Faecal incontinence following radiotherapy for prostate cancer: A systematic review

Radiotherapy and Oncology 98 (2011) 145–153

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Systematic review

Faecal incontinence following radiotherapy for prostate cancer: A systematic review Yasuko Maeda a,⇑, Morten Høyer b, Lilli Lundby c, Christine Norton a,d a

Sir Alan Parks Physiology Unit, St. Mark’s Hospital, Harrow, UK; b Department of Oncology; and c Surgical Research Unit, Aarhus University Hospital, Denmark; d Bucks New University & Imperial College Healthcare NHS Trust, London, UK

a r t i c l e

i n f o

Article history: Received 15 September 2010 Received in revised form 6 December 2010 Accepted 8 December 2010 Available online 21 January 2011 Keywords: Faecal incontinence Radiotherapy Prostate cancer

a b s t r a c t Background: Faecal incontinence (FI) after radiotherapy is a known phenomenon, but has received little attention to date. This article aimed to review current knowledge on faecal incontinence related to radiotherapy for prostate cancer. Methods: PubMed was searched for English-language articles published from January 1966 to December 2009 using the primary keywords ‘faecal incontinence’, ‘prostate cancer’ and ‘radiotherapy’. Prospective, retrospective and controlled trials reporting FI as a complication of radiotherapy for prostate cancer were included. The retrieved titles and abstracts were screened permissively and evaluated as to whether they satisfied the predefined inclusion and exclusion criteria. Results: Nine hundred and ninety four articles were identified from the search. After step-wise review, 213 papers were selected for full article review of which 40 were selected for this review. The incidence of faecal incontinence following radiotherapy for prostate cancer varied from 1.6% to 58%. The mechanism of faecal incontinence was not entirely clear but it is most likely due to injury to the nerve plexus of the rectal muscular layer. Correlation between rectal dose–volume parameters and incidence is equivocal, although some studies suggest parameters confined to the lower rectum and/or anal canal may be of value to predict the extent of the injury and could be used as constraints in the dose planning process. Conclusions: Interpretation of data is limited due to lack of large cohort studies with data on pre-treatment continence status and because variable instruments have been used to assess the severity of the condition. Well-designed prospective studies are needed to investigate dosimetric parameters focusing on the anal canal and sphincter apparatus. Considering the spatial distribution of radiation to the rectum may identify a more direct linkage between radiation damage and faecal incontinence. Ó 2010 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 98 (2011) 145–153

Background Radiotherapy is an established curative treatment for prostate cancer with a significant survival benefit [64]. The technique of administering radiation has evolved and improved, particularly in the last 15 years, which has contributed to a reduction in adverse effects whilst preserving therapeutic effect. Intensity modulated (IMRT) and image guided radiotherapy (IGRT) are the latest advancement of techniques that allow precise and conformal delivery of the radiation to the target whilst minimising the dose to normal tissues. However, some normal tissues surrounding a tumour still receive inadvertent radiation, which may result in irreversible and chronic complications. Faecal incontinence (FI) is a known sequela of radiotherapy but has received little attention to date in comparison to other toxicities and complications. The maintenance of faecal continence is a product of stool consistency, colorectal activity and the harmoni-

⇑ Corresponding author. Address: Sir Alan Parks Physiology Unit, St. Mark’s Hospital, Northwick Park, Watford Road, Harrow HA1 3UJ, UK. E-mail address: [email protected] (Y. Maeda). 0167-8140/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2010.12.004

ous functioning of external and internal anal sphincters [18] and interruption of any of these factors alone or in combination may result in symptoms of incontinence, which can vary from loss of controlling flatus, a small seepage of faecal material on underwear, loss of stool due to failure to resist the urge for timely defaecation, or loss of stool without any advance urge and sensation. FI is thought to be caused by radiation exposure of the ano-rectum and result in complex constellation of changes in bowel frequency, stool consistency, urgency, bleeding, pain and mucous loss. However, the precise mechanism is not known and the relationship between dose–volume parameters and the severity of FI symptoms has not been fully established. This article presents a systematic literature review on current knowledge of incidence, mechanism, assessment and the treatment of FI following radiotherapy for prostate cancer. Methods Search strategy We searched the PubMed database, using the primary keywords ‘faecal incontinence’, ‘prostate cancer’ and ‘radiotherapy’ for

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English-language articles published from January 1966 to December 2009. A search using each keyword was performed, followed by a combination of two of them and finally all three keywords. In the second step, each combination of two primary keywords was combined with one of the following secondary keywords: ‘rectal morbidity’, ‘anal morbidity’, ‘late reaction’, ‘acute reaction’, ‘toxicity’, ‘faecal urgency’ and ‘radiation injuries’ to allow broad and comprehensive yet sufficiently focused search of the literature. The retrieved titles and abstracts were screened by two authors (Y.M., M.H.). Titles and abstracts were screened permissively, such that a study was included if it had any indication of being eligible. The articles selected for full text review were evaluated as to whether they satisfied the inclusion and exclusion criteria. Any disagreement was resolved by the third and fourth author’s opinion. Inclusion criteria Studies regarding primary radiotherapy for prostate cancer and:  Prospective, retrospective and controlled trials reporting FI as a complication of radiotherapy for prostate cancer.  Studies regarding other gastrointestinal and non-gastrointestinal complications relating to radiotherapy for prostate cancer which include mechanism and tissue damage descriptions of the pelvis, rectum and/or anal canal and FI. Exclusion criteria  Studies reporting radiotherapy for a primary cancer other than prostate cancer.  Studies regarding surgical operative techniques or complications of surgical operations for prostate cancer.  Studies focusing on the technical aspects of radiotherapy with no report on adverse effects.  Studies reporting secondary malignancy as a consequence of radiotherapy.  Studies reporting diagnosis and management of non-gastrointestinal complications relating to radiotherapy for prostate cancer, such as urinary incontinence, urinary retention, renal failure and sexual dysfunction.  Studies regarding other gastrointestinal complications associated with radiotherapy, such as enteritis, rectovaginal/rectourethral fistula, bleeding, rectal ulcer without description of mechanism and no description of symptoms associated with FI.  Studies which contain a description of FI, sphincter control or its management, but the data on incontinence cannot be specifically unravelled due to an analysis based on composite scoring which included other complications or toxicity data (such as bleeding, proctitis, etc.).  Studies regarding palliative radiotherapy.  Case reports.  Letters and comments.  Review and seminar articles.  Literature written in languages other than English. Results Nine hundred and seventy four titles (excluding duplicates) were identified through the search of which 40 have been included for this review. The study selection process is illustrated in Fig. 1. The Results section is written solely based on the literature identified by the systematic search. Other papers cited in Background and Discussion sections were chosen outside this search strategy.

974 titles found by search 974 Titles

421 Excluded • 164: Other complications • 129: Radiotherapy outcome and technique • 57: Other primary malignancy • 45: Secondary malignancy and metastasis • 20: Surgical technique and complication • 6: Case report 553 abstracts reviewed

340 Excluded • 193: Other complications • 121: Radiotherapy outcome and technique • 19: Review, comment, letter • 3: Other primary malignancy • 3: Surgical technique and complication • 1: Secondary malignancy and metastasis • 1: Content duplicate 213 Full papers retrieved 173 Excluded • 142: Other complications • 16: Radiotherapy outcome and technique • 7: Other primary malignancy • 6: Review, comment, letter • 2: Content duplication 40 papers included in review Fig. 1. Flow of literature search and selection.

Incidence of faecal incontinence Our search yielded eight studies with incidence data (Table 1). In studies comparing the outcome and complications of surgery (prostatectomy) alone with radiotherapy alone or surgery combined with radiotherapy for locally advanced prostate cancer, it has been reported that the likelihood of prostatectomy patients developing bowel urgency was lower than those who had radiotherapy alone [2,30,51]. Cumulative incidence of soiling and FI after external beam radiotherapy has been estimated to be 58% and 57%, respectively, at 3 years and 5% of patients have a moderate to severe complaint [29]. It appears that FI often presents in the acute phase during or shortly after radiotherapy. It may be persistent as a late radiation related event and does not often resolve spontaneously. One study reported that it is still problematic at 15 years after external beam radiotherapy in 20% of the patients, which was unchanged since follow-up of the same group at 4 years [24]. Other studies report the new onset of FI at 2 years after radiotherapy and this has been observed consistently [14] or incidence has gradually increased throughout the follow-up period [43]. The incidence is similar in patients following brachytherapy. One study of high-dose-rate brachytherapy showed 11–25% of patients reported symptoms of FI that did not remit throughout the follow-up period up to 88 months [10,62]. It is also reported that development of these symptoms during the acute phase of radiotherapy (up to 120 days post-treatment) is a predictor of the same problems in the medium to long-term [29]. Interpretation of these data is difficult as some of the patients present with pre-existing symptoms of soiling and incontinence prior to the treatment for prostate cancer. In a study investigating

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Y. Maeda et al. / Radiotherapy and Oncology 98 (2011) 145–153 Table 1 Incidence and prevalence of faecal incontinence following radiotherapy for prostate cancer. Authors (Year)

Study design

Number of patients

Radiotherapy technique

Follow-up

Pre radiotherapy assessment

Assessment of FI

Symptoms of FI assessed

Incidence

Heemsbergen et al. [29]

Randomised study

Rectangular field (n = 98) Conformal (n = 99)

Conventional (rectangular) vs. conformal radiotherapy, 66 Gy, 2 Gy per fraction

At least one follow-up

Soiling 8%, incontinence 4%, urgency 12%

Questions answered on four-point scales

Urgency, incontinence, soiling

Soiling 58%, incontinence 57%, urgency 35% at 3 years (all estimated cumulative at 3 years)

De Meerleer et al. [15]

Cross-sectional study

114 patients

IMRT (72–78 Gy, 2 Gy per fraction)

At 3 months

No data

Yeoh (2001) and in-house developed questionnaire

Urgency, incontinence

Incontinence 7%

Borchers et al. [10]

Prospective, unrandomised

132 patients

125 I seeds, prescription dose 145 Gy

At 1 year

Weekly to daily incontinence 13%, 1–2/ month 10%

EBSQ: incontinence in 5-scales (never, daily, 1/week, 1–2/ month, bothersome)

Incontinence

Weekly to daily incontinence in 11%

Fiorino et al. [22]

Prospective, observational

718 patients

3D-conformal, P70 Gy, 1.8–2.0 gy per fraction

At 1 month, then every 6 months up to 3 years

No data

Fiorino (2008) questionnaire from AIROPROS 01– 01 study

Urgency, incontinence

7.9% moderate to severe incontinence during posttreatment followup, 2.6% chronic at 36-month followup

Crook et al. [14]

Cross-sectional cohort study

192 patients

4-Field box technique, 65–66 Gy, a few patients (number not specified) received pelvic RT, 10% with hypofractionation

At a mean 33 months (12– 72)

No data

Modified questionnaire, incontinence yes or no

Incontinence

Incontinence 8%

Fransson and Widmark [24]

Prospective, external beam radiotherapy (EBRT) vs. agematched control

EBRT (n = 29), control (n = 37)

4-Field box technique, average total of 64.8 Gy, 2 Gy per fraction

At 4, 8, and 15 years

No data

PCSS

Urgency, incontinence, QoL

20% of quite a bit and very much stool leakage at 15 years

Odrazka et al. [43]

Cross-sectional cohort study

320 patients

3D-conformal, 70 or 74 Gy, 2 Gy per fraction

Every 3 month for the first 2 years, every 6 months for the following 3 years and yearly thereafter

No data

Fox chase modification of RTOG/LENT

Incontinence

Incontinence 1.6%

Wahlgren et al. [62]

Cross-sectional cohort study, comparison with random sampled non prostate cancer population

158 patients

External beam RT and HDR brachytherapy

At 70–88 months post-treatment

No data

EORTC-QLQPR25 and RSSSA-PC

Incontinence

Incontinence 26.5%, daily incontinence 2.5%

FI after brachytherapy [10] 11% of patients reported weekly to daily incontinence at one year after brachytherapy and a further 9% reported incontinence once or twice a month. However, the percentage of patients reporting incontinence prior to brachytherapy was 13% and 10%, respectively. In another study, some patients reported urge incontinence (12%), soiling (8%), or faecal loss (3%) prior to the treatment [36]. The only study which had no patient with incontinence at baseline hence reporting the true incidence of radiotherapy-induced FI showed that 7% of patients developed symptoms of incontinence at 3 months after intensity modulated radiotherapy [15]. Interpretation of the actual incidence of FI post-radiotherapy is also hampered by a variety of assessment tools used across the studies (Table 2). Most have used a 4-point scale, but the questions or items have varied. The most commonly used tool to assess rectal toxicity in general, the RTOG (Radiation Therapy Oncology Group) scale, does not contain assessment of FI. Some studies used self-

assessment questionnaires of bowel symptoms to address incontinence-related symptoms including urgency, mucus leakage and the use of incontinence pads, but the grading applied for severity and frequency was variable. Use of incontinence or sanitary pads may also indicate rectal bleeding rather than FI and assessment of self-reported urgency may be unreliable as shown in test–retest analysis [3]. Commonly used scores to evaluate the severity of FI, such as Wexner’s incontinence score, St. Mark’s incontinence score or the validated Faecal Incontinence Quality of Life instrument have rarely been used in this group of patients and the presented data to date have been small [35]. Effect on quality of life Faecal incontinence after radiotherapy affects patients’ quality of life significantly [25] and persistently [41]. Some patients need to plan their life around toilet visits, which interferes with their

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Table 2 Faecal incontinence assessment tools used in radiotherapy literature. Assessment tool

Item/question

Grading

CTCEA ver 3.0[32]

Faecal incontinence

Grade 1: occasional use of pads

Grade 2: Daily use of pads

Grade 3: Interfering with activities of daily living; operative intervention indicated

Grade 4: Permanent bowel diversion indicated Grade 5: Death

RTOG/FC-LENT late toxicity criteria[28]

Faecal incontinence

Grade 1: no scale for FI

Grade 2: intermittent use of incontinence pads

Grade 3: persistent use of incontinence pads

Grade 4: no scale for FI

EORTC-QLQ-PR25[20]

Have you had any unintentional release (leakage) of stools?

Not at all

A little

Quite a bit

Very much

Yeoh et al. [65]

Frequency of urgency/faecal incontinence Severity of urgency

0: <1 episode/week

1 = <3 episodes/week

2 = P3 episodes/week

3 = 1 episode/day

0 = symptom absent

1 = mild, symptom could be ignored if patient did not think about it 1 = predominantly incontinent of flatus

2 = moderate, symptom could not be ignored, but did not influence daily activities 2 = incontinence necessitating the wearing of pad

3 = severe, symptom influenced daily activities 3 = incontinence necessitating a change of pad more than once a day

Severity of faecal incontinence

De Meerleer (2004) for urgency[15]

No specific question

Grade 1: mild symptom, could be ignored-no influence on daily activity, less than three episodes a week.

Grade 2: medication needed-daily activity impaired, three or more episodes a week

LENT SOMA[1]

Subjective sphincter control Management of sphincter control

Grade 1: Occasional Grade 1: occasional use of incontinence pads

Grade 2: Intermittent Grade 2: intermittent use of incontinence pads

Grade 3: Persistent Grade 3: Persistent use of incontinence pads

Grade 4: refractory Grade 4: Surgical intervention/ Permanent colostomy

Questionnaire from AIROPROS 01–01[59]

Did you ever sense the need to have a bowel movement without being able to pass stool? Did you experience the need to urgently go to the bathroom to have a bowel movement? Did you experience unintentional stool discharge? Did you notice mucous discharge? Did you need sanitary pads for stool/mucous discharge?

1. Never

2. Sometimes

3. Often

4. Continuously

1. Never

2. Sometimes

3. Often

4. Continuously

1. Never

2. Sometimes

3. Often

4. Continuously

1. Never

2. Sometimes

3. Often

4. Continuously

1. Never

2. Sometimes

3. Often

4. Continuously

Do you have faecal incontinence?

L-A 0–1: None

L-A 1.5–4.0: A little

L-A 4.5–7.0: Quite a bit

L-A 7.5–10.0: Very much

Do your stool problems make you plan your visits to the toilet? Do you use diapers (because of stool leakage)?

L-A 0–1: None

L-A 1.5–4.0: A little

L-A 4.5–7.0: Quite a bit

L-A 7.5–10.0: Very much

L-A 0–1: None

L-A 1.5–4.0: A little

L-A 4.5–7.0: Quite a bit

L-A 7.5–10.0: Very much

QUFW94, later renamed PCSS (Prostate Cancer Symptom Scale)[63]

CTCAE, Common Terminology Criteria for Adverse Events; L-A, linear analogue scale.

daily activity. The presence of FI is closely correlated to fatigue [60] and urgency alone is significantly correlated to patients’ distress [13]. However, the effect of incontinence symptoms on quality of life is individual and may be independent of the severity of the symptoms. Patients who have incontinence symptoms on a daily basis are more bothered by faecal leakage as one study showed that 2.5% of patients reported daily incontinence and the same proportion of the patients in the study were ‘very much’ bothered by it. In the same study 37.5% of patients had more than twice a week to occasional stool leakage though the percentage of patients bothered by leakage ‘quite a lot’ or ‘much’ was only 17.5%, suggesting that mild faecal soiling may be common in men of this age group and some are coping without much distress [62]. The interpreta-

tion needs a cautionary approach as there is no evidence that the patients who reported daily symptoms and those who were bothered by the symptoms were the same patients. Potential mechanism of FI related to radiotherapy Radiotherapy may have detrimental effects on the structure of the sphincter complex, either the muscle itself or the myenteric plexus that innervates the sphincters. There have been very few studies evaluating the anorectal function of patients before and after radiotherapy for prostate cancer. Yeoh et al. [70] were the first group to investigate the change of anorectal function and showed a statistically significant difference in both the anal sphincter resting and squeeze pressures (resting pressure 54

Y. Maeda et al. / Radiotherapy and Oncology 98 (2011) 145–153

before vs. 49 mm Hg after and squeeze pressure 111 vs. 102 mm Hg respectively) at 4–6 weeks after radiotherapy. At one year following radiotherapy a reduced rectal volume at threshold sensation was observed (36 ml at baseline vs. 22 ml at one year) [66]. Another study by the same authors showed reduction of both resting and squeeze sphincter pressures as well as decrease in rectal volume at threshold and urge sensation at 2 years after radiotherapy [68], which is normally measured by insufflation of an elastic balloon in the rectum by air or water to assess when the patient starts to sense the presence of rectal content and when they feel the urge to expel the balloon and this has been replicated by other authors [9]. Reduced rectal volume at threshold and urge sensation suggest a nerve injury as the mechanism of radiation induced rectal dysfunction. However, the figures were simply averaged across symptomatic and asymptomatic patients and the subanalysis comparing continent and incontinent patients did not show any difference. An observed increase in external anal sphincter (EAS) thickness of just over 1 mm measured by endorectal ultrasound at 2 year follow-up after two dimensional radiotherapy may be suggestive of radiation fibrosis, which resulted in a less elastic and more rigid sphincter and possibly an associated reduced rectal capacity [68,69]. In contrast, the internal anal sphincter (IAS) did not demonstrate any morphological changes in the above studies. Varma et al. examined rectum excised from patients who developed complications after radiotherapy for bladder and prostate cancer and showed hypertrophy of both the muscularis mucosae and muscularis propria layers in the rectal wall as well as Auerbach’s muscular nerve plexus. Such change was absent in Meissner’s submucosal nerve plexus, suggesting that the radiation damage may be mostly nerve injury to the outer layers of the rectal wall [58]. In the early phase after irradiation, loss of crypts and inflammatory cell infiltration of the rectal wall is present [53]. Whether such damage contributes to subsequent development of chronic and irreversible fibrosis or may also contribute to other potential mechanisms of FI such as rectal hypersensitivity or hyposensitivity has not been investigated. Relationship with radiation dose It is considered that the radiation dose has a proportionate influence on the resultant rectal damage and thus the severity of adverse effects or rectal toxicity. In this regard, most of the studies focused their analysis on a dose–volume histogram (DVH) which summarises radiation dose distribution to a histogram by dose bins on the horizontal axis and the volumes or fractions of the target or organs receiving each bin dose on the vertical axis. The two largest studies to date have given contradictory conclusions regarding the relationship of radiation dose and occurrence of FI. Syndikus et al. found that the subjective perception of sphincter control (evaluated on a 4-point scale) was impaired more in the group treated with dose-escalated conformal radiotherapy (74 Gy) compared to standard conformal radiotherapy (64 Gy), with a hazard ratio of 9.25 for incontinence, which is persistent and refractory in a cumulative 5 years incidence [55]. However, the largest prospective study of conformal radiotherapy found only correlation between late rectal bleeding and DVH-parameters and not any statistically significant relationship between the DVH parameters and FI 3 years after radiotherapy in any dose level tested [21]. In addition, the study concurred with another study which showed that developing symptoms of FI within 90–120 days after radiotherapy was the sole predictor of occurrence of late FI [21,36]. Other studies investigating the correlation between a dose–volume histogram and the occurrence of FI have included only a small number of patients. The most predictive parameter for acute FI (within 90 days from the commencement of radiotherapy) was

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the volume of the rectum which received 40 Gy or more (V40) [22]. In particular, if the V40 was kept to under 75%, the incidence of incontinence was <1.5%, compared with an incidence of about 7% if the V40 was above 75% [22]. In the longer-follow-up data this difference did not persist. In a slightly larger study of 41 patients with FI after intensity modulated radiotherapy the predictor of soiling with flatus or less than three episodes of incontinence per week was V70 [23]. The V70 has also been depicted as a strong predictor of FI by another study [56]. One of the reasons for inconsistency between studies may be the broad definition of rectum. A rectum is commonly defined as the structure from the anal verge to the rectosigmoid junction when radiotherapy is planned [47], therefore, the dosimetric parameters are not confined to a specific site such as the anterior rectal wall where radiation damage is more likely in radiotherapy for prostate cancer. By the same token, when a specific anatomical location is considered, it has been shown that radiation to the lower part of the anorectum has correlation to the incidence of FI. Heemsbergen et al. contoured the rectal wall and projected the dose to the surface onto a two-dimensional angular map and divided it into 10% increments, and found the strongest association of radiation dose to incontinence in the inferior 40–50% of the rectum [29]. Vordermark et al. demonstrated a minimum radiation dose to the anal canal as the sole differentiating factor between severely incontinent and mildly incontinent patients [61]. Peeters et al. have more specifically defined the anal canal to be the caudal 3 cm of the anorectum and the dose–volume parameters, which had strong association with the use of incontinence pads more than twice a week was mean dose to the anal wall volume and the relative percentage of the anal volume receiving 65 Gy or more. This was despite the mean dose received by the anal canal wall (36 Gy) being lower than the rectal wall dose (48 Gy) [47]. Similar data have been presented by others. An increase of rectal volume receiving 60 Gy by 5% was correlated to a loss of subjective sphincter control [27] and 70 Gy was found to be the level of dose giving a 50% probability of complications [40]. For urgency, a statistical dose–volume effect has been demonstrated with an odds ratio of 1:1 for each 10 Gy increment of dose in the interval ranging 40– 60 Gy [27]. In patients who developed urgency, the percentage of rectal wall volume receiving 25–42 Gy was 100% [4]. Urgency has been shown to be related to the dose received by the superior 10–20% of the rectum [29]. The influence of total surface area receiving radiation has been inconclusive as the prevalence of FI after patients received treatment to the prostate only or who received radiation to both the prostate and seminal vesicle has been shown as both no different [57,59] and different [56]. Hypofractionation does contribute to an increase in the incidence of overall bowel toxicity. The use of three-field or four-field [5], sequential boost, or integrated boost using intensity modulated radiotherapy [6] does not apparently influence the incidence of FI. Treatment Only one study was found reporting treatment of FI after radiotherapy [8], despite the incidence reported above. Topical phenylephrine, an a1-adrenoceptor agonist which has been shown to increase internal anal sphincter pressures, was used in a small non-randomised case series (n = 15) in which half of the patients were prostate cancer patients and were reported to improve incontinence scores. Whether the improvement was clinically meaningful remains a question as only half of the patients felt the gel was of use [8]. Faecal diversion can alleviate leakage of stool from the anal canal although only one retrospective study with two patients was found [37]. Enemas of sucralfate and short chain fatty acids may have beneficial effects on radiation proctitis, but have not been

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shown to have specific effects on FI. There has been no report to date concerning other currently available treatments for FI (e.g. anal plug, constipating agents, biofeedback, antegrade/retrograde irrigation, sacral nerve stimulation, artificial bowel sphincter) used for this group of patients. Discussion This review intended to elucidate current knowledge on FI related to radiotherapy for prostate cancer from studies conducted by both coloproctologists and radiation oncologists. Although radiotherapy has been intuitively linked to the occurrence of FI after the treatment it has traditionally received less attention compared to other adverse effects [7] and this is reflected in the sparsity of data found during the course of this review. In addition, some points warrant further discussion in order to increase awareness of the continence mechanism in clinical practice of radiotherapy and promote evaluation of FI. One of the difficulties in interpreting the data was the variability of the definition of FI. In some studies, the definition entailed a combination of urgency, soiling, and tenesmus. Some of the symptoms were reported by a combination of subjective description and RTOG score, which has no specific scoring for FI and contains a constellation of different symptoms such as bleeding and proctitis, thus making it difficult to untangle the data to isolate the component relevant to FI. Traditionally there has been a distinction between acute and late reaction of the bowel with early reaction associated to mucosal changes and late reaction related to changes of the bowel wall. For FI a distinction between acute and late was less clear. Whilst acute toxicity in general is defined as adverse effect within 90– 120 days after commencement of radiotherapy, the timeline has not been clearly defined for ‘late’ faecal incontinence. Although FI is considered as a late complication, often preceded by FI in the acute phase [21,36], it is not clear whether the acute symptoms are different from late symptoms nor if acute symptoms persist as the same chronic symptoms in the same individual. The studies do not enable a clear differentiation of the acute from late effects and the timing of any resolution of acute effects and the subsequent onset of late symptoms is unclear. Furthermore, there was little information on the pre-existing FI and coupled with the lack of data on individual change of continence status it was not possible to work out the true incidence of radiotherapy-associated FI. A time-to-event study with consideration given to the effects of aging [48] has not been conducted and may allow more accurate timing and incidence of FI in this group. The evolution of radiotherapy techniques has made a significant contribution to minimising the amount and volume of irradiated normal tissue. However, modern technique based on IMRT and IGRT utilises 76–81 Gy due to benefit in terms of biochemical progression-free survival conferred by several phase III trials [16,45,49,71]. Data presented in this article are primarily of 3D conformal radiotherapy studies and the delivery of a high radiation dose to a smaller volume by the novel techniques may result in an increase of incontinence and other toxicity on the background of potential increased damage and prolonged survival. Hypofractionation is being tested in several ongoing studies. The excess toxicity by this treatment is compensated by a reduction of the total radiation dose. So far, results of relatively small trials have demonstrated that hypofractionation of prostate cancer can be performed with acceptable toxicity but we do not know the long-term outcome [67]. These technical aspects also warrant further evaluation as there is still a lack of long-term results and specific data on FI. The definition of the rectum used for the analysis of dose–volume relationship is broad. In most studies, the rectum was delineated from the rectosigmoid junction to the anal verge, or from

the ischial tuberosities to the level of the inferior border of the sacroiliac joints, or when the rectum was no longer adjacent to the sacrum. Anal wall volume is often defined as 3 cm from the anal verge or the caudal 3 cm of the above defined rectum [47]. When considering the continence mechanism the anal canal is encircled by the anal sphincter complex which consists of an internal and external anal sphincter. The internal anal sphincter is a smooth involuntary muscle continuous with the circular muscle coat of the rectum and provides continuous tone to maintain the sealing of the anus until timely defaecation. The internal anal sphincter ends 1–1.5 cm below the dentate line but is not present at the anal verge. The external anal sphincter starts from the subcutaneous plane and, therefore, is not present at the level of the anal verge. Therefore the ‘anal wall volume’ calculated in these studies may only contain part of the sphincter apparatus. Calculation of a dose–volume histogram based on a rectum which does not include the sphincter complex may be insensitive to distinguish damage caused by radiotherapy and clinically irrelevant to calculate the level of radiation dose constraints to the normal tissue. The current calculation of total volume of the rectum contains an air-filled hollow and a debate is emerging as to whether the calculation would be more meaningful if restricted to the volume of rectal wall, particularly in IMRT [26]. There have been some studies attempting to identify predictive factors, including parameters relating to radiotherapy and patients’ confounding background, for the onset of late toxicity. One of the factors depicted was history of abdominal surgery [47] with TD50 of the patients without a history of abdominal surgery was 2.5 times higher than those with, showing a lower tolerance of those with a history of abdominal surgery [46]. The attempt to optimise the normal tissue complication probability model is important which may lead to improvement of estimation of toxicity prior to radiotherapy and better dose planning. Although a history of pelvic surgery may be related to increased risk of radiation induced FI it is less clear how surgery outside pelvis, such as gastrectomy, cholecystectomy or a colonic resection may alter the risk of FI. Since there is a steep increase in the use of salvage and adjuvant radiotherapy following radical prostatectomy, the nature and role of surgery performed in past and in relation to prostate cancer treatment should be clarified in future studies when assessing this as a potential risk factor. FI in a male has a few distinct features compared to females. In a previous study nearly 40% of men who report FI are found to have no definable functional or structural sphincter abnormality, in contrast to women who commonly develop FI as a consequence of obstetric related damage [34,39]. Anorectal physiology testing in men with FI tends to show a longer anal sphincter length and a paradoxically high resting pressure [44], which may have an element of anismus with associated urgency. It is thus essential that any anorectal physiology testing is conducted both before and after radiotherapy and compared with normal age-matched controls to obtain data without bias. Furthermore, there are differences in coping behaviours of men and women with FI. Men are thought not to want to wear pads whereas women are often already using pads for other purposes including urinary incontinence and per vaginal losses. Men often use a tissue instead of a pad placed at the anus [39]. The scoring for using incontinence pads in male patients may not be truly reflective of their severity of symptoms. It is also worthy of note that men may be less vigilant to a small amount of soiling on the underwear and this may explain the high percentage of pre-treatment incontinence and the discrepancy in prevalence of FI and those reporting being bothered by it. There was very little data on the possible mechanism of FI postradiotherapy. Compared to obstetric injury, radiation does not cause an evident sphincter defect but may instead impair the structure of the rectum and/or anal canal in a subtle fashion. Fibrous replacement and an increased amount of collagen in the

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circular and longitudinal muscle layers of the rectum and internal anal sphincter have previously been suggested as a potential pathophysiology of FI [19,54] and anal sphincter scarring was prominent in patients after radiotherapy for rectal cancer [50]. It could be hypothesised that irradiation causes change in rectal sensation by increasing scarred tissue in the rectal wall as fibrosis has been depicted as the main culprit of late radiation complication in general [42] or it may alter balance in enteric neural circuitry due to inflammation as it influences the activity of chemical mediators associated with rectal hypersensitivity in visceral sensory fibres at nerve endings of mucosa, submucosa and muscle layers of the rectum [12]. This is an area where further research is needed to elucidate the continence mechanism. More treatment options for FI have become available over the last decade. In addition to dietary advice and anti-diarrhoeal medication, products such as an anal plug to seal the anus for a short time and retrograde irrigation to ensure complete emptying of the rectum to prevent untimely leakage are available. These can be combined with biofeedback which is a package of care including teaching patients bowel control techniques and sphincter exercises, combined with dietary advice, titration of anti-diarrhoeal medication and practical coping skills. Surgical intervention is not limited to a formation of colostomy. Sacral nerve stimulation is a minimally invasive procedure, which has become an established option for the treatment of FI in Europe over the last decade. It is a two-stage operation implanting a lead and pulse generator which stimulates sacral nerve roots and modulates bowel motility and has already been reported in FI related to pelvic radiotherapy for rectal and gynaecological cancer [17,31,33,38,52]. Other operative interventions include implantation of an artificial bowel sphincter, radiofrequency ablation and injection of a bulking agent [11]. In view of the availability of various products and interventions, defining ‘requiring surgical intervention’ as the severest grading for FI used in some radiotherapy scales is subjective and should be amended. Conclusion and implication for future research Faecal incontinence may be a consequence of radiotherapy for prostate cancer, occurring in 1.6–58% of patients receiving 3D conventional RT. It severely affects patients’ quality of life and has not received much attention to date. Most published studies are retrospective or report FI as part of other complications and do not fully elucidate the true scale of this complication nor the mechanism of incontinence in this group. For future studies and reports, it is essential to establish a uniform definition of the anal canal and rectum which is applicable to the IMRT dose planning process leads to clinically useful dose–volume constraints and accurate assessment of the consequences of radiotherapy. Furthermore, well-designed prospective studies are needed to establish the relationship between the accurate dose and volume of rectal wall, anal canal and anal sphincters exposed to radiation and the severity of symptoms using a well-established validated symptom score and quality of life scale. This will enhance our knowledge not only of the mechanism of FI associated with radiation but will also accrue data to build on dose–volume constraints critical to avoid unintentional and severe adverse effects. Damage caused by radiotherapy to the sphincter apparatus and nerve plexus may require further animal studies to clarify the mechanism. Treatment options for FI have increased over the last decade and it is important to increase awareness among radiation oncologists to encourage referring these patients to a specialist colorectal or gastroenterology unit and apply currently available interventions to this group of patients. There is a need for rigorous evaluation of interventions to treat FI in men after prostate radiotherapy.

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Source of support None. List of contribution Yasuko Maeda Acquisition, analysis and interpretation of data. Contribution to conception and design of the study. Drafting the article for important intellectual content. Final approval of the version to be published. Morten Høyer Acquisition, analysis and interpretation of data. Contribution to conception and design of the study. Revising the article critically for important intellectual content. Final approval of the version to be published. Lilli Lundby Contribution to conception of the study. Revising the article critically for important intellectual content. Final approval of the version to be published. Christine Norton Contribution to interpretation of data. Contribution to conception of the study. Revising the article critically for important intellectual content. Final approval of the version to be published. Conflict of interest Morten Høyer is supported by The Danish Cancer Society, Varian Medical Systems Palo Alto, CA and the Lundbeck Foundation Center for Interventional Research in Radiation Oncology, Denmark (CIRRO). Yasuko Maeda, Lilli Lundby and Christine Norton have no conflict of interest to declare. References [1] LENT SOMA tables. Radiother Oncol 1995;35:17–60. [2] Adolfsson J, Helgason AR, Dickman P, Steineck G. Urinary and bowel symptoms in men with and without prostate cancer: results from an observational study in the Stockholm area. Eur Urol 1998;33:11–6. [3] Al-Abany M, Helgason AR, Adolfsson J, Steineck G. Reliability of assessment of urgency and other symptoms indicating anal sphincter, large bowel or urinary dysfunction. Scand J Urol Nephrol 2006;40:397–408. [4] al-Abany M, Helgason AR, Cronqvist AK, et al. Toward a definition of a threshold for harmless doses to the anal-sphincter region and the rectum. Int J Radiat Oncol Biol Phys 2005;61:1035–44. [5] al-Abany M, Helgason AR, Cronqvist AK, Svensson C, Wersall P, Steineck G. Long-term symptoms after external beam radiation therapy for prostate cancer with three or four fields. Acta Oncol 2002;41:532–42. [6] Al-Mamgani A, Heemsbergen WD, Peeters ST, Lebesque JV. Role of intensitymodulated radiotherapy in reducing toxicity in dose escalation for localized prostate cancer. Int J Radiat Oncol Biol Phys 2009;73:685–91. [7] Andreyev HJ, Wotherspoon A, Denham JW, Hauer-Jensen M. Defining pelvicradiation disease for the survivorship era. Lancet Oncol 2010;11:310–2. [8] Badvie S, Andreyev HJ. Topical phenylephrine in the treatment of radiationinduced faecal incontinence. Clin Oncol (R Coll Radiol) 2005;17:122–6. [9] Berndtsson I, Lennernas B, Hulten L. Anorectal function after modern conformal radiation therapy for prostate cancer: a pilot study. Tech Coloproctol 2002;6:101–4. [10] Borchers H, Kirschner-Hermanns R, Brehmer B, et al. Permanent 125I-seed brachytherapy or radical prostatectomy: a prospective comparison considering oncological and quality of life results. BJU Int 2004;94:805–11. [11] Brown SR Nelson RL. Surgery for faecal incontinence in adults. Cochrane Database Syst Rev 2007:CD001757.

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