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Individual Patient Data Meta-Analysis of Docetaxel Administered Once Every 3 Weeks Compared With Once Every Week Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer

Massimo Di Maio, Francesco Perrone, Paolo Chiodini, Ciro Gallo, Carlos Camps, Wolfgang Schuette, Elisabeth Quoix, Chun-Ming Tsai, Cesare Gridelli

From the Clinical Trials Unit, National Cancer Institute; Department of Medicine and Public Health, Second University, Naples; Division of Medical Oncology, Azienda Ospedaliera S. Giuseppe Moscati, Avellino, Italy; Consorcio Hospital General Universitario, Valencia, Spain; Martha-Maria City Hospital Halle-Doelau, Halle, Germany; Hopital Lyautey, Strasbourg Cedex, France; and Section of Thoracic Oncology, Chest Department, Taipei Veterans General Hospital, Shih-Pai, Taipei, Taiwan

Address reprint requests to Cesare Gridelli, MD, Division of Medical Oncology, S.G. Moscati Hospital, Contrada Amoretta, 83100 Avellino, Italy; e-mail: cgridelli{at}libero.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose Although several randomized trials have been performed comparing weekly docetaxel (wD) with standard docetaxel once every 3 weeks (3wD) as second-line treatment of advanced non–small-cell lung cancer (NSCLC), no single trial had sufficient power to detect clinically relevant differences in survival.

Methods We performed a meta-analysis based on individual patient data from all identified randomized trials comparing wD with 3wD as second-line treatment of advanced NSCLC. Baseline characteristics, treatment assigned, and outcome data were collected for each patient. The primary end point was overall survival. All statistical analyses were stratified by trial.

Results Five eligible trials were identified for a total of 865 patients: 433 patients had been assigned to 3wD, and 432 patients had been assigned to wD. Median age was 62 years (range, 26 to 80 years). Performance status was 0 in 23%, 1 in 58%, and 2 in 16% of patients; 91% of the patients had received previous platinum, and 14% had received previous paclitaxel. With 733 deaths recorded (85%), median survival was 27.4 weeks for patients treated with 3wD, and 26.1 weeks for patients treated with wD (P = .24, log-rank test). There was no significant heterogeneity among the five trials. No relevant differential effect was detected in subgroup analyses. Significantly less severe and febrile neutropenia was reported with wD (P < .00001 for both), whereas no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxicity.

Conclusion wD shows similar efficacy compared with 3wD, and represents an alternative for second-line treatment of advanced NSCLC.

	INTRODUCTION

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Treatment with cisplatin-based chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC) has become the most common approach worldwide, based on the evidence of a small survival gain (median, < 2 months) compared with supportive care in a meta-analysis of 11 randomized trials.¹ In the last decade, several new chemotherapeutic agents with activity in NSCLC have become available (paclitaxel, docetaxel, gemcitabine, and vinorelbine). A number of randomized trials performed during recent years ^2-5 have unequivocally shown that there are no substantial differences in the efficacy among several combinations containing cisplatin or carboplatin and one of these new drugs; toxicity and costs are the only outcomes that show variability among the different schemes. This means that with the best treatments available, only one third of patients with advanced NSCLC achieve a significant clinical remission with first-line chemotherapy, and approximately another third achieve temporary disease stabilization. Unfortunately, all of these patients ultimately experience disease progression and die as a result of lung cancer, although at the time of disease progression, many of them still have a good performance status.

In these latter patients, second-line chemotherapy with docetaxel 75 mg/m² administered once every 3 weeks (3wD) has been proven to be a reasonable therapeutic option in two phase III randomized trials.^6,7 Such a treatment prolongs survival compared with best supportive care, and improves some quality of life items such as fatigue and pain.⁶ However, myelosuppression with this docetaxel schedule is extremely frequent and severe: grade 3 to 4 neutropenia has been reported in 67% of patients in one trial,⁶ grade 4 has been reported in 54% of patients in another trial,⁷ and febrile neutropenia has been reported in 2% and 8% of patients, respectively.^6,7

Weekly scheduling of docetaxel may improve the toxicity profile of the drug in pretreated NSCLC patients^8,9 without decreasing antitumor activity. Particularly, a marked reduction in the occurrence of severe and febrile neutropenia is reported when docetaxel is administered in a weekly schedule, compared with the classic administration schedule of 3wD. On the basis of this evidence, several randomized trials have been conducted, with the aim of comparing the once weekly (wD) schedule with the standard schedule of 3wD of docetaxel in the second-line treatment of advanced NSCLC.^10-14 However, sample size of each single trial had insufficient power to detect potentially relevant differences in overall survival.

The main objective of the present meta-analysis, based on individual data from patients enrolled in five randomized trials, was to compare the efficacy of the two different schedules of docetaxel for the second-line treatment of advanced NSCLC. Such a meta-analysis has the advantage of increasing the power of the statistical comparison to detect survival differences.

	METHODS

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Identification of Eligible Trials
A literature search was carried out in December 2005 to identify all randomized trials, comparing the standard 3wD schedule of docetaxel with the experimental wD schedule of docetaxel in second-line treatment of patients with advanced NSCLC. The search was performed using PubMed and the Proceedings of the American Society of Clinical Oncology, from 1995 to 2005, with the following key words in all the possible combinations: "docetaxel," "lung cancer," "NSCLC," "second-line," and "randomized." References of the identified articles were also checked, and principal investigators were asked if they were aware of other trials.

None of the identified trials were excluded from the analysis. Five trials were eligible for meta-analysis, conducted in Italy, Spain, Germany, France, and Taiwan. ^10-14

Data Collection
A simple case report form was arranged and sent to the principal investigators of the five trials. The following data were requested for all participating patients: patient characteristics (patient identifier [eg, patient code or randomization number], date of birth, sex, and performance status); tumor characteristics (stage, histologic type, previous chemotherapeutic drugs, and best response to first-line treatment); treatment assigned by randomization (standard arm [3wD] or experimental arm [wD] and the date of random assignment); outcome data (date of death or the date when last known to be alive); worst grade experienced for the toxicities neutropenia, febrile neutropenia, anemia, thrombocytopenia, neurologic toxicity, diarrhea, fatigue, skin/nail toxicity, and hyperlacrimation; occurrence of any grade 3 to 4 nonhematologic toxicity; and objective response to study treatment.

Statistical Methods
All of the analyses were performed according to the intention-to-treat principle (ie, all patients were assessed according to the treatment group to which they were randomly assigned). All of the analyses were stratified by trial. All tests were two sided.

The primary end point of the meta-analysis was overall survival, defined as the time between the date of random assignment and the date of death, or the last date of follow-up for censored patients. Overall survival curves were estimated using the Kaplan-Meier technique and compared using the stratified log-rank test. The overall hazard ratio and its 95% CI of treatment effect were obtained from a stratified Cox proportional hazards model. The heterogeneity of treatment effect among trials was assessed by likelihood ratios of two trial-stratified models, one with trial-specific treatment estimates and one with overall treatment estimates. Under the null hypothesis of no heterogeneity, this statistic follows approximately a ² distribution on J – 1 (ie, 5 – 1) df.¹⁵

Secondary end points were response rate and toxicities. Progression-free survival was not a study end point because of the ascertainment bias due to the different times of referral in the two treatment arms (3wD or wD). The objective response rate and the toxicities were compared using the stratified Mantel-Haenszel ² test for combining two-by-two tables. ² tests for heterogeneity were used to detect differences in treatment effect among the five trials. For objective response rate, patients obtaining complete response or partial response were considered as responders, and patients with stable disease, progressive disease, or those who were not evaluated were considered as nonresponders. Toxicity variables were dichotomized as severe (grade 3 to 4) and no/mild (grade 2 or below). Additional exploratory analyses were performed in the subgroups based on the main baseline characteristics of the patients to describe possible heterogeneity of treatment effect. No statistical tests were performed within subgroups.¹⁶

Findings of the meta-analysis are depicted in classical Forest plots, with point estimates and 95% CI for each trial and overall; size of the squares is proportional to the study size.

	RESULTS

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The main characteristics of the five randomized trials are listed in Table 1. Three were randomized phase III trials^10,12,14 and two were randomized phase II trials.^11,13

Of the 865 eligible patients, 433 patients (50%) had been assigned to 3wD, and 432 (50%) had been assigned to wD. The main characteristics of the 865 patients are listed in Table 2. Median age was 62 years (range, 26 to 80 years). Most of the patients were male (83%), had a good performance status (0 or 1 in 82%), and had previously received a first-line platinum-based treatment (91%). Paclitaxel was part of first-line treatment in 14% of the patients.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Overall survival (OAS) curves by treatment arm.

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Forest plot of treatment effect on survival.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Treatment effect on survival within major patient subgroups. PS, performance status.

Toxicity data were available for 722 patients, but data on fatigue were available for only 515 patients. Data on hyperlacrimation were reported only sporadically and could not be summarized consistently. A summary of grade 3 to 4 adverse effects is reported in Appendix Table A1 (online only), whereas odds ratios are reported in Figure 4. A clear advantage for the wD arm was found for both severe and febrile neutropenia (P < .00001 for both), whereas no significant differences were observed for anemia, thrombocytopenia, and nonhematologic toxicity. These findings were highly homogeneous among studies (data not shown).

View larger version (8K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Odds ratios of major severe adverse effects.

	DISCUSSION

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Systematic reviews and meta-analyses have been used increasingly in recent years as an important instrument for assessing and interpreting the results from different clinical trials conducted on the same topic. The issue of the comparison between 3wD and wD as second-line treatment of NSCLC represents a good topic for this approach because several underpowered, randomized, and similarly designed trials have been conducted.

Two of the five assessed trials were phase II randomized trials.^11,13 Phase II randomized trials should not be planned to compare the treatments formally,¹⁷ but they can be considered when conducting such an individual patient data meta-analysis because in these studies treatment was assigned randomly, and information on overall survival (ie, the primary end point of the meta-analysis) was collected prospectively.

The wD schedule was similar in the five arms, with some differences in the docetaxel dose (range, 33 to 40 mg/m²) and in the sequence of weeks with and without treatment. Four of the trials (those conducted in Europe^10-12,14) had an identical standard arm (docetaxel administered at 75 mg/m² 3wD); only the Taiwanese trial¹³ had a slightly lower dose in the standard arm (66 mg/m²), because of the higher risk of toxicity when higher doses are administered to Eastern patients.¹⁸ However, all the results of the meta-analysis were completely superimposable even when Taiwanese trial data were excluded (data not shown).

The sample size of each trial did not allow adequate power to detect potentially clinically relevant differences in efficacy between 3wD and wD schedules. Two of the studies were designed with toxicity as the primary end point.^11,13 The trial by Gridelli et al¹⁰ was designed with quality of life as primary end point, and planned sample size allowed 80% power to rule out an optimistic 0.67 HR of death with the weekly schedule. Only the trials by Schuette et al¹² and Camps et al¹⁴ were designed with survival as the primary end point, but with highly optimistic alternative hypotheses.

With such a small power for single studies, it is not surprising that results and their interpretation differed among trials. In particular, German authors (who discussed a median survival that was longer, although not reaching statistical significance for wD) recommended this treatment as a feasible alternative second-line treatment.¹² Italian authors recommended wD as preferable because of some quality of life advantages, lower toxicity, and no evidence of strikingly different effects on survival, but they recognized that no claim could be made about the interpretation of comparison in terms of equivalence.¹⁰ Conversely, in the Spanish trial, survival with wD was slightly shorter (although not significantly) than in the 3wD arm, and the authors did not recommend wD, limiting its potential usefulness to patients at high risk of severe neutropenia.¹⁴ Similarly, in the opinion of French authors, 3wD remained the recommended schedule in the second-line setting, whereas wD administration could be considered as an alternative for patients at high risk of febrile neutropenia.¹¹

In our opinion, this meta-analysis, in which all of the authors agreed to participate with their databases, gives us much more solid results for efficacy. There were no survival differences between the two schedules, with a HR estimate of only 1.09 against relevant benefits in terms of toxicity. The absence of significant heterogeneity among the trials and among subgroups reinforces these findings, and we may be more confident in considering wD as a valid alternative in all patients who are candidates for second-line treatment for advanced NSCLC. Furthermore, patients who have been pretreated with paclitaxel can receive some benefit from second-line treatment with docetaxel. Pretreatment with paclitaxel was allowed in four of the five studies, probably based on the evidence of activity of docetaxel in this category of patients in the previous phase III trial of docetaxel versus vinorelbine/ifosfamide.⁷ In our pooled data, 14% of the patients had received prior paclitaxel, and both schedules of docetaxel showed objective responses also in these patients.

After the literature search for this meta-analysis (performed in December 2005) and after completion of data collection and analysis (completed in April 2006), a sixth trial, performed in Taiwan, was published.¹⁹ This trial randomly assigned 161 patients to receive one of two weekly schedules of docetaxel (35 mg/m² on days 1, 8, and 15 every 4 weeks, or 40 mg/m² on days 1 and 8 every 3 weeks) or the standard schedule of 75 mg/m² 3wD. There were no statistically significant differences in overall survival between the weekly arms and standard arm. However, considering the limited number of patients enrolled onto this trial and the absence of significant difference in efficacy between weekly and standard arms, we believe that the results of this trial would be unlikely to change our results.

Regarding toxicity data, our pooled analysis confirms a significantly different toxicity profile between the two schedules of docetaxel. The most dangerous toxicity with docetaxel is the occurrence of febrile neutropenia, and our pooled analysis confirms that this risk is significantly lower with wD. Of course, with weekly administration of docetaxel, there is an increase in the number of corticosteroid administrations. In some of the trials considered for this meta-analysis, the schedule of dexamethasone for each docetaxel administration was not different between the wD and 3wD regimen. However, as we have shown in the Italian study,¹⁰ the dexamethasone schedule can be simplified safely and reduced in the wD schedule: dexamethasone (8 mg) was given at –12, 0, +12, +24, and +36 hours of every docetaxel administration in the 3wD arm and only at –12, 0, and +12 hours in the weekly arm. This significantly reduced the amount of drug administered in the wD arm (24 mg/wk), although it remains higher than in the 3wD arm (40 mg every 3 weeks). Still, the use of corticosteroids as a premedication for docetaxel is considered safe and useful in improving the chemotherapy toxicity profile. In our analysis, the occurrence of severe nonhematologic toxicity was not different between the wD and 3wD schedules.

In recent years, several new therapeutic options have become available for patients who experience treatment failure after first-line chemotherapy for advanced NSCLC. Pemetrexed was found to be not inferior to 3wD in a large phase III study involving 571 patients in second-line treatment for advanced NSCLC.²⁰ In that study, survival, response rate, and quality of life results were superimposable between the two treatments, but pemetrexed was less toxic, particularly for hematologic toxicity and related hospitalizations and complications. More recently, erlotinib has shown efficacy when compared with placebo as second- or third-line treatment of patients with advanced NSCLC,²¹ and has been approved for clinical use in this category of patients, although a formal comparison with pemetrexed or docetaxel is not yet available.

Several authors who reviewed the evidence about the randomized trials comparing wD and 3wD schedules of docetaxel in this setting have made critical comments about the lack of definite evidence supporting the wD schedule,^22,23 but we believe that the outcome of this meta-analysis rules out their major doubts on the efficacy of the wD schedule.

In conclusion, wD represents a valid alternative to 3wD administration for all patients with NSCLC who are candidates for a second-line chemotherapy, based on an advantageous profile of toxicity and no relevant difference in survival.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Cesare Gridelli, Eli Lilly & Co, Sanofi-aventis, Roche, GlaxoSmithKline Stock: N/A Honoraria: Massimo Di Maio, Sanofi-aventis; Francesco Perrone, Sanofi-aventis; Cesare Gridelli, Eli Lilly & Co, Roche, GlaxoSmithKline, AstraZeneca Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Massimo Di Maio, Francesco Perrone, Ciro Gallo, Cesare Gridelli

Provision of study materials or patients: Carlos Camps, Wolfgang Schuette, Elisabeth Quoix, Chun-Ming Tsai, Cesare Gridelli

Collection and assembly of data: Massimo Di Maio, Carlos Camps, Wolfgang Schuette, Elisabeth Quoix, Chun-Ming Tsai

Data analysis and interpretation: Massimo Di Maio, Francesco Perrone, Paolo Chiodini, Ciro Gallo

Manuscript writing: Massimo Di Maio, Francesco Perrone, Paolo Chiodini, Ciro Gallo, Cesare Gridelli

Final approval of manuscript: Massimo Di Maio, Francesco Perrone, Paolo Chiodini, Ciro Gallo, Carlos Camps, Wolfgang Schuette, Elisabeth Quoix, Chun-Ming Tsai, Cesare Gridelli

	Appendix

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Flow of data collection. 3wD, docetaxel administered once every 3 weeks; wD, docetaxel administered once every week.

	ACKNOWLEDGMENTS

 
We thank all of the investigators and the data managers participating in the trials. In particular, we thank Federika Crudele, Giuliana Canzanella, Fiorella Romano, Sylke Nagel, Evelyne Ecstein-Fraïssé, Chun-Liang Lai, and Gwo-Shu Wang for their help in collection and assembly of data for this project.

	NOTES

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

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted November 7, 2006; accepted January 10, 2007.

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