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Journal of Clinical Oncology, Vol 24, No 22 (August 1), 2006: pp. 3657-3663 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.1044 Phase III Study of Docetaxel Compared With Vinorelbine in Elderly Patients With Advanced Non–Small-Cell Lung Cancer: Results of the West Japan Thoracic Oncology Group Trial (WJTOG 9904)
From the Department of Respiratory Medicine, Osaka City University Medical School; Department of Medical Oncology, Osaka City General Hospital; Department of Medical Oncology, Kinki University Medical School; Department of Respiratory Medicine, Rinku General Medical Center; Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases; Department of Respiratory Medicine, Osaka Medical College, Osaka; Division of Respiratory Medicine, Kobe City General Hospital, Kobe; Department of Internal Medicine, Shikoku Cancer Center, Ehime; Department of Respiratory Medicine, Gifu Municipal Hospital, Gifu; Department of Internal Medicine, Kumamoto Regional Medical Center, Kumamoto; and the Health Service, Kyoto University, Kyoto, Japan Address reprint requests to Shinzoh Kudoh, MD, Department of Respiratory Medicine, Osaka City University Medical School, 1-4-3, Asahimachi, Abeno-ku, Osaka 545-8585, Japan; e-mail: shinzohykudoh{at}med.osaka-cu.ac.jp
PURPOSE: Docetaxel has shown activity in elderly patients with advanced non–small-cell lung cancer (NSCLC). This randomized phase III trial evaluated the efficacy and safety of docetaxel versus vinorelbine (the current standard treatment) in elderly patients. PATIENTS AND METHODS: Chemotherapy-naïve patients age 70 years or older with stage IIIB/IV NSCLC and performance status 2 or lower were eligible. Patients randomly received docetaxel 60 mg/m2 (day 1) or vinorelbine 25 mg/m2 (days 1 and 8) every 21 days for four cycles. The primary end point was overall survival. Overall disease-related symptom improvement was assessed using an eight-item questionnaire. RESULTS: In total, 182 patients were enrolled. Median age was 76 years (range, 70 years to 86 years). There was no statistical difference in median overall survival with docetaxel versus vinorelbine (14.3 months v 9.9 months; hazard ratio, 0.780; 95% CI, 0.561 to 1.085; P = .138). There was a significant difference in median progression-free survival (5.5 months v 3.1 months; P < .001). Response rates were also significantly improved with docetaxel versus vinorelbine (22.7% v 9.9%; P = .019). The most common grade 3 to 4 toxicities were neutropenia (82.9% for docetaxel; 69.2% for vinorelbine; P = .031) and leukopenia (58.0% for docetaxel; 51.7% for vinorelbine). Other toxicities were mild and generally well tolerated. Docetaxel improved overall disease-related symptoms over vinorelbine (odds ratio, 1.86; 95% CI, 1.09 to 3.20). CONCLUSION: Docetaxel improved progression-free survival, response rate, and disease-related symptoms versus vinorelbine. Overall survival was not statistically significantly improved at this time. Docetaxel monotherapy may be considered as an option in the standard treatment of elderly patients with advanced NSCLC.
Due to a general increase in life expectancy in developed countries worldwide, the proportion of the general population in these countries that is elderly is increasing. For example, in 1970 in Japan, 7.9% of the general population was 65 years or older, which increased to 17.3% by 2000, and is estimated to reach 29.6% by 2030.1 As non–small-cell lung cancer (NSCLC) is a common disease in the elderly population, the question of how best to treat elderly NSCLC patients will become increasingly important.2 Chemotherapy in patients with advanced NSCLC improves survival, reduces disease-related symptoms, and improves quality of life (QOL) compared with best supportive care.3 Although platinum-based doublets involving newer agents, such as docetaxel, paclitaxel, gemcitabine, vinorelbine, and irinotecan, are standard first-line chemotherapy for most patients with advanced NSCLC,4,5 the use of these regimens in elderly patients remains a topic of debate.2 The main reasons given for withholding standard platinum-based doublet regimens from elderly patients are age-related impairment of organ function, presence of potentially complicating comorbid conditions, and a lower ability to tolerate the potential toxicity of combination chemotherapy than younger patients. Three prospective randomized trials have investigated the optimal chemotherapy for elderly (70 years or older) NSCLC patients.6-8 The Elderly Lung Cancer Vinorelbine Italian Study Group reported significantly superior survival and QOL with single-agent vinorelbine over best supportive care (median survival time, 6.4 months and 4.8 months, respectively; n = 161).6 Two other studies have attempted to determine whether doublet regimens are optimal over single-agent therapy in elderly patients.7,8 The conclusive results were reported in the Multicenter Italian Lung Cancer in the Elderly Study (MILES), which enrolled more than 700 patients and reported no significant survival difference between single-agent vinorelbine, single-agent gemcitabine, or a regimen with both agents combined.8 Docetaxel has demonstrated activity and acceptable toxicity in the treatment of advanced NSCLC, including elderly patients.9-12 However, to date, no prospective randomized trials of docetaxel in elderly patients have been published. Two phase II trials of tri-weekly docetaxel 60 mg/m2 (the recommended dose and schedule in Japan) have been performed in adult patients with NSCLC.13,14 We conducted an exploratory, combined-subset analysis of the cohorts of patients age 70 years or older from these two trials: in 53 patients with a median age of 74 years (range, 70 years to 80 years), the median survival time was 10.3 months and the response rate was 24.5% (unpublished data). This encouraging retrospective result led us to design a prospective phase III trial to evaluate the efficacy of docetaxel versus vinorelbine in elderly patients with previously untreated advanced NSCLC, the results of which are reported herein.
Eligibility Criteria Chemotherapy- and radiotherapy-naïve patients with histologically or cytologically proven stage IIIB/IV NSCLC were enrolled. Other inclusion criteria included: age 70 years or older with a life expectancy of 3 months or longer; measurable and assessable disease; Eastern Cooperative Oncology Group performance status 2 or lower; adequate function of the bone marrow (leukocyte count, 4,000/µL or higher; absolute neutrophil count, 2,000/µL or higher; hemoglobin concentration, 9.5 g/dL or higher; platelet count, 100,000/µL or higher), kidney (serum creatinine, 1.2 mg/dL or lower), and liver (total bilirubin, 1.5x the institutional upper limits of normal or lower; AST and ALT 2.5x the institutional upper limits of normal or lower). Exclusion criteria included: presence of symptomatic brain metastasis or apparent dementia; active concomitant malignancy; massive pleural effusion or ascites; active infection; severe heart disease or grade 2 or higher ECG abnormality; uncontrolled diabetes mellitus, ileus, pulmonary fibrosis, diarrhea; bleeding tendency. All patients gave written informed consent and the protocol was approved by the institutional review board at each participating center. Before treatment, all patients underwent a complete medical history and physical examination, chest radiography, fiberoptic bronchoscopy, chest and abdominal computed tomography (CT) scan, a brain CT or magnetic resonance imaging scan, an ECG, pulmonary function tests, and arterial blood gas analysis. A radionuclide bone scan was also performed to document the extent of the disease. Laboratory tests included a CBC with WBC differential, liver function tests, serum electrolytes, serum creatinine, blood urea nitrogen, and urinalysis. The physical examination and laboratory tests were performed weekly. Chest radiography and/or CT were repeated every cycle to evaluate tumor response.
Treatment Plan Vinorelbine was delayed on day 8 if leukocyte and platelet counts were lower than 2,000/µL and lower than 50,000/µL, respectively, and was withheld until the counts had recovered to 4,000/µL or higher and 100,000/µL or higher, respectively; patients were withdrawn from the study if longer than 5 weeks had elapsed from the time of the last treatment until these criteria were satisfied. The presence of grade 4 leukopenia and/or neutropenia led to reductions in the doses of docetaxel and vinorelbine by 10 mg/m2 and 5 mg/m2, respectively, in the subsequent cycle. Patients were withdrawn from the study in the event of progressive disease, consent withdrawal or grade 3 or higher nonhematologic toxicity without myelosuppression, nausea, vomiting, or alopecia. Second-line treatment was given at the physician’s discretion. Patients were evaluated for objective response before every cycle using WHO criteria.16 A minimum duration of 4 weeks was required to document a response and the best response was recorded for each patient. Drug-induced toxicity was assessed before every cycle and was classified in accordance with National Cancer Institute Common Toxicity Criteria, version 2.0.17 The worst data for each patient across all chemotherapy cycles were used in the toxicity analysis.
QOL Assessment
Statistical Analysis The primary objective was to determine whether docetaxel improved survival compared with vinorelbine. The study was designed with an 80% power using a two-sided log-rank test at a level of .05 to detect a 60% improvement in median survival time from 6.4 months with vinorelbine to 10.3 months with docetaxel; this required 90 patients per treatment arm. An interim analysis was performed after 120 patients were accrued; after the data had been reviewed, a decision was made to continue the study. Survival analyses were conducted on the intent-to-treat population using follow-up data available at March 28, 2005. Overall survival was calculated from the start of therapy to the date of death from any cause or last follow-up. Progression-free survival was calculated from the start of therapy to the date of disease progression, recurrence, or death from any cause. Survival curves were estimated using the Kaplan-Meier method. A Cox proportional hazards regression model adjusted by the stratification factors (performance status, stage) was applied.
The
Patient Characteristics A total of 182 patients were enrolled and randomly assigned (90 to docetaxel, 92 to vinorelbine) between May 2000 and September 2003 from 32 institutions in WJTOG (Fig 2). Two patients were subsequently considered ineligible due to being entered twice in the study (n = 1, vinorelbine arm) and consent withdrawal immediately after random assignment (n = 1, docetaxel arm). Therefore, the intent-to-treat population comprised 180 patients: 89 assigned to docetaxel and 91 assigned to vinorelbine. One patient assigned to docetaxel developed disease progression before starting chemotherapy and was therefore not treated. Thus, toxicity and response were evaluated in 88 docetaxel patients and 91 vinorelbine patients.
Patients’ baseline characteristics were well balanced between the treatment arms (Table 1). Although more patients receiving vinorelbine than docetaxel had a performance status of 2, the difference was not significant (P = .057).
The median number of treatment cycles was four in the docetaxel arm and three in the vinorelbine arm, which was significantly different (P = .050). Overall, 45 (51.1%) of 88 docetaxel patients and 37 (40.7%) of 91 vinorelbine patients completed four cycles of chemotherapy. The major reasons for treatment withdrawal in the docetaxel versus vinorelbine arms were disease progression (19.3% v 35.2%), adverse events (12.5% v 9.9%), physician’s decision to withdraw patient (6.8% v 5.5%), protocol violation (3.4% v 3.3%), and consent withdrawal (2.3% v 3.3%). The relative dose intensities were 90.7% and 83.1% for docetaxel and vinorelbine, respectively; most patients received the projected dose of chemotherapy in both treatment arms. Second-line chemotherapy was administered to 85 patients (47.5%; 45 docetaxel patients and 40 vinorelbine patients). Among patients initially treated with docetaxel, five patients received second-line vinorelbine, while nine patients enrolled in the vinorelbine arm received crossover treatment with docetaxel. Fifty-two patients (29.0%) received second-line gefitinib: 33 patients (37.5%) in the docetaxel arm and 19 patients (20.9%) in the vinorelbine arm.
Response and Survival
By March 28, 2005, 143 (79.4%) of 180 patients had died (docetaxel, 68; vinorelbine, 75). Median follow-up for survivors was 11.6 months. The median progression-free survival time with docetaxel was significantly longer than with vinorelbine (5.5 months v 3.1 months; hazard ratio, 0.606; 95% CI, 0.450 to 0.816; P < .001; Fig 3). Median survival time was 14.3 months and 9.9 months with docetaxel and vinorelbine, respectively. Although docetaxel prolonged median survival time by 4.4 months, the overall survival distributions were not statistically significant (hazard ratio, 0.780; 95% CI, 0.561 to 1.085; log-rank P = .138 and generalized Wilcoxon test P = .065; Fig 4). One-year survival rates were 58.6% and 36.7% for docetaxel and vinorelbine, respectively.
Toxicity Overall, 179 patients were assessable for toxicity. Table 3 summarizes the major toxicities. Grade 3 to 4 neutropenia occurred in more patients in the docetaxel arm than in the vinorelbine arm (P = .031). However, there were no significant differences between the docetaxel and vinorelbine arms in the occurrence of grade 3 to 4 febrile neutropenia and infection. The incidence of grade 3 to 4 anemia was relatively low and there was no grade 2 or higher thrombocytopenia in either arm (Table 3). Alopecia (any grade) occurred significantly more frequently in the docetaxel arm than the vinorelbine arm (P < .0001). Overall toxicity in both treatment arms was generally mild and well tolerated in elderly patients with NSCLC.
One patient (age 76 years with stage IV disease and a performance status of 1) developed treatment-related interstitial pneumonia after three cycles of docetaxel; despite steroid pulse treatment, the patient died from this toxicity on day 65 after the start of the third treatment cycle.
QOL
This phase III trial showed that docetaxel provided significantly longer progression-free survival (5.5 months v 3.1 months; P < .001), a significantly higher overall response rate (22.7% v 9.9%; P = .019), a more favorable 1-year survival rate (58.6% v 36.7%) and significantly better disease-related symptom improvement than vinorelbine in elderly patients with advanced NSCLC. However, although docetaxel-treated patients also experienced a longer median survival time (14.3 months v 9.9 months) than vinorelbine-treated patients, the primary end point of improved overall survival with docetaxel was not achieved. Possible reasons for failing to detect a significant difference between the docetaxel and vinorelbine survival curves may include an insufficient occurrence of documented events as a result of the study population comprising patients with relatively good prognosis, in addition to a high proportion of patients (47.5%) subsequently receiving second-line therapy. Another reason may have been the small sample size and the prespecified aim of detecting an improvement in survival from 6.4 months to 10.3 months. The selection of a median survival in the reference arm of 6.4 months for the sample size calculation was based on the results of the Elderly Lung Cancer Vinorelbine Italian Study Group study.6 However, more recent survival data from the MILES study8 reporting a median survival of 8.3 months with vinorelbine may have been more appropriate. Had this value been used in the sample size calculation a larger study population would have been required which would likely have allowed the present analysis to detect statistically significant differences between the treatment arms. The survival findings with vinorelbine in this study were similar to or slightly better than those reported in other studies; vinorelbine monotherapy in elderly NSCLC patients has previously shown median survival times of 4.5 months to 8.3 months and 1-year survival rates of 13% to 38%.6-8 One reason for a slightly longer median survival time in our study may be the relatively better prognosis of the enrolled patients. Interestingly, the median survival time of 14.3 months with docetaxel in this study appears to be similar to that reported for platinum-doublet chemotherapies assessed in a recent Japanese randomized trial in chemotherapy-naïve NSCLC patients, which reported median survival times of 11.4 months to 14.8 months.5 The improved overall survival time in the docetaxel arm may be attributed to gefitinib treatment as a second-line treatment. Japanese patients are sensitive to gefitinib, and 37% of patients who were treated with docetaxel also received gefitinib, compared with 20.9% of vinorelbine treated patients although this difference may be attributable to the numerically greater number of patients alive after initial docetaxel treatment. Crossover to second-line chemotherapy was permitted in this protocol and could have also influenced outcomes. However, as only a small number of patients in either treatment arm were treated with alternative chemotherapy as salvage (five patients from the docetaxel arm and nine patients from the vinorelbine arm), outcomes for these patients were not felt to significantly alter the overall results of the study. Age should still be taken into consideration when selecting appropriate chemotherapy in the clinical setting given the likelihood of metabolic changes with advancing age, the increased likelihood of comorbidities, and general lack of clinical trial data specifically in older patients. The toxicity profiles for both treatment arms were generally mild and tolerable in this study. Although severe neutropenia occurred significantly more often with docetaxel, there were no differences in the incidence of febrile neutropenia or other hematologic toxicities between the two arms. The incidence of grade 3 to 4 neutropenia (69.3%) with vinorelbine treatment in our study was somewhat higher than that reported in the MILES (25%).8 The reason for these differences is unclear. In our study, patients treated with docetaxel experienced a relatively higher incidence of severe neutropenia compared with patients treated with vinorelbine, although the incidence with docetaxel was similar to that seen in Japanese phase II studies of docetaxel in patients with advanced NSCLC (87%, grade 3-4 neutropenia).13 However, the incidences of grade 3 febrile neutropenia and grade 3 infection were relatively low and similar between the treatment arms in our study. Importantly, there was no difference in global QOL between the treatment arms. Furthermore, docetaxel significantly improved QOL in terms of disease-related symptoms compared with vinorelbine. The WJTOG 9904 study is the first prospective, randomized, phase III trial of taxane monotherapy for elderly patients with advanced NSCLC, and has shown encouraging efficacy with single-agent docetaxel. To further improve outcomes, we would suggest that the next step for treating elderly patients might be to prospectively investigate platinum-doublet regimens, particularly docetaxel with carboplatin, in phase III trials. Retrospective analyses suggest that platinum doublets are effective and tolerable in fit, elderly patients.2,22-24 For further future studies in elderly patients, it would be of interest to investigate regimens involving docetaxel combined with a molecular-targeted agent (such as gefitinib, erlotinib,25 or bevacizumab), as molecular-targeted agents are associated with relatively mild toxicity profiles compared with cytotoxic agents. In conclusion, docetaxel improved response rate, progression-free survival, and overall disease-related symptoms compared with vinorelbine in elderly patients with advanced NSCLC; overall survival was not significantly improved. Based on these results, docetaxel monotherapy may be considered as an option in the standard treatment of elderly patients with advanced NSCLC.
Other participants and institutions include the following: Dr Takahiko Sugiura, Aichi Cancer Center, Aichi; Dr Hidehiko Yamamoto, Asoiizuka Hospital, Fukuoka; Dr Masashi Yamada, Osaka City Sumiyoshi Hospital, Osaka; Dr Yoshinori Hasegawa, Osaka Saiseikai Nakatsu Hospital, Osaka; Dr Hiroshi Miyawaki, Kagawa Prefectural Central Hospital, Kagawa; Dr Yoichi Nakanishi, Kyusyu University, School of Medicine, Fukuoka; Dr Hiroshi Saitoh, Prefectural Aichi Hospital, Aichi; Dr Hideo Saka, National Hospital Organization Nagoya Medical Center, Aichi; Dr Hiroyuki Akiyama, National Hospital Organization South Wakayama Medical Center, Wakayama; Dr Yoshio Taguchi, Tenriyorodu Hospital, Nara; Dr Kenji Eguchi, Tokai University, School of Medicine, Kanagawa; Dr Eiji Shimizu, Tottori University, School of Medicine, Tottori; Dr Masashi Yamamoto, Nagoya Ekisaikai Hospital, Aichi; Dr Ryuzo Ueda, Nagoya City University, School of Medicine; Dr Kazuya Fukuoka, Nara Medical College, Nara; Dr Hideki Nishiyama, Japanese Red Cross Society Wakayama Medical Center, Wakayama; Dr Takashi Nakano, Hyogo Medical Collage, Hyogo; Dr Yasuo Iwamoto, Hiroshima City General Hospital, Hiroshima; Dr Kazunori Fujitaka, Hiroshima University, School of Medicine, Hiroshima; Dr Yasufumi Yamaji, Mitoyo General Hospital, Kagawa.
The authors indicated no potential conflicts of interest.
We wish to thank the patients who participated in the West Japan Thoracic Oncology Group 9904 clinical trial. We also thank Yuki Inoue and Kazumi Kubota, from the West Japan Thoracic Oncology Group Data Center, for their help with data collection and analysis.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Belani CP, Fossella F.: Elderly subgroup analysis of a randomized phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for first-line treatment of advanced non small cell lung carcinoma (TAX 326).Cancer 104:2766-2774, 2005[CrossRef][Medline] 24. Fossella F, Pereira JR, von Pawel J, et al: Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: The TAX 326 study group. J Clin Oncol 21:3016-3024, 2003 25. Davies AM, Lara PN, Lau DH, et al: Intermittent erlotinib in combination with docetaxel (DOC): Phase I schedules designed to achieve pharmacodynamic separation. Proc Am Soc Clin Oncol 23:630s, 2005 (abstr 7038) Submitted February 11, 2006; accepted June 5, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used in the response rate comparison and the toxicity analysis. For the QOL analyses, the comparison between the arms was conducted using generalized estimating equation regression models by GENMOD procedure in SAS (SAS Institute, Cary, NC).
