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Journal of Clinical Oncology, Vol 23, No 10 (April 1), 2005: pp. 2389-2395 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.061 Study of Anxiety Disorder and Depression in Long-Term Survivors of Testicular CancerFrom the Department of Clinical Cancer Research, The Norwegian Radium Hospital; Departments of Oncology and Psychiatry, Ullevaal University Hospital, University of Oslo, Oslo; Research Centre for Health Promotion, University of Bergen; Department of Oncology, Haukeland University Hospital, Bergen; Department of Oncology, University Hospital of Northern Norway, University of Tromsø, Tromsø; and Department of Oncology, Saint Olav's Hospital, National University for Science and Technology, Trondheim, Norway Address reprint requests to Alv A. Dahl, MD, PhD, The Norwegian Radium Hospital, N-0310 Oslo, Norway; e-mail: alvd{at}ulrik.uio.no
PURPOSE: To increase our knowledge of the prevalence of anxiety disorder and depression in long-term testicular cancer survivors (TCSs), and to identify variables associated with such caseness.
PATIENTS AND METHODS: Participants were 1,408 TCSs treated between 1980 and 1994 in Norway. Participants provided information about their medical, social, and familial situation on a questionnaire. They also completed the Hospital Anxiety and Depression Scale (HADS). Anxiety disorder and depression were defined by a score RESULTS: HADS-defined anxiety disorder was more prevalent in TCSs (19.2%; 95% CI, 17.2% to 21.3%) than in the norm sample (13.5%; 95% CI, 13.1% to 13.9%; P < .001), whereas the prevalence of HADS-defined depression did not differ from the norm (TCSs, 9.7%; 95% CI, 8.1% to 11.2% v norm, 10.1%, 95% CI, 9.5 to 10.5; P = .56). The relative risk for anxiety disorder was 1.49 (95% CI, 1.31 to 1.69) and for depression the relative risk was 0.96 (95% CI, 0.81 to1.14) in TCSs compared with norm. In multivariate analyses, HADS-defined anxiety disorder in TCSs was associated with young age, peripheral neuropathy, economic problems, alcohol problems, sexual problems, relapse anxiety, and having been treated for mental problems. CONCLUSION: Long-term TCSs have an increased risk of HADS-defined anxiety disorder that warrants clinical attention. Checking easily available demographic and TC-related data and use of a simple screening test such as HADS assists the identification of TCSs with anxiety disorder.
As a result of improved prognosis1 and increased incidence of testicular cancer (TC),2 the number of long-term TC survivors (TCSs) is growing in Norway as well as in the Western world. More than 25% of TCSs report somatic side effects, impaired sexual function, and problems regarding fertility in the long term.3 Despite this, health-related quality of life (QOL) in the long term is similar to that in normal controls, and in almost all studies QOL is not influenced by the treatment administered.4 Given that most QOL instruments include subscales covering mental health, one is left with the impression that TCSs do not have specific problems with mental health. However, few studies have specifically examined levels of mental symptoms and prevalence rates of mental disorders, and their association to other relevant variables in TCSs. Only the study by Moynihan et al5 applied a diagnostic psychiatric interview, and among 102 TCSs these authors found a 14% prevalence rate of anxiety disorders and 9% prevalence rate of depression up to 5 years after primary treatment. The presence of these disorders was significantly associated with health worries, fear of relapse, unemployment, and financial difficulties. Nonsignificant associations were observed for treatment strategies, social class, marital status at diagnosis, fertility problems, and sexual problems. Jones and Payne6 used the Hospital Anxiety and Depression Scale (HADS) as a screening for mental disorders in a small sample (N = 47) of TCSs at a mean of 18 months after treatment, and interviewed those for caseness (defined as a patient who exhibits anxiety disorder and/or depression). In their sample the prevalence rate was 8% for anxiety disorders and 11% for depression. Caseness was associated with shorter time since diagnosis, but not with age at diagnosis, marital status, childlessness, or unemployment. In studies using only self-rating scales, TCSs were found to have clearly higher scores on anxiety and somewhat higher scores on depression when compared with normal controls.7-9 Fosså et al10 showed that after a maximum at 6 months after treatment, the prevalence of anxiety disorder and depression became stable, but remained increased at 36 months after treatment. In a multicenter European trial of patients with metastatic TC, the mean level of emotional function improved significantly during the first 6 months after diagnosis and remained stable thereafter.11 Although increased prevalence of anxiety disorder, and to a lesser degree of depression, seems to be a consistent finding, most studies done so far are characterized by short observation times and relatively small and selected samples coming from single treatment centers; therefore, these studies carry a considerable risk for selection bias and type II statistical error. Furthermore, not all studies have used psychometrically validated mental rating scales. The critique of single-institution studies is also valid for results formerly reported in TCSs treated at the Norwegian Radium Hospital (Oslo, Norway).12 The aim of this study was to expand our knowledge concerning levels and caseness of anxiety and depression in unselected long-term TCSs using HADS. The results from TCSs were compared with norm data from the general male population. Our research hypothesis was that TCSs in the long term would show increased levels of anxiety and depression as well as caseness of anxiety disorder and depression compared with age-adjusted norms. In addition, we wanted to retest the associations among caseness of anxiety disorder and depression, and background factors and TC-related factors reported in former studies.5,6
Clinical Material and TC Treatment Groups Norwegian TC patients are treated at five university oncologic departments. In 1998, these departments started a collaborative cross-sectional study of unilaterally orchiectomized TCSs addressing their somatic and psychosocial health and long-term health-related QOL. Patients treated for TC between 1980 and 1994 were identified by the Cancer Registry of Norway and cross checked with the registries of the five departments. Eligibility criteria for invitation to take part in the study were age between 18 and 75 years at the time of invitation and no evidence of disease. Patients with extragonadal germ cell malignancy, bilateral TC, a second non–germ-cell malignancy (except skin cancer), and those in whom the nonaffected testicle had been removed previously due to a benign condition were excluded. By mail we invited 1,814 eligible TCSs to participate in the study. Those who did not comply with the request to participate had emigrated or were without permanent address, were deceased, did not respond, or refused to participate, resulting in a study sample of 1,438 TCSs (compliance rate, 79%). Thirty TCSs delivered invalid forms in relation to the measurements relevant for this study, and the sample examined consists of 1,408 assessable TCSs. Postorchidectomy treatment was preferably administered according to the specified protocols defined by the Swedish-Norwegian testicular cancer project, or by the European Organization for Research and Treatment of Cancer Genitourinary Group, and by the Medical Research Council Testicular Cancer Working Party, as described previously.12 With few exceptions, patients with early seminoma received infradiaphragmatic radiotherapy (mean target dose, 33 Gy). Those with advanced metastatic seminoma had cisplatin-based chemotherapy, which up to about 1988 often was followed by radiotherapy or surgery. During the 1980s, patients with early nonseminoma underwent primary retroperitoneal lymph node dissection (RPLND) followed by adjuvant chemotherapy (three cycles) if metastases had occurred. Early in the 1980s, RPLND was performed as unilateral or bilateral template RPLND, whereas nerve-sparing surgical techniques were introduced about 1990. At the end of the 1980s, the policy of primary RPLND was abandoned, and a surveillance policy was introduced for nonmetastatic low-risk patients, whereas high-risk patients received adjuvant chemotherapy (two cycles). Patients with metastatic stages of nonseminoma had chemotherapy (four to six cycles) and resection of residual masses. Patients who experienced disease relapse (92 patients; 7%) were treated principally with chemotherapy followed by surgery or radiotherapy, although two patients were treated with surgery only. In 68 patients with relapse after surveillance or RPLND, four cycles chemotherapy were applied. The 22 patients who had recurrent disease after previous chemotherapy were treated with four to six cycles of chemotherapy, which except for cisplatin, contained available alternative drugs such as ifosfamide, carboplatin, methotrexate, vinblastine, or vincristine.
Norm Population
Measures The formulation, "Have you ever had the following diseases..." was used for assessment of somatic diseases. Severe somatic illnesses were considered present in those who reported at least one of the following: myocardial infarction, angina pectoris, stroke, diabetes, osteoporosis, fibromyalgia, rheumatoid arthritis, arthrosis, Bechterew's disease, and other long-standing musculoskeletal diseases. These diagnoses, however, were not confirmed by addressing local doctors or hospitals. Treatment for mental disorders was defined by self-reported post-treatment use of psychotropic drugs, or having visited a psychiatrist or clinical psychologist. Cisplatin-related adverse effects such as peripheral neuropathy, Raynaud's phenomena, tinnitus, and reduced hearing were assessed by the testicular cancer module developed in 1996 by Fosså et al14 and since then used in a large prospective European study11 and in several ongoing studies. In that module adverse effects were rated on four-item Likert scales, and those who had scored "quite a bit" or "very much" were counted as patient cases. The same Likert scales and allocations were used for self-rating of "relapse worries" and "infertility worries." The Brief Male Sexual Function Inventory15 was used to investigate the respondent's sexual life. Sexual problems were defined by responses of "2 = moderate problem" or "1 = big problem" on at least one the 11 items of the inventory.
Alcohol problems were screened in TCSs with a four-item version of AUDIT (Alcohol Use Disorders Identification Test) that had shown high sensitivity and specificity as a screening instrument for alcohol-related problems in Norway.16 The four AUDIT items were rated on a five-point Likert scale from 1 (never) to 5 (daily), and the cutoff for alcohol problems was a sum score
HADS
A valid rating of depression or anxiety in this study was defined as at least five completed items on HADS-D and HADS-A. Those who filled in five or six items were also included in the study, and their substitution scores were derived from the sum of completed items multiplied by 7/5 or 7/6, respectively. In this study we examined the prevalence of clinically significant anxiety disorder, defined by a HADS-A score of
On the basis of the HADS scores, we also defined four additional categories of TCSs and the norm population: no disorder, HADS-A less than 8 and HADS-D less than 8; pure anxiety disorder, HADS-A
Data Management and Statistical Analysis
Ethics
Demographic and TC Characteristics The age- and TC-related characteristics of the participants and nonparticipants are listed in Table 1. The nonparticipants were older (P = .021) and had a longer interval from diagnosis to the survey (P < .001), but no differences were found regarding seminoma or nonseminoma, or treatment strategies (Table 1).
In our sample the mean age at follow-up was 44.6 years (SD, 10.2 years), with a mean follow-up time of 11.3 years (SD, 4.2 years; range, 5 to 21 years). Demographic characteristics, as well as the proportion of TCSs with adverse effects, severe somatic illnesses, relapse worries, childlessness, infertility worries, and treatment for mental problems, is listed in Table 2. Demographic findings in the norm population are also listed, and the two groups differed significantly on age, civil status, and education.
Anxiety and Depression The mean level of anxiety was 4.6 in TCSs and 4.1 in the norm population (P < .001). The prevalence of HADS-defined anxiety disorder was 19.2% in TCSs versus 13.5% in the norm population (P < .001; Table 3). The mean level of depression was 2.8 in TCSs compared with 3.5 in the norm population (P < .001). HADS-defined depression showed a prevalence of 9.7% in TCSs versus 10.1% in the norm population (P = .014).
Among TCSs we observed a total of 22.1% patient cases, whereas the norm population showed 18.3% patient cases according to HADS (P < .001). The proportion of patients with pure anxiety disorder and comorbid disorder was significantly higher among TCSs, whereas the proportion of patients with pure depression was significantly higher in the norm population (Table 3). Compared with the norm population, the relative risk of anxiety disorder was 1.49 (95% CI, 1.31 to 1.69) and the relative risk of depression was 0.96 (95% CI, 0.81 to 1.14) in TCSs. Among the 92 TCSs who experienced disease relapse, the prevalence of anxiety disorder was 21.7% and the prevalence of depression was 7.6%, whereas for the TCSs who did not experience disease relapse, the prevalence rates were 19.1% and 9.8%, respectively (P = .53 for anxiety disorder; P = .49 for depression). The correlation between the Likert-scored relapse anxiety and HADS-A was 0.42 (P < .001), and the correlation between Likert-scored infertility worry and HADS-A was 0.17 (P < .001).
Variables Associated With Caseness of Anxiety Disorder
Treatment strategies, time since treatment, and relapse of TC were not associated with caseness of anxiety disorder. In the norm population, univariate analysis of the demographic variables in relation to caseness of anxiety disorder showed the same significant associations as in TCSs (data not shown). In the multivariate logistic regression analysis, the following variables remained significantly associated with caseness of HADS-defined anxiety disorder: young age at follow-up; having economic problems, sexual problems, or relapse anxiety; having alcohol problems; having been treated for mental problems; and having peripheral neuropathy (Table 4).
The main finding of our study is that 19% of TCSs have a HADS-defined anxiety disorder and 10% have a HADS-defined depression at long-term follow-up. Compared with the age-adjusted norm population, the relative risk in TCSs was 1.5 for anxiety disorder and 1.0 for depression. In the univariate analysis, testing positive for anxiety disorder was associated with both demographic and TC-related variables within the cohort of TCSs. In multivariate analysis, age at follow-up, peripheral neuropathy, relapse anxiety, economic problems, sexual problems, alcohol problems, and having been treated for mental problems were associated with caseness of anxiety disorders. HADS-defined anxiety disorder and/or depression in 22.1% of TCSs should mainly be seen as an indication that the prevalence of these mental health problems is increased compared with age-adjusted norm population. Some support to the validity of the total prevalence of these disorders also comes from the information that 18% of TCSs reported that they had used psychotropic drugs, or had seen a mental health professional after their TC treatment. Our study confirms earlier findings from cross-sectional studies of an increased level of anxiety and increased prevalence of anxiety disorder in TCSs.4-9 The essential feature of anxiety is fear of threats in the future. The increased prevalence of HADS-defined anxiety disorder may in part be understood by the surprisingly high proportion of TCSs (31%) who report relapse anxiety even after a median of 10.7 years since primary treatment. The relatively high correlation between the scores on HADS-A and relapse anxiety supports this view. However, prospective studies are needed to clarify if a diagnosis of TC and/or the treatment trigger latent anxiety or produce anxiety de novo. We found approximately the same prevalence of depression in TCSs as reported by Moynihan et al,5 which was approximately the same as that observed among age-adjusted norm population. Basically, depression is a psychological reaction to loss, which is to be expected after a diagnosis of TC. Conversely, long-term response shift, acceptance by partner, redefinition of values, and success in various life arenas, despite the genital malignancy, could explain why TCSs are not more depressed than the norm population in the long term. A new finding was that an adverse effect, such as peripheral neuropathy, was associated with caseness of anxiety disorder. Like Moynihan et al,5 we found an association between caseness and relapse anxiety, unemployment, economic problems, and other somatic illnesses, but no association with treatment strategies. In contrast to their study, we found association with nonpaired civil status, low level of education, infertility worries, and sexual problems, and we observed an association with alcohol problems and treatment for mental problems after becoming a TCS. We did not confirm the association with short follow-up time reported by Jones and Payne,6 however. In contrast to these two studies, we had a sample size that allowed for multivariate analysis of associations, and therefore we have more confidence in our findings. Among the variables associated with anxiety disorder in multivariate analysis, unemployment, economic problems, nonpaired civil status, low level of education, somatic illness, sexual problems, alcohol problems, and help-seeking are general risk factors for mental disorders,24 whereas those unique to TCSs are relapse anxiety and peripheral neuropathy. Our study has several strengths. We had a large population-based sample that allowed for subgroup analyses and was adequately powered to reduce the risk of type II errors. Compliant TCSs did not differ from the noncompliant contacts regarding important TC-related variables, which allowed generalization to the population of TCSs. We used a well-established instrument (HADS) with good psychometric properties for large-scale assessment of mental health, and we had the opportunity to relate our findings to norm data of males from the Norwegian population. The findings of an increased level of anxiety and increased prevalence of anxiety disorder in TCSs are put into a meaningful context, and features of TC survivorship can explain the normal level and prevalence of depression. There are also several weaknesses as to our study. We based our symptom levels and caseness prevalence rates on self-rating only. Validation by structured diagnostic interviews was lacking. We thereby only can report on anxiety disorder and/or depression globally, and not on specific diagnoses. Our study is cross sectional, and the prevalence rates are based on self-reported symptom intensity of anxiety and depression at the time of the survey. We do not have any knowledge of the duration; functional impairment in relation to job, family, or social relations; or comorbid symptoms of mental disorders. However, a significant association between the levels of HADS-A and Medical Outcome Study Short Form 36 (SF-36) –defined mental quality of life has previously been demonstrated in TCSs.25 The main conclusion of our study is indisputable. There is an increased prevalence of anxiety disorder among TCSs in the long term, and this deserves clinical attention. We have identified demographic, mental health–related, and TC-related variables associated with anxiety disorder, and they should help the clinicians to identify TCSs with such disorder.
The authors indicated no potential conflicts of interest.
We thank the Nord-Trøndelag Health Study (The HUNT Study) which is a collaboration between HUNT Research Centre, Faculty of Medicine, Norwegian University of Science and Technology (NTNU, Verdal), Norwegian Institute of Public Health, and Nord-Trøndelag County Council.
Supported by grants from The Norwegian Cancer Association, and Health & Rehabilitation Inc. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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4. Joly F, Hèron J, Kalusinski L, et al: Quality of life in long-term survivors of testicular cancer: A population-based case-control study. J Clin Oncol 20:73-80, 2002 5. Moynihan C: Testicular cancer: The psychosocial problems of patients and their relatives. Cancer Surv 6:477-510, 1987[Medline] 6. Jones GY, Payne S: Searching for safety signals: The experience of medical surveillance among men with testicular teratomas. Psychooncology 9:385-394, 2000[CrossRef][Medline] 7. Douchez J, Droz JP, Desclaux B, et al: Quality of life in long-term survivors of nonseminomatous germ cell testicular tumors. J Urol 149:498-501, 1993[Medline] 8. Rieker PP, Fitzgerald EM, Kalish LA, et al: Psychosocial factors, curative therapies, and behavioral outcomes: A comparison of testis cancer survivors and a control group of healthy men. Cancer 64:2399-2407, 1989[CrossRef][Medline] 9. Fosså SD, Aass N, Kaalhus O: Testicular cancer in young Norwegians. J Surg Oncol 39:43-63, 1988[Medline] 10. Fosså SD, Aass N, Ous S, et al: Long-term morbidity and quality of life in testicular cancer patients. Scand J Urol Nephrol 138:S241-S246, 1991
11. Fosså SD, de Wit R, Roberts T, et al: Quality of life in good prognosis patients with metastatic germ cell cancer: A prospective study of the European Organization for Research and Treatment of Cancer Genitourinary Group/Medical Research Council Testicular Cancer Study Group (30941/TE20). J Clin Oncol 21:1107-1118, 2003
12. Fosså SD, Dahl AA, Loge JH: Fatigue, anxiety, and depression in long-term survivors of testicular cancer. J Clin Oncol 21:1249-1254, 2003 13. Holmen J, Midthjell K, Krüger O, et al: The Nord-Trøndelag Health Study 1995-97 (HUNT-2): Objectives, contents, methods and participation. Scand J Primary Health 13:19-32, 2003 14. Fosså SD, Moynihan C, Serbouti S: Patients' and doctors' perception of long-term morbidity in patients with testicular cancer clinical stage I: A descriptive pilot study. Support Care Cancer 4:118-128, 1996[CrossRef][Medline] 15. O'Leary MP, Fowler FJ, Lenderking WR, et al: A brief male sexual function inventory for urology. Urology 46:697-706, 1995[CrossRef][Medline] 16. Aasland OG, Amundsen A, Bovim G, et al: Identification of patients at risk of alcohol related damage [in Norwegian]. Tidsskr Nor Laegeforen 110:1523-1527, 1990[Medline] 17. Bush B, Shaw S, Cleary P, et al: Screening for alcohol abuse using the CAGE questionnaire. Am J Med 82:231-235, 1987[CrossRef][Medline] 18. Zigmond AS, Snaith RP: The Hospital Anxiety and Depression scale. Acta Psychiatr Scand 67:361-370, 1983[Medline] 19. Bjelland I, Dahl AA, Tangen Haug T, et al: The validity of the Hospital Anxiety and Depression Scale: An updated literature review. J Psychosom Res 52:69-77, 2002[CrossRef][Medline] 20. Sharpe M, Strong V, Allen K, et al: Major depression in outpatients attending a regional cancer centre: Screening and unmet treatment needs. Br J Cancer 90:314-320; 2004[CrossRef][Medline]
21. Mykletun A, Stordal E, Dahl AA: The Hospital Anxiety and Depression Scale (HADS): Factor structure, item analyses, and internal consistency in a large population. Br J Psychiatry 179:540-544, 2001 22. American Psychiatric Association.Diagnostic and Statistical Manual of Mental Disorders (ed 4). Washington, DC, American Psychiatric Press, 1994 23. Stordal E, Bjartveit Krüger M, Dahl NH, et al: Depression in relation to age and gender in the general population: The Nord-Trøndelag Health Study (HUNT). Acta Psychiatr Scand 104:210-216, 2001[CrossRef][Medline] 24. Tsuang MT, Tohen M (eds). Textbook in Psychiatric Epidemiology (ed 2). New York, NY, Wiley-Liss, 2002 25. Fosså SD, Dahl AA. Short Form 36 and Hospital Anxiety and Depression Scale: A comparison based on patients with testicular cancer. J Psychosom Res 52:79-87, 2002[CrossRef][Medline] Submitted May 11, 2004; accepted December 22, 2004.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
8 on the HADS subscales. The prevalence rates were compared with age-adjusted norm data. 
2 test. The relative risk for HADS-defined anxiety disorder and depression was calculated for TCSs in relation to the age-adjusted norm population. We calculated the odds ratio of being a patient with HADS-defined anxiety disorder in TCSs for relevant variables using univariate and multivariate logistic regression models. Given that HADS-A and HADS-D mean scores change with age,
