The Lynx Group

No Survival Benefit with Surgery and Radiation Added to Systemic Therapy in Patients with Newly Diagnosed Stage IV Breast Cancer

August 2020, Vol 11, Special Issue: Payers' Perspectives in Oncology

Early locoregional therapy with surgery and radiation does not improve overall survival (OS) in women with newly diagnosed stage IV breast cancer and an intact primary tumor compared with systemic therapy alone, according to the results of the randomized ECOG-ACRIN E2108 phase 3 clinical trial. The results were presented by lead investigator Seema A. Khan, MD, FACS, MPH, Co-Leader, Lynn Sage Comprehensive Breast Center, Northwestern Memorial Hospital, Chicago, IL, at the plenary session of the ASCO 2020 annual meeting.

At a median follow-up of 59 months, there was no significant difference in OS between patients who received optimal systemic therapy plus locoregional therapy and those who received optimal systemic therapy alone (68.4% vs 67.9%, respectively). The group that received treatment with locoregional therapy did not have a benefit in 3-year progression-free survival either. However, the rate of locoregional recurrence or progression was significantly lower in the group randomized to systemic therapy plus locoregional therapy (10.2%) than for the patients who received systemic therapy alone (25.6%; 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 Dr Khan. “The Indian trial had a similar design to E2108 and showed similar results between the 2 treatment groups.”

Previous studies have had 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 treatment’s benefit. A meta-analysis of more than 15 studies showed 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 OS advantage of 17% with locoregional therapy (Turkish study). The E2108 study was conducted to resolve these conflicting findings, she explained.

E2108 Study Details

The E2108 study enrolled 390 women with de novo stage IV breast cancer. Approximately 50% of the patients had hormone receptor (HR)-positive/HER2-negative disease, 29% had HER2-positive disease, and 10% had triple-negative disease. Approximately 33% of the women had metastases confined to the bone, 26% to the viscera, and 27% had both metastases.

All those enrolled in the study received systemic therapy that was optimized according to their disease characteristics. The most often 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 to early local therapy plus systemic therapy (N = 125). The follow-up was continued for 5 years.

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

On the positive side, locoregional treatment prevented cancer recurrences.

Quality of Life Not Improved

Based on the FACT-B Trial Outcome Index, patients who received 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.

She noted that 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.”

Weighing the Evidence

Taking into consideration the E2108 study and the 3 other clinical trials mentioned above, Julia R. White, MD, Breast Cancer Physician and Radiation Oncologist, the Ohio State University Comprehensive Cancer Center, Columbus, provided 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,” Dr White pointed out.

“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,” she recommended.

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