Standard indications for post-mastectomy radiotherapy (PMRT) still hold true (i.e. tumour >5cm, >4 lymph nodes, and inflammatory breast cancer). The addition of regional nodal irradiation and thus post-mastectomy radiotherapy in patients with 1-3 positive lymph nodes and/or 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
The role of regional nodal irradiation in patients who have undergone breast conservation surgery is also 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 following 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 recent randomized regional nodal radiotherapy trials,rr three axillary surgical trialsrrr and the post-mastectomy radiotherapy trials.rrr
Evidence – Post-mastectomy patients
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 patientsrr and demonstrated a 9% overall survival benefit with the addition of post-mastectomy radiotherapy (54% vs. 45%) 10 year overall survival for premenopausal patients, and 45% vs. 36% overall survival for post-menopausal patients). These trials however, have been criticized 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 trialr 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 post mastectomy radiotherapy in pre-menopausal patients. These trials all used regional nodal irradiation.
There is now further evidence to recommend routine PMRT for patients with 1-3 positive lymph nodes. The EBCTCG meta-analysisr published in 2014 demonstrated a decrease in locoregional recurrence, any first recurrence and breast cancer mortality in patients with 1-3 positive nodes (see below graph). 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,rrr 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 the patients.
We are also awaiting the results of the SUPREMO trial.r This trial (‘Selective Use of Postoperative Radiotherapy after Mastectomy) closed to accrual in April 2013. This Phase III study was used to determine the role of adjuvant chest wall radiotherapy treatment in patients with intermediate risk disease i.e. pT1N1 or pT2N0-1 disease.
The results from both the subgroup analysis of the Danish Breast Cancer Cooperative Group (DBCG) 82b&cr randomized trials and Kyndi et alr 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. The bottom line estimate by Overgaard et alr (below) indicates that post mastectomy radiotherapy is beneficial in the high risk patient cohort and importantly, is independent of the number of positive lymph nodes.
© Radiother & Oncol 2007 Overgaardr
© Lancet 2014r
© Radiother & Oncol 2009, Kyndi et alr
Breast conservation patients - MA20 studyr & EORTC 22922/10925r
There have been two recent publications in the NEJM in 2015 examining the role of locoregional nodal irradiation in patients undergoing breast conservation surgery. The final results of the NCIC MA.20 trial demonstrated a reduction in breast cancer recurrence but not overall survival with addition of regional nodal irradiation (RNI).
The MA.20 trialr randomized 1832 women with node positive (1-3 nodes), or high-risk node-negative breast cancer to whole breast radiotherapy to 50Gy in 25 fractions (+/- boost) with or without regional nodal irradiation to 45Gy in 25 fractions (which included the axilla, SCF and IMC nodes). More than 90% of patients received chemotherapy and 75% received adjuvant endocrine therapy. At a median follow up of 10 years, regional nodal irradiation improved disease free survival (82% vs 77%, CI 0.72-1.13 p=0.01), isolated locoregional disease free survival (95.2% vs 92.2%, CI 0.39-0.88, p=0.009), and distant disease free survival (86.3% vs 82.4%, CI 0.60-0.97, p=0.03) but not overall survival (82.8% vs 81.8%, 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 22922/10925r 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. 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 +/- regional nodal irradiation (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%, CI 0.80-1.00, p=0.04), distant disease free survival (78% vs 75%, CI 0.76-0.98, p=0.02), and breast cancer mortality (12.5% vs 14.4%, 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%, CI 0.76-1.00, p=0.06). There was an increase in rates of pulmonary fibrosis (4.4% vs 1.7%) and lymphedema (12% vs 10.5%).
Z0011 study,r AMAROS studyr & NSAPB 04r
The results of the American College of Surgeon’s Z0011 trial,r 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). 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 JCO 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’ was 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.
This EORTC studyr randomized 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). 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% [CI 0.31-2.98] vs 0.43% [CI 0.00-0.92]). There was however an increased rate of lymphedema 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).
The 25 year follow up results of the NSABP04 trialr were published in the NEJM in 2002 by Fisher et al. This randomized study assessed 1079 patients with clinically node negative axillary lymph nodes. Patients were randomized to three groups: radical mastectomy, total mastectomy without axillary dissection but with post-operative radiotherapy treatment and total mastectomy. There was no difference in locoregional control or overall survival between the groups. Of note, no patients received adjuvant systemic therapy. The radiotherapy fields included the internal mammary and supraclavicular lymph nodes.
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 alr 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). 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 rates 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 ischemic heart disease in the two groups.
Regional nodal radiotherapy should be considered for all node-positive breast cancer patients. The traditional indications for post-mastectomy radiotherapy treatment still hold true. However, 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. Management of the axilla in the setting of breast conservation therapy is more controversial. All patients should be discussed in a breast cancer MDT to assist with treatment recommendations.