The Current Status of Docetaxel for Metastatic Breast Cancer

ABSTRACT: Docetaxel (Taxotere) has been intensively investigated for the treatment of metastatic breast cancer, where it has proved to be one of the most active agents. Initial phase II studies in anthracycline-resistant metastatic breast cancer demonstrated impressive response rates that have been confirmed in phase III randomized trials. Docetaxel remains the only single agent to demonstrate a survival benefit in anthracycline-resistant patients. More recently, the combination of docetaxel with capecitabine (Xeloda) has demonstrated additional improvement in survival over docetaxel alone in a randomized phase III trial. In patients previously treated with an alkylating agent, docetaxel is the only single drug to demonstrate improved efficacy over doxorubicin in a randomized trial. Docetaxel has been investigated in combination with the anthracyclines doxorubicin and epirubicin in randomized trials. The docetaxel-containing regimens have consistently demonstrated improvement over the non-docetaxel-containing regimens. The efficacy and safety of weekly docetaxel has extended the line of investigation for combinations with agents normally administered on a weekly basis, such as vinorelbine [Navelbine], gemcitabine [Gemzar], and trastuzumab [Herceptin], with promising findings. In addition, the results of the triple-drug combination of docetaxel, a platinum salt (cisplatin or carboplatin), and trastuzumab have resulted in impressive response rates and time to progression in a population of metastatic breast cancer patients with HER2/neu-positive tumors. The consistent demonstration of a high level of efficacy with manageable toxicity ensures the continued widespread investigation of docetaxel in metastatic breast cancer. [ONCOLOGY 16(Suppl 6):17-26, 2002]

Breast cancer is the most common malignancy diagnosedin women in industrialized countries. In the United States, an estimated 203,500women will develop breast cancer in 2002 and 39,600 women are expected to diefrom the disease the same year.[1] Effective chemotherapy prolongs survival andprovides important palliation for patients with metastatic breast cancer.Historically, anthracycline-based regimens were considered superior to non-anthracycline-containingregimens. The development of the taxanes in the 1990s opened new avenues for thetreatment of patients with metastatic breast cancer.

Docetaxel (Taxotere) is among the most active agents for metastatic breastcancer. Initial phase II studies of docetaxel administered at 100 mg/m² showedresponse rates of 53% to 68% in patients previously treated withchemotherapy.[2-6] A multicenter phase II study of docetaxel at 75 mg/m² showeda response rate of 52%.[7] Docetaxel is particularly active in patients withanthracycline-resistant breast cancer. In two studies published simultaneously,the objective response rates to docetaxel at 100 mg/m² in patients with breastcancer resistant to anthracyclines were 53% and 57%, respectively.[2,3] Ando etal[8] reported that docetaxel given at a dose of 60 mg/m² produces a responserate of 49% in patients previously exposed to anthracyclines. The high responserates observed with docetaxel in this patient population were confirmed inrandomized phase III trials.

Docetaxel in Anthracycline-Resistant Breast Cancer

In one study, docetaxel at 100 mg/m² was compared with mitomycin (Mutamycin)plus vinblastine in patients with anthracycline-resistant metastatic breastcancer.[9] Patients treated with docetaxel had significantly better responserates (30% vs 11.6%, P < .0001), time to progression (19 vs 11 weeks, P =.01) ), and overall survival (11.4 vs 8.7 months, P = .01). Another sudycompared docetaxel at 100 mg/m² with sequential methotrexate at 200 mg/m² andfluorouracil (5-FU) at 600mg/m², on days 1, 8, administered to patients withadvanced anthracycline-resistant breast cancer.[10] The results from this phaseIII trial indicate that docetaxel is more active than the sequential two-drugcombination. Response rates (42% vs 21%, P < .001) and median time toprogression (6.3 months vs 3 months, P < .001) were significantly better inthe docetaxel arm in comparison with methotrexate/5-FU.

Another phase III study showed a higher response rate for docetaxel comparedwith 5-FU plus vinorelbine (Navelbine) as second-line therapy.[11] Takentogether, these studies demonstrate that docetaxel is effective therapy againstanthracycline-resistant breast cancer, and, to date, docetaxel is the first andonly chemotherapeutic drug to demonstrate a survival benefit in this patientpopulation.

Historically, regimens that contained doxorubicin or epirubicin (Ellence)were considered the first-line treatment of choice for patients with metastaticbreast cancer. This paradigm is being challenged by novel nonanthracyclineregimens. A randomized trial compared docetaxel at 100mg/m² with doxorubicin at75 mg/m² in patients with metastatic breast cancer who had failed analkylating-containing regimen.[12] Docetaxel demonstrated significantly betterresponse rates compared with doxorubicin in this patient population (48% vs 33%,P = .008), with a trend toward improved time to progression. Of the 326evaluable patients, 49% were classified as having resistant disease (progressionon prior chemotherapy), 70% of patients received docetaxel or doxorubicin assecond-line therapy for metastatic breast cancer, and 30% received this regimenas first-line therapy for metastatic disease after having relapsed for 12months or more after adjuvant therapy. These phase III results are the only time that asingle agent (ie, docetaxel) has outperformed the previous standard drug(doxorubicin).[13,14]

The dose-limiting toxicity of docetaxel administered on an every 3-weekschedule is neutropenia. Other reported toxicities include skin reactions, nailchanges, neurosensory toxicity, and hypersensitivity reactions. Fluid retentionwas a major concern in the initial phase I and II clinical trials of docetaxel,in which patients had not received any premedication. A randomized studyconducted by the European Organization for Research and Treatment of Cancer(EORTC) showed that the docetaxel-induced fluid retention could be reduced usinga premedication regimen of corticosteroids.[15]

Currently, docetaxel is approved by the Food and Drug Administration (FDA)for the treatment of patients with locally advanced or metastatic breast cancerafter failure of prior chemotherapy. The approved outpatient regimen is 60 to100 mg/m², administered intravenously for 1 hour every 3 weeks.[16] All patientsshould be premedicated with oral corticosteroids, such as dexamethasone 16 mg/d(eg, 8 mg bid), for 3 days starting 1 day prior to administration of docetaxelin order to reduce the incidence and severity of fluid retention, as well as theseverity of hypersensitivity reactions. Of interest, a randomized clinical trialexploring the efficacy of three doses of docetaxel (60 mg/m², 75 mg/m², and 100mg/m²) has been closed to accrual. The results of this study will provideadditional details on the safety and efficacy of docetaxel in various doses.

Weekly Docetaxel

Docetaxel can be administered safely and effectively at lower doses whengiven on a weekly schedule. Additionally, weekly docetaxel administration allowsfor the possibility of combined use with alternative agents, including thosenormally administered on a weekly basis (eg, trastuzumab [Herceptin],vinorelbine), or those that become feasible in combination because of the changein the hematologic toxicity profile of docetaxel.

In a phase II trial conducted by Loeffler et al, docetaxel 40 mg/m² wasadministered once a week for 6 weeks, followed by a 2-week rest.[17] An overallresponse rate of 47% was reported in 41 metastatic breast cancer patients whohad been previously exposed to chemotherapy, including prior paclitaxel. In thisstudy, no cases of grade 2 or greater neutropenia were seen with doses of lessthan 43 mg/m² per week and grade 2 or higher thrombocytopenia was not observed.In addition to causing minimal hematologic toxicity, the data showed that weeklydocetaxel was likely to be associated with a very low incidence of other acutetoxicities.

Another phase II study by Burstein et al, showed a response rate of 41% in apopulation of 29 metastatic breast cancer patients treated with weeklydocetaxel, 40 mg/m² IV administered over 1 hour.[18] Treatment was administeredweekly for 6 weeks, followed by a 2-week rest. Hematological toxicity in thisstudy was minimal. Grade 3 neutropenia occurred in 14% of patients, and grade 4neutropenia in none. There were no cases of grade 3 or 4 anemia orthrombocytopenia of any grade. The incidence of nonhematologic toxicity was low,in particular the rate of grade 3/4 neurologic toxicity was very low, with 3% ofpatients experiencing neuropathy. Fatigue and asthenia occur with prolongedtherapy—as may fluid retention—although at a higher cumulative dose than isseen with every-3-week schedules. A newly reported toxicity of frequent tearingand visual problems, which is generally mild and manageable, may also occurafter substantial total exposure to weekly docetaxel, but was not reported atthe grade 3/4 level in this trial.

Hainsworth and colleagues reported on the use of docetaxel at 36 mg/m² perweek for 6 consecutive weeks, followed by 2 weeks without treatment.[19] A totalof 41 women with advanced breast cancer who were elderly (65 years or older) or whowere considered poor candidates for combination chemotherapy were enrolled onthe study. When assessed after 8 weeks of treatment, 12 of 36 assessablepatients had an objective response. An additional 14 patients had either a minorresponse or stable disease and continued treatment with weekly docetaxel. One ofthese patients subsequently achieved a partial response. Therefore, an overallresponse rate of 36% was achieved with 72% of patients achieving either apartial response or stable disease. Therapy was well tolerated, with infrequentgrade 3/4 leukopenia (4%). Nonhematologic toxicities included grade 3/4 fatigueand asthenia (20%), which was difficult to distinguish as treatment- orcancer-related.

A large study of weekly docetaxel for the treatment of first- and second-linemetastatic breast cancer patients is being conducted by Stemmler et al inGermany.[20] In the first cycle, patients receive 35 mg/m² per week for 6consecutive weeks and 2 weeks of rest, followed by treatment for 3 consecutiveweeks and 2 weeks of rest. Preliminary results in 33 evaluable patientsdemonstrate an overall response rate of 36%, with stable disease in anadditional 40%. Toxicity data for 40 patients included grade 3 neutropenia (3%),fluid retention (5%), nail toxicity (5%), and lacrimation (5%).

Comandone and colleagues treated 40 heavily pretreated metastatic breastcancer patients, all of whom had received prior anthracyclines, with weeklydocetaxel.[21] Treatment consisted of three cycles of docetaxel at 40 mg/m² for6 weeks, with 1 week of rest (one cycle). An overall response rate of 19% wasreported after two cycles of therapy with stable disease in 47.5% of patients.Toxicity data after one cycle included grade 3 neutropenia (2.5%) and grade 3fatigue (2.5%).

The University of Texas M. D. Anderson Cancer Center is conducting a phaseIII study comparing weekly and every-3-week docetaxel in patients withmetastatic breast cancer. In this study, patients are randomized to docetaxel at100 mg/m² every 3 weeks or docetaxel at 35 mg/m² per week for 6 weeks, followedby 2 weeks of rest.

Docetaxel Plus Anthracyclines

The taxanes and the anthracyclines have different mechanisms of action andare not completely cross resistant. These considerations led to the clinicaltesting of docetaxel in combination with doxorubicin and with epirubicin.[22] Aphase I dose escalation study showed docetaxel could be given safely incombination with doxorubicin, with an overall response rate of 71%.[23] Thedose-limiting toxicity with this regimen was febrile neutropenia—notunexpected with the combination of two bone marrow suppressing drugs. Therecommended phase II doses were doxorubicin at 50 mg/m² plus docetaxel at 75 mg/m²over 1 hour or doxorubicin at 60 mg/m² plus docetaxel at 60 mg/m² over 1hour.

Doxorubicin/Docetaxel Combination

Pharmacokinetics

Pharmacokinetic analyses of the doxorubicin/ docetaxelAT combination (doxorubicin [Adriamycin]/docetaxel [Taxotere]) have beenevaluated. Schüller and colleagues studied the pharmacokinetics of the agentsin sequence (without an interval separating administration) with doxorubicin at50 mg/m² first, followed immediately by docetaxel at 75 mg/m² (Schedule A) orafter a 1-hour interval between drug administration (Schedule B).[24]Doxorubicin pharmacokinetics demonstrated no significant difference with regardto the maximum concentration levels (Cmax), the area under theconcentration-time curve (AUC), or clearance with either dosing schedule. Thedata indicate an absence of a significant interaction on doxorubicinpharmacokinetics as a result of concomitant administration of docetaxel, with orwithout a 1-hour interval between administration. In contrast, doxorubicinsignificantly increased the AUC of docetaxel in both administration schedules. Astatistically significant increase in docetaxel AUC, and Cmax, and a decrease indocetaxel clearance was documented.

A study by Baker et al evaluated the pharmacokinetics of various doses ofdoxorubicin (40-60 mg/m²) and docetaxel (60-100 mg/m²) combinations.[25]Their results demonstrated that doxorubicin at 60 mg/m² in combination withdocetaxel at 75 to 100 mg/m² resulted in significantly lower clearance ofdoxorubicin, as compared with doxorubicin at 40 to 50 mg/m² in combination withdocetaxel at 60 to 75 mg/m². The authors conclude that limiting the doxorubicindose to 50 mg/m² may allow administration of the combination with a lower riskof febrile neutropenia.

Cardiac Toxicity

Additional phase I and II studies of the AT combinationproduced high response rates (up to 81%).[26-29] The doses used ranged from 40to 60 mg/m² for doxorubicin and 50 to 85 mg/m² for docetaxel. In a phase IIstudy conducted by the National Surgical Adjuvant Breast and Bowel Project(NSABP B-57), AT produced a response rate of 53% (PR, 47%; CR, 6%) withmanageable toxicity.[28] In contrast to the initial studies of paclitaxel anddoxorubicin in combination, an increase in anthracycline-induced cardiactoxicity has not been seen with this combination (Table1).[23-35]

Sparano et al[29] reported a phase II trial of doxorubicin and docetaxel plusgranulocyte colony-stimulating factor (G-CSF [Neupogen]) in patients withmetastatic breast cancer. Patients received doxorubicin (60 mg/m²) followed 1hour later by docetaxel (60 mg/m²) every 3 weeks for up to eight cycles. In thisstudy, the AT regimen produced a response rate of 57%. Fifteen patients (28%)were documented to have a decrease in the left ventricular ejection fractionbelow normal, and three patients (6%; 95% confidence interval [CI], 1%-15%)developed congestive heart failure, a rate similar to that reported withdoxorubicin alone.

The results of several large phase III trials comparing the AT combinationswith standard regimens for metastatic and primary breast cancer will assist indetermining the optimal chemotherapy regimen. One such trial compared AT withthe standard AC (doxorubicin [Adriamycin]/cyclophosphamide [Cytoxan]) regimen inpatients with metastatic breast cancer.[30] Preliminary data indicate that ATproduced a superior response rate (60% vs 47%, P = .012) and longer time toprogression (37.1 weeks vs 31.9 weeks, P = .0153) (Table2). Although a higherincidence of hematologic toxicity was noted, it was manageable. Pertinent tothis phase III evaluation was the low incidence of anthracycline-inducedcongestive heart failure; the incidence of congestive heart failure was 3% inthe AT treatment arm and 4% in the AC treatment arm. These results support thedata from phase II trials that found no augmentation of doxorubicin-inducedcongestive heart failure with the concurrent administration of docetaxel.

Preliminary results from another phase III randomized trial comparing TAC(docetaxel [Taxotere]/doxorubicin [Adriamycin]/cyclophosphamide [Cytoxan]) toFAC (fluorouracil [5-FU]/doxorubicin [Adriamycin]/cyclophosphamide [Cytoxan])have been reported.[31] A total of 475 patients with metastatic breast cancerwere randomized to treatment, with 238 patients receiving TAC (docetaxel at 75 mg/m², doxorubicin at 50 m/m2, cyclophosphamide at 500mg/m² every 3 weeks) and237 patients receiving FAC (5-FU at 500 mg/m², doxorubicin at 50 mg/m²,cyclophosphamide at 500 mg/m² every 3 weeks). A significantly higher responserate was reported for TAC (55%) vs FAC (42%, P = .008), with time to diseaseprogression and overall survival data pending final analysis. Therapy with bothTAC and FAC regimens produced primarily hematologic toxicities with grade 3/4neutropenia noted in 94% and 81% of patients, respectively. The incidence ofgrade 3/4 nonhematologic toxicities was low, including the infrequent occurrenceof clinical congestive heart failure reported in 2% and 1% of TAC- andFAC-treated patients, respectively.

Docetaxel/Epirubicin Combination

Several studies have evaluated docetaxel in combination with epirubicin (ET,docetaxel [Taxotere]/epirubicin [Ellence]) as first-line chemotherapy forpatients with metastatic breast cancer. In one study, the dose-limiting toxicitywas neutropenia and G-CSF was required in 44% of patients.[32] Close evaluationof cardiac function revealed that only one patient developed symptomaticcongestive heart failure and six additional patients had decreases in leftventricular ejection fraction with no symptoms. The overall response rate was66%. No pharmacokinetic interactions were observed between docetaxel andepirubicin

In another dose-escalation study, the maximum tolerated dose was achievedwith epirubicin at 60 mg/m² and docetaxel at 80 mg/m².[33] The dose-limitingevents were febrile neutropenia and grade 4 neutropenia. Four (9%) patientspresented a greater than 10% decrease of left ventricle ejection fraction andtreatment discontinuation was required in two of them; none of the patientsdeveloped congestive heart failure. The response rate was 53% in 34 evaluablepatients, with 15% complete and 38% partial response rates.

Trudeau and colleagues also reported a dose-limiting toxicity of febrileneutropenia in their phase I/II study.[34] Most cases occurred in the firstcycle and prophylactic G-CSF managed both its duration and severity. A responserate of 78% reported in the phase II portion of the study suggests a highlyactive regimen.

Results of a large phase II randomized study of the ET combination wererecently presented.[35] A total of 142 first-line metastatic breast cancerpatients were randomized to receive ET (epirubicin at 75 mg/m² plus docetaxel at75 mg/m²) or FEC (5-FU at 500 mg/m², epirubicin [Ellence] at 50 mg/m² andcyclophosphamide [Cytoxan, Neosar] at 500 mg/m²), with both regimensadministered once every 3 weeks. Overall response rates reveal an advantage withthe ET regimen with an overall response rate of 63% vs 34.3% for FEC. Mediantime to tumor progression was also longer in the ET- vs FEC-treated patients at7.8 months vs 5.9 months, respectively. These studies indicate that thedocetaxel/epirubicin combination is feasible and effective. Continued evaluationof the ET regimen in both the metastatic and adjuvant settings is ongoing.

Docetaxel Plus Capecitabine in Refractory Breast Cancer

Capecitabine (Xeloda) is an oral fluoropyrimidine approved by the FDA for thetreatment of patients with metastatic breast cancer who did not respond to priordoxorubicin and paclitaxel chemotherapy.[36] Capecitabine is activated at thetumor site by a series of enzymatic reactions. One of the most importantreactions is mediated by the enzyme thymidine phosphorylase (dThdPase), which isoverexpressed in many breast cancers. Sawada et al [37] showed that docetaxelenhances the efficacy of capecitabine and 5'-dFUrd, in vivo, probably bymodulating dThdPase activity in tumor tissues. In a human xenograft model, theseauthors showed a synergistic interaction between docetaxel and capecitabine.

A phase I/II dose-escalation study showed that capecitabine given orallytwice a day for 14 days plus docetaxel given IV on day 1 of an every 3-weekcycle was well tolerated.[38] In this study, the dose-limiting toxicity wasasthenia at the highest dose level of capecitabine, 1000 mg/m² bid, anddocetaxel at 100 mg/m². The most frequent side effect seen at all dose levelswas uncomplicated grade 3/4 neutropenia. No pharmacokinetic interaction wasdetected between the two drugs. The two dose levels recommended for furthertesting included capecitabine at 825 mg/m² bid, with docetaxel at 75 mg/m², andcapecitabine at 1,250 mg/m² bid, with docetaxel at 75 mg/m².

Villalona-Calero and colleagues administered docetaxel at 36 mg/m² weekly for3 out of 4 weeks (days 1, 8, and 15) plus capecitabine at 625 mg/m² bid or 750 mg/m²bid for 14 days (days 5-18) of the 4-week course in a phase I study.[39]Dose-limiting toxicities occurred in all three patients treated at thecapecitabine 750 mg/m² bid-dose level and included grade 3 hand-foot syndromeand grade 3 diarrhea. No grade 3/4 hematologic toxicities were observed. Thecombination proved efficacious with five partial and two minor responses,including one partial and one minor response in patients withpaclitaxel-refractory breast cancer.

Tonkin et al[40] published preliminary results of a phase I/II dose findingstudy of the combination of weekly docetaxel (30 or 36 mg/m²) and dailycapecitabine at 1,800 mg/ m2 for 14 days on a 21-day cycle. Docetaxel wasadministered on days 1, 8, and 15 every 21 days. Twelve patients were evaluablefor efficacy and toxicity. No grade 4 toxicities were observed. Grade 3toxicities included asthenia (five patients), nail loss (four patients),diarrhea (two patients), and neutropenia, mucositis, and nausea each in onepatient. The objective response rate was 50% (6/12), with a 17% (2/12) completeresponse rate. Two additional patients had stable disease, three had progressivedisease, and one patient was not evaluable.

Phase III Study

O’Shaughnessy and collaborators[41] conducted a phase III study ofdocetaxel at 75 mg/m² in combination with capecitabine at 1,250 mg/m² twicedaily on days 1 to 14 every 3 weeks vs single-agent docetaxel at 100 mg/m² every3 weeks for patients with metastatic breast cancer previously exposed toanthracyclines. The results from this large randomized study indicate that thedocetaxel/capecitabine combination is superior to docetaxel monotherapy. Theoverall response rate was significantly higher for the docetaxel pluscapecitabine combination arm vs docetaxel monotherapy (42% vs 30%, P = .006).The duration of response was 7.2 months in the combination arm vs 6.9 months forthe monotherapy arm, a difference that was not statistically significant.

Time to tumor progression, the primary study objective, was significantlysuperior for the docetaxel plus capecitabine combination at 6.1 months vs 4.2months for docetaxel monotherapy (P = .0001). Significant improved overallsurvival was also demonstrated for the combination arm at 14.5 months vs 11.5months for the monotherapy arm (P = .0112). Furthermore, 12- and 18-monthsurvival rates demonstrated a trend toward improvement for the docetaxel pluscapecitabine arm vs the docetaxel monotherapy arm. Of note, only 15% of patientsinitially randomized to docetaxel received capecitabine at the time of diseaseprogression. It is unclear whether sequential, full-dose, single-agent docetaxelfollowed by capecitabine would be as effective as the combination and possiblyhave less toxicity.

The most frequently reported side effect for both treatment arms was grade3/4 neutropenia, which occurred in 63% of cycles in the combination arm and in72% of cycles in the monotherapy arm. Grade 3/4 toxicities, which occurred in ahigher percentage of patients in the docetaxel plus capecitabine arm, includedhand-foot syndrome, stomatitis, diarrhea, and nausea. In contrast, a slightlyhigher percentage of patients in the docetaxel monotherapy arm experienced grade3/4 fatigue and neutropenic fever.

Ongoing studies of the docetaxel and capecitabine regimen are investigatingalternate dosing strategies, such as weekly docetaxel administration schedulesdiscussed above, in an attempt to enhance the safety and efficacy of thispromising combination.

Docetaxel Plus Other Chemotherapies

Docetaxel/Vinorelbine Combination

A multicenter phase II study of weekly docetaxel plus vinorelbine wasrecently reported.[42] Therapy consisted of vinorelbine at 30 mg/m² on days 1and 15 and docetaxel at 30 mg/m² on days 1, 8, and 15, every 4 weeks. Dependingon the absolute neutrophil counts on the day scheduled for administration ofchemotherapy, a 5-day course of G-CSF 5 µg/kg/d was given. In this study, theresponse rate was 64.3% in patients receiving docetaxel plus vinorelbine asfirst-line chemotherapy, including eight complete (19%) and 19 partialremissions (45.3%); 11 patients (26.2%) had disease stabilization and only four(9.5%) progressed. Second-line treatment with this regimen resulted in eight(53.3%) of 15 objective responses; four had stable disease and three hadprogressive disease. The median time to progression was 12 months in thefirst-line and 9.8 months in the second-line setting, respectively. After amedian follow-up time of 18 months, 38 patients (65%) were still alive withmetastatic disease.

Myelosuppression was commonly observed and was complicated by septicemia infour cases; grade 3 or 4 thrombocytopenia was seen in two patients (4%), andgrade 3 anemia was seen in only one patient (2%). Severe (grade 3)nonhematologic toxicity (except for alopecia) was rarely observed;nausea/vomiting occurred in two patients (4%), and stomatitis, peripheralneuropathy, and skin toxicity, in one patient each. These data suggest thatdocetaxel/vinorelbine, with or without G-CSF, is an effective and fairlywell-tolerated regimen for the treatment of advanced breast cancer. It might beparticularly useful in patients previously exposed to adjuvant or palliativeanthracyclines and/or alkylating agents.

Docetaxel/Gemcitabine Combination

There have been numerous studies testing docetaxel in combination withgemcitabine (Gemzar) for various tumor types. A trial by Spiridonidis et alenrolled 40 patients with advanced malignancies and prior chemotherapy exposureinto a protocol in which they received gemcitabine at 800 mg/m² on days 1, 8,and 15, and docetaxel at 45 to 100 mg/m² on day 1 or day 15.[43] The day1-docetaxel administration schedule proved feasible for administration.Hematologic toxicities included grade 4 neutropenia (n = 16), febrileneutropenia (n = 3), and grade 3/4 thrombocytopenia (n = 9). Nonhematologictoxicities included asthenia, flu-like symptoms, and fluid retention. Activitywas notable; four of the seven evaluable metastatic breast cancer patients (57%)had a partial response.

A phase II study conducted by the same investigators indicated that thecombination is feasible for second-line treatment of metastatic breast cancerwith relatively full doses of both agents utilizing day-1 docetaxel, 100 mg/m²,and gemcitabine, 800 mg/m² on days 1, 8, and 15.[44] A total of 32 previouslytreated metastatic breast cancer patients were enrolled and are evaluable forsafety and efficacy. The overall response rate on an intent-to-treat basis was59%, with three CR and 16 PR. Side effects included grade 4 neutropenia (n =31), febrile neutropenia (n = 3), grade 3 anemia (n = 2), and grade 3/4thrombocytopenia (n = 2). Asthenia (n = 8) was the most prominent nonhematologictoxicity.

Another phase II study has been conducted with the docetaxel and gemcitabinecombination in anthracycline-resistant advanced breast cancer.[45] Treatmentconsisted of docetaxel at 75 mg/m² on day 1 and gemcitabine at 1,000 mg/m² ondays 1 and 8. An overall response rate of 36% was attained, with 3 CR and 11 PR.Toxicities include grade 3/4 neutropenia (49%), anemia (10%), fatigue (10%), andnausea/vomiting (8%). Future studies by the investigators will incorporateprophylactic G-CSF to reduce the incidence of febrile neutropenia and tomaintain dose intensity.

Docetaxel Plus Trastuzumab in HER2-Overexpressing Patients

The HER2/neu gene (aka c-erbB2 or neu) is amplified in 20% to 30% of invasivebreast carcinomas. Overexpression of the HER2 oncoprotein has been associatedwith poor prognosis.[46] Women whose tumors overexpress HER2/neu have a worsesurvival compared with patients whose tumors do not overexpress thisprotein.[47] The HER2/neu gene and protein study can be measured informalin-fixed, paraffin-embedded tissue by fluorescence in situ hybridization(FISH) and immunohistochemistry (IHC), respectively.

Trastuzumab is a humanized monoclonal antibody directed against the HER2protein. The response rate of single-agent trastuzumab ranges from 11% to40%[48,49], depending on the prior exposure to chemotherapy and the method usedfor patient selection. A phase III randomized study showed that addingtrastuzumab to paclitaxel improves response rates, duration of response, time toprogression, and overall survival.[50]

A synergistic interaction between docetaxel and trastuzumab has beendemonstrated in vivo and in vitro.[51] Ongoing phase II studies are evaluatingthe safety and efficacy of docetaxel in combination with trastuzumab. Phase IIstudies are evaluating the safety and efficacy of weekly docetaxel incombination with trastuzumab. In a study conducted at The University of Texas M.D. Anderson Cancer Center, patients received docetaxel at 35 mg/m² andtrastuzumab weekly for 3 weeks, followed by 1 week with no treatment. This studyshowed a response rate of 63%.[52] Nicholson et al are investigating docetaxelat 35 mg/m² given once a week for 6 weeks, followed by 2 weeks of rest.[53]Trastuzumab is given weekly without interruption. The reported response rate todate is 63%.

Triplet Drug Combinations

Two, parallel phase II studies of the triplet drug combination of docetaxel,a platinum agent (cisplatin or carboplatin), plus trastuzumab have beencompleted by the Breast Cancer International Research Group (BCIRG).[54] TheTCarboH triplet (docetaxel [Taxotere], carboplatin, and trastuzumab [Herceptin])study was conducted in North America, with The University of California, LosAngeles (UCLA) serving as the lead institution. The TCisH (docetaxel [Taxotere],cisplatin, trastuzumab [Herceptin]) combination was evaluated in Canada andEurope. Overall response rates of 56% and 79% were reported for the TCarboH andTCisH regimens, respectively. Time to progression was 12 and 9.9 months for theTCarboH and TCisH regimens, respectively. The data is highly promising in thispopulation of poor-prognosis patients. Therapy was well tolerated, with the mostcommon grade 3/4 toxicities of both regimens being febrile neutropenia, anemia,asthenia, and nausea. Importantly, grade 3/4 cardiac toxicities were minimal.

An additional study being conducted at the University of Pittsburghstratifies patients according to HER2/neu status.[55] Patients withHER2/neu-negative tumors are treated with TCarbo (docetaxel [Taxotere] pluscarboplatin), and patients with HER2/neu-positive tumors (2+ or 3+overexpression by IHC or FISH) are treated with TCarboH. Thus far, an overallresponse rate of 88% was reported in HER2/neu-overexpressing patients receivingTCarboH. Continued investigation and analysis of the docetaxel and trastuzumabcombinations in the metastatic, as well as in the adjuvant and neoadjuvantsettings, are ongoing.

Combining Docetaxel With Novel Biologic Agents

There is great interest in developing novel molecular-based therapeuticstargeted at inhibition of tumor cell proliferation pathways. Promising targetsinclude growth factor receptors and their ligands, intracellular signaltransduction molecules, cell-cycle regulatory proteins, and transcriptionfactors.[56] However, drugs directed against these molecular targets are notlikely to produce complete responses in patients with metastatic solid tumors,and it will be critical to combine them with chemotherapy in order to effectmaximal tumor reduction.

Docetaxel is an excellent cytotoxic drug to evaluate the therapeutic role ofnovel biologic therapy. After phase I/II trials are completed to determinesafety and preliminary efficacy data, phase III trials would determine theadditive effects of novel agents over single-agent docetaxel. Using thistreatment paradigm, docetaxel is currently being evaluated in combination withflavopiridol, bcl-2 antisense (G3139, Genasense), monoclonal antibodies directedagainst growth factor receptors, and farnesyl transferase inhibitors, amongothers.

Conclusion

Docetaxel is an excellent choice for the first- and second-line treatment ofpatients with metastatic breast cancer. In patients with anthracycline-resistantbreast cancer, docetaxel activity is impressively and consistently high in alltrials reported in the literature (Table 3).[9-12] Although polychemotherapyregimens produce higher response rates compared with single-agent therapy, thesurvival impact is modest. Anthracycline plus taxane regimens are the mosteffective therapies—although at the price of higher toxicity—and should beconsidered for patients with rapidly growing visceral metastases, lymphangiticspread, or locally advanced breast cancer (Table4).[30-35] For most patients,the available data support the sequential use of single-agent docetaxel, eitheras front-line or after the usual two- or three-drug combination regimens (eg,FAC, FEC, CMF).

Marked progress has been made to devise more tolerable docetaxelchemotherapy, using more effective antiemetics, antibiotics, and hematopoieticgrowth factors. Development of novel therapeutic agents continues, based onexpanded biological understanding of tumorigenesis and tumor progression. All ofthese agents will likely be combined with cytotoxic chemotherapy to achievemaximum benefit. The high efficacy of docetaxel as a single-agent therapy makesit an excellent candidate to evaluate the potential role of novel agents withdifferent mechanisms of action.