Chapter 66: Landmark Clinical Trials that Impacted Surgical Management of Invasive and Noninvasive Breast Cancer

INTRODUCTION

Over the last four decades, there has been a paradigm shift in the management of breast cancer as a result of several landmark clinical trials conducted in the United States and Europe that are responsible for the new standards of breast cancer care worldwide. Advances from these clinical trials transformed the treatment of breast cancer by advocating less radical surgery and introducing the use of innovative techniques in conjunction with other modalities including systemic chemotherapy, endocrine therapy, and radiotherapy (RT). This subsequently led to a multidisciplinary approach to breast cancer and is further leading to individualized treatment for each patient. This chapter provides a review of the significant landmark clinical trials that revolutionized the management and that currently guide the surgical practice of noninvasive and invasive breast cancer.

EARLY BREAST CANCER TRIALS

Before the 20th century, breast cancer was considered a fatal disease with no available treatment options. The Halstedian radical mastectomy—the en bloc radical resection of the breast, overlying skin, pectoralis muscles, and axillary lymph nodes—provided a major advance in the treatment of the disease.¹ This aggressive surgical intervention was based on Halsted’s theory that cancer initially spread from tumor growth within the breast to the pectoralis muscles and regional lymph nodes and was followed by metastasis to distant sites. Investigators at the National Surgical Adjuvant Breast and Bowel Project (NSABP) began to question the Halsted theory in the late 1960s, and in 1971 challenged it with the initiation of the B-04 protocol, one of the most well-known and instrumental trials that altered surgical practice. The NSABP B-04 was designed to determine whether patients with either clinically negative or clinically positive axillary nodes who received local or regional treatments other than radical mastectomy would have outcomes similar to those achieved with radical mastectomy.² A total of 1079 women with clinically negative axillary nodes underwent radical mastectomy, total mastectomy without axillary dissection but with postoperative RT, or total mastectomy plus axillary dissection only if their nodes became positive; 586 women with clinically positive axillary nodes underwent either radical mastectomy or total mastectomy without axillary dissection but with postoperative RT. Results showed that women with clinically negative nodes had a hazard ratio (HR) of 1.08 (95% confidence interval [CI], 0.91 to 1.28; P = 0.38) for death among those who underwent total mastectomy and RT compared to those who underwent radical mastectomy. In addition, the HR for death among those who underwent total mastectomy without radiation compared with those who underwent radical mastectomy was 1.03 (95% CI, 0.87 to 1.23; P = 0.72). In women with positive nodes, the HR for death among those who underwent total mastectomy and radiation compared to those who underwent radical mastectomy was 1.06 (95% CI, 0.89 to 1.27; P = 0.49).² Reports from the NSABP B-04 trial at 3, 5, and 10 years showed no statistically significant differences with respect to disease-free survival (DFS), distant disease-free survival ...