Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Postmastectomy radiation therapy after neoadjuvant chemotherapy: review and interpretation of available data:

Postmastectomy radiation therapy after neoadjuvant chemotherapy: review and interpretation of... 617459 TAM0010.1177/1758834015617459Therapeutic Advances in Medical OncologyAU Kishan and SA McCloskey research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Postmastectomy radiation therapy after 2016, Vol. 8(1) 85 –97 DOI: 10.1177/ neoadjuvant chemotherapy: review and © The Author(s), 2015. Reprints and permissions: interpretation of available data http://www.sagepub.co.uk/ journalsPermissions.nav Amar U. Kishan and Susan A. McCloskey Abstract: Postmastectomy radiotherapy (PMRT) has been shown to decrease locoregional recurrence and improve overall survival in patients with tumors greater than 5 cm or positive nodes. Because neoadjuvant chemotherapy (NAC) can cause significant downstaging, the indications for PMRT in the setting of NAC remain controversial and thus careful consideration of clinical stage at presentation, pathologic response to NAC, and other clinical characteristics, such as grade and biomarker status is required. The current review synthesizes both prospective and retrospective data to provide evidence for recommending PMRT after NAC for patients presenting with cT3–4 disease, cN2–3 disease, and residual nodal disease, as well as rationale for omitting PMRT in patients with cT1-2N0-1 disease who achieve a pathologic complete response. Other scenarios, including nodal complete response in the presence of other risk factors, are also explored. The topics of pre-NAC clinical staging and pathologic axillary nodal staging are reviewed, and radiation portal design is briefly discussed. Keywords: post-mastectomy radiotherapy, neoadjuvant chemotherapy, pathologic complete response Correspondence to: Introduction and general principles of and breast cancer mortality were noted among Susan A. McCloskey, MD postmastectomy radiation subsets with one to three nodes positive or at least Department of Radiation Oncology, 1223 16th The American College of Radiology (ACR) cur- four nodes positive. An earlier EBCTG analysis Street, Santa Monica, rently recommends consideration of postmastec- suggested that an absolute reduction in 5-year CA 90404, USA smccloskey@mednet. tomy radiation (PMRT) for patients with tumors LRR of over 10% would be necessary for a sur- ucla.edu greater than 5 cm or with at least four positive vival benefit to be shown at 15 years [Clarke et al. Amar U. Kishan, MD nodes [Taylor et al. 2009]. This recommendation 2005]. However, some suggest employing PMRT Department of Radiation Oncology, David Geffen is largely based on the results of three randomized even when the absolute LRR risk (not the abso- School of Medicine, controlled trials that demonstrated an overall sur- lute risk reduction) is greater than 10%, citing the University of California, Los Angeles, CA, USA vival (OS) benefit for PMRT in patients with expected long-term survival of these patients. lymph node positive disease (pN+), tumors greater than 5 cm in size, and pectoralis fascia/ Despite the availability of three randomized trials skin involvement [Overgaard et  al. 1997, 1999; and meta-analyses to guide PMRT decision mak- Ragaz et al. 2005]. This OS benefit is thought to ing in the absence of neoadjuvant chemotherapy stem from the fact that PMRT reduces the risk of (NAC), PMRT in this setting is not without con- locoregional recurrence (LRR) by approximately troversy. Several institutional series have noted two thirds [Clarke et al. 2005]. The most recent very low rates of locoregional failure among select iteration of the Early Breast Cancer Trialist’s women with T3N0 or T2N1 disease being treated Collaborative Group (EBCTCG) meta-analysis in the modern era [Taghian et al. 2006; Yu et al. showed that among 3086 women, PMRT reduced 2008; Floyd and Taghian, 2009; Moo et al. 2013; the 10-year first LRR rate from 26.0% to 8.1%, McBride et al. 2014]. Other series have suggested with a corresponding reduction in 20-year breast- expanding the role of PMRT to include select cancer mortality from 66.4% to 58.3% [McGale patients with T1–2N0 breast cancer who have et  al. 2014]. Notably, equivalent gains in LRR particularly high-risk features (e.g. young age, http://tam.sagepub.com 85 Therapeutic Advances in Medical Oncology 8(1) high grade, triple negative) based on high docu- series have attempted to compare women receiv- mented risk of LRR in the absence of PMRT ing and not receiving PMRT. We have in general [Rowell, 2009; Abdulkarim et al. 2011]. The role learned from these studies, which will be detailed of PMRT remains widely debated among women below, that careful consideration of pre-NAC with T3N0 or T1-2N0-1 disease, with most prac- clinical stage, post-NAC pathologic stage, and titioners individualizing radiation decision mak- individual patient and tumor factors is critically ing based on perceived risk. important to rendering appropriate radiation therapy recommendations. The decision to deliver PMRT depends on both the absolute risk of LRR and the magnitude of One of the earliest series suggesting a locoregional reduction in this absolute risk. Prospective data control benefit for PMRT after NAC focused on are lacking to inform PMRT decision making fol- 55 patients with locally advanced breast cancer lowing NAC and, given that NAC commonly (i.e. cT3–4 or cN2–3) [Abdel-Wahab et al. 1998]. alters postmastectomy pathologic findings with at Forty-two patients received PMRT and 13 did least 20–40% of patients receiving NAC having not. With a median follow up of 47 months, the axillary downstaging [Fisher et  al. 1997], it is LRR rates were 31% for patients treated without unclear if we can extrapolate findings from the PMRT and 7% for patients treated with PMRT. available data informing PMRT decision making This translated to a significant 3-year OS benefit in the absence of NAC. In 2008, the National of 88% versus 46%. Cancer Institute published a consensus statement suggesting that PMRT after NAC be delivered The MD Anderson Cancer Center (MDACC) for patients with clinical stage III disease (i.e. T4, then published a series of reports detailing their N2–N3, or T3N1) or ypN+ disease [Buchholz findings from retrospective analysis of robust et al. 2008]. However, a survey of practicing radi- institutional data. In one of the earliest series ation oncologists reported heterogeneity in adher- examining risk factors for LRR among patients ence to the latter portion of the recommendation, undergoing mastectomy after NAC, Buccholz and in decision making with regards to patients and colleagues analyzed outcomes of 150 such with stage II disease in general [Beriwal et  al. patients who did not receive PMRT [Buchholz 2013]. et al. 2002b]. The 10-year actuarial LRR rate was 27% in this cohort, which was largely composed The purpose of this focused review is to analyze of patients with locally advanced disease (55% of the relevant literature examining the benefits or patients had clinical stage IIIA disease or higher). lack thereof for PMRT in the setting of NAC. Predictors of LRR included clinical stage IIIB Additionally, the subjects of pre-NAC staging disease or greater at presentation, at least four workup, pathologic axillary staging, and radiation positive nodes pathologically, and no use of portal design will be briefly considered. tamoxifen. The MDACC group subsequently Conclusions regarding situations for which compared 5-year LRR patterns between the same PMRT following NAC should be considered will 150 patients treated with NAC and no PMRT be provided. and 1031 patients treated with adjuvant chemo- therapy and no PMRT [Buchholz et  al. 2002a]. Despite a large imbalance in clinical stage at pres- Indications for PMRT after NAC: literature entation (55% stage IIIA or higher in NAC versus review 9% in adjuvant), the overall pathologic tumor size and number of involved axillary nodes were the Lessons from retrospective series same. However, the overall 5-year LRR rate was Natural history of LRR: implications for greater for patients receiving NAC (27% versus PMRT. PMRT following NAC is inherently con- 15%), with statistically significant differences troversial due to the lack of prospective data avail- seen in subsets of patients with tumors matched able to guide decision making. We have thus relied for size or magnitude of nodal disease. Taken on retrospective data to inform treatment deci- together, these data strongly suggested that the sions. Retrospective analyses have typically exam- risk of LRR depended on both initial clinical fac- ined LRR risk in subsets of women who have not tors and pathologic factors at the time of surgery received PMRT following NAC to assess overall (i.e. pathologic findings consistent with response LRR risk and risk according to specific patient to NAC do not negate more locally advanced and tumor features. When possible, retrospective clinical presentation). 86 http://tam.sagepub.com AU Kishan and SA McCloskey The MDACC group next demonstrated the mastectomy, with or without PMRT [including potential benefits of PMRT by comparing out- full regional nodal irradiation (RNI)] from 2003 comes of 542 patients treated with NAC, mastec- to 2010 [Nagar et  al. 2015]. The overall 5-year tomy, and PMRT with those of 134 patients LRR rate was 16.1%, with PMRT providing a treated with NAC and mastectomy alone (essen- significant reduction in LRR (HR 0.25), translat- tially the same 150 patients originally studied, less ing into an improved 5-year disease-free survival the 16 who experienced an early recurrence (91.3% versus 64.8%). Residual tumor and nodal within 2 months of treatment) [Huang et  al. status were significantly associated with an 2004]. The 10-year LRR rate was 22% in the increased risk of LRR, but no pre-NAC clinical absence of PMRT and 11% with PMRT with a factors (e.g. clinical T stage or N stage) were pre- hazard ratio (HR) of LRR without PMRT of 4.7. dictive. The authors posit that more accurate The 10-year cause-specific survival (CSS), how- staging leads to upstaging or downstaging with ever, was identical between the two groups (58% respect to what would have been considered the with PMRT and 50% without), but on multivari- clinical stage in the past, thereby diluting the pre- ate analysis PMRT provided a significant benefit, dictive effect of upfront clinical stage. Though with a HR of 2.0. Significant improvement in provocative, the hypothesis requires validation, CSS was detected for patients with at least stage and it should also be recognized that many IIIB disease, cT4 tumors, and at least four patients may not have had extensive staging involved nodes. The authors subsequently workups prior to NAC. reported that five factors predicted for 10-year LRR in this cohort: skin/nipple involvement, Importance of a pCR. Achieving a pCR after NAC, supraclavicular nodal disease, no tamoxifen use, typically defined as having no residual invasive extracapsular extension, and estrogen-receptor disease in the breast or nodes on surgical pathol- negative disease [Huang et al. 2005]. For patients ogy, has been associated with improved survival with two or fewer of these factors (74% of all in both of the prospective trials discussed below, patients), the 10-year LRR rate was less than 8%, as well as numerous other studies [Rastogi et  al. but for those with at least three risk factors, the 2008; Cortazar et al. 2014]. A recent meta-analy- 10-year LRR rate was 28%. sis of 1955 patients confirmed that, on a patient- level analysis, achieving ypT0-TisN0 status was More recently, Wright and colleagues reported significantly associated with improved event-free- the outcomes of 464 patients who received PMRT survival and OS [Cortazar et al. 2014]. The impli- after NAC and mastectomy at the University of cations of pathologic response on LRR rates Miami [Wright et  al. 2013]. Of these, 17.5% warrant detailed review. One could hypothesize received tangent-only radiation [the remainder that a pCR could negate the need for PMRT, had radiation to both the chest wall and supracla- however there are data to suggest high rates of vicular fossa; only a minority were estimated to LRR despite the achievement of pCR in select have radiation covering the internal mammary subsets. nodes (IMNs)]. The investigators noted an over- all 5-year LRR rate of 5.8%, with a rate of 1.9% The aforementioned series from Huang and col- for patients with ypN0 disease. On multivariate leagues found that the 46 patients with clinical analysis, tangent-only PMRT, ypN+ status and stage III disease or higher who experienced a pCR triple negative histology were significantly associ- still had significantly lower 10-year LRR rates ated with LRR (HRs of 3.39, 10.23 and 8.5, with PMRT (33% versus 3%) [Huang et al. 2004]. respectively). Clinical stage III versus stage II dis- This contrasted with patients with clinical stage I ease was a significant predictor of LRR on uni- and II disease and a pCR, for whom PMRT did variate analysis only. The authors concluded that not seem to affect LRR rates. In a follow-up they could not identify a single subtype of patients series, McGuire and colleagues specifically inves- for whom supraclavicular irradiation offered no tigated LRR rates following pCR in 106 patients locoregional control benefit, though they noted with noninflammatory breast cancers treated with that the low rate of LRR in patients with a nodal NAC and mastectomy [McGuire et  al. 2007]. pathologic complete response (pCR) suggests a The 10-year LRR rate was 0% for the 32 patients limited absolute benefit in that cohort. with clinical stage I–II disease, regardless of PMRT use. For the 74 patients with stage III dis- Finally, Nagar and colleagues reported the out- ease, however, PMRT significantly improved the comes of 161 patients treated with NAC and 10-year LRR rate (33.3% versus 7.3%), and this http://tam.sagepub.com 87 Therapeutic Advances in Medical Oncology 8(1) improvement in LRR translated into significant including breast pCR, hormone receptor status, improvements in CSS (40% versus 87%) and OS Her2 status, and receipt of adjuvant chemother- (33.3% versus 77.3%). Notably, few patients in apy (http://www.nsabp.pitt.edu/B-51.asp). The this group had cT3N0 disease, precluding evalu- RAPCHEM study in the Netherlands is a pro- ation of the prognostic significance of achieving a spective nonrandomized study in which patients pCR in this subset of patients. While these data with cT1–2N0-1 (histologically proven nodal dis- strongly suggest that PMRT is indicated for ease, but excluding patients with more than three patients with clinical stage III disease regardless nodes on imaging) who receive NAC undergo of their pathologic response, other studies have risk-adapted radiotherapy after surgery (https:// provided evidence to the contrary. Two recent clinicaltrials.gov/ct2/show/NCT01279304). analyses have examined LRR among women Patients with nodal pCR are considered low risk achieving a pCR in the nodes (as opposed to pCR and, after mastectomy, will not receive PMRT. in the breast and nodes). Investigators at the Institut-Curie evaluated 134 patients with a nodal Specific subsets: stage I/II, molecular subtype, and pCR after NAC, of whom 78 underwent mastec- young age. Investigators at MDACC have issued a tomy followed by PMRT and the remainder had series of reports examining outcomes in specific mastectomy alone [Le Scodan et  al. 2012]. The subsets of interest. Among 132 patients with clini- investigators found numeric differences in 10-year cal stage I or II disease who did not receive PMRT LRR (3.8% with PMRT and 13.2% without) and after NAC, the 10-year LRR rate was 10% [Garg OS (77.2% and 87.7%) that did not reach statis- et  al. 2004]. For patients with cT1–2 disease and tical significance. No difference was also noted in one to three positive nodes, the 5-year LRR was a subset analysis restricted to the 50 patients who 5%; however, cT3N0 disease, at least four nodes at had clinical stage III disease at presentation. surgery, and age up to 40 were significant predic- Presence of residual tumor in the breast did por- tors of LRR. Nagar and colleagues compared out- tend poorer outcomes. Finally, a recent report comes between 119 patients with cT3N0 disease from Korea found no difference in 5-year LRR who underwent PMRT after NAC and mastec- rates among 151 patients with clinical stage II–III tomy with 43 who did not [Nagar et  al. 2011]. disease who had a nodal pCR after NAC, regard- More patients who received PMRT were up to 40 less of PMRT receipt [Shim et al. 2014]. In this years of age and had ypN+ disease, but despite study, both age (⩽40 years old versus >40 years this, the 5-year LRR rate was 24% for patients old) and pathologic T stage were associated with without PMRT and 4% for patients who received higher risks of LRR and CSS, while PMRT was it. In a subset analysis, PMRT had a significant not associated with either. An analysis based on locoregional control benefit for patients with stage was not performed, though with 5-year ypN+ or high-grade disease. The authors did note LRR rates of 1.9% and 7.7% with and without that the 5-year LRR for patients with cT3N0, PMRT, respectively, it is unlikely that a differ- ypN0 disease who did not receive PMRT was ence would have been identified. 14%, nearly double the rate of isolated LRR among patients with pT3N0 disease receiving adjuvant Overall, these data suggest that for patients with chemotherapy followed by PMRT in an earlier stage II disease who achieve a pCR, PMRT is series by Taghian and colleagues [Taghian et  al. unlikely to provide a significant LRR benefit. For 2006]. This discrepancy has been hypothesized to patients with stage II or stage III disease who be due to occult nodal disease in patients present- achieve a nodal pCR, the presence of residual ing with cT3N0 disease [Meric et al. 2000]. breast disease, or young patient age, may portend higher LRR rates, with conflicting evidence Data for other specific subsets are fairly limited. regarding the need for PMRT particularly in Clinical multifocality and multicentricity do not patients with stage III disease. Findings from two appear to be associated with increased risk of prospective trials also suggest a significant prog- LRR [Oh et  al. 2006], nor does Her2 positivity nostic value of nodal pCR for LRR risk (see below) [Buchholz et al. 2004; Nagar et al. 2015]. Triple [Mamounas et  al. 2012]. Two ongoing trials negative status, however, does appear to increase address this issue directly. The NSABP51/RTOG the risk of LRR [Huang et al. 2005; Wright et al. 1308 trial randomizes patients with cT1–3N1 2013]. In the aforementioned study by Wright (pathologically proven) who achieve a nodal pCR and colleagues, the authors reported that seven of after NAC and undergo mastectomy to either nine regional recurrences occurred in patients PMRT or no PMRT, with stratification factors with triple negative histology [Wright et al. 2013]. 88 http://tam.sagepub.com AU Kishan and SA McCloskey Table 1. Ten-year locoregional recurrence rates for patients undergoing neoadjuvant chemotherapy followed by mastectomy. LRR (chest wall and regional) Tumor ⩽5 cm* Tumor >5 cm cN0 ypN0/breast pCR 6.5% 6.2% ypN0/no breast pCR 6.3% 11.8% ypN+ 11.2% 14.6% cN+ ypN0/breast pCR 0.0% 0.0% ypN0/no breast pCR 10.8% 9.2% 17.0% 22.4% ypN+ *Tumor size here is referring to clinical tumor size. LRR, locoregional recurrence; pCR, pathologic complete response. A focused study of LRR and OS outcomes among 11.1% (8.4% local, 2.7% regional; 71% of all 107 patients younger than 35 years treated with LRR were local) among the 1947 patients under- NAC and mastectomy found improved 5-year going mastectomy [Mamounas et al. 2012]. In a LRR (12% versus 37%) and OS (67% versus 48%) multivariate analysis, significant predictors of for patients who received PMRT [Garg et  al. LRR included clinical tumor size (>5 cm versus 2007]. These improvements were present despite ⩽5 cm; HR 1.58), clinical nodal status (cN+ ver- a greater preponderance of adverse features sus cN0; HR 1.53), and pathologic nodal status/ among patients receiving PMRT. On specific breast tumor response (HR 2.21 for ypT+N0 subset analysis, the survival benefit was only sta- versus total pCR, and 4.48 for ypN+ versus total tistically significant for patients with clinical stage pCR). Interestingly, for patients treated with IIB disease, though similar trends were seen in all breast-conserving therapy, clinical tumor size was stages. This finding is consistent with the afore- not a significant predictor, but age (<50 versus mentioned Korean study, which had also found ⩾50) was. Table 1 depicts the 10-year LRR rates age up to 40 to be a significant predictor of LRR stratified by the predictive risk factors; notably, [Shim et al. 2014]. among patients with cN+ disease, only 32 of 424 patients (7.5%) had a pCR (in the breast and In a recent comprehensive review, wherein appro- nodes), so the observed 10-year LRR of 0.0% in priateness of PMRT after NAC was determined that subset of patients must be kept in context. using the ACR Appropriateness Criteria modified Among patients with ypN+ disease, 10-year LRR Delphi methodology, it was concluded that rates were greater than 10% regardless of clinical patients with T1–2N0–1 who were aged over 40 nodal status, clinical tumor size or pathologic N and had estrogen receptor positive disease, with stage. The analysis was limited by lack of infor- less than four positive axillary nodes without lym- mation regarding molecular subtypes of tumors; phovascular space invasion or extracapsular exten- no patient received Her2/neu-directed therapy, sion have a 5-year LRR of less than 10% and thus and all patients in NSABP-27 received tamoxifen may not benefit from PMRT [Fowble et al. 2012]. concurrently with chemotherapy, which was sub- sequently shown to be inferior to sequential administration [Albain et al. 2009]. Lessons from NSABP-18 and NSABP-27 Two large prospective randomized controlled tri- These data suggest that the overall 10-year LRR als of NAC, NSABP-18 and NSABP-27 also rate following NAC and mastectomy is relatively allow an examination of the natural history of low in the absence of PMRT, and have led some LRR following mastectomy, as both prohibited to suggest omission of PMRT in patients with patients from receiving PMRT [Fisher et al. 1997; clinical stage II disease who achieve a pCR [Bellon Bear et al. 2003; Rastogi et al. 2008]. In a recent et al. 2012; Marks and Prosnitz, 2014; White and pooled analysis, the overall 10-year LRR rate was Mamounas, 2014]. It is imperative to note that http://tam.sagepub.com 89 Therapeutic Advances in Medical Oncology 8(1) the patients enrolled in NSABP-18 and 27 were absent hilum, eccentrically widened cortex, and generally at far lower risk of LRR overall than cortical thickening [Mainiero, 2010]. Altered those in the retrospective studies referenced morphology, rather than size, may provide a above: 55% had cT1–2N0 disease, 20% had greater specificity for detecting malignancy cT1–2N1 disease, 16% had cT3N0 disease and [Alvarez et  al. 2006]. Fine-needle aspiration only 9% had cT3N1 disease. (FNA) of suspicious-appearing nodes provides a specificity of nearly 100% for malignant disease [Baruah et al. 2010; Park et al. 2011; Bazan and Summary White, 2015]. We recommend careful consideration of pre- NAC clinical stage, post-NAC pathologic stage Although imperfect, more advanced imaging and individual patient and tumor factors in order modalities, such as magnetic resonance imaging to individualize decision making regarding PMRT (MRI) and 18-fluorodeoxyglucose positron emis- after NAC. In general, we recommend PMRT sion tomography ( FDG-PET) can be particu- after NAC for patients who have presented with larly helpful in evaluating nodal disease burden cT3–4 disease or cN2–3 disease regardless of [Kvistad et  al. 2000; Greco et  al. 2001; Luciani pathologic extent of disease at the time of surgery. et  al. 2004; Wahl et  al. 2004; Mortellaro et  al. We also recommend PMRT for all patients who 2009; Koolen et al. 2012]. An early study reported have residual nodal disease after NAC. For that MRI had a sensitivity of 83% and a specific- patients presenting with clinical stage II disease ity of 90% for nodal disease [Kvistad et al. 2000], (excluding cT3N0) who achieve a pCR, we typi- while a prospective study of FDG-PET reported cally recommend omitting PMRT. For patients a sensitivity of 61% and a specificity of 80% with clinical stage II disease (excluding cT3N0) [Wahl et  al. 2004]. Our recommendation is to who achieve a nodal pCR, we recommend enroll- obtain an axillary ultrasound for all patients with ment on NSABP51; absent that, we would err an invasive breast cancer diagnosis; suspicious towards offering PMRT for patients of young age nodes should be biopsied and clipped. If positive (⩽40 years old), those with greater than 2 cm nodes are found, then advanced imaging is rec- residual tumor in the breast, those with high- ommended, particularly PET-CT which can grade histology and those with triple negative his- delineate regional nodal disease that may benefit tology. These recommendations are largely from targeted radiation therapy [Bazan and consistent with what others have proposed White, 2015]. However, even for patients without [Fowble et al. 2012; Hoffman et al. 2012]. We do histologically confirmed nodes we routinely recommend that all patients who undergo NAC request MRI imaging to better determine the meet with a radiation oncologist, preferably extent of disease in the breast. upfront, to facilitate their multidisciplinary management. The use of advanced imaging to estimate response is an area of active investigation. In a retrospec- tive review, axillary ultrasound was the most sen- Preneoadjuvant chemotherapy imaging and sitive test for detecting ypN+ disease after NAC, nodal assessment with a sensitivity of 69.8% compared with 63.2% Because both pathological and pre-NAC clinical for FDG-PET and 61.0% for MRI [Hieken factors impact risk of LRR following NAC, accu- et  al. 2013]. However, accuracy was the highest rate pre-NAC staging is imperative. Prior to initi- for FDG-PET at 71.9%, followed by ultrasound ating NAC, it is crucial to establish clinical T and at 65.1% and MRI at 60.2%. Two recent studies N stage as definitively as possible in order to opti- also suggest that FDG-PET may be particularly mally inform post-NAC locoregional therapy helpful in restaging patients with triple negative decision making. Physical examination alone is histology [Straver et al. 2010; Koolen et al. 2014], unreliable and upwards of 30% of patients who and carry prognostic significance in certain situa- are considered to have cN0 on examination will tions [Groheux et al. 2012; Groheux et al. 2013]. have occult nodal disease found by sentinel lymph A recently published analysis from the American node biopsy (SLNB) [Chung and Giuliano, 2010; College of Surgeons Oncology Group (ACOSOG) Kuehn et al. 2013]. Axillary ultrasound is a help- Z1071 (ALLIANCE) trial examined axillary ful imaging modality for detecting nodal disease, ultrasound after NAC and its impact on sentinel with concerning features including a longitudinal/ node biopsy [Boughey et  al. 2015]. The authors transverse greatest dimension ratio less than 2, concluded that employing a strategy of limiting 90 http://tam.sagepub.com AU Kishan and SA McCloskey SNB to those with negative axillary ultrasound overall sentinel node identification rate of 89% post NAC could serve to reduce false negative after NAC, with an overall false negative rate rates with SNB to below 10%. As Dialani and (FNR) of 14% [Fu et  al. 2014]. The relatively colleagues concluded in a recent review of imag- higher FNR after NAC, compared with the ing after NAC, there is no currently accepted upfront FNR of less than 10%, was initially cause standard with regards to imaging method for for concern, but results from three recently pub- monitoring response to NAC [Dialani et  al. lished trials provide some insight into minimizing 2015]. In general, we recommend repeat MRI (or this FNR [Boughey et al. 2013; Kuehn et al. 2013; ultrasound if initial MRI is not performed) after Boileau et al. 2015]. the fourth cycle of NAC, as this might also indi- cate which patients have not responded well and In the phase II ALLIANCE trial, 649 women should move forward with local therapy. with cT0–4N1–2 disease who received NAC underwent a SLNB prior to a completion ALND, A further detailed review of this workup is beyond with the primary outcome being the FNR of the scope of this focused review and interested SLNB [Boughey et  al. 2013]. No sentinel node readers are directed to other detailed reviews was found in 7% of patients, and only one node [Pilewskie and King, 2014; Bazan and White, was found in 12% of patients. Overall, the FNR 2015; Dialani et al. 2015]. was 12.6%; for patients with only two sentinel nodes removed, the FNR was 21.1%, compared with 9.1% for patients with at least three sentinel Pathologic nodal staging nodes removed. If a dual identification method In recent years, SLNB has replaced full axillary was used (blue dye and radiolabeled colloid), the lymph node dissection (ALND) in both patients FNR dropped to 10.8%. In the four-arm pro- with cN0 disease and in patients with cT1–2 dis- spective SENTINA study, patients were strati- ease and involvement of up to two nodes on initial fied to receive SLNB before NAC (for cN0 that SLNB [Krag et  al. 2010; Giuliano et  al. 2011; remained ycN0), before and after NAC (for cN0 Galimberti et al. 2013]. Additionally, the recently that were found to be pN0 by upfront SLNB) or published European Organisation for Research after NAC (for cN+ which converted to ycN0) and Treatment of Cancer (EORTC) 10981– [Kuehn et  al. 2013]. The primary outcome was 22023 AMAROS randomized trial has shown that the FNR in patients who had a SLNB done after axillary radiotherapy can replace ALND in NAC in patients with cN+ disease that con- patients with a positive SLNB and a 0.5–3 cm pri- verted to ycN0, which was 14% (with a detection mary [Donker et al. 2014]. Because NAC can lead rate of 80%). The investigators found that if to axillary downstaging in up to 20–40% of cases patients only had one or two sentinel nodes [Fisher et al. 1997], the use of SLNB in the con- removed, the FNRs were 24% and 18%, respec- text of NAC has generated controversy akin to tively, but if they had at least three nodes that seen with the use of PMRT. Initially, SLNB removed, it was less than 5%. If dual tracer meth- was discouraged after NAC, but the recent odology was used, the FNR was 8.6%. Notably, American Society of Clinical Oncology guidelines both the ALLIANCE and the SENTINA studies suggest that it can be offered before or after NAC, focused on patients treated with breast-conserv- with the standard of care for confirmed nodal dis- ing therapy. ease after NAC being a full ALND [Lyman et al. 2005, 2014]. A detailed discussion of the various Most recently, the prospective SN-FNAC study methods of pathological axillary staging in the evaluated the accuracy of SLNB after NAC in context of NAC is beyond the scope of this focused 153 patients with biopsy-proven T0–3N1–2 dis- review (interested readers are directed to recent ease [Boileau et al. 2015]. The investigators found excellent reviews [Mamounas, 2014; Lyman, a sentinel node identification rate of 87.6%, and 2015], but a brief overview will be presented). an FNR of 8.4%. Notably, however, immunohis- tochemistry was mandated and patients with Multiple single-institution reports and multi- ypN0(i+) disease were considered to have posi- center studies have suggested that the sentinel tive sentinel nodes. Had these patients been con- node identification rate following NAC is lower sidered to have negative sentinel nodes, then the than in the upfront setting [Mamounas et  al. FNR would increase to 13.3%. For patients with 2005; Classe et al. 2009; Hunt et al. 2009; Kelly only one node identified, the FNR was 18.2%; it et  al. 2009]. A recent-meta-analysis reported an was also 14.2% for patients with T3 tumors. http://tam.sagepub.com 91 Therapeutic Advances in Medical Oncology 8(1) Taken together, the data suggest that a FN rate of removed in addition to at least one of the follow- less than 10% can be achieved with SLNB after ing: grade 3 histologic categorization, estrogen NAC in women with cN+ disease if certain crite- receptor negativity or lymphovascular invasion) ria are met: at least three sentinel nodes are iden- after breast conserving surgery and surgical nodal tified and removed, dual identification method is evaluation (either SLNB or ALND) to RNI or no used, and biopsy proven nodes pre NAC are RNI [Whelan et al. 2015]. In the MA.20 trial, the clipped and excised. For patients with positive RNI included supraclavicular fossa/level III axilla, sentinel nodes after NAC, the current standard of the IMNs and level I–II of the axilla in selected care is a completion ALND; however, the current circumstances; in the EORTC trial, the RNI A011202 phase III clinical trial [ClinicalTrials. included the medial supraclavicular nodes and the gov identifier: NCT01901094] will randomize IMNs, and radiation of the axilla was performed patients with stage II and IIIA breast cancer who in a small subset (7.4–8.3%) of both arms. Neither have a positive sentinel node after NAC to axil- trial found a 10-year OS benefit with the addition lary radiotherapy versus ALND. For patients with of RNI, although in both trials disease-free sur- at least three sentinel nodes found to be negative, vival, locoregional control and distant metastasis- and for whom PMRT is indicated, the radiation free survival were modestly but significantly portal design can be adjusted accordingly (see improved with the addition of RNI. The decision below). If up to three sentinel nodes are removed to provide RNI versus tangent-only radiation is a and found to be negative, we recommend com- topic of significant controversy and a detailed dis- pletion ALND for full workup, and if this cannot cussion is beyond the scope of this focused review. be done, we suggest a low threshold for providing However, experience related specifically to the PMRT with axillary radiotherapy. In the case of situation of radiation portals for PMRT after patients with histologically confirmed nodal dis- NAC is fairly limited and will be reviewed here. ease prior to NAC, if treatment effect is not com- mented on or a clip is not seen and had been One study from the Centre Jean-Perrin compared placed at the time of the original biopsy, then the outcomes between 39 patients who received case should be reviewed by the surgeon and PMRT, including RNI with 37 patients who had pathologist to ensure adequate axillary sampling tangent-only PMRT [Gilliot et  al. 2010]. The has been performed. investigators found that there was no difference in 10-year LRR rates (95% without and 91% with RNI). However, in the group that did not receive Radiation portal design RNI, the 10-year OS was 96%, while in the group The three large randomized trials that demon- receiving RNI, 10-year OS was 75% (p < 0.05). strated an improved OS with PMRT all included Distant-metastasis-free survival was similarly RNI covering the supraclavicular fossa as well as higher in the patients who did not receive RNI the IMNs [Overgaard et  al. 1997, 1999; Ragaz (97% versus 78%). The treatment groups were et al. 2005]. However, in patients without certain significantly unbalanced, however, with signifi- adverse pathologic features (e.g. lymphovascular cantly more patients in the group treated with space invasion, >50% nodes positive, at least four RNI having cT3–4 tumor and having significantly nodes positive overall, and gross extranodal exten- larger residual tumors at surgery. However, the sion >2 mm), the risk of supraclavicular failure is considerably larger study by Wright and col- low [Strom et al. 2005]. The risk of isolated IMN leagues discussed above suggested a benefit to failure is similarly low in most cases, leading to including a supraclavicular field [Wright et  al. debate over the necessity of IMN irradiation 2013]. Though Wright and colleagues were not [Taghian et al. 2004; Jagsi and Pierce, 2013]. The able to determine whether the IMNs were irradi- EORTC 22922/10925 trial, which included ated for all patients, they estimated that less than women undergoing either mastectomy or lumpec- 5% of patients received IMN radiation. While tomy with ALND or SLNB who either had medial specific studies investigating omission of IMN tumors (regardless of nodal status) or pN+ dis- irradiation in patients receiving NAC are lacking, ease, randomized patients to receive RNI or no a report from the MDACC suggested that up to RNI [Poortmans et  al. 2014]. The National 10% of patients with locally advanced disease Cancer Institute of Canada Clinical Trials Group have clinically detectable IMN adenopathy by (NCIC CTG) MA.20 trial randomized women imaging, and in those patients, directed IMN with node-positive or high-risk node-negative dis- irradiation achieves excellent 5-year IMN and ease (defined as T3 or T2 with <10 nodes locoregional control [Zhang et  al. 2010]. The 92 http://tam.sagepub.com AU Kishan and SA McCloskey current randomized NSABP-51 trial randomizes PMRT. For patients with clinical stage II disease women with cT1–3N1 breast cancer who undergo who achieve a nodal pCR, we recommend enroll- lumpectomy or mastectomy and are found to ment on NSABP51; absent that, we would err have ypN0 to RNI versus no RNI. The Alliance towards offering PMRT for patients with adverse A011202 trial randomizes women with cT1–3N1 features, including young age, greater than 2 cm breast cancer who remain ypN+ on SNB follow- residual tumor in the breast, high-grade or triple ing NAC to axillary node dissection and RNI negative histology. Implicit in these recommen- versus RNI alone. Among women with clinically dations is the requirement for accurate pre-NAC node positive disease pre NAC, these trials are staging. We recommend axillary ultrasound with aiming to answer the questions of whether RNI is FNA of suspicious nodes and preferably MRI for necessary in women who become pathologically all patients and PET-CT for all node-positive node negative and whether RNI can replace axil- patients. Performing a SLNB after NAC is rea- lary surgery in women who remain pathologically sonable as long as at least three nodes are removed node positive. and a dual-tracer method is used. Radiation por- tal design is governed by similar principles as in Our recommendation is to proceed with RNI after the standard PMRT situation. NAC for any patient with ypN+ disease, and for patients presenting with cN2–N3 disease. We Funding would not cover the fully dissected axilla in the This research received no specific grant from any absence of negative risk factors (<10 nodes funding agency in the public, commercial, or not- removed, >50% nodes positive, vascular adher- for-profit sectors. ence). For patients with cN0–N1 disease who remain or convert to ypN0 disease after NAC and Conflict of interest statement have had adequate axillary staging at the time of The author(s) declare(s) that there is no conflict surgery (see above), if treating, we would cover the of interest. chest wall and determine the need for supraclavic- ular or IMN coverage based on careful considera- References Abdel-Wahab, M., Wolfson, A., Raub, W., Mies, C., tion of adverse risk factors (e.g. lymphovascular Brandon, A., Morrell, L. et al. (1998) The importance space invasion, age, extent of node positivity pre of postoperative radiation therapy in multimodality NAC, size and biologic features of residual disease management of locally advanced breast cancer: a in the breast). For patients without adequate axil- phase II trial of neoadjuvant MVAC, surgery, and lary staging, we would err on the side of caution radiation. Int J Radiat Oncol Biol Phys 40: 875–880. and provide RNI (including the undissected Abdulkarim, B., Cuartero, J., Hanson, J., Deschenes, axilla). J., Lesniak, D. and Sabri, S. (2011) Increased risk of locoregional recurrence for women with T-2n0 triple- negative breast cancer treated with modified radical Conclusion mastectomy without adjuvant radiation therapy The decision to provide or omit PMRT after compared with breast-conserving therapy. J Clin Oncol NAC is a complicated one and a consultation 29: 2852–2858. with a radiation oncologist is highly recom- Albain, K., Barlow, W., Ravdin, P., Farrar, W., mended, preferably before NAC is even started. Burton, G., Ketchel, S. et al. (2009) Adjuvant We recommend careful consideration of pre- chemotherapy and timing of tamoxifen in NAC clinical stage, post NAC pathologic stage, postmenopausal patients with endocrine-responsive, and individual patient and tumor factors in order node-positive breast cancer: a phase 3, open-label, to individualize decision making regarding PMRT randomised controlled trial. Lancet 374: 2055–2063. after NAC. Synthesis of both retrospective and Alvarez, S., Anorbe, E., Alcorta, P., Lopez, F., prospective data suggests that the risk of LRR fol- Alonso, I. and Cortes, J. (2006) Role of sonography lowing mastectomy is highest for patients with in the diagnosis of axillary lymph node metastases cT3–4 disease, cN2–3 disease and ypN+ disease, in breast cancer: a systematic review. AJR Am J and thus we recommend PMRT for these Roentgenol 186: 1342–1348. patients. For patients with stage III disease, we would recommend PMRT regardless of patho- Baruah, B., Goyal, A., Young, P., Douglas-Jones, logical response. For patients presenting with A. and Mansel, R. (2010) Axillary node staging by ultrasonography and fine-needle aspiration cytology in clinical stage II disease (excluding cT3N0) who patients with breast cancer. Br J Surg 97: 680–683. achieve a pCR, we typically recommend omitting http://tam.sagepub.com 93 Therapeutic Advances in Medical Oncology 8(1) Bazan, J. and White, J. (2015) Imaging of the axilla National Cancer Institute conference. J Clin Oncol 26: before preoperative chemotherapy: implications for 791–797. postmastectomy radiation. Cancer 121: 1187–1194. Buchholz, T., Tucker, S., Masullo, L., Kuerer, H., Bear, H., Anderson, S., Brown, A., Smith, R., Erwin, J., Salas, J. et al. (2002b) Predictors of local- Mamounas, E., Fisher, B. et al. (2003) The effect regional recurrence after neoadjuvant chemotherapy on tumor response of adding sequential preoperative and mastectomy without radiation. J Clin Oncol 20: docetaxel to preoperative doxorubicin and 17–23. cyclophosphamide: preliminary results from National Chung, A. and Giuliano, A. (2010) Axillary staging in Surgical Adjuvant Breast and Bowel Project Protocol the neoadjuvant setting. Ann Surg Oncol 17: 2401– B-27. J Clin Oncol 21: 4165–4174. Bellon, J., Wong, J. and Burstein, H. (2012) Should Clarke, M., Collins, R., Darby, S., Davies, C., response to preoperative chemotherapy affect Elphinstone, P., Evans, E. et al. (2005) Effects of radiotherapy recommendations after mastectomy for radiotherapy and of differences in the extent of stage II breast cancer? J Clin Oncol 30: 3916–3920. surgery for early breast cancer on local recurrence and Beriwal, S., Shinde, A., Rajagopalan, M., 15-year survival: an overview of the randomised trials. Kannan, N., Heron, D. and Deutsch, M. (2013) Lancet 366: 2087–2106. Recommendations for post-mastectomy radiation Classe, J., Bordes, V., Campion, L., Mignotte, therapy after neo-adjuvant chemotherapy: an H., Dravet, F., Leveque, J. et al. (2009) Sentinel International Survey of Radiation Oncologists. Breast lymph node biopsy after neoadjuvant chemotherapy J 19: 683–684. for advanced breast cancer: results of Ganglion Boileau, J., Poirier, B., Basik, M., Holloway, C., Sentinelle et Chimiotherapie Neoadjuvante, a French Gaboury, L., Sideris, L. et al. (2015) Sentinel node prospective multicentric study. J Clin Oncol 27: biopsy after neoadjuvant chemotherapy in biopsy- 726–732. proven node-positive breast cancer: the SN FNAC Cortazar, P., Zhang, L., Untch, M., Mehta, K., study. J Clin Oncol 33: 258–264. Costantino, J., Wolmark, N. et al. (2014) Pathological Boughey, J., Ballman, K., Hunt, K., McCall, L., complete response and long-term clinical benefit in Mittendorf, E., Ahrendt, G. et al. (2015) Axillary breast cancer: the CTNeoBC pooled analysis. Lancet ultrasound after neoadjuvant chemotherapy and its 384: 164–172. impact on sentinel lymph node surgery: results from Dialani, V., Chadashvili, T. and Slanetz, P. (2015) the American College of Surgeons Oncology Group Role of imaging in neoadjuvant therapy for breast Z1071 trial (Alliance). J Clin Oncol 33: 3386–3393. cancer. Ann Surg Oncol 22: 1416–1424. Boughey, J., Suman, V., Mittendorf, E., Ahrendt, Donker, M., Van Tienhoven, G., Straver, M., G., Wilke, L., Taback, B. et al. (2013) Sentinel Meijnen, P., Van De Velde, C., Mansel, R. et al. lymph node surgery after neoadjuvant chemotherapy (2014) Radiotherapy or surgery of the axilla after in patients with node-positive breast cancer: the a positive sentinel node in breast cancer (EORTC ACOSOG Z1071 (Alliance) clinical trial. JAMA 310: 10981–22023 AMAROS): a randomised, multicentre, 1455–1461. open-label, phase 3 non-inferiority trial. Lancet Oncol Buchholz, T., Huang, E., Berry, D., Pusztai, L., 15: 1303–1310. Strom, E., McNeese, M. et al. (2004) Her2/neu- Fisher, B., Brown, A., Mamounas, E., Wieand, S., positive disease does not increase risk of locoregional Robidoux, A., Margolese, R. et al. (1997) Effect of recurrence for patients treated with neoadjuvant preoperative chemotherapy on local-regional disease doxorubicin-based chemotherapy, mastectomy, in women with operable breast cancer: findings from and radiotherapy. Int J Radiat Oncol Biol Phys 59: National Surgical Adjuvant Breast and Bowel Project 1337–1342. B-18. J Clin Oncol 15: 2483–2493. Buchholz, T., Katz, A., Strom, E., McNeese, M., Floyd, S. and Taghian, A. (2009) Post-mastectomy Perkins, G., Hortobagyi, G. et al. (2002a) Pathologic radiation in large node-negative breast tumors: does tumor size and lymph node status predict for different size really matter? Radiother Oncol 91: 33–37. rates of locoregional recurrence after mastectomy for breast cancer patients treated with neoadjuvant versus Fowble, B., Einck, J., Kim, D., McCloskey, adjuvant chemotherapy. Int J Radiat Oncol Biol Phys S., Mayadev, J., Yashar, C. et al. (2012) Role 53: 880–888. of postmastectomy radiation after neoadjuvant chemotherapy in stage II–III breast cancer. Int J Buchholz, T., Lehman, C., Harris, J., Pockaj, B., Radiat Oncol Biol Phys 83: 494–503. Khouri, N., Hylton, N. et al. (2008) Statement of the science concerning locoregional treatments after Fu, J., Chen, H., Yang, J., Yi, C. and Zheng, S. preoperative chemotherapy for breast cancer: a (2014) Feasibility and accuracy of sentinel lymph 94 http://tam.sagepub.com AU Kishan and SA McCloskey node biopsy in clinically node-positive breast cancer Hoffman, K., Mittendorf, E. and Buchholz, T. after neoadjuvant chemotherapy: a meta-analysis. (2012) Optimising radiation treatment decisions for PLoS One 9: e105316. patients who receive neoadjuvant chemotherapy and mastectomy. Lancet Oncol 13: e270–e276. Galimberti, V., Cole, B., Zurrida, S., Viale, G., Luini, Huang, E., Tucker, S., Strom, E., McNeese, M., A., Veronesi, P. et al. (2013) Axillary dissection Kuerer, H., Buzdar, A. et al. (2004) Postmastectomy versus no axillary dissection in patients with sentinel- radiation improves local-regional control and survival node micrometastases (IBCSG 23–01): a phase 3 for selected patients with locally advanced breast randomised controlled trial. Lancet Oncol 14: cancer treated with neoadjuvant chemotherapy and 297–305. mastectomy. J Clin Oncol 22: 4691–4699. Garg, A., Oh, J., Oswald, M., Huang, E., Strom, E., Huang, E., Tucker, S., Strom, E., McNeese, M., Perkins, G. et al. (2007) Effect of postmastectomy Kuerer, H., Hortobagyi, G. et al. (2005) Predictors radiotherapy in patients <35 years old with stage of locoregional recurrence in patients with locally II–III breast cancer treated with doxorubicin-based advanced breast cancer treated with neoadjuvant neoadjuvant chemotherapy and mastectomy. Int J chemotherapy, mastectomy, and radiotherapy. Int J Radiat Oncol Biol Phys 69: 1478–1483. Radiat Oncol Biol Phys 62: 351–357. Garg, A., Strom, E., McNeese, M., Buzdar, A., Hunt, K., Yi, M., Mittendorf, E., Guerrero, C., Hortobagyi, G., Kuerer, H. et al. (2004) T3 disease Babiera, G., Bedrosian, I. et al. (2009) Sentinel lymph at presentation or pathologic involvement of four or node surgery after neoadjuvant chemotherapy is more lymph nodes predict for locoregional recurrence accurate and reduces the need for axillary dissection in in stage II breast cancer treated with neoadjuvant breast cancer patients. Ann Surg 250: 558–566. chemotherapy and mastectomy without radiotherapy. Jagsi, R. and Pierce, L. (2013) Radiation therapy to Int J Radiat Oncol Biol Phys 59: 138–145. the internal mammary nodal region in breast cancer: Gilliot, O., Durando, X., Abrial, C., Belliere, A., the debate continues. Int J Radiat Oncol Biol Phys 86: Gimbergues, P., Thivat, E. et al. (2010) Does regional 813–815. lymph node irradiation improve the outcome of N0 Kelly, A., Dwamena, B., Cronin, P. and Carlos, R. and PN0 breast cancer? Cancer Invest 28: 195–200. (2009) Breast cancer sentinel node identification and Giuliano, A., Hunt, K., Ballman, K., Beitsch, P., classification after neoadjuvant chemotherapy-systematic Whitworth, P., Blumencranz, P. et al. (2011) Axillary review and meta analysis. Acad Radiol 16: 551–563. dissection vs no axillary dissection in women with Koolen, B., Pengel, K., Wesseling, J., Vogel, W., invasive breast cancer and sentinel node metastasis: a Vrancken Peeters, M., Vincent, A. et al. (2014) randomized clinical trial. JAMA 305: 569–575. Sequential (18)F-FDG PET/CT for early prediction Greco, M., Crippa, F., Agresti, R., Seregni, E., of complete pathological response in breast and axilla Gerali, A., Giovanazzi, R. et al. (2001) Axillary lymph during neoadjuvant chemotherapy. Eur J Nucl Med node staging in breast cancer by 2-fluoro-2-deoxy- Mol Imaging 41: 32–40. D-glucose-positron emission tomography: clinical Koolen, B., Valdes Olmos, R., Elkhuizen, P., Vogel, evaluation and alternative management. J Natl Cancer W., Vrancken Peeters, M., Rodenhuis, S. et al. (2012) Inst 93: 630–635. Locoregional lymph node involvement on 18F-FDG PET/CT in breast cancer patients scheduled for Groheux, D., Giacchetti, S., Hatt, M., Marty, M., neoadjuvant chemotherapy. Breast Cancer Res Treat Vercellino, L., De Roquancourt, A. et al. (2013) 135: 231–240. HER2-overexpressing breast cancer: FDG uptake after two cycles of chemotherapy predicts the outcome Krag, D., Anderson, S., Julian, T., Brown, A., of neoadjuvant treatment. Br J Cancer 109: Harlow, S., Costantino, J. et al. (2010) Sentinel- 1157–1164. lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node- Groheux, D., Hindie, E., Giacchetti, S., Delord, M., negative patients with breast cancer: overall survival Hamy, A., De Roquancourt, A. et al. (2012) Triple- findings from the NSABP B-32 randomised phase 3 negative breast cancer: early assessment with 18F- trial. Lancet Oncol 11: 927–933. FDG PET/CT during neoadjuvant chemotherapy identifies patients who are unlikely to achieve a Kuehn, T., Bauerfeind, I., Fehm, T., Fleige, B., pathologic complete response and are at a high risk of Hausschild, M., Helms, G. et al. (2013) Sentinel- early relapse. J Nucl Med 53: 249–254. lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy Hieken, T., Boughey, J., Jones, K., Shah, S. and (SENTINA): a prospective, multicentre cohort study. Glazebrook, K. (2013) Imaging response and Lancet Oncol 14: 609–618. residual metastatic axillary lymph node disease after neoadjuvant chemotherapy for primary breast cancer. Kvistad, K., Rydland, J., Smethurst, H., Lundgren, Ann Surg Oncol 20: 3199–3204. S., Fjosne, H. and Haraldseth, O. (2000) Axillary http://tam.sagepub.com 95 Therapeutic Advances in Medical Oncology 8(1) lymph node metastases in breast cancer: preoperative McBride, A., Allen, P., Woodward, W., Kim, M., detection with dynamic contrast-enhanced MRI. Eur Kuerer, H., Drinka, E. et al. (2014) Locoregional Radiol 10: 1464–1471. recurrence risk for patients with T1,2 breast cancer with 1–3 positive lymph nodes treated with Le Scodan, R., Selz, J., Stevens, D., Bollet, M., De mastectomy and systemic treatment. Int J Radiat La Lande, B., Daveau, C. et al. (2012) Radiotherapy Oncol Biol Phys 89: 392–398. for stage II and stage III breast cancer patients with negative lymph nodes after preoperative chemotherapy McGale, P., Taylor, C., Correa, C., Cutter, D., and mastectomy. Int J Radiat Oncol Biol Phys 82: Duane, F., Ewertz, M. et al. (2014) Effect of e1–e7. radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer Luciani, A., Dao, T., Lapeyre, M., Schwarzinger, mortality: meta-analysis of individual patient data M., Debaecque, C., Lantieri, L. et al. (2004) for 8135 women in 22 randomised trials. Lancet 383: Simultaneous bilateral breast and high-resolution 2127–2135. axillary MRI of patients with breast cancer: preliminary results. AJR Am J Roentgenol 182: McGuire, S., Gonzalez-Angulo, A., Huang, 1059–1067. E., Tucker, S., Kau, S., Yu, T. et al. (2007) Postmastectomy radiation improves the outcome Lyman, G. (2015) Appropriate role for sentinel node of patients with locally advanced breast cancer biopsy after neoadjuvant chemotherapy in patients who achieve a pathologic complete response to with early-stage breast cancer. J Clin Oncol 33: neoadjuvant chemotherapy. Int J Radiat Oncol Biol 232–234. Phys 68: 1004–1009. Lyman, G., Giuliano, A., Somerfield, M., Benson, Meric, F., Mirza, N., Buzdar, A., Hunt, K., Ames, A., 3rd, Bodurka, D., Burstein, H. et al. (2005) F., Ross, M. et al. (2000) Prognostic implications American Society of Clinical Oncology guideline of pathological lymph node status after preoperative recommendations for sentinel lymph node biopsy chemotherapy for operable T3N0M0 breast cancer. in early-stage breast cancer. J Clin Oncol 23: Ann Surg Oncol 7: 435–440. 7703–7720. Moo, T., McMillan, R., Lee, M., Stempel, M., Lyman, G., Temin, S., Edge, S., Newman, L., Patil, S., Ho, A. et al. (2013) Selection criteria for Turner, R., Weaver, D. et al. (2014) Sentinel lymph postmastectomy radiotherapy in T1-T2 tumors with node biopsy for patients with early-stage breast 1 to 3 positive lymph nodes. Ann Surg Oncol 20: cancer: American Society of Clinical Oncology 3169–3174. clinical practice guideline update. J Clin Oncol 32: 1365–1383. Mortellaro, V., Marshall, J., Singer, L., Hochwald, S., Chang, M., Copeland, E. et al. (2009) Magnetic Mainiero, M. (2010) Regional lymph node staging resonance imaging for axillary staging in patients with in breast cancer: the increasing role of imaging and breast cancer. J Magn Reson Imaging 30: 309–312. ultrasound-guided axillary lymph node fine needle aspiration. Radiol Clin North Am 48: 989–997. Nagar, H., Boothe, D., Ginter, P., Sison, C., Vahdat, L., Shin, S. et al. (2015) Disease-free survival Mamounas, E. (2014) Timing of determining axillary according to the use of postmastectomy radiation lymph node status when neoadjuvant chemotherapy is therapy after neoadjuvant chemotherapy. Clin Breast used. Curr Oncol Rep 16: 364. Cancer 15: 128–134. Mamounas, E., Anderson, S., Dignam, J., Bear, Nagar, H., Mittendorf, E., Strom, E., Perkins, G., H., Julian, T., Geyer, C., Jr. et al. (2012) Predictors Oh, J., Tereffe, W. et al. (2011) Local-regional of locoregional recurrence after neoadjuvant recurrence with and without radiation therapy after chemotherapy: results from combined analysis of neoadjuvant chemotherapy and mastectomy for National Surgical Adjuvant Breast and Bowel Project clinically staged T3n0 breast cancer. Int J Radiat B-18 and B-27. J Clin Oncol 30: 3960–3966. Oncol Biol Phys 81: 782–787. Mamounas, E., Brown, A., Anderson, S., Smith, Oh, J., Dryden, M., Woodward, W., Yu, T., Tereffe, R., Julian, T., Miller, B. et al. (2005) Sentinel node W., Strom, E. et al. (2006) Locoregional control biopsy after neoadjuvant chemotherapy in breast of clinically diagnosed multifocal or multicentric cancer: results from National Surgical Adjuvant Breast breast cancer after neoadjuvant chemotherapy and and Bowel Project Protocol B-27. J Clin Oncol 23: locoregional therapy. J Clin Oncol 24: 4971–4975. 2694–2702. Overgaard, M., Hansen, P., Overgaard, J., Rose, C., Marks, L. and Prosnitz, L. (2014) Reducing local Andersson, M., Bach, F. et al. (1997) Postoperative therapy in patients responding to preoperative radiotherapy in high-risk premenopausal women with systemic therapy: are we outsmarting ourselves? J Clin breast cancer who receive adjuvant chemotherapy. Oncol 32: 491–493. 96 http://tam.sagepub.com AU Kishan and SA McCloskey Danish Breast Cancer Cooperative Group 82b Trial. cancer patients treated with mastectomy without N Engl J Med 337: 949–955. radiotherapy. Int J Radiat Oncol Biol Phys 63: 1508–1513. Overgaard, M., Jensen, M., Overgaard, J., Hansen, P., Rose, C., Andersson, M. et al. (1999) Postoperative Taghian, A., Jagsi, R., Makris, A., Goldberg, S., radiotherapy in high-risk postmenopausal breast- Ceilley, E., Grignon, L. et al. (2004) Results of a cancer patients given adjuvant tamoxifen: Danish survey regarding irradiation of internal mammary Breast Cancer Cooperative Group DBCG 82c chain in patients with breast cancer: practice is culture randomised trial. Lancet 353: 1641–1648. driven rather than evidence based. Int J Radiat Oncol Biol Phys 60: 706–714. Park, S., Kim, M., Park, B., Moon, H., Kwak, J. and Kim, E. (2011) Impact of preoperative Taghian, A., Jeong, J., Mamounas, E., Parda, D., ultrasonography and fine-needle aspiration of axillary Deutsch, M., Costantino, J. et al. (2006) Low lymph nodes on surgical management of primary locoregional recurrence rate among node-negative breast cancer. Ann Surg Oncol 18: 738–744. breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant Pilewskie, M. and King, T. (2014) Magnetic systemic therapy and without radiotherapy: results resonance imaging in patients with newly diagnosed from five national surgical adjuvant breast and bowel breast cancer: a review of the literature. Cancer 120: project randomized clinical trials. J Clin Oncol 24: 2080–2089. 3927–3932. Poortmans, P., Struikmans, H., Collette, S., Kirkove, Taylor, M., Haffty, B., Rabinovitch, R., Arthur, C., Budach, V., Maingon, P. et al. (2014) Lymph D., Halberg, F., Strom, E. et al. (2009) ACR node radiotherapy improves survival in breast cancer: appropriateness criteria on postmastectomy 10 year results of the EORTC ROG and BCG phase radiotherapy expert panel on radiation oncology- III trial 22922/10925. Radiother Oncol 111: S206. breast. Int J Radiat Oncol Biol Phys 73: 997–1002. Ragaz, J., Olivotto, I., Spinelli, J., Phillips, N., Wahl, R., Siegel, B., Coleman, R. and Gatsonis, C. Jackson, S., Wilson, K. et al. (2005) Locoregional (2004) Prospective multicenter study of axillary nodal radiation therapy in patients with high-risk breast staging by positron emission tomography in breast cancer receiving adjuvant chemotherapy: 20-year cancer: a report of the staging breast cancer with PET results of the British Columbia randomized trial. J study group. J Clin Oncol 22: 277–285. Natl Cancer Inst 97: 116–126. Whelan, T., Olivotto, I. and Levine, M. (2015) Rastogi, P., Anderson, S., Bear, H., Geyer, C., Regional nodal irradiation in early-stage breast cancer. Kahlenberg, M., Robidoux, A. et al. (2008) N Engl J Med 373: 1878–1879. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols White, J. and Mamounas, E. (2014) Locoregional B-18 and B-27. J Clin Oncol 26: 778–785. radiotherapy in patients with breast cancer responding to neoadjuvant chemotherapy: a paradigm for Rowell, N. (2009) Radiotherapy to the chest wall treatment individualization. J Clin Oncol 32: 494–495. following mastectomy for node-negative breast cancer: a systematic review. Radiother Oncol 91: 23–32. Wright, J., Takita, C., Reis, I., Zhao, W., Saigal, K., Wolfson, A. et al. (2013) Predictors Shim, S., Park, W., Huh, S., Choi, D., Shin, K., of locoregional outcome in patients receiving Lee, N. et al. (2014) The role of postmastectomy neoadjuvant therapy and postmastectomy radiation. Radiation therapy after neoadjuvant chemotherapy in Cancer 119: 16–25. clinical stage II–III breast cancer patients with pN0: a multicenter, retrospective study (KROG 12–05). Int J Yu, J., Wilson, L., Dasgupta, T., Castrucci, W. Radiat Oncol Biol Phys 88: 65–72. and Weidhaas, J. (2008) Postmastectomy radiation therapy for lymph node-negative, locally advanced Straver, M., Aukema, T., Olmos, R., Rutgers, E., breast cancer after modified radical mastectomy: Gilhuijs, K., Schot, M. et al. (2010) Feasibility of analysis of the NCI surveillance, epidemiology, and FDG PET/CT to monitor the response of axillary end results database. Cancer 113: 38–47. lymph node metastases to neoadjuvant chemotherapy in breast cancer patients. Eur J Nucl Med Mol Imaging Zhang, Y., Oh, J., Whitman, G., Iyengar, P., Yu, T., 37: 1069–1076. Tereffe, W. et al. (2010) Clinically apparent internal mammary nodal metastasis in patients with advanced Strom, E., Woodward, W., Katz, A., Buchholz, breast cancer: incidence and local control. Int J Radiat T., Perkins, G., Jhingran, A. et al. (2005) Clinical Oncol Biol Phys 77: 1113–1119. investigation: regional nodal failure patterns in breast Visit SAGE journals online http://tam.sagepub.com SAGE journals http://tam.sagepub.com 97 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Therapeutic Advances in Medical Oncology SAGE

Postmastectomy radiation therapy after neoadjuvant chemotherapy: review and interpretation of available data:

Loading next page...
 
/lp/sage/postmastectomy-radiation-therapy-after-neoadjuvant-chemotherapy-review-PxT0MzCzAT
Publisher
SAGE
Copyright
Copyright © 2022 by SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses
ISSN
1758-8340
eISSN
1758-8359
DOI
10.1177/1758834015617459
Publisher site
See Article on Publisher Site

Abstract

617459 TAM0010.1177/1758834015617459Therapeutic Advances in Medical OncologyAU Kishan and SA McCloskey research-article2015 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Postmastectomy radiation therapy after 2016, Vol. 8(1) 85 –97 DOI: 10.1177/ neoadjuvant chemotherapy: review and © The Author(s), 2015. Reprints and permissions: interpretation of available data http://www.sagepub.co.uk/ journalsPermissions.nav Amar U. Kishan and Susan A. McCloskey Abstract: Postmastectomy radiotherapy (PMRT) has been shown to decrease locoregional recurrence and improve overall survival in patients with tumors greater than 5 cm or positive nodes. Because neoadjuvant chemotherapy (NAC) can cause significant downstaging, the indications for PMRT in the setting of NAC remain controversial and thus careful consideration of clinical stage at presentation, pathologic response to NAC, and other clinical characteristics, such as grade and biomarker status is required. The current review synthesizes both prospective and retrospective data to provide evidence for recommending PMRT after NAC for patients presenting with cT3–4 disease, cN2–3 disease, and residual nodal disease, as well as rationale for omitting PMRT in patients with cT1-2N0-1 disease who achieve a pathologic complete response. Other scenarios, including nodal complete response in the presence of other risk factors, are also explored. The topics of pre-NAC clinical staging and pathologic axillary nodal staging are reviewed, and radiation portal design is briefly discussed. Keywords: post-mastectomy radiotherapy, neoadjuvant chemotherapy, pathologic complete response Correspondence to: Introduction and general principles of and breast cancer mortality were noted among Susan A. McCloskey, MD postmastectomy radiation subsets with one to three nodes positive or at least Department of Radiation Oncology, 1223 16th The American College of Radiology (ACR) cur- four nodes positive. An earlier EBCTG analysis Street, Santa Monica, rently recommends consideration of postmastec- suggested that an absolute reduction in 5-year CA 90404, USA smccloskey@mednet. tomy radiation (PMRT) for patients with tumors LRR of over 10% would be necessary for a sur- ucla.edu greater than 5 cm or with at least four positive vival benefit to be shown at 15 years [Clarke et al. Amar U. Kishan, MD nodes [Taylor et al. 2009]. This recommendation 2005]. However, some suggest employing PMRT Department of Radiation Oncology, David Geffen is largely based on the results of three randomized even when the absolute LRR risk (not the abso- School of Medicine, controlled trials that demonstrated an overall sur- lute risk reduction) is greater than 10%, citing the University of California, Los Angeles, CA, USA vival (OS) benefit for PMRT in patients with expected long-term survival of these patients. lymph node positive disease (pN+), tumors greater than 5 cm in size, and pectoralis fascia/ Despite the availability of three randomized trials skin involvement [Overgaard et  al. 1997, 1999; and meta-analyses to guide PMRT decision mak- Ragaz et al. 2005]. This OS benefit is thought to ing in the absence of neoadjuvant chemotherapy stem from the fact that PMRT reduces the risk of (NAC), PMRT in this setting is not without con- locoregional recurrence (LRR) by approximately troversy. Several institutional series have noted two thirds [Clarke et al. 2005]. The most recent very low rates of locoregional failure among select iteration of the Early Breast Cancer Trialist’s women with T3N0 or T2N1 disease being treated Collaborative Group (EBCTCG) meta-analysis in the modern era [Taghian et al. 2006; Yu et al. showed that among 3086 women, PMRT reduced 2008; Floyd and Taghian, 2009; Moo et al. 2013; the 10-year first LRR rate from 26.0% to 8.1%, McBride et al. 2014]. Other series have suggested with a corresponding reduction in 20-year breast- expanding the role of PMRT to include select cancer mortality from 66.4% to 58.3% [McGale patients with T1–2N0 breast cancer who have et  al. 2014]. Notably, equivalent gains in LRR particularly high-risk features (e.g. young age, http://tam.sagepub.com 85 Therapeutic Advances in Medical Oncology 8(1) high grade, triple negative) based on high docu- series have attempted to compare women receiv- mented risk of LRR in the absence of PMRT ing and not receiving PMRT. We have in general [Rowell, 2009; Abdulkarim et al. 2011]. The role learned from these studies, which will be detailed of PMRT remains widely debated among women below, that careful consideration of pre-NAC with T3N0 or T1-2N0-1 disease, with most prac- clinical stage, post-NAC pathologic stage, and titioners individualizing radiation decision mak- individual patient and tumor factors is critically ing based on perceived risk. important to rendering appropriate radiation therapy recommendations. The decision to deliver PMRT depends on both the absolute risk of LRR and the magnitude of One of the earliest series suggesting a locoregional reduction in this absolute risk. Prospective data control benefit for PMRT after NAC focused on are lacking to inform PMRT decision making fol- 55 patients with locally advanced breast cancer lowing NAC and, given that NAC commonly (i.e. cT3–4 or cN2–3) [Abdel-Wahab et al. 1998]. alters postmastectomy pathologic findings with at Forty-two patients received PMRT and 13 did least 20–40% of patients receiving NAC having not. With a median follow up of 47 months, the axillary downstaging [Fisher et  al. 1997], it is LRR rates were 31% for patients treated without unclear if we can extrapolate findings from the PMRT and 7% for patients treated with PMRT. available data informing PMRT decision making This translated to a significant 3-year OS benefit in the absence of NAC. In 2008, the National of 88% versus 46%. Cancer Institute published a consensus statement suggesting that PMRT after NAC be delivered The MD Anderson Cancer Center (MDACC) for patients with clinical stage III disease (i.e. T4, then published a series of reports detailing their N2–N3, or T3N1) or ypN+ disease [Buchholz findings from retrospective analysis of robust et al. 2008]. However, a survey of practicing radi- institutional data. In one of the earliest series ation oncologists reported heterogeneity in adher- examining risk factors for LRR among patients ence to the latter portion of the recommendation, undergoing mastectomy after NAC, Buccholz and in decision making with regards to patients and colleagues analyzed outcomes of 150 such with stage II disease in general [Beriwal et  al. patients who did not receive PMRT [Buchholz 2013]. et al. 2002b]. The 10-year actuarial LRR rate was 27% in this cohort, which was largely composed The purpose of this focused review is to analyze of patients with locally advanced disease (55% of the relevant literature examining the benefits or patients had clinical stage IIIA disease or higher). lack thereof for PMRT in the setting of NAC. Predictors of LRR included clinical stage IIIB Additionally, the subjects of pre-NAC staging disease or greater at presentation, at least four workup, pathologic axillary staging, and radiation positive nodes pathologically, and no use of portal design will be briefly considered. tamoxifen. The MDACC group subsequently Conclusions regarding situations for which compared 5-year LRR patterns between the same PMRT following NAC should be considered will 150 patients treated with NAC and no PMRT be provided. and 1031 patients treated with adjuvant chemo- therapy and no PMRT [Buchholz et  al. 2002a]. Despite a large imbalance in clinical stage at pres- Indications for PMRT after NAC: literature entation (55% stage IIIA or higher in NAC versus review 9% in adjuvant), the overall pathologic tumor size and number of involved axillary nodes were the Lessons from retrospective series same. However, the overall 5-year LRR rate was Natural history of LRR: implications for greater for patients receiving NAC (27% versus PMRT. PMRT following NAC is inherently con- 15%), with statistically significant differences troversial due to the lack of prospective data avail- seen in subsets of patients with tumors matched able to guide decision making. We have thus relied for size or magnitude of nodal disease. Taken on retrospective data to inform treatment deci- together, these data strongly suggested that the sions. Retrospective analyses have typically exam- risk of LRR depended on both initial clinical fac- ined LRR risk in subsets of women who have not tors and pathologic factors at the time of surgery received PMRT following NAC to assess overall (i.e. pathologic findings consistent with response LRR risk and risk according to specific patient to NAC do not negate more locally advanced and tumor features. When possible, retrospective clinical presentation). 86 http://tam.sagepub.com AU Kishan and SA McCloskey The MDACC group next demonstrated the mastectomy, with or without PMRT [including potential benefits of PMRT by comparing out- full regional nodal irradiation (RNI)] from 2003 comes of 542 patients treated with NAC, mastec- to 2010 [Nagar et  al. 2015]. The overall 5-year tomy, and PMRT with those of 134 patients LRR rate was 16.1%, with PMRT providing a treated with NAC and mastectomy alone (essen- significant reduction in LRR (HR 0.25), translat- tially the same 150 patients originally studied, less ing into an improved 5-year disease-free survival the 16 who experienced an early recurrence (91.3% versus 64.8%). Residual tumor and nodal within 2 months of treatment) [Huang et  al. status were significantly associated with an 2004]. The 10-year LRR rate was 22% in the increased risk of LRR, but no pre-NAC clinical absence of PMRT and 11% with PMRT with a factors (e.g. clinical T stage or N stage) were pre- hazard ratio (HR) of LRR without PMRT of 4.7. dictive. The authors posit that more accurate The 10-year cause-specific survival (CSS), how- staging leads to upstaging or downstaging with ever, was identical between the two groups (58% respect to what would have been considered the with PMRT and 50% without), but on multivari- clinical stage in the past, thereby diluting the pre- ate analysis PMRT provided a significant benefit, dictive effect of upfront clinical stage. Though with a HR of 2.0. Significant improvement in provocative, the hypothesis requires validation, CSS was detected for patients with at least stage and it should also be recognized that many IIIB disease, cT4 tumors, and at least four patients may not have had extensive staging involved nodes. The authors subsequently workups prior to NAC. reported that five factors predicted for 10-year LRR in this cohort: skin/nipple involvement, Importance of a pCR. Achieving a pCR after NAC, supraclavicular nodal disease, no tamoxifen use, typically defined as having no residual invasive extracapsular extension, and estrogen-receptor disease in the breast or nodes on surgical pathol- negative disease [Huang et al. 2005]. For patients ogy, has been associated with improved survival with two or fewer of these factors (74% of all in both of the prospective trials discussed below, patients), the 10-year LRR rate was less than 8%, as well as numerous other studies [Rastogi et  al. but for those with at least three risk factors, the 2008; Cortazar et al. 2014]. A recent meta-analy- 10-year LRR rate was 28%. sis of 1955 patients confirmed that, on a patient- level analysis, achieving ypT0-TisN0 status was More recently, Wright and colleagues reported significantly associated with improved event-free- the outcomes of 464 patients who received PMRT survival and OS [Cortazar et al. 2014]. The impli- after NAC and mastectomy at the University of cations of pathologic response on LRR rates Miami [Wright et  al. 2013]. Of these, 17.5% warrant detailed review. One could hypothesize received tangent-only radiation [the remainder that a pCR could negate the need for PMRT, had radiation to both the chest wall and supracla- however there are data to suggest high rates of vicular fossa; only a minority were estimated to LRR despite the achievement of pCR in select have radiation covering the internal mammary subsets. nodes (IMNs)]. The investigators noted an over- all 5-year LRR rate of 5.8%, with a rate of 1.9% The aforementioned series from Huang and col- for patients with ypN0 disease. On multivariate leagues found that the 46 patients with clinical analysis, tangent-only PMRT, ypN+ status and stage III disease or higher who experienced a pCR triple negative histology were significantly associ- still had significantly lower 10-year LRR rates ated with LRR (HRs of 3.39, 10.23 and 8.5, with PMRT (33% versus 3%) [Huang et al. 2004]. respectively). Clinical stage III versus stage II dis- This contrasted with patients with clinical stage I ease was a significant predictor of LRR on uni- and II disease and a pCR, for whom PMRT did variate analysis only. The authors concluded that not seem to affect LRR rates. In a follow-up they could not identify a single subtype of patients series, McGuire and colleagues specifically inves- for whom supraclavicular irradiation offered no tigated LRR rates following pCR in 106 patients locoregional control benefit, though they noted with noninflammatory breast cancers treated with that the low rate of LRR in patients with a nodal NAC and mastectomy [McGuire et  al. 2007]. pathologic complete response (pCR) suggests a The 10-year LRR rate was 0% for the 32 patients limited absolute benefit in that cohort. with clinical stage I–II disease, regardless of PMRT use. For the 74 patients with stage III dis- Finally, Nagar and colleagues reported the out- ease, however, PMRT significantly improved the comes of 161 patients treated with NAC and 10-year LRR rate (33.3% versus 7.3%), and this http://tam.sagepub.com 87 Therapeutic Advances in Medical Oncology 8(1) improvement in LRR translated into significant including breast pCR, hormone receptor status, improvements in CSS (40% versus 87%) and OS Her2 status, and receipt of adjuvant chemother- (33.3% versus 77.3%). Notably, few patients in apy (http://www.nsabp.pitt.edu/B-51.asp). The this group had cT3N0 disease, precluding evalu- RAPCHEM study in the Netherlands is a pro- ation of the prognostic significance of achieving a spective nonrandomized study in which patients pCR in this subset of patients. While these data with cT1–2N0-1 (histologically proven nodal dis- strongly suggest that PMRT is indicated for ease, but excluding patients with more than three patients with clinical stage III disease regardless nodes on imaging) who receive NAC undergo of their pathologic response, other studies have risk-adapted radiotherapy after surgery (https:// provided evidence to the contrary. Two recent clinicaltrials.gov/ct2/show/NCT01279304). analyses have examined LRR among women Patients with nodal pCR are considered low risk achieving a pCR in the nodes (as opposed to pCR and, after mastectomy, will not receive PMRT. in the breast and nodes). Investigators at the Institut-Curie evaluated 134 patients with a nodal Specific subsets: stage I/II, molecular subtype, and pCR after NAC, of whom 78 underwent mastec- young age. Investigators at MDACC have issued a tomy followed by PMRT and the remainder had series of reports examining outcomes in specific mastectomy alone [Le Scodan et  al. 2012]. The subsets of interest. Among 132 patients with clini- investigators found numeric differences in 10-year cal stage I or II disease who did not receive PMRT LRR (3.8% with PMRT and 13.2% without) and after NAC, the 10-year LRR rate was 10% [Garg OS (77.2% and 87.7%) that did not reach statis- et  al. 2004]. For patients with cT1–2 disease and tical significance. No difference was also noted in one to three positive nodes, the 5-year LRR was a subset analysis restricted to the 50 patients who 5%; however, cT3N0 disease, at least four nodes at had clinical stage III disease at presentation. surgery, and age up to 40 were significant predic- Presence of residual tumor in the breast did por- tors of LRR. Nagar and colleagues compared out- tend poorer outcomes. Finally, a recent report comes between 119 patients with cT3N0 disease from Korea found no difference in 5-year LRR who underwent PMRT after NAC and mastec- rates among 151 patients with clinical stage II–III tomy with 43 who did not [Nagar et  al. 2011]. disease who had a nodal pCR after NAC, regard- More patients who received PMRT were up to 40 less of PMRT receipt [Shim et al. 2014]. In this years of age and had ypN+ disease, but despite study, both age (⩽40 years old versus >40 years this, the 5-year LRR rate was 24% for patients old) and pathologic T stage were associated with without PMRT and 4% for patients who received higher risks of LRR and CSS, while PMRT was it. In a subset analysis, PMRT had a significant not associated with either. An analysis based on locoregional control benefit for patients with stage was not performed, though with 5-year ypN+ or high-grade disease. The authors did note LRR rates of 1.9% and 7.7% with and without that the 5-year LRR for patients with cT3N0, PMRT, respectively, it is unlikely that a differ- ypN0 disease who did not receive PMRT was ence would have been identified. 14%, nearly double the rate of isolated LRR among patients with pT3N0 disease receiving adjuvant Overall, these data suggest that for patients with chemotherapy followed by PMRT in an earlier stage II disease who achieve a pCR, PMRT is series by Taghian and colleagues [Taghian et  al. unlikely to provide a significant LRR benefit. For 2006]. This discrepancy has been hypothesized to patients with stage II or stage III disease who be due to occult nodal disease in patients present- achieve a nodal pCR, the presence of residual ing with cT3N0 disease [Meric et al. 2000]. breast disease, or young patient age, may portend higher LRR rates, with conflicting evidence Data for other specific subsets are fairly limited. regarding the need for PMRT particularly in Clinical multifocality and multicentricity do not patients with stage III disease. Findings from two appear to be associated with increased risk of prospective trials also suggest a significant prog- LRR [Oh et  al. 2006], nor does Her2 positivity nostic value of nodal pCR for LRR risk (see below) [Buchholz et al. 2004; Nagar et al. 2015]. Triple [Mamounas et  al. 2012]. Two ongoing trials negative status, however, does appear to increase address this issue directly. The NSABP51/RTOG the risk of LRR [Huang et al. 2005; Wright et al. 1308 trial randomizes patients with cT1–3N1 2013]. In the aforementioned study by Wright (pathologically proven) who achieve a nodal pCR and colleagues, the authors reported that seven of after NAC and undergo mastectomy to either nine regional recurrences occurred in patients PMRT or no PMRT, with stratification factors with triple negative histology [Wright et al. 2013]. 88 http://tam.sagepub.com AU Kishan and SA McCloskey Table 1. Ten-year locoregional recurrence rates for patients undergoing neoadjuvant chemotherapy followed by mastectomy. LRR (chest wall and regional) Tumor ⩽5 cm* Tumor >5 cm cN0 ypN0/breast pCR 6.5% 6.2% ypN0/no breast pCR 6.3% 11.8% ypN+ 11.2% 14.6% cN+ ypN0/breast pCR 0.0% 0.0% ypN0/no breast pCR 10.8% 9.2% 17.0% 22.4% ypN+ *Tumor size here is referring to clinical tumor size. LRR, locoregional recurrence; pCR, pathologic complete response. A focused study of LRR and OS outcomes among 11.1% (8.4% local, 2.7% regional; 71% of all 107 patients younger than 35 years treated with LRR were local) among the 1947 patients under- NAC and mastectomy found improved 5-year going mastectomy [Mamounas et al. 2012]. In a LRR (12% versus 37%) and OS (67% versus 48%) multivariate analysis, significant predictors of for patients who received PMRT [Garg et  al. LRR included clinical tumor size (>5 cm versus 2007]. These improvements were present despite ⩽5 cm; HR 1.58), clinical nodal status (cN+ ver- a greater preponderance of adverse features sus cN0; HR 1.53), and pathologic nodal status/ among patients receiving PMRT. On specific breast tumor response (HR 2.21 for ypT+N0 subset analysis, the survival benefit was only sta- versus total pCR, and 4.48 for ypN+ versus total tistically significant for patients with clinical stage pCR). Interestingly, for patients treated with IIB disease, though similar trends were seen in all breast-conserving therapy, clinical tumor size was stages. This finding is consistent with the afore- not a significant predictor, but age (<50 versus mentioned Korean study, which had also found ⩾50) was. Table 1 depicts the 10-year LRR rates age up to 40 to be a significant predictor of LRR stratified by the predictive risk factors; notably, [Shim et al. 2014]. among patients with cN+ disease, only 32 of 424 patients (7.5%) had a pCR (in the breast and In a recent comprehensive review, wherein appro- nodes), so the observed 10-year LRR of 0.0% in priateness of PMRT after NAC was determined that subset of patients must be kept in context. using the ACR Appropriateness Criteria modified Among patients with ypN+ disease, 10-year LRR Delphi methodology, it was concluded that rates were greater than 10% regardless of clinical patients with T1–2N0–1 who were aged over 40 nodal status, clinical tumor size or pathologic N and had estrogen receptor positive disease, with stage. The analysis was limited by lack of infor- less than four positive axillary nodes without lym- mation regarding molecular subtypes of tumors; phovascular space invasion or extracapsular exten- no patient received Her2/neu-directed therapy, sion have a 5-year LRR of less than 10% and thus and all patients in NSABP-27 received tamoxifen may not benefit from PMRT [Fowble et al. 2012]. concurrently with chemotherapy, which was sub- sequently shown to be inferior to sequential administration [Albain et al. 2009]. Lessons from NSABP-18 and NSABP-27 Two large prospective randomized controlled tri- These data suggest that the overall 10-year LRR als of NAC, NSABP-18 and NSABP-27 also rate following NAC and mastectomy is relatively allow an examination of the natural history of low in the absence of PMRT, and have led some LRR following mastectomy, as both prohibited to suggest omission of PMRT in patients with patients from receiving PMRT [Fisher et al. 1997; clinical stage II disease who achieve a pCR [Bellon Bear et al. 2003; Rastogi et al. 2008]. In a recent et al. 2012; Marks and Prosnitz, 2014; White and pooled analysis, the overall 10-year LRR rate was Mamounas, 2014]. It is imperative to note that http://tam.sagepub.com 89 Therapeutic Advances in Medical Oncology 8(1) the patients enrolled in NSABP-18 and 27 were absent hilum, eccentrically widened cortex, and generally at far lower risk of LRR overall than cortical thickening [Mainiero, 2010]. Altered those in the retrospective studies referenced morphology, rather than size, may provide a above: 55% had cT1–2N0 disease, 20% had greater specificity for detecting malignancy cT1–2N1 disease, 16% had cT3N0 disease and [Alvarez et  al. 2006]. Fine-needle aspiration only 9% had cT3N1 disease. (FNA) of suspicious-appearing nodes provides a specificity of nearly 100% for malignant disease [Baruah et al. 2010; Park et al. 2011; Bazan and Summary White, 2015]. We recommend careful consideration of pre- NAC clinical stage, post-NAC pathologic stage Although imperfect, more advanced imaging and individual patient and tumor factors in order modalities, such as magnetic resonance imaging to individualize decision making regarding PMRT (MRI) and 18-fluorodeoxyglucose positron emis- after NAC. In general, we recommend PMRT sion tomography ( FDG-PET) can be particu- after NAC for patients who have presented with larly helpful in evaluating nodal disease burden cT3–4 disease or cN2–3 disease regardless of [Kvistad et  al. 2000; Greco et  al. 2001; Luciani pathologic extent of disease at the time of surgery. et  al. 2004; Wahl et  al. 2004; Mortellaro et  al. We also recommend PMRT for all patients who 2009; Koolen et al. 2012]. An early study reported have residual nodal disease after NAC. For that MRI had a sensitivity of 83% and a specific- patients presenting with clinical stage II disease ity of 90% for nodal disease [Kvistad et al. 2000], (excluding cT3N0) who achieve a pCR, we typi- while a prospective study of FDG-PET reported cally recommend omitting PMRT. For patients a sensitivity of 61% and a specificity of 80% with clinical stage II disease (excluding cT3N0) [Wahl et  al. 2004]. Our recommendation is to who achieve a nodal pCR, we recommend enroll- obtain an axillary ultrasound for all patients with ment on NSABP51; absent that, we would err an invasive breast cancer diagnosis; suspicious towards offering PMRT for patients of young age nodes should be biopsied and clipped. If positive (⩽40 years old), those with greater than 2 cm nodes are found, then advanced imaging is rec- residual tumor in the breast, those with high- ommended, particularly PET-CT which can grade histology and those with triple negative his- delineate regional nodal disease that may benefit tology. These recommendations are largely from targeted radiation therapy [Bazan and consistent with what others have proposed White, 2015]. However, even for patients without [Fowble et al. 2012; Hoffman et al. 2012]. We do histologically confirmed nodes we routinely recommend that all patients who undergo NAC request MRI imaging to better determine the meet with a radiation oncologist, preferably extent of disease in the breast. upfront, to facilitate their multidisciplinary management. The use of advanced imaging to estimate response is an area of active investigation. In a retrospec- tive review, axillary ultrasound was the most sen- Preneoadjuvant chemotherapy imaging and sitive test for detecting ypN+ disease after NAC, nodal assessment with a sensitivity of 69.8% compared with 63.2% Because both pathological and pre-NAC clinical for FDG-PET and 61.0% for MRI [Hieken factors impact risk of LRR following NAC, accu- et  al. 2013]. However, accuracy was the highest rate pre-NAC staging is imperative. Prior to initi- for FDG-PET at 71.9%, followed by ultrasound ating NAC, it is crucial to establish clinical T and at 65.1% and MRI at 60.2%. Two recent studies N stage as definitively as possible in order to opti- also suggest that FDG-PET may be particularly mally inform post-NAC locoregional therapy helpful in restaging patients with triple negative decision making. Physical examination alone is histology [Straver et al. 2010; Koolen et al. 2014], unreliable and upwards of 30% of patients who and carry prognostic significance in certain situa- are considered to have cN0 on examination will tions [Groheux et al. 2012; Groheux et al. 2013]. have occult nodal disease found by sentinel lymph A recently published analysis from the American node biopsy (SLNB) [Chung and Giuliano, 2010; College of Surgeons Oncology Group (ACOSOG) Kuehn et al. 2013]. Axillary ultrasound is a help- Z1071 (ALLIANCE) trial examined axillary ful imaging modality for detecting nodal disease, ultrasound after NAC and its impact on sentinel with concerning features including a longitudinal/ node biopsy [Boughey et  al. 2015]. The authors transverse greatest dimension ratio less than 2, concluded that employing a strategy of limiting 90 http://tam.sagepub.com AU Kishan and SA McCloskey SNB to those with negative axillary ultrasound overall sentinel node identification rate of 89% post NAC could serve to reduce false negative after NAC, with an overall false negative rate rates with SNB to below 10%. As Dialani and (FNR) of 14% [Fu et  al. 2014]. The relatively colleagues concluded in a recent review of imag- higher FNR after NAC, compared with the ing after NAC, there is no currently accepted upfront FNR of less than 10%, was initially cause standard with regards to imaging method for for concern, but results from three recently pub- monitoring response to NAC [Dialani et  al. lished trials provide some insight into minimizing 2015]. In general, we recommend repeat MRI (or this FNR [Boughey et al. 2013; Kuehn et al. 2013; ultrasound if initial MRI is not performed) after Boileau et al. 2015]. the fourth cycle of NAC, as this might also indi- cate which patients have not responded well and In the phase II ALLIANCE trial, 649 women should move forward with local therapy. with cT0–4N1–2 disease who received NAC underwent a SLNB prior to a completion ALND, A further detailed review of this workup is beyond with the primary outcome being the FNR of the scope of this focused review and interested SLNB [Boughey et  al. 2013]. No sentinel node readers are directed to other detailed reviews was found in 7% of patients, and only one node [Pilewskie and King, 2014; Bazan and White, was found in 12% of patients. Overall, the FNR 2015; Dialani et al. 2015]. was 12.6%; for patients with only two sentinel nodes removed, the FNR was 21.1%, compared with 9.1% for patients with at least three sentinel Pathologic nodal staging nodes removed. If a dual identification method In recent years, SLNB has replaced full axillary was used (blue dye and radiolabeled colloid), the lymph node dissection (ALND) in both patients FNR dropped to 10.8%. In the four-arm pro- with cN0 disease and in patients with cT1–2 dis- spective SENTINA study, patients were strati- ease and involvement of up to two nodes on initial fied to receive SLNB before NAC (for cN0 that SLNB [Krag et  al. 2010; Giuliano et  al. 2011; remained ycN0), before and after NAC (for cN0 Galimberti et al. 2013]. Additionally, the recently that were found to be pN0 by upfront SLNB) or published European Organisation for Research after NAC (for cN+ which converted to ycN0) and Treatment of Cancer (EORTC) 10981– [Kuehn et  al. 2013]. The primary outcome was 22023 AMAROS randomized trial has shown that the FNR in patients who had a SLNB done after axillary radiotherapy can replace ALND in NAC in patients with cN+ disease that con- patients with a positive SLNB and a 0.5–3 cm pri- verted to ycN0, which was 14% (with a detection mary [Donker et al. 2014]. Because NAC can lead rate of 80%). The investigators found that if to axillary downstaging in up to 20–40% of cases patients only had one or two sentinel nodes [Fisher et al. 1997], the use of SLNB in the con- removed, the FNRs were 24% and 18%, respec- text of NAC has generated controversy akin to tively, but if they had at least three nodes that seen with the use of PMRT. Initially, SLNB removed, it was less than 5%. If dual tracer meth- was discouraged after NAC, but the recent odology was used, the FNR was 8.6%. Notably, American Society of Clinical Oncology guidelines both the ALLIANCE and the SENTINA studies suggest that it can be offered before or after NAC, focused on patients treated with breast-conserv- with the standard of care for confirmed nodal dis- ing therapy. ease after NAC being a full ALND [Lyman et al. 2005, 2014]. A detailed discussion of the various Most recently, the prospective SN-FNAC study methods of pathological axillary staging in the evaluated the accuracy of SLNB after NAC in context of NAC is beyond the scope of this focused 153 patients with biopsy-proven T0–3N1–2 dis- review (interested readers are directed to recent ease [Boileau et al. 2015]. The investigators found excellent reviews [Mamounas, 2014; Lyman, a sentinel node identification rate of 87.6%, and 2015], but a brief overview will be presented). an FNR of 8.4%. Notably, however, immunohis- tochemistry was mandated and patients with Multiple single-institution reports and multi- ypN0(i+) disease were considered to have posi- center studies have suggested that the sentinel tive sentinel nodes. Had these patients been con- node identification rate following NAC is lower sidered to have negative sentinel nodes, then the than in the upfront setting [Mamounas et  al. FNR would increase to 13.3%. For patients with 2005; Classe et al. 2009; Hunt et al. 2009; Kelly only one node identified, the FNR was 18.2%; it et  al. 2009]. A recent-meta-analysis reported an was also 14.2% for patients with T3 tumors. http://tam.sagepub.com 91 Therapeutic Advances in Medical Oncology 8(1) Taken together, the data suggest that a FN rate of removed in addition to at least one of the follow- less than 10% can be achieved with SLNB after ing: grade 3 histologic categorization, estrogen NAC in women with cN+ disease if certain crite- receptor negativity or lymphovascular invasion) ria are met: at least three sentinel nodes are iden- after breast conserving surgery and surgical nodal tified and removed, dual identification method is evaluation (either SLNB or ALND) to RNI or no used, and biopsy proven nodes pre NAC are RNI [Whelan et al. 2015]. In the MA.20 trial, the clipped and excised. For patients with positive RNI included supraclavicular fossa/level III axilla, sentinel nodes after NAC, the current standard of the IMNs and level I–II of the axilla in selected care is a completion ALND; however, the current circumstances; in the EORTC trial, the RNI A011202 phase III clinical trial [ClinicalTrials. included the medial supraclavicular nodes and the gov identifier: NCT01901094] will randomize IMNs, and radiation of the axilla was performed patients with stage II and IIIA breast cancer who in a small subset (7.4–8.3%) of both arms. Neither have a positive sentinel node after NAC to axil- trial found a 10-year OS benefit with the addition lary radiotherapy versus ALND. For patients with of RNI, although in both trials disease-free sur- at least three sentinel nodes found to be negative, vival, locoregional control and distant metastasis- and for whom PMRT is indicated, the radiation free survival were modestly but significantly portal design can be adjusted accordingly (see improved with the addition of RNI. The decision below). If up to three sentinel nodes are removed to provide RNI versus tangent-only radiation is a and found to be negative, we recommend com- topic of significant controversy and a detailed dis- pletion ALND for full workup, and if this cannot cussion is beyond the scope of this focused review. be done, we suggest a low threshold for providing However, experience related specifically to the PMRT with axillary radiotherapy. In the case of situation of radiation portals for PMRT after patients with histologically confirmed nodal dis- NAC is fairly limited and will be reviewed here. ease prior to NAC, if treatment effect is not com- mented on or a clip is not seen and had been One study from the Centre Jean-Perrin compared placed at the time of the original biopsy, then the outcomes between 39 patients who received case should be reviewed by the surgeon and PMRT, including RNI with 37 patients who had pathologist to ensure adequate axillary sampling tangent-only PMRT [Gilliot et  al. 2010]. The has been performed. investigators found that there was no difference in 10-year LRR rates (95% without and 91% with RNI). However, in the group that did not receive Radiation portal design RNI, the 10-year OS was 96%, while in the group The three large randomized trials that demon- receiving RNI, 10-year OS was 75% (p < 0.05). strated an improved OS with PMRT all included Distant-metastasis-free survival was similarly RNI covering the supraclavicular fossa as well as higher in the patients who did not receive RNI the IMNs [Overgaard et  al. 1997, 1999; Ragaz (97% versus 78%). The treatment groups were et al. 2005]. However, in patients without certain significantly unbalanced, however, with signifi- adverse pathologic features (e.g. lymphovascular cantly more patients in the group treated with space invasion, >50% nodes positive, at least four RNI having cT3–4 tumor and having significantly nodes positive overall, and gross extranodal exten- larger residual tumors at surgery. However, the sion >2 mm), the risk of supraclavicular failure is considerably larger study by Wright and col- low [Strom et al. 2005]. The risk of isolated IMN leagues discussed above suggested a benefit to failure is similarly low in most cases, leading to including a supraclavicular field [Wright et  al. debate over the necessity of IMN irradiation 2013]. Though Wright and colleagues were not [Taghian et al. 2004; Jagsi and Pierce, 2013]. The able to determine whether the IMNs were irradi- EORTC 22922/10925 trial, which included ated for all patients, they estimated that less than women undergoing either mastectomy or lumpec- 5% of patients received IMN radiation. While tomy with ALND or SLNB who either had medial specific studies investigating omission of IMN tumors (regardless of nodal status) or pN+ dis- irradiation in patients receiving NAC are lacking, ease, randomized patients to receive RNI or no a report from the MDACC suggested that up to RNI [Poortmans et  al. 2014]. The National 10% of patients with locally advanced disease Cancer Institute of Canada Clinical Trials Group have clinically detectable IMN adenopathy by (NCIC CTG) MA.20 trial randomized women imaging, and in those patients, directed IMN with node-positive or high-risk node-negative dis- irradiation achieves excellent 5-year IMN and ease (defined as T3 or T2 with <10 nodes locoregional control [Zhang et  al. 2010]. The 92 http://tam.sagepub.com AU Kishan and SA McCloskey current randomized NSABP-51 trial randomizes PMRT. For patients with clinical stage II disease women with cT1–3N1 breast cancer who undergo who achieve a nodal pCR, we recommend enroll- lumpectomy or mastectomy and are found to ment on NSABP51; absent that, we would err have ypN0 to RNI versus no RNI. The Alliance towards offering PMRT for patients with adverse A011202 trial randomizes women with cT1–3N1 features, including young age, greater than 2 cm breast cancer who remain ypN+ on SNB follow- residual tumor in the breast, high-grade or triple ing NAC to axillary node dissection and RNI negative histology. Implicit in these recommen- versus RNI alone. Among women with clinically dations is the requirement for accurate pre-NAC node positive disease pre NAC, these trials are staging. We recommend axillary ultrasound with aiming to answer the questions of whether RNI is FNA of suspicious nodes and preferably MRI for necessary in women who become pathologically all patients and PET-CT for all node-positive node negative and whether RNI can replace axil- patients. Performing a SLNB after NAC is rea- lary surgery in women who remain pathologically sonable as long as at least three nodes are removed node positive. and a dual-tracer method is used. Radiation por- tal design is governed by similar principles as in Our recommendation is to proceed with RNI after the standard PMRT situation. NAC for any patient with ypN+ disease, and for patients presenting with cN2–N3 disease. We Funding would not cover the fully dissected axilla in the This research received no specific grant from any absence of negative risk factors (<10 nodes funding agency in the public, commercial, or not- removed, >50% nodes positive, vascular adher- for-profit sectors. ence). For patients with cN0–N1 disease who remain or convert to ypN0 disease after NAC and Conflict of interest statement have had adequate axillary staging at the time of The author(s) declare(s) that there is no conflict surgery (see above), if treating, we would cover the of interest. chest wall and determine the need for supraclavic- ular or IMN coverage based on careful considera- References Abdel-Wahab, M., Wolfson, A., Raub, W., Mies, C., tion of adverse risk factors (e.g. lymphovascular Brandon, A., Morrell, L. et al. (1998) The importance space invasion, age, extent of node positivity pre of postoperative radiation therapy in multimodality NAC, size and biologic features of residual disease management of locally advanced breast cancer: a in the breast). For patients without adequate axil- phase II trial of neoadjuvant MVAC, surgery, and lary staging, we would err on the side of caution radiation. Int J Radiat Oncol Biol Phys 40: 875–880. and provide RNI (including the undissected Abdulkarim, B., Cuartero, J., Hanson, J., Deschenes, axilla). J., Lesniak, D. and Sabri, S. (2011) Increased risk of locoregional recurrence for women with T-2n0 triple- negative breast cancer treated with modified radical Conclusion mastectomy without adjuvant radiation therapy The decision to provide or omit PMRT after compared with breast-conserving therapy. J Clin Oncol NAC is a complicated one and a consultation 29: 2852–2858. with a radiation oncologist is highly recom- Albain, K., Barlow, W., Ravdin, P., Farrar, W., mended, preferably before NAC is even started. Burton, G., Ketchel, S. et al. (2009) Adjuvant We recommend careful consideration of pre- chemotherapy and timing of tamoxifen in NAC clinical stage, post NAC pathologic stage, postmenopausal patients with endocrine-responsive, and individual patient and tumor factors in order node-positive breast cancer: a phase 3, open-label, to individualize decision making regarding PMRT randomised controlled trial. Lancet 374: 2055–2063. after NAC. Synthesis of both retrospective and Alvarez, S., Anorbe, E., Alcorta, P., Lopez, F., prospective data suggests that the risk of LRR fol- Alonso, I. and Cortes, J. (2006) Role of sonography lowing mastectomy is highest for patients with in the diagnosis of axillary lymph node metastases cT3–4 disease, cN2–3 disease and ypN+ disease, in breast cancer: a systematic review. AJR Am J and thus we recommend PMRT for these Roentgenol 186: 1342–1348. patients. For patients with stage III disease, we would recommend PMRT regardless of patho- Baruah, B., Goyal, A., Young, P., Douglas-Jones, logical response. For patients presenting with A. and Mansel, R. (2010) Axillary node staging by ultrasonography and fine-needle aspiration cytology in clinical stage II disease (excluding cT3N0) who patients with breast cancer. Br J Surg 97: 680–683. achieve a pCR, we typically recommend omitting http://tam.sagepub.com 93 Therapeutic Advances in Medical Oncology 8(1) Bazan, J. and White, J. (2015) Imaging of the axilla National Cancer Institute conference. J Clin Oncol 26: before preoperative chemotherapy: implications for 791–797. postmastectomy radiation. Cancer 121: 1187–1194. Buchholz, T., Tucker, S., Masullo, L., Kuerer, H., Bear, H., Anderson, S., Brown, A., Smith, R., Erwin, J., Salas, J. et al. (2002b) Predictors of local- Mamounas, E., Fisher, B. et al. (2003) The effect regional recurrence after neoadjuvant chemotherapy on tumor response of adding sequential preoperative and mastectomy without radiation. J Clin Oncol 20: docetaxel to preoperative doxorubicin and 17–23. cyclophosphamide: preliminary results from National Chung, A. and Giuliano, A. (2010) Axillary staging in Surgical Adjuvant Breast and Bowel Project Protocol the neoadjuvant setting. Ann Surg Oncol 17: 2401– B-27. J Clin Oncol 21: 4165–4174. Bellon, J., Wong, J. and Burstein, H. (2012) Should Clarke, M., Collins, R., Darby, S., Davies, C., response to preoperative chemotherapy affect Elphinstone, P., Evans, E. et al. (2005) Effects of radiotherapy recommendations after mastectomy for radiotherapy and of differences in the extent of stage II breast cancer? J Clin Oncol 30: 3916–3920. surgery for early breast cancer on local recurrence and Beriwal, S., Shinde, A., Rajagopalan, M., 15-year survival: an overview of the randomised trials. Kannan, N., Heron, D. and Deutsch, M. (2013) Lancet 366: 2087–2106. Recommendations for post-mastectomy radiation Classe, J., Bordes, V., Campion, L., Mignotte, therapy after neo-adjuvant chemotherapy: an H., Dravet, F., Leveque, J. et al. (2009) Sentinel International Survey of Radiation Oncologists. Breast lymph node biopsy after neoadjuvant chemotherapy J 19: 683–684. for advanced breast cancer: results of Ganglion Boileau, J., Poirier, B., Basik, M., Holloway, C., Sentinelle et Chimiotherapie Neoadjuvante, a French Gaboury, L., Sideris, L. et al. (2015) Sentinel node prospective multicentric study. J Clin Oncol 27: biopsy after neoadjuvant chemotherapy in biopsy- 726–732. proven node-positive breast cancer: the SN FNAC Cortazar, P., Zhang, L., Untch, M., Mehta, K., study. J Clin Oncol 33: 258–264. Costantino, J., Wolmark, N. et al. (2014) Pathological Boughey, J., Ballman, K., Hunt, K., McCall, L., complete response and long-term clinical benefit in Mittendorf, E., Ahrendt, G. et al. (2015) Axillary breast cancer: the CTNeoBC pooled analysis. Lancet ultrasound after neoadjuvant chemotherapy and its 384: 164–172. impact on sentinel lymph node surgery: results from Dialani, V., Chadashvili, T. and Slanetz, P. (2015) the American College of Surgeons Oncology Group Role of imaging in neoadjuvant therapy for breast Z1071 trial (Alliance). J Clin Oncol 33: 3386–3393. cancer. Ann Surg Oncol 22: 1416–1424. Boughey, J., Suman, V., Mittendorf, E., Ahrendt, Donker, M., Van Tienhoven, G., Straver, M., G., Wilke, L., Taback, B. et al. (2013) Sentinel Meijnen, P., Van De Velde, C., Mansel, R. et al. lymph node surgery after neoadjuvant chemotherapy (2014) Radiotherapy or surgery of the axilla after in patients with node-positive breast cancer: the a positive sentinel node in breast cancer (EORTC ACOSOG Z1071 (Alliance) clinical trial. JAMA 310: 10981–22023 AMAROS): a randomised, multicentre, 1455–1461. open-label, phase 3 non-inferiority trial. Lancet Oncol Buchholz, T., Huang, E., Berry, D., Pusztai, L., 15: 1303–1310. Strom, E., McNeese, M. et al. (2004) Her2/neu- Fisher, B., Brown, A., Mamounas, E., Wieand, S., positive disease does not increase risk of locoregional Robidoux, A., Margolese, R. et al. (1997) Effect of recurrence for patients treated with neoadjuvant preoperative chemotherapy on local-regional disease doxorubicin-based chemotherapy, mastectomy, in women with operable breast cancer: findings from and radiotherapy. Int J Radiat Oncol Biol Phys 59: National Surgical Adjuvant Breast and Bowel Project 1337–1342. B-18. J Clin Oncol 15: 2483–2493. Buchholz, T., Katz, A., Strom, E., McNeese, M., Floyd, S. and Taghian, A. (2009) Post-mastectomy Perkins, G., Hortobagyi, G. et al. (2002a) Pathologic radiation in large node-negative breast tumors: does tumor size and lymph node status predict for different size really matter? Radiother Oncol 91: 33–37. rates of locoregional recurrence after mastectomy for breast cancer patients treated with neoadjuvant versus Fowble, B., Einck, J., Kim, D., McCloskey, adjuvant chemotherapy. Int J Radiat Oncol Biol Phys S., Mayadev, J., Yashar, C. et al. (2012) Role 53: 880–888. of postmastectomy radiation after neoadjuvant chemotherapy in stage II–III breast cancer. Int J Buchholz, T., Lehman, C., Harris, J., Pockaj, B., Radiat Oncol Biol Phys 83: 494–503. Khouri, N., Hylton, N. et al. (2008) Statement of the science concerning locoregional treatments after Fu, J., Chen, H., Yang, J., Yi, C. and Zheng, S. preoperative chemotherapy for breast cancer: a (2014) Feasibility and accuracy of sentinel lymph 94 http://tam.sagepub.com AU Kishan and SA McCloskey node biopsy in clinically node-positive breast cancer Hoffman, K., Mittendorf, E. and Buchholz, T. after neoadjuvant chemotherapy: a meta-analysis. (2012) Optimising radiation treatment decisions for PLoS One 9: e105316. patients who receive neoadjuvant chemotherapy and mastectomy. Lancet Oncol 13: e270–e276. Galimberti, V., Cole, B., Zurrida, S., Viale, G., Luini, Huang, E., Tucker, S., Strom, E., McNeese, M., A., Veronesi, P. et al. (2013) Axillary dissection Kuerer, H., Buzdar, A. et al. (2004) Postmastectomy versus no axillary dissection in patients with sentinel- radiation improves local-regional control and survival node micrometastases (IBCSG 23–01): a phase 3 for selected patients with locally advanced breast randomised controlled trial. Lancet Oncol 14: cancer treated with neoadjuvant chemotherapy and 297–305. mastectomy. J Clin Oncol 22: 4691–4699. Garg, A., Oh, J., Oswald, M., Huang, E., Strom, E., Huang, E., Tucker, S., Strom, E., McNeese, M., Perkins, G. et al. (2007) Effect of postmastectomy Kuerer, H., Hortobagyi, G. et al. (2005) Predictors radiotherapy in patients <35 years old with stage of locoregional recurrence in patients with locally II–III breast cancer treated with doxorubicin-based advanced breast cancer treated with neoadjuvant neoadjuvant chemotherapy and mastectomy. Int J chemotherapy, mastectomy, and radiotherapy. Int J Radiat Oncol Biol Phys 69: 1478–1483. Radiat Oncol Biol Phys 62: 351–357. Garg, A., Strom, E., McNeese, M., Buzdar, A., Hunt, K., Yi, M., Mittendorf, E., Guerrero, C., Hortobagyi, G., Kuerer, H. et al. (2004) T3 disease Babiera, G., Bedrosian, I. et al. (2009) Sentinel lymph at presentation or pathologic involvement of four or node surgery after neoadjuvant chemotherapy is more lymph nodes predict for locoregional recurrence accurate and reduces the need for axillary dissection in in stage II breast cancer treated with neoadjuvant breast cancer patients. Ann Surg 250: 558–566. chemotherapy and mastectomy without radiotherapy. Jagsi, R. and Pierce, L. (2013) Radiation therapy to Int J Radiat Oncol Biol Phys 59: 138–145. the internal mammary nodal region in breast cancer: Gilliot, O., Durando, X., Abrial, C., Belliere, A., the debate continues. Int J Radiat Oncol Biol Phys 86: Gimbergues, P., Thivat, E. et al. (2010) Does regional 813–815. lymph node irradiation improve the outcome of N0 Kelly, A., Dwamena, B., Cronin, P. and Carlos, R. and PN0 breast cancer? Cancer Invest 28: 195–200. (2009) Breast cancer sentinel node identification and Giuliano, A., Hunt, K., Ballman, K., Beitsch, P., classification after neoadjuvant chemotherapy-systematic Whitworth, P., Blumencranz, P. et al. (2011) Axillary review and meta analysis. Acad Radiol 16: 551–563. dissection vs no axillary dissection in women with Koolen, B., Pengel, K., Wesseling, J., Vogel, W., invasive breast cancer and sentinel node metastasis: a Vrancken Peeters, M., Vincent, A. et al. (2014) randomized clinical trial. JAMA 305: 569–575. Sequential (18)F-FDG PET/CT for early prediction Greco, M., Crippa, F., Agresti, R., Seregni, E., of complete pathological response in breast and axilla Gerali, A., Giovanazzi, R. et al. (2001) Axillary lymph during neoadjuvant chemotherapy. Eur J Nucl Med node staging in breast cancer by 2-fluoro-2-deoxy- Mol Imaging 41: 32–40. D-glucose-positron emission tomography: clinical Koolen, B., Valdes Olmos, R., Elkhuizen, P., Vogel, evaluation and alternative management. J Natl Cancer W., Vrancken Peeters, M., Rodenhuis, S. et al. (2012) Inst 93: 630–635. Locoregional lymph node involvement on 18F-FDG PET/CT in breast cancer patients scheduled for Groheux, D., Giacchetti, S., Hatt, M., Marty, M., neoadjuvant chemotherapy. Breast Cancer Res Treat Vercellino, L., De Roquancourt, A. et al. (2013) 135: 231–240. HER2-overexpressing breast cancer: FDG uptake after two cycles of chemotherapy predicts the outcome Krag, D., Anderson, S., Julian, T., Brown, A., of neoadjuvant treatment. Br J Cancer 109: Harlow, S., Costantino, J. et al. (2010) Sentinel- 1157–1164. lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node- Groheux, D., Hindie, E., Giacchetti, S., Delord, M., negative patients with breast cancer: overall survival Hamy, A., De Roquancourt, A. et al. (2012) Triple- findings from the NSABP B-32 randomised phase 3 negative breast cancer: early assessment with 18F- trial. Lancet Oncol 11: 927–933. FDG PET/CT during neoadjuvant chemotherapy identifies patients who are unlikely to achieve a Kuehn, T., Bauerfeind, I., Fehm, T., Fleige, B., pathologic complete response and are at a high risk of Hausschild, M., Helms, G. et al. (2013) Sentinel- early relapse. J Nucl Med 53: 249–254. lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy Hieken, T., Boughey, J., Jones, K., Shah, S. and (SENTINA): a prospective, multicentre cohort study. Glazebrook, K. (2013) Imaging response and Lancet Oncol 14: 609–618. residual metastatic axillary lymph node disease after neoadjuvant chemotherapy for primary breast cancer. Kvistad, K., Rydland, J., Smethurst, H., Lundgren, Ann Surg Oncol 20: 3199–3204. S., Fjosne, H. and Haraldseth, O. (2000) Axillary http://tam.sagepub.com 95 Therapeutic Advances in Medical Oncology 8(1) lymph node metastases in breast cancer: preoperative McBride, A., Allen, P., Woodward, W., Kim, M., detection with dynamic contrast-enhanced MRI. Eur Kuerer, H., Drinka, E. et al. (2014) Locoregional Radiol 10: 1464–1471. recurrence risk for patients with T1,2 breast cancer with 1–3 positive lymph nodes treated with Le Scodan, R., Selz, J., Stevens, D., Bollet, M., De mastectomy and systemic treatment. Int J Radiat La Lande, B., Daveau, C. et al. (2012) Radiotherapy Oncol Biol Phys 89: 392–398. for stage II and stage III breast cancer patients with negative lymph nodes after preoperative chemotherapy McGale, P., Taylor, C., Correa, C., Cutter, D., and mastectomy. Int J Radiat Oncol Biol Phys 82: Duane, F., Ewertz, M. et al. (2014) Effect of e1–e7. radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer Luciani, A., Dao, T., Lapeyre, M., Schwarzinger, mortality: meta-analysis of individual patient data M., Debaecque, C., Lantieri, L. et al. (2004) for 8135 women in 22 randomised trials. Lancet 383: Simultaneous bilateral breast and high-resolution 2127–2135. axillary MRI of patients with breast cancer: preliminary results. AJR Am J Roentgenol 182: McGuire, S., Gonzalez-Angulo, A., Huang, 1059–1067. E., Tucker, S., Kau, S., Yu, T. et al. (2007) Postmastectomy radiation improves the outcome Lyman, G. (2015) Appropriate role for sentinel node of patients with locally advanced breast cancer biopsy after neoadjuvant chemotherapy in patients who achieve a pathologic complete response to with early-stage breast cancer. J Clin Oncol 33: neoadjuvant chemotherapy. Int J Radiat Oncol Biol 232–234. Phys 68: 1004–1009. Lyman, G., Giuliano, A., Somerfield, M., Benson, Meric, F., Mirza, N., Buzdar, A., Hunt, K., Ames, A., 3rd, Bodurka, D., Burstein, H. et al. (2005) F., Ross, M. et al. (2000) Prognostic implications American Society of Clinical Oncology guideline of pathological lymph node status after preoperative recommendations for sentinel lymph node biopsy chemotherapy for operable T3N0M0 breast cancer. in early-stage breast cancer. J Clin Oncol 23: Ann Surg Oncol 7: 435–440. 7703–7720. Moo, T., McMillan, R., Lee, M., Stempel, M., Lyman, G., Temin, S., Edge, S., Newman, L., Patil, S., Ho, A. et al. (2013) Selection criteria for Turner, R., Weaver, D. et al. (2014) Sentinel lymph postmastectomy radiotherapy in T1-T2 tumors with node biopsy for patients with early-stage breast 1 to 3 positive lymph nodes. Ann Surg Oncol 20: cancer: American Society of Clinical Oncology 3169–3174. clinical practice guideline update. J Clin Oncol 32: 1365–1383. Mortellaro, V., Marshall, J., Singer, L., Hochwald, S., Chang, M., Copeland, E. et al. (2009) Magnetic Mainiero, M. (2010) Regional lymph node staging resonance imaging for axillary staging in patients with in breast cancer: the increasing role of imaging and breast cancer. J Magn Reson Imaging 30: 309–312. ultrasound-guided axillary lymph node fine needle aspiration. Radiol Clin North Am 48: 989–997. Nagar, H., Boothe, D., Ginter, P., Sison, C., Vahdat, L., Shin, S. et al. (2015) Disease-free survival Mamounas, E. (2014) Timing of determining axillary according to the use of postmastectomy radiation lymph node status when neoadjuvant chemotherapy is therapy after neoadjuvant chemotherapy. Clin Breast used. Curr Oncol Rep 16: 364. Cancer 15: 128–134. Mamounas, E., Anderson, S., Dignam, J., Bear, Nagar, H., Mittendorf, E., Strom, E., Perkins, G., H., Julian, T., Geyer, C., Jr. et al. (2012) Predictors Oh, J., Tereffe, W. et al. (2011) Local-regional of locoregional recurrence after neoadjuvant recurrence with and without radiation therapy after chemotherapy: results from combined analysis of neoadjuvant chemotherapy and mastectomy for National Surgical Adjuvant Breast and Bowel Project clinically staged T3n0 breast cancer. Int J Radiat B-18 and B-27. J Clin Oncol 30: 3960–3966. Oncol Biol Phys 81: 782–787. Mamounas, E., Brown, A., Anderson, S., Smith, Oh, J., Dryden, M., Woodward, W., Yu, T., Tereffe, R., Julian, T., Miller, B. et al. (2005) Sentinel node W., Strom, E. et al. (2006) Locoregional control biopsy after neoadjuvant chemotherapy in breast of clinically diagnosed multifocal or multicentric cancer: results from National Surgical Adjuvant Breast breast cancer after neoadjuvant chemotherapy and and Bowel Project Protocol B-27. J Clin Oncol 23: locoregional therapy. J Clin Oncol 24: 4971–4975. 2694–2702. Overgaard, M., Hansen, P., Overgaard, J., Rose, C., Marks, L. and Prosnitz, L. (2014) Reducing local Andersson, M., Bach, F. et al. (1997) Postoperative therapy in patients responding to preoperative radiotherapy in high-risk premenopausal women with systemic therapy: are we outsmarting ourselves? J Clin breast cancer who receive adjuvant chemotherapy. Oncol 32: 491–493. 96 http://tam.sagepub.com AU Kishan and SA McCloskey Danish Breast Cancer Cooperative Group 82b Trial. cancer patients treated with mastectomy without N Engl J Med 337: 949–955. radiotherapy. Int J Radiat Oncol Biol Phys 63: 1508–1513. Overgaard, M., Jensen, M., Overgaard, J., Hansen, P., Rose, C., Andersson, M. et al. (1999) Postoperative Taghian, A., Jagsi, R., Makris, A., Goldberg, S., radiotherapy in high-risk postmenopausal breast- Ceilley, E., Grignon, L. et al. (2004) Results of a cancer patients given adjuvant tamoxifen: Danish survey regarding irradiation of internal mammary Breast Cancer Cooperative Group DBCG 82c chain in patients with breast cancer: practice is culture randomised trial. Lancet 353: 1641–1648. driven rather than evidence based. Int J Radiat Oncol Biol Phys 60: 706–714. Park, S., Kim, M., Park, B., Moon, H., Kwak, J. and Kim, E. (2011) Impact of preoperative Taghian, A., Jeong, J., Mamounas, E., Parda, D., ultrasonography and fine-needle aspiration of axillary Deutsch, M., Costantino, J. et al. (2006) Low lymph nodes on surgical management of primary locoregional recurrence rate among node-negative breast cancer. Ann Surg Oncol 18: 738–744. breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant Pilewskie, M. and King, T. (2014) Magnetic systemic therapy and without radiotherapy: results resonance imaging in patients with newly diagnosed from five national surgical adjuvant breast and bowel breast cancer: a review of the literature. Cancer 120: project randomized clinical trials. J Clin Oncol 24: 2080–2089. 3927–3932. Poortmans, P., Struikmans, H., Collette, S., Kirkove, Taylor, M., Haffty, B., Rabinovitch, R., Arthur, C., Budach, V., Maingon, P. et al. (2014) Lymph D., Halberg, F., Strom, E. et al. (2009) ACR node radiotherapy improves survival in breast cancer: appropriateness criteria on postmastectomy 10 year results of the EORTC ROG and BCG phase radiotherapy expert panel on radiation oncology- III trial 22922/10925. Radiother Oncol 111: S206. breast. Int J Radiat Oncol Biol Phys 73: 997–1002. Ragaz, J., Olivotto, I., Spinelli, J., Phillips, N., Wahl, R., Siegel, B., Coleman, R. and Gatsonis, C. Jackson, S., Wilson, K. et al. (2005) Locoregional (2004) Prospective multicenter study of axillary nodal radiation therapy in patients with high-risk breast staging by positron emission tomography in breast cancer receiving adjuvant chemotherapy: 20-year cancer: a report of the staging breast cancer with PET results of the British Columbia randomized trial. J study group. J Clin Oncol 22: 277–285. Natl Cancer Inst 97: 116–126. Whelan, T., Olivotto, I. and Levine, M. (2015) Rastogi, P., Anderson, S., Bear, H., Geyer, C., Regional nodal irradiation in early-stage breast cancer. Kahlenberg, M., Robidoux, A. et al. (2008) N Engl J Med 373: 1878–1879. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols White, J. and Mamounas, E. (2014) Locoregional B-18 and B-27. J Clin Oncol 26: 778–785. radiotherapy in patients with breast cancer responding to neoadjuvant chemotherapy: a paradigm for Rowell, N. (2009) Radiotherapy to the chest wall treatment individualization. J Clin Oncol 32: 494–495. following mastectomy for node-negative breast cancer: a systematic review. Radiother Oncol 91: 23–32. Wright, J., Takita, C., Reis, I., Zhao, W., Saigal, K., Wolfson, A. et al. (2013) Predictors Shim, S., Park, W., Huh, S., Choi, D., Shin, K., of locoregional outcome in patients receiving Lee, N. et al. (2014) The role of postmastectomy neoadjuvant therapy and postmastectomy radiation. Radiation therapy after neoadjuvant chemotherapy in Cancer 119: 16–25. clinical stage II–III breast cancer patients with pN0: a multicenter, retrospective study (KROG 12–05). Int J Yu, J., Wilson, L., Dasgupta, T., Castrucci, W. Radiat Oncol Biol Phys 88: 65–72. and Weidhaas, J. (2008) Postmastectomy radiation therapy for lymph node-negative, locally advanced Straver, M., Aukema, T., Olmos, R., Rutgers, E., breast cancer after modified radical mastectomy: Gilhuijs, K., Schot, M. et al. (2010) Feasibility of analysis of the NCI surveillance, epidemiology, and FDG PET/CT to monitor the response of axillary end results database. Cancer 113: 38–47. lymph node metastases to neoadjuvant chemotherapy in breast cancer patients. Eur J Nucl Med Mol Imaging Zhang, Y., Oh, J., Whitman, G., Iyengar, P., Yu, T., 37: 1069–1076. Tereffe, W. et al. (2010) Clinically apparent internal mammary nodal metastasis in patients with advanced Strom, E., Woodward, W., Katz, A., Buchholz, breast cancer: incidence and local control. Int J Radiat T., Perkins, G., Jhingran, A. et al. (2005) Clinical Oncol Biol Phys 77: 1113–1119. investigation: regional nodal failure patterns in breast Visit SAGE journals online http://tam.sagepub.com SAGE journals http://tam.sagepub.com 97

Journal

Therapeutic Advances in Medical OncologySAGE

Published: Dec 22, 2015

Keywords: post-mastectomy radiotherapy; neoadjuvant chemotherapy; pathologic complete response

References