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Fatigue, Anxiety, and Depression in Long-Term Survivors of Testicular Cancer

Sophie D. Fosså, Alv A. Dahl, Jon H. Loge

From the the Norwegian Radium Hospital, Department of Oncology and Radiotherapy, Aker University Hospital, Department of Psychiatry, Department of Behavioral Sciences in Medicine, University of Oslo, Oslo, Norway.

Address reprint requests to Sophie D. Fossa, MD, Department of Clinical Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway; email: s.d.fossa{at}klinmed.uio.no.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To investigate the prevalence of chronic fatigue (CF), the levels of anxiety and depression, and the correlation between these conditions in long-term survivors of testicular cancer (TCSs). Occurrence of CF in TCSs is compared with findings in male survivors of Hodgkin’s disease (HDSs) and in males from the general population (GenPop).

Methods: TCSs, HDSs, and two cohorts of the GenPop completed the Fatigue Questionnaire (FQ) and the Hospital Anxiety and Depression Scale (HADS) as part of a questionnaire survey. Cases of CF were identified according to published cut-offs, and the levels of anxiety (HADS-A) and depression (HADS-D) were calculated.

Results: Among 791 TCSs, 16% displayed CF (HDSs, 24%; GenPop, 10%). In the age group younger than 30 years, the prevalence of CF was higher in TCSs than in the GenPop (P <.01). In TCSs, age, anxiety, depression, and comorbidity were independent predictors of CF. The mean HADS-A score in TCSs was significantly above the comparable figure of the GenPop and similar to that of HDSs. The mean HADS-D score in TCSs was below that of the GenPop. The highest and lowest mean scores of HADS-A and HADS-D were observed in the youngest TCSs.

Conclusion: The prevalence of CF is less in TCSs than in HDSs but exceeds that of the GenPop. Together with comorbidity and age, anxiety and depression predict CF in TCSs, warranting psychiatric intervention for cases of CF among TCSs. Anxiety is a larger problem in TCSs than depression, particularly among the youngest TCSs.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
TODAY’S LONG-TERM survival ( 5 years) and cure rates of patients with testicular cancer (TC) are about 90%. The prevalence of TC survivors (TCSs) is consequently increasing, and their life expectancy is considered comparable to that of the age-matched male general population (GenPop). However, modern anticancer treatment may induce somatic long-term sequelae,^1–4 and may negatively affect the health of long-term cancer survivors, an example of this being the development of fatigue.^5–8.

Fatigue is commonly defined as the subjective experience of tiredness or lack of energy.^9,10 Chronic fatigue (CF) is characterized by fatigue of more than 6 months’ duration.¹¹ The CF syndrome includes other symptoms such as musculoskeletal pain, sleep disturbance, and headache.¹² Fatigue may be associated with symptoms of anxiety or depression.^9,10,13–15 Consequently, studies of fatigue should use instruments that try to separate the physical and psychological aspects of fatigue and how it relates to anxiety and depression. Anxiety and depression represent frequent and central aspects of mental health during all phases of cancer,^3,15–21 with anxiety probably being more prevalent than depression in long-term cancer survivors.¹⁶ The relationship among fatigue, anxiety, and depression has, however, not been dealt with extensively in long-term cancer survivors, although these mental health conditions may explain, or at least contribute, to cancer survivors’ experience of fatigue.

Some groups of long-term cancer survivors display increased prevalence of fatigue compared with the GenPop,^5,7,20 with chronic fatigue occurring in about 15% to 30% of patients. Female cancer survivors report fatigue more often than males.⁶ Treatment type and time since treatment are, however, only rarely reported as predictors of long-term fatigue in disease-free cancer survivors.^5,6 In a recent report,²² high levels of proinflammatory cytokines have been observed in fatigued breast cancer survivors. The etiology of fatigue is, however, not generally well understood, and is most probably multifactorial.¹⁵

The prevalence of physical and psychological complications in TCSs has been examined in several cross-sectional studies.^23–36 Dry ejaculation and major fertility problems have been associated with mental distress and decreased quality of life (QOL).^29,30 However, in most studies,^28,32–36 TCSs demonstrated levels of anxiety, depression, and QOL at levels similar to those of the GenPop, although validated mental health questionnaires have rarely been used. Few studies have specifically examined fatigue in TCSs, although the patients themselves have stated that fatigue is an important dimension of their QOL.³⁷ Stoter et al³⁴ observed increased mental fatigability, and listlessness among TCSs. Fatigue was, however, less pronounced in TCSs compared with survivors of Hodgkin’s disease (HDSs) in the study by Bloom et al.²⁷ Joly et al³⁶ reported similar scores of fatigue in TCSs as in the GenPop. Most studies of physical and psychological sequelae in TCSs are characterized by small sample sizes, use of nonvalidated questionnaires, and lack of comparative data from the GenPop or from other cancer survivors.

This principally descriptive study evaluates the prevalence of self-reported CF in a large cohort of long-term TCSs in comparison with similar data from male HDSs and age-matched males from the GenPop (reference groups). A further aim was to assess the levels of anxiety and depression in TCSs by a validated questionnaire to investigate those mental health conditions’ association with fatigue. The levels of anxiety and depression in TCSs were finally compared with those from the reference groups with the aim of increasing the understanding of observed differences concerning fatigue.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Source of Data
TCSs. Between 1998 and 2001, all Norwegian TCSs 18 to 75 years of age treated for unilateral TC between 1980 and 1994 were invited to participate in a cross-sectional postal study assessing somatic and psychosocial health by a 219-item questionnaire that comprised both the Hospital Anxiety and Depression Scale (HADS)³⁸ and the Fatigue Questionnaire (FQ).^13,39 The present report comprises only those TCSs who were treated at the Norwegian Radium Hospital (NRH), representing 99% of all patients within a defined geographic area in Norway. For the purpose of the study, all individuals with a prior diagnosis of cancer were called patients, even though they had been without evidence of disease for many years. Exclusion criteria were bilateral TC, extragonadal germ cell cancer, previous unilateral orchiectomy caused by a benign condition, a second malignancy, and mental retardation. Details as to diagnosis and treatment were retrieved from the medical records.

Since 1980, cisplatin-based chemotherapy, retroperitonal lymph node dissection (RPLND) and infra-diaphragmatic radiotherapy represented the principal postorchiectomy treatment modalities. Patients with early stages of seminoma were treated with infradiaphragmatic radiotherapy. Chemotherapy represented the principal treatment in advanced stages. Up to 1987, patients with early nonseminoma had RPLND followed by the use of adjuvant chemotherapy in case of lymph node metastases. Thereafter, the routine use of diagnostic RPLND was abandoned, and surveillance or adjuvant chemotherapy was applied in nonmetastatic cases. All patients with metastases or relapse had chemotherapy, followed by resection of residual tumor manifestations.

On the basis of these treatment principles, the TCSs were allocated to three management groups: (1) surgery: consisting of survivors who had undergone postorchiectomy RPLND only or who had followed a surveillance program without recurrence; (2) radiotherapy: comprising survivors whose overall treatment had included infra-diaphragmatic radiotherapy; and finally, (3) chemotherapy: consisting of survivors who had received chemotherapy with or without surgery or radiotherapy.

Reference Groups
Data from 249 male HDSs have been published previously as part of a follow-up study of HDS treated at the NRH between 1971 and 1991.^6,40 In 1994, 557 HDSs were contacted by mail and received a questionnaire including FQ and HADS. Only patients 74 years of age or less by the end of 1993 were contacted (response rate, 82%). Responders and nonresponders did not differ in age, disease stage, type of treatment, or time from diagnosis.

GenPop
Data from two different cohorts of men from the Norwegian GenPop were available.^41–44 In 1996, 3,500 Norwegian citizens 19 to 80 years of age were randomly drawn from the National Register by the Norwegian Government Computer Center.⁴² These citizens were representative of the entire Norwegian population. Among these 3,254 normal controls 74 years of age or younger, 2,214 (68%) responded. The figures on fatigue used in this study represent responses from 1,083 men.

Normative data on anxiety and depression were obtained from the Health Study of Nord-Trøndelag County, Norway (HUNT). From 1995 to 1997, all inhabitants of that county who were 20 years of age and older were invited to complete a mailed HADS questionnaire. The compliance rate was 71% (www.folkehelsa.no).^42–44 About 26,000 HADS forms from age-matched men were available for this study.

Measures
Fatigue Questionnaire (FQ). The FQ^13,39 consists of 11 questions that assess the presence and severity of fatigue experienced during the last month compared with how the person felt when he/she last felt well. Seven items cover Physical Fatigue (PF) and four items assess Mental Fatigue (MF). Each item has four response choices, scored on a Likert scale (0, 1, 2, 3) These scores are summarized for calculation of a person’s MF and PF scores, their sum resulting in the Total Fatigue (TF) score. Higher scores imply more fatigue. Two additional questions ask about the duration and extent of fatigue for identification of CF cases. The scores of the above 11 items are dichotomized (0, 0, 1, 1) and subsequently summarized. The FQ has shown good face validity and reasonable discriminant validity.³⁹ The Receiver Operating Curve (ROC) demonstrated that a cutoff of 4 best defined CF cases when the dichotomized item scores were used.³⁹ The combination of dichotomized scores (4) and symptom duration of 6 months is used for definition of CF cases. FQ has shown good face and discriminant validity in primary care.¹³ Discriminant validity is supported by differences in TF scores between subjects in different health states.¹⁶ Internal consistency of FQ in our study was comparable to that in the validation study¹³ (Cronbach’s coefficient for PF, 0.89; MF, 0.76; TF, 0.90). In this study, CF cases represented the primary outcome variable.

HADS questionnaire. The HADS questionnaire in this study consisted of 14 items: seven for anxiety (HADS-A) and seven for depression (HADS-D).³⁸ HADS was developed with the aim of rating negative effects in individuals with somatic disorders. Signs of negative effects that could be caused by such disorders were omitted to avoid circularity of reasoning. HADS-D focuses on the reduced pleasure response aspect (anhedonia) and the negative cognitions of depression, whereas neurovegetative signs are omitted. HADS-A mainly covers general anxiety and apprehensive expectation, with one item for panic attacks. The range of scores for cases is 0 to 7, normal; 8 to 10, mild disorder; 11 to 14, moderate disorder; and 15 to 21, severe disorder. The psychometric properties of HADS are excellent^43,44 according to a recent review with good internal consistency. In this study, the internal consistency measured by Cronbach’s coefficient alpha was 0.85 for HADS-A and 0.82 for HADS-D. This analysis primarily considers HADS-A and HADS-D scores as continuous variables. Prevalence figures of anxiety and depression cases (HADS-A score 8; HADS-D score 8) are only briefly reported.

Comorbidity in TCSs
The questionnaire mailed to the TCSs also contained a question as to long-lasting ( 1 year) health problems persisting at the time of the survey, referred to as "current comorbidity." Patients reporting such morbidity were invited to describe their problems as free-text comments. Patients also recorded whether they had been treated for psychological problems before the diagnosis of TC.

Ethics
The study was approved by the institutional and regional ethical committees

Data Management and Statistics.
Data were analyzed using the SPSS program (SPSS Inc, Chicago, IL) for PC, version 10.0. Means were compared by t-tests or analysis of variance. Differences between categorical variables were assessed by the ² test. After checking for multicollinearity, independent predictors of CF and PF were identified by regression analyses entering variables that were significant at a level of P < .05 by univariate analysis. Because of multiple testing, only P values .01 were considered to be statistically significant, except for the multivariate analysis in which P < .05 was defined as level of significance.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
TCSs and Data Quality
Of 1,013 invited TCSs, 820 (81%) returned completed questionnaires. The median age of the survivors who responded was 44 years (range, 23 to 75 years) at the time of the survey. The median interval between orchiectomy and survey was 12 years (range, 4 to 21 years). A total of 403 (49%) survivors had a seminoma, and 417 (51%) had a nonseminoma. In 163 (20%) of the patients, surgery represented the only treatment (RPLND, 82; surveillance, 81). Postorchiectomy radiotherapy alone was given to 339 (41%) of the patients, and chemotherapy was applied in 308 (39%) patients. Forty-five (15%) of these patients had more than four chemotherapy cycles, and 66 (21%) also had radiotherapy. A total of 165 patients had postchemotherapy RPLND. The 193 noncompliant TCSs were comparable to the compliers with respect to age and treatment. Twenty-nine patients were finally excluded from all analyses, as 50% or more of the responses to at least one of the questionnaire subscales were lacking, leaving 791 TCSs eligible for analysis. If less than 50% of a subscale’s responses were lacking, missing values for HADS-A, HADS-D, and TF were substituted by imputation in 23, 19, and 10 survivors, respectively, using the individual’s mean score of available responses.

Occurrence of CF in TCSs
A total of 125 TCSs were identified as CF patients (Table 1). Associated with CF occurrence were pretreatment psychological distress, current morbidity, and a low level of education (² test P < .01). CF patients tended to be older than non-CF patients (Student’s t-test, P = .03). Type of treatment and interval since orchiectomy did not influence CF occurrence. CF patients reported comorbidity (muscle or bone pain, cardiovascular disorders, reduced hearing or tinnitus, or decreased visus) more often than non-CF patients (², P < .001).

View larger version (48K): [in this window] [in a new window]   Fig 1. Age and chronic fatigue occurrence. (P < .01 [2 test] for GenPop v TCSs ()).

Subgroup analysis revealed that HADS-A decreased with increasing age of TCSs (Fig 2a; ANOVA, P < .01), the youngest TCSs displaying the highest anxiety levels. Statistically significant differences between the GenPop and TCSs were observed in males less than 30 years of age and those 40 to 59 years of age (Student’s t-test, P < .01). HADS-D increased in TCSs with increasing age (Fig 2b) up to age 50 years. Thereafter, the mean scores remained relatively constant with statistically significant differences compared with the GenPop in patients 40 years of age or older (Student’s t-test, P < .01). In the HDSs, age-related changes of HADS-A were similar to those of TCSs in contrast to the development of HADS-D scores, which increased after 50 years of age.

View larger version (21K): [in this window] [in a new window]   Fig 2. Age and mean scores of (a) HADS-A and (b) HADS-D (P < .01 [Student’s t-test] for GenPop v TCSs ().

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Our prevalence figure of CF in TCSs supports previous findings that TCSs represent a relatively healthy cohort of cancer survivors.^23–27 Fatigue seems to be a lesser problem in TCSs than in males with hematological malignancies,⁴⁵ including HD.^6,27 This difference is not explained by variable lengths of the observation periods but indicates different mechanisms of development of fatigue in TCSs and HDSs, such as different prevalence of physical comorbidity. Reduced pulmonary function is, for example, associated with fatigue and is more frequent in HDSs²⁰ than in TCSs. Furthermore, the overall treatment burden in HDSs treated between 1971 and 1991 might have been greater than that applied in TCSs treated from 1980 to 1994.

Most studies of cancer survivors have emphasized the strong correlation between depression and fatigue.^7,46–48 Our results support these observations, but they also show a significant independent association between anxiety and CF. A similar association between anxiety and fatigue was also observed among HDSs¹⁶ and among breast cancer patients.⁴⁸ This association between anxiety and fatigue is a relatively new finding and needs further examination, particularly in relation to age. Though CF in our study generally increased with increasing age of TCSs, as in other studies of long-term cancer survivorship^3,16 and in the GenPop,⁴² our data indicate that anxiety in TCSs may be a larger contributory factor to fatigue in the young TCSs than in those 50 years of age, when somatic comorbidity increases. Though not reaching our level of statistical significance, this may also be true for the very young HDSs (< 29 years of age), who also display high levels of anxiety. To date, our observations support the findings of Stone et al:¹⁵ Fatigue in cancer patients is a multietiological symptom that requires consideration of the patient’s age, type and status of malignancy, and comorbidity.

The principal types of treatment in TCSs were not significantly associated with CF, in agreement with published observations.^28–30,32 The lack of association between CF and treatment modalities has also been observed in HDSs.⁶ One reason may be that with long posttreatment intervals, non-treatment-related comorbidity and increasing age become more relevant for the prevalence of CF than the anticancer treatment. However, Rudberg et al³¹ described reduced health status in long-term TCSs who have had particularly intensive treatment. Recently, Ganz et al³ have reported decreased QOL in long-term breast cancer survivors who have received adjuvant chemotherapy. Psychosocial outcome in TCSs has also been reported to be strongly influenced by treatment-induced problems of sexual life and fertility,^27–30,33 although the reported samples are too small to draw definite conclusions. Future analyses of our series are planned to elucidate the association between modern fertility-preserving and sexuality-saving treatment of TC and mental health problems in TCSs.

The strength of this study lies in the high quality of the data, including a high compliance rate in a large series of consecutive unselected patients treated with the three principal therapeutic modalities for TC patients and assessed after long observation times. In contrast to most other studies,^23–26 our results are based on two internationally well-established self-rating instruments. CF represented our principal outcome variable, as this condition describes clinically relevant long-term morbidity. No detailed attempts were, however, made to analyze MF and PF, as the psychometric properties of these FQ dimensions are not well established. A consensus statement⁴⁹ has recommended HADS as a screening tool for anxiety and depression in cancer patients, a recommendation recently supported by Stark et al.¹⁷ The main weakness is the cross-sectional design, which does not allow for interpretation of causal relationships. Furthermore, we relied on the participants’ self-report of psychological and physical distress, which implies a risk of both under- and overreporting.

In conclusion, chronic fatigue represents a long-term clinical problem in 16% of patients treated for TC and is more prevalent in TCSs than in the GenPop, but less frequent than in HDSs. If physical comorbidity can be excluded as a major cause of CF, in the very young TCSs in particular, the independent associations between fatigue and anxiety and fatigue and depression warrant psychological assessment and treatment of TC survivors complaining of fatigue. Effective treatments of these mental health conditions are well established.

	ACKNOWLEDGMENTS

 
We thank Anne Berit Murstad, RN; Siri Lothe Hess, RN; and Vigdis Opperud for assistance during the study and the Nord-Trødelag Health Study (the HUNT Study), a collaboration between HUNT Research Centre, Faculty of Medicine, Norwegian Univeristy of Science and Technology (NTNU), Verdal, Norwegian Institute of Public Health, and Nord-Trødelag County Council.

	NOTES

 
Supported by The Norwegian Cancer Society (grant E-99064) and the Norwegian Foundation for Health and Rehabilitation (grant 1998/207).

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Submitted August 27, 2001; accepted December 30, 2002.

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				M. J. Hjermstad, S. D. Fossa, L. Oldervoll, H. Holte, A. B. Jacobsen, and J. H. Loge Fatigue in Long-Term Hodgkin's Disease Survivors: A Follow-Up Study J. Clin. Oncol., September 20, 2005; 23(27): 6587 - 6595. [Abstract] [Full Text] [PDF]

				A. Mykletun, A. A. Dahl, C. F. Haaland, R. Bremnes, O. Dahl, O. Klepp, E. Wist, and S. D. Fossa Side Effects and Cancer-Related Stress Determine Quality of Life in Long-Term Survivors of Testicular Cancer J. Clin. Oncol., May 1, 2005; 23(13): 3061 - 3068. [Abstract] [Full Text] [PDF]

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