- Email: [email protected]
Does Hormone Therapy Exacerbate the Adverse Effects of Radiotherapy in Men With Prostate Cancer? A Quality of Life Study
Does Hormone Therapy Exacerbate the Adverse Effects of Radiotherapy in Men With Prostate Cancer? A Quality of Life Study Jonathan D. Grant, Mark S. Litwin, Lorna Kwan, Steve P. Lee, Michael L. Steinberg and Christopher R. King* From the Departments of Radiation Oncology and Urology (MSL, LK), University of California-Los Angeles School of Medicine, Los Angeles, California
Abbreviations and Acronyms ADT ⫽ androgen deprivation therapy AUASI ⫽ American Urological Association symptom index BT ⫽ brachytherapy EBRT ⫽ external beam RT HRQOL ⫽ health related quality of life MCS ⫽ mental composite score PSA ⫽ prostate specific antigen RT ⫽ radiotherapy Submitted for publication September 1, 2010. Study received UCLA institutional review board approval. * Correspondence: Department of Radiation Oncology, University of California-Los Angeles School of Medicine, 200 Medical Pl., Suite B-265, Los Angeles, California 90095 (telephone: 310825-9775; e-mail: [email protected]).
Purpose: We examined whether short course androgen deprivation therapy as an adjunct to radiotherapy would impact health related quality of life outcomes in patients with localized prostate cancer treated definitively with external beam radiation therapy or permanent brachytherapy. Materials and Methods: From 1999 to 2003 patients were enrolled in a prospective study at our institution and completed validated health related quality of life surveys at defined pretreatment and posttreatment intervals. A total of 81 men received radiotherapy alone and 67 received radiotherapy plus androgen deprivation therapy. Median androgen deprivation therapy duration was 4 months. Univariate and multivariate analysis was done to compare time to return to baseline in 6 distinct health related quality of life domains. Results: On univariate analysis the radiotherapy plus androgen deprivation therapy group achieved baseline urinary symptoms more rapidly than the radiotherapy group (5 months, p ⫽ 0.002). On multivariate analysis time to return to baseline in any of the 6 health related quality of life domains was not significantly affected by adding androgen deprivation therapy. Factors associated with longer time to return to baseline mental composite scores on multivariate analysis included nonwhite ethnicity, cerebrovascular disease history and alcohol abuse history. Men treated with permanent brachytherapy monotherapy experienced longer time to return to baseline for urinary function and symptoms. Baseline sexual function and lack of a partner were associated with longer time to sexual recovery. Conclusions: Adding androgen deprivation therapy to definitive radiotherapy does not significantly impact the time to return to baseline health related quality of life. These data may be valuable for patients and physicians when weighing the toxicity and benefits of androgen deprivation therapy when added to definitive radiotherapy. Key Words: prostate, prostatic neoplasms, quality of life, radiotherapy, androgen antagonists
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THE most common noncutaneous cancer, prostate cancer, accounts for 25% of incident cases of malignancy in the United States.1 The treatment of patients with early stage prostate can-
cer, comprising 91% of new diagnoses, is 1 of the most controversial areas in ncology.1,2 Neither prostatectomy, EBRT nor BT has proved to show superior outcomes. Consequently management deci-
0022-5347/11/1855-1674/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 185, 1674-1680, May 2011 Printed in U.S.A. DOI:10.1016/j.juro.2010.12.092
AND
RESEARCH, INC.
HORMONE THERAPY AND RADIOTHERAPY EFFECTS IN MEN WITH PROSTATE CANCER
sions are often based on patient preferences, considering the risks and benefits of each therapy.2 Thus, a number of studies groups have sought to define the toxicity profiles of these treatment modalities in terms of patient reported HRQOL outcomes. The survival benefit of RT may be improved by adding ADT for high and intermediate risk localized prostate cancer.3,4 Potential side effects of hormone blockade include fatigue, hot flushes, weight gain, sexual dysfunction and an increased risk of myocardial infarction.5 However, little is known about the long-term quality of life impact when ADT is used as an adjunct to definitive RT.6 We used patient reported outcomes spanning 4 years to compare HRQOL outcomes in patients with early stage prostate cancer treated with definitive RT with or without adjunctive ADT.
MATERIALS AND METHODS Study Sample Participants were recruited from March 1999 to January 2003 at UCLA Medical Center. Eligible men included those with clinically localized (T1, T2 or limited T3), biopsy proven adenocarcinoma without prior treatment who had elected primary treatment with surgery or RT, as described previously.7 We performed subgroup analysis in men treated with EBRT and/or BT who had at least 1 year of followup data available. The RT plus ADT group included 67 patients who received hormone blockade at primary treatment with RT and the RT alone group comprised 81 who received only EBRT and/or BT. When ADT was used as salvage therapy for recurrence after primary treatment, participants were included in the RT alone group and censored at the time of ADT initiation. All protocols were approved by the UCLA institutional review board and were Health Insurance Portability and Accountability Act compliant. Written informed consent was obtained from each participant.
Data Collection and Followup Patient reported outcome measures were collected via written questionnaires at baseline and at 11 posttreatment intervals, including at 1, 2, 4, 8, 12, 18, 24, 30, 36, 42 and 48 months. Median followup was 48 months and 68% of patients had at least 24 months of followup. General HRQOL was assessed by SF-36®, which generates a physical composite score and an MCS that are standardized to the general American population.8 Prostate cancer specific quality of life was evaluated using 2 instruments, including UCLA-PCI and AUASI. UCLAPCI is a validated instrument that measures urinary, sexual and bowel dysfunction.9 AUASI, which is also validated, measures capacity and voiding urinary symptoms.10 An 11-item comorbidity questionnaire corresponding to the Charlson index was administered, as in previous CaPSURE™ studies. Clinical information collected from the medical records included serum PSA, clinical T stage,
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biopsy Gleason score, EBRT total radiation dose and the number of seeds delivered for BT.
Treatment Treatment with EBRT consisted of 3-dimensional conformal or intensity modulated RT with a mean ⫾ SD dose of 72.2 ⫾ 8.8 Gy when used as monotherapy. In men who received EBRT combined with BT 45 Gy were delivered to the pelvis. BT was done using standard ultrasound guided transperineal techniques and dose prescription with 125I in 90% of patients and 103Pd in the remainder. Mean prostate gland size across all groups was 41.7 ⫾ 26.7 cc. The ADT course using bicalutamide and leuprolide was short term and administered in neoadjuvant, concurrent fashion, consistent with current standards of care. Median ADT duration was 4 months (range 4 to 8). Table 1 lists patient and treatment characteristics.
Statistical Analysis Demographic and clinical variables were compared in the RT and RT plus ADT groups using the generalized chisquare and t tests. We also compared medication use for erectile and bladder dysfunction between the 2 treatment groups. Univariate analysis was done to identify the time required to return to baseline HRQOL scores in the RT and RT plus ADT groups, defined as within 10% of the individual pretreatment value.7 In those who returned to baseline during followup the month of return to baseline was noted for that domain and compared for each outcome using the t test. We tested covariates on each outcome by univariate regression. We also calculated the percent of participants who returned to baseline at each time point and graphed the percents with time using chi-square analysis to detect differences between the RT and RT plus ADT groups. Multivariate analysis was done with forward stepwise linear regression, analyzing months to return to baseline in each HRQOL domain. Covariates included age, race (white vs nonwhite), relationship status (living vs not living with a partner), comorbidity type, comorbidity count (none vs any), pretreatment serum PSA, biopsy Gleason score (less than 7 vs 7 or greater), T stage (T1 vs T2/T3), prior transurethral prostate resection and primary treatment modality (EBRT alone vs BT alone vs EBRT plus BT). In each model ADT use, age and treatment modality were included regardless of significance. Two-sided p ⬍0.05 was considered statistically significant. All statistical analysis was done SAS® 9.2.
RESULTS Men who received ADT were older than those who did not (average age 71.5 vs 67.9 years, p ⫽ 0.0014) and had higher mean PSA (15.3 ⫾ 25.4 ng/ml, median 8.0 vs 7.8 ⫾ 5.5, median 6.7, p ⫽ 0.02), Gleason score (7 or greater in 50% vs 18.5%, p ⬍0.0001) and T stage (T2 or greater in 47.8% vs 16%, p ⬍0.0001). Of participants who received ADT the primary therapy was EBRT in 62.7%, BT in 23.9% and combined in 13.4% (p ⬍0.0001).
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Table 1. Characteristics of 148 study patients
Race: White Nonwhite Partnered Comorbidity: Cardiovascular disease Cerebrovascular disease Diabetes mellitus Gastrointestinal disease Major depression Tobacco use Alcohol abuse Comorbidity score: 0 Greater than 1 Biopsy Gleason score: Less than 7 7 or Greater Tumor stage: T1 T2 T3 Treatment type: EBRT only BT only EBRT ⫹ BT Prior transurethral prostate resection
No. RT Alone (%)
No. RT ⫹ ADT (%)
67 (82.7) 14 (17.3) 63 (77.8)
55 (82.1) 12 (17.9) 54 (80.6)
9 (11.1) 3 (3.7) 5 (6.2) 12 (14.8) 5 (6.2) 38 (46.9) 4 (4.9)
8 (11.9) 2 (3.0) 6 (9.0) 10 (14.9) 3 (4.5) 26 (38.8) 2 (3.0)
25 (30.9) 56 (69.1)
22 (32.8) 45 (67.2)
66 (81.5) 15 (18.5)
33 (50.0) 33 (50.0)
68 (84.0) 13 (16.0) 0
35 (52.2) 28 (41.8) 4 (6.0)
25 (30.9) 47 (58.0) 9 (11.1) 8 (9.9)
42 (62.7) 16 (23.9) 9 (13.4) 6 (9.0)
p Value 0.92
0.67 0.87 0.99 0.55 0.98 0.73 0.32 0.69 0.80
(Fisher’s exact test) (Fisher’s exact test) (Fisher’s exact test) (Fisher’s exact test) (Fisher’s exact test)
⬍0.0001 ⬍0.0001 (Fisher’s exact test)
0.0001
Table 2 shows the prevalence of erectile dysfunction treatments and ␣-blocker use during followup. No significant differences were observed between the RT and RT plus ADT groups. The figure shows the proportion of men who returned to baseline scores in each HRQOL domain in the RT and the RT plus ADT groups. A significantly higher proportion of the RT plus ADT group returned to baseline urinary function and urinary symptoms at 1 and 4 months, respectively. At 12 months a higher proportion of the RT group attained baseline scores in the domain of urinary symptoms.
0.85
Table 3 shows the mean time in months needed to return to baseline HRQOL in the domains of physical composite score (SF-36), MCS (SF-36), urinary function (AUASI), urinary symptoms (UCLA-PCI), sexual function (UCLA-PCI) and bowel function (UCLA-PCI) in the RT and RT plus ADT groups. The only statistically significant difference was in the urinary symptom domain with the RT plus ADT group achieving baseline scores approximately 5 months sooner than the RT alone group (p ⫽ 0.017). A similar but not statistically significant trend was also noted in the urinary function domain.
Table 2. Erectile dysfunction and bladder medication by time after RT with and without ADT
Baseline: Erectile dysfunction Erectile dysfunction Tamsulosin 1 Yr: Erectile dysfunction Erectile dysfunction Tamsulosin 2 Yrs: Erectile dysfunction Erectile dysfunction Tamsulosin 4 Yrs: Erectile dysfunction Erectile dysfunction Tamsulosin
No. RT Alone (%)
No. RT ⫹ ADT (%)
p Value
6 (7.4) 2 (2.5) 9 (11.2)
9 (13.4) 0 12 (17.9)
0.23 0.50 (Fisher’s exact test) 0.25
meds aids
16 (22.5) 1 (1.4) 29 (41.4)
11 (17.7) 1 (1.6) 18 (29.0)
0.49 0.99 (Fisher’s exact test) 0.14
meds aids
14 (22.6) 0 18 (28.6)
9 (16.7) 1 (1.8) 11 (20.4)
0.43 0.46 (Fisher’s exact test) 0.31
meds aids
9 (16.4) 1 (1.8) 13 (23.6)
8 (18.2) 0 9 (20.5)
0.81 0.99 (Fisher’s exact test) 0.71
medication aids
HORMONE THERAPY AND RADIOTHERAPY EFFECTS IN MEN WITH PROSTATE CANCER
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Time dependent proportion of men who returned to baseline score in each HRQOL domain. Asterisk indicates RT vs RT plus ADT p ⬍0.05.
Table 4 shows the univariate modeling results of covariates other than ADT. Race, cerebrovascular disease, depression and alcohol abuse were significantly associated with the MCS domain. Comorbidity count and BT alone were associated with urinary function while comorbidity count, Gleason score, T stage and BT alone were associated with urinary symptoms. Multivariate analysis adjusted for pretreatment quality of life scores was done to identify covariates that affected time to return to baseline for each HRQOL domain. Factors that significantly extended this time were nonwhite ethnicity (2.1 months, p ⫽ 0.008), cerebrovascular disease history (5.9 months, p ⬍0.001) and alcohol abuse history (3.0 months, p ⫽ 0.04). Men treated with BT as monotherapy experienced longer time to return to baseline for urinary control (UCLA-PCI, 2.6 months, p ⫽ 0.001) and urinary symptoms (AUASI, 7.4 months, p ⬍0.001). Longer time to recovery of sexual function was associated with baseline sexual function (0.13 months, p ⫽ 0.005) and not living with a partner (5.1 months, p ⫽ 0.024). The association between ADT and shorter recovery tine in the urinary symptoms
domain on univariate analysis did not remain significant on multivariate analysis and no other HRQOL domain was significantly affected by ADT. Likewise comorbidity count, Gleason score and T stage did not predict urinary function or symptoms on multivariate analysis.
DISCUSSION Adding a short course of hormone therapy to definitive RT when treating men with localized prostate cancer did not exacerbate HRQOL outcomes measured out to 4 years. In fact, men treated with hormones had a shorter mean recovery time for urinary function on univariate analysis. On multivariate analysis adding ADT to definitive RT did not significantly impact time to return to baseline in any of the 6 patient reported HRQOL domains. Nonwhite ethnicity and a history of cerebrovascular disease or alcohol abuse were associated with longer recovery in the MCS domain. The latter 2 conditions are well known to affect mental functioning, and the association between nonwhite ethnicity and worse HRQOL outcomes was also described in
Table 3. Time to return to baseline in each domain RT ⫹ ADT
RT Alone
Physical composite score MCS Urinary function Urinary symptoms Sexual function Bowel function
% Pts
Mean ⫾ SD Mos
% Pts
Mean ⫾ SD Mos
p Value
96 98 96 93 64 96
3.3 ⫾ 5.3 2.4 ⫾ 4.0 4.6 ⫾ 6.4 10.0 ⫾ 11.3 7.0 ⫾ 9.7 5.0 ⫾ 8.3
88 97 95 99 75 94
3.0 ⫾ 4.5 2.4 ⫾ 3.3 3.0 ⫾ 4.4 5.1 ⫾ 6.7 6.6 ⫾ 10.0 4.1 ⫾ 5.6
0.73 0.93 0.07 0.002 0.82 0.45
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HORMONE THERAPY AND RADIOTHERAPY EFFECTS IN MEN WITH PROSTATE CANCER
Table 4. Parameters significant on univariate analysis for months to return to baseline for HRQOL outcomes Urinary (mos)
Nonwhite race No partner Comorbidity count 1 or greater Cerebrovascular disease Diabetes mellitus Major depression Alcohol abuse Gleason score greater than 7 T stage greater than T1 BT alone vs EBRT alone
MCS* (mos)
Urinary Function (mos)
Symptoms*
Function†
2.3
2.3† 1.4† – – 3.2† – – – 1.9† 2.78*
– – 3.5 – – – – 4.7 4. 8.1
– – – – – – 12.4 – – –
2 6.6 – 2.9 3.7 – – –
Sexual† 3.9
* p ⬍0.05. † p ⬍0.10.
prior studies.11,12 The reasons for this racial discrepancy are unclear but may be related to differences in socioeconomic status, partnered status and baseline scores.12 The association between BT and decreased urinary recovery is also well described.6,13 When used as an adjunct to RT, the impact of ADT on HRQOL is the subject of conflicting literature. In a recent study Sanda et al found that neoadjuvant ADT was independently associated with impaired sexual, urinary irritation and vitality domains when added to EBRT in 473 men at a median 30-month followup.6 BT plus ADT was associated with detriments in the urinary incontinence, urinary irritation and vitality domains. Indeed, the impact of ADT on HRQOL when used as an adjunct to RT is the subject of conflicting literature. In an early study in 743 men Zelefsky et al reported that neoadjuvant ADT was an independent predictor of erectile dysfunction when added to EBRT compared to EBRT alone.14 In contrast, a report of Radiation Therapy Oncology Group 86-10 data, which randomized men with locally advanced prostate cancer to RT plus ADT or RT alone, showed no difference in the frequency of or time to return to sexual potency between the treatment groups.15 However, these early reports are limited by the physician reported nature of toxicity analysis, which is known to underestimate HRQOL impairment. Using patient reported HRQOL questionnaires Hollenbeck et al noted that neoadjuvant ADT was independently associated with lower sexual scores 29 months after EBRT for localized prostate cancer.16 In contrast, Chen et al found no significant difference in sexual recovery in men treated with 3-dimensional conformal RT with or without ADT at 21-month followup using a validated sexual health survey.17 Although patients treated with RT alone were more likely to be potent at 1 year than those treated with RT plus ADT, they also had higher potency scores at baseline. Several cross-sectional
studies have shown that adding ADT to BT is independently associated with decreased sexual HRQOL.18,19 However, in other studies this difference lost statistical significance on multivariate analysis.13,20 In a CaPSURE database analysis Speight et al reported an initial decrease in sexual function when adding short-term ADT to EBRT or BT.21 This decrease improved during posttreatment year 1 to a level similar to that of RT alone. The only statistically significant difference thereafter was worse sexual function in the BT plus ADT group at 4 years of followup. Sexual bother showed no statistically significant differences at any point. These findings support the transient nature of side effects from shortterm ADT. The impact of adjuvant ADT on gastrointestinal and genitourinary toxicity has been the subject of conflicting reports. We noted a univariate association between adding ADT and a more rapid return to baseline urinary symptoms. This may be explained by the 30% to 50% reduction in prostate gland volume caused by neoadjuvant ADT, which resulted in a smaller treatment target and the potential for less secondary damage. A meta-analysis by Bria et al showed a 33% decrease in relative risk for gastrointestinal and genitourinary toxicities when ADT was added to EBRT for locally advanced prostate cancer, although this did not attain statistical significance.22 Likewise in a retrospective study in 445 men treated with EBRT with or without ADT Jani and Gratzle found small but statistically significant lower rates of gastrointestinal and genitourinary toxicity in the ADT group on chi-square analysis, although this disappeared on regression analysis.23 Other groups reported an increase in late genitourinary toxicity associated with long-term ADT, in addition to EBRT.4,24 Long-term gastrointestinal toxicity has also been described when ADT was added to RT, although these reports conflict in regard to hormone duration and timing.4,24,25
HORMONE THERAPY AND RADIOTHERAPY EFFECTS IN MEN WITH PROSTATE CANCER
The diversity of treatment protocols, disease stages, ADT duration and timing, and methods of measuring patient outcomes likely contribute to these disparate findings. A plausible explanation for the absent additional toxicity when adding a short course of ADT to RT may lie in the common sexual and vitality detriments that these treatments share as monotherapies. Numerous studies have documented an increase in sexual dysfunction with ADT, which is reversible with time.26 –29 Likewise the 5-year actuarial likelihood of impotence after EBRT and BT as monotherapy is 56% and 24% to 50%, respectively.14,18,30 ADT and BT are also independently associated with decreased vitality scores and men treated with EBRT have worsened physical, emotional and social role restriction.6,28 Briefly, we contend that the reversible detriments caused by a short course of ADT may be eclipsed by the overlapping toxicities of RT, such that the overall effect on long-term HRQOL is not impactful. However, the published literature remains highly controversial. Limitations of the current study include the lack of randomization with the inherent potential for introducing bias. For example, the patient initial choice of treatment may have been influenced by preexisting HRQOL dysfunction at baseline. Men
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treated with ADT in addition to RT had significantly higher risk disease, although this did not translate into worse outcomes. The limited sample size required us to group together EBRT and BT for analysis with the potential that divergent side effect profiles could have concealed an overall difference between the treatment groups. Although our comorbidity instrument has been extensively used in prior studies, it does not capture disease severity and, thus, may not fully estimate the true comorbidity burden. Furthermore, we did not include data after cancer recurrence in the current analysis, which may have had a treatment related impact on longterm HRQOL outcomes.
CONCLUSIONS Despite the limitations this study offers a prospective, longitudinal and long-term analysis of HRQOL outcomes after treatment with RT alone or RT plus ADT for localized prostate cancer. Adding ADT as an adjunct to definitive RT did not significantly impact time to return to baseline in the 6 patient reported HRQOL domains of our study population. These data may be valuable for patients and physicians when weighing the toxicity and benefits of ADT in addition to RT.
REFERENCES 1. Jemal A, Siegel R, Ward E et al: Cancer statistics, 2009. CA Cancer J Clin 2009; 59: 225. 2. Shelley MD, Kumar S, Wilt T et al: A systematic review and meta-analysis of randomised trials of neo-adjuvant hormone therapy for localised and locally advanced prostate carcinoma. Cancer Treat Rev 2009; 35: 9. 3. D’Amico AV, Chen MH, Renshaw AA et al: Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA 2008; 299: 289. 4. Bolla M, Gonzalez D, Warde P et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337: 295.
8. McHorney CA, Ware JE Jr and Raczek AE: The MOS 36-Item Short-Form Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical and mental health constructs. Med Care 1993; 31: 247. 9. Litwin MS, Hays RD, Fink A et al: The UCLA Prostate Cancer Index: development, reliability, and validity of a health-related quality of life measure. Med Care 1998; 36: 1002. 10. Barry MJ, Fowler FJ Jr, O’Leary MP et al: The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992; 148: 1549.
5. Isbarn H, Boccon-Gibod L, Carroll PR et al: Androgen deprivation therapy for the treatment of prostate cancer: consider both benefits and risks. Eur Urol 2009; 55: 62.
11. Eton DT, Lepore SJ and Helgeson VS: Early quality of life in patients with localized prostate carcinoma: an examination of treatment-related, demographic, and psychosocial factors. Cancer 2001; 92: 1451.
6. Sanda MG, Dunn RL, Michalski J et al: Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008; 358: 1250.
12. Jayadevappa R, Johnson JC, Chhatre S et al: Ethnic variation in return to baseline values of patient-reported outcomes in older prostate cancer patients. Cancer 2007; 109: 2229.
7. Litwin MS, Gore JL, Kwan L et al: Quality of life after surgery, external beam irradiation, or brachytherapy for early-stage prostate cancer. Cancer 2007; 109: 2239.
13. Roeloffzen EM, Lips IM, van Gellekom MP et al: Health-related quality of life up to six years after (125)I brachytherapy for early-stage prostate cancer. Int J Radiat Oncol Biol Phys 2010; 76: 1054.
14. Zelefsky MJ, Cowen D, Fuks Z et al: Long term tolerance of high dose three-dimensional conformal radiotherapy in patients with localized prostate carcinoma. Cancer 1999; 85: 2460. 15. Pilepich MV, Krall JM, al-Sarraf M et al: Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology 1995; 45: 616. 16. Hollenbeck BK, Wei JT, Sanda MG et al: Neoadjuvant hormonal therapy impairs sexual outcome among younger men who undergo external beam radiotherapy for localized prostate cancer. Urology 2004; 63: 946. 17. Chen CT, Valicenti RK, Lu J et al: Does hormonal therapy influence sexual function in men receiving 3D conformal radiation therapy for prostate cancer? Int J Radiat Oncol Biol Phys 2001; 50: 591. 18. Potters L, Torre T, Fearn PA et al: Potency after permanent prostate brachytherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2001; 50: 1235. 19. Hollenbeck BK, Dunn RL, Wei JT et al: Neoadjuvant hormonal therapy and older age are associated with adverse sexual health-related quality-
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of-life outcome after prostate brachytherapy. Urology 2002; 59: 480.
cer?: meta-analysis of randomized trials. Cancer 2009; 115: 3446.
cancer on androgen deprivation therapy. J Urol 2000; 163: 1743.
20. Pinkawa M, Fischedick K, Gagel B et al: Association of neoadjuvant hormonal therapy with adverse health-related quality of life after permanent iodine-125 brachytherapy for localized prostate cancer. Urology 2006; 68: 104.
23. Jani AB and Gratzle J: Late radiotherapy toxicity after prostate cancer treatment: influence of hormonal therapy. Urology 2005; 66: 566.
27. Green HJ, Pakenham KI, Headley BC et al: Quality of life compared during pharmacological treatments and clinical monitoring for non-localized prostate cancer: a randomized controlled trial. BJU Int 2004; 93: 975.
21. Speight JL, Elkin EP, Pasta DJ et al: Longitudinal assessment of changes in sexual function and bother in patients treated with external beam radiotherapy or brachytherapy, with and without neoadjuvant androgen ablation: data from CaPSURE. Int J Radiat Oncol Biol Phys 2004; 60: 1066. 22. Bria E, Cuppone F, Giannarelli D et al: Does hormone treatment added to radiotherapy improve outcome in locally advanced prostate can-
24. Peeters ST, Heemsbergen WD, van Putten WL et al: Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys 2005; 61: 1019. 25. Liu M, Pickles T, Agranovich A et al: Impact of neoadjuvant androgen ablation and other factors on late toxicity after external beam prostate radiotherapy. Int J Radiat Oncol Biol Phys 2004; 58: 59. 26. Herr HW and O’Sullivan M: Quality of life of asymptomatic men with nonmetastatic prostate
28. Potosky AL, Reeve BB, Clegg LX et al: Quality of life following localized prostate cancer treated initially with androgen deprivation therapy or no therapy. J Natl Cancer Inst 2002; 94: 430. 29. Lubeck DP, Grossfeld GD and Carroll PR: The effect of androgen deprivation therapy on healthrelated quality of life in men with prostate cancer. Urology 2001; 58: 94. 30. Merrick GS, Butler WM, Wallner KE et al: Erectile function after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2005; 62: 437.
Abbreviations and Acronyms ADT ⫽ androgen deprivation therapy AUASI ⫽ American Urological Association symptom index BT ⫽ brachytherapy EBRT ⫽ external beam RT HRQOL ⫽ health related quality of life MCS ⫽ mental composite score PSA ⫽ prostate specific antigen RT ⫽ radiotherapy Submitted for publication September 1, 2010. Study received UCLA institutional review board approval. * Correspondence: Department of Radiation Oncology, University of California-Los Angeles School of Medicine, 200 Medical Pl., Suite B-265, Los Angeles, California 90095 (telephone: 310825-9775; e-mail: [email protected]).
Purpose: We examined whether short course androgen deprivation therapy as an adjunct to radiotherapy would impact health related quality of life outcomes in patients with localized prostate cancer treated definitively with external beam radiation therapy or permanent brachytherapy. Materials and Methods: From 1999 to 2003 patients were enrolled in a prospective study at our institution and completed validated health related quality of life surveys at defined pretreatment and posttreatment intervals. A total of 81 men received radiotherapy alone and 67 received radiotherapy plus androgen deprivation therapy. Median androgen deprivation therapy duration was 4 months. Univariate and multivariate analysis was done to compare time to return to baseline in 6 distinct health related quality of life domains. Results: On univariate analysis the radiotherapy plus androgen deprivation therapy group achieved baseline urinary symptoms more rapidly than the radiotherapy group (5 months, p ⫽ 0.002). On multivariate analysis time to return to baseline in any of the 6 health related quality of life domains was not significantly affected by adding androgen deprivation therapy. Factors associated with longer time to return to baseline mental composite scores on multivariate analysis included nonwhite ethnicity, cerebrovascular disease history and alcohol abuse history. Men treated with permanent brachytherapy monotherapy experienced longer time to return to baseline for urinary function and symptoms. Baseline sexual function and lack of a partner were associated with longer time to sexual recovery. Conclusions: Adding androgen deprivation therapy to definitive radiotherapy does not significantly impact the time to return to baseline health related quality of life. These data may be valuable for patients and physicians when weighing the toxicity and benefits of androgen deprivation therapy when added to definitive radiotherapy. Key Words: prostate, prostatic neoplasms, quality of life, radiotherapy, androgen antagonists
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THE most common noncutaneous cancer, prostate cancer, accounts for 25% of incident cases of malignancy in the United States.1 The treatment of patients with early stage prostate can-
cer, comprising 91% of new diagnoses, is 1 of the most controversial areas in ncology.1,2 Neither prostatectomy, EBRT nor BT has proved to show superior outcomes. Consequently management deci-
0022-5347/11/1855-1674/0 THE JOURNAL OF UROLOGY® © 2011 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
Vol. 185, 1674-1680, May 2011 Printed in U.S.A. DOI:10.1016/j.juro.2010.12.092
AND
RESEARCH, INC.
HORMONE THERAPY AND RADIOTHERAPY EFFECTS IN MEN WITH PROSTATE CANCER
sions are often based on patient preferences, considering the risks and benefits of each therapy.2 Thus, a number of studies groups have sought to define the toxicity profiles of these treatment modalities in terms of patient reported HRQOL outcomes. The survival benefit of RT may be improved by adding ADT for high and intermediate risk localized prostate cancer.3,4 Potential side effects of hormone blockade include fatigue, hot flushes, weight gain, sexual dysfunction and an increased risk of myocardial infarction.5 However, little is known about the long-term quality of life impact when ADT is used as an adjunct to definitive RT.6 We used patient reported outcomes spanning 4 years to compare HRQOL outcomes in patients with early stage prostate cancer treated with definitive RT with or without adjunctive ADT.
MATERIALS AND METHODS Study Sample Participants were recruited from March 1999 to January 2003 at UCLA Medical Center. Eligible men included those with clinically localized (T1, T2 or limited T3), biopsy proven adenocarcinoma without prior treatment who had elected primary treatment with surgery or RT, as described previously.7 We performed subgroup analysis in men treated with EBRT and/or BT who had at least 1 year of followup data available. The RT plus ADT group included 67 patients who received hormone blockade at primary treatment with RT and the RT alone group comprised 81 who received only EBRT and/or BT. When ADT was used as salvage therapy for recurrence after primary treatment, participants were included in the RT alone group and censored at the time of ADT initiation. All protocols were approved by the UCLA institutional review board and were Health Insurance Portability and Accountability Act compliant. Written informed consent was obtained from each participant.
Data Collection and Followup Patient reported outcome measures were collected via written questionnaires at baseline and at 11 posttreatment intervals, including at 1, 2, 4, 8, 12, 18, 24, 30, 36, 42 and 48 months. Median followup was 48 months and 68% of patients had at least 24 months of followup. General HRQOL was assessed by SF-36®, which generates a physical composite score and an MCS that are standardized to the general American population.8 Prostate cancer specific quality of life was evaluated using 2 instruments, including UCLA-PCI and AUASI. UCLAPCI is a validated instrument that measures urinary, sexual and bowel dysfunction.9 AUASI, which is also validated, measures capacity and voiding urinary symptoms.10 An 11-item comorbidity questionnaire corresponding to the Charlson index was administered, as in previous CaPSURE™ studies. Clinical information collected from the medical records included serum PSA, clinical T stage,
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biopsy Gleason score, EBRT total radiation dose and the number of seeds delivered for BT.
Treatment Treatment with EBRT consisted of 3-dimensional conformal or intensity modulated RT with a mean ⫾ SD dose of 72.2 ⫾ 8.8 Gy when used as monotherapy. In men who received EBRT combined with BT 45 Gy were delivered to the pelvis. BT was done using standard ultrasound guided transperineal techniques and dose prescription with 125I in 90% of patients and 103Pd in the remainder. Mean prostate gland size across all groups was 41.7 ⫾ 26.7 cc. The ADT course using bicalutamide and leuprolide was short term and administered in neoadjuvant, concurrent fashion, consistent with current standards of care. Median ADT duration was 4 months (range 4 to 8). Table 1 lists patient and treatment characteristics.
Statistical Analysis Demographic and clinical variables were compared in the RT and RT plus ADT groups using the generalized chisquare and t tests. We also compared medication use for erectile and bladder dysfunction between the 2 treatment groups. Univariate analysis was done to identify the time required to return to baseline HRQOL scores in the RT and RT plus ADT groups, defined as within 10% of the individual pretreatment value.7 In those who returned to baseline during followup the month of return to baseline was noted for that domain and compared for each outcome using the t test. We tested covariates on each outcome by univariate regression. We also calculated the percent of participants who returned to baseline at each time point and graphed the percents with time using chi-square analysis to detect differences between the RT and RT plus ADT groups. Multivariate analysis was done with forward stepwise linear regression, analyzing months to return to baseline in each HRQOL domain. Covariates included age, race (white vs nonwhite), relationship status (living vs not living with a partner), comorbidity type, comorbidity count (none vs any), pretreatment serum PSA, biopsy Gleason score (less than 7 vs 7 or greater), T stage (T1 vs T2/T3), prior transurethral prostate resection and primary treatment modality (EBRT alone vs BT alone vs EBRT plus BT). In each model ADT use, age and treatment modality were included regardless of significance. Two-sided p ⬍0.05 was considered statistically significant. All statistical analysis was done SAS® 9.2.
RESULTS Men who received ADT were older than those who did not (average age 71.5 vs 67.9 years, p ⫽ 0.0014) and had higher mean PSA (15.3 ⫾ 25.4 ng/ml, median 8.0 vs 7.8 ⫾ 5.5, median 6.7, p ⫽ 0.02), Gleason score (7 or greater in 50% vs 18.5%, p ⬍0.0001) and T stage (T2 or greater in 47.8% vs 16%, p ⬍0.0001). Of participants who received ADT the primary therapy was EBRT in 62.7%, BT in 23.9% and combined in 13.4% (p ⬍0.0001).
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HORMONE THERAPY AND RADIOTHERAPY EFFECTS IN MEN WITH PROSTATE CANCER
Table 1. Characteristics of 148 study patients
Race: White Nonwhite Partnered Comorbidity: Cardiovascular disease Cerebrovascular disease Diabetes mellitus Gastrointestinal disease Major depression Tobacco use Alcohol abuse Comorbidity score: 0 Greater than 1 Biopsy Gleason score: Less than 7 7 or Greater Tumor stage: T1 T2 T3 Treatment type: EBRT only BT only EBRT ⫹ BT Prior transurethral prostate resection
No. RT Alone (%)
No. RT ⫹ ADT (%)
67 (82.7) 14 (17.3) 63 (77.8)
55 (82.1) 12 (17.9) 54 (80.6)
9 (11.1) 3 (3.7) 5 (6.2) 12 (14.8) 5 (6.2) 38 (46.9) 4 (4.9)
8 (11.9) 2 (3.0) 6 (9.0) 10 (14.9) 3 (4.5) 26 (38.8) 2 (3.0)
25 (30.9) 56 (69.1)
22 (32.8) 45 (67.2)
66 (81.5) 15 (18.5)
33 (50.0) 33 (50.0)
68 (84.0) 13 (16.0) 0
35 (52.2) 28 (41.8) 4 (6.0)
25 (30.9) 47 (58.0) 9 (11.1) 8 (9.9)
42 (62.7) 16 (23.9) 9 (13.4) 6 (9.0)
p Value 0.92
0.67 0.87 0.99 0.55 0.98 0.73 0.32 0.69 0.80
(Fisher’s exact test) (Fisher’s exact test) (Fisher’s exact test) (Fisher’s exact test) (Fisher’s exact test)
⬍0.0001 ⬍0.0001 (Fisher’s exact test)
0.0001
Table 2 shows the prevalence of erectile dysfunction treatments and ␣-blocker use during followup. No significant differences were observed between the RT and RT plus ADT groups. The figure shows the proportion of men who returned to baseline scores in each HRQOL domain in the RT and the RT plus ADT groups. A significantly higher proportion of the RT plus ADT group returned to baseline urinary function and urinary symptoms at 1 and 4 months, respectively. At 12 months a higher proportion of the RT group attained baseline scores in the domain of urinary symptoms.
0.85
Table 3 shows the mean time in months needed to return to baseline HRQOL in the domains of physical composite score (SF-36), MCS (SF-36), urinary function (AUASI), urinary symptoms (UCLA-PCI), sexual function (UCLA-PCI) and bowel function (UCLA-PCI) in the RT and RT plus ADT groups. The only statistically significant difference was in the urinary symptom domain with the RT plus ADT group achieving baseline scores approximately 5 months sooner than the RT alone group (p ⫽ 0.017). A similar but not statistically significant trend was also noted in the urinary function domain.
Table 2. Erectile dysfunction and bladder medication by time after RT with and without ADT
Baseline: Erectile dysfunction Erectile dysfunction Tamsulosin 1 Yr: Erectile dysfunction Erectile dysfunction Tamsulosin 2 Yrs: Erectile dysfunction Erectile dysfunction Tamsulosin 4 Yrs: Erectile dysfunction Erectile dysfunction Tamsulosin
No. RT Alone (%)
No. RT ⫹ ADT (%)
p Value
6 (7.4) 2 (2.5) 9 (11.2)
9 (13.4) 0 12 (17.9)
0.23 0.50 (Fisher’s exact test) 0.25
meds aids
16 (22.5) 1 (1.4) 29 (41.4)
11 (17.7) 1 (1.6) 18 (29.0)
0.49 0.99 (Fisher’s exact test) 0.14
meds aids
14 (22.6) 0 18 (28.6)
9 (16.7) 1 (1.8) 11 (20.4)
0.43 0.46 (Fisher’s exact test) 0.31
meds aids
9 (16.4) 1 (1.8) 13 (23.6)
8 (18.2) 0 9 (20.5)
0.81 0.99 (Fisher’s exact test) 0.71
medication aids
HORMONE THERAPY AND RADIOTHERAPY EFFECTS IN MEN WITH PROSTATE CANCER
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Time dependent proportion of men who returned to baseline score in each HRQOL domain. Asterisk indicates RT vs RT plus ADT p ⬍0.05.
Table 4 shows the univariate modeling results of covariates other than ADT. Race, cerebrovascular disease, depression and alcohol abuse were significantly associated with the MCS domain. Comorbidity count and BT alone were associated with urinary function while comorbidity count, Gleason score, T stage and BT alone were associated with urinary symptoms. Multivariate analysis adjusted for pretreatment quality of life scores was done to identify covariates that affected time to return to baseline for each HRQOL domain. Factors that significantly extended this time were nonwhite ethnicity (2.1 months, p ⫽ 0.008), cerebrovascular disease history (5.9 months, p ⬍0.001) and alcohol abuse history (3.0 months, p ⫽ 0.04). Men treated with BT as monotherapy experienced longer time to return to baseline for urinary control (UCLA-PCI, 2.6 months, p ⫽ 0.001) and urinary symptoms (AUASI, 7.4 months, p ⬍0.001). Longer time to recovery of sexual function was associated with baseline sexual function (0.13 months, p ⫽ 0.005) and not living with a partner (5.1 months, p ⫽ 0.024). The association between ADT and shorter recovery tine in the urinary symptoms
domain on univariate analysis did not remain significant on multivariate analysis and no other HRQOL domain was significantly affected by ADT. Likewise comorbidity count, Gleason score and T stage did not predict urinary function or symptoms on multivariate analysis.
DISCUSSION Adding a short course of hormone therapy to definitive RT when treating men with localized prostate cancer did not exacerbate HRQOL outcomes measured out to 4 years. In fact, men treated with hormones had a shorter mean recovery time for urinary function on univariate analysis. On multivariate analysis adding ADT to definitive RT did not significantly impact time to return to baseline in any of the 6 patient reported HRQOL domains. Nonwhite ethnicity and a history of cerebrovascular disease or alcohol abuse were associated with longer recovery in the MCS domain. The latter 2 conditions are well known to affect mental functioning, and the association between nonwhite ethnicity and worse HRQOL outcomes was also described in
Table 3. Time to return to baseline in each domain RT ⫹ ADT
RT Alone
Physical composite score MCS Urinary function Urinary symptoms Sexual function Bowel function
% Pts
Mean ⫾ SD Mos
% Pts
Mean ⫾ SD Mos
p Value
96 98 96 93 64 96
3.3 ⫾ 5.3 2.4 ⫾ 4.0 4.6 ⫾ 6.4 10.0 ⫾ 11.3 7.0 ⫾ 9.7 5.0 ⫾ 8.3
88 97 95 99 75 94
3.0 ⫾ 4.5 2.4 ⫾ 3.3 3.0 ⫾ 4.4 5.1 ⫾ 6.7 6.6 ⫾ 10.0 4.1 ⫾ 5.6
0.73 0.93 0.07 0.002 0.82 0.45
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HORMONE THERAPY AND RADIOTHERAPY EFFECTS IN MEN WITH PROSTATE CANCER
Table 4. Parameters significant on univariate analysis for months to return to baseline for HRQOL outcomes Urinary (mos)
Nonwhite race No partner Comorbidity count 1 or greater Cerebrovascular disease Diabetes mellitus Major depression Alcohol abuse Gleason score greater than 7 T stage greater than T1 BT alone vs EBRT alone
MCS* (mos)
Urinary Function (mos)
Symptoms*
Function†
2.3
2.3† 1.4† – – 3.2† – – – 1.9† 2.78*
– – 3.5 – – – – 4.7 4. 8.1
– – – – – – 12.4 – – –
2 6.6 – 2.9 3.7 – – –
Sexual† 3.9
* p ⬍0.05. † p ⬍0.10.
prior studies.11,12 The reasons for this racial discrepancy are unclear but may be related to differences in socioeconomic status, partnered status and baseline scores.12 The association between BT and decreased urinary recovery is also well described.6,13 When used as an adjunct to RT, the impact of ADT on HRQOL is the subject of conflicting literature. In a recent study Sanda et al found that neoadjuvant ADT was independently associated with impaired sexual, urinary irritation and vitality domains when added to EBRT in 473 men at a median 30-month followup.6 BT plus ADT was associated with detriments in the urinary incontinence, urinary irritation and vitality domains. Indeed, the impact of ADT on HRQOL when used as an adjunct to RT is the subject of conflicting literature. In an early study in 743 men Zelefsky et al reported that neoadjuvant ADT was an independent predictor of erectile dysfunction when added to EBRT compared to EBRT alone.14 In contrast, a report of Radiation Therapy Oncology Group 86-10 data, which randomized men with locally advanced prostate cancer to RT plus ADT or RT alone, showed no difference in the frequency of or time to return to sexual potency between the treatment groups.15 However, these early reports are limited by the physician reported nature of toxicity analysis, which is known to underestimate HRQOL impairment. Using patient reported HRQOL questionnaires Hollenbeck et al noted that neoadjuvant ADT was independently associated with lower sexual scores 29 months after EBRT for localized prostate cancer.16 In contrast, Chen et al found no significant difference in sexual recovery in men treated with 3-dimensional conformal RT with or without ADT at 21-month followup using a validated sexual health survey.17 Although patients treated with RT alone were more likely to be potent at 1 year than those treated with RT plus ADT, they also had higher potency scores at baseline. Several cross-sectional
studies have shown that adding ADT to BT is independently associated with decreased sexual HRQOL.18,19 However, in other studies this difference lost statistical significance on multivariate analysis.13,20 In a CaPSURE database analysis Speight et al reported an initial decrease in sexual function when adding short-term ADT to EBRT or BT.21 This decrease improved during posttreatment year 1 to a level similar to that of RT alone. The only statistically significant difference thereafter was worse sexual function in the BT plus ADT group at 4 years of followup. Sexual bother showed no statistically significant differences at any point. These findings support the transient nature of side effects from shortterm ADT. The impact of adjuvant ADT on gastrointestinal and genitourinary toxicity has been the subject of conflicting reports. We noted a univariate association between adding ADT and a more rapid return to baseline urinary symptoms. This may be explained by the 30% to 50% reduction in prostate gland volume caused by neoadjuvant ADT, which resulted in a smaller treatment target and the potential for less secondary damage. A meta-analysis by Bria et al showed a 33% decrease in relative risk for gastrointestinal and genitourinary toxicities when ADT was added to EBRT for locally advanced prostate cancer, although this did not attain statistical significance.22 Likewise in a retrospective study in 445 men treated with EBRT with or without ADT Jani and Gratzle found small but statistically significant lower rates of gastrointestinal and genitourinary toxicity in the ADT group on chi-square analysis, although this disappeared on regression analysis.23 Other groups reported an increase in late genitourinary toxicity associated with long-term ADT, in addition to EBRT.4,24 Long-term gastrointestinal toxicity has also been described when ADT was added to RT, although these reports conflict in regard to hormone duration and timing.4,24,25
HORMONE THERAPY AND RADIOTHERAPY EFFECTS IN MEN WITH PROSTATE CANCER
The diversity of treatment protocols, disease stages, ADT duration and timing, and methods of measuring patient outcomes likely contribute to these disparate findings. A plausible explanation for the absent additional toxicity when adding a short course of ADT to RT may lie in the common sexual and vitality detriments that these treatments share as monotherapies. Numerous studies have documented an increase in sexual dysfunction with ADT, which is reversible with time.26 –29 Likewise the 5-year actuarial likelihood of impotence after EBRT and BT as monotherapy is 56% and 24% to 50%, respectively.14,18,30 ADT and BT are also independently associated with decreased vitality scores and men treated with EBRT have worsened physical, emotional and social role restriction.6,28 Briefly, we contend that the reversible detriments caused by a short course of ADT may be eclipsed by the overlapping toxicities of RT, such that the overall effect on long-term HRQOL is not impactful. However, the published literature remains highly controversial. Limitations of the current study include the lack of randomization with the inherent potential for introducing bias. For example, the patient initial choice of treatment may have been influenced by preexisting HRQOL dysfunction at baseline. Men
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treated with ADT in addition to RT had significantly higher risk disease, although this did not translate into worse outcomes. The limited sample size required us to group together EBRT and BT for analysis with the potential that divergent side effect profiles could have concealed an overall difference between the treatment groups. Although our comorbidity instrument has been extensively used in prior studies, it does not capture disease severity and, thus, may not fully estimate the true comorbidity burden. Furthermore, we did not include data after cancer recurrence in the current analysis, which may have had a treatment related impact on longterm HRQOL outcomes.
CONCLUSIONS Despite the limitations this study offers a prospective, longitudinal and long-term analysis of HRQOL outcomes after treatment with RT alone or RT plus ADT for localized prostate cancer. Adding ADT as an adjunct to definitive RT did not significantly impact time to return to baseline in the 6 patient reported HRQOL domains of our study population. These data may be valuable for patients and physicians when weighing the toxicity and benefits of ADT in addition to RT.
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