Update on Adjuvant Chemotherapy for Early Breast Cancer

Drs. McCarthy and Swain are to be congratulated for their update on adjuvant chemotherapy for early breast cancer. The review is very thorough and evidence-based. It provides an excellent blend of data, scientific rationale, and historical perspective. The data from randomized trials indicate that adjuvant chemotherapy decreases recurrence and improves survival in both pre- and postmenopausal women with operable breast cancer. We would like to comment on several points in the article that warrant further discussion.

Chemotherapy Plus Tamoxifen(Drug information on tamoxifen) in Premenopausal Women

In the most recent overview analysis by the Early Breast Cancer Trialists’ Collaborative Group,[1] women under 50 years old who received chemotherapy plus tamoxifen (Nolvadex) vs chemotherapy alone reported a 40% ± 19% reduction in recurrence and a 39% ± 22% reduction in mortality, compared to chemotherapy alone. The data are not reliable for this subgroup, however, because of the relatively small number of patients. Hence, although the results suggest that the addition of tamoxifen to chemotherapy may have improved results compared to chemotherapy alone in this subgroup, the results are in no way conclusive.

An ongoing, randomized trial conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) is now addressing this issue. In this study, premenopausal women with node-positive breast cancer who have completed adjuvant chemotherapy are being randomized to tamoxifen or placebo.

Duration of Chemotherapy

Six-month regimens of CMF (cyclophosphamide [Cytoxan, Neosar], methotrexate(Drug information on methotrexate), fluorouracil(Drug information on fluorouracil) [5-FU]) are as effective as longer (12- to 24-month) regimens of this combination. Four cycles of intravenous AC (Adriamycin [doxorubicin], cyclophosphamide(Drug information on cyclophosphamide)) are equivalent to six cycles of oral CMF. That said, how short can the CMF regimen be? Based on two clinical trials—one conducted by the Ontario Clinical Oncology Group[2] and the other by the International Breast Cancer Study Group[4]—three cycles of CMF are likely to be insufficient treatment, and therefore, six cycles of CMF should be administered.

Anthracycline vs CMF Chemotherapy

In the collaborative group’s overview analysis, anthracycline-containing regimens were associated with a modest, but statistically significant, reduction in recurrence and mortality, compared to CMF-type regimens. It is worth noting that the anthracycline-containing regimens were rather heterogeneous in composition. This raises the issue of whether a meta-analysis is even appropriate in this situation.

The Southeastern Cancer Study Group and the International Collaborative Cancer Group trials failed to detect a difference between the anthracycline-containing regimen and CMF. The NCIC CTG and intergroup trials detected a statistically significant improvement of the anthracycline-containing regimen over CMF. More recently, a study by Mourisden in women with node-positive and node-negative breast cancer demonstrated a statistically significant improvement of FEC (5-FU, epirubicin(Drug information on epirubicin) [Ellence], cyclophosphamide) vs CMF.[4] Thus, in three large, well-conducted trials—two with epirubicin and one with doxorubicin(Drug information on doxorubicin)—the anthracycline-based regimen was superior to CMF.

Dose Intensity

Escalation of the cyclophosphamide dose in the AC regimen apparently does not improve outcome. Data from Cancer and Leukemia Group B (CALGB) trial 8541, which compared three different dose intensities of CAF (cyclophosphamide, Adriamycin, 5-FU), suggest that there is likely to be a threshold dose of doxorubicin below which treatment becomes ineffective. The results of CALGB trial 9344 suggest that increasing the dose of doxorubicin in AC chemotherapy does not improve outcome. Results from the NCIC CTG trial of CEF (cyclophosphamide, epirubicin, fluorouracil) vs CMF, combined with the results of a recent French trial of FEC₁₀₀ vs FEC₅₀, suggest a dose-response relationship for epirubicin.[5]

However, the ultimate proof of principle for dose intensity is the administration of high-dose chemotherapy with stem-cell support. To date, results of randomized trials evaluating such therapy have been disappointing.

Toxicities

Drs. McCarthy and Swain appropriately identify concerns about the potential interaction between chest wall or breast irradiation and anthracycline, with respect to long-term cardiac effects. However, the role of adjuvant radiation in systemic therapy is an important consideration, given the results of three recently published randomized trials. These studies demonstrated improvement in disease-free and overall survival when locoregional radiation was added following mastectomy in patients treated with systemic therapy.[6]

Several trials have been initiated to assess the role of radiation therapy in patients treated with modern systemic therapy. The Southwest Oncology Group is comparing locoregional radiation to no radiation therapy in women with one to three positive nodes after mastectomy. The NCIC CTG is examining the addition of regional radiation to breast irradiation in patients with node-positive breast cancer who have undergone lumpectomy.

Predicting Response to Chemotherapy

Several retrospective reports suggest that the overexpression of HER2 (or c-erbB-2), is a predictor of sensitivity to doxorubicin. Drs. McCarthy and Swain state, “The available data suggest that patients with HER2-positive tumors requiring adjuvant chemotherapy should be considered for a doxorubicin-based regimen.” However, what about the other side of the coin? Should a patient who does not overexpress HER2 be offered anthracycline-based chemotherapy?

Unfortunately, some practitioners routinely tailor chemotherapy regimens to the presence or absence of this oncogene’s overexpression. Patients who do not overexpress HER2 are being offered only CMF. Until further prospective data are available, this approach would seem premature.[7]

Recommendations

While the results of clinical trials have demonstrated a benefit associated with chemotherapy, the magnitude of such benefits may be considered modest for some patient subgroups. Patients with node-negative breast cancer with tumors that are < 1 cm, estrogen-receptor positive, and well-differentiated, have a very low risk of recurrence. Tamoxifen can be associated with significant morbidity, including endometrial cancer and thromboembolic disease. Therefore, no systemic therapy is a reasonable option in this patient subgroup.

Clinical trial results indicate that women with estrogen-receptor–positive tumors gain an increased benefit from taking chemotherapy in addition to tamoxifen. However, it is important that the underlying risk of recurrence be considered, particularly for the node-negative patient. The potential increase in morbidity must be weighed against the incremental benefit associated with chemotherapy. In addition, the increased risk of thromboembolism, particularly in the postmenopausal woman, should be kept in mind.

Conclusions

The choice of chemotherapy regimen did not appear among the authors’ recommendations. Reasonable treatment regimens are those using CMF, AC, AC followed by paclitaxel(Drug information on paclitaxel) (Taxol), or CEF. Personal preference and quality of life influence the choice of chemotherapy regimen. Methods to improve communication and patient involvement in treatment decision-making have been developed.[8,9]