original article
Annals of Oncology 18: 241–248, 2007
doi:10.1093/annonc/mdl372
Published online 23 October 2006
Components of the metabolic syndrome in long-term
survivors of testicular cancer
H. S. Haugnes1*, N. Aass2, S. D. Fosså2,3, O. Dahl4,5, O. Klepp6, E. A. Wist7,
J. Svartberg8, T. Wilsgaard9 & R. M. Bremnes1,10
Background: A possible explanation of the excess cardiovascular risk in testicular cancer (TC) survivors is
development of metabolic syndrome. The association between metabolic syndrome and TC treatment is
examined in long-term survivors.
Patients and methods: In a national follow-up study (1998–2002), 1463 TC survivors (diagnosed 1980–1994)
participated. Patients >60 years were excluded in the present study, leaving 1135 patients eligible. The patients were
divided in four treatment groups: surgery (n = 225); radiotherapy (n = 446) and two chemotherapy groups: cumulative
cisplatin dose (Cis) £850 mg (n = 376) and Cis >850 mg (n = 88). A control group consisted of 1150 men from the
Tromsø Population Study. Metabolic syndrome was defined according to a modified National Cholesterol Education
Program definition.
Results: Both chemotherapy groups had increased odds for metabolic syndrome compared with the surgery group,
highest for the Cis >850 group [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.6–4.7]. Also, the Cis >850 group
had increased odds (OR 2.1, 95% CI 1.3–3.4) for metabolic syndrome compared with the control group. The
association between metabolic syndrome and the Cis >850 group was strengthened after adjusting for testosterone,
smoking, physical activity, education and family status.
Conclusion: TC survivors treated with cisplatin-based chemotherapy have an increased risk of developing metabolic
syndrome compared with patients treated with other modalities or with controls.
Key words: cisplatin, metabolic syndrome, radiotherapy, testicular cancer
introduction
Testicular cancer (TC) is the most common malignancy among
young Norwegian men [1]. Due to better diagnostic tools, the
multimodal approach and the introduction of cisplatin-based
chemotherapy [2], TC patients are assumed to have a life
expectancy almost comparable to healthy age-matched men
once they achieve a durable remission. Thus, it is essential to
detect and treat any therapy-related long-term morbidity.
Cardiovascular morbidity and mortality has been described as
late complications among TC survivors [3–6]. An association
between cisplatin treatment and an unfavorable cardiovascular
risk profile has been demonstrated by several authors [6–10].
Radiotherapy (RT) may also increase the risk for cardiovascular
disease [3]. The suggested mechanisms responsible for the
*Correspondence to: Dr H. S. Haugnes, Department of Oncology, Institute of Clinical
Medicine, University of Tromsø, N-9037 Tromsø, Norway. Tel: +47-77-64-54-27;
Fax: +47-77-64-53-00; E-mail: [email protected]
ª 2006 European Society for Medical Oncology
development of cardiovascular morbidity in these long-term
survivors, however, need to be further evaluated.
The metabolic syndrome comprises insulin resistance,
hypertension, dyslipidemia and abdominal obesity. The World
Health Organization (WHO) [11], the National Cholesterol
Education Program (NCEP) expert panel [12] and recently
the International Diabetes Federation [13] have published
definitions of the metabolic syndrome. The syndrome is
important because it is associated with cardiovascular morbidity
and mortality [14–16].
The increased risk for cardiovascular disease in TC survivors
may be mediated via the metabolic syndrome. So far, only one
paper has described the prevalence of metabolic syndrome in
TC survivors [17]. In this study, Nuver et al. [17] reported
a higher prevalence of metabolic syndrome in cisplatin-treated
patients as well as in patients with stage I disease when
compared with healthy controls.
The aim of our study was to assess the prevalence of metabolic
syndrome using a modified NCEP definition in long-term
original
article
Received 16 May 2006; revised 3 August 2006; accepted 30 August 2006
Downloaded from http://annonc.oxfordjournals.org/ at Pennsylvania State University on March 6, 2014
1
Department of Oncology, Institute of Clinical Medicine, University of Tromsø, Tromsø; 2Department of Clinical Cancer Research, Rikshospitalet-Radiumhospitalet
Medical Center, Oslo; 3Medical Faculty, University of Oslo, Oslo; 4Section of Oncology, Institute of Medicine, University of Bergen, Bergen; 5Department of Oncology,
Haukeland University Hospital, Bergen; 6Department of Oncology, St Olav University Hospital, Trondheim; 7Department of Oncology, Ullevål University Hospital, Oslo;
8
Department of Endocrinology, University Hospital of North Norway, Tromsø; 9Institute of Community Medicine, University of Tromsø, Tromsø; 10Department of
Oncology, University Hospital of North Norway, Tromsø, Norway
original article
survivors of TC treated with different modalities (surgery, RT
or chemotherapy) through the following research questions:
(i) Does the prevalence of metabolic syndrome among TC
survivors differ according to previously administered treatment?
(ii) And does it differ from controls?
patients and methods
patients and controls
treatment groups
Principles for treatment of TC in Norway in the period 1980–1994 are
previously described [20]. For this study, the TC survivors were categorized
into four treatment groups according to initial and eventual relapse
treatment: (i) surgery only; (ii) RT only; (iii) chemotherapy with
a cumulative dose of cisplatin £850 mg (Cis £850); (iv) chemotherapy with
a cumulative dose of cisplatin >850 mg (Cis >850).
Patients in the surgery group (n = 225) did not receive treatment with RT
or chemotherapy. Of these, 124 had undergone retroperitoneal surgery,
while the remaining patients had been included in a surveillance program
without subsequent relapse. Patients in the RT group (n = 446) had received
either a modified dog-leg (n = 417) or paraaortic (n = 29) field. Two patients
had received additional mediastinal irradiation. From early 1980s to mid1990s the standard applied RT dose was gradually reduced from 40 to 27 Gy.
The cut-off point for the two chemotherapy groups was set at 850 mg Cis
to separate patients who received standard four courses or less from those
who received more than four courses or ‘higher dose’ chemotherapy
regimens due to very advanced disease, poor response, progression or
relapse. Overall, 464 patients were treated with chemotherapy, of whom 88
were in the Cis >850 group. Most patients (n = 442, 95%) received cisplatinbased chemotherapy, primarily in combination with etoposide and
bleomycin or vinblastine and bleomycin. Twenty-two patients (5%) who
received carboplatin instead of cisplatin were also included in the Cis £850
group, as their risk for the metabolic syndrome did not differ from those
who received standard cisplatin-based chemotherapy (data not shown).
Overall 304 (66%) of the patients treated with chemotherapy underwent
retroperitoneal surgery, and 47 (10%) received additional RT, primarily
infradiaphragmatic.
assessments
Resting blood pressure was measured manually or with an automatic device.
Body mass index (BMI) was calculated as weight in kilograms divided by the
242 | Haugnes et al.
1814 testicular cancer survivors were invited
1463 (81%) participated:
1289 clinical examination
1438 questionnaire
351 (19%) did not
respond to invitation
1264 (70%) completed both
questionnaire and clinical
examination (responders)
Present study:129 above
60 years were excluded
199 with
incomplete data
In total:
550 non-responders
1135 (63%) testicular cancer survivors aged ≤ 60
years form the study population
Figure 1. Number of cases forming the study population.
square of height in meters (kg/m2). Blood samples were drawn nonfasting
by venipuncture at each hospital laboratory between 0800 and 1200 h
to assess the levels of serum cholesterol, serum magnesium (Mg) and
serum testosterone. Levels of serum total testosterone were determined
using a commercial immunoassay, with similar reference ranges at
each hospital.
Information regarding the use of antihypertensive, antidiabetic and/or
lipid-lowering medication, the prevalence of diabetes and demographic
data was obtained from the questionnaire. Respondents with
missing questionnaire data on antihypertensive treatment or diabetes
were categorized as being without such treatment or nondiabetic,
respectively.
Data for family status and educational level were dichotomized according
to married/cohabitant versus living alone, and college/university versus
lower education. Physical activity was assessed by two questionnaire items,
one assessing a low physical activity level (such as walking) and the other
a high level (leading to sweating and breathlessness). Based on responses to
these items, physical activity was divided into three categories (no, moderate
and high activity) as described previously [21]. Cigarette smoking was
assessed by pack-years, calculated as number of cigarette packs smoked per
day multiplied by the number of years smoked. Accordingly, the patients
were categorized into four groups: never smokers, 0.1–9.9 pack-years,
10–19.9 pack-years and ‡20 pack-years.
definition of metabolic syndrome
We applied a modified NCEP definition of the metabolic syndrome
(Table 1) [12]. Hypertension was defined as blood pressure ‡140/90 mmHg
and/or antihypertensive medication according to the WHO Hypertension
Guidelines [22]. As a measure of obesity, we used BMI ‡30 [23].
In lack of serum triglycerides and high-density lipoprotein (HDL)
cholesterol assessments, we used serum total cholesterol.
Hypercholesterolemia was defined as total cholesterol ‡5.2 mmol/l [12] and/
or the use of lipid-lowering drugs. Since blood glucose was measured
nonfasting and only in a subgroup of patients, we instead applied patientreported prevalence of diabetes and/or use of antidiabetic medication.
According to our definition, metabolic syndrome was present if two or
more of the following four components were present: hypertension, obesity,
hypercholesterolemia or diabetes (Table 1). Additionally, we carried out
analyses using a more restrictive definition of metabolic syndrome, defined
as three or more components present.
Volume 18 | No. 2 | February 2007
Downloaded from http://annonc.oxfordjournals.org/ at Pennsylvania State University on March 6, 2014
All Norwegian long-term survivors (‡5 years) of unilateral TC aged 18–75
years were invited to participate in a national multicenter follow-up survey.
The patients were treated in the period 1980–1994, and the follow-up was
conducted during 1998–2002 at five university hospitals. The follow-up
survey consisted of (i) a 219-item questionnaire including questions
regarding medical history and demographic data and (ii) an outpatient
clinical examination including laboratory tests.
Of 1814 eligible patients, 1463 (81%) signed the informed consent form
and participated in the study [7]. Since the metabolic syndrome is highly
prevalent among the elderly [18], patients aged above 60 years were excluded
from the present report, leaving 1135 patients eligible (study population,
Figure 1). The Ethical Review Board of Region South approved the study.
A control group was recruited from the Tromsø Study [19], a populationbased epidemiological study in Tromsø, Northern Norway. The controls have
been described in a previous publication [7]. We selected men from the last
survey (Tromsø 5, 2001) as controls, since it was conducted during the same
time period as our follow-up survey. Control patients aged above 60 years and
those treated with testosterone substitution were excluded. Our control group
consisted of 1150 males with a median age of 48 years (range 30–60).
Annals of Oncology
original article
Annals of Oncology
Table 1. Definitions of the metabolic syndrome
NCEP definition
Our modified definition
At least three of the following:
Blood pressure ‡130/85 mmHg
or medication
Waist circumference >102 cm
Fasting plasma glucose
‡5.6 mmol/l
Serum triglycerides
‡1.7 mmol/l
Serum HDL cholesterol
<1.0 mmol/l
At least two of the following:
Blood pressure ‡140/90 mmHg
or medication
BMI ‡30
Self-reported prevalence
of diabetes or medication
Serum total cholesterol
‡5.2 mmol/l or medication
statistical analysis
The matching of cases and controls were carried out at a group level, not at
an individual level, due to an inadequate number of young controls. Mean
chemotherapy values in the two chemotherapy groups were compared using
Student’s t-test. Multiple logistic regression with metabolic syndrome as
the dependent variable was used to evaluate possible differences between
treatment groups, between cases and controls and to evaluate the influence of
possible predictors for metabolic syndrome. Metabolic syndrome was also
analyzed using ordinal logit regression, with the variable divided into
quintiles (0, 1, 2, 3 or all 4 components). The model calculated the probability
for having a larger number of metabolic syndrome components. A test of
parallel lines confirmed that the proportional odds assumption was met.
Differences between treatment groups with respect to continuous
variables, such as age, total cholesterol, total testosterone and Mg, were
analyzed using multiple linear regression. The surgery group was used as
reference when comparing the impact of different treatment modalities.
Persons with missing values were excluded from the analyses where the
missing variable was the dependent or explanatory variable. All regression
analyses were adjusted for age. All P values are two-tailed, with statistical
significance set at P < 0.05. The data were analyzed using the SPSS 11.0
statistical package (SPSS Inc., Chicago, IL).
results
patient characteristics
Median age at follow-up was 43 years for both responders and
nonresponders (P = 0.62). Stage, histology and treatment were
similar in both groups (data not shown).
Characteristics of study patients and controls are listed in
Table 2. The median observation time was 11.1 years. Compared
with the surgery group, the RT group was older at diagnosis and
at follow-up (P < 0.001, both), while the Cis >850 group was
younger at diagnosis (P = 0.016) and at follow-up (P < 0.001),
and had a shorter observation time (P = 0.001). Patients in the
Cis >850 group were less educated [odds ratio (OR) 0.58, 95%
confidence interval (CI) 0.34–0.99] and had a lower smoking
prevalence (OR 0.58, 95% CI 0.35–0.97) than the surgery group.
Otherwise, there were no differences across the treatment
groups with regard to demographic variables.
Prevalences of the metabolic syndrome, its components,
serum testosterone and serum Mg are presented in Table 3.
Volume 18 | No. 2 | February 2007
metabolic syndrome
‡2 components included. Metabolic syndrome was seen in 40%
of the total patient population. Both the chemotherapy groups
had significantly increased odds for metabolic syndrome
compared with the surgery group, highest for the Cis >850
group with an OR of 2.8 (95% CI 1.6–4.7, Figure 2). When
compared with controls, the odds for metabolic syndrome of
the total patient group did not differ (OR 1.0, 95% CI 0.8–1.2).
Subgroup analysis showed that only the Cis >850 group differed
from the controls, with an OR of 2.1 (95% CI 1.3–3.4).
Adjusting for total testosterone did not significantly change
any of these results.
‡3 components included. On the basis of our more restrictive
definition, metabolic syndrome was observed in 8% of all
patients. Compared with the surgery group, only the Cis >850
group had increased odds for metabolic syndrome, with an OR
of 2.6 (95% CI 1.1–6.0, Figure 3). Compared with the controls,
the total patient group had lower odds for metabolic syndrome
(OR = 0.7, 95% CI 0.5–1.0). The subgroup analysis showed
higher odds for metabolic syndrome in the Cis >850 group
when compared with controls, although not significant (OR =
1.6, 95% CI 0.8–3.2). The other treatment groups had lower
odds than the controls.
ordinal logit regression. Both chemotherapy groups had
increased odds for metabolic syndrome compared with the
surgery group, with highest odds for the Cis >850 group
(OR = 3.1, 95% CI 2.0–5.0; Table 4). When compared with
controls, the surgery and RT groups had lower odds, while
the Cis >850 group had higher odds (Table 4).
factors associated with the metabolic syndrome
Variables known to be associated with the metabolic syndrome
such as total serum testosterone, smoking (pack-years), physical
activity, educational level, family status and treatment group
were first tested through age-adjusted analyses. All variables
doi:10.1093/annonc/mdl372 | 243
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NCEP, National Cholesterol Education Program; BMI, body mass index;
HDL, high-density lipoprotein.
The mean serum total cholesterol was 5.7 (1.1) mmol/l for the
total patient population, without any differences across the
treatment groups. The Cis >850 group had increased odds
for having hypertension, obesity and hypercholesterolemia
compared with the surgery group (Figure 2).
Among 30 patients reporting a diagnosis of diabetes, 22
patients were diagnosed after the TC diagnosis (median interval
7.2 years, range 1.8–16 years). The mean prevalence of diabetes
in all treatment groups was 2.6%. There were no differences
between the treatment groups with regard to odds for diabetes
(Figure 2).
Univariate analyses revealed both age and serum total
testosterone as important predictors for the metabolic
syndrome (P < 0.001, both). The overall mean serum total
testosterone was 15.6 (5.4) nmol/l. The Cis >850 group had the
lowest mean testosterone value, significantly different from
the surgery group (P = 0.01), while the other treatment groups
did not differ from the surgery group. The overall mean serum
Mg was 0.82 (0.07) mmol/l, and the Cis >850 group did not
differ from the surgery group. There was no correlation between
serum Mg and metabolic syndrome (P = 0.48).
original article
Annals of Oncology
Table 2. Characteristics of study patients and controls
Radiotherapy,
n = 446
Cis £850 mg,
n = 376
Cis >850 mg,
n = 88
29 (16–53)
41 (24–60)
11.8 (5–21)
34 (18–51)
45 (28–60)
10.8 (5–21)
29 (15–52)
42 (23–60)
11.8 (5–22)a
26 (15–48)
36 (25–59)
9.4 (5–20)
220 (98)
5 (2)
422 (95)
24 (5)
131
180
15
50
12
23
9
44
219 (97)
6 (3)
2 (0.5)
444 (99.5)
307 (82)
69 (18)
750
300
3005
72
(35)
(48)
(4)
(13)
(185–850)
(30–390)
(104–8550)
(18–108)
Controls,
n = 1150
48 (30–60)
(14)
(26)
(10)
(50)
78 (89)
10 (11)
1143
300
3875
68
(855–2455)
(90–540)
(67–10580)
(19–100)
184 (82)
41 (18)
347 (78)
97 (22)
293 (78)
81 (22)
63 (72)
25 (28)
932 (82)
201 (18)
137 (61)
87 (39)
255 (58)
188 (42)
229 (62)
143 (38)
63 (72)
24 (28)
685 (61)
441 (39)
30 (14)
99 (45)
90 (41)
60 (14)
186 (42)
193 (44)
45 (12)
164 (46)
150 (42)
13 (15)
35 (42)
36 (43)
163 (15)
495 (44)
467 (41)
89
55
30
38
170
81
92
76
144
78
59
70
48
17
11
7
370
253
226
255
(42)
(26)
(14)
(18)
(41)
(19)
(22)
(18)
(41)
(22)
(17)
(20)
(58)
(21)
(13)
(8)
(33)
(23)
(21)
(23)
All data are number (%), except age, observation time and chemotherapy doses, which are median (range). There are some missing data for some
of the variables.
a
One patient had an observation time <5 years (4.3 years).
b
Royal Marsden Staging System [37].
c
Chemotherapy doses are listed for those who received the actual chemotherapy agent.
d
At follow-up, information obtained from questionnaire.
e
Number of cigarette packs per day multiplied by number of smoking years.
were then included in multiple regression models (Table 5).
When analyzing testicular survivors only, treatment group
(Cis >850 mg), total serum testosterone and smoking history
(‡20 pack-years) were independent predictive factors. Table 5
also presents the results of these analyses in patients and
controls, using the controls as reference. Here, treatment
group (Cis >850 mg) and total serum testosterone appeared
as independent predictors.
impact of chemotherapy
Median chemotherapy doses for the agents cisplatin, bleomycin,
etoposide and vinblastine are listed in Table 2. Patients in the
Cis >850 group received more cisplatin (P <0.001) and
etoposide (P <0.001) than patients in Cis £850 group. Mean
vinblastine (P = 0.74) and bleomycin dose (P = 0.06) did not
differ significantly between the two groups.
244 | Haugnes et al.
Metabolic syndrome was positively associated with
cumulative cisplatin (P = 0.001), bleomycin (P = 0.001) and
etoposide doses (P = 0.002) in age-adjusted analyses.
Cumulative vinblastine dose was not associated with metabolic
syndrome (P = 0.27). Logistic regression using a backward
stepwise model with all four chemotherapy agents and age
included, left only age and cumulative cisplatin dose as
significant variables.
discussion
In this study, previously cisplatin-treated TC survivors show an
increased age-adjusted risk of developing metabolic syndrome
in comparison to those treated with surgery, while patients
treated with RT did not differ from the surgery group. The risk
was most pronounced after cumulative cisplatin doses above
Volume 18 | No. 2 | February 2007
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Age at diagnosis, years
Age at follow-up, years
Observation time, years
Initial stageb
I
IM/II
III
IV
Histology
Nonseminoma
Seminoma
Chemotherapy doses, mgc
Cisplatin
Bleomycin
Etoposide
Vinblastine
Family statusd
Married/cohabitant
Living alone
Educational leveld
Primary/middle/high school
College/university
Physical activityd
No activity
Moderate activity
High activity
Number of pack-yearsd,e
0 (never smoker)
0.1–9.9
10–19.9
‡20
Surgery,
n = 225
original article
Annals of Oncology
Table 3. Prevalences of the metabolic syndrome and its components, serum testosterone and Mg levels at follow-up according to treatment
group and controls
Hypertensiona
Obesity (BMI ‡30)
Hypercholesterolemiab
Type 2 diabetes
Metabolic syndrome, ‡2 factors included
Metabolic syndrome, ‡3 factors included
Serum total testosterone, nmol/l, mean (SD)
Serum Mg, mmol/l, mean (SD)
Surgery,
n = 225
Radiotherapy,
n = 446
Cis £850 mg,
n = 376
Cis >850 mg,
n = 88
Controls,
n = 1150
77
28
151
4
72
15
16.2
0.83
201
55
311
13
184
37
15.5
0.81
166
60
246
11
149
29
15.6
0.81
42
23
63
2
42
11
14.8
0.83
568
237
963
33
584
170
14.4
0.82
(34)
(13)
(67)
(1.8)
(33)
(6.7)
(4.9)
(0.07)
(46)
(12)
(70)
(2.9)
(42)
(8.3)
(5.3)
(0.06)
(45)
(16)
(67)
(2.9)
(40)
(7.8)
(5.8)
(0.07)
(48)
(26)
(73)
(2.3)
(48)
(12.6)
(5.8)
(0.07)
(50)
(21)
(84)
(2.9)
(51)
(15)
(5.5)
(0.05)
10
2,76
2,5
Odds Ratio
1,64
1,29
1,45
1,68
1,49
1,74
1,35
0,9
2,76
1,48
0,98
0,93
1,2
1
0,1
Hypertension
Obesity
Hypercholesterolemia
Diabetes
Metabolic
syndrome
Figure 2. Age-adjusted odds ratios (OR) for the different components of
the metabolic syndrome and for the syndrome itself (‡2 components
present) in different treatment groups, using surgery group as reference.
Bars indicate 95% confidence interval for OR. Surgery, Radiotherapy,
Cisplatin £ 850 mg, Cisplatin > 850 mg.
850 mg. This heavily treated group also had an increased risk
compared with the control group. Treatment with surgery or RT
alone did not increase the risk for metabolic syndrome in
comparison to the control group.
The major strengths of this study are the large patient
population permitting subgroup analyses between the different
treatment groups and the case–control design allowing
comparisons between TC survivors and healthy controls.
Another strength is the concurrent assessments of metabolic
syndrome-related factors in patients and controls.
A limitation of the study is the age difference between TC
survivors and controls (median 43 versus 48 years). Ageadjusted analyses may not completely equalize the impact of age
on the metabolic syndrome, but any age bias will underestimate
rather than overestimate the association between cisplatin
treatment and metabolic syndrome. Another limitation is the
inability to evaluate the TC survivors’ complete metabolic
syndrome status at diagnosis. However, in our recently
Volume 18 | No. 2 | February 2007
Figure 3. Age-adjusted odds ratios (OR) for metabolic syndrome
(‡3 components present) in different treatment groups using the surgery
group as reference. Bars indicate 95% confidence interval for OR.
published longitudinal study in this group [7], there were no
differences in BMI and blood pressure between treatment
groups at diagnosis.
As the present study was planned and partially conducted
before the publication of the WHO and NCEP definitions, we
lack necessary data for the correct definition of metabolic
syndrome. Surrogate markers were used for fasting blood
glucose, triglycerides and HDL cholesterol. The prevalence of
diabetes may be underestimated, since those not clearly
reporting a diagnosis of diabetes were classified as being
nondiabetic. Using a modified definition of metabolic syndrome
may complicate comparisons of our results with others.
Nevertheless, the major aim of this study was to compare
doi:10.1093/annonc/mdl372 | 245
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Metabolic syndrome defined as either ‡2 or ‡3 of the following four factors: hypertension, obesity, hypercholesterolemia and diabetes. Data are number (%)
unless otherwise specified. There are missing data for some of the variables.
a
Hypertension is defined as systolic blood pressure ‡140 and/or diastolic blood pressure ‡90 and/or the use of antihypertensive medication.
b
Hypercholesterolemia is defined as serum total cholesterol ‡5.2 mmol/l and/or the use of lipid-lowering drugs.
BMI, body mass index; SD, standard deviation.
original article
Annals of Oncology
and report possible differences between treatment groups
and between these groups and controls, with the same definition
applied.
Hypertension, obesity and hypercholesterolemia all seem to
be involved in the increased risk for metabolic syndrome in our
heavily cisplatin-treated patients. Hypertension and obesity
have been discussed in more detail in our previous publication
[7]. Our hypercholesterolemia rates of 67% and 73% after
standard and high cumulative cisplatin doses, respectively,
Table 4. Ordinal logit regression, with age-adjusted odds ratios (OR)
and 95% confidence intervals (CIs)
Study patients only
OR
95% CI
Study patients and controls
OR
95% CI
Control group
Surgery
Radiotherapy
Cis £ 850 mg
Cis >850 mg
–
1.00
1.11
1.45
3.13
1.00
0.67
0.76
0.99
2.16
–
Reference
0.82–1.50
1.06–1.98
1.95–5.02
Reference
0.51–0.89
0.61–0.93
0.78–1.25
1.41–3.30
OR indicates the probability for having a larger number of metabolic
syndrome components (0, 1, 2, 3 or all 4 components).
Table 5. Logistic regression, with metabolic syndrome (‡2 components present) as the dependent variable
Multiple-adjusted resultsa,b
OR
95% CI
P value
d
Treatment group
Control group
Surgery
Radiotherapy
Cis £ 850 mg
Cis >850 mg
Total testosterone
Pack-yearse
0 (never smoker)
0.1–9.9
10–19.9
‡20
Physical activity
No activity
Moderate activity
Hard activity
Educational level
Low
High (college/university)
Family status
Living alone
Married/cohabitant
Age-adjusted resultsc
OR
95% CI
0.002
–
1.00
1.22
1.44
3.05
0.96
–
Reference
0.84–1.78
0.98–2.12
1.72–5.40
0.93–0.98
1.00
1.05
1.10
1.48
Reference
0.73–1.50
0.75–1.60
1.00–2.18
1.00
0.96
0.75
Reference
0.64–1.44
0.50–1.15
1.00
0.93
Reference
0.70–1.23
1.00
0.91
Reference
0.66–1.26
0.001
0.273
P value
Multiple-adjusted resultsb,c
OR
95% CI
P value
0.002
1.00
0.75
0.89
1.11
2.10
0.95
Reference
0.54–1.03
0.71–1.12
0.85–1.43
1.31–3.36
0.93–0.96
1.00
1.09
1.02
1.23
Reference
0.86–1.38
0.80–1.31
0.96–1.58
1.00
1.08
0.85
Reference
0.83–1.41
0.65–1.11
1.00
0.81
Reference
0.67–0.96
1.00
1.00
Reference
0.80–1.25
0.200
<0.001
0.40
0.003
1.00
0.80
0.96
1.15
2.43
0.95
Reference
0.57–1.12
0.75–1.24
0.87–1.52
1.46–4.04
0.93–0.96
1.00
1.16
1.04
1.29
Reference
0.90–1.49
0.80–1.35
0.98–1.69
1.00
1.19
0.97
Reference
0.90–1.58
0.73–1.30
1.00
0.83
Reference
0.68–1.01
1.00
1.01
Reference
0.80–1.29
0.041
0.61
0.12
0.018
0.57
<0.001
0.27
0.065
0.99
0.91
Odds ratio (OR) and 95% confidence interval (CI) for different predictors of the metabolic syndrome.
a
For testicular cancer survivors only.
b
Adjusted for age and all listed variables
c
For control population and testicular cancer survivors.
d
There are missing data for 18 patients and nine controls in age-adjusted analyses. There are missing data for 125 patients and 117 controls in the
multiple-adjusted analyses.
e
Number of cigarette packs per day multiplied by number of smoking years.
246 | Haugnes et al.
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Treatment
group
are in line with previous studies reporting rates at 67% to
84% [6, 8–10].
The first study examining the association between metabolic
syndrome and treatment of TC in 86 cisplatin-treated patients,
44 stage I patients treated with orchiectomy and 47 healthy
controls was recently published [17]. These investigators
reported higher prevalence of metabolic syndrome in both
cisplatin-treated (26%) and stage I patients (36%) compared
with healthy controls (9%). Surprisingly, they found the highest
prevalence of metabolic syndrome in stage I patients. These
results are inconsistent with our data since the Cis >850 group
alone had a significantly higher prevalence of metabolic
syndrome when compared with controls. A possible explanation
for the discrepancy between our results and those presented by
Nuver et al. [17] may in part be the different criteria applied in
the definition of metabolic syndrome. Besides the larger number
of cases and controls in our study, our control group may be
more representative for the general population. The median
follow-up time of 11 years in our study, compared with
7 years in the Dutch study, may also influence the results.
It has been demonstrated that a low serum total testosterone
level is an independent predictor for the development of
metabolic syndrome [24]. Gonadal dysfunction is a possible
long-term complication after treatment of TC, particularly after
high cumulative doses of cisplatin [25]. In line with this, both
original article
Annals of Oncology
Volume 18 | No. 2 | February 2007
regularly with respect to the development of metabolic
syndrome.
acknowledgements
Supported in part by grants from Erna and Olav Aakres Legacy,
the Odd Fellow Medical-Scientific Research Fund and the
Norwegian Foundation for Health and Rehabilitation (grant no.
1998/27). Thanks to project secretary Vigdis Opperud for
assistance with the database. The study is a national clinical study
as part of the Norwegian Urological Cancer Group III project.
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original article
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Annals of Oncology