Introduction
Metastatic breast cancer is considered an incurable disease, with a median overall survival of 18 to 24 months and a 5-year survival ranging from 3% to 12%. Even if chemotherapy can induce high response rates, its main objective is symptom palliation. However, patients who achieve a complete response to first-line chemotherapy can become long-term survivors. Of the many cytotoxic drugs tested in metastatic breast cancer, anthracyclines have shown superior activity. For this reason, anthracycline-based regimens are considered the standard of care.[1]
Both FAC (fluorouracil [5-FU]/doxorubicin [Adriamycin]/cyclophosphamide [Cytoxan, Neosar]) and CEF (cyclophosphamide/fluorouracil/epirubicin [Ellence]), the commonly used anthracycline-based regimens, produce response rates of 50% to 60%. However, only 10% to 20% of patients achieve a complete response. Interestingly, among complete response patients, 18% remain disease-free for more than 5 years, and 10% are alive for more than 20 years.[2,3] Therefore, the availability of new active agents and new combinations might improve the outcome of patients with metastatic breast cancer.
The possible strategies to introduce a new agent are either the development of new combination regimens or the sequential administration of active agents at full doses. The latter approach is based on a theoretical model predicting that tumor-cell killing is maximized with the sequential administration of non-cross-resistant drugs. The feasibility of this method has been proven in high-risk, early breast cancer; the concept of dose-dense sequential treatment is being tested in metastatic breast cancer patients. An ongoing study of our cooperative group, Gruppo Oncologico Nord Ovest (GONO), compares eight courses of epirubicin(Drug information on epirubicin) given in combination with paclitaxel(Drug information on paclitaxel) (Taxol) with four doses of epirubicin followed by four doses of paclitaxel.
Anthracycline/Taxane Trials
Clearly, if combination regimens can be administered with individual drugs given at optimal dose, the complete response rate may increase, and hopefully, more long-term survivors will be observed. Thus, based on high activity and incomplete cross resistance, several trials have evaluated the feasibility and toxicity of anthracyclines combined with taxanes. The results from nonrandomized phase II trials have shown that this association is very active; overall response rates range from 75% to 95%, with complete response rates as high as 40%.[4-6]
In particular, the combination epirubicin and paclitaxel (Taxol) (ET) can be administered at optimal doses with a response rate of 84%, which includes a 19% complete response rate.[7] We have also shown that pharmacokinetic interactions between epirubicin and paclitaxel could account for the activity and toxicity of this association.[8]
Phase III Trials
These results have been partially confirmed by recently reported phase III randomized studies. A large, randomized Eastern Cooperative Oncology Group trial has shown that, in terms of activity and time to disease progression without any survival advantage, the combination of doxorubicin(Drug information on doxorubicin) (Adriamycin) plus paclitaxel (Taxol) (AT) administered over 24 hours is significantly superior to doxorubicin or paclitaxel given as single agents.[9]
A French Canadian study (TAX 306) comparing AC (doxorubicin [Adriamycin]/cyclophosphamide) vs AD (doxorubicin/docetaxel [Taxotere]) showed a significant increase in overall response rate and progression-free survival for the AD arm.[10] These data have been recently confirmed by an Eastern European trial where patients were randomized to receive either FAC or AT, showing a significant increase in both overall and progression-free survival for the AT arm.[11]
Finally, a German trial of ET vs EC (epirubicin/cyclophosphamide) reported a slight increase in time to progression in favor of ET with no difference in overall response rates.[12] A European Organization for Research and Treatment of Cancer (EORTC) trial of AT vs AC showed no difference in overall response rates and progression-free survival.[13]
Unfortunately, the complete response rates in all these trials were lower than expected. There are some possible reasons why the anthracycline/taxane combinations have shown only a slight superiority over the anthracycline/alkylator combinations. First, it may be due to negative pharmacokinetic interactions between doxorubicin and paclitaxel. A second possibility is the administration of suboptimal doses (in particular in the EORTC trial) with more dose reductions in the anthracycline/taxane arms. Or it could be the use of taxanes as salvage treatment in control arms.
Conclusions
We can conclude from these trials that (1) the pharmacokinetic interferences of epirubicin/paclitaxel combinations produce less pharmacodynamic effect than doxorubicin/paclitaxel regimens, (2) paclitaxel is more easily combined when infused over 3 hours, and (3) administration of optimal doses of both agents is important.
The GET Trials
Based on these premises, we were interested in verifying whether it was possible to increase the activity of the ET combination by adding a third active drug. Gemcitabine(Drug information on gemcitabine) (Gemzar) seemed to be the ideal candidate because of its low myelotoxicity, tolerability profile, new mechanism of action, and interesting single-agent activity.[14]
Data from phase II studies have shown that single-agent gemcitabine produces an objective response rate of up to 25% to 46% in metastatic breast cancer patients.[15,16] Moreover, gemcitabine has a mild toxicity profile with a low incidence of myelotoxicity and nonhematologic toxicity. When administered in association with taxanes in pretreated metastatic breast cancer patients, gemcitabine has shown an overall response rate ranging from 41% to 51%.[17,18]
Study Design and Dosing
We, therefore, performed a phase II study with the combination of gemcitabine, epirubicin, and paclitaxel (Taxol) (GET) as first-line chemotherapy in advanced breast cancer. The study was designed to evaluate the feasibility and activity of this regimen and to study the pharmacokinetic interactions of these three drugs.
Metastatic breast cancer patients with bidimensionally measurable disease were eligible to receive gemcitabine at 1,000 mg/m2 on days 1 and 4, plus epirubicin at 90 mg/m2 on day 1, plus paclitaxel at 175 mg/m2/d every 21 days. After six courses of GET, patients less than 60 years old and in complete or partial remission were treated with high-dose chemotherapy as consolidation treatment.
Study Results
The study enrolled 36 patients. Grade 4 neutropenia was observed in 64% of patients, with four episodes of febrile neutropenia. Other hematologic toxicities were mild; grade 3/4 anemia and thrombocytopenia occurred in 10% of the courses. Mild to moderate peripheral neuropathy was experienced by 36% of patients; grade 2 or 3 mucositis occurred in 25% and 17%, respectively.
After six courses of GET, the overall response rate was 92% (95% confidence interval: 77.53% to 98.25%), with a 31% complete response rate. Of the 36 patients, 25 received high-dose chemotherapy, achieving a final overall response rate of 97%, with a 47% complete response rate. At a median follow-up of 25 months (range: 8 to 39 months), median progression-free survival is 21 months, while median overall survival has not yet been reached.[19]
The pharmacokinetic data show that gemcitabine does not influence the interactions between epirubicin and paclitaxel, while gemcitabine kinetics remain unchanged. Moreover, the GET regimen can efficiently mobilize the peripheral blood progenitor cells and might be considered as an induction treatment before high-dose chemotherapy.[20]
Multicenter GET Trial
On the basis of these results and to confirm the feasibility of the GET regimen, a multicenter trial has been started in seven Italian centers. The study has completed the planned accrual of 47 patients; preliminary results are available for 36 patients. A total of 69% of patients had previously received adjuvant chemotherapy; 17% had received chemotherapy with anthracyclines.
Predominant metastatic sites were viscera (86%) and soft tissue (14%); 21% of patients had one metastatic site, 52% two metastatic sites, and 27% three or more metastatic sites. Grade 3/4 neutropenia occurred in 59% of cycles with four episodes of febrile neutropenia, while grade 3/4 anemia and thrombocytopenia were mild (2% and 7% of cycles, respectively). Grade 3/4 mucositis occurred in 8% of cycles, while a grade 2 cutaneous toxicity was observed in 20% of cycles. The toxicities observed in the multicenter study are similar to those reported in our institution. Final data on response rates will be available soon.
Future Developments
Based on the results of these phase II studies, an international trial will compare GET with ET in patients with metastatic breast cancer. More than 600 patients will be randomized, and the primary focus of the study will be survival. This large trial will clarify if the combined administration of the most active agents up front can improve the outcome of advanced breast cancer.
It is, however, clear that the GET regimen might produce the best results in potentially curable patients. A prospective, randomized trial will include more than 1,000 high-risk, early breast cancer patients to be randomized to GET or to anthracycline/cyclophosphamide and paclitaxel.
Finally, to better define the activity and biologic effects of this combination, we have started a phase II study with primary chemotherapy in operable breast cancer. Patients with large primary tumors (> 3 cm) will be surgically biopsied, treated with four courses of GET, and then submitted to definitive surgery. The biologic profile of the tumor will be assessed before and after chemotherapy by evaluating parameters of proliferation (MIB 1, S phase, cyclines A and D1), apoptosis (bcl2, P53, and apoptotic index), neoangiogenesis (VEGF receptor, vessel count), and c-erb B2 as a prognostic factor.
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