Reducing rectal injury during external beam radiotherapy for prostate cancer

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Department of Radiation Oncology 1 (R. Valdagni), Prostate Cancer Program (R. Valdagni, T. Rancati), Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, Milan 20133, Italy.

Correspondence to: T. Rancati [email protected]

Reducing rectal injury during external beam radiotherapy for prostate cancerRiccardo Valdagni and Tiziana Rancati

Abstract | Rectal bleeding and faecal incontinence are serious injuries that men with prostate cancer who receive radiotherapy can experience. Although technical advances—including the use of intensity-modulated radiotherapy coupled with image-guided radiotherapy—have enabled the delivery of dose distributions that conform to the shape of the tumour target with steep dose gradients that reduce the dose given to surrounding tissues, radiotherapy-associated toxicity can not be avoided completely. Many large-scale prospective studies have analysed the correlations of patient-related and treatment-related parameters with acute and late toxicity to optimize patient selection and treatment planning. The careful application of dose–volume constraints and the tuning of these constraints to the individual patient’s characteristics are now considered the most effective ways of reducing rectal morbidity. Additionally, the use of endorectal balloons (to reduce the margins between the clinical target volume and planning target volume) and the insertion of tissue spacers into the region between the prostate and anterior rectal wall have been investigated as means to further reduce late rectal injury. Finally, some drugs and other compounds are also being considered to help protect healthy tissue. Overall, a number of approaches exist that must be fully explored in large prospective trials to address the important issue of rectal toxicity in prostate cancer radiotherapy.

Valdagni, R. & Rancati, T. Nat. Rev. Urol. advance online publication 14 May 2013; doi:10.1038/nrurol.2013.96

IntroductionThe aim of radical radiotherapy is to maximize tumour control while reducing or avoiding injury to surrounding healthy tissues. The latter goal has received considerable attention with the development of increasingly cura-tive treatments following the introduction of intensity- modulated radiation therapy (IMRT), which is often used in combination with image-guided radiotherapy (IGRT).1 Technical advances have enabled oncologists to achieve dose distributions that conform to the shape of the tumour target and steep dose gradients from the tumour to the surrounding tissue. These advances also enable reductions in radiation-induced toxicity, as well as the modelling of acute and late injury in healthy tissue. The resulting optimization of radiotherapy has greatly improved local tumour control and quality of life for patients.2 However, radiotherapy-associated toxicity has not been completely negated for two major reasons. Firstly, radiotherapists are increasingly applying higher doses to achieve higher rates of local tumour control.3

Secondly, subgroups of radiosensitive patients have been identified who have specific clinical or genetic risk factors that independently predict the development of toxicity.4–10

Late rectal injury is a major concern in prostate cancer external beam radiotherapy (EBRT). Radio-induced rectal injury includes increased frequency of bowel movements, which can be accompanied by

bowel urgency, tenesmus, diarrhoea or incontinence. Rectal bleeding and abdominal pain are also possible symptoms. All these symptoms can have moderate or severe effects on the quality of life of the patient.11 Many large-scale prospective studies have analysed the cor-relations between patient-related and treatment-related para meters with acute and late toxicity to optimize patient selection and treatment planning.12–16 These studies resulted in the determination of dose–volume relationships for rectal injury,17–20 as well as the develop-ment of predictive models for radiotherapy-induced rectal toxicity, which include dosimetric and clinical risk factors.21–26 The careful application of dose–volume constraints and the possibility of tuning these constraints according to the characteristics of the individual patient are now c onsidered the most effective way of reducing rectal injury.27–31

Daily use of IGRT also enables radio-oncologists to reduce the margin between the clinical target volume (the clinical extension of the tumour, the true target of radiotherapy) and the planning target volume (the effec-tive target of radiotherapy, which is larger than the clini-cal target volume and takes into account possible organ and patient movement).32,33 Such a reduction decreases the percentage of the rectum that is included in the high-dose region,34 without compromising the coverage of the tumour target (Figure 1). Other efforts to reduce rectal toxicity include the insertion of spacers into the region between the prostate and anterior rectal wall.35–38 Displacement of the anterior rectal wall can effectively

Competing interestsThe authors declare no competing interests.

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reduce—to a negligible value—the radiation dose applied to the rectum. Although this procedure has limited effect in conventional fractionated IMRT, where careful opti-mization of the treatment plan (for example, using pre-dictive models) results in very low rectal toxicity rates, the use of spacers could be helpful when considering prostate stereo tactic radiotherapy.39 For this approach, EBRT is delivered with a very high dose per fraction, often exceeding 5–6 Gy per fraction, and a small pro-portion of the rectal wall is included in the high-dose region. Other strategies to reduce rectal injury include the use of endorectal balloons (as a means to reduce prostate motion),40 and drugs and other compounds that help protect healthy tissue.41–43 If the protective effects of these strategies are confirmed in clinical trials, they could be used in radiosensitive patients to reduce their risk of rectal morbidity.

In this Review, we summarize the available methods used to reduce rectal injury after radical radiotherapy for prostate cancer. We focus not only on the technical advancements to IMRT and IGRT that have enabled precise dose shape and delivery, but also on methods, such as endorectal balloons that can reduce organ motion and tissue spacers that can decrease rectal expo-sure to high doses. We also examine the available evi-dence concerning the use of topical drugs in preventing tissue toxicity.

Radiotherapy-induced rectal injuryFor many years, late rectal bleeding (that is, bleeding occurring at least 6 months after the end of radio therapy treatment) has been considered the only rectum-related end point in studies evaluating the outcomes of radio-therapy in patients with prostate cancer because it was considered an objective end point. However, acute and late gastro intestinal injuries can cause a variety of s ymptoms—such as rectal bleeding, stricture, diminished rectal compliance and decreased storage c apacity—as a result of rectal incontinence or frequent bowel move-ments, which are often included under the heading ‘rectal syndrome’.11 Injury to the anal and rectal m usculature can lead to faecal incontinence or stricture.11

The pathophysiology of rectal toxicity is complex; several elements are involved in the main tenance of an

adequate continence mechanism. Factors that poten-tially cause rectal damage include rectal mucosal injury; impairment of rectal capacity, sensory function and rectal distensibility; anal sphincter dysfunction; anato-mical disturbances of the pelvic floor caused by anal pressure changes; neuropathy and stool consistency.44 Taking into account all these possible factors, different rectum-related complaints can reasonably arise from speci fic anorectal subsites (such as the rectal and anal wall or pelvic floor muscles).45 The knowledge of which specific sites are involved in the progress of late mor-bidity might enable us to avoid or mitigate the adverse effects observed in patients undergoing radiotherapy. Indeed, this goal is potentially achievable with modern EBRT, which uses IMRT coupled with IGRT to selec-tively spare small, well-defined volumes of the rectum from radiation.

The Radiation Therapy Oncology Group (RTOG) and European Organisation for Research and Treatment of Cancer (EORTC) toxicity scale46 and the Late Effect on Normal Tissue: Subjective, Objective, Management, and Analytical scale (LENT SOMA) scoring system47 are the most frequently used methods for scoring gastro-intestinal toxicity. The reported rates of gastrointestinal toxicity vary from just a few per cent (2–5%) of patients to approximately 20% when referring to moderate to severe toxicity (Table 1). These rates vary depending on several factors, for example, the prescribed total dose (from 70 Gy to 86–90 Gy in the past 10 years), radio therapy techniques (conventional radiotherapy, conformal radio-therapy, IMRT or IGRT), the clinical target (prostate, prostate and seminal vesicles or whole pelvis) and the concomitant use of androgen deprivation therapy.

When considering toxicity rates, we must consider the follow-up time and the definition of the toxicity end point. Importantly, radiotherapy-induced rectal injury is a late effect and, therefore, following-up patients for at least 30–36 months is required to reliably assess the true toxi city rate. The classic definition of peak t oxicity—a single moderate or severe event that does not take into account the dynamic evolution of that specific m orbidity—is worthwhile for some specific end points (such as rectal bleeding), which are characterized by a peak event that usually resolves with medical interven-tion and do not have a chronic effect on the patient’s quality of life. However, other toxicity end points (such as faecal incontinence) that are characterized by a chronic, evolutionary biological component seem to be better described and measured using a longitudinal definition of toxicity, which takes into account the mean grade of toxicity over a long period of time.20,48,49 This longitudinal definition provides a measure of the severity and persis-tence of symptoms, is related to the patient’s impaired quality of life and shows good correlations with clinical and dosimetric risk factors.

Definition of the gastrointestinal symptoms, follow-up duration, grade and duration of toxicity, choice between peak toxicity definition and mean toxicity definition are all relevant aspects to be considered when describing radiotherapy-induced rectal injury.

Key points

■ Understanding the dose–volume effects involved in rectal injury following pelvic radiotherapy has enabled the development of toxicity models to guide treatment optimization towards favourable dose distributions in the rectum and anal canal

■ Intensity-modulated radiotherapy and image-guided radiotherapy are powerful tools to shape doses and reduce margins between the clinical target volume and planning target volume, reducing normal tissue volumes in the high-dose regions and, consequently, toxicity

■ Endorectal balloons can reduce intrafraction motion and tissue spacers can move the rectum away from the high-dose regions; these tools are beneficial when using external-beam radiotherapy with high doses per fraction

■ Some studies have confirmed that certain patients are remarkably radiosensitive; consequently, clinicians should be particularly vigilant towards patients with predisposing risk factors for rectal toxicity

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Applying dose–volume constraintsThe approach used to define the organ at risk (the rectum in this case) is an important research topic in radiotherapy that is tightly related to the dose–volume constraints. Different studies have used different approaches to determine the rectal contour, including solid volume (including filling), manual definition of the rectal wall and delineation of the rectal wall by nega-tive isotropic expansion of the outer contour (Box 1). Consequently, these approaches have yielded different dose–volume histograms.

Overall, the results have yielded similar dose–volume constraints across the dose range 70–80 Gy and two reviews have focused on this issue.50,51 Specifically, to keep the rates of grade ≥2 and grade ≥3 late rectal toxicity below 15% and 10%, respectively, the dose–volume constraints to be used in treatment planning can be derived from different regions of the dose spec-trum (between 40 Gy and 75 Gy). Although the exact values identified vary among studies, a dose of ≥40 Gy should be applied to <60–80% of the entire rectum (defined as V40 Gy <60–80%). Other reported con-straints include V60 Gy <35–45%, V70 Gy <15–25% and V75 Gy <5–10%.12,13,15,17–19,50–61

Importantly, these constraints were mostly derived from trials that focused on late rectal bleeding, which, for some time, was the only widely evaluated morbidity. Only since 2006 have researchers started to report results on other toxi cities, such as late faecal incontinence and increased stool frequency. Although these toxicities occur infrequently (in approximately 5% of patients),13,20,51,52 they are often chronic symptoms that severely affect the patient’s quality of life. For this reason, a dose–volume constraint of V40 Gy <80% (or a mean rectal dose of <45–50 Gy),12,13,20,45,50–53,60,62,63 has been determined to keep the incidence rates of these symptoms below 1–2%. These constraints, which are very feasible when using IMRT, have been extremely valuable for reduc-ing rectal injury. With 3D conformal radiotherapy (3DCRT), the possibility of applying such a constraint depends on the anatomical geometry of the patient and the prescribed dose.

In 2012, a dose–volume relationship between indivi-dual pelvic floor muscles and faecal incontinence and urgency was reported.45 The study proposed several con-straints on the mean doses needed to reduce the risk of faecal urgency and incontinence: 30 Gy to the internal anal surface, 10 Gy to the external anal surface, 50 Gy to the puborectalis muscle and 40 Gy to the levator ani muscles. Importantly, the study suggested that dose distri bution over the rectal mucosa, other anorectal structures and probably over the whole pelvic region has to be considered when searching for dosimetric determinants of rectal toxicity.45 Indeed, some methods for considering 3D dose distributions in the whole pelvic region—going beyond the definition of organ at risk—are being considered and developed.64,65

Applying predictive modelsSeveral large prospective studies have sought to find correlations between late rectal injury and clinical and dosimetric risk factors, and have unveiled the roles of patient-related variables in the emergence of toxi-city.12,13,26,50–53 The widespread use of IMRT and IGRT, which enable steep dose gradients between the tumour volume and anterior rectal wall, is dramatically redu-cing the dose being applied to the rectum and, con-sequently, enhances the importance of patient-related risk factors. Unsurprisingly, comorbidities are associated with an increased risk of gastrointestinal toxicity, which include a history of abdominal surgery before radio-therapy,4,13,50–52 the presence of cardiovascular disease or diabetes, the use of anticoagulants and the presence of haemorrhoids.13,50–52 Some studies have also highlighted the importance of a sequential effect between late and acute lower gastro intestinal toxicity.28,66,67 That is, acute gastrointestinal toxicity is a significant independent predictor of late gastrointestinal injury, which suggests the existence of a sequential component underlying the development of this late morbidity.

Despite our knowledge of the dosimetric and clinical factors that influence rectal toxicity, some patients still exhibit unpredicted toxicity, which suggests that sensi-tivity to radiotherapy can be attributed to genetic factors

0 10 20 30Dose (Gy)

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Figure 1 | Example of dose distribution in a patient with prostate cancer. Intensity-modulated radiotherapy was used (the prescribed dose was 78 Gy), with gold markers for daily imaging of the prostate. a | The clinical target volume contour is drawn in orange, the planning target volume is contoured in yellow and the rectum contour is presented in magenta. b | Cumulative dose–volume histograms for the same patient of the rectum (magenta), clinical target volume (orange) and planning target volume (yellow).

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in these patients. Indeed, evidence for genetic predis-position for late rectal bleeding has been reported; for example, Burri et al.9 and Damaraju et al.8 showed that susceptibility to late adverse effects after radiotherapy for prostate cancer was associated with single nucleotide polymorphisms (SNPs) in SOD2, XRCC1 and XRCC3 or in XRCC3, LIG4, MLH1, CYP2D6 and ERCC2. In addi-tion, we reported that reduced microRNA expression of AKR1B1, BAZB1, LSM7, NUDT1, PSMB4, SEC22L1 and UBB was significantly associated with enhanced sensitivity to late toxicity.10 Moreover, increased microRNA expression of DDX17, DRAP1, RAD23 (including RAD23A, RAD23B, RAD23BLP, RAD23BP1 and RAD23BP2) and SRF predicted resistance to radio-therapy-induced late rectal bleeding.10 However, these associations were shown in individual studies, and validation studies have reported some serious difficul-ties in replicating results; for example, one independent validation study of several SNPs previously found to be

associated with rectal injury was unable to confirm any association.68 Thus, this field of research lacks a suffi-cient number of patients enrolled in genetic studies and requires high-powered statistics to support the role of genetics in influencing rectal toxicity. Furthermore, several methodological concerns must be addressed in an appropriate manner. For example, careful stratifica-tion of patients that accounts for the dose to the rectum and clinical risk factors has to be considered; acute and late toxicities might be considered separately. 

Aside from biomarker-based strategies, statistical models that couple dosimetric and clinical information have been developed with the goal of reliably predict-ing radiotherapy-induced toxicity in individual patients. Such models might optimize or modify the treatment procedure if the predicted toxicity is too high for a given patient. Alternatively, models can be used to select another treatment modality, such as brachytherapy or prostatectomy, if further optimization of EBRT is not

Table 1 | Acute and late gastrointestinal toxicity rates in selected prospective studies

Study n Dose (Gy) EBRT modality

Median follow-up duration (years)

Acute toxicity (%)

Late toxicity (%)

Kuban et al.75 149 70.0 Conventional 8.7 NR G2: 10.1G3: 1.3

Kuban et al.75 151 78.0 Conventional + conformal boost

8.7 NR G2: 18.5G3: 6.6

Zietman et al.76 196 70.2 3DCRT 5.5 G2: 41.3G3: 1.0

G2: 7.7G3: 0.5

Zietman et al.76 195 79.2 3DCRT 5.5 G2: 57.4G3: 0

G2: 16.9G3: 0.5

Dutch multicentre randomized phase III trial12,24,79,80

284 68.0 3DCRT 4.3 G2: 41.0G3: 6.0

G3 bleeding: 3.5G3 stool frequency: 6.0G3 incontinence: 7.0

Dutch multicentre randomized phase III trial12,24,79,80

228 78.0 3DCRT 4.3 G2: 47.0G3: 4.0

G3 bleeding: 8.3G3 stool frequency: 7.0G3 incontinence: 11.0

MRC RT01 trial14,81 421 64.0 3DCRT 5.0 ≥G2: 12.0 ≥G2 bleeding: 25.0≥G2 diarrhoea: 10.0≥G2 stool frequency: 9.0≥G2 loose stool: 17.0

MRC RT01 trial14,81 422 74.0 3DCRT 5.0 ≥G2: 28.0 ≥G2 bleeding: 32.0≥G2 diarrhoea: 15.0≥G2 stool frequency: 14.0≥G2 loose stool: 21.0

AIROPROS 0102 trial13,109

718 70.0–78.0* 3DCRT 3.0 ≥G2: 26.1 ≥G2 bleeding: 7.2≥G2 incontinence: 3.5

EORTC 22991 trial82 625 70.0–78.0 3DCRT NR ≥G2 (70 Gy): 23.0≥G2 (74 Gy): 18.6≥G2 (78 Gy): 9.9

NR

EORTC 22991 trial82 139 74.0–78.0 IMRT NR ≥G2 (74 Gy): 7.1≥G2 (78 Gy): 22.5

NR

RTOG 94-0615,17 1,010 68.4–78.0 3DCRT 7.2 ≥G2: 15.7 ≥G2: 15

GICOR 05/99 Study110 426 64.2–82.6‡ 3DCRT 3.0 ≥G2: 14.0 NR

Zelefsky et al.27 561 81.0 IMRT 8.0 NR ≥G2: 1.6

Cahalon et al.29 478 86.4 IMRT 5.5 ≥G2: 37.0 ≥G2: 4.4

Kupelian et al.30 770 70.0§ IMRT 3.8 ≥G2: 9.0 ≥G2: 4.4

Zelefsky et al.34 186 86.4 IMRT + IGRT 2.8 ≥G2: 1.1 ≥G2: 1.0

*Median 74 Gy. ‡Median 72 Gy. §2.5 Gy per fraction. Abbreviations: 3DCRT, 3D conformal radiotherapy; EBRT, external-beam radiotherapy; IGRT, image-guided radiotherapy; IMRT, intensity-modulated radiotherapy; G2, grade 2 toxicity; G3, grade 3 toxicity; NR, not reported.

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feasible. Accordingly, these predictive models could help us further reduce gastrointestinal toxicity in prostate cancer radiotherapy.

The first group of models include radiobiological models, collectively known as normal tissue complica-tion probability (NTCP) models.69 NTCP models are mathematical, biophysical models that calculate the probability that a certain percentage of patients will exhibit unfavourable reactions in the healthy tissues surrounding the target tumour. These models are calcu-lated from a nonuniform dose distribution throughout the target organ based on the dose–volume histogram and derive a numerical risk of toxicity.69 All reported models of this type predict an increase in NTCP when increasing the dose and irradiated volume, and depict the dose–NTCP relationship with a sigmoidal curve. Although the dose–volume relationship differs between organs, the relationship is generally defined as a mixture of two extreme situations of cellular organization pat-terns (Figure 2).70 Cellular organization affects the way nonuniform dose distributions (summarized in the dose–volume histogram) are incorporated into the NTCP model: serial organs are essentially described by their maximum dose, whereas parallel organs are described by their mean dose. Cases of mixed organs are described with an e ffective dose that is between the mean and maximum dose.

Recently, NTCP models with explicit inclusion of known clinical risk factors have been proposed.21,24,25 DeFraene et al.24 developed models (512 patients, 36 months of follow-up data) for grade 3 rectal bleed-ing (including abdominal surgery and cardiovascular disease), for grade 3 late faecal incontinence (including abdominal surgery and diabetes) and for grade 3 late stool frequency (including baseline stool frequency). We published results on NTCP models25 (669 patients, 36 months of follow-up data) on grade 2–3 late rectal bleeding (including abdominal surgery and acute toxi-city), severe chronic faecal incontinence and mean faecal incontinence (both including disease of the colon or abdominal surgery). NTCP models can be used in treatment planning to guide biological optimiza-tion and these models that include clinical risk factors, in general, enable improved personalization of the o ptimization phase.

A second group of models takes a slightly differ-ent approach by developing predictive multivariable (logistic) models that incorporate all relevant vari-ables (including dosimetric and clinical factors, as well as potential genetic and molecular factors) to yield an indivi dualized estimation of the risk of toxicity. The use of these tools during radiotherapy optimization can reduce toxicity, even in patients with clinical factors known to enhance the risk of toxicity (for example, abdominal surgery, presence of diabetes, haemorrhoids or presence of cardiovascular disease). In fact, indivi-dualized pretreatment prediction of high or unaccept-able toxicities will compel radio-oncologists to employ stricter dose–volume constraints or dose de-escalation in target regions lacking clonogenic cells. Such models

have been described for the prediction of late rectal bleeding and late faecal incontinence and are based on multivariate logistic analysis—which have been translated into user-friendly visual schemes, such as n omograms—as well as artificial neural networks or random forest (Table 2).20,22,23,71–74

Although useful, none of the reported models have been externally validated to establish their applicability in populations other than those used for their develop-ment. Furthermore, implicitly integrating an individual’s specificities (such as medical history) and concomitant treatments into these models is difficult. Finally, no model reported hitherto takes into account any poten-tial deviations between planned and delivered dose and none correlates the treatment outcome with spatial patterns of dose to consider organs as having hetero-geneous radiosensitivity. This possible spatial effect is particularly important in the actual scenario of modern image-guided IMRT, in which steep dose gradients are obtained and reduced fractions of the normal structures are irradiated.

Despite these flaws, these models can help guide the reduction in radiotherapy-induced rectal injury in radio-sensitive patients. At the level of the individual, a further benefit is the possibility of identifying patients at high risk of toxicity, enabling us to closely monitor their status and predict interventions with supportive drugs.

Box 1 | Technical terms in rectal injury radiotherapy

Rectal contour ■ The outer contour of rectum as it is drawn on CT slices.

Solid volume ■ The rectum is considered a solid organ when the whole volume inside the outer

rectal contour is considered as the organ at risk (that is, a solid rectum is the rectal wall and the rectal filling [with air or stool]).

Negative isotropic expansion ■ A means by which an artificial rectal wall is obtained, starting from the outer

rectal contour and automatically adding an inner contour of fixed thickness. The rectal wall is the organ that is included between the two contours.

3D conformal radiotherapy (3DCRT) ■ A radiotherapy technique that uses computers to create a 3D picture of the

tumour so that multiple radiation beams can be shaped exactly to conform to the contour of the treatment area.

Intensity-modulated radiation therapy (IMRT) ■ An advanced mode of high-precision radiotherapy that enables the radiation

dose to conform precisely to the shape of the tumour by modulating the intensity of the radiation beam in multiple small volumes. Treatment is carefully planned by using CT or MRI in conjunction with computerized dose calculations to determine the dose intensity pattern that will best conform to the tumour shape.

Image-guided radiotherapy (IGRT) ■ Use of frequent imaging during a course of radiotherapy to improve the

precision and accuracy of the delivery of treatment. In IGRT, instruments that deliver radiation are equipped with imaging technology so the physician can image the tumour immediately before or during the time radiation is delivered, while the patient is positioned on the treatment table.

Stereotactic body radiotherapy (SBRT) ■ A new procedure for treating patients with cancer that uses high doses per

fraction of radiation delivered to a precise target, which is only feasible when IMRT is used combination with IGRT.

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Improvements in radiation technologyNumerous studies in prostate cancer have shown that local control is improved by increasing the prescribed dose.75–78 However, this benefit is counterbalanced by increased radiotherapy-induced gastrointestinal and genitourinary toxicity, particularly when 3DCRT t echniques are used.12,14,76,79–82

Advances in treatment planning systems, together with the development of multi-leaf collimator techno-logy, have led to the introduction of IMRT.78 This tech-nique enables the distribution of steep dose gradients that can conform to concave targets, such as the pros-tate and seminal vesicles. Several studies—particularly those performed at the Memorial Sloan–Kettering Cancer Center—have shown the possibility of reducing toxicity associated with high-dose IMRT. For example, Zelefsky et al.28 conducted a study on 1,571 patients treated with 3DCRT or IMRT with doses ranging from 66 Gy to 81 Gy; all patients treated with IMRT were prescribed a dose of 81 Gy. In this study, the incidence of grade ≥2 gastrointestinal toxicity was significantly lower in the IMRT group than in those treated with conventional 3DCRT (5% versus 13%, P <0.0001) over a median follow-up duration of 10 years, despite the fact that patients in the IMRT group received higher prescribed doses of radiation. In a study by Cahlon and colleagues,29 the rates of grade 2 and grade 3 toxicity reported over a median follow-up duration of 4.4 years were 3% and 1%, respectively, among 478 patients prescribed IMRT at a dose of 86.4 Gy. These data suggest that IMRT can be applied to the prostate at a dose of 78–80 Gy, with a toxicity rate similar to that obtained with a standard dose of 70 Gy delivered by c onformal radiotherapy.

Importantly, IMRT is usually delivered with reduced margins with respect to 3DCRT and, consequently, it can be difficult to demonstrate that reduced toxicity is truly attributable to different IMRT dose distributions rather than to margin reduction. Margin reduction must be considered as a confounding factor when comparing conventional 3DCRT and IMRT.

Toxicity can be further reduced when IMRT is per-formed in combination with daily imaging (that is, with IGRT),34,83 which enables the careful evalu ation of the target organ’s position. Several approaches are now available that are extensively used in prostate cancer radiotherapy. These techniques include tracking radio-opaque (nonradioactive) seeds that are implanted into the prostate,84 daily CT scans of the pelvis85 and implanting magnetic transponders into the prostate.86 Magnetic transponders are small devices that transmit safe radiofrequency waves to an external electro magnetic array, which determines the transponder coordinates and informs the clinician of the position and move-ment of the prostate. Rajendran et al.87 evaluated the dosimetric effects of daily isocentric correction using magnetic transponders in 28 men with prostate cancer treated at 79.2 Gy. They reported that a mean excess of 10 Gy was delivered to 70% of the rectal volume if daily e lectromagnetic localization was not used.

All these methods help the radiotherapist readjust the treatment beam according to the prostate’s loca-tion. Crucially, IGRT is used to conduct imaging in the treatment room to improve IMRT delivery, and is not a replacement for IMRT. IMRT focuses the radiation on the prostate, whereas IGRT ensures that each dose is delivered correctly. In fact, IGRT can help to reduce the margin around the prostate compared with the wider margins defined for prostate cancer with IMRT alone,83 thereby enhancing the accuracy of therapy delivery and protecting a greater proportion of the rectum from unnecessary radiation.

Endorectal balloonsEndorectal balloons (latex or silicon balloons filled with air or water) can be inserted daily into the rectum and used to reduce intrafraction organ motion in concert with IMRT and IGRT.40 Several studies have been con-ducted to assess the differences in prostate motion between patients using endorectal balloons and those not using them (Table 3). Generally, advantages in the balloon-using groups were reported for intrafraction motion, enabling the restriction of margins between clinical target volume (CTV) and planning target volume (PTV). Nevertheless, definitive conclusions cannot be drawn because of the interstudy variation in, for example, balloon-filling methods, techniques, sched-ules and result reporting. For these reasons, verification and correction protocols should be maintained, even if endorectal balloons are used to prevent possible large interfraction displacements.

When focusing on dosimetric advantages related to the use of endorectal balloons, several 3DCRT studies have demonstrated that intermediate or high doses delivered

ma

n

cb

Figure 2 | Schematic representation of tissue architectures. a | In serial organs, functional subunits (a cell or a group of organized cells) are organized in chains. Damage to one subunit results in toxicity that affects the whole tissue. For these tissues, the volume parameter (n) is equal to 0 and the maximum dose is related to toxicity. As an example, the rectal mucosa is a fairly serial organ. b | By contrast, parallel organs are those in which the functional subunits are organized in parallel strings so that tissue toxicity is caused by damage to a substantial number of chains. In this case, marked functional impairment leads to complications when a significant percentage of the total tissue volume is irradiated. For these tissues, the volume parameter (n) is equal to 1 and the mean dose is related to toxicity. As an example, the lung is a parallel organ. c | Mixed organs have combined features of serial and parallel tissues. The tissue can be represented by a number (k) of serial strings, each containing m cells, organized in a parallel structure. In this case, the tissue is characterised by its ‘relative seriality’, which is calculated as the ratio s = (m/k × m). Here, the volume parameter n is a number between 0 and 1, and the dose–volume histogram of the organ can be reduced to an equivalent uniform dose through the use of the volume parameter.77 The majority of organs are mixed organs.

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to the posterior rectal wall were being decreased,88–93 with increasing sparing of the posterior wall with increasing balloon volumes.94 That is, the balloon fills the rectum with air and this pushes the anterior rectal wall towards the prostate and, consequently, towards the high-dose region. Simultaneously, the posterior wall is pushed away from the high-dose region. Large balloon volumes are particularly required when the seminal vesi cles are included in the CTV.92 By contrast, fewer dosi metric studies have considered the effect of the balloon in IMRT. Gains in posterior rectal wall doses have been reported,90,94 but no significant advantage could be demonstrated in the calculated rectal NTCP.94 Similar to posterior rectal wall sparing, anal wall sparing was also demonstrated when using endorectal balloons, both for 3DCRT and IMRT.95

Clinical data comparing rectal toxicity rates when using balloons are scarce and definite conclusions on this issue are not achievable at present. Only one trial96 directly compared patients treated with 67.5 Gy using conven-tional 3DCRT with (n = 24) or without (n = 24) endo-rectal balloons. Less late rectal toxicity and less mucosal damage (assessed by rectal endoscopy) was observed in the balloon- using group than in the nonusers. However,

statistical significance was not reached because of the small study size. Thus, although endorectal balloons seem to present posterior-rectal-wall and anal-wall dosi-metric advantages, large prospective clinical trials are still needed to confirm the translation of these dosimetric gains into clinically significant decreased toxicity.

Tissue spacersAs radiation intensity decays as a function of distance, displacement of healthy tissues from the irradiated target could reduce the percentage volume of the organ at risk included in the high-dose region, and the result-ing radiotherapy- induced toxicity. In this regard, the anatomical organization of the prostate and rectum is particularly suitable for the use of tissue spacers. The Denonvilliers’ fascia (also known as the rectoprostatic fascia)—which is the membrane that separates the pros-tate and urinary bladder from the rectum—is placed immediately posterior to the prostate. This single-fused fascia is composed of dense collagen, smooth muscle and coarse elastic fibres.97 Analysis of radical prostatectomy specimens have shown that tumour progression is possi-ble in the Denonvilliers’ fascia, but no invasion occurred beyond this region.98

Table 2 | Predictive models including clinical and dosimetric risk factors for late radiotherapy-induced rectal toxicity

Study n Follow-up duration (months)

End point Model Included risk factors

Gulliford et al.71 119 Mean 42.6 Grade 2–3 late rectal bleeding ANN Rectal volume;Rectal DVH;Prescribed dose;Margin between CTV and PTV

Valdagni et al.23 718 36.0 Grade 2–3 late rectal bleeding* orGrade 3 late rectal bleeding

MVA (nomogram)

Abdominal surgery;Nomogram prediction of grade 2–3 acute toxicity;Rectal V75 Gy

Fiorino et al.20 506 36.0 Severe chronic faecal incontinence‡

MVA (nomogram)

Diseases of the colon;Use of antihypertensive drugs;Abdominal surgery;Rectal V40 Gy

Fiorino et al.20 506 36.0 Mean grade of late faecal incontinence ≥1‡

MVA (nomogram)

Diseases of the colon;Use of antihypertensive drugs;Presence of haemorrhoids;Grade 3 acute incontinence;Abdominal surgery;Rectal V40 Gy

Tomatis et al.72 718 36.0 Grade 2–3 late rectal bleeding ANN Rectal EUD;Abdominal surgery;Presence of haemorrhoids;Use of anticoagulants;Androgen deprivation therapy (neoadjuvant or adjuvant)

Carrara et al.73 506 36.0 Mean grade of late faecal incontinence ≥1‡

ANN Abdominal surgery;Seminal vesicle irradiation;Use of anticoagulants;Presence of haemorrhoids;Rectal V40 Gy

Ospina et al.74 437 Median 62.0 (range 6.0–155.0)

Grade 2–3 late rectal bleeding Random forest

Age;Rectal V14 Gy;Rectal V21 Gy;Rectal V70 Gy

*Additional risk factors included previous abdominal surgery. ‡Longitudinal definition. Abbreviations: ANN, artificial neural network; CTV, clinical target volume; DVH, dose–volume histogram; EUD, equivalent uniform dose (calculated with n = 0.03);25 MVA, multivariate logistic analysis; PTV, planning target volume; VxGy, per cent volume of the rectum receiving a dose >x Gy.

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Importantly, separation of the Denonvilliers fascia from the mesorectum is possible and, hence, the distance between these two anatomical regions can be increased. Consequently, several pilot clinical studies have been conducted, examining different approaches for separat-ing these anatomical features to save the rectum from radiation exposure. These methods include the injec-tion of collagen between the prostate and the rectum,35

injection of hyaluronic acid between the prostate and rectum,36,99–101 injection of a synthetic poly ethylene glycol (PEG)-based hydrogel as a prostate–rectum spacer37,38,102,103 and insertion of a biodegradable balloon that is inflated in situ with physiological saline.104,105 All these devices were tested in small patient series and had

four overarching goals: to assess the safety of the pro-cedure, to evaluate the stability of the spacer during the course of radiotherapy and its degradation over time, to evaluate the dimensions of the prostate–rectum interface that can be protected with organ spacers and to deter-mine the dosimetric effect of an increased space between the target and the organ at risk (Table 4).

All these studies confirmed the efficacy of using spacers to separate the anterior rectal wall from the pros-tate, and the approaches used significantly decreased the volume of the rectum receiving medium to high radia-tion doses (50–75 Gy). However, whether the decreases in dose translate to a clinically meaningful reduction in toxicity remains unclear because of the small numbers of

Table 3 | Effects of endorectal balloons on intrafraction and interfraction prostate motion

Study n Radiotherapy technique (dose)

Balloon fill (volume)

Verification procedure

Prostate displacement

Single arm

D’Amico et al.111*

10 LDR brachytherapy

Air (60 cm3)

Intrafraction motion;3 CT scans at 1 min intervals

1 mm maximum in all directions (with balloon);4 mm maximum in all directions (no balloon)

Wachter et al.88*

10 3DCRT (66 Gy)

Air (40 cm3)

Interfraction motion;3 CT scans‡

Maximum (with balloon): 3.5 mm (anterior) and 3.6 mm (posterior)Maximum (without balloon): 6.6 mm (anterior) and 7.4 mm (posterior)

McGary et al.112

10 IMRT (dose NR)

Air (100 cm3)

Interfraction motion;CT scans (twice weekly)

0.42 mm ± 0.35 mm (anterior–posterior)0.83 mm ± 0.38 mm (lateral)0.92 mm ± 1.78 mm (cranio–caudal)

El-Bassiouni et al.113

15 3DCRT (70 Gy)

Air (60 cm3)

Interfraction motion;Portal imaging (weekly)

3.8 mm ± 4.0 mm (anterior–posterior)2.1 mm ± 1.2 mm (lateral)2.2 mm ± 2.4 mm (cranio–caudal)

Vargas et al.114*

7 NR Air (100 cm3)

Intrafraction motioncineMRI

0.55 mm (variation prostate position, balloon supine set-up)1.2 mm (variation prostate position, no balloon supine set-up)1.48 mm (variation prostate position, balloon prone set-up)2.15 mm (variation prostate position, no balloon prone set-up)

Both et al.115

24 IMRT (79.2 Gy)

Water (100 cm3)

Intrafraction motion;Real-time tracking with electromagnetic transponders

Mean percentage time§ with prostate displacement >5 mm within 6 min:0.1 (anterior–posterior)0.0 (lateral)0.1 (cranio–caudal)0.7 (3D displacement)

Double arm

van Lin et al.116||

30 (without balloon) versus 22 (with balloon)

IMRT (dose NR)

Air (80 cm3)

Interfraction motion;Portal imaging (daily)

0.6 mm ± 4.3 mm versus 0.0 mm ± 3.1 mm (anterior–posterior)0.3 mm ± 2.8 mm versus 1.3 mm ± 2.6 mm (lateral)0.2 mm ± 2.3 mm versus –0.4 mm ± 4.7 mm (cranio–caudal)

Wang et al.117*

30 (with balloon) versus 29 (without balloon)

IMRT (79.2 Gy)

Water (100 cm3)

Intrafraction motion;Real-time tracking with electromagnetic transponders

Mean percentage time§ with prostate displacement >5 mm within 6 min0.7 versus 3.1 (3D displacement)0.0 versus 0.0 (left)0.0 versus 0.0 (right)0.3 versus 0.0 (cranial)0.2 versus 0.0 (caudal)0.9 versus 0.1 (anterior)0.5 versus 0.0 (posterior)

Smeenk et al.118

15 (with balloon) versus 15 (without balloon)

IMRT (80 Gy) NR Interfraction motion;||

Intrafraction motion;*Real-time tracking with electromagnetic transponders

Interfraction random displacement:3.8 mm versus 3.9 mm (anterior–posterior)5.4 mm versus 6.3 mm (lateral)2.7 mm versus 3.0 mm (cranio–caudal)Mean percentage time§ with prostate displacement >5 mm within 6 min1.2 versus 0.0 (anterior–posterior)0.0 versus 0.0 (lateral)0.4 versus 0.2 (cranio–caudal)4.6 versus 0.7 (3D displacement) 

*Study found statistically significant differences in prostate motion. ‡At the beginning, middle and end of the radiotherapy. §The time during which the prostate shows a displacement greater than a fixed value. ||Study found differences in prostate motion that are not statistically significant. Abbreviations: 3DCRT, 3D conformal radiotherapy; cineMRI, cine-magnetic resonance imaging; IMRT, intensity-modulated radiotherapy; LDR, low-dose-rate; NR, not reported.

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patients involved in these studies (173 patients in total) and the relatively short follow-up duration (median fol-low-up time was <12 months in most studies). Indeed, current EBRT practices for prostate cancer involve high doses (>75 Gy), standard fractionation (2 Gy per frac-tion) or moderate hypofractionation (2.2–3.5 Gy per fraction), the use of IMRT (with or without IGRT) and dose–volume constraints. Consequently, the rate of late rectal morbidity is very low; the rate of grade 2–3 toxi-city is <3% (Table 1). For this reason, it would be difficult to assess whether the introduction of organ spacers into routine clinical practice would further decrease the rate of late rectal morbidity.

Nevertheless, organ spacers are likely to be very useful for EBRT when very high doses per fraction (>5 Gy per fraction) are to be delivered and this field is receiving increasing attention. The objective of this approach—known as stereotactic body radiotherapy (SBRT)39—is to obtain a dose distribution similar to that for brachy-therapy using an external beam. SBRT is an attractive option because it enables us to achieve the same dose distri bution as for high-dose-rate brachytherapy, but with better cost- effectiveness and without the risks of invasive procedures, anaesthesia or prolonged bed rest.39 Importantly, with SBRT, the risk of acute rectal

toxicity increases because a small—but not negligible—p ercentage of the rectum receives a dose similar to the prescribed dose per fraction. In these situations, in which small volumes of the rectum receive 7–10 Gy in a single dose, ablative damage can occur to the rectal mucosa, which is an e xcellent r ationale for testing the use of organ separators.

Drugs and other compoundsA few studies have investigated the possible role of drugs and other compounds to prevent acute rectal injury, and to relieve the symptoms associated with acute rectal syndrome. Prevention and mitigation of acute damage are crucial issues because clinical data suggest that early damage to the intestinal mucosa or vascular endo thelium is significantly associated with late mucosal damage. Consequently, acute toxicity is one of main factors a ssociated with late toxicity.

Butyrate and short-chain fatty acids have been pro-posed to prevent and alleviate the acute symptoms. These compounds have an important role in the regu-lation of mucosal proliferation because they promote mucosal repair,106 dilate resistance arteries (precapillary vessels that contribute passively to the resting resistance and actively to the blood-flow control during altered

Table 4 | Effects of spacers on the prostate–rectum distance, dosimetric gain and rectal toxicity rates

Study n Radiotherapy technique (dose)

Prostate–rectum distance

Dosimetric evaluation (rectal dose)without spacer versus with spacer

Rectal toxicity rate

Hyaluronic acid injection

Prada et al.36 27 HDR brachytherapy (2 × 11.5 Gy) + 3DCRT (46 Gy)*

Mean: 2 cm Mean: 6.1 Gy ± 1.2 Gy versus 5.1 Gy ± 1.3 Gy‡

Maximum: 7.1 Gy ± 1.4 Gy versus 5.1 Gy ± 1.2 Gy‡

NR

Prada et al.99 40 HDR brachytherapy(19 Gy per fraction)

NR NR 12.5% asymptomatic acute grade 1 anal mucositis§

Wilder et al.101 10 IMRT (50.4 Gy) + HDR brachytherapy (4 × 22 Gy)

Mean: 1.3 cm ± 0.3 cm V60Gy: 33% ± 13% versus 12% ± 9%V70Gy: 25% ± 12% versus 4% ± 4%

No acute toxicity observed

Polyethylene glycol gel injection

Pinkawa et al.37 18 3DCRT|| (78 Gy) Base: 1 cm ± 0.4 cmMedial plane: 0.9 cm ± 0.3 cmApex: 1.1 cm ± 0.7 cm

Mean: 41.7 Gy ± 7.3 Gy versus 38.1 ± 6.7 GyV76Gy: 6.4% ± 7.8% versus 2.1% ± 3.8%V70Gy: 14.4% ± 11.2% versus 6.1% ± 6.4%V50Gy: 34.4% ± 15.1% versus 24.2% ± 15.7%

NR

Pinkawa et al.37 18 IMRT¶ (78 Gy) Base: 1 cm ± 0.4 cmMedial plane: 0.9 cm ± 0.3 cmApex: 1.1 cm ± 0.7 cm

Mean: 41.2 Gy ± 6.9 Gy versus 36.1 Gy ± 7.1 GyV76Gy: 1.9% ± 2.2% versus 0.2% ± 0.3%V70Gy: 17.2% ± 6.5% versus 7.5% ± 5.2%V50Gy: 40.8% ± 12.8% versus 31.9% ± 13.8%

NR

Song et al.38 25 IMRT (dose NR) Mean: 0.8 cm V50Gy:# 32.1% versus 13.6%V70Gy:# 14.1% versus 3.0%

NR

Hatiboglu et al.103 29 IMRT (78 Gy) Mean: 9.9 cm ± 5.9 cm V70Gy: 14.6% versus 5.8% NR

Human collagen injection

Noyes et al.35 11 IMRT (75.6 Gy) Mean: 1.3 cm (range 0.8–1.9 cm)

V50Gy:** 7.8% versus 2%V60Gy:** 3.3% versus 0.6%V75.6Gy:** 0.6% versus 0%

No gastrointestinal toxicity observed

Inflatable balloon

Garg et al.105 13 IMRT (75.6 Gy) Mean: 2.6 cm (range 1.4–3.3 cm)

V65Gy: 14.5% versus 4.3%V70Gy: 12.1% versus 3.0%

NR

*Treatment is the sum of the two schedules. ‡Doses were only evaluated for the HDR boost. §No other gastrointestinal toxicity was recorded in the follow-up period. ||The predicted grade ≥2 normal tissue complication probability without spacer versus with spacer was 4.7% ± 3.8% versus 2.1% ± 1.9%. ¶The predicted grade ≥2 normal tissue complication probability without spacer versus with spacer was 5.1% ± 2.5% versus 2.6% ± 1.9%. #Median values. **Data derived from the published figure.35 Abbreviations: 3DCRT, 3D conformal radiotherapy; HDR, high-dose-rate; IGRT, image-guided radiotherapy; IMRT, intensity-modulated radiation therapy; NR, not reported; VxGy, per cent volume of the rectum receiving a dose >x Gy.

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demands) and increase mucosal blood flow and oxygen uptake.107,108 Vernia et al.41 conducted a study in which topical butyrate was administered to treat acute radia-tion proctitis in 58 patients receiving 35–52 Gy to the pelvis (using nonconformal techniques) for either cer-vical or prostate cancer. Overall, 25 patients presenting with acute rectal toxicity were enrolled in a randomized double- blind study. The topical administration of buty-rate for 3 weeks led to the alleviation of symptoms in eight of nine patients, which was confirmed by endo-scopy and histology.41 Hille et al.42 evaluated the effect of sodium butyrate enemas in 31 patients who experi-enced grade 2 acute proctitis during 60–72 Gy conformal radiotherapy for prostate cancer. Overall, 74% of patients experienced a decrease in grade of acute toxicity within a median of 8 days. Despite this encouraging result in terms of acute toxicity, butyrate enema use was not cor-related with the development of late rectal toxicity, as the rates of grade 1 and grade 2 late toxicity were 29% and 6.5%, respectively, over a median follow-up duration of 50 months.

A hypothesis-generating study proposed the use of soy isoflavones in combination with radiotherapy.43

Soy isoflavones have considerable antioxidant and anti-inflammatory properties, which might help to prevent radiotherapy-induced injury. This small randomized study included 26 patients treated with 73.8–77.5 Gy using 3DCRT or IMRT.43 Toxicity evaluation after 6 months revealed reduced rectal and urinary morbid-ity in patients who received soy isoflavones, including lower rates of rectal cramping and diarrhoea (7.7% versus 21.4%) and abdominal pain (0% versus 14.8%) compared with patients who did not receive soy iso-flavones. However, these differences did not reach statis-tical significance because of the small number of patients enrolled in the study.

In summary, some studies have suggested that the adverse rectal effects of radiotherapy for prostate cancer can be reduced or ameliorated by administering various drugs or other compounds. These agents could

be particu larly beneficial for patients exhibiting clini-cal risk factors and those at high risk of rectal toxicity. Nevertheless, these results are preliminary and need to be confirmed in larger populations. Until the effective-ness of these drugs is demonstrated in high-quality clini-cal trials, they should only be administered within the framework of clinical, controlled studies.

ConclusionsReducing rectal injury during prostate cancer radio-therapy is a topic of great interest within the radiotherapy community. Over the past 15 years, a great deal of know-ledge has been acquired on the dose–volume effects of radiotherapy, which has enabled researchers to develop models to predict toxicity and guide treatment optimiza-tion towards favourable dose distributions. When used together with IMRT and IGRT, these models can be powerful tools to reduce morbidity. Furthermore, results of some studies have confirmed that some patients are remarkably radiosensitive because of their individual characteristics. True (perhaps genetic) determinants of this enhanced radiosensitivity have yet to be identified, but clinicians should be particularly vigilant when treat-ing patients harbouring rectal-toxicity-predisposing risk factors. Finally, a number of physical and medical inter-ventions could provide some safeguards against radio-toxicity, but these must be rigorously assessed in large clinical trials before being widely applied.

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Review criteria

An extensive MEDLINE search was performed including the following search terms: (“rectal” OR “rectum” OR “anal”); (“injury” OR “toxicity” OR “morbidity”); (“radiotherapy” OR “radiation therapy”); “prostate cancer”. In addition, conference abstracts and papers in press were considered for the Review using appropriate key words. The bibliographies of selected papers were also reviewed to identify additional references. Results were limited to English-language articles published up to 31 May 2012.

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Author contributionsBoth authors researched the data for the article, contributed to the discussion of its content, wrote and edited the manuscript before submission.

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