Does Post-Mastectomy Radiotherapy Confer Survival Benefits on Patients With 1-3 Clinically Positive Lymph Nodes Rendered Pathologically Negative After Neoadjuvant Systemic Chemotherapy: Consensus from A Pooled Analysis?

Systematic Review Eur J Breast Health 2024; 20(2): 81-88 DOI: 10.4274/ejbh.galenos.2024.2023-12-14 Does Post-Mastectomy Radiotherapy Confer Survival Benefits on Patients With 1-3 Clinically Positive Lymph Nodes Rendered Pathologically Negative After Neoadjuvant Systemic Chemotherapy: Consensus from A Pooled Analysis? Munaser Alamoodi Department of Surgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia ABSTRACT The advent of taxane-based chemotherapy has revolutionized breast cancer care. This advance has helped improve the response to downstaging tumors that might otherwise be inoperable. It has also helped in rendering clinically (cN+) positive lymph nodes (LNs) pathologically negative (ypN0). The standard of care for cN+ patients included post-mastectomy radiotherapy (PMRT), regardless of the response to neoadjuvant chemotherapy. However, PMRT in patients with 1–3 positive LNs still lacks definitive guidelines. Numerous retrospective results have been inconclusive about the benefit of PMRT on survival in patients with 1–3 positive LNs. This pooled analysis attempts to reach a consensus. The PubMed database was searched through October 2023. The search yielded 27 papers, of which 11 satisfied the inclusion criteria. The locoregional recurrence-free survival (LRRFS), disease-free survival (DFS), and overall survival (OS) for each study were tabulated when given, and two groups were created, the PMRT and NO PMRT, respectively. The results were then pooled for analysis. The total number of patients was 8340, 4136 in the PMRT group, and 4204 in the NO PMRT group, respectively. The LRRFS, DFS, and OS were 96.9%, 82.1%, and 87.3% for the PMRT group and 93.2%, 79.6%, and 84.8% for the NO PMRT group, respectively. There was no statistical significance in LRRFS, DFS, or OS between the two groups (p = 0.61, p = 0.61, and p = 0.38, respectively). PMRT does not seem to confer survival benefits in patients with pN1 rendered ypN0 for stages T1-3. This pooled analysis’s findings should be confirmed prospectively with a longer period of follow-up. Keywords: Post-mastectomy radiotherapy; neoadjuvant chemotherapy; regional nodal irradiation; clinically positive lymph nodes; pathological complete response Cite this article as: Alamoodi M. Does Post-Mastectomy Radiotherapy Confer Survival Benefits on Patients With 1-3 Clinically Positive Lymph Nodes Rendered Pathologically Negative After Neoadjuvant Systemic Chemotherapy: Consensus from A Pooled Analysis? Eur J Breast Health 2024; 20(2): 81-88 Key Points • Taxane-based neoadjuvant chemotherapy has improved response to downstaging and pathological complete response. • The benefits on survival of post-mastectomy radiotherapy (PMRT) in breast cancer patients with T1-3 and 1-3 positive lymph nodes rendered pathologically negative post-neoadjuvant chemotherapy is not yet established. • PMRT does not seem to confer survival benefits on breast cancer patients with T1-3 and 1-3 positive lymph nodes rendered pathologically negative post-neoadjuvant chemotherapy. • Long-term follow-up of patients for 10 years or more is essential to determine the effect of forgoing PMRT on locoregional recurrence. • Clinicopathological factors such as age, lymphovascular invasion, and tumor size have to be taken into consideration before forgoing PMRT. • Ongoing prospective studies will determine the basis of radiotherapy administration in these specific groups. Introduction The role of post-mastectomy radiotherapy (PMRT) in patients with more than four positive lymph nodes (LNs) has been shown to improve survival. These trials have also shown improvement regardless of tumor Corresponding Author: Munaser Alamoodi; ©Copyright size or the number of positive LNs (1). However, the benefit to lowtumor burden LNs (1–3 positive LNs) was debated due to these trials being based on the pre-taxane and human epidermal growth factor receptor 2 (HER2) targeted therapy eras. In addition, some studies Received: 29.12.2023 Accepted: 16.02.2024 Available Online Date: 01.04.2024 2024 by the Turkish Federation of Breast Diseases Societies / European Journal of Breast Health published by Galenos Publishing House. 81 Eur J Breast Health 2024; 20(2): 81-88 indicated that these patients demonstrated a low rate of LRR (2, 3). In a series from the Cleveland Clinic, a 10% locoregional recurrence (LRR) rate was reported among patients with 1–3 positive LNs treated with mastectomy and chemotherapy without radiation (4). Other studies placed the LRR rate in the range of 4–10% (5, 6). However, in patients less than forty years of age with lymphovascular invasion (LVI), the five-year LRR rate was 24.3% (7). It is imperative that long-term follow-up be implemented, as 95% of LRRs occur within 10 years after surgical intervention (8). The conflicting results and lack of evidence led the National Comprehensive Cancer Network to recommend that PMRT be “strongly considered” in patients with 1–3 positive LNs while also taking into account other clinical characteristics, such as life expectancy, age, comorbidities, tumor size, and LVI (9). Furthermore, a joint panel comprised of the American Societies of Clinical, Radiation, and Surgical Oncology recommended PMRT in patients with 1–3 positive LNs and T1-2 as the benefits outweigh the potential toxicities (10). The advent of taxane-based chemotherapy has revolutionized breast cancer (BC) management. This advance has become a first-line treatment for responders, achieving a higher percentage of pathological complete response (pCR) in both the breast and axilla. Moreover, the addition of anti-HER2 therapy became standard due to its survival benefits (11, 12). The de-escalation in the management of the axilla both surgically and medically is made possible in such patients. PMRT can lead to numerous side effects, both early and late after treatment. Early side effects, which occur weeks to months apart, can include skin thickening, pleural effusion, and radiation-induced pneumonia. The intermediate to late period, which can take months to years, includes breast fibrosis, pulmonary fibrosis, and fracture of overlying bone, among others (13). and tumor stage T1-4. The data was collected, and patients were then divided into two groups, each exclusively made up of cN+ and ypN0 post-NAC: PMRT and NO PMRT. When given, the number of patients who had RNI was recorded as part of the PMRT group. The number of patients for LRRFS, DFS, and OS rates was calculated for each study when given. The results were then pooled for analysis. A chisquare test with Yates’s correction was applied. Confidence intervals (CI) were determined based on a non-central chi-square distribution for Q (a common effect measure). The pooled mean follow-up period was calculated. Subgroup pooled analysis of LRRFS, DFS, and OS was carried out for T1-2 and T2-3 studies, respectively, and the p-values were tabulated. Results The PubMed search yielded (...truncated)