The Role of Postmastectomy Radiation Therapy After Neoadjuvant Chemotherapy in Clinical Stage II-III Breast Cancer Patients With pN0: A Multicenter, Retrospective Study (KROG 12-05)

doi:10.1016/j.ijrobp.2013.09.021

International Journal of Radiation OncologyBiologyPhysics

Volume 88, Issue 1, 1 January 2014, Pages 65-72

https://doi.org/10.1016/j.ijrobp.2013.09.021 Get rights and content

Purpose

The purpose of this study was to investigate the role of postmastectomy radiation therapy (PMRT) after neoadjuvant chemotherapy (NAC) in clinical stage II-III breast cancer patients with pN0.

Methods and Materials

We retrospectively identified 417 clinical stage II-III breast cancer patients who achieved an ypN0 at surgery after receiving NAC between 1998 and 2009. Of these, 151 patients underwent mastectomy after NAC. The effect of PMRT on disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), and overall survival (OS) was evaluated by multivariate analysis including known prognostic factors using the Kaplan-Meier method and compared using the log–rank test and Cox proportional regression analysis.

Results

Of the 151 patients who underwent mastectomy, 105 (69.5%) received PMRT and 46 patients (30.5%) did not. At a median follow-up of 59 months, 5 patients (3.3%) developed LRR (8 sites of recurrence) and 14 patients (9.3%) developed distant metastasis. The 5-year DFS, LRRFS, and OS rates were 91.2, 98.1, and 93.3% with PMRT and 83.0%, 92.3%, and 89.9% without PMRT, respectively (all P values not significant). By univariate analysis, only age (≤40 vs >40 years) was significantly associated with decreased DFS (P=.027). By multivariate analysis, age (≤40 vs >40 years) and pathologic T stage (0-is vs 1 vs 2-4) were significant prognostic factors affecting DFS (hazard ratio [HR] 0.353, 95% confidence interval [CI] 0.135-0.928, P=.035; HR 2.223, 95% CI 1.074-4.604, P=.031, respectively). PMRT showed no correlation with a difference in DFS, LRRFS, or OS by multivariate analysis.

Conclusions

PMRT might not be necessary for pN0 patients after NAC, regardless of clinical stage. Prospective randomized clinical trial data are needed to assess whether PMRT can be safely omitted in pN0 patients after NAC and mastectomy for clinical stage II-III breast cancer.

Introduction

Neoadjuvant chemotherapy (NAC) is widely used for patients with locally advanced, operable breast cancer and is also a valid treatment option for patients with early-stage breast cancer 1, 2. NAC allows the eradication of micrometastases without postoperative recovery and the assessment of tumor response to chemotherapy. Additionally, NAC decreases tumor size and allows breast-conserving surgery for patients who would otherwise have required a mastectomy 3, 4. Randomized trials have established that administration of postmastectomy radiation therapy (PMRT) to appropriately selected women who receive adjuvant chemotherapy after mastectomy reduces locoregional recurrence and improves breast cancer survival 5, 6, 7.

However, no randomized trials have been performed to define who benefits from PMRT after NAC 8, 9, 10, 11, 12, 13. In a retrospective study at the University of Texas MD Anderson Cancer Center (MDACC), breast cancer patients with clinical stage II-III disease who were treated with NAC and mastectomy but without PMRT were at significant risk for locoregional recurrence (LRR), even when there was no pathologic evidence of lymph node (LN) involvement or when the patients were in complete remission. In 2008, a multidisciplinary expert panel organized by the National Cancer Institute published a statement that PMRT should be considered for patients presenting with clinical stage III disease or with histologically positive lymph nodes after preoperative chemotherapy (14). However, the background studies for the statement were retrospective analyses with small sample sizes and only included patients treated at the MDACC. Recently, results from studies performed in France have shown no increase in the risk for distant metastasis, LRR, or death when PMRT was omitted after NAC and mastectomy in clinical stage II-III breast cancer patients with pN0 status 15, 16. Given these conflicting results, the purpose of this study was to investigate the role of PMRT in clinical stage II-III breast cancer patients with pN0 after NAC.

Section snippets

Patient population

We retrospectively identified 417 breast cancer patients with tumor size >5 cm or axillary LN metastasis who achieved pN0 after receiving NAC at 9 institutions in Korea between January 1998 and December 2009 according to the date of treatment initiation. Patients with distant metastases, clinically positive supraclavicular or internal mammary lymph nodes, inflammatory or bilateral breast cancer, another previous or concurrent malignancy except for thyroid cancer, previous chemotherapy, or

Patients and tumor characteristics

Of the 151 patients with pN0 status after NAC and mastectomy, 105 (69.5%) patients received PMRT and 46 (30.5%) did not. The clinical and pathologic characteristics of the patient are compared in Table 1. The median age was 47 years (range, 29-78 years). There were no significant differences between the patients in the PMRT and the non-PMRT groups with respect to age, clinical T-stage, N-stage, pathologic T-stage, hormonal status, HER 2/neu receptor status, and tumor grade. A greater percentage

Discussion

NAC is being used more frequently in patients with clinical stage II or III operable breast cancer. However, there are limited data on the appropriate use of PMRT for patients treated with NAC and mastectomy. In this study, we selected clinical stage II and III breast cancer patients with pN0 after NAC and mastectomy. Patients without PMRT had favorable outcomes compared with patients with PMRT, regardless of clinical stage.

Traditionally, the indications for adjuvant PMRT have been determined

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Multidisciplinary considerations in the management of breast cancer patients receiving neoadjuvant chemotherapy
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In December, 2021, the NSABP B-51/RTOG 1304 (NRG 9353) trial completed enrolling patients with clinical stage II-III breast cancer (T1-3N1M0) with biopsy-proven axillary nodal disease. Patients received NAC with anti-HER2-targeted therapy for HER2-positive disease.286 Patients with ypN0 status (by axillary dissection or SLNB) were randomized to breast RT alone (lumpectomy) or no RT (mastectomy) vs breast RT with regional nodal irradiation (lumpectomy) or PMRT with regional nodal irradiation (mastectomy).
Adjuvant locoregional radiation therapy in breast cancer patients with pathologic complete response after neoadjuvant chemotherapy: A systematic review and meta-analysis
2022, Clinical and Translational Radiation Oncology
The aim of the present meta-analysis was to investigate the impact of adjuvant locoregional radiation therapy (LRRT) in breast cancer patients with clinical lymph node metastatic disease achieving ypN0 after neoadjuvant chemotherapy (NACT).
A systematic review of studies on PubMed was performed. A meta-analysis was conducted by computing extracted hazard ratios (HRs) and 95% confidence intervals (CIs) into a fixed-effects model.
Thirteen studies were included in the meta-analysis. Adjuvant LRRT significantly reduced the risk of locoregional recurrence (LRR) in patients with N+ at diagnosis and ypN0 (HR 0.59; 95% CI 0.42–0.81). However, no statistically significant difference on disease-free survival (DFS) or overall survival (OS) was found.
LRRT significantly reduced the risk of LRR in patients with ypN0 after NACT whereas no impact on DFS or OS was observed. The low level of evidence should be considered when interpreting the results in clinical practice.
De-escalation of axillary irradiation for early breast cancer – Has the time come?
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In patients with stage III disease, the 5-year LRR and DFS rates were 1.9% and 14.4% (p = 0.041) and 91.9% and 67.4% (p = 0.022), respectively, whereas in stage II patients the 5-year distant metastasis and DFS rates were 0 and 11.5% (p = 0.044), and 100.0% and 84.9% (p = 0.023), respectively. In contrast, in a similar multicenter retrospective study from Korea (KROG 12–05) the 5-year DFS, LRRFS, and OS rates, although numerically in favor of PMRT (91.2, 98.1, 93.3% with PMRT vs 83.0%, 92.3%, and 89.9% without PMRT), weren’t statistically different [65]. No effect from PMRT on LRR, DFS and OS was also seen in a series from Institut Curie (Paris, France) [66].
Introduction of sentinel lymph node biopsy, initially in clinically node-negative and subsequently in patients presenting with involved axilla and downstaged by primary systemic therapy, allowed for significant decrease in morbidity compared to axillary lymph node dissection. Concurrently, regional nodal irradiation was demonstrated to improve outcomes in most node-positive patients. Additionally, over the last decades, introduction of more effective systemic therapies has resulted in improvements not only at distant sites, but also in locoregional control, creating space for de-escalation of locoregional treatments. We discuss the data on de-escalation in axillary surgery and irradiation, both in patients undergoing upfront surgery and primary systemic therapy, with special emphasis on the feasibility of omission of nodal irradiation in patients undergoing primary systemic therapy. In view of the accumulating evidence, omission of axillary irradiation may be considered in clinically node-positive patients converting after primary systemic therapy to pathologically negative nodes on sentinel lymph node biopsy (preferably also with in-breast pCR), presenting with lower initial nodal stage, older age and were treated with breast-conserving surgery followed by whole breast irradiation. Omission of regional nodal irradiation in patients with aggressive tumor phenotypes achieving a pCR is under investigation. In patients undergoing preoperative endocrine therapy the adoption of axillary management strategies utilized in case of upfront surgery seems more suitable than those used in post chemotherapy-based primary systemic therapy setting.
Loco-regional adjuvant radiation therapy in breast cancer patients with positive axillary lymph-nodes at diagnosis (CN2) undergoing preoperative chemotherapy and with complete pathological lymph-nodes response. Development of GRADE (Grades of recommendation, assessment, Development and Evaluation) recommendation by the Italian Association of radiation therapy and Clinical Oncology (AIRO)
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All the four identified studies reported OS rates. Three out of four studies showed that loco-regional RT in breast cancer patients with cN2 at diagnosis who experience ypN0 after PST did not improve OS [31,33,35] while only Liu et al. showed a significant advantage for loco-regional RT in patients with breast staged as IIIB-IIIC or T3/T4 (HR for patients receiving RT 0.82 (0.63–1.068). Only two studies reported CSS rates, showing that loco-regional RT did not improve CSS [31,35].
To perform a meta-analysis to determine the effect of loco-regional radiation therapy (RT) compared to no loco-regional RT for operated patients in clinical stage cN2 breast cancer at diagnosis and ypN0 after preoperative chemotherapy (PST).
Eligible studies were identified through a systematic search of the medical literature performed independently by two researchers using a validated search strategy. An electronic search of Medline via PubMed and Embase (Breast cancer AND preoperative chemotherapy AND radiation therapy) was conducted with no language or publication status restrictions. The effect of loco-regional RT on overall (OS), disease free (DFS), loco-regional recurrence-free (LRRFS) survival and local recurrence was evaluated. An electronic search of Medline via PubMed and Embase (Toxicity AND radiation therapy breast cancer AND preoperative therapy; toxicity AND breast surgery AND preoperative chemotherapy) was conducted for outcomes of harm: major acute and late skin toxicity, lymphedema and cardiac events.
Of 333 studies identified, 4 retrospective studies reporting on a total of 1107 patients were included in the meta-analysis. Six and 3 reported data of acute and late skin toxicity, while 2 studies provided information on cardiac events. Pooled results showed no difference in terms of hazard ratio for loco-regional RT versus no loco-regional RT [hazard ratio (HR) = 0.82, 95% confidence interval (CI) 0.63–1.68]. Loco-regional RT was associated with an OS benefit in the subgroup analysis: IIIB-C (loco-regional RT 79.3% vs no loco-regional RT 71.2%, p = 0.027) and T3-T4 (loco-regional RT 82.6% vs no loco-regional RT 76.6%, p = 0.025). No difference was shown in terms of 5-year DFS (loco-regional RT 91.2% vs no loco-regional RT 83%, p = 0.441) and LRRFS (loco-regional RT 98.1% vs no loco-regional RT 92.3%, p = 0.148). There was no significant difference between the groups in terms of acute and late skin toxicities, lymphedema and cardiac events.
Because of the limitations due to the small number of studies and heterogeneity in the analysis, the present study does not allow to draw any definitive conclusion, highlighting the need for well-controlled trials to determine the effect of loco-regional RT in patients with cN2 having a pathological complete response in the axillary nodes after preoperative chemotherapy.
Postmastectomy Radiation Therapy Based on Pathologic Nodal Status in Clinical Node-Positive Stage II to III Breast Cancer Treated with Neoadjuvant Chemotherapy
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The present study aimed to evaluate the effect of postmastectomy radiation therapy (PMRT) after neoadjuvant chemotherapy in patients with node-positive stage II to III (cT1-4N1-2M0) breast cancer.
A total of 1813 patients from 12 institutions were retrospectively reviewed. Patients were classified into 1 of 3 groups based on the pathologic lymph node status after neoadjuvant chemotherapy: ypN0, ypN1, and ypN2-3. The role of PMRT was separately evaluated in each group. Locoregional control, disease-free survival, and overall survival (OS) were estimated using the Kaplan-Meier method. The effect of PMRT was assessed by propensity score–matched analyses and multivariate Cox analyses.
With a median follow-up of 72.9 months, 5-year locoregional control, disease-free survival, and OS rates were 86.3%, 68.4%, and 83.1% for the entire cohort, respectively. There were 490 (27.0%), 567 (31.3%), and 756 (41.7%) patients in the ypN0, ypN1, and ypN2-3 groups, respectively. PMRT significantly improved 5-year OS in the ypN2-3 group (74.2% vs 55.9%; P < .001) but had no effect on 5-year OS in the ypN0 group (93.1% vs 95.5%; P = .517) and ypN1 group (88.4% vs 87.8%; P = .549).
With modern systemic therapy, PMRT significantly improved OS in the ypN2-3 group but not in the ypN0 and ypN1 groups. Whether PMRT can be safely omitted in the ypN0 and ypN1 groups should be addressed prospectively.
The 2018 assisi think tank meeting on breast cancer: International expert panel white paper
2020, Critical Reviews in Oncology/Hematology
We report on the second Assisi Think Tank Meeting (ATTM) on breast cancer which was held under the auspices of the European Society for RadioTherapy & Oncology (ESTRO). In discussing in-depth current evidence and practice it was designed to identify grey areas in diverse forms of the disease. It aimed at addressing uncertainties and proposing future trials to improve patient care.
Before the meeting, three key topics were selected: 1) primary systemic therapy, mastectomy, breast reconstruction and post-mastectomy radiation therapy, 2) therapeutic options in ductal carcinoma in situ, and 3) therapy de-escalation in early stage breast cancer. Clinical practice in these areas was investigated by means of an online questionnaire. The time lapse period between the survey and the meeting was used to review the literature and on-going clinical trials. At the ATTM both were discussed in depth and research protocols were proposed.

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: Conflict of interest: none.

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Clinical InvestigationThe Role of Postmastectomy Radiation Therapy After Neoadjuvant Chemotherapy in Clinical Stage II-III Breast Cancer Patients With pN0: A Multicenter, Retrospective Study (KROG 12-05)

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Patient population

Patients and tumor characteristics

Discussion

Lancet

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27

J Clin Oncol

Preoperative therapy in invasive breast cancer: Pathologic assessment and systemic therapy issues in operable disease

J Clin Oncol

Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more

J Natl Cancer Inst

Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18

J Clin Oncol

Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b trial

N Engl J Med

Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer

N Engl J Med

Clinical Investigation
The Role of Postmastectomy Radiation Therapy After Neoadjuvant Chemotherapy in Clinical Stage II-III Breast Cancer Patients With pN0: A Multicenter, Retrospective Study (KROG 12-05)