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
ABSTRACT: Several trials have shown that anthracyclines and taxanes can becombined to achieve response rates ranging from 70% to 90%, with completeresponses ranging from 19% to 41%. In an attempt to increase the activity whilemaintaining tolerability, gemcitabine (Gemzar) was added to the epirubicin(Ellence)/paclitaxel (Taxol) regimen. Among 36 metastatic breast cancer patientstreated with this new combination, the overall response rate was 92%, including31% with a complete response. Another attempt to improve the outcome ofmetastatic breast cancer patients involves a phase III multicentric randomizedtrial (MANTA-1) to evaluate if paclitaxel maintenance therapy afteranthracycline/taxane combination therapy can improve time to progression andoverall survival. Although anthracyclines are more frequently used in theadjuvant setting, it is important for the clinicians to know whether this classof drugs can be used again for those patients who develop metastatic disease. Ananalysis of 312 patients treated with epirubicin containing regimens asfirst-line treatment for metastatic disease shows that epirubicin-based regimensare active in patients already exposed to anthracyclines in the adjuvantsetting, and that the risk of cardiac toxicity is low up to a cumulativeepirubicin dose of 990 mg/m2. [ONCOLOGY 15(Suppl 7):24-27, 2001]
Anthracyclines, such as doxorubicin and epirubicin(Ellence), and taxanes, such as paclitaxel (Taxol) and docetaxel (Taxotere), arethe most active cytotoxic agents for the treatment of metastatic breast cancer.Because of the high level of activity and the lack of complete cross-resistancebetween these two drug classes, several trials have been performed to evaluatethe feasibility and the toxicity of anthracycline/taxane combinations. Inpatients who had not previously received chemotherapy, the combination ofdoxorubicin and paclitaxel has been extremely active, inducing an overallresponse rate of approximately 90% and a complete response rate (CR) as high as41%.[1-4] Moreover, the combination of epirubicin and paclitaxel has resulted inan interesting level of activity in previously untreated metastatic breastcancer patients, who achieved an overall response rate of 84% and a CR rate of19%.
Despite this high level of activity, chemotherapy for patientswith metastatic breast cancer is still considered palliative. A strategy thatmay improve outcome for such patients is to increase the complete response tofirst-line chemotherapy. Data indicate that only complete responders have thepotential to survive long-term.[6,7] Therefore, achieving CR is particularlyimportant. One possible way to increase the percentage of patients achieving CRis the addition of an active drug with a different mechanism of action andnonoverlapping toxicity.
Good candidates for such treatments are the antimetabolites, andone in particular is gemcitabine (Gemzar), a pyrimidine nucleoside analog.Gemcitabine demonstrated an interesting level of activity with a good toxicityprofile when used as a single agent in the treatment of advanced breast cancerpatients. The overall response rate was up to 37% in patients who hadnot previously received chemotherapy and 28% in previously treatedpatients.[8,9]
Based on these findings, we performed a phase II study of thegemcitabine-epirubicin-paclitaxel (GET) combination as first-line therapy formetastatic breast cancer. Study goals were to determine the rates of CR andobjective 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 at90 mg/m2 on day 1, and paclitaxel at 175 mg/m2 on day 1. Treatment was repeatedevery 3 weeks for up to eight courses.
A total of 36 patients were enrolled in the trial. Median agewas 49 years (range: 25-64 years); median Eastern Cooperative Oncology Group(ECOG) performance status was 0 (range: 0-2); hormonal status was positive in20 patients (56%), negative in 9 (25%), and unknown in 7 (19%). Eighteenpatients had received previous adjuvant treatment that included epirubicin intwo cases. In these patients, the previous cumulative epirubicin dose was 360mg/m2. Two patients had previously received hormonal therapy for metastaticdisease. Sixteen patients (44%) had at least three metastatic sites and 23patients (64%) had dominant visceral disease.
The GET regimen was well tolerated. Dose delays were necessaryin 24% of courses and dose reductions in 14%. Eleven patients (31%) had a CR and22 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 thenreceived high-dose chemotherapy with peripheral blood stem cell support. Ofthese 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 afteridarubicin treatment received one additional course of thiotepa (Thioplex) (600mg/m2), plus melphalan (Alkeran) (160 mg/m2). Another 12 patients (5 who hadachieved a PR and 7 who had achieved a CR) after six GET courses received onecourse of thiotepa plus melphalan.
A conversion to a better response was observed in 39% of thepatients, leading to an overall response rate of 97%, including 47% CR. After amedian of 12 months of follow-up, the median progression-free survival was 19.4months. Median overall survival has not yet been reached (Figure1).
Another possible strategy to improve outcome of patients withmetastatic breast cancer is to try to maintain the obtained response byprolonging the duration of chemotherapy. Results of several randomized phase IIIstudies have indicated that prolonged administration of chemotherapy results ina longer time to disease progression, and may improve survival and quality oflife.[10-15]
The importance of chemotherapy duration has also been confirmedby clinical data showing that although most metastatic breast cancer patientswho respond to anthracycline/taxane combinations do so within four treatmentcourses, the best response is often reached after six or more courses.Furthermore, the proportion of CR has been shown to increase when chemotherapyis prolonged with administration of single-agent paclitaxel after an objectiveresponse is achieved with the doxorubicin/paclitaxel combination.
The potential benefit of prolonging chemotherapy administrationis supported by the breast cancer practice guidelines recently issued by theNational Comprehensive Cancer Network (NCCN). These guidelines recommendcontinuing chemotherapy until disease progression in patients withestrogen-receptor- and progesterone-receptor- tumors, symptomatic visceralmetastases, or disease refractory to hormonal therapy.
Management of metastatic breast cancer, however, requires abalance between the potential benefits of prolonging chemotherapy and toxicitiesinduced by such treatment. In particular, prolonged treatment with thepaclitaxel/anthracycline combination, the most active drugs in advanced breastcancer, is not feasible because of cumulative, anthracycline dose-relatedcardiotoxicity. On the other hand, paclitaxel may be a good candidate formaintenance 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 todisease 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 21days;
doxorubicin at 50 mg/m2 followed 16 hours later bypaclitaxel at 200 mg/m2 every 21 days; or
doxorubicin at 50 mg/m2 day 1 plus paclitaxel at 200 mg/m2day 2 every 21 days for eight courses.
Following induction therapy, only responding patients arerandomly assigned to receive an additional eight courses of paclitaxel at 175mg/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%, andsoft tissue 15%.
Another potential strategy to improve outcome of patients withadvanced breast cancer is to re-treat patients whose disease progresses afterhaving received an anthracycline-containing regimen with the same drug. To thisend, we have analyzed the effects of anthracycline-containing adjuvant treatmenton overall response rate, progression-free survival, and overall survival ofmetastatic breast cancer patients who receive epirubicin-containing first-linechemotherapy.
A total of 312 patients with metastatic breast cancer whoreceived first-line epirubicin-containing chemotherapy were included in theanalysis. Of these, 182 patients received FEC (fluorouracil, epirubicin,cyclophosphamide [Cytoxan, Neosar]) (group A) and 130 patients receivedepirubicin plus paclitaxel (group B).
In group A, 39 of 182 patients had received anthracyclines inthe adjuvant setting (25 FEC; 14 doxorubicin). The median patient age was 54years (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 diseasewere viscera in 44%, bone in 23%, and soft tissue in 33% of patients. Amongpatients who had received adjuvant anthracyclines, the overall response rate was44%, with a median progression-free survival of 6.6 months and median overallsurvival of 15.8 months.
In group B, 27 of 130 patients had received anthracyclines inthe adjuvant setting (3 FAC [fluorouracil, Adriamycin (doxorubicin), andcyclophosphamide (Cytoxan, Neosar)],one Abeloff regimen, 23 FEC). The median patient age was 52 years (range: 25 to72 years); median performance status was 0 (range: 0 to 2); and 34% of patientshad estrogen-receptor-positive tumors. Dominant sites of metastatic diseasewere viscera in 64% of patients, bone in 30%, and soft tissue in 6%. The overallresponse rate was 85%, median progression-free survival was 12.6 months, andmedian overall survival was 24.7 months. These response rates apply only tothose patients who had received adjuvant anthracycline therapy.
Among the 246 patients who had not received an anthracycline inthe adjuvant setting, 143 received first-line FEC and had an overall responserate of 43%, median disease-free survival of 9 months, and median overallsurvival of 15 months. Another 103 patients received first-lineepirubicin/paclitaxel and had an overall response rate of 84%, mediandisease-free survival of 15 months, and overall survival of 27 months (Figure2).
In conclusion, these data indicate that epirubicin is active inmetastatic breast cancer patients who have previously received anthracyclinetreatment in the adjuvant setting. Furthermore, the toxicity profile ofepirubicin is favorable in that the risk of developing congestive heart failureis low up to a cumulative dose of 990 mg/m2.
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