Lymph nodes irradiation for breast cancer – outlines from the Early Breast Cancer Trialists’ Collaborative Group meta-analysis

An important article for clinical practice  was recently published in “The Lancet”. The conclusions are based on the meta-analysis of 16 trials and represents a trustable proof on impact of radiotherapy of the lymph node regions in breast cancer radiotherapy.

It is important to mention that individual patient data  from 14 324 women was analyzed, which is an impressive effort and brings high quality results. Sixteen trials run between 1961 and 2008 were included, in order to have enough data and follow-up time for evaluating long-term outcomes and side effects (1). We will briefly comment on some aspects related to this relevant news.

What was already known?

Previously published data supported the radiation therapy role for reducing breast cancer recurrence and mortality after breast-conserving surgery and even after mastectomy, in node-positive disease. However, it was not clear if the protective effect was due to irradiation of breast or chest wall, or if the lymph node region irradiation had a contribution, too.

What were the main findings?

Interestingly, the results were different when analyzing trials which involved treating patients with older vs newer techniques. This separate analysis is justified by the extensive time-span of the included studies and the significant technological changes implemented in this interval.

More precise treatments were translated into better target coverage and lower dose for the organs at risk, mainly to the heart. Fortunately, this lower dose did not increase the cardiovascular mortality. As a result, the benefit of radiotherapy on breast cancer survival was not canceled by late morbidity and cardiac-related death.

The way we are treating breast cancer now is more similar to the trials started after 1990, than those before that, so their outcomes are more relevant. The analysis of data from patients  included in these trials showed different improvements on different risk categories. There was an absolute risk reduction in 15-years breast cancer mortality for all patients, but those with four or more positive lymph nodes benefited the most.

What were the differences between older and newer trials?

Radiotherapy is not the only component of breast cancer multidisciplinary treatment that changed over time.  Table 1 underlines a few aspects of variation in the way breast cancer was treated in older and newer trials.

* Axillary dissection was recommended for all patients in 12 trials, sentinel node biopsy or axillary dissection in two trials, and no axillary surgery in two trials.

Lymphoedema rates in patients with vs without nodal radiotherapy to internal mammary chain, supraclavicular fossa, and axilla, after axillary dissection or sentinel node biopsy, was not significantly increased (8·3% vs 4·5%) according to the results of one of the newer studies (the (MA.20 trial, that randomised axillary radiotherapy).

Why no recurrence benefit or survival benefit for regional node irradiation in the older trials was found?

Regional node radiotherapy significantly increased non breast-cancer mortality in older trials. Little effect was observed during the first 15 years, but a substantial excess was identified thereafter, leading to a net increase in overall mortality. One of the trials was the main cause of this deviation.  Direct cobalt-60 internal mammary chain fields were used in this study, leading to a high dose to the heart. In older trials the values of mean heart dose was around 15 Gy for left breast cancer and 10 Gy for right breast cancer.  In contrast, in the largest newer trial (the DBCG trial), only 1 Gy was received by the heart in right-internal mammary chain radiotherapy.

Moreover, six of the eight older trials did not include chest wall radiotherapy after mastectomy in women with node-positive cancer. Recurrences in the chest wall and lower axilla might have decreased any beneficial effect of nodal radiotherapy.

Is there a different impact of irradiating different node levels?

In the newer trials, most of the evidence was on radiotherapy to the internal mammary chain alone or to the internal mammary chain and supraclavicular fossa combined, but no significant heterogeneity in the rate ratios for different irradiated nodal regions was found. Interestingly, the main effect of radiotherapy in these newer trials was on distant recurrence, rather than on locoregional recurrence. A possible explanation could be that internal mammary chain recurrences are not readily detected, so clearing the microscopic disease at this level might be reflected predominantly in reductions of distant disease, rather than locoregional recurrence.

What other factors influenced the treatment outcomes?

There was no significant variation in the rate ratios for any recurrence or breast cancer mortality according to type of breast surgery, nodal regions irradiated, use of systemic therapy, or period of follow-up.

What is the practical meaning?

The results show that there is a benefit of irradiating the regional lymph nodes, including in women who receive systemic therapies. The absolute breast cancer mortality decrease could be lower than in the trials due to the decrease of breast cancer death rates, but proportional benefits could be even greater these days due to additional improvements in radiotherapy.

Regional node radiotherapy has the potential to improve breast cancer survival without a significant cost, so the clinicians and the patients can use this information  in a shared decision making process.

How does MVision support radiation oncologists to provide quality care for breast cancer?

Delineating the lymph nodes is a time-consuming task, but it represents a necessity for high conformal radiotherapy. Contour+ breast radiotherapy model offers fast and precise delineation for 72 regions of interest, including 30 options for lymph node regions (based on ESTRO or RADCOMP guidelines, depending on local protocols. Composite volumes of breast/chest wall and different lymph node regions were created to simplify the workflow even further. Additionally, the model includes cardiac substructures useful for further treatment planning optimisation and research projects.

The performance of the MVision AI breast cancer models was already evaluated in some independent studies, with excellent results (2-7). Time saved had a median of 48% and a maximum of 63% in the study by Strolin et al, with an average satisfaction score of 4.45 of 5 (2). The use of MVision Contour+ allowed the doctors from Newcastle-Upon-Tyne, United Kingdom, to replace the traditional field-based target structure with both the Segmental Multi Leaf Collimator breast planning technique and a newly introduced VMAT technique for Internal Mammary Node positive disease. More than two thirds of the AI-based predicted contours did not need any edits, or only minor ones (4).

Quality treatments are translated into saved lives, as this recent meta-analysis showed. Using highly conformal techniques require complex and time consuming  contours, which should not cause treatment delays. MVision is offering this solution to improve the workflow, accuracy and consistency of contouring for your patients.

References

1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Radiotherapy to regional nodes in early breast cancer: an individual patient data meta-analysis of 14 324 women in 16 trials [published online ahead of print, 2023 Nov 3]. Lancet. 2023;S0140-6736(23)01082-6. doi:10.1016/S0140-6736(23)01082-6

2. Strolin S, Santoro M, Paolani G, et al. How smart is artificial intelligence in organs delineation? Testing a CE and FDA-approved Deep-Learning tool using multiple expert contours delineated on planning CT images. Front Oncol. 2023;13:1089807. Published 2023 Mar 2. doi:10.3389/fonc.2023.1089807

3. Doolan PJ, Charalambous S, Roussakis Y, et al. A clinical evaluation of the performance of five commercial artificial intelligence contouring systems for radiotherapy. Front Oncol. 2023;13:1213068. Published 2023 Aug 4. doi:10.3389/fonc.2023.1213068

4. Wowk A et al. Introduction of AI segmentation to drive improvements in Breast Cancer.  Radiotherapy ESTRO 2023

5. Ehrhardt V et al. The Possibility of AI-based Contours for Automatic Target Volume Determination in Adjuvant Radiotherapy of Breast cancer. DEGRO, 2022

6. Mehrhof F et al. Establishment of an AI-Based Contouring of Cardiac Substructures in the Adjuvant Irradiation of Breast Cancer, DEGRO, 2022

7. Morcillo AB et al. Impact of an Auto-Contouring Software Program on Treatment Preparation Time. SEOR, 2022

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