SURGERY AND RADIOTHERAPY
Scientific understanding of the biology of breast cancer has changed radically in the past 50 years. Results of large randomised trials have played a major role in this transition. From the nineteenth century and up into the 1970s, breast cancer was understood to be a local/regional disease that spread by direct extension along lymphatic pathways to distant sites. This concept gave rise to the surgical methods promoted by W.S. Halsted14-16 around the turn of the twentieth century, i.e., extensive resection of the breast, regional lymphatics, lymph nodes and muscle. This surgical technique, known as radical mastectomy, remained the principal approach to treatment of breast cancer throughout the first half of the century, sometimes combined with radiotherapy.
When the concept of large-scale randomised clinical trials to investigate alternative therapies was proposed in the 1960s, controversy arose among breast cancer researchers as well as in other medical fields. In a heated exchange, a prominent breast cancer surgeon denounced such studies as 'a great leap backward in the treatment of breast cancer'.17 Despite such opposition, pioneers in the field persisted in designing trials to address important therapeutic questions of the time, and moreover, were able to persuade patients to participate in this novel idea of assigning treatment by randomisation. These early trials compared various surgical and radiotherapy approaches. In a trial of almost 1700 women implemented in 1971, there were no significant survival differences between conventional radical mastectomy, total mastectomy with radiation, and total mastectomy with removal of axillary nodes.1819 Results of this and other trials of the era challenged long-held views of the disease and gradually convinced researchers that their concept of breast cancer as a local disease which could best be treated by radical local treatment techniques was incorrect. Rather, breast cancer came to be understood as a systemic disease that could benefit from systemic therapy, and radical local therapies were no longer regarded as essential for prolonging survival.
Cytotoxic agents for treatment of solid tumours were first developed in the 1950s. Breast cancer proved to be highly sensitive to several of these, when used as single agents in small trials. Subsequently, combinations of these cytotoxic agents were evaluated, one of the earliest being the Cooper regimen (cyclophosphamide, methotrex-ate, 5-fluorouracil, vincristine and prednisone).20 With the understanding of breast cancer as a systemic disease and the proven sensitivity of breast cancer cells to cytotoxic agents, the stage was set for the rapid development of adjuvant chemotherapy once this concept was introduced in the
1970s. A randomised trial comparing surgery followed by combination chemotherapy to surgery alone demonstrated that disease recurrence could be significantly reduced using this adjuvant therapy approach.21
The introduction of doxorubicin for treatment of breast cancer is illustrative of the series of clinical trials typically undertaken for the development of new agents. Small trials conducted in solid tumours in the early 1970s established safety and dosing, and these were quickly followed by Phase II trials of the agent in metastatic breast cancer. Subsequently, doxorubicin was evaluated in combination with other agents, and randomised trials established that higher response rates could be achieved in metastatic disease with combinations that included doxorubicin. These successes prompted the introduction of various doxorubicin and other anthracycline-containing combinations as adjuvant therapy for primary breast cancer. Known by such acronyms as 'FAC' = 'CAF', 'FEC', 'AC', these combinations continue to play a prominent role in the treatment of breast cancer.22 23 Anthracycline-containing therapies further reduce the risk of recurrence and favourably impact survival in early breast cancer.24
Hormonal therapy is a key component of therapy when tumours are hormone-receptor positive. Early trials focused on ovarian ablation by surgery or chemical means. The anti-oestrogen agent tamoxifen was introduced in the 1970s, at a time when there was high regard for the potential of cytotoxic agents, but little interest in hormonal therapies. Early small trials in metastatic breast cancer were equivocal and could have led to abandoning the agent. However, the weight of evidence from laboratory studies and several small trials pointed to superior efficacy with prolonged administration in ER positive disease. After a series of large randomised trials, tamoxifen is now regarded as standard therapy for pre- and post-menopausal women with ER positive tumours.25 Tamoxifen may be the single most important advance in treating breast cancer. Questions remain about the optimum treatment duration even though a trial conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) comparing 5 and 10 years of tamoxifen therapy concluded there was little or no advantage to longer therapy.26
HIGH-DOSE CHEMOTHERAPY WITH BONE MARROW TRANSPLANT OR STEM CELL SUPPORT
An unresolved question in therapy of breast cancer that has presented an unusual challenge for the conduct of clinical trials is that of highdose chemotherapy supported by autologous bone marrow transplant or peripheral blood progenitor cells. Ten trials addressing the question of highdose versus standard-dose chemotherapy have been reported. Two of these were subsequently discredited following an international investigation. Only two of the remaining eight trials entered more than 200 patients. Financial issues, patient and physician acceptance and competing treatment strategies have compromised accrual, and it is unclear if ongoing trials can be completed. The available evidence suggests that highdose therapy provides little or no benefit for patients regardless of their disease stage.27 28
Eight large randomised trials conducted since 1963 assessed the value of screening mam-mography for reducing breast cancer mortality. These are of particular interest for the scrutiny they have undergone in recent years. The preponderance of evidence from the randomised trials indicates a benefit associated with screening mammography.29-31 However, a meta-analysis concluded that six of the eight trials were seriously flawed and the remaining two trials showed insignificant breast-cancer mortality differences between the screened and non-screened groups.32 The National Cancer Institute recommends screening mammography every 1 to 2 years for women aged 40 and older, while recognising that there are risks associated with false-positive results.
Beginning in the 1990s, coinciding with the detection of methods for identifying women at high risk of breast cancer, the first large-scale trials were mounted to determine if the incidence of breast cancer could be reduced in targeted high-risk groups. These trials established that breast cancer incidence could be greatly reduced by daily doses of tamoxifen.33 34 This reduction was due entirely to a lower incidence of ER positive tumours with no change in the incidence of ER negative tumours. This suggests that prophylactic tamoxifen will not have as great an impact on survival as it does on incidence, although none of the prevention trials address survival as an endpoint. An ongoing trial (STAR: the Study of Tamoxifen and Raloxifene) will recruit 22 000 women at high risk of breast cancer in order to compare the effects of tamoxifen and another SERM, raloxifene, on the incidence of primary breast cancer.35
One of the largest cooperative groups conducting trials in breast cancer in the US is the NSABP. Trials from this group are often referred to by their 'B' numbers, e.g., B-06, which established the equivalence of lumpectomy to total mastectomy.36 Other major cooperative groups conducting clinical trials in breast cancer are the Eastern Cooperative Oncology Group (ECOG), Cancer and Leukemia Group B (CALGB), Southwest Oncology Group (SWOG), Breast Cancer International Research Group (BCIRG), European Organisation for Research and Treatment of Cancer (EORTC), North Central Cancer Treatment Group (NCCTG), and the National Cancer Institute of Canada (NCIC).
An important information resource regarding the benefits of treatment for early breast cancer is the Early Breast Cancer Trialists' Collaborative Group (EBCTCG). This group, based at
Oxford University, serves as a centre for data synthesis rather than actual conduct of clinical trials. Beginning in 1983, this group has collected data from virtually all major randomised trials conducted in early breast cancer, published or not. Data from more that 200 000 women have been analysed, using statistical techniques for meta-analysis, with results published at the end of each five-year analysis cycle, beginning in 1985. These publications have addressed the role of radiation, ovarian ablation, polychemotherapy, tamoxifen and quality of life; these 'overview' articles are frequently cited in support of treatment approaches.7'24'25'37-42 The weaknesses of meta-analysis have been widely discussed in the statistical literature, chief among these being the issue of heterogeneity among the trials being combined. For example, the overviewers combine various therapeutic regimens under the single rubric 'polychemotherapy'. However, these overview reports have allowed researchers to reliably assess moderate-size treatment effects which could not have been detected in individual trials. Treatments causing even moderate reductions in mortality, if implemented widely among women with breast cancer, could prevent or delay thousands of deaths due to the disease. The meta-analysis has also addressed questions of treatment efficacy within subsets, for example the confirmation of benefit of adjuvant tamoxifen in ER positive pre-menopausal women7 as well as in post-menopausal women.
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