Post mastectomy radiotherapy
Standard indications for post mastectomy radiotherapy (PMRT) still hold true (i.e. tumour >5cm, >4 lymph nodes, and inflammatory breast cancer). Other high risk pathological features becomes more controversial. In day-to day practice, we are guided by the post-mastectomy trialsrrrr surgical trialsr and also by the regional nodal irradiation trialsrr of which a subset of patients underwent mastectomy.
Breast conservation surgery & regional nodal irradiation (RNI)
The role of RNI in patients who have undergone breast conservation surgery is controversial. Treatment paradigms have shifted and often patients present for their initial radiotherapy consult with a positive sentinel lymph node biopsy without a complete axillary nodal dissection since the publication of the ACOSOG Z0011 trial.r This is also occurring in the era of modern systemic therapy with improved chemotherapy agents (taxanes & anthracyclines) biological therapies (trastuzumab) and newer and prolonged endocrine therapy regimens with subsequent improved locoregional control rates. In day-to-day practice, we are guided by the two randomised RNI trials,rr three axillary surgical trialsrrr and the post-mastectomy radiotherapy trials.rrr
Post-mastectomy radiotherapy has been shown to improve overall survival and locoregional control.rrrrr The risk of locoregional recurrence is reduced by approximately two-thirds with post-mastectomy radiotherapy.
Three randomised controlled trials have demonstrated this locoregional control and overall survival benefit. The Danish Breast Cancer Co-operative Group studied both pre-menopausal and post-menopausal patients and demonstrated a 9% overall survival benefit with the addition of post-mastectomy radiotherapy (54% vs. 45%), and 45% vs. 36% overall survival for post-menopausal patients.rr These trials however, have been criticised in the modern era because of the out-dated systemic therapy (CMF in the pre-menopausal study) and tamoxifen alone (in the post-menopausal study) and the inadequate axillary lymph node dissection performed (<10 lymph nodes dissected). The third trial is the British Columbia trial which demonstrated a 10% reduction in mortality at 10 years (47% vs 37% ) and a 27% reduction in mortality at 20 years with the addition of PMRT in pre-menopausal patients.r These trials all used RNI, including internal mammary nodal coverage.
There is now further evidence to recommend PMRT for patients with 1-3 positive lymph nodes. The EBCTCG meta-analysis published in 2014 demonstrated a decrease in locoregional recurrence, any first recurrence and breast cancer mortality in patients with 1-3 positive nodes (see figure 2).r The breast cancer mortality at 20 years was 50.2% without RT and 42.3% with post-mastectomy radiotherapy. However, the chemotherapy regimen used in these studies was CMF and the locoregional recurrence rates quoted are much higher than current rates of locoregional recurrence. As per the Danish and British Columbia post-mastectomy trials, the axilla, supraclavicular fossa and internal mammary lymph nodes were included in the radiotherapy field together with the chest wall. Thus, the risks and benefits of PMRT for patients with T1-2, N1 disease should be discussed with patients.rrr
The SUPREMO randomised control trial investigated radiotherapy in intermediate risk breast cancer patients (pT1-2N1, pT3N0 or pT2N0 if G3 or LVI) who underwent mastectomy and if node positive, axillary surgery, and randomised patients to chest wall radiotherapy or no radiotherapy.r The primary endpoint was 10 year overall survival. We await the results from this study, however a 2 year quality of life substudy is now available. At two years the chest wall symptoms were worse in the radiotherapy group with a mean score of 14.1 (SD 15.8) versus 11.6 (SD 14.6) with effect estimate 2.17, 95% CI: 0.40-3.94, p=0.06).r
Wang et al. randomised 820 patients with stage pT3-4 or at least 4 positive axillary nodes who had undergone mastectomy to receive PMRT with conventional fractionation (50Gy/25 fractions) or 43.5Gy/15 fractions to the chest wall, supraclavicular fossa and level III axillary nodal region.r Hypofractionation was found to be non-inferior to conventional fractionation at a median follow-up of 58.5 months in terms of locoregional recurrences (8.3% vs. 8.1%, p < 0.0001).
The results from both the subgroup analysis of the Danish Breast Cancer Cooperative Group (DBCG) 82b&c randomised trials and Kyndi et al. strongly indicate that the benefit of post-operative radiotherapy is equally pronounced in patients with 1-3 nodes positive and in patients with 4+ nodes.rr The bottom line estimate by Overgaard et al. (see figure 1) indicates that PMRT is beneficial in the high risk patient cohort and importantly, is independent of the number of positive lymph nodes.r
Figure 1: Relative and absolute risk reduction and number of patiented need to treat to achieve benefit of PMRT
© Radiother Oncol 2007r
Figure 2: Effect of radiotherapy after mastectomy and axillary dissection on 10 year risks of locoregional and overall recurrence and 20 year mortality risk
© Lancet 2014r
Figure 3: Kaplan-Meier plots of local recurrence, breast cancer specific survival and overall survival
© Radiother Oncol 2009r
Breast conservation - MA20 studyr & EORTC 22922/10925r
There have been two publications in the New England Journal of Medicine in 2015 examining the role of locoregional nodal irradiation in patients undergoing breast conservation surgery. The final results of the MA.20 trial demonstrated a reduction in breast cancer recurrence but not overall survival with addition of RNI.
The MA.20 trial randomised 1832 women with node positive (1-3 nodes), or high-risk node-negative breast cancer to whole breast radiotherapy, 50Gy in 25 fractions (+/- boost) with or without RNI or 45Gy in 25 fractions (which included the axilla, SCF and IMC nodes).r More than 90% of patients received chemotherapy and 75% received adjuvant endocrine therapy. At a median follow up of 10 years, RNI improved disease free survival (82% vs 77%, 95% CI: 0.72-1.13, p=0.01), isolated locoregional disease free survival (95.2% vs 92.2%, 95% CI: 0.39-0.88, p=0.009), and distant disease free survival (86.3% vs 82.4%, 95% CI: 0.60-0.97, p=0.03) but not overall survival (82.8% vs 81.8%, 95% CI: 0.73-1.13, p=0.38). There was also higher rates of toxicity with RNI, with increased rates of grade 2 pneumonitis (1.2% vs 0.2 %, p=001) and ≥ grade 2 lymphoedema (8.4% vs 4.5%, p=0.001). It is also important to note that this trial closed early.
The EORTC 22922/10925 study demonstrated, at a median follow up of 10.9 years, an improvement in disease free survival, distant disease free survival and a reduction in breast cancer mortality.r There was however, no improvement in overall survival. The EORTC study randomised patients with a central or medially located primary tumour (node negative or positive) or patients with a node positive, laterally placed tumour to either whole breast/chest wall radiotherapy +/- RNI (axilla, medial SCF, and IMCs) to 50Gy in 25 fractions (76.1% of patients underwent breast conserving surgery). Disease free survival (72.1% vs 69.1%, 95% CI: 0.80-1.00, p=0.04), distant disease free survival (78% vs 75%, 95% CI: 0.76-0.98, p=0.02), and breast cancer mortality (12.5% vs 14.4%, 95% CI: 0.70-0.97, p=0.02) were improved with RNI. However, there was no improvement in overall survival (82.3% vs 80.7%, 95% CI: 0.76-1.00, p=0.06). There was an increase in rates of pulmonary fibrosis (4.4% vs 1.7%) and lymphoedema (12% vs 10.5%).
IMC irradiation DBCG-IMNr
The 8 year follow up results of a large population-based cohort study by the Danish Breast Cancer Cooperative group were published in 2015 by Thorsen et al. where overall survival was found to be increased for patients with early stage node-positive breast cancer with the use of internal mammary node irradiation (IMNI).r Of the 3089 patients, those with right sided disease were allocated to receive IMNI (n=1492) and patients with left sided disease (n=1597) allocated to no IMNI due to the risk of radiation induced heart disease. The overall survival rate was 75.9% for IMNI compared with 72.2% without IMNI and the adjusted HR for death with vs without IMNI was 0.82 (95% CI: 0.72-0.94, p=0.005). Outcomes were worse for increasing tumour size, increased number of positive nodes, higher grade and medial/central location. Similar numbers of patients died of ischaemic heart disease in the two groups.
Z0011 study,r AMAROS studyr & NSAPB 04r
The results of the American College of Surgeon’s Z0011 trial, which randomised 891 patients to completion axillary dissection or no further surgery, suggested that axillary dissection in patients with up to 2 positive sentinel nodes had no impact on 5-year overall survival (92.5% for no ALND versus 91.8% for ALND) or disease-free survival (83.9% versus 82.2% respectively).r This suggests that aggressive management of axillary disease may not result in better outcomes. However, it is important to note that many of these patients had level 1 of the axilla included in the breast tangential fields and these patients had lower risk breast cancers compared with the MA20 cohort of patients. The radiotherapy QA for this trial was subsequently published in the Journal of Clinical Oncology in 2014.r In patients in whom detailed treatment details were available, 50% of patients in both arms of the study received high tangents and approximately 20% of patients underwent direct nodal radiotherapy. These percentages were balanced in both arms of the trial. ‘High tangents’ were defined as the superior border of the field located within 2cm of the humeral head. This trial has changed the surgical management of the axilla.
The IBCSG 23-01 trial, randomised 934 patients to axillary dissection (AD) or no AD in patients with minimal sentinel node involvement.r Five year disease free survival was 87.8% (95% CI: 84.4% to 91.2%) in the no AD group and 84.4% (95% CI: 80.7% to 88.1%) in the AD group (log-rank p= 0.16) (HR no AD vs. AD= 0.78, 95% CI: 0.55 to 1.11). The study suggested that AD in patients with minimal sentinel node involvement could be avoided.
This EORTC study randomised 4823 patients with pT1-2 (<3cm tumour), clinically node negative tumours, but with a positive sentinel lymph node biopsy to completion axillary lymph node dissection or axillary radiotherapy (50Gy in 25 fractions to level 1-3 axilla, medial supraclavicular fossa).r This phase III, non-inferiority trial demonstrated at a median follow up of 6.1 years, that there was no difference in axillary control in radiotherapy vs surgery (1.19% [95% CI: 0.31-2.98] vs 0.43% [95% CI: 0.00-0.92]). There was however an increased rate of lymphoedema in the surgical group (23% vs 11% at 5 years, p≤0.0001). There was no statistically significant difference in disease free survival (82.7% vs 86.9%, p=0.18) or overall survival (92.5% vs 93.3%, p=0.34).
Regional nodal radiotherapy should be considered for all node-positive breast cancer patients. The traditional indications for post-mastectomy radiotherapy treatment (stage III disease) still hold true. In patients with 1-3 lymph nodes positive, patient tumour and treatment factors need to be considered prior to a recommendation of RNI in this setting. Indications and target selection for RNI in node positive patients undergoing SLNB alone remain controversial.