No Survival Benefit for Early Locoregional Therapy in De Novo Stage IV Breast Cancer

September 2020 Vol 11, No 9


Breast Cancer

Early locoregional therapy (with surgery and radiation) does not improve overall survival in women with newly diagnosed stage IV breast cancer and an intact primary tumor compared with systemic therapy alone, according to results of the ECOG-ACRIN E2108 randomized phase 3 trial presented at the Plenary Session of the ASCO20 Virtual Scientific Program.

At a median follow-up of 59 months, there was no significant difference in overall survival between optimal systemic therapy plus locoregional therapy versus optimal systemic therapy alone: 68.4% versus 67.9%, respectively. The group treated with locoregional therapy did not have a benefit in 3-year progression-free survival either. However, locoregional recurrence or progression was significantly lower in the group randomized to locoregional therapy: 25.6% for systemic therapy alone versus 10.2% for systemic therapy plus locoregional therapy, respectively (P = .003).

“Women who present with a new diagnosis of breast cancer already in stage IV should not be offered surgery and radiation for the primary breast tumor with the expectation of a survival benefit. When combined with the results of an earlier trial in Mumbai, India, these results tip the scales against the possibility that local therapy to the breast tumor will help women live longer,” said lead author Seema Khan, MD, Bluhm Family Professor of Cancer Research at Northwestern University Feinberg School of Medicine. “The Indian trial had a similar design to E2108 and showed similar results between the 2 treatment groups.”

Previous studies have shown inconsistent results regarding the survival benefit of locoregional therapy in de novo stage IV breast cancer, and there is a lack of consensus on this issue. A meta-analysis of more than 15 studies found an estimated 30% reduction in risk with the addition of surgery and radiotherapy, “but these studies had younger, healthier women with smaller tumors and a lower metastatic burden,” Dr Khan said.

Over the past several years, 2 randomized trials showed no survival advantage (study at Tata Memorial Hospital, Mumbai, India) and an overall survival advantage of 17% (Turkish study) with locoregional therapy. The present study, E2108, was conducted to resolve conflicting findings, she explained.

Study Description

E2108 enrolled 390 women with de novo stage IV breast cancer. About 50% had hormone receptor–positive/HER2-negative disease; 29% had HER2-positive disease; and 10% had triple-negative disease. One-third had metastases confined to the bone; 26% to the viscera; and 27% had both.

All women enrolled in the trial received systemic therapy optimized according to disease characteristics. The most frequently used systemic therapy included chemotherapy plus anti-HER2 agents. Of the 390 women enrolled, 256 did not have progression of distant disease after 4 to 8 months of therapy; these women were randomized to continued systemic therapy alone (n = 131) or early local therapy plus systemic therapy (n = 125). Follow-up was continued for 5 years.

At a median follow-up of 53 months, median overall survival was 54 months in both arms. No difference in survival was observed between the 2 treatment arms for hormone receptor–positive/HER2-negative patients or HER2-positive patients. However, patients with triple- negative disease had worse survival with early locoregional treatment.

On the positive side, locoregional treatment prevented locoregional recurrences.

Health-Related Quality of Life

On the FACT-B Trial Outcome Index, patients treated with locoregional therapy had significantly worse quality of life at 18 months after randomization.

“The quality-of-life results were a little surprising since one of the reasons for considering surgery and radiation is the idea that the growth of the tumor will impair quality of life. Instead, we find that the adverse effects of surgery and radiation appear to balance out the gains in quality of life that were achieved with better control of the primary tumor,” Dr Khan said.

Dr Khan said there is a role for locoregional therapy “in stage IV patients whose systemic disease is well controlled with systemic therapy, but the primary site is progressing.”

Balanced View

Taking into consideration the E2108 trial and the 3 other trials mentioned by Dr Khan, discussant of this trial Julia R. White, MD, professor of radiation oncology at The Ohio State University, Columbus, made the following recommendation:

“Based on these 4 trials, should patients with primary intact tumors always have primary surgery for de novo metastatic breast cancer? Clearly the answer is no. None of the trials met the primary end point of improving survival.

“Should this approach be used sometimes? Based on these trials, the answer is yes. Up to 20% of patients will have locoregional symptoms or progression that will need a surgical approach for palliation.”

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