Radiat Oncol Biol Phys. 2006;66:48 –55. 6. Merrick GS, Butler WM, Wallner KE, et al. Rectal function following

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brachytherapy with or without supplemental external beam radiation: results of two prospective randomized trials. Brachytherapy. 2003;2: 147–157. Merrick GS, Butler WM, Dorsey AT, et al. Rectal function following prostate brachytherapy. Int J Radiat Oncol Biol Phys. 2000;48:667– 674. Merrick GS, Butler WM, Wallner KE, et al. Late rectal function after prostate brachytherapy. Int J Radiat Oncol Biol Phys. 2003;57:42– 48. Bishoff JT, Motley G, Optenberg SA, et al. Incidence of fecal and urinary incontinence following radical perineal and retropubic prostatectomy in a national population. J Urol. 1998;160:454 – 458. Shekarriz B, Upadhyay J, Wood D. Intraoperative, perioperative, and long-term complications of radical prostatectomy. Urol Clin N Am. 2001;28:639 – 653. Zelefsky MJ, Fuks Z, Hunt M, et al. High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol. 2001;166:876 – 881. Merrick GS, Wallner KE, Butler WM. Prostate cryotherapy: more questions than answers. Urol. 2005;66:9 –15. Litwin MS. Health related quality of life in older men without prostate cancer. J Urol. 1999;161:1180 –1184. Howard A, Wallner K, Han B, et al. Clinical course and dosimetry of rectal fistulas after prostate brachytherapy. J Brachyther Int. 2001;17: 37– 42. Theodorescu D, Gillenwater J, Koutrouvelis P. Prostatourethral-rectal fistula after prostate brachytherapy: incidence and risk factors. Cancer. 2000;89:2085–2091. Tran A, Wallner KE, Merrick GS et al. Rectal fistulas after prostate brachytherapy. Int J Radiat Onc Biol Phys. 2005;62:150 –154. Merrick GS, Butler WM. Modified uniform seed loading for prostate brachytherapy: rationale, design, and evaluation. Tech Urol. 2000;6:78 – 84. Merrick GS, Butler WM, Dorsey AT, et al. The effect of prostate size and isotope selection on dosimetric quality following permanent seed implantation. Tech Urol. 2001;7:233–240. Merrick GS, Butler WM, Wallner KE, et al. Extracapsular radiation dose distribution following permanent prostate brachytherapy. Am J Clin Oncol. 2003;25:E178 –E189. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. Med Phys. 1995;22:209 –234. Merrick GS, Butler WM, Dorsey AT, et al. Rectal dosimetric analysis following prostate brachytherapy. Int J Radiat Oncol Biol Phys. 1999; 43:1021–1027. Talcott JA, Clark JA, Stark PC, et al. Long-term treatment related complications of brachytherapy for early prostate cancer: a survey of patients previously treated. J Urol. 2001;166:494 – 499. Wallner K, Merrick G, True L, et al. I-125 versus Pd-103 for low risk

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prostate cancer: Morbidity outcomes from a prospective randomized multicenter trial. CancerJ Sci Am. 2002;8:67–73. 24. Miller DC, Sanda MG, Dunn RL, et al. Long-term outcomes among localized prostate cancer survivors: health-related quality-of-life changes after radical prostatectomy, external radiation, and brachytherapy. J Clin Oncol. 2005;12:2772–2779. 25. Merrick GS, Butler WM, Wallner KE, et al. Influence of hormonal

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therapy on late rectal function after permanent prostate brachytherapy with or without supplemental external beam radiotherapy. Int J Oncol Radiat Biol Phys. 2004;58:68 –74. 26. Jani AB, Hand CM, Lujan AE, et al. Biological effective dose for comparison and combination of external beam and low-dose rate interstitial brachytherapy prostate cancer treatment plans. Med Dosim. 2004; 29:42– 48.

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