Radiation Therapy Following Breast-Conserving Surgery

Radiation Therapy Following Breast-Conserving Surgery

Jennifer L. Pretz

Laura E. G. Warren

In 2019, an estimated 270,000 women were diagnosed with breast cancer, making the disease the most common nonskin malignancy in women. Radiation therapy (RT) is an integral component of breast cancer care for many women (1). Fifty years ago, RT was only used after mastectomy in patients with high-risk disease. However, as surgical techniques evolved from radical mastectomy to less invasive and less morbid procedures, RT became an important adjuvant treatment after lumpectomy as a means to reduce the risk of local recurrence (LR) in the setting of a less aggressive surgical resection.

Over the last several decades, several prospective clinical trials have been conducted to demonstrate the equivalence of less extensive surgical techniques to radical mastectomy. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial (2), initiated in 1971, led to a paradigm shift away from radical mastectomy to modified radical mastectomy (MRM). Contemporaneously, investigators at the Milan Cancer Institute compared MRM with breast-conserving surgery (BCS) and adjuvant RT and demonstrated equivalent long-term survival rates (3). Additional studies confirmed the equivalence of breast conserving therapy with MRM (4,5,6,7,8). Given the potential physical and psychosocial morbidity of mastectomy, BCS followed by radiotherapy became the standard of care for the treatment of early-stage breast cancer in the late 1980s.

RT planning and delivery techniques were relatively rudimentary at the time of these early trials. Over the subsequent decades, breast RT evolved and improved. The adoption of computed tomography (CT) into radiation planning allowed for three-dimensional (3D) dose calculation. It also allowed for direct visualization of a patient’s unique anatomy. By directly visualizing the tumor bed and/or area at risk, dose delivery could be optimized to avoid neighboring normal tissues and maximize delivery to the target. CT imaging could also confirm patient positioning and reduce uncertainty in patient setup.

This same period saw similar improvements in surgical techniques, imaging, and pathologic evaluation. Multidisciplinary improvements in care led to decreased risks of locoregional recurrence; the risk of LR is now thought to be approximately 0.5% per year (9,10,11). Many studies have also now confirmed the relationship between breast cancer subtype and LR, with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive, human epidermal growth factor receptor (HER-2)–negative patients and ER+/PR+/HER-2+ patients demonstrating low rates of LR compared to patients with triple-negative (ER−/PR−/HER-2−) or ER−/PR−/HER-2+ subtypes (12,13,14). For some patients, such excellent local control outcomes have compelled attempts to reduce the total volume of breast tissue treated (by using partial breast irradiation) or to consider omission of RT in select populations. For women undergoing BCS with involvement of their axillary lymph nodes, recent trials have attempted to better understand the role of RT directed at the regional draining nodal basins given the potential toxicities associated with larger radiation fields. This chapter will address the evolving role of adjuvant RT after BCS including current practices and future directions.

Invasive Disease

Radical mastectomy, introduced by Halsted and Meyer, was the standard of care for the surgical management of breast cancer for most of the 20th century. In 1971, the NSABP initiated the B-04 clinical trial to determine if radical mastectomy was equivalent to other locoregional treatment approaches; treatment approaches were stratified based on clinical lymph node involvement. Although the study was not powered to detect small differences between arms, no statistically significant advantages in either disease-free or overall survival (OS) were seen with more aggressive surgery after 20 years of follow-up (2).

After radical surgery was not shown to improve outcomes, several groups began to investigate breast-conserving therapy with lumpectomy or quadrantectomy followed by whole breast RT. Several prospective, randomized trials were initiated to determine whether a breast conserving approach would be equivalent to mastectomy. The largest U.S. breast-conservation trial, NSABP B-06, randomized women to mastectomy, lumpectomy alone, or lumpectomy
followed by radiotherapy. After greater than 20 years of follow-up, no significant differences in either local control or survival were observed between patients treated with mastectomy and those treated with lumpectomy and radiotherapy (5). The results of six modern trials are shown in Table 12-1. With long-term follow-up available, these trials consistently demonstrate no adverse effect on survival with breast-conservation therapy versus mastectomy (3,4,5,6,7,8).

TABLE 12-1 Prospective Randomized Trials of Mastectomy Versus Breast-Conserving Treatment for Invasive Breast Cancer

Trial N Follow-Up (Yr) Inclusion Criteria (T,N,M) Local Recurrence (%) Overall Survival (%)
Institute Gustave Roussy, France (4) 179 14.5 ≤2 cm, N0–1, M0 18 13 65 73
National Tumor Institute, Milan, Italy (3) 701 20 ≤2 cm, N0–1, M0 2.3 8.8 58.8 58.3
NSABP B-06 (5) 1,444 20 ≤4 cm, N0–1, M0 10.2 14.3 47 46
National Cancer Institute (6) 247 10 ≤5 cm, N0–1, M0 10 5a 75 77
EORTC (7) 868 8 ≤5 cm, N0–1, M0 12.2 19.7 66 65
Danish Breast Cancer Group (8) 731 20 Any, N0–1, M0 6.9 4.5 50.6 57.8
a Recurrences salvaged by mastectomy were censored from the analysis.
BCS + RT, breast-conserving surgery followed by radiotherapy; EORTC, European Organization for Research and Treatment of Cancer; M, mastectomy; NSABP, National Surgical Adjuvant Breast and Bowel Project; N, number of patients in the study analysis; TNM, staging classification of the primary tumor, lymph nodes, and metastatic disease; M0, no evidence of metastatic disease; N0, no involved lymph nodes; N1, clinically palpable axillary lymph nodes (classification used at the time of study entry).

After the results of these trials became available, the National Institutes of Health held a consensus development conference on the treatment of early-stage breast cancer. The panel concluded that BCS followed by radiotherapy was preferable to mastectomy because it provides equivalent outcome while preserving the breast and reducing physical and psychological morbidity (15).

The trials cited above demonstrated that BCS and adjuvant RT could afford patients with breast cancer the opportunity to preserve their breast and receive equivalent cancer-directed therapy to mastectomy. However, the relative contribution of RT to these comparable outcomes was an active question of research. Therefore, several randomized trials were undertaken to see if BCS alone would result in similar outcomes to BCS and adjuvant RT (5,16,17,18,19,20). In NSABP B-06 described above, patients treated with lumpectomy alone compared to lumpectomy followed by RT showed a significantly increased incidence of LR at 20 years. Specifically, the addition of radiotherapy decreased the risk of LR after BCS from 39.2% to 14.3% (5). The long-term results of these trials are summarized in Table 12-2. These trials consistently demonstrated that adjuvant RT decreased the relative risk of LR by approximately 55% to 80%; however, they failed to show a survival benefit with the addition of adjuvant RT to BCS.

TABLE 12-2 Prospective Randomized Trials of Breast-Conserving Surgery With or Without Radiotherapy for Invasive Breast Cancer

Trial N Follow-Up (Yr) Local Recurrence (%) Overall Survival (%)
NSABP B-06 (5) 1,137 20 39.2 14.3 46 46
National Tumor Institute, Milan, Italy (13) 567 10 23.5 5.8 76.9 82.4
Ontario Clinical Oncology Group, Canada (14) 837 8 35 11 76 79
Uppsala–Orebro Breast Cancer Group, Sweden (15) 381 10 24 8.5 78 77.5
Tampere–Helsinki, Finland (16) 263 12 27.2 11.6 79.8 84.8
NSABP B-21 (17) 668 8 16.5 2.8 94 93.4
N, number of patients in the study analysis; BCS, breast-conserving surgery; NSABP, National Surgical Adjuvant Breast and Bowel Project; RT, radiotherapy.

However, in 2005, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) published the results of a meta-analysis of 42,000 women in 78 randomized treatment comparisons. These patients included 7,300 women treated in 10 trials with BCS, with or without radiotherapy. In this first publication, radiotherapy reduced the risk of LR from 26% to 7% at 5 years. Notably, the addition of radiotherapy decreased the 15-year breast cancer mortality risk from 35.9% to 30.5%, with
an overall mortality reduction of 5.3% (21). In 2011, the EBCTCG published an updated analysis, now including 10,801 women (with both pathologically involved and uninvolved axillary lymph nodes) and again demonstrated a significant reduction in the 10-year risk of any (i.e., locoregional or distant) first recurrence from 35.0% to 19.3% and a reduction in the 15-year risk of breast cancer deaths from 25.2% to 21.4% (absolute reduction 3.8%, confidence interval 0.8% to 5.8%) (22). These benefits were consistent across subgroups of women. While individual trials could not confirm a survival benefit to adjuvant RT despite a significant benefit in LR, the EBCTCG analysis provided evidence that adjuvant RT after BCS reduced the risk of dying from breast cancer.

Ductal Carcinoma in Situ

As with invasive disease, ductal carcinoma in situ (DCIS) was initially managed with mastectomy, but breast conservation was subsequently offered as an alternative option given equivalent outcomes when compared to mastectomy. Investigators again questioned the relative benefit of RT after BCS, resulting in four large, prospective trials randomizing patients with DCIS to adjuvant RT or no RT after BCS. These trials consistently showed significant reductions in LR with radiotherapy and are summarized in Table 12-3. In the NSABP B-17 trial, 818 patients were randomized to BCS versus BCS plus RT. At a median follow-up of 17.3 years, adjuvant RT reduced the risk of an ipsilateral breast event from 35% to 19.7% (23). The European Organization for Research and Treatment of Cancer (EORTC) 10853 trial similarly randomized 1,010 patients to BCS with or without adjuvant RT (24). RT reduced the risk of local failure at 10 years from 26.4% to 15.0% (24). A United Kingdom, Australia, and New Zealand (UK/ANZ) group conducted a trial designed with a 2 × 2 factorial approach to assess the effects of both radiotherapy and tamoxifen after lumpectomy. Long-term results of this trial were published at a median follow-up of 12.7 years and showed that in 1,701 women, RT reduced the incidence of ipsilateral invasive disease and DCIS from 19.4% to 7.1% in 10 years (25). In a Swedish trial, 1,046 patients were randomized to resection with or without radiotherapy. At a mean follow-up of 8 years, the absolute risk reduction from RT on ipsilateral breast events was 16% at 10 years (26). A meta-analysis of these four randomized trials reported that the addition of radiotherapy reduces the risk of LR by approximately 60% (27). Although no trial was sufficiently powered to demonstrate a significant improvement in OS, the trials that reported event-free or disease-free survival (DFS) consistently showed a significant benefit from radiotherapy (24,26).

TABLE 12-3 Prospective Randomized Trials of Lumpectomy With or Without Radiotherapy for Ductal Carcinoma in Situ

Trial N Follow-Up (yr) Tamoxifen %LR INV OBS %LR INV RT %LR DCIS OBS %LR DCIS RT
NSABP B-17 (23) 818 17.3 No 19.6 10.7 15.4 9.0
EORTC 10853 (24) 1,010 10.5 NR 13.1 7.9 13.3 7.1
SweDCIS (26) 1,067 8.4 <4% 12.3 7.2 14.8 4.9
UK/ANZ (25) 1,701 12.7 52% 9.6 3.7 15.8 5.2
N, number of patients in the study analysis; RT, radiation therapy; LR, local recurrence; INV, invasive; OBS, observation; DCIS, ductal carcinoma in situ; EORTC, European Organisation for Research and Treatment of Cancer; NR, not reported; NSABP, National Surgical Adjuvant Breast and Bowel Project; SweDCIS, Swedish multi-institutional randomized trial for radiotherapy and DCIS; UK/ANZ; United Kingdom, Australia, New Zealand.

Omission of Radiation Therapy in Select Populations

As demonstrated in the multiple randomized trials reviewed above, adjuvant breast RT decreases the risk of a LR and may in some cases improve OS. Indeed, postoperative whole breast RT remains the standard of care for most patients treated by BCS.

In some select cases, however, the risk of a LR is quite low, and studies have suggested that there may be a subgroup of patients in whom adjuvant radiation may provide only modest benefit (20,28,29,30,31). This subgroup generally includes older women with early-stage, hormone-positive invasive breast cancer. This raises the question of whether radiation can be reasonably omitted without compromising clinical outcomes.

This question was investigated in a randomized fashion by the Cancer and Leukemia Group B (CALGB), who ran the CALGB 9343 trial that compared adjuvant tamoxifen alone versus adjuvant tamoxifen and RT in elderly women with favorable disease (32). In this study, 636 women aged 70 or older who had clinical T1N0 and ER+ breast cancer treated with lumpectomy were randomized to receive tamoxifen alone for 5 years, or tamoxifen in combination with whole breast RT. With a median follow-up of 12.6 years the 10-year freedom from local regional recurrence was 98% in the tamoxifen and RT arm versus 90% in the tamoxifen-alone arm. Of the patients who had recurrences, there was no difference in
time to mastectomy or time to distant metastases (DM). Further, there was no difference in 10-year breast cancer–specific survival or OS between the arms (10-year OS was 67% in the tamoxifen and RT arm vs. 66% in the tamoxifen-alone arm).

Another randomized trial aimed to address the omission of radiation in a favorable population was reported in the United Kingdom. The PRIME II study was a multicenter trial that randomized 1,326 women aged 65 or older with hormone-positive, low-risk, invasive breast cancer who were receiving adjuvant endocrine therapy, to whole breast radiation versus no radiation (33). Low risk was defined by the study investigators as tumors that were less than or equal to 3 cm in size with excision to at least 1-mm margins, and pathologic axillary node negative. Patients could have a grade 3 tumor or lymphovascular invasion but not both. After a median follow-up of 5 years, ipsilateral breast recurrence rates were 1.3% in the RT group and 4.1% in the no-RT group (p = 0.0002). There was no difference in regional recurrence, DM, or breast cancer–specific survival. The 5-year OS was also the same (93.9% in both groups). Taken together, these two large randomized studies are consistent in showing that while RT does lower ipsilateral breast tumor recurrence, recurrence rates in these select populations are overall quite low. Furthermore, the absolute difference in LR between the RT and no-RT arms does not translate into differences in other important endpoints, including OS.

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Aug 25, 2021 | Posted by in Aesthetic plastic surgery | Comments Off on Radiation Therapy Following Breast-Conserving Surgery
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