Definitive radiotherapy with adjuvant long-term antiandrogen ... - Nature

Prostate Cancer and Prostatic Diseases (2009) 12, 269–276 & 2009 Nature Publishing Group All rights reserved 1365-7852/09 $32.00 www.nature.com/pcan

ORIGINAL ARTICLE

Definitive radiotherapy with adjuvant long-term antiandrogen treatment for locally advanced prostate cancer: health-related quality of life and hormonal changes A Berg1, AA Dahl1,2, ØS Bruland1,2, T Bjro3,4, MS Aanensen1 and SD Fossa˚1,2 1

Faculty Division the Norwegian Radium Hospital, Faculty of Medicine, University of Oslo, Oslo, Norway; 2Division of Cancer Medicine and Radiotherapy, The Norwegian Radium Hospital, Oslo, Norway; 3Division of Laboratory Medicine, Rikshospitalet University Hospital, Oslo, Norway and 4Faculty Division Rikshospitalet, Faculty of Medicine, University of Oslo, Oslo, Norway

We assessed self-reported health-related quality of life (HRQoL) and longitudinal changes in sex hormones among 86 prostate cancer (PCa) patients without distant metastases 5 years after radiotherapy (RT) combined with ongoing antiandrogen (AA) treatment. HRQoL outcomes were compared with scores from age-matched controls without a cancer diagnosis (NORM). Compared with NORM, patients scored statistically (Po0.05) and clinically (effect size X0.4) lower on sexual domains, and statistically (Po0.05) lower on physical function and vitality. Estimated free testosterone and measured serum estradiol had increased from baseline in most patients, but did not correlate with HRQoL outcomes 5 years after the start of treatment. Prostate Cancer and Prostatic Diseases (2009) 12, 269–276; doi:10.1038/pcan.2009.8; published online 17 March 2009

Keywords: antiandrogens; health-related quality of life; radiotherapy

Introduction Comparison of health-related quality of life (HRQoL) between cancer patients and the general population provides insight into the total load of cancer-related morbidity and is of importance for the counselling of patients.1,2 Such a comparison has not been performed in patients who receive an oral nonsteroidal antiandrogen (AA) adjuvant to definitive radiotherapy (RT) for nonmetastatic prostate cancer (PCa). Such combined treatment may improve the overall survival compared with RT alone3 or AA alone4 in patients with high risk of relapse. Low serum androgen concentration because of age- or treatment-related hypogonadism is associated with decreased HRQoL within physical, mental, emotional, social and sexual function domains.5,6 These domains may also be affected by androgen receptor blockade in the presence of normal serum testosterone. For example, the prevalence of erectile dysfunction (ED) has shown a steady increase during the initial years of monotherapy with the nonsteroidal AA flutamide.7 Many clinicians, however, have observed that nonsteroidal AAs are associated with less reduction of HRQoL compared with castration. This view has partly been supported by a

Correspondence: Dr A Berg, Faculty Division the Norwegian Radium Hospital, University of Oslo, Montebello, 0310 Oslo, Norway. E-mail: [email protected] Received 20 November 2008; revised 13 January 2009; accepted 28 January 2009; published online 17 March 2009

randomized trial that showed significantly more sexual interest and better physical function after 1 year on bicalutamide compared with medical castration for locally advanced PCa.8 Maintained gonadal production of testosterone during nonsteroidal AA treatment has been offered as an explanation.9 The primary aim of this study was to assess selfreported HRQoL in men with PCa who had used a nonsteroidal AA continuously for 5 years adjuvant to definitive RT within the frames of a randomized trial, and to compare these with HRQoL findings in cancerfree, age-matched men from the general population (NORM). The secondary aims were to investigate longitudinal changes in serum sex hormone concentrations after such a long follow-up and to explore correlations between sex hormone concentrations and HRQoL.

Participants and methods Patient selection During 1996–2003, all patients were enrolled in a randomized multi-center phase III trial comparing AA alone with definitive RT þAA for locally advanced or localized aggressive PCa (SPCG-7).4 For the purpose of this side study, we identified 125 men who were randomized to the RT arm at our institution (The Norwegian Radium Hospital, NRH). In relation to a scheduled 5-year post-RT visit, nonmetastatic subjects, who still used AA as their only anticancer agent, were asked to complete a questionnaire (n ¼ 89).

Radiotherapy and antiandrogens for prostate cancer A Berg et al

270

Staging, treatment and follow-up The diagnostic makeup included clinical TNM categorization, technetium bone scan, chest X-ray, and measurements of prostate-specific antigen (PSA) and sex hormones. Staging lymphadenectomy was performed if PSA was 410 mg l–1 and subsequent RT required a pN0 status. Diagnostic needle biopsies were centrally revised. For the purpose of this study, biopsies that originally were scored according to the WHO grading system10 were reviewed for Gleason score .11,12 Treatment comprised complete androgen blockade (leuprorelinacetate 3.75 mg per month s.c. þ flutamide 250 mg 3 p.o.) for 3 months, followed by definitive RT and continuous flutamide. Bicalutamide 150 mg 1 replaced flutamide in cases of intolerance. Three-dimensional conformal RT was given using a multileaf collimator. The gross tumor volume included the prostate and seminal vesicles. The clinical target volume encompassed the gross tumor volume with a 20 mm margin (15 mm posterior to the rectum). For tumors that did not involve the seminal vesicles, the gross tumor volume was reduced to encompass the prostate only after 50 Gy. The total prescribed central dose to the target volume was 70 Gy during 1996–2000 and thereafter 74 Gy. All patients received megavolt photon energy, 15 MV, with daily fractions of 2 Gy, five days per week. The patients were regularly followed up by their local urologists and scheduled for a 5-year post-RT visit at the NRH that included digital rectal examination, bone scan and blood tests. Biochemical parameters Nonfasting blood samples were obtained from a cubital vein, preferably between 0900 and 1200 hours, for the determination of serum PSA, testosterone, estradiol, sex hormone binding globulin (SHBG), luteinizing hormone (LH) and follicle-stimulating hormone (FSH). An inhouse time-resolved fluoroimmunometric assay for PSA was applied until June 2006,13 and the AutoDELFIA ProStatus PSA Free/Total kit (Perkin-Elmer, Waltham, MA, USA) was used after June 2006. The two methods are identical in format and calibration, and both have a detection limit of 0.05 mg l–1. Testosterone concentration was measured with a Spectria coated tube (Orion Diagnostica, Espoo, Finland). The concentrations of estradiol and SHBG were measured using the Autodelfia method (Wallac, Turku, Finland) and the concentrations of FSH and LH were measured by the Access method (Beckman, Fullerton, CA, USA). The coefficients of variation were less than 10% for each method. The reference ranges were testosterone 8–35 nmol l–1, estradiol o0.13 nmol l–1, SHBG 25–65 nmol l–1, LH o12IU l–1 and FSH o12 IU l–1. The formula testosterone 10/SHBG was used as an estimate of free testosterone (EFT), that is, the biologically active component of total testosterone. Questionnaires Before the 5-year visit, the patients received a form by mail that included several established questionnaires. Additional questions were related to demographic variables, including paired relation (yes/no) and level of education (p12 years versus 412 years).

Prostate Cancer and Prostatic Diseases

Instrument scoring The Short Form-36 (SF-36)14 comprises eight multi-item HRQoL domains that again are grouped into the physical component summary (PCS) and the mental component summary (MCS). Dimension scores are transformed to a scale from 0 to 100.15 PCS and MCS are transformed by linear T-score transformation so that the general population has a mean of 50 and s.d. of 10.16 The Hospital Anxiety and Depression Scale (HADS)17 consists of 14 items scored by 4-point Likert scales (0–3). Seven items add up to the Depression score (0–21) and seven to the Anxiety score (0–21). Caseness of depression and anxiety are defined as a total score of at least 8 within each scale. The Fatigue Questionnaire (FQ)18 measures mental (four items) and physical (seven items) features of fatigue by 4-point Likert scales (0–3). Mental fatigue and physical fatigue are the sums of the scores within each dimension (0–12 and 0–21, respectively). Total fatigue is the sum of all 11 items (0–33). Two additional questions are asked regarding the duration and extent of the symptoms. Caseness of fatigue is defined as the total dichotomized scores (0,0,1,1) above four and a duration at least six months.19 The Brief Male Sexual Function Inventory (BSFI)20 measures sexual drive (two items), erections (three items), ejaculation (two items), sexual problem assessment (three items) and overall sexual satisfaction (one item) by 5-point Likert scales (0–4).20 Total sexual score is calculated from the first 10 items in accordance with earlier factor analysis.21 The scores used in this study represent the mean item score within each domain. In this study, the single item domain ‘overall sexual satisfaction’ identifies sexual dissatisfaction if the patient was ‘very dissatisfied’ or ‘mostly dissatisfied’ with his sex life for the past 30 days. Other selected items are categorized in order to illuminate certain aspects of sexuality: Lack of sexual drive was scored if the patient rated his level of sexual drive for the last 30 days as ‘none at all’. The presence of ED was quoted if the patient never had erections firm enough for sexual intercourse over the past 30 days. Missing responses were replaced by the mean of the completed scale items if at least half of the items were filled in. Otherwise, the scale score was considered as missing. The internal consistency was satisfactory in both patient and NORM samples, with Cronbach’s a varying between 0.66 and 0.95. Normative groups Using public data lists, the NRH collected several samples of normative data from the general population for comparison with cancer patients. In 2004, a sample of 2100 males aged 50–79 years received a questionnaire including the BFSI, and 756 (36%) responded. In 2005, 473 of 1380 (34%) males within the same age range completed the HADS and FQ. Respondents reporting cancer were excluded. Based on these NORM samples, we were able to retrieve age-matched control cohorts. Normative cases for the SF-36 were selected from the Living Condition Study of 2002 conducted by Statistics Norway on a representative sample of the population. Among 1028 males aged 50–79 years, we selected two age-matched cancer-free controls per patient.


Statistical considerations Standard descriptive statistical analyses were performed applying the Statistical Package for Social Science 15.0 (SPSS, Chicago, IL, USA). Continuous variables were compared by parametric or nonparametric tests as appropriate. Categorical variables were compared by w2 tests. Significant findings on continuous variables and on 2 2 contingency tables were calculated as Cohen’s effect size. Values X0.40 were considered as clinically significant.22,23 The internal consistency of scales was examined using Cronbach’s coefficient a. Spearman’s r was calculated for correlation analyses between HRQoL scores and sex hormone concentrations. The level of statistical significance was defined as Po0.05 and all tests were two-sided. Ethical considerations The study was approved by the regional committee for medical ethics, the protocol review committee of the NRH and the Norwegian Data Inspectorate. Written informed consent was obtained from all the participants.

Results Among 125 men who originally had received the described treatment, 89 were eligible for this study. Out of these, 86 (97%) responded and were included for further analyses. The questionnaires were completed at a median 5.1 years (range 4.4–5.9 years) after the start of treatment. The median age at the time of the survey was 71 years (range 56–79). Eighty-five percent of the patients lived in paired relations and 24% of them had education for 412 years. Patient and NORM samples were similar regarding paired relation and level of education (data not shown).

Clinical characteristics Before treatment, 90% of the patients had cT3 tumours (Table 1). Nine patients with cT1–2 tumors had originally been graded as moderately or poorly differentiated according to the WHO grading system. According to the regrading, which was performed in relation to this

PSA o10 mg l–1 X10 mg l–1

271

Measurement outcomes Compared with NORM the patients had lower scores on the SF-36 domains of physical functioning, general health and vitality (Table 3). In contrast, patients had better outcomes in role emotional functioning and mental health. Further, the SF-36 PCS was higher in NORM, whereas the opposite was found for the MCS. Although these differences were statistically significant, the effect sizes did not reach the level of clinical significance (40.4). All sexual domains were scored significantly lower in patients compared with NORM, and all these differences were clinically significant. Significantly more patients than NORM reported sexual dissatisfaction, lack of sexual drive and ED. Sex hormones The sex hormone concentrations had been measured before treatment and at follow-up in most patients. The serum concentrations of testosterone, SHBG, estradiol, LH and FSH increased significantly from baseline as well as EFT (Table 4 and Figure 1). None of the HRQoL domains were significantly correlated with EFT, estradiol, FSH or LH 5 years after treatment (data not shown).

Discussion Compared with NORM, the PCa survivors in this study had statistically and clinically significant impairment of all sexual functions. More patients than controls reported

Table 1 Clinical characteristics before treatment Variables

current study, four of these had GS ¼ 6, four had GS ¼ 7 and one had GS ¼ 8. Median PSA was 15.0 mg l–1 (range 2.4–69). The dose to the target volume was 70 Gy in 56 patients and 74 Gy in 30 patients, depending on the year of treatment. At the 5-year follow-up, 85% had PSA o0.2 mg l–1 and only one had PSA 42 mg l–1 (Table 2). Except for one asymptomatic patient with a suspected local relapse at the 5-year follow-up, digital rectal examinations did not show any local tumour progression. None of the included patients had overt metastatic lesions and there was no indication of affected bone homeostasis in most of them based on serum bone specific alkaline phosphatase and carboxyterminal telopeptide type 1 (data not shown). During follow-up time, the type of AA had been changed from flutamide to bicalutamide in 30% of the patients.

N (%) Table 2 23 (27) 63 (73)

T-category T1-2 T3

9 (10) 77 (90)

Gleason score o7 7 47 Missing

25 46 13 2

(29) (53) (15) (2)a

Abbreviation: PSA; prostate specific antigen. a Both were originally graded as moderately differentiated according to the WHO grading system.

Clinical characteristics at follow-up

Variables PSA o0.2 mg l–1 0.2–1.9 mg l–1 42 mg l–1 Missing Local relapse Distant metastases Type of antiandrogen Flutamide Bicalutamide

N (%) 73 11 1 1 1 0

(85) (13) (1) (1) (1)a

60 (70) 26 (30)

Abbreviation: PSA; prostate specific antigen. a The patient was asymptomatic and not aware of the local progression when he completed the questionnaire.



272

Table 3 Self-reported outcomes among 86 prostate cancer patients after 5 years of antiandrogen treatment adjuvant to definitive radiotherapy compared with cancer-free, age-matched controls Measure

Patients Mean±s.d.

Controlsa Mean±s.d.

Pb

Effect size

SF-36c Physical functioning Role physical Bodily pain General health Physical component summary Vitality Social functioning Role emotional Mental health Mental component summary

n ¼ 83 78.1±18.2 57.6±41.6 69.1±26.7 64.5±19.2 43.6±9.8 58.5±20.8 83.4±19.9 88.4±29.9 80.2±16.8 54.4±8.4

n ¼ 166 81.4±19.0 67.2±39.3 71.7±26.4 70.4±20.4 47.2±10.2 64.3±21.1 85.8±20.7 82.0±32.6 75.5±9.2 52.0±6.3

0.04 0.09 0.48 0.02 0.004 0.04 0.23 0.04 o0.001 o0.001

0.18

n ¼ 83 4.0±3.6 4.0±3.6 14 (17) 14 (17)

n ¼ 83 4.1±2.8 4.5±3.9 9 (11) 15 (18)

0.37 0.33 0.26 0.84

FQd Mental fatigue Physical fatigue Total fatigue Cases of chronic fatigue, N (%)

n ¼ 84 4.9±1.7 9.2±3.2 14.0±4.5 14 (16)

n ¼ 84 4.4±1.2 8.4±2.8 12.9±3.5 10 (12)

0.29 0.28 0.25 0.38

BSFIc Sexual drive Erections Ejaculation Sexual problem Assessment Total sexual score

n ¼ 83 0.7±0.7 0.4±0.7 0.6±1.1 2.0±1.5 9.1±6.5

n ¼ 166 1.8±0.9 2.1±1.2 2.7±1.4 2.7±1.2 23.4±10.1

o0.001 o0.001 o0.001 0.001 o0.001

1.31 1.60 1.60 0.54 1.58

Selected items Sexual dissatisfaction, N (%) Lack of sexual drive, N (%) Erectile dysfunction, N (%)

49 (64) 45 (55) 61 (78)

31 (19) 13 (8) 26 (16)

o0.001 o0.001 o0.001

0.95 1.10 1.34

HADSd Depression Anxiety Cases of depression, N (%) Cases of anxiety, N (%)

0.30 0.35 0.28 0.20 0.39 0.34

Abbreviations: BSFI, brief sexual function inventory; FQ, fatigue questionnaire; HADS, hospital anxiety and depression scale; s.d., standard deviation; SF, short form. a The controls were age-matched with patients in 5 year categories. b Mann–Whitney test for continuous and Pearson’s w2-test for categorical variables. c Higher score represents better function. d Higher score represents more symptoms.

sexual dissatisfaction, lack of sexual drive and ED. Patients also scored statistically significant poorer in the HRQoL domains of physical functioning, general health, PCS and vitality, but had better scores in role emotional functioning, mental health and MCS compared with NORM. No significant differences were found in anxiety, depression or fatigue. Median concentrations of testosterone, EFT, estradiol, LH and FSH had increased significantly from baseline. The concentrations of EFT, estradiol, LH and FSH at the time of the survey did not correlate with any of the HRQoL domains. The poorer outcomes in physical functioning, general health and vitality among patients did not reach the predefined effect size for clinical significance. However, these poorer outcomes may still be of clinical interest because of the biological effects of AA treatment, and they should be studied further in larger samples. The better outcomes in role emotional functioning and mental health among patients compared with NORM may reflect a response shift related to post-traumatic growth.24 The sexual function reported by the patients in our study is probably confounded by radiotoxicity as the Prostate Cancer and Prostatic Diseases

post-RT prevalence of ED increases with time.25 The magnitude of RT as a confounding factor is impossible to estimate because we did not have a control group that received RT monotherapy in our study and the post-RT rates of ED reported in the literature vary from 8 to 85%.26 Among 875 patients in the SPCG-7 study, the proportions of men with physician-reported ED at baseline and at the 5-year follow-up were 33% and 81% in those who received AA monotherapy and 36% and 89% in those who received AA þ RT.4 These results show that long-term AA treatment, even though applied alone, is associated with severe impairment of sexual function. We therefore believe that the poor self-reported sexual function in our patients in the current side study was to a considerable degree related to AA treatment. This assumption finds further support in a prospective trial showing a steady decrease in erectile function during the first 2–6 years of flutamide monotherapy.7 In contrast to these findings, impotence was reported in only 12.7% following RT þ bicatulamide in the Early Prostate Cancer Programme,3 giving the impression that ED is a minor problem during AA treatment. However, that study implies a considerable risk of underreporting because

0.05 0.07 0.15 o0.001 o0.001 o0.001 (5.5–26.6) (28–90) (1.3–9.5) (0.03–0.18) (3.0–35.7) (3.0–52.8) 19.8 50 3.5 0.16 10.7 17.5 (9.0–28.7) (21–81) (1.9–5.2) (0.03–0.15) (2.1–7.9) (2.3–19.4) 14.2 45 3.3 0.08 4.8 7.9 Abbreviations: EFT, estimated free testosterone; FSH, follicle stimulating hormone; LH, luteinizing hormone; SHBG, sex hormone binding globulin. a Wilcoxon matched pairs signed-rank test. b EFT ¼ testosterone 10/SHBG.

19 18 18 18 19 19 0.001 0.06 o0.001 o0.001 o0.001 o0.001 (1.4–50.0) (17–105) (0.3–10.0) (0.03–0.29) (4.2–32.2) (3.3–79.7) 21.3 47 4.4 0.15 12.4 14.9 (5.9–33.6) (18–95) (2.3–7.8) (0.00–0.15) (1.1–20.9) (2.1–71.0) 17.3 46 3.7 0.09 4.8 6.2 58 53 53 50 58 58 o0.001 0.009 o0.001 o0.001 o0.001 o0.001 (1.4–50.0) (17–105) (0.33–10.00) (0.03–0.29) (3.0–79.7) (3.0–35.7) 21.0 48 4.22 0.15 15.2 12.4 (5.9–33.6) (18–95.) (1.91–7.78) (0.00–0.15) (2.1–71.0) (1.1–20.9) 16.9 45 3.68 0.08 6.6 4.8

5 year followup Median (range) Pretreatment Median (range) 5 year followup Median (range) Pretreatment Median (range) N Pa

All patients

5 year follow up Median (range) Pretreatment Median (range) N

77 71 71 68 77 77 Testosterone, nmol l–1 SHBG, nmol l–1 EFTb Estradiol, nmol l–1 FSH, IE l–1 LH, IE l–1

Table 4

Median serum levels of sex-hormones at baseline and 5 years after treatment start

Patients on flutamide

Pa

N

Patients on bicalutamide

Pa


adverse events were reported ‘spontaneously’ by the patients.27 Further, the median duration of bicatulamide treatment was only 1.8 years. Our findings may be somewhat provocative to the opinion that sexual function is maintained during AA treatment and is at least better than during medical castration.28 The only randomized study that has so far assessed sexual function following these treatments for nonmetastatic PCa showed relative reductions from baseline in sexual interest of 23% and 47% following bicatulamide monotherapy and castration, respectively (P ¼ 0.03).8,9 However, the follow-up was only for 1 year. Based on our results, it can be speculated that longer follow-up would provide different results. One has to bear in mind, however, that a gradual decrease in sexual function may be a considerable benefit for the individual patient compared with a more sudden decrease that often occurs from medical castration. Patients on AA can use several months, eventually years, to adjust themselves to the aspect of unavoidable reduction of sexual function. In clinical practice, physicians and cancer patients often attribute symptoms like depression, anxiety and fatigue to the ongoing cancer treatment. We found no significant differences in such symptoms between patients and NORM. This is a reminder that these symptoms are common in the general population, and may have other causes, even though they occur during cancer treatment. However, we cannot exclude the possibility that long-term AA treatment partly explains such symptoms in some patients. The increased serum testosterone concentration during AA treatment is known from earlier studies with shorter follow-up than ours,29,30 and is probably caused by lack of inhibition of the LH production in the pituitary gland. Estradiol is synthesized from testosterone and increases as a secondary effect. In our study, the median serum estradiol concentration was doubled from baseline. Medical castration by estrogens is associated with increased risk of cardiovascular morbidity and mortality.31 This risk may also be relevant for patients with high estradiol concentration during long-term AA treatment. This question has been actualized as bicalutamide monotherapy compared with placebo for localized PCa tended to increase the mortality rate in an earlier study.32 The authors could not identify a specific diagnosis causing the excess deaths and found a direct link between bicalutamide and cardiovascular toxicity unlikely.28 However, currently, an increasing number of patients with acute cardiovascular diseases survive. To examine potential cardiovascular toxicity from treatment of PCa, cardiovascular morbidity, including cardiac infarction, may therefore be a better endpoint than mortality. Some men might be particularly vulnerable to hormonal changes. It has recently been shown in a randomized trial that even though complete androgen blockade adjuvant to RT compared with RT alone resulted in a mortality benefit, this was not true for subgroups with moderate or severe comorbidity.33 Such identification of patients for whom side effects from adjuvant treatment outweigh the antitumour effects is important in order to individualize therapy. In our opinion, precautions should be made until the possible relation between AAs and cardiovascular morbidity is clarified.

273



274

FSH (IE/L)

LH (IE/L) 40

80

35

70 60 Follow up

Follow up

30 25 20 15

50 40 30

10

20

5

10 0

0 0

5 10 15 20 25 30 35 40 Pretreatment

0 10 20 30 40 50 60 70 80 Pretreatment Estradiol (nmol/L)

Testosterone (nmol/L) 0.30

50

0.25 Follow up

Follow up

40 30 20 10

0.20 0.15 0.10 0.05 0.00

0 0

10

20 30 40 Pretreatment

50

0.00

0.10 0.20 Pretreatment

0.30

Estimated free testosterone 10

Follow up

8 6 4 2 0 0

2

4 6 8 Pretreatment

10

Figure 1 Scatter plots showing longitudinal serum changes in sex hormones after 5 years of treatment with an oral nonsteroidal antiandrogen. Dotted lines represent upper reference limits (and lower reference limit for testosterone). Abbreviations: LH; luteinizing hormone, FSH; follicle-stimulating hormone.

In normal cells, AAs have weaker affinity for androgen receptors than natural androgens.34,35 Theoretically, the receptor blockade from AAs could therefore be insufficient to affect HRQoL domains such as libido and vitality as these domains are considered to be at least partially androgen dependent. Better HRQoL in patients with particularly high sex hormone concentrations might therefore have been expected. However, we found no significant correlation between EFT and HRQoL in our patients. This finding is in accordance with the pharmacological action of AAs, but may be in some contrast to the assumption that maintained gonadal androgen production protects against reduction of these domains. Prostate Cancer and Prostatic Diseases

Some limitations must be considered when the results are interpreted, in addition to the cross-sectional design with lack of baseline HRQoL data: First, all patients had pelvic high-dose irradiation with its risk of decreased sexual function. Isolated effects from AAs on sexual function could therefore not be assessed. Second, the study did not cover those who were withdrawn from AA treatment before 5 years. Furthermore, the response rates for NORM were only B35%, similar to other populationbased surveys addressing sexual function (1). Hence, possible selection bias with loss of representativity could be operating in both patients and NORM. In addition, a small sample size, with risk of statistical type II error, and different types of AA treatment may have influenced


the results. The strengths of the study include the long observation period, 97% response rate among patients, use of validated questionnaires and longitudinal measures of sex hormones. In spite of the cross-sectional design of our study, the results may contribute to the pretreatment information of patients in whom RT is planned in combination with long-term AA.

Conclusions Men with PCa receiving both high-dose pelvic RT and long-term AA should be informed about the considerably long-term risk of impaired sexual function and possible risk of reduced physical function and vitality. Possible long-term cardiovascular toxicity due to increased serum estradiol concentration associated with AAs should be addressed in future studies.

12

13

14

15

16

17

Acknowledgements The authors acknowledge Aasmund Berner, MD, PhD for Gleason grading and professor Elisabeth Paus, PhD for her efforts related to PSA measurements.

18

19

20

References 1 Bestmann B, Loetters C, Diemer T, Weidner W, Kuchler T, Rohde V. Prostate-specific symptoms of prostate cancer in a German general population. Prostate Cancer Prostatic Dis 2006; 10: 52–59. 2 Fossa SD, Dahl AA, Loge JH. Fatigue, Anxiety, and Depression in Long-Term Survivors of Testicular Cancer. J Clin Oncol 2003; 21: 1249–1254. 3 See WA, Tyrrell CJ. The addition of bicalutamide 150 mg to radiotherapy significantly improves overall survival in men with locally advanced prostate cancer. J Cancer Res Clin Oncol 2006; 132 (Suppl 1): S7–S16. 4 Widmark A, Klepp O, Solberg A, Damber JE, Angelsen A, Fransson P et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 2008; 373: 301–308 e-pub ahead of print). 5 Alibhai SM, Gogov S, Allibhai Z. Long-term side effects of androgen deprivation therapy in men with non-metastatic prostate cancer: a systematic literature review. Crit Rev Oncol Hematol 2006; 60: 201–215. 6 Novak A, Brod M, Elbers J. Andropause and quality of life: findings from patient focus groups and clinical experts. Maturitas 2002; 43: 231–237. 7 Schroder FH, Collette L, de Reijke TM, Whelan P. Prostate cancer treated by anti-androgens: is sexual function preserved? EORTC Genitourinary Group. European Organization for Research and Treatment of Cancer. Br J Cancer 2000; 82: 283–290. 8 Iversen P, Tyrrell CJ, Kaisary AV, Anderson JB, Baert L, Tammela T et al. Casodex (bicalutamide) 150-mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer: results from two multicenter randomized trials at a median follow-up of 4 years. Urology 1998; 51: 389–396. 9 Iversen P. Quality of life issues relating to endocrine treatment options. Eur Urol 1999; 36 (Suppl 2): 20–26. 10 Mostofi FK, Davis Jr CJ, Sesterhenn IA. Pathology of carcinoma of the prostate. Cancer 1992; 70 (1 Suppl): 235–253. 11 Murphy GP, Busch C, Abrahamsson PA, Epstein JI, McNeal JE, Miller GJ et al. Histopathology of localized prostate cancer. Consensus Conference on Diagnosis and Prognostic Parameters

21

22 23 24

25

26

27

28 29

30

31

32

in Localized Prostate Cancer. Stockholm, Sweden, May 12–13, 1993. Scand J Urol Nephrol Suppl 1994; 162: 7–42. Epstein JI, Allsbrook Jr WC, Amin MB, Egevad LL. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol 2005; 29: 1228–1242. Paus E, Nilsson O, Bormer OP, Fossa SD, Otnes B, Skovlund E. Stability of free and total prostate specific antigen in serum from patients with prostate carcinoma and benign hyperplasia. J Urol 1998; 159: 1599–1605. Stewart AL, Hays RD, Ware Jr JE. The MOS short-form general health survey. Reliability and validity in a patient population. Med Care 1988; 26: 724–735. Ware Jr JE, Snow KK, Kosinski M. SF-36 Health Survey: Manual and Interpretation Guide. QualityMetric Incorporated: Lincoln, RI, 2000. Ware Jr JE, Gandek B, Kosinski M, Aaronson NK, Apolone G, Brazier J et al. The equivalence of SF-36 summary health scores estimated using standard and country-specific algorithms in 10 countries: results from the IQOLA Project. International Quality of Life Assessment. J Clin Epidemiol 1998; 51: 1167–1170. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361–370. Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D et al. Development of a fatigue scale. J Psychosom Res 1993; 37: 147–153. Pawlikowska T, Chalder T, Hirsch SR, Wallace P, Wright DJ, Wessely SC. Population based study of fatigue and psychological distress. BMJ 1994; 308: 763–766. O’Leary MP, Fowler FJ, Lenderking WR, Barber B, Sagnier PP, Guess HA et al. A brief male sexual function inventory for urology. Urology 1995; 46: 697–706. Mykletun A, Dahl AA, O’Leary MP, Fossa SD. Assessment of male sexual function by the Brief Sexual Function Inventory. BJU Int 2006; 97: 316–323. Cohen J. Statistical power analysis fo the behavioural sciences, (2nd ed) Lawrence Earlbaum Associates: Hillsdale, NJ, 1998. Lipsey MW, Wilson DB. Practical meta-analysis. Thousand Oaks, CA: SAGE publications, inc, 2001. Thornton AA, Perez MA. Posttraumatic growth in prostate cancer survivors and their partners. Psychooncology 2006; 15: 285–296. Korfage IJ, Essink-Bot ML, Borsboom GJ, Madalinska JB, Kirkels WJ, Habbema JD et al. Five-year follow-up of healthrelated quality of life after primary treatment of localized prostate cancer. Int J Cancer 2005; 116: 291–296. Burnett AL, Aus G, Canby-Hagino ED, Cookson MS, D’Amico AV, Dmochowski RR et al. Erectile Function Outcome Reporting After Clinically Localized Prostate Cancer Treatment. J Urol 2007; 178: 597–601. Tyrrell CJ, Payne H, See WA, McLeod DG, Wirth MP, Iversen P et al. Bicalutamide (0 Casodex0 ) 150 mg as adjuvant to radiotherapy in patients with localised or locally advanced prostate cancer: results from the randomised Early Prostate Cancer Programme. Radiother Oncol 2005; 76: 4–10. Iversen P. The third analysis of the bicalutamide Early Prostate Cancer programme. BJU Int 2006; 97: 438–439. Boccon-Gibod L, Fournier G, Bottet P, Marechal JM, Guiter J, Rischman P et al. Flutamide versus orchidectomy in the treatment of metastatic prostate carcinoma. Eur Urol 1997; 32: 391–395. Eri LM, Haug E, Tveter KJ. Effects on the endocrine system of long-term treatment with the non-steroidal anti-androgen Casodex in patients with benign prostatic hyperplasia. Br J Urol 1995; 75: 335–340. Byar DP. Proceedings: The Veterans Administration Cooperative Urological Research Group’s studies of cancer of the prostate. Cancer 1973; 32: 1126–1130. McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP. Bicalutamide 150 mg plus standard care vs

275



276

standard care alone for early prostate cancer. BJU Int 2006; 97: 247–254. 33 D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA 2008; 299: 289–295.


34 Singh SM, Gauthier S, Labrie F. Androgen receptor antagonists (antiandrogens): structure-activity relationships. Curr Med Chem 2000; 7: 211–247. 35 Kolvenbag GJ, Furr BJ, Blackledge GR. Receptor affinity and potency of non-steroidal antiandrogens: translation of preclinical findings into clinical activity. Prostate Cancer Prostatic Dis 1998; 1: 307–314.