Digital Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Medicine 969
Diet and Gastrointestinal
Symptoms in Patients with
Prostate Cancer Treated with
Radiotherapy
ANNA PETTERSSON
ACTA
UNIVERSITATIS
UPSALIENSIS
UPPSALA
2014
ISSN 1651-6206
ISBN 978-91-554-8861-1
urn:nbn:se:uu:diva-215410
Dissertation presented at Uppsala University to be publicly examined in Enghoffsalen, Ing
50, Akademiska sjukhuset, Uppsala, Friday, 7 March 2014 at 09:15 for the degree of Doctor
of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty
examiner: PhD Clare Shaw (Department of Nutrition and Dietetics, The Royal Marsden NHS
Foundation Trust).
Abstract
Pettersson, A. 2014. Diet and Gastrointestinal Symptoms in Patients with Prostate Cancer
Treated with Radiotherapy. Digital Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Medicine 969. 93 pp. Uppsala: Acta Universitatis Upsaliensis.
ISBN 978-91-554-8861-1.
Objective The main objective of this thesis was to explore the effects of diet on gastrointestinal
symptoms in prostate cancer patients treated with local curative radiotherapy, by evaluating
dietary intake prior to treatment (Study I), the psychometric properties of a new questionnaire on
patient-reported gastrointestinal side effects (Study II), and the effect of a dietary intervention
on acute and long-term gastrointestinal symptoms up to 2 years after radiotherapy completion
(Study III-IV).
Methods A total of 130 men with localized prostate cancer referred to dose-escalated
radiotherapy (ED2 87-102 Gy, α/β=3 Gy) were recruited to a dietary intervention trial. Patients
were randomized to receive either standard care plus the dietary intervention of a fibre- and
lactose-restricted diet (intervention group, IG; n=64) or standard care alone (standard care group,
SCG; n=66). Data on gastrointestinal symptoms and dietary intake were collected pre-treatment
and at seven time points during a follow-up period of 26 months.
Results Prior to treatment, grain products and milk products were major sources of energy.
Unbalanced fatty acid intake and low intake of selenium were observed (Study I). Validation
of the Gastrointestinal Side Effects Questionnaire (GISEQ) revealed satisfactory internal
consistency, moderate concurrent validity and adequate responsiveness (Study II). There were
no significant effects of the intervention on acute or long-term gastrointestinal symptoms, but a
tendency towards lower prevalence and severity of bloating and diarrhoea in the IG compared
to the SCG during radiotherapy. Gastrointestinal symptoms were predominantly mild, and the
frequency of clinically relevant symptoms was merely a few percent. Dietary adherence in the
IG was initially good, but tended to decline beyond 12 months post-radiotherapy (Study III-IV).
Conclusions A fibre- and lactose-restricted diet was not superior to the habitual diet
in reducing gastrointestinal symptoms in patients undergoing high-dose, small-volume
radiotherapy for localized prostate cancer. The GISEQ enables assessment of patient-perceived
change in symptoms, but further work is needed to strengthen its psychometric qualities. It is
suggested that continued research in this area target patient categories referred to irradiation
of larger pelvic volumes with a higher risk of gastrointestinal symptoms, and that dietary
interventions incorporate established strategies to enhance adherence and effectiveness.
Keywords: Dietary intervention, gastrointestinal symptoms, prostate cancer, radiotherapy,
randomized controlled trial, health-related quality of life, questionnaire design, nutritional
assessment
Anna Pettersson, Department of Radiology, Oncology and Radiation Science, Oncology,
Akademiska sjukhuset, Uppsala University, SE-751 85 Uppsala, Sweden.
© Anna Pettersson 2014
ISSN 1651-6206
ISBN 978-91-554-8861-1
urn:nbn:se:uu:diva-215410 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-215410)
“The real voyage of discovery consists
not in seeking new landscapes,
but in having new eyes.”
Marcel Proust, French author
List of Papers
This thesis is based on the following papers, which are referred to in the text
by their Roman numerals.
I
Pettersson, A., Andersson, A., Persson, C., Turesson, I., Johansson,
B. (2013) Dietary intake in men recently diagnosed with prostate
cancer. Submitted
II
Pettersson, A., Turesson, I., Persson, C., Johansson, B. (2013)
Assessing patients' perceived bother from the gastrointestinal side
effects of radiotherapy for localized prostate cancer: Initial
questionnaire development and validation. Acta Oncologica,
Published online (ahead of print) 19 Aug 2013
III
Pettersson, A., Johansson, B., Persson, C., Berglund, A., Turesson, I.
(2012) Effects of a dietary intervention on acute gastrointestinal side
effects and other aspects of health-related quality of life: A randomized controlled trial in prostate cancer patients undergoing radiotherapy. Radiotherapy and Oncology, 103(3):333-40
IV
Pettersson, A., Nygren, P., Persson, C., Berglund, A., Turesson, I.,
Johansson, B. (2013) Effects of a dietary intervention on gastrointestinal symptoms after prostate cancer radiotherapy: Long-term results
from a randomized controlled trial. Manuscript
Reprints were made with permission from the respective publishers.
Front cover: photography by A. Ottenblad, 2014.
Contents
Introduction ................................................................................................... 11
Nutritional interventions in pelvic radiotherapy....................................... 11
Dietary fibre and lactose modification................................................. 12
Gastrointestinal symptoms from pelvic radiotherapy............................... 15
Prostate cancer ..................................................................................... 15
Outcome assessment ................................................................................ 17
Health-related quality of life ................................................................ 18
Gastrointestinal symptoms in prostate cancer patients ........................ 20
Nutritional status assessment ............................................................... 22
Adherence to dietary interventions........................................................... 22
Dietary assessment............................................................................... 23
Rationale for this thesis ............................................................................ 25
Aims .............................................................................................................. 26
Methods ........................................................................................................ 27
Participants ............................................................................................... 27
Radiotherapy treatment ........................................................................ 29
Randomization ......................................................................................... 29
Dietary intervention ............................................................................. 29
Standard care ....................................................................................... 31
Data collection procedure......................................................................... 31
Primary outcome.................................................................................. 32
Secondary outcome.............................................................................. 34
Dietary assessments ............................................................................. 35
Nutritional status assessments ............................................................. 35
Power........................................................................................................ 36
Data preparation and statistical analysis .................................................. 37
General preparations ............................................................................ 37
Paper I .................................................................................................. 37
Paper II ................................................................................................ 38
Paper III-IV.......................................................................................... 39
Ethical considerations .............................................................................. 41
Results ........................................................................................................... 42
Dietary intake prior to radiotherapy onset – Paper I ................................ 43
Validation of the GISEQ – Paper II ......................................................... 44
Effects of the dietary intervention on acute and persistent
gastrointestinal symptoms – Paper III-IV ................................................ 45
Gastrointestinal symptoms................................................................... 45
Other domains of health-related quality of life .................................... 49
Dietary adherence ................................................................................ 50
Nutritional status.................................................................................. 55
Discussion ..................................................................................................... 56
Main findings ........................................................................................... 56
Effects of the dietary intervention ............................................................ 56
Adherence to the dietary intervention .................................................. 59
Assessment of gastrointestinal symptoms ................................................ 61
Pre-treatment nutritional status ................................................................ 63
Methodological discussion ....................................................................... 64
Conclusions ................................................................................................... 67
Clinical implications and future research ................................................. 68
Sammanfattning på svenska .......................................................................... 69
Bakgrund .................................................................................................. 69
Syfte och metod ........................................................................................ 69
Studie I ................................................................................................. 70
Studie II ............................................................................................... 70
Studie III-IV ........................................................................................ 70
Slutsats ..................................................................................................... 71
Acknowledgements ....................................................................................... 72
References ..................................................................................................... 75
Appendix ....................................................................................................... 89
Abbreviations
24-HDR
ANOVA
AR
BMI
BMRest
CTCAE
DRV
EAR
EBRT
EORTC QLQ-C30
EORTC QLQ-PR25
FFQ
GEE
GISEQ
GISEQ-PR
HRQOL
IG
LI
NNR
PG-SGA
PRO
PROM
PSA
RCT
SCG
WHO
24-hour dietary recall
Analysis of variance
Average requirement
Body mass index
Estimated basal metabolic rate
Common Toxicity Criteria for Adverse Events
Dietary reference value
Estimated average requirement
External beam radiotherapy
European Organization for Research and Treatment
of Cancer Quality of Life Questionnaire Core 30
European Organization for Research and Treatment
of Cancer Quality of Life Questionnaire Prostate 25
Food frequency questionnaire
Generalized estimating equations
Gastrointestinal Side Effects Questionnaire
Gastrointestinal Side Effects Questionnaire PreRadiotherapy
Health-related quality of life
Intervention group
Lower intake level
Nordic Nutrition Recommendations
Patient-Generated Subjective Global Assessment
Patient-reported outcome
Patient-reported outcome measures
Prostate-specific antigen
Randomized controlled trial
Standard care group
World Health Organization
Introduction
Radiotherapy is a well-established treatment option for pelvic malignancies1,
but it entails a risk of unfavourable side effects [1, 2]. Adjacent healthy tissue is encompassed in the radiation field, and such exposure can cause both
acute and chronic gastrointestinal symptoms [3]. Tissue with rapidly dividing cells, such as the alimentary tract, is most susceptible to radiation damage [4] and as a consequence, digestive and absorptive functions may be
negatively affected [5]. Such radiation-induced nutrition impact symptoms
may lead to reduced quality of life, malnutrition and, in some cases, may
limit possibilities for curative treatment [6, 7]. Consequently, therapeutic
nutritional intervention before, during and after pelvic radiotherapy may be
beneficial in the management of gastrointestinal side effects of pelvic radiotherapy.
Nutritional interventions in pelvic radiotherapy
Malnutrition is a possible complication in patients with cancer and commonly occurs even before the commencement of anti-cancer treatment [8]. Reported incidence of malnutrition before pelvic radiotherapy onset ranges
from 11% to 36% and is dependent on the evaluation criteria, diagnosis, etc.
[9-11]. Fatigue, loss of appetite and weight loss may occur during radiotherapy, thus adding to the nutritional complications [12, 13]. Nutritional status
and pelvic radiotherapy have effects on each other, in that impaired bowel
functionality caused by radiation damage to the gastrointestinal tract may
comprise patients’ nutritional status [14], but poor nutritional status is also a
risk factor in terms of outcome and therapy-related toxicity [10, 15].
Worsened gastrointestinal symptoms during pelvic radiotherapy may be the
result of a variety of specific aberrations in gastrointestinal functionality.
The causes of diarrhoea during pelvic radiotherapy may include a combination of different factors, such as accelerated small and large bowel transit
[16-19], reduced production of lactase enzyme and the development of lactose intolerance [18, 20], malabsorption of fat, bile salt and carbohydrates
1
Pelvic malignancies include a variety of cancers involving the structures and organs of the
pelvis, e.g. prostate, rectal and gynaecological cancer.
11
[19, 21], and changes in the bacterial flora of the large bowel [22, 23]. Gastrointestinal side effects may be managed with various medications such as
anti-diarrhoeals, bulking agents and laxatives, as part of standard care. In
addition, attention to nutritional aspects following radiotherapy is of importance, and nutritional support interventions, integrated with the anticancer treatment, may be beneficial. Studies in patients undergoing pelvic
radiotherapy have found that nutritional interventions may improve dietary
intake, treatment tolerance including symptom incidence and severity, nutritional status and quality of life [24-27].
Nutritional interventions encompass a wide range of possible approaches and
techniques, and may comprise one or more of the following: dietary counselling, dietary modification, supplementary/fortified foods or drinks, oral nutrition supplements, enteral nutrition, or parenteral nutrition [25, 28]. Interventions may be provided at any stage of treatment, either before/during
radiotherapy to induce a protective effect from irradiation for healthy tissue,
or during/after radiotherapy to reduce or resolve symptoms once gastrointestinal side effects of treatment have occurred [28, 29]. Examples of the latter
are dietary modification interventions, which may comprise modification of
fat, lactose or dietary fibre or combinations of these dietary changes, as well
as reduced intake of motility stimulants (caffeine, alcohol), elemental diets
or total replacement of diet with elemental formulas, micronutrient therapy,
and preparations of probiotics and/or synbiotics [28-30]. A meta-analysis in
a recent review indicated a reduction in diarrhoea from nutritional interventions [28]. However, there is currently a lack of evidence-based guidelines
on dietary treatments for radiation-induced gastrointestinal symptoms following pelvic radiotherapy [31].
Dietary fibre and lactose modification
The definition of dietary fibre has been debated for many years [32], but in
2008, the Codex Committee on Nutrition and Foods for Special Dietary Uses
agreed on the following “Dietary fibre means carbohydrate polymers with
ten or more monomeric units, which are not hydrolysed by endogenous enzymes in small intestine of human beings” [33]. Naturally occurring dietary
fibre comprises both soluble and insoluble fractions with distinct properties
and benefits. Insoluble fibres do not absorb or dissolve in water, undergo
minimal change in the digestive tract, add bulk and increase the faecal mass,
and have a marked laxative effect with shortened colonic transit time [3437]. Insoluble fibres lend structure to plant cells and are found in bran, whole
grains and vegetables (cellulose, hemicelluloses) as well as mature vegetables, fruits and edible skins and seeds (lignin) [13]. Soluble dietary fibres
attract water, have the ability to form gels and swell when mixed with water,
which slow down digestion. Soluble fibres are fermented to a high degree,
12
showing a trophic effect by enhancing colonic epithelial proliferation [38,
39]. Short chain fatty acids, fermented by colonic bacteria from mainly soluble dietary fibre [40], may have some anti-inflammatory effect and have
been tested in the treatment of radiation proctitis [41]. Examples of soluble
fibre food sources include vegetables, fruits and berries (pectin) as well as
legumes, oats and barley (gums).
Lactose, or milk sugar, is a disaccharide composed of glucose and galactose,
and the principal sugar in mammalian milk [13]. Damage to the intestinal
villi caused by radiotherapy may result in a reduction or loss of lactase enzyme, which is essential in the digestion of milk and milk products. Unabsorbed lactose contributes to an osmotic load in the colon causing watery
diarrhoea. Moreover, radiation-induced lactose intolerance may occur in
about 15% of patients and contribute to gastrointestinal toxicity [20, 22, 42].
Results from previous studies evaluating the effect of lactose-restricted diets
on radiation-induced diarrhoea are inconsistent [43, 44].
The causes of radiation-induced diarrhoea mentioned above, together with
the effects of lactose and different types of dietary fibres on gastrointestinal
function, have led to exploration of the potential benefits of dietary fibre and
lactose modifications in reducing gastrointestinal symptoms following pelvic
radiotherapy. A number of modifications have been tested, namely lactose
restriction, reduction of foods containing fibre (low-fibre diet, low-residue
diet) and fibre supplementation (soluble dietary fibre), and some may help to
reduce acute gastrointestinal toxicity, according to two recent reviews2
(Table 1) [28-30]. The small number of studies eligible for review over a 35year period demonstrates that this is an under-researched area. Generally,
there is a need for nutritional intervention studies of higher quality [28, 30].
2
It should be noted that some of the studies are dated and comparison of outcomes should be
made with caution, given that a general reduction in side effects has been achieved by technical improvements in radiotherapy during the past decade.
13
Gynaecological
Gynaecological,
prostate
Gynaecological,
prostate, sigmoid
Prostate
10
Murphy (2000) 84
64
156
22
24
30
Lodge (1995)
Stryker (1986)
Liu (1997)
McNair (2011)
Stryker (1978)
Weiss (1982)
CS
CS
CS
CS
RCT
RCT
RCT
RCT
Design
Intervention
Results
No difference between groups
Favourable effects of fibre supplement
Favourable effects of a low-fat, low-lactose
diet
Fibre supplement significantly less effective
than standard medication. (Early study termination)
Favourable effects of reduced fibre consumption
Favourable effects of increased fibre consumption
Investigated the incidence of lactose malabsorp- 50% patients exhibited significantly reduced
tion
lactose absorption
Investigated the impact of volume of small
Reduced lactose absorption in patients with a
bowel irradiated on lactose malabsorption
larger volume of the small intestine irradiated,
compared with patients with smaller volumes.
Regular hospital diet vs. lactose- and fatrestricted diet
Low-fibre diet to all patients. On presentation of
treatment-induced diarrhoea: standard medication (codeine phosphate) vs. fibre supplement
a
(psyllium )
Low-fibre, low-fat, low-stimulant (caffeine and
alcohol) diet plus fibre supplement (psyllium a)
vs. low-fibre, low-fat, low-stimulant diet alone
Normal lactose vs. low-lactose vs. normal lactose plus enzyme
b
Low-residue diet and avoidance of spicy foods
and alcohol
Individualized fluid and fibre dietary prescription
a) Psyllium contains a high level of soluble dietary fibre.
b) Residue refers to any food (including fibre) that is not digested, remains in the intestinal tract and contributes to stool bulk. The low-residue diet is similar to a low-fibre
diet, but also excludes foods that are believed to stimulate bowel contractions.
Abbreviations: CS, case study; RCT, randomized controlled trial
Mixed pelvic sites
Gynaecological
Prostate
Gynaecological
143
Bye (1992)
Population
n
First author
Table 1. Summary of dietary intervention studies on modification of fibre and/or lactose during pelvic radiotherapy
Gastrointestinal symptoms from pelvic radiotherapy
During the 5-7 weeks of pelvic radiotherapy, acute gastrointestinal toxicity
have been reported to occur in as many as 70-90% of patients [23, 45, 46].
Acute symptoms include diarrhoea, abdominal pain, tenesmus3 and more
frequent or urgent bowel movements and incontinence [45]. However, subsequent long-term changes in bowel function such as abdominal pain, intermittent diarrhoea and incontinence can occur after a few months or years,
and about 50% of patients have chronic gastrointestinal symptoms that negatively affect their quality of life [47, 48]. The frequency of persistent gastrointestinal symptoms may vary across diagnostic groups, because gastrointestinal side effects are partly dose-volume dependent [23].
Prostate cancer
Prostate cancer is the second most prevalent cancer in men worldwide [49],
and the most common type of cancer in Swedish men, accounting for a third
of all new cases [50]. The risk factors for prostate cancer are currently not
well known, but a few have been identified, namely increasing age, heredity
and ethnic origin [51, 52]. Moreover, large international variations in prostate cancer incidence, together with results from migration studies, indicate
that that lifestyle factors, particularly diet, play an important role in disease
aetiology [53]. Foods containing lycopene and selenium probably protect
against prostate cancer and diets high in calcium probably increase the risk
[54-59]. In addition, limited and inconsistent evidence suggests an association between prostate cancer risk and dietary fat and dairy products [60-62]
The incidence of prostate cancer rapidly increased from the late 1990’s, and
in 2009, the incidence rate reached its highest level yet, when 10,512 Swedish men were diagnosed with prostate cancer (Figure 1) [63]. The progressive trend in incidence is explained to a large degree by increased public
awareness and early detection methods. The introduction of ProstateSpecific Antigen (PSA) testing has led to earlier diagnosis, predominantly of
low-risk4 tumours. Consequently, the increased number of cases diagnosed is
a ‘new addition’ that was not previously discovered. About 85% of men are
diagnosed after age 65 years and the mean age of patients with prostate cancer is 72–74 years [64]. The mortality rate has remained relatively stable
over time, with approximately 2,400 deaths per year.
3
4
A feeling of constantly needing to pass stools.
Low-risk: T1-T2, Gleason score ≤6, PSA <10 ng/ml.
15
Figure 1. Age-standardized5 incidence and mortality of prostate cancer in Sweden
per 100,000 men from 1970 to 2011. Reprinted with permission [63].
Prostate cancer radiotherapy
The treatment options for radiotherapy have increased during recent years
and several modalities are available today, including different types of external beam radiotherapy (EBRT) including intensity-modulated radiotherapy.
Dose-escalation is also achieved by proton therapy and brachytherapy, usually added as a boost in addition to EBRT [65, 66]. The most frequent radiation treatment in Sweden is EBRT, or brachytherapy in combination with
EBRT. The number of Swedish men undergoing radiotherapy with such
modalities as primary treatment has varied between about 1,000 and 1,700
yearly during the past 10 years [63]. Compared with EBRT radiation, both
brachytherapy and proton therapy reduce radiation to non-targeted adjacent
tissue [67-69]. Technical advances in the planning and delivery of radiotherapy during the past decade have reduced the side effects of treatment. Despite such improvements, however, symptoms of gastrointestinal radiation
injury are still the main dose-limiting factors in curative radiotherapy for
prostate cancer [70].
Gastrointestinal symptoms from prostate radiotherapy
The side effects of prostate radiotherapy can partly be explained by the anatomical localization of the prostate, close to the mucosal tissue of the bladder, urethra and the rectum as well as the erectile nerves. Radiation exposure
may irritate the lower part of the large intestine, especially the rectum, be5
Age-standardized according to the population of Sweden (incidence) and the Nordic countries (mortality) in 2000. Source: National Board of Health and Welfare (incidence),
www.socialstyrelsen.se, and NORDCAN (mortality), www.ancr.nu.
16
cause the front part of the rectum lies very close to the prostate gland [71].
The colon delivers stool to the rectum, and the rectum serves as a reservoir
for stool. Radiotherapy toxicity is commonly classified as acute, consequential or late effects, based on the time before appearance of symptoms. By
definition, acute side effects are those occurring during the course of treatment and up to 3 months after radiotherapy onset [72]. Consequential late
effects appear later, and are caused by persistent acute damage [73]. Late
side effects may present months to years after treatment and are progressive
over time in a dose-dependent manner [74]. The incidence and severity of
acute and late symptoms are also volume-dependent. Persistent symptoms
are probably also dependent on a complex interaction of physical, genetic,
patient-, and treatment-related factors [23, 75]. Moreover, there is a higher
probability of chronic problems among patients with greater and longer
acute toxicity [1].
Acute toxicity typically develops within 2-4 weeks after treatment onset and
usually resolves 2-3 weeks after treatment completion [74]. Symptoms include diarrhoea, rectal tenesmus, urgency of defecation, faecal incontinence,
mucous discharge, abdominal and rectal pain, bloating and intermittent
bleeding [68, 71, 74, 76]. Of these symptoms, diarrhoea is generally
acknowledged as the most common [68]. Long-term symptoms include altered bowel habits with intermittent diarrhoea, urgency and incontinence,
pain and rectal bleeding, and may present months to years after the completion of therapy [77]. Also, fibrosis and stricture formation lead to altered
colonic motility with constipation as a result [70, 71, 74]. Although recent
improvements in radiotherapy have lowered the prevalence of severe symptoms after prostate radiotherapy to merely a few percent (0-10%) [70, 7882], moderate acute gastrointestinal symptoms are still present in 6-55% of
patients, and 2-33% of patients have persistent gastrointestinal symptoms
[70, 78-82]. Note, however, that estimating toxicity occurrence is complicated and that estimates vary greatly owing to the different definitions, grading
and reporting methods used, as explained further below.
Outcome assessment
It is generally important to determine whether a nutritional intervention has
an impact on outcomes such as side effects and quality of life, as well as to
assess its effects on dietary intake and nutritional status. Moreover, in prostate cancer patients, outcomes such as side effects and quality of life are
important factors in the choice of primary treatment [83], because previous
research has not been able to state that one treatment option for localized
prostate cancer is superior to another regarding survival [84, 85]. Gastrointestinal side effects, especially problems of incontinence and urgency, are
17
known to negatively affect the patient’s quality of life after prostate radiotherapy [86, 87].
Previously, reports on side effects often relied on physician-based evaluation
of symptoms using toxicity scales. A number of measures of toxicity exist,
including the toxicity grading system of the Radiation Therapy Oncology
Group/European Organization for Research and Treatment of Cancer
(RTOG/EORTC), the Late Effects Normal Tissue/Subjective Objective
Management Analytic system (LENT/SOMA), or the National Cancer Institute/Common Toxicity Criteria for Adverse Events (NCI/CTCAE), that assign a physician-based toxicity grade based on patient-reported symptoms
[88-90]. The grading of toxicity (Grade 0-5) is based on the severity of side
effects, where Grade 2 represents moderate symptoms that require only conservative medical treatment, and Grade 3 effects are considered severe and
may require surgical intervention [89, 91]. However, physician-based ratings
do not include assessment of a wide variety of patient-experienced symptoms affecting the daily well-being, meaning that the true picture of radiation
side effects is likely concealed and underestimated [92].
Since the 1990s, there has been increasing recognition of patient-based outcomes as valid measures of treatment consequences and the symptoms recognised by the patient. The U.S. Food and Drug Administration recently
introduced the comprehensive term patient-reported outcome (PRO), which
is any report of the status of a patient’s health condition that comes directly
from the patient, without interpretation of the patient’s response by a clinician or anyone else [93]. Instruments to capture PRO data have been introduced in various clinical trials, cancer research being just one example.
Nowadays, PRO measures (PROM) are part of routine assessment in clinical
cancer research and are recognized for providing added value to usual clinical outcomes [94, 95]. PROMs can provide insights into treatment- and/or
disease-related consequences that are directly experienced by patients, such
as symptoms and other domains of health-related quality of life (HRQOL)
[96, 97].
Health-related quality of life
The concept ‘quality of life’ is patient-focused and traditionally defined as
the impact of an illness or treatment on an individual’s physical, psychological, social, and somatic functioning and general well-being [98-100]. However, the concept has been criticized as too general to be of use in health care
research [101]. HRQOL is a narrower concept, preferable in the field of
medicine owing to its focus on health. There is a general consensus that
HRQOL is also an important clinical trial outcome. A person’s HRQOL is
influenced by his/her lived experience of illness across a broad range of di18
mensions or domains. Along with impacts on the person’s functioning and
well-being, these domains also commonly include the symptoms of disease
and side effects of its treatment. There are a great variety of cancer-specific
PROMs of HRQOL available, but the most widely used are the questionnaires included in the EORTC Quality of Life Questionnaire (QLQ) and the
Functional Assessment of Chronic Illness Therapy (FACIT) suites [102].
Both suites follow similar formats in that they consist of a core measure, the
EORTC QLQ Core30 (EORTC QLQ-C30) and the Functional Assessment
of Cancer Therapy - General (FACT-G), that assess symptoms, functioning,
and overall well-being experienced by individuals, regardless of the specific
cancer with which they have been diagnosed [103, 104].
The increasing use of the EORTC QLQ-C30 to assess HRQOL in oncology
entails a need for meaningful interpretations of its aggregated scores, which
range from 0–1006. Although asking patients about their HRQOL may be
clinically intuitive, simple and easy to do, interpreting differences – both
within and between persons and groups – is challenging. In large sample
sizes, statistically significant results can be obtained when numerical differences in scores are small and not likely to be clinically meaningful. Osoba
et al. defined differences of 10 points or more as clinically relevant, and
suggested that changes in scores of 5-10 represented a small difference, 1020 a moderate difference, while those above 20 represented large differences
[105]. It is not clear, however, that a 10-point difference is applicable to all
scales in the QLQ-C30, and it has recently been recommended that a minimum for detection of moderate differences ranges from 9 to 19 points, depending on the subscale in question [106]. Other attempts to facilitate clinical interpretation of scores have incorporated dichotomization or thresholds
for symptoms, commonly differentiating between EORTC scores <67 as
non-symptomatic (i.e., EORTC raw score 1 and 2 interpreted as no, minor or
mild symptoms) and scores ≥67 as clinically relevant (i.e., EORTC raw
score 3 and 4 interpreted as moderate or severe symptoms) [107-109].
Previous assessments using the EORTC QLQ-C30 in prostate cancer patients indicate that physical symptoms such as pain, fatigue and insomnia
may increase during radiotherapy [110-112]. Global health status is generally high or only slightly impaired, and there is usually little change in emotional and social functional capacity [111-113].
6
In EORTC QLQ-C30, the Likert item response scales (raw score 1-4- or 1-7) are transformed into a 0-100 scale. Higher scores represent a higher level of functioning or symptoms.
19
Gastrointestinal symptoms in prostate cancer patients
Core HRQOL questionnaires can be supplemented by tumour-, treatment-,
or symptom-specific modules, which is beneficial because use of a module
offers enhanced sensitivity to disease and treatment effects. There are several
available PROMs for men with prostate cancer (Table 2), with varying psychometric properties according to two reviews of disease-specific modules
[97, 114]. The Patient-reported Outcome Measurement Group identified nine
prostate-specific PROMs, and concluded that the available literature supported the EORTC and the FACT instruments [114]. Reindunsdatter et al.
reported six prostate-specific PROMs [97, 115-118]. All six modules consisted of items on toxicity concerning intestinal, urinary and sexual function,
but the measurement procedures varied considerably. The modules also differed in number of items used, item dimensions (symptoms, function and/or
bother) and the intended time interval for the questions. All modules contained items on the dimensions of gastrointestinal, urinary and sexual symptoms, and more recently developed modules (UCLA-PCI and EPIC) assessed these symptoms using the sub-dimensions bother and function (Table
2). The psychometric properties ranged from acceptable to not satisfactory.
There is currently no consensus on the best method for measuring the side
effects of radiotherapy for prostate cancer.
Assessment of change in patient-reported outcomes is important when evaluating interventions [119]. Condition-specific PROMs provide valuable estimates of the impact of treatment on the patient’s life, including the consequences of treatment and the patient’s actual symptom experience [96].
However, HRQOL is a subjective and dynamic construct, and as health status changes, individuals may change their internal standards, values and
conceptualization of HRQOL [120]. This process, known as ‘response shift’,
may be beneficial to patients in adapting to new situations during the course
of illness and treatment, but it complicates the interpretation of change in
HRQOL scores in research and clinical evaluations [120-123]. Ergo, conventional calculation of a change score (post-treatment minus pre-treatment)
may not accord with the patient’s perception of change [119, 124].
20
UCLA Prostate Cancer Index
UCLA-PCI
Patient Oriented Prostate Utility Scales
PORPUS
Prostate Cancer Treatment Outcomes - Questionnaire
PCTO-Q
Prostate Cancer Symptom Scale
PCSS (formerly named QUFW94)
Prostate Cancer - Quality of Life
PC-QoL
No name, developed by Dale et al
HRQOL instrument
FACT Advanced Prostate Symptom Index
FAPSI-8
FACT - Prostate Version
FACT-P
Expanded Prostate Index Composite
EPIC
EORTC Quality of Life Questionnaire Prostate
Module
4- to 6-point Likert
10
3- to 5-point Likert scale
Dichotomous (yes/no)
and 4- to 5-point Likert
scale
41
20
Dichotomous (yes/no),
10-point Likert scale and
open questions
3- to 7-point Likert scale
5- to 7-point Likert scale
5-point Likert scale
5-point Likert scale
3- to 5-point Likert scale
43
52
35
8
12
26 or 50
Function and bother, for each of bowel, urinary and sexual
issues.
Bowel function, urinary frequency and incontinence, sexual
function and desire. Plus five generic domains.
Bowel function, urinary function, sexual function.
General quality-of-life, intestinal problems, urinary problems,
sexual function.
Function, role activity limitations and bother, for each of
bowel, urinary and sexual issues. One scale on worry/anxiety.
Bowel function, urinary function, sexual function.
Pain, fatigue, weight loss, urinary and concern about the
condition becoming worse. (Extracted from the FACT-P)
Bowel function, urinary function, sexuality, and pain.
Function and bother, for each of bowel, urinary, hormonal
and sexual issues. (Full-length EPIC-50 or abbreviated EPIC-26)
Domains
Bowel symptoms, urinary symptoms, hormonal treatmentrelated symptoms, sexual activity, sexual functioning.
EORTC QLQ-PR25
4-point Likert scale
No. of items Response options
25
Instrument
Table 2. Summary of prostate-specific patient-reported outcome measures
A prospective study of HRQOL in Swedish prostate cancer patients using
the QLQ-PR25 revealed that the prevalence of mild persistent symptoms of
unintentional stool leakage and blood in stools ranged from 15-29% and 621%, respectively, and that 4% reported moderate persistent problems of
both symptoms [111]. Previous reports using the EORTC questionnaires for
prostate-specific acute HRQOL during and after radiotherapy have observed
mean symptom scores (on a 0-100 scale) in the intervals of 5-8 for constipation, 12-13 for diarrhoea, and 8-11 for general bowel symptoms [125, 126].
The reported mean scores of late symptoms were in the interval of 6-15 for
constipation, 8-28 for diarrhoea, and 8-19 for general bowel symptoms [111,
125-128].
Nutritional status assessment
Because malnutrition increases the risk of treatment toxicity and decreases
HRQOL [129, 130], it is crucial that cancer patients undergo nutritional
screening and assessment so that the presence or risk of malnutrition can be
detected [131]. The World Health Organization (WHO) defined nutritional
status as the condition of the body resulting from the intake, absorption and
utilization of nutrients and the influence of particular physiological and
pathological statuses [132, 133]. A comprehensive nutritional status assessment includes four parameters, namely anthropometric, biochemical, clinical, and dietary assessments [133]. Body weight and body mass index (BMI)
are common outcome measures, but do not reflect the body composition
changes that may in cancer patients. Because the reduced functional status
and other negative outcomes associated with malnutrition are due to loss of
fat-free mass, it is important to incorporate body composition into the nutritional status assessment. Recommended and commonly used nutritional status assessment tools include Mini Nutritional Assessment (MNA), Malnutrition Universal Screening Tools (MUST), Nutritional Risk Screening 2002
(NRS2002), and Subjective Globe Assessment (SGA) [134-137]. The Patient-Generated Subjective Global Assessment (PG-SGA) is a modified version of the SGA that has been widely used for nutritional screening in cancer
patients [138].
Adherence to dietary interventions
The terms compliance and adherence have been used interchangeably in the
health care literature. Compliance is the extent to which the patient’s behaviour7 coincides with clinical prescriptions [139]. Adherence, on the other
hand, has been defined as the active, voluntary and collaborative involve7
In terms of executing lifestyle changes (taking medications, following diet, etc.)
22
ment of the patient in a mutually acceptable course of behaviour that results
in a desired preventative or therapeutic outcome [140]. The core elements of
compliance and adherence thereby differ, by implying a power relationship8
versus a partnership between the healthcare professional and the patient
[141].
Interventions targeting lifestyle changes often result in impressive rates of
initial behaviour change, but frequently are not converted into long-term
maintenance [142]. Several factors influence a person’s ability to adopt and
maintain a new dietary behaviour. Physiological factors such as the individual’s consideration of the anticipated benefits and his perceived satisfaction
with the outcomes associated with the new behaviour pattern affect adherence [143, 144]. Other factors that may influence adherence include age, sex,
comorbidity, somatic factors related to side effects, self-efficacy, social support and of course, the knowledge levels and skills of the individual. Although older adults generally have better adherence, some may have barriers
that negatively influence adherence, such as poor health and living alone
[144]. Issues unique to dietary adherence, in contrast to adherence to physical activity or medication regimens, include decision-making regarding food
choices, the acquired social and cultural meaning of food, the individual’s
perceptions and preferences regarding food, and environmental barriers such
as costs and availability [145].The most efficacious and effective cognitivebehavioural strategies for implementing dietary interventions among adult
individuals include goal setting, feedback, self-monitoring, long-term follow-up and support, motivational interviewing and self-efficacy [144].
Dietary assessment
Measuring dietary intake is complex, but use of an appropriate measurement
tool will enhance the likelihood of accurate detection of any change in intake. The dietary assessment methods used to measure food consumption can
either be retrospective (i.e., remembered or recalled) or prospective (i.e.,
recorded concurrently) [146]. The available retrospective methods include
dietary recall, food frequency questionnaires (FFQ) and dietary histories,
whereas the prospective methods include weighed or estimated food diaries
and dietary checklists. Three dietary assessment methods were used in this
thesis, and the incorporation of dietary assessment was twofold. First, it is
essential to estimate changes in dietary intake when evaluating dietary interventions. Second, evaluation of dietary intake pre-treatment in men recently
diagnosed with prostate cancer provides valuable information on the nutritional adequacy, with respect to food items and nutrients, in this patient category.
8
An imbalance of power, whereby the provider of care exerts power over the recipient.
23
Food frequency questionnaires
A FFQ is a quantitative assessment of habitual diet, where the respondent
reports the frequency of consumption of food items or specific food groups
over a defined period of time. The number of food items in the FFQ may
vary widely, depending on the purpose of a study [147]. The frequency of
food consumption is assessed using a multiple response grid, usually containing 5-9 categories ranging from ‘rarely or never’ up to ‘≥6 per day’
[148]. Frequency categories should always be continuous, with no gaps, to
facilitate the answering. The FFQ can be self-administered (reported via
paper-format questionnaires or via the Internet) or interviewer administered
(face-to-face or telephone) [147]. Because FFQs are often designed to assess
the ranking of intakes within a population, they cannot be relied on to produce reliable estimates of absolute intake. Measurement error using FFQs is
likely to be greater than that with other dietary assessment methods, and
over-estimation is common [149, 150].
Estimated food diary
An estimated food diary provides detailed data on food and nutrient intakes.
Individuals record details of foods and beverages consumed, including brand
names, cooking and preparation methods. Portion sizes should be estimated,
and photographs, household measures or natural unit sizes (e.g., slices of
bread) are commonly used for this [151]. Foods can also be weighed and
recorded if an individual chooses, but the main purpose of using this method
is to avoid the burden of weighing foods. Traditionally, the food diary is in
paper format, but the electronically recorded food diary is a viable alternative.
Dietary recall
A 24-hour dietary recall (24-HDR) is an interview in which an individual is
asked to recall his/her food and beverage consumption during the previous
day or the preceding 24 hours. The 24-HDR is traditionally structured in
chronological order, usually with probing questions to help the respondent
remember all foods consumed. Recently, a multiple-pass method for dietary
recall has gained recognition, as it minimizes the problem of underreporting
of energy intake [152]. The multiple-pass method includes 3 to 5 steps, beginning with a free and uninterrupted recall of intake, followed by detailed
and probing questions about intake (including quantities consumed) and
concluding with a review of everything that was previously recalled, allowing for the addition of any items not remembered up to this point.
24
Rationale for this thesis
The idea for this thesis originated from physician-based clinical experience
over the past two decades, and the planning and design of the studies were
developed during a time when the occurrence of clinically relevant gastrointestinal symptoms following prostate radiotherapy was more pronounced.
The twofold concepts of A) physician-based advice on dietary modification
to reduce gastrointestinal side effects in prostate cancer patients and B) assessment of patient-perceived changes in radiation-induced symptoms have
shown potential for uses in clinical practice. These concepts were further
elaborated and resulted in the present thesis.
Curative radiotherapy in localized prostate cancer is associated with gastrointestinal side effects that may have acute and long-term consequences for
the patient’s HRQOL. Thus, finding ways to decrease clinically relevant
symptoms in this growing patient category is crucial to improving outcomes,
including decreased acute and long-term symptoms, improved HRQOL, and
decreased healthcare costs. Making changes in the diet is an evident method
to reduce undesirable gastrointestinal side effects during pelvic radiotherapy.
In addition, nutritional interventions to improve the acute inflammatory process could potentially protect against persistent gastrointestinal problems,
given the consequential component of late symptoms. However, there is a
lack of high-quality randomized controlled dietary intervention trials to improve gastrointestinal symptoms following pelvic radiotherapy. Previous
research has indicated positive effects from dietary modification of dietary
fibre and lactose, but such interventions have rarely been evaluated in a controlled manner or in long-term follow-ups.
Better knowledge of treatment outcomes is important to both patients and
clinicians. Also, assessment of change in patient-reported outcomes is important when evaluating interventions. There are several prostate cancer
PROMs available, but there is currently no consensus as to the best instrument or method for evaluating score change. A questionnaire that could
measure the patient’s perception of change in gastrointestinal symptoms
could prove to be a convenient method of assessing the current status of
symptoms and a change for the worse regarding radiation side effects.
25
Aims
The overall objective of this thesis was to expand the knowledge on dietary
intake and its effect on gastrointestinal side effects in patients with localized
prostate cancer treated with radiotherapy. The specific aims of Paper I-IV
were as follows:
26
I
To evaluate current dietary intake prior to radiotherapy in a cohort of Swedish men recently diagnosed with prostate cancer.
II
To report on the development and validation of the Gastrointestinal Side Effects Questionnaire (GISEQ), a questionnaire on
patient-reported gastrointestinal side effects from prostate radiotherapy.
III
To study the effects of a dietary intervention on acute gastrointestinal side effects and other domains of HRQOL in prostate
cancer patients treated with radiotherapy.
IV
To report the long-term effects of a dietary intervention on gastrointestinal symptoms and other domains of HRQOL up to 2
years after prostate cancer radiotherapy
Methods
This thesis is based on four studies within the scope of a longitudinal randomized controlled trial (RCT), the focus of which was on exploring a dietary intervention for the prevention and management of gastrointestinal side
effects of prostate cancer radiotherapy.
Participants
Inclusion of participants in the dietary intervention RCT continued for two
years, from January 2006 until January 2008. During this period, all patients
recently diagnosed with localized prostate cancer at the Department of Oncology at Uppsala University Hospital were assessed for eligibility. Patients
referred to local curative radiotherapy with EBRT, in combination with either high-dose-rate brachytherapy or proton therapy, were invited to participate in the study. The exclusion criteria were previous radiotherapy to the
pelvic/bowel area, diagnosis of inflammatory bowel disease, cognitive function impairment, long-term hospitalization and inability to speak or understand Swedish. A total of 130 patients agreed to participate (Figure 2). Four
patients dropped out before the baseline assessment, and three patients
dropped out within the 26-month study period. The final assessment was
completed by 102 patients (78%). Retrospectively, 58 patients were identified as possible participants, but were missed for eligibility assessment during the inclusion process due to administrative failure. This was due to highly varying time periods between the decision to treat and onset of radiotherapy, which hampered the screening of eligible patients.
27
282 subjects
possible during the
inclusion period
58 not approached due to
administrative failure
224 assessed for
eligibility
82 did not meet inclusion
criteria
142 eligible and
approached
12 declined participation
130 enrolled and
randomized
STANDARD CARE
INTERVENTION GROUP
66 assigned to standard care
1 excluded before T0 (ineligible)
2 withdrew before T0
64 assigned to intervention
2 withdrew before T0
63 received standard care
and completed T0 evaluation
T0
Baseline
62 received intervention
and completed T0 evaluation
58 completed follow-up
5 lost to follow-up
T1
4 weeks
61 completed follow-up
1 withdrew
60 completed follow-up
3 lost to follow-up
T2
8 weeks
51 completed follow-up
10 lost to follow-up
58 completed follow-up
4 lost to follow-up, 1 withdrew
T3
2 months post RT
55 completed follow-up
6 lost to follow-up
36 completed follow-up
3 lost to follow-up, 1 deceased
22 not approached a
T4
7 months post RT
35 completed follow-up
5 lost to follow-up
21 not approached a
55 completed follow-up
6 lost to follow-up
T5
12 months post-RT
51 completed follow-up
7 lost to follow-up, 2 deceased
1 withdrew
50 completed follow-up
10 lost to follow-up, 1 deceased
T6
18 months post-RT
53 completed follow-up
5 lost to follow-up
50 completed follow-up
9 lost to follow-up, 1 deceased
T7
24 months post-RT
52 completed follow-up
5 lost to follow-up, 1 deceased
Figure 2. Flow chart
a) 43 patients had already passed the time point at 7 months post-RT when the long-term
assessment was made possible.
‘Lost to follow-up’ indicates the number of patients who failed to complete the specific assessment but who did not withdraw.
Abbreviation: RT, radiotherapy.
28
Radiotherapy treatment
All patients were treated with EBRT, in combination with either high-doserate brachytherapy (n=80) or proton therapy (n=50). The clinical target volume was confined to the prostate gland, including the seminal vesicles for
T3 tumours and excluding pelvic nodes. The overall treatment time for both
techniques was seven weeks. EBRT was administered as 2 Gy fractions daily to a total dose of 50 Gy. Brachytherapy was given as two 10 Gy fractions
separated by a fortnight’s pause half-way in the EBRT [153, 154]. Proton
therapy was given as a perineal boost as four daily 5 Gy fractions, followed
by a one-week pause and then EBRT as detailed above [155]. The total dose
prescribed to the prostate was 70 Gy according to ICRU 50 and ICRU 63 for
both treatment modalities. The dose restriction to the anterior wall of the
rectum was at maximum 70 Gy in 2 Gy fractions and α/β=3. The biologically effective dose (ED2) is 102 Gy of the EBRT-Brachytherapy technique and
87 Gy of the EBRT-Proton therapy technique in 2 Gy fractions and α/β=3
[154, 155].
Randomization
Patients stratified by radiation technique (brachytherapy or proton therapy)
were randomized to receive either standard care plus the dietary intervention
(intervention group; IG, n=64) or standard care alone (standard care group;
SCG, n=66). Randomization was performed by personnel unrelated to the
study, using Efron’s biased coin design [156]. This design procedure promotes a balance between two treatment groups in a sequential trial. All patients were told which group they had been randomized to after completion
of the baseline assessment.
Dietary intervention
The dietary intervention was designed to modify intake of dietary fibre and
lactose, through the restriction of foods high in insoluble dietary fibre and
lactose, and replacement with foods with a higher proportion of soluble fibre
and low in lactose during the entire study period. Dietary counselling was
provided to patients in the IG by a registered dietitian, in two face-to-face
individual-based sessions (at baseline and at 4 weeks after radiotherapy onset), and in one telephone session (at 8 weeks after radiotherapy onset). In
addition, all IG patients received a study-specific pamphlet with the dietary
advice at all time points except for the final assessment. The face-to-face
sessions were carried out in conjunction with the patient’s regular visits to
the Department of Oncology. The total time for the sessions was about 45-60
minutes at baseline and 30-45 minutes at follow-ups, with the main focus on
29
the intervention but also including assessments and data collection. If they
wanted to, patients were welcome to bring their wife/partner along to sessions.
Dietary counselling sought to encourage the patient to modify his dietary
habits to improve food intake in line with the intervention. Strategies for
promoting dietary modification included individual-oriented sessions, feedback on dietary assessments and adherence, and planned follow-up contacts
[144]. The research dietitian provided the IG patients with standardized dietary intervention instructions, with distinctions made between recommended
and restricted foods, based on their content and type of dietary fibres and
lactose and recommendations used in previous reports [157, 158]. In sessions and in the brochure, common food groups and food items were categorized and communicated as either recommended food (ad libitum intake) or
food intake to be avoided (preferably restricted intake) (Table 3). In addition,
patients were shown pictures and names of lactose-free or lactose-reduced
brands to facilitate such purchases. The intervention was pragmatic in nature
in that the dietary instructions were delivered as ‘advice’ and ‘recommendations’. However, the individualized counselling allowed personalization of
the dietary instructions to the individual’s particular health and life context,
based on the preceding dietary assessments (Table 4).
Patients in the IG completed a 4-day estimated food diary in their homes,
prior to the first two follow-up sessions (at 4 weeks and 8 weeks following
radiotherapy onset). The food diaries were used during the sessions as a basis for reinforcement of dietary advice and provision of feedback. Patients
were given detailed written and oral explanations of how to carry out the
dietary recording by the research dietitian at the preceding clinic visit. The
amounts of all food and beverages consumed were recorded in household
measures and natural unit sizes. For additional serving size estimations, patients received a copy of the Meal Model (Swedish: ‘Matmallen’), a booklet
with portion size photographs developed by the Swedish National Food
Agency [159]. Respondents were asked to provide brand names, preparation
and cooking methods, and to record the time and location of all eating occasions. Upon return of the food diary, the research dietitian interviewed the
patient to clarify any omissions and collected additional information if required, such as the cooking methods used and the portion sizes if these were
unclear.
30
Table 3. Some examples of the standardized instructions of the dietary intervention.
Food group
Examples of foods
recommended
Examples of foods
to avoid
Bread and biscuits
White bread and light rye bread Bread containing whole-grain
flours, bran or seed
Grains and cereals
Cooked, refined and prepared
cereals
Whole-grain cereals
Rice and pasta
White pasta or rice
Whole-grain pasta and wild rice
Fruits and berries
Fruit juice, canned or tender
fruit
Prune juice, fruit with tough
skins
Roots and vegetables
Canned or cooked, tender
vegetables
Raw vegetables with tough
seeds or skins
Leguminous plants
Not recommended
All leguminous plants
Nuts and seeds
Not recommended
All nuts and seeds
Dairy products
Lactose-free or lactose-reduced High-lactose foods
foods
Standard care
Standard practice in the routine clinical care of prostate cancer patients at the
Department of Oncology does not include dietary counselling. Consequently, at the end of the baseline assessment, all SCG patients were recommended to continue their habitual diet. Patients in the SCG were free and able to
receive conventional dietary counselling from a clinical dietitian when needed (e.g., prescription of nutritional drinks, etc.), through initiation by the
responsible physician or by the patient himself.
Data collection procedure
Data were collected at eight time points during the total period of 26 months
(Figure 2): at baseline (in the week prior to radiotherapy and before randomization), at 4 weeks following radiotherapy onset (in the middle of the treatment period), at 8 weeks following radiotherapy onset (one week after radiotherapy completion), and also at 2, 7, 12, 18 and 24 months after radiotherapy completion (hereafter referred to as ‘post-radiotherapy’). A summary of
the data collection procedure is presented in Table 4. Increased funding after
study commencement entailed the possibility to extend the study duration up
to 2 years after radiotherapy completion. Hence, nine months into the study,
it was decided to include long-term data collection. At that time, 43 patients
had already passed the 7 months post-radiotherapy assessment. A small
31
sample size implies a potential risk of reduced statistical power, and thus the
7 months post-radiotherapy assessment point was not included in the longterm reports (Paper IV and the current thesis).
All patient-reported data were collected as self-administered paper-format
questionnaires. Questionnaires were sent with pre-paid return envelopes, and
a single reminder was sent if patients had not answered within two weeks.
Patients’ demographics and baseline clinical characteristics were collected
from the medical records, and included data on age, common clinical features of prostate cancer and marital status.
Primary outcome
Gastrointestinal symptoms
Gastrointestinal status was measured at all assessment points, using multiple
patient-reported questionnaires. The EORTC QLQ-C30 (version 3.0) and the
prostate-specific module QLQ-PR25 [103, 115, 160] were developed to assess HRQOL in cancer patients and both include questions on bowel symptoms (six single items and one aggregated scale in total). In the present trial,
the prevalence of constipation and diarrhoea was assessed by the QLQ-C30,
whereas the QLQ-PR25 assessed blood in stools, bloated abdomen, limitations on daily activities, unintentional leakage of stools and general bowel
symptoms. Hence, bowel symptoms from the QLQ-PR25 were reported at
both the individual item level and the aggregate level, according to previous
recommendations [115]. Patients were asked to report symptoms during the
past week on a 4-point Likert-type response scale (1, “Not at all”; 2 “A little”; 3 “Quite a bit”; and 4, “Very much”). In accordance with the EORTC
guidelines, the subscale and individual item responses were transformed into
a 0-100 scale, where a higher score represents a higher (”worse”) level of
symptoms [161].
32
a
X
X
BMI
X
X
X
X
X
X
X
IG
X
X
X
X
X
SCG
X
X
X
X
X
X
IG
4 weeks
X
X
X
X
X
SCG
X
X
X
X
X
X
IG
8 weeks
X
X
X
X
X
SCG
X
X
X
X
X
IG
2 months
post-RT
X
X
X
X
X
SCG
X
X
X
X
X
IG
X
X
X
X
X
X
SCG
X
X
X
X
X
X
IG
X
X
X
X
X
SCG
X
X
X
X
X
IG
X
X
X
X
X
X
X
SCG
X
X
X
X
X
X
X
IG
7 months 12 months 18 months 24 months
post-RT
post-RT
post-RT
post-RT
a) GISEQ-PR was collected at the baseline assessment, and GISEQ was collected at all follow-up assessments.
Abbreviations: AID, bother due to the use of incontinence aid; AP, appetite loss; BA, bloated abdomen; BMI, body mass index; BOW, bowel symptoms; BS, blood in stools;
CF, cognitive functioning; CO, constipation; DI, diarrhoea; DY, dyspnoea; EF, emotional functioning; FA, fatigue; FFQ, Food Frequency Questionnaire; FI, financial difficulties;
GI, gastrointestinal; HRQOL, health-related quality of life; HTR, hormonal treatment-related symptoms; LDA, limitations on daily activities; NV, nausea and vomiting; PA,
pain; PF, physical functioning; PG-SGA, Patient-Generated Subjective Global Assessment; QL, global health status; RF, role functioning; RT, radiotherapy; SAC, sexual activity;
SF, social functioning; SFU, sexual functioning; SL, insomnia; UL, unintentional leakage of stools; URI, urinary symptoms.
X
X
X
X
X
Nutritional status assessment
Scored PG-SGA
61
28 + 21
8
2+4
SCG
24-hour dietary recall
Food Diary (4-day, estimated )
Dietary assessment
FFQ (Dietary fibre and lactose consumption )
Scales: QL, PF, RF, EF, CF, SF, FA, NV, PA, DY,
SL, AP, FI, URI, AID, HTR, SAC, SFU
Secondary outcome: General HRQOL
EORTC QLQ-C30 and QLQ-PR25
GISEQ-PR and GISEQ
Scales: CO, DI, LDA, UL, BS, BA, BOW
Primary outcome: GI symptoms
EORTC QLQ-C30 and QLQ-PR25
Items
Baseline
Table 4. Data collection procedure in the Standard care group (SCG) and the Intervention group (IG).
Two different patient-reported questionnaires on gastrointestinal side effects
were developed and validated within the scope of the present RCT. The Gastrointestinal Side Effects Questionnaire Pre-Radiotherapy (GISEQ-PR) assessed pre-treatment gastrointestinal bother from diarrhoea, constipation,
blood in stools, mucus discharge, intestinal cramps, intestinal pain, intestinal
gas and flatulence. In GISEQ-PR, questions read “To what extent have you
been bothered by … during the past week?”. Answers were scored on a numerical rating scale anchored from 0 (“Not at all”) to 10 (“To a very large
extent”). At all follow-up assessments, the study-specific Gastrointestinal
Side Effects Questionnaire (GISEQ) assessed side effects of diarrhoea, constipation, blood in stools, mucus discharge, intestinal cramps, intestinal pain,
intestinal gas and flatulence. In GISEQ, questions read “To what extent have
you been bothered by … during the past week, compared to before radiotherapy?” Answers were scored on a numerical rating scale anchored from 0
(“To the same or a lesser extent”) to 10 (“To a much larger extent“).
Through the wording of this retrospective question, the GISEQ aimed at
measuring radiation-induced gastrointestinal symptoms by assessing patientperceived change in gastrointestinal status compared to pre-treatment conditions. The reason for choosing this approach was that asking patients to rate
their current gastrointestinal symptoms in comparison with their current
perspective on pre-treatment status results in a straightforward indication of
radiation-induced side effects.
Secondary outcome
Other domains of health-related quality of life
The QLQ-C30 and QLQ-PR25 were used to assess general HRQOL (i.e.,
global health status, functional capacity and other symptoms besides gastrointestinal symptoms). Thus, the QLQ-C30 rendered data for global health
status, five functional scales (physical, role, emotional, cognitive and social),
three symptom scales (fatigue, pain, nausea or vomiting) and four single
items (dyspnoea, insomnia, loss of appetite and financial impact of the disease). Additionally, the QLQ-PR25 rendered data for four domains assessing
urinary symptoms (eight items plus one item evaluating bother due to the use
of incontinence aids), hormonal treatment-related symptoms (six items),
sexual activity (two items) and sexual functioning (four items). All items
were scored on the 4-point scale detailed above, with the exception of the 7point global quality of life scale (1 ‘very poor’ to 7 ‘excellent’). All scores
were transformed to a 0-100 scale, with higher scores reflecting better quality of life, higher levels of functioning or more symptoms [161].
34
Dietary assessments
Food Frequency Questionnaire
A study-specific FFQ was developed within the scope of this RCT, and its
design regarding the multiple response grid and frequency categories was
influenced by a similar FFQ in a previous report [162]. The FFQ was completed by both groups at all assessments. The FFQ consisted of 61 specific
foods chosen for the explicit purpose of assessing dietary fibre (n= 46) and
lactose (n=15) intake. Patients indicated their average frequency of consumption during the past month on an eight-level ordinal scale (‘never/less
than once a month’ to ‘≥3 times/day’) and their subjective assessment of
portion size (small, medium, large). The evaluation of the FFQ focused primarily on the frequency of consumption, and so the data on portion sizes
were not used in further analyses. Food items were ordered in terms of broad
food groups, rather than by meal. Three additional questions concerned use
of lactose-free or lactose-reduced dairy products, as the FFQ dairy food
items did not differentiate between ordinary and lactose-free/-reduced products.
24-hour dietary recall
The main objective of the single 24-HDR conducted at baseline was to determine whether the IG and the SCG differed in dietary intake prior to randomization. Furthermore, it was used to evaluate current dietary intake and
nutritional adequacy in the whole patient sample, in order to gain insight into
the potential of dietary changes following the intervention. The 24-HDR was
based on the multiple-pass approach [152], where the patient’s free and uninterrupted recall of intake was followed by detailed and probing questions
about intake and concluded with a recall review. The baseline 24-HDR was
administered as a face-to-face interview by a research dietitian. The interview concerned the patient’s consumption of food and beverages during the
previous day, and patients also reported any use of dietary supplements or
other forms of complementary and alternative medicine [163].
Nutritional status assessments
Cancer patients may present with malnutrition or develop poor nutritional
status during the course of treatment. Initial nutritional status assessment
should be performed early, and assessment should be repeated regularly in
order to evaluate the evolution of nutritional status over time [131].
The scored Patient-Generated Subjective Global Assessment
The PG-SGA is developed specifically for cancer patients and incorporates
medical history and physical examination [138, 164]. The scored PG-SGA
incorporates a numerical score and provides a global rating of nutritional
35
status (well-nourished, moderately or suspected of being malnourished, or
severely malnourished) [165-167]. Higher scores indicate poorer status, and
a score ≥9 indicates a need for urgent nutritional management. The first section contains four patient-reported components of medical history (weight
loss history, changes in food intake, nutritional impact symptoms and functional capacity). The second section includes a physical examination performed by a healthcare professional (a subjective evaluation of body composition focused on fat, muscle and fluid status). In the present study, the
scored PG-SGA was completed in its entirety at the baseline assessment and
the examination was performed by the research dietitian. Additionally, all
patients completed the first section of the PG-SGA at 12 and 24 months
post-radiotherapy.
Body mass index
BMI was calculated as weight/height2 (kg/m2) at all assessments. The research dietitian recorded the patients’ weight at the baseline clinic visit, using a digital scale. All patients were weighed in light clothing; coats, jackets
and shoes were removed. Patients’ self-reported height was collected
through the scored PG-SGA, as detailed above, and self-reported weight was
collected at all follow-up assessments. Patients were classified according to
the criteria defined by the WHO, underweight if BMI was <18.5 kg/m2,
normal weight if BMI was 18.5-24.9 kg/m2, overweight if BMI was 25.029.9 kg/m2, and obese if BMI was ≥30 kg/m2 [168].
Power
Previous research with prostate cancer patients using EORTC QLQ-PR25
reported a mean value of 5.4 for bowel symptoms and a standard deviation
of 9.4 three months after treatment onset [115]. In the present study, all
power calculations were undertaken using a power of 80% with a 0.05 twotailed significance level. In QLQ-PR25, a sample size of 49 patients in each
group was required to detect a difference of 5 for the mean bowel symptom
score using analysis of variance (ANOVA) with repeated measures. Hence,
the power analysis was based on mean bowel symptom score differences
from previous research, assuming normally distributed data – an assumption
that turned out to be incorrect, as detailed below.
36
Data preparation and statistical analysis
General preparations
In the EORTC questionnaires, missing item data were treated according to
the recommendations given in the scoring manual. Accordingly, missing
values on scales were substituted with the mean of the patient's responses,
provided that at least half of the subscale items had been completed (essentially assuming that the patient’s score for the missing items would equal the
average of his scores for other items on the same scale) [161]. The assumption of a normal distribution was not fulfilled, as a substantial proportion of
patients reported the lowest possible score on symptoms and side effects in
the QLQ-C30, QLQ-PR25 and GISEQ over the study period. Hence, to
achieve a sufficient number of events for statistical analyses in Paper II-IV,
all EORTC and GISEQ scores were dichotomized according to the following
thresholds for having ‘a little’ up to ‘very much’ problems. In the EORTC
questionnaires, patients were defined as having problems if a symptom scale
score was 1-100, or a functioning scale score or the global health status score
was 0-99. In GISEQ, patients were defined as having problems if a scale
score was 1-10. Patients were defined as having no problems if a EORTC or
GISEQ symptom score was 0, or a EORTC functioning scale score or the
global health status score was 100.
The 24-HDRs and the food diaries were calculated using the commercial
dietary calculation software DIETIST XP for Windows, version 3.2 (Kost
och näringsdata AB, Bromma, Sweden), based on the official Swedish Food
Composition Database that includes about 2000 food items [169]. The food
composition database takes into account average nutrient loss during food
preparation. The DIETIST XP calculates total dietary fibre in foods, without
distinguishing the content of soluble and insoluble dietary fibres.
Paper I
Paper I evaluated current dietary intake prior to radiotherapy onset, thereby
giving insights about the patients’ prerequisites for the dietary intervention.
The evaluation was based on the single 24-HDRs conducted at baseline (before randomization). The estimated basal metabolic rate (BMRest) was calculated for each individual using equations from the report of a joint Food and
Agriculture Organization of the United Nation/ the World Health Organization/ the United Nations University (FAO/WHO/UNU) expert consultation
[170]. An internal validation of unrealistically high or low reported energy
intake was conducted in the 24-HDRs (n=125), using the Goldberg cut-off
method, wherein participants with food intake levels (i.e., ratio of reported
energy intake over BMRest) ≤0.90 or ≥2.82 were classified as under-reporters
37
or over-reporters, respectively [171, 172]. Sixteen (13%) patients were classified as under-reporters, but there were no over-reporters. Out of 125 participants, 109 (87%) were classified as acceptable energy-reporters and extracted for further analyses. Food intake was categorized in major food groups
according to the Swedish Food Composition Database [173]. The consumption prevalences for the 12 selected food groups were evaluated using foodbased guidelines of the 4th edition of the Nordic Nutrition Recommendations
(NNR 2004) [174]. Daily median nutrient intake was estimated for energy,
macronutrients, micronutrients and alcohol. The adequacy of macronutrient
and micronutrient intake was evaluated using the applicable dietary reference values (DRV) of the NNR 2004 [174], and the Estimated Average Requirement (EAR) cut-point method [175], respectively (see Paper I). In micronutrients without established average requirement (AR) (vitamin D, calcium and potassium), the lower intake level (LI) was used instead [174].
Estimates of usual micronutrient intake were calculated by the Iowa State
University method [176, 177].
Paper II
Evaluation of the GISEQ included, e.g., validity, responsiveness, reliability,
sensitivity and specificity. Response rates, missing items and floor/ceiling
effects were also evaluated. The evaluation in Paper II comprised GISEQ
data collected from 4 weeks after radiotherapy onset up to 2 months postradiotherapy, where variations of side effects over time correlating with the
effects of radiation were expected. It was considered feasible to combine the
data collection from the IG and the SCG into a larger patient sample (n=111119) in the analysis in Paper II, because no statistically significant betweengroup differences regarding acute gastrointestinal symptoms were observed
in Paper III. The QLQ-C30 and the QLQ-PR25 were chosen as the comparator measures, and three EORTC single items were considered to match GISEQ items (constipation, diarrhoea and blood in stools). The absolute scores
of 1-4 of these items were transformed into conventional change scores (follow-up scores minus baseline scores) in order to resemble the relative follow-up scores reported in the GISEQ. The cut-off value for positive moderate correlation was set at the statistically significant correlation coefficient
rho>0.41 when assessing concurrent validity [178]. The GISEQ’s responsiveness of increased bother between the assessments was analysed with
McNemar’s test regarding differences in prevalence, and the Wilcoxon
Rank-Sum test regarding differences in score changes. Internal consistency
of the GISEQ items was estimated using Cronbach's alpha, where a level of
0.70 or higher was considered desirable [179].
38
Paper III-IV
Paper III reported the first part of the longitudinal RCT, and included data
collected from baseline up to 2 months post-radiotherapy from patients in the
SCG (n=58-63) and the IG (n=51-62). Paper IV reported the second and last
part of the longitudinal RCT, and included data from baseline and 12 to
24 months post-radiotherapy in the SCG (n=50-55) and the IG (n=51-53).
EORTC and GISEQ data were used to evaluate the effect of the intervention
on gastrointestinal symptoms and HRQOL. Statistical analyses focused on
the primary outcome variables (gastrointestinal symptoms), while other
HRQOL domains were checked in an exploratory manner only. Because
assumptions of normal distribution, equal variances, and independence between variables were not fulfilled, generalized estimating equations (GEE)
were used to evaluate the effect of the intervention on acute (Paper III) and
long-term (Paper IV) gastrointestinal symptoms. The GEE models were adjusted for covariates (please see Paper III and IV). The effect of the dietary
intervention on persistent blood in stools from QLQ-PR25 could not be estimated because there were too few events. Frequencies of patients with
problems were calculated, and descriptive data on EORTC and GISEQ
scores were presented as median (minimum-maximum) values only for those
patients with problems. Note that for all EORTC single-symptom items, a
scale score of 0 was equivalent to ‘not at all’, 33 to ‘a little’, 67 ‘quite a bit’,
and 100 ‘very much’. In Paper IV, frequencies and descriptive EORTC data
on patients with clinically relevant late gastrointestinal symptoms were presented, where clinically relevant symptoms were defined as a single item
scale score ≥67 (‘quite a bit’ to ‘very much’ symptomatic), in accordance
with previous research [107, 108, 180]. The relationships between pretreatment and persistent gastrointestinal symptoms were further explored
descriptively.
The median frequency of intake (times/day) of food groups high or low in
dietary fibre and lactose was calculated for the SCG and the IG at each assessment time point9, based on FFQ data from baseline up to 24 months
post-radiotherapy (Paper IV). Food items were grouped into grain products,
vegetables and dairy products, and therein categorized as ‘high’ or ‘low’
based on their content of dietary fibres and lactose in relation to the dietary
advice of the intervention [157, 158]. The 28 most frequently consumed food
items were clustered as high-fibre grain products (n=2; wholemeal bread and
rye crisp bread), low-fibre grain products (n=8; oatmeal cereals, rolled oats,
white bread, wheat crisp bread and bread from sifted rye flour), high-fibre
vegetables (n=6; leguminous plants and raw roots, vegetables, fruits and
9
The FFQ data management differed between Paper III and Paper IV. Please see Paper III for
further information.
39
berries with tough skins), low-fibre vegetables (n=6; cooked or canned
fruits, vegetables, roots and potatoes), high-lactose dairy products (n=4;
liquid milk, soured milk, yoghurt, ice cream) and low-lactose dairy products
(n=2; cream and crème fraiche). Short-term and long-term dietary adherence
were evaluated using the GEE method to model the intake frequency of food
groups as a function of time from baseline up to 2 months post-radiotherapy,
and from baseline and 12 months to 24 months post-radiotherapy, respectively.
Further explorations
Paper IV reported descriptive data on clinically relevant persistent gastrointestinal symptoms (at least ‘quite a bit’, i.e. a score ≥67) from the EORTC
data. Using the same definition, data on clinically relevant pre-treatment and
acute gastrointestinal symptoms were reported for the first four assessment
time points (baseline up to 2 months post-radiotherapy) to complement the
results in Paper III. In addition, the association between pre-treatment gastrointestinal symptoms and acute gastrointestinal toxicity was further explored descriptively. The question of whether patients with and without
baseline symptoms (defined as score ≥33 on at least one of the six single
EORTC items versus scale <33 on all six items) differed regarding acute
toxicity (defined as symptom scale ≥67 on at least one of the six single
items) was investigated.
The revelation that the vast majority of patients were either entirely free of
gastrointestinal symptoms or experiencing only mild acute and persistent
symptoms, together with the lack of intervention effect on these symptoms
changed the preparation and presentation of the data on other domains of
HRQOL. Statistical analyses in Paper III-IV focused on gastrointestinal
symptom variables in the EORTC and GISEQ questionnaires, and other
domains of HRQOL were checked in an exploratory manner only and merely reported as descriptive data. In order to provide further information in this
thesis on HRQOL, results from the EORTC questionnaires collected at baseline, 8 weeks, and 24 months post-radiotherapy were presented as mean (SD)
values.
In order to complement the evaluation of dietary adherence based on FFQ
data in Paper IV, further exploration of data from the food diaries was conducted. Daily median intake was estimated for energy, macronutrients, micronutrients, dietary fibres and alcohol in IG patients at 4 weeks and 8 weeks
following radiotherapy onset. Moreover, the paired t-test was used to test for
statistically significant differences between intake of dietary fibre at baseline
as opposed to intake levels at 4 weeks and 8 weeks following radiotherapy
onset, respectively. Each individual’s dietary fibre intake changes in grams
were explored descriptively.
40
Long-term data on nutritional status were further examined to complement
reporting in Paper III and Paper IV. The PG-SGA scores and BMI values
were tested for normality with the Shapiro-Wilks test, revealing non-normal
distributions of PG-SGA scores. Consequently, descriptive data on PG-SGA
scores were presented as median (minimum-maximum) values and betweengroup differences were evaluated using the Friedman test. Data on BMI were
presented descriptively as mean (SD) values. The effect of time and randomization on BMI from baseline to 24 months post-radiotherapy was tested
using ANOVA with repeated measures.
Ethical considerations
The RCT was approved by the Regional Ethical Review Board in Uppsala
(Reg.no. 2005:274). Eligible patients received study information by their
oncologist or oncology nurse and through an information folder, including
information on the study purpose, procedure, duration, etc. Potential participants were assured that study participation was absolutely voluntary, that
they were free to discontinue participation at any time and that refusal to
participate or a decision to withdraw would not affect the standard of care.
Patients who consented to participate signed and received a copy of the informed consent form. A telephone number and contact address were provided to patients for any queries they might have during the study period.
Questions about HRQOL, disease-related events and dietary intake may be
perceived as distressing and may remind the patient of his disease in a negative way. However, our experience is that most patients do not mind accounting for their dietary habits, and previous studies have revealed that
measurement of HRQOL per se can have positive effects [181]. Patients in
the IG may also benefit from a dietary modification that could possibly reduce gastrointestinal side effects, and from the contact and support of the
dietitian including evaluation of and feedback on dietary intake at several
occasions. The 4-day food diary monitored the patient’s dietary intake to
ensure that the dietary modification did not give rise to an unbalanced diet.
Dietary counselling is not part of the routine clinical care of prostate cancer
patients at the Department of Oncology. When necessary, patients in SCG
were free and able to receive conventional dietary counselling, as detailed
above. Two patients included in SCG received counselling from a clinical
dietitian on their own initiative during the study period. Counselling was
given by phone and did not lead to any further appointments.
41
Results
Demographics and baseline clinical characteristics are presented in Table 5.
Median patient age was 66 years (range 50-77), 81% of patients were married/cohabitant and 19% were singles. The SCG and the IG were comparable
at baseline, as judged by clinical characteristics, dietary intake, gastrointestinal symptoms or general aspects of HRQOL. Patients were referred from 5
different county councils, within a distance of up to about 300 km from the
Uppsala University Hospital. Patients living a great distance from Uppsala
were offered the chance to commute by bus transport service or to stay at a
hotel for patients nearby the hospital during the weekdays.
Table 5. Demographics and baseline clinical characteristics
Parameter
Standard Care Group
Intervention Group
n=66
n=64
41
25
39
25
65 (54-76)
67 (50-77)
8.9 (0.7-100)
10 (3.0-60)
7 (5-8)
7 (5-9)
21
19
2
17
7
14
25
5
18
2
33
33
36
28
48
6
11
1
47
4
8
5
Treatment (n)
EBRT + Brachytherapy (n)
EBRT + Proton therapy (n)
Age (y)
Median (min-max)
PSA (ng/ml)
Median (min-max)
Gleason Score (min 2, max 10)
Median (min-max)
Clinical stage (n)
T1
T2
T2-T3
T3
Not available
Pre-irradiatory endocrine therapy (n)
Yes
No
Marital status (n)
Married
Cohabitant
Single/Divorcee
Widower
All parameters lack statistically significant differences between the SCG and the IG.
42
Dietary intake prior to radiotherapy onset – Paper I
The main food group sources of energy were ‘Grain or grain products’
(29%) and ‘Milk or milk products’ (15%). Median daily intake of bread was
100 g (Table 6), and the type of bread consumed was wholemeal bread
(47%), wholemeal crisp bread (14%) and non-wholemeal bread (39%). Median daily intake of milk was 200 g, which contains about 10 grams of lactose. Daily median total dietary fibre intake was 25 g (min-max: 6-46 g), and
the main dietary fibre source was cereal (47%), followed by vegetables including potatoes (26%), and fruits and berries (16%).
Table 6. Self-reported daily intake and consumption prevalence of selected food
groups in men with prostate cancer (n=109).
Median
Mean
Min-max
g
g
g
274
299
100
115
Fine bakery ware
20
Vegetable or veg prod
355
Grain or grain products
Bread
Potatoes
Consumption prevalence
%
n
0-816
99
108
0-360
99
108
42
0-321
54
59
340
0-1113
88
96
225
190
0-700
64
70
110
150
0-628
82
89
Fruits or fruit products
125
174
0-1000
76
83
Milk or milk products
335
400
0-2200
94
103
200
213
0-1500
68
74
Vegetables
Liquid milk
a
a) Vegetables: excluding potatoes.
Abbreviation: veg prod, vegetable products.
For the majority of patients, E% of carbohydrates and PUFA were lower
than the DRV and E% of fat and SFA was higher than the DRV (Table 7).
After statistical adjustments for usual micronutrient intake distribution, the
prevalence of inadequate usual intake was 22% for selenium and 3% for
vitamin C (adequate usual intake of all other examined micronutrients, see
Paper I).
43
Table 7. Self-reported daily intake of macronutrients, and the proportion and number of patients (n=109) with reported intakes below and above the applicable dietary reference values (DRV) of the Nordic Nutrition Recommendations (NNR 2004).
Median intake
Below DRV
Above DRV
NNR 2004
g
E%
%
n
%
n
DRV
Protein
91
15
1
1
8
9
10-20E%
Fat
88
35
10
11
50
54
25-35 E%
SFA
34
14
NA
NA
88
96
<10 E%
MUFA
32
13
18
20
20
22
10-15 E%
PUFA
11
4
51
56
2
2
5-10 E%
266
45
66
72
2
2
50-60 E%
25
2
48
52
15
16
Carbohydrates
Dietary fibre
25-35 per day
Abbreviations: E%, percentage of total energy intake; MUFA, monounsaturated fatty acids; NA, not
applicable; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids.
Validation of the GISEQ – Paper II
The GISEQ had high response rates (>85%) and low levels of missing items
(<0.8%). A clear ‘floor effect’ was revealed, whereby 28-98% versus 0-5%
of patients responded with the lowest versus the highest possible score on
any item. The expert panel considered the GISEQ to be satisfactory regarding face validity as well as content relevance and coverage. In the openended question on any other gastrointestinal problems, patients’ responses
included rectal pain and/or irritation, increased stool frequency, feeling of
having to pass stools when urinating, and problems of leakage and urgency.
Regarding concurrent validity, there was a positive moderate correlation
(rho >0.41, p<0.001) between items on diarrhoea, constipation and blood in
stool from the GISEQ and the comparative measures at all assessments, with
the exception of blood in stools at 8 weeks after radiotherapy onset.
Changes in prevalence and severity of side effects between follow-up assessments were evaluated as indicators of the GISEQ’s responsiveness.
There were no statistically significant changes in prevalence in any of the
eight items from 4 weeks to 8 weeks following radiotherapy onset, or from
8 weeks to 2 months post-radiotherapy, with the exception of abdominal
pain for which the prevalence was significantly lower at the final assessment
(30% versus 17%, p<0.02). Regarding the severity of side effects, item
scores were stable or higher for six out of eight items at 8 weeks following
radiotherapy onset compared to the assessment at 4 weeks. On the other
hand, item scores were stable or lower at 2 months post-radiotherapy, compared to 8 weeks after radiotherapy onset. These changes in distribution of
44
scores for patients with bother were statistically significant (p<0.03) between
8 weeks and 2 months post-radiotherapy for all items, but not between
4 weeks and 8 weeks following radiotherapy onset.
The overall Cronbach’s alpha was ≥0.73 at all three assessments. The sensitivity of the individual GISEQ items in determining ‘worsening symptoms’
was 79-92% for diarrhoea, 88-100% for constipation, and 50-100% for
blood in stools. The specificity was 68-71% for diarrhoea, 79-82% for constipation, and 92-100% for blood in stools.
Effects of the dietary intervention on acute and
persistent gastrointestinal symptoms – Paper III-IV
Gastrointestinal symptoms
There were no statistically significant differences between the groups regarding gastrointestinal symptoms, and acute and persistent gastrointestinal
symptoms were predominantly mild10 (Table 8 and Table 9). Consequently,
the prevalence of clinically relevant symptoms was relatively low (Table
10). Even in the SCG, at least 50-60% of patients were free of symptoms or
bother from diarrhoea both during and after radiotherapy. The most commonly reported symptoms over time were diarrhoea and problems of intestinal gas, including bloating and flatulence, as well as limitations on daily
activities due to gastrointestinal problems (Table 8 and Table 9). For all patients regardless of group assignment, the long-term prevalence of limitations on daily activities, unintentional leakage of stools and mucus discharge
was significantly higher compared to baseline (p≤0.006), indicating incomplete recovery for such problems (Table 8 and Table 9). Adjustment for radiation technique in the GEE models did not change the estimate between the
randomized groups.
At 4 weeks, 3% (n=2) of patients in the IG reported clinically relevant symptoms of bloated abdomen compared to 17% (n=10) in the SCG (Table 10).
At 8 weeks after radiotherapy onset, clinically relevant diarrhoea were less
prevalent in the IG (4%, n=2) compared with the SCG (12%, n=7). In addition, 9% (n=5) in the IG versus 20% (n=11) in the SCG reported any problems of unintentional stool leakage at 2 months post-radiotherapy (Table 8).
These numerical between-group differences revealed a non-significant trend
towards lower prevalence and severity of acute symptoms in the IG compared to the SCG.
10
Indicated by median EORTC and GISEQ scores in the lower range (see Paper III-IV).
45
25
32
33
SCG
IG
BOW
20
20
15
18
2
0
5
3
3
3
8
12
48
29
31
20
55
24
33
4
7
10
7
10
16
43
7
13
16
13
16
29
18
23
40
30
12
17
20
29
n
47
48
31
33
4
7
16
21
27
28
30
33
18
20
%
23
28
15
19
2
4
8
12
13
16
14
19
9
12
n
SCG: n=60, IG: n=51
8 weeks
53
45
44
30
2
2
9
20
20
20
26
28
13
7
%
29
25
24
17
1
1
5
11
11
11
14
16
7
4
n
SCG: n=58, IG: n=55
2 months
post-RT
43
44
24
16
14
7
22
14
20
24
39
31
18
16
%
22
24
12
9
7
4
11
8
10
13
20
17
9
9
n
SCG: n=55, IG: n=51
12 months
post-RT
57
48
43
30
23
10
21
16
24
26
36
30
13
20
%
30
24
23
15
12
5
11
8
13
13
19
15
7
10
n
SCG: n=50, IG: n=53
18 months
post-RT
44
42
29
24
21
8
21
14
21
24
35
16
19
16
%
23
21
15
12
11
4
11
7
11
12
18
8
10
8
n
SCG: n=50, IG: n=52
24 months
post-RT
a) Patients who reported a score above 0 on the 0–100 EORTC scale (i.e., a score ≥ 33 on the single symptom items or a score ≥8 on the bowel symptom scale).
Abbreviations: BA, bloated abdomen; BOW, bowel symptoms; BS, blood in stools; CO, constipation; DI, diarrhoea; IG, Intervention group; LDA, limitations on daily activities; RT, radiotherapy; SCG, Standard care group; UL, unintentional leakage of stools.
29
3
IG
IG
Symptom scale
0
SCG
5
8
SCG
5
IG
IG
5
SCG
19
13
SCG
IG
7
5
8
12
%
SCG: n=58, IG: n=61
n
%
SCG: n=63, IG: n=60
SCG
BA
BS
UL
LDA
DI
IG
Group
Symptom items
CO
SCG
4 weeks
Baseline
Table 8. The proportion and number of patients with at least ‘a little’ gastrointestinal symptoms a according to the EORTC QLQ-C30 and
QLQ-PR25.
Group
IG
SCG
56
64
SCG
IG
SCG
IG
Flatulence
39
35
34
35
5
9
6
7
4
3
5
1
10
%
n
43
41
67
43
74
70
39
18
67
23
30
10
15
40
16
26
21
34
4
22
38
7
9
17
28
16
22
24
41
29
36
50
69
75
67
75
22
37
14
27
41
40
10
10
24
32
44
45
%
35
45
34
45
11
22
7
16
21
24
5
6
12
19
22
27
n
SCG: n=60, IG: n=51
8 weeks
71
62
67
59
16
17
9
19
27
31
2
2
24
28
42
43
%
39
36
37
34
9
10
5
11
15
18
1
1
13
16
23
25
n
SCG: n=58, IG: n=55
2 months
post-RT
a) Patients who reported score 1-10 on the 0-10 scale.
Abbreviation: IG, Intervention group; post-RT, after radiotherapy completion; SCG, Standard care group.
56
56
8
14
10
11
gas
IG
cramps
Intestinal
SCG
Abdominal
7
SCG
IG
discharge
8
5
IG
SCG
Mucus
Abdominal
IG
stools
2
16
11
9
17
15
n
14
22
%
SCG: n=58, IG: n=61
SCG: n=63, IG: n=60
pain
SCG
Blood in
IG
Constipation SCG
Diarrhoea
4 weeks
Baseline
74
78
70
69
22
31
22
25
45
36
20
14
25
31
49
49
%
38
43
36
38
11
17
11
14
23
20
10
8
13
17
25
27
n
SCG: n=55, IG: n=51
12 months
post-RT
66
70
68
66
28
20
21
24
36
32
26
16
23
28
49
36
%
35
35
36
33
15
10
11
12
19
16
14
8
12
14
26
18
n
SCG: n=50, IG: n=53
18 months
post-RT
Table 9. The proportion and number of patients with gastrointestinal symptoms a according to the GISEQ-PR and GISEQ.
63
66
58
66
27
20
21
22
40
34
27
14
25
24
38
46
%
33
33
30
33
14
10
11
11
21
17
14
7
13
12
20
23
n
SCG: n=50, IG: n=52
24 months
post-RT
5
7
IG
0
IG
SCG
0
0
SCG
0
IG
0
SCG
0
IG
2
SCG
2
IG
0
IG
SCG
3
SCG
4
3
0
0
0
0
0
0
1
1
0
2
n
3
2
0
10
0
17
1
1
2
3
2
2
2
3
5
4
3
n
5
3
3
5
9
6
5
%
SCG: n=58, IG: n=61
%
SCG: n=63, IG: n=60
6
5
0
0
0
5
4
5
4
12
0
5
%
3
3
0
0
0
3
2
3
2
7
0
3
n
SCG: n=60, IG: n=51
8 weeks
7
5
0
0
2
2
4
3
5
5
2
2
%
4
3
0
0
1
1
2
2
3
3
1
1
n
SCG: n=58, IG: n=55
2 months
post-RT
12
5
4
0
6
0
8
0
8
5
4
0
%
6
3
2
0
3
0
4
0
4
3
2
0
n
SCG: n=55, IG: n=51
12 months
post-RT
11
6
4
2
6
0
6
2
9
4
4
2
%
6
3
2
1
3
0
3
1
5
2
2
1
n
SCG: n=50, IG: n=53
18 months
post-RT
6
4
4
2
8
2
4
6
6
2
6
8
%
3
2
2
1
4
1
2
3
3
1
3
4
n
SCG: n=50, IG: n=52
24 months
post-RT
a) Patients who reported a score ≥67 on the 0–100 EORTC scale. A scale score of 67 equals ‘quite a bit’, and 100 ‘very much’.
Abbreviations: BA, bloated abdomen; BS, blood in stools; CO, constipation; DI, diarrhoea; IG, Intervention group; LDA, limitations on daily activities; post-RT, after radiotherapy completion; SCG, Standard care group; UL, unintentional leakage of stools.
BA
BS
UL
LDA
DI
CO
Group
4 weeks
Baseline
Table 10. The proportion and number of patients with clinically relevant gastrointestinal symptoms a according to the EORTC QLQ-C30 and
QLQ-PR25.
Results from Paper IV pointed to an association between already having
gastrointestinal symptoms pre-treatment and having clinically relevant persistent symptoms. There were numerical differences between patients with
and without pre-existing symptoms, with regard to the long-term prevalence
levels of bloated abdomen (39-69% versus 10-23%) and limitations on daily
activities (36-42% versus 13-18%) from 12 to 24 months post-radiotherapy.
Further explorations revealed notable differences between patients with and
without pre-existing symptoms, with regard to the prevalence of clinically
relevant acute toxicity as well (11% versus 34%).
Other domains of health-related quality of life
There was notable deterioration in urinary symptoms and sexual functioning
following radiotherapy (Table 11).
Table 11. Mean (SD) scores of the EORTC QLQ-C30 for all patients (n=102-123).
Scale
Baseline
8 weeks
24 months post-RT
n=123
n=110
n=102
Mean
SD
Mean
SD
Mean
SD
QL
77
20
72
21
78
20
PF
RF
EF
CF
SF
FA
NV
PA
92
88
86
90
87
16
1
12
14
23
17
15
19
19
4
24
88
82
87
88
83
24
2
16
15
25
16
17
18
22
8
24
88
88
88
87
85
20
4
12
18
23
17
16
23
22
12
24
DY
15
24
18
24
19
28
SL
17
25
19
26
14
22
AP
2
11
4
12
5
17
FI
4
15
4
14
4
15
17
14
29
18
23
18
0
0
11
24
21
31
HTR
13
12
17
15
16
13
SAC
31
26
22
24
28
25
SFU
68
25
55
26
55
23
URI
AID
a
a) Completed by fewer patients (n=0-14).
Abbreviations: AID, bother due to the use of incontinence aid; AP, appetite loss; CF, cognitive functioning; DY, Dyspnoea; EF, emotional functioning; FA, fatigue; FI, financial difficulties; HTR, hormonal
treatment-related symptoms; NV, nausea and vomiting; PA, pain; PF, physical functioning; post-RT,
after radiotherapy completion; QL, global health status; RF, role functioning; SAC, sexual activity; SF,
social functioning; SFU, sexual functioning; SL, insomnia; URI, urinary symptoms.
49
Dietary adherence
The FFQ data revealed that the IG reported lower intake of high-fibre grain
products at all assessments compared to the SCG (p≤0.017) (Table 12). Accordingly, the IG reported higher intake of low-fibre grain products at all
follow-up assessments compared to pre-treatment (i.e., the baseline assessment), whereas the intake remained relatively stable over time in the SCG
(p≤0.029). Changes over time in short-term high-fibre vegetable intake also
differed significantly between groups, where the IG reported lower intake at
follow-up assessments compared to pre-treatment, whereas the intake remained fairly stable over time in the SCG (p=0.003). The IG reported lower
intake of high-lactose products at short-term follow-up compared to pretreatment and the SCG, but this between-group difference was not statistically significant (p=0.057). The use of lactose-free or lactose-reduced dairy
products was more common in the IG, especially in the short-term followup. The proportion of consumers of such products at follow-ups ranged from
13-41% in the IG, versus 6-14% in the SCG.
In the FFQ, the most commonly consumed food item in each food group was
rye crisp bread in high-fibre grain products, buns in low-fibre grain products,
fresh fruit with tough skins in high-fibre vegetables, potatoes in low-fibre
vegetables, milk in high-lactose dairy products, slightly soured thick cream
in low-lactose dairy products. This trend was consistent across the IG and
the SCG over time, although the IG generally lowered their intake of food
items in high-fibre and high-lactose food groups after the baseline assessment and dietary counselling.
Dietary assessments in the IG
Evaluation of the IG diets during and immediately following radiotherapy
indicated that nutrient intake at a group level was relatively unchanged compared to baseline assessments (see Paper I), with the exception of decreased
intake of total dietary fibre (Table 13 and Table 14). Accordingly, E% of
carbohydrates and PUFA were lower than the DRV and E% of SFA was
higher than the DRV for a majority of IG patients, at both 4 and 8 weeks
following radiotherapy onset. Regarding micronutrient intake distribution,
apparent prevalence of inadequate intake (% of patients below the AR) was
observed in vitamin A, thiamin, riboflavin, folate, vitamin C and selenium,
varying between 17-30%.
50
4 weeks
8 weeks
2 months
post-RT
12 months
post-RT
18 months
post-RT
24 months
post-RT
2.0 (0-6.0)
1.0 (0-3.0)
1.5 (0.2-4.4)
2.6 (0-7.3)
2.4 (0-8.1)
1.4 (0-4.6)
1.5 (0-4.4)
1.2 (0-5.1)
3/49
11/41
2.0 (0-6.0)
0.3 (0-3.1)
1.5 (0-8.4)
3.0 (0.4-8.3)
2.4 (0.2-7.4)
1.2 (0-3.6)
1.4 (0-4.6)
1.1 (0-4.1)
3/44
19/46
3/45
12/50
2.0 (0-5.0)
1.4 (0-4.0)
2.0 (0-6.1)
1.5 (0-6.0)
1.6 (0-3.8)
2.3 (0.2-7.4)
2.0 (0.2-5.0)
1.0 (0-4.0)
7/51
6/47
1.8 (0-4.4)
1.4 (0-4.1)
2.2 (0-6.4)
1.5 (0-5.4)
1.4 (0-6.5)
1.7 (0-6.2)
2.0 (0-5.0)
1.0 (0-3.0)
3/44
8/52
1.3 (0-4.1)
1.3 (0-4.0)
2.3 (0-6.1)
1.5 (0-5.1)
1.5 (0-7.6)
2.1 (0.3-7.2)
1.6 (0-4.0)
1.0 (0-4.0)
3/43
8/48
1.4 (0-4.4)
1.3 (0-3.3)
2.0 (0-6.1)
1.5 (0-5.2)
1.2 (0-5.9)
1.6 (0.1-7.5)
2.0 (0-5.0)
1.1 (0-5.0)
The maximum intake frequency of each food item corresponded to ‘≥3 times a day’. The number of food items in each group ranged from 2 to 8. Hence, the frequency
of food group intake range from 0-6 for high-fibre grain products up to 0-24 for low-fibre grain products.
a) Indicated as: users / respondents in total.
Abbreviations: IG, Intervention group; LF, lactose-free; LR, lactose-reduced; post-RT, after radiotherapy completion; SCG, Standard care group.
High-fibre grain products
SCG
2.0 (0-5.0)
IG
1.6 (0-5.0)
Low-fibre grain products
SCG
1.4 (0-7.2)
IG
1.5 (0.1-4.6)
High-fibre vegetables
SCG
2.5 (0.1-7.4)
IG
2.4 (0.3-7.2)
High-lactose dairy products
SCG
1.6 (0-4.1)
IG
2.0 (0-3.6)
a
Use of LF or LR dairy products
SCG
4/42
IG
4/40
SCG: n=62, IG: n=62 SCG: n=57, IG: n=60 SCG: n=60, IG: n=50 SCG: n=58, IG: n=55 SCG: n=53, IG: n=49 SCG: n=50, IG: n=52 SCG: n=49, IG: n=51
Baseline
Table 12. The median (min-max) frequency of intake of selected food groups, reported as times/day, and the proportion of patients reporting
use of lactose-free or lactose-reduced dairy products.
a
min-max
0-88
8-37
130-364
6-19
16-56
16-82
48-174
58-124
1281-3719
5.4-15.6
2
2
44
4
12
13
32
17
NA
NA
median
0-27
1-2
26-57
3-9
9-18
9-21
24-47
10-22
NA
NA
min-max
E%
4
b
18
220
10
27
33
76
81
2084
8.7
median
0-72
5-33
98-420
3-20
13-42
9-54
34-119
44-141
1224-3018
5.1-12.6
min-max
Intake
2
2
46
4
12
13
32
16
NA
NA
median
IG at 8 weeks (n=56)
4-day food diary
0-31
1-4
25-58
2-10
7-17
5-23
19-49
10-24
NA
NA
min-max
E%
NA
25-35 g daily
50-60 E%
5-10 E%
10-15 E%
<10 E%
25-35 E%
10-20 E%
NA
NA
DRV
NNR 2004
a) Number of patients reporting alcohol intake and the median (min-max) for those patients: n=44, 10 g (1-88)
b) Number of patients reporting alcohol intake and the median (min-max) for those patients: n=41, 9 g (1-72)
Abbreviations: CHO, carbohydrates; DF, dietary fibre; E%, percentage of total energy intake; MUFA, monounsaturated fatty acids; NA, not applicable; PUFA, polyunsaturated fatty acids; SFA, saturated fatty acids.
5
18
Alcohol (g)
DF (g)
28
MUFA (g)
10
31
SFA (g)
230
75
Fat (g)
CHO (g)
89
Protein (g)
PUFA (g)
2110
Energy (kcal)
median
8.8
Energy (MJ)
Intake
IG at 4 weeks (n=58)
4-day food diary
Table 13. Self-reported daily intake of energy and macronutrients in the IG at 4 and 8 weeks following radiotherapy onset, as well as the dietary reference values (DRV) of the Nordic Nutrition Recommendations (NNR 2004).
6-25
8-20
896
1460
3.5
11
12
45
Calcium (mg)
Phosphorus (mg)
Potassium (g)
Iron (mg)
Zinc (mg)
Selenium (μg)
2.6-66.7
a
a
a
20.7
0
5.2
0
0
3.4
32.8
0
19.0
3.4
0
22.4
17.2
5.2
5.2
20.7
%
Patients below AR
42
11
10
3.8
1452
976
91
5.9
258
2.0
35
1.7
1.4
9
6.0
769
median
16-106
5-20
5-32
1.4-5.9
805-2293
295-1799
10-334
1.9-42.2
84-1086
0.8-4.0
18-52
0.7-3.8
0.6-2.2
3-23
1.4-28.7
143-6153
min-max
Intake
a
a
a
28.6
1.8
3.6
3.6
0
3.6
30.3
0
28.6
8.9
0
23.2
25.0
10.7
1.8
23.2
%
Patients below AR
IG at 8 weeks (n=56)
4-day food diary
AR <35
AR <6
AR <7
LI <1.6
AR <450
LI <400
AR <60
AR <1.4
AR <200
AR <1.3
AR <15
AR <1.4
AR <1.2
AR <6
LI <2.5
AR <600
DRV
NNR 2004
a) LI when AR is not available.
Abbreviations: α-TE, α-tocopherol equivalents; AR, average requirement; IG, Intervention group; LI, lower intake level, NE, niacin equivalents; RE, retinol equivalents.
13-78
2.1-6.7
951-2080
243-1574
6-481
6.4
79
Vitamin C (mg)
101-1615
1.1-4.0
24-56
1.0-4.6
0.8-2.8
4-19
1.9-21.9
346-13377
min-max
Intake
Vitamin B12 (μg)
2.2
258
Vitamin B6 (mg)
Folate (μg)
1.7
40
Riboflavin (mg)
Niacin (NE)
9
1.7
Vitamin E (α-TE)
7.4
Vitamin D (μg)
Thiamin (mg)
918
Vitamin A (RE)
median
IG at 4 weeks (n=58)
4-day food diary
Table 14. Self-reported daily intake of micronutrients in the IG at 4 and 8 weeks following radiotherapy onset, as well as the dietary reference
values (DRV) of the Nordic Nutrition Recommendations (NNR 2004).
The IG patients consumed lower amounts of dietary fibre at 4 weeks (18.2
±4.5) as opposed to baseline (25.1 ±8.6), a statistically significant decrease
of 6.9 g, t(49) = 6.40, p<0.001 (Table 13). Likewise at 8 weeks, the consumption of dietary fibre was lower (19.0 ±6.7) as opposed to baseline (25.3
±8.8), a statistically significant decrease of 6.3 g, t(46) = 5.16, p<0.001. The
range of dietary fibre intake in the IG was lower at 4 weeks compared to
8 weeks (8-37 g versus 6-46 g). The majority of patients reduced total daily
dietary fibre intake from baseline to 4 weeks (43 of 50 patients) and from
baseline to 8 weeks (34 of 47 patients) following radiotherapy onset (Figure
3 and Figure 4).
15
10
5
Daily dietary fibre intake (gram)
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
-5
-10
-15
-20
-25
-30
Figure 3. Each IG individual’s (n=50) dietary fibre intake change (in grams) between baseline and 4 weeks following radiotherapy onset.
15
10
5
0
Daily dietary fibre intake (gram)
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
-5
-10
-15
-20
-25
-30
Figure 4. Each IG individual’s (n=47) dietary fibre intake change (in grams) between baseline and 8 weeks following radiotherapy onset. (Note that patient no. 33,
36 and 40 did not complete their food diaries at 8 weeks.)
54
Nutritional status
Nutritional status parameters were stable over time in both groups, and patients were predominantly assessed as well-nourished (Table 15). At baseline, 90% of patients had a PG-SGA score of ≤2 and there were no patients
with a PG-SGA score ≥9. There was no statistically significant difference in
PG-SGA scores between groups over time. At baseline, no patients were
underweight, 25 (20%) had normal weight, 73 (58%) were overweight, and
27 (22%) were obese. The SCG had significantly higher BMI values
throughout all assessments compared to the IG, F(1,79) = 4.83, p=0.031.
Table 15. Nutritional status assessment, with mean (SD) BMI values, and median
(p10-p90) PG-SGA scores.
Baseline
4 weeks
8 weeks
2 months 12 months
post-RT
post-RT
18 months
post-RT
24 months
post-RT
SCG: n=63
IG: n=62
SCG: n=56
IG: n=61
SCG: n=57
IG: n=50
SCG: n=58
IG: n=55
SCG: n=55
IG: n=51
SCG: n=50
IG: n=52
SCG: n=50
IG: n=52
2
BMI (kg/m )
SCG
28.3 (3.3)
28.4 (3.4)
28.6 (3.2)
28.7 (3.4)
28.4 (3.2)
28.3 (3.2)
28.1 (3.3)
IG
26.9 (3.2)
27.0 (3.2)
27.1 (3.2)
27.4 (3.1)
27.1 (2.9)
27.0 (3.0)
27.0 (3.0)
PG-SGA score
a
SCG
0 (0-2)
0 (0-2)
0 (0-2)
IG
0 (0-2)
0 (0-1)
0 (0-2)
a) The first section of the scored PG-SGA, with evaluation on weight loss history, changes in food
intake, nutritional impact symptoms and functional capacity.
th
th
Abbreviations: IG, Intervention group; p10, the 10 percentile; p90, the 90 percentile; PG-SGA, Patient-Generated Subjective Global Assessment; RT, radiotherapy; SCG, Standard care group.
55
Discussion
To our knowledge, this is the first randomized trial of a prospective dietary
intervention for reducing gastrointestinal symptoms, reporting data up to 2
years after curative prostate radiotherapy. Previous dietary intervention studies comprising fibre and lactose modifications in prostate cancer or other
pelvic tumours have indicated some beneficial effects, but there is a paucity
of randomized controlled trials and none have included long-term follow-up.
Main findings
There were no significant effects of the intervention in acute or persistent
gastrointestinal symptoms, but a tendency towards lower prevalence and
severity of bloating and diarrhoea in the IG compared to the SCG during
radiotherapy. In line with the intervention, the IG managed to reduce intake
of foods high in fibre and lactose during the entire study period, but the adherence tended to decline beyond 12 months post-radiotherapy. The frequency of clinically relevant gastrointestinal symptoms was merely a few
percent. The fact that the vast majority of patients were either entirely free of
gastrointestinal symptoms or experiencing only mild symptoms was also
evident in the validation process of the GISEQ. Consequently, the GISEQ
displayed a clear floor-effect and modest responsiveness, sensitivity and
specificity. The eight items were internally consistent, but extension of items
is a potential improvement based on patient input. As predicted, because of
the different question wording, the degree of relationship between three
matching items (diarrhoea, constipation and blood in stools) in the GISEQ
and the comparative measures was moderate. Prior to radiotherapy and intervention onset, grain products and dairy products were staple foods in this
patient sample and such products are major sources of dietary fibre and lactose. Regarding nutritional adequacy, unbalanced fatty acid intake and low
selenium intake were noted.
Effects of the dietary intervention
Although there was a trend towards lower prevalence and severity of acute
symptoms of diarrhoea and bloated abdomen in the IG compared to the
56
SCG, the dietary intervention had no statistically significant effect on acute
or long-term gastrointestinal symptoms. Several factors could be responsible
for this observation. First, the low number of events impeded the possibility
of detecting an intervention effect. Second, a modest reduction in insoluble
dietary fibre and lactose intake does not sufficiently prevent and manage
symptoms. Moreover, higher rates of dietary intervention adherence were
observed during radiotherapy compared to the long-term assessments. Finally, the development of acute and long-term symptoms might be related to
other patient- and treatment-related factors. These issues will be discussed in
subsequent sections.
The prevalence of clinically relevant acute and long-term symptoms was 010% for all patients, which is in line with previous reports [70]. The most
prevalent acute symptoms for all patients were bloated abdomen (5-10%)
and diarrhoea (7-8%). Notably, the prevalence of clinically relevant acute
bloating in the IG was actually lower 4 weeks into radiotherapy compared to
the pre-treatment level. Moreover, the prevalence of bloating in the IG was
higher at 12 and 18 months post-radiotherapy than during and immediately
after radiotherapy. These are interesting observations in relation to the findings regarding dietary intake and adherence over time in the IG. Generally,
interpretation of the results on gastrointestinal symptoms may have been
obstructed by the small number of events. The vast majority of patients were
either entirely free of symptoms or experiencing only mild symptoms, both
during radiotherapy and up to 2 years after radiotherapy completion. This
thesis was based on ideas from clinical experience and data generated in a
time when the occurrence of gastrointestinal symptoms in this patient category was more pronounced. Over the past decade, however, much improvements have been made towards more site-specific delivery of radiotherapy
treatment, thus decreasing radiation exposure to normal tissue, such as the
bowel organs [70]. This progress is one of the main reasons why so few patients in the present studies are symptomatic, and part of the explanation for
the lack of an intervention effect.
The trend towards lower prevalence and severity of diarrhoea in the IG support previous indications that nutritional interventions may reduce symptoms
of diarrhoea during pelvic radiotherapy [28]. Out of the nutritional intervention studies summarized in Table 1, two studies are similar to the present
trial, based on their interventional approach and patient categories. In the
study by Liu et al, 156 patients with localized prostate cancer were encouraged to eat a low-residue diet [158]. All patients who self-reported nonadherence experienced side effects, but problems subsided when they started
or returned to the recommended diet. It was concluded that the dietary restriction had a positive impact on acute gastrointestinal toxicity. In the study
by Murphy et al, 60 patients with prostate or gynaecological cancer undergo57
ing radiotherapy were advised to follow a low-fibre diet and randomly assigned to take psyllium fibre supplementation up to 1 month postradiotherapy [182]. The report indicated that psyllium fibre supplementation
was associated with a reduction in the incidence and severity of acute diarrhoea. These reports together with the result of the present trial point to a
reduction in radiation-induced acute gastrointestinal symptoms through restriction of foods high in insoluble fibres and residue, and replacement with
foods high in soluble fibres or supplementation thereof.
The approach to fibre modification taken in the intervention was primarily to
reduce intake of insoluble fibres and subsequently, to instead consume foods
with a higher proportion of soluble fibres. Both insoluble and soluble dietary
fibre increase faecal mass, and fermentation of soluble fibre as well as lactose digestion problems result in production of gas [38]. Hence, it could be
speculated that the total reduction in dietary fibre and lactose observed during and immediately after radiotherapy is related to the simultaneous tendency towards lower prevalence of bloating and unintentional leakage of stools
in the IG patients compared to the SCG, and the reduction in clinically relevant bloating from baseline to initial follow-ups in the IG. Supposedly, these
effects were not prolonged due to gradually increasing intakes of foods high
in fibre and lactose after radiotherapy completion. In relation to this, however, the distinction between insoluble and soluble dietary fibre is complex
[32]. Although the solubility of fibre to some extent determines its physiological properties, this categorization may be too simplistic as it neglects the
metabolism in the colon [183]. For instance, grading according to viscosity,
gel-forming capabilities, or fermentation rate by the gut microbiota may be
equally relevant to the physiological and health effects of fibre [184, 185].
The information and instructions in the present intervention were standardized and implemented to all patients randomly assigned to the intervention.
This type of ‘generic’ intervention method does not take into consideration
the characteristics of those to whom it will be offered. Other approaches
include targeted (designed for specific subgroups) and tailored (individualized) nutritional interventions, and studies have demonstrated that such
methods may be more effective than generic interventions [186]. A recent
Cochrane review on nutritional interventions during pelvic radiotherapy
revealed that the most common method was to provide a single intervention
to all patients from the onset of treatment, but criticized the assumption that
there is a 'one size fits all' solution and the likelihood that there is a 'magic
bullet' to treat toxicity [28]. The approach of targeting single interventions
primarily to patients identified as symptomatic, and to introduce that intervention on presentation of treatment-induced symptoms is an appealing approach that would probably have been more effective in the present study,
given the low number of events. Using a tailoring approach in order to de58
velop dietary interventions for each specific patient based on the individual
characteristics could be potentially beneficial in pelvic radiotherapy, given
the many causes of radiation-induced gastrointestinal side effects and the
wide spectrum thereof. However, differences in development time, costs,
effectiveness and ethics of these alternatives warrant consideration [186].
The findings regarding nutritional adequacy in the IG during the intervention
based on the food diaries were in line with findings on pre-treatment dietary
intake in the same patient sample (see Paper I). However, a larger proportion
of patients in the IG were below AR for riboflavin at 4 and 8 weeks following radiotherapy onset, compared to the prevalence in the whole population
at baseline. Speculatively, this may be related to a general reduction in dairy
consumption, because dairy products are the main source of riboflavin in the
general Swedish population [187].
Regarding change in other domains of HRQOL following radiotherapy, only
urinary symptoms and sexual functioning deteriorated to a degree that would
be considered clinically relevant [105]. Urinary and sexual functioning are
known to be negatively affected by prostate radiotherapy [188, 189].The
patients reported better global health status and lower levels of fatigue immediately after radiotherapy compared to a previous report on similar patient
categories[110].
Adherence to the dietary intervention
The IG managed to reduce their intake of foods high in insoluble fibre and
lactose below pre-treatment levels during the entire study period, and compensated that with increased intake of foods low in insoluble fibre and lactose. This is a very positive finding, given the pragmatic nature and longterm duration of the intervention. Although there was no specified target for
reduction of fibre and lactose intake in the present intervention, the effort of
dietary fibre reduction in the IG could be interpreted in light of recommended dietary fibre content of low-fibre diets. Generally, a maximum upper level
of 9-15 g daily appears to be common practice [190-193]. In the IG, the daily median dietary fibre intake was 18 g at both 4 and 8 weeks after radiotherapy onset according to the food diaries. Based on that, the majority of
patients in the IG changed their dietary fibre intake to a level that would be
considered modest in relation to a low-fibre diet. However, interpretations
based on such a comparison must be made with caution because of uncertainties and differences regarding dietary fibre classifications and estimations. In any case, incorporation of goal setting, with specified upper intake
levels, could probably have improved patients’ adherence to and understanding of the diet modification and the evaluation thereof [144]. As an example,
tools enabling patients to count daily fibre intake have been proven useful in
59
a more recent study, where booklets listing fibre content in points were used
[194].
The highest reduction in dietary fibre and lactose intake in the IG was noted
during and immediately after radiotherapy. Notably, higher short-term reduction rates in the IG coincided with more frequent dietary counselling
sessions. More frequent contact and reinforced counselling after radiotherapy completion would probably have improved long-term adherence, based
on the fact that adherence to a new behaviour often decreases as the frequency of contact and follow-up decreases [144]. Repeated long-term contact by
telephone to monitor dietary intervention adherence has proved to be successful elsewhere [195], and could have been an efficient approach in the
present study due to the wide-spread catchment area. Still, dietary adherence
depends on many factors besides the frequency of contact and support. In
this patient sample, grain products and dairy products were staple foods prior
to intervention onset. Consequently, the men in the IG were recommended to
make considerable changes to their habitual diet and preferred food choices.
In addition, the higher cost of lactose-free or lactose-reduced products may
have caused patients to gradually give up this dietary change in favour of
less expensive ordinary dairy products. The present patient category consisted of older men, many of whom indicated during the baseline visit that they
were not primarily responsible for buying and preparing food. Moreover, a
large proportion of them had to travel several hours a day to get to the Department of Radiotherapy or stay at the hotel for patients. Consequently,
barriers and aggravating circumstances such as personal preferences about
diet, availability, economic and environmental barriers as well as patients’
characteristics, knowledge and skills may have contributed further to challenges regarding adherence [144, 145]. Overall, the dietary intake in the
SCG remained relatively stable over time, although tendencies towards more
infrequent consumption of high-fibre grain products and vegetables were
indicated in the long-term assessment. This trend could presumably be related to the spontaneous decrease of vegetables, dietary fibres and polysaccharides intake in cancer patients when they experienced gastrointestinal symptoms such as diarrhoea [196].
The dietary fibre intake change in the IG between baseline and the first to
follow-up assessments indicated that those individuals who reported more
noticeable reductions tended to perpetuate this change, while those who
failed to make the initial noticeable changes did not seem to improve after
follow-up. Future research could explore possible determinants of and barriers to dietary adherence in the present patient sample.
60
Assessment of gastrointestinal symptoms
Measurement of change is important in HRQOL and other patient-reported
outcomes when evaluating interventions. However, such subjective constructs are susceptible to ‘recalibration response shift’, which makes evaluation of change score in longitudinal trials complicated [119, 124]. There are
several currently available PROMs for measuring gastrointestinal symptoms
in prostate cancer patients, and the predominant approach is to measure current status of functioning and bother without consideration to pre-treatment
status or response shift [97, 114]. The GISEQ captures a new dimension in
the assessment of gastrointestinal side effects from radiotherapy, in that it
aims to measure patient-perceived change in symptoms. Through its retrospective wording of questions and relative subjective scores, the GISEQ
makes it possible to assess change in gastrointestinal status from the pretreatment situation using a single questionnaire at one point in time.
The clear floor effect of the GISEQ was most likely influenced by the fairly
low prevalence of gastrointestinal side effects in general, shown both in the
GISEQ as well as in the EORTC QLQ-C30 and QLQ-PR25. About one half
of patients were free from bowel symptoms during radiotherapy, and those
with symptom occurrence reported relatively low levels of bother and symptoms. Gastrointestinal side effects are related to total dose of radiation and
the total volume of tissue irradiated [197], and technical advances in prostate
radiotherapy during the past decade have reduced the side effects of treatment [70]. Also, combining EBRT with either brachytherapy or proton therapy, as in the present patient sample, minimizes irradiation fields to proximal
organs and only involves a small part of the rectum [67, 68]. These factors
have clearly improved outcomes for this patient category in recent years, and
in comparison with the occurrence of symptoms reported prior to the initiation of the present study. This development is satisfactory, but hindered the
ability to detect an intervention effect. Henceforth, it could be advantageous
to evaluate the impact of a fibre- and lactose-restricted diet further in pelvic
cancer patient categories with larger irradiated target volumes and thereby a
greater risk of radiation-induced intestinal injury, where beneficial effects of
a dietary intervention would be more likely.
The modest results on sensitivity and specificity of the GISEQ, as well its
moderate correlation with the three matching items of the EORTC questionnaires, can be partly explained by the fact that the GISEQ and the chosen
‘gold standard’ assess conceptually different issues (patient-perceived
change in bother due to symptoms versus symptom prevalence). The conversion of the EORTC questionnaire absolute scores into change scores seemed
to be the most appropriate way to handle this discrepancy. The lack of evaluation of concurrent validity, sensitivity and specificity of the five items for
61
abdominal pain, abdominal cramps, mucus discharge, intestinal gas and flatulence, due to the absence of matching items in the comparator measures
EORTC QLQ-C30 and QLQ-PR25, is a limitation to the study.
Overall, the GISEQ seem to be acceptable and clear to the patients, as it
rendered high response rates and very few missing items. However, the retrospective comparative reporting in the GISEQ may be cognitively challenging for some patients. The patients must first assess their current level of
bother from side effects, recollect the level of bother at the pre-treatment
assessment and then mentally compare the two and estimate the difference.
Although seemingly straightforward, the risk of misinterpretation and that
patients may simply report their symptoms heuristically should be considered. Subsequently, recall bias could potentially confound longitudinal evaluation of patient-perceived change using the GISEQ’s design. It has been
implied that prostate cancer patients do not accurately recall pre-treatment
status when asked more than one year after treatment [198]. The relative
contribution of the response shift versus recall bias phenomena to the GISEQ
in this population and over this time frame remains unknown. These issues
are important and warrant further investigation of the quality and usefulness
of the questionnaire. Moreover, the question wording and design of the GISEQ attach great importance to the pre-treatment assessment of gastrointestinal symptoms. In the GISEQ, a score of 0 is indicative of bother ‘to the same
or a lesser extent’ compared to baseline status. Theoretically, a follow-up
score of 0 may thereby comprise patients from the full range of the 0-10
baseline scale, i.e., patients reporting neither pre-treatment nor follow-up
symptom bother, but also patients reporting bother ‘to a very large extent’ at
baseline and indicating the same extent of bother by scoring 0 in the GISEQ
at follow-up. Hence, a valid baseline assessment and thorough follow-up are
needed to successfully identify and manage patients with pre-treatment
symptoms.
In GISEQ, a retrospective comparison is comprised in the wording of the
questions, where the patient takes his current perspective of pre-treatment
status into account when rating present symptoms. Through this approach, a
change for the worse regarding radiation side effects quickly becomes evident. The GISEQ was developed on the basis of physician-based experience
of rating side effects in clinical practice in the present patient category, and
the method of assessing patients’ current perception is amenable to such
clinical situations. This strategy can potentially diminish the confounding
factor of ‘response shift’ when used at one point in time, although it might
be susceptible to recall bias [119]. However, when the GISEQ is used repeatedly in longitudinal clinical trials, the relative contribution of response
shift and recall bias is most likely to affect the comparison of scores from
different points in time after all.
62
Findings from Paper II-IV indicate that both acute and persistent radiationinduced side effects were associated with pre-existing symptoms, which is in
line with earlier findings [199]. Out of all patients, 16-26% reported diarrhoea and bloated abdomen already before radiotherapy. The occurrence of
these pre-existing symptoms could, in part, reflect the estimated 11-12.5%
prevalence of functional gastrointestinal disorders in the general Swedish
population [200, 201]. Although the observed association must be interpreted with caution because of the small number of clinically relevant events, it
underlines the importance of screening for symptoms both prior to and continuously following treatment.
Pre-treatment nutritional status
No patients were underweight at baseline and the vast majority of patients
were considered well-nourished. This is a positive finding given that poor
nutritional status is a risk factor in terms of outcome and therapy-related
toxicity [10, 15]. According to the WHO classification of BMI, 80% of the
patients were considered overweight and obese (BMI ≥25 kg/m2) [168].
Considering the changes in body composition in older adults, however, it has
been proposed that for individuals 65 years and older a BMI of 22–27 kg/m2
is an optimal range [202]. If this classification was to be applied to the present patient sample, the prevalence of overweight and obesity would drop to
66%, and 32% would be normal weight. Nevertheless, the median BMI in
the present sample is slightly higher than that of Swedish men with prostate
cancer in a prospective cohort study, which indicated a link between obesity
and incident prostate cancer risk [203].
Regarding the nutritional adequacy of the pre-treatment dietary intake, the
findings of proportionally high intakes of fat and SFA and proportionally
low intakes of carbohydrates, dietary fibres and PUFA are in line with reports on macronutrient intake (percentage of total energy intake, E%) in
adults from Scandinavia and other European countries [204-206]. Notably,
one-fifth of the patients were at risk for inadequate intake of selenium, which
is interesting given the suggested inverse association between selenium intake and risk of prostate cancer [207, 208].
Grain products and dairy products were staple foods prior to radiotherapy
and intervention onset, and such products are major sources of dietary fibre
and lactose. The prostate cancer patients consumed higher amounts of bread
and milk compared to their male peers from the general population (n=477,
45-80 y) in a recent Swedish national dietary survey [187]. Median daily
fibre intake was higher in the men with prostate cancer (25 g versus 20-22 g)
[187], although 48% of the prostate cancer patients had dietary fibre intake
63
below the DRV [174]. These findings are noteworthy, given the direction of
the dietary intervention that half of the cohort was randomized to shortly
thereafter.
When evaluating baseline data in cancer patients, it is important to remember that they are collected after the persons have been diagnosed with cancer.
Baseline values can be biased, because patients may already be psychologically affected by the diagnosis and may suffer from symptoms [209]. Therefore, reference data from the general population is a good complement to
baseline HRQOL data [210], and this reasoning should presumably also
relate to the pre-treatment dietary evaluation. At baseline, 33% of patients
reported at least ‘a little’ general bowel symptoms. The prevalence of clinically relevant symptoms was merely a few percent, and only reported for
diarrhoea, constipation and bloated abdomen (highest in bloated abdomen,
6%). Available normative data for EORTC QLQ-C30 of the general male
population (aged 40-79 y) indicate that clinically relevant problems of diarrhoea and constipation are reported by 2.4% and 2.2%, respectively [109].
The equivalent prevalence was 1.6% for diarrhoea and 1.6% for constipation
in the present patient sample, which would rule out the risk of notable bias.
Previous studies using the QLQ-C30 in prostate cancer patients have reported baseline prevalence rates of 5-6% for diarrhoea and 2-3% for constipation
[125, 126].
Methodological discussion
The evidence for the efficacy of fibre and/or lactose modification in reducing
gastrointestinal complications during and following pelvic irradiation is limited and inconclusive, and previous reports lack a number of the strengths of
the present study [44, 158, 182, 211, 212]. First, unlike the majority of existing studies, the present study was randomized and gastrointestinal symptoms
were the primary outcomes. Second, the present study measured dietary adherence at multiple time points. Moreover, the study included longitudinal
2-year follow-up data from three patient-reported questionnaires on gastrointestinal symptoms and other domains of HRQOL as well as nutritional status
assessments. The drop-out rate (4%) and final assessment completion rate
(78%) were highly satisfactory. Similarly to indications from other intensive
long-term dietary intervention trials in cancer patients, the results from the
present RCT indicated that drop-outs occur at or soon after randomization
[213, 214].
The compromise between internal and external validity is of particular concern in the design of a RCT, and it is difficult to maximize both aspects of
study validity. In the present trial, the intervention was designed so that it
64
would be plausible in a clinical environment. However, internal validity may
have been overly compromised in an effort to ensure that the intervention
used in the RCT could be directly applied for use in clinical practice. More
rigorous control of components within the intervention would have increased
internal validity. However, efforts to increase internal validity should be
weighed against the feasibility and added costs of such procedures, to ensure
that the costs are not excessive in relation to the expected benefits from the
intervention.
Interpretation of the results regarding gastrointestinal symptoms was obstructed by the small number of events. Thus, the possibility of detecting an
intervention effect in outcome may have been impeded by the underpowered
study sample. The power analysis was based on mean bowel symptom score
differences from previous research, assuming normally distributed data – an
assumption that turned out to be incorrect. In addition, 58 possible participants were not considered for eligibility owing to administrative failure. This
was due to the highly varying time intervals between treatment decision and
radiotherapy onset, which hampered screening of eligible patients and indirectly contributed to the underpowered study sample. It should be stressed
that the decision to dichotomize data was taken only because of the skewness in the data from this patient sample. Dichotomization of variables results in loss of information on the variance contained in the original data,
which leads to loss of power in statistical testing. Obviously, it would have
been preferable to report data from all steps of the scale.
The selection of instruments for primary outcome assessment deserves some
comment. First, the EORTC QLQ-C30 and QLQ-PR25 are validated to
measure HRQOL, but not to identify gastrointestinal toxicity. Hence, the use
of these questionnaires in the present study was not in full accordance with
their intended area, which should be taken into account when interpreting
and drawing conclusions based on the findings. According to a recent
Cochrane review on nutritional interventions for reducing gastrointestinal
toxicity after pelvic radiotherapy, the CTCAE Pelvic Symptom Questionnaire is the only available validated PROM in that patient category [28, 215].
The CTCAE Pelvic Symptom Questionnaire was developed and first reported after the commencement of the trial in this thesis.
In the present trial, data from a study-specific FFQ were used to estimate
frequency of dietary fibre and lactose consumption. This new FFQ has not
been validated, and the relevancy of content, coverage of food items and
continuous frequency categories are suggestions for further areas of improvement. In addition, the FFQ evaluated adherence. There are currently no
widely accepted measures of adherence, but the FFQ has become popular as
a means of determining adherence in clinical diet trials. The trial by Liu
65
et al. measured adherence through self-report, which is another common
approach [158]. However, subjective self-reported measurements of dietary
intake are known to be unreliable, although self-reports on non-adherence
seem to be more reliable than self-reports on adherence [216].
Some limitations regarding the dietary assessment methodology exist. First,
it could be argued that the single 24-HDR used in Paper I is not an appropriate method to represent the habitual diet of an individual owing to the dayto-day variation in an individual’s diet. As demonstrated in Paper I, however, that shortcoming can be compensated for using statistical methods [217].
The 24-HDR was part of the baseline assessment in the present trial and
selected based on its advantages of being reasonably quick and giving detailed information, while at the same time reducing respondent burden. Nevertheless, the lack of repeated recalls in this report hampered the assessment
of usual dietary intake. Second, the nutrient calculation program used in this
RCT estimated total dietary fibre intake, but did not differentiate between
insoluble and soluble dietary fibres, nor did it give lactose intake levels. This
limited the potential evaluation of the food diaries and, subsequently, an indepth exploration of diet change in the IG.
66
Conclusions
•
A dietary intervention with insoluble dietary fibre and lactose restriction was not superior to habitual diet in reducing gastrointestinal symptoms following prostate radiotherapy. Adherence to the
dietary intervention was best during the radiotherapy treatment period, which coincided with a tendency towards lower prevalence
and severity of diarrhoea and bloated abdomen in the intervention
group. The low number of clinically relevant events probably impeded the possibility of revealing a clear interventional effect.
•
Curative radiotherapy for localized prostate cancer seems highly
tolerable to patients, regarding acute and late gastrointestinal toxicity. The vast majority of patients in this trial were either entirely
free of symptoms or experiencing only mild symptoms, both during radiotherapy and up to 2 years after radiotherapy completion.
•
The GISEQ provides a novel approach to outcome assessments by
enabling quick evaluation of patient-perceived change in symptoms, but further work is needed to strengthen its psychometric
qualities.
•
Patients recently diagnosed with localized prostate cancer were
generally well-nourished prior to radiotherapy onset. Their pretreatment dietary intake was mostly nutritionally adequate, although unbalanced fatty acid intake and low selenium intake were
indicated. Grain and dairy products were staple foods in this patient sample prior to radiotherapy onset, which is noteworthy given the restriction on insoluble fibre and lactose that half of the
men were advised to adhere to for two years in the present trial.
67
Clinical implications and future research
68
•
The present trial provides no support for routinely recommending
a fibre- and lactose-restricted diet instead of habitual diet to patients undergoing radiotherapy for localized prostate cancer, based
on the low prevalence of clinically relevant symptoms. As a suggestion for future work, it could be advantageous to further evaluate the impact of a fibre- and lactose-restricted diet in patient categories with larger irradiated target volumes, as that could entail a
greater risk of radiation-induced intestinal injury and beneficial effects of a dietary intervention would be more likely. Also, targeted
and/or tailored interventions may be more effective than generic
interventions.
•
When implementing dietary interventions, efforts should be made
to incorporate appropriate and effective cognitive-behavioural
strategies to enhance adherence, and also to include a reliable
method for measuring adherence. Such efforts could facilitate future explorations of determinants of dietary adherence and associations between adherence and gastrointestinal symptoms in prostate cancer patients.
•
The use of PROMs has become more or less routine practice in
clinical cancer trials, and recently, there have been promising attempts to include patient-reported outcome measures in standard
clinical practice. However, methods concerning how to determine
clinically significant change and the magnitude of response shift
deserve continuing research.
•
It is important to assess patient-reported outcome in a valid, reliable and efficient fashion. Generally, selection of the optimal set of
PROMs should be undertaken with consideration to the specific
aims, patient sample, treatment and available resources.
•
Additional work is needed to strengthen the psychometric qualities and to evaluate clinical use of the GISEQ. Future potential
improvements of content and coverage of the GISEQ include review and modification of items and response scales, with emphasis on patient input.
•
Further research on nutritional adequacy in this patient category is
warranted, as the present dietary assessment in prostate cancer patients revealed some nutritional factors that may be linked to the
disease.
Sammanfattning på svenska
Bakgrund
Cancer i bäckenregionen, såsom prostatacancer, rektalcancer och gynekologisk cancer, utgör vanliga cancerformer i Sverige. Behandlingsalternativen
innefattar bland annat strålbehandling. Även om strålbehandlingen riktas
mot tumören medför behandlingen risk för strålpåverkan på närliggande
vävnad, vilket kan ge upphov till både tidiga/akuta och sena/kroniska biverkningar från urinblåsa och tarm. Biverkningar från tarmen kan ge diarré,
ökad avföringsfrekvens, gaser, uppspändhet, slem eller blod i avföringen,
smärta och ibland förstoppning. Sådana ogynnsamma biverkningar kan i sin
tur leda till sänkt livskvalitet i dessa patientgrupper och i vissa fall begränsande möjligheter till kurativ behandling. Dessutom påverkar patientens
nutritionsstatus toleransen av behandlingen och undernäring är förknippat
med en högre risk för biverkningar från tarmen. Tidigare forskning har visat
att modifiering av normalkosten, med avseende på t.ex. kostfibrer och laktos,
kan lindra förekomsten av strålningsinducerade tarmsymtom. Resultaten är
dock inte entydiga och antalet randomiserade, kontrollerade studier inom
området är begränsat.
Syfte och metod
Syftet med denna avhandling var att öka kunskapen om kostens betydelse för
tarmsymtom hos patienter med prostatacancer som genomgår kurativ strålbehandling, genom att studera effekterna av en kostomläggning på tarmsymtom och hälsorelaterad livskvalitet. Avhandlingen baseras på data från en
randomiserad, kontrollerad studie på en kostintervention (kostomläggning)
med långtidsuppföljning. Till studien rekryterades 130 män med nyupptäckt
lokaliserad prostatacancer som skulle genomgå kurativt syftande strålbehandling. Patienterna randomiserades till att få antingen sedvanlig vård med
tillägg av kostomläggning (Interventionsgrupp, n=64), eller enbart sedvanlig
vård (Kontrollgrupp, n=66). Kostomläggningen innebar att patienterna rekommenderas en kost med lågt innehåll av olösliga kostfibrer och laktos
under hela studieperioden om 26 månader.
69
Studie I
Studie I utvärderade patientgruppens kost- och näringsintag före strålbehandlingsstart, och gav därigenom insikter om patienternas kostmässiga
utgångsläge i förhållande till den kostomläggning som hälften av gruppen
skulle komma att randomiseras till. Undersökningen baserades på matvanemätningsmetoden 24-timmarsintervju (s.k. 24-hour dietary recall), där deltagarna beskrev sitt kostintag det föregående dygnet. Intag av livsmedel och
näringsämnen utvärderades med hjälp av fjärde upplagan av Nordiska näringsrekommendationer (NNR 2004). Resultaten visade att spannmåls- och
mejeriprodukter var huvudsakliga energikällor i kosten, och genomsnittliga
konsumtionen av bröd, mjölk och kostfiber i patientgruppen var högre jämfört med jämnåriga män i den senaste nationella kostundersökningen. Detta
var intressanta fynd med tanke på kostomläggningens inriktning och att
spannmåls- och mjölkprodukter kan vara rika fiber- respektive laktoskällor.
Trefjärdedelar av patienterna uppnådde inte rekommendationen om ≥ 500
gram frukt och grönsaker dagligen. Patientgruppen hade generellt sett ett
relativt välbalanserat näringsintag, men intaget av selen var lågt och obalanserat fettsyraintag noterades också.
Studie II
Studie II syftade till att validera det nya patient-rapporterade frågeformuläret
Gastrointestinal Side Effects Questionnaire (GISEQ). GISEQ mäter patientens upplevda förändring av tarmsymtom, genom en jämförelse mellan nuvarande symtomstatus och status före strålbehandlingsstart, för att på så vis
belysa de strålinducerade symtomen. Hög svarsfrekvens och få obesvarade
frågor tydde på att GISEQ är lätt för patienterna att besvara. De åtta frågorna
i GISEQ uppvisade god samstämmiget (Cronbach’s alpha > 0.70), även om
patienternas kommentarer tydde på att GISEQ skulle kunna utökas med ytterligare symtomfrågor. Samtidig validering av tre frågor i GISEQ med tre
matchade frågor i ett välkänt, validerat frågeformulär med liknande ändamål,
visade på måttlig korrelation mellan formulärens frågor. Detta var väntat,
givet frågeformulärens något olika design och frågeformuleringar. Den låga
förekomsten av patientrapporterade tarmsymtom under pågående strålbehandling bidrog troligen till att GISEQ uppvisade måttlig responsiveness,
sensitivitet och specificitet.
Studie III-IV
Studie III och Studie IV syftade till att studera effekterna av kostomläggningen på akuta och sena tarmsymtom och andra aspekter av hälsorelaterad
livskvalitet. Resultaten visade inte någon uppenbar skillnad mellan interventionsgruppen och kontrollgruppen gällande tarmsymtom. Det fanns dock en
70
tendens (ej statistiskt säkerställd) till lägre förekomst och svårighetsgrad av
kortsiktiga besvär av diarré och uppspändhet i interventionsgruppen jämfört
med kontrollgruppen, men kostomläggningen hade ingen uppenbar effekt på
långsiktiga tarmbesvär. En övervägande majoritet av patienterna var antingen helt fria från symtom eller rapporterade endast milda symtom, både under
pågående strålbehandling och upp till 2 år efter avslutad behandling. Även i
kontrollgruppen var exempelvis 50-60 % av patienterna helt symtomfria
gällande diarré både under och efter strålbehandling. Förekomsten av kliniskt relevanta besvär var relativt låg, och varierade mellan 0-10% över hela
studieperioden. Gällande övrig hälsorelaterad livskvalitet rapporterade patienterna tilltagande problem av urinvägsbesvär under strålbehandlingsperioden.
Slutsats
Kostomläggningen, med minskat intag av olösliga kostfibrer och laktos,
hade inte någon tydlig effekt på tarmsymtom från strålbehandling mot lokaliserad prostatacancer. Detta resultat kan ha flera orsaker. Att en förhållandevis liten andel av patienterna hade påtagliga tarmsymtom hade troligen
stor inverkan. Den låga förekomsten av biverkningar kan kopplas till en
snabb utveckling av strålbehandlingstekniken under det senaste decenniet.
Föreliggande studie ger därför inte stöd för att rutinmässigt rekommendera
en fiber- och laktosreducerad kost framför normalkost till denna patientgrupp, med tanke på att majoriteten av patienterna – oavsett kosthållning –
var helt besvärsfria eller rapporterade endast milda biverkningar. Möjligen
kan denna kostomläggning medföra lindring för undergrupper av patienter
som upplever svårare tarmsymtom eller för andra patientgrupper som genomgår strålbehandling där en större del av tarmen inkluderas i strålfältet
och där det föreligger större risk för påtagliga tarmsymtom. Dock krävs mer
forskning inom detta område. Mycket tyder också på att interventioner som
skräddarsys mot individen eller inriktas mot undergrupper av patienter vore
mer framgångsrika än generella interventioner. För att förstärka följsamheten
och effekten av kostomläggningar i framtida studier bör beteendepåverkande
strategier ingå i studiedesignen. Utformningen av GISEQ ger nya möjligheter till bedömning av tarmsymtom i samband med strålbehandling, genom att
enkelt kunna bedöma patientens upplevda förändring av symtombörda. Ytterligare arbete krävs dock för att förbättra formulärets psykometriska egenskaper, samt att utvärdera dess kliniska relevans och användbarhet.
71
Acknowledgements
This thesis originated as a study performed at the Department of Oncology,
Uppsala University Hospital. I would like to thank everyone who has contributed to the thesis, and everyone who has supported me during my thesis
work. I especially wish to thank:
The prostate cancer patients in this study, for generously giving of your time
by participating in this long-term study. Your willingness to share your experiences through the data collection and in sessions has been enriching,
inspiring and instructive.
The staff of the Department of Oncology, for all the practical help with recruitment of patients, your support in questions regarding oncology and radiotherapy, and for your accommodating and friendly manner towards me
and the participants in the study.
I also wish to express my sincere gratitude to:
Ingela Turesson, Birgitta Johansson and Christina Persson, my supervisors.
Your research and personal qualities complement each other in an exemplary
manner, which has made my thesis work very enriching, rewarding and educational. Thank you for always sharing your knowledge and experience in an
enthusiastic and constructive way. Ingela, for broadening my scientific
thinking and for allowing me to grow as an independent researcher. Birgitta,
for generously sharing your scientific knowledge, and for your constant support and interest in my work. Christina, for believing in me from the start
and for your never-ending encouragement.
Anders Berglund, Agneta Andersson and Peter Nygren, co-authors, for your
skilful contribution to the manuscripts. Your productive input and positive
attitudes have been valuable not only for the text but also in my learning
process.
Annika Thalén-Lindström, PhD-student colleague, for your never-ending
support and encouragement throughout the years. Thank your for our interesting and insightful discussions about research and other things in life. Your
wisdom and warmth are truly appreciated – you are a gem!
72
Marina Forslund and Anna Hauffman, colleagues in the research group, for
the helpful and joyful atmosphere at work. Thank you for broadening my
knowledge by sharing information and giving feedback on our joint research.
Present and former members of the PROKOST-project group, the UPO network, the Cancer rehab network, and Dietister inom onkologi (DIO), for
fruitful discussions and interesting insights based on your important work
and research. Thank you for giving invaluable feedback on the thesis.
Didde Simonsson Westerström, Christl Richter-Frohm and Inger Hjertström
Östh, for administrative and practical help during the years. Thank you for
always taking time to help me out in such a friendly manner.
The staff of the Clinical Research and Development Unit (KFUE), for your
support and encouragement, and for the pleasant atmosphere around coffee
breaks and lunch breaks.
My colleagues at the Section of Clinical Nutrition, for generously sharing
your knowledge, and supporting me in various ways that have allowed me to
combine clinical practice and research. My special thanks to Karin Blom
Malmberg and Mia Hansdotter, for your support and positive attitudes towards my postgraduate studies.
To my dear family and to all my friends outside academia, for your encouragement and support and for letting me be part of your lives – lives that continue regardless of research successes or setbacks. You have helped and inspired me with good advice, fun experiences, and so many other things that
provide positive energy. Thank you for all the good times we spend together!
I would especially like to thank my parents Gun and Magnus, for being a
constant source of support throughout my life.
Last but not least, to Anders, my love and soul mate. Thank you for always
being there for me, no matter what, and for wholeheartedly and unconditionally supporting me every step of the way. Your honest advice and encouraging words are truly invaluable. You have an amazing ability to instil confidence and tranquillity in me – even at difficult moments. No challenge is too
great with you by my side. Thank you so much for enriching my life with
love, warmth and joy.
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Funding
The financial support of the Faculty of Medicine at Uppsala University,
Uppsala County Council, the CancerRehabFonden, an agreement on medical
training and clinical research (ALF) between Uppsala County Council and
Uppsala University, the Research Foundation of the Department of Oncology at Uppsala University Hospital, the Swedish Cancer Society, and the
Swedish Association of Clinical Dietitians (DRF), is gratefully acknowledged.
74
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87
88
Appendix
89
Studienummer:
GISEQ
BESVÄR FRÅN MAG- TARMKANALEN JÄMFÖRT MED FÖRE
STRÅLBEHANDLINGENS START
Det här frågeformuläret innehåller frågor om vilka besvär du har haft från magtarmkanalen den senaste veckan i jämförelse hur mycket besvär du hade före
du fick strålbehandling mot prostatacancer.
1.
I vilken utsträckning har du besvärats av diarré jämfört med före strålbehandlingen?
Ange endast 1 svar.
0
1
2
3
4
5
6
7
8
9
I samma
eller mindre
utsträckning
2.
I vilken utsträckning har du besvärats av förstoppning jämfört med före
strålbehandlingen? Ange endast 1 svar.
0
1
2
3
4
5
6
7
8
9
I samma
eller mindre
utsträckning
3.
I vilken utsträckning har du besvärats av blod i avföringen jämfört med före
strålbehandlingen? Ange endast 1 svar.
0
1
2
3
4
5
6
7
8
9
10
I mycket
större
utsträckning
I vilken utsträckning har du besvärats av slem i avföringen jämfört med före
strålbehandlingen? Ange endast 1 svar.
0
1
2
3
4
5
6
7
8
9
10
I mycket
större
utsträckning
I samma
eller mindre
utsträckning
5.
10
I mycket
större
utsträckning
I samma
eller mindre
utsträckning
4.
10
I mycket
större
utsträckning
I vilken utsträckning har du besvärats av kramp i tarmen jämfört med före
strålbehandlingen? Ange endast 1 svar.
0
1
2
3
4
I samma
eller mindre
utsträckning
5
6
7
8
9
10
I mycket
större
utsträckning
VAR GOD VÄND!
© Birgitta Johansson. Enheten för onkologi, Uppsala universitet. 2005
6.
I vilken utsträckning har du besvärats av smärtor från tarmen jämfört med före
strålbehandlingen? Ange endast 1 svar.
0
1
2
3
4
5
6
7
8
9
I samma
eller mindre
utsträckning
7.
I vilken utsträckning har du besvärats av gaser i magen jämfört med före
strålbehandlingen? Ange endast 1 svar.
0
1
2
3
4
5
6
7
8
9
I samma
eller mindre
utsträckning
8.
10
I mycket
större
utsträckning
I vilken utsträckning har du besvärats av att du måste ”släppa dig” jämfört med före
strålbehandlingen? Ange endast 1 svar.
0
1
2
3
4
I samma
eller mindre
utsträckning
9.
10
I mycket
större
utsträckning
5
6
7
8
9
10
I mycket
större
utsträckning
Har du haft några andra besvär från tarmen som du inte hade före strålbehandlingen?
Nej
Ja, nämligen:
10. Har du använt något preparat mot mag-tarmbesvär under pågående strålbehandling
eller efter avslutad strålbehandling?
Nej
Ja, nämligen:
11. Din aktuella vikt?
Jag väger nu c:a ____________ kg
© Birgitta Johansson. Enheten för onkologi, Uppsala universitet. 2005
Studienr: _______
Datum: ________
Hur ofta och hur stora portioner äter Du av följande livsmedel?
Vi ber dig ange ditt intag av angivna livsmedel så noga du kan. Sätt ett kryss i den ruta som bäst stämmer
överens med ditt intag av varje enskilt livsmedel. Ange både hur ofta och hur stora portioner du äter.
Svaren ska gälla för den senaste månaden.
(Kryssa i kolumnen ”Aldrig” om du inte intaget det aktuella livsmedlet den senaste månaden.)
Per dag
Aldrig
≥3
2
Per vecka Per månad
1
2
1
2
1
Portion
Liten Medel Stor
Mjölk
Filmjölk
Yoghurt
Grädde
Crème fraîche-produkter
Mesost, messmör
Glass
Getost, getmjölk
Gräddfil
Kesella, kvarg
Mjukost, Philadelphiaost
Dessertost
Milda Mat (färdig sås/grädde)
Kelda (färdiga soppor/grädde)
RisiFrutti, MiniMeal
Potatis
Råa rotfrukter
Kokta rotfrukter
Rotfrukter i maträtter
Råa grönsaker
Kokta grönsaker
Grönsaker i maträtter
Bönor bruna/vita/röda/gröna etc
Linser
Ärtsoppa
Ris, polerat/vitt
Råris/fullkornsris
Pasta (makaroner etc), nudlar
Fullkornspasta
FORTSÄTT PÅ NÄSTA SIDA – VAR GOD VÄND!
© Christina Persson. Enheten för onkologi, Uppsala universitet. 2005
Sida 1 av 2
Per dag
Aldrig
≥3
2
Per vecka Per månad
1
2
1
2
Portion
1
Liten Medel Stor
□ Annan/Vet ej
□ Använder ej mjölk
Bär
Färsk frukt
Skalad färsk frukt
Konserverad frukt
Torkad frukt
Nötter
Mandel
Frön; solros, lin, sesam
Havregryn, Havrefras
Fiberhavregryn
Rågflingor
Korngryn
Corn flakes, majsflingor
Fullkornsflingor, Branflakes
Müsli (bas)
Müsli med frukt
Vetegroddar
Vetekli
Havrekli
Hårt bröd, råg
Hårt bröd, havre
Hårt bröd, vete
Mjukt bröd, vitt
Mjukt bröd, rågsikt
Mjukt bröd, fullkorn
Mjukt bröd m frön, kärnor
Vetebröd (kaffebröd)
Skorpor, vete
Skorpor, råg
Skorpor, graham
Kex, fullkorn
Kex, vete
1. Vilken typ av mjölk använder du?
□ Minimjölk
□ Lättmjölk
□ Mellanmjölk
□ Standardmjölk
2. Använder du laktosreducerade produkter (t.ex. låglaktos-mjölk eller laktosfri mjölk/filmjölk/grädde)?
□ Ja
□ Nej
Om ja, vilka? ________________________________________________________________________________
© Christina Persson. Enheten för onkologi, Uppsala universitet. 2005
Sida 2 av 2
Acta Universitatis Upsaliensis
Digital Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Medicine 969
Editor: The Dean of the Faculty of Medicine
A doctoral dissertation from the Faculty of Medicine, Uppsala
University, is usually a summary of a number of papers. A few
copies of the complete dissertation are kept at major Swedish
research libraries, while the summary alone is distributed
internationally through the series Digital Comprehensive
Summaries of Uppsala Dissertations from the Faculty of
Medicine.
Distribution: publications.uu.se
urn:nbn:se:uu:diva-215410
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