Radiation Therapy in Male Breast Cancer

In the US, male breast cancer (MBC) comprises approximately 1 % of all breast cancer cases and less than 1 % of all male cancers. An estimated 2,240 cases of MBC will be diagnosed in the US in 2013 compared with 232,340 cases of female breast cancer (FBC).¹ Due to its rarity, large prospective studies and randomised controlled trials focused on treatment options for MBC are not available. Management, therefore, has been largely dependent on results from large trials in women with breast cancer. Several unique challenges exist in men with breast cancer that influence the role of adjuvant radiotherapy (RT). Men are not screened for breast cancer and commonly present at an older age and higher stage than women, and are more likely to present with a palpable mass that is centrally located.^2,3 Due to the location and the low volume of normal breast tissue in men, there is a high propensity for nipple, chest wall and nodal involvement^3,4 resulting in more advanced stage at diagnosis and possibly greater need for post-mastectomy radiation (PMRT).² Based on data from randomised clinical trials, adjuvant RT improves locoregional control (LRC) following lumpectomy and radiation in many circumstances.5–8 In this article, we review the literature associated with the role of adjuvant RT in MBC.

Role of Radiation Therapy in Locoregional Control
Post-mastectomy Radiotherapy
In the US, PMRT has traditionally been indicated in women with four or more positive lymph nodes, T3 tumours or stage III disease.^9,10 Multiple randomised trials have demonstrated improvement in LRC and overall survival (OS) with the addition of PMRT (see Table 1). The Danish 82b trial demonstrated the use of PMRT, in conjunction with systemic chemotherapy, reduced local failure (LF) by 23 % and improved diseasefree survival (DFS) and OS by 14 % and 9 %, respectively.⁷ In the Danish 82c trial the use of PMRT, in addition to hormonal therapy, reduced LF by 27 % and improved OS by 9 %.8 The British Columbia trial similarly demonstrated a reduction in LF of 16 % with an OS improvement of 10 % with the addition of PMRT to adjuvant chemotherapy.¹¹

For women with one to three positive nodes, the indications for PMRT are more controversial. A subgroup analysis of the Danish 82b and 82c trials included only patients with eight or more nodes removed, demonstrating that PMRT improved 15-year survival in all patients, and reduced LF rates in both groups of women with one to three positive nodes and four or more positive nodes.¹² The presence of high-risk features including young age, nodal ratio (number of positive nodes compared with number of nodes examined), lymphovascular invasion, extracapsular extension, margin status and histological grade13 also influence physician recommendations for PMRT. The standard treatment for PMRT is currently 30 treatments to the chest wall, level I–III axillary nodes, supraclavicular nodes and, in certain cases, internal mammary nodes, delivered 5 days per week. Hypofractionated regimens, or shorter treatment courses with larger doses of RT per treatment, are not commonly offered post-mastectomy due to limited data.

Breast Conservation Therapy
Breast conservation therapy (BCT) is defined as partial mastectomy (e.g. lumpectomy, segmentectomy, quandrectomy) followed by RT with or without adjuvant hormonal or systemic chemotherapy. Since the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial demonstrated equivalent survival outcomes among women with breast cancer undergoing radical mastectomy, total mastectomy with PMRT or simple mastectomy with axillary node dissection (ALND), there has been a shift to less extensive surgery.⁶ NSABP B-06 compared modified radical mastectomy (MRM), lumpectomy and lumpectomy with adjuvant RT, demonstrating that the addition of RT to lumpectomy reduced ipsilateral recurrence from 39.2 % to 14.3 %.5 Similar results have been demonstrated for women with ductal carcinoma in situ (DCIS) in the European Organisation for Research and Treatment of Cancer (EORTC) 1085314 and United Kingdom Coordinating Committee On Cancer Research trials.¹⁵ The NSABP B-17 and B-24 randomised trials reinforced the results of B-06, with reduction in ipsilateral invasive and non-invasive recurrences with the addition of RT to lumpectomy.^16–18 The accepted fractionation for adjuvant RT after lumpectomy usually involves 30–33 treatments, delivered 5 days per week. Hypofractionated whole-breast RT delivered in 16–20 treatments has proved its safety in randomised trials^19–21 and is gaining acceptance in the US.

Axillary Radiation
Currently, the primary indication for adding dedicated axillary RT in FBC is four or more positive lymph nodes following ALND or inadequate ALND.²² The decision to add a field for supraclavicular nodal RT in patients with one to three positive nodes depends on other high-risk features (e.g. lymphovascular invasion, extracapsular extension, etc.) Regional nodal RT in women with more than four positive lymph nodes results in improved regional, axillary and supraclavicular LRC.²³ The percentage of involved nodes is also predictive of axillary control rates, with improved rates when the percent of involved nodes is less than, or equal to, 50 %.²⁴ This topic remains an area of investigational interest.

Role of Radiation Therapy in Overall Survival
The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) metaanalysis published in 2005²⁵ is an important study showing a survival benefit with adjuvant RT in FBC. Although none of the included breast cancer specific trials independently demonstrated a survival advantage, this meta-analysis found a 5.3 % improvement in OS with the addition of adjuvant RT to partial mastectomy. In patients who were node positive, PMRT improved OS by 4.4 %. Adjuvant RT did not demonstrate a survival benefit in node negative patients. Importantly, the survival benefit was only shown after 15-year follow up with thousands of patients, suggesting that subtle differences in survival may not be detectable in small trials with a short follow up. The EBCTCG analysis concluded that for every four recurrences prevented with adjuvant RT, one breast cancer death was avoided.²⁵

Radiation Therapy in Male Breast Cancer
The management of MBC has evolved considerably over the past several decades. Similar to the B-04 trial in women,⁶ several studies found equivalent rates of LRC and OS with MRM and PMRT compared to radical mastectomy in MBC.^26,27 Furthermore, after sentinel lymph node biopsy (SLNB) became the gold standard tool for investigating nodal status in node-negative women,^28–30 studies have demonstrated oncological equivalency between ALND and SLNB in men.³¹ More recent evidence suggests that BCT may even be an acceptable option for men with breast cancer, producing similar outcomes to mastectomy.³² Many of the shifts in treatment paradigms would not be possible without the addition of adjuvant RT to surgery. We review the retrospective evidence for adjuvant RT in MBC (see Table 2) and note that, controlled for stage, RT results in similar outcomes compared with those in FBC.³³

Retrospective series of men with breast cancer undergoing adjuvant RT demonstrate reductions in LF, ranging from 12 to 88 % (see Table 3). As early as the 1980s, a retrospective analysis of 89 men (81.4 % T1-2 and 55.9 % N1) receiving adjuvant RT showed improvements in LRC between 28 % to 55 %.³⁴ A series from Ireland published in 1984 showed that men who underwent PMRT had longer mean time to LF (mean 2.9 years compared with 1.8 years).³⁵ In 1990, a review of 16 patients demonstrated no LF in patients who received adjuvant RT, but a 66.7 % LF rate in patients after surgery alone.³⁶ A large series from Milan showed significant reductions in LF, as low as 1.6 %, with PMRT and nodal radiation.³⁷ A matched comparison of MBC and FBC patients demonstrated a dramatic reduction of ipsilateral axillary node recurrence, from 47 % to 20 %, with the addition of adjuvant RT.³⁸ An analysis of high-risk patients with positive nodes, stage III disease and unknown or <2 mm resection margins, showed a reduction in LR rates with the addition of PMRT from 17 % to 0 %, and in all patients a reduction from 24 % to 4 %.³⁹ In a German cohort, all patients with surgery alone suffered a LF compared with only 11.8 % with the use of adjuvant RT.40 In addition, an Austrian cohort of 31 men with stage I–III disease treated with adjuvant RT showed only a 3.2 % LF rate.⁴¹ Data from Stanford also shows excellent control rates, with no isolated LF at 23 month in 22 men treated with adjuvant RT from 1960 to 2011.⁴² Despite strong associations between PMRT and LRC, there remains a lack of evidence demonstrating survival benefit in men.^{34,39,43–45}

There are no published guidelines for the use of adjuvant RT in MBC, but a few articles have outlined specific recommendations. A study from the UK encourages adjuvant RT for men with T3 tumours or T1–2 tumours with high-risk features, such as positive nodes, stage III disease and unknown or <2 mm resection margins.³⁸ PMRT is also considered in cases of younger patient age, positive or close margins, positive nodes, high grade, large primary tumour size, involvement of the skin, areola, chest wall or pectoralis muscle, lymphovascular invasion, extracapsular extension or multifocal disease.¹³ Chung et al. advise including the ipsilateral internal mammary nodes, supraclavicular and infraclavicular nodes in addition to the chest wall based on the fact that most tumours in men are centrally located.³⁶ Veronesi et al.⁴⁶ showed that internal mammary node involvement is more common in women with inner quadrant tumours, positive axillary nodes and large tumour size. Many of these characteristics are common in MBC and therefore inclusion of the internal mammary nodes could be considered in PMRT for certain patients.

Complications
Common acute complications after RT include fatigue, skin erythema and desquamation. Rare, but serious, long-term complications include contracture of a reconstructed breast, telangiectasia, skin fibrosis, cardiomyopathy, pulmonary toxicity including radiation pneumonitis, lymphedema especially in patients who have undergone ALND, brachial plexopathy, costochondritis, rib fractures and radiation-induced malignancies.^13,47 There is limited literature available on complications of RT in MBC. An Austrian review of men who received adjuvant RT reported no cases of a second malignancy in the irradiated field, a maximum of grade II skin toxicity scored by the Radiation Therapy Oncology Group (RTOG)/EORTC grading system and no severe late complications.⁴¹ Bratman et al.⁴² reported low toxicity rates with grade 1–2 dermatitis and fatigue, and Schuchardt et al.⁴⁰ reported similar acute and late toxicity with a maximum of grade II dermatitis.

Emerging Concepts
Breast Conservation Therapy in Male Breast Cancer
Although the majority of women with breast cancer are now treated with BCT, there has been a slower adoption in MBC. The majority of male patients are still treated with mastectomy. A recent Surveillance Epidemiology and End Results (SEER) analysis by Cloyd et al.³² was the largest report of MBC patients treated with lumpectomy to date. This retrospective review demonstrated that, despite significant differences between patients who received lumpectomy versus those who received mastectomy, the type of surgery did not affect breast cancer specific survival or OS. Interestingly, only 35 % of BCS patients underwent adjuvant RT, significantly less than women undergoing BCS, and only 21 % of mastectomy patients received PMRT,³² suggesting that adjuvant RT is possibly underutilised in men. Lumpectomy with adjuvant whole breast RT in select situations may be an acceptable option for men with early breast cancer.

Hypofractionation
The standard treatment for adjuvant RT is a 6-week daily treatment course, and the efficacy of shorter course RT has been investigated. A trial from Canada compared standard fractionation (50 Gray [Gy] in 25 fractions) to a hypofractionated regimen (42.5 Gy in 16 fractions) and showed no difference in LRC, DFS or OS in women who underwent lumpectomy.²¹ The UK trials Standardisation of Breast Radiotherapy(START) A and B compared standard fractionation (50 Gy in 25 fractions) to hypofractionated regimens (39 or 42.6 Gy in 13 fractions and 40 Gy in 15 fractions, respectively) in women undergoing mastectomy (15 % in START A; 8 % START B) and lumpectomy.^19,20 Both trials demonstrated equivalent LRC and lower patient-reported toxicity rates in the hypofractionated arms. Trials examining hypofractionated regimens are ongoing, although the majority exclude men with breast cancer.⁴⁸

Accelerated Partial Breast Irradiation
Acelerated partial breast irradiation (APBI) is RT delivered to the lumpectomy cavity alone in a 10-day treatment course, allowing for a shorter course of treatment and decreased dose to the contralateral breast, heart and lungs. In the US, APBI is considered in women if the lumpectomy cavity to whole breast tissue ratio is less than or equal to 30 %,¹³ along with other pathological features that help guide recommendations.⁴⁹ Men, having a smaller volume of breast tissue overall, are less likely to meet criteria for this treatment. A recently closed trial randomised women to either whole breast RT in 25–30 treatments or APBI in a 5-day, 10-treatment course,⁴⁸ and men were excluded. Nevertheless, APBI has been reported in MBC in certain situations.⁴²

Conclusions
Due to its relative rarity, management of MBC typically follows that of FBC. Randomised controlled trials in women overwhelmingly support the use of adjuvant RT to maintain LRC, and to a lesser extent, OS. The retrospective data presented in this review suggests that adjuvant RT in MBC provides a LRC benefit,^{34–37,40–43} as has been shown in women. Survival data in men are limited due to the small numbers and lack of long-term follow up. New data suggest that MBC patients may safely undergo lumpectomy followed by adjuvant whole-breast RT. Although caution is warranted in interpreting retrospective studies, these data corroborate proven findings in large female trials. Since similar trials of large cohorts of MBC patients are unlikely to be performed, the management of MBC should continue to follow guidelines of FBC and retrospective studies will continue to play a vital role in the analysis of outcomes for men with breast cancer.