Adjuvant chemotherapy for breast cancer represents the triumph of clinical trials and the scientific method over preconceived notions, assumptions, and anecdotes. Precisely because its impact is too modest and its toxicities variably onerous, clinicians and investigators needed many years, numerous studies, and thousands of patients to be convinced of the certainty of its benefits. Now we can say definitively that adjuvant chemotherapy represents a critically important component of care for many patients with nonmetastatic invasive breast cancer.
In this issue of Oncology, Drs. McCarthy and Swain provide a focused and balanced view of the current controversies surrounding the use of adjuvant chemotherapy, as well as the directions in which ongoing research is taking us. Appropriately, they rely on the Oxford overview analysis to provide a foundation for their discussion, followed by detailed portraits of high-dose therapy, the taxanes, and newer modalities, such as immunotherapy. Importantly, they highlight the need for useful predictive factors, while also providing a balanced view of the complex, controversial role that HER2 may play in this regard.
It is clear that a major reason for the large impact seen with tamoxifen(Drug information on tamoxifen) (Nolvadex) stems from our ability to eliminate from consideration those patients who have virtually no chance of response. Therefore, a predictive test for specific chemotherapy agents would also likely produce the same effect and might significantly change our view of the effectiveness of conventional drugs and regimens. Unfortunately, no such test now exists, and so for now, we must continue to apply chemotherapy broadly and consistently to achieve maximal benefits.
Success of the Meta-analysis
The meta-analysis has become one of the most important undertakings in our study of the treatment of patients with early-stage breast cancer, and its worth grows stronger with the passage of time. Readers should be aware that the Early Breast Cancer Trialists Collaborative Group meets every 5 years, with the next cycle of review planned for September 2000. Hence, it is possible that the coming year will see some revision and fine-tuning of the numbers and results reported in this issue of Oncology.
However, the strength of the collaborative groups overview is, in part, its reliance on multiple trials and prolonged follow-up, thereby ensuring results that are unlikely to dramatically change over time. Indeed, the need to confirm the stability of the results of included trials means that many of our most important recent trials will not be assessed, even at this years meeting.
Drs. McCarthy and Swain accurately report that despite the overview, evolution and controversy continue to exist in clinical research with the use of chemotherapy for early-stage breast cancer. Examples include the use of anthracyclines, taxanes, and high-dose therapy, as well as their use in specific patient subsets.
Questions of Higher Dosing
As is well detailed in the article, neither cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) nor doxorubicin(Drug information on doxorubicin) has been shown to be more effective at moderately higher doses in patients with node-positive disease. This disappointment arrived just as we learned the first results of randomized studies of high-dose chemotherapy, which similarly did not show major differences.
As highlighted by the authors, it is clearly too soon to say whether or not high-dose therapy is effective, and it is important to note that the absolute benefits of chemotherapy are generally very modest and only affirmed through very large trials or in the overview (as described above).
Hence, the relatively small trials that are testing high-dose chemotherapy with autologous stem-cell support could miss an effect that is statistically modest, yet clinically relevant. This possibility, coupled with the provocative results reported by Rodenhuis at this years American Society of Clinical Oncology conference, should motivate clinicians to support the current Southwest Oncology Groupled intergroup trial, which is testing high-dose and dose-dense therapies for women with four or more positive nodes.
Promise of the Taxanes
The taxanesthe most important chemotherapeutic drugs for breast cancer to be introduced to the clinic in over a decadehold great promise in the adjuvant setting. Exciting results of the Cancer and Leukemia Group B (CALGB) study 9344, which tested paclitaxel(Drug information on paclitaxel) (Taxol) following AC (Adriamycin [doxorubicin], cyclophosphamide), are placed in proper perspective in this article. In addition, many relevant ongoing or completed studies are also well described.
It is worth emphasizing, however, that even as we await confirmation of the CALGB studys results, its size and power were such that a large number of subsequent studies are already using AC followed by paclitaxel as a standard arm. For example, this regimen is now being used to determine the impact of scheduling changes (weekly dose-dense therapy), the addition of trastuzumab(Drug information on trastuzumab) (Herceptin), the substitution of docetaxel (Taxotere), and the value of utilizing epirubicin(Drug information on epirubicin) (Ellence) in place of doxorubicin. Moreover, in viewing these new studies in the context of the Oxford overview, the reader should note the tremendous increase in study size, and, at the same time, the remarkable shortening of accrual durations for contemporary trials.
For example, the first two randomized efficacy studies of paclitaxel as adjuvant therapy (CALGB study 9344 and the National Adjuvant Breast and Bowel Project study B-28) both accrued patients for 3 to 4 years, enrolling over 6,000 patients. These two studies are more homogeneous in design, patient mix, and enrollment period than almost any of the older trials using CMF (cyclophosphamide, methotrexate(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil))type regimens included in the overview. Most impressively, these two trials contain about as many patients as those in the nearly dozen trials that were assembled for the overview addressing the role of anthracyclines.
If the apparent trend toward bigger, faster adjuvant chemotherapy trials continues, we can anticipate even more meaningful overview analyses in the years to come. For this, we should be grateful, as it will allow a more expedient improvement in patient care.
Finally, if we follow the lead suggested by Drs. McCarthy and Swain, we will be able to accomplish this not only through increasingly larger studies, but also through the use of more targeted treatments. Whether this means new drugs, more focused use of drugs already at our disposal, or both, remains to be seen.