As reported in The Lancet Oncology by Philip M. Poortmans, PhD, Department of Radiation Oncology of the Iridium Netwerk and the Faculty of Medicine and Health Sciences, University of Antwerp, and colleagues, 15-year outcomes of the phase III EORTC 22922/10925 trial show continued reduction in breast cancer mortality and recurrence with postsurgery internal mammary and medial supraclavicular (IM-MS) lymph node chain irradiation vs no IM-MS irradiation in patients with stage I to III breast cancer, with no significant difference in overall survival.¹

Philip M. Poortmans, PhD

As stated by the investigators, “10-year results from several studies showed improved disease-free survival and distant metastasis–free survival, reduced breast cancer–related mortality, and variable effects on overall survival with the addition of partial or comprehensive regional lymph node irradiation after surgery in patients with breast cancer. We present the scheduled 15-year analysis of the … EORTC 22922/10925 trial, which aims to investigate the impact on overall survival of elective … IM-MS irradiation.”

In the nonblinded trial from sites in 13 countries, 4,004 women aged ≤ 75 years with unilateral stage I to III breast adenocarcinoma with involved axillary nodes or a central or medially located primary tumor were randomly assigned between August 1996 and January 2004 to receive IM-MS irradiation at 50 Gy in 25 fractions (n = 2,002) or no IM-MS irradiation (control group; n = 2,002). Surgery consisted of mastectomy or breast-conserving surgery and axillary staging.

The primary endpoint was overall survival on intention-to-treat analysis. Secondary endpoints were disease-free survival, distant metastasis–free survival, breast cancer mortality, any breast cancer recurrence, and cause of death. Follow-up is ongoing for 20 years after randomization.

Efficacy Endpoints

Median follow-up was 15.7 years (interquartile range = 14.0–17.6 years). IM-MS irradiation was given to 97.1% of patients in the IM-MS group and to 2.0% of the control group.

Overall, death from any cause occurred in 27.7% of the IM-MS irradiation group and 28.4% of patients in the control group. Overall survival at 15 years was 73.1% vs 70.9% (hazard ratio [HR] = 0.95, 95% confidence interval [CI] = 0.84–1.06, P = .36). Median overall survival was not reached in either group; the duration of overall survival associated with the 75% survival probability (third quartile overall survival) was 14.2 years vs 13.0 years. In an analysis excluding 25 patients without data on final pathologic T and N stage, the difference in overall survival remained nonsignificant (HR = 0.92, 95% CI = 0.82–1.04, P = .18).

In an exploratory analysis of factors predictive of overall survival, an association was observed only for the number of axillary lymph nodes examined, with improved survival being observed in the IM-MS irradiation group among patients with fewer than 10 nodes examined (HR = 0.69, 95% CI = 0.52–0.91). No significant differences between groups were observed in analysis by breast tumor side, age, external or internal location of dominant lesion, menopausal status, type of surgery, type of axillary dissection, pathologic T or N stage, disease stage, receipt of adjuvant treatment, or hormone receptor status.

Overall, 37.5% vs 39.1% of patients had breast cancer recurrence or a second breast cancer or died. Disease-free survival at 15 years was 60.8% vs 59.9% (HR = 0.93, 95% CI = 0.84–1.03, P = .18). Overall, 29.2% vs 30.7% of patients developed distant metastases or died, with 15-year distant metastasis–free survival rates being 70.0% vs 68.2% (HR = 0.93, 95% CI = 0.83–1.04, P = .18). The cumulative incidence of any type of breast cancer recurrence at 15 years was 24.5% vs 27.1% (HR = 0.87, 95% CI = 0.77–0.98, P = .024).

Among patients who died, the cause of death was breast cancer in 56.7% of the IM-MS irradiation group vs 66.4% of the control group. Non–breast cancer death accounted for 30.9% vs 26.4% of deaths, and cause of death was unknown for 12.5% vs 7.2% of deaths. The cumulative incidence of breast cancer mortality at 15 years was 16.0% vs 19.8% (HR = 0.81, 95% CI = 0.70–0.94, P = .0055). At 15 years, the cumulative incidence of death not due to breast cancer was 7.8% vs 7.0% (HR = 1.13, 95% CI = 0.91–1.40, P = .29), and the cumulative incidence of death from an unknown cause was 3.1% vs 2.3% (HR = 1.66, 95% CI = 1.13–2.44, P = .010).

Second Cancers and Late Adverse Effects

Second cancers occurred in 14.1% vs 14.8% of patients, including ipsilateral breast cancer in 0.6% vs 0.5% and contralateral breast cancer in 6.2% vs 6.9%. Second non–breast cancers occurred in 8.3% vs 8.5% of patients. The distribution of non–breast cancers indicated no obvious increase in lung, thyroid, esophageal, mediastinal malignancies in the IM-MS group, with the exception of in-field tumors in four patients.

Late adverse effects were evaluated in 1,922 patients in the IM-MS irradiation group and 1,944 in the control group who received study treatment at every follow-up visit until disease progression or development of a new primary cancer. Any-grade pulmonary fibrosis occurred in 5.1% vs 2.3%,;cardiac fibrosis, in 2.0% vs 1.1%; and any cardiac disease, in 8.6% vs 7.2%.

Among the 935 vs 952 patients with right breast cancer, 2.0% vs 0.9% had clinical evidence of cardiac fibrosis and 8.3% vs 6.3% had any evidence of cardiac disease. Among the 987 vs 992 patients with left breast cancer, 1.9% vs 1.3% had clinical evidence of cardiac fibrosis and 8.8% vs 8.0% had any evidence of cardiac disease. Among the total study population, death due to cardiovascular disease occurred in 1.2% of patients in each group.

The investigators concluded: “The 15-year results show a significant reduction of breast cancer mortality and any breast cancer recurrence by IM-MS irradiation in stage I to III breast cancer. However, this is not converted to improved overall survival.”

They noted: “Although overall disease-free survival was not significantly longer with IM-MS irradiation, breast cancer recurrence at 15 years was significantly lower. The fact that this does not translate into longer overall survival might be explained by non–breast cancer–related deaths or those from an unknown cause, which together constituted 38% of all deaths, an imbalance in missing data on the cause of death between treatment groups, and salvage treatment after recurrence. Finally, the overall outcomes were better than expected, resulting in smaller absolute differences than expected based on historical results.” 

DISCLOSURE: The study was funded by the Ligue Nationale contre le Cancer, and KWF Kankerbestrijding. Dr. Poortmans serves in a consulting role for Sordina IORT Technologies Spa.

REFERENCE

1. Poortmans PM, Weltens C, Fortpied C, et al: Internal mammary and medial supraclavicular lymph node chain irradiation in stage 1–3 breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase III trial. Lancet Oncol 21:1602-1610, 2020.