Advances in Breast Cancer Radiotherapy

Implications for Current and Future Practice

Chirag Shah, MD; Zahraa Al-Hilli, MD; Frank Vicini, MD

Disclosures

J Oncol Pract. 2021;17(12):697-706. 

In This Article

Abstract and Introduction

Abstract

Radiation therapy (RT) is an essential component in the management of breast cancer. Following breast-conserving surgery (BCS), adjuvant RT is the standard of care for most patients. Traditionally, RT was delivered with standard whole breast irradiation (WBI) over 5–7 weeks following BCS. However, WBI regimens have evolved; hypofractionated WBI now represents the standard approach, reducing the duration of treatment to 3–4 weeks. Over the past year, five-fraction WBI regimens have also emerged as standard of care for some patients based on data from the FAST and FAST-Forward trials. An alternative to WBI that is also available for patients with early-stage breast cancer following BCS is partial breast irradiation, which can reduce the duration of treatment and the volume of breast tissue irradiated. Outcomes from multiple randomized trials with over a 10-year follow-up have demonstrated the safety and efficacy of partial breast irradiation approaches. Single-fraction intraoperative RT has also been evaluated in two prospective trials although the outcomes available, as well as current guidelines, do not support its utilization outside of prospective studies. For patients requiring RT to the regional lymph nodes, data have demonstrated the safety of hypofractionated approaches for those undergoing BCS or mastectomy without reconstruction. Future directions for early-stage breast cancer radiotherapy include the study of even shorter regimens and studies evaluating the omission of RT versus omission of endocrine therapy for favorable-risk patients. Furthermore, studies are also underway evaluating shorter courses of radiation in patients undergoing breast reconstruction and the use of tumor genomics to identify appropriate patients for omission of radiation with limited nodal involvement.

Introduction

Radiation therapy (RT) plays an essential role in the overall management of patients with breast cancer, ranging from early-stage disease to locally advanced and metastatic cases. Paralleling advances in RT technology and treatment planning, breast RT has undergone a revolution over the past few decades, transforming its delivery from two-dimensional treatment over 5–7 weeks to a collection of techniques that not only reduce the duration of treatment but also improve the therapeutic ratio by reducing acute and chronic toxicities and increase local control. Given the rapid changes in RT for breast cancer, the purpose of this clinical review is to provide an update on evolving RT techniques and to discuss future directions.

Radiation Technology

Older techniques to deliver RT were considered relatively less technologically advanced, with two-dimensional radiotherapy being used to deliver radiation. As such, some long-term data demonstrated higher rates of cardiac and pulmonary toxicities with these approaches (although overall toxicity rates were still relatively low).[1] In the 1980s and 1990s, RT evolved to incorporate three-dimensional (3D) treatment planning with the use of a computed tomography scanner resulting in substantially more accurate treatment delivery. These advances allowed for dose to the breast to be more precisely calculated and allowed for techniques to reduce doses to nontarget organs at risk (eg, heart and lungs). Additional advances in technology have included refinements to standard linear accelerators allowing for normal tissue blocking (eg, multileaf collimators), real-time 3D imaging (eg, cone beam computed tomography), advances in cardiac sparing techniques (eg, deep inspiratory breath hold and prone positioning), and improvements in treatment planning and delivery such as intensity-modulated radiation therapy (IMRT).[2] Taken together, these advances have allowed for the advances in breast RT with respect to dose fractionation and targets.

Breast-conserving Therapy

With more than 20 years of follow-up, multiple prospective randomized trials have consistently demonstrated that breast-conserving therapy is equivalent to mastectomy in terms of local control and overall survival.[3] Importantly, all these studies used adjuvant RT delivered with standard fractionation, requiring 5–7 weeks of daily whole breast irradiation (WBI). The advancements in RT described above have, however, allowed for a reduction in treatment duration with WBI and reductions in the target of radiotherapy. Figure 1 summarizes adjuvant RT options following breast-conserving surgery (BCS). For example, three prospective randomized trials comparing standard WBI with hypofractionated WBI (shortening the duration of treatment to 3–4 weeks) are now available. With long-term follow-up, these studies demonstrated no difference in local recurrence or survival with comparable toxicity profiles.[4–6] As such, current guidelines support the use of hypofractionated WBI for most patients with early-stage breast cancer not requiring nodal treatment.[7]

Figure 1.

RT options in the management of early-stage breast cancer (pT1–2N0) following BCS. 3D-CRT, three-dimensional conformal radiation therapy; BCS, breast-conserving surgery; ER, estrogen receptor; IMRT, intensity-modulated radiation therapy; PBI, partial breast irradiation; RT, radiation therapy; WBI, whole breast irradiation.

Since the publication of these trials, shorter WBI regimens have been investigated. The recently published FAST trial randomly assigned women with early-stage breast cancer (pT1–2N0) to standard WBI or one of two (28.5 Gy or 30 Gy) five-fraction regimens delivered once weekly with no tumor bed boost. With a 10-year follow-up, the study found the 28.5 Gy arm to have no difference in moderate or marked tissue effects as compared with standard WBI, although increased rates of toxicity were seen in the 30 Gy arm. Only 11 locoregional failures occurred overall with no significant differences between the three arms of the study.[8] Subsequently, the FAST-Forward trial compared hypofractionated WBI with two (26 Gy or 27 Gy) five-fraction regimens delivered over 1 week (five treatment days). At 5 years, the five-fraction treatment regimens were associated with a nonsignificant reduction in local recurrence, with the 26 Gy arm having similar rates of moderate or marked normal tissue effects as compared to hypofractionated WBI.[9] As these studies illustrate, over the course of two decades, the duration of WBI has gone from 5–7 weeks (25-33+ fractions) to 5 days (five fractions) in appropriately selected patients. Table 1 summarizes the key studies associated with this paradigm shift.[4,5,8–13]

As previously mentioned, the randomized trials that demonstrated the safety and efficacy of breast-conserving therapy used adjuvant WBI. However, over the past three decades, more than seven prospective randomized trials have compared WBI with more targeted forms of radiation (ie, partial breast irradiation [PBI]), demonstrating no statistically significant differences in local recurrence in most of the trials (Table 2).[14–25] PBI can be delivered with multiple techniques including (1) interstitial brachytherapy (catheters placed through the breast with temporary radiation sources placed), (2) applicator-based brachytherapy (temporary device placed in the lumpectomy cavity), or (3) external beam RT (three-dimensional conformal radiation therapy [3D-CRT], IMRT, or proton therapy) with outcomes summarized in Table 2. The first modern randomized trial investigating PBI was performed at the National Institute of Oncology in Hungary, and 20-year outcomes have confirmed no difference in local recurrence between PBI and WBI with data demonstrating improved cosmetic outcomes in the PBI arm.[15] Subsequently, the larger GEC-ESTRO prospective randomized trial compared interstitial brachytherapy (as the PBI technique) with WBI; 5-year outcomes demonstrated no difference in local recurrence, with toxicity data reporting reduced rates of skin toxicity and breast pain with PBI.[16,17] An alternative to interstitial brachytherapy is applicator-based brachytherapy, although no randomized trial has exclusively used this technique. The MammoSite Registry trial prospectively evaluated more than 1,400 cases of PBI using the original single-lumen MammoSite device. At 5 years, the rate of local recurrence was 3.8%, with toxicity data demonstrating 90% excellent or good cosmesis.[26,27]

An alternative to brachytherapy-based PBI (which is an invasive procedure) is PBI delivered using external beam radiation. The initial technique used was 3D-CRT; early results were promising, but with longer follow-up, concerns arose regarding toxicity including fibrosis and inferior cosmetic outcomes.[28–31] This was observed in the RAPID trial, which randomly assigned patients to WBI or 3D-CRT PBI; at 8 years, no difference in local recurrence was noted although increased late toxicity with PBI was noted.[20] By contrast, the NSABP B-39/RTOG 0413 prospective randomized trial compared PBI delivered with brachytherapy or 3D-CRT, with the majority of patients receiving 3D-CRT to WBI. Outcomes from the 3D-CRT arm did not demonstrate any toxicity concerns, with similar rates of local recurrence seen between PBI and WBI and no statistically significant differences in cosmesis or late toxicity.[19,32] Similarly, no toxicity concerns were noted with PBI delivered on the IMPORT LOW trial, which used a once-a-day schedule (over 3 weeks) as compared with the twice-daily regimens used in the aforementioned trials.[22] In light of the toxicity concerns observed in the RAPID trial with 3D-CRT PBI, IMRT has been evaluated as an alternative method. The randomized trial from Florence, Italy, compared IMRT PBI with WBI; with 10-year follow-up, no difference in local recurrence was noted with reduced rates of acute and chronic toxicities with PBI.[18] In light of these studies, current guidelines support the use of PBI for appropriately selected patients, with the American Brachytherapy Society guidelines giving a strong recommendation for interstitial brachytherapy and IMRT, moderate recommendation for applicator brachytherapy and 3D-CRT PBI, and a weak recommendation for protons and electronic brachytherapy techniques.[33,34]

Intraoperative radiation therapy (IORT) has also been evaluated as an alternative to WBI or PBI in selected patients (Table 2). IORT offers the potential for a single treatment at the time of surgery for most patients, translating into a significant reduction in the duration of therapy. Two randomized trials evaluating IORT as compared with WBI have recently been published with updated results. The ELIOT trial randomly assigned women to WBI or electron IORT, with limited IORT patients receiving additional radiation. Long-term outcomes demonstrated increased rates of recurrence with IORT (11% IORT v 2% WBI). Even among low-risk patients, IORT was associated with increased rates of recurrence (8.1% v 3.1%).[23] In contrast, the TARGIT-A trial randomly assigned patients to WBI or IORT, with risk-adapted WBI for IORT patients. IORT was delivered with low-energy photons at the time of initial surgery (this group was defined as the prepathology cohort) or as a second procedure (this group was defined as the postpathology cohort); of note, these cohorts were not defined as two separate trials when published initially. Additional WBI was given to 15% of IORT patients (21.6% prepathology and 3.6% postpathology). Initial outcomes demonstrated increased rates of recurrence with IORT (3.3% IORT v 1.3% WBI), within the noninferiority criteria.[35] Updated results were recently published although outcomes for the whole IORT group were not presented, raising methodologic concerns.[36] Consistent with earlier results, the postpathology group had increased rates of local recurrence at 5 years (5.3% v 1.7%), exceeding the noninferiority threshold of the study. The prepathology group also had increased rates of recurrence (2.11% v 0.95%), although within the noninferiority design. However, despite an 8-year follow-up, unlike other breast radiation studies, long-term local recurrence rates (eg, 8 or 10 years) were not provided. Also, local recurrence-free survival was presented despite concerns with composite end points;[37] when evaluating the data provided, a 2–3× fold increase in local recurrence with IORT was noted in the prepathology group (60 recurrences with IORT v 24 recurrences with WBI).[25] Additionally, with more than 20% of the prepathology group receiving WBI, local recurrence outcomes were not presented for those receiving IORT with or without WBI.[25] At this time, current guidelines do not support the use of IORT outside of prospective studies with the American Brachytherapy Society providing a weak recommendation for the technique.[33,34]

One of the evolving questions faced by oncologists are the indications for omitting adjuvant radiation following BCS. Traditionally, adjuvant RT has been recommended for most patients following BCS given the reduction in local control and improvement in breast cancer mortality.[3] However, over the past decade, long-term outcomes from two randomized trials that evaluated the role of omitting RT in low-risk patients were published. Both the CALGB 9343 and PRIME II trials found that the omission of adjuvant RT was associated with increased rates of local recurrence but had no impact on survival.[38,39] Given the inability of traditional clinical and pathologic features to identify low-risk patients who do not derive a significant benefit in local control from RT, subsequent studies have evolved to evaluate tumor biology and genetics in the decision-making process.[40] At this time, numerous prospective studies are underway evaluating the use of such stratifications (eg, luminal A breast cancer) and techniques (ARCTIC, PAM50, and Oncotype) to better identify low-risk patients.[40–43] Unfortunately, since the publication of the NSABP B-21 trial, few prospective studies have evaluated an alternative de-escalation pathway, which would be omission of endocrine therapy in lieu of omitting RT. Given the different toxicity profiles and challenges with compliance with endocrine therapy, this strategy has been found to likely have comparable outcomes with an opportunity for reduced duration of therapy and improved quality of life, particularly with shorter courses of RT.[44,45] Currently, the EUROPA trial is evaluating RT alone as compared with endocrine therapy alone with results expected in the years to come.[46]

Management of the Axilla and RT

For patients with clinically node-negative breast cancer undergoing sentinel lymph node (SLN) biopsy who were found to have nodal involvement, the previous standard of care had been to proceed to axillary lymph node dissection (ALND). However, several landmark trials have changed this paradigm (Figure 2). The AMAROS trial randomly assigned patients to completion ALND or axillary radiation in those patients with a positive SLN. At 10 years, no difference in locoregional recurrence (LRR) was noted with reduced toxicities seen with axillary RT.[47] Similarly, the ACOSOG Z011 trial randomly assigned patients to ALND or no further axillary surgery. Although the trial did not allow for the use of a third field of radiation (ie, regional nodal treatment), review of the study found substantial use of high tangent radiation to cover the lower axilla or the use of a third field.[48] With long-term follow-up, no difference in recurrence rates or survival was noted.[49] Taken together, these data support the use of axillary radiation in lieu of ALND in patients with one to three sentinel nodes involved and can be considered for patients undergoing breast conservation or mastectomy. In patients with a micrometastasis on SLN biopsy, the long-term outcomes from the IBCSG 23–01 study confirmed that ALND can be omitted.[50]

Figure 2.

Management of the axilla for clinically node-negative patients. ALND, axillary lymph node dissection; BCS, breast-conserving surgery; ECE, extracapsular extension; ER, estrogen receptor; RNI, regional nodal irradiation; RT, radiation therapy; SLN, sentinel lymph node; WBI, whole breast irradiation.

In those patients undergoing ALND, the role of regional nodal irradiation (RNI) remains a controversial topic with patients with four or more nodes involved and those with extracapsular extension commonly offered RNI that can include the dissected axilla, supraclavicular fossa, and/or the internal mammary nodes.[51,52] In patients with one to three nodes involved the role of RNI is controversial. Outcomes from the Early Breast Cancer Trialists Group meta-analysis confirmed the benefit of adjuvant RT (including RNI) in patients with one to three nodes involved after axillary dissection, even demonstrating a benefit with a single node involved.[53] However, concerns have existed regarding whether this holds true with current surgical and systemic therapy approaches. However, modern data have found the results to be consistent with the results of the MA20 trial supporting the use of RNI; the trial randomly assigned patients (85% with one to three nodes involved after ALND) to RNI or not following BCS. Long-term outcomes demonstrated that the addition of RNI was associated with a reduction in LRR and distant metastases with estrogen receptor–negative patients having an overall survival advantage; similar results were seen in a multi-institutional modern analysis as well.[54,55] As such, RNI can be considered for all patients with macrometastatic nodal involvement following ALND. Planning for RNI in this population may involve blocking the dissected axilla (therefore reducing dose to the axilla and potentially lymphedema rates) while incorporating the supraclavicular fossa and/or the internal mammary nodes.

The role of RNI has primarily been defined by studies that delivered adjuvant chemotherapy including the original postmastectomy randomized trials (except Danish 82c trial) and the recently published MA-20 trial.[53,54] However, increasingly, patients are receiving neoadjuvant systemic therapy, with human epidermal growth factor receptor 2–positive and triple-negative patients having higher rates of pathologic complete response. As such, a key clinical question is management of the axilla in patients receiving neoadjuvant therapy. In patients presenting with clinical N2/N3 disease, adjuvant RT with RNI remains the standard of care, irrespective of treatment response, as does adjuvant radiation in patients with clinical T4 breast cancers. In patients with clinical N1 disease before neoadjuvant therapy, treatment paradigms have evolved. For those patients with residual nodal involvement (even with isolated tumor cells or micrometastases), ALND followed by adjuvant radiation remains the standard of care, with the Alliance A011202 trial evaluating ALND with radiation as compared with axillary radiation alone.[56] In patients with clinical N1 disease in the axilla having a complete pathologic response at the time of surgery, data have demonstrated low rates of LRR.[57] In light of these findings, the NSABP B-51 study randomly assigned this patient population to radiation (breast and RNI for BCS patients and postmastectomy radiation therapy [PMRT] for mastectomy patients) or no RNI (breast only for BCS patients or no RT for mastectomy patients).[58] The study recently completed accrual with results expected in the years to come. At this time, the role of adjuvant RT with RNI should be based on informed discussions with assessment of the risk of LRR based on tumor biology, age, and other clinico pathologic features.

PMRT

With long-term follow-up, multiple randomized trials have demonstrated that the addition of PMRT is associated with reduced rates of LRR and improved survival.[59–61] The studies evaluating the use of PMRT primarily used standard radiation giving treatment daily over 5–6 weeks (although the British Columbia trial did use a hypofractionated approach). However, more recently, the role of hypofractionation has been evaluated. A randomized trial from China compared standard with hypofractionated PMRT in patients undergoing mastectomy. At 5 years, no difference in local recurrence or toxicity profiles was noted.[62] Additionally, long-term data from the START trial found low rates of shoulder or arm toxicity with hypofractionation among patients receiving RNI.[63] Importantly, the role of hypofractionation in patients undergoing mastectomy with reconstruction remains investigational; although prospective data are available, the Alliance trial is currently randomly assigning patients with outcomes expected in the years to come.[64,65]

Indications for PMRT have continued to evolve. On the basis of the aforementioned randomized trials, PMRT was considered for T3-T4 cancers and those with nodal involvement or positive margins following surgery.[53] PMRT is still considered standard for those patients with T4 cancers, T3 node–positive cancers, positive margins, four or more nodes, or extracapsular extension.[52] For those patients undergoing mastectomy with a SLN, data from the AMAROS trial can be extrapolated such that PMRT with RNI can be used in lieu of an ALND.[47,66] The role of PMRT in patients with one to three nodes involved following ALND remains controversial; although some studies have shown low rates of LRR without PMRT, a recent large multi-institutional analysis demonstrated the benefit of PMRT, as does extrapolation from the MA-20 trial (which included patients undergoing BCS with 85% of patients having 1–3 nodes involved following ALND) and the older Early Breast Cancer Trialists Group meta-analysis.[54,55] At this time, the MA39 trial is evaluating the role of tumor genetics in identifying those patients who can forgo radiation with limited nodal involvement.[67,68] With respect to T3N0 cancers, the data remain mixed.[51,52] At this time, the role of PMRT in patients with pathologic T3N0 breast cancers should be based on a case-by-case discussion with consideration of patient age, receptor status, margin status, and the presence of lymphovascular space invasion.

Future Directions

Despite significant changes in breast RT over the past few years, treatment paradigms continue to evolve. With respect to patients with early-stage breast cancer, even shorter regimens of PBI are being evaluated, which will allow for completion of adjuvant radiation in one to three treatments, whereas in the postmastectomy setting, hypofractionation is being evaluated for patients undergoing breast reconstruction.[65,69,70] Additionally, further data are expected on ultrashort five-fraction WBI regimens, providing long-term follow-up similar to that seen already with PBI.[8,9] Treatment deintensification is also being re-evaluated. In the EUROPA trial, patients are randomly assigned to adjuvant radiation or adjuvant endocrine therapy;[46] this trial is consistent with results of the older NSABP B-21 trial, which showed that RT was associated with lower rates of local recurrence and no difference in distant metastases as compared to endocrine therapy.[71]

An additional area of evaluation is tumor genetics and RT. For example, the recently opened and accruing NRG BR-007 prospective trial is using tumor genomics (Oncotype) to determine the use of radiation.[43] Low-risk patients are randomized to standard adjuvant RT or no radiation. Similarly, the MA39 trial is using tumor genomics to evaluate the role of adjuvant radiation in patients with limited nodal involvement.[67] In patients with ductal carcinoma in situ (DCIS), tumor genomics are also being evaluated. Studies using an older assay (Oncotype DCIS) demonstrated similar rates of recurrence as compared with traditional clinical and pathologic features and has not identified a low-risk group that fails to benefit from adjuvant radiation.[72] However, a new assay (DCISionRT) has demonstrated the ability to identify a low-risk cohort with limited benefit to adjuvant RT.[73,74]

Patients with metastatic breast cancer are also eligible for new RT techniques and paradigms. Patients with oligometastatic breast cancer (synchronous or metachronous to original diagnosis) may be eligible for definitive treatment of their metastases with stereotactic body RT, with promising initial outcomes with respect to local control and survival.[75,76]

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