We evaluated the efficacy of tamoxifen for the management of breast events induced by non-steroidal antiandrogens in patients with prostate cancer. Our findings suggest that tamoxifen is more effective for both the prevention and treatment of gynecomastia and breast pain compared to other therapies, such as radiotherapy or the selective aromatase inhibitor anastrozole.
We included data from studies evaluating tamoxifen compared to any other therapy for the management of breast events. The criteria for diagnosis of gynecomastia, however, varied among the included studies. The assessment was performed by either examination or patient questioning. This discrepancy could have led to different incidences of breast events in the studies. Additionally, the grading of the severity of breast pain was different in the included studies and ranged from no pain to severe pain. However, breast pain was assessed in all of the studies by direct patient questioning, and even if the severity of breast events is reported to be moderate, this disease is often a reason for patients withdrawing from therapy.
We included tamoxifen with dosages of 10 mg or 20 mg daily in the meta-analysis because Fradet et al. found no significant differences in their dose-response study when tamoxifen 20 mg daily was compared to 10 mg daily . However, we included only studies using tamoxifen continuously without interruption. Therapy with tamoxifen is likely to be most effective if it is administered continuously. Bedognetti et al. demonstrated that the beneficial effects of tamoxifen 20 mg daily after eight weeks for the prevention of gynecomastia were only significant when administering the drug continuously as opposed to weekly [23, 24]. However, there is also evidence that tamoxifen 20 mg once weekly might be superior to no additional therapy . Conversely, Fradet et al. noted that in all of the groups (irrespective of dose), a high incidence (> 90%) of breast events occurred after stopping tamoxifen therapy [12, 20].
Our results suggest that tamoxifen has a beneficial effect if compared to no treatment for the prevention of breast events. However, not all patients need prophylaxis to prevent the development of breast events induced by non-steroidal antiandrogen therapy [26, 27], and not all patients with gynecomastia require treatment . Therefore, a patient-oriented, pragmatic approach appears reasonable. This approach was also proposed by van Poppel and by Di Lorenzo et al. [14, 15, 27]. Before starting non-steroidal antiandrogen treatment (either with non-steroidal monotherapy or in combination with LHRH analogues), patients should be informed about the likelihood of breast events and about possible prophylactic therapy options. As recommended earlier by Di Lorenzo et al. [14, 15], we also suggest that the physician could wait for the occurrence of breast events in selected patients. Prophylaxis should be started only if the patient is afraid of developing gynecomastia or breast pain.
Our findings regarding the comparison of tamoxifen versus radiotherapy show a beneficial effect favoring tamoxifen for the prevention of breast events, but these results are based on a single study. There is evidence, however, that radiotherapy is also an effective treatment option for breast events. A randomized trial compared a single dose of radiotherapy (10 Gy) with sham radiotherapy for the prevention of breast events and found a significant difference favoring interventional treatment (P < 0.001) . Additionally, a non-randomized, comparative study of 253 patients participating in a Scandinavian trial demonstrated a decreased risk for the development of gynecomastia and breast pain with radiotherapy compared with no additional treatment . An expert recommended using radiotherapy as the therapy of choice for the prevention of breast events .
Most adverse events were rare in both groups and we found no significant differences for any single adverse event comparing tamoxifen with anastrozole [See Additional file 1, Table S3]. Only the risks for nipple erythema and skin irritation were increased with radiotherapy compared to tamoxifen. Several retrospective and non-comparative studies have suggested that radiotherapy is an option with few and mild acute side effects and with no long-term adverse events [31–33]. The most common side effect with radiotherapy was reversible skin erythema . However, Nieder et al. provided data demonstrating that exposing the heart to prophylactic radiotherapy of the mammillary region might contribute to cardiac side effects . A narrative review evaluating safety and tolerability did not conclude either these cardiac side effects or secondary malignancies or pulmonary events, but it noted that no studies have evaluated the long-term effects of radiotherapy in men .
We were not able to identify any studies that compared tamoxifen with surgical therapies, such as subcutaneous mastectomy and/or liposuction. Therefore, we cannot draw any conclusions regarding this potential alternative therapy option. Surgical therapies aim to reduce breast size to a normal body contour and to eliminate painful tissue [15, 16, 36]. Experts in the field of gynecomastia treatment have suggested that surgical liposuction is a valuable therapy option in very early stages and that it is a simple and acceptable technique [15, 16]. Other experts have only considered surgical therapies in patients with reduced quality of life due to breast events or to distinct or long-standing gynecomastia [28, 36]. This option appears reasonable because gynecomastia presenting for longer than 12 months is unlikely to resolve due to irreversible changes in the breast tissue [5, 36]. However, surgical therapies always have potential side effects, such as infections, necrosis, loss of sensation and postoperative body deformity, and should therefore be reserved as a secondary treatment for selected patients.
Our results show that the antiestrogen tamoxifen is a useful therapeutic option for the prevention and treatment of breast events. However, in addition to the discussion of our results, it should be mentioned that treatment with antiestrogens for hormone-dependent tumors, such as prostate cancer, raises some concerns. On the one hand, blocking the effect of estrogens results in effective prevention of breast events induced by non-steroidal antiandrogens . On the other hand, this hormonal manipulation could increase androgen secretion by blocking the negative feedback control of estrogens . Although several trials have investigated the potential effects of tamoxifen co-administration on prostate-specific antigen (PSA) inhibition and on the levels of sex hormones [8, 12, 13, 18, 23–25], none of them presented long-term follow-up data. Therefore, the impact of tamoxifen therapy on outcomes, such as long-term adverse events, progression and survival, remains unclear and should be considered when prescribing this treatment.
We did not identify any studies with long-term follow-ups, and evidence for treatment with tamoxifen is limited because there are only a few studies with few events. Despite its potential limitations, this systematic review provides evidence-based guidance to clinicians on this clinically relevant topic. It demonstrates good efficacy of tamoxifen for the prevention and treatment of breast events induced by non-steroidal antiandrogens. This important question, however, requires more definitive answers, and further research with high-quality RCTs and longer-term follow-up is warranted.