Postmastectomy Radiotherapy After Neoadjuvant Chemotherapy: A Review of the Evidence

September 15, 2015

Multiple randomized trials and their meta-analysis have demonstrated an overall survival benefit from postmastectomy radiotherapy in women with node-positive breast cancer. However, none of the patients treated in these trials received neoadjuvant chemotherapy, which is now an increasingly common approach.

Multiple randomized trials and their meta-analysis have demonstrated an overall survival benefit from postmastectomy radiotherapy (PMRT) in women with node-positive breast cancer. However, none of the patients treated in these trials received neoadjuvant chemotherapy, which is now an increasingly common approach. It is unclear how best to apply data from trials conducted in patients treated with adjuvant chemotherapy to this population. To illuminate these issues, this article first reviews the history of PMRT and the current indications for its use based on contemporary data. It focuses on the ways in which staging and outcomes differ for patients who undergo neoadjuvant chemotherapy before mastectomy (as compared with those who receive postoperative adjuvant therapy) and how pathologic features such as response to therapy are correlated with recurrence and survival outcomes. It highlights key information obtained from analysis of the pooled data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) prospective neoadjuvant chemotherapy trials B-18 and B-27 and separate retrospective single-institution studies; this includes the low risk of locoregional recurrence in early-stage patients in whom a pathologic complete response (pCR) was achieved after neoadjuvant chemotherapy without PMRT and the high risk of recurrence in patients with stage III disease, even in the setting of a pCR. It also discusses the ongoing NSABP B-51/Radiation Therapy Oncology Group 1304 and Alliance A011202 trials, which will provide information on whether PMRT can be omitted in patients who have a pathologic complete response (pCR) in the lymph nodes, and whether axillary lymph node dissection will improve recurrence rates compared with sentinel lymph node biopsy and radiotherapy in patients who do not achieve a pCR in the lymph nodes. Finally, it identifies directions for future research.

Rationale For and Against Postmastectomy Radiotherapy

Postmastectomy radiotherapy (PMRT) has been investigated in a number of trials over the past few decades as a strategy to improve outcomes in women with breast cancer. Subsets of women are at high risk for locoregional recurrence (LRR) after mastectomy, even with negative margins, adequate axillary lymph node dissection (ALND), and adjuvant systemic therapy.

PMRT may improve breast cancer outcomes via a number of mechanisms. Prevention of LRR is the most direct potential benefit. Surgically resectable, isolated LRRs are often associated with significant morbidity and may ultimately be unsalvageable even with the addition of systemic therapy and radiotherapy, and nonresectable gross recurrences are unlikely to be eradicated with radiotherapy or systemic therapy.[1,2]

PMRT may also prevent distant failure, albeit in a less direct fashion. Most women at high risk for LRR after mastectomy also have a significant risk of distant failure, which may arise from detectable LRRs after initial therapy; prevention of these recurrences could decrease subsequent distant failure. Some women may harbor occult residual microscopic locoregional disease that never manifests as a clinically detectable local recurrence yet can seed distant sites. These distant recurrences could potentially be prevented by delivering locoregional radiotherapy that eradicates those reservoirs of disease in the upfront setting.

Although there is an established benefit of PMRT, no treatment is devoid of associated morbidity, burden, and expense, so interest remains in optimizing patient selection for PMRT. Expense and patient convenience are important factors to consider in this regard. Toxicity can develop, including late cardiac effects, even though modern treatment planning techniques help reduce this risk. Additionally, radiation therapy can lead to complications associated with breast reconstruction and can limit the options offered to patients.

In this article, we focus on the particularly challenging situation of determining when to offer PMRT to patients treated with neoadjuvant systemic therapy. We begin by reviewing the evidence regarding the role of radiotherapy after mastectomy more generally, which has largely derived from studies of patients treated without systemic therapy or with postoperative systemic therapy alone. We then discuss emerging evidence that suggests how one might incorporate information about response to systemic therapy in patients treated preoperatively in order to optimize patient selection for therapy and perhaps even for delivery of radiotherapy in this setting.

Evidence Regarding PMRT

Early randomized trials

The evidence regarding the role of radiotherapy after mastectomy has largely derived from studies of patients treated without systemic therapy or with postoperative systemic therapy alone. Although benefits in locoregional control with PMRT were observed in early trials, the trials did not demonstrate overall survival (OS) benefits.[3,4] However, systemic therapy was not administered to most patients who received PMRT in these trials. When more effective systemic therapies arose, which decreased rates of distant failure, locoregional control reemerged as an important problem. Trials were subsequently initiated that investigated PMRT in the setting of systemic therapy. Although local and regional benefits were again observed, survival benefits appeared to be offset by increased toxicity, presumably related to cardiac and pulmonary damage associated with older radiotherapy techniques.[5,6]

Danish and Canadian randomized trials

In the late 1990s and early 2000s, three landmark trials (two from Denmark and one from British Columbia, Canada) independently demonstrated OS benefits with PMRT in node-positive patients who received systemic therapy.[7-10] These trials, which used newer radiotherapy techniques (no en face photon fields were used for the chest wall) and presumably avoided some of the treatment toxicity observed in the former studies, revitalized interest in examining the benefits of PMRT. As detailed in the Table, the trials showed a substantial benefit from PMRT, both in local control and OS.

The British Columbia trial, published in 2005, showed a statistically significant survival benefit with PMRT in patients who received adjuvant chemotherapy.[9] Although statistical significance was lost when OS was analyzed by the number of involved lymph nodes, the hazard ratios for 1 to 3 vs ≥ 4 nodes were 0.76 and 0.70, respectively, suggesting a benefit that might have reached significance with a larger sample size. Not only did the original analyses of the Danish Breast Cancer Cooperative Group 82b and 82c trials (which were subsequently criticized for inadequate node dissection in many patients) suggest a benefit in all patients, including the subset of patients with 1 to 3 involved nodes,[7,8] but so did a subsequent 2007 analysis that evaluated the subset of patients with 1 to 3 involved nodes who were felt to have adequate ALND; patients with fewer than 8 nodes removed were excluded.[11] That study revealed a statistically significant OS benefit with the addition of PMRT in patients with 1 to 3 involved nodes (57% vs 48%; P = .03) that was both substantial and similar in magnitude to the survival benefit observed in patients with larger numbers of involved nodes. Nevertheless, questions remained about whether patients with a low burden of nodal disease really benefit from PMRT even in the setting of adequate axillary surgery.

Patterns-of-failure analyses among unirradiated patients after adequate axillary surgery

The National Surgical Adjuvant Breast and Bowel Project (NSABP) conducted a number of trials in breast cancer patients treated with mastectomy and did not permit PMRT in those trials, given the lack of survival benefit observed in earlier studies. Therefore, these data provided a particularly useful source of information regarding patterns of failure in the setting of more complete axillary surgery. Data from these trials confirmed that locoregional failure (LRF) remained problematic even with more effective anthracycline-based chemotherapy regimens. A patterns-of-failure analysis of five NSABP trials, published in 2004, in which patients did not receive PMRT, showed that in patients with node-positive disease, the rate of isolated LRF as a first event was greater than 10% in most patient subsets (and greater than 10% in all patient subsets when simultaneous distant recurrence was included), whether stratified by age, menopausal status, hormone receptor status, tumor size, number of nodes removed, or number of nodes dissected.[12]

Nevertheless, isolated LRF without PMRT was only 8.1% in patients with 1 to 3 positive nodes, and LRF with or without distant failure, at 13.0%, was still significantly lower than in patients with larger numbers of involved nodes.[12] It was therefore concluded that the risk of failure in patients with 1 to 3 involved nodes might not be sufficiently high to justify PMRT. More recent studies have also suggested that rates of failure may be even lower in more recent cohorts.[13]

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) radiotherapy meta-analyses

In 2005, the EBCTCG landmark individual patient data meta-analysis that included all patients from the previously discussed British Columbia and Danish trials examined the benefits of adjuvant radiotherapy among patients who underwent mastectomy and ALND. In node-negative women who underwent mastectomy and ALND, the 5-year risk of local recurrence was low (6%), and no reduction in 15-year breast cancer mortality was demonstrated.[14] However, in patients with node-positive disease who underwent ALND, 5-year local recurrence was reduced from 23% to 6%, 15-year breast cancer mortality from 60.1% to 54.7% (P = .0002), and 15-year all-cause mortality from 72.3% to 68.8% (P = .0009).

Given the concerns about the potential impact of inadequate axillary surgery, the EBCTCG more recently conducted an updated meta-analysis that included only patients with adequate axillary surgery, with mortality data up to 2009. This 2014 report showed a statistically significant reduction in 20-year breast cancer mortality in women with 1 to 3 involved nodes after mastectomy and adequate axillary dissection, even when they received some form of systemic therapy (relative risk, 0.78; P = .01).[15] Nonetheless, some degree of controversy remains regarding recommendations for PMRT in patients with 1 to 3 involved nodes, given that contemporary patients may hav e lower absolute failure risks after receiving anthracycline-based chemotherapy regimens, which were not routinely available in earlier eras. Additionally, previous trials of PMRT do not provide information on how to evaluate patients with micrometastases and isolated tumor cells, which are relatively new classifications and levels of disease unlikely to have been detected prior to the advent of techniques for sentinel node identification.

Use of PMRT in T3N0 breast cancer

Another matter of controversy is whether the small subset of patients with T3N0 tumors should receive PMRT, as was recommended historically. Although these patients were included and observed to benefit from PMRT in the Danish trials, a 2006 retrospective pooled analysis of five NSABP trials and other sources of retrospective data has suggested that the risk of isolated LRF as a first event for patients with tumors 5 cm or larger was lower than previously expected (at 7.1%) after mastectomy, even without radiotherapy.[16] Given this, management recommendations are controversial, and many radiation oncologists no longer routinely advise radiotherapy for this entire subset, recommending instead that risk factors such as tumor size, receipt of an inadequate axillary dissection, close or positive margins, and the presence of lymphovascular invasion be considered.[17]

Considerations in the Context of Neoadjuvant Chemotherapy

Despite the considerable historical evidence evaluating the role of PMRT in breast cancer management, it is important to note that none of these studies included patients who received preoperative systemic therapy. This has posed a major challenge for patient selection for radiation therapy in the modern era, given the increased uptake of the neoadjuvant approach. Researchers, clinicians, and patients alike have been particularly intrigued by the possibility that response to systemic therapy might be used to better select patients who are likely to benefit from radiation therapy after mastectomy.

To attempt to better identify a population at low risk for recurrence even in the absence of postoperative radiotherapy, a number of studies have focused on investigating predictive and prognostic factors in patients who undergo neoadjuvant chemotherapy. Pretreatment factors include clinical stage, receptor status, and age, and posttreatment factors include margin status and response to neoadjuvant chemotherapy.

MD Anderson retrospective data

Retrospective data from MD Anderson Cancer Center provide useful information on recurrence patterns after neoadjuvant chemotherapy. Particularly intriguing have been observations in patients in whom a pathologic complete response (pCR) was achieved after neoadjuvant chemotherapy.[18,19] The cohort included primarily patients with stage II or III disease who underwent a modified radical mastectomy with a level I or II axillary dissection. Most of the 106 patients received modern chemotherapy regimens, including anthracyclines and taxanes in 92% and 38%, respectively. PMRT was delivered based on physician and patient preference, which resulted in its delivery in 72 patients and its omission in the remaining 34. This allowed for a retrospective comparison between the two groups.

Radiotherapy techniques generally included delivery of 50 Gy in 25 fractions to the chest wall and lymphatics, followed by a 10-Gy boost. An electron field was used to treat the internal mammary chain and medial chest wall, while a photon field was used to treat undissected lymphatics in the supraclavicular fossa and axilla.

There were no significant differences between the irradiated and nonirradiated patients with respect to age; menopausal status; histologic subtype; estrogen, progesterone, or human epidermal growth factor receptor 2 (HER2) status; grade; presence of lymphovascular invasion; or use of hormonal therapy. As might be expected, however, a larger proportion of patients in the irradiated group were at a more advanced clinical stage at presentation. Clinical stage in the nonirradiated vs irradiated cohorts was as follows: IB, 6% vs 0%; IIA, 38% vs 1%; IIB, 21% vs 17%; IIIA, 15% vs 37%; IIIB, 17% vs 29%; and IIIC, 3% vs 15%.

Despite the fact that there were more patients with advanced-stage disease in the radiation cohort, 10-year rates of LRR did not differ significantly between the two groups (10% nonirradiated vs 5% irradiated; P = .40). No patients with clinical stage I or II disease (2 were at stage IB and 14 at stage II) experienced LRR, regardless of whether PMRT was delivered. However, among patients with clinical stage III disease, LRR, distant metastasis–free survival (DMFS), cancer-specific survival (CSS), and OS were all significantly lower in irradiated patients (LRR, 7.3% vs 33.3%, P = .04; DMFS, 87.9% vs 40.7%, P = .0006; CSS, 87% vs 40%, P = .0014; OS, 77.3% vs 33.3%, P = .0016). This led radiation oncologists to recommend PMRT in all patients who present with clinically locally advanced disease, regardless of pathologic response.

Regarding factors that could predict for LRR, there was a trend toward an association between the presence of lymphovascular invasion and increased LRR, and no correlation with age, menopausal status, histology, estrogen/progesterone receptor status, nuclear grade, or number of involved nodes.

The low rates of failure in early-stage patients who achieved a pCR after neoadjuvant chemotherapy regardless of whether PMRT was delivered support the inclusion of this population in prospective studies that evaluate omission of radiotherapy. Given that lower-risk patients are generally more likely to be observed, and higher-risk patients to be irradiated, the bias would likely be toward the null in this setting. The observed difference in failure rates in advanced-stage patients who either did or did not receive PMRT after a pCR is therefore important, since it suggests that radiotherapy should not be omitted in patients who present with locally advanced disease, regardless of their response to neoadjuvant chemotherapy.

Patterns of failure after neoadjuvant chemotherapy and mastectomy with radiotherapy: combined NSABP B-18 and B-27 analysis

Although the MD Anderson Cancer Center analyses provided important, seminal data on outcomes after neoadjuvant chemotherapy, these studies are limited by the facts that PMRT was administered in a nonrandomized fashion and that relatively few patients with early-stage disease were included. The NSABP B-18 and B-27 trials of neoadjuvant therapy prohibited PMRT and included a sample of patients at somewhat less locally advanced stages, allowing for additional retrospective analysis of patterns of failure in these trials to provide further illuminating insights.[20] The NSABP trials were performed in the era when it was unknown whether PMRT was associated with an OS radiotherapy benefit, and it was NSABP policy at that time not to provide radiotherapy to patients who received mastectomy. This provides a unique opportunity to examine recurrence rates in the absence of radiotherapy among patients treated with a neoadjuvant approach.

Both studies had neoadjuvant arms consisting of doxorubicin/cyclophosphamide (AC), and B-27 had an additional neoadjuvant arm that added docetaxel to AC. For patients who underwent mastectomy, 10-year LRR rates were reported based on tumor size, clinical node stage, and type of pathologic response. A pCR in the breast was defined as the absence of invasive disease in the breast.

Ten-year LRR rates in patients with a pCR in both the nodes and breast were less than 10% after mastectomy, regardless of tumor size (less than, equal to, or greater than 5 cm) and regardless of whether they had a clinically node-negative or node-positive axilla. No chest wall or regional recurrences occurred in patients with clinically positive nodes with a pCR in both the breast and nodes, although this group only included 32 patients. Of the 94 total patients who experienced a pCR at both sites, only 1 experienced failure in the chest wall, with the remaining 3 failures occurring regionally.

In patients with pathologically positive nodes after neoadjuvant chemotherapy, LRR rates were close to 25%. The highest rates of recurrence within this subgroup were in patients with clinically node-positive disease. Patients with a CR in the nodes but not in the breast generally had an intermediate risk of recurrence relative to the two other groups.

Although the subgroups of patients in whom a pCR was achieved were small, the low rates of recurrence provide support for the inclusion of these patients in prospective analyses of omission of PMRT. Moreover, the substantial risks of failure in patients with residual nodal disease highlight these patients as requiring radiation therapy and perhaps even as candidates for intensification of standard approaches to PMRT.

Relationship between pCR and outcomes: CTNeoBC pooled analysis

A 2014 analysis by the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) investigators of over 13,000 patients enrolled in 12 trials of neoadjuvant chemotherapy attempted to combine information about pCR with information about tumor biology to further optimize decisions about locoregional management in this setting.[21,22] There was significant heterogeneity across trials with respect to enrollment criteria: 61% of patients had T2 tumors, 46% had clinically involved nodes, 30% had hormone receptor–negative disease, and 17% had HER2-positive disease (although in many trials, no HER2 testing was performed). Most patients received anthracycline- and/or taxane-based regimens, with a few trials including trastuzumab. While all patients with hormone receptor–positive tumors were supposed to receive at least 5 years of endocrine therapy, over half of patients with HER2-positive disease did not receive trastuzumab because they were treated before results were reported from the adjuvant trastuzumab trials. Criteria for radiotherapy differed across the studies, and it was not administered in a randomized fashion.

The CTNeoBC investigators analyzed pCR based on three different definitions: (1) absence of invasive cancer and in situ cancer in both the breast and nodes (ie, ypT0 ypN0); (2) absence of invasive cancer in the breast and nodes, irrespective of the presence of in situ disease in the breast (ie, ypT0/is ypN0); and (3) absence of invasive cancer in the breast irrespective of in situ cancer in the breast or disease in the nodes (ie, ypT0/is).

The overall frequency of pCR was low (22%, ypT0/i; 18%, ypT0/is ypN0; and 13%, ypT0 ypN0). The analysis revealed that eradication of invasive tumor from the breast and nodes, irrespective of in situ disease in the breast (ypT0 ypN0 or ypT0/is ypN0), had a stronger association with both event-free survival and OS than did eradication of invasive tumor from the breast alone (ypT0/is). The ypT0/is ypN0 definition was thereafter adapted as the definition of pCR in their analysis.

In general, more aggressive subtypes had higher rates of pCR, ranging from 7.5% for hormone receptor–positive, HER2-negative grade 1/2 tumors, to 33.6% for triple-negative tumors, to 50.3% for HER2-positive, hormone receptor–negative tumors that were treated with trastuzumab. Trastuzumab increased pCR rates in all HER2-positive tumors, regardless of whether they were hormone receptor–positive or –negative. The strongest association between long-term outcomes and pCR was seen for patients with triple-negative and HER2-positive, hormone receptor–negative cancers who received trastuzumab.

Preliminary analyses have also suggested that LRR rates varied widely across the study population when analyses were performed by pathologic response and biological subsets. For example, in hormone receptor–positive, HER2-negative mastectomy patients, there were no LRRs in the setting of a pCR regardless of grade, but among ypN+ patients, grade 3 patients experienced higher LRR than grade 1 or 2 patients (13.9% vs 5.3%). In lumpectomy patients, a similar trend was observed in the hormone receptor–positive, HER2-negative subset (low recurrence rates with a pCR regardless of grade), but when ypN+ patients were stratified by age, the difference in recurrence between grade 3 and grade 1 or 2 patients was even larger (age < 50 years: 20.6% vs 1.5%; age ≥ 50: 12.7% vs 1.1%). Although treatments were not uniform across the populations, this suggests that grade may be an important factor to consider in adjuvant therapy decisions when a pCR is not achieved.

Interesting trends were also observed in patients with triple-negative disease. Although these patients are generally thought of as having more aggressive disease, 5-year LRRs were low (6.2%) for mastectomy patients with a pCR, but they remained high (22.1%) for patients with residual nodal disease. A large difference in recurrence rates was similarly observed in hormone receptor–negative, HER2-positive patients who underwent mastectomy (ypT0/is ypN0: 4.1% vs ypN+: 24.4%). It might, therefore, be reasonable to include triple-negative and hormone receptor–negative, HER2-positive ypN+ patients in trials that involve intensification of locoregional therapy (more extensive fields, higher dose, or radiosensitizers) while including those with a pCR in trials that omit radiotherapy altogether.

Special Considerations: Axillary Management in Patients Receiving Neoadjuvant Chemotherapy

Given the rapid evolution of strategies for axillary evaluation and management in all settings, these issues merit consideration in the context of the current discussion. Practices vary widely regarding the nature and timing of axillary evaluation in patients treated with neoadjuvant therapy. Some institutions continue to perform upfront sentinel lymph node biopsy (SLNB) to provide pathologic information as similar as possible to the sort of “prechemotherapy” pathology that was evaluated in the trials of PMRT. Other institutions perform upfront axillary ultrasonography but not SLNB prior to chemotherapy. Two 2013 studies that evaluated SLNB in patients who underwent neoadjuvant chemotherapy found that false-negative rates were unacceptably high after neoadjuvant chemotherapy.[23,24] However, given lower rates of false-negative results among patients with 3 or more nodes retrieved and the desire to spare patients the morbidity of axillary dissection, some institutions do perform SLNB in patients with clinically negative axillae after neoadjuvant chemotherapy. Accounting for differences in axillary surgical approaches adds further complexity to the determination of appropriate radiotherapeutic management in this setting. Patients treated with upfront SLNB (the general approach at the University of Michigan) may be at higher risk for overtreatment with radiotherapy; patients treated with SLNB after chemotherapy may be at higher risk for false-negative results and residual disease that is undertreated by radiotherapy. Ultimately, in such settings, a patient’s personal preferences and tolerance of risk of recurrence vs treatment-related morbidity are particularly important considerations.

Current Guidelines for Radiotherapy After Neoadjuvant Chemotherapy

The National Comprehensive Cancer Network (NCCN) guidelines state that “indications for radiation therapy and fields of treatment should be based on the worst stage pretreatment or posttreatment tumor characteristics in patients treated with neoadjuvant chemotherapy.”[25] They then divide recommendations for patients with early-stage disease (I, IIA, IIB, and T3N1) and locally advanced disease (all stage III patients except T3N1). For patients with early-stage disease who undergo mastectomy, the guidelines refer to the general guidelines on PMRT, which typically recommend the following:

• ≥ 4 involved axillary nodes: administer.

• 1 to 3 involved axillary nodes: strongly consider.

• Negative nodes and tumor > 5 cm or positive margins:
consider.

• Negative nodes and tumor ≤ 5 cm and negative margins but < 1 mm: consider to chest wall only.

• Negative nodes, tumor ≤ 5 cm, and margins > 1 cm: omit.

Regarding axillary staging, the NCCN recommends fine-needle aspiration (FNA) or core biopsy of any clinically or radiographically suspicious nodes prior to the administration of neoadjuvant chemotherapy. If FNA or core biopsy specimens are negative, NCCN guidelines recommend SLNB, which can be performed before or after neoadjuvant chemotherapy. If FNA or core biopsy specimens are positive, they recommend restaging with ALND after neoadjuvant chemotherapy if there are clinically positive nodes, and with ALND or SLNB if nodes are clinically negative.

For patients with locally advanced noninflammatory breast cancer, NCCN guidelines state that if a patient has a response to preoperative systemic therapy, subsequent treatment should include either lumpectomy or total mastectomy, level I/II axillary dissection, and radiotherapy to the breast/chest wall and infraclavicular and supraclavicular nodes.[25] Regarding coverage of the internal mammary nodes, the guidelines state that treatment is recommended if they are clinically involved and should be strongly considered if they are not clinically involved (level 2B recommendation).

The NCCN guidelines attempt to provide a conservative recommendation that accommodates the wide variation in pretreatment assessment procedures. In recommending that patients be treated based on the worst pre- or posttreatment staging, the NCCN guidelines place stronger weight on the lack of prospective data for omission of PMRT than on the retrospective B-18 and B-27 data[20] showing low recurrence rates in some patient subsets. Additionally, for early-stage patients who undergo neoadjuvant chemotherapy, NCCN guidelines refer to guidelines for PMRT that were largely designed for patients who did not undergo neoadjuvant chemotherapy. However, clinicians may want to factor in response to chemotherapy in ways that are not explicitly addressed by the recommendations. For example, although the recommendation in patients with involvement of 1 to 3 nodes is to strongly consider PMRT, in the B-18/B-27 analysis,[20] the 10-year incidence of LRR was greater than 10% (10.6% to 14.7%) for all mastectomy patients with 1 to 3 positive nodes after neoadjuvant chemotherapy, suggesting that perhaps PMRT should be recommended to all patients in this category.

The National Cancer Institute published a statement in 2008 regarding locoregional treatments after preoperative chemotherapy for breast cancer.[26] The statement discussed the MD Anderson and NSABP data, which suggest the importance of considering nodal status both before and after neoadjuvant chemotherapy, and subsequently recommended that radiotherapy be considered for patients who (1) present with clinical stage III disease or (2) have pathologically proven nodal involvement after neoadjuvant chemotherapy. However, the statement also discusses the lack of evidence for the value of PMRT in patients with stage II disease and says that prospective trials are needed.

Ongoing Trials: PMRT After Neoadjuvant Chemotherapy

Prospective trials provide an opportunity to answer a number of important questions regarding the utility of PMRT after neoadjuvant chemotherapy. One major question is whether pathologic response rates in either the breast or lymph nodes can be used prospectively to identify a group of patients who will have a low rate of recurrence if PMRT is omitted. Additionally, in patients who do not achieve a pCR, the most appropriate extent of axillary surgery and radiotherapy is unclear. Trials have recently been initiated to address these important questions.

NSABP B-51/RTOG 1304 trial

NSABP B-51/Radiation Therapy Oncology Group (RTOG) 1304, a trial that began in August 2013, will evaluate the benefit of radiotherapy in patients who have had a complete response in the axilla after neoadjuvant chemotherapy. It is enrolling women with clinical T1–T3 N1 disease based on palpation, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET), who have undergone pathologic confirmation of axillary involvement.[27] SLNB is not permitted, given that this would prohibit assessment of response to neoadjuvant chemotherapy; the involved node must be pathologically confirmed but left in place. Patients must complete a minimum of 12 weeks of standard neoadjuvant chemotherapy consisting of an anthracycline- and/or taxane-based regimen. Additional adjuvant chemotherapy is allowed for up to 12 weeks. HER2-positive patients must receive a regimen that includes anti-HER2 therapy (eg, trastuzumab, pertuzumab). Patients with metastatic disease, T4 tumors, clinical or radiographic N2 or N3 disease, histologically positive nodes after neoadjuvant chemotherapy, or microscopically positive margins after definitive surgery are excluded (negative margins via reexcision are allowed).

Allowed methods of axillary staging after chemotherapy include ALND, SLNB alone, or SLNB followed by ALND. Patients are eligible whether or not there is a pCR in the breast and also if isolated tumor cells are detected by hematoxylin and eosin stain, immunohistochemistry, or positive molecular findings, without other evidence of lymph node metastases (ie, ypN0[i+] or ypN0[mol+]).

Patients who undergo mastectomy will be randomly assigned to no radiotherapy or chest wall and regional nodal radiotherapy. Regional nodal irradiation will include the chest wall, undissected axilla, supraclavicular nodes, and internal mammary nodes in the first three intercostal spaces. The dose to the chest wall and regional nodal areas will be 50 Gy, and a chest-wall boost of 12 or 14 Gy will be permitted in cases with close (≤ 2 mm) margins.

The primary endpoint is invasive breast cancer recurrence–free interval, defined as time from randomization until invasive local, regional, or distant recurrence or death from breast cancer. Secondary aims and endpoints include OS, LRR-free interval, distant recurrence–free interval, disease-free survival–ductal carcinoma in situ (DCIS; patients with DCIS are not counted as disease-free), secondary primary invasive cancer, quality of life, toxicity, treatment adequacy, comparison of radiotherapy effects in lumpectomy and mastectomy patients, and molecular predictors of recurrence. This important trial will therefore address critical, previously unanswered questions.

Alliance trial

The Alliance 011202 trial will enroll patients who are not eligible for NSABP B-51/RTOG 1304 due to the presence of positive sentinel nodes after neoadjuvant chemotherapy.[28] Patients will be randomly assigned to completion ALND and nodal radiation therapy or axillary radiation and nodal radiation therapy. In the ALND group, complete level I and II dissection is recommended, with removal of a minimum of 8 nodes. Radiotherapy will be delivered over 5 to 6 weeks to the breast/chest wall, undissected axilla, supraclavicular nodes, and internal mammary nodes in the first three intercostal spaces. For the axillary radiation group, radiotherapy will be delivered to the breast/chest wall, full axilla (levels I, II, and III), supraclavicular nodes, and internal mammary nodes in the first three intercostal spaces.

The primary outcome is invasive breast cancer recurrence–free interval. Secondary outcomes include OS and ipsilateral/local/regional invasive breast cancer recurrence. Additional outcomes to be reported include development of breast or arm lymphedema, adequacy of radiation fields, and residual cancer burden.

Future directions

The NSABP B-51/RTOG 1304 and Alliance 011202 trials will contribute much needed data to the topic of PMRT after neoadjuvant chemotherapy. However, given the previously discussed data on SLNB after neoadjuvant therapy, the safety of SLNB will remain unclear if not enough women are enrolled in NSABP B-51/RTOG 1304 who undergo SLNB alone. Additionally, these trials will not answer the question of what the appropriate extent of the radiation field should be: for example, must internal mammary nodes always be included, and should the entire axilla be irradiated in a patient with low residual nodal burden after neoadjuvant chemotherapy? Further trials are also in development (eg, Southwest Oncology Group 1509) to answer questions that may arise at the other end of the spectrum of risk: for example, should treatment be intensified in certain patients based on their response (or lack thereof) to neoadjuvant therapy? Radiosensitizer studies may be particularly valuable in certain patients who do not respond to neoadjuvant therapy.

Conclusions

There is a lack of evidence from randomized trials demonstrating the benefits of delivery or the safety of omission of PMRT in patients who receive neoadjuvant chemotherapy. Ongoing trials will answer many important questions, but additional issues will need to be addressed, either through prospective trials or consensus guidelines incorporating retrospective studies or extrapolated data in the absence of level I evidence. In the interim, the ideal approach is to enroll eligible patients in clinical trials and to otherwise make recommendations regarding PMRT to patients based on their highest clinical or pathologic stage, while attempting to account for individual patient variations in preferences for avoidance of recurrence vs minimization of treatment-related toxicity and burden.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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