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Gemcitabine/Epirubicin/Paclitaxel Trials in Advanced Breast Cancer

Gemcitabine/Epirubicin/Paclitaxel Trials in Advanced Breast Cancer

ABSTRACT: Numerous trials have shown that the pharmacokinetic interferences of epirubicin (Ellence)/paclitaxel (Taxol) combinations produce less pharmacodynamic effect than doxorubicin/paclitaxel regimens. Paclitaxel is more easily combined when infused over 3 (as compared to 24) hours; the administration of optimal doses of both agents is important. Based on these findings, a phase II study was performed to evaluate the feasibility and activity of the combination of gemcitabine (Gemzar), epirubicin, and paclitaxel as first-line therapy in advanced breast cancer. Patients received 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 on day 1 every 21 days. After six courses, patients less than 60 years old and in complete or partial remission or stable disease were treated with high-dose chemotherapy as consolidation treatment. The overall response rate was 92%, with 31% complete responses; 25 patients received high-dose chemotherapy, achieving a final overall response rate of 97%, with 47% complete responses. At a median follow-up of 25 months, median progression-free survival is 21 months. Grade 4 neutropenia was observed in 64% of patients. Other hematologic toxicities were mild. Mild to moderate peripheral neuropathy was experienced by 39% of patients; grade 2 or 3 mucositis occurred in 25% and 17% of patients, respectively. Based on these results, a multicenter trial has been started in seven Italian centers to confirm the feasibility of this regimen. [ONCOLOGY 15(Suppl 3):41-43, 2001]

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 given in combination with 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 (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 (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.

References

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2. Falkson G, Holcroft C, Gelman RS, et al: Ten year follow-up study of premenopausal women with metastatic breast cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 13:1453-1458, 1995.

3. Rahman ZU, Frye DK, Smith TL, et al: Results and long term follow-up for 1,581 patients with metastatic breast carcinoma treated with standard dose doxorubicin containing chemotherapy. Cancer 85:104-111, 1999.

4. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in dose-finding and sequence finding study. J Clin Oncol 13:2688-2699, 1995.

5. Gehl J, Boesgard M, Paaske T, et al: Combined doxorubicin and paclitaxel in advanced breast cancer. Effective and cardiotoxic. Ann Oncol 7:687-693, 1996.

6. Valagussa P, Gianni L, Capri G, et al: Three-year follow-up in women with metastatic breast cancer after bolus doxorubicin and paclitaxel infused over 3 hours (abstract 429). Proc Am Soc Clin Oncol 17:111, 1998.

7. Conte PF, Baldini E, Gennari A, et al: Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over 3 hours: A regimen with high activity and low cardiotoxicity in advanced breast cancer. J Clin Oncol 15:2510-2517, 1997.

8. Danesi R, Conte PF, Del Tacca M, et al: Pharmacokinetic optimisation of treatment schedules for anthracyclines and paclitaxel in cancer patients. Clin Pharmacokinet 37:195-211, 1999.

9. Sledge GW, Neuberg D, Ingle J, et al: Phase III trial of doxorubicin vs Taxol vs doxorubicin plus Taxol as first line therapy for metastatic breast cancer: An intergroup trial. Proc Am Soc Clin Oncol 16:1a, 1997.

10. Nabholtz JM, Falkson G, Campos D, et al: A phase III trial comparing doxorubicin and docetaxel to doxorubicin and cyclophosphamide as first line chemotherapy for metastatic breast cancer. Proc Am Soc Clin Oncol 17:485, 1999.

11. Pluzanska A, Jassem J, Jelic S, et al: Randomized open label phase III multicenter trial comparing Taxol/doxorubicin versus 5-fluorouracil/doxorubicin and cyclophosphamide as first line treatment for patients with metastatic breast cancer (abstract 1260). Proc ECCO 10:S314, 1999.

12. Luck HJ, Thomssen C, Untch M, et al: Multicentric phase III study in first line treatment of advanced metastatic breast cancer, epirubicin/paclitaxel vs epirubicin/cyclophosphamide: A study of the AGO Breast Cancer Group. Proc Am Soc Clin Oncol 18:280, 2000.

13. Biganzoli L, Cufer T, Bruning P, et al: Doxorubicin/Taxol versus doxorubicin/cyclophosphamide as first line chemotherapy in metastatic breast cancer: A phase III study. Proc Am Soc Clin Oncol 18:282, 2000.

14. Aapro MS, Martin C, Hatty S: Gemcitabine—A safety review. Anticancer Drugs 9:191-201, 1998.

15. Carmichael J, Possinger K, Philip P, et al: Advanced breast cancer: A phase II trial with gemcitabine. J Clin Oncol 13:2731-2736, 1995.

16. Blackstein M, Vogel CL, Ambinder R, et al: Phase II study of gemcitabine in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 15:117, 1996.

17. Mavroudis D, Malamos N, Alexopulos A, et al: Salvage chemotherapy in anthracycline-pretreated metastatic breast cancer patients with docetaxel and gemcitabine: A multicentric phase II trial. Greek Breast Cooperative Group. Ann Oncol 10:211-215, 1999.

18. Rothenberg JL, Shaima A, Weiss GR, et al: Phase I trial of Taxol and gemcitabine administered every 2 weeks in patients with refractory solid tumor. Ann Oncol 9:733-738, 1999.

19. Conte PF, Gennari A, Donati S, et al: Gemcitabine plus epirubicin plus Taxol in advanced breast cancer patients: A phase II study with pharmacokinetic evaluation. (Submitted.)

20. Bengala C, Danesi R, Pazzagli I, et al: Sequential high-dose idarubicin (IDA) and alkylating agents with blood cell support following epirubicin-paclitaxel-gemcitabine combination in metastatic breast cancer: A phase I/II study with pharmacokinetic profile analysis (abstract 258). Proc Am Soc Clin Oncol 19:66a, 2000.

 
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