Docetaxel/Doxorubicin/Cyclophosphamide in the Treatment of Metastatic Breast Cancer

ABSTRACT: Preliminary results fromphase I trials suggest that the use of docetaxel (Taxotere) and doxorubicin(Adriamycin) is a well tolerated and highly active combination regimenfor patients with metastatic breast cancer. The maximum tolerated doseof this combination was 50 mg/m² of doxorubicin given as an intravenousbolus followed 1 hour later with 75 mg/m² of docetaxel given as a1-hour intravenous infusion. Because cardiotoxicity was not observed withthis combination, we added cyclophosphamide (Cytoxan, Neosar) in a phaseII trial to determine the antitumor activity and tolerability of this 3-drugcombination as first-line therapy in patients with metastatic breast cancer.Preliminary results from this study indicate that the Taxotere/Adriamycin/Cyclophosphamide(TAC) combination produces response rates of up to 80%. However, frequentgrade 4 neutropenia was seen in 68% of cycles, febrile neutropenia in 5.5%of cycles, and grade 3 to 4 infection in .8% of cycles. Cardiac toxicitywas rare, with 1 case of reversible congestive heart failure (2%), whichoccurred 2 months after completion of chemotherapy. These preliminary datashow that TAC is highly active and that docetaxel did not significantlyincrease the cardiotoxicity of doxorubicin. Phase III studies in both thefirst-line and adjuvant settings are warranted. [ONCOLOGY 11(Suppl 8):37-41,1997]

Introduction

The integration of the taxanes in combination chemotherapy regimensfor a variety of cancers, including metastatic breast cancer, is becominga fundamental therapeutic approach in oncology. In patients with anthracycline-resistantmetastatic breast cancer, 100 mg/m² of Taxotere (docetaxel) administeredas a 1-hour intravenous infusion once every 3 weeks produced overall responserates of up to 57%.[1,2] This lack of cross-resistance, in addition tothe substantial antitumor activity of both docetaxel and doxorubicin (Adriamycin)provides the rationale for investigating this combination in patients withmetastatic breast cancer.

Kalla and colleagues[3] recently reported that an intravenous bolusdose of 50 mg/m² of doxorubicin followed by 75 mg/m² of docetaxeladministered as a 1-hour infusion once every 3 weeks, without granulocytecolony-stimulating factor support (G-CSF) (filgrastim [Neupogen]), produceda response rate of 90% in patients with metastatic breast cancer. The mostencouraging finding from this trial, as well as from a trial by Itoh andcolleagues,[4] was the lack of clinically significant cardiac toxicity.

Kalla et al[3] found that none of the 42 patients treated with thiscombination developed congestive heart failure, which typically occursata rate of 3% to 4% in patients who receive a cumulative dose of 450 mg/m²of doxorubicin single-agent therapy.[5-7] This is in contrast to the findingsobserved with the combination of doxorubicin and paclitaxel (Taxol), asreported by Gianni et al[8] and Gehl et al,[9] who noted, respectively,that 18% and 20% of patients with metastatic breast cancer developed reversiblecongestive heart failure.

TAC for First-Line Therapy

Based on these preliminary data, our group performed a phase II trialto determine the antitumor activity and tolerability of Taxotere and Adriamycinwith cyclophosphamide (TAC) as first-line therapy without prophylacticG-CSF support, in patients with metastatic breast cancer.[10] In additionto measuring response rate, duration of response, and time to progression,we were interested in confirming the favorable toxicity profile--in particular,the lack of cardiac side effects as reported previously[3,4] with the combinationof docetaxel and doxorubicin.

The inclusion criteria for this study consisted of patients with bidimensionallymeasurable (80% of cases) or evaluable (20%) metastatic breast cancer whohad received no prior chemotherapy for metastatic disease and were anthracyclinenaive. In addition, study participation was open to patients with a Karnofskyperformance status of at least 60% and who had normal left ventricularejection fractions on a multiple-gated acquisition scan at baseline.

The schema of treatment was doxorubicin, given at a dose of 50 mg/m²as an intravenous bolus over 3 to 5 minutes, followed by 500 mg/m²of cyclophosphamide, also as an intravenous bolus, and then 1-hour later,75 mg/m² of docetaxel, administered as a 1-hour intravenous infusion.This cycle was repeated once every 3 weeks. Patients also received 500mg of oral ciprofloxacin (Cipro) twice daily on days 5 through 15 of eachcycle for prophylaxis against infection and 8 mg of dexamethasone twicedaily for 3 days, beginning the day prior to chemotherapy. As mentionedpreviously, no prophylactic G-CSF was given in this trial.

Demographics and Treatment Discourse

Of 55 patients accrued in this trial, preliminary results are availablefor 52 patients. Median patient age was 52 years (range: 33 to 70 years),with a good median Karnofsky performance status of 90% (range: 60% to 100%).A total of 31% of patients had received prior adjuvant chemotherapy, whichconsisted exclusively of cyclophosphamide, methotrexate, and fluorouracil(5-FU). The median number of organs involved by the disease was 3 (range:1 to 6), with 3 or more organs involved in 52% of patients. Visceral diseasewas seen in 60% of cases (liver involvement: 32% of patients). Bone metastaseswere seen in 48% of patients.

To date, a total of 251 cycles are evaluable, with a median of 5 cyclesper patient (range: 1 to 8). The median cumulative doses were 254 mg/m²(range: 49 to 419 mg/m²) for doxorubicin and 379 mg/m² (range:75 to 617 mg/m²) for docetaxel. The relative dose intensity was .99for doxorubicin and .98 for docetaxel.

Antitumor Activity

To date, 38 patients are evaluable for response. In 31 patients withmeasurable disease, the preliminary response rate is 80%, consisting of2 complete responses and 23 partial responses (Table1). The overall response rate, which included 7 patients with evaluabledisease, was 74%. Overall, there were 3 cases of complete response and25 cases of partial response. In addition, the objective response rateof this combination was consistent across sites of involvement: liver (83%),lung (76%), visceral disease (76%), and soft tissue (75%). The preliminaryactivity of this combination is similar to that seen with other docetaxel/doxorubicincombinations.[3]

Tolerability

A total of 49 patients were included in the preliminary safety evaluation.As expected with a combination regimen consisting of 3 myelosuppressiveagents, grade 4 neutropenia was common, occurring in approximately 68%of the cycles and 96% of patients (Table2). Febrile neutropenia, with or without sepsis, which appears to bea more clinically relevant indicator of toxicity, occurred in 24.5% ofpatients, but in only 5.5% of administered cycles. Similarly, grade 3 to4 infections were noted in 4% of patients and .8% of cycles. Despite thehigh incidence of grade 4 neutropenia, the median absolute neutrophil counton day 21 of each cycle was greater than 2,000/mm³, which allowedfor the continuation of treatment without delay and with high dose intensity.

Interestingly, no grade 4 acute nonhematologic toxicities were noted.Grade 3 nonhematologic toxicities were infrequent and consisted primarilyof nausea (8%), stomatitis (6%), and diarrhea (4%). Of the chronic nonhematologictoxicities, severe asthenia was noted in 10% of patients and severe fluidretention in 1%. The classical toxicities, such as fluid retention, hypersensitivityreactions, skin toxicity, and nail changes, seen with Taxotere alone wererarely seen with the TAC combination. This contrasts with the toxicityprofile seen with 100 mg/m² of docetaxel in single-agent chemotherapy.One could hypothesize the existence of a partial threshold of toxicitybetween 75 and 100 mg/m² of docetaxel, which could favor the use ofTAC.

Evaluation of cardiotoxicity was a primary endpoint in this study. Therewere no cases of congestive heart failure in the 35 patients who receiveddoxorubicin as a median cumulative dose of less than 360 mg/m². Ofthe 14 patients who received a cumulative dose of more than 360 mg/m²,1 patient (2%) developed congestive heart failure, which occurred 60 daysafter completing the combination regimen. Overall, only 1 patient had anasymptomatic reduction of left ventricular ejection fraction on multiple-gatedacquisition scan (Table 3).

The low incidence of clinical cardiotoxicity observed with the docetaxel/doxorubicincombination in this trial is consistent with the results from earlier phaseI trials (Table 4).[3,11] These resultssuggest that the addition of docetaxel to doxorubicin does not appear toincrease the incidence and severity of cardiotoxicity typically seen withdoxorubicin used as a single-agent[12] or with the 5-FU/doxorubicin/cyclophosphamideregimen.[13] This contrasts with the apparent increase in congestive heartfailure reported with the addition of paclitaxel to doxorubicin in patientswith metastatic breast cancer.[8,9] Until further trials are performed,one can only speculate as to why there appears to be a difference betweenthese two taxanes with respect to cardiotoxicity when combined with doxorubicin.

Discussion

The preliminary results from this trial demonstrate that the combinationof 75 mg/m² of docetaxel, 50 mg/m² of doxorubicin, and 500 mg/m²cyclophosphamide as first-line chemotherapy is an active combination, witha response rate of 80% among patients with measurable metastatic breastcancer. Overall, the hematologic toxicity associated with this combinationis acceptable, not dose-limiting, and easily manageable. The low incidenceof febrile neutropenia by cycle (5.5%) observed with TAC is in contrastwith the incidence observed by Kalla et al[3] (11.8%) and raises the issuerelated to the potential role of prophylactic antibiotherapy in the contextof this type of chemotherapy combination. No cytokines were used in thistrial.

The nonhematologic toxicities noted in this trial were usually mild,with only 8% of patients experiencing grade 3 nausea (no grade 3 vomiting),6% grade 3 stomatitis, and 4% diarrhea. Severe asthenia was seen in 10%of patients. Docetaxel-specific toxicities (fluid retention, allergic reactions,and skin and nail changes) were not a clinical issue, with no reports oftreatment discontinuation related to these effects.

The favorable extrahematologic toxicity profile of TAC chemotherapyleads to the hypothesis of a potential partial threshold of docetaxel-specifictoxicities between doses of 75 mg/m², as in TAC, and the 100 mg/m²dose used in single-agent chemotherapy. This series also confirms the lackof added cardiac toxicity for the docetaxel/doxorubicin combination andis in sharp contrast with the data available with short-infusion paclitaxelplus doxorubicin (Table 4).[8,9] In theseconditions, phase III trials are warranted to define further the potentialrole of TAC as first-line therapy as well as its use in the adjuvant settingin patients with metastatic breast cancer.

Future Directions

The promising results from the use of TAC as first-line treatment formetastatic breast cancer have led to the development of two phase III trialslooking at this combination Taxotere/Adriamycin/Cyclophosphamide in theadjuvant setting. These trials are being conducted by the Breast CancerInternational Research Group.

The first trial is a multicenter, randomized phase III study comparing75 mg/m² of docetaxel in combination with 50 mg/m² of doxorubicinand 500 mg/m² of cyclophosphamide with 500 mg/m² of 5-FU, 50mg/m² of doxorubicin, and 500 mg/m² of cyclophosphamide. Patientswith operable breast cancer who have positive axillary nodes will be randomizedto receive 1 of the 2 combinations for 6 cycles.

A second trial is addressing the role of high-dose chemotherapy followinginduction chemotherapy with TAC. This prospective, randomized phase IIItrial, which is being conducted in tandem with the previous trial, is designedto compare 6 cycles of TAC to 4 cycles of TAC followed by 1 cycle of high-dosechemotherapy. The patient population consists of operable breast cancerpatients with 4 or more positive axillary nodes.

Finally, a separate group, known as the Breast European Adjuvant StudiesTeam, is conducting a randomized study based on the concept of sequentialchemotherapy. Patients in this study will be randomized to receive doxorubicinfollowed by cyclophosphamide/methotrexate/5-FU, docetaxel plus doxorubicinfollowed by cyclophosphamide/methotrexate/5-FU, or doxorubicin followedby docetaxel followed by cyclophosphamide/methotrexate/5-FU.

The taxanes are a major entry in the armamentarium of medical therapyfor breast cancer and will be recalled in the future as the new breastcancer drugs of the 1990s. Docetaxel appears to be the most promising ofthese agents. Further, docetaxel/doxorubicin-based combinations, such asthe TAC regimen, are currently being compared in a randomized fashion withstandard therapy in the first-line treatment setting of patients with metastaticbreast cancer, and in the near future, the adjuvant setting. These studieswill assess the real role of the taxanes in breast cancer and help definetheir potential for improving treatment.

References:

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