Radiotherapy and Regional Nodes

Introduction

Regional nodal irradiation (RNI) for localized breast cancer exemplifies the measurable oncologic advances of recent decades. While nodal status was previously considered a main prognostic and predictive factor to inform treatment, a constellation of other clinicopathologic parameters and molecular markers are now increasingly used to define how breast cancer is managed. A series of trials has demonstrated that the aggressive surgical procedures of the last century do not improve long-term disease control or survival outcomes. To that end, radiotherapy has been increasingly employed in the management of the regional lymph nodes, in particular for patients who undergo more limited surgical management. Now, regional management is defined largely by the extent of nodal involvement and a host of clinicopathologic features, while further refinement in the application of RNI continues.

Of note is the relevance of recent trials of RNI to both the breast-conserving and mastectomy settings. Historically, these two groups were studied independently, but for many common presentations they have converged in terms of locoregional recurrence risk, and there now exist many parallels in the regional management of lumpectomy patients and their counterparts who undergo mastectomy.

Breast-conserving surgery (BCS) remains a relatively recent innovation, such that historic studies focused on the role of adjuvant radiation in the mastectomy setting. Early studies demonstrated the survival benefit of postmastectomy radiotherapy to the chest wall and regional lymph nodes, largely in those with significant axillary involvement and in the setting of outdated chemotherapy. While adjuvant radiotherapy yielded a reduction in locoregional recurrence and improvements in survival among mastectomy patients, several studies were criticized for exhibiting rather high baseline recurrence rates (in both the treated and untreated arms) and for including patients who had suboptimal surgical axillary management by today’s standards.

More recently, three major trials set out to comprehensively address the role for RNI in the setting of contemporary surgical and systemic management. While these landmark trials generally allowed for the enrollment of patients with multiple involved lymph nodes and/or high-risk features, the vast majority of accrued patients had one to three positive nodes. As a result, these studies filled the gap of knowledge for those patients who were not at exceedingly high risk but who exhibited some adverse features, typically including a modest amount of axillary nodal disease. For patients with locally advanced breast cancer, including those with four or more involved nodes, comprehensive RNI remains the standard of care, regardless of the extent of surgical management. This paradigm is based on a large and growing body of literature demonstrating locoregional control and survival benefits among such patients. A central controversy surrounds whether to irradiate the internal mammary lymph node chain, typically that component of RNI that poses the most technical challenges in terms of sparing the heart and lungs. Moreover, decades of follow-up suggest that internal mammary nodal (IMN) recurrences are rare in practice, calling into question the benefit of always including this nodal basin. Such controversies surrounding RNI will be covered in detail throughout the chapter.

Principles of Regional Nodal Management

Several important trials in recent decades have facilitated the rapid evolution from wholesale axillary lymph node dissection (ALND) to more limited surgery with a nuanced application of nodal irradiation. Early among these was the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial. This study was developed at a time when sentinel lymph node biopsy (SLNB) was a routine diagnostic maneuver used to determine whether to proceed with ALND The standard at the time was to proceed to an ALND for patients with a positive sentinel node. This pioneering trial was designed to question the therapeutic benefit of completion ALND among patients with just one or two positive sentinel nodes and an otherwise limited disease burden (cT1–2 tumors and clinically negative axillary nodes). Patients were excluded if more than two involved nodes were identified or if matted nodes or gross extranodal disease were present. While overall survival was the primary endpoint of the study, after 5 years an unexpectedly low mortality rate prompted study closure. Systemic therapy was at the discretion of the treating physician; radiotherapy was mandated to include the breast but “no third-field nodal irradiation.” At a median follow-up of 6.3 years, the study showed no difference in overall survival or locoregional recurrence between those who were randomized to ALND versus no further surgery in the setting of a positive sentinel node. This study was practice-changing at the time, as it was canonically held that any positive node carried an elevated risk of additional axillary disease associated with subsequent regional recurrence and survival.

While “Z11,” as it is known, remains among the most recognizable of contemporary breast trials, several nuances must be considered in its application. First, this was a trial of breast conservation surgery only and included no mastectomy patients. Thus, these findings ought not be extrapolated to the mastectomy setting. The main issue is that all Z11 patients received whole-breast radiotherapy, typically via tangential beams that incidentally cover the lower axillary levels I and II (a practice that may have mitigated the risk of residual axillary disease among those patients assigned to no ALND). However, mastectomy patients may not receive chest wall radiation, leaving the lower axilla untreated in the absence of an ALND following a positive SLNB, and thus representing a distinct population from that studied by the Z11 trial. To address this concern, Morrow and colleagues conducted a study of similar breast conservation patients, some of whom were treated in the prone position (limiting incidental axillary coverage), demonstrating no increase in the rate of regional recurrences and suggesting that lower axillary radiation is not critical to explaining the feasibility of avoiding ALND per Z11.

Another concern relates to the actual radiotherapeutic field design in Z11. Although whole-breast tangents only were uniformly mandated per protocol, a number of study patients did receive nodal coverage. To evaluate radiotherapy (RT) technique, completed case report forms from the Z11 study were reviewed in detail. Surprisingly, 15% of all women in the study were treated with a third field over the supraclavicular nodes, and from the smaller subset of patients for whom details of field design were available, about half who received breast tangent fields only had “high tangents” (defined as a superior field edge ≤2 cm from the humeral head) covering more of the axillary nodal region. While no significant differences in radiation field design were noted between the two Z11 treatment arms, these findings suggest that some patients had more nodal irradiation than the study originally intended. As a result, it remains unclear whether patients now managed per this trial (i.e., positive SLNB without ALND following BCS) should receive “high tangent” radiotherapy, given that many on the study received that approach.

The International Breast Cancer Study Group (IBCSG) 23-01 trial had a design similar to Z11 while allowing mastectomy (9% of the cohort), and included only patients with micrometastatic nodal disease (i.e., excluding macrometastases) and T1–T2 tumors. The protocol mandated that radiotherapy not be given after mastectomy and that nodal RT only be allowed in the event of IMN involvement. In this study, additional axillary disease was identified in 13% of patients who had a completion dissection (vs. 27% in Z11) and noted the added morbidity with completion dissection without a commensurate benefit in disease control. The discussion suggested that ALND may not benefit patients with T1–T2 tumors and micrometastases only.

In 2001 the European Organisation for Research and Treatment of Cancer (EORTC) initiated the 10981–22023 AMAROS trial, a phase III noninferiority study randomizing patients with a positive sentinel node to ALND or nodal radiotherapy (not including IMN coverage). Breast conservation and mastectomy patients were eligible, as were those with tumors up to 5 cm. For those patients randomized to radiation, targets included the breast/chest wall, axilla, and supraclavicular fossa. Patients were randomly assigned before any surgery to axillary dissection or axillary radiation if they had a positive sentinel node. Of the 4806 patients who were randomized, 30% had positive sentinel nodes: 60% with macrometastasis, and 40% with micrometastasis or isolated tumor cells. In the axillary dissection arm, 33% of patients had additional axillary disease. Five-year axillary recurrence was 0.43% (95% confidence interval [CI] 0.00–0.92) after ALND versus 1.19% (95% CI 0.31–2.08) after nodal RT. Of note, despite similar disease control, axillary dissection more than doubled the rate of clinical lymphedema at 5 years (11% vs. 23%). Thus, the AMAROS trial concluded that, if further axillary treatment is needed in clinically node-negative, sentinel-node–positive patients, axillary RT might be preferable to ALND because of lymphedema morbidity.

And so, while surgical management of the axilla (via SLNB or ALND) was thoroughly addressed by ACOSOG Z0011, IBCSG 23-01, and AMAROS, the radiation oncologist remained in the position of evaluating patients with limited axillary disease who could readily fit into one or more of these trials. Thus, if ALND can be avoided, when and what RNI is required in addition to whole-breast or chest-wall RT?

In 2015 three large national trials were published, offering guidance specifically relating to this question. Data from these studies have lent strong support for the use of RNI in patients with one to three involved nodes, although controversy persists, and clinical decision-making remains highly individualized.

The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) MA.20 trial evaluated BCS patients who were node-positive or high-risk node-negative (i.e., T3N0 or T2N0 with ER-negative, LVI, or high-grade disease). Patients were randomized to receiving breast RT with RNI (inclusive of the axilla, supraclavicular fossa, and internal mammary basin) or whole-breast radiotherapy alone. Interestingly, while the trial permitted patients with any number of positive lymph nodes to be enrolled, most harbored one to three positive lymph nodes, demonstrating the range for which there was clinical equipoise regarding RNI (i.e., clinicians likely sought to avoid RNI for those without nodal involvement and did not enroll them while, conversely, seeking comprehensive treatment for those with more than three involved nodes, choosing not to enroll them in a study where they might forego RNI). Thus, the MA.20 results primarily address those with one to three positive nodes.

At 10 years of follow-up, the trial showed no survival benefit to RNI; but locoregional control (95.2% with RNI vs. 92.2% without), disease-free survival (DFS; 82% vs. 77%), and distant disease-free survival (86.3% vs. 82.4%) were all superior with RNI. In a prespecified subgroup analysis, patients with ER-negative disease in the nodal irradiation group had a higher 10-year rate of overall survival than did patients in the control group (81.3% vs. 73.9%), a difference that approached statistical significance but should be viewed with caution, as described later (hazard ratio 0.69; 95% CI 0.47–1.00; P =0.05).

The EORTC 22922 trial was published in the same issue of the New England Journal of Medicine as the MA.20 trial and yielded similar results. This trial included patients who had undergone BCS or mastectomy and also found that the use of RNI resulted in statistically significant reductions in regional recurrence (2.7% with RNI vs. 4.2% without) and distant recurrence (15.9% vs. 19.6%) with improved DFS (72.1% vs. 69.1%) and a trend toward improved overall survival (82.3% vs. 80.7%; P =0.06). Similar to MA.20, eligible patients had axillary involvement, but unlike MA.20, node-negative patients were eligible if their tumors were central or medial. So, in contrast to MA.20, where less than 10% of patients were node-negative, EORTC22922 included 45% who were N0, and an additional 55% with one to three positive nodes (74% of whom had ER-positive disease). Notably, more than 90% of patients underwent ALND in both studies, which is somewhat different from the contemporary standard of SLNB alone based on the Z11 trial.

Whereas the MA.20 and EORTC 22922 studies set out to evaluate the benefit of comprehensive RNI, a third study by the Danish Breast Cancer Group (DBCG) specifically evaluated the role of RT to the IMN chain. Radiation to the IMNs can be technically challenging, given the proximity of this nodal basin to the heart when treating left-sided cancer. Dosimetric consequences of treating the IMNs typically include increased dose to both the heart and lungs, calling into question the putative benefit of IMN treatment, as the risk:benefit calculus may carry more risk than for other nodal targets. Thus DBCG-IMN was a large, prospective, population-based study including all six Danish radiotherapy departments and one German department, where all patients were treated according to national guidelines. Among patients receiving RNI, those with right-sided disease were treated to the IMNs, whereas those with left-sided disease were not because of the risk of radiation-induced heart disease. Although this study was not randomized, its unique design was robust, using tumor laterality to effectively mimic randomization. Between 2003 and 2007, 3089 patients were treated, with 1492 allocated to receive IMN RT based on right-sided disease and 1597 allocated to no IMN RT based on left-sided disease. The patient characteristics were nearly identical between the two groups, as would be expected from a randomized trial. Sixty percent of patients had one to three positive nodes: 40% were medially located, 42% had T1 tumors, 29% were grade 3, and 20% were ER-negative. Notably, and in contrast to MA.20 and EORTC 22922, this study found that IMN RT reduced 8-year breast cancer mortality from 23.4% to 20.9% ( P =0.03), and overall survival improved from 72.2% to 75.9% ( P =0.005). With this evidence of a potential survival benefit related to IMN inclusion, it remains prudent to continue including the IMNs when planning RNI.

Given a series of randomized trials showing that RNI improves nearly all measures of disease control, but without a clear effect on overall survival, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted a meta-analysis of 14 such trials encompassing close to 13,500 patients. In an analysis separating older (pre-1989) from newer (1989 onward) trials, the newer trials included nearly 11,000 women and showed an absolute 2.9% improvement in 10-year overall mortality among those receiving regional RT (25.2% 10-year overall mortality without RNI vs. 22.3% with; P =0.0003). These findings translated to a relative risk of 10-year breast cancer morality of 0.82 with RNI (95% CI 0.75–0.90). Thus, mirroring prior efforts to improve power among parallel randomized studies, the EBCTCG demonstrated that RNI may confer an overall survival benefit among appropriate patients.

As mentioned, MA.20 conducted prespecified subgroup analyses by receptor status, showing that more of the RNI benefit accrued to ER-negative patients (10-year DFS hazard ratio [HR] 0.56; 95% CI 0.39–0.81) than to their ER-positive counterparts (HR 0.88; 95% CI 0.68–1.15; P =0.04). While EORTC 22922 did not report outcomes by subtype, supplemental data suggest that ER-positive patients sustained greater benefit from RNI. This inference arises from the observation that those receiving hormonal therapy (HR 0.82; 95% CI 0.63–1.06) or both hormonal and chemotherapy (HR 0.72; 95% CI 0.55–0.94) benefitted more from RNI than those receiving no adjuvant therapy (HR 0.91; 95% CI 0.59–1.39) or chemotherapy alone (HR 1.05; 95% CI 0.84–1.32). Thus, among patients on EORTC 22922, since greater benefit accrued to those who received hormonal therapy, the supposition appears to be that RNI was more beneficial among ER-positive patients. This discordance between MA.20 and EORTC 22922 remains unresolved and illustrates the caution that must be exercised in interpreting subgroup analyses, even among randomized trials.