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Phase III Study of Second-Line Chemotherapy for Advanced Non–Small-Cell Lung Cancer With Weekly Compared With 3-Weekly Docetaxel

From the Martha-Maria City Hospital Halle-Doelau, Halle; Martin-Luther- University of Halle-Wittenberg; Johanniter-Krankenhaus, Oberhausen; Klinikum Chemnitz, Chemnitz; Lungenklinik Lostau, Lostau; Carl-Thiem-Klinikum Cottbus, Cottbus; Klinikum St Marien, Amberg; HELIOS Klinikum Wuppertal, Wuppertal; Friedrich-Schiller University of Jena, Jena; Lungenklinik Heckeshorn, Berlin, Germany

Address reprint requests to Wolfgang Schuette, MD, Martha-Maria City Hospital Halle-Doelau, Roentgenstraße 1, Halle 06120, Germany; e-mail: wolfgang.schuette{at}medizin.uni-halle.de

	ABSTRACT

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PURPOSE: A phase III study to determine whether a weekly docetaxel schedule improves the therapeutic index compared with the classic 3-weekly schedule.

PATIENTS AND METHODS: Patients with stage IIIB-IV non–small-cell lung cancer (NSCLC) were randomly assigned to docetaxel 75 mg/m² on day 1 every 3 weeks (3-weekly) and 35 mg/m² on days 1, 8, and 15 (weekly) for eight cycles. End points included survival (primary), toxicity, and response.

RESULTS: Of 215 patients enrolled, 208 (103 in the 3-weekly arm and 105 in the weekly arm) were assessable for response. At baseline, 24.5% of patients (51 out of 208) had received prior paclitaxel therapy and 43.3% of patients (90 out of 208) had been progression-free for more than 3 months after first-line therapy. After 12 months' follow-up, median survival was 6.3 months (95% CI, 4.68 to 7.84 months) with 3-weekly docetaxel and 9.2 months (95% CI, 5.83 to 12.59 months) with weekly docetaxel (P = .07) after a median of four (range, one to eight) and two (range, one to eight) treatment cycles, respectively. Overall, response rates were 12.6% v 10.5% with 3-weekly versus weekly docetaxel. Significantly fewer patients reported grade 3 to 4 toxicities with weekly docetaxel versus 3-weekly docetaxel (P .05). There were significantly lower rates of grade 3 to 4 anemia (P .05), leucopenia (P < .0001), and neutropenia (P .001) with weekly versus 3-weekly treatment. No grade 3 to 4 thrombocytopenia or mucositis was reported.

CONCLUSION: Weekly docetaxel 35 mg/m² demonstrated similar efficacy and better tolerability than standard 3-weekly docetaxel 75 mg/m² and can be recommended as a feasible alternative second-line treatment option for patients with advanced NSCLC.

	INTRODUCTION

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Lung cancer is the most common cancer worldwide, with an estimated 1.2 million new cases globally (12.3% of all cancers) and 1.1 million deaths (17.8% of all cancer deaths) in 2000.¹ The estimated global incidence of non–small-cell lung cancer (NSCLC) in 2000 was approximately 1 million, which accounted for approximately 80% of all cases of lung cancer.²

Treatment of advanced NSCLC is palliative; the aim is to prolong survival with less deterioration in quality of life.³ The recommended first-line treatment of advanced NSCLC currently involves up to four cycles of platinum-based combination chemotherapy, with no one combination recommended over others.⁴ Although this treatment improves survival rates, a substantial proportion of patients do progress and should be offered second-line treatment. With unsurpassed efficacy compared with other chemotherapeutic regimens or best supportive care,^5,6 docetaxel is the current standard as second-line chemotherapy for advanced NSCLC. The recommended regimen of docetaxel 75 mg/m² given intravenously every 3 weeks as second-line therapy has been associated with median survival times of 5.7 months to 7.5 months^5,6 and is also associated with better quality of life outcomes compared with best supportive care.³

The most common toxicity associated with the standard 3-weekly docetaxel regimen is myelosuppression (in particular, neutropenia), which is manageable with the use of granulocyte-colony-stimulating factor. Nevertheless, there has been increasing interest in the use of a weekly docetaxel regimen as a way of reducing this toxicity. Data from noncomparative phase II studies in patients with advanced NSCLC indicate that weekly dosing with docetaxel 35 or 36 mg/m² appears to be well tolerated^7-9; specifically, incidences of grade 3 to 4 myelosuppression and hematologic toxicity were low. This has led to speculation that weekly dosing may increase the therapeutic index of docetaxel as treatment for advanced NSCLC, compared with 3-weekly dosing, and there is already some direct support for this hypothesis from recent randomized, comparative phase II and III studies.^10,11

The aim of this multicenter phase III study was to ascertain whether a weekly schedule of docetaxel improved survival, toxicity profile, and quality of life when compared with the classic 3-weekly schedule.

	PATIENTS AND METHODS

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This was a multicenter, randomized phase III study. The study protocol was approved by the Ethics Commission, and all patients provided written, informed consent before enrollment.

Patients
Patients enrolled had advanced or metastatic NSCLC (confirmed histologically, with a tumor that was measurable by clinical and/or radiologic examination), were aged 18 to 75 years, and had received more than one previous chemotherapy regimen for their disease. Patients who had received prior paclitaxel chemotherapy were permitted providing their disease had not progressed within 3 months of completing paclitaxel treatment. Patients were also required to have an Eastern Cooperative Oncology Group performance status 0 to 2, and adequate renal, cardiac, hepatic, and hematologic function as indicated by the following parameters: absolute neutrophil count 2 x10⁹/L, thrombocytes 100 x10⁹/L, hemoglobin 10 g/dL, total bilirubin 1.25x the upper limit of normal range (ULN), ALT and AST 1.5x ULN, alkaline phosphatase 5x ULN, creatinine 1.15x ULN. Exclusion criteria were: disease progression while undergoing prior paclitaxel chemotherapy, known brain metastases or secondary neoplasia, myocardial insufficiency or myocardial infarction within the preceding 6 months, severe renal or hepatic insufficiency, pre-existing motor or sensor neurotoxicity WHO grade 2, severe psychologic disease, active infection, or other condition that could compromise protocol compliance, simultaneous administration of other antineoplastic medications, and pregnancy and/or lactation.

Stratification and Treatment Plan
Patients were randomly assigned to one of two treatment groups: 3-weekly regimen, docetaxel 75 mg/m² given intravenously on day 1 of a 21-day cycle; weekly regimen, docetaxel 35 mg/m² given intravenously on days 1, 8, and 15 of a 28-day cycle. Patients in both treatment groups could receive a maximum of eight cycles of their allocated regimen.

Patients received antiemetics as required and granulocyte colony-stimulating factor at the physicians' discretion. Palliative and supportive treatment for tumor-related symptoms was available for all patients. All patients received dexamethasone (8 mg twice daily orally the day before and after docetaxel infusion; 8 mg intravenously 30 minutes before docetaxel infusion). In the event of a hypersensitivity reaction, dimethindene maleate, epinephrine, and intravenous fluids (if required) were given.

Docetaxel therapy was discontinued if the patient experienced a significant hypersensitivity reaction or unacceptable toxicity (eg, fluid retention, neurologic side effects of WHO grade 3 to 4, severe persistent skin reactions, or serious organ toxicity). A treatment delay of 1 to 2 weeks was permitted in cases of severe hematologic or nonhematologic toxicity. The dose was reduced by one dose level in the case of severe mucositis, or continuing severe diarrhea, nausea, or vomiting that was not controllable with usual antidiarrheal/antiemetic medication.

Clinical Assessments
At baseline, patients underwent clinical and neurologic examinations, and were assessed for blood biochemistry and cardiac function. Blood biochemistry tests were repeated weekly throughout the study. Thoracic x-ray and ECG were performed before every cycle.

Outcomes
The primary outcome was overall survival. Tumor response was assessed after every second cycle using International Union Against Cancer standard criteria. Complete response (CR) was defined as the disappearance of all tumor indications, confirmed by two examinations 4 weeks apart. Partial response (PR) was defined as an estimated 50% decrease in tumor size, confirmed by two examinations 4 weeks apart with no new lesions detected. Progressive disease was defined as the appearance of any new tumor lesions or a 25% increase in the size of existing tumor lesions. Where responses did not qualify as CR, PR, or progressive disease (ie, no significant changes over 4 weeks), they were reported as stable disease. Toxicity was assessed after every cycle and graded using WHO criteria. Quality of life was self-assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C-30 questionnaire at baseline, after every second cycle and at the end of treatment in both treatment arms. After completion of therapy, patients were monitored at 12-weekly intervals until disease progression or death.

Statistical Analysis
Overall survival was assessed using the Kaplan-Meier method. The primary end points were 1-year survival and median survival. Exploratory subgroup analyses of survival data were performed by progression-free interval following first-line treatment ( 3 months or > 3 months) and by paclitaxel pretreatment status. Secondary end points were tumor response, time to progression, toxicity, and quality of life (see Outcomes section for details of how these end points were assessed).

The study was designed to detect whether or not there was a significant difference in the 1-year survival rates between the 3-weekly and weekly treatment arms, using an equivalence tolerance of 2%. On the basis of a minimum expected 1-year survival rate of 15% and maximum expected 1-year survival rate of 30%, 102 patients per group were required to test the equivalence of the two regimens with a certainty of 80%. The test significance level was = .05.

	RESULTS

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Patients
Between April 2000 and September 2003, a total of 215 patients were recruited from 19 centers in Germany and randomly assigned to receive either 3-weekly or weekly regimens of docetaxel. Of these, seven patients did not receive study treatment because of death before treatment was initiated (two patients), ineligibility,² and consent withdrawal.³ Therefore, 208 patients (96.7%) (103 patients in the 3-weekly group, 105 patients in the weekly group) completed at least one cycle of study treatment and were assessable for survival and tumor response (Fig 1). A total of 102 3-weekly patients and 105 weekly patients were assessable for toxicity (data were not available for one patient in the 3-weekly group because of consent withdrawal after one chemotherapy cycle). Reasons for treatment discontinuation in the 3-weekly and weekly groups, respectively, were: disease progression (47.6% v 52.4% of patients), death (1.9% v 7.6%, all because of disease progression), toxicity (9.7% v 12.4%), consent withdrawal (3.9% for each group), lost to follow-up (0% v 1.9%), other reasons (8.7% v 11.4%), and unknown reasons (1.0% v 0%).

View larger version (19K): [in this window] [in a new window]   Fig 1. Flow of participants through each stage of the study.

View larger version (22K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curve of survival after 12 months' follow-up for patients receiving 3-weekly (n = 103) versus weekly (n = 105) docetaxel.

Exploratory analyses showed that prior paclitaxel treatment status did not significantly alter the survival outcomes seen with docetaxel treatment (P = .81). The median survival time in patients who had received paclitaxel pretreatment was 8.3 months (range, 5.9 to 10.7 months) compared with 7.0 months (range, 5.2 to 8.8 months) in patients who had not previously received paclitaxel.

Responses
Tumor responses were similar for both treatment groups (Table 2). Disease control (ie, CR, PR, or stable disease) was achieved in 52 patients (50.5%) in the 3-weekly group and 46 patients (43.8%) in the weekly group. Overall response rates were 12.6% and 10.5% in the 3-weekly and weekly treatment groups, respectively.

View larger version (21K): [in this window] [in a new window]   Fig 3. Kaplan-Meier curve of time to progression (TTP) for patients receiving 3-weekly (n = 103) versus weekly (n = 105) docetaxel.

View this table: [in this window] [in a new window]   Table 3. WHO Grade 3-4 Toxicities Reported in 5% of Patients in Either Treatment Group

Quality of Life
Global quality of life scores from the self-assessed EORTC QLQ C-30 questionnaire were not significantly different between the two treatment groups (P > .05; data to be presented in a separate publication).

	DISCUSSION

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Several noncomparative phase II studies have indicated that weekly docetaxel 25 mg/m^2,12,13 or docetaxel 35 to 36 mg/m^2,7–9 is an effective and well-tolerated treatment for advanced NSCLC. These studies indicated that a weekly regimen may reduce the hematologic toxicity seen with the standard 3-weekly docetaxel 75 mg/m² regimen, raising interest in whether the docetaxel risk:benefit ratio could be improved by dividing the 3-weekly dose into smaller, more frequent doses. Hence, we compared the efficacy and toxicity of weekly docetaxel 35 mg/m² versus 3-weekly docetaxel 75 mg/m² as second-line therapy for advanced NSCLC

In this phase III study involving 208 patients, weekly docetaxel was as effective as 3-weekly docetaxel. Response and survival results were consistent with those reported for other phase III studies of 3-weekly docetaxel.^5,6 We noted a trend toward increased median survival with weekly versus 3-weekly docetaxel (9.2 months v 6.3 months, respectively), although the difference was not statistically significant (P = .07). As may be expected, patients with a longer progression-free interval (> 3 months) after first-line therapy had a better overall survival outcome than those who had progressed quickly ( 3 months) after initial chemotherapy. However, within these two stratified groups, there was no significant difference in survival outcome between the two treatment arms, supporting the finding that low-dose weekly docetaxel is at least as effective as standard 3-weekly docetaxel. Analyses also suggested that patients who had previously received paclitaxel treatment fared as well as those who had not received paclitaxel (P = .81).

We found that the toxicity rates for 3-weekly docetaxel 75 mg/m² were generally consistent with those reported in other phase III studies,^5,6 although grade 3 to 4 neutropenia was considerably less frequent in our study (21% of patients v 67%⁵ and 54%⁶). Weekly docetaxel 35 mg/m² demonstrated a significantly improved toxicity profile compared with 3-weekly docetaxel 75 mg/m²; in particular, the weekly schedule was associated with significantly fewer cases of alopecia and grade 3 to 4 hematologic toxicities. These toxicity findings for weekly docetaxel are supported by several^7-9,12,13—but not all^14,15—earlier reports from phase II studies of single-agent weekly docetaxel as second- or third-line therapy for advanced NSCLC.

Two recent randomized studies—one phase II¹⁰ and one phase III¹¹—have also directly compared weekly versus 3-weekly docetaxel regimens as second-line therapy in advanced NSCLC. In the phase II study by Gervais et al¹⁰ (n = 125), weekly docetaxel 40 mg/m² for 6 out of 8 weeks produced efficacy results comparable to 3-weekly docetaxel 75 mg/m² (median survival, 5.5 v 5.8 months, respectively), with significantly lower rates of grade 3 to 4 neutropenia (16% v 48% patients, respectively; P = .001). There were no reported cases of febrile neutropenia with the weekly docetaxel regimen. The survival times were shorter and hematologic toxicity rates were generally higher than those seen in our study but are in keeping with the results of other phase III studies of 3-weekly docetaxel.^5,6 In the phase III study by Gridelli et al¹¹ (n = 220), efficacy was similar for the two schedules; reduced toxicity was observed for weekly docetaxel (33.3 mg/m²) versus 3-weekly docetaxel, including a significant reduction in the incidence of hematologic grade 3 to 4 events (P = .0003). Importantly, quality of life (the primary outcome of the Gridelli et al¹¹ study) generally favored the weekly schedule. Gridelli et al¹¹ observed no significant difference in global quality of life (measured on the EORTC QLQ C-30 scale) between the two treatment arms; however, the weekly regimen was associated with significant advantages for hair loss, pain, and cough (measured on the disease-specific EORTC QLQ LC13), thus demonstrating palliative relief for advanced NSCLC symptoms.¹¹

Interestingly, similar investigations have been made in phase II studies for second-line weekly paclitaxel therapy. Median survival ranged from 3.5 to 9.7 months,^14,16-19 compared with 5.3 to 9.2 months for weekly docetaxel (including data from our study).^7-11 A phase II trial directly comparing weekly docetaxel and weekly paclitaxel suggested a longer median survival time with docetaxel (6.1 v 3.5 months, respectively), although the difference was not statistically significant.¹⁴

A recent phase III study (n = 571) by Hanna et al²⁰ compared 3-weekly pemetrexed 500 mg/m² with 3-weekly docetaxel 75 mg/m² as second-line therapy for advanced NSCLC.²⁰ Efficacy outcomes (survival and response rates) were similar for the two treatments. The authors reported greater toxicity with 3-weekly docetaxel than 3-weekly pemetrexed —in particular, a higher incidence of grade 3 to 4 hematologic toxicity and alopecia of all grades. However, as shown in our study and those of others, there is growing evidence that weekly docetaxel regimens have improved tolerability profiles compared with the 3-weekly regimen. Indeed, as Gridelli et al¹¹ also noted, weekly docetaxel may be at least as interesting as 3-weekly pemetrexed and worthy of direct comparison with this agent in clinical trials.¹¹ Notably, in the study by Hanna et al,²⁰ patients receiving pemetrexed required regular folic acid and vitamin B12 supplements to reduce the risk of hematologic and nonhematologic toxicity. Our study showed a significantly lower incidence of toxicities—particularly hematologic—with weekly docetaxel compared with the same 3-weekly docetaxel regimen used by Hanna et al,²⁰ but without requiring vitamin supplementation.

In conclusion, second-line therapy with weekly docetaxel 35 mg/m² demonstrated similar survival outcomes with a trend toward improved survival compared with standard 3-weekly docetaxel 75 mg/m². While both docetaxel regimens had an acceptable toxicity profile and could be administered on an outpatient basis, weekly docetaxel was associated with improved tolerability and significantly fewer severe hematologic adverse events. Thus, weekly docetaxel provides a feasible alternative second-line treatment option for patients with advanced NSCLC.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank the following investigators for their participation in this study: Dr Zwadlo, Erkelenz; Dr Lange, Duisburg; Dr Siering, Ansbach; Dr Riha, Coswig; Dr Wollschläger, Halle; Dr Welslau, Aschaffenburg; Dr Schroeder, Duisburg.

	NOTES

 
Supported by a research grant from Aventis Pharmaceuticals, a member of the sanofi-aventis group.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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3. Dancey J, Shepherd FA, Gralla RJ, et al: Quality of life assessment of second-line docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy: Results of a prospective, randomized phase III trial. Lung Cancer 43:183-194, 2004[CrossRef][Medline]

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6. Fossella FV, DeVore R, Kerr RN, et al: Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens: The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18:2354-2362, 2000[Abstract/Free Full Text]

7. Hainsworth JD, Burris HA 3rd, Litchy S, et al: Weekly docetaxel in the treatment of elderly patients with advanced nonsmall cell lung carcinoma: A Minnie Pearl Cancer Res Network Phase II trial. Cancer 89:328-333, 2000[CrossRef][Medline]

8. Lilenbaum RC, Schwartz MA, Seigel L, et al: Phase II trial of weekly docetaxel in second-line therapy for nonsmall cell lung carcinoma. Cancer 92:2158-2163, 2001[CrossRef][Medline]

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10. Gervais R, Ducolone A, Breton JL, et al: Phase II randomised trial comparing docetaxel given every 3 weeks with weekly schedule as second-line therapy in patients with advanced non-small-cell lung cancer (NSCLC). Ann Oncol 16:90-96, 2005[Abstract/Free Full Text]

11. Gridelli C, Gallo C, Di Maio M, et al: A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer: The DISTAL 01 study. Br J Cancer 91:1996-2004, 2004[CrossRef][Medline]

12. Ardizzoia A, Acquati M, Fagnani D, et al: Second line therapy with weekly low-dose docetaxel for pretreated non-small-cell lung carcinoma patients: A multicenter Italian phase II study. Lung 182:1-8, 2004[CrossRef][Medline]

13. Petrioli R, Pozzessere D, Messinese S, et al: Weekly low-dose docetaxel in advanced non-small cell lung cancer previously treated with two chemotherapy regimens. Lung Cancer 39:85-89, 2003[CrossRef][Medline]

14. Esteban E, Gonzalez de Sande L, Fernandez Y, et al: Prospective randomised phase II study of docetaxel versus paclitaxel administered weekly in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. Ann Oncol 14:1640-1647, 2003[Abstract/Free Full Text]

15. Rossi D, Graziano F, Ugolini M, et al: Weekly docetaxel as second-line therapy in non-small cell lung cancer: A phase II study. Tumori 90:50-53, 2004[Medline]

16. Chang AY, Rubins J, Asbury R, et al: Weekly paclitaxel in advanced non-small cell lung cancer. Semin Oncol 28:10-13, 2001 (4 suppl 14)

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Submitted April 20, 2005; accepted August 9, 2005.

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