Therapy and Non-Invasive Prevention of Gastrointestinal ... · group. For follow-up by a gastroenterologist, compared to the standard booklet, a pair-wise mean difference in change

Therapy and Non-Invasive Prevention

of Gastrointestinal Toxicity caused by

Radiotherapy for Pelvic Neoplasms

Nele Vandemaele Student number: 01408925

Supervisors: Prof. Dr. Katrien Vandecasteele, Prof. Dr. Hannelore Denys

A dissertation submitted to Ghent University in partial fulfilment of the requirements for the

degree of Master of Medicine in Medicine

Academic year: 2017 – 2019

“The author and the promotor give the permission to use this thesis for consultation and to

copy parts of it for personal use. Every other use is subject to the copyright laws, more

specifically the source must be extensively specified when using results from this thesis.”

13/12/2018

Nele Vandemaele Prof. Dr. Katrien Vandecasteele

1. ACKNOWLEDGEMENTS

I would like to thank my promotor, prof. Dr. Katrien Vandecasteele for her supervision. Her

constructive feedback made the writing of this dissertation possible and transformed it into a

valuable learning process.

A special thank you goes out to my family and friends as well, for reading this dissertation

many times. Their input and support have been a great help.

p.4 Therapy and Non-Invasive Prevention of Gastrointestinal Toxicity caused by Radiotherapy for Pelvic Neoplasms

2. ABSTRACT

2.1 ABSTRACT Goal of this dissertation: The purpose of this dissertation is to provide an overview of the

existing treatments and non-invasive prevention methods for the radiation-induced toxicity,

more specifically the gastrointestinal toxicity.

Methods: A literature search was performed in Embase and Pubmed databases. In total 6618

articles were found using a search strategy including non-invasive prevention and treatment

methods for patients with gastrointestinal toxicity caused by radiotherapy or chemo

radiotherapy for pelvic neoplasms. Because of the great amount of research on the subject of

this dissertation, only randomized controlled trials or phase III clinical trials, written in English,

were included. After reviewing title, study type and abstract, 34 articles were assessed by full

text. Ultimately, 27 studies were selected.

Results: Because of the enormous amount of data, only the most statistically, clinically

significant and promising interventions were mentioned in this abstract. For acute GI toxicity:

Grade 2 or worse GI toxicity occurred in 20% of the sulphasalazine group, compared to 63%

in the placebo group (p=0.017). For a high-fiber diet, the reduction of IBDQ was -3.7, compared

to -10.8 for a habitual-fiber diet. (p=0.011). For chronic GI toxicity: orgotein was at 90d, 12, 18

and 24m respectively 13.9%, 13.5%, 21.9% and 19.4% significantly better than the placebo

group. For follow-up by a gastroenterologist, compared to the standard booklet, a pair-wise

mean difference in change of 5.47 in IBDQ-B score could be seen (p=0.01). For follow-up by

a nurse, compared to follow-up with a booklet, this was 4.12 (p=0.04). For a high-fiber diet the

change in IBDQ-score was 0.01 vs.-8.4 for habitual-fiber (p=.0004) and vs.-4.9 for low-fiber

(p= 0.005). For radiation enteritis/ diarrhoea: 27% of the sulphasalazine group suffered from

grade 2 or worse diarrhoea, compared to 49% of the placebo group (p=0.038). For radiation

proctitis: balsalazide and Aloe Vera could have beneficial potential, but require further

research, mainly due to very small study populations. For rectal bleeding: formalin 4% and

formalin 10% reduced the RPSAS score with 10 and 12 points respectively (both p<0.001).

However, with formalin 10% therapy, 15.4% more patients suffered from adverse events

(p=0.03). BEC and APC had 93% and 80% success rate respectively (p=0.589), but BEC had

53.4% more complications (p=0.003). APC and topical formalin both reduced the rectal

bleeding scores with 2 (APC: p=0.001; topical formalin: p=0.001). No significant differences

between both therapies could be found.

Therapy and Non-Invasive Prevention of Gastrointestinal Toxicity caused by Radiotherapy for Pelvic Neoplasms p.5

The quality of the included studies was evaluated through a Risk of Bias Table. Almost every

study contained limitations.

Conclusion: Practically no research concerning today’s standard care could be found. The

daily used methods should be critically reviewed. As a general concern, this dissertation

concludes that there is a need for more standardization of research, for example by means of

a unified toxicity reporting manner. Also, more attention should be given to patient-reported

outcomes. The included studies report several methods with beneficial potential, however the

evidence is not strong enough to make definite conclusions. This dissertation urges for further

research.

2.2 NEDERLANDSTALIG ABSTRACT Doel van de thesis: Het doel van deze thesis is om een overzicht te bieden van de bestaande

therapieën en niet-invasieve preventie methodes voor gastro-intestinale radiotoxiciteit.

Methode: Er werd een literatuurstudie in de Embase en Pubmed databases uitgevoerd. In

totaal werden 6618 artikels gevonden. De zoekstrategie was gericht op therapieën en niet-

invasieve preventiemethodes voor patiënten met gastro-intestinale toxiciteit na radiotherapie

of chemoradiotherapie voor tumoren in het klein bekken. Enkel randomized controlled trials en

fase III clinical trials werden weerhouden. Artikels die niet in het Engels geschreven waren,

zijn geëxcludeerd. Na het evalueren van de titels, abstracts en studie types, bleven er nog 34

artikels over. Na full text analyse werden uiteindelijk 27 artikels geselecteerd.

Resultaten: Door het grote aantal resultaten is besloten om hier enkel de statistisch en klinisch

meest relevante resultaten te vermelden. Voor acute GI toxiciteit: In de sulphasalazine-groep

werd 20% graad 2 of hoger GI toxiciteit gevonden, tegenover 63% in de placebogroep

(p=0.017). Voor een dieet met een hoge vezelconcentratie werd in de IBDQ-score een

verandering van -3.7 gevonden, terwijl dit in de groep met een gewone hoeveelheid vezels

-10.8 was (p=0.011). Voor chronische GI toxiciteit: De toxiciteit in de orgoteïne-groep was

13.9%, 13.5%, 21.9% en 19.4% significant beter dan de placebogroep op respectievelijk dag

90 en maand 12, 18 en 24. Voor opvolging door een gastro-enteroloog, vergeleken met een

schriftelijke opvolging via een standaard infoboekje, kon een pairwise mean difference in

verandering voor IBDQ-B-score van 5.47 gevonden worden (p=0.01). Voor opvolging door een

verpleegster, in vergelijking met het infoboekje, was dit 4.12 (p=0.04). Bij een dieet met een

hoge vezelconcentratie was de chronische IBDQ verandering 0.01 vs.-8.4 voor een gewone

vezelconcentratie (p=.0004) en vs.-4.9 voor een lage vezelconcentratie (p= 0.005). Voor

radiation enteritis/ diarree: 27% van de sulphasalazine groep had graad 2 of hoger diarree,


tegenover 49% van de placebogroep (p=0.038). Voor radiation proctitis: balsalazide en Aloë

Vera kunnen voordelig zijn. Door de enorm kleine studiepopulaties echter, is er eerst verder

onderzoek nodig. Voor rectale bloedingen: Formaline 4% en formaline 10% therapie

verminderden de RPSAS-score met respectievelijk 10 en 12 punten (Voor beide: p<0.001).

Echter, met formaline 10% therapie hadden 15.4% meer patiënten last van complicaties

(p=0.03). BEC en APC hadden respectievelijk een 93% en 80% succesgraad (p=0.589), maar

BEC veroorzaakt 53.4% meer complicaties (p=0.003). APC en topische formaline reduceren

beide de rectale bloedingsscore met 2 punten (APC: p=0.001; topische formaline: p=0.001).

Er werden geen significante verschillen gevonden tussen deze therapieën.

De kwaliteit van alle geïncludeerde studies werd geëvalueerd door een Risk of Bias tabel.

Zoals te zien is in de tabel, bevat bijna elke studie enkele beperkingen.

Conclusie: Opvallend is het gebrek aan onderzoek naar de dagelijks gebruikte therapieën en

preventies. Deze moeten dringend kritisch bekeken en onderzocht worden. Als algemene

opmerking geeft deze thesis mee dat er ook nood is aan een gestandaardiseerde manier van

rapporteren van gastro-intestinale toxiciteit tijdens bestralingsbehandelingen en dat er in

toekomstig onderzoek ook meer aandacht moet besteed worden aan rapportering door

patiënten. Een aantal studies tonen veelbelovende resultaten. Toch moet er voorzichtig met

de conclusies omgegaan worden, wegens de vaak gebrekkige kwaliteit en beperkte

hoeveelheid data. Verder onderzoek is aangewezen om tot klinische richtlijnen te komen.


3. CONTENTS

1. Acknowledgements ......................................................................................................................... 3

2. Abstract ........................................................................................................................................... 4

2.1 Abstract ................................................................................................................................... 4

2.2 Nederlandstalig Abstract ......................................................................................................... 5

4. Abbreviations .................................................................................................................................. 8

5. Introduction .................................................................................................................................... 9

5.1 Pelvic Neoplasms ..................................................................................................................... 9

5.2 Gastrointestinal Radiotoxicity ................................................................................................. 9

6. Methodology ................................................................................................................................. 12

6.1 Search Strategy ..................................................................................................................... 12

6.2 Process of Selection .............................................................................................................. 13

7. Results ........................................................................................................................................... 14

7.1 Radiation-induced Gastrointestinal Toxicity ......................................................................... 15

7.2 Radiation Enteritis/Diarrhoea ............................................................................................... 23

7.3 Radiation Proctitis ................................................................................................................. 28

7.4 Quality Assessment ............................................................................................................... 38

8. Discussion ...................................................................................................................................... 39

8.1 Acute Radiation-induced GI Toxicity ..................................................................................... 39

8.2 Late/chronic Radiation-induced GI Toxicity .......................................................................... 41

8.3 Individual Symptoms ............................................................................................................. 41

8.4 Limitations of the Dissertation .............................................................................................. 48

8.5 Conclusions ........................................................................................................................... 49

9. References ..................................................................................................................................... 51

10. Addendum .................................................................................................................................... I

10.1 Toxicity ..................................................................................................................................... I

10.2 Search Strategy Embase ........................................................................................................ VII

10.3 Search strategy Pubmed ........................................................................................................ IX


4. ABBREVIATIONS

APC Argon Plasma Coagulation

BDP Beclomethasone Dipropionate

BEC Bipolar Electrocoagulation

CTC of the NCI Common Toxicity Criteria of the National

Cancer institute

CTCAE Common Terminology Criteria for Adverse

Events

FODMAP Fermentable Oligo-, Di-, Mono-saccharides

and Polyols

GI Gastrointestinal

IBDQ-B The Inflammatory Bowel Disease

Questionnaire – Bowel subset

LAO Long-Acting Octreotide Acetate

LENT-SOMA scoring system The Late Effects Normal Tissue Task

Force– Subjective, Objective, Management,

Analytic scoring system

mSCCAI Modified Simple Clinical Colitis Activity

Index

RPSAS The Radiation Proctopathy Assessments

Scale

RT Radiotherapy

RTOG/EORTC The Radiation Therapy Oncology Group/

European Organization for Research and

Treatment of Cancer

VAS Visual Analogue Scale


5. INTRODUCTION

Radiotherapy is a frequently used form of therapy for pelvic neoplasms. As suspected, it is

unfortunately not without adverse effects. Many have already mapped the different toxic

effects. The purpose of this dissertation is to provide an overview of the existing treatments

and non-invasive prevention methods for the radiation-induced toxicity, more specifically the

gastrointestinal toxicity. Due to the large amount of research on this topic, only randomized

controlled trials are included.

5.1 PELVIC NEOPLASMS The group of pelvic neoplasms in this article are restricted to tumours of the bladder, prostate,

urinary tract, rectum, colon, sigmoid, vagina, endometrium, cervix/uterus and ovaries. The

incidence rates of these tumours are listed in Table 1 (1).

Table 1: incidence rates of tumours Age standardized incidence rate

in Belgium in 2016 (n/100000

person years)

Female Male

Bladder tumours 506 1841

Ureter tumours 54 118

Urinary Organs/ NOS 8 53

Prostate tumours / 9050

Rectal tumours 917 1490

Colon tumours 2777 3130

Rectosigmoid junction tumours 60 94

Vaginal tumours 51 /

Endometrium tumours 1438 /

Cervix tumours 640 /

Uterus tumours 13 /

Ovarian tumours 752 /

5.2 GASTROINTESTINAL RADIOTOXICITY Radiation induced gastrointestinal symptoms can be acute (occurring during radiotherapy or

within three months) or chronic (persisting or appearing after three months). Radiation toxicity

can have a large impact on the patients’ quality of life (2).

The main mechanism of toxicity in the gastrointestinal tissue, caused by radiation therapy,

exists of four different phases. Firstly, the radiation injury induces an acute inflammatory

process. In a second phase, the inflammation leads to blood vessel damage. This causes an

inadequate blood supply to the tissue, with the appearance of ischaemia. Thirdly, the

ischaemia induces tissue fibrosis: a thickening and scarring of the tissue. Finally, this ends in

loss of the stem cells (3).


This is the main mechanism of most gastrointestinal symptoms that can occur after pelvic

radiation therapy. Of course it should be noted that this process is more complicated than

described above and that more factors have influence on this process (4-6).

There are treatment-related risk factors and patient-related risk factors for the occurrence of

radiation-induced toxicity. Treatment-related risk factors can be, but are not limited to: radiation

dose, fractionation scheme, field size, radiation technique and combined modality approaches.

Patient-related risk factors can be, but are not limited to: individual factors (age, body habitus,

smoking, previous surgery…), medical co-morbidities and its medication (IBD, collagen

vascular diseases, HIV…) and genetic susceptibility (6).

ACUTE SYMPTOMS

Acute gastrointestinal radiation-induced symptoms can be for example: rectal bleeding, acute

diarrhoea, abdominal pain, faecal urgency… These symptoms typically begin during the

second week of treatment and are mostly at their worst at the end of the therapy, which is

typically after four to five weeks (7, 8). Usually, these symptoms are self-limiting. They often

resolve within three months and normally only require supportive measures. However,

sometimes it can limit the patient’s endurance for the therapy, which leads to necessary dose

reductions and treatment interruptions (9-11). These actions could have a negative influence

on the curative effect of the treatment. The occurrence of acute radiation-induced side effects

also has a predicting value for the occurrence of late gastrointestinal side-effects (12, 13).

CHRONIC SYMPTOMS

Chronic side effects can be for example: faecal incontinence, chronic loose stool, faecal

urgency, chronic abdominal pain, chronic rectal bleeding… These can follow acute symptoms

or occur on their own. Gastrointestinal symptoms are the most common chronic physical side-

effects of radiation therapy and have the greatest effect on daily activity. Of all patients, 50%

say that the toxicity has an impact on their life. By 20-30%, this impact is even reported as

moderate or severe (7, 14, 15).

TOXICITY CLASSIFICATION METHODS

Articles use different classifying methods to grade toxicity. The most frequently used are:

The Radiation Therapy Oncology Group/ European Organization for Research and

Treatment of Cancer (RTOG/EORTC);

The Common Toxicity Criteria of the National Cancer institute (CTC of the NCI).

Sometimes this classification is also described as the common terminology criteria for


adverse events (CTCAE). Different versions of this system exist. The ones used in the

included articles are version 3.0 and version 4.3;

The Late Effects Normal Tissue Task Force– Subjective, Objective, Management,

Analytic scoring system (LENT-SOMA scoring system);

The Inflammatory Bowel Disease Questionnaire – Bowel subset (IBDQ-B);

The Radiation Proctopathy Assessments Scale (RPSAS);

VAS for rectal bleeding – Visual analogue scale for rectal bleeding;

mSCCAI – The modified Simple Clinical Colitis Activity Index.

These can be found in Addendum 10.1.


6. METHODOLOGY

6.1 SEARCH STRATEGY The research question of this dissertation is: “What is the best treatment and non-invasive

prevention for gastro-intestinal toxicity caused by radiotherapy for pelvic neoplasms?”. This

question was framed in terms of population, interventions, controls, and outcome (PICO

frame). The result is as follows:

Population: Patients with gastrointestinal toxicity caused by radiotherapy or chemo

radiation for pelvic neoplasms.

Intervention: Treatment/ Non-invasive prevention of the gastrointestinal toxicity,

caused by the radiotherapy or chemo radiation therapy.

Controls: No treatment/ No non-invasive prevention/ Standard therapy of the

gastrointestinal toxicity, caused by the radiotherapy or chemo radiation therapy.

Outcome: Evidence based guidelines for the treatment or prevention of gastrointestinal

toxicity caused by radiotherapy or chemo radiation therapy.

In Figure 1 each term used to build up a search strategy can be seen. For each term, a

selection of appropriate MeSH descriptors were selected, as well as relevant text words,

synonyms and variable spelling alternatives to include suitable articles. The complete search

strategy can be found in Addendum 10.2 and 10.3.

Figure 1: Build-up of the search strategy

Radiotherapy Gastrointestinal

Toxicity

Pelvic

Neoplasms Therapy

Prostate

Rectum

Sigmoid

Colon

Vagina

Bladder

Urinary

Tract/Urologic Ovary

Uterus/Cervix

Endometrium


6.2 PROCESS OF SELECTION

Potential articles were selected in the Embase and Pubmed databases. No limitations were

set for the publication year.

Using the search strategies (Addendum 10.2 and 10.3), a total of 6618 articles were found:

3547 in Pubmed (15/09/2018) and 3071 in Embase (01/03/2018). Firstly, 699 duplicates were

removed. Of the remaining 5919 articles, title, abstract and study type were reviewed for

relevance to the research question. Eventually, 34 articles were assessed by full text.

Ultimately, 27 studies were selected.

Studies were excluded if they did not meet the PICO framework. Therefore only articles with

toxicity and/or quality of life as primary endpoint were selected. Furthermore, articles on the

subject of invasive prevention, for example hydrogel spacers, were excluded as well. Because

of the great amount of research on the subject of this dissertation, only randomized controlled

trials or phase III clinical trials were included. Other sorts of publication types and studies, such

as reviews, editorials, commentaries, cohort studies, retrospective studies etc. were excluded.

Articles without available full text, as well as articles written in another language than English

were excluded.

The selection process can be seen in the PRISMA diagram below (Figure 2).

Figure 2: PRISMA diagram for literature selection

Pubmed search on:

3547 articles found

Embase search on:

3071 articles found

699 duplicates

removed

34 articles screened on

full text

5919 articles screened

on title, abstract and

study type

27 studies selected

5885 articles excluded:

- Not according to PICO

- No RCT

- Language other than

English

7 articles excluded:

- 5: No full text

- 1: Not according to

PICO

- 1: Poster presentation


7. RESULTS

Twenty-seven studies were considered appropriate for the dissertation. To provide a more

approachable overview of the results, the selected articles were grouped according to toxicity.

For this dissertation, the articles were divided in three main groups:

Radiation-induced gastrointestinal toxicity in general;

Radiation enteritis;

Radiation proctitis.

Radiation-induced gastrointestinal toxicity was used as a general term including all radiation-

induced toxicity of the entire lower gastrointestinal tract. Articles were included in this category

for two different reasons. Firstly, when the symptoms weren’t specified or appointed to a

specific region of the GI tract. Secondly, when patient-reported outcomes (IBDQ-B) were used,

which mostly concern all possible symptoms of the GI tract.

Radiation enteritis is a term traditionally used to define injury to the small intestine resulting

from radiotherapy. This excludes injury to the colon and rectum. Radiation enteritis usually

presents with symptoms such as, but not limited to: diarrhoea, faecal urgency, higher

frequency of stool and abdominal cramps. The articles in this dissertation often focus on

diarrhoea as a main symptom (10).

Radiation proctitis or radiation proctopathy is a term used to define injury to the rectum resulting

from radiation therapy. This includes symptoms such as, but not limited to: rectal bleeding,

mucous discharge, rectal tenesmus, rectal pain, faecal urgency and flatus. Often consistency

of stool and frequency of stool are described with this subject as well, but the main focus is on

the symptoms in the rectal area. In this dissertation, articles that only reported rectal bleeding

were also reported in this category (10).

The secondary endpoints of the articles were included as well, if they matched primary

outcomes of other articles (the secondary endpoints are shown in cursive in the tables below).

7.1 RADIATION-INDUCED GASTROINTESTINAL TOXICITY Table 2: Results of radiation-induced gastrointestinal toxicity

Name Study type Population Exp. (n) Contr. (n) Primary and

secondary1 outcome

Result exp. vs. Contr. P-value

Dale, P. S.

(16)

Open RPCT Cervical Cancer Enzyme (60) Placebo

(60)

Mean max grades,

measured weekly for 5

weeks, than at

intervals of 6 weeks

and 3 months after RT,

RTOG/EORTC

1,12/1,30 0,12

Esco, R.

(17)

Open RPCT Rectal Cancer Orgotein (50) Placebo

(50)

≥G2. Incidence, late GI

toxicity, RTOG/EORTC

90d (%) 4,3/18,2 0,047

6m (%) 2,3/7,3 0,354

9m (%) 2,4/15,0 0,057

12m (%) 0/13,5 0,025

18m (%) 0/21,9 0,003

24m (%) 0/19,4 0,007

Rad, S. M.

M. (18)

DBRPCT Prostate cancer Celecoxib (19) Placebo

(20)

Patients with GI

toxicity,

RTOG/EORTC,

observed weekly

during therapy and

monthly after.

Grade 0 and 1(%) 100/ 95 0,32

Grade 2 or worse (%) 42/ 50 0,62

1 All secondary endpoints are written in cursive

Andreyev,

H. J. (19)

Open RCT All patients with

new GI symptoms

after pelvic RT

Gastroenterologist

(GE) (70) and nurse

(N) group (80)

Standard

booklet (B)

group (68)

Mean toxicity score.

Late GI- toxicity, IBDQ-

B (GE vs. N vs. B)

R 52,1/ 53,0/ 51,8

6m 62,3/ 62,0/ 57,5

12m 62,7/ 59,6/ 60,6

Soto-Lugo,

J. H. (20)

Open RCT Cervical/

Endometrial

Cancer

Low-FODMAP diet

(13)

Standard

Mexican

diet (13)

Incidence of max grade

of acute GI toxicity,

NCI CTCAEv4.03 (%)

G0: 15/ 0; G1-2: 85/ 77;

G3: 0/ 23; G4: 0/ 0

0,16

Wedlake,

L. J. (2012)

(21)

Open RCT 48% urological

tumours, 32% GI

tumours, 20%

gynaecological

Low fat group (LoFa)

(39), modified fat

group (MoFa) (38)

Normal fat

(NoFa)

(38)

Mean change, IBDQ-B

score (LoFa vs. MoFa

vs. NoFa)

Ba to 2W -4,9/ -8,6/ -5,8 No p-values

available

Ba to 4W -7,1/ -7,3/ -7,6 LoFa vs. MoFa:

0,914; LoFa vs.

NoFa: 0,890;

MoFa vs. NoFa:

0,890

Ba to 1y -1,0/ -5,0/ -3,4 No p-values

available

Wedlake,

L. (2017)

(22)

Open RCT Gynaecologic and

lower GI tumours

Low-fiber group

(LoF) (55), high-fiber

group (HiF) (56)

Habitual-

fiber group

(HaF) (55)

Mean change, IBDQ-B-

score

(LoF vs. HiF vs. HaF)

Start to nadir -11,8/ -10,2/ -15,5 0,093

Start to end of

radiotherapy

-7,9/ -3,7/ -10,8 0,014 (LoF vs.

HaF: 0,711, HiF

vs. HaF: 0,011,

LoF vs. HiF:

0,251)

Start to 1-year post

radiotherapy

-4,9/ 0,1/ -8,4 0,005 (LoF vs.

HaF: 0,546, HiF

vs. HaF: 0,004,

loF vs. HiF: 0,172 )

McGough,

C. (23)

Open RCT Gynaecological,

urological or lower

GI tumours

Elemental diet (25) Standard

diet (25)

Median IBDQ-B score

Ba, median IBDQ-B 68/ 68

W3 57/ 60

W5 58/ 60

W10 68/ 69

Median RTOG score

Ba 0/ 0

W3 1/ 2

W5 2/ 2

W10 0,5/ 0,5

Kiliç, D.

(2001) (24)

DBRPCT Pelvic RT Sulphasalazine (15) Placebo

(16)

Max acute GI toxicity,

LENT-SOMA,

evaluated for 5W (%)

G0: 13/ 19; G1: 66/ 19;

G2: 20/ 56; G3: 0/ 6;

G4: 0/ 0

0,0172

Kiliç, D.

(2000) (25)

DBRPCT Pelvic RT Sulphasalazine (44) Placebo

(43)

Max acute GI toxicity

grade, LENT-SOMA,

evaluated for 5WFout!

Bladwijzer niet

gedefinieerd. (%)

G0: 20/ 7; G1: 66/ 14;

G2: 14/ 74; G3: 0/ 4;

G4: 0/ 0

0.073

2 Represents the difference in patient numbers between grades 0–1 and ≥ grade 2 according to sulfasalazine and placebo administration. 3 For the difference between grade 1-3

Abbreviations: Double-blind (DB), randomized (placebo-)controlled trial (R(P)CT), gastroenterologist group (GE), nurse group (N), standard booklet group (B), low fat group (LoFa), modified fat group (MoFa), normal fat (NoFa), low-fiber group (LoF), high-fiber group (HiF), habitual-fiber group (HaF), grade (G), days (D), weeks (W), months (m), year (y), at baseline (Ba) , at randomization (R), radiotherapy (RT), maximum (max)


Ten studies researched gastrointestinal toxicity in general. One studied the effect of an enzyme

combination, one the effect of orgotein, one the effect of celecoxib and one the therapeutic

effect of follow-up by a practitioner. Furthermore, there are four articles that are studying the

preventive effect of changes in diet on toxicity. Finally the last two articles are about the

prevention of sulphasalazine in GI toxicity. These studies are all listed in Table 2.

Dale et al. investigated in an open randomized placebo-controlled trial if an enzyme

combination could reduce or prevent the acute side effects of radiation therapy in patients with

locally advanced cervix cancer. Both groups contained 60 patients. The study used

RTOG/EORTC to grade the toxicity.

Although the study showed a reduction for the gastrointestinal toxicity with or without the

enzymes, the difference was not statistically significant (p=0.12). This can be seen in Table 2.

It should be noted that 31.6% of patients in the control arm was observed to have treatment

requiring diarrhoea, compared to 11.7% in the enzyme group (no p-value was given). In both

groups most of the patients expressed a slight increase in stool frequency, change in the

quality of bowel habits and rectal discomfort. Adverse effects of the enzyme therapy were not

discriminated between being radiation-induced or related to the enzymes. Typical side effects

of enzyme therapy are normally stomach aches, diarrhoea and flatulence in 3 to 4% of the

patients (26). These side effects are very similar to the radiation effects. This could be one of

the reasons why the difference in GI toxicity is not significantly better with the enzyme therapy

(16).

The study of Esco et al. explored in an open randomized placebo-controlled trial the

effectiveness of 7 weeks orgotein prophylaxis in preventing late radiation-induced effects after

radiation therapy for rectal cancer. Both groups contained 50 patients. RTOG acute toxicity

grade 0 or 1 was seen as non-relevant and RTOG grade 2 or worse was seen as relevant. It

was stated that non-relevant grades had little to no impact on the quality of life, in contradiction

to the relevant grades.

As can be seen in Table 2, at 90 days and at 12, 18 and 24 months, the orgotein group had

statistically significantly less relevant GI toxicity, compared to the control group (p=0.047;

0.025; 0.003; 0.007 respectively). At 6 and 9 months, the same trend could be observed.

However this was not statistically significant.

The odds ratios and relative risk reductions for relevant late GI toxicity showed that patients

treated with orgotein had a lower risk of GI toxicity at the follow-up evaluations done at 12, 18,

and 24 months (7, 11.4, and 10.5 times less, respectively) (17).


To assess the effect of celecoxib, Rad et al. conducted a double-blind randomized placebo-

controlled study for acute radiation-induced bowel toxicity during radiation therapy for prostate

cancer. The celecoxib group and the placebo group contained 19 and 20 patients respectively.

The RTOG scale was used to assess acute toxicity (within 90 days after the start of the

treatment).

The patients in the celecoxib group seemed to experience a lesser extent of grade 2 or more

gastrointestinal toxicity (p=0.62). In particular the symptoms diarrhoea, rectal and abdominal

pain were better in the treatment group (see Table 2) (18).

Andreyev et al. assessed in an open randomized controlled trial whether patients with chronic

gastrointestinal toxicity after pelvic radiotherapy could be helped if they were followed by a

practitioner (a nurse or a gastroenterologist), using an investigative and management

algorithm. The booklet group was considered the standard of care. The gastroenterologist, the

nurse and the booklet group contained 70, 80 and 68 patients respectively. The IBDQ-B was

used to evaluate toxicity and quality of life.

In the booklet group the mean improvement in IBDQ-B score at 6 months was 4.9 (95%CI 1.4-

8.4), but the difference isn’t considered clinically significant. By contrast, they did record a

statistically and clinically significant improvement (no exact p-value was given) in both the

gastroenterologist group, of 10.4 (95%CI 7.7-13.1) and the nurse group, of 9.1 (95%CI 6.9-

11.2).

Andreyev et al. also calculated a pair-wise mean difference in change of gastroenterologist

versus booklet of 5.47 (95%CI 1.14 – 9.81; p=0,01) and nurse versus booklet of 4.12 (95%CI

0.04-8.19; p=0.04). Thus, the gastroenterologist group and the nurse group showed

significantly better results compared to the booklet group. The mean difference in IBDQ-B

scores between the gastroenterologist and nurse groups at 6 months was 1.36. The one sided

95% confidence interval was –1.48, which suggests that the outcomes were not worse in the

nurse group compared to the gastroenterologist group. For the gastroenterologist group and

the nurse group, the improvements between the baseline and 12 months also proved to be

significant.

It should be noted that the confidence intervals (CI) are reported here because of the

discrepancies between the differences reported in the text of the study and the absolute values

given in the tables (19).

Four studies researched the influence of a nutritional intervention on the reduction of

gastrointestinal toxicity.


The first one, Soto-Lugo et al., studied in an open, randomized controlled trial the effectiveness

of a low-FODMAP diet versus a standard Mexican diet on reduction of GI toxicity, after external

beam radiotherapy in women with gynaecological tumours. The FODMAP group and the

standard diet group both contained 13 patients. The degree of acute toxicity was assessed

weekly according to the NCI v4.03 scale.

Although the normal diet group suffers more from worse toxicity, the differences aren’t

statistically significant (Table 2). As a secondary endpoint, the incidence according to the

individual type and grade of toxicity was studied. In both groups, the low-FODMAP group and

the Mexican diet group, nausea (77% vs. 77%) was the most common toxicity. Vomiting (54%

vs. 46%) and diarrhoea (62% vs. 69%) were frequent as well. Bloating, pain, proctitis, rectal

pain and constipation were also evaluated. All data was very alike and no significant

differences were found between both groups. No grade 3 GI toxicity events occurred in the

low-FODMAP diet, but in the Mexican group there were several cases (20).

Secondly, Wedlake L.J. et al. (2012) published an open randomized controlled trial to review

the efficacy of a low or modified fat diet in the prevention of GI toxicity in patients receiving

radiation therapy for pelvic malignancies. The low fat, the modified fat and the normal fat group

contained 39, 38 and 38 patients respectively. The primary outcome was evaluated through

the IBDQ-B.

As seen in Table 2, there is a mean fall in paired group (from baseline to 4 weeks) of 7.1, 7.3

and 7.6 for the low fat, the modified fat and the normal fat group respectively. No significant

differences between any of the groups were found. The p-values of the other reductions in the

table were not given in the article. By 1 year, the mean decrease in IBDQ-B for all groups was

2.9. At this time, one could say that the presenting symptoms were less severe. One of the

secondary endpoints evaluated was RTOG/EORTC toxicity. The exact data of toxicity wasn’t

given, so this endpoint was not included for comparison to other articles (21).

Thirdly, Wedlake L. et al. (2017) conducted another open randomized controlled trial to

investigate the influence of fibers on the prevention of GI toxicity in patients undergoing pelvic

radiotherapy. The primary endpoint of the trial was the difference between low-fiber (n=55),

habitual-fiber (n=55) and high-fiber (n=56) diets in IBDQ-B starting and nadir scores during

treatment.

The differences in decrease from start to nadir were not significant between groups (p=0.093).

However, the differences in mean IBDQ change from the baseline to the end of radiotherapy

and from the baseline to 1-year post radiotherapy were significant between groups. The

change in score from the start compared to the end, was significantly smaller in the high-fiber

group than in the habitual group (p=0.011). The difference between the low-fiber group and


the habitual- fiber group was also smaller. However, this was not significant (p=0.711). The

difference between low-fiber and high-fiber was also not significant (p=0.251). At 1-year post

radiotherapy, the same trend could be observed. In the high-fiber group, the score even

returned to the baseline values. The difference between the high-fiber and the habitual-fiber

group was significant (p=0.004). The other differences (between the low-fiber and the habitual-

fiber, and the low- and high-fiber group) were not significant (p=0.546 and p=0.172) (Table 2)

(22).

The fourth and last study concerning nutritional interventions is an open randomized controlled

trial of McGough C. et al.. The trial replaced one-third of a normal diet with an elemental diet

in the first three weeks of pelvic radiotherapy to research a possible reduction of acute GI

toxicity. The elemental diet group and the standard diet group both contained 25 patients. The

utilized tool was the IBDQ-B. RTOG toxicity was assessed as a secondary endpoint.

The IBDQ-B values were slightly lower in the intervention group, compared to the control

group. No p-values were given, so no conclusions about significance could be made. In both

groups could be seen that the RTOG score (secondary endpoint) had significantly increased

in week 3 and 5 compared to the baseline (p<0.001). The change in symptoms between

baseline and week 3 was worse in the intervention group than in the control arm (p=0.214).

From the end of the therapy to week 10, so one month after treatment, the symptoms improved

significantly in both groups (intervention group p<0.001; control group p<0.01).

It should be noted that patients achieved only 65% compliance with elemental prescription,

equivalent to 21% of their nutritional requirements (23).

Kiliç, D. et al. (2001) wrote a double-blind randomized placebo-controlled trial about the effect

of sulphasalazine on the reduction of acute gastrointestinal complications. The sulphasalazine

and the placebo group contained 15 and 16 patients respectively. The toxicity was graded

according to LENT-SOMA.

The percentage of overall toxicity grade 1-4 was 87% for the sulphasalazine group and 81%

for the placebo group (no p-value was given for this difference). Grade 2 or higher toxicity

occurred in 20% and 63% for sulphazalazine and the control group respectively (p=0.017) (24).

Kiliç, D.et al. (2000) conducted another double-blind placebo-controlled trial about the

influence of sulphasalazine on the prevention of acute GI toxicity. The sulphasalazine and the

placebo group contained 44 and 43 patients respectively. As a secondary endpoint, the GI

toxicity was evaluated using LENT-SOMA. (The primary endpoint concerning radiation enteritis

will be discussed below.)


There was no grade 4 occurrence in either of the groups. Grade 1-3 occurred in in 80% and

90% of the sulphasalazine and the placebo group respectively (p=0.07). It should also be noted

that the placebo group seems to contain a higher incidence of the higher toxicity grades,

compared to sulphasalazine group. The results can be reviewed in Table 2 (25).

7.2 RADIATION ENTERITIS/DIARRHOEA Table 3: Results of radiation enteritis/diarrhoea

Name Study type Population Exp.(n) Contr.(n) Primary and

secondary4 outcome

Result Exp. vs. Contr. P-value

Kiliç, D.

(2000) (25)

DBRPCT

Patients

receiving pelvic

radiation

therapy

Sulphasalazine

(44)

Placebo

(43)

Diarrhoea toxicity

grading5 (%)

G0: 46/ 14; G1: 27/ 37; G2:

20/ 19; G3: 7/ 14; G4: 0/ 16

0,0386

Zachariah, B.

(27)

DBRPCT

Rectal or anal

tumours

Long-acting

octreotide

acetate (109)

Placebo

(106)

Acute diarrhoea,

CTCAE v3.0

Grade 2-4 (%) 44/ 49 0,21

Grade 3-4 (%) 23/ 27 0,23

Rotovnik

Kozjek, N.

(28)

DBRPCT

Rectal tumours Glutamine (14) Placebo

(19)

The frequency of self-

reported diarrhoea

toxicity, NCI

G0: 5/ 8; G1: 4/ 2; G2: 4/ 4;

G3: 1/ 2; G4: 0/ 1

Incidence:

p=0,5;

intensity:

p=0,39

Vidal-

Casariego,

A. (29)

DBRPCT

Urologic, rectal

or

gynaecological

tumours

Glutamine (34) Placebo

(35)

Acute radiation

enteritis,

RTOG/EORTC,

evaluated before, in

the middle and after

RT (%)

55,9/ 22,0 0,002

Visit 2 (%) G0: 55,9/ 93,9; G1: 23,5/ 6,1;

G2: 20,6/ 0; G3: 0/ 0; G4: 0/ 0

0,001

Visit 3 (%) G0 :69,7/ 82,9; G1: 9,1/ 8,6;

G2: 21,2/ 5,7; G3: 0/ 2,9; G4:

0/ 0

0,22

Henriksson,

R. (30)

DBRPCT

Prostatic or

urinary bladder

Sucralfate (35) Placebo

(35)

Bowel symptoms, self-

assessment calendar

4 All secondary endpoints are written in cursive 5 Own classification 6 For grade 2 or worse

tumours

(without distant

metastases) Diarrhoea score

(acute; late response)

G0-1: 18;24/ 7;20

G2-3: 14;4/ 27;8

0,003; 0,18

NO. stools (acute; late

response

0-2: 13; 24/ 7; 14

3-4: 16; 3/ 16; 10

>5: 3; 1/ 11; 4

0,04; 0,01

Occurrence of mucous


17; 7/ 19; 16 0,82; 0,01

Occurrence of blood


3; 4/ 5; 9 0,51; 0,11

Abdominal cramps


2; 5/ 2; 8 0,45; 0,34

Loperamide

consumption (acute;

late response)

3; 4/14; 9 0,003; 0,11

Weight decrement

(kg)7

1,2; 0,7/ 1,9; 2,3 0,81; 0,04

Stool consistency (only

acute)

Normal: 29/ 24; Loose: 3/ 10

0,04

Martenson,

J. A. (31) DBRPCT

Patients

receiving pelvic

radiation

therapy to a

minimum of 45

Gy at 1,7 to 2,1

Gy/day

Sucralfate (62) Placebo

(61)

Incidence and severity

of diarrhoea toxicity

grades, NCI CTC,

evaluated weekly until

4w after RT, and at 10

to 12m after RT (%)

G0: 26/ 28; G1: 21/ 31; G2:

35/ 23; G3: 13/ 15; G4: 5/ 3

0,43

7 Relative initial values

Abbreviations: Double-blind (DB), randomized (placebo-)controlled trial (R(P)CT), days (D), weeks (W), months (m), year (y), at baseline (Ba) , at randomization (R)


Six studies were found regarding the reduction of radiation-induced diarrhoea or radiation

enteritis. The first two articles studied the influence of sulphasalazine and long-acting

octreotide acetate in the prevention of acute radiation-induced diarrhoea. Secondly, two

articles researched the effect of glutamine. The last two articles evaluated the effect of

sucralfate on radiation enteritis. These articles are listed in Table 3.

Kiliç D.; Egehan I. et al. (2000) conducted a double-blind placebo-controlled trial about the

influence of sulphasalazine on the prevention of acute radiation enteritis. The sulphasalazine

and the placebo group contained 44 and 43 patients respectively. “Standard toxicity criteria”

[sic] were used to grade the diarrhoea. These criteria were further defined in the article (the

secondary endpoint (LENT-SOMA) was discussed above).

In the sulphasalazine group, 55% of the patients suffered from any kind of diarrhoea. In the

placebo group this was 86% (p<0.001). Diarrhoea of grade 2 and worse could be found in 27%

of sulphasalazine group and in 49% of the placebo group (p=0.038). The differentiation of the

patients by grade of toxicity can be seen in Table 3 for each group (25).

Zachariah B. et al. determined in a double-blind randomized placebo-controlled trial the

efficacy of long-acting octreotide acetate (LAO) in preventing the onset of acute diarrhoea after

chemo radiation for rectal or anal cancer. The LAO and the placebo group contained 109 and

106 patients respectively. The primary endpoint was a difference in incidence rate of grades

2-4 acute diarrhoea, according to the CTCAE v3.0 scale.

In total, 49% of the placebo group and 44% of the LAO group had grade 2-4 acute diarrhoea

(p=0.21). The article also assessed the toxicity by different stratification factors (sex,

chemotherapy administration and radiation dose), but none of the differences were proven to

be statistically significant.

It should be noted that 7 of the 219 eligible patients reacted badly to a test-dose before the

study started and weren’t permitted to start the study (27).

As stated before, the effect of glutamine was researched by two different randomized

controlled trials.

Rotovnik Kozjek et al. studied in a double-blind randomized placebo-controlled trial the

influence of oral glutamine on diarrhoea during radiotherapy for rectal tumours. The glutamine

group and the placebo group contained 14 and 19 patients respectively. The incidence and

severity of diarrhoea was graded at the end of the 5-weeks period using an adapted NCI

questionnaire.


No significant differences were found between the groups for the incidence of diarrhoea

(p=0.50). The frequencies can be found in Table 3. The difference in intensity between groups

was not significant either (p=0.39). (It was stated that data of 3 patients were not reliable, so

these were not included in the analysis.) (28).

The second article about glutamine was a double-blind randomized placebo-controlled trial by

Vidal-Casariego et al.. The main aim of the study was to research if glutamine prevented

radiation enteritis during pelvic radiation therapy. The glutamine group and the placebo group

contained 34 and 35 patients respectively. The RTOG grading scale was used to assess the

enteritis (based on diarrhoea, frequency of stools, cramping and incontinence).

In this article there was a significant difference between the placebo group and glutamine group

(p=0.002). 55.9% of the patients with glutamine developed enteritis, in contradiction to the

placebo group where only 22.0% developed enteritis with a hazard ratio of 1.59. The grades

of acute enteritis are shown in Table 3 (29).

The effect of sucralfate on radiation enteritis was studied by two articles as well.

Henriksson, R., et al. investigated in a double-blind randomized placebo-controlled trial the

possible effect of sucralfate in preventing diarrhoea, caused by radiotherapy for prostate or

bladder tumours. The sucralfate and the placebo group both contained 35 patients. Toxicity

was assessed by a diarrhoea score based on a self-assessment calendar.

Five weeks after initiation of radiotherapy the mean diarrhoea score, the frequency of

defaecation and the consumption of loperamide were significantly lower in the sucralfate

group, compared to the placebo group. The stool consistency was also significantly (p=0.04)

more loose in the placebo group. For occurrence of mucous, blood, abdominal cramps and

weight decrement no significant difference could be found.

At 12 to 14 months following radiotherapy, there was still a significant difference between stool

frequencies (p=0.01). However, the difference in diarrhoea score, although still lower in the

sucralfate group, was no longer significant (p=0.18). The occurrence of mucous and the weight

decrement was significantly lower in the sucralfate group, compared to the placebo group

(p=0.01, p=0.04). The occurrence of blood, abdominal cramps and the consumption of

loperamide was lower in the sucralfate group (p=0.11, 0.34, 0.11) (30).

Martenson et al. designed a double-blind randomized placebo-controlled trial to evaluate the

effect of oral sucralfate on treatment-related bowel toxicity during pelvic radiation therapy and

at 10 to 12 months after the therapy. The sucralfate group and the placebo group contained


62 and 61 patients respectively. The primary endpoint was worst diarrhoea reported during the

therapy, according to the NCI CTC.

No significant differences were found in diarrhoea incidence and severity between the placebo

and sucralfate group (p=0.43). Of all patients, 53% had grade 2 or worse diarrhoea in the

sucralfate group, compared to 41% in the placebo group. These data can be found in Table 3.

The proportion of patients who used antidiarrheal agents during RT in the sucralfate and

placebo arms of the study, was 65% and 59% respectively (p=0.58). As a secondary outcome,

physicians also researched the maximal grade of tenesmus, abdominal cramping, rectal

bleeding, nausea and constipation. Overall, it could be said that the maximum grade found in

the sucralfate group is worse than in the control group. The differences weren’t significant,

except for nausea (p=0.03). 16% of the sucralfate group suffered from nausea, compared to

4% in the control group. It should be noted that in the sucralfate arm, 19% of the patients

discontinued the trial and in the placebo arm, this was 26% (p=0.69) (31).

7.3 RADIATION PROCTITIS Table 4: Results of radiation proctitis

Name Study

type

Populati

on

Exp. (n) Contr.(n) Primary and secondary8 outcome Result Exp. vs. Contr. P-value

Kneebone,

A. (2001)

(32)

DBRPCT Prostate Sucr (164) Plac. (171) Bowel symptoms, daily diary, RTOG/EORTC

Frequency (per day) 2,51/ 2,46 0,4111

Flatus (per day) 0,87/ 1,08 0,2511

Blood (% of days with) 13,6/ 8,3 0,00611

Blood (% of patients with) 64,0/ 46,8 0,00111

Mucous (% of days with) 18,8/ 21,2 0,5411

Non-solid consistency9 (% of days) 43,0/ 53,8 0,1111

Consistency score (av. score per day)10 0,44/ 0,56 0,2011

Pain score (av. Score per day) 1,37/ 1,31 0,7311

Pain score (maximum score) 3,89/ 4,15 0,4111

Acute toxicity (%) G0: 13/ 15; G1: 44/ 44; G2:

43/ 40; G3: 0/ 0; G4: 0/ 0

0,5611

Kneebone,

A. (2004)

(33)

DBRPCT

Prostate Sucr. (143) Plac. (155) ≥ G2 cumulative incidence, late rectal toxicity,

RTOG/EORTC (%)

22/ 28 0,23

Incidence of grades, RTOG/EORTC (%) G0: 26/ 24; G1: 52/ 48; G2:

20/ 26; G3: 2/ 2; G4: 0/ 0

0,29

Bowel symptoms, 2 y cumulative incidence (%)

Frequency, ≥4 movements/ day 15,6/ 15,7 0.99

Blood, ≥ G2 16,9/ 22,9 0.18

Mucous , ≥ G1 45/ 43 0.64

Faecal incontinence, ≥G1 33/ 33 0.90

Bowel symptoms. Main symptom prevalence per

3m, for period from 3m to 2y

8 All secondary endpoints are put in cursive 9 Liquid or liquid/solid combined 10 Higher score is more liquid 11 Adjusted for base values

RTOG toxicity, ≥G2/ 3 months 5,4/ 8,7 0.063

Frequency, movements/ d 1,9/ 1,9 0.82

Blood, days/ 3 m 2,3/ 3,5 0.12

Blood, ≥G2/ 3 m 4,1/ 7,3 0.050

Mucous, any mucous/3m 19,3/ 18,2 0.71

Faecal incontinence (any/3months) 10,3/ 12,1 0.44

O'Brien, P.

(1997) (34)

DBRPCT Prostate Sucr. (43) Plac. (43) Peak incidences of acute rectal toxicity,

RTOG/EORTC (%)

G0: 12/ 5; G1: 27/ 24; G2:

56/ 66; G3: 5/ 5; G4: 0/ 0

0,3

Bowel frequency, peak incidence (%) ≤1: 0/ 0; 2: 22/ 19; 3-4: 44/

26; ≥5: 34/ 55 NS

Diarrhoea, peak incidence (%) None: 34/ 10; Mild:46/ 54;

Moderate: 19/ 24; Severe:

10/ 12

NS

Rectal Pain, peak incidence (%) None: 14/ 14; Mild: 36/ 26;


34/ 22

NS

Mucous discharge, peak incidence (%) None: 36/ 26; Mild: 43/ 38;


5/ 5

NS

Faecal urgency, peak incidence (%) ≤1h: 17/ 7; ≤ minutes: 43/

57; Immediate: 30/ 29;

Incontinence: 10/ 7

NS

Bleeding, peak incidence (%)

None: 44/ 36; Occasional:

46/ 52; Pad required: 10/ 7;

Treatment necessary: 0/ 5

NS

O'Brien, P.

C. (2002)

(12)

DBRPCT Prostate Sucralfate (43) Placebo (43) Probability of late G2 rectal toxicity,

RTOG/EORTC, 6-monthly follow up of 5y12

5/ 12 0,26

Bowel frequencyFout! Bladwijzer niet

gedefinieerd., peak incidence (%)

≤ 1: 17/ 22; 2: 51/ 39; 3-4:

22/ 32; ≥5: 10/ 7

NS

Diarrhoea, peak incidence (%) None: 49/ 37; Mild: 41/ 58;

Moderate: 5/ 5; Severe: 5/

0

NS

12 The data in O’Brien (2002) is a secondary endpoint of O'Brien (1997). O’Brien (1997) evaluated acute toxicity until four weeks after RT. O’Brien (2002) is a continuation of

O’Brien (1997). They reported the chronic toxicity until 5 years after RT. / No cases of grade 3 toxicity occurred.

Rectal Pain, peak incidence (%) None: 54/ 64; Mild: 41/ 32;


2

NS

Mucous discharge, peak incidence (%) None: 56/ 58; Mild: 39/ 37;


0

NS

Faecal urgency, peak incidence (%) ≤ 1h: 31/ 29; ≤ minutes: 37/

47; Immediate: 27/ 17;

Incontinence: 5/ 7

NS

Bleeding, peak incidence (%) None: 49/ 42; Occasional:

51/ 58; Often: 0/ 0

NS

Sanguineti,

G. (35)

Single-

blind RCT

Prostate Sucr. (S) (63) Mesal. (M) (8)

or hydroc. (H)

(63)

≥G2 cumulative Incidence, RTOG/EORTC (%) 61,9/ 87,5/ 52,4 S. vs. M:

p=0,03; S.

vs. H: p=0,2

Hille, A. (36) DBRPCT Prostate Misoprostol

(50)

Plac. (50) Incidence / severity of acute rectal toxicity, NCI

CTC, evaluated weekly during RT (%)

G0: 24/ 24; G1: 76/ 76; G2:

36/ 26; G3: 0/ 0; G4: 0/ 0

G1: 0,87;

G2: 0,27 Bowel movements, peak incidence (%) Normal: 40/ 32; 1-3 more

than normal: 40/ 48; 4-8

more than normal: 20/ 20

NS

Rectal tenesmus, pain, peak incidence (%) None: 48/ 70; Mild: 36/ 22;

limits daily activities:16/ 10

NS

Faecal urgency, peak incidence (%) None: 50/ 46; Mild: 26/ 38;

Limits daily activities: 24/

16

NS

Mucous discharge, peak incidence (%) None: 94/ 96; Yes: 6/ 4 NS

Rectal bleeding, peak incidence (%) None: 68/ 86;

blood -tinged bowel

movements: 28/ 14;

significant blood with bowel

movements: 4/ 0

0,03

Jahraus, C.

D. (37)

DBRPCT Prostate Balsalazide

(12)

Plac.(13) Mean proctitis index13, evaluated weekly, acute

toxicity

35,3/ 74,1 0,04

Mean diarrhoea index13, evaluated weekly,

acute toxicity

29,8/ 40,7 NS

13 NCI CTC grades multiplied by duration and summed for each grade

Sahebnasa

gh, A. (38)

DBRPCT Acute

radiation

proctitis

Aloe Vera (9) Plac. (11) Median symptom index between the start and

the end (RTOG/EORTC)

Haemorrhage W1: 0,89/ 0,64;

W4: 0,22/ 0,55

0,5614

Abdominal/rectal pain W1: 1,89/ 1,27;

W4: 0,78/ 1,09 0,9314

Diarrhoea W1: 0,67/ 1,3

W4: 0,11/ 1 0,00814

Faecal urgency W1: 0,89/ 1;

W4: 0,11/ 0,82 0,02714

Proctitis W1: 1,78/ 1,64;

W4: 0,33/ 1,36 0,09414

RTOG total W1: 2,89/ 0,89;

W4: 3,64/ 3,09 0,001614

Fuccio, L.

(39)

DBRPCT Prostate BDP (55) Plac. (59) Late toxicity, evaluated until 12m after RT,

incidence and severity, RTOG/EORTC (%)

G0: 31/ 31; G1: 19/ 20; G2:

4/ 4; G3: 1/ 4; G4: 0/ 0

NS

Rectal bleeding, mSCCAI (%) Absent: 78,2/ 57,6;

Present: 21,8/ 42,4

0,0215

Bowel frequency, mSCCAI (%) During the day: 1-3: 92,7/

93,2; >3: 7,3/ 6,8;

During the night:1-3: 92,7/

100; >3: 7,3/ 0

During the

day: 1,0;

During the

night: 0,051 Urgency of defaecation, mSCCAI (%) No: 80/ 78; Yes: 20/ 22 0,79

Guo, G.H.

(40)

Open RCT Uterine

cervix

10% formalin

(58)

4% formalin

(57)

Before treatment, incidence of RPSAS- score

(%)

6-10: 5,2/ 3,5; 11-15: 12,1/

8,8; 16-20: 39,7/ 40,4; 21-

25: 31,0/ 38,6; 26-30: 12,1/

8,8

0,87

After treatment, incidence of RPSAS- score (%) 6-10: 72,4/ 68,4; 11-15:

12,1/ 15,8; 16-20: 8,6/ 8,8;

21-25: 6,9/ 5,3; 26-30: 0/

1,8

0,83

14 P-value: time x group effect 15 Intention-to-treat: 0.38

Lenz, L. (41) Open RCT Rectal

bleeding

after RT

APC (15) BEC (15) Efficacy analysis (%) Intention-to-treat: 80/ 93,3;

per-protocol: 92,3/ 93,3

ITT: 0,598;

PP: 1,0

Complications16, incidence (%)

Minor: 33,3/ 66,7; Major:

6,7/ 33,3; Total: 33,316;

86,716

Mi:0,068;

Ma: 0,169;

To: 0,003

Relapse, incidence (%) 8,3/ 14,3 1,0

Sessions, mean 3,7/ 2,9 0,313

Yeoh, E.

(42)

Open RCT Rectal

bleeding

after RT

for rectal

tumours

APC (17) Topical

formalin (13)

Rectal bleeding scores, LENT-SOMA (median) Before treatment: 3/ 3;

after treatment: 1/ 1

APC: 0,0001

Formalin:

0,001

VAS for rectal bleeding, median (mm) Before treatment: 52/ 50;


APC: 0,05

Formalin:

0,01 Faecal incontinence scores, LENT-SOMA Before treatment: 0/ 0;


NS

Urgency of defecation scores, LENT-SOMA Before treatment: 3/ 4;


NS

No. of bowel actions, LENT-SOMA Before treatment: 14/ 16;


NS

No of treatment sessions, median 2/ 2 NS

Duration of treatment, median (months) 6/ 6 NS

Haemoglobin, median (g/L) 136/ 137 NS

Rectal bleeding scores, median 1/ 1 NS

VAS for rectal bleeding, median (mm) 14/ 13 NS

Follow- up since completion of treatment,

median (months)

110/ 113 NS

16One patient in the APC group and 2 in the BEC group had both minor and major complications

Abbreviations: Double-blind (DB), randomized (placebo-)controlled trial (R(P)CT), days (D), weeks (W), months (m), year (y), at baseline (Ba) , at randomization (R), radiotherapy (RT), not significant (NS), sucralfate (Sucr.), placebo (Plac.), average (av.), grade (G), mesalazine (Mesal./M.), hydrocortisone (hydroc./H.), beclomethasone dipropionate (BDP), argon plasma coagulation (APC), bipolar electrocoagulation (BEC)


Eight articles searched for a possible therapy for radiation proctitis. Five of them are about

sucralfate. The other three studied the effect of misoprostol, balsalazide and Aloe Vera. Then,

four other articles are described here as well. These specifically studied therapy and non-

invasive prevention of rectal bleeding. The topics of these four articles are: formalin,

beclomethasone diproprionate (BDP), argon plasma coagulation (APC) vs. bipolar

electrocoagulation (BEC) and APC vs. formalin. The articles are listed in Table 4.

The first of the sucralfate series, Kneebone et al. (2001) is a double-blind randomized placebo-

controlled trial. They studied acute proctitis, caused by radiation therapy for prostate cancer,

through six different symptoms: frequency and consistency of motions, flatus, presence of

blood, mucous per rectum and the degree of pain on passing a motion. The sucralfate group

and the placebo group contained 164 and 171 patients respectively. RTOG/EORTC was used

to classify the toxicity.

There were more days of bleeding (p=0.006) and more patients suffering from bleeding

(p=0.001) in the sucralfate group than in the placebo group. For all other symptoms, no

significant differences were found. The exact data can be found in Table 4 .

The article also reported the unadjusted p-values (not included in Table 4). There was a

significant difference between the consistencies of the groups as well. The placebo group had

a higher consistency score and more days with non-solid consistency. However, it should be

noted that the adjusted p-values weren’t significant and that for the baseline values the placebo

group already had a significantly more liquid consistency score (p=0.004). So the statistical

value of the scores is likely to be spurious (32).

Kneebone et al. (2004) wrote another double-blind randomized placebo-controlled trial to

evaluate the influence of sucralfate on late rectal toxicity, caused by radiation therapy for

prostate cancer. The sucralfate group and the placebo group contained 143 and 155 patients

respectively. The primary endpoint here was to assess a difference in grade 2 or worse RTOG

toxicity between the sucralfate and the placebo group at 2 years. As secondary endpoints, the

different symptoms were individually evaluated as well.

The frequency of Grade 2 or worse RTOG late toxicity decreased by 6.7%, from 28% in the

placebo group to 22% in the sucralfate group (p=0.23).

No statistical significant differences for the individual symptoms were found, except for

bleeding. There was less bleeding (grade 2 or worse, per 3 months) in the sucralfate group

(p=0.050) (33).

O'Brien, P.C. et al; (1997) conducted a double-blind randomized placebo-controlled trial to

evaluate the protective effect of a daily enema of sucralfate against acute rectal proctitis,


induced by radiation therapy for prostate tumours. The sucralfate group and the placebo group

both contained 43 patients. To assess toxicity, the EORTC/RTOG acute toxicity criteria and a

patient self-assessment diary were used.

Slightly less toxicity was observed in the sucralfate group (p=0.30). O’Brien et al. (1997) also

evaluated the individual symptoms as a secondary endpoint (Table 4). No significant

differences between the groups could be found (34).

O’Brien, P.C. et al. (2002) published another article about the double-blind randomized

placebo-controlled trial about the effect of daily enema of sucralfate (already described above).

As already mentioned, the sucralfate group and the placebo group both contained 43 patients.

In this article late radiation proctitis, after radiotherapy for prostate cancer, was assessed

through late RTOG/EORTC toxicity and self-assessment questionnaires. It should be said that

the data in this article is a secondary endpoint of O’Brien (1997), which could lead to some

bias because this was not the study’s primary goal.

The grade 2 late toxicity at 5 years was 12% in the placebo group and 5% in the sucralfate

group (Table 4, p=0.26).

Through a self-assessment diary the individual symptoms were evaluated as well. No

significant differences were found. The probability of self-assessment endpoint late rectal

bleeding at 5 years was 59% for the placebo group and 54% for the sucralfate group (p=0.31)

(12).

Sanguineti et al. studied, in a single-blind randomized controlled trial, if the topical use of

mesalazine (5-aminosalicicylic acid) or hydrocortisone is better in reduction of acute rectal

toxicity than sucralfate. The sucralfate group, the mesalazine group and the hydrocortisone

group contained 63, 8 and 63 patients with prostate tumours respectively. The difference in

grade 2 or worse toxicity, using RTOG/EORTC, was the primary endpoint.

Overall, 80 patients developed grade 2 or worse toxicity. 41 of these 80 were grade 3. No

grade 4 toxicity was detected. There was 25.6% more toxicity in the mesalazine group than in

sucralfate group (p=0.03). The difference between the sucralfate and the hydrocortisone group

is not significant (p=0.20) (35).

Two more articles on the subject of sucralfate are included in this dissertation. The study of

Martenson, J. A., et al. was described under the title of diarrhoea/radiation enteritis. The

primary endpoint of this study was worst diarrhoea reported. The study of Henriksson et al.,

had diarrhoea as a primary endpoint as well, and is, just like Martenson et al., described above.

Three more ways to prevent or treat radiation proctitis were investigated.


Hille et al. conducted a double-blind randomized placebo-controlled trial, in which they tested

misoprostol (suppository) in the prevention of acute proctitis, induced by radiation therapy for

prostate cancer. The misoprostol group and the placebo group both contained 50 patients. To

assess toxicity, the CTC of the NCI was used.

For grade 1, no difference between the misoprostol and placebo group was found (p=0.87). In

the misoprostol group 36% of the patients suffered from grade 2 toxicity, compared to 26% in

the placebo group (p=0.27). However, the data did show a trend for a shorter duration of grade

2 toxicity in the misoprostol group, although not statistically significant (placebo group: 20 days

vs. misoprostol: 12 days, p=0.07). The median duration of grade 1 toxicity was quite similar

(placebo group 28 days vs. misoprostol group 27 days).

Hille et al. also investigated the peak incidence of the individual symptoms as a secondary

endpoint. There was less bleeding in the placebo group (p=0.03). For daily bowel movements,

rectal tenesmus, pain, faecal urgency and mucous discharge, no significant differences were

found (36).

Jahraus et al. researched, in a double-blind randomized placebo-controlled trial, the effect of

orally given balsalazide (a 5-acetylsalicylacid drug) in the prevention of acute radiation

proctosigmoiditis, caused by radiotherapy for prostate cancer. The balsalazide group and the

placebo group contained 12 and 13 patients respectively. The NCI CTC v2.0 was used to

evaluate toxicity.

There was a significant decrease for mean proctitis index from 74.1 in the placebo group to

35.3 in the balsalazide group (p=0.04). Although not statistically significant (no exact p-value

was given), the diarrhoea symptom index was also lower in the balsalazide group, compared

to the placebo group (Table 4) (37).

A last article concerning acute radiation proctitis is a double-blind randomized placebo-

controlled trial conducted by Sahebnasagh et al.. In this study the role of a topical preparation

of Aloe Vera in the treatment of acute radiation proctitis, caused by pelvic radiation therapy,

was evaluated. The Aloe Vera and the placebo group contained 9 and 11 patients respectively.

The RTOG acute toxicity criteria were used to assess toxicity.

There was a significant improvement in the symptom index, pre-treatment compared to post-

treatment with Aloe Vera, for diarrhoea (median score: 0.67 vs. 0.11, p=0.008), faecal urgency

(median score: 0.89 vs. 0.11; p=0.027) and RTOG total (median score: 2.89 vs. 0.89;

p=0.0016). Haemorrhage and abdominal/rectal pain did not improve significantly (Table 4).

The odds ratios showed a significant clinical advantage for Aloe Vera over placebo for

diarrhoea (OR 4.6; p=0.015), proctitis (OR 3.0; p=0.037) and RTOG total (OR 5.9; p=0.007).


For the other symptoms an advantage was also seen, but this was not statistically significant

(38).

Four articles looked for ways to specifically treat or prevent rectal bleeding.

In 2011, Fuccio et al. assessed in a double-blind randomized placebo-controlled trial the effect

of topical beclomethasone dipropionate (BDP) in the prevention of radiation-induced proctitis,

caused by radiotherapy for prostate cancer. The BDP and the placebo group contained 55 and

56 patients respectively. For the primary endpoint, toxicity was evaluated through the

RTOG/EORTC scale. Patients were followed for 12 months.

As can be seen in Table 4, no significant differences were found between the two treatment

groups based on the RTOG/EORTC scale.

The overall assessment of rectal side effects through the mSCCAI did not show any differences

between the BDP group and the placebo group. However, after individual assessment of each

item of the mSCCAI score, a significantly lower bleeding rate was observed in the BDP arm

(BDP: 22%; placebo: 42%; p=0.02). After evaluation of the first occurrence of blood in stools,

the patients of the BDP arm presented a later onset of blood in stool than patients of the

placebo arm (p=0.032) (39).

Guo et al. studied in an open randomized controlled trial the effectiveness and safety of 4%

and 10% formalin for the treatment of chronic rectal bleeding, after radiotherapy for uterine

cervical tumours, up to a year after treatment. The 10% formalin and the 4% formalin group

contained 58 and 57 patients respectively. Symptoms were graded according to the RPSAS.

The median RPSAS score decreased from 20 before treatment to 10 after treatment in the 4%

formalin group (p<0.001). In the 10% formalin group, the median RPSAS score decreased

from 21 to 9 after treatment (p<0.001). No significant differences were found between the two

groups, either before or after treatment (p=0.87 and p=0.83).

In the 4% formalin group, 10.5% of the patients suffered from adverse events after application

of formalin, compared to 25.9% of the patients in the 10% formalin group (p=0.03). The

adverse events in the 4% group were restricted to mild, self-resolving pain. In the 10% group,

this was anal pain and spasms (resolving with medication), fistulas, vaginal discharge and

deep ulcerations. By the end of the follow-up period, five patients of the 4% formalin group had

a recurrence of symptoms after initial improvement in RPSAS score. They needed further

treatment (again with 4% formalin or with 10% formalin) (40).

Lenz et al. searched in an open randomized controlled trial for the optimal endoscopic

treatment of active and chronic rectal bleeding, caused by radiotherapy. The efficacy and


safety of bipolar electrocoagulation (BEC) and argon plasma coagulation (APC) were

evaluated and compared. Both groups consisted of 15 patients. To assess the toxicity, the

Saunders score, consisting of a clinical evaluation and an endoscopic evaluation, was used.

Overall, endoscopic therapy was successful for 26 patients (86.7 %). Rectal bleeding

decreased significantly after endoscopic therapy (p< 0.0001). The mean number of sessions

needed, was slightly higher in the APC group (3.7, compared to 2.9 in the BEC group,

p=0.313). No statistical significant differences were found for efficacy (evaluated through

intention-to-treat numbers and per-protocol numbers) between both lasers. The success rate

was 80.0% for APC and 93% for BEC. The per-protocol rates were 92.3% and 93.3%

respectively. In the APC group, 33.3% and 6.3% of the patients suffered from minor and major

complications respectively. For the BEC group, this was 66.7% and 33.3%. Although the

differences between groups for the minor and major complications weren’t proven to be

statistically significant, the difference comparing one group to the other for total rate of

complications was significant. The total rate of complications in the BEC group was significantly

worse than in the APC group (p=0.003). The difference in number of relapse patients in both

groups was not significant (Table 4) (41).

A last article, the study of Yeoh et al. is an open randomized controlled trial that compares the

effect of argon plasma coagulation (APC) and topical formalin on rectal bleeding after radiation

therapy for prostate cancer. The APC and the formalin group contained 17 and 13 patients

respectively. The primary endpoint was reduction of bleeding, defined as a LENT-SOMA grade

less than 2, a VAS score less than 25 mm and not needing any blood transfusions.

Both therapies showed a significant decrease in rectal bleeding scores (APC: p=0.0001 and

formalin: p=0.001) and VAS for rectal bleeding (APC: p=0.05 and formalin: p=0.01). No blood

transfusions were needed for APC nor formalin. Neither of the therapies had a significant

difference for any of the other anorectal symptoms (Table 4). The treatment endpoint was

achieved in 94% of the patients in the APC group and 100% of the topical formalin group (no

p-value was given) (42).

To compare both therapies, the number of treatment sessions, efficacy and durability

measures were assessed as a secondary endpoint. No significant differences can be observed

(Table 4). It should be noted that one patient of the APC group crossed over to the topical

formalin group to achieve control (42).


7.4 QUALITY ASSESSMENT

To consider the potential limitations of the included studies, the Risk of Bias tool of the

Cochrane Collaboration was used. The tool makes it possible to provide a critical appraisal of

the methodological quality of the articles. It addresses the different possible domains of bias

(43, 44). As can be seen in Table 5, most studies contain a possible risk of bias. The possible

limitations found in the quality assessment, are further described below and should be

regarded carefully before making any recommendations based on the outcome of this

dissertation.

Table 5: Risk of Bias quality assessment

Risk of Bias

1 Adequate sequence

generation?

2 Adequate allocation

concealment?

3 Blinding of participants,

personnel and outcome

assessors?

4 Incomplete data outcome

addressed?

5 Free of selective

reporting?

6 Free of other bias?

Name 1 2 3 4 5 6

Andreyev, H. J., et al. + ? - + - +

Dale, P. S., et al. + ? - + + -

Esco, R., et al. + ? - + + +

Fuccio, L., et al. + + + + + -

Guo, G. H., et al. + ? - + - +

Henriksson, R., et al. + ? + + - ?

Hille, A., et al. + ? + + + ?

Jahraus, C. D., et al. + - + + + -

Kilic, D., et al. (2000) + ? + + - ?

Kilic, D., et al. (2001) + ? + + - ?

Kneebone, A., et al. (2001) + ? + + + -

Kneebone, A., et al. (2004) + ? + + + -

Lenz, L., et al. + - - + - +

Martenson, J. A., et al. + ? + - + ?

McGough, C., et al. + ? - + - -

O'Brien, P. C., et al. (1997) + ? + + + ?

O'Brien, P. C., et al. (2002) + ? + + + ?

Rad, S. M. M., et al. + ? + + + +

Rotovnik Kozjek, N., et al. + - + + - +

Sahebnasagh, A., et al. - ? + + - +

Sanguineti, G., et al. + - - + - ?

Soto-Lugo, J. H., et al. - ? - + + +

Vidal-Casariego, A., et al. + ? + + - ?

Wedlake, L. J., et al. (2012) + ? - + + +

Wedlake, L., et al. (2017) + ? - + + +

Yeoh, E., et al. - - - + + ?

Zachariah, B., et al. + ? + + - +


8. DISCUSSION

A general concern in this dissertation is the difficulty of comparing the results of the different

randomized controlled trials due to classification differences. It urges for a standardisation of

toxicity grading for future references.

8.1 ACUTE RADIATION-INDUCED GI TOXICITY

Several studies looked for ways to reduce the acute gastrointestinal side effects in general,

instead of researching specific symptoms.

Enzyme therapy is one of the studied methods. Dale et al. showed a not-significant reduction

of the toxicity (16). A possible explanation of why this reduction is not higher, is that the side

effects of the enzyme therapy are mostly gastrointestinal. This was already seen in previous

research (26). These side effects were not reported separately from radiation toxicity, thus

making a report bias probable. The quality of the study is dubious, because of the open study

design and the influence of a pharmaceutical company in this article. However, enzyme

therapy could play a role in the treatment/prevention of radiation toxicity (16).

Another possible way to prevent acute GI toxicity is celecoxib. It showed insignificant decrease

in grade 2 or more toxicity. However, because of the low number of included patients,

conclusions cannot be made with certainty (18).

Different aspects of the influence of a diet on toxicity were investigated as well.

Soto-Lugo et al. found that there is a slightly, not significant, lower toxicity with a low-FODMAP

diet compared to the standard Mexican diet. The open study only contained 26 patients. Thus,

the value of this study is highly doubtful (20).

Wedlake et al. discovered that a low fat diet had a slightly higher decrease in acute

gastrointestinal toxicity compared to a modified fat diet or a normal fat diet. However, no

significant difference was found between the groups. The influence of fat on toxicity is still

uncertain: a strict selection of patient and not significant results call for further research (21).

Wedlake et al. (2017) also found a significantly better result for a high-fiber diet at the end of

radiotherapy and at 1-year post radiotherapy, compared to a habitual-fiber diet. A low-fiber diet

though was not significantly better, compared to a habitual-fiber diet. This study states that a

high-fiber diet should be recommended to the patients at risk for GI toxicity. However, it is


dangerous to jump to this conclusion immediately: it is only one study and there could be

possible bias. The study was not blinded and it should be noted that 417 of the 538 eligible

patients refused to participate. The article states that the main reason for declining participation

was an unwillingness to change diet (22).

Sotu-Lugo et al. suggest that a low-FODMAP diet is beneficial, which is contradictory to the

study of Wedlake et al. that claims a high-fiber level is more favourable. It can be presumed

that low-FODMAP mostly is accompanied by a low-fiber level. Further research with both

methods included is definitely necessary to investigate the connection between both diets (20,

22).

The effect of a partial elemental diet was studied as well. McGough et al. found a slightly better,

not significant, result in the elemental diet group. It should be noted that the compliance of the

diet was only 65%. Furthermore, not blinding of the study, a small study population and funding

by the manufacturer of the elemental supplement could cause a possible bias. For now, an

elemental diet should not be recommended, however future research should be conducted

with a different percentage of elemental diet and a better compliance (23).

The effect of sulphasalazine on acute gastrointestinal symptoms was also investigated.

Two studies with a limited amount of patients by Kiliç et al. (2000 and 2001) showed less

toxicity in the groups treated with sulphasalazine. Both studies show a promising future for the

use of sulphasalazine in the prevention of gastrointestinal toxicity. Although, it should be noted

that the results in the 2000 study were not statistically significant. Furthermore, both articles

were written by the same first author and neither of the articles mentioned their study protocol,

which could lead to bias (24, 25). So to consolidate the benefit of sulphasalazine, more

randomized controlled trials with a larger study population should be conducted.

The primary endpoint of the study of Kiliç et al. (2000) was diarrhoea and will be discussed

below (25).

To summarize, the evidence of the two sulphasalazine articles points in the direction of a

possible valuable reduction of gastrointestinal radiotoxicity. A high-fiber diet could also be a

promising intervention.

Both enzyme therapy and celecoxib showed a slight reduction in toxicity grades, although not

significant.

The value of a low-FODMAP, a low fat or a modified fat diet is not clear at the moment. The

contradictory link between a low-FODMAP diet and a high-fiber diet should be investigated.

The compliance, when replacing a normal diet by a partial elemental diet, was very poor and

the statistically not-significant added value of this diet is highly doubtful.


8.2 LATE/CHRONIC RADIATION-INDUCED GI TOXICITY

Different studies investigated methods to reduce or prevent late or chronic gastrointestinal side

effects as well.

Orgotein showed a significant lower risk at relevant GI toxicity compared to the control group

at 90 days and at 12, 18 and 24 months after radiation therapy. However, due to the open

study design of Esco et al. and the wide focus of the study, it might suffer from bias. The effect

of orgotein is very promising and should be explored further in studies with a main focus on

toxicity of the GI tract (17).

Andreyev et al. found that follow-up by a nurse or a gastroenterologist, using a management-

based algorithm, proved to be significantly better at 6 months than the standard follow-up with

a booklet. No differences between the nurse group and the gastroenterologist group could be

found. It should be noted that the study wasn’t blinded, which could be a possible cause for

bias. As mentioned above, there also seem to be discrepancies in the reporting of the data, so

the data should be interpreted with caution. However, the results are promising and the

possibility of a follow-up by a nurse or a gastroenterologist should be investigated further (19).

The study of Wedlake that investigated the amount of fiber in a diet, also observed the long-

term effects of this diet. As already partly discussed above with the acute GI radiation

symptoms, Wedlake et al. did a follow-up until a year after radiotherapy. The high-fiber group

was significantly better than the habitual-fiber group. The high-fiber group was better than the

low-fiber group as well, but not significantly. As mentioned above, the not-blinding and high

refusal rate could cause bias. Thus, the high-fiber diet is promising for acute and chronic GI

toxicity (22).

In summary, orgotein, follow-up by a nurse or a gastroenterologist, according to a

management-based algorithm, and a high-fiber diet could be potentially beneficial in

preventing late radiation-induced symptoms, and needs to be explored more profoundly.

8.3 INDIVIDUAL SYMPTOMS

RADIATION ENTERITIS/DIARRHOEA

The enzyme therapy, as researched by Dale et al., showed in the secondary endpoints a

difference in diarrhoea of 31.7% patients in the control arm, compared to 11.7% in the enzyme

group. In both groups, most of the patients expressed a slight increase in stool frequency,


change in the quality of bowel habits and rectal discomfort. However, these were only

secondary endpoints, there was no mention of significance and, as mentioned above, the

quality of the study is dubious, so no conclusions can be made. It can be interesting to include

radiation enteritis as a primary endpoint in further studies on enzyme therapy (16).

In the study of celecoxib by Rad et al., there was a not significant lesser extent of diarrhoea in

the treatment group, compared to placebo. However, some questions about the value of this

secondary endpoint are raised. The specific data on diarrhoea was not described in the article

and very few patients were included in this study. So momentarily, it should not be

recommended, but future studies could include diarrhoea as a primary endpoint as well (18).

Kiliç et al. (2000) investigated sulphasalazine with diarrhoea as a primary endpoint. There was

a statistically significant decrease in toxicity in the sulphasalazine group, compared to the

placebo group. Overall, there was 31% less toxicity and for grade 2 or worse, there was 22%

less toxicity in the sulphasalazine group. The quality assessment shows that there might be

selective reporting, because the study protocol could not be found. Notwithstanding, the results

of this study display a potential therapeutic benefit (25).

Sulphasalazine showed promising results for the prevention of acute GI symptoms as well (see

above) (24, 25).

Zachariah et al. found for long-acting octreotide acetate (LAO) a small, not significant decrease

for grade 2 or worse acute diarrhoea. However, the results of this article could be doubted. As

can be seen in the quality assessment, this article could contain selective reporting, because

the primary endpoint was modified after the start of the study. It should be noted as well that

before the start of the study, 7 of the 219 eligible patients showed adverse reactions to a test

dose. If LAO would be considered for therapeutic use, it should be investigated how these

allergic reactions would translate to the population level. Based on the current knowledge, LAO

should not be recommended (27).

The effect of glutamine on diarrhoea was investigated as well. The study of Rotovnik Kozjek

et al. found no significant differences between the placebo and the glutamine group. The

quality of this study is very dubious, due to the very small study population, the inadequate

allocation concealment and not mentioning any study protocol (28). The second study on

glutamine of Vidal-Casariego et al. even found a significant higher toxicity with glutamine

group. However, it should be noted that there are some quality issues with this article as well.

There was no mention of any study protocol here (29). Based on these two studies, glutamine

should not be considered in the prevention of radiation enteritis (28, 29).


Another studied prevention method is sucralfate. Martenson et al. observed that there was

12% less moderate or worse diarrhoea in the placebo arm. This was a not significant

difference. It should be noted that the percentage of drop-outs is quite high in both groups. The

reasons for these drop-outs should be explored further (31). Henriksson et al. contradicted the

study of Martenson et al. by finding a significantly better diarrhoea score, stool frequency and

less loperamide consumption in the sucralfate group and a more loose consistency of stool in

the placebo group. The quality of the Henriksson et al. study could be questioned, because

data was collected through a self-assessment calendar and there was no mention of the study

protocol (30). The results of both studies are not consistent (30, 31).

Sucralfate was also researched in other studies, in which diarrhoea or symptoms of radiation

enteritis were included as a secondary endpoint or as a part of the primary endpoint. So the

following results should be interpreted with caution. These articles and the quality of these

articles will be discussed more profoundly elsewhere in this dissertation (p.44, 45).

Kneebone et al. (2001) observed a non-significant higher frequency of stool, but a non-

significant lower stool consistency in the sucralfate group (32). Kneebone et al. (2004) did

another study in 2004 where no significant differences were found between the groups for

faecal incontinence and bowel movements (33).

O’Brien et al. found, in 1997, not significantly more diarrhoea and more urgency in the placebo

group than in the sucralfate group (34). In 2002, O’Brien et al. conducted another article about

sucralfate with diarrhoea as a secondary endpoint. Again, less diarrhoea was found in the

sucralfate group. However, there was a higher bowel frequency in the sucralfate group.

Urgency was quite similar in both groups. These differences were not significant (12).

To summarize, it can be stated that results on the effect of sucralfate are inconsistent and thus

cannot be recommended for standard prevention therapy. Data suggests that sucralfate could

potentially worsen the toxicity, so a large phase II clinical trial should be conducted to be sure

it is beneficial and that the advantages outweigh the adverse effects.

Jahraus et al. found a not significant lower mean diarrhoea index in the balsalazide group,

compared to the placebo group. However, the quality of the study is dubious. First of all, there

was no adequate allocation concealment. Secondly, one of the authors works for a

pharmaceutical company and finally, the study population is very small. Thus, it can be said

that the effect of balsalazide is not clear (37).

A study by Sahebnasagh et al. researching the effectiveness of Aloe Vera, found a lower

diarrhoea score and a lower faecal urgency with significant time/group p-values. The odds ratio

of 4.6 for diarrhoea was significant better for Aloe Vera. However, the quality of this study is


uncertain due to the very low patient number: only 20 patients were included. It cannot be

concluded that Aloe Vera is really beneficial, before other studies with a larger patient

population are conducted (38).

Fuccio et al. studied beclomethasone dipropionate (BDP). Frequency and urgency were

included as secondary endpoints. No significant differences were found between the groups.

The study was funded by a pharmaceutical company, which could be the cause of possible

bias. Based on this study, it seems that BDP doesn’t have an influence on radiation enteritis

or diarrhoea. However, it is difficult to make a definite conclusion based on one study. The

primary endpoint, researching acute radiation-induced proctitis, will be discussed below (39).

Argon plasma coagulation (APC), investigated as a therapy for rectal bleeding, had no

influence on urgency. Bowel actions were slightly worse in the APC group than in the topical

formalin control group. This was not significant. There are several concerns for the quality of

the study of Yeoh et al.: not only was there a small amount of patients (only 30 patients were

included), but there were several other possible causes for bias, as can be seen in the quality

assessment (Table 5). Momentarily, APC should not be used in the treatment of radiation-

induced enteritis and it should be taken into account, if used for bleeding, that it could

potentially worsen the bowel actions of the patient. However, it is not possible to make a

definite conclusion based on one article with a highly doubtful quality (42) .

In summary, sulphasalazine presents real potential for the treatment of acute radiation

enteritis. It should urgently be investigated more extensively.

Enzyme therapy, celecoxib, balsalazide and Aloe Vera could be potentially beneficial, but

should first be researched further.

BDP and APC did not show any benefit, however definite conclusions cannot be made with

the present evidence.

The data of LAO and sucralfate is very uncertain and should be researched further. Glutamine

potentially worsens the toxicity and should not be considered.

RADIATION PROCTITIS

Sucralfate is one of the most studied methods in this dissertation. Five of the seven studies

investigated its effect on radiation induced proctitis.

The effect on acute proctitis, according to Kneebone et al. (2001), is not very promising. One

of the six symptoms of proctitis, bleeding, proved to be significantly worse. (Bleeding as a

separate symptom is discussed more extensively below.) No significant differences could be


found for the other symptoms. The unadjusted p-values showed a significantly better

consistency score and significantly less non-solid consistency days in the sucralfate group.

However the adjusted p-values weren’t significant and at baseline the placebo group had

already significantly more liquid consistency score, which could explain the differences.

For RTOG toxicity, a secondary endpoint, no differences were found between both groups. It

should be noted that there could be some bias since the study was funded by a pharmaceutical

company (32).

O’Brien et al. (1997) also studied the effect of sucralfate on acute radiation-induced proctitis.

Slightly less toxicity was found in the sucralfate group. However this was not significant. No

differences between the individual symptoms were found. The study could contain bias,

because data was collected through self-assessment (34).

For acute radiation proctitis, sucralfate was also compared to mesalazine and hydrocortisone

by Sanguineti et al. This study showed that mesalazine was significantly worse than sucralfate.

On the other hand, the hydrocortisone group displayed not significant, slightly less toxicity than

the sucralfate group. Of the 134 patients included in the study only 8 of the patients were part

of the mesalazine group. This could show a distorted image of the study. The study was open

as well and had an inadequate allocation concealment (35).

Based on these three studies, the therapeutic value of sucralfate for acute radiation proctitis is

highly doubtful.

The effect of sucralfate on late radiation-induced proctitis was investigated as well.

Kneebone et al. (2004) found a statistically insignificant difference for grade 2 or worse toxicity

between the sucralfate and the placebo group, in favour of the sucralfate group. This study

was, like the other Kneebone et al. study in 2001, funded by a pharmaceutical company and

should therefore be interpreted with care (33).

O’Brien et al. (2002) confirmed these results. This study also found a not significant, slightly

better toxicity rate in the sucralfate group. It should be noted that this study is a continuation

of the 1997 study and this result was originally not calculated as a primary endpoint. This fact

and the self-assessment method could be the cause of bias (12).

The use of sucralfate for late radiation-induced proctitis could be beneficial, however the

evidence of these articles is not very strong. More trials should be conducted. It should also

be taken into account that sucralfate is most likely not beneficial for acute radiation proctitis.

Hille et al. tested misoprostol in the prevention of acute radiation-induced proctitis. There was

a statistically insignificant worse effect on grade II toxicity in the treatment group. However, the

duration of toxicity in the treatment group was shorter. The article ascribes this paradox due to

the enhanced mucosal blood flow and vascular permeability, caused by misoprostol. Based


on this article, misoprostol should not be considered for the prevention of acute radiation-

induced proctitis. However, it is hard to make a definite decision based on one study (36).

The influence of balsalazide on the prevention of acute radiation proctitis was investigated as

well. The study showed a significant difference in mean proctitis index between the treatment

group and the placebo group, in favour of the treatment group. The value of this study can be

debatable, because the study population is very small and, as can be seen in the quality

assessment, inadequate allocation concealment and a conflict of interest could cause bias.

Thus, balsalazide shows potential, but should be investigated more profoundly (37).

Sahebnasagh et al. discovered, in a study researching acute radiation proctitis, a significant

better toxicity score in the Aloe Vera group, compared to the placebo group. The odds ratio

was 3 for proctitis and 5.9 for RTOG toxicity overall. This was statistically significant. For the

individual symptoms the study claims that Aloe Vera causes an insignificant improvement as

well. However, as said above, the quality of this study is very doubtful because of the small

study population. To summarize, Aloe Vera can be promising, but no definite conclusions can

be made (38).

Beclomethasone dipropionate or BDP was studied in the prevention of acute proctitis by Fuccio

et al.. However, except for bleeding (which is discussed below), no improvements were found

with BDP prevention. No significant differences were found on the RTOG scale or in the

mSCCAI, compared to the placebo group. Furthermore, it should be noted that the study was

funded by a pharmaceutical company. Thus, at this moment and based on this evidence, BDP

should not be recommended for the prevention of acute proctitis in general. Its effect on rectal

bleeding will be discussed further below (39).

In summary, it can be stated that momentarily, balsalazide and Aloe Vera could have beneficial

potential, but require further research, mainly due to very small study populations.

For late radiation-induced proctitis, the effect of sucralfate should be studied more thoroughly

before making any conclusions. Sucralfate should not be used for acute radiation-induced

proctitis.

Misoprostol and BDP should not be recommended for the prevention of proctitis.

RECTAL BLEEDING

In the study of Guo et al., both the 4% and the 10% formalin group significantly decreased the

bleeding, but between these treatment groups, no significant difference was found. The study

claims that they are equally effective, however in the 10% group significantly more adverse


events were registered. It should be noted that the 10% formalin was necessary in some

persistent cases of recurrent bleeding. Bias in this study could be caused by an open study

model and not mentioning the study protocol. Based on this study, both methods are effective

to stop rectal bleeding, however the 4% formalin is safer. In severe recurrent cases of bleeding,

the 10% formalin might be considered. More research could provide better indications of the

use of 10% formalin (40).

Yeoh et al. compared topical formalin to argon plasma coagulation (APC). In both groups the

bleeding was significantly decreased, but no difference could be found between the groups.

According to this study, these methods should be considered equally effective. As already

mentioned above, the quality of this study is debatable and the study population is very small.

Therefore, the results should be interpreted with care. Further research to explore the

difference between both methods is necessary (42).

Argon plasma coagulation (APC) was also compared to bipolar electrocoagulation. The study

showed that rectal bleeding significantly decreased in both groups. No significant differences

were seen between groups, but it should be noted that more treatment sessions were needed

with APC. It could be said that the efficacy is slightly better for BEC (not significant). However,

BEC caused significantly more adverse events. Bias in this study could be caused by the open

study design, the small study population and the inadequate allocation concealment. Based

on this study, it seems that, although they are both effective, APC should be preferred over

BEC (41).

Fuccio et al. found in the 12-month follow up, a significantly rectal bleeding rate in the BDP

group compared to the placebo group. A later onset of blood loss was seen in the BDP group

as well. It should be noted that the study was funded by a pharmaceutical company, so it

should be critically analysed. Although the primary aim of the study was to reduce radiation

proctitis in general, future studies should be conducted to assess the effect of BDP on bleeding

specifically (39).

It should be mentioned that in the studies of Kneebone et al. in 2001 and 2004 rectal bleeding

was included as a secondary endpoint. In the 2001 study of acute proctitis, the sucralfate group

had significantly more days of bleeding and more patients with bleeding, compared to the

placebo group. In 2004, in the study on late rectal toxicity, the sucralfate group showed

significantly less days of bleeding and not significantly less patients with bleeding at the 2-year

point. O’Brien et al. also included rectal bleeding as a secondary endpoint in 1997 and 2002.

In 1997, acute rectal bleeding was slightly, but not significantly better in the sucralfate group.


The same statistically not significant trend could be observed in 2002, at 5 years post-

radiotherapy. It should be noted that there are some quality issues with these studies (these

are already mentioned above). The data of sucralfate is inconsistent. It can be stated that

sucralfate probably has an effect on rectal bleeding, however it is not clear if it is positive or

negative. A possible explanation could be that it has different effects on late and acute rectal

bleeding (12, 32-34).

The effect of misoprostol on acute radiation-induced proctitis was studied by Hille et al. They

found that misoprostol caused significantly more grade 1 or grade 2 rectal bleeding, compared

to the placebo group. However, it should not be forgotten that this was only a secondary

endpoint. Based on this study, misoprostol should not be given to patients who are suffering

from rectal bleeding. Moreover, it should be taken into account that it could worsen bleeding,

when considered for use for any other treatment of toxicity (36).

In summary, for rectal bleeding, APC and formalin 4% therapy could be beneficial. However

the amount of studies on these topics is still limited. More research is necessary to confirm

these results.

BEC seems to be an effective technique as well, although it should be used with care since

the higher occurrence of adverse events.

A formalin 10% therapy could be considered for persistent recurrent bleeding. Further research

could be helpful in the determination of indications for this therapy.

BDP could prevent radiation-induced bleeding, but studies with BDP and rectal bleeding as a

primary endpoint are required.

Sucralfate should be handled with caution with patients suffering from rectal bleeding, due to

the uncertainty of the effect.

Based on the evidence in this dissertation, misoprostol should not be given to patients suffering

from rectal bleeding.

8.4 LIMITATIONS OF THE DISSERTATION

SELECTION PROCESS

Firstly, there could be a possible bias because only articles in English were included: studies

written in other languages were omitted.

Secondly, five articles were excluded because the full text could not be found. This could have

an effect on the outcome of this dissertation.

Thirdly, it should be noted that the selection of articles was only done by one person and not

repeated, which could cause a certain bias as well.


At last for the selection process, only two databases (PubMed and Embase) were used.

Although a high number of articles was found, this limited number of databases could

potentially influence the outcome of this dissertation.

QUALITY OF THE ARTICLES

The quality of the studies themselves is also an important factor in this process. Only

randomized controlled trials were selected and further assessed for quality. The possible

limitations, found in the quality assessment, are described above and should be regarded

carefully before making any recommendations based on the outcome of this thesis.

8.5 CONCLUSIONS

STANDARD OF CARE

Almost no studies exist about today’s standard care for GI radiation-induced toxicity. A possible

explanation is that there is no real standard of care: treatments are mostly symptomatic and

based on experience in other situations. However, this dissertation urges for a critical review

of the daily used methods and more research in the situation of radiation-induced GI toxicity.

NEW METHODS

As seen above, most included studies investigate more recent methods for prevention and

therapy of gastrointestinal toxicity. As described, there are some methods that could have a

beneficial potential, however the evidence is not strong enough to make definite conclusions.

This dissertation urges for further research. There are multiple studies with promising results,

for example: the studies on sulphasalazine, APC and formalin 4% therapy.

GENERAL CONCERNS

In this dissertation, it also becomes clear that there is a need for more standardization of

research. A clear and unified method of reporting toxicity should be implemented. In the future,

this would make it easier to compare studies and facilitate the use of evidence-based medicine.

Future studies should also give more attention to patient-reported outcomes. Most articles only

investigate the objective side of the GI toxicity, while it is known that the GI toxicity has an

enormous impact on the quality of life of patients as well. Standardized registration of patient-

reported outcomes can be a valuable asset in the investigation of treatments.

It is clear that there are many aspects that need to be considered in treatment of radiation-

induced toxicity. Recent studies show some promising strategies. Hopefully future studies


can provide more definitive data for an evidence based standard of care for therapy or

prevention in patient treated with radiation for pelvic neoplasms.


9. REFERENCES

1. Belgian Cancer Registry. Cijfers 2016 [cited 2018 20 Nov]. Available from: https://kankerregister.org/Statistieken_cijfers. 2. Lawrie TA, Green JT, Beresford M, Wedlake L, Burden S, Davidson SE, et al. Interventions to reduce acute and late adverse gastrointestinal effects of pelvic radiotherapy for primary pelvic cancers. Cochrane Database of Systematic Reviews. 2018;2018(1). 3. Denham JW, Hauer-Jensen M. The radiotherapeutic injury--a complex 'wound'. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2002;63(2):129-45. 4. Rieder F, Brenmoehl J, Leeb S, Scholmerich J, Rogler G. Wound healing and fibrosis in intestinal disease. Gut. 2007;56(1):130-9. 5. Potten CS, Merritt A, Hickman J, Hall P, Faranda A. Characterization of radiation-induced apoptosis in the small intestine and its biological implications. Int J Radiat Biol. 1994;65(1):71-8. 6. Shadad AK, Sullivan FJ, Martin JD, Egan LJ. Gastrointestinal radiation injury: symptoms, risk factors and mechanisms. World journal of gastroenterology. 2013;19(2):185-98. 7. Andreyev HJ. Gastrointestinal problems after pelvic radiotherapy: the past, the present and the future. Clinical oncology (Royal College of Radiologists (Great Britain)). 2007;19(10):790-9. 8. Khalid U, McGough C, Hackett C, Blake P, Harrington KJ, Khoo VS, et al. A modified inflammatory bowel disease questionnaire and the Vaizey Incontinence questionnaire are more sensitive measures of acute gastrointestinal toxicity during pelvic radiotherapy than RTOG grading. International journal of radiation oncology, biology, physics. 2006;64(5):1432-41. 9. Morris KA, Haboubi NY. Pelvic radiation therapy: Between delight and disaster. World J Gastrointest Surg. 2015;7(11):279-88. 10. Stacey R, Green JT. Radiation-induced small bowel disease: latest developments and clinical guidance. Ther Adv Chronic Dis. 2014;5(1):15-29. 11. Do NL, Nagle D, Poylin VY. Radiation proctitis: current strategies in management. Gastroenterol Res Pract. 2011;2011:917941. 12. O'Brien PC, Franklin CI, Poulsen MG, Joseph DJ, Spry NS, Denham JW. Acute symptoms, not rectally administered sucralfate, predict for late radiation proctitis: longer term follow-up of a phase III trial--Trans-Tasman Radiation Oncology Group. International journal of radiation oncology, biology, physics. 2002;54(2):442-9. 13. Barnett GC, De Meerleer G, Gulliford SL, Sydes MR, Elliott RM, Dearnaley DP. The impact of clinical factors on the development of late radiation toxicity: results from the Medical Research Council RT01 trial (ISRCTN47772397). Clinical oncology (Royal College of Radiologists (Great Britain)). 2011;23(9):613-24. 14. Maeda Y, Hoyer M, Lundby L, Norton C. Faecal incontinence following radiotherapy for prostate cancer: a systematic review. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2011;98(2):145-53. 15. Andreyev HJ, Davidson SE, Gillespie C, Allum WH, Swarbrick E. Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer. Gut. 2012;61(2):179-92. 16. Dale PS, Tamhankar CP, George D, Daftary GV. Co-medication with hydrolytic enzymes in radiation therapy of uterine cervix: evidence of the reduction of acute side effects. Cancer chemotherapy and pharmacology. 2001;47 Suppl:S29-34. 17. Esco R, Valencia J, Coronel P, Carceller JA, Gimeno M, Bascón N. Efficacy of orgotein in prevention of late side effects of pelvic irradiation: A randomized study. International Journal of Radiation Oncology Biology Physics. 2004;60(4):1211-9. 18. Rad SMM, Bakhshandeh M, Aghamiri MR, Rohani-Rassf M, Moghani MM, Khoshghadam A, et al. Evaluation of the celecoxib effect against radiotherapy induced acute toxicities in the patients with prostate cancer compared with placebo group. International Journal of Cancer Management. 2017;10(12). 19. Andreyev HJ, Benton BE, Lalji A, Norton C, Mohammed K, Gage H, et al. Algorithm-based management of patients with gastrointestinal symptoms in patients after pelvic radiation treatment (ORBIT): a randomised controlled trial. Lancet (London, England). 2013;382(9910):2084-92. 20. Soto-Lugo JH, Souto-Del Bosque MA, Vázquez-Martínez CA. Effectiveness of nutritional intervention in reduction of gastrointestinal toxicity during external beam radiotherapy in women with gynecological tumors. Gaceta Mexicana de Oncologia. 2017;16(2):84-90.

https://kankerregister.org/Statistieken_cijfers


21. Wedlake LJ, McGough C, Shaw C, Klopper T, Thomas K, Lalji A, et al. Clinical trial: Efficacy of a low or modified fat diet for the prevention of gastrointestinal toxicity in patients receiving radiotherapy treatment for pelvic malignancies. Journal of human nutrition and dietetics : the official journal of the British Dietetic Association. 2012;25(3):247-59. 22. Wedlake L, Shaw C, McNair H, Lalji A, Mohammed K, Klopper T, et al. Randomized controlled trial of dietary fiber for the prevention of radiation-induced gastrointestinal toxicity during pelvic radiotherapy. American Journal of Clinical Nutrition. 2017;106(3):849-57. 23. McGough C, Wedlake L, Baldwin C, Hackett C, Norman AR, Blake P, et al. Clinical trial: normal diet vs. partial replacement with oral E028 formula for the prevention of gastrointestinal toxicity in cancer patients undergoing pelvic radiotherapy. Alimentary pharmacology & therapeutics. 2008;27(11):1132-9. 24. Kilic D, Ozenirler S, Egehan I, Dursun A. Sulfasalazine decreases acute gastrointestinal complications due to pelvic radiotherapy. Annals of Pharmacotherapy. 2001;35(7-8):806-10. 25. Kilic D, Egehan I, Ozenirler S, Dursun A. Double-blinded, randomized, placebo-controlled study to evaluate the effectiveness of sulphasalazine in preventing acute gastrointestinal complications due to radiotherapy. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2000;57(2):125-9. 26. Wittenborg A, Bock PR, Hanisch J, Saller R, Schneider B. [Comparative epidemiological study in patients with rheumatic diseases illustrated in a example of a treatment with non-steroidal anti- inflammatory drugs versus an oral enzyme combination preparation]. Arzneimittelforschung. 2000;50(8):728-38. 27. Zachariah B, Gwede CK, James J, Ajani J, Chin LJ, Donath D, et al. Octreotide acetate in prevention of chemoradiation-induced diarrhea in anorectal cancer: Randomized RTOG trial 0315. Journal of the National Cancer Institute. 2010;102(8):547-56. 28. Rotovnik Kozjek N, Kompan L, Soeters P, Oblak I, Mlakar Mastnak D, Mozina B, et al. Oral glutamine supplementation during preoperative radiochemotherapy in patients with rectal cancer: a randomised double blinded, placebo controlled pilot study. Clin Nutr. 2011;30(5):567-70. 29. Vidal-Casariego A, Calleja-Fernandez A, de Urbina-Gonzalez JJ, Cano-Rodriguez I, Cordido F, Ballesteros-Pomar MD. Efficacy of glutamine in the prevention of acute radiation enteritis: a randomized controlled trial. JPEN J Parenter Enteral Nutr. 2014;38(2):205-13. 30. Henriksson R, Franzen L, Littbrand B. Effects of sucralfate on acute and late bowel discomfort following radiotherapy of pelvic cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1992;10(6):969-75. 31. Martenson JA, Bollinger JW, Sloan JA, Novotny PJ, Urias RE, Michalak JC, et al. Sucralfate in the prevention of treatment-induced diarrhea in patients receiving pelvic radiation therapy: A North Central Cancer Treatment Group Phase III Double-Blind Placebo-Controlled Trial. Journal of Clinical Oncology. 2000;18(6):1239-45. 32. Kneebone A, Mameghan H, Bolin T, Berry M, Turner S, Kearsley J, et al. The effect of oral sucralfate on the acute proctitis associated with prostate radiotherapy: a double-blind, randomized trial. International journal of radiation oncology, biology, physics. 2001;51(3):628-35. 33. Kneebone A, Mameghan H, Bolin T, Berry M, Turner S, Kearsley J, et al. Effect of oral sucralfate on late rectal injury associated with radiotherapy for prostate cancer: A double-blind, randomized trial. International journal of radiation oncology, biology, physics. 2004;60(4):1088-97. 34. O'Brien PC, Franklin CI, Dear KB, Hamilton CC, Poulsen M, Joseph DJ, et al. A phase III double-blind randomised study of rectal sucralfate suspension in the prevention of acute radiation proctitis. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 1997;45(2):117-23. 35. Sanguineti G, Franzone P, Marcenaro M, Foppiano F, Vitale V. Sucralfate versus mesalazine versus hydrocortisone in the prevention of acute radiation proctitis during conformal radiotherapy for prostate carcinoma. A randomized study. Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft [et al]. 2003;179(7):464-70. 36. Hille A, Schmidberger H, Hermann RM, Christiansen H, Saile B, Pradier O, et al. A phase III randomized, placebo-controlled, double-blind study of misoprostol rectal suppositories to prevent acute radiation proctitis in patients with prostate cancer. International journal of radiation oncology, biology, physics. 2005;63(5):1488-93. 37. Jahraus CD, Bettenhausen D, Malik U, Sellitti M, St Clair WH. Prevention of acute radiation-induced proctosigmoiditis by balsalazide: a randomized, double-blind, placebo controlled trial in prostate cancer patients. International journal of radiation oncology, biology, physics. 2005;63(5):1483-7.


38. Sahebnasagh A, Ghasemi A, Akbari J, Alipour A, Lashkardoost H, Ala S, et al. Successful Treatment of Acute Radiation Proctitis with Aloe Vera: A Preliminary Randomized Controlled Clinical Trial. J Altern Complement Med. 2017;23(11):858-65. 39. Fuccio L, Guido A, Laterza L, Eusebi LH, Busutti L, Bunkheila F, et al. Randomised clinical trial: preventive treatment with topical rectal beclomethasone dipropionate reduces post-radiation risk of bleeding in patients irradiated for prostate cancer. Alimentary pharmacology & therapeutics. 2011;34(6):628-37. 40. Guo GH, Yu FY, Wang XJ, Lu F. A randomized controlled clinical trial of formalin for treatment of chronic hemorrhagic radiation proctopathy in cervical carcinoma patients. Support Care Cancer. 2015;23(2):441-6. 41. Lenz L, Tafarel J, Correia L, Bonilha D, Santos M, Rodrigues R, et al. Comparative study of bipolar eletrocoagulation versus argon plasma coagulation for rectal bleeding due to chronic radiation coloproctopathy. Endoscopy. 2011;43(8):697-701. 42. Yeoh E, Tam W, Schoeman M, Moore J, Thomas M, Botten R, et al. Argon plasma coagulation therapy versus topical formalin for intractable rectal bleeding and anorectal dysfunction after radiation therapy for prostate carcinoma. International journal of radiation oncology, biology, physics. 2013;87(5):954-9. 43. Henderson LK, Craig JC, Willis NS, Tovey D, Webster AC. How to write a Cochrane systematic review. Nephrology (Carlton). 2010;15(6):617-24. 44. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. Bmj. 2011;343:d5928. 45. LENT SOMA tables. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 1995;35(1):17-60. 46. Cheung WY, Garratt AM, Russell IT, Williams JG. The UK IBDQ-a British version of the inflammatory bowel disease questionnaire. development and validation. J Clin Epidemiol. 2000;53(3):297-306. 47. Walmsley R, Ayres R, Pounder R, Allan RJG. A simple clinical colitis activity index. 1998;43(1):29-32.

Therapy and Non-Invasive Prevention of Gastrointestinal Toxicity caused by Radiotherapy for Pelvic Neoplasms p.I

10. ADDENDUM

10.1 TOXICITY

It should be noted that not all different versions of the different toxicity scales are included.

The ones displayed below are found or referenced by the articles included in this

dissertation. These are provided to give a rough idea on what each criteria is based on.

THE RADIATION THERAPY ONCOLOGY GROUP/ EUROPEAN ORGANIZATION FOR

RESEARCH AND TREATMENT OF CANCER (RTOG/EORTC)

RTOG/EORTC early and late GI toxicity, according to the study of O’Brien et al. (2002) (12):

THE COMMON TOXICITY CRITERIA OF THE NATIONAL CANCER INSTITUTE (CTC OF

THE NCI)

Sometimes this classification is also described as the common terminology criteria for adverse

events (CTCAE). Different versions of this system exist. The ones used in the included articles

are version 3.0 and version 4.3.

The CTC for acute radiation injury, according to Hille et al. (36):

p.II Therapy and Non-Invasive Prevention of Gastrointestinal Toxicity caused by Radiotherapy for Pelvic Neoplasms

THE LATE EFFECTS NORMAL TISSUE TASK FORCE– SUBJECTIVE, OBJECTIVE,

MANAGEMENT, ANALYTIC SCORING SYSTEM (LENT-SOMA SCORING SYSTEM)

The LENT-SOMA for the small intestine and the colon, according to the journal of

Radiotherapy and Oncology in 1995 (45), referenced by the included studies of Kiliç et al.

(24, 25):

Therapy and Non-Invasive Prevention of Gastrointestinal Toxicity caused by Radiotherapy for Pelvic Neoplasms p.III

THE INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE – BOWEL SUBSET (IBDQ-B)

The IBDQ-B, according to Cheung et al. (46), referenced by the included study of Wedlake et

al. (2012) (21):

p.IV Therapy and Non-Invasive Prevention of Gastrointestinal Toxicity caused by Radiotherapy for Pelvic Neoplasms

Therapy and Non-Invasive Prevention of Gastrointestinal Toxicity caused by Radiotherapy for Pelvic Neoplasms p.V

THE RADIATION PROCTOPATHY ASSESSMENTS SCALE (RPSAS)

The RPSAS, according to the study of Guo et al. (40):

VAS FOR RECTAL BLEEDING – VISUAL ANALOGUE SCALE FOR RECTAL BLEEDING

No references or explanation of the VAS score could be found in the included articles.

p.VI Therapy and Non-Invasive Prevention of Gastrointestinal Toxicity caused by Radiotherapy for Pelvic Neoplasms

THE MODIFIED SIMPLE CLINICAL COLITIS ACTIVITY INDEX

The mSCCAI, according to Walmsley et al. (47), referenced by the included study of Fuccio

et al. (39):

Therapy and Non-Invasive Prevention of Gastrointestinal Toxicity caused by Radiotherapy for Pelvic Neoplasms p.VII

10.2 SEARCH STRATEGY EMBASE

('radiotherapy'/exp OR 'radiotherapy':ti,ab,kw OR 'radiation therapy':ti,ab,kw OR

'radiotherapy'/lnk) AND ('gastrointestinal toxicity'/exp OR 'gastrointestinal toxicity':ab,ti,kw)

AND (('pelvis tumor'/exp OR 'pelvis tumor':ti,ab,kw OR 'pelvis tumour':ti,ab,kw OR 'pelvis

tumors':ti,ab,kw OR 'pelvis tumours':ti,ab,kw OR 'pelvic tumor':ti,ab,kw OR 'pelvic

tumour':ti,ab,kw OR 'pelvic tumors':ti,ab,kw OR 'pelvic tumours':ti,ab,kw OR 'pelvic

neoplasms':ti,ab,kw OR 'pelvis neoplasms':ti,ab,kw OR 'pelvic neoplasm':ti,ab,kw OR 'pelvis

neoplasm':ti,ab,kw OR (('pelvic' OR 'pelvis') NEAR/2 (‘neoplasm’ OR ‘neoplasms’ OR

‘cancer’ OR ‘tumor’ OR ‘tumors’ OR ‘tumour’ OR ‘tumours’)):ti,ab,kw) OR ('bladder

tumor'/exp OR 'bladder cancer'/exp OR 'bladder tumor':ti,ab,kw OR 'bladder tumour':ti,ab,kw

OR 'urinary bladder neoplasms':ti,ab,kw OR 'bladder cancer':ti,ab,kw OR 'bladder

tumors':ti,ab,kw OR 'bladder tumours':ti,ab,kw OR 'urinary bladder neoplasm':ti,ab,kw

(('bladder' OR 'urinary bladder') NEAR/2 (‘neoplasm’ OR ‘neoplasms’ OR ‘cancer’ OR ‘tumor’

OR ‘tumors’ OR ‘tumour’ OR ‘tumours’)):ti,ab,kw) OR ('prostate tumor'/exp OR ‘prostate

cancer’/exp OR 'prostate tumor':ti,ab,kw OR ‘prostate tumour’:ti,ab,kw OR ‘prostatic

neoplasms’:ti,ab,kw OR 'prostate tumors':ti,ab,kw OR ‘prostate tumours’:ti,ab,kw OR

‘prostatic neoplasm’:ti,ab,kw OR ‘prostate cancer’:ti,ab,kw OR ((‘prostate’ OR ‘prostatic’)

NEAR/2 (‘neoplasm’ OR ‘neoplasms’ OR ‘cancer’ OR ‘tumor’ OR ‘tumors’ OR ‘tumour’ OR

‘tumours’)):ti,ab,kw) OR ('urinary tract tumor'/exp OR 'urinary tract cancer'/exp OR 'urinary

tract neoplasms'/exp OR 'urinary tract tumor':ti,ab,kw OR 'urinary tract tumors':ti,ab,kw OR

'urinary tract tumour':ti,ab,kw OR 'urinary tract tumours':ti,ab,kw OR 'urologic neoplasms/exp'

OR 'urologic neoplasms':ti,ab,kw OR 'urinary tract neoplasm':ti,ab,kw OR 'urinary tract

neoplasms':ti,ab,kw OR 'urologic neoplasm':ti,ab,kw OR 'urinary tract cancer':ti,ab,kw OR

(('urologic' OR ‘urinary tract’) NEAR/2 (‘neoplasm’ OR ‘neoplasms’ OR ‘cancer’ OR ‘tumor’

OR ‘tumors’ OR ‘tumour’ OR ‘tumours’)):ti,ab,kw) OR ('rectum tumor'/exp OR ‘rectum

neoplasms’/exp OR ‘rectum cancer’/exp OR 'rectum tumor':ti,ab,kw OR 'rectum

tumour':ti,ab,kw OR ‘rectal neoplasms’:ti,ab,kw OR ‘rectum neoplasms’:ti,ab,kw OR ‘rectum

cancer’:ti,ab,kw OR 'rectum tumors':ti,ab,kw OR 'rectum tumours':ti,ab,kw OR ‘rectum

neoplasm’:ti,ab,kw OR ‘rectal neoplasm’:ti,ab,kw OR ((‘rectal’ OR ‘rectum’) NEAR/2

(‘neoplasm’ OR ‘neoplasms’ OR ‘cancer’ OR ‘tumor’ OR ‘tumors’ OR ‘tumour’ OR

‘tumours’)):ti,ab,kw) OR ('colorectal tumor'/exp OR 'colorectal cancer'/exp OR 'colon

tumor'/exp ‘colon cancer’/exp OR 'colorectal tumor':ti,ab,kw OR 'colorectal tumour':ti,ab,kw

OR 'colon tumor’:ti,ab,kw OR ‘colorectal neoplasms’:ti,ab,kw OR 'colon tumour':ti,ab,kw OR

‘colonic neoplasms’:ti,ab,kw OR 'colorectal tumors':ti,ab,kw OR 'colorectal tumours':ti,ab,kw

OR 'colon tumors’:ti,ab,kw OR ‘colorectal neoplasm’:ti,ab,kw OR 'colon tumours':ti,ab,kw OR

‘colonic neoplasm’:ti,ab,kw OR ‘colon cancer’:ti,ab,kw OR ‘colorectal cancer’:ti,ab,kw OR

((‘colonic’ OR ‘colon’ OR ‘colorectal’) NEAR/2 (‘neoplasm’ OR ‘neoplasms’ OR ‘cancer’ OR

‘tumor’ OR ‘tumors’ OR ‘tumour’ OR ‘tumours’)):ti,ab,kw) OR ‘sigmoid cancer’/exp OR

‘sigmoid neoplasms’:ti,ab,kw OR (‘sigmoid cancer’:ti,ab,kw OR ‘sigmoid tumor’:ti,ab,kw OR

‘sigmoid tumour’:ti,ab,kw OR ‘sigmoid tumors’:ti,ab,kw OR ‘sigmoid tumours’:ti,ab,kw OR

‘sigmoid neoplasm’:ti,ab,kw OR (‘sigmoid’ NEAR/2 (‘neoplasm’ OR ‘neoplasms’ OR ‘cancer’

OR ‘tumor’ OR ‘tumors’ OR ‘tumour’ OR ‘tumours’)):ti,ab,kw) OR ('vagina tumor'/exp OR

‘vagina cancer’/exp OR ‘vaginal neoplasms’/exp OR 'vagina tumor':ti,ab,kw OR 'vagina

tumour':ti,ab,kw OR ‘vaginal neoplasms’:ti,ab,kw OR 'vagina tumors':ti,ab,kw OR 'vagina

tumours':ti,ab,kw OR ‘vaginal neoplasm’:ti,ab,kw OR ‘vagina cancer’:ti,ab,kw OR ((‘vaginal’

OR ‘vagina’) NEAR/2 (‘neoplasm’ OR ‘neoplasms’ OR ‘cancer’ OR ‘tumor’ OR ‘tumors’ OR

‘tumour’ OR ‘tumours’)):ti,ab,kw) OR ('endometrium tumor'/exp OR ‘endometrium cancer’/exp

p.VIII Therapy and Non-Invasive Prevention of Gastrointestinal Toxicity caused by Radiotherapy for Pelvic Neoplasms

OR 'endometrium tumor':ti,ab,kw OR 'endometrium tumour':ti,ab,kw OR ‘endometrial

neoplasms’:ti,ab,kw OR 'endometrium tumors':ti,ab,kw OR 'endometrium tumours':ti,ab,kw

OR ‘endometrial neoplasm’:ti,ab,kw OR ‘endometrium cancer’:ti,ab,kw OR (‘endometrium’

NEAR/2 (‘neoplasm’ OR ‘neoplasms’ OR ‘cancer’ OR ‘tumor’ OR ‘tumors’ OR ‘tumour’ OR

‘tumours’)):ti,ab,kw) OR ('ovary tumor'/exp OR ‘ovary cancer’/exp OR 'ovary tumor':ti,ab,kw

OR 'ovary tumour':ti,ab,kw OR ‘ovarian neoplasms’:ti,ab,kw OR 'ovary tumors':ti,ab,kw OR

'ovary tumours':ti,ab,kw OR ‘ovarian neoplasm’:ti,ab,kw OR ‘ovary cancer’:ti,ab,kw OR

((‘ovarian’ OR ‘ovary’) NEAR/2 (‘neoplasm’ OR ‘neoplasms’ OR ‘cancer’ OR ‘tumor’ OR

‘tumors’ OR ‘tumour’ OR ‘tumours’)):ti,ab,kw) OR ('uterus cancer'/exp OR ‘uterus tumor’/exp

OR 'uterine cervix tumor'/exp OR 'uterus cancer':ti,ab,kw OR ‘uterine tumor’:ti,ab,kw OR

‘uterine tumour’:ti,ab,kw OR ‘uterine neoplasms’:ti,ab,kw OR ‘uterine tumors’:ti,ab,kw OR

‘uterine tumours’:ti,ab,kw OR ‘uterine neoplasm’:ti,ab,kw OR ((‘uterus’ OR ‘uterine’) NEAR/2

(‘neoplasm’ OR ‘neoplasms’ OR ‘cancer’ OR ‘tumor’ OR ‘tumors’ OR ‘tumour’ OR

‘tumours’)):ti,ab,kw OR 'uterine cervix tumor':ti,ab,kw OR 'uterine cervix tumour':ti,ab,kw OR

‘uterine cervical neoplasms’:ti,ab,kw OR 'uterine cervix tumors':ti,ab,kw OR 'uterine cervix

tumours':ti,ab,kw OR ‘uterine cervical neoplasm’:ti,ab,kw OR ‘cervix cancer’:ti,ab,kw OR

(‘cervix’ NEAR/2 (‘neoplasm’ OR ‘neoplasms’ OR ‘cancer’ OR ‘tumor’ OR ‘tumors’ OR

‘tumour’ OR ‘tumours’)):ti,ab,kw)) AND ('therapy'/exp OR ‘therapy’:ti,ab,kw OR

‘therapeutics’:ti,ab,kw OR 'therapy'/lnk)

Therapy and Non-Invasive Prevention of Gastrointestinal Toxicity caused by Radiotherapy for Pelvic Neoplasms p.IX

10.3 SEARCH STRATEGY PUBMED

(("radiotherapy"[Subheading] OR "radiotherapy"[All Fields] OR "Radiotherapy"[MeSH] OR

“Radiation therapy”[All Fields]) AND (("toxicity"[Subheading] OR "toxicity"[All Fields] OR

“toxic effects” [All Fields] OR “toxic” [All Fields] OR "Gastrointestinal Tract/radiation

effects"[MeSH]) AND ("Gastrointestinal Tract"[MeSH] OR "gastrointestinal"[All Fields] OR

"gastrointestinal tract"[All Fields])) AND (("Pelvic Neoplasms"[MeSH] OR "Pelvic

Neoplasms/radiotherapy"[MeSH] OR "pelvic neoplasms"[All Fields] OR "pelvis

neoplasms"[All Fields] OR "pelvic tumours"[All Fields] OR “pelvic tumors”[All Fields] OR

"pelvis tumours"[All Fields] OR “pelvis tumors”[All Fields] OR "pelvic neoplasm"[All Fields]

OR "pelvis neoplasm"[All Fields] OR "pelvic tumour"[All Fields] OR “pelvic tumor”[All Fields]

OR "pelvis tumour"[All Fields] OR “pelvis tumor” [All Fields] OR (("pelvic"[All Fields] OR

“pelvis”[All Fields]) AND (“neoplasm”[All Fields] OR “neoplasms”[All Fields] OR “cancer”[All

Fields] OR “tumor”[All Fields] OR “tumors”[All Fields] OR “tumour”[All Fields] OR

“tumours”[All Fields]))) OR ("urinary bladder neoplasms"[MeSH Terms] OR "urinary bladder

neoplasms"[All Fields] OR "urinary bladder neoplasm"[All Fields] OR "bladder cancer"[All

Fields] OR “bladder tumor"[All Fields] OR “bladder tumour"[All Fields] OR “bladder

tumors"[All Fields] OR “bladder tumours"[All Fields] OR (("bladder"[All Fields] OR “urinary

bladder”[All Fields]) AND (“neoplasm”[All Fields] OR “neoplasms”[All Fields] OR “cancer”[All

Fields] OR “tumor”[All Fields] OR “tumors”[All Fields] OR “tumour”[All Fields] OR

“tumours”[All Fields]))) OR("prostatic neoplasms"[MeSH Terms] OR "prostatic neoplasms"[All

Fields] OR "prostatic neoplasm"[All Fields] OR "prostate cancer"[All Fields] OR “prostate

tumor"[All Fields] OR “prostate tumour"[All Fields] OR “prostate tumors"[All Fields] OR

“prostate tumours"[All Fields] OR (("prostate"[All Fields] OR “prostatic”[All Fields]) AND

(“neoplasm”[All Fields] OR “neoplasms”[All Fields] OR “cancer”[All Fields] OR “tumor”[All

Fields] OR “tumors”[All Fields] OR “tumour”[All Fields] OR “tumours”[All Fields]))) OR

("urologic neoplasms"[MeSH Terms] OR "urologic neoplasms"[All Fields] OR "urologic

neoplasm"[All Fields] OR "urinary tract cancer"[All Fields] OR “urinary tract tumor”[All Fields]

OR “urinary tract tumors”[All Fields] OR “urinary tract tumour”[All Fields] OR “urinary tract

tumours”[All Fields] OR “urinary tract neoplasm”[All Fields] OR “urinary tract neoplasms”[All

Fields] OR (("urologic"[All Fields] OR “urinary tract”[All Fields]) AND (“neoplasm”[All Fields]

OR “neoplasms”[All Fields] OR “cancer”[All Fields] OR “tumor”[All Fields] OR “tumors”[All

Fields] OR “tumour”[All Fields] OR “tumours”[All Fields])))OR ("rectal neoplasms"[MeSH

Terms] OR "rectal neoplasms"[All Fields] OR "rectum cancer"[All Fields] OR “rectum

tumor”[All Fields] OR “rectum tumour”[All Fields] OR “rectum neoplasms”[All Fields] OR

“rectum tumors”[All Fields] OR “rectum tumours”[All Fields] OR “rectum neoplasm”[All Fields]

OR “rectal neoplasm”[All Fields] OR (("rectum"[All Fields] OR “rectal”[All Fields]) AND



("Colorectal Neoplasms"[Mesh] OR "colonic neoplasms"[MeSH Terms] OR "colonic

neoplasms"[All Fields] OR "colon cancer"[All Fields] OR “colorectal tumor”[All Fields] OR

“colorectal tumour”[All Fields] OR “colon tumor”[All Fields] OR “colorectal neoplasms”[All

Fields] OR “colon tumour”[All Fields] OR “colorectal tumors”[All Fields] OR “colorectal

tumours”[All Fields] OR “colon tumors”[All Fields] OR “colorectal neoplasm”[All Fields] OR

“colon tumours”[All Fields] OR “colonic neoplasm”[All Fields] OR “colorectal cancer”[All

Fields] OR (("colon"[All Fields] OR “colonic”[All Fields] OR “colorectal”[All Fields]) AND



("sigmoid neoplasms"[MeSH Terms] OR "sigmoid neoplasms"[All Fields] OR "sigmoid

p.X Therapy and Non-Invasive Prevention of Gastrointestinal Toxicity caused by Radiotherapy for Pelvic Neoplasms

neoplasm"[All Fields] OR "sigmoid cancer"[All Fields] OR “sigmoid tumor”[All Fields] OR

“sigmoid tumour”[All Fields] OR “sigmoid tumors”[All Fields] OR “sigmoid tumours”[All Fields]

OR ("sigmoid"[All Fields] AND (“neoplasm”[All Fields] OR “neoplasms”[All Fields] OR

“cancer”[All Fields] OR “tumor”[All Fields] OR “tumors”[All Fields] OR “tumour”[All Fields] OR

“tumours”[All Fields]))) OR ("vaginal neoplasms"[MeSH Terms] OR "vaginal neoplasms"[All

Fields] OR "vaginal neoplasm"[All Fields] OR "vagina cancer"[All Fields] OR “vagina

tumor”[All Fields] OR “vagina tumour”[All Fields] OR (("vaginal"[All Fields] OR “vagina”[All

Fields]) AND (“neoplasm”[All Fields] OR “neoplasms”[All Fields] OR “cancer”[All Fields] OR

“tumor”[All Fields] OR “tumors”[All Fields] OR “tumour”[All Fields] OR “tumours”[All Fields])))

OR ("endometrial neoplasms"[MeSH Terms] OR "endometrial neoplasms"[All Fields] OR

"endometrial neoplasm"[All Fields] OR "endometrium cancer"[All Fields] OR “endometrium

tumor”[All Fields] OR “endometrium tumors”[All Fields] OR (("endometrial"[All Fields] OR

“endometrium”[All Fields]) AND (“neoplasm”[All Fields] OR “neoplasms”[All Fields] OR

“cancer”[All Fields] OR “tumor”[All Fields] OR “tumors”[All Fields] OR “tumour”[All Fields] OR

“tumours”[All Fields]))) OR ("ovarian neoplasms"[MeSH Terms] OR "ovarian neoplasms"[All

Fields] OR "ovarian neoplasm"[All Fields] OR "ovary cancer"[All Fields] OR “ovary tumor”[All

Fields] OR “ovary tumour”[All Fields] OR “ovary tumors”[All Fields] OR “ovary tumours”[All

Fields] OR (("ovarian"[All Fields] OR “ovary”[All Fields]) AND (“neoplasm”[All Fields] OR

“neoplasms”[All Fields] OR “cancer”[All Fields] OR “tumor”[All Fields] OR “tumors”[All Fields]

OR “tumour”[All Fields] OR “tumours”[All Fields]))) OR ("uterine cervical neoplasms"[MeSH

Terms] OR "uterine cervical neoplasms"[All Fields] OR "uterine cervical neoplasm"[All Fields]

OR "cervix cancer"[All Fields] OR “uterine cervix tumor”[All Fields] OR “uterine cervix

tumour”[All Fields] OR "uterine cervix tumors"[All Fields] OR ("cervix"[All Fields] AND



("uterine neoplasms"[MeSH Terms] OR "uterine neoplasms"[All Fields] OR "uterine

neoplasm"[All Fields] OR "uterus cancer"[All Fields] OR “uterine tumor”[All Fields] OR

“uterine tumour”[All Fields] OR “uterine tumors”[All Fields] OR “uterine tumours”[All Fields]

OR (("uterus"[All Fields] OR “uterine”[All Fields]) AND (“neoplasm”[All Fields] OR

“neoplasms”[All Fields] OR “cancer”[All Fields] OR “tumor”[All Fields] OR “tumors”[All Fields]

OR “tumour”[All Fields] OR “tumours”[All Fields])))) AND ("therapy"[Subheading] OR

"therapy"[All Fields] OR "therapeutics"[MeSH Terms] OR "therapeutics"[All Fields]))

Therapy and Non-Invasive Prevention of Gastrointestinal ... · group. For follow-up by a gastroenterologist, compared to the standard booklet, a pair-wise mean difference in change

Documents