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From the Division of Surgical Oncology, Virginia Commonwealth University Health System, Richmond, Virginia.
Correspondence: 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: 804-828-4808; E-mail: hbear{at}hsc.vcu.edu
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 agreement with the results presented by Petit et al., overall and disease-free survival in the two arms of B-18 were virtually identical.10 Do these results mean that the Goldie-Coldman hypothesis is incorrect? This is a possible but not necessarily valid conclusion. Instead, it may be that the time scale over which increasing numbers of drug-resistant tumor cells develop is much longer than is possible to examine with these relatively short-term shifts in treatment timing. In other words, starting chemotherapy 3 to 6 months earlier may simply not have any impact on a process that extends over several years. In fact, the Goldie-Coldman hypothesis may explain the relatively large impact that systemic treatment makes on patients with relatively small tumors with only a few positive lymph nodes, as well as the persistently high recurrence rates in women with very large tumors and/or many positive nodes, despite the addition of new drugs or high-dose chemotherapy. The latter groups, with tumors that have presumably been growing for a much longer period of time (measured in years) likely have a much larger fraction of chemoresistant cells on board than women with earlier stages of disease, if the Goldie-Coldman hypothesis is right.
So, if drug resistance develops over years of tumor growth, and therefore is unlikely to be overcome by giving chemotherapy "up front," which at most can be given a few months earlier than standard adjuvant treatment, is there any useful role for primary or neoadjuvant chemotherapy? Yes. Clearly, this approach has dramatically altered the outlook for women with inoperable breast cancer, and as the B-18 trial and other reports have shown, primary chemotherapy can also make breast-conservation therapy feasible in women whose tumors are initially too large for such treatment. Primary chemotherapy also has the advantage of permitting us to evaluate the response of the primary tumor during treatment, and this, in turn, appears to be a powerful predictor of overall survival.6,10,11 Thus, primary chemotherapy trials might permit us to compare treatment regimens more rapidly than would be possible in the adjuvant setting, where the only end points depend on long-term follow-up. An important caveat must be noted, however: no trial has yet to show that a change in treatment, which increases the response rate of the primary tumor will also improve long-term survival. Even if this proves not to be the case, primary chemotherapy may still be useful as a platform for testing the predictive value of biologic and molecular markers relative to chemotherapy responsiveness. Thus, primary chemotherapy will continue to have practical value for women with large cancers, as well as research value as a tool for dissecting tumor biology.
Received for publication February 28, 2003. Accepted for publication March 12, 2003.
REFERENCES
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  H. H. Q. Heng The Conflict Between Complex Systems and Reductionism JAMA, October 1, 2008; 300(13): 1580 - 1581. [Full Text] [PDF]
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