Quality of Life of Testicular Cancer Survivors Fleer, Joke

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Quality of life of testicular cancer survivors

Joke Fleer

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Joke Fleer Quality of life of testicular cancer survivors Thesis University of Groningen ISBN 90-771-1340-1

Cover design STUDIO FRANK & LISA (www.studiofrank-lisa.nl) Lay out

FYN Werk (www.fynwerk.nl)

Printed by

Drukkerij C. Regenboog Groningen

This research was supported by a grant from The Dutch Cancer Society, no. RUG 99-2130

Financial support for this thesis was kindly given by AstraZenecaBV; Fleremaheerd Erfgoedlogies (www.fleremaheerd.nl); Integraal Kankercentrum Noord-Nederland; KWF Kankerbestrijding; Northern Centre for Healthcare Research Groningen; Stichting Werkgroep Interne Oncologie Groningen

©2006, Joke Fleer, Groningen, The Netherlands All rights reserved

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Rijksuniversiteit Groningen

Quality of Life of Testicular Cancer Survivors

Proefschrift

ter verkrijging van het doctoraat in de Medische Wetenschappen aan de Rijksuniversiteit Groningen op gezag van de Rector Magnificus, dr. F. Zwarts, in het openbaar te verdedigen op woensdag 1 maart 2006 om 13.15 uur

door

Joke Fleer geboren op 10 september 1974 te Niehove

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Promotores Prof. dr. H.J. Hoekstra Prof. dr. D.Th. Sleijfer Prof. dr. E.C. Klip

Copromotor Dr. J.E.H.M. Hoekstra-Weebers

Beoordelingscommissie Prof. dr. J.W. Groothoff Prof. dr. J.M. Nijman Prof. dr. M.A.G. Sprangers

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Contents 1 Introduction

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2 Quality of life of survivors of testicular germ cell cancer: a review of the literature

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3 Quality of life of testicular cancer survivors and the relationship with sociodemographics, cancer-related variables and life events

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4 The role of meaning in the prediction of psychosocial well-being of testicular cancer survivors

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5 Objective and subjective predictors of cancer-related stress symptoms in testicular cancer survivors

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6 Prevalence, changes in, and correlates of fatigue the first year after diagnosis of testicular cancer

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7 Different recruitment methods identify different individuals

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8 General discussion

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9 Summary

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10 Samenvatting

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Dankwoord

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Introduction

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Introduction Only 25 years ago, disseminated testicular cancer was the leading cause of cancer death in men between 15 and 45 years of age. After the introduction of cisplatinum into the chemotherapeutic regimen in the late 1970s, testicular cancer has become a curable disease for approximately 90% of the patients [1;2]. Because of the young age at diagnosis, testicular cancer survivors have an additional life expectancy of up to 50 years and, consequently, they have to face possible sequel of diagnosis and treatment for the rest of their lives. At the University Medical Center Groningen (UMCG), in The Netherlands, a tertiary referral center for patients with testicular cancer, considerable institutional research has been performed into the epidemiology, genetic susceptibility, and short- and long-term medical and sexual sequel of testicular cancer [3-10]. However, the possible impact of the experience with testicular cancer on the quality of life of survivors has not received empirical attention yet. This thesis addresses the quality of life of testicular cancer survivors treated at the UMCG between 1977 and 2003. This introductory chapter starts with an elaboration on the concept of quality of life and the possible effects of cancer on the quality of life of patients and survivors. After that, factors that may influence quality of life will be discussed. Lastly, the aim of the thesis and an overview of the chapters will be presented. Quality of life Calman [11] defines quality of life as the gap between the hopes, expectations, and desires of persons during a particular period of time and their present life experiences. In the same tenor, Cella [12] refers to quality of life as the patient’s appraisals of and satisfaction with their current level of functioning compared with what they perceive to be possible or ideal. The greater the gap between the actual and the ideal situation, the lower a person’s quality of life will be. The perception of a person’s quality of life varies between individuals. This means that people with different expectations will report a different quality of life, even when they have the same objective health status. Therefore, insight into a patient’s quality of life can only be obtained by asking a patient’s perspective. Quality of life encompasses several life domains, usually physical, psychological and social well-being [13-15]. Recently, investigators have started to include spirituality as a separate domain, because they have recognized that the experience of life as meaningful and the need to find meaning in life events may be important in determining a person’s quality of life [16;17]. Ferrell and Dow [18] have defined the domains for cancer survivors as follows: • Physical well-being is the control or relief of symptoms and the maintenance of function and independence. • Psychological well-being is the attempt to maintain a sense of control in the face of lifethreatening illness characterized by emotional distress, altered life priorities, and fear of the unknown as well as positive life changes. • Social well-being is the effort to deal with the impact of cancer on individuals, their roles and relationships.

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• Spiritual well-being is the ability to maintain hope and derive meaning from the cancer experience which is characterized by uncertainty.’ Research has found that sequel from cancer diagnosis and treatment may affect all these domains in survivors, months or even years after successful completion of treatment. For example, the cancer experience has been found to induce fatigue [19-21], infertility [22-25], cardiovascular diseases [26;27], posttraumatic stress disorder, and fear for recurrence and death [28-30], and to negatively affect social support systems [31], marital relationships [32], job performance [33-35], and outlook on life [36]. The specific combination of clinical features of testicular cancer may make the population of testicular cancer survivors especially vulnerable for an impaired quality of life. Testicular cancer strikes at an age when health is taken for granted and life-threatening illnesses and the possibility of dying do not fit their outlook on life [2;37;38]. It assaults an organ associated with sexuality and reproduction at a time of life when sexual desire and performance, sense of masculinity, body image, and fertility are central themes [5;39]. And it mostly occurs in a period of life characterized by major social life changes. Between the ages of 15 and 45, important decisions about marriage, starting a family and a professional career are generally made [14]. Thus, the life stage in which testicular cancer occurs has its specific developmental tasks and social roles, and therefore it may make testicular cancer a particularly distressing experience. The confrontation with testicular cancer may continue to influence the well-being of the survivors months or even years after treatment completion, when sequel of the cancer experience continue to interfere with involvements in valued activities, interests, and desires. Factors that may affect quality of life

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The effect of a disease on people’s lives is generally examined by measuring the outcomes as well as the predictors of outcomes [17]. Quality of life as an outcome has been studied quite extensively in psychosocial oncology. Increasingly, research focuses on risk and resilience factors associated with quality of life. It is important to identify factors predictive of an impaired qua­ lity of life, because it may help health care providers to detect distressed individuals at an early stage and refer them for psychosocial care [40]. Based on the stress-coping literature, Holland and colleagues have developed a research model for the field of psycho-oncology [16], in which they have identified variables that may influence quality of life. In this model, cancer is the stressful life event and the disease- and treatment-related variables are the measurable characteristics of the event that may affect the patient’s functioning. The personal variables and life stresses represent the resources of a patient that may be relevant for the outcome of the adjustment process (e.g., quality of life). Figure 1 is a schematic representation of the model of Holland [16] and summarizes the specific variables that were identified as possibly relevant predictors of (domains of ) quality of life in the cancer population. The effect of these variables on quality of life will be investigated in the current thesis. Disease and treatment variables Time since treatment, type of treatment, and the experience of a second cancer event will be studied in the present thesis. There is some evidence that cancer patients who have been diagnosed more recently, who have been treated with more extensive treatment, or who

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have experienced a recurrence are at a higher risk for an impaired quality of life and cancerrelated stress [28;40]. Furthermore, hemoglobin and testosterone levels will be examined in relation to fatigue during the first year after the diagnosis of testicular cancer. Chemotherapy can lower the levels of hemoglobin (mainly a short-term effect) and testosterone (mainly a long-term effect) which can cause excessive tiredness [27;41-43]. Associations between hemoglobin and testosterone levels and fatigue in testicular cancer patients have never received attention before. Personal variables Sociodemographic characteristics (e.g., age, educational level, marital status, employment status) have been found to be associated to some extent with how well people adjust to ha­ ving (had) cancer [40], and should thus be included in studies that aim to elucidate factors that affect quality of life. In general, having a sense of meaning has been identified as an important contributor to a person’s quality of life [16;17]. Stressful life events, such as testicular cancer, may threaten the belief that life is meaningful and this may have a negative effect on well-being. Therefore, it may be relevant to assess meaning and its relationship with psychosocial well-being and cancer-related distress in testicular cancer survivors. Trait anxiety will be investigated in relation to cancer-related fatigue. Little research has focused on this relationship, but there are indications that cancer patients with an anxious disposition pay more attention to physical sensations than less anxious patients [44;45]. So, it might be that this personality trait increases the sensitivity to fatigue. Life stresses The main focus of this thesis is on the quality of life of testicular cancer survivors who have been treated over a period of 25 years (1977-2003). This large range in time since treatment is associated with a methodological problem, because in long-term survivors it is more difficult to distinguish effects caused by cancer and its treatment, from those attributable to other factors, such as additionally experienced life events and comorbidities [46]. The probability of experiencing additional major life events and of developing a functional limitation or chronic disease increases with advancing age, and this may influence the quality of life more than the earlier experience with cancer. Aims of the thesis The general aims of the thesis are: 1. To study the quality of life of testicular cancer survivors; 2. To investigate the extent to which characteristics of the disease and treatment, personal variables, and additional life stresses affect (domains of ) quality of life of testicular cancer survivors. Chapter 2 offers a review of the literature on the quality of life of testicular cancer survivors. The aims of this review are (1) to gain insight into the current state of knowledge on the physical, psychological, and social well-being of testicular cancer survivors, and (2) to assess the impact of disease and treatment characteristics on these domains of quality of life. The

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study that is presented in chapter 3, describes the quality of life (physical, psychological and social domains) of testicular cancer survivors in comparison to a reference group of Dutch men. Furthermore, relationships between quality of life and disease-and treatment-related variables, sociodemographic characteristics, concurrent chronic diseases and recently experienced life events are examined to identify testicular cancer survivors at risk for an impaired quality of life. In chapter 4, a study is presented that examines meaning among testicular survivors and describes the relative contribution of meaning in the prediction of psychosocial well-being and cancer-related distress, in addition to sociodemographics, disease- and treatment-related variables, concurrent chronic disease and recently experienced life events. The primary goal of the study described in chapter 5, is to investigate the prevalence of cancer-related stress symptoms among survivors of testicular cancer. The second goal is to gain insight into the relationships between such stress symptoms and disease- and treatment-related variables and sociodemographics, and to examine whether objective and subjective aspects of cancer diagnosis and treatment are associated with posttraumatic stress symptoms. Chapter 6 describes the levels of and changes in fatigue among testicular cancer patients at three time points during the first year after diagnosis. Also, relationships between fatigue on the one hand and sociodemographics, hemoglobin- and testosterone levels, and trait anxiety on the other hand are examined. In chapter 7 testicular cancer survivors recruited through the UMCG database are compared with survivors recruited through a patient association on sociodemographic and disease- and treatment-related characteristics and quality of life to investigate heterogeneity and differences in the quality of life between individuals recruited through different sources. Finally, in chapter 8, a discussion of the findings of the present study is presented.

Figure 1. Schematic representation of the model of research in psycho-oncology of Holland and colleagues [16] Testicular cancer

Related variables

Outcome variables

Personal variables - sociodemographic characteristics - meaning - trait anxiety

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Life stresses - concurrent chronic disease - recently experienced life events

Disease and treatment variables - time since treatment - type of treatment - second cancer event - hemoglobin level - testosterone level

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Quality of life (multidimensional) Cancer-related stress symptoms Meaning Satisfaction with life Fatigue (multidimensional)

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21. Stasi R, Abriani L, Beccaglia P, Terzoli E, Amadori S (2003) Cancer-related fatigue - Evolving concepts in evaluation and treatment. Cancer 98:1786-1801

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14 22. Schover LR (1999) Psychosocial aspects of infertility and decisions about reproduction in young cancer survivors: A review. Medical and Pediatric Oncology 33:53-59 23. Schover LR (1997) Sexuality and infertility after cancer. John Wiley and sons, Inc., New York 24. Schover LR, Rybicki LA, Martin BA, Bringelsen KA (1999) Having children after cancer. A pilot survey of survivors’ attitudes and experiences. Cancer 86:697-709 25. Wallace WH, Anderson RA, Irvine DS (2005) Fertility preservation for young patients with cancer: who is at risk and what can be offered? Lancet Oncology 6:209-218 26. Meinardi MT, Gietema JA, van der Graaf WT, van Veldhuisen DJ, Runne MA, Sluiter WJ, de Vries EG, Willemse PB, Mulder NH, van den Berg MP, Koops HS, Sleijfer DT (2000) Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. Journal of Clinical Oncology 18:1725-1732 27. Nuver J, Smit AJ, Sleijfer DT, van Gessel AI, van Roon AM, van der Meer J, van den Berg MP, Hoekstra HJ, Sluiter WJ, Gietema JA (2005) Left ventricular and cardiac autonomic function in survivors of testicular cancer. European Journal of Clinical Investigation 35:99-103 28. Kangas M, Henry JL, Bryant RA (2002) Posttraumatic stress disorder following cancer - A conceptual and empirical review. Clinical Psychology Review 22:499-524 29. Smith MY, Redd WH, Peyser C, Vogl D (1999) Post-traumatic stress disorder in cancer: a review. Psycho Oncology 8:521-537 30. Taieb O, Moro MR, Baubet T, Revah-Levy A, Flament MF (2003) Posttraumatic stress symptoms after childhood cancer. European Child & Adolescent Psychiatry 12:255-264 31. Helgeson VS, Cohen S (1996) Social support and adjustment to cancer: reconciling descriptive, correlational, and intervention research. Health Psychology 15:135-148 32. Manne S (1998) Cancer in the marital context: a review of the literature. Cancer Investigations 16:188-202 33. Abrahamsen AF, Loge JH, Hannisdal E, Holte H, Kvaloy S (1998) Socio-medical situation for long-term survivors of Hodgkin’s disease: a survey of 459 patients treated at one institution. European Journal of Cancer 34:1865-1870 34. Bradley CJ, Bednarek HL (2002) Employment patterns of long-term cancer survivors. Psycho Oncology 11:188-198 35. Short PF, Vasey JJ, Tunceli K (2005) Employment pathways in a large cohort of adult cancer survivors. Cancer 103:1292-1301 36. White CA (2004) Meaning and its measurement in psychosocial oncology. Psycho Oncology 13:468-481 37. Jones GY, Payne S (2000) Searching for safety signals: The experience of medical surveillance amongst men with testicular teratomas. Psycho Oncology 9:385-394 38. Van ’t Spijker A, Trijsburg RW, Duivenvoorden HJ (1997) Psychological sequelae of cancer diagnosis: a meta-analytical review of 58 studies after 1980. Psychosomatic Medicine 59:280-293 39. Tross S (1990) Psychological adjustment in testicular cancer. In: Holland JC, Rowland JH (eds) Handbook of psychooncology. Oxford University Press, New York, pp 240-245

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40. Parker PA, Baile WF, Moor CC, Cohen L (2003) Psychosocial and demographic predictors of quality of life in a large sample of cancer patients. Psycho Oncology 12:183-193 41. Pujade-Lauraine E, Gascon P (2004) The burden of anaemia in patients with cancer. Oncology 67:1-4 42. Nord C, Bjoro T, Ellingsen D, Mykletun A, Dahl O, Klepp O, Bremnes RM, Wist E, Fossa SD (2003) Gonadal hormones in long-term survivors 10 years after treatment for unilateral testicular cancer. European Urology 44:322-328 43. Brennemann W, StoffelWagner B, Helmers A, Mezger J, Jager N, Klingmuller D (1997) Gonadal function of patients treated with cisplatin based chemotherapy for germ cell cancer. Journal of Urology 158:844850

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15 44. Stark D, Kiely M, Smith A, Morley S, Selby P, House A (2004) Reassurance and the anxious cancer patient. British Journal of Cancer 91:893-899 45. Cameron LD, Leventhal H, Love RR (1998) Trait anxiety, symptom perceptions, and illness-related responses among women with breast cancer in remission during a tamoxifen clinical trial. Health Psychology 17:459-469 46. Gotay CC, Muraoka MY (1998) Quality of life in long-term survivors of adult-onset cancers. Journal of the National Cancer Institute 90:656-667

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Quality of life of survivors of testicular germ cell cancer: a review of the literature

Joke Fleer Harald J Hoekstra Dirk Th Sleijfer Josette EHM Hoekstra-Weebers Supportive Care in Cancer (2004) 12: 476-486

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Introduction Men between 15 and 45 years are in the prime of life. Major issues that concern them are career, interpersonal relationships and starting a family. Life-threatening illnesses and the possibility of dying do not fit their outlook in this period of life [1;2]. Nevertheless, a small percentage of these men will develop the most common neoplasm in young men: testicular germ cell cancer (TC). Despite increases in incidence, TC is an uncommon di­ sease. It accounts for approximately 1% of all malignancies in men, although the incidence varies according to geographical area and race. Compared to other malignancies, the age distribution of TC is unusual in that the incidence declines with advancing age. Since the introduction of cisplatin-based polychemotherapy in the late 1970s, (disseminated) TC has become one of the most curable malignancies [3;4]. There are two histological types of TC: seminomatous and nonseminomatous tumors. Treatment for TC depends on histological type and stage of disease. Nowadays, treatment for stage I nonseminomatous disease consists of surgical removal of the affected testis (orchidectomy) and surveillance or nerve-sparing retroperitoneal lymph node dissection. Initial treatment for disseminated disease (stages II-IV) is cisplatin-based polychemotherapy followed by resection of residual retroperitoneal or pulmonary tumor mass if necessary. Patients with a stage I and IIA/B seminoma are treated with orchidectomy and radiotherapy, while those with stages IIC-IV are treated with chemotherapy [4]. At present, almost 90% of testicular cancer patients can be cured with existing treatment modalities. Owing to the excellent prognosis, the young age and an increasing incidence, the number of testicular cancer survivors (TCSs) is growing. These men may have an additional life expectancy of perhaps 50 years after treatment and consequently they will have to face possible sequel of diagnosis and treatment for the rest of their lives [5]. The first reports that dealt with the quality of life (QoL, an umbrella term for physical, psychological and social well-being) of TCSs appeared a few years after the breakthrough in medical treatment. Since that time, studies have been performed on the consequences of the experience with TC for a variety of QoL domains. Unfortunately, a critical overview of the current state of knowledge on the QoL of survivors has not been published at this point in time, while the group of survivors is growing and the literature continuous to expand. A thorough review of the literature may guide clinicians when providing patients with information on possible short- and long term effects of the experience with TC on their lives, and it may provide insight into areas that need more research. The aims of this study were: 1) to review the literature on the QoL (physical, psychological and social wellbeing) of TCSs, and 2) to assess the impact of treatment-related characteristics, such as time since diagnosis and type of treatment, on the QoL of survivors.

Patients and methods MEDLINE, EMBASE, PsycINFO and CancerLIT databases were used to identify relevant publications, as were the references of these papers. Keywords were ‘testicular cancer’, ‘testicular neoplasm’, ‘neoplasm’, ‘cancer’, ‘cancer survivors’, ‘survivors’ and ‘quality of life’. To encompass a wide range of QoL outcomes, we also used the following descrip-

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tor terms: ‘d epression’, ‘anxiety’, ‘d istress’, ‘marital functioning’, ‘social functioning’ and ‘work-related problems’. Selection criteria were: 1) papers published in English between 1980 and October 2003, 2) studies on patients with TC who were in complete remission, 3) studies on physical, psychological and social well-being, and 4) papers in which subgroups of TCSs could be clearly identified. Operationalisations of physical, psychological and social well-being were based on the literature on QoL in cancer survivors [6-11]. For physical well-being, the focal points were subjective perceptions of general health, fatigue, and body image. Physical side-effects of the treatment for TC were not included, because these aspects have been addressed in previous studies [4;12-14]. For psychological wellbeing, distress (including anxiety and depression), health worries and psychological wellbeing were chosen from the variety of possible operationalisations. In addition, distress about infertility due to treatment was evaluated. For social well-being, the focal points were marital functioning, social support and functional life. Although sexual well-being is also an important outcome variable, it was not included, because this issue has received extensive attention recently [15;16]. Methodological aspects were not used as an inclusion criterion, because the aim was to make an inventory of the literature on the QoL of TCSs. Studies with methodological shortcomings, such as non-standardized questionnaires and small sample sizes, may have detected relevant and valuable (site-specific) information that strong methodological studies overlooked. These studies may be of value in providing directions for future research. However, this decision not to use methodological aspects as selection criteria may decrease the power of the findings in the current study [17]. Therefore, it was decided to assess the quality of the studies first. There is no golden standard to determine which criteria should be used in quality assessments [18], but one critical issue is the internal validity of the studies, which is derived from procedures and design of the study. Furthermore, with regard to the research questions of this review, we considered treatmentrelated aspects to be important criteria as well. Therefore, the following methodological and treatment-related aspects were used for the quality assessment: design, sample size, use of comparison groups, measurement instruments, type of treatment, and time since diagnosis. It needs to be pointed out that results of individual studies involving comparison of groups or correlational analyses are only reported when they were statistically significant at a level of p ≤ .05 in the analyses.

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Results A total of 23 studies met the inclusion criteria. Table 1 shows the data on the aspects that were considered in the quality assessment. Quality assessment revealed that studies differed greatly in quality. Seven studies were considered as stronger [5;19-24], because on the whole these studies used suitable designs, had adequate sample sizes, used validated questionnaires and comparison groups (with exception of the two prospective studies) [19;20], and had large ranges in time since treatment (with exception of the two prospective studies). Furthermore, these studies considered time since treatment in their analyses, whereas in total, only nine studies investigated whether time since diagnosis was related to

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one of the outcome variables [21-29]. None of these studies found a relationship between time since diagnosis and any of the dimensions of QoL. Five of the qualitatively stronger studies were published recently (between 2000 and 2003). However, the remai­ning two stronger studies were published in 1989, indicating that the poorer-quality studies were not necessarily the earlier studies. Because it is probable that the findings from the stronger-quality studies will have more power and would best answer the research questions of this review, it was decided to discuss the results of these studies first. The results of the remaining studies will be related to these seven studies, and possible differences in results will be explained using the quality criteria. One last remark should be made about type of treatment. Eight retrospective/cross-sectional studies included both TCSs that had been treated before and after 1978 (when cisplatin-based chemotherapy was introduced) [24;25;27-32]. However, it was not possible to compare the two time periods, because the studies did not consider changes due to developments in treatment in their analyses. Furthermore, most studies only considered treatment-related characteristics as independent variables. Other factors that could possibly influence the outcome, such as sociodemographic characteristics and the patient’s support system, were usually not considered. All factors reported on by the studies that have a significant effect on the outcome variable are reported in the current review. Physical well-being Health perception Four of the qualitatively stronger studies reported on health perception. Prospectively, it was shown that physical functioning of TCSs treated with chemotherapy recovered to baseline levels during the 2 years following diagnosis [20]. At time of study, over 70% of the TCSs assessed their general health as good [23], and perceived their health and physical functioning as equal to that of age-matched healthy men [22;23]. None of these qualitatively stronger studies compared treatment groups. The poorer-quality studies reported comparable findings. Several studies reported that TCSs experienced no change in health status compared to the pretreatment situation and between 63 and 90% assessed their general health as good [25;26;30;33;34]. Two studies found no differences in perceived health and physical functioning between TCSs and agematched healthy men or men treated for Hodgkin’s disease [26;35]. However, one study that did not use a validated questionnaire reported that TCSs assessed their own health as better than that of controls [36]. No differences in physical well-being were found between men treated with different treatment modalities [30;34;36]. Fatigue Fatigue was studied relatively comprehensively by the qualitatively stronger studies. Prospectively, an improvement of fatigue was reported in TCSs treated with chemotherapy, although 19% experienced deterioration in fatigue 2 years after treatment [23]. Eightyfour percent experienced no chronic fatigue at time of study [21]. Two studies found that fatigue scores did not differ from those of age-matched healthy men or the general population [5;22], but Fossa et al. [21] reported that TCSs younger than 30 years of age expe-

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rienced more fatigue than the same age cohort of the general population. Furthermore, it was found that TCSs who experienced more fatigue reported a poorer overall QoL [22]. Fatigue was associated with pretreatment distress, morbidity, lower educational level, older age, comorbidity, and higher levels of depression and anxiety [21]. Differences between treatment groups were not found [21, 22]. Overall, results of the poorer-quality studies were in line with those of the qualitatively stronger studies. Two studies reported that most TCSs felt energetic (75% [33] and 82% [25]), although it took an average of nine months for energy levels to return to normal [33]. Compared to men treated for Hodgkin’s disease, energy levels returned to normal in more TCSs, and they reported less fatigue at the time of data collection [26;32]. Fatigue scores of TCSs did not differ from those of norm groups or age-matched healthy men [28;33;37]. In contrast with the qualitatively stronger studies, one study reported that men treated for seminoma experienced more fatigue than men treated for non-seminoma [33], but this last study had a much smaller sample size than the stronger studies [21;22]. Body image The loss of a testicle, which is an organ associated with masculinity and sexuality, may result in an impaired body image [38]. The body image of TCSs returned to normal in the course of time, and at the time of data collection, most TCSs in the qualitatively strong studies did not report feeling less attractive (77.3% [43] and 84.8% [23]) or less masculine than before TC (79%) [20]. Men who felt less attractive had lower scores in most healthrelated QoL domains, reported more fatigue, and were less satisfied with their family life than those who did not feel less attractive [5;23]. These results were supported by the poorer-quality studies, which found that the majority of TCSs had no changed body image (56-94%) [25;26;29;39]. In addition, these studies reported that the body image of TCSs did not differ from that of men treated for Hodgkin’s disease and their feelings of masculinity were equal to those of sociodemographically matched men [26;31]. None of the reviewed studies compared treatment modalities. Psychological well-being

2

Psychological distress In the qualitatively stronger studies, the levels of psychological distress experienced by TCSs varied between 9 and 27% [21;23;24]. One of these studies reported that TCSs as a group experienced significantly less distress than controls [24]. However, Fossa et al. [20] found that TCSs experienced more anxiety but less depression than the general population. One study found that a quarter of the TCSs became more anxious after diagnosis and treatment [24]. The contradictory results may be explained by the different aspects of distress addressed in these studies and the use of different validated questionnaires. None of the qualitatively stronger studies compared treatment modalities. A study of poorer quality reported that 13% of the TCSs experienced depression and 16% tension [25]. In retrospect, TCSs reported more anxiety, depression and distress during the first 6 months after diagnosis than male college students, but levels decreased over time [29;33;35;36]. One study stated that scores did not return to baseline levels, another study found that 12 months after diagnosis, TCSs treated with radiotherapy ex-

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perienced less distress than male college students [25;35]. A significant number of TCSs experienced more depression since treatment [30]. Partly in contrast with the results of Fossa et al. [20], two poorer-quality studies using self-developed questionnaires, reported that TCSs experienced more anxiety, depression and psychosocial problems than agematched men and controls [35;36]. Furthermore, three studies using validated questionnaires but small sample sizes, found no differences in levels of anxiety and depression between TCSs and age-matched men, psychiatric patients, male college students, and other cancer patients [28;33;37]. In line with Rieker et al. [24], two studies reported that TCSs experienced less distress than healthy sociodemographically matched men, male college students and psychotherapy patients [26;33]. In addition, one study found that men treated with radiotherapy reported more depression, but two other studies did not show any differences between treatment groups [30;34;36]. The small sample sizes of the different treatment groups and the use of self-developed questionnaires may explain these contradictory results. Health worries Seventeen percent of the TCSs in the qualitatively stronger study of Fossa et al. [20] reported an increase of fear of recurrence 2 years after baseline measurement, whereas anxiety had decreased in 36%. Since their experience with TC, 19% of the TCSs reported more fear of dying, while 32% reported less fear [24]. None of the stronger studies reported on differences between treatment modalities in health worries. In concurrence with Fossa et al., [20] decreases in fear of recurrence (from 45 to 12%) and in fear of developing a second primary malignancy (from 50 to 21%) were reported in the poorer-quality studies, although health worries were still present in 54-76% of the TCSs [29;30;32-34]. TCSs who reported more anxiety and depression were more afraid of a tumor recurrence, spent more time worrying about their health and had more concerns about their health [29]. One study found no differences in health worries between men who received different treatment modalities; a second study reported that radiotherapy patients worried more about their health after treatment; a third study showed that men treated with chemotherapy experienced greater fear of a tumor recurrence than men treated with radiotherapy [30;33;34]. As mentioned earlier, a likely explanation for the contradictory results between studies that compared treatment groups are the small sample sizes and the use of nonvalidated questionnaires to assess health worries. Fertility distress TC strikes men at an age when fertility is a major concern. Cancer treatment modalities are known to result in infertility [26]. Prospectively, it was found that fertility distress decreased during the 2 years after treatment in 28% of the TCSs, but it increased in 11% [20]. Compared to sociodemographically matched healthy men, TCSs reported more overall problems with being infertile (5% compared to 22%) [24]. Infertility distress was reported most by TCSs with posttreatment ejaculatory dysfunction, those without children, of younger age, with a lower income, and those treated with chemotherapy and retroperitoneal lymph-node dissection (RPLND) [24;28]. Across the treatment groups, percentages of fertility distress varied from 11% in the radiotherapy group to 33% in the men treated with chemotherapy and RPLND [24].

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The poorer-quality studies reported that during and after treatment, TCSs were more anxious about infertility than before diagnosis, but men who were infertile and those who were uncertain about their fertility status were not significantly more depressed and anxious than those who were fertile [29;40]. The majority of the 11 TCSs that were interviewed reported discomfort and regret about possible infertility [39]. Only one study reported on fertility distress in men treated for bilateral TC. Surprisingly, these men reported few problems with their fertility status, but the sample size was small and the study used one question only to assess fertility distress [32]. Psychological well-being Although many QoL studies have shown that cancer and its treatment have detrimental effects on patient’s lives, there is a growing awareness that there may also be positive effects. The prospective studies showed that the QoL of TCSs improved progressively after orchidectomy or chemotherapy [19;20]. At time of study, TCSs and age-matched men reported a similar QoL, and there were no differences between treatment modalities [22]. The results of the poorer-quality studies were rather positive as well. One study found that TCSs reported being more satisfied with their lives than age-matched men [36], and two studies reported a similar QoL in TCSs, and norm-group men, and controls [31;32]. Over 73% of the TCSs experienced good QoL after treatment [25]. A positive rather than negative impact was experienced by over half of the TCSs (exact percentages unknown), while 76% considered that surviving cancer was a worthwhile achievement [28]. Several positive effects were mentioned, including the ability to enjoy oneself, renewed appreciation of life, emotional growth and the resetting of priorities and values [28;39]. The experience of cancer benefited the psychological well-being of most patients treated with chemotherapy (77%) and radiotherapy (82%) [34]. In one study men treated with radiotherapy or chemotherapy reported greater satisfaction with life than men in the surveillance group, but this result was not confirmed by another study [30;36]. Again, a probably explanation for the contradictory results are the small samples and the use of self-developed questionnaires. Social well-being

2

Marital functioning Treatment for TC is known to have repercussions on marital functioning [41]. The qualitatively stronger studies reported that most TCSs did not experience a change in the relationship with their partner after their experience with TC [23;24] and that treatment groups did not differ in their responses to questions about changes in the partner relationship since treatment [19]. The subject of marital functioning has received much more attention in the poorer-qua­ lity studies. Quite similar to the results of the stronger studies, most of the TCSs in these studies reported that the relationship with their partner had not changed or had become stronger after their experience with TC [29;30;34;39]. Anxiety about separation from the spouse was not a concern before, during, or after treatment in most TCSs (84-94%), while scores on spouse importance and quality of communication did not differ over the course of time. The degree of support from the spouse increased during treatment as compared

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to the situation prior to diagnosis and decreased again afterwards [40]. In TCSs, of patients who experienced a change in their partner relationship after TC, most married men indicated that it had strengthened (68%), whereas 74% of unmarried men reported that it had become strained [28]. TCSs appeared to be more satisfied with their partner relationship than sociodemographically matched men [31]. Treatment groups did not differ in their responses to questions about changes in the partner relationship since treatment, although men treated with the most extensive treatment modality (radiotherapy, chemotherapy and/or RPLND) reported less satisfaction with family life than the other treatment groups [30]. This finding was in line with the qualitatively stronger study. Single TCSs may have difficulties starting a relationship not only on account of the above-mentioned problems with infertility, sexual functioning, and altered body image, but also due to the feeling of estrangement from their peers without a history of cancer. No qualitatively stronger studies considered this issue, and only one poorer-quality study reported on TCSs who were not involved with a partner or were not married at the time of their diagnosis and treatment. This study showed that two out of the ten patients who got married after treatment found that having had TC caused difficulties in the marital process, while 35% of the 28 men who were single at the time of data collection thought that the cancer experience would form a problem in planning a marriage [40]. Social support Only one qualitatively stronger study focussed on social functioning after TC. This study reported that TCSs experienced fewer changes in relationships with friends than sociodemographically matched healthy men [22]. The qualitatively poorer studies showed that the experience of TC did not result in changed relationships with family (66-93%) and friends (77-95%) [25;30;34]. Furthermore it was reported that 92% of the TCSs were satisfied with the support they received during treatment [29]. They mentioned more ‘enriching’ relationships with family and friends, although they had become more selective [39]. One study showed no differences between treatment groups, but another study reported improved relationships with family and friends in patients treated with chemotherapy [30;34]. Functional life Long-term side-effects of treatment (such as fatigue, psychosocial problems and fear of tumor recurrence), may cause difficulties in resuming work or study after treatment [42]. The qualitatively stronger studies reported that at the time of data collection, 76-90% of the TCSs were employed [22-24] and that their employment status was no different from that of age-matched healthy men [22]. Furthermore, Joly et al. [22] reported that TCSs and controls had similar problems in their professional lives, although TCSs were less ambitious than controls. The poorer-quality studies reported more extensively on functional life. These studies also showed that most TCSs were employed at the time of data collection (82-98%) [26-29;43]. Their employment status after treatment appeared to be the same as before [25;27;28;34] and it was better than that of men treated for Hodgkin’s disease [43]. Over 90% of the TCSs who returned to work perceived no effect on their career mobility, 45% experienced no effect on their ambition and career plans (while 26% reported a positive

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effect), and 52% experienced no effect on their satisfaction with work (while 32% reported more satisfaction) [28]. In line with the results of Joly et al. [22], two studies found that work and ambition had become less important since TC, because men had reorganized their priorities and had adopted a new philosophy of working to live rather than living to work [27;39]. Compared to men treated for Hodgkin’s disease, the TCSs were better able to work at their former pace [26]. Compared to age-matched controls, TCSs felt less physically exhausted after a working day, and could maintain significantly better concentration and attention at work [36]. Small percentages of TCSs reported negative effects of the cancer treatment on their work satisfaction (16%), career mobility (10%), ambitions and career planning (29%), and relationships with supervisors and co-workers (5-14%), while 12-25% were unable to work at their former pace, finish tasks and had problems with concentration [26-28;43]. In terms of treatment groups, between 12-31% of men treated with radiotherapy or chemotherapy reported job loss and loss of job prospects because of their illness [30;34]. Deterioration in professional performance was reported by 17% of the radiotherapy group and 3% of the other treatment modalities [40]. Men in the surveillance group were less comfortable with their work than TCSs treated with chemotherapy or radiotherapy and had more problems with concentration and attention at work than TCSs treated with chemotherapy. However, another study found no differences between treatment groups [30;36]. Men treated with radiotherapy were more satisfied with their work than those treated with chemotherapy or those in the surveillance group and they felt that work was more worthwhile than those in the surveillance group [30]. There was no diffe­rence between treatment groups with respect to physical exhaustion after work [30;36]. All of these poorer quality studies had serious methodological shortcomings: the sample sizes of the total groups (only two studies included more than 100 TCSs), and the treatment groups were small, all studies used nonvalidated questionnaires or questionnaires of which the psychometric qualities were not reported, and no study compared TCSs with sociodemographically matched healthy men.

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See Gritz et al. [33] Control: median=28.0

M=35.0

Testicular: see Gritz et al. [33] Control: 85

Non-seminoma: 11

Bloom et al. (1988) [43], (1993) [26] Retrospective

Brodsky (1995) [39] Retrospective

Qualitative interview with open-ended questions

Bloom et al. (1988, 1993): work-related questions developed by Barofsky (1978) [51] (psychometric qualities n.r.) Bloom et al. (1993): POMS and CES-D (standardized questionnaires, proven psychometric qualities), SAS (psychometric qualities n.r.), self-developed questions (psychometric qualities not assessed)

Surveillance=8.4 RT=50.6 CT±RRTM=41.0

%

Treatment in addition to orchidectomy

n.r.

n.r.

See Gritz et al. [33] See Gritz et al. [33]

I=57.8 II=19.3 III=22.9

SWL (validated); self-developed and translated questions, based on Stuart 18.0-60.0, M=33.8 et al., 1990 [34]; Kaasa et al., 1991 [36]; Aaronson et al., 1987 [50] (psychometric qualities n.r.)

Stage of disease %

Measurement instruments

years

Age at time of data collection

83

N

Subjects

Arai et al. (1996) [30] Retrospective

Study + Design

Table 1. Studies included in this review (alphabetical order) and information on criteria used for quality assessment

>3 after treatment

See Gritz et al. [33] Control: median=3.0

1.0-21.8, M=8.0

years

Time since diagnosis

27

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Edbril & Rieker (1989) [27], Rieker 74 et al. (1985) [28] Cross-sectional

19.0-59.0, median=30

POMS; CPBS (abbreviated; psychometric qualities n.r.); BMS; self-developed n.r. questions (psychometric qualities n.r.)

I=53.2 II=39.5 III=7.3

Non-seminoma: 24.0-66.0, M=39.4 Self-developed questions (psychometric Control: agequalities n.r.) matched

Non-seminoma: 109 Control: 107

Douchez et al. (1993) [35] Retrospective

n.r.

%

Stage of disease

I=65.0 >I=35.0

Self-developed questionnaire (validated)

Measurement instruments

Seminoma: 22.0-67.0, M=41.0 POMS; self-developed questions (psyControl: chometric qualities n.r.) 25.0-75.0, M=42.9

26.0-85.0, median=48.0

years

N

Seminoma: 98

Age at time of data collection

Cassileth & SteinSeminoma: 39 feld (1986) [31] Control: 39 Cross-sectional

Caffo et al. (2001) [25] Retrospective

Study + Design

Subjects

2

Table 1 continued

M=9.1

RRTM=3.7 RT+CT=9.2 RT±RRTM=4.6 CT±RRTM=65.1 RT+CT+RRTM=17.4

RT=8.0 CT=27.0 2.0-10.0, median=4.0 RRTM=16.0 after treatment RT+CT+RRTM=50.0

1.0-20.0, M=7.3

1.25-36.0, median=10.3 after treatment

years

Time since diagnosis

RT=100

RT=100

%

Treatment in addition to orchidectomy

28

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1-7.5, M=4 after treatment

POMS; CES-D; OLQ (sense of coherence); FES (standardized questionnaires, n.r. proven psychometric qualities)

M=37.7

34

Surveillance=2.9 RT=44.1 CT=8.8 RRTM=20.6 RT+CT=2.9 CT+RRTM=20.6

Gritz et al. (1990) [37] Cross-sectional

1.0-7.5, M=3.8 after treatment

RT=42.0 CT=47.0 RRTM=50.0

I=48.0 II=37.0 III=15.0

4.0-21.0, median=12.0

After orchidectomy, 3 months, 6 months, 1 year, 2 years

POMS; CES-D; self-developed questions (psychometric qualities n.r.)

88

Gritz et al. (1988) [33] Cross-sectional

CT=100

18.0-60.0, M=35.2

Testicular: 23.075.0, median=44.0 Control 1: I

n.r.

n.r.

16.0-63.0, M=31.0

666

Fossa et al. (2003) [20] Prospective

1st-2nd orchidectomy surveillance=16.3-67.8 RT=58.1-18.6 RRTM=11.6-0.0 CT±others=14.0-18.6

1st-2nd orchidectomy I=74.4-81.5 II=9.3-11.6 III=7.0-2.3 IV=9.3-4.7

years

Time since diagnosis

Surveillance ±RRTM=20.0 RT=41.0 CT±others=39.0

EORTC QLQ C-30 + TC module

31.0-75 median=41.0

Bilateral: 43

%

Treatment in addition to orchidectomy

%

Stage of disease

HADS; FQ (standardized questionnaires, proven psychometric qualities)

EORTC QLQ C-30; IES; GHQ-28 (standardized questionnaires, proven psychometric qualities)

Measurement instruments

Fossa et al. (1999) [32] Cross-sectional

Age at time of data collection

years

Subjects

N

Study + Design

Table 1 continued

29

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15.0-≥40.0

PSE (standardized instrument)

Up to 5.0

I=43.1 >I=56.9

Surveillance=19.0 RT=4.0 CT=5.0 RT+CT=31.0 CT+surgery=29.0 RT+CT+surgery=12.0

97

Total: 3.0-9.0, M=5.1

RT=26.2 RRTM=21.5 CT+RRTM=30.8 CT+RT±RRTM=21.5

M=2.0 I=51.0 II=32.2 III=2.7 IV=12.1

Moynihan (1987) [29] Retrospective

HSCL (standardized questionnaire, proven psychometric qualities); selfdeveloped questions (psychometric qualities n.r.)

Testicular: 17-64, M=34 Control groups: age-matched

Testicular: 149 Control 1: 6277 Control 2: 1638 Control 3: 520

Kaasa et al. (1991) [36] Cross-sectional

5.0-20.0, M=11.0

I=64.8 >I=35.2

Testicular: 71 Control: 119

Surveillance=9.0 RT=48.2 CT±RRTM=36.8 RT+CT=5.9 RRTM=19.7

Testicular: EORTC QLQ C-30; SF-36 (standard29.0-67.0, M=47.0 ized questionnaire, proven psychometric Control: qualities) 29.0-67.0, M=48

Joly et al. (2002) [22] Case-control

Time since diagnosis years

Treatment in addition to orchidectomy %

%

years

Stage of disease

N

Measurement instruments

Age at time of data collection

Study + Design

Subjects

Table 1 continued

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140

N

Subjects

Rudberg et al. (2000) [23] Retrospective

Testicular: 277 Control: 122

Rieker et al. (1989) Testicular: 223 [24] Control: 120 Retrospective

Ozen et al. (1998) [40] Cross-sectional

Study + Design

Table 1 continued

Testicular: 18-83, M=42.2 Control: 25-54, M=39

SWEDQUAL (standardized questionnaire, proven psychometric qualities); self-developed questions (psychometric qualities n.r.)

Testicular: 17.0-65.0, See Edbril and Rieker (1989) and Rieker median=33.0 et al. (1985) Control: 19.0-60.0, median=30.5

I=45.1 >I=54.9

I=32.0 >I=68.0

I=83.9 qualities n.r.)

Self-developed questions (psychometric qualities n.r.)

CT: 19-48, median=29 RT: 20-48, median=33

Stuart et al. (1990) [34] 62 Retrospective

Measurement instruments

GQL (only symptom checklist; reliable, validity n.r.); self-developed questions (psychometric qualities n.r.)

years

N

Testicular: 277 Control: 392

Age at time of data collection

Testicular: 18-83, M=42.2 Control: M=45

Rudberg et al. (2002) [5] Retrospective

Study + Design

Subjects

2

Table 1 continued

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Discussion The goal of this study was to give a comprehensive review of the literature of primary studies examining physical, psychological and social well-being of TCSs. A total of 23 studies, published between 1985 and 2003, met the inclusion criteria. Because these studies used such a broad variety of methodologies and research questions, this review was by necessity descriptive. However, a quality assessment was performed to interpret and explain contradictory results and to increase the power of this review. Based on methodological and treatment-related criteria, seven studies appeared to be qualitatively stronger. Results of both stronger- and poorer-quality studies appeared quite similar. Prospective and retrospective studies showed that QoL after completion of treatment increased and that the negative consequences of TC on life decreased compared to the situation directly after diagnosis when a poorer QoL was observed. For example, energy levels returned to normal, fatigue decreased and the TCSs became used to their changed body image. Decreases were found in psychological distress, anxiety, depression, and fear of tumor recurrence. The stronger-quality studies paid little attention to the social dimension (marital functioning, social support, and functional life) and positive effects of the experience with TC. Poorer-quality studies reported that, besides a decrease in negative consequences of TC on the patients’ lives, the experience of TC seemed to have positive effects. A considerable proportion of the TCSs reported that they had experienced emotional growth, were appreciating life more, and had stronger relationships with family and friends. Results on functional life were mainly contradictory. Based on this summary of the results one could assume that in general TCSs experience a good QoL. However, this could be an arguable assumption because of the methodological shortcomings of most studies and because the stronger-quality stu­dies did not investigate all dimensions of QoL with the same extensiveness. Below we discuss various methodological issues. Firstly, many studies used a retrospective design to evaluate the well-being of TCSs and to compare their well-being before and/or after treatment. Data obtained in re­ trospect are less reliable for two reasons: [2] the chance is great that recall was distorted (selective memory bias), because 1-36 years had passed between data collection and diagnosis [17;23;28;44] under the influence of certain life events (such as experience with cancer) internal standards can change (response shift) and cause people to evaluate new situations according to other standards [45]. For example, people can become accustomed to a higher level of fatigue and after a certain amount of time, report the same QoL as that prior to the illness [46;47]. Such changes in internal standards cannot be reproduced accurately in retrospective studies. The only way that conclusions can be drawn from cross-sectional or retrospective studies about the relationship between TC and QoL is to compare the current QoL of TCSs to that of a sociodemographically-matched group. Secondly, a considerable number of studies had no comparison group. Some studies used norm groups, but these often differed from TC patients in sociodemographic areas. In studies that compared TCSs to other cancer patients, it often appeared that

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2

the other cancer patients had a poorer prognosis and had received other forms of treatment. Thirdly, a wide variety of both validated and non-validated measurement instruments were used to evaluate the same aspects of QoL, which made it difficult to compare results. Therefore, some differences in findings may be due to the different instruments that were used, even if they were validated measures. In the studies that used non-validated instruments, some variables (e.g., body image) were measured with only one or two items. This affected the reliability of study results, and it is not clear whether their scope is of sufficient depth [48]. Fourthly, descriptive and comparison analysis methods were generally used, whereas techniques such as regression analyses would have enabled the identification of possible risk groups. Fifthly, in a large proportion of the studies, reliability and generalizability were affected by small numbers (fewer than 100 TCSs). A small study group means that there is insufficient power to determine the possible influence of demographic and treatmentrelated variables [22]. Sixthly, the majority of studies did not correct for confounding variables such as age, marital status, education level, time since diagnosis, treatment modality and disease stage, although they aimed to measure the negative impact of illness or treatment on QoL. To identify possible groups of men, who are at risk of developing problems, it is essential to control for demographic and treatment-related variables. In addition to these methodological issues, the studies showed limitations in how they applied the treatment-related variables. Only nine studies considered time since diagnosis in their analyses, and the categorizations of treatment modalities were rough. None of the studies reflected on changes in treatment over time, which may have caused a threat to the internal validity. From a historical point of view the differences in methodologies between studies and the methodological shortcomings of most studies are well explainable. The earlier stu­ dies had to use explorative designs, self-developed and non-validated questionnaires and could only focus on short-term sequel of survivorship. In contrast, the more recent studies could make use of well-validated and reliable instruments developed over the years. Furthermore, the number of survivors has greatly increased due to advances in medical treatment, making methodological stronger studies possible. Therefore, it was not surprising that five of the seven methodological stronger studies were published between 2000 and 2003, although the poorer-quality studies were not necessarily the earlier studies. A problem of studies with methodological shortcomings is that their results may not always concur with reality. This can be illustrated with three examples from this review. Firstly, it would have been reasonable to expect that more extensive treatment would cause more short- and long-term physical and psychosocial side effects. It may be that the lack of documented effect of treatment reflects inadequate methodology, lack of adequately powered and comprehensive studies and the rough categorizations of treatment modalities. A second example that illustrates the distorting effect of methodological shortcomings on the outcomes of this review is the wide variety of

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35 percentages of TCSs reporting negative effects between studies. For example, the level of psychological distress varied between 8% and 27%, while 5% to 29% were experiencing work-related problems since TC. A third example is the result that men with bilateral TC have less fertility issues. There is only one study that states this, and given the lack of biological rationale for this observation, it may be regarded as casuistry and not as a reflection of reality. As regard to content, more research is needed as well. The qualitatively stronger stu­ dies did not exhaustively delve into any of the outcome variables, indicating that more research is needed on all dimensions of QoL but most of all in the area of social wellbeing and the impact of treatment-related characteristics. The poorer-quality studies provided some directions for future research. In particular, issues that may be of major concern for young men dealing with sequel of cancer diagnosis and treatment, such as body image, fertility issues, intimate relationships, social support and work-related issues need more attention. Surprisingly few studies attacked these issues, and all these studies suffered from methodological shortcomings (non-validated questionnaires and small sample sizes). For example, the effects of TC on casual relationships and on men who did not have a partner at the time of TC have received very little attention. One study showed that TC had a negative effect on casual relationships, whereas the relationship of many married men with their spouse became stronger. The only study that investigated whether men who were single at the time of diagnosis experienced problems with starting a new relationship found that 20% of men reported problems. It would seem worthwhile to conduct more research into the effects of TC on casual relationships and on single men, because TC particularly affects young men who are more likely to be single or have a relationship without being married. Future directives In conclusion, because of the above-mentioned methodological shortcomings, it would not be justified to provide a general conclusion on the QoL of TCSs. In order to obtain such data and to gain clearer insight into the impact of TC on later QoL, more methodological strong, cross-sectional, and prospective research is needed. The studies should include large groups of patients and sociodemographically matched comparison groups, and the analyses should aim to identify subgroups that are at risk of developing psychosocial problems. To identify risk groups, it is necessary to establish the predictive value of, for example, demographic variables (age, marital status, education level), treatment-related variables (treatment modalities, time since diagnosis, disease stage, experience of a second cancer event), social support, and personality factors. In addition, on a content level, future research should pay more attention to body image, fertility distress, issues concerning intimate relationships, social support and workrelated problems. Furthermore, more attention should be paid to possible long-term side-effects of treatment with radiotherapy or chemotherapy, such as an increased risk of secondary leukemia, second primary malignancies, decreased renal functioning, hearing deficits and cardiovascular disease [14;49]. As knowledge of the long-term

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36 side-effects of cancer treatment has only started to increase fairly recently, very little research has been performed as yet into their possible impact on QoL.

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38 20. Fossa SD, de Wit R, Roberts JT, Wilkinson PM, de Mulder PH, Mead GM, Cook P, de Prijck L, Stenning S, Aaronson NK, Bottomley A, Collette L (2003) 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). Journal of Clinical Oncology 21:1107-1118 21. Fossa SD, Dahl AA, Loge JH (2003) Fatigue, anxiety, and depression in long-term survivors of testicular cancer. Journal of Clinical Oncology 21:1249-1254 22. Joly F, Heron JF, Kalusinski L, Bottet P, Brune D, Allouache N, Mace-Lesec’h J, Couette JE, Peny J, HenryAmar M (2002) Quality of life in long-term survivors of testicular cancer: a population-based case-control study. Journal of Clinical Oncology 20:73-80 23. Rudberg L, Nilsson S, Wikblad K (2000) Health-related quality of life in survivors of testicular cancer 3 to 13 years after treatment. Journal of Psychosocial Oncology 18:19-31 24. Rieker PP, Fitzgerald EM, Kalish LA, Richie JP, Lederman GS, Edbril SD, Garnick MB (1989) Psychosocial factors, curative therapies, and behavioral outcomes. A comparison of testis cancer survivors and a control group of healthy men. Cancer 64:2399-2407 25. Caffo O, Amichetti M, Tomio L, Galligioni E (2001) Quality of life after radiotherapy for early-stage testicular seminoma. Radiotherapy and Oncology 59:13-20 26. Bloom JR, Fobair P, Gritz E, Wellisch D, Spiegel D, Varghese A, Hoppe R (1993) Psychosocial outcomes of cancer: a comparative analysis of Hodgkin’s disease and testicular cancer. Journal of Clinical Oncology 11:979-988 27. Edbril SD, Rieker PR (1989) The impact of testicular cancer on the work lives of survivors. Journal of Psychosocial Oncology 7:17-29 28. Rieker PP, Edbril SD, Garnick MB (1985) Curative testis cancer therapy: psychosocial sequelae. Journal of Clinical Oncology 3:1117-1126 29. Moynihan C (1987) Testicular cancer: the psychosocial problems of patients and their relatives. Cancer Surveys 6:477-510 30. Arai Y, Kawakita M, Hida S, Terachi T, Okada Y, Yoshida O (1996) Psychosocial aspects in long-term survivors of testicular cancer. Journal of Urology 155:574-578 31. Cassileth BR, Steinfeld AD (1987) Psychological preparation of the patient and family. Cancer 60:547-552 32. Fossa SD, Opjordsmoen S, Haug E (1999) Androgen replacement and quality of life in patients treated for bilateral testicular cancer. European Journal of Cancer 35:1220-1225 33. Gritz ER, Wellisch DK, Landsverk JA (1988) Psychosocial sequelae in long-term survivors of testicular cancer. Journal of Psychosocial Oncology 6:41-63 34. Stuart NS, Grundy R, Woodroffe CM, Cullen MH (1990) Quality of life after treatment for testicular cancer--the patient’s view. European Journal of Cancer 26:291-294 35. Douchez J, Droz JP, Desclaux B, Allain Y, Fargeot P, Caty A, Charrot P (1993) Quality of life in long-term survivors of nonseminomatous germ cell testicular tumors. Journal of Urology 149:498-501

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36. Kaasa S, Aass N, Mastekaasa A, Lund E, Fossa SD (1991) Psychosocial well-being in testicular cancer patients. European Journal of Cancer 27:1091-1095 37. Gritz ER, Wellisch DK, Siau J, Wang HJ (1990) Long-term effects of testicular cancer on marital relationships. Psychosomatics 31:301-312 38. van Basten JP, Jonker-Pool G, van Driel MF, Sleijfer DT, van de Wiel HB, Mensink HJ, Schraffordt-Koops H, Hoekstra HJ (1996) Fantasies and facts of the testes. British Journal of Urology 78:756-762 39. Brodsky MS (1995) Testicular cancer survivors’ impressions of the impact of the disease on their lives. Quality of Life Research 5:78-96 40. Ozen H, Sahin A, Toklu C, Rastadoskouee M, Kilic C, Gogus A, Kendi S (1998) Psychosocial adjustment after testicular cancer treatment. Journal of Urology 159:1947-1950

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39 41. Hannah MT, Gritz ER, Wellisch DK, Fobair P, Hoppe RT, Bloom JR, Sun G, Varghese A, Cosgrove MD, Spiegel D (1992) Changes in marital and sexual functioning in long-term survivors and their spouses: testicular cancer versus Hodgkin’s disease. Psycho Oncology 1:89-103 42. Fobair P, Hoppe RT, Bloom J, Cox R, Varghese A, Spiegel D (1986) Psychosocial problems among survivors of Hodgkin’s disease. Journal of Clinical Oncology 4:805-814 43. Bloom JR, Hoppe RT, Fobair P, Cox RS, Varghese A, Spiegel D (1988) Effects of treatment on the work experience on long-term survivors of Hodgkin’s disease. Journal of Psychosocial Oncology 6:65-80 44. de Haes J, Curran D, Young T, Bottomley A, Flechtner H, Aaronson N, Blazeby J, Bjordal K, Brandberg Y, Greimel E, Maher J, Sprangers M, Cull A (2000) Quality of life evaluation in oncological clinical trials. European Journal of Cancer 36:821-825 45. Sprangers MA, Schwartz CE (1999) Integrating response shift into health-related quality of life research: a theoretical model. Social Science & Medicine 48:1507-1515 46. Richardson A (1998) Measuring fatigue in patients with cancer. Supportive Care in Cancer 6:94-100 47. Stone P, Richards M, A’Hern R, Hardy J (2001) Fatigue in patients with cancers of the breast or prostate undergoing radical radiotherapy. Journal of Pain and Symptom Management 22:1007-1015 48. Maguire P (1992) Psychosocial well-being in testicular cancer patients. European Journal of Cancer 28A:722 49. Travis LB, Curtis RE, Storm H, Hall P, Holowaty E, Van Leeuwen FE, Kohler BA, Pukkala E, Lynch CF, Andersson M, Bergfeldt K, Clarke EA, Wiklund T, Stoter G, Gospodarowicz M, Sturgeon J, Fraumeni JF, Jr., Boice JD, Jr. (1997) Risk of second malignant neoplasms among long-term survivors of testicular cancer. Journal of the National Cancer Institute 89:1429-1439 50. Aaronson NK, Bakker W, Stewart AL, van Dam FS, van Zandwijk N, Yarnold JR, Kirkpatrick A (1987) Multi-dimensional approach to the measurement of quality of life in cancer clinical trials. In: Aaronson NK, Beckman J (eds) The quality of life of cancer patients. Raven Press, New York, p 63 51. Barofsky I (1978) Compliance, adherence and the therapeutic alliance: Steps in the development of selfcare. Social Science & Medicine 12:369-376

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Quality of life of testicular cancer survivors and the relationship with sociodemographics, cancer-related variables and life events

Joke Fleer Harald J Hoekstra Dirk Th Sleijfer Marrit A Tuinman Ed C Klip Josette EHM Hoekstra-Weebers Supportive Care in Cancer (2005): published online Sep 17

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Introduction Testicular cancer (TC) affects men in a period of life when intimate relationships, star­ ting a family, and career are major concerns. Since the introduction of cisplatin-based chemotherapy in the late 1970s, TC has become one of the most curable malignancies, with cure rates between 85 and 90% [1;2]. As a consequence, the majority of men diagnosed with TC will live the largest part of their lives as cancer survivors and they may have to face sequel of diagnosis and treatment on different domains of their lives. The term “quality of life” (QoL) is generally used to refer to an individual’s perception of his well-being on, among others, the physical, psychological, and social domains [3]. In the research on testicular cancer survivors (TCSs), these domains already have received attention. For example, research on the physical domain shows that TCSs who were treated for metastetic disease have an increased risk of infertility, fatigue, second primary malignancies, decreased renal functioning, hearing deficits, and cardiovascular disease [4;5]. Studies that focused on the psychological and social domains showed that the majority of TCSs experiences good levels of functioning, although subsamples report psychosocial problems such as anxiety, depression, fertility distress, and work-related problems [6]. However, a review of the literature on the QoL of TCSs revealed that most of the exis­ ting literature on the QoL of TCSs suffers from methodological shortcomings, such as small sample sizes and the use of nonvalidated questionnaires [6]. Furthermore, there is a lack of research into the QoL of the growing group of long-term TCSs. Currently, there are only a few studies that did include long-term survivors [7-10], whereas at this point in time, approximately 25 years after the medical breakthrough in treatment, the group of long-term survivors has grown large enough to provide adequate statistical power to examine their QoL. Then again, the inclusion of long-term survivors does confront researchers with specific methodological concerns. In long-term survivors, it is more difficult to distinguish effects caused by cancer and its treatment, from those attributable to other factors, such as aging, comorbidities [11], and additionally experienced life events. The probability of having a functional limitation or chronic disease increases with advancing age [11], and this may affect QoL. In addition, it is likely that, over time, other life events may influence the current QoL more than the experience with cancer. Therefore, to be able to draw reliable conclusions about the QoL of TCSs, it is essential to investigate the impact of age, comorbidities, and recently experienced life events as well as that of cancer-related variables. Lastly, based on the available data, it is not possible to identify TCSs at risk for an impaired QoL. Because the endpoint of research should always be to bridge the gap with clinical practice [12], the identification of risk groups should be a primary focus of QoL studies. Risk profiles may help clinicians to detect distressed TCSs in an early stage. This may lead to earlier referral to psychosocial services and as a consequence more patients may be spared from protracted distress [13]. The present study aims to attack the above-mentioned issues by (1) examining the QoL of a large sample of TCSs by comparing them to a reference group of Dutch men; (2) investigating the relationship of sociodemographics, cancer-related variables, and recently experienced life events with QoL and (3) identifying TCSs with an impaired QoL,

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based on sociodemographic variables, cancer-related variables, and recently experienced life events.

Patients and methods Procedure All men treated for TC between 1977 and 2003 at the University Medical Center Groningen (UMCG) in The Netherlands were approached in writing for the present study. In 1977, cisplatin-based chemotherapy, which led to the improved survival rates, was introduced into the treatment of metastetic TC at the UMCG. Exclusion criteria were age younger than 18 years at study entry, insufficient command of the Dutch language, and time since completion of treatment shorter than 3 months. The decision to use the criterion of 3 months after completion of the last treatment was based on the clinical consideration that TC patients have a very good prognosis. A letter with information about the objectives of the study and an informed consent form were sent to the 702 eligible TCSs. The study was approved of by the Medical Ethics Committee of the University Medical Center Groningen. Measurements

3

Data on the following sociodemographic variables were collected: age, educational level, marital status, employment status, and chronic disease. Highest educational level completed was measured on a seven-point scale: primary school (1), lower vocational degree (2), lower secondary (3), middle secondary (4), high secondary (5), higher vocational (6) and university (7). We define chronic disease as an illness marked by long duration or frequent recurrence and used two questions to measure the prevalence of a chronic disease. TCSs first responded to a yes/no question: “Do you have a chronic disease (e.g., asthma, multiple sclerosis, rheumatoid arthritis)?” If a TCS reported that he had a chronic disease, he was asked to describe the disease. In addition, the following cancer-related data were collected: age at diagnosis, time since completion of treatment, type of treatment, and whether they had experienced a second cancer event (either a tumor relapse or a second primary malignancy). Type of treatment could comprise: orchidectomy (surgical removal of the affected testicle), orchidectomy and a retroperitoneal lymph node dissection (RPLND), orchidectomy and radiotherapy, orchidectomy and chemotherapy, or orchidectomy and chemotherapy and resection of residual tumor mass (RRTM). The RAND-36 [14] is an internationally used valid and reliable generic self-report questionnaire to assess QoL. The Dutch version of the RAND-36 [15] was used. It contains eight subscales: physical functioning (ten items), social functioning (two items), role limitations in work or other activities due to physical problems (four items), role limitations in work or other activities due to emotional problems (three items), mental health (five items), vitality (two items), pain (two items), and general health perception (five

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items). After recoding and transforming, scores of the subscales could range from 0 to 100, with a higher score indicating better functioning. In the present study, internal consistency (Cronbach alpha) of the subscales for the total group of TCSs varied between 0.80 and 0.92. We used reference scores from the Dutch manual for the RAND-36 as comparison to the TCSs. These comprised the mean scores from a group of 372 nonselected men from a random sample of 1,063 persons aged 18 years and older from the population register of a municipality in the north of the Netherlands (number of inhabitants = 108,000). The mean age of the persons in the total random sample was 44.1 years (range 18-89 years) [15]. Life events were measured with the Vragenlijst Recent Meegemaakte Gebeurtenissen (VRMG), a Dutch questionnaire to measure recently experienced life events [16]. This questionnaire contains 25 events around five themes: health, illness and death; pregnancy/birth; work; relationships, and miscellaneous (e.g., financial gain/loss, moving house, passing an exam). TCSs were asked to report whether they had experienced any of the 11 positive events and 14 negative events during the past year. Sum scores were calculated for the two subscales. For TCSs, one self-constructed question was added to relate their experience with TC to their current QoL. TCSs responded to the question: “Do you think that your experience with testicular cancer affects your current QoL?” The following answers could be given: 1) “TC affects my current QoL very negatively”, 2) “TC affects my current QoL negatively”, 3) “TC affects my current QoL positively as well as negatively”, 4) “TC affects my current QoL positively”, 5) “TC affects my current QoL very positively”, 6) “TC does not affect my current QoL”. Statistical analyses To investigate differences between the TCSs and the reference group, independent Ttests were performed. Effect sizes were calculated with Cohen’s d to assess the clinical significance of differences between TCSs and the reference group on the RAND-36. The interpretation of effect sizes is that a difference greater than 0.8 is large, between 0.5 and 0.8 is moderate, between 0.2 and 0.5 is small, and a difference smaller than 0.2 is insignificant [17]. Pearson correlations, T-tests, ANOVAs, and Mann-Whitney U tests were conducted to examine which sociodemographic variables, life events, and cancer-related variables were significantly related to the RAND-36 subscales. For employment status, a dichotomous variable was created with the categories “not employed for wages” (consisting of students, being unemployed, being unable to work and being retired) and “employed for wages” (consisting of being employed for wages). The effect of time since completion of treatment was evaluated in two ways. First, correlational analyses were performed, and se­condly, ANOVAs were conducted to compare survivors divided into five groups accor­ ding to time elapsed since completion of treatment. Group I, 3 months-2 years; Group II, 2-5 years; Group III, 5-10 years; Group IV, 10-15 years; Group V, more than 15 years. The

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effect of type of treatment was investigated on the basis of two classifications. Firstly, the four treatment groups were compared. Secondly, two treatment groups were compared: “surgical treatment” (consisting of the categories orchidectomy and orchidectomy plus RPLND) and “combined treatment” (consisting of the categories orchidectomy plus radiotherapy, orchidectomy plus chemotherapy and orchidectomy plus chemotherapy plus RRTM). The variables that were significantly related to the dependent variables in the univariate analyses were included in forward regression analyses. Results were considered statistically significant if the probability of occurrence was 0.05 or less. Inasmuch as this is a descriptive study, no formal adjustments were employed to correct for multiple testing. Therefore, caution is warranted in interpretation of findings of p > 0.01.

Results Descriptives

3

Fifty percent (n = 354) of the TCSs approached agreed to participate. Of the TCSs who did not participate, 74 (21%) indicated their reason for refusal. Main reasons mentioned were lack of interest, the disease period was considered to be a closed book, and too much of a burden. Nonparticipants did not differ significantly on age, time since diagnosis, and type of treatment from the participants. The descriptives of the participants are summarized in Table 1. Mean age was 43.7 years, ranging from 18 to 78 years. Highest educational level completed varied from primary school to university degree, but the mean educational level was high secondary education. Furthermore, most survivors were married or cohabiting (85%), employed for wa­ ges (78%), and did not have a chronic disease (85%). The TCSs who did have a chronic disease mainly reported having rheumatoid and degenerative diseases (26%), pulmonary diseases (23%) and cardiovascular diseases (19%). Noticeable, only one TCS reported that his lungs were damaged due to treatment with bleomycin. The mean time since completion of treatment was 10 years, ranging from 3 months to 24 years. Because age at diagnosis correlated highly with age (r = 0.83, p < 0.001), it was decided to leave age at diagnosis out of further analyses. The correlation between age and time since completion of treatment was lower (r = 0.43, p = 0.001), and therefore, both variables were taken into account in further analyses. The minority of TCSs (34.5%) was treated with surgical treatment (orchidectomy ± RPLND) and almost 9% of the survivors had experienced a second cancer event (recurrence, second TC, or other cancer tumor) (Table 1). QoL of TCSs: comparison with a reference group Independent T-tests showed that TCSs reported better physical functioning (t = 2.4, p < .05) and less pain (t = 3.3, p = .001) than the reference group of men, but a worse mental health (t = -2.03, p < 0.05) and less vitality (t = -3.5, p < 0.001). However, the effect sizes of the differences were small for the subscales vitality and pain and insignifi-

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47 Table 1. Sample characteristics

TCSs (N = 354*) Age (in years) mean, range

43.7

Educational level mean, SD

4.2

a

18.4-78.5 1.7

Marital status N, % Single/divorced/separated

53

15

Married/cohabiting/LAT

300

85

Employment status N, % Employed for wages

275

77.9

Student

12

3.4

Out of work

6

1.7

(Partly) unable to work

28

7.9

Retired

32

9.1

Children N, % No

127

36

Yes

226

64

No

299

84.9

Yes

53

15.1

Chronic disease N, %

Life events mean, SD Positive

1.6

Negative Time since treatment (in years) mean, SD

2.0

1.3

1.6

10.0

6.7

Treatment N,% Surgical treatment

121

34.5

Orchidectomy

99

28.2

Orchidectomy + RPLNDb

22

6.3

230

65.6

Orchidectomy + radiotherapy

68

19.4

Orchidectomy + chemotherapy

53

15.1

109

31.1

Yes

31

8.8

No

322

91.2

Combined treatment

Orchidectomy + chemotherapy + RRTM

c

Second cancer event N, %

*N is slightly variable because of missing data. a educational level was measured on a seven-point scale, ranging from primary school (1) to university degree (7); bRPLND = retroperitoneal lymph node dissection; cRRTM = resection of residual tumor mass

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cant for the other subscales. This indicates that the statistically significant differences are not clinically relevant (Table 2). Associations between sociodemographic and cancer-related variables and life events and QoL of TCSs A significant negative correlation was found between age and physical functioning, pain, and general health perception (all p < 0.001). Furthermore, a significant positive relationship was found between educational level and physical functioning (p < 0.001). Positive life events was not significantly correlated to any of the RAND-36 subscales, but a significant negative association was found between the experience of more negative life events and social functioning (p < 0.05), role limitations (emotional) (p < 0.01) and mental health (p < 0.05). Time since treatment correlated significantly negatively with physical functioning (p < 0.05) (Table 3). When TCSs were divided in time-cohorts based on time since treatment, it appeared that no significant differences were found between the cohorts on any of the RAND-36 subscales. Table 2. Means and standard deviations for the RAND-36 subscales for TCSs and the reference group and T-tests between the two groups TCSs Mean

SD

Mean

SD

t

p-value

Effect size

88

19

85

22

2.41

0.02

0.18

Social functioning

86

20

88

20

-1.84

0.07

-0.14

Role limitations (physical)

84

31

82

34

1.05

0.29

0.08

Physical functioning

3

Reference group

Role limitations (emotional)

85

31

87

29

-0.85

0.40

-0.06

Mental health

77

16

79

17

-2.03

0.04

-0.15

Vitality

64

20

70

21

-3.50