The main aim of an individual patient data meta-analysis of 14324 women included in 16 studies was to assess the effects of regional node radiotherapy on breast cancer recurrence and mortality, reporting separate meta-analyses of the newer and older trials. The trials in this meta-analysis span half a century. During this time, there were major changes in breast cancer radiotherapy, as reflected in findings.
Regional node radiotherapy in the early trials, which started during the 1960s and 1970s, had little effect on overall recurrence or breast cancer mortality and increased non-breast-cancer mortality, leading to a net increase in overall mortality. In contrast, regional node radiotherapy in the newer trials, which would have been delivered in the 1990s and 2000s, significantly reduced breast cancer recurrence and mortality, with no apparent increase in non-breast-cancer mortality, resulting in significantly reduced overall mortality. The findings are reported by investigators from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) on 3 November 2023 in The Lancet.
The EBCTCG investigators wrote in the background that studies have shown that, following breast-conserving surgery or following mastectomy for node-positive disease, postoperative radiotherapy can reduce breast cancer mortality. However, some of those studies irradiated just the breast or chest wall, but others also irradiated some of the regional lymph nodes. In an accompanied comment, Prof. Mark N Levine of the Department of Oncology, McMaster University in Hamilton, ON, Canada wrote that it is unclear how much of the effect of the radiotherapy occurred because of regional nodal irradiation.
The meta-analysis performed by EBCTCG investigators shows that regional lymph node irradiation clearly reduces breast cancer mortality and that the effect appears to be driven by internal mammary node radiotherapy.
Several studies have been conducted in which the only difference between the two treatment groups involved irradiation of regional lymph nodes in one or more of three sites: the internal mammary chain, supraclavicular fossa, and axilla.
The studies included in this meta-analysis recruited patients over many decades and during this time regional node radiotherapy changed substantially. In the 1960s and 1970s, radiotherapy typically involved photon beams that often irradiated the heart and lungs. In the 1980s and 1990s, these techniques were replaced by more tailored methods that involved much lower exposure of the heart and lungs, and more uniform coverage of target regions. The EBCTCG investigators categorised regional node radiotherapy studies as older if conducted from 1961 to 1978 or newer if conducted from 1989 to 2008.
Radiotherapy has become much better targeted since the 1980s, also improving safety. The main mortality risks from the side-effects of regional node radiotherapy, heart disease and lung cancer, vary according to organ dose. The risks from regimens can be estimated by combining regimen-specific heart and lung doses with dose–response relationships.
In this meta-analysis of individual patient data, the EBCTCG investigators sought data from all randomised studies of regional lymph node radiotherapy versus no regional lymph node radiotherapy in women with early breast cancer, including one study that irradiated lymph nodes only if the cancer was right-sided. Studies were identified through the EBCTCG's regular systematic searches of databases including MEDLINE, Embase, the Cochrane Library, and meeting abstracts.
Studies were eligible if they began before 1 January 2009. The only systematic difference between treatment groups was in regional node radiotherapy to the internal mammary chain, supraclavicular fossa, or axilla, or any combinations of these. Primary outcomes were recurrence at any site, breast cancer mortality, non-breast-cancer mortality, and all-cause mortality. Data were supplied by trialists and standardised into a format suitable for analysis. A summary of the formatted data was returned to trialists for verification. Log-rank analyses yielded first-event rate ratios (RRs) and confidence intervals (CIs).
The EBCTCG investigators found 17 eligible studies, 16 of which had available data for 14324 participants, and one of which had unavailable data for 165 participants, and it was therefore excluded. In 8 newer studies with 12167 patients, which started during a period from 1989 to 2008, regional node radiotherapy significantly reduced recurrence (RR 0.88, 95% CI 0.81–0.95; p = 0.0008). The main effect was on distant recurrence as few regional node recurrences were reported. Radiotherapy significantly reduced breast cancer mortality (RR 0.87, 95% CI 0.80–0.94; p = 0.0010), with no significant effect on non-breast-cancer mortality (0.97, 0.84–1.11; p = 0.63), leading to significantly reduced all-cause mortality (0.90, 0.84–0.96; p = 0.0022).
In an illustrative calculation, estimated absolute reductions in 15-year breast cancer mortality were 1.6% for women with no positive axillary nodes, 2.7% for those with one to three positive axillary nodes, and 4.5% for those with four or more positive axillary nodes.
In 8 older studies that included 2157 patients and which started during a period from 1961 to 1978, regional node radiotherapy had little effect on breast cancer mortality (RR 1.04, 95% CI 0.91–1.20; p = 0.55), but significantly increased non-breast-cancer mortality (1.42, 1.18–1.71; p = 0.00023), with risk mainly after year 20, and all-cause mortality (1.17, 1.04–1.31; p = 0.0067).
The authors commented that there are two main differences between the older and newer trials. First, breast cancer regional node radiotherapy techniques improved substantially. The greatest improvements were during the 1980s and 1990s when visualisation of radiation dose on cross-sectional images started to be used in radiotherapy planning. These improvements substantially reduced the incidental radiation doses received by organs near the breast and lymph nodes, such as the heart and lungs. Second, 6 of the 8 older studies in this meta-analysis did not include chest wall radiotherapy after mastectomy in women with node-positive cancer, which would be considered suboptimal today.
Radiotherapy has improved further since the newer trials were conducted. Techniques now include intensity-modulated beams to improve target coverage, deep inspiratory breath-hold to minimise heart and lung doses, and imaging during treatment to enable consistent dose delivery. Additionally, there are international guidelines for nodal contouring, target coverage, and organ avoidance.
This work was funded by the Cancer Research UK, Medical Research Council.
References
- Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Radiotherapy to regional nodes in early breast cancer: an individual patient data meta-analysis of 14324 women in 16 trials. The Lancet; Published online 3 November 2023. DOI: https://doi.org/10.1016/S0140-6736(23)01082-6
- Levine MN. Effective and safe regional node irradiation in early breast cancer. The Lancet; Published online 3 November 2023. DOI: https://doi.org/10.1016/S0140-6736(23)01614-8