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© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Chronic fatigue in 812 testicular cancer survivors during long-

term follow up: increasing prevalence and risk factors

M. Sprauten1, H. S. Haugnes2,3, M. Brydøy4, C. Kiserud1, T. Tandstad5, T. Bjøro6,7, J.

Bjerner8, M. Cvancarova1, S. D. Fosså1, J. Oldenburg9

1National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital,

Oslo, Norway

2Institute of Clinical Medicine, Oncology, University of Tromsø, Tromsø, Norway

3Department of Oncology, University Hospital of North Norway, Tromsø, Norway

4Department of Oncology, Haukeland University Hospital, Bergen, Norway

5The Cancer Clinic, St Olavs University Hospital, Trondheim, Norway

6Department of Medical Biochemistry, Oslo University Hospital, Norway

7Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway

8Fürst Medical Laboratory, Oslo, Norway

9Department of Oncology, Oslo University Hospital, Oslo, Norway

Corresponding author: Dr. Jan Oldenburg, Department of Oncology, Akershus University

Hospital, Lørenskog, Norway, & University of Oslo, Norway, Telephone: +47 915 02900, E-

mail: jan.oldenburg@medisin.uio.no

Key Message: "This longitudinal study reveals a substantial increase in CF during 12 to 19 years after

treatment, with higher levels of anxiety, depression, and neurotoxicity, and lower levels of

testosterone, being associated with CF at the second assessment. Moderate and high physical

activity indicated a protective effect. These findings might indicate means to prevent or treat CF.

Health care professionals should have early prevention of CF through life style interventions and

early detection, and treatment and follow-up of comorbid conditions in mind when caring for TCSs

and probably other cancer survivors as well."

Annals of Oncology Advance Access published August 11, 2015 at U

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Abstract

Background: Chronic fatigue (CF) has been reported to be slightly more prevalent in

Testicular Cancer Survivors (TCSs) than in the general population. In this study, we wanted

to explore possible determinants of CF in TCSs median 12 (Survey I) and 19 years (Survey II)

after treatment, in particular the relation to late effects after treatment.

Patients & Methods: Overall, 812 TCSs treated between 1980-1994 provided blood samples

(Testosterone and Luteinizing Hormone) and completed questionnaires at Survey I (1998-

2002), and Survey II (2007-2008). Hormone levels were categorized according to quartile

thresholds for decadal age groups of controls. Associations between CF and possible risk

factors including the Hospital Anxiety and Depression Scale (HADS), treatment, physical

activity, hormone levels, neurotoxicity, and comorbidity, were analyzed by logistic

regression.

Results: Prevalence of CF increased from 15% at Survey I to 27% at Survey II (p<0.001). At

Survey II, risk for CF was increased 3-4-fold for high levels of neuropathy compared with no

neuropathy, and 2-3-fold for high levels of Raynaud like phenomena and having testosterone

levels in the lowest quartile, while being moderately and highly physically active had a

protective effect. Risk for CF in TCSs with higher levels of HADS-Anxiety and HADS-

Depression was increased 2-5-fold, respectively.

Conclusion: The increasing prevalence of CF in TCSs is a novel finding. Life style

interventions, early detection and treatment of depression and anxiety and possibly

testosterone substitution might reduce the risk of CF. Extended long-term follow-up seems

important.

Keywords: Fatigue, survivorship, testicular cancer, physical activity, testosterone,

hypogonadism

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Introduction

Chronic Fatigue (CF) has been described as one of the most common and distressing adverse

effects of cancer and its treatment.[1] Research on the development of CF, possible risk-

factors and long-term prevalence in cancer survivors represents an area of particular clinical

interest. Population-based studies and longitudinal assessments might be prerequisite to

answer some of these conundrums, however, such studies are exceedingly rare. Testicular

cancer (TC) is regarded a model for a curable neoplasm with 5-year relative survival rates

exceeding 97% in Norway.[2] Thereby the increasing cohort of young TC survivors (TCSs) is

regarded as optimal for cancer survivorship research, including late effects like cardiovascular

disease (CVD), secondary cancer, neurotoxicity, fatigue and hypogonadism.[3,4]

Premature hormonal ageing might represent a particular threat for the well-being of cancer

survivors and this long-term complication in TCSs was recently reported by our group.[5]

Primary endocrine hypogonadism, i.e. a decreased testosterone production, accompanied by

increased levels of Luteinizing Hormone (LH), may result in reduced energy levels,

diminished libido, erectile dysfunction, depressed mood, reduced muscle mass and strength,

anaemia, osteoporosis, CVD and metabolic syndrome. [6-12]

CF, defined as fatigue above a certain level with duration ≥ 6 months, is more common in

TCSs (16%) than in the general male population (10%).[13-15] The prevalence of CF

increases with age in the general male population (from 9.6% to 12.2% for the decadal age

groups 40-49 and 50-59, respectively).[15] Currently, little is known about the longitudinal

development of CF in cancer survivors and a relevant question is whether the observed

increase of CF in the general population will be more or possibly less pronounced in TCSs.

Anxiety, depression and comorbidity have been shown to be associated with CF, whereas

other factors associated with fatigue have rarely been assessed in TCSs, and to our knowledge

not with follow-up data up to 20 years after treatment.[14]

The number of cancer survivors referred due to CF to the Norwegian Advisory Unit on Late

Effects after Cancer Treatment has been increasing and includes TCSs with debut of CF

several years after treatment. Intrigued by this observation, we wanted to assess the

prevalence of CF and its possible determinants in TCSs after longer time of observation than

previous reports,[14] and in particular assess CF in relation to the comorbidity and toxicities

commonly observed in TCSs like CVD, anxiety, depression, hypogonadism, and

neurotoxicity.[4]

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Aims of this explorative study were: 1) to describe the prevalence of CF in a

population-based cohort of TCSs at two late time points after treatment, 2) to assess the

relationship between CF and possible risk factors including serum levels of testosterone and

LH, treatment type, long-term toxicities, depression, anxiety, and comorbidities.

Methods

Design and Study Population

This longitudinal study originates from two national population-based surveys

conducted during 1998-2002 (SI) and 2007-2008 (SII), assessing somatic and psychosocial

health in long-term TCSs. All men aged 18-75 years treated for unilateral germ cell TC in

Norway from 1980 through 1994 were invited (n=1,814, SI). Exclusion criteria were:

Extragonadal germ cell cancer or secondary malignancies except skin cancer, bilateral

orchiectomy, or mental retardation. Treatment details for TCSs during the study period have

been described previously.[16]

A total of 1,463 males (81%) participated at SI. However, exclusion of those with

missing hormone samples, questionnaire data, and other reasons, resulted in 812 men eligible

at both surveys (Figure 1).

At SI, median 12 years (range 5-21 years) after TC treatment, participants underwent a

clinical examination. Serum for hormone analyses was generally collected before 11 am. SII

was performed median 19 years (range 13- 28 years) after treatment, and blood samples were

collected before 12 noon at the primary care physician’s office, and all samples were sent to

central analysis.

At SI and SII, the participants completed a questionnaire including the Fatigue

Questionnaire (FQ), the Scale for Chemotherapy-Induced Neurotoxicity (SCIN), and

questions addressing comorbidities, medication, tobacco use, and marital status.[17,18]

Both surveys were approved by the Regional Committee for medical and health

research ethics of the South Eastern Health Region in Norway.

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Questionnaires

The FQ includes 11 items (7 items covering physical fatigue, 4 items covering mental

fatigue).[18,19] Each item has four response alternatives (0-3). Summation of the 11 item

scores yields a total fatigue score between 0 and 33, with higher scores indicating higher

levels of fatigue. Two additional questions evaluate the extent and duration of fatigue (less

than a week = 0, less than three months = 1, between three and six months =2, and more than

six months =3). For case definition, the 11 item-scores were dichotomized (0 and 1 = 0, and 2

and 3 = 1) and summarized, with a sum score of ≥ 4 and duration of symptoms ≥ 6 months

defining CF.[13,20]

The Hospital Anxiety and Depression Scale (HADS) consists of 7 items covering

anxiety (HADS-A) and 7 items covering depression (HADS-D), with item-scores of 0-3.

Total sum scores (0-21) are calculated by summation of 7 item-scores with higher scores

indicating higher symptom levels, and with scores of 8 or above defining caseness of both

HADS-A and HADS-D.[21]

Comorbidity was recorded based on self-reported diabetes, cardiac disease (incident

angina or heart attack) or pulmonary disease (yes/no).

Levels of physical activity were categorized into three groups (inactive, moderately

active, highly active) as previously published.[22]

Neurotoxicity was assessed by the SCIN.[17] The TCSs responded to how bothered

they were (not at all=0, a little=1, quite a bit=2, very much=3), by each of the six symptoms

(neuropathy in hands/fingers and/or feet/toes, Raynaud’s phenomenon in hands/fingers and/or

feet/toes, tinnitus and/or reduced hearing). To reduce the number of variables in the

multivariate analyses, the two questions regarding neuropathy (hands/fingers and feet/toes)

were combined into one item, recording the worst score for any of these two symptoms with

corresponding procedures for Raynaud’s phenomenon and ototoxicity.

Laboratory analyses

Testosterone and LH levels were measured at both surveys by routine immunoassays.

During the study period the laboratory changed the analytic method. However, for both

testosterone and LH the correlations between assays were within biological variations. Cross

reactivity between LH and Human Chorionic Gonadotropin was minimal.

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The reference intervals reported by Bjerner et al were used for both study periods.[23]

Testosterone and LH levels from TCSs were categorized into quartiles according to the cutoff

values for the 25, 50, and 75 percentiles of the reference intervals for each decadal age group,

thereby adjusting for age-related variations, as previously published.[5] This categorization

yields more information than a dichotomization according to cut-off levels.

Statistical Methods

Crude associations between continuous variables were assessed with paired t-tests and

with χ2-test for trend for ordered categorical variables. Additional univariate logistic

regression analyses were performed to evaluate associations between CF and testosterone

levels, LH levels, and treatment.

Age was not linear in the logit, moreover, when entered as decades it was not

statistically significant and therefore not included into the final model in order to save

statistical power.

When selecting the best final model, we used both the objective criteria, the Akaiki

information criterion (AIC) and our clinical knowledge. Our modeling process focused on

variables that were both of clinical interest and statistically significantly associated with the

dependent variable. We have tried several models and chose to present the one with the

smallest AIC.[24] We did not use any automated variable selection methods like backward or

forward selection because the number of possible covariates and models was rather limited.

Multivariate logistic regression analyses were performed to investigate the

associations between CF at SI and SII separately, and hormone levels, type of treatment,

neurotoxicity and comorbid conditions. Variables considered of high clinical relevance (e.g.

treatment) and variables associated with CF (p≤0.05) in the univariate analyses, were included

in the multivariate analyses.

All tests were two-sided, and p-values ≤ 0.05 were considered statistically significant.

Our analyses were considered exploratory, so adjustment for multiple testing was not

performed. All analyses were performed using SPSS version 19·0 (SPSS, Chicago, IL).

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Results

Patient characteristics

Of the 812 TCSs included, 29% had metastatic disease at diagnosis (Table 1). In total

164 men (20%) had been treated with surgery alone, while 343 men (42%) received

radiotherapy and 305 (38%) received chemotherapy. In the latter group, 32 males had also

received radiotherapy. Median age at SII was 50 years in the surgery and chemotherapy

group, and 55 years in the radiotherapy group. Testosterone substitution was initiated in 19

men between the surveys, due to contralateral testicular cancer in seven. These 19 men were

excluded from all analyses at SII.

Participants and non-participants did not differ with regard to age, stage and treatment

type.

Prevalence of CF and comparisons between TCSs with CF at SII only, or at both

surveys

At SI, 126 males (15%) had CF, whereas at SII, 215 TCSs (27%) had CF. Two thirds

(n=85) of the 126 TCSs with CF at SI were also classified with CF at SII, while there were

130 new cases of CF at SII. Univariate analyses comparing those with CF at SII only, and

those with CF at both surveys for all variables did not reveal any significant differences

except for a significantly higher mean score at SII for total fatigue (21·0, p=0·005) and

HADS-A (7·4, p=0·012), for TCSs having CF at both surveys.

Variables associated with CF, univariate analyses

At both surveys, CF was statistically significantly associated with increased levels of

anxiety (HADS-A), depression (HADS-D), higher levels of neuropathy, Raynaud’s

phenomenon and tinnitus and/or reduced hearing (all p-values <0.001) (Table 2). At SII, a

low educational level, ever smoking, physical inactivity, diabetes, cardiac disease and

pulmonary disease, were also significantly associated with CF. In total, 21%, 30%, and 28%

of those treated by surgery, radiotherapy, or chemotherapy, respectively, reported CF at SII.

Logistic regression analyses assessing associations between treatment groups or age-adjusted

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hormone levels with CF revealed that radiotherapy, but not chemotherapy, was associated

with an increased risk of CF at SII when compared to surgery only (p=0.028 and p=0.106,

respectively). Furthermore, having testosterone in the lowest versus the highest quartile was

associated with increased risk of CF (p=0.023), while no significant associations emerged for

LH levels, (data not shown),

Age was not significantly associated with CF at any of the surveys (Table 2). There

were no significant associations between CF and hormone levels at SI.

Multivariate analyses

At SI, TCSs with higher levels of anxiety and depression had a roughly 3-fold

increased risk of CF compared to those with lower levels of anxiety and depression, while

those with the highest level of neuropathy, and the second highest level of Tinnitus/decreased

hearing had roughly 2-3-fold increased risks of CF compared to those with none of these

symptoms (Table 3). No other significant associations emerged at SI.

At SII, TCSs being moderately or highly physically active had a protective effect

against CF compared with those being inactive (reference), with ORs of 0.47 and 0.31,

(95%CI; 0.25- 0.87 and 0.17- 0.60, respectively). TCSs with testosterone in the lowest and

second highest quartile had significantly elevated risks of CF when compared to TCSs with

testosterone in the highest quartile (ORs of 3.2 and 2.6, respectively), testosterone levels in

the second quartile, had a similar OR of 2.2 but did not reach statistical significance (Table 3).

There was a stepwise increase in the risk of CF with increasing levels of neuropathy with OR

of 3.4 (95%CI; 1.7- 7.0) for the highest level compared with no neuropathy. The highest level

of Raynaud’s phenomenon was significantly associated with a higher risk of CF with an OR

of 2.4. No significant associations emerged for CF and tinnitus/reduced hearing. Prevalent

cardiac disease displayed borderline significant risk for CF with OR of 1.9 (95%CI; 0.9- 3.7),

compared with no cardiac disease (p-value 0.08).

CF was not significantly associated with level of education, smoking, diabetes,

pulmonary disease, age, or treatment. Sensitivity analyses when excluding the 32 males who

received both radiotherapy and chemotherapy did not change our results, indicating robust

associations and no major impact from the combination of radiotherapy and chemotherapy on

CF.

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Discussion

On the background of a 10% prevalence of CF in the Norwegian general male population,[15]

the increasing prevalence of CF in TCSs from 15% after 12 years to 27% 19 years after

treatment, is remarkable and might have ramifications for long-term cancer survivors in

general. Two thirds of those with CF at SI also had CF at SII. Those with CF at both surveys

had significantly higher total fatigue scores and anxiety levels than those only having CF at

SII.

In univariate analyses at SI, only few of the examined covariates were associated with

CF (all three symptoms assessed by the SCIN, the score of HADS-A and HADS-D). At SII,

however, most of the 17 variables examined were significantly associated with CF.

Also in the multivariate analysis an increase of variables associated with CF from SI to

SII became apparent. Results from SI should, however, be interpreted with caution due to the

low number of disease events at this time point. Higher levels of anxiety, depression, and

neurotoxicity (neuropathy and Raynaud’s phenomenon) and lower quartiles of testosterone

were all significantly associated with CF at SII, while moderate and high physical activity had

a protective effect. The increase in factors associated with CF accompanying an increase in

the prevalence of fatigue might represent a shared development: reduced stress coping.

Presumably, TCSs being fatigued will be less able to filter out the stress from e.g. neuropathy

in fingers or toes. On the other hand, chronic neuropathy might tire out cancer survivors,

finally resulting in fatigue. Apparently the development of CF is a slow process in the

relatively young TCSs, as it took up to 2 decades until about one of four TCSs reported CF.

Prior radiotherapy was significantly associated with CF at SII in univariate- (logistic

regression), but not in the multivariate analysis. Possibly, late-effects known to be associated

with radiotherapy (e.g. hypogonadism, diabetes, CVD, neuropathy), and ageing competed

with radiotherapy itself as risk factors for CF.[4] This may to some extent have contributed to

the different proportions of CF after radiotherapy and surgery of 30% versus 21%,

respectively. Lack of significant associations between CF and type of treatment, but with

treatment-related toxicities and self-reported comorbidity is in accordance with the majority

of studies on CF in cancer survivors.[25-27] Fewer TC patients are currently treated with RT

than during the study period, and modern radiation techniques, reduced volumes and target

doses will probably render radiotherapy-induced side-effects a less prominent problem among

future TCSs.

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The risk of CF was significantly decreased for moderately and highly active men when

compared with those reporting being inactive at SII. Whether CF results in inactivity, and/or

inactivity contributes to the development of fatigue, is still open for discussion. However,

fatigue after cancer treatment may be reduced by initiating or maintaining adequate levels of

physical activity according to meta-analyses, systematic reviews, and randomized trials.[28]

Contributing factors (e.g. medical and substance-induced) should be assessed and treated in

cancer survivors with moderate to severe fatigue, before intervening through physical activity

programs.

Low testosterone levels were significantly associated with CF at SII. Importantly, the

majority of TCSs (428 of the 793) had testosterone levels in the lowest quartile, rendering this

the strength of this association more important than the borderline association between CF

and more normal testosterone levels.

This finding contrasts with Huddart et al, who found no significant relationship

between testosterone and fatigue in TCSs, possibly due to a shorter follow-up time. Different

categorizations of testosterone in the two studies, (levels below 10 nmol/l versus ordinal

categorization according to quartile thresholds for decadal age groups), might also have

contributed to the varying results. Importantly, our observations do not imply testosterone

substitution as a means to treat chronic fatigued in general, but rather that high testosterone

levels are associated with the absence of CF. Nevertheless, as testosterone replacement in a

study of severely hypogonadal males yielded increased energy levels, such treatment may be

considered in fatigued TCSs with consistently low testosterone levels.[29]

Strengths of our study comprise the large population-based and well-characterized

cohort of TCSs, and the longitudinal study design. Blood samples were collected at relatively

consistent diurnal time points, with available hormone levels and FQ for 812 men. Detailed

information regarding previous cancer treatment was available through collaboration between

the five University hospitals in Norway, with all TCSs treated according to international

guidelines. High participation rates of roughly 80% at both surveys, implies validity of our

findings and renders selection bias less likely, although the rigorous selection including only

those with complete blood samples and questionnaires at both surveys reduced the number of

eligible men to 812. Hormone levels represent the only objective measure in this study, and

reliance on subjective factors might be considered a limitation. However, CF is not

objectively measurable, and self-reported comorbidity might actually better represent the

impact on CF than physiological assessments of cardiac or pulmonary function.[17,30] The

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lack of assessment of CF before treatment poses a limitation as we cannot assess a potential

impact of TC treatment on CF before SI.

In conclusion, this longitudinal study reveals a substantial increase in CF during 12 to

19 years after treatment, with higher levels of anxiety, depression, and neurotoxicity, and

lower levels of testosterone, being associated with CF at the second assessment. Moderate and

high physical activity indicated a protective effect. These findings might indicate means to

prevent or treat CF. Health care professionals should have early prevention of CF through life

style interventions and early detection, and treatment and follow-up of comorbid conditions in

mind when caring for TCSs and probably other cancer survivors as well. Testosterone

substitution may be considered in order to ameliorate or treat CF in hypogonadal males after

repeated testosterone evaluations. CF may dramatically impair quality of life, and its

disturbing increase in TCSs and the association with partly treatable side effects, underlines

the importance of continued long-term assessments of cancer survivors.

Funding: The Norwegian Cancer Society (salary HSH) and the South-Eastern Norway

Regional Health Authority (Grant No. 39247, MS).

Acknowledgement; Professor Jon Håvard Loge for valuable comments. His generous

contribution of time and expertise were greatly appreciated.

The authors declare to have no conflict of interest.

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Table and figure legends

Figure 1. Overview of included TCSs with available hormone samples and Fatigue

Questionnaires at both surveys

Table 1. Patient characteristics

Table 2. Univariate associations with Chronic Fatigue

Table 3. Presence of Chronic Fatigue, multivariate logistic regression

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Abbreviations: FQ= Fatigue Questionnaire, SI= Survey I, SII= Survey II, T= Testosterone,

TC= Testicular Cancer

1,814 TCSs invited to

participate in SI

812 had complete FQ and

hormone analyses from both SI

and SII and were included in the

study

1,463 TCSs accepted invitation

to SI (81%) Excluded for current study: (n=256) Irradiated scrotum (n= 1) Hyperprolactinoma at SI (n= 1) Substitution with T before SI (n=43) Removed retained testicle before SI (n= 2) Removed other testicle after trauma (n= 1) DHEA use at SI (n= 1) Missing hormone samples or FQ (n=207)

Noneligible men at SII (n=395) Deceased between SI and SII (n= 49) Emigrated or untraceable (n= 18) Non-responders: (n=125) Recurrence of TC at time for SII (n= 2)

Methadon user (n= 1)

Missing hormone samples or FQ (n=200)

Non-responders: (n=351)

1,207 TCSs eligible for SI

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Patients participating in Study, N=812

Age at TC diagnosis, years, median (range) 31.9 (14.8- 64.0)

Age at SI, years, median (range) 44.3 (23.0- 74.0)

Age at SII, years, median (range) † 51.7 (31.0- 81.0)

Time between TC diagnosis and SI, years,

median (range)

11.5 (5.0- 21-0)

Time between TC diagnosis and SII, years,

median (range)†

19.0 (13.1- 28.2)

Histology, number (%)

Seminoma

Nonseminoma

404 (49.8)

408 (50.2)

Royal Marsden Hospital Stage, number (%)‡

I

IM

II

III

IV

577 (71.1)

5 (0.6)

160 (19.7)

18 (6.4)

52 (6.4)

Surgery, number (%)

Orchiectomy only

RPLND

164 (20.2)

77 (9.5)

87 (10.7)

Chemotherapy, number (%)

Standard dose regimens

BEP

CVB

Others

Dose intensive regimens

305 (37.6)

285 (35.1)

148 (18.2)

115 (14.2)

22 (2.7)

20 (2.5)

Radiotherapy, number (%)

Para aortic field

Dog-leg field

Others

Median dose (Gy) (range)

343 (42.2)

21 (2.6)

310 (38.2)

12 (1.5)

27.0 (23.0-50.0)

Chemo- and Radiotherapy, number (%) 32 (3.9)

Abbreviations:

BEP= Chemotherapy regimen with cisplatin, etoposide, and bleomycin

CVB= Chemotherapy regimen with cisplatin, vinblastine, and bleomycin

SI= Survey I

SII= Survey II †At Survey II, 19 men commencing testosterone substitution between surveys were removed from

these analyses. ‡ As the males were treated in the time period 1980 until 1994, they were classified according to the

Royal Marsden Hospital classification system in their medical journals.

In the Chemotherapy group, 32 men also received RT. A total of 284 men received 3 cycles of

chemotherapy or more.

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Presence of Chronic Fatigue

Survey I Survey II Ⱡ

Characteristics

No CF

N=686 (84%)

CF

N=126 (16%) p-value

No CF

N=578 (73%)

CF

N=215‡ (27%) p-value

Treatment

Surgeryβ 142 (87) 22 (13) 0.707

128 (80) 33 (21) 0.088

Radiotherapy 288 (84) 55 (16) 234 (70) 99 (30)

Chemotherapy¥ 256 (84) 49 (16) 216 (72) 83 (28)

Partnered relation

No 143 (82) 32 (18) 0.289

107 (69) 49 (31) 0.192

Yes 539 (85) 94 (15) 470 (74) 166 (26)

Years of education

>12 years 257 (87) 40 (14) 0.295

212 (82) 48(19) <0.001

11-12 years 315 (84) 60 (16) 280 (71) 116 (29)

7- 10 years 109 (81) 26 (19) 69 (64) 39 (36)

Ever smoker

No 283 (87) 41 (13) 0.075

245 (76) 71 (23) 0.018

Yes 403 (83) 85 (17) 333 (70) 144 (30)

Level of physical activity

Inactive 96 (84) 19 (17) 0.149

41 (55) 33 (45) <0.001

Minimally active 293 (82) 64 (18) 219 (69) 97 (31)

Highly active 297 (87) 43 (13) 318 (79) 85 (21)

DiabetesῩ

No 667 (84) 123 (16) 1.0

541 (74) 189 (26) 0.012

Yes 19 (86) 3 (14) 37 (59) 26 (41)

Cardiac disease‡

No 668 (85) 120 (15) 0.245

544 (74) 189 (26) 0.006

Yes 18 (75) 6 (25) 34 (57) 26 (43)

Pulmonary disease#

No 679 (85) 122 (15) 0.076

529 (74) 183 (26)) 0.012

Yes 7 (64) 4 (36) 49 (61) 32 (40)

HADS-D 2.2 (2.5) 5.2 (4.0) <0.001§ 2.2 (2.3) 5.6 (3.7) <0.001§

HADS-A 4.0 (3.1) 7.2 (4.3) <0.001§ 3.5 (3.1) 6.5 (4.2) <0.001§

Testosterone level

≥75 percentile 67 (86) 11 (14) 0.174 61 (84) 12 (16) 0.104

>50- 75 percentile 96 (91) 10 (9) 75 (71) 31(29)

>25- 50 percentile 177 (86) 30 (15) 140 (75) 46 (25)

≤25 percentile 346 (82) 75 (18) 302 (71) 126 (29)

LH level

≤25 percentile 135 (85) 23 (15) 0.737

45 (75) 15 (25) 0.301

>25- 50 percentile 112 (86) 18 (14) 87 (78) 25 (22)

>50-75 percentile 149 (86) 25 (14) 109 (68) 52 (32)

≥75 percentile 290 (83) 60 (17) 337 (73) 123 (27)

Neuropathy hands/feet

No 384 (89) 47 (11) <0.001†

268 (87) 40 (13) <0.001†

A little 175 (87) 26 (13) 181 (76) 56 (24)

Quite a bit 93 (75) 31 (25) 95 (58) 69 (42)

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NOTE. Chi test for trend was applied if not stated otherwise. All P < 0.05 (2-sided) were considered

statistically significant and are depicted in bold. Numbers are presented with number (%) unless for

years since orchiectomy and age at survey, which are presented as mean (SD).

β Surgery applies for orchiectomy alone or orchiectomy combined with RPLND.

¥Chemotherapy applies for the 305 men receiving chemotherapy, including 32 men who received both

chemotherapy and radiotherapy.

Ῡ Diabetes applies for those reporting diabetes and/or the use of diabetes medication.

‡ Cardiac disease applies for those reporting having angina or having had a heart attack.

# Pulmonary disease at SI applies for the use of asthma medication. At SII it applies for those reporting

chronic obstructive pulmonary disease, chronic bronchitis, asthma, emphysema or the use of asthma

medication.

† Chi square, linear trend.

§ T-test.

Mean (SD).

Ⱡ At Survey II, 19 men commencing testosterone substitution between surveys were removed from the

analyses.

Very much 33 (61) 21 (39) 34 (41) 50 (60)

Raynaud’s hands/feet

No 375 (87) 54 (13) <0.001†

276 (84) 53 (16) <0.001†

A little 140 (86) 23 (14) 159 (75) 53 (25)

Quite a bit 106 (84) 20 (16) 99 (64) 56 (36)

Very much 61 (9) 28 (22) 43 (45) 53 (55)

Tinnitus/reduced hearing

No 352 (89) 43 (11) <0.001†

217 (80) 54 (20) <0.001†

A little 201 (84) 39 (16) 201 (73) 75 (27)

Quite a bit 85 (75) 28 (25) 105 (67) 52 (33)

Very much 46 (75) 15 (25) 53 (61) 34 (39)

Years since orchiectomy 11.8 (4.1) 12.4 (4.5) 0.156§ 19.4 (4.0) 20.0 (4.2) 0.063§

Age at survey, years 45.3 (9.9) 46.6 (9.2) 0.169§ 52.9 (9.9) 53.7 (9.9) 0.352§

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Survey I Survey IIⱠ

Explanatory

variable Odds

Ratio 95% CI p-value

Odds

Ratio 95% CI p-value

Treatment

Surgery

Radiotherapy 1.27 0.70- 2.29 0.44 1.68 0.95- 2.96 0.08

Chemotherapy 0.91 0.49- 1.73 0.78 1·43 0.80- 2.56 0.23

Years of education

>12 years

11-12 years 0.87 0.45- 1.68 0.68 1.51 0.82- 2.78 0.18

7-10 years 0.89 0.54- 1.46 0.63 1.21 077- 1.91 0.42

Ever smoker

No

Yes 1.32 0.82- 2.11 0.25 1.01 0.66- 1.53 0.98

Level of physical activity

Inactive

Moderately active 1.21 0.63- 2.32 0.57 0.47 0.25- 0.87 0.02

Highly active 0.80 0.41- 1.57 0.51 0.31 0.17- 0.60 <0.001

DiabetesῩ

No

Yes 0.69 0.16- 2.99 0.61 1.16 0.58- 2.32 0.67

Cardiac disease‡

No

Yes 1.53 0.52- 4.50 0.44 1.86 0.94- 3.70 0.08

Pulmonary disease#

No

Yes 3.34 0.75- 14.89 0.11 1.17 0.62- 2.19 0.62

HADS-A 3.18 1.94- 5.21 <0.001 2.53 1.49- 4.29 0.001

HADS-D 3.42 1.78- 6.57 <0.001 5.41 2.73- 10.73 <0.001

Testosterone levels

≥75 percentile

>50-75 percentile 1.10 0.52- 2.34 0.80 2.63 1.15- 6.00 0.02

>25- 50 percentile 0.82 0.36- 1.85 0.64 2.21 0.91- 5.35 0.08

≤25 percentile 0.51 0.19- 1.39 0.19 3.20 1.26- 8.15 0.02

Neuropathy

Not at all

A little 0.98 0.56- 1.72 0.94 1.49 0.89- 2.50 0.13

Quite a bit 1.58 0.87- 2.88 0.14 3.08 1.79- 5.31 <0.001

Very much 2.76 1.29- 5.87 0.01 3.43 1.68- 7.03 0.001

Raynaud’s phenomenon

Not at all

A little 0.71 0.39- 1.29 0.26 1.29 0.78- 2.13 0.33

Quite a bit 0.77 0.39- 1.49 0.43 1.47 0.85- 2.55 0.17

Very much 1.64 0.83- 3.22 0.15 2.37 1.23- 4.58 0.01

Tinnitus/reduced hearing

Not at all

A little 1.35 0.79- 2.30 0.27 1.10 0.68- 1.78 0.71

Quite a bit 2.13 1.17- 3.89 0.01 1.12 0.64- 1.96 0.69

Very much 1.88 0.88- 4.01 0.10 1.23 0.63- 2.38 0.55

Abbreviations:

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CI=Confidence Interval

Reference category.

Ῡ Diabetes applies for those reporting diabetes or using medication for diabetes.

‡ Cardiac disease applies for those reporting having angina or having had a heart attack.

# Pulmonary disease at SI applies for the use of asthma medication. At SII it applies for those reporting

chronic obstructive pulmonary disease, chronic bronchitis, asthma, emphysema or the use of asthma

medication.

Ⱡ At Survey II, 19 men commencing testosterone substitution between surveys were removed from the

analyses.

ORs and p-values considered statistically significant are depicted in bold.

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