Table 4 Large Bowel studies - details and quality assessment

Chopra [11]

Large bowel

2 cm above target, individual loops of large bowel (unclear how differentiated from small bowel)

CTCAE v3.0 Gr ≥ 3

9/71 (12.6%)

V15 associated with ≥gr 3 toxicity.

Constraints: V15 < 250 cc, V30 < 100 cc, V40 < 90 cc to reduce toxicity from 26.7 to 5.4%

1, 4, 6

(n/a 2,3)

Isohashi [10]

Large bowel

Single loop continuing from end of sigmoid to ascending colon

RTOG/EORTC, Gr ≥ 2

16/97 (16.5%)

No constraint found for large bowel

1,7

(n/a 2–6)

Fonteyne [17]

Sigmoid colon

Where rectum sweeps anteriorly to one slice above aortic bifurcation

RTOG and “RILIT” Gr 1 and 2

Gr 1112/241 (46%), Gr 2 32/241 (13%).

V40 associated with gr1 diarrhoea & blood loss.

Constraints: V40 < 10%, V30 < 16% to avoid gr1–2 diarrhoea

1, 7

(n/a 3)

Mouttet-Audouard [6]

Sigmoid colon

Anterior curvature of sigmoid colon to anterior abdominal wall

CTCAE v4.0

Gr1–3 diarrhoea and “whole digestive toxicity”

8/37 (21.6%) diarrhoea; 17/37

(46%) (whole tox)

‘Whole late digestive toxicity’ associated with V30–40. No specific constraints.

1,7

(n/a 2–6)

Lind [12]

Sigmoid colon

From where rectum deviates from its mid- position to where it turns cranially in left abdomen connecting to colon descendens

Defecation into clothing without warning > 1 in last 6 months

63/519 (12.1%)

Mean dose>50Gy to small bowel or sigmoid or anal sphincter region associated with symptom (findings for individual organs not clarified)

1, 7

(n/a 2–6)

al-Abany [18]

Anal sphincter region

Caudal 3 cm of the rectum from anal verge (including filling)

Own questionnaire; Faecal leakage >2X/week

9/65 (13.8%) faecal leakage

Increased risk with mean dose of 45-55Gy.

Constraints: V35 < 60%, V40 < 40% associated with no risk of faecal leakage.

1, 7

(n/a 2,3)

Alsadius [19]

Anal sphincter region

Caudal part of large bowel, from end of rectal ampulla where bowel no longer had visible content or air.

Own questionnaire;

Faecal leakage >once per month

51/403 (12.7%) faecal leakage

Dmean<40Gy reduces risk from 17 to 4%.

1,2,4,7

(n/a 3)

Fokdal [14]

Anal canal

Outer contour of the structure extending from anal verge 2 cm cranially

LENT SOMA score

Urge: 27/71 (38%); Incontinence: 21/71 (30%)

Urgency related to Dmed> 33.8: increases toxicity 31 to 47%

Incontinence related to Dmax> 53.8 increases 14 to 44%

1,2,4,5,7

(n/a 3)

Vordermark [23]

Anal canal

Anal verge to the section below visible rectal lumen, corresponding to the upper border of the

levator ani muscle

“Solid soiling” (Severe incontinence)

Own continence questionnaire

6/44 (14%)

Severe incontinence

- associated with Dmin (23.1Gy)

- related to portals extending 2 mm below ischial tuberosities (compared with 5 mm above)

1, 7

(n/a 2–3)

Koper [25]

Anal canal

Caudal 3 cm of the intestine

RTOG gr1 + 2;

Plus symptom questionnaire.

141/248 (57%)

D90% (=54.9Gy) to associated with ≥ gr1 rectal toxicity

1, 7

(n/a 2–6)

Taussky [37]

Anal canal

Most distal 2-3 cm of rectum

10 questions from UCLA-PCI, FACT-P & EORTC QLQ -PR25

Unclear

no relation with anal canal DVH found

7

(N/a: 2–3)

Buettner [20]

Anal canal

Caudal 3 cm of rectum

Common grading scheme; subjective sphincter control at highest grade

57/388 (14.7%)

DSH data: Toxicity correlated with dose to anal surface: lateral extent 53Gy > 56%.

DVH data: Dmean 47Gy to anal sphincter volume correlated with sphincter toxicity. Constraints: Dmean<30Gy.NTCP modeling to LKB model TD50 = 120, m = 0.42.

1,3,6,7

(n/a 2)

Peeters [21]

Anal wall

Wall of caudal 3 cm of anorectum (method described)

RTOG/EORTC ≥ gr 2 and ≥ gr 3 Plus incontinence pad use>2x/wk.

≥gr 2165/641 (25.7%) ≥ gr 3 27/641 4.2%

Dmean increase from 19Gy to 52Gy increased gr2 toxicity: 16 to 31%.

V65 & Dmean most significant for incontinence. Dmean increase by 33Gy increased incontinence by 12%

1,2,4,6,7

(n/a 3)

Mavroidis [27]

Anal sphincter region

Musculaure layer around the rectal aperture, 3 cm caudal from anal verge

Own questionnaire

faecal leakage 19/65 (29%); blood/mucus 22/65 (34%)

Relative seriality NTCP model of anal sphincter for incontinence, blood/mucus. Parameters for incontinence: D50 = 70.2Gy, γ = 1.22, s = 0.35. Parameters for blood/mucus: D50 = 74.0Gy, γ = 0.75, s ≈ 0

1, 3, 5, 6, 7

(n/a 2)

Peeters [28]

Anal canal wall

Wall of caudal 3 cm of anorectum (method described)

Incontinence requiring pad

use>2x/wk.;

32/368 (7%)

NTCP LKB model of incontinence with anal wall dose. Parameters found were n = 7.48; TD50 = 105; m = 0.46

1,3,4,5,6,7

(n/a: 2)

Smeenk [26]

Anal sphincter muscles

Individual muscles defined (Internal anal sphincter (IAS), external anal sphincter (EAS), puborectalis & levator ani)

Frequency, Urgency, Incontinence

21/48 (44%)

For complication <5% Dmean<30Gy to IAS; <10Gy to EAS, < 50Gy to puborectalis, <40Gy to levator ani

1, 4,5

(n/a 2)

Smeenk [22]

Anal wall

Continuation of rectal wall from anal verge to slice below lowest slice with a rectal balloon

Frequency, urgency, incontinence

39% frequency, 31% urgency, 31% incontinence

For urgency:

Anal wall Dmean<38Gy risk < 15%, >38Gy risk is 62%

1,4,7

(n/a 2,3,5,6)

Lind [12]

Anal sphincter region

Inner muscle layer of the sphincter up to anal verge

Defecation into clothing without warning > 1 in last 6 months

63/519 (12.1%)

Mean dose>50Gy to small bowel or sigmoid or anal sphincter region associated with this symptom

(findings for individual organs not clarified)

1, 7 (n/a 2,3)

Yeoh [24]

Anal wall

From anorectal junction (not clearly defined)

LENT-SOMA total score

72%

Anal wall V40 > 65% associated with chronic toxicity.

1,5 (n/a 2,3)

Thor [29]

Anal sphincter

Anal canal, inner and outer sphincter (not clearly defined)

Questionnaire of 19 questions in 4 domains: pain urgency, mucus & incontinence.

Specific to each of 19 question

5 LKB models proposed for anal sphincter doses.

Low anal sphincter dose associated with faecal leakage and pain. High anal sphincter dose associated with leakage.

1,3,6 (n/a 2)

Ebert [35]

Anal Canal

Caudal 3 cm of anorectum

LENT-SOMA – 8 symptoms

Specific to each symptom

Bleeding associated with >40Gy, proctitis with 36-63Gy, frequency with 8-85Gy, urgency and tenesmus with 5-34Gy to anal canal.

1,5,7 (n/a 2)