This nonblinded, multicenter, randomized phase III study compares the median time to progression (primary endpoint), response rate, and quality of life, safety, and survival of
ABSTRACT: This nonblinded, multicenter, randomized phaseIII study compares the median time to progression (primary endpoint), responserate, and quality of life, safety, and survival of docetaxel (Taxotere)vs mitomycin (Mutamycin) plus vinblastine (Velban) in patients with metastaticbreast cancer in whom previous anthracycline-containing chemotherapy hasfailed. Patients were randomized to receive an intravenous infusion ofeither 100 mg/m² of docetaxel for 1 hour every 3 weeks, or 12 mg/m²of mitomycin (Mutamycin) every 6 weeks plus 6 mg/m² of vinblastineevery 3 weeks. This preliminary analysis presents data on 200 patientsamong 392 patients recruited. Median time to progression was longer inthe group treated with docetaxel compared with the mitomycin/vinblastinegroup (17 vs 9 weeks). The overall response rates were higher with docetaxel(28% vs 13%, respectively), and fewer patients in the docetaxel group hadprogressive disease as their best overall response (29% vs 48%). As expected,thrombocytopenia was more common in the mitomycin/vinblastine group, andneutropenia occurred more frequently in the docetaxel group. Severe fluidretention in the docetaxel group (8.7%) resulted in treatment discontinuationin 5 patients (5%). Severe thrombocytopenia (12%) and constipation (6%)led to treatment discontinuation in 7 and 3 patients, respectively, inthe mitomycin/vinblastine group. Based on this preliminary analysis, docetaxelappears to be equally as safe as and more active than mitomycin/vinblastinein patients with metastatic breast cancer in whom previous anthracycline-containingchemotherapy has failed. These results are subject to cautious interpretationbecause this analysis was conducted on the first 200 patients who finishedthe study treatments, and these preliminary results may underestimate responseand overstate treatment discontinuation rates. Thus, the final analysison the entire patient population is necessary to confirm these preliminaryfindings. [ONCOLOGY 11(Suppl 8):25-30, 1997]
Metastatic breast cancer is an incurable disease, and, to date, thereis no standard chemotherapy for patients with metastatic breast cancerin whom anthracycline-containing chemotherapy has failed. Tubulin-bindingagents, such as vinblastine (Velban), vindesine (Eldisine), vinorelbine(Navelbine), or paclitaxel (Taxol) have yielded response rates of 15% to35%[1-6] and mitomycin (Mutamycin), another commonly used agent in second-lineregimens, has achieved objective response rates ranging from 15% to 25%at doses of 10 to 20 mg/m² administered every 4 to 8 weeks.[7,8]
Before the approval of paclitaxel and docetaxel (Taxotere), mitomycinand vinblastine (bolus or continuous infusion), either alone or in combination,were the backbone of most combinations used in patients in whom a prioranthracycline-containing regimen had failed. Several authors regardthe combination of mitomycin and vinblastine as producing the highest antitumoractivity compared with each drug used as a single agent[7,9-16], even thoughno advantage in survival was observed. So far, no large phase III studycomparing paclitaxel to another chemotherapy regimen in patients with anthracycline-resistantadvanced breast cancer has been reported.
Data from numerous phase II studies indicate that 100 mg/m² ofdocetaxel administered as a 1-hour infusion once every 3 weeks producesresponse rates of up to 58% in this group of patients.[17-21] These resultsappear significantly superior to other single agents and at least equivalentto the various combination therapy regimens.
This present trial represents the first phase III randomized study comparinga taxane (docetaxel) to an accepted salvage regimen (mitomycin/vinblastine)in patients in whom an anthracycline-containing regimen has failed. Thispreliminary analysis performed on 200 patients among the 392 recruitedpresents comparative data on the median time to progression, response rates,and toxicity profiles following treatment with docetaxel or the mitomycin/vinblastinecombination regimen.
Women aged 18 to 75 years who had histologically or cytologically provenprogressive metastatic adenocarcinoma of the breast and measurable and/orevaluable disease were considered for study participation provided theymet the following criteria: Karnofsky performance status of at least 60%and failure of previous therapy with an anthracycline-containing regimendefined as:
Laboratory entry criteria included the following values: absolute neutrophilcount ³ 2.0 × 109/L; a platelet count ³ 100.0 × 109/L; total bilirubin £ 27.5 µM/L(1.5 g/dL); aspartate aminotransferase (ASAT) or alanine aminotransferase(ALAT) £ 3 × upper normal limit (UNL); alkaline phosphatase £ 6 × UNL; ASAT or ALAT or both 1.5 or less × UNL associatedwith alkaline phosphatase £ 2.5 × UNL; serum creatinine £ 175 µM/L (2 mg/dL); normal cardiac function using multiple-gatedacquisition scan or echocardiography in patients who have received cumulativedoses of doxorubicin exceeding 550 mg/m² or 900 mg/m² of epirubicin.
Specific criteria for exclusion were: more than one line of chemotherapyfor advanced or metastatic disease; presence of brain or leptomeningealmetastases; prior or concurrent malignancies, with the exception of adequatelytreated in situ carcinoma of the uterine cervix and cured nonmelanoma skincancer, and/or an osteoblastic skeletal lesion, and/or a single osteolyticlesion, and/or lymphedema, and/or pulmonary lymphangitic metastases andskin lymphangitis, and/or pleural effusion, and/or ascites, as the onlysite of disease; symptomatic peripheral neuropathy of at least grade 2according to National Cancer Institute (NCI) Common Toxicity Criteria;unstable heart disease requiring treatment; congestive heart failure; anginapectoris or significant arrhythmias; and history of myocardial infarctionwithin 6 months of study entry.
Patients were recruited from 49 centers worldwide. Ethics committeeapproval and patient written informed consent were obtained before thestart of the trial.
Study Design and Treatment Plan
This was a nonblinded, randomized, multicenter phase III study. Therandomization list was stratified by center, and patients were assignedrandomly to receive an intravenous infusion of either 100 mg/m² ofdocetaxel for 1 hour every 3 weeks, or 12 mg/m² of mitomycin every6 weeks plus 6 mg/m² of vinblastine every 3 weeks (1 cycle is definedon the basis of vinblastine administration; ie, every 3 weeks).
Premedication was specified for patients in the docetaxel group only,comprising 8 mg of oral dexamethasone, given 13 hours, 7 hours, and 1 hourbefore docetaxel infusion, and for an additional 4 days at a dose of 8mg twice daily, starting after the docetaxel infusion.
The maximum duration of treatment was 10 cycles, unless progressionor unacceptable toxicity occurred. If a patient failed to respond to theassigned treatment, further treatment was at the discretion of the investigator.Patients withdrawn from the study before progression could not receiveother antitumor therapy until progression was documented, unless deemednecessary by the investigator. Patients were assessed every 3 months duringfollow-up until death, to document time to progression and survival.
Dose reductions were permitted for severe hematologic and nonhematologictoxicities other than alopecia and anemia, graded according to NCI CommonToxicity Criteria. A maximum of 2 dose reductions were allowed per patient--ie,from 100 to 75 mg/m² and from 75 to 55 mg/m² for docetaxel, from12 to 8 mg/m² and from 8 to 5 mg/m² for mitomycin, and from 6to 4 mg/m² for vinblastine.
Tumor Assessments and Outcome Analysis
A complete tumor assessment was performed during the 3 weeks beforethe first infusion of study medication, comprising physical examination,chest x-ray, bone scintigraphy and bone radiological examination, abdominalcomputed tomography scan or ultrasound, and physical examination. All evaluableand nonevaluable lesions were to be assessed at cycles 3, 6, 8, and 10.Weekly blood counts were performed.
The primary efficacy variable was time to progression, calculated fromthe date of randomization to the first progression. Response rate, definedas the percentage of patients in the group who achieved a complete or partialresponse, was a secondary efficacy variable. Patients with disease progressionbefore the end of the second treatment cycle were considered to have earlyprogression, whereas patients who received at least 2 cycles of therapyhad their response to treatment classified as follows: complete response,partial response, stable disease, or progressive disease, according tothe World Health Organization response criteria. All patients who receivedat least one infusion of study medication were evaluable for safety.
A two-tailed log-rank test was used to compare median time to progressionbetween treatment groups. A significance level of 0.001, according to Petosequential procedure, was used for this interim evaluation, which wasperformed after patient accrual was completed. Times to event variableswere analyzed by the Kaplan-Meier method. All analyses were performed atleast on the randomized (intent-to-treat) population.
This preliminary analysis reports on data from 200 patients randomizedto receive either docetaxel (105 patients) or mitomycin plus vinblastine(95 patients). No difference in patient and tumor characteristics was foundin the treatment groups (Table 1). Withregard to metastatic sites, patients in this study had large tumor burdens,as indicated by the incidence of visceral involvement (74% in the docetaxelgroup and 73% in the mitomycin/vinblastine group), liver metastases (43%and 48%), and by 46% of patients having 3 or more metastatic sites involved.Measurable disease (as opposed to evaluable disease) was noted in a highpercentage of cases (80% for the docetaxel group and 76% for mitomycin/vinblastine).
A median of 6 cycles (range: 1 to 12) of docetaxel was administeredto 104 patients and a median of 3 cycles (range: 1 to 10) of mitomycin/vinblastinewas administered to 94 patients. The median relative dose intensity was0.96 (range: 0.62 to 1.04) for docetaxel and 0.99 (range: 0.67 to 1.43)for mitomycin and 0.98 (range: 0.66 to 1.24) for vinblastine. A high percentageof patients in both treatment groups received a relative dose intensityof more than 70% of the planned dose (94% for the docetaxel group and 98%for the mitomycin/vinblastine group).
Response Rate and Median Time to Progression
The overall response rate for patients (intent-to-treat analysis) receivingdocetaxel was 28% (range: 20% to 36%; 95% confidence interval) comparedwith 13% (range: 7% to 21%; 95% confidence interval) for the mitomycin/vinblastinegroup (Table 2). This trend in responserates was also seen in patients with bidimensionally measurable lesions,with 32% (range: 21% to 44%; 95% confidence interval) of docetaxel patientsresponding compared with 12% (range: 5% to 23%; 95% confidence interval)of patients receiving mitomycin/vinblastine. Of the docetaxel-treated patients,5% achieved a complete response compared with 2% of the mitomycin/vinblastinegroup. More patients in the mitomycin/vinblastine group (48%) experienceddisease progression as their best response to treatment compared with docetaxel-treatedpatients (29%).
Preliminary analysis indicates that patients who received docetaxelhad a longer median time to progression (17 weeks) compared with patientstreated with mitomycin/vinblastine (9 weeks) (P = .015) (Figure1).
The primary hematologic toxicity noted during the study was grade 3to 4 neutropenia, which was seen in 89% of patients treated with docetaxeland 67% of patients receiving mitomycin/vinblastine (Table3). Febrile neutropenia was more prevalent in the docetaxel-treatedpatients (11%) compared with patients in the mitomycin/vinblastine group(1%). Grade 3 to 4 infections due to neutropenia were also more commonin the docetaxel group (12%) compared with the mitomycin/vinblastine group(1%). In contrast, more patients in the mitomycin/vinblastine group (12%)experienced grade 3 to 4 thrombocytopenia than docetaxel-treated patients(6%).
With regard to acute nonhematologic toxicities, patients receiving docetaxelexperienced more severe stomatitis (12% vs 1%) and diarrhea (9% vs 0%)compared with mitomycin/vinblastine-treated patients (Table4). Grade 3 to 4 vomiting and nausea were uncommon in both treatmentgroups. The grade 3 to 4 or severe chronic nonhematologic toxicities notedin the docetaxel and mitomycin/vinblastine treatment groups included asthenia(16% vs 9%), constipation (1% vs 6%), and pulmonary disorder (3% vs 6%).Reports of grade 3 to 4 docetaxel-specific side effects were infrequentin this treatment group: fluid retention (10%), nail disorders (4%), andneurosensory toxicity (2%). Alopecia was more frequent with docetaxel (64%vs 17%).
The most common reason for treatment discontinuation among the 200 patientswas disease progression: docetaxel (54% of cases; 57 of 105 patients) andmitomycin/vinblastine group (61%; 58 of 95 patients). Disease progressionled to the deaths of 4 patients in each treatment group. The 2 groups differedwith regard to the adverse events that led to discontinuing treatment.Thrombocytopenia in the mitomycin/vinblastine arm (7% of patients) andfluid retention (6% of patients) in the docetaxel arm were the main treatment-endingadverse events.
The preliminary analysis of this large, multicenter phase III trialsuggests that 100 mg/m² of docetaxel administered as a 1-hour infusiononce every 3 weeks is more active than 12 mg/m² of mitomycin every6 weeks plus 6 mg/m² vinblastine every 3 weeks in patients with metastaticbreast cancer in whom previous anthracycline-containing chemotherapy hasfailed.
The overall response rate achieved with docetaxel (28%) was greaterthan that achieved by the combination regimen (13%) in a population ofpatients with a high proportion of true resistance (primary and secondary)to anthracyclines. An advantage in response rate was also seen in patientswith bidimensionally measurable disease (32% vs 12%). In addition, therewere fewer patients in the docetaxel group who had progressive diseaseas a best response (29% vs 48%), and in this preliminary analysis, therewas already a difference in terms of median time to progression (17 vs9 weeks) in favor of docetaxel compared with mitomycin/vinblastine.
The present trial represents the first large phase III trial comparinga taxane (docetaxel) to mitomycin plus vinblastine in patients with metastaticbreast cancer in whom previous anthracycline-containing chemotherapy hadfailed. The response rates and median times to progression reported inthis preliminary analysis were consistent with those from earlier phaseII trials.
Diéras and colleagues reported a median response rate of15% and time to progression of 15 weeks in 36 patients receiving 175 mg/m²of paclitaxel administered as a 3-hour intravenous infusion once every3 weeks. In contrast, 36 patients receiving 12 mg/m² of mitomycinonce every 6 weeks achieved a response rate of 5% and a median time toprogression of 7 weeks. However, the results from this study are limiteddue to the small sample size (72 patients) and the dose of mitomycin (12mg/m²), which was lower than what is typically used for monotherapywith this agent. Survival data were not yet available at the time of thispreliminary analysis.
Both agents were myelosuppressive; neutropenia and its clinical consequences(febrile neutropenia and grade 3 to 4 infection) were more common in thedocetaxel arm. However, the incidence of febrile neutropenia was in keepingwith the data known from phase I and II trials using the same dose of docetaxel.Patients treated with mitomycin/vinblastine experienced more thrombocytopeniathan patients in the docetaxel arm.
In terms of gastrointestinal toxicity, diarrhea and stomatitis weremore frequent in the docetaxel arm, whereas nausea and vomiting were seldomseen in both arms. Alternatively, constipation was more common in the grouptreated with mitomycin/vinblastine. Severe docetaxel-specific toxicities,such as (fluid retention, skin toxicity, nail disorders, and neurosensorytoxicity) were infrequent, in keeping with the observations from phaseII trials using the same corticosteroid premedication given over 5 days.
The preliminary results of this multicenter, randomized phase III studyin patients with metastatic breast cancer in whom previous anthracycline-containingchemotherapy has failed, indicate that docetaxel is more active than themitomycin/vinblastine combination, with higher response rates and a differencein terms of time to progression. Toxicity profiles were acceptable in botharms, in keeping with previous reports.
These results should be interpreted with caution because this analysiswas conducted on the first 200 patients who finished the study treatments,and these preliminary results may underestimate response and overstatetreatment discontinuation rates. Thus, the final analysis on the entirepatient population is necessary to confirm these findings.
1. Henderson IC: Principles in the management of metastatic disease:Chemotherapy for metastatic disease, in Harris JR, Hellman S, HendersonIC, et al (eds): Breast Diseases, pp 604-665. Philadelphia, Lippincott,1991.
2. Walker BK, Raich PC, Fontana J, et al: Phase II study of vindesinein patients with advanced breast cancer. Cancer Treat Rep 66:1729-1732,1982.
3. Yau JC, Yap YY, Buzdar AU, et al: A comparative randomized trialof Vinca alkaloids in patients with metastatic breast carcinoma. Cancer55:337-340, 1985.
4. Degardin M, Bonneterre J, Heequet B, et al: Vinorelbine (Navelbine)as a salvage treatment for advanced breast cancer. Ann Oncol 5:423-426,1994.
5. Holmes FA, Valero V, Walters RS, et al: The M.D. Anderson CancerCenter experience with Taxol in metastatic breast cancer. Monogr Natl CancerInst 15:161-169, 1993.
6. Nabholtz JM, Gelmon K, Bontenbal M, et al: Multicenter, randomizedcomparative study of two doses of paclitaxel in patients with metastaticbreast cancer. J Clin Oncol 14:1858-1867, 1996.
7. Garewal HS: Mitomycin-C in the chemotherapy of advanced breast cancer.Semin Oncol 15:74-79, 1988.
8. Walters RS, Frye D, Buzdar AU, et al: A randomized trial of two dosageschedules of mitomycin-C in advanced breast carcinoma. Cancer 69:476-481,1992.
9. Sedlacek S: Salvage therapy for metastatic diseases. Semin Oncol17:45-49, 1990.
10. Buzdar AU: Chemotherapeutic approaches to advanced breast cancer.Semin Oncol 15:65-70, 1988.
11. Radford JA, Knight RK, Rubens RD: Mitomycin C and vinblastine inthe treatment of advanced breast cancer. Eur J Cancer Clin Oncol 21:1475-1477,1985.
12. Konits PH, Aisner JK, van Echo DA, et al: Mitomycin C and vinblastinechemotherapy for advanced breast cancer. Cancer 48:1295-1298, 1981.
13. Garewal HS, Brooks RJ, Jones SE, et al: Treatment of advanced breastcancer with mitomycin C combined with vinblastine or vindesine. J ClinOncol 1:772-775, 1983.
14. Navarro M, Bellmunt J, Balana C, et al: Mitomycin-C and vinblastinein advanced breast cancer. Oncology 46:137-142, 1989.
15. Denefrio JM, East DR, Troner MB, et al: Phase II study of mitomycinC and vinblastine in women with advanced breast cancer refractory to standardcytotoxic therapy. Cancer Treat Rep 62:2113-2115, 1978.
16. Van Oosterom AT, Schrijvers D: Docetaxel (Taxotere), a review ofpreclinical and clinical experience. Part II: Clinical experience. AnticancerDrugs 6:356-368, 1995.
17. ten Bokkel Huinink WW, Prove AM, Piccart M, et al: A phase II trialof docetaxel (Taxotere) in second line treatment with chemotherapy foradvanced breast cancer: A study of the EORTC Early Clinical Trials Group.Ann Oncol 5:527-532, 1994.
18. Ravdin P, Burris HA, Cook G, et al: Phase II trial of docetaxelin advanced anthracycline-resistant or anthracenedione-resistant breastcancer. J Clin Oncol 13:2879-2885, 1995.
19. 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.
20. Guastalla JP, Bonneterre J, Fumoleau P, et al: A phase II trialof docetaxel in patients with anthracycline-resistant metastatic breastcancer (MBC) (abstract 348). Eur J Cancer 31A:S75-S76, 1995.
21. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomizedclinical trials requiring prolonged observation of each patient. I. Introductionand design. Br J Cancer 34:585-612, 1976.
22. Dieras V, Marty M, Tubiana N, et al: Phase II randomized study ofpaclitaxel versus mitomycin in advanced breast cancer. Semin Oncol 22(4suppl 8):33-39, 1995.