Prophylactic Breast Irradiation for Prevention of Bicalutamide-induced Painful Gynecomastia in Patients with Low- and Intermediate-risk Prostate Cancer.

BACKGROUND: Bicalutamide monotherapy (BMT) is an option for androgen deprivation therapy (ADT) in patients with low- and intermediate-risk prostate cancer (LIR-PC). Painful gynecomastia (PG) is a common side effect of BMT. Few therapeutic options are available for preventing BMT-induced PG. OBJECTIVES: To assess the efficacy and side effects of single fraction (SF) prophylactic breast irradiation (PBI) to prevent painful gynecomastia (PG) in patients LIR-PC treated with BMT. METHODS: We reviewed the results of bilateral PBI in a prospective cohort of LIR-PC patients who received 150 mg bicalutamide daily as a first-line treatment for at least 12 months. A single fraction of 8 Gy was administered to both breasts by a stationary field of 10 × 10 cm, using 10-15 MeV electron beam. PBI was commenced on the same day as BMT, but prior to the first dose of bicalutamide. A radiotherapy treatment plan was designed to cover breast tissue by the 90% isodose line. Subsequent monthly physical examinations were scheduled for all patients during the first year of BMT to evaluate any PG symptoms. RESULTS: Seventy-six patients received BMT and PBI, 80% (61/76) showed no signs of PG; 20% (15/76) experienced mild gynecomastia. The main adverse effect of PBI was grade 1 radiation dermatitis. CONCLUSIONS: PBI using a SF of 8 Gy is an effective, safe, and low-cost strategy for the prevention of BMT-induced PG in LIR-PC patients.

Treatment strategies to prevent and reduce gynecomastia and/or breast pain caused by antiandrogen therapy for prostate cancer : Statement from the DEGRO working group prostate cancer.

AIM: To provide an overview on the available treatments to prevent and reduce gynecomastia and/or breast pain caused by antiandrogen therapy for prostate cancer. METHODS: The German Society of Radiation Oncology (DEGRO) expert panel summarized available evidence published and assessed the validity of the information on efficacy and treatment-related toxicity. RESULTS: Eight randomized controlled trials and one meta-analysis were identified. Two randomized trials demonstrated that prophylactic radiation therapy (RT) using 1â€¯× 10 Gy or 2â€¯× 6 Gy significantly reduced the rate of gynecomastia but not breast pain, as compared to observation. A randomized dose-finding trial identified the daily dose of 20 mg tamoxifen (TMX) as the most effective prophylactic dose and another randomized trial described that daily TMX use was superior to weekly use. Another randomized trial showed that prophylactic daily TMX is more effective than TMX given at the onset of gynecomastia. Two other randomized trials described that TMX was clearly superior to anastrozole in reducing the risk for gynecomastia and/or breast pain. One comparative randomized trial between prophylactic RT using 1â€¯× 12 Gy and TMX concluded that prophylactic TMX is more effective compared to prophylactic RT and furthermore that TMX appears to be more effective to treat gynecomastia and/or breast pain when symptoms are already present. A meta-analysis confirmed that both prophylactic RT and TMX can reduce the risk of gynecomastia and/or breast pain with TMX being more effective; however, the rate of side effects after TMX including dizziness and hot flushes might be higher than after RT and must be taken into account. Less is known regarding the comparative effectiveness of different radiation fractionation schedules and more modern RT techniques. CONCLUSIONS: Prophylactic RT as well as daily TMX can significantly reduce the incidence of gynecomastia and/or breast pain. TMX appears to be an effective alternative to RT also as a therapeutic treatment in the presence of gynecomastia but its side effects and off-label use must be considered.

Isoniazid-induced gynaecomastia: report of a paediatric case and review of literature.

BACKGROUND: Gynaecomastia is a fairly common condition in puberty but is rare in prepubertal boys. While it is necessary to exclude possible endocrinopathay in prepubertal gynaecomastia, medication is an important and potentially reversible cause to consider in new onset gynaecomastia. Isoniazid-induced gynaecomastia has been reported in adult males, but none was reported in the paediatric population and general paediatricians may not be aware of this uncommon side effect. CASE PRESENTATION: We hereby report a 11-year-old prepubertal boy who developed gynaecomastia while taking anti-tuberculosis drugs. Investigations excluded endocrinopathies. Gynaecomastia subsided 8 weeks after stopping isoniazid. CONCLUSION: This case is the first paediatric case report describing the association of gynaecomastia with isoniazid use. It is important for general paediatricians to recognize this entity, as prompt diagnosis and cessation of the offending drug can lead to resolution of the problem.

Tamoxifen for the management of breast events induced by non-steroidal antiandrogens in patients with prostate cancer: a systematic review.

BACKGROUND: Tamoxifen has emerged as a potential management option for gynecomastia and breast pain due to non-steroidal antiandrogens, and it is considered an alternative to surgery or radiotherapy. The objective of this systematic review was to assess the benefits and harms of tamoxifen, in comparison to other treatment options, for either the prophylaxis or treatment of breast events induced by non-steroidal antiandrogens in prostate cancer patients. METHODS: We searched CENTRAL, MEDLINE, EMBASE, reference lists, the abstracts of three major conferences and three trial registers to identify ongoing randomized controlled trials (RCTs). Two authors independently screened the articles identified, assessed the trial quality and extracted data. The protocol was prospectively registered (CRD42011001320; http://www.crd.york.ac.uk/PROSPERO). RESULTS: Four studies were identified. Tamoxifen significantly reduced the risk of suffering from gynecomastia (risk ratio 9RR0 0.10, 95% CI 0.05 to 0.22) or breast pain (RR 0.06, 95% CI 0.02 to 0.17) at six months compared to untreated controls. Tamoxifen also showed a significant benefit for the prevention of gynecomastia (RR 0.22, 95% CI 0.08 to 0.58) and breast pain (RR 0.25, 95% CI 0.10 to 0.64) when compared to anastrozole after a median of 12 months. One study showed a significant benefit of tamoxifen for the prevention of gynecomastia (RR 0.24, 95% CI 0.09 to 0.65) and breast pain (RR 0.20, 95% CI 0.06 to 0.65) when compared with radiotherapy at six months. Radiotherapy increased the risk of suffering from nipple erythema and skin irritation, but there were no significant differences for any other adverse events (all P>0.05). CONCLUSIONS: The currently available evidence suggests good efficacy of tamoxifen for the prevention and treatment of breast events induced by non-steroidal antiandrogens. The impact of tamoxifen therapy on long-term adverse events, disease progression and survival remains unclear. Further large, well-designed RCTs, including long-term follow-ups, are warranted. Also, the optimal dose needs to be clarified.

Radiotherapy for prevention and therapy of gynecomastia due to antiandrogen treatment in prostate cancer patients: a patterns-of-care study.

BACKGROUND: Gynecomastia is a frequent side effect of antiandrogen therapy for prostate cancer and may compromise quality of life. Although it has been successfully treated with radiotherapy (RT) for decades, the priority of RT as a preferred treatment option has recently been disputed as tamoxifen was also demonstrated to be effective. The aim of the present paper is to provide an overview of indications, frequency, and technique of RT in daily practice in Germany, Switzerland, and Austria. PATIENTS AND METHODS: On behalf of the DEGRO-AG GCG-BD (German Cooperative Group on Radiotherapy of Benign Diseases) a standardized questionnaire was sent to 294 RT institutions. The questionnaires inquired about patient numbers, indications, RT technique, dose, and - if available - treatment results. Moreover, the participants were asked whether they were interested in participating in a prospective study. RESULTS: From a total of 294 institutions, 146 replies were received, of which 141 offered RT for gynecomastia. Seven of those reported prophylactic RT only, whereas 129 perform both preventive and symptomatic RT. In 110 of 137 departments, a maximum of 20 patients were treated per year. Electron beams (76%) were used most often, while 24% of patients received photon beams or orthovolt x-rays. Total doses were up to 20 Gy for prophylactic and up to 40 Gy for therapeutic RT. Results were reported by 19 departments: prevention of gynecomastia was observed in 60-100% of patients. Only 13 institutions observed side effects. CONCLUSION: Prophylactic and symptomatic RT is widely used in the German-speaking countries, but patient numbers are small. The clinical results indicate that RT is a highly effective and well-tolerated treatment.

Drug-induced gynecomastia in children and adolescents.

QUESTION: I frequently see adolescent boys in my practice with transient gynecomastia. My management includes reassuring the boys and their families; however, I also understand that specific medication, alcohol, and drugs can cause gynecomastia. How common is this phenomenon, and what medications can induce gynecomastia? ANSWER: While gynecomastia is a physiologic phenomenon in most newborns and adolescents, it is important to consider pathologic conditions and medications that can cause breast enlargement. Antibiotics, antiulcer drugs, growth hormones, and chemotherapy have been reported to induce gynecomastia. Adolescents who use anabolic steroids, or who abuse alcohol, marijuana, heroin, or amphetamines, should be alerted to the fact that gynecomastia might develop. Treatment of drug-induced gynecomastia includes discontinuation of the offending drug. Very rarely is surgical intervention required.

Does Prophylactic Radiation Therapy to Avoid Gynecomastia in Patients With Prostate Cancer Increase the Risk of Breast Cancer?

PURPOSE: Prostate cancer (PC) patients who undergo antiandrogen monotherapy are offered prophylactic radiation therapy (PRT) to the breast buds to avoid gynecomastia. The aim of the present study was to evaluate whether the risk of breast cancer (BC) in men with PC as their first cancer diagnosis was influenced by PRT. METHODS AND MATERIALS: From the Norwegian Cancer Registry, we collected data from all patients with PC as their first cancer diagnosis from 1997 to 2014. We registered all RT given to the patients in the same period and the occurrence of BC diagnosed ≥3 months after the PC diagnosis. The histopathologic diagnoses of all BC cases were collected. Subdistribution hazard ratios for the risk of BC in the PRT and non-PRT groups were estimated. A standardized incidence ratio for BC was calculated by comparing our cohort to the standard male population. RESULTS: We analyzed 59,169 patients with PC, of whom 7864 (13.3%) had received PRT. The median follow-up time was 4 years. Of the 12 men with a diagnosis of BC, 3 had received PRT, and 2 of the 3 were phyllodes tumors. The risk of BC was not significantly different statistically for the patients given PRT compared with the non-PRT group (subdistribution hazard ratio 1.62, 95% confidence interval 0.41-5.62, adjusted for age and time of diagnosis). The standardized incidence ratio was 0.996 (95% confidence interval 0.57-1.75). CONCLUSIONS: In this registry-based study, we did not find an increased risk of BC in PC patients who received PRT. The number of BC cases in our study was low, and the risk of secondary BC after PRT seems to be negligible. The incidence of BC could, however, increase with additional follow-up. Also, 2 patients who had received PRT developed a malignant phyllodes tumor, an extremely rare type of BC associated with gynecomastia.

[Gynecomastia as a complication of hormonotherapy for prostate cancer: effect of prophylactic breast irradiation].

Gynecomastia is a benign condition characterized by proliferation of mammary glandular tissue. Hormonotherapy with bicalutamide for prostate cancer is one of the causes of gynecomastia. The well known aim of treatment is to decrease psychological distress and to improve cosmetic appearance. Prophylactic breast irradiation may prevent the appearance of gynecomastia.

Gynecomastia and hormones.

Gynecomastia-the enlargement of male breast tissue in men-is a common finding, frequently observed in newborns, adolescents, and old men. Physiological gynecomastia, occurring in almost 25 % of cases, is benign and self-limited; on the other hand, several conditions and drugs may induce proliferation of male breast tissue. True gynecomastia is a common feature often related to estrogen excess and/or androgen deficiency as a consequence of different endocrine disorders. Biochemical evaluation should be performed once physiological or iatrogenic gynecomastia has been ruled out. Non-endocrine illnesses, including liver failure and chronic kidney disease, are another cause of gynecomastia which should be considered. Treating the underlying disease or discontinuing medications might resolve gynecomastia, although the psychosocial burden of this condition might require different and careful consideration.

Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer.

PURPOSE: To determine whether tamoxifen or anastrozole prevents gynecomastia and breast pain caused by bicalutamide (150 mg) without compromising efficacy, safety, or sexual functioning. PATIENTS AND METHODS: A double-blind, placebo-controlled trial was performed in patients with localized, locally advanced, or biochemically recurrent prostate cancer. Patients (N = 114) were randomly assigned to either bicalutamide (150 mg/d) plus placebo or in combination with tamoxifen (20 mg/d) or anastrozole (1 mg/d) for 48 weeks. Gynecomastia, breast pain, prostate-specific antigen (PSA), sexual functioning, and serum levels of hormones were assessed. RESULTS: Gynecomastia developed in 73% of patients in the bicalutamide group, 10% of patients in the bicalutamide-tamoxifen group, and 51% of patients in the bicalutamide-anastrozole group (P < .001); breast pain developed in 39%, 6%, and 27% of patients, respectively (P = .006). Baseline PSA level decreased by > or = 50% in 97%, 97%, and 83% of patients in the bicalutamide, bicalutamide-tamoxifen, and bicalutamide-anastrozole groups, respectively (P = .07); and adverse events were reported in 37%, 35%, and 69% of patients, respectively (P = .004). There were no major differences among treatments in sexual functioning parameters from baseline to month 6. Elevated testosterone levels occurred in each group; however, free testosterone levels remained unchanged in the bicalutamide-tamoxifen group because of increased sex hormone-binding globulin levels. CONCLUSION: Anastrozole did not significantly reduce the incidence of bicalutamide-induced gynecomastia and breast pain. In contrast, tamoxifen was effective, without increasing adverse events, at least in the short-term follow-up. These data support the need for a larger study to determine any effect on mortality.

[Management of gynecomastia induced by bicalutamide]. / Prise en charge des gynécomasties induites par le bicalutamide.

Adjuvant bicalutamide monotherapy after radical prostatectomy improves the overall survival in patients with locally advanced prostate cancer. The main adverse event of the nonsteroidal antiandrogen is the development of gynecomastia against which prophylactic breast irradiation can be administered. Therapeutic local radiotherapy using a very small number of fractions is a well-tolerated management option. Symptom improvement is observed in about half of the patients. Radiotherapy-related adverse effects are often mild (erythema, skin irritation) and transient. Tamoxifen has been also shown to be effective in prevention and treatment of gynecomastia induced by adjuvant therapy by bicalutamide in two-third of patients. Long-term safety of this prophylactic and therapeutic approach needs to be investigated through appropriate trials. Further evaluation of the optimal dose and duration of treatment with tamoxifen in this setting is required.

Exploratory study of drug plasma levels during bicalutamide 150 mg therapy co-administered with tamoxifen or anastrozole for prophylaxis of gynecomastia and breast pain in men with prostate cancer.

OBJECTIVE: A randomized multicenter (14 centers) trial was conducted in 114 men with prostate cancer to determine whether the antiestrogen tamoxifen ('Nolvadex') 20 mg or the aromatase inhibitor anastrozole ('Arimidex') 1 mg prevent gynecomastia and breast pain during treatment with the non-steroidal antiandrogen bicalutamide ('Casodex') 150 mg, without compromising efficacy, safety, or quality of life. Plasma samples were collected in a subgroup of these patients to investigate whether trough (pre-dose) concentrations of bicalutamide 150 mg are influenced by concomitant administration of tamoxifen 20 mg or anastrozole 1 mg; the results of this pilot study are reported in this article. METHODS: A subpopulation of patients from a randomized placebo-controlled trial evaluating tamoxifen 20 mg and anastrozole 1 mg for the prevention of gynecomastia and breast pain in men receiving bicalutamide 150 mg for early or recurrent prostate cancer were selected on a voluntary basis from three of the trial centers. Plasma samples were collected on days 7, 14, 28, and 84 of therapy and analyzed to determine the plasma concentrations of (R)-bicalutamide and (S)-bicalutamide. In addition, plasma concentrations of tamoxifen, N-desmethyltamoxifen, and anastrozole were determined. RESULTS: A total of 21 patients were selected. There was no significant difference between treatment groups with respect to the trough plasma concentrations of either bicalutamide enantiomer at any point during the study. Plasma concentrations of the enantiomers, and the relative proportion of the (R))- and (S)-enantiomers, were consistent with those reported in previous studies. Plasma concentrations of tamoxifen, N-desmethyltamoxifen, and anastrozole were also similar to those described elsewhere in the literature. CONCLUSIONS: The findings of this pilot study suggest that trough plasma concentrations of bicalutamide enantiomers following administration of bicalutamide 150 mg are not markedly influenced by concomitant administration of tamoxifen 20 mg or anastrozole 1 mg. However, an effect of tamoxifen on bicalutamide pharmacokinetics can not be completely excluded due to the size of this study. Further studies are needed to clarify the effect of tamoxifen on bicalutamide pharmacokinetics and prostate cancer control in bicalutamide-treated patients. 'Arimidex', 'Casodex', and 'Nolvadex' are trademarks of the AstraZeneca group of companies.

Prevention and management of bicalutamide-induced gynecomastia and breast pain: randomized endocrinologic and clinical studies with tamoxifen and anastrozole.

A randomized, double-blind, placebo-controlled multicenter trial involving 107 men receiving bicalutamide ('Casodex') 150 mg/day therapy following radical therapy for prostate cancer assessed tamoxifen ('Nolvadex') 20 mg/day and anastrozole ('Arimidex') 1 mg/day for the prophylaxis and treatment of gynecomastia/breast pain. Tamoxifen, but not anastrozole, significantly reduced the incidence of gynecomastia/breast pain when used prophylactically and therapeutically. Serum testosterone levels increased with tamoxifen relative to placebo but prostate-specific antigen levels declined in all treatment groups. Further studies are needed to define the optimum tamoxifen dose and to assess any impact on cancer control. The use of tamoxifen in this setting remains to be investigated.

Radiotherapeutic prophylaxis of estrogen-induced gynecomastia: a study of late sequela.

Radiation therapy is an effective means of preventing the development of hormone-induced gynecomastia in men with cancer of the prostate. The efficacy and morbidity of this type of radiation was studied in a retrospective analysis of 87 patients referred for treatment from 1972 to 1982. Patients receiving DES as treatment for prostate carcinoma were treated with irradiation to the breast tissue. Patients were treated with 4 MV, 60Co superficial X rays. Doses range from 1200 to 1500 cGy in 3 fractions. The majority of patients had satisfactory results in terms of prevention of gynecomastia and mammalgia. There were few acute reactions noted and no evidence of long term sequela.

[Andromastectomy for avoidance of gynecomastia in treatment of prostate carcinoma (author's transl)]. / Die Andromastektomie zur Verhinderung der Gynäkomastie bei der Behandlung des Prostatakarzinoms.

An operation is described for the prevention of hormone-related gynecomastia that has not yet been published in the literature. In the hands of an experienced plastic surgeon, the operation has proved to be without problems. However, certain guidelines for the operative technique which will be described in more detail elsewhere must be observed.

[Irradiation for prevention of gynecomastia prior to estrogen therapy in cases of carcinoma of the prostate (author's transl)]. / Bestrahlung zur Gynäkomastie-Prophylaxe vor der Oestrogen-Therapie beim Prostata-Carcinom

The most frequent and most unpleasant side-effect of therapy with estrogen hormones in patients with carcinoma of the prostate is the painful gynecomastia. Since 1969, we have been performing the prophylactic irradiation of the mammary glands on 284 patients in order to prevent a hormone-induced gynecomastia. The majority (262 patients) was irradiated with 600 rad surface dose in fractions of 150 rad prior to the hormone therapy. One hundred and two patients, having been treated endocrinologically for 2-75 months, had a follow-up examination. After irradiation, only 19% of the patients did not develop a gynecomastia, and 60% had no mamillary hyperesthesias. Compared to other authors, the therapy was less efficient, the symptoms, however, were discrete. As a consequence, an increase of the radiation dose as well as an alteration of the fractionation must be used.

[Radiotherapy indications for non-malignant diseases in 2014]. / Indications non oncologiques de la radiothérapie : quelles indications en 2014 ?

This review updates the radiotherapy indications for non-malignant diseases, except those treated by radiosurgery. Since the last 2005 review, there have been no major changes in the indications: the prevention of heteropic bone formation and keloids remain classical indications, while the treatment of macular degeneration or the prevention of coronary restenosis are now past history. Nevertheless, the radiation treatment for benign diseases should have the same criteria as for malignant diseases: information of the patient on risks, benefits and treatment quality.

Prevention of gynecomastia and breast pain caused by androgen deprivation therapy in prostate cancer: tamoxifen or radiotherapy?

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 = 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] = 0.21, 95% confidence interval [CI] = 0.12-0.37, p < 0.0001, and OR = 0.34, 95% CI 0.20-0.57, 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 = 0.04, 95% CI = 0.02-0.08, p < 0.0001 and OR = 0.07, 95% CI = 0.0-0.14, p < 0.00001). TMX resulted in an ARR = 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.

A randomized trial comparing tamoxifen therapy vs. tamoxifen prophylaxis in bicalutamide-induced gynecomastia.

BACKGROUND: Tamoxifen (TAM) has been shown to be active against the bicalutamide-induced breast events (BEs) gynecomastia, and breast pain in patients with prostate cancer (PC). Optimal doses and schedules are not yet established. Debate still exists about whether prophylaxis with TAM is more effective than treatment of BEs when diagnosed. The results of a randomized study comparing TAM prophylaxis vs. TAM therapy are presented. METHODS: One hundred seventy-six patients with prostate cancer (PC) who were candidates for bicalutamide monotherapy were randomized to receive TAM 20 mg daily orally within 1 month from the onset of BEs (arm A) vs. TAM 10 mg daily starting simultaneously with bicalutamide (arm B). TAM was administered for up to 1 year. BEs were evaluated by a self-administered visual analogue scale. Neither ultrasonography nor calipers were used to measure the degree of gynecomastia. RESULTS: In arm A, BEs showed a prevalence, increasing with time up to 78.3%. After therapy with TAM they persisted in 27.7% of cases. Two patients (3%) interrupted TAM therapy because of dizziness, and 3 patients (4%) interrupted bicalutamide therapy because of painful gynecomastia. In arm B, the prevalence of BEs was 35% after 12 months of therapy. The difference in BEs between the 2 arms was statistically significant (P < .0001). The differences in prevalence of gynecomastia and breast pain between the 2 arms both favored TAM prophylaxis (P < .0001 and P < .001, respectively). Up to 35% of patients had BEs of low intensity, never requiring bicalutamide withdrawal. Two patients (3%) interrupted the treatment because of gastrointestinal intolerance. No difference emerged between the 2 arms in terms of prostate-specific antigen (PSA) response, plasma testosterone levels, and tumor progression. CONCLUSION: Bicalutamide-induced BEs can be prevented to a significant degree by prophylaxis with TAM 10 mg/day or effectively treated with TAM therapy 20 mg/day. Persisting BEs are of higher intensity after therapy than after prophylaxis.