Originally published as JCO Early Release 10.1200/JCO.2008.17.1405 on December 15 2008

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Phase III Study of Immediate Compared With Delayed Docetaxel After Front-Line Therapy With Gemcitabine Plus Carboplatin in Advanced Non–Small-Cell Lung Cancer

From the Massachusetts General Hospital, Boston, MA; Penrose Cancer Center of Kansas, Wichita, KS; Missouri Baptist Cancer Center, St Louis, MO; Central Indiana Cancer Centers; Eli Lilly & Co, Indianapolis, IN; Oncology Hematology Care, Inc, Cincinnati, OH; and University of Texas Southwestern Medical Center, Dallas, TX.

Corresponding author: Panos M. Fidias, MD, Massachusetts General Hospital, Center for Thoracic Cancers, 55 Fruit St, Boston, MA 02114; e-mail: pfidias2{at}partners.org.

	ABSTRACT

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Purpose Gemcitabine plus carboplatin (GC) is active as front-line treatment for advanced non–small-cell lung cancer (NSCLC). For patients without progression, timing of second-line chemotherapy for optimum clinical benefit remains uncertain. This phase III, randomized trial assessed the efficacy and safety of docetaxel administered either immediately after GC or at disease progression.

Patients and Methods The chemotherapy-naïve patients enrolled had either stage IIIB NSCLC with pleural effusion or stage IV NSCLC. Gemcitabine (1,000 mg/m²) was administered on days 1 and 8 followed by carboplatin (area under the curve = 5) on day 1. After four 21-day cycles, patients who did not have progression were randomly assigned either to an immediate docetaxel group (docetaxel 75 mg/m² on day 1 every 21 days, with maximum of six cycles) or to a delayed docetaxel group. The primary end point was overall survival (OS) measured from random assignment. Additional analyses included tumor response, toxicity, progression-free survival (PFS), and quality of life (QOL).

Results Enrollment totaled 566 patients; 398 patients completed GC; 309 patients were randomly assigned equally to the two docetaxel treatment groups. Toxicity profiles were generally comparable for the docetaxel groups. Median PFS for immediate docetaxel (5.7 months) was significantly greater (P = .0001) than for delayed docetaxel (2.7 months). Median OS for immediate docetaxel (12.3 months) was greater than for delayed docetaxel (9.7 months), but the difference was not statistically significant (P = .0853). QOL results were not statistically different (P = .76) between docetaxel groups.

Conclusion We observed a statistically significant improvement in PFS and a nonstatistically significant increase in OS when docetaxel was administered immediately after front-line GC, without increasing toxicity or decreasing QOL.

	INTRODUCTION

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Non–small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the United States.¹ Current treatment strategy for advanced NSCLC includes front-line chemotherapy using a platinum-based regimen, with the addition of the targeted agent bevacizumab for certain patients.² A number of chemotherapy agents, including gemcitabine, docetaxel, and paclitaxel, are active in front-line treatment as part of a platinum-based combination.^3,4 The combination of gemcitabine plus carboplatin (GC), with known activity in advanced NSCLC,^5–8 was used as front-line chemotherapy in the current trial.

On the basis of reports of several randomized trials evaluating the duration of front-line chemotherapy, full efficacy benefit for NSCLC patients is achieved after three to four treatment cycles.⁹ A high percentage of treated patients will respond or have their disease stabilized. However, prolonged front-line, platinum-based chemotherapy does not seem to provide additional benefit.¹⁰

After front-line therapy, historical practice has included monitoring NSCLC patients who do not have progression and initiating treatment with a non–cross-resistant agent on progression of disease (PD). Several chemotherapy agents, including docetaxel, erlotinib, and pemetrexed, have shown efficacy and been approved by the US Food and Drug Administration for second-line treatment of patients with locally advanced or metastatic NSCLC.^11–14 A number of studies have evaluated regimens using either sequential or maintenance chemotherapy as second-line treatment for NSCLC patients who are not experiencing disease progression. A review of these studies suggests that optimal timing and duration of second-line therapy remain unclear.¹⁵

The current randomized phase III trial compared the efficacy and safety of docetaxel administered for a fixed duration to patients without progression either immediately after completion of front-line GC therapy or at the time of PD. Our primary end point was overall survival (OS). Secondary end points were response rate, progression-free survival (PFS), toxicity, and quality of life (QOL).

	PATIENTS AND METHODS

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Patient Eligibility
Enrolled patients were 18 years old with histologically or cytologically confirmed stage IIIB plus pleural effusion or stage IV NSCLC; life expectancy of 12 weeks; Eastern Cooperative Oncology Group performance status (PS) of 0, 1, or 2; and adequate renal, hepatic, and bone marrow function. Exclusion criteria included prior adjuvant or neoadjuvant chemotherapy for NSCLC, active or ongoing infection, and symptomatic brain metastases (treated stable brain metastases were allowed). Radiation therapy (< 25% of bone marrow) was allowed 3 weeks before enrollment provided that patients had recovered from all adverse effects.

All patients provided written informed consent. Institutional review boards approved the trial protocol before patient enrollment. This study complied with the principles of good clinical practice, the Helsinki Declaration, and federal and institutional guidelines. A data safety monitoring board at Dana-Farber/Harvard Cancer Center provided interim reviews of safety and efficacy.

Treatment Plan
During the GC phase, gemcitabine 1,000 mg/m² was administered as a 30- to 60-minute intravenous (IV) infusion on days 1 and 8 followed by IV carboplatin (area under the curve = 5.0) over 30 to 60 minutes on day 1. Cycles were repeated every 21 days for four cycles. Patients with no progression (ie, patients without PD after four GC cycles) were randomly assigned to one of two docetaxel treatment arms. Patients entering the immediate docetaxel arm received IV docetaxel 75 mg/m² over 60 minutes on day 1 of a 3-week cycle until PD, to a maximum of six cycles. Patients who entered the delayed docetaxel arm received best supportive care (BSC) until first evidence of PD. Patients fit for chemotherapy at that time received the same docetaxel regimen as in the immediate docetaxel arm. Patients with PD who were unfit for chemotherapy received BSC and continuous follow-up. Patients were premedicated with oral dexamethasone 4 mg twice daily on the day before, the day of, and the day after docetaxel treatment.

Dose adjustments were based on absolute neutrophil count, platelets, and nonhematologic toxicities. Granulocyte colony-stimulating factor was used only for patients with absolute neutrophil count less than 0.5 x 10⁹/L, febrile neutropenia, or documented infection with neutropenia. Use of erythropoietin was allowed. Patients who had drug withheld during GC treatment resumed therapy if toxicities resolved to grade 2. Patients who had drug withheld during docetaxel therapy resumed therapy at a 25% dose reduction if nonhematologic toxicities were resolved to grade 1. During docetaxel therapy, treatment was discontinued if patients experienced grade 3 neurotoxicity, grade 4 hypersensitivity reaction, or grade 3 aberration in liver function lasting more than 3 weeks.

Patient Evaluations
Before entry, patients received a complete history; physical examination; baseline evaluations of PS, QOL, and toxicity symptoms; comprehensive laboratory tests; and radiologic imaging plus physical evaluation of palpable lesions to assess known disease. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors¹⁶ for measurable disease in combination with assessments of nonmeasurable disease. Patients underwent disease assessment before cycle 3 of GC treatment and at restaging after cycle 4. Patients experiencing PD during or immediately after GC treatment were discontinued from the trial and observed for survival.

For patients assigned to immediate docetaxel therapy, docetaxel treatment was initiated from day 21 up to day 35 after the start of cycle 4 during the GC phase, and disease scans obtained during docetaxel treatment were compared with baseline scans administered before GC therapy. Patients assigned to delayed docetaxel therapy were given standard evaluations including physical examinations; laboratory tests; and PS, toxicity, and QOL assessments every 3 weeks after random assignment until PD. Patients in the delayed docetaxel arm underwent disease assessment every 3 months until PD. During docetaxel therapy, standard evaluations were performed for each arm at the time of each cycle visit, and disease assessments were completed immediately after cycles 2 and 4 and 21 to 25 days after completion of cycle 6. Patients experiencing PD during docetaxel treatment were observed for survival, and patients discontinuing for reasons other than PD were observed for PD and survival.

Patients were assessed for QOL using the Lung Cancer Symptom Scale (LCSS) questionnaire¹⁷ 2 weeks before starting GC and at restaging after GC cycle 4. For the delayed docetaxel arm, LCSS was administered every 3 weeks until PD. During docetaxel therapy, LCSS was administered before cycles 2 to 6. Patients who completed six docetaxel cycles and achieved complete response (CR), partial response (PR), or stable disease (SD) were given the LCSS 21 to 30 days after last dose and at 3 months after last dose unless the patient received subsequent therapy or PD was noted.

Statistical Considerations
Before trial, the expected OS for delayed second-line docetaxel therapy was 9 months. To measure a meaningful improvement (4 months) in OS, 238 death events were required to achieve 80% statistical power with a two-sided = .05. Anticipating that 40% of GC-treated patients would have PD, an enrollment of 550 patients to GC treatment was expected to deliver 294 patients for random assignment to the docetaxel treatment arms. Interim efficacy analysis using Pocock stopping rules¹⁸ was performed when 50% of patients in each arm had died, were lost to follow-up less than 24 months after random assignment, or were observed for 24 months after random assignment.

Patients were centrally randomly assigned by Ingenix Pharmaceutical Services (Basking Ridge, NJ). Patients not randomly assigned because of PD, toxicity, or other reasons were included in the description of patient discontinuations. Randomly assigned patients who did not receive docetaxel treatment, for whatever reason, were incorporated into the intent-to-treat analysis, encompassing the phase of the study from random assignment onward. Patients receiving at least one dose of treatment were included in the safety analysis.

OS and PFS were estimated from the date of random assignment using the Kaplan-Meier method,¹⁹ and results for each treatment arm were compared using the log-rank test.²⁰ For response rate, 95% CIs were calculated using the exact method based on the binomial distribution. Distributions of changes from baseline in the average symptom burden index (ASBI) of the patient LCSS for each treatment arm were compared using the Mantel-Haenszel ² test.²¹ Patient characteristics and toxicities were summarized in descriptive statistics. Toxicities were defined using the National Cancer Institute Common Toxicity Criteria, version 2.0.²²

	RESULTS

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Patient Characteristics
From February 2002 through October 2005, 566 patients were enrolled at 51 institutions in the United States. Figure 1 provides a flow diagram for patient disposition throughout the trial. Three patients were excluded before starting GC; one patient died, a second patient was lost to follow-up, and the reason was unknown for the third patient. Table 1 lists patient characteristics for all treatment groups.

View larger version (52K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Patient disposition diagram. GC, gemcitabine and carboplatin.

Treatment Administration and Toxicity
Table 2 lists treatment administration results. The mean number of cycles delivered in the immediate docetaxel arm (4.4 cycles) was slightly higher than in the delayed docetaxel arm (3.8 cycles) or in the GC phase (3.4 cycles). There was a higher percentage of dose modifications in the GC phase compared with either the immediate or delayed docetaxel arm. The median dose-intensities for all treatment drugs were similar in each group.

Survival
At trial end, 256 death events (immediate docetaxel, n = 124; delayed docetaxel, n = 132) had been recorded. Figure 2 shows both PFS and OS results. Median PFS was significantly greater (P = .0001) in the immediate docetaxel arm (5.7 months) compared with the delayed docetaxel arm (2.7 months). Median OS for all registered patients receiving at least one dose of GC (n = 563) was 10.1 months (95% CI, 9.4 to 10.8 months). OS for the 254 patients who discontinued the trial before random assignment was 4.7 months (95% CI, 4.2 to 5.4 months). OS for randomly assigned patients was greater by 2.6 months in the immediate docetaxel arm (12.3 months, n = 153) compared with the delayed docetaxel arm (9.7 months, n = 156). The difference in OS between docetaxel arms did not reach statistical significance (P = .0853). OS for patients in the delayed arm who actually received docetaxel therapy (n = 98) was 12.5 months (95% CI, 9.6 to 14.6 months), which was identical to the OS observed for the safety population (n = 145) in the immediate docetaxel arm (12.5 months; 95% CI, 10.6 to 15.8). The 12-month survival rate was 51.1% (95% CI, 43.0% to 59.3%) for immediate docetaxel and 43.5% (95% CI, 35.5% to 51.4%) for delayed docetaxel.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. (A) Progression-free survival (PFS). Median PFS time was 5.7 months (95% CI, 4.4 to 6.9 months) for the immediate docetaxel am and 2.7 months (95% CI, 2.6 to 2.9 months) for the delayed docetaxel group (log-rank test, P = .0001); seven (4.6%) and nine patients (5.8%), respectively, were censored from each group. (B) Overall survival (OS). Median OS time was 12.3 months (95% CI, 10.4 to 15.2 months) for the immediate docetaxel group and 9.7 months (95% CI, 8.4 to 12.5 months) for the delayed group (log-rank test, P = .0853). Median 12-month survival rates were 51.1% (95% CI, 43.0% to 59.3%) for the immediate docetaxel group and 43.5% (95% CI, 35.5% to 51.4%) for the delayed group; 29 (19.0%) and 24 patients (15.4%) were censored, respectively.

	DISCUSSION

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Any attempt to evaluate the timing of second-line chemotherapy for patients with advanced NSCLC will be judged by balancing improvement in patient OS against increased toxicities or diminished QOL. The goal of the current randomized phase III trial was to assess this balance in NSCLC patients without progression after GC treated with docetaxel either immediately after front-line GC therapy or with the onset of PD.

Our results show that front-line GC therapy was well tolerated, with myelosuppression being the major cause of toxicities and only 22 patients (3.9%) in the GC phase discontinuing treatment as a result of adverse events. These results are consistent with previous reports for GC therapy^5–8 and support an earlier analysis that area under the curve of 5 may be the optimal dose of carboplatin delivered as part of front-line GC therapy for NSCLC patients in terms of both response and control of thrombocytopenia.²³

Previous studies of NSCLC patients who had received prior platinum-based chemotherapy reported manageable toxicities for docetaxel administered as second-line therapy.^11,13 Our results show that immediate docetaxel therapy had a manageable toxicity profile compared with delayed docetaxel therapy. These observations are also consistent with the toxicity results of an earlier study using a 28-day GC regimen with equivalent GC dosages followed by docetaxel at 75 mg/m².²⁴

Another important consideration for the timing of second-line therapy in advanced NSCLC is the possible impact on patient QOL. Previous studies have shown that providing second-line docetaxel therapy to patients with advanced NSCLC enhanced QOL compared with BSC.^11,13 Our results showed no statistical difference in QOL between patients in the two docetaxel treatment arms; these results are consistent with the observed toxicity profiles.

Earlier studies have been unable to demonstrate a significant improvement in OS for NSCLC patients treated with sequential or maintenance chemotherapy after front-line treatment.^25–34 Similar to the current trial design, several reports included evaluation of patients randomly assigned after completion of front-line chemotherapy. Buccheri et al²⁷ evaluated continued treatment with a regimen of methotrexate, doxorubicin, cyclophosphamide, and lomustine compared with BSC in NSCLC patients with stable disease after front-line treatment with methotrexate, doxorubicin, cyclophosphamide, and lomustine. There was no significant improvement in OS, whereas toxicity increased and QOL diminished in the group continuing treatment. In another trial, Westeel et al²⁸ compared maintenance vinorelbine with BSC in NSCLC patients who responded to a front-line regimen of mitomycin, ifosfamide, and cisplatin either alone or combined with radiation therapy. There was no significant improvement in either OS or PFS with maintenance therapy compared with BSC. In another phase III trial, Brodowicz et al²⁹ showed that gemcitabine administered to NSCLC patients without progression after front-line treatment with a gemcitabine/cisplatin combination provided significant improvement in time to progression compared with BSC. However, OS was not significantly lengthened, except for a limited subset of patients with a Karnofsky performance score of more than 80. More recently, Park et al³⁵ evaluated NSCLC patients without progression who were treated with two cycles of a platinum doublet therapy and randomly assigned to continue with either two or four additional cycles of treatment. Although there were no differences in toxicity or OS between the two groups, there was significant improvement in PFS for the group receiving the greater amount of therapy.

Our study also showed a statistically significant improvement in PFS by 3 months (P = .0001) for patients receiving immediate docetaxel therapy. However, our study is one of the first to show a trend toward improvement in OS for maintenance therapy, with OS increased by 2.6 months for patients in the immediate docetaxel arm. The improvement in OS did not reach statistical significance (P = .0853), perhaps because our study was not powered to detect a difference in survival of less than 4 months. It is also possible that the observed increase in OS might be related to the use of a non–cross-resistant agent as maintenance therapy. In most of the earlier trials, the maintenance regimen was an extension of the same chemotherapy administered during front-line treatment.

One interesting observation of our trial was the notable difference between treatment arms in the number of patients receiving docetaxel therapy. In the immediate docetaxel arm, most patients (145 of 153 patients; 94.8%) received docetaxel, whereas in the delayed docetaxel arm, a large number of patients (58 of 156 patients; 37.2%) never received docetaxel treatment. This observation is further underscored by results showing that the median OS time (12.5 months) was identical for the safety populations in each docetaxel arm. Thus, it seems that patients benefited from docetaxel therapy and the randomly assigned patients in the immediate docetaxel arm trended toward improved OS because more patients were able to receive treatment.

The major reasons for discontinuation before delayed docetaxel treatment were PD and patient decision. Additional patient review revealed that many of these patients experienced significant symptomatic deterioration by the time they reached PD and were unable to receive docetaxel therapy. These results suggest that NSCLC patients may be healthier and more likely to proceed to additional therapy if it is offered immediately after front-line treatment. These observations could merit further consideration in the design of future clinical trials for the treatment of advanced NSCLC.

On the basis of these encouraging results, evaluation of new regimens using non–cross-resistant agents delivered as maintenance therapy to NSCLC patients in appropriately powered studies may be warranted. A large phase III trial comparing maintenance pemetrexed plus BSC versus placebo plus BSC after front-line therapy was recently completed.³⁶ This trial was statistically powered to evaluate an OS benefit for maintenance therapy in advanced NSCLC.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: Jane L. Bromund, Eli Lilly & Co (C); Ruqin Chen, Eli Lilly & Co (C); Maria Hristova-Kazmierski, Eli Lilly & Co (C); Joseph Treat, Eli Lilly & Co (C); Coleman K. Obasaju, Eli Lilly & Co (C); Martin Marciniak, Eli Lilly & Co (C); John Gill, Eli Lilly & Co (C) Consultant or Advisory Role: David M. Loesch, AstraZeneca (U); Joan H. Schiller, Eli Lilly & Co (C), Sanofi-aventis (C) Stock Ownership: Jane L. Bromund, Eli Lilly & Co; Ruqin Chen, Eli Lilly & Co; Maria Hristova-Kazmierski, Eli Lilly & Co; Joseph Treat, Eli Lilly & Co; Coleman K. Obasaju, Eli Lilly & Co; Martin Marciniak, Eli Lilly & Co; John Gill, Eli Lilly & Co Honoraria: Panos M. Fidias, Eli Lilly & Co, Genentech; David M. Loesch, AstraZeneca Research Funding: Joan H. Schiller, Eli Lilly & Co Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Jane L. Bromund, Maria Hristova-Kazmierski, Coleman K. Obasaju, Joan H. Schiller

Administrative support: Jane L. Bromund, Maria Hristova-Kazmierski

Provision of study materials or patients: Panos M. Fidias, Shaker R. Dakhil, Alan P. Lyss, David M. Loesch, David M. Waterhouse, Joan H. Schiller

Collection and assembly of data: Panos M. Fidias, Shaker R. Dakhil, Alan P. Lyss, David M. Waterhouse, Jane L. Bromund, Maria Hristova-Kazmierski

Data analysis and interpretation: Panos M. Fidias, Jane L. Bromund, Ruqin Chen, Joseph Treat, Coleman K. Obasaju, Martin Marciniak, John Gill, Joan H. Schiller

Manuscript writing: Panos M. Fidias, David M. Waterhouse, Jane L. Bromund, Ruqin Chen, Joseph Treat, Martin Marciniak, John Gill, Joan H. Schiller

Final approval of manuscript: Panos M. Fidias, Shaker R. Dakhil, Alan P. Lyss, David M. Loesch, David M. Waterhouse, Jane L. Bromund, Ruqin Chen, Maria Hristova-Kazmierski, Joseph Treat, Coleman K. Obasaju, Martin Marciniak, John Gill, Joan H. Schiller

	Acknowledgment

 
We thank Elizabeth Zobre, Jian Yu, and Andrea Koehler for their support.

	NOTES

 
Supported by Eli Lilly & Co, Indianapolis, IN.

Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA, and the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL.

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

Clinical Trials repository link available on JCO.org.

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Submitted March 27, 2008; accepted September 17, 2008.

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