A lifestyle intervention among elderly men on active surveillance for non-aggressive prostate cancer: a randomised feasibility study with whole-grain rye and exercise
Eriksen et al. Trials
A lifestyle intervention among elderly men on active surveillance for non-aggressive prostate cancer: a randomised feasibility study with whole-grain rye and exercise
Anne Kirstine Eriksen 0
Rikke Dalgaard Hansen 0
Ryan Godsk Larsen
Jeppe Munthe Jensen
Cecilie Kyrø 0
Anja Olsen 0
Anne Tjønneland 0
0 Unit of Diet, Genes and Environment, Danish Cancer Society Research Center , Strandboulevarden 49, 2100 Copenhagen , Denmark
Background: The prognosis for men with non-aggressive prostate cancer is good, and several studies have investigated the impact of lifestyle changes including physical activity and diet on the prognosis. Despite positive results in animal studies and a few human interventions with whole-grain rye on markers of prostate cancer progression, the feasibility of trials investigating such dietary changes in combination with physical activity remains largely unstudied. The primary aim was to investigate the feasibility of an intervention with high whole-grain rye intake and vigorous physical activity for 6 months in men diagnosed with prostate cancer. Methods: In total, 26 men (53-72 years) recently diagnosed with non-aggressive prostate cancer and on active surveillance, were enrolled in 2011-2012 and randomly assigned to an intervention or a control group. The intervention included 170 g/day of whole-grain rye and 3 × 45 minutes/week of vigorous physical activity. The duration of the intervention was 6 months and end of follow-up 12 months after baseline. Clinic visits were scheduled at baseline and 3, 6 and 12 months after baseline. Compliance with the intervention was evaluated by diaries, food frequency questionnaires, biomarkers, and heart rate monitor data. The effect of the intervention was evaluated by linear multiple regression analysis. Results: In the intervention group, the mean daily intake of whole-grain rye measured from diaries was 146 g (SD: 19) for the first 3 months and 125 g (SD: 40) for the last 3 months of the intervention. The median level (5th and 95th percentiles) of vigorous physical activity was 91 (17, 193) min/week for the first 3 months and 66 (13, 259) min/week for the last 3 months. No recordings of physical activity were done for the control group. Aerobic fitness (VO2 peak) increased in the intervention group compared to the control group after the intervention. No effects were found on other cardio-metabolic outcomes or prostate cancer progression. Conclusions: The lifestyle intervention appeared feasible for 6 months among Danish men and the results are encouraging for conducting full-scale studies, where the impact of whole-grain rye and vigorous physical activity on prostate cancer progression and metabolic parameters can be evaluated.
Whole-grain rye; Physical activity; Prostate cancer; Intervention; Feasibility
Prostate cancer is the most commonly diagnosed cancer
among men in the Western part of the world . In
Denmark, it is the most common cancer and the second
most common cause of cancer death among the male
population . The incidence of prostate cancer, especially
indolent prostate cancers, has increased dramatically after
the introduction of the prostate-specific antigen (PSA)
testing in the 1990s . Despite generally good prognoses,
prostate cancer treatments, such as hormone-,
radiationor chemotherapy and prostatectomy surgery, often lead to
a number of side effects such as urinary and erectile
dysfunction and loss of typical male characteristics .
Therefore, an alternative strategy of long-term observation
has been introduced called active surveillance, where men
with prostate cancer considered to be non-aggressive are
followed regularly by monitoring PSA levels and prostate
biopsies. However, men on active surveillance living with
an untreated prostate cancer have been reported to
experience distress, from the uncertainty of whether the
disease will progress , and pressure from relatives to
choose an active treatment instead . The current study
was initiated to investigate if active involvement of the
patient through lifestyle changes with diet and exercise
was feasible in a group of men with non-aggressive
prostate cancer on active surveillance.
One of the specific foods that has been in focus is
whole-grain rye. Whole-grain rye and rye bran have a
high content of dietary fibre, lignans and a number of
other compounds with anticipated health effects . In a
small 3-week pilot intervention study in Sweden, high
intakes of rye bran increased tumour apoptosis in men
with prostate cancer , and a 6-week randomised
crossover study found that high intakes of whole-grain rye
resulted in lowered concentrations of PSA, fasting glucose,
insulin, urinary C-peptide, and C-reactive protein in men
with early-stage prostate cancer . Furthermore, in
animal studies, whole-grain rye reduced early prostate
tumour growth, reduced concentrations of PSA, and
increased epithelial cell apoptosis [10–12]. Whole-grain rye
is rich in alkylresorcinols, phenolic lipids exclusively found
in the outer layer of whole-grain wheat and rye among
commonly consumed foods  that have been validated
as concentration biomarkers of whole-grain wheat and rye
Physical activity has been suggested to improve
prognosis , quality of life, and physical fitness and well-being
 among men with prostate cancer. In observational
studies, both amount and intensity of physical activity
have been associated with better prognosis and survival
among prostate cancer cases [17–19]. Vigorous physical
activity, for at least 3 hours/week compared to less than 1
hour/week, was associated with 61% lower risk of prostate
cancer-specific mortality in a US cohort study . The
feasibility of increasing physical activity in combination
with dietary changes in men with prostate cancer has
been investigated  – also currently in ongoing
studies [21, 22]. In all these studies, dietary interventions
included reduced fat intake and increased plant-based
foods, whereas neither included rye in the diets.
The primary aim of the present study was to evaluate
the feasibility of introducing a comprehensive lifestyle
intervention, with vigorous exercise and high
wholegrain rye intake for 6 months, in a group of men with
non-aggressive prostate cancer. Second, the effect of the
intervention on cardio-metabolic outcomes, and further
PSA levels, was evaluated.
In brief, 26 Danish men aged 53–72 years, recently
diagnosed (maximum 24 months from baseline) with
non-aggressive prostate cancer and on active surveillance,
were enrolled continuously over a period from March 2011
to November 2012 from the Department of Urology,
Aarhus University Hospital, Denmark
(www.ClinicalTrials.gov, identification number NCT01300104). At the time of
diagnosis or as part of regular active surveillance visits at
the Department of Urology, prostate cancer patients were
informed about the Nordic Lifestyle Intervention Trial on
Prostate Cancer Progression (NILS) study. The number of
participants was based on the predicted number that the
study centre was able to recruit within the time provided,
and that the sample size would be sufficient to test
the recruitment, randomisation, intervention,
followup processes, and participant drop-out. The inclusion
and exclusion criteria are described in Table 1. Eligible
participants were informed about the NILS study orally
and in writing as recommended in the current guidelines
Table 1 Inclusion and exclusion criteria for study participation
in the NILS feasibility study
Biopsy-proven prostate cancer
within 2 years prior to enrolment
PSA ≤ 10, Gleason score ≤ 6,
clinical classification ≤ cT2a or
PSA ≤ 10, Gleason score ≤ 7,
clinical classification ≤ cT2a
Maximum 1/5 tumour-positive
On active surveillance
(elected to forgo treatment)
Prior history of cancer, except for
non-melanoma skin cancer, unless
considered cured without signs of
treatment failure for at least 5 years
Conditions or behaviours likely to
affect the capability of participating
fully in the intervention
Moderate to severe co-morbidity
(kidney, liver, heart, or respiratory
Inflammatory bowel disease or
aWas adjusted to include the age span of 53–72 years
of the National Committee on Health Research Ethics
(Denmark). After the participants had given informed
consent, they were randomly allocated by a
computergenerated list of random numbers to an intervention
group (17 men) or a control group receiving standard
active surveillance care (9 men) in a 2:1 scheme. In
practice, the study nurse entered the participant
number into a computer whereafter a program output
specified which group the participant was randomised
to. Neither participants nor practitioners were blinded
to the group allocation. The duration of the
intervention was 6 months and end of follow-up was 12
months after baseline. All participants attended
regular scheduled clinic visits at baseline and 3, 6 and 12
months after baseline to monitor prostate cancer
progression and general health through laboratory
assessments and for collection of biological samples (blood
and 24-hour urine samples at all four time points,
and prostate tissue samples at baseline and 6 months
after baseline) for subsequent biomarker analyses. At
baseline, all participants were given a pamphlet on
the at that time current dietary recommendations
“The Eight Danish Dietary Recommendations” .
These include to walk a minimum of 10,000 steps per
day and to consume fish, foods rich in fibre such as
fruit and vegetables, and whole-grain products in the
everyday diet, and to reduce the intake of saturated
fat by use of low-fat meat, soft margarines and
The NILS feasibility study was approved by the
Regional Ethics Committees on Human Studies in
Copenhagen and Aarhus, Denmark (H-1-2010-073) in
September 2010 and by the Danish Data Protection
Agency (2010-41-5520) in February 2011.
The intervention group
Participants in the intervention group were prescribed
to consume a minimum of 170 g whole-grain rye per
day as part of their daily diet. A list of whole-grain rye
products accessible at local groceries and stores and an
electronic scale was provided to all participants in the
intervention group. Photographs of the products were
included with information on whole-grain rye content
per serving (e.g. one slice of bread, one portion of cereal)
and the weight/size in grams of one serving. A point
system with whole-grain rye content for the different
products was developed to ease the task of reaching 170
g of whole-grain rye per day. The participants bought
their own food, but three products were offered for free;
milled whole-grain rye for breakfast meals (rye porridge)
and baking, whole-grain rye pasta, and an instant
powder to make the Danish dessert or breakfast dish
“øllebrød” (a porridge-like dish made of rye bread and
non-alcoholic beer). It was recommended to consume as
much of the milled whole-grain rye as possible. The
products provided were all 100% whole-grain rye. The
target of 170 g of whole-grain rye per day was based on
Dietary habits in Denmark 2003 to 2008 , where a
mean intake of bread, rice, pasta and cereals in men
aged 18–75 years was 245 g per day. The NILS study
participants were in the older range (53–72 years),
presumably with a lower energy intake and furthermore,
rice was not included as no similar rye product exists.
Therefore, 170 g was chosen as a realistic amount of
whole-grain rye per day assuming that all bread, pasta
and cereals were substituted with whole-grain rye
products during the intervention period.
Additionally, the intervention group was prescribed to
exercise at a target intensity of 70% of maximal heart
rate for at least 45 minutes three times per week and
encouraged to walk at least 10,000 steps every day. Steps
per day were monitored by pedometers provided to the
participants for daily use, however, these data are not
included as the step counts were unreliable. The 3 × 45
minutes were chosen to get a sufficient level of physical
activity to be able to see a significant health beneficial
effect , and at the same time a realistic level for the
men in order to ensure compliance. The participants
were instructed to exercise according to customised
endurance training programmes. The training sessions
were non-supervised, but the subjects were instructed to
monitor and upload their activity using a GPS/heart rate
monitor provided at the beginning of the intervention.
The participants were further instructed to register all
physical activity in diaries during the intervention
period. For help and support to improve and maintain
the regimen of the intervention, individual counselling
sessions were prescribed with a dietician and a sports
physiologist at baseline, week 2 and 5, and 3 months and
6 months after baseline. Additionally, two informal
evening get-togethers were held to give the participants the
opportunity to meet and to receive information about
the intervention. The participants’ spouses were
encouraged to attend the regular clinical meetings, counselling
sessions and evening get-togethers.
The control group
The participants in the control group were advised to
follow the “The Eight Danish Dietary Recommendations”
and encouraged to walk 10,000 steps every day. The
control group was included in the study to allow for a
randomised design, but also to test whether it was
possible to have an actual control group who maintained
their habitual lifestyle despite not receiving any
treatment. For a future larger-scale study, this consideration
is important for estimating drop-out rates and other
Participants were examined at the research clinic (baseline,
3, 6 and 12 months after baseline) after an overnight fast.
At each clinic visit, blood samples were drawn (26 mL)
and spun to separate into plasma, serum, erythrocytes and
buffy coat. The samples were then stored at -80 °C.
Anthropometric measurements and seated resting blood
pressure were performed at each visit. At baseline and after
6 months, participants had ten transrectal
ultrasoundguided random prostate needle biopsies taken. Four extra
biopsies were taken for research analyses. As part of
normal procedure to avoid sepsis, a dose of 2 × 500 mg of
the antibiotic Ciproxin (ciprofloxacin) was given prior to
and 6–8 hours after the biopsy was taken. Peak aerobic
capacity, a measure of aerobic fitness (peak oxygen
consumption per unit time [VO2 max]) was assessed using a
maximal progressive stepwise cycle ergometer test, a
respiratory gas exchange analyzer (AMIS 2001; Innovision,
Odense, Denmark), and a heart rate monitor (Polar Electro
Oy, Kempele, Finland).
Analysis of plasma lipids, serum insulin and plasma
glucose concentrations were performed by established
routine methods at the certified laboratory of the
Department of Clinical Chemistry at Uppsala University
Hospital, Sweden. Total PSA was analysed at the
Biochemical Laboratory at Aarhus University Hospital,
Denmark. For alkylresorcinols, five different homologues
were analysed (C17:0. C19:0, C21:0, C23:0 and C25:0) in
plasma by a rapid gas chromatography-mass spectrometry
method . This made it possible to use the C17:0/C21:0
ratio as a measure of whether whole-grain intake primarily
originated from wheat or rye.
Information on diet was collected at baseline, 6 months
and 12 months after baseline using semi-quantitative
food frequency questionnaires (FFQ). The questionnaire
given at baseline was similar to the validated FFQ from
the Danish Diet, Cancer and Health cohort . The
questionnaire included 92 different foods covering the
average intake of the preceding 6 months. A rye-specific
FFQ was constructed for the present study for the
6month visit restricted to 16 questions on specific rye
products in a format similar to the baseline and
followup FFQ. At the 12-month visit, participants were given
the baseline FFQ along with the 16 rye-specific questions.
Furthermore, the intervention group was instructed to
complete daily diaries of rye intake including type and
amount of rye products consumed. FFQ data were
evaluated for all participants, at baseline, 6 months, and 12
months from baseline. Additionally, for the intervention
group, the completed rye diaries were evaluated from
baseline to 3 months and from baseline to 6 months. The
whole-grain rye intake was calculated by multiplying the
percentage of whole grains in the product using
information from the manufacturers of the products. For bread
and crispbread intake, participants reported consumed
slices, which were translated to grams using standard
portion sizes of 25 g for half a slice of rye bread and 12 g
for a slice of crispbread.
The statistical analyses were based on the participants
who completed the 6-month intervention period only
(as opposed to intention-to-treat). Baseline
characteristics, reported whole-grain rye intake, physical activity
diary and heart rate monitor data, alkylresorcinols
concentrations, and all physical and cardio-metabolic
outcomes, and PSA levels are presented as means with
standard deviations (SD) for the intervention and
control group separately.
The effect of the intervention was evaluated by a linear
multiple regression analysis model. The difference
between the groups’ mean changes from baseline to 6
months were then tested by the linear multiple regression
model using least square means, adjusted for baseline level
of the outcome variable. Furthermore, the same analyses
were made to test for differences in compliance markers
(plasma alkylresorcinols concentrations, and the
alkylresorcinol C17:0/C21:0 ratio) between the groups.
Since the NILS study was set up as a feasibility study,
no power calculations were made.
The statistical analyses were conducted using the
procedure general linear model (GLM) in the SAS®
statistical software, release 9.3 (SAS Institute, Cary,
Twenty-one participants completed the 6-month
intervention period; 14 in the intervention group and 7 in
the control group (Fig. 1). Five participants dropped out
due to prostate cancer progression (n = 1), work-related
reasons (n = 1), discus prolapse (n = 1), death in the
family (n = 1) and colorectal cancer (n = 1), of which three
were from the intervention group and two from the
control group. Further, two of the 14 participants in the
intervention group dropped out before the 12-month
examination (6 months after intervention ended) due to
prostate cancer progression. Baseline characteristics of
the participants, as shown in Table 2, were similar for
the two groups.
Whole-grain rye intake
Compliance with the whole-grain rye intervention diet
was generally good, though slightly lower than the target
of an average of 170 g of whole-grain rye per day
Fig. 1 Flowchart of participants and drop-out in the NILS feasibility study
(Table 3). In the intervention group, as reported in the
daily rye diaries, the mean daily intake of whole-grain
rye was 146 g (SD: 19) for the first 3 months and 125 g
(SD: 40) for the last 3 months of the intervention. The
whole-grain content of the rye products consumed in
the intervention group ranged from 50–100%. The most
common sources of whole-grain rye were 100%
wholegrain rolled rye flakes for breakfast and rye bread with
60% whole-grain rye for lunch. Additionally, other rye
cereals and rye pasta were consumed regularly. Twelve
months after baseline (six months after end of
intervention), the FFQ reported whole-grain rye intake was
continued at a similar level as reported after 6 months of
intervention. The FFQ reported rye intake was lower
than the intake reported in the rye diaries since only
whole-grain rye bread and crispbread, not cereals, pasta
etc., was included in all three FFQs enabling a
comparison only based on the baseline version (Table 3).
Both total alkylresorcinols and C17:0/C21:0 ratio,
markers of compliance, increased and especially between
baseline and 3 months. At end of follow-up, total
alkylresorcinols concentration was lower, but the mean
C17:0/C21:0 ratio was 0.49 (SD: 0.21) indicating a
continued high proportion of whole-grain rye to
wholegrain wheat intake (Table 3). There was a tendency of a
higher mean change in the intervention group compared
to the control group for total alkylresorcinols (mean
change from baseline to 6 months: 93 nmol/L, 95% CI:
-30–215) and for the C17:0/C21:0 ratio (mean change
from baseline to 6 months: 0.08, 95% CI: -0.07–0.22).
The control group did not change their habitual intake
of whole-grain rye from baseline to the end of the
intervention period, as reported in the FFQs. This was
supported by the C17:0/C21:0 ratio, which did not show
any increase over the intervention period. Conversely, the
concentration of total alkylresorcinols, reflecting the total
whole-grain wheat and rye intake, increased in the control
group during the intervention. However, the C17:0/C21:0
ratio decreased, suggesting that the proportion of
wholegrain wheat intake must have increased. At 12 months (end
of follow-up and 6 months after the intervention ended),
the C17:0/C21:0 ratio was doubled in the control group,
but no changes in the FFQ reported rye intake was seen.
Of the 14 men in the intervention group, 12 provided
physical activity data from their heart rate monitors. Of
these, there were missing or unrecorded data for a period
of 2–3 weeks of the 26 weeks for four participants.
According to the heart rate monitor data (Fig. 2), a median
level of 91 (P5-P95: 17, 193) min/week of vigorous activity
for the first 3 months and 66 (P5-P95; 13, 259) min/week
for the last 3 months was performed. The total amount of
physical activity, assessed both by heart rate monitor and
the physical activity diaries, was 285 (P5-P95: 58, 452)
min/week per week for the first 3 months and 225
(P5P95: 77, 355) min/week for the last 3 months (Table 3).
Effects of the intervention
Aerobic fitness evaluated by VO2 peak increased by 2.8
(95% CI: 0.1, 5.4) ml O2/min/kg in the intervention group
compared to the control group after 6 months. There was
no statistically significant difference in mean change of
body composition, cardio-metabolic outcomes, or PSA
levels between the intervention and the control group after
6 months (Table 4). However, there was a tendency for a
Table 2 Baseline characteristics for intervention and control
group – the NILS feasibility study
Age at baseline (y)
Age at PC diagnosis (y)
Hip circumference (cm)
Waist circumference (cm)
Fat-free mass (kg)
Fat mass (%)
VO2 max (ml O2/min/kg)
Systolic BP (mmHg)
Diastolic BP (mmHg)
HDL cholesterol (mmol/L)
LDL cholesterol (mmol/L)
Total cholesterol (mmol/L)
Fasting plasma glucose (mmol/L)
Fasting blood glucose (mmol/L)
Blood glucose 2 h (mmol/L)
Fasting insulin (mmol/L)
Alkylresorcinols total (nmol/L)
C17:C21 alkylresorcinol ratio
Plasma enterolactone (nM)
Prostate-specific antigen (PSA) (ng/ml)
SD standard deviation, PC prostate cancer, BMI body mass index, VO2 max
peak oxygen consumption per unit time, BP blood pressure, HDL high-density
lipoprotein, LDL low-density lipoprotein
decrease in waist circumference and plasma concentrations
of cholesterols in the intervention group compared to the
control group. The difference in mean change for waist
circumference was -3 cm (95% CI: -7, 1). For LDL
cholesterol and total cholesterol, mean changes of -0.3 mmol/l
(95% CI: -0.7, 0.0) and -0.4 mmol/l (95% CI: -0.8, 0.1)
respectively, were observed. In general, cardio-metabolic
outcomes and PSA levels were similar from end of
intervention to end of follow-up, and the increased aerobic
fitness level was also maintained 6 months after end of
intervention. The PSA levels did not change in any clear
direction according to the intervention, as shown in Fig. 3.
Information on side effects from the intervention was
not systematically collected for the study, but some of
the participants discussed problems with increased
flatulence and stomach pain with the study dietician.
In this feasibility study, men diagnosed with non-aggressive
prostate cancer managed to consume a high amount of
whole-grain rye and to engage in vigorous physical activity
during a 6-month intervention period, and thus the study
found that it was feasible to complete such an intervention.
Aerobic fitness increased significantly in the intervention
group compared to the control group and this was
maintained 6 months after end of intervention. No significant
effects were found on cardio-metabolic outcomes or PSA
levels between the intervention and control group, which
was not surprising with the limited power due to the small
sample size of the feasibility study. However, tendencies for
lower waist circumference and cholesterol levels were
observed in the intervention group compared to the control
group. A full-scale intervention study is needed to
investigate the health effects of the intervention further.
Strengths and limitations
The study participants were selected by strict criteria,
ensuring a homogenous group, and with the randomised
design, the risk of potential confounding or uneven
distribution hereof is minimised.
The regular follow-up meetings, physical examinations,
diaries, monitors and biomarkers made it possible to
evaluate compliance to the intervention during the entire
study period. The compliance was generally good,
however, the participants failed to fully meet the targets of 170
g of whole-grain rye per day and 3 × 45 minutes of
vigorous physical activity per week on average over the
6month intervention period. Five out of twenty-six (20%)
randomised participants did not complete the 6-month
intervention, which was as expected. Furthermore, two
participants out before the 12-month follow-up. We do
not suspect drop-out to have influenced our results, as the
explanations seems unrelated to the intervention.
Dropout due to prostate cancer progression was, however,
reported only for participants in the intervention group,
but since the intervention group included two times the
number in the control group, this could be purely due to
chance. Furthermore, two of the participants who
experienced prostate cancer progression and dropped out, did
so during the 6 months after the active intervention
period, making an association to the intervention itself
unlikely. In future studies, it is important to retain the
participants that drop out in the study, thus enabling
The NILS study was designed to test the feasibility of
a lifestyle intervention with whole-grain rye and vigorous
physical activity in a group of men with prostate cancer
considered to be non-aggressive. The sample size of 21
participants with complete data for the 6-month
intervention was small, and statistical tests therefore had limited
power. The focus was accordingly on the implementation
of whole-grain rye and physical activity in the daily
life of men with prostate cancer. Blinding to the
intervention/control arm was not possible in this
study as no corresponding treatment was offered to
the control group. This is a general problem in both
whole-grain and exercise interventions as taste and
appearance of cereals (and especially rye) are difficult
to mask, as is introducing placebo exercise. The NILS
study did draw attention in the media, and it is likely
that this also reached men in the control group.
Hence, it is possible that participants in the control
group changed their habits by, for example, increased
whole-grain rye intake and physical activity. The
alkylresorcinol C17:0/C21:0 ratio, however, did not
increase in the control group during the intervention
period and therefore we do not suspect whole-grain
rye intake to have increased in this group. Data to
quantify physical activity level of participants in the
control group were not collected during the
intervention period. However, VO2 peak did not increase
notably, suggesting no apparent change in physical
activity pattern in the control group.
Feasibility of a high whole-grain rye intake during 6 months
We addressed compliance with the intervention by
independent measures, i.e. self-reported whole-grain rye
intake and with biomarkers reflecting total whole-grain
wheat and rye intake and the proportion of whole-grain
rye to total whole-grain wheat and rye intake: total
alkylresorcinols and C17:0/C21:0 ratio. The high
reported intakes of whole-grain rye were supported by
high alkylresorcinols concentrations during the study
period and with a high C17:0/C21:0 ratio, showing that
the dietary intervention was successful in regards to
whole-grain rye intake. The participants, however,
decreased their intake during the last 3 months of the
intervention compared to the first 3 months, which could
indicate that the aim of 170 g of whole-grain rye per day
was too high for a realistic long-term intake during 6
months. Even though Danish men have a generally high
whole-grain intake, many participants complained about
stomach pain and increased flatulence especially at the
beginning of the intervention as the whole-grain rye intake
increased significantly. If participants complained about
such side effects, they were instructed to stepwise increase
the amount of whole-grain rye per day during
approximately 2 weeks before reaching the full amount. Reduced
intake of fibre-rich fruits and vegetables for this run-in
period was also suggested by the study dietician to avoid
problems. For a potential future full-scale study, this is an
important consideration as stomach pain and increased
flatulence can lead to unnecessary drop-out or
noncompliance with target intake and a run-in period could
be introduced to avoid such problems. Furthermore, to
ensure compliance, it may also be relevant to follow the
participants even closer e.g. using modern technology (e.g.
mobile applications) and to involve the spouses of the
prostate cancer patients .
Feasibility of implementing vigorous physical activity
during 6 months
The physical activity part of the intervention was evaluated
by heart rate monitors and physical activity diaries. The aim
of 3 × 45 minutes of vigorous physical activity per week was
not achieved (Fig. 2). However, the total amount of reported
physical activity was of more than 4 hours per week, of
which at least 1–1.5 hours was completed at a vigorous
level (70% of maximal heart rate) indicating an acceptable
compliance for this training intervention, despite the lack of
supervised exercise sessions. The physical fitness level at
baseline for the study participants corresponded to a low
physical fitness level for men in the age group between 50–
70 years compared to results from a subsample from the
Danish Health Examination Survey 2007–2008 .
The observed improvement in VO2 peak in the
intervention group of around 3 ml O2/min/kg is in accordance with
similar studies with participants in the same age group and
with baseline fitness levels in the same low range (25–28 ml
O2/kg/min), but with physical activity interventions of 12
weeks  and 6 months  durations, respectively.
Whether the improved fitness level obtained in NILS is of
clinical relevance is important to consider in future
initiatives. An increase of 3.5 ml O2/min/kg (equal to 1 MET)
was in a meta-analysis associated with 13–15% lower risk of
all-cause mortality and cardiovascular disease in healthy
men and women . The impact on prostate cancer
progression is of course more relevant for this study and this
has been investigated in prospective study designs where
moderate-vigorous physical activity was associated with
lower risks (44–61%) of prostate cancer-specific mortality
[17, 19] and lower rate of progression .
Effects of the intervention
Evaluation of the effect of the intervention on
cardiometabolic outcomes and PSA levels was a secondary aim of
this feasibility study and the power was not sufficient for
statistical testing. Individual change in PSA levels during the
intervention and 6 months after, showed large variation with
no clear pattern, which might not have been the case with a
larger sample size. However, we regard the implementation of
whole-grain rye and physical activity as feasible, and further
positive tendencies on aerobic fitness, waist circumference
and cholesterols were observed. Therefore, a full-scale study
should be encouraged for further exploration of the effects of
a feasible lifestyle prevention strategy on cardio-metabolic
outcomes and prostate cancer disease progression.
Men with prostate cancer managed to consume large
amounts of whole-grain rye, reported in whole-grain rye
diaries and confirmed by whole-grain rye compliance
biomarkers. The level of vigorous physical activity
increased during the intervention and as a result, aerobic
fitness improved among participants in the intervention
group. There was no statistical difference between the
intervention and control group on cardio-metabolic
outcomes or PSA levels, but this was as expected as the
power was low due to the feasibility focus of the study.
However, we find that the successful lifestyle
implementations of whole-grain rye and physical activity
encourage a full-scale study powered to investigate effects on
prostate cancer progression specifically.
The authors thank the participants of the NILS feasibility study and their spouses for
highly committed participation and for sharing their experiences with the research
team. We also thank the project nurses Birgit Kaa Bach and Helene Holm Pedersen,
Aarhus University Hospital, Denmark, for excellent assistance on NILS study design
and implementation, Claus Brasen for providing laboratory analyses, the HELGA
group from which the NILS feasibility study emanated and Nick Martinussen and
Katja Boll for invaluable assistance on data managing. Il Fornaio and Skaertoft Mølle
kindly contributed with whole-grain rye products for the study.
This study was conducted in the context of the CHANCES project funded in
the FP7 framework program of DG-RESEARCH in the European Commission
(grant no. 242244). The CHANCES project was coordinated by the Hellenic
Health Foundation, Greece. Further funding was obtained from Innovation
Fund Denmark (ELIN: 0603-00580B).
Availability of data and material
The dataset generated and analysed during the current study are not
publicly available, but can be requested if approved by the Danish Data
AKE performed the data analysis and wrote the manuscript. AT, Michael B and
RDH designed the study, and RDH led the intervention. Michael B was the
responsible medical doctor and saw all participants during the recruitment
period and performed the prostate cancer progression (biopsy) examinations.
Mette B saw the participants for dietary advice and dietician counselling. RGL,
JMJ and KO made the individualised exercise programmes and performed the
physical activity tests and examinations. Samples were analysed in RL’s
laboratory and RL contributed with statistical advice in both design and data
analyses. AO and CK contributed in design and analyses and in the writing
process. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
The NILS feasibility study was approved by the Regional Ethics Committees
on Human Studies in Copenhagen and Aarhus, Denmark (H-1-2010-073)
September 2010 and by the Danish Data Protection Agency (2010-41-5520)
February 2011. All participants signed informed consent.
1. Ferlay J , Soerjomataram I , Dikshit R , Eser S , Mathers C , Rebelo M , Parkin DM , Forman D , Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 . Int J Cancer . 2015 ; 136 ( 5 ): E359 - 86 .
2. Engholm G FJ , Christensen N , Johannesen TB , Khan S. , Køtlum JE , Milter MC , Ólafsdóttir E , Pukkala E , Storm HH : NORDCAN: Cancer incidence, mortality, prevalence and survival in the Nordic countries , Version 6. 1 ( 25 .04. 2014 ). Association of the Nordic Cancer Registries , Danish Cancer Society; 2014 . Available from: http://www-dep.iarc.fr/NORDCAN/english/frame.asp. Accessed 18 Nov 2014 .
3. International Agency for Research on Cancer. World Cancer Report 2014 . Edited by Stewart BW and Wild CP . International Agency for Research on Cancer, Lyon. 2014 . p. 453 - 464 .
4. Hegarty JM , Wallace M , Comber H. Uncertainty and quality of life among men undergoing active surveillance for prostate cancer in the United States and Ireland . Am J Mens Health . 2008 ; 2 ( 2 ): 133 - 42 .
5. Xu J , Neale AV , Dailey RK , Eggly S , Schwartz KL. Patient perspective on watchful waiting/active surveillance for localized prostate cancer . J Am Board Fam Med . 2012 ; 25 ( 6 ): 763 - 70 .
6. Daubenmier JJ , Weidner G , Marlin R , Crutchfield L , Dunn-Emke S , Chi C , Gao B , Carroll P , Ornish D. Lifestyle and health-related quality of life of men with prostate cancer managed with active surveillance . Urology . 2006 ; 67 ( 1 ): 125 - 30 .
7. Fardet A. New hypotheses for the health-protective mechanisms of wholegrain cereals: what is beyond fibre? Nutr Res Rev . 2010 ; 23 ( 1 ): 65 - 134 .
8. Bylund A , Lundin E , Zhang JX , Nordin A , Kaaks R , Stenman UH , Aman P , Adlercreutz H , Nilsson TK , Hallmans G , et al. Randomised controlled short-term intervention pilot study on rye bran bread in prostate cancer . Eur J Cancer Prev . 2003 ; 12 ( 5 ): 407 - 15 .
9. Landberg R , Andersson SO , Zhang JX , Johansson JE , Stenman UH , Adlercreutz H , Kamal-Eldin A , Aman P , Hallmans G . Rye whole grain and bran intake compared with refined wheat decreases urinary C-peptide, plasma insulin, and prostate specific antigen in men with prostate cancer . J Nutr . 2010 ; 140 ( 12 ): 2180 - 6 .
10. Bylund A , Zhang JX , Bergh A , Damber JE , Widmark A , Johansson A , Adlercreutz H , Aman P , Shepherd MJ , Hallmans G . Rye bran and soy protein delay growth and increase apoptosis of human LNCaP prostate adenocarcinoma in nude mice . Prostate . 2000 ; 42 ( 4 ): 304 - 14 .
11. Wikstrom P , Bylund A , Zhang JX , Hallmans G , Stattin P , Bergh A. Rye bran diet increases epithelial cell apoptosis and decreases epithelial cell volume in TRAMP (transgenic adenocarcinoma of the mouse prostate) tumors . Nutr Cancer . 2005 ; 53 ( 1 ): 111 - 6 .
12. Landstrom M , Zhang JX , Hallmans G , Aman P , Bergh A , Damber JE , Mazur W , Wahala K , Adlercreutz H. Inhibitory effects of soy and rye diets on the development of Dunning R3327 prostate adenocarcinoma in rats . Prostate . 1998 ; 36 ( 3 ): 151 - 61 .
13. Linko-Parvinen AM , Landberg R , Tikkanen MJ , Adlercreutz H , Penalvo JL. Alkylresorcinols from whole-grain wheat and rye are transported in human plasma lipoproteins . J Nutr . 2007 ; 137 ( 5 ): 1137 - 42 .
14. Landberg R , Kamal-Eldin A , Andersson A , Vessby B , Aman P. Alkylresorcinols as biomarkers of whole-grain wheat and rye intake: plasma concentration and intake estimated from dietary records . Am J Clin Nutr . 2008 ; 87 ( 4 ): 832 - 8 .
15. Newton RU , Galvao DA . Accumulating evidence for physical activity and prostate cancer survival: time for a definitive trial of exercise medicine? Eur Urol . 2016 ; 70 ( 4 ): 586 - 7 .
16. Bourke L , Smith D , Steed L , Hooper R , Carter A , Catto J , Albertsen PC , Tombal B , Payne HA , Rosario DJ . Exercise for men with prostate cancer: a systematic review and meta-analysis . Eur Urol . 2016 ; 69 ( 4 ): 693 - 703 .
17. Kenfield SA , Stampfer MJ , Giovannucci E , Chan JM. Physical activity and survival after prostate cancer diagnosis in the health professionals follow-up study . J Clin Oncol . 2011 ; 29 ( 6 ): 726 - 32 .
18. Richman EL , Kenfield SA , Stampfer MJ , Paciorek A , Carroll PR , Chan JM . Physical activity after diagnosis and risk of prostate cancer progression: data from the cancer of the prostate strategic urologic research endeavor . Cancer Res . 2011 ; 71 ( 11 ): 3889 - 95 .
19. Friedenreich CM , Wang Q , Neilson HK , Kopciuk KA , McGregor SE , Courneya KS . Physical activity and survival after prostate cancer . Eur Urol . 2016 ; S0302 - 2838 ( 15 ): 01241 - 5 .
20. Demark-Wahnefried W , Nix JW , Hunter GR , Rais-Bahrami S , Desmond RA , Chacko B , Morrow CD , Azrad M , Fruge AD , Tsuruta Y , et al. Feasibility outcomes of a presurgical randomized controlled trial exploring the impact of caloric restriction and increased physical activity versus a waitlist control on tumor characteristics and circulating biomarkers in men electing prostatectomy for prostate cancer . BMC Cancer . 2015 ; 16 : 61 .
21. Focht BC , Lucas AR , Grainger E , Simpson C , Thomas-Ahner JM , Clinton SK . The Individualized Diet and Exercise Adherence Pilot Trial (IDEA-P) in prostate cancer patients undergoing androgen deprivation therapy: study protocol for a randomized controlled trial . Trials . 2014 ; 15 : 354 .
22. Hackshaw-McGeagh L , Lane JA , Persad R , Gillatt D , Holly JM , Koupparis A , Rowe E , Johnston L , Cloete J , Shiridzinomwa C , et al. Prostate cancer - evidence of exercise and nutrition trial (PrEvENT): study protocol for a randomised controlled feasibility trial . Trials . 2016 ; 17 ( 1 ): 123 .
23. Fødevarestyrelsen: De 8 officielle kostråd . Edited by Administration TDVaF . http://altomkost.dk/deofficielleanbefalingertilensundlivsstil/de-officiellekostraad/ 2008 . Accessed 18 Nov 2014 .
24. Pedersen ANFS , Velsing Groth M , et al. Danskernes kostvaner 2003-2008 (Dietary habits in Denmark 2003 to 2008) . Søborg, Denmark: DTU Fødevareinstituttet ; 2010 .
25. Garber CE , Blissmer B , Deschenes MR , Franklin BA , Lamonte MJ , Lee IM , Nieman DC , Swain DP . American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise . Med Sci Sports Exerc . 2011 ; 43 ( 7 ): 1334 - 59 .
26. Landberg R , Man P , Kamal-Eldin A. A rapid gas chromatography-mass spectrometry method for quantification of alkylresorcinols in human plasma . Anal Biochem . 2009 ; 385 ( 1 ): 7 - 12 .
27. Tjonneland A , Overvad K , Haraldsdottir J , Bang S , Ewertz M , Jensen OM . Validation of a semiquantitative food frequency questionnaire developed in Denmark . Int J Epidemiol . 1991 ; 20 ( 4 ): 906 - 12 .
28. Rossen S , Hansen-Nord NS , Kayser L , Borre M , Borre M , Larsen RG , Trichopoulou A , Boffetta P , Tjonneland A , Hansen RD . The impact of husbands' prostate cancer diagnosis and participation in a behavioral lifestyle intervention on spouses' lives and relationships with their partners . Cancer Nurs . 2016 ; 39 ( 2 ): E1 - 9 .
29. Eriksen L , Gronbaek M , Helge JW , Tolstrup JS . Cardiorespiratory fitness in 16 025 adults aged 18-91 years and associations with physical activity and sitting time . Scand J Med Sci Sports . 2015 . doi:10.1111/sms.12608
30. Ho SS , Dhaliwal SS , Hills AP , Pal S. The effect of 12 weeks of aerobic, resistance or combination exercise training on cardiovascular risk factors in the overweight and obese in a randomized trial . BMC Public Health . 2012 ; 12 : 704 .
31. Davidson LE , Hudson R , Kilpatrick K , Kuk JL , McMillan K , Janiszewski PM , Lee S , Lam M , Ross R. Effects of exercise modality on insulin resistance and functional limitation in older adults: a randomized controlled trial . Arch Intern Med . 2009 ; 169 ( 2 ): 122 - 31 .
32. Kodama S , Saito K , Tanaka S , Maki M , Yachi Y , Asumi M , Sugawara A , Totsuka K , Shimano H , Ohashi Y , et al. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis . JAMA . 2009 ; 301 ( 19 ): 2024 - 35 .