Randomized trials have established that breast-conserving surgery followed by radiation therapy is equivalent to mastectomy for appropriately selected patients with early-stage breast cancer. In all of these trials, segmental mastectomy combined with breast irradiation resulted in survival and local control rates similar to those achieved by modified radical or radical mastectomy.

In 1973 Veronesi et al. began a prospective trial in Milan comparing radical mastectomy to breast-conserving surgery followed by radiation [16]. The study enrolled 701 patients with no palpable axillary lymph nodes and tumors up to 2 cm in diameter. Patients were randomly assigned to receive Halsted radical mastectomy, or quadrantectomy, axillary dissection, and radiation. A radiation dose of 50 Gy given over 5 weeks was delivered to the breast followed by a boost dose of 10 Gy. Patients found to have positive axillary lymph nodes at surgery received 12 cycles of adjuvant cyclophosphamide, methotrexate, and fluorouracil. The 20-year mortality rate from all causes was 41.2% in the radical-mastectomy arm and 41.7% in the breast-conserving surgery plus radiation arm (P = 1.0). Mortality from breast cancer was not significantly different, at 24.3 and 26.1%, respectively (P = 0.8). The cumulative incidence of local failure was 2.3% in the mastectomy group and 8.8% in the breast-conserving surgery and radiation group (P < 0.001). There was no difference between the groups in the incidence of contralateral breast cancer, distant metastases, or second primary cancers.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated the NSABP B-06 trial in the United States in 1976 which enrolled 1843 women with clinical stage I or II breast cancer [17]. Patients were randomly assigned to treatment with total mastectomy, lumpectomy, or lumpectomy with radiation. The prescribed radiation dose was 50 Gy to the breast without a lumpectomy cavity boost. At 20-year follow-up, there was no significant difference in overall survival, disease-free survival, or distant disease-free survival among any of the groups. However, the addition of radiation to lumpectomy significantly decreased the local recurrence rate by half compared to lumpectomy alone with the cumulative ipsilateral breast recurrence being 14.3% in the lumpectomy and radiation group and 39.2% in the lumpectomy alone group (P < 0.001).

EORTC 10801 was a randomized trial which compared mastectomy to breast-conserving therapy in 868 women with stage I and II breast cancer [18]. The European Organization for Research and Treatment of Cancer (EORTC) conducted the trial in the United Kingdom, the Netherlands, Belgium, and South Africa and initiated enrollment in 1980. Patients were randomized to modified radical mastectomy or breast-conserving therapy. Breast-conserving therapy consisted of lumpectomy with a 1 cm margin, axillary dissection, and whole-breast irradiation prescribed to 50 Gy with a 25 Gy lumpectomy site boost. At 20-year follow-up, the mortality rate was 55% in the modified radical mastectomy group and 61% in the breast-conserving therapy group, with no significant difference in time to death (HR 1.11; p = 0.23). There was also no significant difference in time to distant metastases (HR 1.13; P = 0.23) with a distant metastasis rate of 42% in the modified radical mastectomy group and 46% in the breast-conserving therapy group. Time to distant metastases and overall survival were stratified by age less than 50 versus age greater than or equal to 50, and there was no difference between treatment groups. The 15-year overall survival rate was 53.6% in the mastectomy group and 51.6% in the breast-conserving therapy group.

The Institut Gustave Roussy conducted a prospective trial in which 179 patients under age 70 with T1 N0-N1 M0 invasive breast cancer were randomized to modified radical mastectomy or wide lumpectomy, axillary surgery, and adjuvant radiation [19, 20]. Eligible patients had tumors macroscopically measuring 2 cm or less on frozen section at the time of surgery. Lymph node-negative patients received a whole-breast irradiation dose of 45 Gy given in 18 fractions with a 15 Gy tumor bed boost. Patients with positive lymph nodes received whole-breast irradiation and were randomized to radiation treatment of the regional lymph nodes. The 15-year rates of local recurrence, locoregional recurrence, contralateral breast cancer, distant metastases, and overall survival were not statistically different between surgical treatment arms and radiation treatment arms. The 15-year cumulative local recurrence rate was 13% in the lumpectomy and radiation group and 18% in the mastectomy group (P = 0.48). The 15-year rate of any first event was 45% with lumpectomy and radiation and 56% with mastectomy (P = 0.23) with 15-year overall death rates of 27 and 35%, respectively (P = 0.19).

There have been at least nine clinical trials evaluating endocrine therapy as a substitute for radiation. All trials have shown that radiation therapy alone provides improved local control compared to endocrine therapy alone.

There have been a number of randomized trials investigating the local control benefit of the addition of postoperative radiation to breast-conserving surgery. In these studies, the addition of postoperative radiation reduced the risk of local recurrence by 50% or more compared to breast-conserving surgery alone. These studies support the role of adjuvant radiation as part of standard-of-care treatment for younger women who select breast-conserving treatment.

Beginning in 1981, the Uppsala-Orebro Breast Cancer Study conducted a randomized trial of breast-conserving surgery with or without radiation in 381 Swedish women with stage I breast cancer [21]. Patients were treated with sector resection and axillary dissection and then randomized adjuvant breast irradiation to 54 Gy or observation. At 5 years, the local recurrence rate was 2.3% in the group that received adjuvant radiation versus 18.4% in the group in which radiation was omitted. Overall survival, regional recurrence-free survival, and distant recurrence-free survival were not different between groups.

As discussed above, NSABP B-06 compared total mastectomy, lumpectomy alone, and lumpectomy plus radiation in 1851 women with clinical stage I and II breast cancer. In 1137 women with negative surgical margins, the 20-year cumulative incidence of ipsilateral breast tumor recurrence was 39.2% in the lumpectomy alone group compared to 14.3% in the lumpectomy plus radiation group (p < 0.0001) [17]. For women with negative lymph nodes, the 20-year ipsilateral breast tumor recurrence rates were 36.2% with lumpectomy alone and 17.0% with lumpectomy plus radiation; for women with positive lymph nodes, the ipsilateral breast tumor recurrence rates were 44.2% without radiation versus 8.8% with radiation. Disease-free survival, distant disease-free survival, and overall survival did not differ between any of the groups. Breast cancer-specific mortality was decreased in patients treated with lumpectomy plus radiation compared to lumpectomy alone (HR 0.82, P = 0.04). This marginally significant decrease in breast cancer mortality may have been partially offset by deaths from other causes (HR 1.23; P = 0.23).

Because of the uncertainty regarding the need for radiation in women with favorable risk factors, the NSABP initiated NSAPB B-21 which enrolled 1009 women with tumors clinically or pathologically <1 cm in size who were treated with lumpectomy and axillary dissection [22]. Patients were required to have negative lymph nodes and negative margins on pathology review. Patients were randomized to tamoxifen only, radiation and placebo, or radiation and tamoxifen. At 8 years, the cumulative incidence of local relapse was 16.5% in the tamoxifen alone group, 9.3% in the radiation and placebo group, and 2.8% in the radiation and tamoxifen group. The respective hazard ratios for ipsilateral breast tumor recurrence were HR 0.51 (P = 0.008) for radiation plus placebo versus tamoxifen alone, HR 0.37 (P = 0.01) for radiation plus tamoxifen versus radiation plus placebo, and HR 0.19 (P < 0.0001) for radiation plus tamoxifen versus tamoxifen alone. Tamoxifen decreased the occurrence of contralateral breast cancer compared to radiation plus placebo (HR 0.45; P = 0.039). There was no difference in overall survival or distant metastases between groups.

Veronesi et al. at the Milan National Cancer Institute also investigated the efficacy of breast-conserving surgery without radiation in a study where 579 women under the age of 70 with breast cancer less than 2.5 cm in size were randomized to quadrantectomy, axillary dissection, and radiation, or the same surgery without radiation [23]. The 10-year crude ipsilateral breast tumor recurrence rate was 23.5% for patients treated without radiation and 5.8% for patients who received radiation. The cumulative hazard rate for ipsilateral recurrence was significant (P < 0.001). Overall survival was not statistically different between the treatment arms; however, on subset analysis, patients with node-positive disease had improved survival with radiation (P = 0.038) with a crude mortality rate of 34.1% in the radiation omission group versus 19.1% for group who received radiation. Subset analysis also showed that the group which radiation provided the greatest decrease in ipsilateral recurrence was patients aged 45 and younger. In older age groups, the difference in ipsilateral recurrence tended decrease until no difference was seen after age 65.

Two comprehensive meta-analyses of the benefit of postoperative radiation added to breast-conserving surgery suggest that adjuvant radiation significantly decreases local recurrence, breast cancer mortality, and overall mortality.

In 2005, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) published a meta-analysis of individual patient data from 7311 patients with invasive breast cancer treated on clinical trials comparing breast-conserving surgery with radiation to breast-conserving surgery without radiation [24]. The meta-analysis showed that radiation significantly improved 15-year local recurrence and 15-year breast cancer-specific survival compared to no radiation and radiation significantly improved 15-year overall mortality by 5.3% (35.2 versus 40.5%). The analysis also showed three-fourths of breast recurrences occurred in the first 5 years following treatment.

The Early Breast Cancer Trialists’ Collaborative Group updated the meta-analysis in 2011 to include individual data on 10,801 patients treated on 17 randomized trials comparing adjuvant radiation versus observation after breast-conserving surgery [25]. The update showed that compared to observation, adjuvant radiation significantly decreased the 10-year risk of any first recurrence from 35.0 to 19.3% (RR 0.52). Radiation also significantly reduced the 10-year risk of breast cancer mortality from 25.2 to 21.4% (RR 0.82) and significantly decreased the 15-year risk of overall mortality from 37.6 versus 34.6% (RR 0.92). For women with node-positive disease, the benefits of radiation were even greater with radiation reducing the 10-year risk of any first recurrence from 63.7 to 42.5% and improving the 15-year risk of breast cancer mortality from 51.3 to 42.8%.

Lumpectomy followed by radiation is a standard of care option for the majority of women with early-stage invasive breast cancer. As observed in randomized trials, lumpectomy without radiation results in increased local relapse. However, trials examining the omission of radiation found that in elderly women, local relapse rates were lower and radiation provided a lower absolute local control benefit without improving overall survival. The question of whether radiation can be safely eliminated following breast-conserving therapy for elderly patients has been studied with retrospective and prospective studies which are reviewed below. In sum, these studies show adjuvant radiation improves local control for older women with favorable-risk disease without improving overall survival. For patients aged 70 or older who will receive 5 years of endocrine therapy and who have small (T1), low- or intermediate-grade, estrogen receptor-positive tumors resected with good margins, the risk of disease recurrence may be acceptably low such that adjuvant radiation may be omitted if the patient accepts the increased risk of recurrence associated with radiation omission.

CALGB (Cancer and Leukemia Group B) 9343 was a trial which evaluated the effect of radiation omission in older patients with favorable-risk breast cancer [26]. The trial evaluated 636 women aged 70 or older with clinically node-negative, estrogen receptor-positive breast cancer measuring 2 cm or less who were treated with lumpectomy with negative pathological margins. Axillary dissection was permissible but not required. Patients were randomized to receive tamoxifen 20 mg for 5 years plus whole-breast irradiation with a boost or tamoxifen alone for 5 years. With a median follow-up of 12.6 years, the 10-year rate of locoregional recurrence was 10% in the tamoxifen alone arm versus 2% in the tamoxifen plus radiation arm (HR 0.18; p < 0.001). The published study did not analyze pathologic tumor size or margin width. Overall survival at 10 years was 67% in the tamoxifen plus radiation group and 66% in the tamoxifen alone group. Overall survival, breast cancer-specific survival, time to mastectomy, and time to distant metastasis were not statistically different between groups.

Fyles et al. performed a trial in Canada which enrolled 769 women aged 50 or older with node-negative invasive breast cancer and tumor size of 5 cm or less on pathologic review [27]. Patients were treated with breast-conserving surgery with negative pathologic margins and then randomized to whole-breast irradiation plus tamoxifen 20 mg for 5 years or tamoxifen alone. Most patients were aged 60 or older, most tumors were less than 2 cm, and more than 80% of tumors were hormone receptor positive. The 5-year rate of local recurrence was 0.6% for patients receiving radiation plus tamoxifen and 7.7% for patients receiving tamoxifen alone (HR 8.3; P < 0.001). The 5-year disease-free survival rates were 91% for patients receiving radiation and tamoxifen versus 84% for patients receiving tamoxifen alone (P = 0.004). In a planned subset analysis of women with the most favorable-risk disease, the 5-year rate of local recurrence of women with estrogen receptor-positive tumors measuring 2 cm or less was 0.5% for patients receiving radiation and tamoxifen and 5.9% for patients receiving tamoxifen alone (P < 0.001). The 5-year rate of axillary recurrence was also less with radiation versus no radiation (0.5 versus 2.5% (P = 0.049), respectively). Overall survival and distant recurrence rates were not statistically different between groups.

The most recent study evaluating the role of radiation omission in patients with low-risk invasive breast cancer is the PRIME II which enrolled 1326 women in the United Kingdom, Greece, Australia, and Serbia from 2003 to 2009 [28]. All women were 65 years or older and had low-risk disease defined as node-negative, hormone receptor-positive breast cancer measuring 3 cm or less. The study allowed for tumors with lymphovascular invasion or nuclear grade 3 histology, but not both. Following surgical axillary staging and breast-conserving surgery with pathologic margins of 1 mm or more, patients were randomized to receive endocrine therapy and whole-breast irradiation with a boost or endocrine therapy alone. The 5-year rate of ipsilateral breast tumor recurrence was 4.1% in the endocrine therapy alone arm and 1.3% in the endocrine therapy plus radiation arm. The hazard ratio for ipsilateral breast tumor recurrence for the endocrine therapy alone arm was 5.19 (P = 0.0007). Five-year overall survival was 93.9% in both treatment arms. Regional recurrence, distant metastases, contralateral breast cancers, and new breast cancers were not significantly different between groups. Analysis of patient characteristics showed 88% of patients had tumors 2 cm or smaller with roughly 40% of tumors measuring 1 cm or less. In more than half of patients, the surgical margin was either greater than 5 mm or re-excision was performed. Ninety percent of patients had estrogen receptor-rich tumors, and more than 95% of patients had tumors of low or intermediate grade.

Collectively these studies suggest the local control benefit of adjuvant radiation for elderly patients with low-risk features is statistically significant, but the absolute value may be relatively small. Adjuvant radiation for this subgroup of patients has not been shown to improve overall survival or distant metastasis-free survival. The decision to give radiation to these patients must weigh improvement in local recurrence against the overall risk of disease recurrence and the risk of radiation treatment side effects. Patient longevity must also be considered because the cumulative risk of disease recurrence increases over time so patients with a long life expectancy will experience a higher risk of disease recurrence than patients with a shorter life expectancy.

Whole-breast irradiation often includes treatment of level 1 and part of level 2 axillary lymph nodes. The addition of regional nodal irradiation expands the treated nodal basins to include level 3 axillary nodes, supraclavicular nodes, and internal mammary nodes. The addition of regional nodal radiation to whole-breast radiation typically occurs when encountering positive axillary lymph nodes and its role in breast-conserving treatment has historically been extrapolated from trials evaluating locoregional radiotherapy in the postmastectomy setting. Two recently published randomized trials have explored the benefit of regional nodal radiotherapy in the setting of breast conservation and whole-breast radiotherapy. Although the results are supportive of a benefit of regional nodal irradiation in high-risk or node-positive patients, the relative benefit is small and the trials have generated discussion regarding how to best identify those patients who will receive a meaningful benefit from added therapy in both the breast conservation and postmastectomy scenarios. The NCIC (National Cancer Institute of Canada) Clinical Trials Group MA.20 trial evaluated the benefit of regional nodal irradiation in node-positive or high-risk early-stage invasive breast cancer patients treated with breast-conserving surgery and adjuvant chemotherapy [29]. Eligible patients underwent breast-conserving surgery and axillary staging with sentinel lymph node biopsy or axillary dissection. Patients were required to have positive axillary nodes on pathologic review or have apathologically negative axilla, but have high-risk features. High-risk features included a primary breast tumor measuring at least 5 cm, or a breast tumor measuring at least 2 cm with fewer than ten axillary nodes removed and at least one of the following: estrogen receptor negativity, grade 3 histology, or lymphovascular invasion. Following surgery, patients received adjuvant chemotherapy, endocrine therapy, or both. The study enrolled 1832 eligible patients who were randomized to adjuvant whole-breast irradiation (control arm) or adjuvant whole-breast and regional nodal irradiation which included treatment of the internal mammary, supraclavicular, and axillary lymph nodes. The radiation dose was 50 Gy given over 25 fractions. Ninety-nine percent of patients had T1 or T2 disease and 75% of patients had estrogen receptor-positive tumors. Two-thirds of patients had ten or more axillary lymph nodes removed. Half of patients had one pathologically positive node, and three-fourths of patients had one or two positive nodes. At 10 years of follow-up, the primary outcome of overall survival was not statistically different between groups, 81.8% in the whole-breast irradiation group and 82.8% in the whole-breast and regional nodal irradiation group (HR 0.91; P = 0.38). Disease-free survival was improved with regional nodal irradiation compared to whole-breast irradiation (82 versus 77%; HR 0.76; P = 0.01). Regional nodal irradiation also improved 10-year isolated locoregional disease-free survival compared to whole-breast-only irradiation (95.2 versus 92.2%; HR 0.59; P = 0.009) and 10-year distant disease-free survival (86.3 versus 82.4%; HR 0.76; P = 0.03). Breast cancer-specific mortality did not differ statistically between groups. On preplanned subgroup analysis of patients with estrogen receptor-negative disease, regional nodal irradiation improved 10-year overall survival compared to whole-breast-only irradiation (81.3 versus 73.9%; HR 0.69; P = 0.05).

The European Organization for Research and Treatment of Cancer (EORTC) 22922/10925 trial enrolled 4004 women in 13 countries to evaluate the survival benefit of elective internal mammary and medial supraclavicular irradiation in patients with stage I, II, or III invasive breast cancer [30]. Patients were eligible if their primary breast tumor was centrally or medially located, with or without axillary nodal involvement, or if the primary breast tumor was externally located with axillary nodal involvement. Following mastectomy or breast-conserving surgery, patients were randomized to elective radiation to the internal mammary and medial supraclavicular nodal basins or no radiation treatment to these nodal basins. Most patients (76%) underwent breast-conserving surgery followed by whole-breast irradiation, and 85% received a tumor bed boost. A minority of patients (24%) underwent mastectomy of which approximately three-fourths received chest wall irradiation. Systemic therapy was given to almost all node-positive patients (99%) and to two-thirds of node-negative patients. The axillary disease burden was low in most patients with 44.5% of patients having no pathologically involved lymph nodes and 43% of patients having 1–3 pathologically involved nodes. Sixty percent of patients had a primary breast tumor 2 cm or smaller, and 36% of patients had a primary breast tumor measuring 2–5 cm. The median patient age was 54. Ten-year overall survival was borderline statistically different between groups, with an 82.3% overall survival rate in the elective nodal irradiation group and 80.7% in the group without elective nodal irradiation (HR 0.87; P = 0.06). Elective nodal radiation improved 10-year breast cancer mortality from 14.4 to 12.5% (HR 0.082; P = 0.02) and improved 10-year disease-free survival from 69.1 to 72.1% (HR 0.89; P = 0.04). Distant disease-free survival was also higher in the elective nodal irradiation group compared to no elective irradiation, 78 versus 75%, respectively (HR 0.86; P = 0.02).

A radiation boost is a short course of focused tumor bed irradiation additional to whole-breast irradiation. Studies have shown that a tumor bed boost improves local control, especially in younger patients.

The EORTC boost trial was a multicenter trial which examined the benefit of a lumpectomy cavity boost in 2657 patients with early-stage breast cancer [31]. Patients were eligible if they were age 70 or younger and had T1-T2 N0-1 M0 invasive breast cancer. Patients underwent axillary dissection and local excision of the primary breast tumor with a 1–2 cm margin. Patients with microscopically negative margins underwent whole-breast irradiation of 50 Gy over 5 weeks and were then randomized to a 16 Gy boost to the tumor bed or no boost. Overall survival at 20 years was not statistically different between groups with survival at 59.7% in the boost group compared to 61.1% in the no boost group (HR 1.05; P = 0.323). The boost group had decreased local recurrence as the first treatment failure compared to the no boost group (9 versus 13%) (HR 0.65; P < 0.001). Twenty-year ipsilateral breast tumor recurrence was 12.0% in the boost group compared to 16.4% in the no boost group. At 20 years, a higher rate of severe fibrosis was seen in the boost group compared to the no boost group, 5.2 versus 1.8% (P < 0.0001). The absolute reduction in local recurrence provided by a boost was greatest in younger patients and progressively decreased in older subgroups of patients. For example, the boost decreased 20-year local recurrence in patients younger than age 40 from 36.0 to 24.4%, while in patients older than age 60, local recurrence decreased from 12.7 to 9.7%.

The Lyon Breast Cancer Trial also investigated the role of a tumor bed boost. The study enrolled 1024 patients less than 70 years of age with invasive ductal carcinoma measuring up to 3 cm [32]. All patients underwent breast-conserving surgery with negative pathologic margins followed by whole-breast irradiation of 50 Gy in 20 fractions. Patients were randomized to a 10 Gy boost to the tumor bed or no further treatment. With a median follow-up of 3.3 years, the 5-year rate of local recurrence was 3.6% in the patients who received a boost versus 4.5% in the patients who received no boost (P = 0.044). Although the rate of grade 1 or 2 telangiectasia was higher in the boost group (12.4 versus 5.9%), patient-reported assessment of cosmetic result was not different between treatment groups.

Traditionally, patients treated with whole-breast irradiation received 25–28 daily fractions (treatments) given at a dose of 1.8–2 Gy per day, potentially followed by a boost. Hypofractionation is treating patients with a fewer number of fractions than would traditionally take place usually with goal of reducing overall treatment duration. Hypofractionation typically involves giving patients a higher daily dose of radiation than one would receive with traditionally fractionated treatment. Hypofractionated treatment in breast cancer has reduced the number of whole-breast treatments from 25 to 28 fractions potentially followed by a boost to 15 or 16 fractions +/- a boost. This reduces treatment duration from 5–7 to 3–4 weeks.

The validity of hypofractionated whole-breast radiation treatment was established by three large randomized trials comparing hypofractionated to conventionally fractionated treatment. These trials suggest hypofractionated treatment provides equivalent local control and toxicity compared to traditionally fractioned treatment in appropriately selected patients.

The Ontario Clinical Oncology Group’s hypofractionation trial was a multicenter trial in Canada which enrolled patients from April 1993 to September 1996 [29]. The trial included 1230 women with pathologically node-negative invasive breast cancer treated with lumpectomy. Patients were excluded if they had a tumor larger than 5 cm, clinical T4 disease, or breast width greater than 25 cm. Patients were randomized to whole-breast irradiation of 42.5 Gy in 16 fractions over 22 days or 50 Gy in 25 fractions over 35 days. Ten-year local recurrence was not significantly different between groups (6.2% in the 42.6 Gy group and 6.7% in the 50 Gy group). Ten-year overall survival was the same between groups (84%).

The START-A and START-B trials were multicenter hypofractionation trials which ran concurrently in the United Kingdom between 1999 and 2002 [33]. Eligible patients had pT1-T3a pN0-N1 M0 invasive breast cancer treated with breast-conserving surgery or mastectomy. The majority of patients received tamoxifen and/or chemotherapy.

The START-A trial randomized 2236 patients to three different radiation treatment schedules, all given over 5 weeks: 39 Gy in 13 fractions, 41.6 Gy in 13 fractions, or 50 Gy in 25 fractions (control group) [33]. A sequential tumor bed boost was allowed as was treatment of the regional lymph nodes if lymph nodes were positive. Eighty-five percent of patients received breast-conserving surgery and 61% received a tumor bed boost; 29% of patients had positive lymph nodes and 14% received locoregional irradiation. At a median follow-up of 9.3 years, the 10-year rate of locoregional relapse did not differ statistically between the 41.6 and 50 Gy groups (6.3 versus 7.4%, respectively; HR 0.91; P = 0.65) or between the 39 and 50 Gy groups (8.8 versus 7.4%, respectively; HR 1.18; P = 0.41).

The START-B hypofractionation trial enrolled patients concurrently with the START-A trial. Similar to the START-A trial, eligible patients on START-B were women who had pT1-T3a pN0-N1 M0 invasive breast cancer treated with breast-conserving surgery or mastectomy [33]. A majority of patients received tamoxifen and/or chemotherapy. The START-B trial randomized 2215 patients to two different radiation treatment schedules with differing durations of treatment: 40 Gy in 15 fractions over 3 weeks (experimental group) or 50 Gy in 25 fractions over 5 weeks (control group). A sequential tumor bed boost was allowed. Ninety-two percent of patients received breast-conserving surgery and 43% received a tumor bed boost; 23% of patients had positive lymph nodes but only 7% underwent locoregional irradiation. At a median follow-up of 9.9 years, the 10-year rate of locoregional relapse was not significantly different between the 40 Gy group and the 50 Gy group (4.3 versus 5.5%; HR 0.65; P = 0.21).

In START-A trial, there was significantly less breast edema, telangiectasias, and moderate or marked breast induration in the 39 Gy group compared to the 50 Gy group; there was no significant difference in toxicity between the 41.6 and 50 Gy groups. In START-B, there was significantly less breast edema, breast shrinkage, and telangiectasia development in the 40 Gy group compared to the 50 Gy group.

In 2011, the American Society for Radiation Oncology issued an evidence-based guideline for fractionation for whole-breast irradiation [34]. The guideline stated that for patients aged 50 or older with pT1-T2 pN0 breast cancer treated with breast-conserving surgery without adjuvant chemotherapy, hypofractionated whole-breast irradiation provides equivalent local control and toxicity compared to conventional fractionated whole-breast irradiation. When using hypofractionation, they recommended the radiation dose along the central axis of the breast deviate no more or less than 7% from the prescription dose. The task force behind the guideline favored giving hypofractionated radiotherapy using a dose schedule of 42.5 Gy in 16 fractions when a boost is not used. There was no consensus regarding the use of a tumor bed boost with hypofractionation. Additionally, the task force recommended the heart should be excluded from the primary treatment fields when hypofractionated whole-breast radiation is used due to the uncertainty regarding late effects of hypofractionation on cardiac function.

In 2014, the American Society for Radiation Oncology, as part of its Choosing Wisely campaign, recommended that in women who are aged 50 years or older with early-stage invasive breast cancer, whole-breast irradiation following breast-conserving surgery should not be given without consideration of shorter treatment schedules [35].

The previous sections have covered the literature supporting adjuvant whole-breast irradiation therapy as part of standard of care treatment after breast-conserving surgery, with hypofractionation shown to be a reasonable alternative to conventional fractionation in appropriately selected patients. However, whole-breast radiation therapy may be overtreating a significant volume of uninvolved breast tissue, and many hypothesize that this treatment of uninvolved tissue may be responsible for some of the acute and chronic toxicity associated with breast-conserving therapy. Accelerated partial-breast irradiation (APBI) has been investigated as a possible alternative to whole-breast radiation therapy for select patients with DCIS or low-risk invasive breast cancer [36]. The rationale behind APBI is that the majority of breast relapses occur within or near the tumor bed. Pathological studies from mastectomy specimens have demonstrated a lower probability of subclinical microscopic disease with increasing distance from the primary tumor [16, 36–40]. APBI targets only the surgical bed and a limited volume of normal tissue surrounding the surgical bed (Figs. 5.3 and 5.4). The accelerated treatment schedule reduces the overall radiation treatment duration to 1 week or less, which is more feasible for women with difficulty traveling to a radiation treatment center or women may not want to commit to the longer treatment duration associated with conventional or hypofractionated whole-breast radiation. The advantages of APBI extend beyond convenience. APBI limits radiation exposure to only the part of the breast surrounding the tumor bed and can effectively minimize dose to the lungs, heart, chest wall, ribs, and normal breast or nodal tissue. APBI may also reduce certain radiation treatment-related toxicities, which may improve overall quality of life [41].

Historically, the first utilized APBI technique was multicatheter interstitial brachytherapy, which was primarily used as a boost technique after whole-breast irradiation [42, 43]. This technique involves the use of multiple catheters that are generally positioned at 1.0–1.5 cm intervals. The total number of catheters and planes employed is dependent on the size, extent, and shape of the tumor cavity. Multiple studies utilizing this technique have established multicatheter interstitial brachytherapy as an acceptable treatment option for appropriately selected patients [44–46]. Among partial-breast irradiation techniques, this technique has the longest patient follow-up, allowing for more accurate outcome analyses. However, it is both complex and technically challenging, limiting its widespread use.

Starting in 1998, the Hungarian National Institute of Oncology performed a prospective trial which enrolled 258 women with pT1 pN0-1mic, grade 1–2, non-lobular breast cancer resected with negative margins and randomized participants to conventionally fractionated whole-breast irradiation to 50 Gy in 2 Gy fractions (n = 130) or partial-breast irradiation. Partial-breast irradiation was delivered with HDR interstitial brachytherapy to a dose of 36.4 Gy given over seven twice-daily fractions of 5.2 Gy (n = 88) or electrons to a dose of 50 Gy in 2 Gy fractions (n = 40) [1]. With 10 years of follow-up, there was no statistical difference in local recurrence between whole-breast irradiation group and the partial-breast irradiation groups (5.9 vs. 5.1%, respectively; p = 0.77). Overall survival, disease-free survival, and cause-specific survival did differ between treatment arms. However, there was an improved good-excellent cosmetic outcome with partial-breast irradiation techniques.

From 2004 to 2009, the Groupe European de Curietherapie—European Society of Therapeutic Radiology and Oncology (GEC-ESTRO) conducted a multi-institutional, multinational, phase III, non-inferiority trial which randomized 1184 early-stage breast cancer patients to whole-breast irradiation or accelerated partial-breast irradiation using multicatheter interstitial brachytherapy [47]. Eligible patients had unifocal and unicentric stage 0, I, or IIa breast cancer (lesions ≤3 cm, pN0 or N1mi) treated with breast-conserving surgery with at least 2 mm margins. Whole-breast irradiation (n = 551) was prescribed to a dose of 50–50.4 Gy given in 1.8–2 Gy fractions followed by a 10 Gy boost. Accelerated partial-breast irradiation using a multicatheter interstitial technique was delivered using twice-daily high-dose rate brachytherapy to a dose of 32.0 Gy given in 8 fractions (8 × 4.0 Gy) or 30.3 Gy in 7 fractions (7 × 4.3 Gy), or pulsed-dose rate brachytherapy to a dose of 50 Gy with pulses of 0.60–0.80 Gy/h (1 pulse per hour, 24 h/day). The 5-year rate of local recurrence was 0.9% for the whole-breast irradiation group and 1.4% for the accelerated partial-breast irradiation group (p = 0.42) with the accelerated partial-breast technique being statistically non-inferior to whole-breast irradiation at 5 years. There was also no difference in the 5-year rates of grade 2–3 late skin side effects, grade 2–3 subcutaneous tissue late side effects, or grade 3 fibrosis. No patients experienced grade 4 toxicity.