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Longitudinal Study of Intestinal Symptoms and Fecal Continence in Patients With Conformal Radiotherapy for Prostate Cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 79, No. 5, pp. 1373–1380, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter
doi:10.1016/j.ijrobp.2010.01.033
CLINICAL INVESTIGATION
Prostate
LONGITUDINAL STUDY OF INTESTINAL SYMPTOMS AND FECAL CONTINENCE IN PATIENTS WITH CONFORMAL RADIOTHERAPY FOR PROSTATE CANCER HANS GEINITZ, M.D.,* REINHARD THAMM, M.D.,* MONIKA KELLER, M.D.,y SABRINA T. ASTNER, M.D.,* CHRISTINE HEINRICH, M.D.,* CHRISTIAN SCHOLZ,* CHRISTIAN PEHL, M.D.,z SIMONE KERNDL,* NINA PRAUSE,* RAYMONDE BUSCH, M.SC.,x MICHAEL MOLLS, M.D.,* AND FRANK B. ZIMMERMANN, M.D.* y
*Klinik und Poliklinik fu¨r Strahlentherapie und Radiologische Onkologie, Technische Universita¨t Mu¨nchen, Mu¨nchen, Germany; Sektion Psychoonkologie, Klinik fu¨r Psychosomatische und Allgemeine Klinische Medizin, Universita¨tsklinik Heidelberg, Heidelberg, Germany; zMedizinische Klinik, Kreiskrankenhaus Vilsbiburg, Vilsbiburg, Germany; xInstitut fu¨r Medizinische Statistik und Epidemiologie, Technische Universita¨t Mu¨nchen, Mu¨nchen, Germany Purpose: To prospectively assess the intestinal symptoms and fecal continence in patients who had undergone conformal radiotherapy (CRT) for prostate cancer. Methods and Materials: A total of 78 men who had undergone definitive CRT for prostate cancer were evaluated. The patients were assessed before, during (treatment Weeks 4 and 6), and 2, 12, and 24 months after CRT completion. The intestinal symptoms and fecal continence were evaluated with comprehensive standardized questionnaires. Results: The intestinal symptoms were mostly intermittent, with only a small minority of patients affected daily. Defecation pain, fecal urge, and rectal mucous discharge increased significantly during therapy. Defecation pain and rectal mucous discharge had returned to baseline levels within 8 weeks and 1 year after CRT, respectively. However, fecal urge remained significantly elevated for #1 year and then returned toward the pretreatment values. The prevalence of rectal bleeding was significantly elevated 2 years after CRT. Fecal continence deteriorated during CRT and remained impaired at 1 year after treatment. Incontinence was mostly minor, occurring less than once per week and predominantly affecting incontinence for gas. Conclusion: Intestinal symptoms and fecal incontinence increased during prostate CRT. Except for rectal bleeding, the intestinal symptoms, including fecal incontinence, returned to baseline levels within 1–2 years after CRT. Thus, the rate of long-term late radiation-related intestinal toxicity was low. Ó 2011 Elsevier Inc. Prostate cancer, Conformal radiotherapy, Intestinal symptoms, Fecal continence, Intestinal bother.
weeks after RT. In contrast, chronic side effects can occur months or even years after the initiation of CRT and can persist for longer periods. Severe chronic side effects after CRT for prostate cancer are rare, with a frequency of <5%. Recently, fecal incontinence has also been recognized as a side effect of prostate RT. Although some prospective data on the deterioration of fecal continence after non-CRT for prostate cancer (3–5) exist, data for CRT remain rare (6, 7). In the present study, we prospectively evaluated the intestinal symptoms, fecal incontinence, and bother from intestinal symptoms before, during, and 1 and 2 years after definitive prostate CRT using standardized questionnaires.
INTRODUCTION Prostate cancer is one of the most frequent malignancies in men in the Western hemisphere. The curative treatment options include definitive radiotherapy (RT) and radical prostatectomy. Because modern RT and radical prostatectomy have been judged to be equally effective (1), a special emphasis has been placed on treatment-related side effects. Although surgery carries a greater risk of adverse effects in the urogenital tract, external beam RT has been associated with more intestinal side effects. Since the introduction of computed tomography-based three-dimensional conformal radiotherapy (CRT), the side effects from external beam RT for prostate cancer have significantly decreased (2). Intestinal symptoms during or after CRT include increased defecation frequency, intermittent rectal bleeding, rectal mucous discharge, defecation pain, and fecal urge. Acute toxicity during CRT normally ceases within several days or a few
METHODS AND MATERIALS Eligibility criteria All patients underwent CRT at the Department of Radiation Oncology, Technische Universitaet Munich. The participants for the
Reprint requests to: Hans Geinitz, M.D., Klinik und Poliklinik fu¨r Strahlentherapie der Technischen Universita¨t Mu¨nchen, Ismaninger Straße 22, 81675 Mu¨nchen, Germany. Tel: (++49) 89-4140-5412; Fax: (++49) 89-4140-4587; E-mail: [email protected]
Supported by a grant from the Deutsche Krebshilfe. Conflict of interest: none. Received June 26, 2009, and in revised form Nov 17, 2009. Accepted for publication Jan 9, 2010. 1373
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present prospective study on the symptoms and quality of life were recruited between December 2001 and February 2003. All patients who had undergone CRT for localized (Stage cN0 cM0) prostate cancer, either as definitive treatment or in the adjuvant setting, were eligible. Participants had to have a sufficient command of the German language and to give written informed consent. The local ethics committee approved the study, which was performed in accordance with the Helsinki Declaration. We report on the intestinal symptoms and fecal continence of patients undergoing definitive CRT. The data on quality of life and from patients receiving adjuvant treatment will be reported separately.
Treatment Conformal RT (6–15-MeV photons) was used throughout the whole RT course. None of the patients received treatment to the pelvic lymphatics. The dose per fraction was 2.0 Gy (International Commission on Radiation Units and Measurements report 50). Three-dimensional planning was performed using the HELAX TMS planning system (Nucletron, Veenendaal, The Netherlands). The dose prescription and clinical target volumes were defined according to the risk group. Low-risk patients (Stage T1-T2a, Grade 1 or 2, Gleason score 2–6, and pretreatment prostate-specific antigen [PSA] level <10 ng/mL) were treated with 70 Gy to the prostate. The intermediate-risk patients (Stage T1-T2, Grade 3, Gleason score 7–10, and/or PSA level >10 but <20 ng/mL) were treated with 70 Gy to the prostate and the base of the seminal vesicles. The highrisk patients (Stage T3 or PSA level >20 but <50 ng/mL) were treated with 74 Gy to the prostate and the base of the seminal vesicles. The intermediate- and high-risk patients were offered neoadjuvant hormonal therapy for 3–6 months before and during RT. Additional adjuvant hormonal therapy was recommended to patients with high-risk prostate cancer. The safety margins for the planning target volume were 1 cm in all directions, except for in patients who received 74 Gy, for whom the safety margin in the dorsal direction was 0.5 cm for the first 8 Gy. A rectal balloon catheter for internal immobilization of the prostate was used in 69 patients (89%) during CRT (8). The dose constraint for the rectum was that not more than 25% of the rectum should receive >70 Gy.
Patient assessment and instruments The patients were evaluated 1 week before the onset of CRT, at the end of treatment weeks 4 (40 Gy) and 6 (60 Gy), and at 8 weeks and 1 and 2 years after CRT completion. The rectal symptoms and fecal continence were assessed by one of us using the corresponding questionnaires (see the following sections). In addition, general data on patient and disease characteristics were collected. The symptom questionnaires were returned by the patients after they had completed additional quality-of-life material.
Rectal symptoms The rate of rectal symptoms was assessed using an ad hoc constructed eight-item questionnaire (rectal toxicity score, see Appendix) (9). Owing to the intermittent occurrence of most acute or chronic rectal symptoms in patients undergoing pelvic RT, the frequency, rather than the magnitude, of symptoms was scored. The score ranged from 0 (no symptoms, no stool medication) to 32 (daily occurrence of all seven symptoms and daily stool medication).
Fecal continence The fecal continence score of Jorge and Wexner (10) was used to evaluate fecal continence. The score ranged from 0 (perfect continence) to 20 (complete incontinence, see Appendix).
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Bother scale Bother from intestinal symptoms was evaluated with an ad hoc constructed five-point scale (see Appendix) (9).
Concomitant disease All patients were interviewed for the occurrence of concomitant disease before the onset of RT and at 12 and 24 months after therapy.
PSA values and biochemical recurrence Biochemical recurrence was defined according to the Radiation Therapy Oncology Group–American Society for Therapeutic Radiology and Oncology Phoenix definition (11) as an increase by $2 ng/mL greater than the nadir PSA level. Also, the start of hormonal therapy after RT was regarded as a biochemical failure.
Statistical analysis For the computation of the prevalence of intestinal symptoms or fecal continence and the calculation of changes over time, only the data from patients responding at any of the six follow-up points, were selected. The Friedman test was used to detect changes over time. When significant, the Wilcoxon test was performed to determine the differences to the pretreatment values. Bivariate correlations were calculated using the Spearman correlation coefficient. Stepwise linear regression analysis was performed to determine the independent predictors of long-term fecal symptoms and fecal incontinence (multivariate analysis). Significance was set at 5%. All tests were two sided.
RESULTS Recruitment Between December 2001 and February 2003, 105 patients who were scheduled to receive definitive CRT were informed of the present study. Of the 105 patients, 85 (81%) agreed to participate in the study, 12 (12%) denied participation, 6 (6%) had insufficient command of the German language, and 2 (2%) were unable to respond to the questionnaires because of psychiatric disorders. Of the 85 included patients, 8 failed to return their questionnaires before the start of therapy. Thus, 78 patients were evaluable. The response rate was high, with >90% of the patients responding to the questionnaires at 1 and 2 years after treatment (72 and 71 patients, respectively). Patient and treatment characteristics The sociodemographic and clinical characteristics are listed in Table 1. Within the 2-year follow-up period, 1 patient died of prostate cancer and 2 patients developed distant metastases. Dose–volume histogram data The dose constraint for the rectum (<25% of the rectum to receive >70 Gy) was fulfilled for 76 of the 78 patients. Of the 2 remaining patients, 1 received 70 Gy and 1 received 78 Gy. The median percentage of the volume of the rectum that received $35, $50, $55, $60, $65, and $70 Gy was 47%, 35%, 32%, 27%, 22%, and 9%, respectively. No significant difference was seen in these dose–volume histogram data between the patients with prostate doses
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Table 1. Sociodemographic and clinical characteristics Variable
Value
Patients (n) Age (y) Median Range Educational level Low Intermediate High Unknown Marital status Single Married/partner Unknown Risk group* Low Intermediate High Prostate dose (Gy) Median Range Neoadjuvant hormonal therapy Duration (mo) Median Range Adjuvant hormonal therapy Duration (mo) Median Range Disease status 2 y after CRT Biochemical relapse (Phoenix criteria) Distant metastasis Deceased Hormonal therapy for biochemical recurrence Concomitant disease Total (n) Mean Range Cardiovascular disease Gastrointestinal disease Diabetes mellitus Second tumor Pulmonary disease Depression
78 70 51–86 1 (1) 43 (55) 31 (40) 3 (4) 9 (12) 64 (82) 5 (6) 31 (40) 19 (24) 28 (36) 70.0 64.0–74.0 73 (94) 3 1–19 32 (41) 2 1–26 5 (7) 2 (3) 1 (1) 2 (3) 1.5 0–6 48 (62) 14 (18) 10 (13) 9 (12) 9 (12) 3 (4)
Abbreviations: CRT = conformal radiotherapy; PSA = prostatespecific antigen. Data in parentheses are percentages. * Low, Stage T1-T2, World Health Organization Grade 1 or 2, and initial PSA level of #10 ng/mL; intermediate, Stage T1-T2, Grade 3, and/or PSA level >10 but #20 ng/mL; and high, Stage T3-T4 or PSA level >20 ng/mL.
of 70 Gy and 74 Gy, except for the median percentage of the volume of the rectum that received $70 Gy, which was lower in the patients receiving 70 Gy (8% vs. 18%, p <.001). Patients with a rectal balloon catheter (n = 69) had a significantly lower median percentage of the volume of the rectum that received $35, $50, $55, and $60 Gy than those without a balloon catheter (46% vs. 58%, p = .004; 35% vs. 45%, p = .007; 33% vs. 40%, p = .010; 29% vs. 35%, p = .024).
Fig. 1. Course of rectal symptom score. Greater values indicate more symptoms. Mean score standard error of mean. #p <.01; z p <.001 compared with pre-CRT values.
Intestinal symptoms The rectal symptom score increased during CRT and stayed elevated throughout the 2 years after CRT (p = .002, Fig. 1). The rectal symptoms were mostly intermittent and occurred daily only in a few of the symptomatic patients (Table 2). Defecation pain (p <.001) and fecal urge (p <.001) increased significantly and the rectal mucous discharge increased with borderline significance (p = 0.051) during therapy. Although defecation pain and rectal mucous discharge returned to baseline levels within 8 weeks and 1 year after CRT, respectively, fecal urge remained significantly elevated for #1 year and then returned toward the pretreatment values. The prevalence of rectal bleeding did not increase within 1 year after CRT, but it was significantly elevated at 2 years after CRT (p = .002). Stool frequency increased during CRT (p <.001) and had returned to baseline levels within 8 weeks after CRT. Fecal continence Fecal incontinence, as measured using the fecal continence score, increased during therapy and did not return to baseline levels throughout 1 year after CRT (p = .006, Fig. 2). At 2 years after treatment, the fecal continence score was not significantly different from baseline levels. Although incontinence for solid and liquid stool did not augment significantly within the observation period (p = .086 and p = .066), an increase in incontinence for gas occurred during RT (p = .014) and remained significantly greater than pretreatment levels at 1 year after therapy. At 2 years after therapy, incontinence for gas did not differ significantly from baseline levels. Patients reported an increase in lifestyle alterations during and 8 weeks after CRT (p = .009) with a return toward baseline levels at 1 year after therapy. The use of pads for fecal incontinence did not increase significantly. Daily incontinence episodes were absent before and during CRT. The rate of daily incontinence had increased to 2% at
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Table 2. Intestinal symptoms and stool frequency before CRT, at 60 Gy, and 2 years after CRT Before CRT (%) Variable Blood Mucous Defecation pain Tenesmus Flatulence Diarrhea Fecal urge Stool frequency Mean (n) Range (n) >2/d (%)
Any 8 4 4 13 60 49 38 1.5 1–3 7
At 60 Gy (%)
Weekly
Daily
0 0 0 0 11 0 2
0 0 0 0 4 0 0
Any
2 y After CRT (%)
Weekly
Daily
p*
2 4 0 2 17 2 4
0 0 6 0 9 0 2
NS 0.016 0.002 NSy NSy NSy <0.001 <.001
9 15 30 17 72 50 66 2.0 1–24 27
Any 28 8 2 6 58 40 44
Weekly
Daily
p*
4 0 0 0 17 4 6
1 0 0 0 8 2 6
0.004 NS NS NSy NSy NSy NS NS
1.4 1–4 2
Abbreviations: CRT = conformal radiotherapy; NS: not significant. * p Values for entire distribution compared with pre-CRT values (Wilcoxon signed rank test, used only when Friedman test result was significant) y Friedman test result not significant.
2 years after RT; however, it involved only incontinence for gas. The rate of any incontinence (from <1/mo through daily) for solid stool, liquid stool, and gas was 6%, 12%, and 25% at baseline, 12%, 22%, and 44% at 60 Gy, and 10%, 24%, and 27% at 2 years after RT (Table 3). The fecal continence score correlated with the rectal symptom score throughout the observation period (Spearman rho, 0.398–0.619, p <.001).
Intestinal bother Bother from intestinal symptoms increased during RT, remained significantly elevated throughout 1 year after CRT (p <.001), and had returned to baseline levels at 2 years after CRT. Before CRT, 19% of the patients reported bother from intestinal symptoms with no patient bothered ‘‘a lot.’’ At 60 Gy, 64% reported intestinal bother and 2% stated they were ‘‘bothered a lot.’’ The corresponding percentages were 33% and 2% at 2 years after RT. The following symptoms most closely correlated with bother from intestinal symptoms at 2 years after CRT: fecal urge (rho = 0.537, p <.001) and fecal incontinence (rho = 0.468, p <.001).
Pretreatment predictors of long-term fecal continence and fecal symptoms The following variables were tested in stepwise linear regression analysis for their association with the 2-year fecal continence score and 2-year rectal toxicity score: age at the start of therapy (continuously), number of concomitant diseases (zero to six), diabetes mellitus (no vs. yes), smoking (no vs. yes), body mass index (continuously), neoadjuvant hormonal therapy (yes vs. no), total radiation dose (continuously), rectal balloon (no vs. yes). The only negative predictor for long-term fecal continence on multivariate analysis was diabetes mellitus (p = .028). The only predictor of long-term fecal symptoms was a high number of concomitant diseases (p = .021).
DISCUSSION In the present prospectively assessed patient population we observed that intestinal symptoms and fecal incontinence increased during CRT for prostate cancer. Although most of the symptoms, including fecal incontinence, had returned to baseline levels within 1–2 years after CRT, the prevalence of rectal bleeding had increased significantly beyond baseline levels at 2 years after CRT. Intestinal symptoms and fecal incontinence were mostly intermittent and occurred only in a few patients daily. Fecal incontinence was predominantly minor at a frequency of less than once per week and encompassed mainly incontinence for gas. The symptoms most closely associated with intestinal bother were fecal urge and fecal incontinence. Prospective longitudinal studies on the prevalence of intestinal symptoms in patients with CRT for prostate cancer have
Fig. 2. Course of fecal continence score. Greater values equal more incontinence. Mean score standard error of mean. *p <.05; #p <.01 compared with pre-CRT values.
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Table 3. Fecal incontinence before CRT, at 60 Gy, and 2 years after treatment Variable
Never Rarely Sometimes Usually Always (%) (%) (%) (%) (%)
Before CRT Solid stool 94 Liquid stool 88 Gas 75 Wears pad 100 Lifestyle alteration 87 At 60 Gy Solid stool 89 Liquid stool 78 Gas 56 Wears pad 96 Lifestyle alteration 72 At 2 y after CRT Solid stool 90 Liquid stool 76 Gas 73 Wears pad 94 Lifestyle alteration 94
4 12 13 0 7
2 0 10 0 4
0 0 2 0 2
0 0 0 0 0
8 16 21 2 9
4 6 13 2 13
0 0 10 0 2
0 0 0 0 4
4 8 8 4 4
6 14 6 0 0
0 2 11 0 2
0 0 2 2 0
Abbreviation: CRT = conformal radiotherapy. Never, 0; rarely, <1/mo; sometimes, <1/wk, $1/mo; usually, <1/d; $1/wk; always, $1/d.
been infrequent; however, the results were mostly compatible with the findings in our patient sample. Fransson et al. (12) reported a prospective analysis of bowel symptoms before and 1, 3, and 5 years after CRT for prostate cancer. A total of 363 patients were included in the study, but 79 did not respond to the baseline questionnaire. Patients were treated with doses of 60.8–78 Gy, and 46% received additional hormonal therapy. As assessed using the Prostate Cancer Symptom Scale self-assessment questionnaire, ‘‘blood in stools,’’ ‘‘stool leakage,’’ and ‘‘mucous in stools’’ increased after therapy and remained elevated at 5 years after treatment. Staff et al. (13) evaluated intestinal symptoms in 100 patients who received definitive CRT at doses of 70–74 Gy at #10 months after treatment. Patients were treated between 1998 and 2000, and 68 of the 100 patients had received neoadjuvant hormonal therapy. Post-treatment information was collected 1–3 months and 5–10 months after the end of treatment. In agreement with the findings from our study, bowel frequency and bowel urgency significantly increased in the whole patient set. In contrast, bowel bleeding and bowel cramping did not display significant changes over time. Hovdenak et al. (14) reported on 96 patients who had undergone CRT for localized prostate cancer with doses of 66–70 Gy. Symptoms were recorded before treatment, at 2, 4, and 6 weeks into treatment, and 2 and 8 weeks after CRT. ‘‘Loose stools,’’ ‘‘tenesmus,’’ ‘‘abdominal pain,’’ ‘‘bloating,’’ and ‘‘blood in stools’’ increased significantly during CRT and remained elevated at 8 weeks after treatment completion. Beard et al. (15) evaluated gastrointestinal symptoms in 25 patients who had undergone CRT with 66.2 Gy for localized prostate cancer before RT and at 3 and 12 months after the initiation of treatment. The investigators reported an increase in
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‘‘diarrhea/two to three loose stools’’ from 0% before CRT to 32% at 3 months and 48% at 12 months (15). They also reported an increase in ‘‘urgency/tenderness’’ from 0% to 80% and 64%, respectively; however, no p values were provided. It has been recognized in the published reports that pelvic and abdominal RT impairs fecal continence (3, 5, 7, 9, 16–25). The pathophysiologic basis of radiation-induced fecal incontinence is not entirely well understood and seems to be caused by a variety of sensory and/or motor dysfunctions. Impaired reservoir function and disturbed rectoanal sensory performance (3, 26–28), as well as an impaired function of the external (27–29) and internal (16, 28) sphincter muscle, might contribute to clinically overt incontinence. Histologic examinations have disclosed hypertrophy of the muscularis mucosae and muscularis propia, damage to the myenteric plexus and to the extrinsic innervation, and fibrosis of the anorectum (16, 28, 30). Although retrospective data have shown a rate of 5–58% of varying degrees of fecal incontinence after CRT for prostate cancer (9, 19, 21, 23), few prospective studies with a longitudinal assessment have been published. Yeoh et al. prospectively analyzed 38 patients who had undergone definitive nonconformal RT and 29 patients who had undergone CRT for prostate cancer using 55 Gy in 20 fractions or 64 Gy in 32 fractions (3–6). The anorectal symptoms were assessed by questionnaire. In addition, anorectal manometry was performed before and at various times after CRT. Fecal incontinence was impaired 4–6 weeks and 1 and 2 years after the end of treatment. Progressive reductions occurred in basal anal pressure and anal pressure in response to squeeze and rectal compliance, irrespective of the treatment modality (CRT vs. non-CRT). Kushwaha et al. (31) prospectively evaluated patients who had undergone non-CRT to the pelvis for prostate or bladder cancer. They found deterioration in fecal continence at 6 weeks and 6 months after treatment completion. Manometry disclosed a reduction in the basal and voluntary anal pressure and in the ‘‘maximum tolerated rectal volume.’’ Retrospective studies, correlating fecal incontinence to the doses to the anal canal or rectum using dose–volume histograms derived from the initial planning computed tomography scan, have shown only minor to moderate associations between the incontinence of stool and the dose–volume parameters (7, 21, 23–25, 32–34). Possible explanations for the generally weak correlations between fecal incontinence and anorectal dose–volume histogram parameters could include difficulties in identifying the anal canal on the planning computed tomography scan. Also, the radiationsensitive structures responsible for incontinence might not only be the anal canal, but also structures such as the pelvic floor muscles, including the puborectalis and ischiorectalis muscles; the anal and rectal mucosa, including the anal vessel cushions; pelvic nerves, such as the hypogastric nerve and pudendal nerve; and the small vessels responsible for the supply of the anorectal sphincter apparatus. In addition to the radiation dose at the anosphincter, other factors that alter
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the pelvic innervation (e.g., abdominopelvic surgery, diabetes) or stool consistency (including radiation to the small bowel) might play a major role in the integrity of fecal continence after pelvic RT. One limitation of our study was that we did not assess intestinal symptoms and fecal continence before the onset of neoadjuvant hormonal therapy, because most of the patients were already receiving antiandrogen treatment at their first visit to our department. This situation probably reflects a common circumstance in many radio-oncology departments in Germany. Almost all patients receiving neoadjuvant hormonal therapy (n = 73) received that therapy until the end of CRT. The short-term effects of CRT on intestinal symptoms and fecal continence were most likely, therefore, not influenced by hormonal therapy (because its prevalence did not change during that period). The number of patients receiving antiandrogen therapy declined to 10 and 9 at 1 and 2 years after CRT, respectively. Because androgen deprivation therapy can cause diarrhea (35), we could not rule out that some bias was introduced by the total duration of neoadjuvant/adjuvant hormonal therapy. In contrast, neither the duration of neoadjuvant/adjuvant hormonal therapy nor the prevalence of hormonal therapy at 1 and 2 years correlated significantly with the rectal symptom score or fecal continence score. The prevalence or duration of hormonal therapy did not correlate with the incidence of diarrhea or stool frequency at any point. Rectal balloon catheters were used in our study for internal immobilization of the prostate and sparing of the dorsal rectal wall. The insertion of a rectal balloon catheter leads to an anterior shift of the anterior rectal wall with or without a posterior shift of the dorsal rectal wall, resulting in an increased distance between the prostate and posterior rectal wall (8, 36). This effect causes a reduction in the dose to posterior rectal wall, without changing the dose to the anterior rectal wall significantly (8, 37). In a small randomized trial, the use of a rectal balloon was associated with a reduction of
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high-grade telangiectasia in the rectal mucosa and a reduction of greater than Grade 1 late rectal toxicity (37). Nevertheless, a larger randomized clinical trial with sufficient follow-up has not yet been published. Regarding the application of our study results to those from institutions not using balloon catheters, we do not believe the results would change fundamentally, except for possibly a slightly greater level of rectal symptoms during and after CRT in those patients without a balloon catheter. In our patients, fecal incontinence was associated with greater levels of intestinal bother. We reported, in a previous study, that patients with fecal incontinence after CRT for prostate cancer also noted a lower quality of life (9). Thus, one aim of future trials of CRT or intensity-modulated RT for prostate cancer might be to identify the radiosensitive structures responsible for fecal incontinence, and, subsequently, design radiation plans to spare those regions from high radiation doses, without compromising the dose to the planning target volume. However, one must remember that most of our patients were not affected by radiation-induced fecal incontinence, and, if they were, the symptoms were mostly minor, with a tendency to regress >1 year after RT. Because the number of patients in our study was limited, the result should be confirmed in a larger prospective trial.
CONCLUSION In the present prospectively analyzed patient cohort, we observed that intestinal symptoms and fecal incontinence increased during CRT for prostate cancer. All the symptoms, except for rectal bleeding, had returned to baseline levels within 1–2 years after CRT. Thus, the rate of long-term late radiationrelated intestinal toxicity was low. Intestinal symptoms and fecal incontinence were mostly intermittent and occurred daily only in a few patients. Fecal incontinence was predominantly minor and mainly involved incontinence for gas.
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12. Fransson P, Bergstrom P, Lofroth PO, et al. Five-year prospective patient evaluation of bladder and bowel symptoms after dose-escalated radiotherapy for prostate cancer with the BeamCathÒ technique. Int J Radiat Oncol Biol Phys 2006;66: 430–438. 13. Staff I, Salner SA, Bohannon R, et al. Disease-specific symptoms and general quality of life of patients with prostate carcinoma before and after primary three-dimensional conformal radiotherapy. Cancer 2003;98:2335–2343. 14. Hovdenak N, Karlsdottir A, Sorbye H, et al. Profiles and time course of acute radiation toxicity symptoms during conformal radiotherapy for cancer of the prostate. Acta Oncol 2003;42: 741–748. 15. Beard CJ, Propert KJ, Rieker PP, et al. Complications after treatment with external-beam irradiation in early-stage prostate cancer patients: A prospective multiinstitutional outcomes study. J Clin Oncol 1997;15:223–229. 16. Varma JS, Smith AN, Busuttil A. Function of the anal sphincters after chronic radiation injury. Gut 1986;27:528–533. 17. Widmark A, Fransson P, Tavelin B. Self-assessment questionnaire for evaluating urinary and intestinal late side effects after pelvic radiotherapy in patients with prostate cancer compared with an age-matched control population. Cancer 1994;74: 2520–2532. 18. Crook J, Esche B, Futter N. Effect of pelvic radiotherapy for prostate cancer on bowel, bladder, and sexual functioning: The patients’ perspective. Urology 1996;47:387–394. 19. Hanlon A, Watkins Bruner D, Peter R, et al. Quality of life study in prostate cancer patients treated with three-dimensional conformal radiation therapy: Comparing late bowel and bladder quality of life symptoms to that of the normal population. Int J Radiat Oncol Biol Phys 2001;49:51–59. 20. Fransson P, Damber JE, Tomic R, et al. Quality of life and symptoms in a randomized trial of radiotherapy versus deferred treatment of localized prostate carcinoma. Cancer 2001;92: 3111–3119. 21. Vordermark D, Schwab M, Ness-Dourdoumas R, et al. Association of anorectal dose-volume histograms and impaired fecal continence after 3D conformal radiotherapy for carcinoma of the prostate. Radiother Oncol 2003;69:209–214. 22. Koper PC, Jansen P, van Putten W, et al. Gastro-intestinal and genito-urinary morbidity after 3D conformal radiotherapy of prostate cancer: Observations of a randomized trial. Radiother Oncol 2004;73:1–9. 23. Fokdal L, Honore H, Hoyer M, et al. Dose-volume histograms associated to long-term colorectal functions in patients receiving pelvic radiotherapy. Radiother Oncol 2005;74:203–210. 24. al-Abany M, Helgason AR, Cronqvist A-KA, et al. Toward a definition of a threshold for harmless doses to the analsphincter region and the rectum. Int J Radiat Oncol Biol Phys 2005;61:1035–1044.
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25. Peeters ST, Hoogeman MS, Heemsbergen WD, et al. Rectal bleeding, fecal incontinence, and high stool frequency after conformal radiotherapy for prostate cancer: normal tissue complication probability modeling. Int J Radiat Oncol Biol Phys 2006;66:11–19. 26. Iwamoto T, Nakahara S, Mibu R, et al. Effect of radiotherapy on anorectal function in patients with cervical cancer. Dis Colon Rectum 1997;40:693–697. 27. Kim GE, Lim JJ, Park W, et al. Sensory and motor dysfunction assessed by anorectal manometry in uterine cervical carcinoma patients with radiation-induced late rectal complication. Int J Radiat Oncol Biol Phys 1998;41:835–841. 28. Berndtsson I, Lennernas B, Hulten L. Anorectal function after modern conformal radiation therapy for prostate cancer: A pilot study. Tech Coloproctol 2002;6:101–104. 29. Yeoh EE, Sun W, Russo A, et al. A retrospective study of the effects of pelvic irradiation for gynecological cancer on anorectal function. Int J Radiat Oncol Biol Phys 1996;35:1003–1010. 30. Varma JS, Smith AN, Busuttil A. Correlation of clinical and manometric abnormalities of rectal function following chronic radiation injury. Br J Surg 1985;72:875–878. 31. Kushwaha RS, Hayne D, Vaizey CJ, et al. Physiologic changes of the anorectum after pelvic radiotherapy for the treatment of prostate and bladder cancer. Dis Colon Rectum 2003;46: 1182–1188. 32. Fiorino C, Fellin G, Rancati T, et al. Clinical and dosimetric predictors of late rectal syndrome after 3D-CRT for localized prostate cancer: Preliminary results of a multicenter prospective study. Int J Radiat Oncol Biol Phys 2008;70:1130–1137. 33. Fonteyne V, De Neve W, Villeirs G, De Wagter C, De Meerleer G. Late radiotherapy-induced lower intestinal toxicity (RILIT) of intensity-modulated radiotherapy for prostate cancer: the need for adapting toxicity scales and the appearance of the sigmoid colon as co-responsible organ for lower intestinal toxicity. Radiother Oncol 2007;84:156–163. 34. Valdagni R, Rancati T, Fiorino C, et al. Development of a set of nomograms to predict acute lower gastrointestinal toxicity for prostate cancer 3D-CRT. Int J Radiat Oncol Biol Phys 2008; 71:1065–1073. 35. Mason M. What implications do the tolerability profiles of antiandrogens and other commonly used prostate cancer treatments have on patient care? J Cancer Res Clin Oncol 2006;132(Suppl. 1):S27–S35. 36. Elsayed H, Bolling T, Moustakis C, et al. Organ movements and dose exposures in teletherapy of prostate cancer using a rectal balloon. Strahlenther Onkol 2007;183:617–624. 37. van Lin EN, Kristinsson J, Philippens ME, et al. Reduced late rectal mucosal changes after prostate three-dimensional conformal radiotherapy with endorectal balloon as observed in repeated endoscopy. Int J Radiat Oncol Biol Phys 2007;67: 799–811.
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Variable Blood Mucous Defecation pain Tenesmus Flatulence Diarrhea Fecal urge Stool medication
APPENDIX
Bother scale
Rectal symptom score
During the past month, how much have you been bothered by alterations in bowel habits?
Never Rarely Sometimes Usually Always 0 0 0 0 0 0 0 0
1 1 1 1 1 1 1 1
2 2 2 2 2 2 2 2
3 3 3 3 3 3 3 3
4 4 4 4 4 4 4 4
Never, 0; rarely, <1/mo; sometimes, <1/wk; >1/mo; usually, <1/d; >1/wk; always, >1/d. 0: no rectal symptoms; 32: greatest extent of rectal symptoms. Data from Geinitz et al. (9). Fecal continence score Variable Solid Liquid Gas Wears pad Lifestyle alteration
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Never Rarely Sometimes Usually Always 0 0 0 0 0
1 1 1 1 1
2 2 2 2 2
3 3 3 3 3
4 4 4 4 4
Solid, incontinence for solid stool; liquid, incontinence for liquid stool; gas, incontinence for gas. Never, 0; rarely, <1/mo; sometimes, <1/wk, >1/mo; usually, <1/d; >1/wk; always, >1/d. Score 0 indicates perfect continence and 20, complete incontinence. Data from Jorge and Wexner (10).
Not at all
Hardly
A little
Quite a bit
A lot
0
1
2
3
4
doi:10.1016/j.ijrobp.2010.01.033
CLINICAL INVESTIGATION
Prostate
LONGITUDINAL STUDY OF INTESTINAL SYMPTOMS AND FECAL CONTINENCE IN PATIENTS WITH CONFORMAL RADIOTHERAPY FOR PROSTATE CANCER HANS GEINITZ, M.D.,* REINHARD THAMM, M.D.,* MONIKA KELLER, M.D.,y SABRINA T. ASTNER, M.D.,* CHRISTINE HEINRICH, M.D.,* CHRISTIAN SCHOLZ,* CHRISTIAN PEHL, M.D.,z SIMONE KERNDL,* NINA PRAUSE,* RAYMONDE BUSCH, M.SC.,x MICHAEL MOLLS, M.D.,* AND FRANK B. ZIMMERMANN, M.D.* y
*Klinik und Poliklinik fu¨r Strahlentherapie und Radiologische Onkologie, Technische Universita¨t Mu¨nchen, Mu¨nchen, Germany; Sektion Psychoonkologie, Klinik fu¨r Psychosomatische und Allgemeine Klinische Medizin, Universita¨tsklinik Heidelberg, Heidelberg, Germany; zMedizinische Klinik, Kreiskrankenhaus Vilsbiburg, Vilsbiburg, Germany; xInstitut fu¨r Medizinische Statistik und Epidemiologie, Technische Universita¨t Mu¨nchen, Mu¨nchen, Germany Purpose: To prospectively assess the intestinal symptoms and fecal continence in patients who had undergone conformal radiotherapy (CRT) for prostate cancer. Methods and Materials: A total of 78 men who had undergone definitive CRT for prostate cancer were evaluated. The patients were assessed before, during (treatment Weeks 4 and 6), and 2, 12, and 24 months after CRT completion. The intestinal symptoms and fecal continence were evaluated with comprehensive standardized questionnaires. Results: The intestinal symptoms were mostly intermittent, with only a small minority of patients affected daily. Defecation pain, fecal urge, and rectal mucous discharge increased significantly during therapy. Defecation pain and rectal mucous discharge had returned to baseline levels within 8 weeks and 1 year after CRT, respectively. However, fecal urge remained significantly elevated for #1 year and then returned toward the pretreatment values. The prevalence of rectal bleeding was significantly elevated 2 years after CRT. Fecal continence deteriorated during CRT and remained impaired at 1 year after treatment. Incontinence was mostly minor, occurring less than once per week and predominantly affecting incontinence for gas. Conclusion: Intestinal symptoms and fecal incontinence increased during prostate CRT. Except for rectal bleeding, the intestinal symptoms, including fecal incontinence, returned to baseline levels within 1–2 years after CRT. Thus, the rate of long-term late radiation-related intestinal toxicity was low. Ó 2011 Elsevier Inc. Prostate cancer, Conformal radiotherapy, Intestinal symptoms, Fecal continence, Intestinal bother.
weeks after RT. In contrast, chronic side effects can occur months or even years after the initiation of CRT and can persist for longer periods. Severe chronic side effects after CRT for prostate cancer are rare, with a frequency of <5%. Recently, fecal incontinence has also been recognized as a side effect of prostate RT. Although some prospective data on the deterioration of fecal continence after non-CRT for prostate cancer (3–5) exist, data for CRT remain rare (6, 7). In the present study, we prospectively evaluated the intestinal symptoms, fecal incontinence, and bother from intestinal symptoms before, during, and 1 and 2 years after definitive prostate CRT using standardized questionnaires.
INTRODUCTION Prostate cancer is one of the most frequent malignancies in men in the Western hemisphere. The curative treatment options include definitive radiotherapy (RT) and radical prostatectomy. Because modern RT and radical prostatectomy have been judged to be equally effective (1), a special emphasis has been placed on treatment-related side effects. Although surgery carries a greater risk of adverse effects in the urogenital tract, external beam RT has been associated with more intestinal side effects. Since the introduction of computed tomography-based three-dimensional conformal radiotherapy (CRT), the side effects from external beam RT for prostate cancer have significantly decreased (2). Intestinal symptoms during or after CRT include increased defecation frequency, intermittent rectal bleeding, rectal mucous discharge, defecation pain, and fecal urge. Acute toxicity during CRT normally ceases within several days or a few
METHODS AND MATERIALS Eligibility criteria All patients underwent CRT at the Department of Radiation Oncology, Technische Universitaet Munich. The participants for the
Reprint requests to: Hans Geinitz, M.D., Klinik und Poliklinik fu¨r Strahlentherapie der Technischen Universita¨t Mu¨nchen, Ismaninger Straße 22, 81675 Mu¨nchen, Germany. Tel: (++49) 89-4140-5412; Fax: (++49) 89-4140-4587; E-mail: [email protected]
Supported by a grant from the Deutsche Krebshilfe. Conflict of interest: none. Received June 26, 2009, and in revised form Nov 17, 2009. Accepted for publication Jan 9, 2010. 1373
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present prospective study on the symptoms and quality of life were recruited between December 2001 and February 2003. All patients who had undergone CRT for localized (Stage cN0 cM0) prostate cancer, either as definitive treatment or in the adjuvant setting, were eligible. Participants had to have a sufficient command of the German language and to give written informed consent. The local ethics committee approved the study, which was performed in accordance with the Helsinki Declaration. We report on the intestinal symptoms and fecal continence of patients undergoing definitive CRT. The data on quality of life and from patients receiving adjuvant treatment will be reported separately.
Treatment Conformal RT (6–15-MeV photons) was used throughout the whole RT course. None of the patients received treatment to the pelvic lymphatics. The dose per fraction was 2.0 Gy (International Commission on Radiation Units and Measurements report 50). Three-dimensional planning was performed using the HELAX TMS planning system (Nucletron, Veenendaal, The Netherlands). The dose prescription and clinical target volumes were defined according to the risk group. Low-risk patients (Stage T1-T2a, Grade 1 or 2, Gleason score 2–6, and pretreatment prostate-specific antigen [PSA] level <10 ng/mL) were treated with 70 Gy to the prostate. The intermediate-risk patients (Stage T1-T2, Grade 3, Gleason score 7–10, and/or PSA level >10 but <20 ng/mL) were treated with 70 Gy to the prostate and the base of the seminal vesicles. The highrisk patients (Stage T3 or PSA level >20 but <50 ng/mL) were treated with 74 Gy to the prostate and the base of the seminal vesicles. The intermediate- and high-risk patients were offered neoadjuvant hormonal therapy for 3–6 months before and during RT. Additional adjuvant hormonal therapy was recommended to patients with high-risk prostate cancer. The safety margins for the planning target volume were 1 cm in all directions, except for in patients who received 74 Gy, for whom the safety margin in the dorsal direction was 0.5 cm for the first 8 Gy. A rectal balloon catheter for internal immobilization of the prostate was used in 69 patients (89%) during CRT (8). The dose constraint for the rectum was that not more than 25% of the rectum should receive >70 Gy.
Patient assessment and instruments The patients were evaluated 1 week before the onset of CRT, at the end of treatment weeks 4 (40 Gy) and 6 (60 Gy), and at 8 weeks and 1 and 2 years after CRT completion. The rectal symptoms and fecal continence were assessed by one of us using the corresponding questionnaires (see the following sections). In addition, general data on patient and disease characteristics were collected. The symptom questionnaires were returned by the patients after they had completed additional quality-of-life material.
Rectal symptoms The rate of rectal symptoms was assessed using an ad hoc constructed eight-item questionnaire (rectal toxicity score, see Appendix) (9). Owing to the intermittent occurrence of most acute or chronic rectal symptoms in patients undergoing pelvic RT, the frequency, rather than the magnitude, of symptoms was scored. The score ranged from 0 (no symptoms, no stool medication) to 32 (daily occurrence of all seven symptoms and daily stool medication).
Fecal continence The fecal continence score of Jorge and Wexner (10) was used to evaluate fecal continence. The score ranged from 0 (perfect continence) to 20 (complete incontinence, see Appendix).
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Bother scale Bother from intestinal symptoms was evaluated with an ad hoc constructed five-point scale (see Appendix) (9).
Concomitant disease All patients were interviewed for the occurrence of concomitant disease before the onset of RT and at 12 and 24 months after therapy.
PSA values and biochemical recurrence Biochemical recurrence was defined according to the Radiation Therapy Oncology Group–American Society for Therapeutic Radiology and Oncology Phoenix definition (11) as an increase by $2 ng/mL greater than the nadir PSA level. Also, the start of hormonal therapy after RT was regarded as a biochemical failure.
Statistical analysis For the computation of the prevalence of intestinal symptoms or fecal continence and the calculation of changes over time, only the data from patients responding at any of the six follow-up points, were selected. The Friedman test was used to detect changes over time. When significant, the Wilcoxon test was performed to determine the differences to the pretreatment values. Bivariate correlations were calculated using the Spearman correlation coefficient. Stepwise linear regression analysis was performed to determine the independent predictors of long-term fecal symptoms and fecal incontinence (multivariate analysis). Significance was set at 5%. All tests were two sided.
RESULTS Recruitment Between December 2001 and February 2003, 105 patients who were scheduled to receive definitive CRT were informed of the present study. Of the 105 patients, 85 (81%) agreed to participate in the study, 12 (12%) denied participation, 6 (6%) had insufficient command of the German language, and 2 (2%) were unable to respond to the questionnaires because of psychiatric disorders. Of the 85 included patients, 8 failed to return their questionnaires before the start of therapy. Thus, 78 patients were evaluable. The response rate was high, with >90% of the patients responding to the questionnaires at 1 and 2 years after treatment (72 and 71 patients, respectively). Patient and treatment characteristics The sociodemographic and clinical characteristics are listed in Table 1. Within the 2-year follow-up period, 1 patient died of prostate cancer and 2 patients developed distant metastases. Dose–volume histogram data The dose constraint for the rectum (<25% of the rectum to receive >70 Gy) was fulfilled for 76 of the 78 patients. Of the 2 remaining patients, 1 received 70 Gy and 1 received 78 Gy. The median percentage of the volume of the rectum that received $35, $50, $55, $60, $65, and $70 Gy was 47%, 35%, 32%, 27%, 22%, and 9%, respectively. No significant difference was seen in these dose–volume histogram data between the patients with prostate doses
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Table 1. Sociodemographic and clinical characteristics Variable
Value
Patients (n) Age (y) Median Range Educational level Low Intermediate High Unknown Marital status Single Married/partner Unknown Risk group* Low Intermediate High Prostate dose (Gy) Median Range Neoadjuvant hormonal therapy Duration (mo) Median Range Adjuvant hormonal therapy Duration (mo) Median Range Disease status 2 y after CRT Biochemical relapse (Phoenix criteria) Distant metastasis Deceased Hormonal therapy for biochemical recurrence Concomitant disease Total (n) Mean Range Cardiovascular disease Gastrointestinal disease Diabetes mellitus Second tumor Pulmonary disease Depression
78 70 51–86 1 (1) 43 (55) 31 (40) 3 (4) 9 (12) 64 (82) 5 (6) 31 (40) 19 (24) 28 (36) 70.0 64.0–74.0 73 (94) 3 1–19 32 (41) 2 1–26 5 (7) 2 (3) 1 (1) 2 (3) 1.5 0–6 48 (62) 14 (18) 10 (13) 9 (12) 9 (12) 3 (4)
Abbreviations: CRT = conformal radiotherapy; PSA = prostatespecific antigen. Data in parentheses are percentages. * Low, Stage T1-T2, World Health Organization Grade 1 or 2, and initial PSA level of #10 ng/mL; intermediate, Stage T1-T2, Grade 3, and/or PSA level >10 but #20 ng/mL; and high, Stage T3-T4 or PSA level >20 ng/mL.
of 70 Gy and 74 Gy, except for the median percentage of the volume of the rectum that received $70 Gy, which was lower in the patients receiving 70 Gy (8% vs. 18%, p <.001). Patients with a rectal balloon catheter (n = 69) had a significantly lower median percentage of the volume of the rectum that received $35, $50, $55, and $60 Gy than those without a balloon catheter (46% vs. 58%, p = .004; 35% vs. 45%, p = .007; 33% vs. 40%, p = .010; 29% vs. 35%, p = .024).
Fig. 1. Course of rectal symptom score. Greater values indicate more symptoms. Mean score standard error of mean. #p <.01; z p <.001 compared with pre-CRT values.
Intestinal symptoms The rectal symptom score increased during CRT and stayed elevated throughout the 2 years after CRT (p = .002, Fig. 1). The rectal symptoms were mostly intermittent and occurred daily only in a few of the symptomatic patients (Table 2). Defecation pain (p <.001) and fecal urge (p <.001) increased significantly and the rectal mucous discharge increased with borderline significance (p = 0.051) during therapy. Although defecation pain and rectal mucous discharge returned to baseline levels within 8 weeks and 1 year after CRT, respectively, fecal urge remained significantly elevated for #1 year and then returned toward the pretreatment values. The prevalence of rectal bleeding did not increase within 1 year after CRT, but it was significantly elevated at 2 years after CRT (p = .002). Stool frequency increased during CRT (p <.001) and had returned to baseline levels within 8 weeks after CRT. Fecal continence Fecal incontinence, as measured using the fecal continence score, increased during therapy and did not return to baseline levels throughout 1 year after CRT (p = .006, Fig. 2). At 2 years after treatment, the fecal continence score was not significantly different from baseline levels. Although incontinence for solid and liquid stool did not augment significantly within the observation period (p = .086 and p = .066), an increase in incontinence for gas occurred during RT (p = .014) and remained significantly greater than pretreatment levels at 1 year after therapy. At 2 years after therapy, incontinence for gas did not differ significantly from baseline levels. Patients reported an increase in lifestyle alterations during and 8 weeks after CRT (p = .009) with a return toward baseline levels at 1 year after therapy. The use of pads for fecal incontinence did not increase significantly. Daily incontinence episodes were absent before and during CRT. The rate of daily incontinence had increased to 2% at
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Table 2. Intestinal symptoms and stool frequency before CRT, at 60 Gy, and 2 years after CRT Before CRT (%) Variable Blood Mucous Defecation pain Tenesmus Flatulence Diarrhea Fecal urge Stool frequency Mean (n) Range (n) >2/d (%)
Any 8 4 4 13 60 49 38 1.5 1–3 7
At 60 Gy (%)
Weekly
Daily
0 0 0 0 11 0 2
0 0 0 0 4 0 0
Any
2 y After CRT (%)
Weekly
Daily
p*
2 4 0 2 17 2 4
0 0 6 0 9 0 2
NS 0.016 0.002 NSy NSy NSy <0.001 <.001
9 15 30 17 72 50 66 2.0 1–24 27
Any 28 8 2 6 58 40 44
Weekly
Daily
p*
4 0 0 0 17 4 6
1 0 0 0 8 2 6
0.004 NS NS NSy NSy NSy NS NS
1.4 1–4 2
Abbreviations: CRT = conformal radiotherapy; NS: not significant. * p Values for entire distribution compared with pre-CRT values (Wilcoxon signed rank test, used only when Friedman test result was significant) y Friedman test result not significant.
2 years after RT; however, it involved only incontinence for gas. The rate of any incontinence (from <1/mo through daily) for solid stool, liquid stool, and gas was 6%, 12%, and 25% at baseline, 12%, 22%, and 44% at 60 Gy, and 10%, 24%, and 27% at 2 years after RT (Table 3). The fecal continence score correlated with the rectal symptom score throughout the observation period (Spearman rho, 0.398–0.619, p <.001).
Intestinal bother Bother from intestinal symptoms increased during RT, remained significantly elevated throughout 1 year after CRT (p <.001), and had returned to baseline levels at 2 years after CRT. Before CRT, 19% of the patients reported bother from intestinal symptoms with no patient bothered ‘‘a lot.’’ At 60 Gy, 64% reported intestinal bother and 2% stated they were ‘‘bothered a lot.’’ The corresponding percentages were 33% and 2% at 2 years after RT. The following symptoms most closely correlated with bother from intestinal symptoms at 2 years after CRT: fecal urge (rho = 0.537, p <.001) and fecal incontinence (rho = 0.468, p <.001).
Pretreatment predictors of long-term fecal continence and fecal symptoms The following variables were tested in stepwise linear regression analysis for their association with the 2-year fecal continence score and 2-year rectal toxicity score: age at the start of therapy (continuously), number of concomitant diseases (zero to six), diabetes mellitus (no vs. yes), smoking (no vs. yes), body mass index (continuously), neoadjuvant hormonal therapy (yes vs. no), total radiation dose (continuously), rectal balloon (no vs. yes). The only negative predictor for long-term fecal continence on multivariate analysis was diabetes mellitus (p = .028). The only predictor of long-term fecal symptoms was a high number of concomitant diseases (p = .021).
DISCUSSION In the present prospectively assessed patient population we observed that intestinal symptoms and fecal incontinence increased during CRT for prostate cancer. Although most of the symptoms, including fecal incontinence, had returned to baseline levels within 1–2 years after CRT, the prevalence of rectal bleeding had increased significantly beyond baseline levels at 2 years after CRT. Intestinal symptoms and fecal incontinence were mostly intermittent and occurred only in a few patients daily. Fecal incontinence was predominantly minor at a frequency of less than once per week and encompassed mainly incontinence for gas. The symptoms most closely associated with intestinal bother were fecal urge and fecal incontinence. Prospective longitudinal studies on the prevalence of intestinal symptoms in patients with CRT for prostate cancer have
Fig. 2. Course of fecal continence score. Greater values equal more incontinence. Mean score standard error of mean. *p <.05; #p <.01 compared with pre-CRT values.
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Table 3. Fecal incontinence before CRT, at 60 Gy, and 2 years after treatment Variable
Never Rarely Sometimes Usually Always (%) (%) (%) (%) (%)
Before CRT Solid stool 94 Liquid stool 88 Gas 75 Wears pad 100 Lifestyle alteration 87 At 60 Gy Solid stool 89 Liquid stool 78 Gas 56 Wears pad 96 Lifestyle alteration 72 At 2 y after CRT Solid stool 90 Liquid stool 76 Gas 73 Wears pad 94 Lifestyle alteration 94
4 12 13 0 7
2 0 10 0 4
0 0 2 0 2
0 0 0 0 0
8 16 21 2 9
4 6 13 2 13
0 0 10 0 2
0 0 0 0 4
4 8 8 4 4
6 14 6 0 0
0 2 11 0 2
0 0 2 2 0
Abbreviation: CRT = conformal radiotherapy. Never, 0; rarely, <1/mo; sometimes, <1/wk, $1/mo; usually, <1/d; $1/wk; always, $1/d.
been infrequent; however, the results were mostly compatible with the findings in our patient sample. Fransson et al. (12) reported a prospective analysis of bowel symptoms before and 1, 3, and 5 years after CRT for prostate cancer. A total of 363 patients were included in the study, but 79 did not respond to the baseline questionnaire. Patients were treated with doses of 60.8–78 Gy, and 46% received additional hormonal therapy. As assessed using the Prostate Cancer Symptom Scale self-assessment questionnaire, ‘‘blood in stools,’’ ‘‘stool leakage,’’ and ‘‘mucous in stools’’ increased after therapy and remained elevated at 5 years after treatment. Staff et al. (13) evaluated intestinal symptoms in 100 patients who received definitive CRT at doses of 70–74 Gy at #10 months after treatment. Patients were treated between 1998 and 2000, and 68 of the 100 patients had received neoadjuvant hormonal therapy. Post-treatment information was collected 1–3 months and 5–10 months after the end of treatment. In agreement with the findings from our study, bowel frequency and bowel urgency significantly increased in the whole patient set. In contrast, bowel bleeding and bowel cramping did not display significant changes over time. Hovdenak et al. (14) reported on 96 patients who had undergone CRT for localized prostate cancer with doses of 66–70 Gy. Symptoms were recorded before treatment, at 2, 4, and 6 weeks into treatment, and 2 and 8 weeks after CRT. ‘‘Loose stools,’’ ‘‘tenesmus,’’ ‘‘abdominal pain,’’ ‘‘bloating,’’ and ‘‘blood in stools’’ increased significantly during CRT and remained elevated at 8 weeks after treatment completion. Beard et al. (15) evaluated gastrointestinal symptoms in 25 patients who had undergone CRT with 66.2 Gy for localized prostate cancer before RT and at 3 and 12 months after the initiation of treatment. The investigators reported an increase in
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‘‘diarrhea/two to three loose stools’’ from 0% before CRT to 32% at 3 months and 48% at 12 months (15). They also reported an increase in ‘‘urgency/tenderness’’ from 0% to 80% and 64%, respectively; however, no p values were provided. It has been recognized in the published reports that pelvic and abdominal RT impairs fecal continence (3, 5, 7, 9, 16–25). The pathophysiologic basis of radiation-induced fecal incontinence is not entirely well understood and seems to be caused by a variety of sensory and/or motor dysfunctions. Impaired reservoir function and disturbed rectoanal sensory performance (3, 26–28), as well as an impaired function of the external (27–29) and internal (16, 28) sphincter muscle, might contribute to clinically overt incontinence. Histologic examinations have disclosed hypertrophy of the muscularis mucosae and muscularis propia, damage to the myenteric plexus and to the extrinsic innervation, and fibrosis of the anorectum (16, 28, 30). Although retrospective data have shown a rate of 5–58% of varying degrees of fecal incontinence after CRT for prostate cancer (9, 19, 21, 23), few prospective studies with a longitudinal assessment have been published. Yeoh et al. prospectively analyzed 38 patients who had undergone definitive nonconformal RT and 29 patients who had undergone CRT for prostate cancer using 55 Gy in 20 fractions or 64 Gy in 32 fractions (3–6). The anorectal symptoms were assessed by questionnaire. In addition, anorectal manometry was performed before and at various times after CRT. Fecal incontinence was impaired 4–6 weeks and 1 and 2 years after the end of treatment. Progressive reductions occurred in basal anal pressure and anal pressure in response to squeeze and rectal compliance, irrespective of the treatment modality (CRT vs. non-CRT). Kushwaha et al. (31) prospectively evaluated patients who had undergone non-CRT to the pelvis for prostate or bladder cancer. They found deterioration in fecal continence at 6 weeks and 6 months after treatment completion. Manometry disclosed a reduction in the basal and voluntary anal pressure and in the ‘‘maximum tolerated rectal volume.’’ Retrospective studies, correlating fecal incontinence to the doses to the anal canal or rectum using dose–volume histograms derived from the initial planning computed tomography scan, have shown only minor to moderate associations between the incontinence of stool and the dose–volume parameters (7, 21, 23–25, 32–34). Possible explanations for the generally weak correlations between fecal incontinence and anorectal dose–volume histogram parameters could include difficulties in identifying the anal canal on the planning computed tomography scan. Also, the radiationsensitive structures responsible for incontinence might not only be the anal canal, but also structures such as the pelvic floor muscles, including the puborectalis and ischiorectalis muscles; the anal and rectal mucosa, including the anal vessel cushions; pelvic nerves, such as the hypogastric nerve and pudendal nerve; and the small vessels responsible for the supply of the anorectal sphincter apparatus. In addition to the radiation dose at the anosphincter, other factors that alter
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the pelvic innervation (e.g., abdominopelvic surgery, diabetes) or stool consistency (including radiation to the small bowel) might play a major role in the integrity of fecal continence after pelvic RT. One limitation of our study was that we did not assess intestinal symptoms and fecal continence before the onset of neoadjuvant hormonal therapy, because most of the patients were already receiving antiandrogen treatment at their first visit to our department. This situation probably reflects a common circumstance in many radio-oncology departments in Germany. Almost all patients receiving neoadjuvant hormonal therapy (n = 73) received that therapy until the end of CRT. The short-term effects of CRT on intestinal symptoms and fecal continence were most likely, therefore, not influenced by hormonal therapy (because its prevalence did not change during that period). The number of patients receiving antiandrogen therapy declined to 10 and 9 at 1 and 2 years after CRT, respectively. Because androgen deprivation therapy can cause diarrhea (35), we could not rule out that some bias was introduced by the total duration of neoadjuvant/adjuvant hormonal therapy. In contrast, neither the duration of neoadjuvant/adjuvant hormonal therapy nor the prevalence of hormonal therapy at 1 and 2 years correlated significantly with the rectal symptom score or fecal continence score. The prevalence or duration of hormonal therapy did not correlate with the incidence of diarrhea or stool frequency at any point. Rectal balloon catheters were used in our study for internal immobilization of the prostate and sparing of the dorsal rectal wall. The insertion of a rectal balloon catheter leads to an anterior shift of the anterior rectal wall with or without a posterior shift of the dorsal rectal wall, resulting in an increased distance between the prostate and posterior rectal wall (8, 36). This effect causes a reduction in the dose to posterior rectal wall, without changing the dose to the anterior rectal wall significantly (8, 37). In a small randomized trial, the use of a rectal balloon was associated with a reduction of
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high-grade telangiectasia in the rectal mucosa and a reduction of greater than Grade 1 late rectal toxicity (37). Nevertheless, a larger randomized clinical trial with sufficient follow-up has not yet been published. Regarding the application of our study results to those from institutions not using balloon catheters, we do not believe the results would change fundamentally, except for possibly a slightly greater level of rectal symptoms during and after CRT in those patients without a balloon catheter. In our patients, fecal incontinence was associated with greater levels of intestinal bother. We reported, in a previous study, that patients with fecal incontinence after CRT for prostate cancer also noted a lower quality of life (9). Thus, one aim of future trials of CRT or intensity-modulated RT for prostate cancer might be to identify the radiosensitive structures responsible for fecal incontinence, and, subsequently, design radiation plans to spare those regions from high radiation doses, without compromising the dose to the planning target volume. However, one must remember that most of our patients were not affected by radiation-induced fecal incontinence, and, if they were, the symptoms were mostly minor, with a tendency to regress >1 year after RT. Because the number of patients in our study was limited, the result should be confirmed in a larger prospective trial.
CONCLUSION In the present prospectively analyzed patient cohort, we observed that intestinal symptoms and fecal incontinence increased during CRT for prostate cancer. All the symptoms, except for rectal bleeding, had returned to baseline levels within 1–2 years after CRT. Thus, the rate of long-term late radiationrelated intestinal toxicity was low. Intestinal symptoms and fecal incontinence were mostly intermittent and occurred daily only in a few patients. Fecal incontinence was predominantly minor and mainly involved incontinence for gas.
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7. Heemsbergen WD, Hoogeman MS, Hart GA, et al. Gastrointestinal toxicity and its relation to dose distributions in the anorectal region of prostate cancer patients treated with radiotherapy. Int J Radiat Oncol Biol Phys 2005;61: 1011–1018. 8. Wachter S, Gerstner N, Dorner D, et al. The influence of a rectal balloon tube as internal immobilization device on variations of volumes and dose–volume histograms during treatment course of conformal radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2002;52:91–100. 9. Geinitz H, Zimmermann F, Thamm R, et al. Late rectal symptoms and quality of life after conformal radiation therapy for prostate cancer. Radiother Oncol 2006;79:341–347. 10. Jorge JM, Wexner SD. Etiology and management of fecal incontinence. Dis Colon Rectum 1993;36:77–97. 11. Roach M III, Hanks G, Thames H Jr., et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65:965–974.
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12. Fransson P, Bergstrom P, Lofroth PO, et al. Five-year prospective patient evaluation of bladder and bowel symptoms after dose-escalated radiotherapy for prostate cancer with the BeamCathÒ technique. Int J Radiat Oncol Biol Phys 2006;66: 430–438. 13. Staff I, Salner SA, Bohannon R, et al. Disease-specific symptoms and general quality of life of patients with prostate carcinoma before and after primary three-dimensional conformal radiotherapy. Cancer 2003;98:2335–2343. 14. Hovdenak N, Karlsdottir A, Sorbye H, et al. Profiles and time course of acute radiation toxicity symptoms during conformal radiotherapy for cancer of the prostate. Acta Oncol 2003;42: 741–748. 15. Beard CJ, Propert KJ, Rieker PP, et al. Complications after treatment with external-beam irradiation in early-stage prostate cancer patients: A prospective multiinstitutional outcomes study. J Clin Oncol 1997;15:223–229. 16. Varma JS, Smith AN, Busuttil A. Function of the anal sphincters after chronic radiation injury. Gut 1986;27:528–533. 17. Widmark A, Fransson P, Tavelin B. Self-assessment questionnaire for evaluating urinary and intestinal late side effects after pelvic radiotherapy in patients with prostate cancer compared with an age-matched control population. Cancer 1994;74: 2520–2532. 18. Crook J, Esche B, Futter N. Effect of pelvic radiotherapy for prostate cancer on bowel, bladder, and sexual functioning: The patients’ perspective. Urology 1996;47:387–394. 19. Hanlon A, Watkins Bruner D, Peter R, et al. Quality of life study in prostate cancer patients treated with three-dimensional conformal radiation therapy: Comparing late bowel and bladder quality of life symptoms to that of the normal population. Int J Radiat Oncol Biol Phys 2001;49:51–59. 20. Fransson P, Damber JE, Tomic R, et al. Quality of life and symptoms in a randomized trial of radiotherapy versus deferred treatment of localized prostate carcinoma. Cancer 2001;92: 3111–3119. 21. Vordermark D, Schwab M, Ness-Dourdoumas R, et al. Association of anorectal dose-volume histograms and impaired fecal continence after 3D conformal radiotherapy for carcinoma of the prostate. Radiother Oncol 2003;69:209–214. 22. Koper PC, Jansen P, van Putten W, et al. Gastro-intestinal and genito-urinary morbidity after 3D conformal radiotherapy of prostate cancer: Observations of a randomized trial. Radiother Oncol 2004;73:1–9. 23. Fokdal L, Honore H, Hoyer M, et al. Dose-volume histograms associated to long-term colorectal functions in patients receiving pelvic radiotherapy. Radiother Oncol 2005;74:203–210. 24. al-Abany M, Helgason AR, Cronqvist A-KA, et al. Toward a definition of a threshold for harmless doses to the analsphincter region and the rectum. Int J Radiat Oncol Biol Phys 2005;61:1035–1044.
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25. Peeters ST, Hoogeman MS, Heemsbergen WD, et al. Rectal bleeding, fecal incontinence, and high stool frequency after conformal radiotherapy for prostate cancer: normal tissue complication probability modeling. Int J Radiat Oncol Biol Phys 2006;66:11–19. 26. Iwamoto T, Nakahara S, Mibu R, et al. Effect of radiotherapy on anorectal function in patients with cervical cancer. Dis Colon Rectum 1997;40:693–697. 27. Kim GE, Lim JJ, Park W, et al. Sensory and motor dysfunction assessed by anorectal manometry in uterine cervical carcinoma patients with radiation-induced late rectal complication. Int J Radiat Oncol Biol Phys 1998;41:835–841. 28. Berndtsson I, Lennernas B, Hulten L. Anorectal function after modern conformal radiation therapy for prostate cancer: A pilot study. Tech Coloproctol 2002;6:101–104. 29. Yeoh EE, Sun W, Russo A, et al. A retrospective study of the effects of pelvic irradiation for gynecological cancer on anorectal function. Int J Radiat Oncol Biol Phys 1996;35:1003–1010. 30. Varma JS, Smith AN, Busuttil A. Correlation of clinical and manometric abnormalities of rectal function following chronic radiation injury. Br J Surg 1985;72:875–878. 31. Kushwaha RS, Hayne D, Vaizey CJ, et al. Physiologic changes of the anorectum after pelvic radiotherapy for the treatment of prostate and bladder cancer. Dis Colon Rectum 2003;46: 1182–1188. 32. Fiorino C, Fellin G, Rancati T, et al. Clinical and dosimetric predictors of late rectal syndrome after 3D-CRT for localized prostate cancer: Preliminary results of a multicenter prospective study. Int J Radiat Oncol Biol Phys 2008;70:1130–1137. 33. Fonteyne V, De Neve W, Villeirs G, De Wagter C, De Meerleer G. Late radiotherapy-induced lower intestinal toxicity (RILIT) of intensity-modulated radiotherapy for prostate cancer: the need for adapting toxicity scales and the appearance of the sigmoid colon as co-responsible organ for lower intestinal toxicity. Radiother Oncol 2007;84:156–163. 34. Valdagni R, Rancati T, Fiorino C, et al. Development of a set of nomograms to predict acute lower gastrointestinal toxicity for prostate cancer 3D-CRT. Int J Radiat Oncol Biol Phys 2008; 71:1065–1073. 35. Mason M. What implications do the tolerability profiles of antiandrogens and other commonly used prostate cancer treatments have on patient care? J Cancer Res Clin Oncol 2006;132(Suppl. 1):S27–S35. 36. Elsayed H, Bolling T, Moustakis C, et al. Organ movements and dose exposures in teletherapy of prostate cancer using a rectal balloon. Strahlenther Onkol 2007;183:617–624. 37. van Lin EN, Kristinsson J, Philippens ME, et al. Reduced late rectal mucosal changes after prostate three-dimensional conformal radiotherapy with endorectal balloon as observed in repeated endoscopy. Int J Radiat Oncol Biol Phys 2007;67: 799–811.
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Variable Blood Mucous Defecation pain Tenesmus Flatulence Diarrhea Fecal urge Stool medication
APPENDIX
Bother scale
Rectal symptom score
During the past month, how much have you been bothered by alterations in bowel habits?
Never Rarely Sometimes Usually Always 0 0 0 0 0 0 0 0
1 1 1 1 1 1 1 1
2 2 2 2 2 2 2 2
3 3 3 3 3 3 3 3
4 4 4 4 4 4 4 4
Never, 0; rarely, <1/mo; sometimes, <1/wk; >1/mo; usually, <1/d; >1/wk; always, >1/d. 0: no rectal symptoms; 32: greatest extent of rectal symptoms. Data from Geinitz et al. (9). Fecal continence score Variable Solid Liquid Gas Wears pad Lifestyle alteration
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Never Rarely Sometimes Usually Always 0 0 0 0 0
1 1 1 1 1
2 2 2 2 2
3 3 3 3 3
4 4 4 4 4
Solid, incontinence for solid stool; liquid, incontinence for liquid stool; gas, incontinence for gas. Never, 0; rarely, <1/mo; sometimes, <1/wk, >1/mo; usually, <1/d; >1/wk; always, >1/d. Score 0 indicates perfect continence and 20, complete incontinence. Data from Jorge and Wexner (10).
Not at all
Hardly
A little
Quite a bit
A lot
0
1
2
3
4