Doxorubicin/paclitaxel (Taxol) combinations are very active in advanced breast cancer, with objective response rates up to 90%, but have shown a high incidence of cardiotoxicity. A phase I/II trial replacing
ABSTRACT: Doxorubicin/paclitaxel (Taxol) combinations are very active inadvanced breast cancer, with objective response rates up to 90%, but have showna high incidence of cardiotoxicity. A phase I/II trial replacing doxorubicinwith epirubicin (Ellence), a less cardiotoxic analog, produced an objectiveresponse rate of 84%, but with a low rate of cardiotoxicity. A careful cardiacmonitoring in more than 100 patients treated with this combination hasdemonstrated that the risk of congestive heart failure is below 10% up to acumulative epirubicin dose of 990 mg/m2. To examine the possibility that thepharmacokinetic and pharmacodynamic interactions that occur when anthracyclineand paclitaxel are administered together might result in subadditive antitumoractivity, a phase III study is comparing concomitant vs sequentialadministration of epirubicin and paclitaxel in patients with advanced breastcancer. A phase I/II study of epirubicin plus docetaxel as first-linechemotherapy for advanced breast cancer patients evaluated the maximum tolerateddoses and for subsequent studies recommended epirubicin at 75 mg/m2 plusdocetaxel at 80 mg/m2. In the adjuvant setting, an ongoing phase III trial iscomparing epirubicin plus paclitaxel vs FEC (fluorouracil, epirubicin, andcyclophosphamide [Cytoxan, Neosar]) in node-positive patients. Preliminary dataconfirm the cardiac safety of these treatments. [ONCOLOGY 15(Suppl 7):21-23,2001]
The anthracyclines and the taxanes have been shown to be themost active single-agent therapies for breast cancer. The incorporation ofanthracyclines in combination regimens has increased response rate, remissionduration, and survival of patients with advanced disease. Approximately 20%of patients remain disease-free 10 years after achieving a complete response(CR). Moreover, a recently published meta-analysis of adjuvantpolychemotherapy showed that anthracycline-containing regimens were moderatelysuperior to non-anthracycline regimens.
The use of anthracyclines is limited, however, by cumulativedose-related cardiotoxicity. Among the possible strategies to decrease thislife-threatening toxicity, the development of epirubicin (Ellence), adoxorubicin analog, is of particular interest. Epirubicin retains antitumoractivity comparable to that of doxorubicin, but is less cardiotoxic (althoughit does not eliminate cardiotoxicity) and less myelotoxic than the parentcompound at equimolar doses. The need to reduce or avoid cardiac toxicity isevidenced by results of studies of anthracycline/taxane combinations.
The combination of doxorubicin plus paclitaxel (Taxol) proved tobe very active as first-line chemotherapy for advanced breast cancer, with anoverall response rate of approximately 90% and CR rates as high as 41%.[6,7] Thecombination of doxorubicin plus paclitaxel, however, was associated withenhanced cardiotoxicity, which became apparent at cumulative doxorubicin dosessignificantly lower than those recommended when doxorubicin is administeredalone or combined with other drugs. Two independent studies by Gianni andDombernowsky reported a 20% incidence of congestive heart failure (CHF)among metastatic breast cancer patients receiving the doxorubicin pluspaclitaxel combination.
To maintain the high activity of this combination whileameliorating the cardiac toxicity, we have studied an anthracycline/paclitaxelcombination that replaced doxorubicin with epirubicin. Study end points were todetermine the maximum tolerated dose (MTD) of paclitaxel over 3 hours with afixed dose of epirubicin, and to evaluate the toxicity and activity inpreviously untreated metastatic breast cancer patients.
Fifty patients were enrolled in the trial. The MTD was reachedwith doses of epirubicin at 90 mg/m2 plus paclitaxel at 200 mg/m2. Thiscombination was found to be feasible, with a low rate of cardiotoxicity (6%incidence of CHF). The overall response rate was 84% and CR rate was 19%.[11-13]
The excellent cardiac tolerability of this combination comparedwith that associated with doxorubicin/paclitaxel cannot be explained solelybased on epirubicin’s lower rate of cardiotoxicity. Another possibleexplanation may include better patient selection. Moreover, recent data fromGianni and our group showed that coadministration of epirubicin and paclitaxelinduces an increase in glucuronidation of epirubicin, leading to increasedurinary elimination and decreased plasma levels of epirubicinol, the cardiotoxicmetabolite of epirubicin.[14,15]
In contrast, coadministration of doxorubicin with paclitaxelcauses nonlinear disposition of doxorubicin, which results in increased plasmaconcentrations of doxorubicin and its main metabolite doxorubicinol, a majordeterminant of myocardial damage.[15,16] Thus, the pharmacokinetic interactionsof anthracyclines/paclitaxel are different depending on the particularanthracycline used.
We conducted a trial of epirubicin plus paclitaxel to evaluatethe incidence of clinically significant cardiac toxicity and to identifypatients at high risk of developing CHF. We thought it would be particularlyimportant to identify patients for whom the benefits of chemotherapy might benegated by the occurrence of CHF.
In this study of 105 patients with metastatic breast cancer,none developed CHF during the treatment, but nine patients (9%) developed CHFafter cumulative epirubicin doses of 1,080 mg/m2 (n = 4), 720 mg/m2 (n = 2), 630mg/m2 (n = 1), and 540 mg/m2 (n = 2). One of the patients who developed CHFafter epirubicin cumulative doses of 540 mg/m2 had received high-doseconsolidation chemotherapy. Median time to manifestation of cardiac symptoms was3 months after completion of chemotherapy (range: 3 to 6 months).
The incidence of CHF was 13% in patients with pre-existingcardiac risk factors (age, diabetes, hypertension, previous radiotherapy to thechest) and 4% in patients without these risk factors. This analysis showed thatthe incidence of CHF after epirubicin/paclitaxel treatment is low up tocumulative epirubicin doses of990 mg/m2, thus allowing safe administration of this regimen even in patientswho may have received epirubicin in the adjuvant setting. The risk of developingCHF does, however, increase when the cumulative epirubicin dose exceeds 990 mg/m2 and when additional cardiac risk factors are present.
Overall, no clear role for the proposed risk factors forcardiotoxicity was observed in this analysis. Nine patients developed CHF, 7(13%) of 54 patients with and 2 (4%) of 51 patients without risk factors.
Based on the pharmacokinetic and pharmacodynamic interactionsthat occur when anthracyclines and paclitaxel are administered together, wewanted to examine the possibility that combinations of these agents result insubadditive antitumor activity. In a phase III study (MIG 6), concomitant vssequential administration of epirubicin and paclitaxel are being compared inpatients with advanced breast cancer. The primary study end point is overallresponse rate; secondary end points include CR rates, toxicity, quality of life,pharmacoeconomic, and pharmacokinetic analyses.
To date, 112 patients have been enrolled, all of whom have beenevaluated for response. The overall response rate is 60% (CR rate, 13%), with amedian progression-free survival of 12.3 months, and a median overall survivalof 26.3 months.
Available data on use of docetaxel (Taxotere) in combinationwith anthracyclines indicate that this regimen has antitumor activity similar tothat of paclitaxel/anthracycline combinations. The rationale for combiningepirubicin and docetaxel includes the high level of activity and tolerability ofeach drug as a single agent, and preliminary evidence suggesting thatcoadministration of epirubicin and docetaxel does not result in pharmacokineticinteractions that lead to increased risk of cardiotoxicity.
Based on these data, we are conducting a phase I/II study ofepirubicin plus docetaxel as first-line chemotherapy for advanced breast cancerpatients. The purpose of the study is to evaluate the MTD of docetaxel incombination with epirubicin at two different dose levels (75 and 90 mg/m2),administered every 21 days to breast cancer patients with locally advanced(LABC) or metastatic (MBC) disease.
At the time of this report, 58 patients (35 LABC and 23 MBC)have been treated and are evaluable for toxicity and response. Grade 4neutropenia occurred in 69% of cycles, with fever in 11%. Dose-limitingtoxicities were febrile neutropenia and grade 4 neutropenia lasting more than 7days.
The following MTDs have been identified: epirubicin at 90 mg/m2plus docetaxel at 60 mg/m2, epirubicin at 75 mg/m2 plus docetaxel at 80mg/m2,and epirubicin at 90 mg/m2 plus granulocyte-colony colony stimulating factor(G-CSF). The recommended doses for subsequent studies are epirubicin at 75 mg/m2/docetaxel at 80mg/m2 without G-CSF. The overall response rate was 73% (7%complete and 66% partial response.
The high level of activity of anthracycline/taxane regimens inpatients with metastatic breast cancer has prompted investigations of the roleof these regimens in the adjuvant setting.
Italian investigators are performing the Gruppo OncologicoNord-Ouest (GONO)-MIG 5 multicenter randomized trial in which epirubicin pluspaclitaxel (Taxol) (ET) is being compared with fluorouracil, epirubicin, andcyclophosphamide (Cytoxan, Neosar) (FEC) as adjuvant chemotherapy fornode-positive breast cancer patients. Because the potential for cardiotoxicityis an important issue in the adjuvant setting, the study includes an analysis ofthe incidence of CHF.
A total of 631 patients have been evaluated, of whom 314 havereceived FEC and 317 ET. Follow-up time exceeds 1 year in 92% of patients. Grade1 (World Health Organization [WHO] criteria) cardiotoxicity was reported in fivepatients receiving FEC, which occurred from 65 to 127 days after randomization,and in four patients receiving ET, 23 to 29 days after randomization. Onepatient receiving ET had grade 2 cardiotoxicity after the second chemotherapycourse, consisting of sinus block with syncope followed by atrial fibrillationthat lasted 24 hours.
Of note, no episodes of CHF were observed among patientsreceiving the ET combination. In addition to epirubicin’s advantages relatedto reduced potential for cardiotoxicity, the excellent cardiac tolerability ofthe adjuvant ET regimen might be related to the low cumulative epirubicin dose(ie, 360 mg/m2) and the good performance status of patients in this trial.However, because epirubicin/paclitaxel combinations have been associated with alow incidence of cardiotoxicity in patients with metastatic breast cancer, theGONO-MIG 5 investigators have recommended continued clinical monitoring duringstudy treatment and follow-up.
The combination of epirubicin and taxanes is feasible andmaintains an interesting level of activity. Moreover, cardiotoxicity, which wasan important complication of concomitant doxorubicin and paclitaxel treatment,is not a major issue when epirubicin is used instead of doxorubicin. Thisobservation should be considered when planning clinical trials in the adjuvantand neoadjuvant settings.
1. A’Hern RP, Smith IE, Ebbs SR: Chemotherapy and survival inadvanced breast cancer patients: The inclusion of doxorubicin in Cooper typeregimens. Br J Cancer 67:801-805, 1993.
2. Greenberg PAC, Hortobagyi G, Smith TL, et al: Long-termfollow-up of patients with complete remission following combination chemotherapyfor metastatic breast cancer. J Clin Oncol 14:2197-2205, 1996.
3. Early Breast Cancer Trialists’ Collaborative Group:Polychemotherapy for early breast cancer: An overview of the randomised trials.Lancet 352:930-942, 1998.
4. Pawan KS, Iliskovic N: Doxorubicin-induced cardiomiopathy. NEngl J Med 339(13):900-905, 1998.
5. Coukell AJ, Faulds D: Epirubicin. An updated review of itspharmacodynamic and pharmacokinetic properties and therapeutic efficacy in themanagement of breast cancer. Drugs 53(3):453-482, 1997.
6. Gehl J, Boesgard M, Paaske T, et al: Combined doxorubicin andpaclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann Oncol7:687-693, 1996.
7. Amadori D, Frassineti GL, Zoli W, et al: A phase I/II studyof sequential doxorubicin and paclitaxel in the treatment of advanced breastcancer. Semin Oncol 23(suppl 11):16-22, 1996.
8. Valagussa P, Gianni L, Capri G, et al: Three-year follow upin women with metastatic breast cancer after bolus doxorubicin and paclitaxelinfused over 3 hours (AT) (abstract 429). Proc Am Soc Clin Oncol 17:111, 1998.
9. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3 hourinfusion in combination with bolus doxorubicin in women with untreatedmetastatic breast cancer: High antitumor efficacy and cardiac effects in adose-finding and sequence-finding study. J Clin Oncol 13:2688-2699, 1995.
10. Dombernowsky P, Gehl J, Boesgaard M, et al: Doxorubicin andpaclitaxel: A highly active combination in the treatment of metastatic breastcancer. Semin Oncol 23(suppl 11):23-27, 1996.
11. Conte PF, Baldini E, Gennari A, et al: Dose-finding studyand pharmacokinetics of epirubicin and paclitaxel over 3 hours: A regimen withhigh activity and low cardiotoxicity in advanced breast cancer. J Clin Oncol15:2510-2517, 1997.
12. Catimel G, Spielmann M, Dieras V, et al: Phase I study ofpaclitaxel and epirubicin in patients with metastatic breast cancer: Apreliminary report on safety. Semin Oncol 23(suppl 11):28-31, 1996.
13. Luck HJ, Thomssen C, Du Bois A, et al: Metastatic breastcancer: Experience with the combination paclitaxel plus epirubicin. Oncology12(suppl 1):36-39, 1998.
14. Danesi R, Conte PF, Del Tacca M, et al: Pharmacokineticoptimization of treatment schedules for anthracyclines and paclitaxel in cancerpatients. Clin Pharmacokin 37:195-211, 1999.
15. Gianni L, Vigano L, Locatelli A, et al: Humanpharmacokinetic characterization and in vitro study of the interaction betweendoxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol15:1906-1915, 1997.
16. Minotti G, Cavaliere AF, Mordente A, et al: Secondaryalcohol metabolites mediate iron delocalization in cytosolic fractions ofmyocardial biopsies exposed to anticancer anthracyclines. Novel linkage betweenanthracycline metabolism and iron-induced cardiotoxicity. J Clin Invest95(4):1595-1605, 1995.
17. Gennari A, Salvadori B, Donati S, et al: Cardiotoxicity ofepirubicin/paclitaxel-containing regimens: Role of cardiac risk factors. J ClinOncol 17:3596-3602, 1999.
18. Venturini M, Papaldo P, Michelotti A, et al: Identificationof the highest dose of docetaxel associable with active doses of epirubicin.Results from a dose-finding study in advanced breast cancer patients. Ann Oncol.In press.