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Dose-Dense and Sequential Strategies in Adjuvant Breast Cancer Therapy

Dose-Dense and Sequential Strategies in Adjuvant Breast Cancer Therapy

ABSTRACT: 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]

Introduction

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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