Multimodality Treatment of Gynecomastia in Patients

Review Received: March 5, 2012 Accepted after revision: September 17, 2012 Published online: November 2, 2012

Oncology 2013;84:92–99 DOI: 10.1159/000343821

Multimodality Treatment of Gynecomastia in Patients Receiving Antiandrogen Therapy for Prostate Cancer in the Era of Abiraterone Acetate and New Antiandrogen Molecules Daniele Alesini Roberto Iacovelli Antonella Palazzo Amelia Altavilla Emanuela Risi Federica Urbano Chiara Manai Antonio Passaro Valentina Magri Enrico Cortesi Department of Radiological, Oncological and Anatomopathological Sciences, Sapienza University of Rome, Rome, Italy

Key Words Gynecomastia ⴢ Androgen deprivation ⴢ Prostate cancer ⴢ Abiraterone acetate ⴢ MDV3100

Abstract Gynecomastia is a pathological enlargement of male breasts due to hormonal imbalance and elevation of estrogens at the expense of testosterone. It is very important to diagnose this disease precociously because it can be the expression of different underlying pathologies. Besides genetic, chromosomal or chronic diseases, drugs often represent the principal cause of this hormonal disequilibrium. In the elderly population, antiandrogen therapy for prostate cancer frequently induces gynecomastia, thus negatively affecting the patients’ compliance to treatment because of physical and psychological discomfort deriving from this condition; gynecomastia can in fact be associated with severe breast pain, and it can modify how patients see their own body. During the past decades and even today, many different surgical, radiotherapeutic or clinical approaches have been proposed to prevent or treat this hypertrophy. This article focuses on gynecomastia associated with antiandrogen-based hormonal treatment and shortly reviews the currently most often used therapeutic options for preventing and treating this pathology. Copyright © 2012 S. Karger AG, Basel

© 2012 S. Karger AG, Basel 0030–2414/13/0842–0092$38.00/0 Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ocl

Introduction

Gynecomastia is a pathological volumetric increase of the mammary glands which can occur solely or is associated with an unpleasant sensation of tension, cutaneous hypersensitivity or, more frequently, pain; it can be limited to a small portion of the gland or involve the entire gland. From a histological point of view, this hypertrophy derives from an abnormal and initially reversible proliferation of glandular ducts which, if untreated, can evolve into progressive and irreversible tissue hyalinization and then, within a year, to fibrosis [1]. Although diagnosis of gynecomastia requires a biopsy-based histological confirmation, it is usually made based on clinical parameters such as an increase of the volume and/or the consistency of the mammary gland associated with other symptoms. Its staging is also based on simple measurement of the tumefaction or on specific calipers; although the use of the Marshall and Tanner staging scale for breast changes during puberty has been suggested, it is still not widely accepted [2]. It is very important to diagnose and treat this pathology precociously since it can both derive from a druginduced hormonal alteration and be an indication of different pathologies, which sometimes need a surgical approach. Dr. Daniele Alesini Department of Radiological, Oncological and Anatomopathological Sciences Sapienza University of Rome Viale Regina Elena 324, IT–00161 Rome (Italy) E-Mail danielealesini @ yahoo.it

Hypothalamus CRH GnRH

Testosterone LH

LHRH analogues Estrogen

ACTH Pituitary gland

Steroids

Testes

Adrenal glands

Testosterone

Androstenedione

Peripheral aromatases

Aromatase inhibitors

Estradiol

Peripheral aromatases

Estron

Antiestrogens

Gynecomastia

Exogenous estrogens

Fig. 1. Physiopathology of gynecomastia.

Besides the possible physical consequences of the alterations which initiated it, gynecomastia must not be underestimated as it often compromises the patients’ quality of life and their compliance to the causing treatment [3–5].

Pathogenesis

Gynecomastia derives from an alteration of the normal ratio of estrogens and testosterone, with a pathological imbalance on behalf of the former ones (fig. 1); this increases the peripheral conversion of circulating androstenedione (most of all by the aromatases of the adipose tissue) to estrone, which is in turn transformed into estradiol, the hormone responsible for glandular hypertrophy. The imbalance between estrogens and testosterone also provokes a reduction in the normal inhibiting feedback carried out by the latter on the hypothalamus and mammary glands. In fact, this hormone physiologically induces a blockade of hypothalamic Multimodality Treatment of Gynecomastia in Prostate Cancer Patients

LHRH release and a reduction in glandular duct proliferation. Therefore, the reduction in testosterone-circulating levels overloads the alterations due to the associated hyperestrogenism [3, 6]. Hormonal imbalance provoking gynecomastia can derive from different causes such as older age, chronic liver diseases, alcoholism, tumors, chromosomal alterations, orchiectomy and, of course, various classes of drugs such as diuretics, antipsychotics, steroids and antiandrogens [3]. Nevertheless, although gynecomastia has a similar physiopathology in all these cases, it is possible to define the different causes as endogenous or exogenous. In the first class, we can group those forms deriving from serious and pathological obesity, chromosomal abnormalities (Klinefelter’s syndrome), genetic disorders (defects in 3␤-hydroxysteroid dehydrogenase, 17-ketosteroid reductase or other testicular enzymes) or endocrine activity of tumors. For example, choriocarcinomas, Leydig cell tumors, Sertoli cell tumors, prolactinomas and adrenal tumors have been often associated with the onset of some form of gynecomastia deriving from the Oncology 2013;84:92–99

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abnormal production of estrogen, LH, FSH and ␤-hCG or the activity of tumoral aromatase which interferes with the delicate hormonal balance [7]. In some cases, gynecomastia is the result of hormonal disorders caused by exogenous factors such as chronic alcoholism, where the levels of circulating testosterone and the clearance of estrogens are altered, or different classes of drugs [5, 8]. It is also worth remembering those cases of gynecomastia deriving from unusual causes such as the use of highly estrogen-containing creams or those cases resulting from the consumption of meat from animals fed with estrogen by-products [7, 9].

Incidence

The incidence of gynecomastia is quite variable within different studies and ranges from 13 to 80% [1, 10–13]; this wide range is influenced first by the type of hormonal treatment, with clearly lower incidence rates among patients treated with bicalutamide alone than among those receiving a complete androgenic blockade [12]. Besides this important difference, we must also underline that gynecomastia is a pathological condition difficult to diagnose: first of all, because a pre-treatment evaluation of patients’ breasts is rarely done; secondly because a reliable assessment method has not yet been established, and finally because often a prior investigation of the possible concomitant causes of gynecomastia is not carried out [3]. As a consequence, it is difficult to realistically determine the incidence of this side effect as well as the extent to which it is caused by the antiandrogen therapy.

Therapy

Gynecomastia can be treated using various approaches: surgery, radiotherapy and medical treatment were all used, generating different results in terms of efficacy and tolerability. Here, we discuss these three therapeutic options in the order of their introduction in clinical practice. Surgery The surgical approach has probably been the first to be used for the prophylactic as well as therapeutic treatment of gynecomastia. In 1946, Webster [14] described the use of an intra-areolar incision to perform prophylactic radical mastectomy in patients about to begin estrogen-based hormonal treatment for prostate cancer. Out of 78 pa94

Oncology 2013;84:92–99

tients, 84% did not develop gynecomastia. Similar results were found in subsequent experiments [15], where the surgical techniques were modified in order to prevent injury to the nipples. Despite progressive improvement, surgery is still associated with possible postoperative complications (hematomas, seromas), and often the final result is esthetically unsatisfactory because of the presence of asymmetry, scars or excessive residual skin [3]. In order to overcome the limits of a ‘classic’ approach, it has been tried to render surgical techniques less invasive; in addition to the ‘classic’ mastectomy, nowadays alternative techniques are available such as liposuction combined with subcutaneous mastectomy [16] and minimally invasive excision [17]. The former procedure is characterized by lower invasiveness and esthetically much appreciated results, but it does not completely eliminate the possible complications (such as altered peri-areolar sensation or keloid formation) of an open procedure, and it may also be slightly effective when fat excess has been definitely substituted by fibrosis. The second procedure offers shorter incision and excellent esthetic results confirmed by patient evaluation. Unfortunately, no clinical studies exist that definitively established which technique among the variety of possible surgical approaches is the most efficient one. Radiotherapy Since the early 60s, radiotherapy has been evaluated as a possible prophylactic as well as therapeutic approach by different authors such as Alfthan and Kettunen [18], Gangai et al. [19] and Chou et al. [20]. More recently (tables 1, 3), in a large Scandinavian trial [10], 540 patients with localized or locally advanced prostatic carcinoma were treated for 3 months with a total androgenic blockade (leprolin + flutamide) and then with an antiandrogen only up to progression. All patients could choose whether to undergo a prophylactic radiation treatment in the breast area before starting the hormonal treatment. Of 253 evaluable patients, 174 underwent the radiation treatment and 79 refused. Clinical evaluation after 3, 6 and 12 months showed a clear and progressive increase of the incidence of gynecomastia among the untreated patients. Already after 6 months, 48% of the untreated patients showed some kind of augmentation of their breast volume compared to 25% of the treated patients, and this discrepancy further increased after 12 months (71 vs. 28%, p ! 0.001). Regarding the increased breast tenderness, it is not surprising that, initially, the incidence was higher among the treated patients; however, after 12 months this percentage became lower than that of the Alesini/Iacovelli/Palazzo/Altavilla/Risi/ Urbano/Manai/Passaro/Magri/Cortesi

Table 1. Studies evaluating radiotherapy as prophylactic or therapeutic approach Study [Ref]

Treatment for prostate cancer

Treatment for gynecomastia

Patients

Setting

Incidence of gynecomastia, %

Incidence of breast pain, %

6 months

12 months

6 months

12 months

Widmark et al. [10] 1999–2000

Leprolin 11.25 mg/3 months + flutamide 250 mg daily ] flutamide 250 mg daily

RT vs. no RT

253

Prophylactic

25 vs. 48 (p < 0.001)

28 vs. 71 (p < 0.001)

52 vs. 39 (p = 0.301)

43 vs. 75 (p < 0.001)

Van Poppel et al. [11] 2000–2002

Bicalutamide 150 mg daily

RT

51

Therapeutic

33.3

NA

39.5

NA

Tyrrell et al. [21] 1999–2001


RT vs. no RT

106

Prophylactic

40 vs. 87 (p < 0.001)

52 vs. 85 (p < 0.001)

NA

83 vs. 91 (p = 0.221)

Ozen et al. [22] 2003–2005


RT vs. no RT

133

Prophylactic

19.6 vs. 40.3 (p = 0.02)

15.8 vs. 50.8 (p < 0.001)

52.2 vs. 40.3 (p = 0.146)

36.4 vs. 49.2 (p = 0.134)

untreated patients (75 vs. 43%, p ! 0.001). The radiation treatment was generally very well tolerated. One of the methodological limits of this study is that the different Centers used various sources of energy (electrons vs. roentgen), doses (from 12 to 15 Gy) and schedules (single dose vs. three fractions). In a 2004 study, Tyrrell et al. [21] randomized 106 patients with prostate cancer to receive bicalutamide 150 mg daily with or without preventive irradiation of the breasts with a single radiation dose of 10 Gy. The final results showed that radiotherapy was effective in reducing the occurrence of gynecomastia (85% of the untreated patients vs. 52% of the treated patients, p ! 0.001). It was also observed that radiotherapy postponed the onset of gynecomastia and significantly reduced its severity. The difference in breast pain was not statistically significant between the groups (91 vs. 83%, p = 0.221). The collateral effects associated with the radiotherapeutic treatment in this study were also minimal (erythema, dry skin). Similar results were found by Ozen et al. [22]. In their study, patients were randomized to receive bicalutamide 150 mg daily alone or combined with a radiotherapy dose of 12 Gy in two fractions of 6 Gy in each breast. After a 12-month follow-up, 50.8% of the unirradiated patients showed gynecomastia compared to 15.8% of the treated patients (p ! 0.001). Unfortunately, the difference of the incidence of breast pain between the two groups did also not reach statistical significance in this study (49.2 vs. 36.4%). These three studies demonstrate the efficacy and tolerability of radiotherapy in preventing antiandrogen-re-

lated gynecomastia, although treatment doses and schedules still need to be standardized. Regarding the therapeutic role of radiotherapy, in a 2004 study by Van Poppel et al. [11], patients were treated with bicalutamide 150 mg daily, and those developing gynecomastia (80.4%) and/or breast pain (72.5%) were irradiated on the breast area (two 6-Gy doses of externalbeam radiation). In total, 33.3% of the patients with gynecomastia and 39.5% of those with breast pain obtained improvement or complete resolution of their symptoms, whereas stability of their condition was reached in 25.9 and 31.6%, respectively. The limits of this study are the absence of a control group, the low and maybe inadequate radiation dose [23] and the small number of patients. Although these data must be confirmed, the question remains whether it is worth to postpone the treatment and to dispense it only to patients developing breast enlargement or breast pain. The high incidence of these side effects, the satisfactory results reached with prophylactic breast irradiation and the low response rate to therapeutic radiotherapy might suggest a preventive attitude.

Multimodality Treatment of Gynecomastia in Prostate Cancer Patients

Oncology 2013;84:92–99

Medical Treatment Medical treatment for gynecomastia is based on different drugs with antiestrogenic activity; as for radiotherapy, their possible prophylactic and therapeutic role has already been evaluated (tables 2, 3). In a study by Boccardo et al. [6], 114 patients with nonmetastatic prostate cancer were randomized to receive bicalutamide (150 mg daily) combined with placebo or tamoxifen (20 mg daily) or anastrozole (1 mg daily); treatment was continued for 48 weeks or up to progression or 95

Table 2. Studies evaluating medical treatments as prophylactic or therapeutic approach Study [Ref]



Patients

Setting



6 months

12 months

6 months

12 months

Boccardo et al. [6] 2000–2002


Tamoxifen vs. placebo/ anastrozole vs. placebo

114

Prophylactic

NA

10 vs. 73 (p < 0.001)/ 51 vs. 73 (p = 0.06)

NA

6 vs. 39 (p < 0.001)/ 27 vs. 39 (p = n.s.)

Fradet et al. [13] 2002–2003


Tamoxifen vs. placebo

282

Prophylactic

5.9 vs. 71.7 (p ≤ 0.002)

14.7 vs. 81.7 (p ≤ 0.002)

2.9 vs. 95 (p ≤ 0.0002)

11.8 vs. 96.7 (p ≤ 0.002)

Saltzstein et al. [24] 2005


Tamoxifen vs. placebo/ anastrozole vs. placebo

107

Prophylactic

11.8 vs. 69.4 (p < 0.0001)/ 63.9 vs. 69.4 (p = 0.749)

NA

11.8 vs. 69.4 (p < 0.0001)/ 63.9 vs. 69.4 (p = 0.749)

NA

Bedognetti et al. [25] 2003–2006


Daily tamoxifen vs. weekly tamoxifen

81

Prophylactic

NA

31.7 vs. 74.4 (p ≤ 0.0001)

NA

12.2 vs. 46.1 (p ≤ 0.001)

Serretta et al. [26] 2005–2007


Tamoxifen 20 mg vs. tamoxifen 10 mg

176

Prophylactic and therapeutic

NA

61.4 vs. 31.3 (p < 0.0001)

NA

57.8 vs. 35 (p < 0.00)

Table 3. Studies evaluating radiotherapeutic and medical treatments as prophylactic or therapeutic approach Study [Ref]



Patients

Perdonà et al. [27] 2002–2004


Tamoxifen vs. control/ radiotherapy vs. control

151

Di Lorenzo et al. [28] 2002–2004


Tamoxifen vs. control/ radiotherapy vs. control

102

Setting



6 months

9 months

6 months

9 months


8 vs. 69 (p < 0.0009)/ 34 vs. 69 (p < 0.008)

11.7 (tamoxifen) vs. 55.5 (radiotherapy) (p < 0.02)

6 vs. 57 (p < 0.009)/ 30 vs. 57 (p < 0.02)

9 (tamoxifen) vs. 80 (radiotherapy) (p < 0.045)


8 vs. 67 (p < 0.001)/ 34 vs. 67 (p < 0.01)


7 vs. 58 (p < 0.001)/ 30 vs. 58 (p < 0.25)


toxicity. After a 12-month follow-up, the incidence of gynecomastia was 73% in the bicalutamide group, 10% in the bicalutamide-tamoxifen group (p ! 0.001) and 51% in the bicalutamide-anastrozole group (p = 0.06); breast pain was reported in 39%, 6% (p = 0.001) and 27% (p = n.s.), respectively. Considering the possible side effects on sexual functioning, patients were given a questionnaire about their sexual activity: after 6 months, no difference was highlighted between the three groups, although a minimal reduction of sexual interest was found in the tamoxifen group (p = 0.005). Patients well tolerated the therapy, and side effects were marginal.

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In a similar study, Saltzstein et al. [24] randomized 106 patients to receive bicalutamide 150 mg daily combined with tamoxifen 20 mg daily or anastrozole 1 mg daily or placebo for 3 months; only treatment with bicalutamide was continued for 9 months. After the induction period, the incidence of gynecomastia and/or breast pain was 69.4% in the placebo group, 11.8% in the tamoxifen group (p ! 0.0001) and 63.9% in the anastrozole group (p = 0.749); there was also a significant prolongation of the gynecomastia-free interval in the tamoxifen group (170 vs. 73 days, p ! 0.001). Patients experiencing gynecomastia despite prophylactic treatment were then assigned to receive tamoxifen (those in the placebo or tamoxifen group) Alesini/Iacovelli/Palazzo/Altavilla/Risi/ Urbano/Manai/Passaro/Magri/Cortesi

or anastrozole (those in the anastrozole group); 6 months after randomization, complete resolution of gynecomastia was experienced by 71.8% (former placebo group), 65.4% (tamoxifen group) and 18.8% (anastrozole group) of the patients. Data at 9 and 12 months were not reported because of confounding effects of some patients’ re-treatment. These results confirm the unsatisfactory effect of anastrozole on bicalutamide-induced gynecomastia; on the contrary, tamoxifen shows more beneficial effects. The preventive activity of this antiestrogen and the most adequate dose have been evaluated in a study where 278 patients were randomized to receive bicalutamide (150 mg daily) combined with placebo or increasing doses of tamoxifen (1, 2.5, 5, 10 or 20 mg daily) [13]. The combination treatment was administered for 12 months, whereas bicalutamide was continued for another year. After the first 12 months, 81.7% of the patients in the bicalutamide group showed some kind of gynecomastia, and this percentage was statistically higher than that of each association group (p ! 0.002) except for the 1-mg group (82.8%). The incidence of gynecomastia progressively decreased with the increase of the dose of tamoxifen (from 53.3% in the 2.5-mg group to 14.7% in the 20mg group). Also considering breast pain, an inverse correlation with tamoxifen doses could be observed. When the association was interrupted, a quick increase in the incidence rate of gynecomastia in all previously treated group became detectable. In that study, side effects were also limited, minimal and not dose related (except for hot flushes). In a non-inferiority study, Bedognetti et al. [25] tried out two different schedules of tamoxifen as prophylactic treatment for patients treated with bicalutamide. A total of 81 patients were recruited and received tamoxifen 20 mg daily; after 8 weeks of treatment, they were randomized to continue this schedule or to start a weekly administration of 20 mg tamoxifen. The subject recruitment of this study was precociously interrupted because of the large number of patients developing gynecomastia in the weekly tamoxifen group. Although after 6 months of treatment there was no significant difference in the incidence of gynecomastia or breast pain between the two groups, after 12 months these incidence rates were 74.4 and 46.1% in the weekly group versus 31.7% (p ! 0.0001) and 12.2% (p ! 0.001) in the daily group, respectively. Both treatments were well tolerated. In a recent study, Serretta et al. [26] randomized 176 patients selected for bicalutamide monotherapy to receive tamoxifen 20 mg daily – starting within 30 days from the onset of gynecomastia or breast pain – or tamoxifen Multimodality Treatment of Gynecomastia in Prostate Cancer Patients

10 mg daily starting simultaneously with bicalutamide. After 12 months, the prevalence of breast events was 78.3 and 35%, respectively (p ! 0.0001). This study confirmed the activity of tamoxifen both in preventing and treating gynecomastia and breast pain; in fact, the prevalence of these symptoms in the first group decreased from 78.3 to 27.7% (p ! 0.0001) since the administration was started. To assess the different prophylactic and therapeutic activities of tamoxifen and radiotherapy on bicalutamide-associated gynecomastia, Perdonà et al. [27] randomized 151 patients to receive bicalutamide (150 mg daily) alone or associated with tamoxifen (10 mg daily for 24 weeks) or with radiotherapy on breast area (single dose of 12 Gy). Patients of the first group who had developed gynecomastia were further randomized in one of the two other study arms. After 6 months, 69% of the patients in the first group developed gynecomastia compared to 8% of the patients in the tamoxifen group (p = 0.0009) and 34% of the patients in the radiotherapy group (p = 0.008). These results were confirmed by those reached after the second randomization when 35 patients from the bicalutamide group who had developed gynecomastia were treated with radiotherapy or tamoxifen: the incidence of gynecomastia in these groups was 55.5 and 11.7%, respectively (p = 0.002). Comparable results were obtained in a methodologically quite similar study involving 102 patients [28]. In these two studies, neither radiotherapy nor tamoxifen had relevant side effects to bicalutamide therapy. These results show that tamoxifen could be more active than radiotherapy both in preventing and treating bicalutamide-induced gynecomastia, and the question remains whether it would be even more effective if a higher dose of tamoxifen were used.

Gynecomastia as Adverse Event of New Hormonal Treatments for Prostate Cancer

Although gynecomastia is a predictable side effect of ‘classic’ antiandrogen therapy, it seems that it is not so frequent among patients treated with last-generation antiandrogens such as MDV3100 [29] and abiraterone acetate [30, 31]. In these studies, in fact, gynecomastia is not reported as significant side effect, thus allowing us to suppose that it is infrequent or worthless of note in severity. Although the small number of patients enrolled in the phase I–II study with MDV3100 (140 patients) does not allow any final consideration, these preliminary data about abiraterone have been confirmed in a recent phase Oncology 2013;84:92–99

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III study [31], in which gynecomastia is not mentioned as significant side effect of the treatment. It would be interesting to understand the physiological mechanisms underlying the discrepancy between ‘old’ and ‘new’ antiandrogen therapies; for now, we can only say that the more targeted antiandrogen activity of MDV3100 and abiraterone acetate [32] seems to interfere less with hormonal balance. Although the above-mentioned studies reported different incidence rates, they agreed on the interval between the beginning of the treatment and the onset of gynecomastia. Gynecomastia does not appear immediately but only after about 6–9 months of treatment. This was also predictable and not surprising if we consider that gynecomastia depends on a hormonal block, which is known requiring several weeks for complete and definitive activity. This quite long interval could raise another question about the gynecomastia-free activity of MDV3100: the mentioned studies with ‘old’ antiandrogens involved patients with local or locally advanced prostate cancer, so the hormonal therapy has been given in an adjuvant setting for much more than 6 months; studies with MDV3100, however, involved patients with metastatic prostate cancer who all received treatment for less than 6 months. This shorter period of treatment could influence the possible incidence of gynecomastia. On the contrary, a phase III study with abiraterone [31] reached a median follow-up of 12.8 months without a significant incidence of gynecomastia; it is therefore reasonable to affirm that this hormonal treatment seems to be completely safe from this point of view.

count. After that, we must decide which type of treatment is the most adequate one. When choosing between a medical and a radiotherapeutic approach, first of all we may consider that tamoxifen could have a detrimental effect on bicalutamide activity. Although data about its effect on progression and survival are still lacking because of short follow-up periods, no studies have shown a negative effect on PSA levels [6, 13, 24–26, 28]. Second, the side effects associated with each approach must be considered. Although they are both characterized by minimal collateral problems, we must remember that, as already verified by Fradet et al. [13], hormonal prophylaxis should be continued throughout the entire period of treatment with bicalutamide. This would increase treatment costs in terms of incidence of important tamoxifenrelated side effects such as the possible alteration of the patients’ sexual activity – which could represent an important deterrent, especially for younger patients – and cardiovascular events; tamoxifen is in fact associated with venous thromboembolism [33, 34], and its effect could be strengthened by the association with bicalutamide. All that could favor radiotherapy as prophylactic treatment – also considering its long-term activity – despite the fact that doses and timing of treatment are still not standardized. In conclusion a possible approach could be based on a preventive breast irradiation followed by tamoxifen-based therapy for those patients developing gynecomastia despite prophylactic treatment, as already suggested by Van Poppel [35]. The surgical option is, in our opinion, too invasive and should be reserved to chronic or particularly serious or not responsive forms of gynecomastia.

Conclusions

Gynecomastia is a symptom occurring with high frequency in patients receiving bicalutamide for prostate carcinoma. It is sometimes associated with breast pain but can in every case negatively influence compliance to treatment. It is therefore appropriate that patients about to begin hormonal treatment are previously informed about the possible onset of this side effect, and it is also necessary that the different prophylactic and therapeutic options are correctly presented. First of all, we have to choose between a prophylactic and a therapeutic approach. Considering the high incidence of gynecomastia during bicalutamide-based treatment, in our opinion a prophylactic treatment may be preferred or should, at least, be strongly taken into ac98

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Multimodality Treatment of Gynecomastia in Prostate Cancer Patients

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