Annals of Oncology Advance Access originally published online on December 21, 2005
Annals of Oncology 2006 17(3):467-472; doi:10.1093/annonc/mdj115
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© 2005 European Society for Medical Oncology
Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated advanced non-small-cell lung cancer: a Spanish Lung Cancer Group trial
1 Consorcio Hospital General Universitario de Valencia, Valencia, Spain; 2 Hospital General de Alicante, Alicante, Spain; 3 Hospital de Alcorcón, Alcorcón, Spain; 4 Hospital Virgen de los Lirios, Alcoy, Spain; 5 Hospital Gregorio Marañón, Madrid, Spain; 6 Hospital Clínico Lozano Blesa, Zaragoza, Spain; 7 Hospital Clínico San Carlos, Madrid, Spain; 8 Hospital Dr. Peset, Valencia, Spain; 9 Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain; 10 Hospital General de Elche, Elche, Spain; 11 Hospital Clínico de Barcelona, Barcelona, Spain; 12 Hospital Universitario de Canarias, Tenerife, Spain; 13 Hospital General Yagüe, Burgos, Spain; 14 Hospital de Sagunto, Sagunto, Spain; 15 Hospital Marqués de Valdecilla, Santander, Spain; 16 Consorcio Sanitario de Terrassa, Terrassa, Spain; 17 Clínica Puerta de Hierro, Madrid, Spain; 18 Hospital de León, León, Spain; 19 Hospital Valle de Hebrón, Barcelona, Spain
* Correspondence to: Dr R. Rosell, Medical Oncology Service, Scientific Director of Oncology Research, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet, s/n 08916 Badalona, Barcelona, Spain. Tel: +34-93-497-89-25; Fax: +34-93-497-89-50; E-mail: rrosell{at}ico.scs.es
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Abstract |
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Background: Docetaxel is a widely accepted second-line treatment in advanced non-small-cell lung cancer (NSCLC) with a risk of myelotoxicity. This study evaluated the efficacy and toxicity profile of two docetaxel regimens in NSCLC patients who had failed first-line non-docetaxel-based chemotherapy.
Patients and methods: A total of 259 patients from 33 Spanish centers were randomized to receive either docetaxel 75 mg/m2 administered every 3 weeks (3W arm) or docetaxel 36 mg/m2 given weekly (1W arm) for 6 weeks followed by 2 weeks of rest. The primary end point was 1-year survival; secondary end points were median survival, time to progression, response and toxicity.
Results: One-year survival was 27% in the 3W and 22% in the 1W arm. Median time to progression was also similar in the two arms. Median survival was 6.6 months in the 3W arm versus 5.4 months in the 1W arm (P = 0.075). Response rates were 9.3% in the 3W arm and 4.8% in the 1W arm. More patients in the 1W arm experienced mucositis [1W, nine patients (7.2%); 3W, two patients (1.6%); P = 0.032], while febrile neutropenia was significantly higher in the 3W arm [3W, 10 patients (7.8%); 1W, one patient (0.8%); P = 0.010].
Conclusions: Both weekly and 3-weekly docetaxel were effective and well-tolerated, with different toxicity profiles. In general, there was no indication to recommend the weekly schedule. However, the significant lower rate of febrile neutropenia observed in the weekly schedule makes it a good alternative for patients at risk of severe neutropenia.
Key words: docetaxel, non-small-cell lung cancer, second-line chemotherapy
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Lung cancer is the main cause of cancer-related death worldwide; non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all cases and the majority of patients present with advanced or metastatic disease [1
]. The standard first-line treatment for advanced NSCLC in patients with good performance status (PS) consists of platinum-based combinations, which offer a modest survival advantage over best supportive care alone [2]. The vast majority of patients with advanced NSCLC will progress after first-line chemotherapy; however, patients with a good PS who had responded to first-line treatment are candidates for second-line chemotherapy. In this setting, docetaxel has demonstrated superiority in 1-year survival and quality of life compared with ifosfamide, vinorelbine or best supportive care alone [3, 4]. The recommended dose is 75 mg/m2 every 3 weeks; however, febrile neutropenia is observed in 12%–16% of patients using the 3-week schedule, prompting a search for new dose-schedules. Phase I and II trials have demonstrated the efficacy and acceptable toxicity of lower doses of docetaxel administered weekly [5, 6]. Based on these findings, the Spanish Lung Cancer Group carried out a second-line randomized phase III study in advanced NSCLC patients, comparing docetaxel 75 mg/m2 every 3 weeks with docetaxel 36 mg/m2 weekly for 6 consecutive weeks followed by 2 weeks of rest. |
patients and methods |
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patient eligibility
All patients had histologically or cytologically confirmed recurrent advanced NSCLC previously treated with at least one platinum-based chemotherapy regimen that did not include docetaxel. Before study entry, a minimum of 28 days had to have elapsed since previous chemotherapy. In addition, patients had to have measurable or evaluable disease, an Eastern Cooperative Oncology Group (ECOG) PS
2, be older than 18 years, and have a life expectancy of at least 12 weeks. Adequate hematologic (absolute neutrophil count 
1500/ml, platelet count >100 000/ml), hepatic (total bilirubin level 1.5x the upper limit of normal), and renal (creatinine concentration 2x the upper limit of normal) parameters were required. Patients were excluded if they had symptomatic or uncontrolled brain metastases or peripheral neuropathy equal to or greater than the National Cancer Institute grade 2. Patients who had received prior radiation therapy were considered eligible provided 30% or less of their total bone marrow had been irradiated, but 28 days had to have elapsed after radiation therapy before entering the study. The institutional ethics committees of each participating center approved the study protocol. Written informed consent was obtained from each patient prior to study entry.
treatment plan
Eligible patients were randomly assigned to receive docetaxel every 3 weeks (3W arm) or weekly (1W arm). Randomization was performed by each center using a dynamic balancing algorithm of the Pocock–Simon type [7], to reduce any imbalance in treatment assignment. Patients in the 3W arm received docetaxel 75 mg/m2 as a 1-h i.v. infusion every 21 days, and those in the 1W arm received docetaxel 36 mg/m2 as a 30-min i.v. infusion administered weekly for 6 consecutive weeks followed by 2 weeks of rest. In both arms, patients were premedicated with oral dexamethasone. Docetaxel was administered until disease progression, unacceptable toxicity, withdrawal of patient consent or at the discretion of the treating physician.
Dose reductions were planned in the event of severe hematologic and/or non-hematologic toxicity. Dose adjustments were based on absolute neutrophil count, platelet count and hepatic function showing the greatest degree of toxicity, according to the Cancer and Leukemia Group B (CALGB) criteria [8].
Within 7 days of study entry and before each docetaxel dose, all patients underwent a complete history and physical examination including determination of ECOG PS, vital signs, toxicities and concomitant medications, as well as a complete blood cell count and biochemistry profile, with differential and platelet count including serum levels of creatinine, transaminases, bilirubin, electrolytes and calcium. Patients had radiologic examinations to document all lesions. Chest X-ray and thoracic–abdominal computed tomography scans were performed if clinically indicated to evaluate measurable disease in the 28 days prior to study entry. Response was evaluated every 9 weeks according to the Response Evaluation Criteria in Solid Tumor Group (RECIST) [9]. Clinical and laboratory toxicities were graded according to the CALGB criteria. Toxicity was calculated based on the worst reported event per patient. After treatment discontinuation, all patients were followed every 2 months until death.
statistical analysis
The trial was designed to assess whether 1-year survival in patients receiving docetaxel every 3 weeks was inferior to that of patients receiving weekly docetaxel. Calculation of sample size of the study was based on the assumption of an equal expected 1-year survival for both arms, i.e. 20%, and the maximum allowed difference was 15%. A total of 123 patients per group was estimated on the basis of an alpha level of 5% (two-sided) and a power of 80% to compare the groups, assuming a 10% drop-off of patients.
The primary end point was 1-year survival, calculated using the Kaplan–Meier method. One-year survival rates and 95% confidence intervals (CI) were compared between groups for the difference between proportions. Secondary end points included time to progression, median survival and duration of response. Time to progression was calculated from the date of randomization until progression or death due to malignant disease; patients who received follow-up therapy prior to documented disease progression were censored at the time of the secondary therapy. Median survival was calculated from the date of randomization to the date of death or date of last contact. Duration of response was calculated from the date of the first response until progression or death due to malignant disease. All secondary end point calculations were performed using the Kaplan–Meier method. All randomly assigned patients who received at least one dose of docetaxel were included in the intention-to-treat survival and efficacy analysis. Patients who received one dose of docetaxel were also analyzed for safety. Adverse events between treatment arms were compared using Fisher's exact text for 2 x 2 tables.
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results |
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Between July 2000 and February 2003, 259 patients from 33 Spanish centers were enrolled in the trial. One hundred and thirty-one patients were randomized to the 3W arm (docetaxel every 3 weeks) and 128 were randomized to the 1W arm (weekly docetaxel). Five patients did not receive their treatment as allocated: three died before receiving the first docetaxel dose (one in the 3W arm and two in the 1W arm); and two patients, one in each arm, were found not to meet major eligibility criteria after randomization and were withdrawn from the study (Figure 1).
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patient characteristics
Patient characteristics are shown in Table 1. The two arms were well-balanced for all demographic factors and for number of prior chemotherapy lines. Ninety-six percent of the patients had received platinum-based chemotherapy. More than 80% of patients had good PS (0–1). A total of 107 patients (82.9%) in the 3W arm and 106 (84.8%) in the 1W arm had stage IV disease.
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treatment administered
A total of 577 cycles in the 3W arm and 154 in the 1W arm were administered, with a median number of three and one cycles, respectively. Dose reduction was necessary in 14 cycles in each treatment group (2.4% and 1.3%, respectively). Forty-one patients (31.8%) in the 3W arm and 35 (28%) in the 1W arm had a delayed cycle. Median docetaxel dose intensity and median relative dose intensity (actually delivered mg/m2/week divided by the planned mg/m2/week) were 24.6 mg/m2 and 0.98 in the 3W arm and 26.7 mg/m2 and 0.99 in the 1W arm.
efficacy
At the time of the analysis, 105 patients (81.4%) in the 3W arm and 110 (88%) in the 1W arm had died. The 1-year survival rate was 27% (95% CI 18.9% to 35.1%) in the 3W arm and 22.0% (95% CI 14.6% to 29.4%) in the 1W arm. Median survival time was 6.6 months (95% CI 5.5–7.7 months) in the 3W arm and 5.4 months (95% CI 4.5–6.4 months) in the 1W arm (P = 0 .076) (Figure 2). Overall, patients with PS 2 had significantly shorter survival than those with PS 0–1, with median survival times of 3.8 months and 6.6 months, respectively (P = 0.0001). Statistically significant differences in survival were also found between patients with PS 0 and PS 1; median survival was 8.1 months (95% CI 3.7–12 months) in patients with PS 0 and 6 months (95% CI 5.3–6.8 months) in patients with PS 1 (P = 0.0067) (Figure 3). Median survival was further analyzed according to PS within each arm. In the 3W arm, median survival was 10.1 months for patients with PS 0 and 6.3 months for those with PS 1 (P = 0.0152), while in the 1W arm it was 6.6 months for patients with PS 0 and 6 months for those with PS 1 (P = 0.3666).
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Median time to progression was similar in the two arms: 2.7 months (95% CI 1.6–3.8 months) in the 3W arm and 2.9 months (95% CI 2.1–3.6 months) in the 1W arm (Figure 4). No statistically significant differences were observed in median time to progression between patients with PS 2 and those with PS 0–1, either overall or when broken down by treatment arm. However, when patients with PS 0 were compared with those with PS 1, statistically significant differences in time to progression emerged; median time to progression was 4.1 months (95% CI 1.6–6.6 months) for patients with PS 0 and 2.8 months (95% CI 2.2–3.5 months) for those with PS 1 (P = 0.0061).
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Response rates are shown in Table 2. The overall response rate was 9.3% (95% CI 4.3% to 14.3%) in the 3W arm and 4.8% (95% CI 1.1% to 8.6%) in the 1W arm. Two complete responses were observed, one in each group. Significant differences were found in response between patients with PS 0 and PS 1, with response rates of 15.2% and 3.6%, respectively (P = 0.009). When response was further analyzed within each arm according to PS, in the 3W arm the response rate was 12.9% for patients with PS 0 and 6.5% for patients with PS 1 (P = 0.275). In the 1W arm the response rate was 20% for patients with PS 0 and 1.1% for those with PS 1 (P = 0.009). Median response duration was 12.1 months (95% CI 6.1–18.0 months) in the 3W arm and was not reached in the 1W arm.
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Thirty-nine of 129 (30%) patients in the 3W arm and 28 of 125 (22%) in the 1W arm received additional anticancer drug therapy after going off-study. Patients treated with additional chemotherapy after the study had significantly longer survival than those who did not receive additional treatment. In the 3W arm, median survival was 13.2 months (CI 95% 9.6–16.6 months) in patients receiving further treatment and 5.1 months (CI 95% 4.4–5.9 months) in patients without further treatment (P <0.0001). In the 1W arm, median survival was 12.2 months (CI 95% 8.6–15.9 months) in treated patients and 4.4 months (CI 95% 3.4–5.4 months) in patients who received no further chemotherapy.
toxicity
Toxicity data were available for 254 patients who received at least one dose of therapy. Non-hematologic toxicities were generally mild to moderate in both treatment arms (Table 3). The most frequent severe adverse events (grade 3 or 4) observed among patients in the 3W arm were asthenia (14%), pain (3.1%) and hyperglycemia (3.1%). Among patients in the 1W arm, the most frequent severe adverse events were asthenia (14.4%), dyspnea (9.6%), mucositis (7.2%), anorexia (5.6%), neurotoxicity (3.2%), diarrhea (3.2%) and nausea-vomiting (3.2%). There was significantly more grade 3 or 4 mucositis in the 1W arm (P = 0.032). Overall, hepatic toxicity and alopecia were less frequent in the 1W arm while diarrhea was less common in the 3W arm.
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Hematologic toxicities are summarized in Table 4. Grade 3 or 4 neutropenia was more common in the 3W arm [12 patients (9.3%)] than in the 1W arm [four patients (3.2%)]. Significantly more patients in the 3W arm than in the 1W arm developed febrile neutropenia [7.8% versus 0.8%, respectively (P = 0.010)].
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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This multicenter phase III randomized study compared 3-weekly to weekly docetaxel in previously-treated advanced NSCLC patients. Although toxicity profiles differed, median survival, 1-year survival, time to progression and response were found to be similar in the two groups.
Second-line treatment with docetaxel has been associated with significantly longer survival and improved symptom palliation when compared to best supportive care [3, 4, 10]. Three-weekly docetaxel has been shown to be active in several different studies, with response rates ranging from 6.7% to 8.8% in previous studies [3, 4, 11] compared with 9.3% in the present study. In the present study, weekly docetaxel yielded a slightly lower response rate (4.8%), but without a statistically significant difference between arms. The median survival for 3-weekly docetaxel in previous studies ranged from 5.7 to 7.9 months [3, 4, 11], which is similar to the 6.6 months observed in the present study. In our trial, median survival with weekly docetaxel was 5.4 months. Higher doses do not improve outcome but can lead to greater toxicity. In a phase II study, 182 previously-treated NSCLC patients were randomized to receive docetaxel 75 mg/m2 or 100 mg/m2 every 3 weeks [12]. Both doses achieved similar efficacy but the 100 mg/m2 dose produced greater toxicity.
Our findings are in line with those from three previous randomized studies comparing weekly and 3-weekly docetaxel schedules in second-line NSCLC treatment [13–15]. None of the studies found any significant differences in median survival, 1-year survival, time to progression or response rates between the 3-weekly and weekly docetaxel schedules. A randomized phase II trial [13] comparing docetaxel 75 mg/m2 every 3 weeks with docetaxel 40 mg/m2 weekly in 125 previously treated NSCLC patients found that the two regimens had similar efficacy, but a significantly lower incidence of severe neutropenia was observed in the weekly arm; grade 3–4 neutropenia occurred in 48% of patients in the 3-weekly arm compared with 16% in the weekly arm. However, grade 3–4 asthenia was more frequent in the weekly arm. A randomized phase III trial [14] comparing docetaxel 75 mg/m2 every three weeks with docetaxel 33.3 mg/m2 weekly in 220 NSCLC patients found no differences in response rate or survival between the two regimens, but grade 3–4 hematologic toxicity was significantly more frequent in the 3-weekly arm. Finally, in a phase III trial [15], 251 patients were randomized to receive docetaxel 75 mg/m2 every 3 weeks or docetaxel 35 mg/m2 weekly for 3 weeks followed by 1 week without therapy. Median survival tended to be longer with weekly docetaxel although the difference was not statistically significant. Moreover, patients treated with the weekly regimen experienced a significantly lower rate of febrile neutropenia.
In first-line chemotherapy, better pretreatment PS has been associated with longer survival, with a substantial difference between PS 0 and PS 1 [18]. In the present study, the influence of PS 0 in second-line treatment has been demonstrated for the first time. In future studies, the effect of PS 0 should be further clarified.
In summary, our findings suggest that both weekly and 3-weekly docetaxel are effective and well-tolerated, with different toxicity profiles. In general, there is no indication to recommend the weekly schedule since it requires more outpatient visits, which will increase treatment costs and patient inconvenience.
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Acknowledgements |
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The authors express their gratitude to Juan Luis Sanz and Oscar Salamanca, from Biometrica, Madrid, Spain, for their contribution to the statistical analyses.
Received for publication June 16, 2005. Revision received November 18, 2005. Accepted for publication November 23, 2005.
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References |
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