Review of Docetaxel/Doxorubicin Combination in Metastatic Breast Cancer

August 1, 1997

Docetaxel (Taxotere) and doxorubicin (Adriamycin) have each demonstrated significant activity in metastatic breast cancer. Thus, the combination of docetaxel and doxorubicin has been evaluated in phase I trials to

ABSTRACT: Docetaxel (Taxotere) anddoxorubicin (Adriamycin) have each demonstrated significant activity inmetastatic breast cancer. Thus, the combination of docetaxel and doxorubicinhas been evaluated in phase I trials to establish the dose-limiting toxicity,maximum tolerated dose, recommended dose for future phase II and III studies,and toxicity profile of the two agents used in combination. Results fromphase I trials in patients with metastatic breast cancer indicate thatthe docetaxel/doxorubicin combination is well tolerated. The recommendeddose for the combination regimen is either 50 mg/m² of doxorubicinfollowed by 75 mg/m² of docetaxel or 60 mg/m² of both drugs,without granulocyte colony-stimulating factor (G-CSF) (filgrastim [Neupogen])support. Febrile neutropenia complicated by grade 3 infection was the dose-limitingeffect at the maximum tolerated dose. The response rate at this dose levelwas 90%. Based on the preliminary results of phase I studies, further phaseII and III studies of a docetaxel/doxorubicin combination regimen are warranted. [ONCOLOGY11(Suppl 8):31-33, 1997]

Introduction

Docetaxel (Taxotere) and doxorubicin (Adriamycin) are considered 2 ofthe most active chemotherapeutic agents for patients with metastatic breastcancer. When used as first-line therapy, single-agent docetaxel, administeredat a dose of 100 mg/m² as an intravenous infusion over 1-hour onceevery 3 weeks, has produced response rates ranging from 57% to 69%.[1]At the same dose, docetaxel also has a high level of activity in second-and third-line regimens,[1] as well as in anthracycline-resistant or -refractorypatients with metastatic breast cancer.[2,3]

Doxorubicin is widely considered the agent of choice for metastaticbreast cancer in first-line therapy. Response rates with doxorubicin infirst-line regimens range from 29% to 43%, and the median survival timeis approximately 2 years.[4] The rationale for using docetaxel and doxorubicinin combination for patients with metastatic breast cancer includes thefacts that doxorubicin-containing regimens are among the most active andthat there is at least a partial clinical cross-resistance between thetwo agents.[2]

Docetaxel/DoxorubicinCombination Trials

Two phase I trials, one being performed in France[5,6] and the otherin Japan[7], characterize the ongoing ef forts to investigate the potentialbenefit of docetaxel/doxorubicin combination regimens in patients withmetastatic breast cancer. Both trials are designed to determine the dose-limitingtoxicity, the maximum tolerated dose, the recommended dose for phase IIand III trials, and the safety profile of the combination.

The study by Itoh and colleagues[7] also examined the clinical and pharmacokineticimpact of the sequence of administration of docetaxel and doxorubicin.Inclusion criteria for study participation in both trials included patientswith measurable and/or evaluable disease who had not received prior chemotherapyfor metastatic disease and no prior adjuvant chemotherapy for at least1 year.

In the French study,[5,6] prior adjuvant anthracycline therapy was allowed,provided patients had received a cumulative dose that was less than orequal to the following: 300 mg/m² of doxorubicin, 500 mg/m² ofepirubicin, or 500 mg/m² of tetrahydropyranyl (THP) doxorubicin. Inthe Japanese study,[7] no anthracycline-based chemotherapy was allowed,and Eastern Cooperative Oncology Group (ECOG) performance status had tobe less than 3. Patients were also required to have normal baseline leftventricular ejection fraction levels by multiple-gated acquisition scan.

Dose-Escalation Study

Treatment Plan

In the French study,[5,6] the treatment plan included doxorubicin administeredintravenously as a bolus over 15 minutes, followed 1 hour later by docetaxel,which was given by intravenous infusion over 1 hour. This schedule waslater repeated every 3 weeks on an outpatient basis. A total of 6 doselevels of doxorubicin/docetaxel were studied: 40 mg/m² of doxorubicin/50 mg/m² of docetaxel (level 1); 40 mg/m²of doxorubicin/60 mg/m²of docetaxel (level 2); 50 mg/m² of doxorubicin/60 mg/m²of docetaxel(level 3); 50 mg/m² of doxorubicin/75 mg/m² of docetaxel (level4); 50 mg/m² of doxorubicin/85 mg/m² of docetaxel (level 5);60 mg/m² of doxorubicin/60 mg/m² of docetaxel (level 6) (Table1).

Patients did not receive prophylactic granulocyte colony-stimulatingfactor (G-CSF) (Granocyte). Premedication for the prevention of hypersensitivityreactions and fluid retention included 8 mg of dexamethasone administeredevery 6 hours for 3 days, beginning the day prior to chemotherapy; 10 mgof cetirizine (Zyrtec) administered 7 hours and 1 hour before the infusionwith docetaxel; and 300 mg of ranitidine (Zantac) administered once dailyfor 3 days, starting 1 day prior to chemotherapy.

Preliminary Results

Currently, there are 42 patients entered in this trial. Median age is48 years (range: 30 to 69 years). A total of 24 of 42 patients (57%) hadreceived prior adjuvant chemotherapy, of whom 22 of 24 (92%) received anthracycline-basedadjuvant chemotherapy. Of these 42 patients, 79%, had visceral involvement,36% with 2 or more metastatic sites, 43% with liver involvement, and 41%with bone lesions.

Overall, the median number of cycles of the combination administeredwas 7 (range: 2 to 10). The overall median cumulative dose of doxorubicinwas 310 mg/m² (range: 99 to 534 mg/m²) and of docetaxel 423 mg/m²(range: 149 to 707 mg/m²). At all dose levels, the most frequent toxicitywas neutropenia (Table 1). Although grade4 neutropenia occurred in more than 73% of the cycles for dose levels 2through 6, febrile neutropenia occurred in less than 14% of the cycles.Febrile neutropenia was complicated by infection in 2 patients at doselevel 5, thus defining the maximum tolerated dose as 50 mg/m² of doxorubicincombined with 85 mg/m² of docetaxel without prophylactic G-CSF support.

The nonhematologic toxicities associated with the combination of doxorubicinand docetaxel were minor, with maximum severity being a grade 2 or less.The most common nonhematologic toxicities were those typically seen withmost chemotherapeutic regimens, namely, nausea, vomiting, diarrhea, andstomatitis. Of particular note was the lack of severe fluid retention inthis study, with a mean cumulative dose of docetaxel of 460 mg/m²and the lack of grade 3 mucositis. Moderate fluid retention was noted in19% of the patients.

Decreased left ventricular ejection fraction was noted in 4 patients,and no patient presented with congestive heart failure after a median follow-upof 18 months and a median cumulative dose of doxorubicin of 392 mg/m²(range: 240 to 559 mg/m²). No patients were discontinued from thestudy, even though most of the patients (55%) had received doxorubicinat cumulative doses greater than 360 mg/m².

The overall response rate across all dose levels was 72%. However, atthe dose level of 50 mg/m² of doxorubicin combined with 75 mg/m²of docetaxel, the response rate was 90%. In addition, patients with metastasisto the liver achieved a response rate of 83% at all dose levels.

Dose-Sequence Study

Itoh and colleagues[7] recently reported the preliminary results ofan ongoing trial that assessed the impact of alternating the sequence ofadministration of doxorubicin and docetaxel when used in combination forpatients with advanced breast cancer. The treatment plan includes 4 doselevels. For dose level 1, patients receive 50 mg/m² of docetaxel followedby 40 mg/m² of doxorubicin for 1 cycle. In the second cycle, 40 mg/m²of doxorubicin was administered first followed by 50 mg/m² of docetaxel.

Similarly, patients in dose level 2 receive 60 mg/m² of docetaxelfollowed by 40 mg/m² of doxorubicin for 1 cycle. In the second cycleof dose level 2, 40 mg/m² of doxorubicin is administered first, followedby 60 mg/m² of docetaxel. In dose level 3, patients receive 50 mg/m²of doxorubicin followed by 60 mg/m² of docetaxel. Patients in doselevel 4 receive 50 mg/m² of doxorubicin followed by 70 mg/m²of docetaxel. The sequences in dose levels 3 and 4 are not switched.

Dose-limiting toxicity was defined as: grade 4 neutropenia for 7 daysor longer, grade 4 neutropenia for more than 3 days, accompanied by feverassociated with an infection, grade 4 thrombocytopenia; or any grade 3or 4 nonhematologic toxicity, except alopecia, vomiting, and general malaise.

The maximum tolerated dose has not been reached for the sequence ofdoxorubicin followed by docetaxel. Profound grade 4 neutropenia was notedin 3 patients with the sequence of 60 mg/m² of docetaxel, followedby 40 mg/m² of doxorubicin. Although the sequence of administrationdid not affect the pharmacokinetic parameters of either drug, these preliminaryresults suggest that drug sequence may play a role in the duration of neutropenia.The authors noted that patient accrual is ongoing at dose level 2, withthe sequence of 50 mg/m² of doxorubicin followed by 60 mg/m²of docetaxel.

Discussion

Based on the results from the phase I trial by Dieras and colleagues,[6]the regimen of doxorubicin followed by docetaxel appears to be a very activecombination, with an overall response rate of 90% at the highest feasibledose without G-CSF support.

The recommended dose and sequences for future phase II and III trialsis 50 mg/m² of doxorubicin followed by 75 mg/m² of docetaxel,or 60 mg/m² of both drugs, once every 3 weeks without prophylacticG-CSF support. In 10 patients at the former dose level, the response ratewas 90%.

Although asymptomatic abnormal left ventricular function was noted in4 patients (and reversible in 3 patients), there were no cases of doxorubicin-relatedcongestive heart failure. This is of particular importance because retrospectivestudies have estimated that the incidence of doxorubicin-related congestiveheart failure is 3% to 4% in patients who receive a cumulative dose of450 mg/m² of doxorubicin as single-agent therapy.[8-10]

The incidence of congestive heart failure following the combined useof doxorubicin and paclitaxel (Taxol) was reported by Gianni and colleagues.[11]These authors noted that reversible congestive heart failure occurred in21% (range: 7% to 35%; 95% confidence interval) of patients who had receiveda 3-hour infusion of paclitaxel combined with a bolus dose of doxorubicin.Of the 6 affected patients 5 had received a total dose of 480 mg/m²of doxorubicin, with the remaining 1 patient experiencing congestive heartfailure only after receiving a total dose of 120 mg/m².[11]

The same cardiotoxicity profile was observed in another study of thecombination of paclitaxel and doxorubicin. Gehl et al[12] reported that50% of the patients developed an abnormal left ventricular ejection fraction,resulting in congestive heart failure in 20% of the patients.

In summary, doxorubicin followed by docetaxel appears to be a promisingcombination regimen for patients with untreated metastatic breast cancer.Except for grade 4 neutropenia and/or its complications, no severe nonhematologictoxicities were observed with this combination. Based on the high levelof activity noted, additional studies are warranted to determine the optimalintegration of docetaxel in combination with anthracyclines in the adjuvantsetting.

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2. Ravdin P, Burris HA, Cook G, et al: Phase II trial of docetaxel inadvanced anthracycline- resistant or anthracenedione-resistant breast cancer.J Clin Oncol 13:2879-2885, 1995.

3. Valero V, Holmes FA, Walters RS, et al: Phase II trial of docetaxel,a new, highly antineoplastic agent in the management of patients with anthracycline-resistantmetastatic breast cancer. J Clin Oncol 13:2886-2894, 1995.

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6. Dieras V, Gruia G, Pouillart P, et al: A phase I study of the combinationof docetaxel (D) and doxorubicin (Dx) in first line CT treatment of metastaticbreast cancer (MBC). Preliminary results (abstract 313). Breast CancerRes Treat 37:(suppl) 91, 1996.

7. Itoh K, Fujii H, Minami H, et al: Phase I and pharmacological studyof docetaxel (Doc) combined with doxorubicin (Dox) for advanced breastcancer (abstract 610). Proc Am Soc Clin Oncol 16, 1997.

8. Myers CE, Chabner BA: Anthracyclines, in Chamber BA, Collins JM (eds):Cancer Chemotherapy: Principles and Practice, pp 356-381. 2nd ed, Philadelphia,JB Lippincott, 1990.

9. Minow RA, Benjamin RS, Gottlieb JA, et al: Adriamycin (NSC 123127)cardiomyopathy. An overview with determination of risk factors. CancerChemother Rep 6:185-190, 1975.

10. Alexander J, Dainiak N, Thorning D, et al: Serial assessment ofdoxorubicin cardiotoxicity with quantitative radionuclide angiocardiography.N Engl J Med 300:278-283, 1979.

11. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusionin combination with bolus doxorubicin in women with untreated metastaticbreast cancer: High antitumor efficacy and cardiac effects in a dose-findingand sequence-finding study. J Clin Oncol 13:2688-2699, 1995.

12. Gehl J, Boesgaard M, Paaske T, et al: Combined doxorubicin and paclitaxelin advanced breast cancer: Effective and cardiotoxic. Ann Oncol 7:687-693,1996.