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Dose-Dense and Sequential Strategies in Adjuvant Breast Cancer Therapy

Dose-Dense and Sequential Strategies in Adjuvant Breast Cancer Therapy

Several attempts have been made to improve the survival rates of breast cancer patients. The benefit of adjuvant chemotherapy was clearly shown, but the absolute difference of 2% to 11% in overall survival, depending on the patient group, is disappointingly small. In particular, high-risk patients, such as those with ³ 10 involved lymph nodes, extracapsular spread, or vascular invasion, still have an excessive risk of recurrence even after standard adjuvant chemotherapy. To increase the survival rates after adjuvant therapy, new chemotherapeutic agents and new strategies of application are currently being evaluated in clinical trials. Chemotherapy with cyclophosphamide (Cytoxan, Neosar), methotrexate, and fluorouracil (CMF) seems to be safe and effective in patients with breast cancer. In addition, in metastatic patients, dose-intensified chemotherapy is being investigated. The introduction of epirubicin (Ellence), an agent less cardiotoxic and equally active compared to doxorubicin, enabled the escalation of anthracyclines in adjuvant therapy without serious cardiotoxic effects. The combination of dose-intensified chemotherapy and sequential application in the treatment of breast cancer is reviewed. [ONCOLOGY 15(Suppl 7):14-20, 2001]


Data from the meta-analysis of the Early Breast Cancer Trialists’ Collaborative Group regarding adjuvant chemotherapy clearly showed the benefit of adjuvant chemotherapy.[1] The absolute difference in overall survival (OS) of 2% to 11%, depending on the patient group, is, however, disappointingly small. In particular, high-risk patients, for example patients with ³ 10 involved lymph nodes, extracapsular spread, or vascular invasion, still have an excessive risk of recurrence even after standard adjuvant chemotherapy. To increase the survival rates after adjuvant therapy, new chemotherapeutic agents and new strategies of application are being evaluated in clinical trials.

From CMF to Anthracyclines

Chemotherapy with cyclophosphamide (Cytoxan, Neosar), methotrexate, and fluorouracil (CMF), as shown by Bonadonna et al, produces the greatest benefit in patients with one to three involved lymph nodes, but is of limited efficacy in patients with four or more involved lymph nodes.[2] Overall survival rates with CMF in this study were 38% after 20 years for patients with one to three positive lymph nodes and 24% for untreated patients with one to three positive lymph nodes. CMF-treated patients with more than three positive lymph nodes had virtually the same survival rate as controls (24% vs 23%).

Even anthracycline-containing regimens in standard dose are of limited efficacy in high-risk patients with 10 or more involved lymph nodes.[3] In an Italian study, for example, 10-year follow-up data showed that sequential treatment with four cycles of doxorubicin 75 mg/m2 every 3 weeks followed by eight cycles of CMF was superior to alternating treatment with doxorubicin and CMF at the same total drug doses. However, overall survival in patients with 10 or more lymph nodes was the same regardless of whether patients had received sequential or alternating treatment.

Because even CMF is associated with a significant rate of severe adverse events, it is highly questionable whether one should advise patients to undergo such treatments when no major success can be expected. The duration of treatment is approximately 6 months, and the increase in survival time or disease-free survival (DFS) should be substantially longer to justify the increased side effects.

New Strategies Suggested

To address these shortcomings, several strategies have been suggested and partially evaluated in clinical trials. The use of high-dose chemotherapy with bone marrow transplantation (BMT) or peripheral blood progenitor cell (PBPC) support remains controversial due to the small number of prospective, randomized trials comparing it with standard therapy. Gianni et al,[4] who assessed high-dose chemotherapy in patients with 10 to 20 positive lymph nodes, found a 20% improvement in DFS after 5 years when compared with a historical patient group treated with CMF.

Although some promising results were presented at the American Society of Clinical Oncology (ASCO) meeting in 1999, an external audit of this trial could not verify these results.[5, 5a]. High-dose therapy with PBPC support for high-risk breast cancer cannot be recommended at present. The rate of serious adverse events, including fatalities, is still enormous. Depending on the toxicity of the regimen, treatment-related death rates can be as high as 5%.[6] The risks of secondary malignancies and treatment-related concurrent diseases, as well as the effects of such treatments on the immune system, remain uncertain.

A similar, but less radical, strategy is the intensification of standard chemotherapy. This can be achieved by several means.[7] The limiting factor for all attempts at dose intensification is toxicity, mainly hematotoxicity. Higher doses lead to lower granulocyte nadirs and a higher incidence of febrile neutropenia. Shortening of cycle intervals is limited by the recovery of blood counts. The introduction of hematopoietic growth factors, such as recombinant granulocytecolony stimulating factor (r-metHuG-CSF) and erythropoietin, has helped to overcome some of the limitations. Dhingra et al and others showed that by using r-metHuG-CSF, the intended dose could be achieved more easily.[8]

Dose Intensification

Several chemotherapeutic agents have shown a relevant in vitro dose-response relationship. In patients with metastatic disease, dose-intensified chemotherapy could achieve higher remission rates.[9,10] According to a retrospective analysis of 901 patients done by Bonadonna and Valagussa, only those who received at least 85% of the planned CMF dose benefited from adjuvant chemotherapy. Patients who received less than 65% of the planned dose had DFS and OS similar to that in the untreated control group.[11]

Several prospective, randomized studies of dose-intensified chemotherapy have been published. Three trials evaluated dose-intensified anthracyclines (doxorubicin, epirubicin [Ellence]).[12-14] The French Adjuvant Study Group compared the combination of fluorouracil (5-FU), epirubicin, cyclophosphamide (FEC) (500/50/500 mg/m2 q3wk) with an epirubicin-intensified FEC (500/100/500 mg/m2 q3wk) regimen in high-risk breast cancer patients. The findings of this study suggested that dose escalation of epirubicin without use of granulocytecolony stimulating factor (G-CSF) generates a significant improvement in OS and DFS.[12]

The National Cancer Institute of Canada Clinical Trials Group was the first to show a significant improvement in DFS and OS in premenopausal patients with involved axillary lymph nodes. This study compared dose-intensified CEF (75 mg/m2 po days 1-14, 60/500 mg/m2 days 1+8, q4wk × 6) with a standard CMF (100 mg/m2 po days 1-14, 40/600 mg/m2 days 1+8, q4wk × 6) therapy.[13] Keeping in mind that National Surgical Adjuvant Breast and Bowel Project (NSABP)-15 showed that equitoxic doses of Adriamycin (doxorubicin)/cyclophosphamide (AC) and CMF were equally effective as adjuvant therapy for node-positive breast cancer patients, the superior efficacy seen in this trial could likely be based on the use of dose-intensified epirubicin.[14] Alternative hypotheses involve the presence of fluorouracil in the FEC regimen, compared to AC/EC, and the administration of six cycles for FEC, compared to four cycles for AC/EC.

Another clinical trial that has demonstrated a significant benefit in OS and DFS for a dose-intensified anthracycline-containing regimen was the Cancer and Leukemia Group B (CALGB) 8541 protocol. In this study, DFS was 75% after 3 years in patients receiving FEC (600/60/600 mg/m2 q4wk × 4) while it was 65% in patients receiving FEC (400/40/400 mg/m2 q4wk × 6). Dose-related differences in outcome were observed exclusively in the HER2-positive population. The total dose was identical in both treatment groups while the dose intensity was higher in the first group. In a third group, patients received half the total dose of the two other groups at half the dose intensity of the first group, and they had the worst outcome.[15]

Sequential Therapy

Another promising treatment strategy for breast cancer is the sequential application of chemotherapeutic agents. In 1995, Bonadonna published results of a trial demonstrating the superior effects of sequential vs alternating application at the same total drug doses. In this study, sequential administration of doxorubicin followed by CMF proved significantly beneficial compared with alternating doxorubicin/CMF therapy. In the sequential arm, 10-year DFS was 42% and 10-year OS was 58%, while in the alternating arm, the respective rates for DFS and OS were 28% and 44%.[3]

In addition to its positive effects on survival, sequential therapy seems to have an advantage in terms of overlapping toxicities often experienced by patients receiving combination chemotherapy regimens. Thus, sequential administration allows for dose escalation of non-cross-resistant agents to an optimal dose.

To evaluate dose-intensified doxorubicin (Adriamycin) (A) with sequential paclitaxel (Taxol) (T) as adjuvant therapy, CALGB trial 9344 was initiated in 1994. This large study compared three different dose intensities of an AC regimen, containing 60, 75, or 90 mg/m2 doxorubicin, given every 3 weeks. To evaluate the additional benefit of paclitaxel, patients were randomized a second time (Figure 1). The outcome of this study showed no difference in the AC regimens based on doxorubicin dose intensity, whereas the addition of sequential paclitaxel significantly reduced the relative risk of disease recurrence (22%) and death (26%).[16]


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