Radiation Therapy for Locally Advanced Breast Cancer: Historical Review to Current Approaches

Definition

LABC represents tumors with advanced progression of disease that is confined to the breast and regional lymph node basins. The majority of patients with LABC have clinical or pathologic anatomic group stage III disease, with a minority diagnosed with anatomic group stage IIB disease comprising large node-negative breast cancers (clinical or pathologic T3N0). While the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual for breast has introduced prognostic group staging that integrates biomarkers including grade and hormone receptor status, only anatomic group staging should be utilized for the determination of LABC. Patients with LABC can be further subdivided into those with operable versus inoperable disease based on impression by the multidisciplinary team regarding likelihood of upfront surgery to achieve complete resection with pathologically negative margins.

Advanced tumor (T) stage includes primary breast tumors with an invasive component greater than 5 cm (T3), direct extension to the chest wall apart from the pectoralis muscle, including the ribs, intercostal muscles, and serratus anterior muscle (T4a), clinically appreciable infiltration of the skin as edema ( peau d’orange ), ipsilateral satellite nodules or direct ulceration of the skin (T4b), or a combination thereof (T4c). Advanced nodal stage includes patients bulky, fixed, or matted axillary lymphadenopathy (cN2a), clinical or radiologic involvement of nodes within the ipsilateral internal mammary nodal chain (IMC), infraclavicular (ICLV) fossa (cN3a) supraclavicular (SCLV) fossa (cN3c), and/or pathologic tumor involvement of at least four axillary lymph nodes (pN2a/pN3a).

IBC is characterized by the classic triad of breast swelling (prominence of dermal hair follicles or peau d’orange ), skin discoloration (erythema or hyperpigmentation), and nipple change with or without a palpable underlying mass. While pathologic confirmation of invasive carcinoma is required, inflammatory carcinoma is a clinical diagnosis based on the rapid emergence of skin changes occupying at least one-third of the breast over a period of less than 6 months from symptom onset to diagnosis, and should be distinguished from neglected locally advanced disease presenting with secondary lymphatic congestion.

Inoperable breast cancer, as originally defined in 1943 by Haagensen and Stout, included disease with extensive skin edema, chest wall fixation, skin satellite nodules, parasternal deposits, fixed axillary nodes, or arm lymphedema secondary to lymphatic infiltration. These criteria were based on the authors’ observation that, locoregional recurrence (LRR) exceeded 50% following radical mastectomy alone.

Incidence and Outcomes

Breast cancer accounts for approximately one-third of all newly diagnosed cancers among women each year. In 2022, there will be an estimated 290,560 new cases of breast cancer in the United States alone, while approximately 44,000 individuals will die from their disease. Approximately two-thirds of individuals with breast cancer in the United States present with disease confined to the breast, while 25% demonstrate regional lymph node involvement, and 5% to 6% have distant metastatic disease. While the overall incidence for breast cancer continues to increase by approximately 0.5% per year, there has been a concomitant decline of 0.8% per year among patients with regional involvement, potentially reflecting a shift toward diagnosis at an earlier stage of disease. Breast cancer mortality (BCM) rates overall have similarly declined more than 40% between 1989 and 2018, attributed primarily to an increase in early disease detection as well as advances in systemic therapies.

Approximately 20% of breast cancer cases are considered to be locally advanced at diagnosis. While patients with LABC have historically experienced poor outcomes, 5-year breast cancer–specific survival (BCSS) has significantly improved for patients diagnosed with stage III breast cancer, now approximately 75% among those diagnosed between 2009 and 2015. The mortality declines appreciated in the 1990s and 2000s have significantly slowed, however, from an annual decrease of 1.9% (1998–2011) to 1.3% (2011–17) and for younger patients have stopped altogether. Of importance, there remains substantial disparities in clinical outcomes by race at each stage of diagnosis, most significantly appreciated for patients diagnosed with stage III disease, with non-Hispanic Black patients experiencing 5-year BCSS of 64% compared with 76% to 77% for non-Hispanic White or Asian patients, respectively.

General Treatment Paradigms

Treatment management decisions for patients with LABC are based on whether disease burden is anticipated to be operable either at time of diagnosis or following neoadjuvant therapy. This is reflected in current treatment algorithms recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for Breast Cancer. Patients with operable LABC are recommended to be treated with trimodality therapy, consisting of systemic therapy preferentially delivered in the neoadjuvant setting, definitive surgical resection with axillary staging, and adjuvant radiotherapy to areas at risk of harboring subclinical residual disease ( Fig. 50.1 ). The optimal management of LABC includes upfront multidisciplinary assessment with integration of recommendations regarding workup, imaging studies, and management decisions.

Historically, surgery was performed upfront for patients with operable LABC, followed by adjuvant chemotherapy and radiotherapy. Surgery generally consisted of total mastectomy with axillary lymph node dissection (ALND), while radiotherapy was delivered to the chest wall and regional draining lymphatics. The preferred treatment paradigm has since evolved, with preference for upfront systemic therapy as the recommended approach for the majority of patients with LABC. This strategy has facilitated increased consideration of breast conservation in place of total mastectomy, as well as nodal evaluation with sentinel lymph node biopsy (SLNB) and targeted axillary dissection of clipped nodes without complete ALND for those patients with significant reduction in burden of disease. Clinical and pathologic response to upfront systemic therapy also now provides important prognostic information and can guide adjuvant and maintenance systemic treatment recommendations. Following completion of radiotherapy, adjuvant systemic therapies are recommended for several subsets of patients, including those with tumors that are hormone receptor–positive, or overexpress the HER2/neu (HER2) receptor, those with triple-negative breast cancer (TNBC) who do not achieve pathologic complete response (pCR) at time of surgery, as well as those found to have a germline mutation within the BRCA1/2 gene. Patients who receive upfront surgery may also be recommended to undergo adjuvant or maintenance systemic therapy based on certain high-risk criteria including tumor subtype, final pathology, and germline status.

Current international consensus guidelines for IBC recommend trimodality therapy as the standard treatment strategy, comprising upfront systemic therapy completed prior to total mastectomy with ALND followed by postmastectomy radiotherapy (PMRT) with comprehensive regional nodal irradiation (RNI) including the axilla, IMC, ICLV, and anterior and posterior SCLV nodal basins. Patients with IBC who do not demonstrate response to preoperative systemic therapy are recommended to proceed with additional systemic chemotherapy and/or preoperative radiotherapy followed by consideration of mastectomy.

The general treatment strategy for inoperable breast cancer is upfront systemic therapy, reassessment for resectability, and, if appropriate, transition to the operable treatment paradigm. Patients with persistently unresectable disease or progression of disease during upfront systemic therapy may transition to an alternate systemic regimen or consider either induction radiotherapy, reassessment for surgical resection, or palliative radiotherapy for the purpose of locoregional control.

Radical Mastectomy Alone

In the seminal series of papers published beginning in the 1940 to 1950s, Haagensen and Stout describe clinical outcomes of patients with LABC treated between 1915 and 1934 and then 1935 and 1942. It is through this retrospective analysis that the criteria for operability were originally defined given a 0% cure rate following radical mastectomy among those patients with skin ulceration, erythema, or edema ( peau d’orange ), satellite skin nodules, or “third degree” fixation to the chest wall musculature. Indeed, the observation was made that “radical mastectomy, when performed in patients whose disease is so far advanced that cure cannot be obtained, shortens life by almost ten months.” Among patients with “operable” LABC diagnosed between 1935 and 1942, radical mastectomy alone “with a more meticulous operative technic” was associated with a 50% rate of “cure.”

“Radical” Radiation Therapy

Given the appreciated morbidity associated with radical mastectomy for patients with high-risk or inoperable LABC in the setting of low potential for cure, definitive or upfront radiotherapy with or without systemic therapy was considered. In an initial retrospective series, 158 patients diagnosed with stage III to IV breast cancer between 1960 and 1972 were treated with definitive radiotherapy to a dose ranging from 50 Gray (Gy) to 110 Gy to the regional lymphatics over 8 weeks using a Cobalt-60 unit. While this regimen of “high dose protracted RT” was associated with a 72% rate of locoregional control at time of last evaluation or death, severe fibrosis and necrosis were experienced by 100% of patients, with persistent emergence of symptoms throughout 10 years of clinical follow-up.

Similar results were appreciated, although with less overall toxicity, in a subsequent retrospective series of 137 patients diagnosed with nonmetastatic LABC between 1968 and 1978 treated with “radical radiation therapy” with or without systemic therapy. Of those patients treated with radiation alone, defined as 4 to 7 weekly doses of 10 Gy to the breast, axilla, SCLV basin, and IMC, complete clinical response was demonstrated by 90%, although 5-year rates of disease-free survival (DFS) and overall survival (OS) were 28% and 30%, respectively.On multivariable analysis, treatment with radiation therapy (total dose >60 Gy) or adjuvant systemic therapy were both associated with improved local control and decreased risk of distant recurrence.

In an analysis of tumor- and dose-parameters among 463 patients with LABC treated with radiotherapy alone between 1958 and 1972 at the Princess Margaret Hospital, a further increase in total dose from 50 to 65 Gy was associated with a two-fold relative decrease in risk of LRR. Patients who did not achieve at least 50% “complete response” experienced significantly worse 3-year OS (39% vs. 67%) and were significantly more likely to have tumors larger than 8 cm, skin involvement, and both axillary and SCLV nodal involvement.

Combined Modality Therapy: Chemotherapy + Surgery or Radiation

With the acknowledgment that a majority of patients with LABC at this time experienced distant recurrence and eventually succumbed to their disease despite aggressive locoregional management, greater focus on a combined treatment paradigm was pursued. The first pilot for feasibility of combining radiotherapy with chemotherapy for the treatment for LABC was attempted in the 1970s, with a series of 24 patients with T3-4 or N2-3 operable breast cancer randomized to receive either sandwich or sequential chemotherapy with 4000 rad in 10 fractions over 4 weeks with a subsequent 900 to 1200 rad radiation “boost” to residual disease over three to four fractions. The median duration of clinical response across all patients was significantly longer compared to that seen among historical controls treated with radiation alone (33 vs. 10.5 months, P < 0.001), suggesting for the first time that combined modality therapy may hold promise.

To determine if radiotherapy or mastectomy would be best suited for locoregional therapy following upfront chemotherapy, the Cancer and Leukemia Group B (CALGB) randomized women with stage III disease between 1978 and 1983 following NAC to receive either radical mastectomy or definitive radiotherapy consisting of 50 Gy in 5 weeks with 15 to 20 Gy boost to the axillary nodes, followed by 2 years of consolidative chemotherapy. Results demonstrated no significant difference in disease control or survival between surgery or RT (39 months in both arms). Importantly, the addition of systemic therapy to locoregional therapy was acknowledged as facilitating longer disease control compared with that reported in historical studies without a combined modality approach.