Psychological Functioning Associated with Prostate Cancer: Cross-Sectional Comparison of Patients Treated with Radiotherapy, Brachytherapy, or Surgery

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1 474 Journal of Pain and Symptom Management Vol. 30 No. 5 November 2005 Original Article Psychological Functioning Associated with Prostate Cancer: Cross-Sectional Comparison of Patients Treated with Radiotherapy, Brachytherapy, or Surgery Séverine Hervouet, MPs, Josée Savard, PhD, Sébastien Simard, MPs, Hans Ivers, MPs, Jacques Laverdière, MD, Éric Vigneault, MD, Yves Fradet, MD, and Louis Lacombe, MD School of Psychology (S.H., J.S., S.S., H.I.) and Cancer Research Center (S.H., J.S., S.S., H.I., Y.F., L.L.), Laval University; and L Hôtel-Dieu de Québec (J.L., E.V., Y.F., L.L.), Québec, Québec, Canada Abstract This study compared the prevalence of psychological difficulties (i.e., anxiety and depression), psychophysiological problems (i.e., insomnia and fatigue), and sexual difficulties across three modalities of treatment for prostate cancer (radiotherapy, brachytherapy, and radical prostatectomy). A total of 861 men completed a battery of questionnaires assessing anxiety, depression, fatigue, insomnia, and quality of life. Patients who initially received radiotherapy had higher levels of depression, anxiety, and fatigue and a lower quality of life, and were more likely to report clinical levels of depression and fatigue. Patients who initially received surgery were more likely to report clinical levels of sexual difficulties but less likely to report clinical levels of depression and fatigue, while patients who received brachytherapy were less likely to report sexual difficulties. Although cross-sectional, these findings raise the possibility of a differential influence of treatments for prostate cancer on some aspects of psychological functioning. J Pain Symptom Manage 2005;30: Ó 2005 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Prostate cancer, treatment, depression, anxiety, insomnia, fatigue Introduction The choice of treatment for prostate cancer is primarily determined on the basis of stage of cancer, but also with consideration of the patient s age, medical comorbidities, and treatment preferences. It is increasingly recognized Address reprint requests to: Josée Savard, PhD, Laval University Cancer Research Center, 11 Côte du Palais, Québec, Québec, Canada G1R 2J6. Accepted for publication: May 3, Ó 2005 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. that the impact of these treatments on quality of life must also be considered, especially since no study has yet found one of these options to be superior to another in terms of survival. 1 The physical side effects most frequently associated with treatment for prostate cancer are well documented. Generally, studies have revealed that incontinence and sexual difficulties are reported more frequently by patients who have received radical prostatectomy (RP) than by those who have received external radiotherapy (RAD) or brachytherapy (BR), /05/$--see front matter doi: /j.jpainsymman

2 Vol. 30 No. 5 November 2005 Psychological Functioning and Prostate Cancer Treatments 475 while bowel dysfunction (e.g., diarrhea, rectal discomfort) is more frequent in patients who have received RAD or BR However, the effect of these treatments on psychological well-being has been less frequently studied, and this, too, may be an important consideration in treatment selection. A recent longitudinal study conducted in patients with localized prostate cancer showed that RAD was associated with the worst mental health profile over time compared to RP and watchful waiting. 5 Although this study is extremely informative and has several merits, particularly the use of a longitudinal design, the authors used scales from a quality-of-life questionnaire (i.e., Medical Outcome Study Short-Form Health Survey, or SF-36) that provides only a broad assessment of psychological well-being and is difficult to translate into clinical terms. Indeed, quality-of-life scales do not say much about the particular psychological needs of patients and the clinical significance of these difficulties. To our knowledge, four studies evaluated the prevalence of depression and anxiety in prostate cancer patients using a validated instrument assessing specifically these disturbances, and all used the Hospital Anxiety and Depression Scale (HADS) These studies revealed prevalence rates of clinical level of depression varying from 3% to 15% and of anxiety varying from 11% to 33%. However, none of these studies compared the prevalence of depression and anxiety across the treatment modalities for prostate cancer. Fatigue and insomnia are also fairly prevalent conditions in patients with prostate cancer. One study showed a prevalence of fatigue of 10%, 15%, and 8% and a prevalence of sleep difficulties of 15%, 13%, and 8% among men who had been treated for localized prostate cancer by RP, RAD, and watchful waiting, respectively. 10 In sum, although there is some evidence that psychological well-being varies among different treatment modalities, there is a need for more research comparing treatments for prostate cancer on more specific and clinically meaningful measures of psychological and psychophysiological disturbances, which take into account the multidimensional nature of these difficulties and allow identification of the specific psychological needs of this population. The primary objective of this cross-sectional study, conducted with patients followed for prostate cancer, was to compare the severity and the prevalence of psychological difficulties (i.e., anxiety, depression), psychophysiological problems (i.e., fatigue, insomnia), and sexual difficulties as a function of the type of treatment received (RAD, BR, and RP) and the time from diagnosis. Methods Participants Recruitment. The participants were recruited from February 2000 to January 2002 at the Cancer Surgery Clinic (CSC) and at the Department of Radio-Oncology (DRO) of L Hôtel-Dieu de Québecdeither in person (CSC: n 5 363; DRO: n 5 293) or by mail (n 5 868). To be eligible for the study, the men had to meet the following inclusion criteria: 1) should have received RAD, BR, or RP as an initial treatment for prostate cancer within the past 7 years; 2) should be able to easily understand and read French; and 3) should be under 80 years of age at study entry. The exclusion criteria were as follows: 1) antecedents of any other type of cancer; 2) having undergone an orchidectomy; 3) having received chemotherapy; and 4) having a severe cognitive impairment (e.g., mental retardation, dementia) as indicated in the medical file or as noted during recruitment. Description of the Sample. Overall, 1524 patients were invited to participate in the study. Of these, 1017 (66.7%) initially consented to participate and 944 (61.9%) actually completed and returned the questionnaire. Of these, 83 were subsequently excluded for the following reasons: medical file inaccessible (n 5 10), missing medical information in their file (n 5 56), and poorly completed questionnaire (n 5 17). The total sample was thus composed of 861 participants (56.6% of the 1524 men who were invited to participate). The mean age of the participants who completed the questionnaire was 67.9 years (range ; SD 5 6.9). Tables 1 and 2 show the principal sociodemographic and medical characteristics of the study participants separated into three groups according to the initial treatment received for

3 476 Hervouet et al. Vol. 30 No. 5 November 2005 Table 1 Demographic Characteristics of Participants by Treatment Group Variables RAD (n 5 392) BR (n 5 188) RP (n 5 281) M (SD) M (SD) M (SD) F Age (y) 70.7 (6.3) a 66.9 (6.4) b 64.8 (6.6) c a %(n) % (n) % (n) c 2 Marital or relationship status 6.46 Married/cohabitation 82.4 (322) 82.9 (155) 86.0 (240) Single 5.4 (21) 3.2 (6) 4.7 (13) Separated/divorced 8.2 (32) 8.0 (15) 4.3 (12) Widowed 4.1 (16) 5.9 (11) 5.0 (14) Education a Less than a primary diploma 19.1 (75) 8.5 (16) 12.1 (34) Primary or high school diploma 51.0 (200) 44.7 (84) 42.4 (119) College degree 15.3 (60) 21.8 (41) 20.3 (57) University degree 14.5 (57) 25.0 (47) 25.3 (71) Current occupation a Working full- or part-time 10.5 (41) 21.3 (40) 28.1 (79) Not working/retired 89.5 (351) 78.7 (148) 71.9 (202) Annual household income (Canadian dollars) a Less than $20, (109) 15.4 (29) 14.6 (41) $20,001--$30, (107) 23.9 (45) 17.1 (48) $30,001--$40, (77) 20.7 (39) 23.5 (66) $40,001--$50, (41) 13.3 (25) 16.4 (46) More than $50, (58) 26.6 (50) 28.5 (80) RAD 5 radiotherapy; BR 5 brachytherapy; RP 5 radical prostatectomy. Means (M) with different subscripts are significantly different with a at 0.05, using the REGW-Q or c 2 test. Because of missing data in some categories, sums do not always equal the total n for that column. a P! their prostate cancer: RAD (n 5 392), BR (n 5 188), or RP (n 5 281). In the RP group, 82 patients received RAD following surgery because the stage of cancer was advanced at initial diagnosis (n 5 34) or because of the subsequent development of local recurrence (n 5 36) or metastasis (n 5 12). Significant differences in all sociodemographic and medical characteristics were observed among the three groups, with the exception of marital status. The means and frequencies (see Table 1) indicate that the patients in the RAD group were older, had a lower level of education, were more often retired, and had a lower family income than patients in the other groups. In addition, the prognosis of patients in the RAD group was less favorable as indicated by a more advanced stage of cancer as well as a higher Gleason score and a higher prostate-specific antigen (PSA) value at initial diagnosis, while patients who received BR had a much better prognosis (Table 2). Finally, the patients who received RAD were also more likely to have received hormone therapy and to have a comorbid physical illness. Procedure Ethical approval was obtained from the Ethics Committee of L Hôtel-Dieu de Québec and Laval University and all participants gave their written consent. The participants were recruited either in person when they came for a follow-up appointment at the CSC or the DRO or by mail. In both cases, questionnaires were completed at home and returned by mail. Measures The participants medical files were consulted to obtain information concerning the stage of cancer, initial PSA score, Gleason score, the start and finish dates for each treatment received, and the dates of local or systemic recurrence (if applicable). In addition, the patients filled in sociodemographic and medical data (e.g., age, marital status, presence of other physical illness), as well as the following validated self-report scales. Hospital Anxiety and Depression Scale. 11,12 This questionnaire contains 14 items, of which 7 assess depression (HADS-D) and 7 assess anxiety

4 Vol. 30 No. 5 November 2005 Psychological Functioning and Prostate Cancer Treatments 477 Table 2 Clinical Characteristics of Participants by Treatment Group Variables RAD (n 5 392) BR (n 5 188) RP (n 5 281) %(n) % (n) % (n) c 2 Clinical T stage T (57) 32.5 (61) 24.2 (68) T (140) 52.7 (99) 30.6 (86) T (193) 14.9 (28) 44.8 (126) T4 0.5 (2) 0.0 (0) 0.4 (1) Biopsy Gleason score (259) 97.9 (184) 71.7 (200) (124) 2.1 (4) 28.3 (79) Initial PSA (28) 13.3 (25) 6.5 (18) (164) 70.4 (133) 55.8 (154) 10.1 and more 50.8 (198) 16.0 (30) 37.7 (104) Hormone therapy Lifetime 93.6 (367) 77.1 (145) 54.5 (153) Current 10.2 (40) 4.8 (9) 20.6 (58) Recurrence since initial dx Local recurrence 4.3 (17) 5.3 (10) 17.4 (49) Systemic recurrence 3.1 (12) 0.5 (1) 5.7 (16) Physical comorbidity Yes 64.3 (252) 53.7 (101) 41.3 (116) No 35.7 (140) 46.3 (87) 58.7 (165) Time since diagnosis (months) Time since last treatment (months) M (SD) M (SD) M (SD) 39.4 (19.45) a 32.6 (21.03) b 40.3 (22.18) a 30.1 (19.22) a 24.1 (19.24) b 36.7 (22.00) c RAD 5 radiotherapy; BR 5 brachytherapy; RP 5 radical prostatectomy; PSA 5 prostatic specific antigen; dx 5 diagnosis. Mean (M) values with different subscripts are significantly different with a at 0.05, using the REGW-Q or c 2 test. Because of missing data, in some categories sums do not always equal the total n for that column. a P! a a a a a a a a (HADS-A). The HADS does not contain any somatic items that could be confounded with symptoms associated with a physical illness. Some studies suggest that a score of 7 or higher on one of the subscales indicates the presence of a clinical level of depression or anxiety. 8,13 A total (sum of subscales: HADS-T) score of 15 or more has been suggested to identify clinical levels of global psychological distress. 14 The French--Canadian version used was the one validated by our research group. 12 This version possesses psychometric properties equivalent to those of the original English version. Insomnia Severity Index. 15,16 The Insomnia Severity Index (ISI) contains seven items assessing the severity of difficulty in falling asleep, nocturnal awakenings, and early morning awakenings, as well as the level of dissatisfaction with sleep, interference with daytime functioning, level of worry associated with sleep difficulties, and noticeability of impairments. It has been suggested that a score of 8 or more indicates the presence of a clinical level of insomnia. 17 We recently validated the French-- Canadian version of the ISI among cancer patients. 18 Multidimensional Fatigue Inventory. 19 The French--Canadian version, which possesses adequate psychometric properties, 20 is a short form of the original Multidimensional Fatigue Inventory (MFI). It contains 15 items (scale from 1 to 5 ) divided into four subscales, including general and physical fatigue, reduction in activities, reduction in motivation, and mental fatigue. A global score of fatigue is obtained by calculating a mean for all items. For this study, a mean of 3 or more on the total

5 478 Hervouet et al. Vol. 30 No. 5 November 2005 fatigue score was taken to represent a clinical level of fatigue. European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30). 21 Four functioning scales (physical, cognitive, social, and role) and the global health and quality-of-life scale of this questionnaire were used in this study. Three types of scales are used for responding to questions: a dichotomous scale (yes or no), a Likert scale from 1 (not at all) to 4 (a lot), and another 7- point Likert scale from 1 (very poor) to 7 (excellent). These scores are all transformed to obtain a uniform scale from 0 to 100. The French version has not yet been empirically validated, but it was developed by the authors of the original English version. Prostate Cancer-Specific Module (PCSM) Supplementing the EORTC QLQ-C30 version In this study, the following scales of this questionnaire were administered: the sexuality scale (four items), the urinary symptom scale (four items), and the intestinal symptom scale (five items). To assess androgen blockade-related symptoms, three questions (i.e., night sweats, excessive perspiration, and reduction of physical strength) were added to the item assessing hot flashes. A Likert scale from 1 (not at all) to 4 (a lot) is used to respond to these questions, and scores are transformed to obtain a uniform scale from 0 to 100. For the needs of the study, the clinical cutoff for sexual difficulties was fixed at 50% (sexuality scale). The French-- Canadian version of the module was translated by our research team and has not been empirically validated. Statistical Analyses In order to test for significant differences in the demographic and medical characteristics among the three groups (RAD, BR, and RP), analyses of covariance were conducted, followed by Ryan--Einot--Gabriel--Welsch (REGW-Q) and Chi-squared tests. Then, a factorial (3 3 7) multivariate analysis of covariance (MAN- COVA) was conducted, followed by factorial univariate analyses of covariance (ANCOVAs), was done to compare the mean scores obtained on measures of psychological difficulties, psychophysiological problems, and functioning (i.e., physical, role, cognitive, social, global quality of life, urinary, sexual, intestinal, and androgen blockade-related symptoms) by treatment and by time from initial cancer diagnosis. Time from diagnosis was categorized into seven 1-year bins. The demographic variables (i.e., age, marital status, education, occupation, and family income) and medical variables (i.e., initial clinical stage, Gleason score, and PSA value, current and lifetime hormone therapy received, cancer recurrence since initial diagnosis, presence of another illness, time since diagnosis, and time since last treatment) were studied as potential covariates by a step-down approach, allowing the identification of variables associated with a significant reduction in the error term. 23 A series of three paired comparisons was done to verify differences among the groups for each dependent variable. The Type I error rate was controlled at the level of the family of nonorthogonal contrasts by Bonferroni correction, a pc / In addition, odds ratios with a 95% confidence interval were calculated to estimate the likelihood of reporting clinical levels of psychological distress or psychophysiological problems. Finally, additional ANCOVAs were performed to examine psychological difficulties, psychophysiological problems, and global quality of life by three hormone therapy categories: no hormone therapy in lifetime, previous hormone therapy, and current hormone therapy. All statistical analyses were conducted using SAS 8.2 software. 24 Results Prevalence of Symptoms Table 3 presents the prevalence of psychological difficulties, psychophysiological problems, and sexual difficulties for the total sample (n 5 861). This table indicates that sexual difficulties were the most frequently reported problem (70.5%), followed by insomnia (31.9%), anxiety (23.7%), fatigue (18.5%), and depression (17.0%). Controlled Variables for ANCOVAs The exploratory ANCOVAs allowed the identification of potential covariates that contributed significantly to at least three dependent variables. The retained variables were

6 Vol. 30 No. 5 November 2005 Psychological Functioning and Prostate Cancer Treatments 479 Table 3 Prevalence of Psychological, Psychophysiological, and Sexual Difficulties for the Total Sample Variables % n Clinical Cutoff Range HADS Anxiety Depression Global distress ISI Insomnia MFI Fatigue PCSM Sexual difficulties HADS 5 Hospital Anxiety and Depression Scale; ISI 5 Insomnia Severity Index; MFI 5 Multidimensionnel Fatigue Inventory; PCSM 5 Prostate Cancer-Specific Module Supplementing the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire. age, family income, presence of a comorbid illness, presence of cancer recurrence since initial diagnosis, current use of hormone therapy, initial PSA level, and initial clinical stage of cancer. These variables were kept as covariates in the subsequent ANCOVA factorial analyses. Symptom Severity as a Function of Time and Cancer Treatments The MANCOVA conducted on mean scores showed a significant treatment effect, F(38, 1588) , P! , and a significant time effect, F(114, 4578) , P! , but no significant interaction effect, F(228, 8125) , P! Table 4 shows the results of subsequent ANCOVAs. The results of these analyses indicated a significant time effect for all physical symptoms. More precisely, lower levels of urinary, sexual, intestinal, and androgen blockade-related symptoms were observed with increased time from cancer diagnosis. In addition, higher scores for the EORTC QLQ-C30 role functioning scale were observed with increased time from cancer diagnosis. However, no significant time effect was observed for the psychological variables, psychophysiological variables, and the other QLQ-C30 scales (i.e., physical, cognitive, social, and global quality of life). Table 4 also shows that there was a significant treatment effect for all the psychological variables, most of the psychophysiological variables, and most of the functioning scales. Specifically, patients who received an initial treatment of RAD reported significantly higher levels of depressive symptoms, global psychological distress, and general and global fatigue, as well as lower levels of physical functioning, compared to patients who received BR or RP, after controlling for the covariates. Moreover, the patients who were initially treated with RAD had significantly higher levels of anxiety symptoms and lower levels of role functioning compared to those who were treated with BR. In addition, the patients who were treated with RAD reported significantly lower levels of cognitive functioning and global quality of life compared to those who had undergone RP. There was apparent variation among treatments in insomnia scores; however, after Bonferroni correction, these differences were not significant. Finally, no significant treatment effect was observed for motivational fatigue, mental fatigue, or social functioning. Significant differences were also observed among the treatment types for all the physical symptoms (see Table 4). Patients who underwent RP reported lower levels of urinary difficulties compared to those who received RAD or BR, and they reported lower levels of intestinal and androgen blockade-related symptoms compared to those who received RAD, after controlling for the covariates. On the other hand, the RP group reported higher levels of sexual difficulties compared to patients who had received BR. Severity of Psychological and Psychophysiological Symptoms as a Function of Hormone Therapy Although hormone therapy was used as a covariate in the preceding analyses, the role of hormone therapy was further explored with additional ANCOVAs. The results showed that receiving current hormone therapy had no significant effect on mean scores of most psychological or psychophysiological symptoms. However, scores for fatigue motivation were significantly higher in the group currently receiving hormone therapy compared to those who had never received hormone therapy or had received it in the past, F(2, 855) , P! In addition, significantly lower levels of role functioning, F(2, 859) , P! 0.05, and global quality of life, F(2, 855) , P! 0.01, were found among patients who

7 480 Hervouet et al. Vol. 30 No. 5 November 2005 Table 4 Adjusted Means, Standard Errors, and Results Obtained with ANCOVAs Comparing the Severity of Each Problem as a Function of Time and Treatment Type Dependent Variables RAD (n 5 392) BR (n 5 188) RP (n 5 281) F M (SE) M (SE) M (SE) Time Treatment Interaction R 2 (%) Psychological symptoms Anxiety (HADS-A) 4.8 (0.22) a 3.8 (0.31) b 4.2 (0.24) ab a Depression (HADS-D) 3.8 (0.21) a 2.9 (0.29) b 2.7 (0.22) b b Global distress (HADS-T) 8.5 (0.39) a 6.7 (0.55) b 6.9 (0.42) b c Psychophysiological symptoms Insomnia (ISI) 6.6 (0.33) a 5.3 (0.47) a 5.5 (0.36) a a,d General fatigue (MFI) 2.6 (0.05) a 2.4 (0.07) b 2.3 (0.05) b a Fatigue activity (MFI) 1.9 (0.05) a 1.7 (0.07) ab 1.7 (0.05) b a Fatigue motivation (MFI) 2.8 (0.06) a 2.6 (0.08) a 2.6 (0.06) a Mental fatigue (MFI) 2.3 (0.06) a 2.2 (0.08) a 2.3 (0.06) a Global fatigue (MFI) 2.4 (0.04) a 2.2 (0.06) b 2.3 (0.05) b c Functioning and quality of life (QLQ-C30) Physical 88.8 (1.03) a 94.3 (1.45) b 94.0 (1.11) b b Role 85.6 (1.27) a 93.1 (1.79) b 87.9 (1.36) ab 3.44 c 5.68 c Cognitive 85.1 (1.06) a 88.8 (1.49) ab 90.4 (1.14) b c Social 83.8 (1.36) a 89.1 (1.90) a 87.6 (1.45) a Global 71.5 (1.24) a 75.2 (1.74) ab 77.4 (1.33) b c Physical symptoms (PCSM) Urinary 19.8 (1.08) a 21.2 (1.51) a 14.3 (1.15) b b 8.18 b 1.75 c 14.9 Sexual 69.5 (1.84) ab 55.8 (2.58) b 75.9 (1.96) a 5.13 b b Intestinal 12.9 (0.83) a 9.5 (1.16) ab 7.4 (0.89) b 3.75 b 9.63 b Androgen blockade-related 29.3(1.57) a 22.9 (2.20) ab 20.0 (1.68) b 7.31 b 7.76 b RAD 5 radiotherapy; BR 5 brachytherapy; RP 5 radical prostatectomy; HADS 5 Hospital Anxiety and Depression Scale; ISI 5 Insomnia Severity Index; MFI 5 Multidimensional Fatigue Inventory; QLQ-C30 5 Quality-of-Life Questionnaire of the European Organization for Research and Treatment of Cancer; PCSM 5 Prostate Cancer-Specific Module Supplementing the EORTC QLQ-C30. Means (M) with different subscripts are significantly different using a t-test with an adjusted alpha, a pc a P! b P! c P! d F is significant with ANCOVA but not after Bonferroni correction. had never received hormone therapy compared to the other two groups. Likelihood of Clinical Levels of Psychological and Psychophysiological Problems by Treatment Table 5 shows the proportion of patients surpassing the clinical cutoff for each dependent variable as a function of initially having received each treatment. Also, the odds ratios shown in Table 5 indicate that men who received RAD were more likely to report clinical levels of depression and fatigue than those who did not receive RAD initially. Men who received BR were less likely to report clinical levels of sexual difficulties than those who did not Table 5 Proportion of Patients Whose Scores Exceeded Clinical Cutoffs for Each Dependent Variable as a Function of Initially Receiving Each Treatment and Odds Ratios Obtained Clinical Difficulties RAD (n 5 392) BR (n 5 188) RP (n 5 281) %(n) OR (95% CI) % (n) OR (95% CI) % (n) OR (95% CI) Anxiety (HADS-A O 7) 23.5 (92) 0.98 ( ) 23.4 (44) 0.98 ( ) 24.2 (68) 1.04 ( ) Depression (HADS-D O 7) 20.9 (82) 1.67 a ( ) 16.0 (30) 0.91 ( ) 12.1 (34) 0.58 a ( ) Global distress (HADS-T O 14) 16.3 (64) 1.28 ( ) 13.3 (25) 0.87 ( ) 13.2 (37) 0.84 ( ) Insomnia (ISI O 8) 35.0 (137) 1.29 ( ) 28.9 (54) 0.83 ( ) 29.9 (84) 0.86 ( ) Fatigue (MFI O 3) 23.6 (88) 1.68 a ( ) 19.8 (36) 1.05 ( ) 12.7 (35) 0.51 a ( ) Sexual difficulties (PCSM O 50%) 75.8 (278) 1.08 ( ) 57.3 (102) 0.34 a ( ) 85.7 (227) 2.59 a ( ) RAD 5 radiotherapy; BR 5 brachytherapy; RP 5 radical prostatectomy; CI 5 confidence interval; OR 5 odds ratio; HADS5 Hospital Anxiety and Depression Scale; ISI 5 Insomnia Severity Index; MFI 5 Multidimensional Fatigue Inventory; PCSM 5 Prostate Cancer-Specific Module Supplementing the EORTC QLQ-C30. a P! 0.05.

8 Vol. 30 No. 5 November 2005 Psychological Functioning and Prostate Cancer Treatments 481 receive this treatment. Conversely, men who underwent RP were more likely to report clinical levels of sexual difficulties, but less likely to report clinical levels of depression and fatigue, than men who did not receive RP initially. No significant difference was observed among the treatments for anxiety, global psychological distress, or insomnia. Discussion Results of this study indicate that sexual difficulties constitute the most frequent problem (70.5%) in men being followed for prostate cancer, followed by insomnia (31.9%) and anxiety (23.7%). The prevalence rates of clinical levels of anxiety (23.7%) and depression (17%) observed in this study sample (patients with diverse stages and treatments) are consistent with those obtained by Roth et al., 8 who used the same clinical cutoff score for each subscale (i.e., score of 7). The observed prevalence of fatigue (18.5%) is similar to the rate found in previous studies. 25,26 The present study also revealed that 31.9% of patients reported a clinical level of insomnia, which agrees with studies done with mixed samples of cancer patients, showing that 30%--50% of cancer patients report sleep difficulties. 27 Finally, the elevated prevalence of sexual difficulties post-treatment (70.5%) agrees with previous studies showing that erectile dysfunction, with urinary difficulties, is the most frequent physical side effect of prostate cancer treatment. 28,29 In other respects, the results of the study indicated no significant difference across time for psychological symptoms (i.e., anxiety and depression). Yet, the proportion of patients who had received their diagnosis within the previous 6 months was very low in the present study (4%), and this may be the period most likely to be associated with mood variations. The results of this study, however, did show lower levels of urinary, sexual, intestinal, and androgen blockade-related symptoms with increased time from diagnosis, which is consistent with longitudinal studies showing that several physical symptoms improve over time following treatment for prostate cancer. 10,30,31 Results of this study also showed that patients who initially received RAD had higher levels of depression, anxiety, and fatigue (general and global) and a lower quality of life (physical, cognitive, and role functioning). These observations were made while controlling for age, family income, initial clinical stage, initial PSA level, presence of a comorbid illness, presence of cancer recurrence since initial diagnosis, and current use of hormone therapy. Therefore, they cannot be attributed to differences among the groups in these variables. It may be argued that group differences obtained in mean scores (see Table 4) were small in magnitude and are statistically significant mostly because of the large sample size. However, the clinical significance of some of these findings is highlighted by the additional group differences obtained (see Table 5), showing a significantly higher proportion of patients treated with RAD having clinical levels of depression (21%) and fatigue (24%) compared to patients treated with RP (depression: 12%; fatigue: 13%). There is already indication in the literature that fatigue is common among patients with prostate cancer treated with RAD. 32,33 Fatigue is a well-documented side effect of radiation therapy 34 and may be implicated in the development of depression. Thus, our results indicating higher levels of fatigue and depression in patients treated with RAD may be related. Indeed, depression could be a consequence of fatigue and reduced physical activity, which is a detrimental coping strategy often used by fatigued patients. 35 This idea is supported by a study showing that a lower level of physical functioning and the presence of fatigue in patients with lung cancer were major risk factors for developing depressive symptoms. 36 Conversely, since fatigue is a core symptom of depressive disorders, 37 it may be depression that leads to fatigue. Alternatively, increased psychological distress in patients treated with RAD may be related to the longer delay before a treatment effect is observed on the reduction of the PSA level. While the PSA level becomes undetectable shortly after the RP, it declines less rapidly after RAD and it never reaches undetectable levels. 38 Likewise, patients treated with RP may be more likely to believe that all cancer cells have been removed with the prostate compared to RAD patients who retain their prostate. Both factors may lead to a higher

9 482 Hervouet et al. Vol. 30 No. 5 November 2005 level of confidence that cancer has been cured in patients treated with RP, and consequently reduced psychological distress. Another factor that could explain the higher levels of fatigue and depression in patients treated with RAD in this study is the use of hormone therapy. Indeed, some studies have suggested that hormone therapy administered for the treatment of prostate cancer is associated with a higher risk of depression 39,40 and fatigue. 7,41 In the present study, the proportion of patients who received hormone therapy in the RAD group was higher (93.6%) than that in the other groups (BR: 77.1%; RP: 54.5%). Still, the variable hormone therapy was statistically controlled in ANCO- VAs and the specific analysis conducted on its role revealed few differences associated with its use. However, because this information was unavailable in the patients medical files, we could not control for the duration and type of hormone therapy received, which may exert an influence. Long-term hormone therapy and total androgen blockade (i.e., analogs of luteinizing hormone-releasing hormone combined with an antiandrogen) are more likely to be associated with severe side effects, while intermittent androgen deprivation is associated with fewer side effects. 42 Thus, this study cannot completely rule out the possibility that the higher levels of depression and fatigue found in patients treated with RAD are attributable to increased use of hormone therapy in this group. Future longitudinal studies are needed to answer this question. The finding that RP was associated with a lower likelihood of clinical levels of depression compared to not having this surgery is somewhat surprising, considering the higher prevalence of sexual difficulties in the RP group. It suggests that sexual difficulties are not necessarily associated with mood impairments, a hypothesis that is supported by a significant but small correlation obtained between sexual difficulties on the PCSM and the HADS depression score in patients who received RP, r (281) , P! Two other findings deserve comments. The finding showing decreased quality of life (role functioning and global) for patients who had never received hormone therapy is difficult to explain, considering the severity of side effects associated with its use. However, it may be due to a sampling bias making hormone therapy less often initiated in patients with lower quality of life to avoid affecting their functioning even more. Finally, the finding that patients who were treated with BR were less likely to experience sexual difficulties compared to patients who did not have this treatment is consistent with other studies. 43,44 It thus supports the view that BR is an advantageous treatment option for preserving sexual functioning. Although the present study takes a new look at the association of different treatments for prostate cancer with quality of life, it has certain methodological limitations. First, the cross-sectional research design limits the evaluation of the evolution of symptoms over time. Moreover, it is impossible to make conclusions about causal relationships between the treatments and the psychological factors that were measured. In fact, it is possible that the differences found among the treatment groups existed before patients received their treatment, although some longitudinal data suggest that the treatment differences in mental health occur with treatment. 5 Second, the heterogeneity of the sociodemographic and medical characteristics of the three treatment groups was only statistically controlled in the analyses of covariance. However, given that the choice of treatment depends, in part, on characteristics such as age, stage of cancer, and the presence of another illness, having perfect equivalence among the groups receiving various treatments is practically impossible. In spite of these study limitations, it is reasonable to conclude that men receiving RAD for their prostate cancer should be followed more closely to effectively screen for psychological disturbances. Indeed, regardless of whether the higher prevalence of psychological distress found among these men is caused by radiation therapy or was preexistent, these men appear to be a vulnerable group for psychological disturbances. A recent study showed that brief routine screening of depression is possible and effective in radiation oncology clinics. 45 Longitudinal studies that more specifically assess psychological disturbances (rather than general psychological well-being) associated with prostate cancer treatment are now needed to better identify risk factors and potential areas for preventive interventions.

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