Earlier chemotherapy for breast cancer: perhaps too late but still useful.

Over the past three decades, our understanding of the biology of breast cancer and its treatment have changed dramatically, and it has become clear that systemic treatment is the critical component for improving survival in patients with this disease. With this realization, much effort has been expended on determining the optimal timing, duration, intensity, and composition of this systemic treatment. The Goldie-Coldman hypothesis suggests that the frequency of chemotherapy-resistant cancer cells increases over time.1 The corollary of this theory is that the earlier chemotherapy is initiated, the greater the impact will be on the disease. In fact, one of the earliest demonstrations of the worth of adjuvant chemotherapy came from a Swedish study in which half of the women were given a single dose of cyclophosphamide immediately after the completion of definitive breast cancer surgery.2 In this issue of the Annals of Surgical Oncology, Petit et al. report on a European multicenter, randomized prospective trial that was intended to address the hypothesis that earlier initiation of chemotherapy would improve survival compared with standard treatment.3 Among 552 patients receiving a variety of other treatments, half were randomly allocated to receive a single infusion of mitoxantrone immediately after excision of the tumor (i.e., perioperative chemotherapy). This trial was started in 1988, and because of slow accrual, was stopped short of the number of patients that were really needed for adequate statistical power. Nevertheless, the addition of perioperative chemotherapy in this trial did not significantly improve overall or disease-free survival. Unfortunately, despite a valiant effort, the design of this trial probably doomed it to reach this result from the beginning, for a number of reasons. First, since two thirds of the patients in this trial were postmenopausal and received no other chemotherapy, any benefit that might have been seen in these patients could have been the result of any chemotherapy versus none, rather than a reflection of early administration. Conversely, postmenopausal patients have generally benefitted least from chemotherapy, especially when added to tamoxifen, and a single dose of chemotherapy would be unlikely to overcome this relative lack of advantage. For the premenopausal women, more than two thirds of whom received full course chemotherapy (six cycles of a multidrug regimen including mitoxantrone), the single dose given perioperatively would be unlikely to add much impact. The “ultimate” in giving chemotherapy as early as possible is the use of primary or neoadjuvant chemotherapy before surgical intervention. Following on the successes of primary chemotherapy in the treatment of locally advanced inoperable breast cancer, a number of nonrandomized and randomized trials have tested the value of preoperative treatment for earlier stages of disease.4–7 Although a number of early trials (which were going on about the same time as this trial) purported to show an advantage to preoperative treatment for operable breast cancer, these trials were flawed by omission of any chemotherapy in a large fraction of the control arm patients.4,5 Furthermore, later follow-up of these trials did not substantiate the advantage in the preoperatively treated groups.8,9 Perhaps the “purest” test of the advantage of giving chemotherapy as early as possible was the National Surgical Adjuvant Breast and Bowel Project’s Protocol B-18, which randomized patients with operable breast cancer to four cycles of primary chemotherapy versus the same chemotherapy given postoperatively. In Received February 28, 2003; accepted March 12, 2003. From the Division of Surgical Oncology, Virginia Commonwealth University Health System, Richmond, Virginia. Address correspondence to: Harry D. Bear, MD, PhD, Division of Surgical Oncology, Virginia Commonwealth University Health System, P.O. Box 980011, Richmond, VA 23298-0011; Fax: 804-8284808; E-mail: hbear@hsc.vcu.edu.