The main benefits of NAC for the treatment of breast cancer are its ability to increase a woman’s chance for breast conservation and to provide in vivo chemosensitivity information.27,28 Although this change in treatment paradigm has facilitated surgery and helped to predict outcomes in certain subsets of patients, it has also caused some confusion with respect to the role of adjuvant radiation therapy. For instance, the estimation of LRR and subsequent decision for adjuvant radiation is based on clinical and pathologic factors identified perioperatively (e.g., Haagensen’s 5-grave characteristics or clinical TNM staging) or postoperatively (extent of tumor, number of positive lymph nodes, etc.). Importantly, the estimated risk of LRR was informed by clinicopathologic factors from heretofore undisturbed/untreated tumor (i.e., prior to any systemic therapy). With the advent of NAC, and the resulting shift in treatment sequence, the peri- and postoperative clinicopathologic information obtained is no longer from an undisturbed/untreated tumor. Consequently, the ways in which clinicopathologic factors are used to predict LRR may need to be reassessed. A typical conundrum would be the patient with positive lymph nodes prior to NAC, but at the time of mastectomy had no identifiable nodal metastases. Should this pathologic N0 patient be offered PMRT?
This section will focus on multiple topics inherent to NAC such as evaluation of the axilla following NAC, candidacy for conversion from mastectomy to BCT, and adjuvant radiation therapy recommendations in the NAC setting. An important point is that the decision to offer radiation for nodal management is applied independent of surgical treatment of the breast.
NAC and Evaluation of the Axilla
As described in previous sections, evaluation of axillary lymph node status is one of the strongest prognostic factors for breast cancer patients and is used to guide adjuvant systemic and radiation therapeutic decisions. Because sentinel lymph node biopsy (SLNB) has been shown to provide an accurate assessment of nodal status and is associated with decreased morbidity compared to axillary dissection, it has been adopted as the primary staging procedure in clinical node-negative non-NAC patients.29-31 However, NAC alters the treatment sequence so that clinicopathologic factors are no longer obtained from an undisturbed/untreated tumor perhaps recommendations for surgical evaluation of the axilla may require modification.
The recently published Sentinel Lymph Node Surgery after Neoadjuvant Chemotherapy in Patients with Node-Positive Breast Cancer (Alliance) Trial, and the Sentinel-Lymph-Node Biopsy in Patients with Breast Cancer Before and After Neoadjuvant Chemotherapy (SENTINA) Trial were designed to provide reliable data for the feasibility and accuracy of a standardized SLNB after NAC.32,33 The Alliance Trial studied women with clinically node-positive disease treated with NAC, followed by an evaluation of the axilla with SLNB and axillary dissection in order to determine the false-positive rate of SLNB. There were 525 patients with cN1 disease who had at least two SLNs excised and went on to have a complete ALND. Of the 310 patients who did not achieve a pathologic complete response, residual nodal disease was confined to the SLNs in 108 patients, confined to the nodes removed on ALND in 39 patients, and present in nodes from both procedures in 163 patients. Thus, 39 of the 310 patients with residual nodal disease had a false-negative SLN finding, an FNR of 12.6%. However, the FNR decreased to a predetermined acceptable level when three or more SLNs were examined (p = .007; FNR, 9.1% for ≥3 SLNs vs. 21.1% for 2 SLNs). Bivariable analyses also found that the likelihood of a false-negative SLN finding was significantly decreased when the mapping was performed with the combination of blue dye and radiolabeled colloid (p = .05; FNR, 10.8% combination vs. 20.3% single agent). Multivariable logistic modeling revealed that, once the number of SLNs examined (2 vs. ≥3) were accounted for, no other factors were significant predictors of a false-negative SLNB finding.33
Additionally, the SENTINA trial was a prospective, multicenter cohort study with four arms (A to D). For the purposes of this topic we will limit our discussion to Arm C which is most similar to those treated in the Alliance trial. Arm C, consisted of women with clinically node-positive disease (n = 592) who received NAC, and who converted to clinically node-negative disease after chemotherapy and were treated with SLNB and axillary dissection. In this group, the FNR was 14.2% (95% CI 9.9 to 19.4; 32 of 226). Similar to the Alliance Trial, the FNR was consistently less than 10% for patients who had three or more sentinel lymph nodes removed. Also, multivariate analysis showed that a combined detection procedure (radiocolloid and blue dye) compared to radiocolloid tracer alone was associated with an improved detection rate in Arm C (p = 0.046). However, it was not associated with a statistically significant reduction in FNR (p = 0.145, 8.6% vs. 16%).
In conclusion, the Alliance and SENTINA trials demonstrate that SLNB with a sampling of three or more nodes is associated with an acceptable FNR (<10%). while a sampling of fewer nodes is associated with an unacceptable FNR (>10%). Both trials support that SLNB with a combined detection procedure (radiocolloid and blue dye) result in an improved evaluation of the axilla.34 Based on the results of these prospective trials, patients, who present with clinically node-positive disease, subsequently convert to clinically node-negative disease after NAC, and undergo an SLNB, may trust the results of the SLNB if three or more sentinel nodes are sampled. If fewer nodes are sampled then the FNR is unacceptably high and an ALND should be seriously considered.
NAC and PMXRT Recommendations
The recommendations for PMRT in the setting of NAC are complicated by the persistent controversy concerning patients with one to three positive lymph nodes. This issue was previously discussed in the section "One to Three Node-Positive Breast Cancer" of this chapter. The U.S. literature for PMRT in the setting of NAC is mostly derived from two large prospective randomized trials, NSABP B-18 and B-27, and serial retrospective studies from MD Anderson Cancer Center (MDA).27,35,36-40 In study B-18, patients were randomized to either pre- or postoperative doxorubicin and cyclophosphamide (AC).40 In study B-27, patients were randomized to preoperative AC, preoperative AC followed by preoperative paclitaxel or preoperative AC followed by postoperative paclitaxel.36 Mamounas and colleagues examined patterns and predictors or LRR, following mastectomy without PMRT, from the B-18 and B-27 trials. Significant predictors of LRR following mastectomy included clinical tumor size, clinical nodal status, and pathologic nodal status/pathologic breast tumor response.41 Because of the complexity associated with the discussion of adjuvant treatment recommendations after NAC, it is perhaps best to consider the risk of LRR, and thus the need for PMRT, first as a function of clinical stage at presentation and second, according to pathologic nodal status at the time of definitive surgery.
FUNCTION OF CLINICAL STAGE
Because NAC is less frequently used in patients with clinical stage I/II disease, there is a paucity of information to guide recommendations for PMRT in this group. MDA retrospectively reviewed 542 patients from 1974 to 2000 who were treated with NAC, mastectomy, and PMRT and compared them to 134 patients similarly treated but without radiation.42 In patients with clinical stage IIB or greater disease (n = 646), there was a significant decrease in LRR at 10 years with PMRT (11% vs. 26%; p < .001).42 However, in patients with clinical stage I or IIA (n = 30) breast cancer, there was no significant difference in LRR at 10 years between those who did and did not receive PMRT. Notably, the data on patients with clinical stage I/II disease were limited and thus the recommendations concerning PMRT in this group should be viewed judiciously. This report would suggest that, simply based on stage at presentation, patients with clinical stage IIB disease or greater should receive PMRT after NAC.
FUNCTION OF RESPONSE TO NAC (NODAL STATUS)
Based on retrospective studies from MDA, patients who were clinical stage II prior to NAC, were pathologically node negative at time of mastectomy, and did not receive PMRT had an LRR rate of less than 10% at 8 years of follow-up.43,44
MDA investigators reported that among those who achieved a pCR, the addition of PMRT did not improve the rate of LRR.42 Their results also showed that women with clinical stage III prior to NAC who were pathologically node negative at mastectomy and did not receive PMRT (n = 12) had a higher 10-year LRR rate than those women who received PMRT (n = 62) (33% vs. 7%; p = 0.04). This difference in LRR translated into a statistically significant 10-year OS benefit (33% vs. 77%; p = 0.0016).36-42,45 This finding is not universal. A retrospective analysis by Le Scodan et al45 evaluated clinical stage II and III NAC patients who were node negative at the time of mastectomy. Much like the study by Huang et al,42 there was no significant difference in LRR at 5 years between clinical stage II patients who did (n = 39) or did not (n = 44) receive PMRT (93% vs. 97%; P > 0.4). However, Le Scodan et al45 also reported no significant difference in LRR at 5 years between clinical stage III patients with negative nodes at mastectomy who did (n = 38) and did not (n = 12) receive PMRT (95% vs. 91%; P > 0.2).
With an analysis of the NSABP B-18/27 data Mamounas and colleagues41 identified predictors of LRR following mastectomy which included clinical tumor size, clinical nodal status, and pathologic nodal status/pathologic breast tumor response. Based on these predictors, a Cox proportion hazard model of the 10-year probability of LRR for patients treated with mastectomy showed that patients with residual nodal disease had an (approximate) risk of 18% to 25% of LRR depending on primary tumor size following NAC. Many would consider this risk sufficient, independent of tumor size, to offer PMRT. This decision is further supported by the modern PMRT and the MA.20 trials.5-7,15,37,46
Although the data presented here are limited and partly based on retrospective studies from a single institution, some generalized observations/recommendations can be made. Women who have clinical stage II disease prior to NAC and are pathologically node negative at the time of mastectomy appear to have a risk of LRR insufficient to warrant routine use of PMRT. Recommendations are less certain for patients with clinical stage III disease prior to NAC but are node negative at the time of mastectomy. However, the data from MDA supports treatment with PMRT in this population, the article by Le Scodan et al suggests that observation may suffice. In the absence of more data, it is perhaps most prudent to offer PMRT to these clinical stage III, pathologically node-negative patients.45 Patients with any positive lymph nodes after NAC appear to have an LRR rate sufficiently high to warrant PMRT. Additional prospective randomized trials are needed to further evaluate the role of PMRT in the setting of NAC. One such trial is NSABP B-51. In this trial women who convert from node-positive to pathologically node-negative breast cancer after NAC are randomized to regional nodal irradiation.
NAC and Conversion from Mastectomy to BCT
The discussion of BCT versus mastectomy was reviewed in a previous chapter. Briefly, several randomized trials have shown that mastectomy and BCT are equivalent with respect to overall survival. There are multiple factors that influence the appropriateness for BCT, but for the purpose of this discussion, we will address mainly the size of the primary tumor since it is a commonly accepted limiting factor for BCT. A randomized BCT trial that accepted tumors up to 5 cm had a remarkably high rate of local failure (20% at 8 years).47 By comparison, a trial that only accepted tumors ≤2.5 cm in size had one of the lowest rates of local recurrence of all the BCT trials (2% at 20 years).48 Based on these studies and others, it is commonly accepted that women with smaller tumors (approximately <4 cm) are among the best candidates for BCT.
With the advent of NAC and its ability to decrease the size of the tumor prior to surgery, should these pretreatment upper size limits for BCT remain? For example, should a patient with a 6-cm primary tumor prior to NAC, but a 2-cm tumor after NAC, be considered now an appropriate candidate for BCT? To answer this question, it is most useful to turn to the randomized trials evaluating NAC and ask (1) how often does NAC result in conversion from a mastectomy to BCT? and (2) are breast cancer outcomes (OS, LRR) worse in those converted to BCT compared to those who were originally BCT candidates or those ultimately treated with mastectomy?
NAC AND CONVERSION RATES OF MASTECTOMY TO BCT
The NSABP B-18 randomized patients to preoperative or postoperative doxorubicin and cyclophosphamide (AC). This trial showed a 12% difference in the number of patients able to undergo BCT in favor of preoperative AC.35 If one were to limit the analysis to patients with tumors >5 cm, the percentage of patients who underwent BCT in the post and preoperative chemotherapy arms was 3% and 21%, respectively. This corresponds to a sevenfold increase in BCT eligibility with the use of NAC. Similar increases were seen in European Organisation for Research and Treatment of Cancer (EORTC) 10902, which randomized patients to pre or postoperative fluorouracil, epirubicin, and cyclophosphamide.49 The authors reported that 23% of the patients originally planned for mastectomy in the preoperative group became eligible for and received BCT. This increase in the rate of BCT with preoperative chemotherapy has been further substantiated in two meta-analyses.50,51 While each of these studies demonstrate that NAC increases the rate of BCT, the question remains as to whether outcomes are affected by this conversion from mastectomy to BCT.
OUTCOMES FOLLOWING CONVERSION FROM MASTECTOMY TO BCT
In NSABP B-18, there was no statistically significant difference in local recurrence between the pre and postoperative chemotherapy arms (13% vs. 10%; p = 0.21).35 Similarly, there was no statistically significant difference with respect to LRR between the pre and postoperative chemotherapy arms of EORTC 10902.49 Additionally, a combined analysis of B-18 and B-27 identified predictors of LRR following BCT including age (>50), clinical nodal status, and pathologic nodal status/pathologic breast tumor response.41 However, this general analysis may not be the best metric by which to analyze the risk of local recurrence because these values do not consider separately patients who were converted from mastectomy to BCT from those patients who were originally candidates for BCT.
In a subset analysis of NSABP B-18, there was a statistically significant increase in ipsilateral breast tumor recurrence (IBTR) in those patients downsized from mastectomy to BCT compared to those in which BCT was originally planned (15% vs. 9%; p = 0.04). Interestingly, in EORTC 10902, a similar subset analysis revealed a worse OS in those downsized to BCT. These types of analyses are further examined in an interesting article by Fitzal et al.52 When the authors compared patients who had a partial or complete response to NAC (n = 104) and were downsized from a planned mastectomy to BCT to patients who did not have a response and were treated with mastectomy (n = 67), there was no statistically significant difference in local recurrence-free survival (81% vs. 91%; p = 0.79).
However, if there were no downsizing or if there were progression of disease, the risk of local recurrence with BCT (n = 6) was increased compared to mastectomy (n = 44) (66% vs. 90%; p = 0.04). One must remember that these are all unplanned subset analyses, and therefore should be considered with caution.
Meta-analyses may provide further insight. Mauri et al50 reported the results of a meta-analysis specifically addressing OS, DFS, and LRR in nine randomized trials of patients treated either preoperatively or postoperatively with the same chemotherapy regimen. They found no statistically or “clinically” significant difference between neoadjuvant and adjuvant chemotherapy with respect to death, disease progression, or distant disease recurrence. This is not a surprise as nearly all trials had similar results in this regard. However, the authors did find that NAC was associated with an increase in LRR. Within the Mauri et al50 meta-analysis there were three studies in which patients were able to receive radiation without breast-conserving surgery. As this is nonstandard BCT, the authors analyzed these studies separately. In the separate analysis of nonstandard BCT trials, there was a strong association between NAC and LRR (RR 1.53, p = 0.002). Importantly, in the analysis of the remaining studies (i.e., those that used standard BCT techniques), there was no association between NAC and LRR (RR 1.10, p = 0.44). These results were echoed in a later Cochrane meta-analysis of 14 NAC trials reported by Mieog et al.51 Although the authors reported no difference in OS or DFS between adjuvant and NAC, they identified an association between increased LRR and NAC. Again, as in the analysis by Mauri et al, when the same three trials that used nonstandard BCT were removed from analysis, there was no significant difference in LRR between adjuvant chemotherapy and NAC in the remaining trials.50 The importance of standard BCT after NAC is also nicely demonstrated in a retrospective analysis from Daveau et al.53 The authors report that even when considering only patients who achieve a clinical complete response to NAC, there is a greater LRR rate in patients treated with radiation alone (n = 100) compared to those treated with standard breast-conserving surgery and radiation (n = 65) (31% vs. 17% at 10 years, p = 0.06).
Unfortunately, it is not possible to detail all of the criteria used by each individual trial to determine eligibility for BCT, nor is it possible to be certain that commonly accepted risk factors for IBTR were minimized. Risk factors that are likely to influence outcomes when one converts from mastectomy to BCT after NAC include postchemotherapy T size, stage, ER/PR or Her2 status, multifocality, and imaging characteristics.52,54-56 Nevertheless, and generally speaking, the individual analyses of the major prospective randomized trials and the review of two meta-analyses support the conclusion that standard BCT, after a sufficient response to NAC, is feasible and does not appear to result in a significantly increased risk of local failure.