Neoadjuvant systemic therapy in breast cancer: use and trends in radiotherapy practice

Original Article

Neoadjuvant systemic therapy in breast cancer: use and trends in radiotherapy practice


T.A. Koulis, MD*, K. Beecham, MD, C. Speers§, S. Tyldesley, MD, D. Voduc, MD, C. Simmons, MD#, R. Olson, MD*



doi: https://doi.org/10.3747/co.24.3558


ABSTRACT

Background

The use of neoadjuvant systemic therapy (nast) in the treatment of breast cancer is increasing, and the role of adjuvant radiation therapy (rt) in that setting is uncertain. We sought to review and report the use of nast, its trends over time, and its relationship with the prescribing patterns of locoregional rt in a provincial cancer system.

Methods

Patients with stages iiii breast cancer diagnosed during 2007–2012 were identified using a provincial database. Patient, tumour, and treatment characteristics were extracted. Multivariable logistic regression analyses were used to assess associations with the use of nast. Kaplan–Meier and Cox regression were used for survival analyses.

Results

Of the 11,658 patients who met the inclusion criteria, 602 (5%) had received nast. Use of nast was more frequent in stage iii patients (53%) than in stages i and ii patients (2%). In clinically lymph-node positive patients, a pathology assessment was made approximately 50% of the time. Higher clinical tumour stage and increasing clinical nodal stage predicted for increasing use of nast and of nodal rt after nast, but pathologic nodal status after nast was not associated with use of nodal rt. A statistically significant survival difference was observed between patients in the nast and no-nast groups, but that significance disappeared in a multivariable Cox regression analysis.

Conclusions

This population-based study demonstrated 5% use of nast for breast cancer. Most patients received nodal rt after nast, and nodal rt was not associated with pathologic stage after nast. Findings likely reflect the realities of clinical practice and show that reliance on clinical nodal staging results in outcomes similar to those reported in the literature.

KEYWORDS: Breast cancer, neoadjuvant systemic therapies, radiotherapy, nodal irradiation, nodal staging

INTRODUCTION

Interest in and use of neoadjuvant systemic therapy (nast) in breast cancer (bca) has been increasing13. The National Surgical Adjuvant Breast and Bowel Project (nsabp) B-18 clinical trial demonstrated that neoadjuvant therapy was not superior to adjuvant chemotherapy for the primary endpoints of disease-free survival or overall survival (os), but did appear to facilitate more breast-conserving surgery4. As a result, although nast was historically used to enable resection of otherwise unresectable or locally advanced bca, it is increasingly used for less-advanced tumours to facilitate breast-conserving surgery. Other emerging uses of nast include the study of novel systemic agents, enabling smaller studies to determine the activity of an agent in a shorter period of time5,6.

The indications for regional radiotherapy (rt) after mastectomy in non-locally-advanced bca have been based on nodal status (level 1 evidence)711. As nast becomes more commonplace, standardization is needed in the delivery of adjuvant locoregional (lr) rt in this context. The lack of evidence in this setting has made such standardization difficult and could affect patient care and lr outcomes.

In the context of adjuvant systemic therapy, the addition of adjuvant lr rt lowers lr relapse rates. It also offers a bca-free survival benefit in node-positive patients treated with either mastectomy or breast-conserving surgery7,8,12,13 and, in some trials, an os advantage911. The decision to offer lr rt has largely been based on the presence or number of positive axillary lymph nodes and tumour size, assessed before chemotherapy7,8,10,12,13.

Although it seems logical to offer lr rt when nodal disease is identified after nast, whether to offer lr rt when no nodal disease is detected after nast is unclear, especially if the “clinically involved” nodes were not pathologically sampled before systemic treatment. Diagnostic imaging—including ultrasonography, magnetic resonance imaging, or combined positron-emission tomography and computed tomography—does not have sufficient specificity or sensitivity to replace pathology assessment14,15. Several recent publications have shown a lower risk of recurrence after pathologic complete response; however, a pathologic complete response after nast does not entirely eliminate the risk of recurrence1619 [a question that is currently under examination (https://clinicaltrials.gov/ct2/show/NCT01872975)]. In the mean-time, we sought to review and report on the use of nast, its trends over time, and its relationship with the prescribing patterns of lr rt in a provincial cancer system.

METHODS

Data Source and Extraction

The BC Cancer Agency (bcca) is the sole provider of rt in British Columbia. Patients with nonmetastatic bca diagnosed between July 2012 and June 2012 were identified through the Breast Cancer Outcomes Unit database, which prospectively records tumour, stage, treatment, and outcome data. The proportion of patients who received nast as part of their initial therapy was determined. Prognostic and treatment factors were extracted from the Breast Cancer Outcomes Unit database, and the patient’s electronic medical chart was reviewed to determine additional information, including the method of lymph node assessment before nast.

Statistical Analysis

Patient characteristics are presented as descriptive statistics, and the chi-square and Fisher exact tests were used to assess associations with the use of nast, treatment facility, and year of treatment. Multivariable logistic regression analyses were used to assess the associations between variables and the subsequent use of nast. All p values were 2-sided, and values less than 0.05 were considered statistically significant. Kaplan–Meier analysis was used to estimate os, locoregional relapse-free survival (lrrfs), and distant metastasis–free survival (dmfs), with os being calculated from the date of diagnosis to date of death, lrrfs being calculated from the date of diagnosis to time to relapse in breast or regional lymph nodes as a first event, and dmfs being calculated from the date of diagnosis to the date of first metastatic event. Cox regression analysis was used to analyze the effect of risk factors on os, lrrfs, and dmfs. The analyses were conducted using the SPSS software application (version 14.0: SPSS, Chicago, IL, U.S.A.). The study was approved by the bcca–University of British Columbia research ethics board.

RESULTS

Overall Demographics

During the study period, 11,658 patients were diagnosed and referred to the bcca with nonmetastatic bca. Of those patients, 602 (5%) received nast, 330 of whom (55%) were clinical stage iii and 272 of whom (45%) were stages iii. The nast consisted mainly of chemotherapy (92%) as opposed to endocrine therapy. Table i summarizes additional patient, tumour, and treatment characteristics, demonstrating a marked difference between patients who did and did not receive nast. As expected, patients in the nast cohort had more advanced disease: 63% compared with 5% in the no-nast cohort had cT3 or cT4 disease (p < 0.001), and 61% compared with just 10% in the no-nast cohort had clinically node-positive disease (p < 0.001). Stage iii bca was more common in the nast cohort than in the no-nast cohort (55% vs. 3%, p < 0.001). The patients who received nast received more aggressive surgery: 90% compared with 40% in the no-nast cohort underwent mastectomy, and 77% compared with 26% in the no-nast cohort underwent axillary lymph node dissection (p < 0.001). Compared with patients having stages iii disease, patients with stage iii bca were significantly more likely to receive nast (53% vs. 2%, p < 0.001).

TABLE I Patient, tumour, and treatment characteristics

 

Temporal Trends in NAST Use

Table ii shows that use of nast did not increase during the study period; it remained at 5%–6% per year (p = 0.13). A statistically significant increase in the use of nast to 3% from 2% (p < 0.001) was seen in all stage iii patients and corresponds to a 50% relative increase in patients treated with nast to 51% in 2012 from 37% in 2007 (p = 0.003). We observed no statistical difference in the proportion of stage iii patients treated with nast during the study period (p = 0.3). On multivariable regression analysis (Table iii), year of treatment was not significantly associated with the use of nast.

TABLE II Use of neoadjuvant systemic therapy, 2007–2012

 

TABLE III Lymph node assessment before neoadjuvant systemic therapy

 

Assessment of Lymph Node Status Before NAST

Table iv shows that, before nast, clinical exam was the most frequent method of assessing lymph node status and only a small number of patients underwent pathology assessment. In clinically lymph node–positive patients, a pathology assessment based on a fine-needle aspiration or core biopsy was performed roughly 50% of the time (47%, 42%, and 50% for cN1, cN2, and cN3 respectively). In clinically node-negative patients, 4% underwent sentinel lymph node biopsy (slnb) before nast. Axillary staging by methods other than clinical exam alone increased during the study period to 45% in 2010–2012 from 30% in 2007–2009 (p < 0.001, Table v).

TABLE IV Multivariable logistic regression analysis

 

TABLE V Method of axillary nodal staging for patients receiving neoadjuvant systemic therapya

 

Use of Nodal Irradiation

Compared with the no-nast patients, patients treated with nast were more likely to receive nodal irradiation (85% vs. 27%, p < 0.001, Table i). The use of nodal rt differed between the patients with lower-stage (iii) and higher-stage (iii) disease (80% vs. 89% respectively, p = 0.002). A statistically significant association of increasing use of nodal rt with increase in clinical nodal stage was evident: 78%, 89%, 90%, and 94% for cN0, cN1, cN2, and cN3 respectively (p = 0.002). Pathologic nodal status after chemotherapy (yp stage) was not associated with subsequent delivery of nodal rt (p = 0.80, Table vi).

TABLE VI Nodal irradiation in patients receiving neoadjuvant systemic therapy by stage and nodal status

 

Multivariable Analysis

To find associations with the use of nast, a multivariable regression analysis controlling for age, stage, year, bcca facility, tumour characteristics, and use of non-systemic treatment was performed. Increasing age was significantly associated with decreasing use of nast (odds ratio: 0.95 per year; 95% ci: 0.93 to 0.96; p ≤ 0.001). Increased use of nast was associated with increasing clinical tumour and clinical nodal stage and with her2-positive disease (1.84; 95% ci: 1.4 to 2.4; p < 0.001; Table iii).

When a multivariable regression analysis was performed to look at the use of nodal rt in the nast group, clinical T2 [hazard ratio (hr): 6.46; 95% ci: 1.21 to 34.54; p = 0.029], T3 (hr: 9.52; 95% ci: 1.44 to 62.84; p = 0.019), and T4 disease (hr: 16.9; 95% ci: 2.27 to 126.0; p = 0.006), and high grade (hr: 7.4; 95% ci: 1.9 to 28.88; p = 0.004) were predictive of the use of nodal rt. Increasing age (hr: 0.91; 95% ci: 0.85 to 0.98; p = 0.01), estrogen receptor negativity (hr: 0.23; 95% ci: 0.06 to 0.89; p = 0.03), undergoing slnb (hr: 0.22; 95% ci: 0.6 to 0.89; p = 0.03), having breast-conserving surgery (hr: 0.12; 95% ci: 0.03 to 0.5; p = 0.004), and being treated at centre 2 (hr: 0.11; 95% ci: 0.02 to 0.64; p = 0.014) were found to be predictive of less nodal rt. The remaining variables, including clinical nodal status, pathologic T or N status, lymphovascular space invasion, her2 status, and year of treatment were not significant (data not shown).

Survival and Control Analysis

Patients in the nast and no-nast groups showed statistically significant differences in 5-year os, lrrfs, and dmfs estimates: os, 74% (95%ci: 71% to 78%) and 89% (95% ci: 88% to 90%) respectively, p < 0.001; lrrfs, 94% (95% ci: 92% to 96%) and 97% (95% ci: 97% to 97%), p < 0.001; and dmfs, 73% (95% ci: 70% to 77%) and 92% (95% ci: 91% to 92%), p < 0.001 (Figure 1). When Cox regression incorporating age, stage, histologic features, and treatment was applied, the hr between the nast and no-nast groups did not reach significance (os hr: 1.15; 95% ci: 0.93 to 1.42; p = 0.21; lrrfs hr: 0.92; 95% ci: 0.61 to 1.4; p = 0.71; dmfs hr: 0.95; 95% ci: 0.76 to 1.18; p = 0.62).

 


 

FIGURE 1 Kaplan–Meier survival estimates for (A) overall survival, (B) locoregional relapse-free survival, and (C) distant metastasis-free survival, comparing all patients treated with (dark grey) and without (light grey) neoadjuvant systemic therapy.

In stage iii patients, no significant difference for the lrrfs at 5 years [90% (95% ci: 86% to 93%) vs. 87% (95% ci: 82% to 91%), p = 0.31] or for the dmfs [64% (95% ci: 58% to 69%) vs. 61% (95% ci: 55% to 67%), p = 0.35] was found between the nast and the no-nast groups [Figure 2(B,C)]. A difference in os at 5 years was seen between the groups: 65% (95% ci: 60% to 70%) in the nast group compared with 55% (95% ci: 49% to 61%) in the no-nast group, p = 0.001 [Figure 2(A)], although the difference was nonsignificant on multivariable Cox regression analysis when controlling for patient, tumour, and treatment factors (hr: 1.01; 95% ci: 0.79 to 1.47; p = 0.64).

 


 

FIGURE 2 Kaplan–Meier survival estimates for (A) overall survival, (B) locoregional relapse-free survival, and (C) distant metastasis-free survival, comparing only stage iii patients treated with (dark grey) and without (light grey) neoadjuvant systemic therapy.

DISCUSSION

This multicentre population-based study found a 5% rate of nast use for nonmetastatic bca between 2007 and 2012, while the use of nast in stages iii patients increased statistically significantly during the study period. Nodal assessment before nast rarely included imaging or pathology confirmation of involvement. Delivery of rt included nodal regions in most cases, regardless of the pathologic nodal stage after nast.

The incidence of nast in British Columbia is similar to that in other reports, including the reported 3.8% use of nast in 4 large U.S. treatment centres20 and the 8.5% use in another Canadian province21. Use of nast was quite a bit lower than in another American study, which reported a nast rate of 17.4%22. All of those studies demonstrated variability by stage, centre20, surgeon21, and geographic region22, as in our cohort, for whom use of nast varied by cancer centre—a finding showing that, despite widely published guidelines23,24, potential biases based on region and training can affect patient care.

We had hypothesized that use of nast would increase during the study period, as reported by others21,22; however, in our cohort, use of nast was relatively stable. The difference might be explained by our shorter time period (5 years compared with the 8 years used by Mougalian et al.22) or by significant increases in nast use after 2012 (the period used by Graham et al.21). Notably, use of nast increased for early-stage disease (iii), but stayed stable for stage iii disease. Given that observation, it is possible that the increase in nast use for early-stage patients was not enough to cause a statistically significant change in the overall use of nast, resulting in stable nast use over the period studied.

Since the publication of the nsabp B-18 trial4, a growing number of reports have described the use of nast to allow for breast conservation and improved cosmetic outcomes3,5,19,25. In the research community, interest is also growing in the use of nast as a way to evaluate in vivo tumour response to chemotherapy and to assess systemic agents that are active against bca26a. Given the expanded potential indications for nast, education of oncologists in its possible uses are needed to ensure that all eligible patients are considered for nast, while at the same time ensuring that the effects of nast on other treatment modalities are also considered.

Multiple institutions have proposed approaches to axillary staging and the use of slnb3,14,23,27. In our population-based cohort, no consistent approach to axillary staging was observed. Clinical examination alone was the most frequent method; however, the use of methods other than clinical exam increased. The rate of clinical assessment alone that we observed is not dissimilar to the 45% rate reported by Kilbride et al.27, despite a standardized nodal staging guideline being in place at their centre. When pathology assessment was performed before nast in our cohort, the most common method was fine-needle aspiration or core-needle biopsy. The accuracy of those methods has been investigated, and in clinically suspicious lymph nodes, the sensitivity falls into the 60%–70% range, with the specificity approaching 100%14,15,27.

In our cohort, use of slnb before nast was low (only 4% for cN0). The clinically negative axilla poses a challenge in terms of adequate assessment and potentially makes the decision about future nodal rt difficult. A concern with upfront slnb is delay in the start of systemic treatment. Kilbride et al.27 reported that, even with slnb, only 4 weeks elapsed between initial diagnosis and the start of systemic treatment, but whether that timeline is achievable at all centres without directed resources for the purpose is unclear. Some physicians advocate for the use of slnb only after completion of nast, but the accuracy of slnb in that setting is not conclusive. Data from a retrospective analysis28 and a meta-analysis29 showed that results from slnb after nast seem similar to those obtained upfront. However, a large randomized trial investigating slnb in the nast setting has cast doubt on the reliability of that observation, concluding that the false-negative rate is greater than 10% and that results should be interpreted with caution30. The best use of slnb in the nast setting has yet to be determined.

Compared with reports emerging from randomized controlled trials3032, the non-uniform approach to axillary staging seen in our cohort likely reflects the reality of clinical practice and the balance between requesting staging investigations and initiating treatment in a timely fashion. With emerging data suggesting that a pathology assessment of response in lymph nodes might inform the need for nodal irradiation16,33, the importance of adequate initial nodal staging is increasing. At a minimum, fine-needle aspiration should be attempted before nast [adequate for eligibility to enrol in nsabp B-51/Radiation Therapy Oncology Group 1304 (nrg 9353)20 and recommended by the U.S. National Comprehensive Cancer Network23].

The use of lr rt after nast was high (86%), more frequent in stage iii patients, and increased in frequency with increasing clinical nodal stage. Pathologic nodal stage was not associated with the use of nodal rt after nast, which might be attributable to the uncertainty of omitting nodal rt in that setting. Recent randomized trials in the adjuvant setting12,13 have shown that patients with 1–3 positive nodes benefit from nodal irradiation, with improved local control and improved distant disease-free survival. However, a meta-analysis and subgroup analysis of the nsabp B-18 and B-27 trials indicate that patients with a pathologic complete response in the axilla have a low risk of lr relapse16,33. That observation has led to the current nsabp B-51/Radiation Therapy Oncology Group 1304 (nrg 9353)20 trial addressing the question of whether nodal rt can be omitted after nodal pathologic complete response with nast. Until those results are available (in 2025 or beyond), uncertainty will remain about whether post-nast nodal status can be used to exclude the benefit of regional rt for pathologically positive nodes.

In the present study, 5-year os, lrrfs, and dmfs were not, on multivariable analysis, different for the stage iii patients in the nast and no-nast cohorts. That finding was expected, based on the randomized trial data4,34, and it continues to support the understanding that the timing of chemotherapy does not seem to influence survival outcomes.

The results of our study should be interpreted within the context of its strengths and limitations. Given the retrospective nature of the study, we were not fully able to explore physician rationale for prescribing or not prescribing lr rt. Additionally, the study examined an era during which nast was not commonly used to enable breast-conserving surgery. Before nast, too few patients underwent pathologic axillary staging, and that non-uniform pre-nast axillary staging limits our ability to comment on the effect of nast treatment response, subsequent irradiation, and outcomes. Since 2012, the use of nast might have continued to increase; our report might therefore not reflect the most current rates of nast use. However, no level 1 evidence to support a change in use of rt in the setting of nast has been published, and therefore the pattern of rt practice observed here is likely still to be representative of current practice. Additionally, our study undertook a large population-based analysis in a jurisdiction with universal health coverage and a single provider of rt services, thus limiting referral and selection bias. It therefore describes the observed prescription pattern of lr rt for bca after nast for all patients referred to the bcca during the study period.

CONCLUSIONS

Our population-based study found a 5% use of nast for bca, with a statistically significant increase in its use in early-stage disease during the study period. Most patients received lr rt after nast, even in the context of clinical stage i and ii cancers, independent of pathologic stage after nast. Our study likely reflects the current realities of clinical practice and shows that reliance on clinical staging of the axilla results in survival outcomes similar to those reported in the literature. Hopefully, future research will provide further guidance about which patients can avoid lr rt after nast and clarity about the most robust method of axillary staging before nast.

ACKNOWLEDGMENTS

We acknowledge the Canadian Association of Radiation Oncology for support through a fellowship grant.

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: TAK received fellowship funding from caro while this work was being done. RO has received funding from Varian, but not in relation to the present work. The other co-authors have no conflicts of interest to disclose.

AUTHOR AFFILIATIONS

*BC Cancer Agency–Centre for the North, Radiation Oncology Department, Prince George, BC (currently: BC Cancer Agency–Sindi Ahluwalia Hawkins Centre for Southern Interior, Kelowna, BC);,
University of British Columbia, Vancouver, BC;,
Sweden Ghana Medical Centre, Accra, Ghana; and,
§BC Cancer Agency, Breast Cancer Outcomes Unit,
BC Cancer Agency–Vancouver Centre, Radiation Oncology Department, and,
#BC Cancer Agency–Vancouver Centre, Medical Oncology Department, Vancouver, BC..

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Correspondence to: Robert Olson, BC Cancer Agency, 600 W 10th Avenue, Vancouver, British Columbia V5Z 4E6. E-mail: rolson2@bccancer.bc.ca

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aAlso see NCT02413320 and NCT02413320 at https://ClinicalTrials.gov. ( Return to Text )


Current Oncology, VOLUME 24, NUMBER 5, October 2017








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