*2.3.2 Experimental protocol*

The 30 eligible patients were randomized to treatment with APC (n = 17) or topical formalin (n = 13).

Each patient underwent evaluations of (i) anorectal symptoms (validated questionnaires including modified LENT-SOMA scales for GI symptoms and visual analogue scales for rectal bleeding), (ii) anorectal motor and sensory function (manometry with a perfused sleeve and multiport assembly incorporating a highly compliant polyethylene bag in the rectum) and (iii) anal sphincteric morphology (endoanal ultrasound) before and after the treatment endpoint (defined as reduction


*† Manometric port distances from anal verge.*

*From Yeoh et al. [14], with permission.*

#### **Table 5.**

*Residual anorectal pressures in response to rectal distension (RD), with 10 ml, 20 ml, 40 ml, 60 ml and 100 ml\**

of rectal bleeding to 1x per month or better, reduction of visual analogue scales to ≤25 mm, no longer needing blood transfusions). Cross-over to the other therapy was allowed if the treatment endpoint was not reached after 4 treatment sessions.

#### *2.3.3 Data presentation and interpretation*

Rectal bleeding was controlled in twenty nine of the 30 patients after a median of 2 treatment sessions of APC or topical formalin. One patient, initially treated with APC, failed after 4 treatment sessions but achieved control after 3 sessions of cross-over topical formalin, Control of rectal bleeding was evidenced by reductions of its frequency to ≤1x per month, VAS ≤ 25 mm (**Figures 4** and **5**, **Table 6**) and no further requirement for blood transfusion in the 2 patients (1 each in APC and topical formalin groups) needing this before randomization to therapy.

The durability of control of rectal bleeding by APC and topical formalin was evidenced by only 1 patient in each group needing further therapy after a median (range) follow-up of 111 (29–170) months [15].

No effect on other anorectal symptoms, such as increased frequency and urgency of defecation and fecal incontinence, was observed (**Table 6**).

*Pathophysiology, Natural History and Approaches to Treatment and Prevention of Radiation… DOI: http://dx.doi.org/10.5772/intechopen.99269*

#### **Figure 2.**

*Rectal volumes at which patients and normal subjects felt desire to defaecate. (From Yeoh et al. [14], with permission).*

Other than a reduction in rectal compliance and volumes of sensory perception after APC, no effects on parameters of anorectal function and anal sphincteric morphology were observed (**Table 7**).

APC and topical formalin had comparable efficacy in the durable control of rectal bleeding associated with chronic radiation proctitis but no beneficial effect on anorectal dysfunction.

### **2.4 Pudendal nerve injury impairs anorectal function and health related quality of life measures** ≥**2 years after 3D conformal radiotherapy for prostate cancer**

#### *2.4.1 Subject selection criteria*

The 25 patients, median age = 76 (range 64–83) years, selected for the above study met the following eligibility criteria:


**Figure 3.** *Pressure/volume relationship in patients and controls associated with rectal distension (from Yeoh et al. [14], with permission).*

*Pathophysiology, Natural History and Approaches to Treatment and Prevention of Radiation… DOI: http://dx.doi.org/10.5772/intechopen.99269*

#### **Figure 5.**

*Visual analogue scale (VAS) before (pre) and after (post) topical formalin treatment. (From Yeoh et al. [15], with permission).*


*Abbreviations: NS, not significant; VAS, visual analogue scale; Values are median (range). From Yeoh et al. [15], with permission.*

#### **Table 6.**

*Effect on anorectal symptom parameters of argon plasma coagulation therapy (APC) and topical formalin treatment.*


Of the 80 patients invited to participate in the study, 48 refused, 7 were ineligible (6 had APC for rectal bleeding, 1 patient had received 2D radiotherapy).

25 age matched patients with localized prostate carcinoma in a recent randomized radiotherapy study served as control subjects [21].

#### *2.4.2 Experimental protocol*

Each subject underwent the following evaluations: (i) GI symptoms (modified LENT-SOMA scales), (ii) generic and disease specific HRQoL measures (EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires), (iii) anorectal motor and sensory function


Abbreviations*: NS, not significant; EAS, external anal sphincter; IAS, internal anal sphincter; Values are mean SE. From Yeoh et al. [15], with permission.*

#### **Table 7.**

*Effect on anorectal function and anal sphincteric morphology parameters of argon plasma coagulation therapy (APC) and topical formalin treatment.*

(manometry with a perfused sleeve and multiport assembly incorporating a highly compliant polyethylene bag in the rectum), (iv) pudendal nerve function (terminal motor nerve latency) and (v) anal sphincteric morphology (endoanal ultrasound).

The data of the 25 patients ≥2 years after 3D conformal radiotherapy for prostate cancer were compared with the before radiotherapy (baseline) data of the 25 control subjects.

The data of symptomatic (defined as patients with Total LENT-SOMA GI symptom scores ≥5, n = 13) and asymptomatic (defined as patients with Total LENT-SOMA GI symptom scores ≤4, n = 12) patients among the 25 patients ≥2 years after 3D conformal radiotherapy were also compared.

#### *2.4.3 Data presentation and interpretation*

### *2.4.3.1 Comparisons of modified LENT-SOMA GI symptoms and EORTC HRQoL measures*

Patients in this study had significantly higher modified LENT – SOMA frequency and urgency of defaecation, rectal bleeding and mucous discharge scores ≥2 years after 3D conformal radiotherapy compared to the age matched control subjects before radiotherapy (**Table 8**). The patients also had worse (lower) EORTC QLQ-C30 cognitive functioning scores and worse (higher) EORTC QLQ-PR25 bowel symptom scores compared to the controls before radiotherapy (**Table 8**).

Symptomatic patients had significantly higher (i) modified LENT SOMA urgency of defaecation and rectal bleeding scores and (ii) EORTC QLQ-PR25 bowel and urinary symptom scores compared with asymptomatic patients (**Table 9**). Symptomatic patients also had worse (lower) EORTC QLQ-C30 social and emotional functional as well as global health scores compared to asymptomatic patients (**Table 9**).

### *2.4.3.2 Comparisons of anorectal and pudendal nerve function data and anal sphincter morphology measurements*

All parameters of anorectal motor and sensory function except for threshold volumes for sensory perception were significantly worse ≥2 years after 3D


*Pathophysiology, Natural History and Approaches to Treatment and Prevention of Radiation… DOI: http://dx.doi.org/10.5772/intechopen.99269*

Abbreviations*: ns, not significant; LENT-SOMA, late effect normal tissue – subjective objective management analytic; EORTC, European Organization for Research and Treatment of Cancer; QLQ, quality of life questionnaire; Values are median (range).*

*From Yeoh et al. [16], with permission.*

#### **Table 8.**

*Comparison of modified LENT-SOMA GI symptoms and EORTC generic (QOL-C30) and disease specific (QLQ-PR25) HRQoL data between whole patient group and age matched patients before radiotherapy.*

conformal radiotherapy compared to age matched control subjects before radiotherapy (**Table 10**).

Unilateral and/or bilateral pudendal nerve responses were delayed in 13/24 (54%) of the patients compared to only 2/20 (10%) aged matched controls before radiotherapy (p < 0.0001, data not shown).

The thickness of both IAS and EAS was significantly less in the patients compared to the control subjects before radiotherapy (**Table 10**).

Fecal incontinence scores were worse in the symptomatic compared to the asymptomatic patients but no differences were detected in thickness of either IAS or EAS in the patient sub-groups (**Table 11**).


Abbreviations*: ns, not significant; LENT-SOMA, late effect normal tissue – subjective objective management analytic; EORTC, European Organization for Research and Treatment of Cancer; QLQ, quality of life questionnaire; Values are median (range). From Yeoh et al. [16], with permission.*

Urinary symptoms 25(0–58) 10(0–25) <.05 Bowel symptoms 25(8–42) 0(0–25) <.001 Hormonal treatment-related symptoms 11(0–50) 6(0–33) ns

#### **Table 9.**

*Comparison of modified LENT-SOMA GI symptoms and EORTC generic (QOL-C30) and disease specific (QLQ-PR25) HRQoL data between symptomatic and asymptomatic patients.*

Unilateral and/or bilateral pudendal nerve responses were delayed in 9/13 (69%) of symptomatic compared to only 4/11 (36%) of asymptomatic patients (p < 0.0001, data not shown).

Rectal and anal (i) V40Gy > 65%, (ii) Dmax >60 Gy, (iii) pudendal nerve Dmax >60 Gy and (iv) Anal V60 Gy >40% were associated with a greater prevalence of pudendal nerve function [16].

3D radiotherapy high dose rate brachytherapy (HDR) for localized prostate carcinoma impairs functional measures including HRQoL, anorectal and pudendal nerve function ≥2 years after treatment. Radiation dose constraints are proposed for reducing the prevalence of pudendal nerve dysfunction.

**ARM Whole patient group Age matched patient group** *P* **Value** Basal pressure (mmHg) 46 4 63 3 <.01 Squeeze pressure (mmHg) 105 8 154 8 <.0001 ↑Intra-abdominal pressure (mmHg) 82 5 106 5 <.01 IAS (mm) 2.1 0.1 2.6 0.1 <.05 EAS (mm) 8.0 0.3 9.3 0.3 <.01 Threshold perception (mL) 14 1 16 2 ns Desire to defecate sensation (mL) 68 8 97 9 <.05 Rectal compliance (mL/mmHg) 3.3 0.3 5.1 0.4 <.01 FI score 2(0–8) 0(0–1) <.001 Urgency score 2(0–6) 0(0–3) <.001 Number of bowel actions/week 10.5(7–24.5) 7(3.5–21) <.05

*Pathophysiology, Natural History and Approaches to Treatment and Prevention of Radiation… DOI: http://dx.doi.org/10.5772/intechopen.99269*

Abbreviations*: ns, not significant; IAS, internal anal sphincter; EAS, external anal sphincter; FI, fecal incontinence; Values are mean SE.*

*From Yeoh et al. [16], with permission.*

#### **Table 10.**

*Comparison of anorectal function and anal sphincter morphology data between whole patient group and age matched patients before radiotherapy.*


Abbreviations*: ns, not significant; IAS, internal anal sphincter; EAS, external anal sphincter; FI, fecal incontinence; Values are means SE. From Yeoh et al. [16], with permission.*

#### **Table 11.**

*Comparison of anorectal function and anal sphincter morphology data between symptomatic and asymptomatic patients.*
