Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer

Authors


  • Presented in part at the 42nd American Society of Clinical Oncology Annual Meeting, Atlanta, Georgia, June 2–6, 2007.

Abstract

BACKGROUND

Previous studies have evaluated 3-week and weekly docetaxel schedules in patients with metastatic breast cancer (MBC). The varying efficacy results and toxicity profiles noted in these earlier studies led to a comparison of the schedules to determine which was safer and more efficacious.

METHODS

A phase 3 clinical trial was conducted in patients with MBC who were treated with docetaxel either every 3 weeks or once weekly to determine and compare response rate and duration, time to disease progression, progression-free survival (PFS), overall survival (OS), and toxicity. Patients were randomized to receive docetaxel at a starting dose of either 75 mg/m2 every 3 weeks or 35 mg/m2 weekly for 3 consecutive weeks followed by 1 week of rest.

RESULTS

A total of 118 patients underwent efficacy analysis; 59 patients were randomized to the every-3-week treatment arm and 59 to the weekly arm. The response rate was 35.6% (95% confidence interval [95% CI], 23.6–49.1%) for the every-3-week arm versus 20.3% (95% CI, 11.0–32.8%) for the weekly arm. There was no statistical difference between the every 3-week and the weekly treatment arms with regard to median PFS (5.7 months vs 5.5 months; P = .46) or OS (18.3 months vs 18.6 months, respectively; P = .34). There was a higher overall toxicity rate (grades 3 and 4, according to the National Cancer Institute Common Toxicity Criteria [version 2.0]) in the every-3-week treatment arm versus the weekly treatment arm (88.1% vs 55.9%, respectively; P = .0001).

CONCLUSIONS

Compared with patients who received weekly docetaxel, those who received docetaxel every 3 weeks had a higher response rate but experienced similar PFS and OS and a more pronounced toxicity. Cancer 2008. © 2008 American Cancer Society.

Docetaxel is a semisynthetic taxane, a class of anticancer agents that has a novel mechanism of action in that its cellular target is the β subunit of the tubulin heterodimer, which is the key component of microtubules.1, 2 Drugs in this class bind to β-tubulin and hyperstabilize the microtubules, thereby inducing cell cycle arrest and subsequent apoptosis.1–3

Docetaxel was first approved for the treatment of anthracycline-refractory locally advanced metastatic breast cancer (MBC), with response rates ranging from 53% to 61%.4, 5 Several phase 3 trials confirmed the activity of docetaxel in the first-line treatment of and in anthracycline-resistant MBC.6–10 Single-agent docetaxel and docetaxel-based regimens demonstrated clinical activity in stage II to III breast cancer11–13 and were later approved for the adjuvant treatment of early high-risk breast cancer14 as well as other solid tumors, including advanced nonsmall cell lung, gastric, and hormone-refractory prostate cancers.6 The most common toxic effect observed with the 3-week administration of docetaxel was myelosuppression and its complications, neutropenic fever and/or infection.4–14 Other observed toxic effects have included alopecia; gastrointestinal toxicity, manifested by brief and mild nausea, vomiting, and diarrhea; rare acute anaphylactoid-type reaction manifested by pruritus, flushing, and rash; and mild to moderate cumulative fluid retention.4–14

In an attempt to alter the toxicity profile and improve the therapeutic index of docetaxel, investigators conducted several phase 1 trials of docetaxel administered by weekly schedule in patients with advanced cancers, including breast cancer.15, 16 These trials demonstrated that the toxicity profile of docetaxel was markedly altered when administered weekly. Fatigue and asthenia were the dose-limiting toxicities, and myelosuppression was mild and uncommon. Several phase 2 studies have described the use of weekly docetaxel, with doses ranging from 30 to 45 mg/m2 for the treatment of patients with MBC. The response rates ranged from 21% to 48%.17–19 The evidence of efficacy and the different toxicity profiles observed with weekly docetaxel led us to compare the 2 schedules, weekly versus every 3 weeks, to determine the safer schedule with the higher efficacy.

MATERIALS AND METHODS

Eligibility Criteria

To be eligible for our phase 3 clinical trial, patients had to meet the following criteria: 1) patients had to have histologic proof of breast cancer and evidence of metastatic disease; 2) patients must not have received >1 prior chemotherapy regimen for their metastatic disease (prior anthracycline-based chemotherapy was permitted but prior treatment with docetaxel was not, and prior adjuvant paclitaxel was permitted if the last dose had been taken at least 12 months previously); 3) patients must have had measurable disease, a life expectancy of ≥12 weeks, and a performance status score of ≤2 on the Zubrod scale20; and 4) patients were required to have adequate bone marrow function, defined as an absolute granulocyte count of ≥1500/μL; a platelet count of ≥100,000/μL; adequate renal function, defined as a serum creatinine concentration <2.0 mg/dL; and a total bilirubin level less than the upper limit of normal.

Patients were not eligible for the study if they had evidence of uncontrolled brain metastases or other serious uncontrolled illnesses. All participants signed an informed consent form as approved by the University of Texas M. D. Anderson Cancer Center Institutional Review Board.

Treatment Plan

Before patients entered the study, a complete medical history was obtained and they underwent a physical examination that included an evaluation of performance status and weight. Laboratory data included a complete blood cell count, blood chemistry studies, and a serum pregnancy test in women of childbearing potential.

Patients were randomized to receive either docetaxel infused over 1 hour on Day 1 of a 3-week cycle or docetaxel infused over 30 minutes on Days 1, 8, and 15 of a 4-week cycle. For patients randomized to the 3-week treatment arm, the starting dose of docetaxel in the first cycle was 75 mg/m2. If no grade 4 neutropenia lasting >7 days or associated with fever or infection was observed, the dose for the second cycle was increased to 100 mg/m2. For patients randomized to the weekly treatment arm, the starting dose of docetaxel during the first 3 treatment cycles was 35 mg/m2/week. If no grade 4 neutropenia, as previously described, was observed, the dose for the second cycle was increased to 40 mg/m2/week. Doses for both treatment arms were escalated at the discretion of the investigator. Before receiving each dose, patients randomized to the 3-week treatment arm were premedicated with dexamethasone at a dose of 8 mg orally twice a day for 3 days, starting the day before chemotherapy. Patients randomized to the weekly treatment arm received a total of 3 doses of dexamethasone, each consisting of 4 mg given orally every 12 hours, starting 12 hours before each administration of docetaxel.

Toxic effects were graded using the National Cancer Institute Common Toxicity Criteria (version 2.0). For grade 3 and 4 nonhematologic toxic effects, treatment was withheld until the toxic effect resolved to ≤grade 1 and was then reinstituted at a 25% dose reduction. If treatment was withheld for longer than 3 weeks because of a grade 3 or 4 nonhematologic toxicity, the patient was withdrawn from the study. A maximum of 2 dose reductions of 25% was allowed per patient. In case of an unacceptable hematologic toxicity, the next treatment cycles were administered at the same dose but with the addition of prophylactic granulocyte–colony-stimulating factor. Unacceptable hematologic toxicity was defined as grade 4 neutropenia lasting ≥7 days, repeatedly low daily absolute neutrophil counts at ≤1000/mm3, grade 4 neutropenia associated with fever (1 oral temperature >38.5°C or 3 oral temperatures of >38.0°C in a 24-hour period), or grade 4 neutropenia with infection.

Treatment Assessments

Within 7 days of their entry into the study and before treatment randomization, the patients' medical history was obtained and a physical examination performed; within 30 days before study entry a radiologic evaluation was performed. Before receiving each dose of docetaxel, patients underwent a complete blood cell count. Blood chemistry studies were repeated before each treatment cycle. Radiologic assessments were performed after every 2 treatment cycles (6 or 8 weeks, depending on the schedule) unless required sooner because of the clinical situation. After a response had been documented, a confirmatory study was obtained 4 weeks later.

Statistical Analyses

A maximum of 160 patients were to be accrued and assigned treatment by a 1:1 randomization using a permuted block design. The randomization was stratified by previous taxane use (yes or no) and the number of previous chemotherapy regimens received for metastatic disease (0 or 1). The primary outcome was 2-dimensional and consisted of both response (complete or partial) and toxicity. The historical probabilities of these 2 events with the standard schedule were πresponse = .3 and πtoxicity = .2. The goal of the trial was to improve both of these values to πresponse ≥ .32 and πtoxicity ≤ .10. Values of either πresponse ≤ .20, a drop of ≥ .10 below the null response rate, or πtoxicity ≥ .20, at or above the null toxicity rate, were considered unacceptable.

In the comparison of toxicity rates, data from 160 patients would provide 80% power to detect an absolute difference of 0.14, assuming that the higher rate of toxicity is 0.20 (ie, severe toxicity rates of 6% vs 20%) at a 2-sided significance level of 0.05. Accrual of 160 patients randomized on a 1:1 basis between groups would provide 80% power to detect this difference at a 1-sided significance level of 0.05, assuming an overall response rate of 0.30. A recommendation for trial termination would be made only for superiority of the weekly regimen in response (1P < .005) and severe toxicity (2P < .001). The factors duration of response, time to disease progression, progression-free survival (PFS), and overall survival (OS) were analyzed using the Kaplan-Meier method. Outcomes were compared using log-rank tests.

All patients who received at least 1 drug infusion were analyzed for toxic effects. Nausea, vomiting, and/or diarrhea that responded to symptom-directed measures were excluded.

RESULTS

Between January 2001 and September 2004, 125 patients were enrolled in this study, with 62 patients randomized to the every-3-week treatment arm and 63 patients randomized to the weekly treatment arm. The patients' characteristics are shown in Table 1. Overall, the groups were well balanced.

Table 1. Patient Characteristics
CharacteristicEvery-3-week treatment arm (n = 62)Weekly treatment arm (n = 63)
No. of patientsNo. of patients
  1. IHC indicates immunohistochemistry; FISH, fluorescent in situ hybridization; ER, estrogen receptor; PR, progesterone receptor; +, positive; −, negative.

Age, y
 Median5654
 Range36–8232–86
Race
 White3948
 Black138
 Hispanic95
 Asian12
No. of metastatic sites
 Median3.53.5
 Range1–61–6
HER-2 status (IHC/FISH)
 Positive83
 Negative4342
 Unknown1118
ER/PR status
 ER+/PR+2023
 ER+/PR−1012
 ER−/PR+12
 ER−/PR−2719
 Status unknown46
Prior chemotherapy
Adjuvant
  Yes3640
  No2623
Metastatic regimen(s)
  04345
  11918
Adjuvant/metastatic78
Anthracycline therapy
None2124
Adjuvant2431
Metastatic136
Adjuvant/metastatic42
Paclitaxel therapy
None5248
Adjuvant1015
Prior hormonal therapy2435
Prior radiotherapy3240

The median number of delivered cycles was 9.5 cycles (range, 1–34 cycles) for the every-3-week treatment arm and 7 cycles (range, 1–43 cycles) for the weekly arm. The median cumulative dose of docetaxel was 609.5 mg/m2 (range, 75–2646 mg/m2) for the every-3-week treatment arm and 429.5 mg/m2 (range, 35–2975 mg/m2) for the weekly treatment arm. The patients in the every-3-week treatment arm received a median dose intensity of 25.65 mg/m2/week (range, 17.4–33.6 mg/m2/week), which reflects the finding that most of these patients were able to receive the planned dose of chemotherapy. Conversely, the patients in the weekly treatment arm received a median dose intensity of 27.65 mg/m2/week (range, 13.5–35 mg/m2/week), or 79% of the planned dose of chemotherapy. Ten patients in the every-3-week treatment arm and 13 in the weekly treatment arm were able to tolerate an escalated dose of docetaxel after their first cycle of chemotherapy. Another 10 patients in the every-3-week treatment arm, but only 4 in the weekly treatment arm, were able to tolerate an escalated dose of docetaxel after their second cycle of chemotherapy.

On the basis of efficacy and toxicity findings from an interim analysis performed in June 2005 and a slow accrual rate, the Data Monitoring Committee recommended early termination of the trial.

Efficacy

Seven patients were found to be either ineligible or not evaluable for both toxic effects and response, none of whom received treatment in this study. Specifically, 2 patients did not meet the eligibility criteria, 2 decided to undergo treatment at an outside institution, 1 decided to initiate hormonal therapy, and 2 started a different chemotherapy regimen. Thus, of the 118 patients eligible for an efficacy analysis, 59 were randomized to the every-3-week treatment arm and 59 to the weekly treatment arm.

The objective response rate was 35.6% (95% confidence interval [95% CI], 23.6–49.1%) in the every-3-week treatment arm compared with 20.3% (95% CI, 11.0–32.8%) in the weekly treatment arm. No complete responses were reported in either treatment arm. Twenty-one partial responses were observed in the every-3-week treatment arm and 12 in the weekly treatment arm. Patients who did not achieve a partial response were considered nonresponders. The difference in the objective response rates between both treatment arms was 15.3% (95% CI, −3.4% to 33.5%).

The response duration was measured from the date of response to the date of disease progression or death. In the every-3-week treatment arm, 16 of the 21 responders experienced either disease progression or death, with a median time to event of 7.9 months. In the weekly treatment arm, 10 of the 12 responders experienced either disease progression or death, with a median time to event of 6.9 months. The response duration was not found to be statistically different between the 2 groups (P = .87).

The median duration of follow-up was 15.1 months (range, 0.5–51.6 months). PFS was calculated from the start of treatment to the date of disease progression or death. PFS data are shown in Figure 1. In the every-3-week treatment arm, 50 patients experienced either disease progression or death, with a median time to event of 5.7 months. In the weekly treatment arm, 55 patients experienced either disease progression or death, with a median time to event of 5.5 months. PFS was not found to be statistically different between the 2 groups (P = .46).

Figure 1.

Progression-free survival time. E indicates the number of patients who experienced disease progression or death; N, the total number of patients in the treatment arm.

OS time was calculated from the start of treatment to the date of death. OS is shown in Figure 2. In the every-3-week treatment arm, 36 patients died, with a median time to death of 18.3 months. In the weekly treatment arm, 39 patients died, with a median time to death of 18.6 months. OS was not found to be statistically different between the 2 groups (P = .34).

Figure 2.

Overall survival time. E indicates the number of patients who died; N, the total number of patients in the treatment arm.

Toxicity

The toxicity analysis included data from the 118 patients who received at least 1 drug infusion. Overall, 52 patients in the every-3-week treatment arm, but only 33 in the weekly treatment arm, experienced a serious toxic effect. The difference in the toxicity rate between the 2 treatment arms was found to be statistically significant, with a rate of 88.1% (95% CI, 77.1–95.1%) for the every-3-week treatment arm compared with 55.9% (95% CI, 42.4–68.8%) for the weekly treatment arm (P = .0001). A grade 3/4 hematologic toxicity level was observed more frequently in the every-3-week treatment arm compared with the weekly treatment arm. Granulocytopenia was reported in 48 patients (81%) in the every-3-week treatment arm compared with 6 patients (10%) in the weekly treatment arm. Neutropenic fever was also observed more commonly in the every-3-week treatment arm (6 patients [10%]) compared with the weekly treatment arm (2 patients [3%]). Serious nonhematologic toxicity was also more common in patients with fatigue and myalgia in the every-3-week treatment arm than in the weekly treatment arm (15 [25%] vs 8 [14%], respectively, in patients with fatigue and 16 [27%] vs 2 [3%], respectively, in those with myalgia).

Although serious toxic effects were noted more frequently in the every-3-week treatment arm compared with the weekly treatment arm, more toxic effects were occasionally observed in the weekly treatment arm. Among patients who developed grade 2 and 3 epiphora, for example, 11 patients (19%) and 3 patients (5%), respectively, were in the every-3-week treatment arm compared with 14 patients (24%) and 10 patients (17%), respectively, in the weekly treatment arm. There were also fewer patients who developed severe effusions in the every-3-week treatment arm (2 patients [3%]) than in the weekly treatment arm (7 patients [12%]). Additional details regarding the grade 3/4 toxicity for each arm are shown in Table 2.

Table 2. Grade 3/4 Toxic Effects Reported*
Toxic effectEvery-3-week treatment arm (n = 59)Weekly treatment arm (n = 59)
No. % of patientsNo. (%) of patients
  • *

    Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (v. 2.0).

Granulocytopenia48 (81)6 (10)
Neutropenic fever6 (10)2 (3)
Anemia1 (2)2 (3)
Fatigue15 (25)8 (13)
Myalgia16 (27)2 (3)
Neuropathy6 (10)3 (5)
Nausea2 (3)5 (8)
Vomiting1 (2)5 (8)
Nail changes0 (0)1 (2)
Epiphora (grade 3)3 (5)10 (17)
Effusions2 (3)7 (12)
Death0 (0)0 (0)

Dose reductions secondary to treatment-related toxicity were made in 7 patients (12%) in the every-3-week treatment arm and in 15 (25%) in the weekly treatment arm. One patient in the every-3-week treatment arm had 2 dose reductions. The median dose reduction for patients in the every-3-week treatment arm was 22.5% (range, 20–25%) compared with 15% (range, 12.5–25%) for those in the weekly treatment arm. No treatment-related deaths were reported.

DISCUSSION

Docetaxel is active in the treatment of metastatic and early-stage breast cancer. However, uncertainty remains concerning the best schedule to use for its administration. Recent reports of studies with paclitaxel in patients with metastatic and early breast cancer suggest that activity is enhanced when it is administered weekly rather than every 3 weeks.21, 22 This could be in part because paclitaxel's activity is directly related to the cell cycle; therefore, more frequent or continuous administration would potentially result in higher efficacy. Conversely, docetaxel is a schedule-independent drug. The current study was specifically designed to determine the differences in the efficacy and toxicity of docetaxel used either every 3 weeks or weekly in patients with MBC. To our knowledge, previous single-arm studies and 1 randomized phase 2 study have addressed this issue. In the study by Tabernero et al.23 the population of patients with MBC was similar to that in the current study, with the primary endpoint being an evaluation of drug activity and tolerability. Eighty-three patients were randomized to receive 100 mg/m2 of docetaxel every 3 weeks or 40 mg/m2 weekly for 6 consecutive weeks followed by 2 weeks of rest. That study demonstrated no difference in response rates between treatment arms, although the toxicity level was greater with the every-3-week schedule compared with the weekly schedule.23 Their study was smaller than the current one and used a different weekly schedule and doses, which possibly accounted for the lack of difference noted with regard to efficacy in either treatment arm, in contrast with the difference in efficacy we found. However, the incidence of grade 3/4 adverse events in both treatment arms of that study was similar to that in the current study (76% in the every-3-week treatment arm and 49% in the weekly treatment arm23).

Di Maio et al.24 recently reported the meta-analysis of 5 small randomized studies comparing 3-week versus weekly docetaxel as second-line therapy in patients with advanced nonsmall cell lung cancer in whom a previous platinum-based regimen had failed. The authors concluded that weekly docetaxel demonstrated similar efficacy, including OS, compared with 3-week docetaxel. However, neutropenic-related events were significantly lower for the weekly docetaxel schedule. To the best of our knowledge, the current study is the largest ever reported in MBC patients to evaluate the use of docetaxel on an every-3-week versus weekly schedule. Unlike the 2 previously reported studies, the current study demonstrated a significant difference in response rate in favor of the every-3-week compared with the weekly schedule. However, no significant differences in PFS and OS were observed between study arms in any of the reported studies. This may have been related to the low number of patients enrolled in all 3 studies. All of these studies, including the current one, are significantly underpowered. Therefore, it is unknown whether a larger study would have demonstrated an improvement in OS for the 3-week treatment arms. Conversely, a modest increase in response rate is unlikely to impact OS in patients with advanced MBC.

It is interesting to note that both studies found significantly increased grade 3/4 toxicity with the every-3-week treatment schedule compared with the weekly administration of docetaxel. Of more importance is that in all the studies, hematologic toxicity was the most commonly observed grade 3/4 toxicity and increased the risk of morbidity and mortality in the every-3-week treatment arm. As demonstrated in a previous report,25 docetaxel administered weekly has a unique nonhematologic toxicity profile, although it is associated more frequently with disabling epiphora and its anatomic correlate, canalicular stenosis, than when it is administered every 3 weeks.

These study results strongly suggest that the clinical benefit of docetaxel is not heavily dependent on its schedule of administration. The clinical findings from these studies correlate with the pharmacokinetics findings of an evaluation of the every-3-week and the weekly treatment schedules. Baker et al.26 found no differences in the clearance or half-life of docetaxel when it was administered at a dose of 100 mg/m2 every 3 weeks or at a dose of 35 mg/m2 weekly.

Sparano et al.27 recently reported the second analysis of Eastern Cooperative Oncology Group (ECOG) 1199, a phase 3 study of adjuvant weekly versus 3-week paclitaxel or docetaxel after doxorubicin plus cyclophosphamide in patients with previously untreated stage II/III breast cancer. Neutropenic-related events, fever, and/or infection were found to be higher in the 3-week docetaxel treatment arm. However, excessive tearing was higher in the weekly treatment arm. The 5-year disease-free survival rate was numerically higher in the 3-week docetaxel treatment arm (81.2%) versus the weekly treatment arm (77.6%). However, OS was similar in both arms.

In summary, the decision of which docetaxel schedule to use in patients with MBC should be based on the patient's convenience and on the risk of developing a specific docetaxel-related toxic effect. In elderly patients or in those at risk of developing neutropenic complications, for example, weekly docetaxel should be chosen. In addition, although the response rate in our study favored the every-3-week treatment schedule, the lack of survival benefit noted between the 2 treatment arms and the lower toxicity rate observed with the weekly dosing arm support consideration of the weekly schedule for patients about to begin docetaxel treatment for MBC.

Ancillary