- Email: [email protected]
Prevention of Gynecomastia and Breast Pain Caused by Androgen Deprivation Therapy in Prostate Cancer: Tamoxifen or Radiotherapy?
International Journal of
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Genitourinary Cancer
Prevention of Gynecomastia and Breast Pain Caused by Androgen Deprivation Therapy in Prostate Cancer: Tamoxifen or Radiotherapy? Gustavo Arruda Viani, M.D., Lucas Godo´i Bernardes da Silva, M.D., and Eduardo Jose Stefano, M.D. Department of Radiation Oncology, Marilia Medical School, Marı´lia, Sa˜o Paulo, Brazil Received Sep 26, 2011
Summary Antiandrogen monotherapy or adjuvant therapy is used frequently in men with carcinoma of the prostate. Although generally tolerated quite well, gynecomastia and breast pain can occur, being the most common side effects. In this scenario as prophylatic radiotherapy as tamoxifen are effective methods to prevent it. Our data shows that radiotherapy should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors.
Purpose: To determine, in a meta-analysis, whether gynecomastia and breast pain rates in men with prostate cancer treated with androgen deprivation therapy (ADT) are reduced if treated with prophylactic radiotherapy (RT) or tamoxifen (TMX). Methods and Materials: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing RT or TMX with observation for men with prostate cancer using ADT. Results: Six RCTs (three RT trials and three TMX trials, N Z 777 patients total) were identified that met the study criteria. Pooled results from these RCTs comparing RT vs. observation showed a significant reduction in the incidence of gynecomastia and breast pain rates in patients treated with RT (odds ratio [OR] Z 0.21, 95% confidence interval [CI] Z 0.12e0.37, p < 0.0001, and OR Z 0.34, 95% CI 0.20e0.57, p < 0.0001, respectively). Use of RT resulted in an absolute risk reduction (ARR) of 29.4% and 19.9%, with a number needed to treat (NNT) of 3.4 and 5 to avoid one case of gynecomastia and breast pain, respectively. Pooled results from trials comparing TMX vs. observation showed a statistical benefit for breast pain and gynecomastia in favor of TMX arms (OR Z 0.04, 95% CI Z 0.02e0.08, p < 0.0001 and OR Z 0.07, 95% CI Z 0.0e0.14, p < 0.00001). TMX resulted in an ARR Z 64.1% and 47.6%, with an NNT of 1.56 and 2.1 to avoid one case of gynecomastia and breast pain, respectively. Considering adverse effects, TMX was 6 times more adverse effects than RT. Conclusions: Our data have shown that both TMX and RT prevented gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. Although TMX was two times more effective in preventing gynecomastia, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis. Ó 2012 Elsevier Inc. Keywords: Gynecomastia, Prostate cancer, Prophylatic radiotherapy, Prophylatic tamoxifen
Reprint requests to: Gustavo Arruda Viani, M.D., Department of Radiation Oncology, Marilia Medical School, Maria Cecilia Alves, 192
Int J Radiation Oncol Biol Phys, Vol. 83, No. 4, pp. e519ee524, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2012.01.036
Marilia, Sa˜o Paulo, Brazil. Tel: (5514) 3454-2065; Fax: (5514) 34321780; E-mail: [email protected] Conflict of interest: none.
e520 Viani et al.
International Journal of Radiation Oncology Biology Physics
Introduction
Interventions
Gynecomastia is common in men with prostate cancer undergoing androgen deprivation therapy (ADT). The prevalence of gynecomastia is approximately 15% in men treated with gonadotropinreleasing hormone (GnRH) agonists combined with an antiandrogen. The risk of gynecomastia is reduced with total androgen blockade with a GnRH analogue and an antiandrogen (1e3). However, the prevalence is as high as 75% when antiandrogen monotherapy is used (4e6). However, despite of high prevalence, this treatment complication has received considerably less attention than sexual dysfunction, and the full clinical impact of gynecomastia in this patient population has yet to be determined. Given that many patients with prostate cancer receive long-term ADT, an appraisal of the prevention of gynecomastia in this patient group is warranted. Both drug therapy and radiotherapy (RT) have limited benefit once gynecomastia is established in this setting; as a result, prevention of breast development is the goal of therapy. Strategies that have been used for prevention include pharmacologic therapy (antiestrogens or aromatase inhibitors) or RT (7). Evidence from several small studies suggests that prophylactic breast irradiation can reduce the incidence of estrogen-induced gynecomastia in patients with prostate cancer (8, 9). In the last years, a few works have been published on hormonal treatment for the reduction of gynecomastia in patients with prostate cancer. Recent data from randomized clinical trials also support the use of TMX to prevent gynecomastia (1, 10). However, doubt still remains about its influence on PSA inhibition and testosterone levels in these patients. There has been no systematic appraisal of this body of literature to allow practitioners to evaluate the evidence base of these aspects of patients with prostate cancer. Consequently, this meta-analysis was performed to evaluate the effectiveness of prevention of gynecomastia caused by ADT in patients with prostate cancer using TMX or RT.
Prophylatic RT for patients with prostate cancer receiveing ADT could consist of photon or electron therapy or combinations. TMX could consist of any dosage and any time of administration. Thus, RCTs that compared RT vs. observation or RT vs. TMX, or TMX vs. observation for patients with prostate cancer using ADT were considered.
Methods and Materials Search criteria for studies eligible for inclusion in this metaanalysis are described below.
Studies Studies were required to be either complete reports of studies of randomized, controlled trials (RCTs) and/or overviews of RCTs of RT and/or TMX to prevent gynecomastia in patients with prostate cancer receiving ADT published in peer-reviewed journals. Randomized, controlled trials reported in other sources (e.g., abstracts in proceedings of relevant scientific meetings) for which full details were available from the investigators were also eligible.
Study population The men in the studies had to have histologically confirmed localized prostate cancer and to have undergone ADT (monotherapy or total androgen blockade with a GnRH analogue and/ or an antiandrogen) with or without pelvic RT and radical prostatectomy.
Outcome measures The primary end point was the incidence of gynecomastia and/or breast pain, as assessed by physical examination and direct questioning by the investigator. When possible, data on gynecomastia measured by calipers in the sagittal and coronal planes were collected. Complications were also considered a primary end point. For TMX arms, complications such as hot flushes, dizziness, constipation, asthenia, and cardiologic or neurologyc effects were collected. For RT arms, the following complications were considered: skin reaction, erythema, and pruritus. The secondary objectives were PSA inhibiton and testosterone levels in TMX arms.
Strategy for study identification The MEDLINE (Ovid) (1996eDecember 2010), CANCERLIT (Ovid) (1996eDecember 2010), and Cochrane Library (Issue 2, 2010) databases were searched using the terms “(prostate OR prostatic) AND (cancer OR carcinoma OR tumor OR tumor) AND (conformal OR CDRT) AND (radiation OR radiotherapy) AND (dose escalation) AND (mortality OR survival OR biochemical failure OR relapse OR failure OR recurrence OR outcome).” These terms were then combined with the search terms for the following study designs: practice guidelines, systematic reviews or meta-analyses, reviews, randomized controlled trials, and controlled clinical trials. In addition, the Physician Data Query clinical trial database on the Internet (http://cnetdb.nci.nih.gov/ search/clinical_trials/) and the proceedings of the 1997e2010 annual meetings of the American Society of Clinical Oncology were searched for reports on new or ongoing trials. Relevant articles and abstracts were selected and reviewed by two methodologists, and the reference lists published with these sources were searched to identify any additional trials. All RCTs identified by this search were then assessed by two independent reviewers (G.A.V. and E.J.S.) to determine whether they met the inclusion criteria. Any discrepancies in the results of the assessments were resolved by a third reviewer (B. L.G.).
Review analysis All analyses were carried out on an intention-to-treat basis; that is, all patients randomly assigned to a treatment group were included in the analyses according to the assigned treatment, irrespective of whether they received the treatment or were excluded from the analysis by the study investigators. For categoric variables, weighted risk ratios and their 95% confidence intervals (95% CIs) were calculated using comprehensive meta-analysis software according to the Peto method. Results were tested for heterogeneity at a significance level of p < 0.05, according to the methods outlined by Der Simonian and Laird (11). A fixed-effects model
Volume 83 Number 4 2012 Table 1
Prevention of gynecomastia caused by androgen deprivation e521
Characteristic of trials evaluating radiotherapy (RT) and tamoxifen (TMX) for gynecomastia and breast pain
First author (reference)
Patients (N)
Intervention
Ozen (14)
125
RT vs. no RT
Fradet (12) Perdona` (1)
282 150
TMX (different dosing schedules) TMX vs. RT vs. Placebo
Boccardo (15) Tyrrell (13)
114 106
TMX vs. anastrozole vs. placebo RT vs. sham RT
was used if there was no evidence of heterogeneity between studies; if there was evidence of heterogeneity, a random-effects model was used for the metaanalysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each trial and presented in a forest plot. To compare effectiveness of interventions, we calculated the number needed to treat (NNT) and number needed to harm (NNH). The NNT was calculated from the simple formula: 1/ARR 100, where ARR Z control event rate (CER) experimental event rate (EER). Also, the NNH was calculated from the simple formula: 1/ARR 100, where ARI Z experimental event rate (EER) control event rate (CER).
Dose RT 10 Gy/1 fraction Electron beam RT TMX 20 mg/day for 12 mo TMX 10 mg for 6 mo RT 12 Gy/1 fraction Electron beam RT TMX 20 mg/day for 12 mo RT 12 Gy/1 fraction Electron beam RT
gynecomastia rates were less in the RT arm (46 of 140, 32.8%) than in the observation arm (99 of 159, 62.2%). The pooled OR for all of the trials was 0.21(95% CI 0.12e0.37, p < 0.00001). The result of the test for heterogeneity was not statistically significant (p Z 0.89). The overall OR suggests that there was a statistically significant difference between the RT and observation arms in terms of the gynecomastia rate (p < 0.00001; Fig. 1). The ARR for gynecomastia in 12 months comparing RT with observation was 29.4%, resulting in an NNT of 3.4 (Table 2).
RT vs. observation: Breast pain
Results The electronic and manual searches revealed 141 citations. After further screening, five full-text articles were retrieved for further assessment (1, 12e15). Study characteristics are shown in Table 1. The studies had a randomized design with 156 patients submitted to RT and 121 patients submitted to TMX treatment and 274 treated with observation or placebo. There was one randomized study (114 patients) that assessed the efficacy and safety comparing ADT plus placebo, ADT plus TMX and ADT plus anastrozole. One study (150 patients) tested the efficacy of ADT plus RT vs. ADT plus placebo and ADT plus TMX, 3 studies (314 patients) assessed the efficacy and safety of ADT plus RT vs. ADT plus observation. The parameters evaluated in these studies were gynecomastia, breast pain, PSA inhibition and testosterone levels. Adverse effects such as: asthenia, constipation, hot flushes, rash/erythema, cardiovascular events, dizziness and pruritus were evaluated.
RT vs. observation: Gynecomastia Three studies, with a total population of 299 patients, analyzed gynecomastia as one of the outcomes. The incidence of
Fig. 1.
Three studies, with a total patient population of 299 patients, examined breast pain as one of outcomes. The breast pain rates were 49.2 in the RT arm and 69.1% in the observation arm. The overall OR was 0.34 (95% CI Z 0.20e0.57), as shown in Fig. 2. The ARR for gynecomastia in 12 months comparing RT with observation was 19.9%, resulting in NNT Z 5, as described in Table 2. The result of the test for heterogeneity was not statistically significant (p Z 0.78), which allowed the results to be pooled (Fig. 2).
TMX vs. observation: Gynecomastia Three studies, with a total population of 272 patients, analyzed gynecomastia as one of the outcomes. The incidence of gynecomastia rates were less in the TMX arm (13/121, 10.7%) than in the observation arm (113/159, 74.8%). The pooled OR for all of the trials was 0.04 (95% CI Z 0.02e0.08). The result of the test for heterogeneity was not statistically significant (p Z 0.98). The overall OR suggests that there was a statistically significant difference between the TMX and observation arms in terms of the gynecomastia rate (p < 0.00001) (Fig. 3). The ARR for
Forest graph shows the result of meta-analysis for RT to prevent gynecomastia.
International Journal of Radiation Oncology Biology Physics
e522 Viani et al. Table 2
Incidence of gynecomastia, breast pain, and complications comparing radiotherapy (RT) and tamoxifen (TMX)
Comparation
Prophylatic
Observation
EER (%)
CER (%)
ARR (%)
NNT
46/140 13/121
99/159 113/151
32.8 10.7
62.2 74.8
29.4 64.1
3.4 1.56
Incidence of all degrees of breast pain RT vs. observation 69/140 TMX vs. observation 9/121
110/159 83/151
49.2 7.4
69.1 55
19.9 47.6
5 2.1
Incidence of gynecomastia RT vs. observation TMX vs. observation
Comparation Incidence of complications* RT vs. observation TMX vs. observation
Prophylatic
Observation
EER (%)
CER (%)
ARI (%)
NNH
45/155 47/121
48/175 44/151
29 38.8
27.4 29
1.6 9.8
62.5 10
Abbreviations: ARR Z absolute risk reduction; ARI Z absolute risk increase; CER Z control event rate; EER Z experimental event rate; NNH Z number need to harm; NNT Z number needed to treat. * RT complications include skin reaction, erythema, pruritus, and hyperpigmentation. TMX complications include hot flushes, dizziness, constipation, asthenia, and cardiologic or neurologic effects.
gynecomastia in 12 months comparing TMX with observation was 64.1%, resulting in an NNT of 1.56 (Table 2).
TMX vs. observation: Breast pain Three studies, with a total patient population of 272 patients, examined breast pain as one of outcomes. The breast pain rates were 7.4% in the TMX arms and 55% in the observation arms. The overall OR was 0.07 (95% CI Z 0.03e0.14) (Fig. 3). The ARR for gynecomastia in 12 months comparing TMX with observation was 47.6%, resulting in an NNT of 2.1 (Table 2). The result of the test for heterogeneity was not statistically significant (p Z 0.82), which allowed the results to be pooled (Fig. 4).
PSA inhibition Three RCTs evaluated the PSA inhibition as one outcome. In all trials, the median PSA levels declined 30% to 80% from baseline values at 12 months in the ADT plus TMX arms. None of trials showed an increased in PSA level compared with placebo arms.
Testosterone levels Three RCTs evaluated the testosterone levels as one outcome. In two trials, free testosterone levels after 6 months remains unchanged compared with baseline values. One trial showed an increased in free testosterone level compared with the placebo arm.
Adverse effects
Discussion
Adverse effects were reported in all three RCTs, with a total population of 330 patients. The incidence of adverse effects (erythema, pruritus or hyperpigmentation) were highest in the RT arms (45/155; 29%) compared with observation arms (48/175; 27.4%), resulting in an absolute risk increase (ARI) to harm of 1.6% and number needed to harm (NNH) of 62.5. On the other hand, three trials reported the adverse effects, with a total population of 272 patients. The incidence of adverse effects was highest in TMX arms (47/121; 38.8%) compared with observation arms (44/151; 29%) with an ARI of 9.8% and a NNH of 10 (Table 2).
Gynecomastia is the most common breast disorder in men. It can result from physiological changes in growth and development or be caused pathologically. Also, it can be induced by drug treatments that affect the balance between estrogens and androgens, such as hormonal treatments for prostate cancer (3). Patients with prostate cancer are increasingly being offered treatment with nonsteroidal antiandrogen monotherapy, which offers potential quality-of-life benefits compared with other treatment. Nonsteroidal antiandrogens directly antagonize androgen action in breast tissue, and indirectly increase the estrogen concentration. Thus, the most troublesome side effects of monotherapy with these
Fig. 2.
Forest graph shows the result of meta-analysis for RT to prevent breast pain.
Volume 83 Number 4 2012
Fig. 3.
Prevention of gynecomastia caused by androgen deprivation e523
Forest graphic shows the result of meta-analysis for TMX to prevent gynecomastia.
drugs are gynecomastia and breast pain. Several interventions have been used as prevention, including surgery, hormone therapy, and radiation (16). To our knowledge no meta-analysis evaluating RT and hormone therapy as prevention options for ADT induced gynecomastia and breast pain have been reported to date. This meta-analysis was specifically designed to explore the value of RT or TMX in gynecomastia and breast pain of patients with prostate cancer using ADT. So, the basic premise of this meta-analysis was that by grouping together data from a number of studies using RT or TMX, we could obtain a large and homogeneous enough sample to reveal a possibly significant difference between RT or TMX and observation in terms of gynecomastia and breast pain in patients with prostate cancer treated by ADT. The planned sample size was 110 patients in each arm to detect an absolute difference in gynecomastia of 20% at 12 months with a power of 90% and a unilateral significance level of 5%. The study was powered to detect a hypothesized decrease in gynecomastia from 62.2% to 32.8% in favor of RT. With a total population of 726 patients (three RCT of RT and three RCTs of TMX), our meta-analysis comparing RT or TMX with observation demonstrated a statistically significant difference in rates of gynecomastia and breast pain for both prevention treatments when compared with observation. Comparing the effectiveness of TMX and RT, TMX resulted in an NNT of 1.56, whereas RT resulted in an NNT of 3.4 to avoid one case of gynecomastia. If we divide the NNT of TMX by the NNT of RT, we can conclude that for each case of gynecomastia avoided with TMX, we need to treat with RT 2 more patients than with TMX. So, although these data show us that TMX is more effective than RT, this difference is so small that it cannot justify the use of TMX for long-term (6e12 months) treatment to avoid gynecomastia. Use of TMX is associated with well-documented side effects that might be additive to those produced by ADT, which would adversely affect treatment safety and tolerability. In our data, the most common adverse effect from TMX was dizziness and hot flushes. However, when we combined all adverse effects
Fig. 4.
considered in that review, we observed that TMX was associated with an increase of all adverse effects compared with placebo or observation, suggesting that ADT plus TMX may have a safety profile but with an increase in the number of patients who experienced no severe adverse events. In all trials that tested TMX as prophylactic treatment for preventing gynecomastia, the rates of serious adverse effects such as cardiovascular or neurologic events did not exceed 2%. Currently, the majority of authors recommended administering TMX 20 mg once daily. This dose was compared with 1, 2.5, 5, 10 mg per day in a randomized clinical trial conducted by Fradet et al. (12). In this study, the authors found that TMX 20 mg per day was more effective in preventing gynecomastia and breast pain than lower TMX doses, and with similar profile of adverse effects (12). When we compared the adverse effects of TMX with the RT adverse effects, we observed that TMX is associated with six times more adverse effects than RT. Moreover, another inconvenient from the use of TMX is that it must be given concurrently and throughout the course of ADT to maintain this prophylactic effect. Although no data are available assessing longer-term end points such as disease progression or longer durations of TMX treatment, no data from RCTs included in that meta-analysis indicate that TMX treatment has a detrimental effect on PSA suppression. The most common adverse effect in the RT group was rash or erythema induced by RT; however, these events were transient and well tolerated in all trials. Furthermore, the majority of trials, to minimize the risk of adverse events and also minimize patient inconvenience, administered a single low-dose of radiation over a small (5-cm- diameter) area using electron beam irradiation (thus reducing exposure of surrounding tissues to the radiation). The total RT doses from RCTs that were included in this meta-analysis range of 10 to 12 Gy. It is possible that these doses may have been insufficient to completely inhibit breast cell proliferation and breast tenderness. Alfthan and Holsti (17) performed a histologic examination of an irradiated breast and its nonirradiated control 1 year after breast irradiation, and reported that 12.5 Gy (applied in three
Forest graphic shows the result of meta-analysis for TMX to prevent breast pain.
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International Journal of Radiation Oncology Biology Physics
fractions) significantly reduced, but did not completely inhibit, diethylstilbestrol-induced gynecomastia. Since gynecomastia has been characterized into two distinct subtypes (Type I, characterized by an increased number of ducts and marked proliferation of ductal epithelia; and Type II, characterized by minimal proliferation but changes to the stroma and structural components of the breast), it is possible that RT prevents only one aspect of these changes, for example, the proliferative change in Type I (9). Thus, more studies using different schedules of fractionation achieving high biological doses and field size with conformal RT and IMRT forward should be performed to reduce the incidence of gynecomastia and breast pain without increasing the risk of adverse events associated with RT. The risk of potential late effects of RT, such as secondary malignancies (e.g., lung/breast cancer), and cardiopulmonary complications is another concern in relation to the use of prophylatic RT. Although that issue is outside the scope of this meta-analysis, no cases of this were reported by two committees of the British Institute of Radiology (the Radiation Physics and Dosimetry Committee and the Oncology Committee) that discussed the risk of complications and secondary malignances after RT for benign diseases (18).
2. Johnson RE, Kermott CA, Murad MH. Gynecomastiadevaluation and current treatment options. Ther Clin Risk Manag 2011;7:145e148. 3. Gikas P, Mokbel R. The current management of gynecomastia: An update. Int J Fertil Womens Med 2006;51:233e240. 4. Chang A, Yeap B, Davis T, et al. Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: Flutamide versus diethylstilbestrol. J Clin Oncol 1996;14:2250e2257. 5. Dobs A, Darkes MJ. Incidence and management of gynecomastia in men treated for prostate cancer. J Urol 2005;174:1737e1742. 6. Schroder FH, Collette L, de Reijke TM, et al. 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;82:283e290. 7. Di Lorenzo G, Autorino R, Perdona S, et al. Management of gynaecomastia in patients with prostate cancer: A systematic review. Lancet Oncol 2005;6:972e979. 8. Fass D, Steinfeld A, Brown J, et al. Radiotherapeutic prophylaxis of estrogen-induced gynecomastia: A study of late sequela. Int J Radiat Oncol Biol Phys 1986;12:407e408. 9. Corvalan JG, Gill WM, Jr., Egleston TA, et al. Irradiation of the male breast to prevent hormone produced gynecomastia. Am J Roentgenol Radium Ther Nucl Med 1969;106:839e840. 10. Van Poppel H, Tyrrell CJ, Haustermans K, et al. Efficacy and tolerability of radiotherapy as treatment for bicalutamide-induced gynaecomastia and breast pain in prostate cancer. Eur Urol 2005;47:587e592. 11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177e188. 12. Fradet Y, Egerdie B, Andersen M, et al. Tamoxifen as prophylaxis for prevention of gynaecomastia and breast pain associated with bicalutamide 150 mg monotherapy in patients with prostate cancer: A randomised, placebo-controlled, dose-response study. Eur Urol 2007; 52:106e114. 13. Tyrrell CJ, Payne H, Tammela TL, et al. Prophylactic breast irradiation with a single dose of electron beam radiotherapy (10 Gy) significantly reduces the incidence of bicalutamide-induced gynecomastia. Int J Radiat Oncol Biol Phys 2004;60:476e483. 14. Ozen H, Akyol F, Toktas G, et al. Is prophylactic breast radiotherapy necessary in all patients with prostate cancer and gynecomastia and/or breast pain? J Urol 2010;184:519e524. 15. Boccardo F, Rubagotti A, Battaglia M, et al. Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer. J Clin Oncol 2005;23:808e815. 16. Gruntmanis U, Braunstein GD. Treatment of gynecomastia. Curr Opin Investig Drugs 2001;2:643e649. 17. Alfthan O, Kettunen K. The effect of roentgen ray treatment of gynecomastia in patients with prostatic carcinoma treated with estrogenic hormones: A preliminary communication. J Urol 1965;94:604e606. 18. Abson C. Radiotherapy for benign diseases. Br J Radiol 2000;73: 121e122.
Conclusion Our data have shown that both TMX and RT are effective in preventing gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. However, despite the fact that prophylactic RT has been shown to significantly reduce side effects induced by ADT, TMX ensures better rates of success (especially in terms of breast pain) despite by higher, albeit generally mild, complications. Nevertheless, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis. In addition, RT should be also considered a good option in patients with a long-term use of ADT and TMX, because a possible and unknown influence on survival. Further trials using TMX with longer follow-up and comparisons with different RT schedules are needed.
References 1. Perdona S, Autorino R, De Placido S, et al. Efficacy of tamoxifen and radiotherapy for prevention and treatment of gynaecomastia and breast pain caused by bicalutamide in prostate cancer: A randomised controlled trial. Lancet Oncol 2005;6:295e300.
Radiation Oncology biology
physics
www.redjournal.org
Clinical Investigation: Genitourinary Cancer
Prevention of Gynecomastia and Breast Pain Caused by Androgen Deprivation Therapy in Prostate Cancer: Tamoxifen or Radiotherapy? Gustavo Arruda Viani, M.D., Lucas Godo´i Bernardes da Silva, M.D., and Eduardo Jose Stefano, M.D. Department of Radiation Oncology, Marilia Medical School, Marı´lia, Sa˜o Paulo, Brazil Received Sep 26, 2011
Summary Antiandrogen monotherapy or adjuvant therapy is used frequently in men with carcinoma of the prostate. Although generally tolerated quite well, gynecomastia and breast pain can occur, being the most common side effects. In this scenario as prophylatic radiotherapy as tamoxifen are effective methods to prevent it. Our data shows that radiotherapy should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors.
Purpose: To determine, in a meta-analysis, whether gynecomastia and breast pain rates in men with prostate cancer treated with androgen deprivation therapy (ADT) are reduced if treated with prophylactic radiotherapy (RT) or tamoxifen (TMX). Methods and Materials: The MEDLINE, EMBASE, CANCERLIT, and Cochrane Library databases, as well as proceedings of annual meetings, were systematically searched to identify randomized, controlled studies comparing RT or TMX with observation for men with prostate cancer using ADT. Results: Six RCTs (three RT trials and three TMX trials, N Z 777 patients total) were identified that met the study criteria. Pooled results from these RCTs comparing RT vs. observation showed a significant reduction in the incidence of gynecomastia and breast pain rates in patients treated with RT (odds ratio [OR] Z 0.21, 95% confidence interval [CI] Z 0.12e0.37, p < 0.0001, and OR Z 0.34, 95% CI 0.20e0.57, p < 0.0001, respectively). Use of RT resulted in an absolute risk reduction (ARR) of 29.4% and 19.9%, with a number needed to treat (NNT) of 3.4 and 5 to avoid one case of gynecomastia and breast pain, respectively. Pooled results from trials comparing TMX vs. observation showed a statistical benefit for breast pain and gynecomastia in favor of TMX arms (OR Z 0.04, 95% CI Z 0.02e0.08, p < 0.0001 and OR Z 0.07, 95% CI Z 0.0e0.14, p < 0.00001). TMX resulted in an ARR Z 64.1% and 47.6%, with an NNT of 1.56 and 2.1 to avoid one case of gynecomastia and breast pain, respectively. Considering adverse effects, TMX was 6 times more adverse effects than RT. Conclusions: Our data have shown that both TMX and RT prevented gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. Although TMX was two times more effective in preventing gynecomastia, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis. Ó 2012 Elsevier Inc. Keywords: Gynecomastia, Prostate cancer, Prophylatic radiotherapy, Prophylatic tamoxifen
Reprint requests to: Gustavo Arruda Viani, M.D., Department of Radiation Oncology, Marilia Medical School, Maria Cecilia Alves, 192
Int J Radiation Oncol Biol Phys, Vol. 83, No. 4, pp. e519ee524, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2012.01.036
Marilia, Sa˜o Paulo, Brazil. Tel: (5514) 3454-2065; Fax: (5514) 34321780; E-mail: [email protected] Conflict of interest: none.
e520 Viani et al.
International Journal of Radiation Oncology Biology Physics
Introduction
Interventions
Gynecomastia is common in men with prostate cancer undergoing androgen deprivation therapy (ADT). The prevalence of gynecomastia is approximately 15% in men treated with gonadotropinreleasing hormone (GnRH) agonists combined with an antiandrogen. The risk of gynecomastia is reduced with total androgen blockade with a GnRH analogue and an antiandrogen (1e3). However, the prevalence is as high as 75% when antiandrogen monotherapy is used (4e6). However, despite of high prevalence, this treatment complication has received considerably less attention than sexual dysfunction, and the full clinical impact of gynecomastia in this patient population has yet to be determined. Given that many patients with prostate cancer receive long-term ADT, an appraisal of the prevention of gynecomastia in this patient group is warranted. Both drug therapy and radiotherapy (RT) have limited benefit once gynecomastia is established in this setting; as a result, prevention of breast development is the goal of therapy. Strategies that have been used for prevention include pharmacologic therapy (antiestrogens or aromatase inhibitors) or RT (7). Evidence from several small studies suggests that prophylactic breast irradiation can reduce the incidence of estrogen-induced gynecomastia in patients with prostate cancer (8, 9). In the last years, a few works have been published on hormonal treatment for the reduction of gynecomastia in patients with prostate cancer. Recent data from randomized clinical trials also support the use of TMX to prevent gynecomastia (1, 10). However, doubt still remains about its influence on PSA inhibition and testosterone levels in these patients. There has been no systematic appraisal of this body of literature to allow practitioners to evaluate the evidence base of these aspects of patients with prostate cancer. Consequently, this meta-analysis was performed to evaluate the effectiveness of prevention of gynecomastia caused by ADT in patients with prostate cancer using TMX or RT.
Prophylatic RT for patients with prostate cancer receiveing ADT could consist of photon or electron therapy or combinations. TMX could consist of any dosage and any time of administration. Thus, RCTs that compared RT vs. observation or RT vs. TMX, or TMX vs. observation for patients with prostate cancer using ADT were considered.
Methods and Materials Search criteria for studies eligible for inclusion in this metaanalysis are described below.
Studies Studies were required to be either complete reports of studies of randomized, controlled trials (RCTs) and/or overviews of RCTs of RT and/or TMX to prevent gynecomastia in patients with prostate cancer receiving ADT published in peer-reviewed journals. Randomized, controlled trials reported in other sources (e.g., abstracts in proceedings of relevant scientific meetings) for which full details were available from the investigators were also eligible.
Study population The men in the studies had to have histologically confirmed localized prostate cancer and to have undergone ADT (monotherapy or total androgen blockade with a GnRH analogue and/ or an antiandrogen) with or without pelvic RT and radical prostatectomy.
Outcome measures The primary end point was the incidence of gynecomastia and/or breast pain, as assessed by physical examination and direct questioning by the investigator. When possible, data on gynecomastia measured by calipers in the sagittal and coronal planes were collected. Complications were also considered a primary end point. For TMX arms, complications such as hot flushes, dizziness, constipation, asthenia, and cardiologic or neurologyc effects were collected. For RT arms, the following complications were considered: skin reaction, erythema, and pruritus. The secondary objectives were PSA inhibiton and testosterone levels in TMX arms.
Strategy for study identification The MEDLINE (Ovid) (1996eDecember 2010), CANCERLIT (Ovid) (1996eDecember 2010), and Cochrane Library (Issue 2, 2010) databases were searched using the terms “(prostate OR prostatic) AND (cancer OR carcinoma OR tumor OR tumor) AND (conformal OR CDRT) AND (radiation OR radiotherapy) AND (dose escalation) AND (mortality OR survival OR biochemical failure OR relapse OR failure OR recurrence OR outcome).” These terms were then combined with the search terms for the following study designs: practice guidelines, systematic reviews or meta-analyses, reviews, randomized controlled trials, and controlled clinical trials. In addition, the Physician Data Query clinical trial database on the Internet (http://cnetdb.nci.nih.gov/ search/clinical_trials/) and the proceedings of the 1997e2010 annual meetings of the American Society of Clinical Oncology were searched for reports on new or ongoing trials. Relevant articles and abstracts were selected and reviewed by two methodologists, and the reference lists published with these sources were searched to identify any additional trials. All RCTs identified by this search were then assessed by two independent reviewers (G.A.V. and E.J.S.) to determine whether they met the inclusion criteria. Any discrepancies in the results of the assessments were resolved by a third reviewer (B. L.G.).
Review analysis All analyses were carried out on an intention-to-treat basis; that is, all patients randomly assigned to a treatment group were included in the analyses according to the assigned treatment, irrespective of whether they received the treatment or were excluded from the analysis by the study investigators. For categoric variables, weighted risk ratios and their 95% confidence intervals (95% CIs) were calculated using comprehensive meta-analysis software according to the Peto method. Results were tested for heterogeneity at a significance level of p < 0.05, according to the methods outlined by Der Simonian and Laird (11). A fixed-effects model
Volume 83 Number 4 2012 Table 1
Prevention of gynecomastia caused by androgen deprivation e521
Characteristic of trials evaluating radiotherapy (RT) and tamoxifen (TMX) for gynecomastia and breast pain
First author (reference)
Patients (N)
Intervention
Ozen (14)
125
RT vs. no RT
Fradet (12) Perdona` (1)
282 150
TMX (different dosing schedules) TMX vs. RT vs. Placebo
Boccardo (15) Tyrrell (13)
114 106
TMX vs. anastrozole vs. placebo RT vs. sham RT
was used if there was no evidence of heterogeneity between studies; if there was evidence of heterogeneity, a random-effects model was used for the metaanalysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each trial and presented in a forest plot. To compare effectiveness of interventions, we calculated the number needed to treat (NNT) and number needed to harm (NNH). The NNT was calculated from the simple formula: 1/ARR 100, where ARR Z control event rate (CER) experimental event rate (EER). Also, the NNH was calculated from the simple formula: 1/ARR 100, where ARI Z experimental event rate (EER) control event rate (CER).
Dose RT 10 Gy/1 fraction Electron beam RT TMX 20 mg/day for 12 mo TMX 10 mg for 6 mo RT 12 Gy/1 fraction Electron beam RT TMX 20 mg/day for 12 mo RT 12 Gy/1 fraction Electron beam RT
gynecomastia rates were less in the RT arm (46 of 140, 32.8%) than in the observation arm (99 of 159, 62.2%). The pooled OR for all of the trials was 0.21(95% CI 0.12e0.37, p < 0.00001). The result of the test for heterogeneity was not statistically significant (p Z 0.89). The overall OR suggests that there was a statistically significant difference between the RT and observation arms in terms of the gynecomastia rate (p < 0.00001; Fig. 1). The ARR for gynecomastia in 12 months comparing RT with observation was 29.4%, resulting in an NNT of 3.4 (Table 2).
RT vs. observation: Breast pain
Results The electronic and manual searches revealed 141 citations. After further screening, five full-text articles were retrieved for further assessment (1, 12e15). Study characteristics are shown in Table 1. The studies had a randomized design with 156 patients submitted to RT and 121 patients submitted to TMX treatment and 274 treated with observation or placebo. There was one randomized study (114 patients) that assessed the efficacy and safety comparing ADT plus placebo, ADT plus TMX and ADT plus anastrozole. One study (150 patients) tested the efficacy of ADT plus RT vs. ADT plus placebo and ADT plus TMX, 3 studies (314 patients) assessed the efficacy and safety of ADT plus RT vs. ADT plus observation. The parameters evaluated in these studies were gynecomastia, breast pain, PSA inhibition and testosterone levels. Adverse effects such as: asthenia, constipation, hot flushes, rash/erythema, cardiovascular events, dizziness and pruritus were evaluated.
RT vs. observation: Gynecomastia Three studies, with a total population of 299 patients, analyzed gynecomastia as one of the outcomes. The incidence of
Fig. 1.
Three studies, with a total patient population of 299 patients, examined breast pain as one of outcomes. The breast pain rates were 49.2 in the RT arm and 69.1% in the observation arm. The overall OR was 0.34 (95% CI Z 0.20e0.57), as shown in Fig. 2. The ARR for gynecomastia in 12 months comparing RT with observation was 19.9%, resulting in NNT Z 5, as described in Table 2. The result of the test for heterogeneity was not statistically significant (p Z 0.78), which allowed the results to be pooled (Fig. 2).
TMX vs. observation: Gynecomastia Three studies, with a total population of 272 patients, analyzed gynecomastia as one of the outcomes. The incidence of gynecomastia rates were less in the TMX arm (13/121, 10.7%) than in the observation arm (113/159, 74.8%). The pooled OR for all of the trials was 0.04 (95% CI Z 0.02e0.08). The result of the test for heterogeneity was not statistically significant (p Z 0.98). The overall OR suggests that there was a statistically significant difference between the TMX and observation arms in terms of the gynecomastia rate (p < 0.00001) (Fig. 3). The ARR for
Forest graph shows the result of meta-analysis for RT to prevent gynecomastia.
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e522 Viani et al. Table 2
Incidence of gynecomastia, breast pain, and complications comparing radiotherapy (RT) and tamoxifen (TMX)
Comparation
Prophylatic
Observation
EER (%)
CER (%)
ARR (%)
NNT
46/140 13/121
99/159 113/151
32.8 10.7
62.2 74.8
29.4 64.1
3.4 1.56
Incidence of all degrees of breast pain RT vs. observation 69/140 TMX vs. observation 9/121
110/159 83/151
49.2 7.4
69.1 55
19.9 47.6
5 2.1
Incidence of gynecomastia RT vs. observation TMX vs. observation
Comparation Incidence of complications* RT vs. observation TMX vs. observation
Prophylatic
Observation
EER (%)
CER (%)
ARI (%)
NNH
45/155 47/121
48/175 44/151
29 38.8
27.4 29
1.6 9.8
62.5 10
Abbreviations: ARR Z absolute risk reduction; ARI Z absolute risk increase; CER Z control event rate; EER Z experimental event rate; NNH Z number need to harm; NNT Z number needed to treat. * RT complications include skin reaction, erythema, pruritus, and hyperpigmentation. TMX complications include hot flushes, dizziness, constipation, asthenia, and cardiologic or neurologic effects.
gynecomastia in 12 months comparing TMX with observation was 64.1%, resulting in an NNT of 1.56 (Table 2).
TMX vs. observation: Breast pain Three studies, with a total patient population of 272 patients, examined breast pain as one of outcomes. The breast pain rates were 7.4% in the TMX arms and 55% in the observation arms. The overall OR was 0.07 (95% CI Z 0.03e0.14) (Fig. 3). The ARR for gynecomastia in 12 months comparing TMX with observation was 47.6%, resulting in an NNT of 2.1 (Table 2). The result of the test for heterogeneity was not statistically significant (p Z 0.82), which allowed the results to be pooled (Fig. 4).
PSA inhibition Three RCTs evaluated the PSA inhibition as one outcome. In all trials, the median PSA levels declined 30% to 80% from baseline values at 12 months in the ADT plus TMX arms. None of trials showed an increased in PSA level compared with placebo arms.
Testosterone levels Three RCTs evaluated the testosterone levels as one outcome. In two trials, free testosterone levels after 6 months remains unchanged compared with baseline values. One trial showed an increased in free testosterone level compared with the placebo arm.
Adverse effects
Discussion
Adverse effects were reported in all three RCTs, with a total population of 330 patients. The incidence of adverse effects (erythema, pruritus or hyperpigmentation) were highest in the RT arms (45/155; 29%) compared with observation arms (48/175; 27.4%), resulting in an absolute risk increase (ARI) to harm of 1.6% and number needed to harm (NNH) of 62.5. On the other hand, three trials reported the adverse effects, with a total population of 272 patients. The incidence of adverse effects was highest in TMX arms (47/121; 38.8%) compared with observation arms (44/151; 29%) with an ARI of 9.8% and a NNH of 10 (Table 2).
Gynecomastia is the most common breast disorder in men. It can result from physiological changes in growth and development or be caused pathologically. Also, it can be induced by drug treatments that affect the balance between estrogens and androgens, such as hormonal treatments for prostate cancer (3). Patients with prostate cancer are increasingly being offered treatment with nonsteroidal antiandrogen monotherapy, which offers potential quality-of-life benefits compared with other treatment. Nonsteroidal antiandrogens directly antagonize androgen action in breast tissue, and indirectly increase the estrogen concentration. Thus, the most troublesome side effects of monotherapy with these
Fig. 2.
Forest graph shows the result of meta-analysis for RT to prevent breast pain.
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Fig. 3.
Prevention of gynecomastia caused by androgen deprivation e523
Forest graphic shows the result of meta-analysis for TMX to prevent gynecomastia.
drugs are gynecomastia and breast pain. Several interventions have been used as prevention, including surgery, hormone therapy, and radiation (16). To our knowledge no meta-analysis evaluating RT and hormone therapy as prevention options for ADT induced gynecomastia and breast pain have been reported to date. This meta-analysis was specifically designed to explore the value of RT or TMX in gynecomastia and breast pain of patients with prostate cancer using ADT. So, the basic premise of this meta-analysis was that by grouping together data from a number of studies using RT or TMX, we could obtain a large and homogeneous enough sample to reveal a possibly significant difference between RT or TMX and observation in terms of gynecomastia and breast pain in patients with prostate cancer treated by ADT. The planned sample size was 110 patients in each arm to detect an absolute difference in gynecomastia of 20% at 12 months with a power of 90% and a unilateral significance level of 5%. The study was powered to detect a hypothesized decrease in gynecomastia from 62.2% to 32.8% in favor of RT. With a total population of 726 patients (three RCT of RT and three RCTs of TMX), our meta-analysis comparing RT or TMX with observation demonstrated a statistically significant difference in rates of gynecomastia and breast pain for both prevention treatments when compared with observation. Comparing the effectiveness of TMX and RT, TMX resulted in an NNT of 1.56, whereas RT resulted in an NNT of 3.4 to avoid one case of gynecomastia. If we divide the NNT of TMX by the NNT of RT, we can conclude that for each case of gynecomastia avoided with TMX, we need to treat with RT 2 more patients than with TMX. So, although these data show us that TMX is more effective than RT, this difference is so small that it cannot justify the use of TMX for long-term (6e12 months) treatment to avoid gynecomastia. Use of TMX is associated with well-documented side effects that might be additive to those produced by ADT, which would adversely affect treatment safety and tolerability. In our data, the most common adverse effect from TMX was dizziness and hot flushes. However, when we combined all adverse effects
Fig. 4.
considered in that review, we observed that TMX was associated with an increase of all adverse effects compared with placebo or observation, suggesting that ADT plus TMX may have a safety profile but with an increase in the number of patients who experienced no severe adverse events. In all trials that tested TMX as prophylactic treatment for preventing gynecomastia, the rates of serious adverse effects such as cardiovascular or neurologic events did not exceed 2%. Currently, the majority of authors recommended administering TMX 20 mg once daily. This dose was compared with 1, 2.5, 5, 10 mg per day in a randomized clinical trial conducted by Fradet et al. (12). In this study, the authors found that TMX 20 mg per day was more effective in preventing gynecomastia and breast pain than lower TMX doses, and with similar profile of adverse effects (12). When we compared the adverse effects of TMX with the RT adverse effects, we observed that TMX is associated with six times more adverse effects than RT. Moreover, another inconvenient from the use of TMX is that it must be given concurrently and throughout the course of ADT to maintain this prophylactic effect. Although no data are available assessing longer-term end points such as disease progression or longer durations of TMX treatment, no data from RCTs included in that meta-analysis indicate that TMX treatment has a detrimental effect on PSA suppression. The most common adverse effect in the RT group was rash or erythema induced by RT; however, these events were transient and well tolerated in all trials. Furthermore, the majority of trials, to minimize the risk of adverse events and also minimize patient inconvenience, administered a single low-dose of radiation over a small (5-cm- diameter) area using electron beam irradiation (thus reducing exposure of surrounding tissues to the radiation). The total RT doses from RCTs that were included in this meta-analysis range of 10 to 12 Gy. It is possible that these doses may have been insufficient to completely inhibit breast cell proliferation and breast tenderness. Alfthan and Holsti (17) performed a histologic examination of an irradiated breast and its nonirradiated control 1 year after breast irradiation, and reported that 12.5 Gy (applied in three
Forest graphic shows the result of meta-analysis for TMX to prevent breast pain.
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fractions) significantly reduced, but did not completely inhibit, diethylstilbestrol-induced gynecomastia. Since gynecomastia has been characterized into two distinct subtypes (Type I, characterized by an increased number of ducts and marked proliferation of ductal epithelia; and Type II, characterized by minimal proliferation but changes to the stroma and structural components of the breast), it is possible that RT prevents only one aspect of these changes, for example, the proliferative change in Type I (9). Thus, more studies using different schedules of fractionation achieving high biological doses and field size with conformal RT and IMRT forward should be performed to reduce the incidence of gynecomastia and breast pain without increasing the risk of adverse events associated with RT. The risk of potential late effects of RT, such as secondary malignancies (e.g., lung/breast cancer), and cardiopulmonary complications is another concern in relation to the use of prophylatic RT. Although that issue is outside the scope of this meta-analysis, no cases of this were reported by two committees of the British Institute of Radiology (the Radiation Physics and Dosimetry Committee and the Oncology Committee) that discussed the risk of complications and secondary malignances after RT for benign diseases (18).
2. Johnson RE, Kermott CA, Murad MH. Gynecomastiadevaluation and current treatment options. Ther Clin Risk Manag 2011;7:145e148. 3. Gikas P, Mokbel R. The current management of gynecomastia: An update. Int J Fertil Womens Med 2006;51:233e240. 4. Chang A, Yeap B, Davis T, et al. Double-blind, randomized study of primary hormonal treatment of stage D2 prostate carcinoma: Flutamide versus diethylstilbestrol. J Clin Oncol 1996;14:2250e2257. 5. Dobs A, Darkes MJ. Incidence and management of gynecomastia in men treated for prostate cancer. J Urol 2005;174:1737e1742. 6. Schroder FH, Collette L, de Reijke TM, et al. 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;82:283e290. 7. Di Lorenzo G, Autorino R, Perdona S, et al. Management of gynaecomastia in patients with prostate cancer: A systematic review. Lancet Oncol 2005;6:972e979. 8. Fass D, Steinfeld A, Brown J, et al. Radiotherapeutic prophylaxis of estrogen-induced gynecomastia: A study of late sequela. Int J Radiat Oncol Biol Phys 1986;12:407e408. 9. Corvalan JG, Gill WM, Jr., Egleston TA, et al. Irradiation of the male breast to prevent hormone produced gynecomastia. Am J Roentgenol Radium Ther Nucl Med 1969;106:839e840. 10. Van Poppel H, Tyrrell CJ, Haustermans K, et al. Efficacy and tolerability of radiotherapy as treatment for bicalutamide-induced gynaecomastia and breast pain in prostate cancer. Eur Urol 2005;47:587e592. 11. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177e188. 12. Fradet Y, Egerdie B, Andersen M, et al. Tamoxifen as prophylaxis for prevention of gynaecomastia and breast pain associated with bicalutamide 150 mg monotherapy in patients with prostate cancer: A randomised, placebo-controlled, dose-response study. Eur Urol 2007; 52:106e114. 13. Tyrrell CJ, Payne H, Tammela TL, et al. Prophylactic breast irradiation with a single dose of electron beam radiotherapy (10 Gy) significantly reduces the incidence of bicalutamide-induced gynecomastia. Int J Radiat Oncol Biol Phys 2004;60:476e483. 14. Ozen H, Akyol F, Toktas G, et al. Is prophylactic breast radiotherapy necessary in all patients with prostate cancer and gynecomastia and/or breast pain? J Urol 2010;184:519e524. 15. Boccardo F, Rubagotti A, Battaglia M, et al. Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer. J Clin Oncol 2005;23:808e815. 16. Gruntmanis U, Braunstein GD. Treatment of gynecomastia. Curr Opin Investig Drugs 2001;2:643e649. 17. Alfthan O, Kettunen K. The effect of roentgen ray treatment of gynecomastia in patients with prostatic carcinoma treated with estrogenic hormones: A preliminary communication. J Urol 1965;94:604e606. 18. Abson C. Radiotherapy for benign diseases. Br J Radiol 2000;73: 121e122.
Conclusion Our data have shown that both TMX and RT are effective in preventing gynecomastia and breast pain in patients with prostate cancer receiving ADT for prostate cancer. However, despite the fact that prophylactic RT has been shown to significantly reduce side effects induced by ADT, TMX ensures better rates of success (especially in terms of breast pain) despite by higher, albeit generally mild, complications. Nevertheless, RT should represent an effective and safe treatment option, to take into account mainly in patients with cardiovascular risk factors or thrombotic diathesis. In addition, RT should be also considered a good option in patients with a long-term use of ADT and TMX, because a possible and unknown influence on survival. Further trials using TMX with longer follow-up and comparisons with different RT schedules are needed.
References 1. Perdona S, Autorino R, De Placido S, et al. Efficacy of tamoxifen and radiotherapy for prevention and treatment of gynaecomastia and breast pain caused by bicalutamide in prostate cancer: A randomised controlled trial. Lancet Oncol 2005;6:295e300.