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New Combinations With Epirubicin in Advanced Breast Cancer

New Combinations With Epirubicin in Advanced Breast Cancer

ABSTRACT: Several trials have shown that anthracyclines and taxanes can be combined to achieve response rates ranging from 70% to 90%, with complete responses ranging from 19% to 41%. In an attempt to increase the activity while maintaining tolerability, gemcitabine (Gemzar) was added to the epirubicin (Ellence)/paclitaxel (Taxol) regimen. Among 36 metastatic breast cancer patients treated with this new combination, the overall response rate was 92%, including 31% with a complete response. Another attempt to improve the outcome of metastatic breast cancer patients involves a phase III multicentric randomized trial (MANTA-1) to evaluate if paclitaxel maintenance therapy after anthracycline/taxane combination therapy can improve time to progression and overall survival. Although anthracyclines are more frequently used in the adjuvant setting, it is important for the clinicians to know whether this class of drugs can be used again for those patients who develop metastatic disease. An analysis of 312 patients treated with epirubicin containing regimens as first-line treatment for metastatic disease shows that epirubicin-based regimens are active in patients already exposed to anthracyclines in the adjuvant setting, and that the risk of cardiac toxicity is low up to a cumulative epirubicin dose of 990 mg/m2. [ONCOLOGY 15(Suppl 7):24-27, 2001]

Introduction

Anthracyclines, such as doxorubicin and epirubicin (Ellence), and taxanes, such as paclitaxel (Taxol) and docetaxel (Taxotere), are the most active cytotoxic agents for the treatment of metastatic breast cancer. Because of the high level of activity and the lack of complete cross-resistance between these two drug classes, several trials have been performed to evaluate the feasibility and the toxicity of anthracycline/taxane combinations. In patients who had not previously received chemotherapy, the combination of doxorubicin and paclitaxel has been extremely active, inducing an overall response rate of approximately 90% and a complete response rate (CR) as high as 41%.[1-4] Moreover, the combination of epirubicin and paclitaxel has resulted in an interesting level of activity in previously untreated metastatic breast cancer patients, who achieved an overall response rate of 84% and a CR rate of 19%.[5]

Despite this high level of activity, chemotherapy for patients with metastatic breast cancer is still considered palliative. A strategy that may improve outcome for such patients is to increase the complete response to first-line chemotherapy. Data indicate that only complete responders have the potential to survive long-term.[6,7] Therefore, achieving CR is particularly important. One possible way to increase the percentage of patients achieving CR is the addition of an active drug with a different mechanism of action and nonoverlapping toxicity.

Good candidates for such treatments are the antimetabolites, and one in particular is gemcitabine (Gemzar), a pyrimidine nucleoside analog. Gemcitabine demonstrated an interesting level of activity with a good toxicity profile when used as a single agent in the treatment of advanced breast cancer patients. The overall response rate was up to 37% in patients who had not previously received chemotherapy and 28% in previously treated patients.[8,9]

The GET Regimen

Based on these findings, we performed a phase II study of the gemcitabine-epirubicin-paclitaxel (GET) combination as first-line therapy for metastatic breast cancer. Study goals were to determine the rates of CR and objective response as well as progression-free survival and overall survival. The treatment included gemcitabine at 1,000 mg/m2 on days 1 and 4, epirubicin at 90 mg/m2 on day 1, and paclitaxel at 175 mg/m2 on day 1. Treatment was repeated every 3 weeks for up to eight courses.

A total of 36 patients were enrolled in the trial. Median age was 49 years (range: 25-64 years); median Eastern Cooperative Oncology Group (ECOG) performance status was 0 (range: 0-2); hormonal status was positive in 20 patients (56%), negative in 9 (25%), and unknown in 7 (19%). Eighteen patients had received previous adjuvant treatment that included epirubicin in two cases. In these patients, the previous cumulative epirubicin dose was 360 mg/m2. Two patients had previously received hormonal therapy for metastatic disease. Sixteen patients (44%) had at least three metastatic sites and 23 patients (64%) had dominant visceral disease.

The GET regimen was well tolerated. Dose delays were necessary in 24% of courses and dose reductions in 14%. Eleven patients (31%) had a CR and 22 patients (61%) had a partial response (PR). The overall response rate was 32% after two treatment courses and increased to 92% (95% confidential interval, 77.53% to 98.25%) after six or more courses.

Twenty-five patients who had responded to the GET regimen then received high-dose chemotherapy with peripheral blood stem cell support. Of these 25, 13 patients who had achieved a PR (n = 10) or stable disease (SD) (n = 3) after six GET courses, received one course of high-dose idarubicin (Idamycin) (40 to 70 mg/m2). Ten of 13 patients who did not achieve a CR after idarubicin treatment received one additional course of thiotepa (Thioplex) (600 mg/m2), plus melphalan (Alkeran) (160 mg/m2). Another 12 patients (5 who had achieved a PR and 7 who had achieved a CR) after six GET courses received one course of thiotepa plus melphalan.

A conversion to a better response was observed in 39% of the patients, leading to an overall response rate of 97%, including 47% CR. After a median of 12 months of follow-up, the median progression-free survival was 19.4 months. Median overall survival has not yet been reached (Figure 1).

Maintenance Therapy

Another possible strategy to improve outcome of patients with metastatic breast cancer is to try to maintain the obtained response by prolonging the duration of chemotherapy. Results of several randomized phase III studies have indicated that prolonged administration of chemotherapy results in a longer time to disease progression, and may improve survival and quality of life.[10-15]

The importance of chemotherapy duration has also been confirmed by clinical data showing that although most metastatic breast cancer patients who respond to anthracycline/taxane combinations do so within four treatment courses, the best response is often reached after six or more courses. Furthermore, the proportion of CR has been shown to increase when chemotherapy is prolonged with administration of single-agent paclitaxel after an objective response is achieved with the doxorubicin/paclitaxel combination.[1]

The potential benefit of prolonging chemotherapy administration is supported by the breast cancer practice guidelines recently issued by the National Comprehensive Cancer Network (NCCN). These guidelines recommend continuing chemotherapy until disease progression in patients with estrogen-receptor- and progesterone-receptor- tumors, symptomatic visceral metastases, or disease refractory to hormonal therapy.[16]

Management of metastatic breast cancer, however, requires a balance between the potential benefits of prolonging chemotherapy and toxicities induced by such treatment. In particular, prolonged treatment with the paclitaxel/anthracycline combination, the most active drugs in advanced breast cancer, is not feasible because of cumulative, anthracycline dose-related cardiotoxicity. On the other hand, paclitaxel may be a good candidate for maintenance therapy due to its favorable toxicity profile.

We are conducting a phase III, multicenter randomized trial (MANTA) to evaluate whether paclitaxel maintenance treatment improves time to disease progression and overall survival in metastatic breast cancer patients. Patients first receive induction treatment with one of the following regimens:

  • epirubicin at 90 mg/m2 plus paclitaxel at 200 mg/m2 every 21 days;

  • doxorubicin at 50 mg/m2 followed 16 hours later by paclitaxel at 200 mg/m2 every 21 days; or

  • doxorubicin at 50 mg/m2 day 1 plus paclitaxel at 200 mg/m2 day 2 every 21 days for eight courses.

Following induction therapy, only responding patients are randomly assigned to receive an additional eight courses of paclitaxel at 175 mg/m2 every 21 days or no further treatment. The trial will accrue 400 patients.

Characteristics of the 243 patients enrolled so far are:

  • median age, 55 years;

  • median performance status, 0;

  • 29% of patients are premenopausal;

  • 58% are estrogen-receptor positive;

  • 50% have previously received adjuvant chemotherapy and 19% have received hormonal treatment for metastatic disease;

  • dominant metastatic sites are viscera 64%, bone 21%, and soft tissue 15%.

Epirubicin After Adjuvant Anthracycline Treatment

Another potential strategy to improve outcome of patients with advanced breast cancer is to re-treat patients whose disease progresses after having received an anthracycline-containing regimen with the same drug. To this end, we have analyzed the effects of anthracycline-containing adjuvant treatment on overall response rate, progression-free survival, and overall survival of metastatic breast cancer patients who receive epirubicin-containing first-line chemotherapy.

A total of 312 patients with metastatic breast cancer who received first-line epirubicin-containing chemotherapy were included in the analysis. Of these, 182 patients received FEC (fluorouracil, epirubicin, cyclophosphamide [Cytoxan, Neosar]) (group A) and 130 patients received epirubicin plus paclitaxel (group B).

In group A, 39 of 182 patients had received anthracyclines in the adjuvant setting (25 FEC; 14 doxorubicin). The median patient age was 54 years (range: 25 to 72 years); median performance status was 0 (range: 0 to 1); and 23% of patients were estrogen-receptor positive. Sites of metastatic disease were viscera in 44%, bone in 23%, and soft tissue in 33% of patients. Among patients who had received adjuvant anthracyclines, the overall response rate was 44%, with a median progression-free survival of 6.6 months and median overall survival of 15.8 months.

In group B, 27 of 130 patients had received anthracyclines in the adjuvant setting (3 FAC [fluorouracil, Adriamycin (doxorubicin), and cyclophosphamide (Cytoxan, Neosar)], one Abeloff regimen, 23 FEC). The median patient age was 52 years (range: 25 to 72 years); median performance status was 0 (range: 0 to 2); and 34% of patients had estrogen-receptor-positive tumors. Dominant sites of metastatic disease were viscera in 64% of patients, bone in 30%, and soft tissue in 6%. The overall response rate was 85%, median progression-free survival was 12.6 months, and median overall survival was 24.7 months. These response rates apply only to those patients who had received adjuvant anthracycline therapy.

Among the 246 patients who had not received an anthracycline in the adjuvant setting, 143 received first-line FEC and had an overall response rate of 43%, median disease-free survival of 9 months, and median overall survival of 15 months. Another 103 patients received first-line epirubicin/paclitaxel and had an overall response rate of 84%, median disease-free survival of 15 months, and overall survival of 27 months (Figure 2).

In conclusion, these data indicate that epirubicin is active in metastatic breast cancer patients who have previously received anthracycline treatment in the adjuvant setting. Furthermore, the toxicity profile of epirubicin is favorable in that the risk of developing congestive heart failure is low up to a cumulative dose of 990 mg/m2.[17]

References

1. 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 a dose-finding and sequence-finding study. J Clin Oncol 13:2688-2699, 1995.

2. Amadori D, Frassinetti GL, Zoli W, et al: A phase I/II study of sequential doxorubicin and paclitaxel in the treatment of advanced breast cancer. Ann Oncol 23 (suppl. 11):16-22, 1996.

3. Sledge GW, Neuberg D, Ingle J, et al: Phase III trial of doxorubicin and paclitaxel vs doxorubicin + paclitaxel as first line therapy for metastatic breast cancer: An intergroup trial (abstract 2). Proc Am Soc Clin Oncol 16:1a, 1997.

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

5. 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.

6. 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.

7. Rahaman ZU, Frye DK, Smith TL, et al: Results and long term follow-up for 1581 patients with metastatic breast carcinoma treated with standard dose doxorubicin-containing chemotherapy: A reference. Cancer 85:104-111, 1999.

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

9. 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.

10. Coates A, Gebski V, Bishop JM, et al: Improving the quality of life during chemotherapy for advanced breast cancer. A comparison of intermittent and continuous treatment strategies. N Engl J Med 317:1490-1495, 1987.

11. Muss HB, Douglas Case L, Richards F, et al: Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. N Engl J Med 325:1342-1348, 1991.

12. Ejlertsen B, Pfeiffer P, Pedersen D, et al: Decreased efficacy of cyclophosphamide, epirubicin and 5-fluorouracil in metastatic breast cancer when reducing treatment duration from 18 to 6 months. Eur J Cancer 29a:527-531, 1993.

13. Gregory RK, Powles TJ, Chang JC, et al: A randomized trial of six versus twelve courses of chemotherapy in metastatic carcinoma of breast. Eur J Cancer 33:2194-2197, 1997.

14. Janvier M, Spielman M, Nogues C: A randomized trial of maintenance therapy for non-metastatic inflammatory breast cancer (abstract 524). Proc Am Soc Clin Oncol 16:150a, 1997.

15. Falkson B, Gelman RS, Pandya KJ, et al: Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol 16:1669-1676, 1998.

16. Carlson RW, et al: NCCN practice guidelines for breast cancer. Oncology 11 (11A):33-49, 2000.

17. Gennari A, Salvadori B, Donati S, et al: Cardiotoxicity of epirubicin/paclitaxel-containing regimens: Role of cardiac risk factors. J Clin Oncol 17:3596-3602, 1999.

 
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