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Phase III Randomized Trial of Docetaxel Plus Cisplatin Versus Vindesine Plus Cisplatin in Patients With Stage IV Non-Small-Cell Lung Cancer: The Japanese Taxotere Lung Cancer Study Group

From the National Cancer Center Hospital E, Kashiwa; Yokohama Municipal Citizen’s Hospital; Kanagawa Cancer Center, Yokohama; National Cancer Center Hospital; Nippon Medical School; Tokyo University; Tokyo Cooperative Oncology Group, Tokyo; National Kyushu Cancer Center, Fukuoka; Kobe City General Hospital, Kobe; Aichi Cancer Center, Nagoya; National Kinki Central Hospital for Chest Disease, Sakai; Niigata Cancer Center, Niigata; Toneyama National Hospital, Toyonaka; Saitama Cancer Center, Kitaadachi; Osaka Prefectural Habikino Hospital, Habikino; Osaka City University Hospital, Osaka; Hiroshima University, Hiroshima; National Shikoku Cancer Center, Matsuyama; National Cancer Center Hospital E, Kashiwa, Japan; and the Japanese Taxotere Lung Cancer Study Group (other members of the study group are listed in the Appendix)

Address reprint requests to Kaoru Kubota, MD, Thoracic Oncology Division, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan; e-mail: kkubota{at}east.ncc.go.jp.

	ABSTRACT

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PURPOSE: Few randomized trials have demonstrated survival benefit of combination chemotherapy involving new agents plus cisplatin compared with classic combination chemotherapy in advanced non-small-cell lung cancer (NSCLC). The primary aim of this study was to test whether docetaxel plus cisplatin (DC) improves survival compared with vindesine plus cisplatin (VdsC) in patients with previously untreated stage IV NSCLC.

PATIENTS AND METHODS: Eligible, stage IV, chemotherapy-naive patients (n = 311) were randomly assigned to receive docetaxel 60 mg/m² intravenously on day 1 plus cisplatin 80 mg/m² intravenously on day 1 of a 3- or 4-week cycle, or vindesine 3 mg/m² intravenously on days 1, 8, and 15 plus cisplatin 80 mg/m² intravenously on day 1 of a 4-week cycle. Cross-over administration of docetaxel and vindesine was prohibited for both treatment groups.

RESULTS: Overall, 302 patients were eligible for evaluation. The DC arm demonstrated significant improvements compared with the VdsC arm in overall response rates (37% v 21%, respectively; P < .01) and median survival times (11.3 v 9.6 months, respectively; P = .014). Two-year survival rates were 24% for the DC arm compared with 12% for the VdsC arm. The physical domain of the Quality of Life for Cancer Patients Treated with Anticancer Drugs measure was significantly better in the DC arm than in the VdsC arm (P = .020). Toxicity was predominantly hematologic and was more severe in the VdsC arm.

CONCLUSION: As first-line treatment for stage IV NSCLC, DC resulted in greater clinical benefit in terms of response rate (with marked improvements in overall and 2-year survival rates) and quality of life than did treatment with VdsC.

	INTRODUCTION

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Lung cancer has been a leading cause of cancer death in industrialized countries in the 20th century [1]. Non-small-cell lung cancer (NSCLC) accounts for 75% to 80% of all lung cancer histology. Meta-analyses of randomized trials comparing chemotherapy with supportive care in patients with advanced NSCLC have demonstrated that cisplatin-based combination chemotherapy prolongs survival, whereas some studies showed palliative effects of cancer-related symptoms with chemotherapy [2,3]. Although significant long-term survivors have been observed in the treatment of stage III NSCLC with chemoradiotherapy [4-6], improvements in stage IV disease have been dismal, with only 10% to 15% of stage IV patients surviving 1 year after diagnosis with best supportive care (BSC) alone and 20% to 25% of stage IV patients surviving 1 year after diagnosis with cisplatin-based chemotherapy [7]. In the 1990s, randomized trials using platinum in combination with new agents (vinorelbine and gemcitabine) have shown 1-year survival rates ranging between 36% and 39% [8,9]. However, many trials have failed to show a significant survival advantage of new compared with older combinations [10-12].

Docetaxel, a new agent, is a semisynthetic taxoid derived from the European yew Taxus baccata [13]. It is active against NSCLC and shows survival benefits not only in chemotherapy-naive patients, but also in those patients who have previously received platinum-based chemotherapy [14-21]. Phase II trials of docetaxel and platinum combinations have resulted in median survival rates ranging between 8.4 and 13.9 months, indicating that such combinations are active as first-line therapies [22-25]. Response rates of 30% to 67% for docetaxel with a platinum agent have also been demonstrated. Although docetaxel is usually administered as a 75 mg/m² dose, a phase II trial demonstrated that a response rate of 42% with an acceptable toxicity profile [26] could be achieved when 60 mg/m² of docetaxel and 80 mg/m² of cisplatin were administered to patients with stage IV NSCLC.

We conducted a randomized trial that compared docetaxel plus cisplatin (DC) with vindesine plus cisplatin (VdsC). The primary aim of this study was to compare the overall survival of stage IV NSCLC patients between the two regimens. Secondary end points included the response rate, duration of response, safety, and quality of life (QoL).

	PATIENTS AND METHODS

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Eligibility Criteria
This multicenter, randomized trial was conducted at 58 institutions in Japan between March 1998 and March 2000. Eligible patients were between the ages of 20 and 75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2; life expectancy 3 months; and previously untreated, stage IV, histologically or cytologically proven NSCLC with measurable lesions. Patients with PS of 3 because of pain from bone metastases were admitted to the study. Other eligibility criteria included leukocyte count 4,000/µL and 12,000/µL, neutrophil count 2,000/µL, platelet count 10⁵/µL, hemoglobin 9.5 g/dL, blood urea nitrogen less than or equal to the upper limit of the institutional normal range (ULN), serum creatinine less than or equal to the ULN, creatinine clearance 60 mL/min, serum bilirubin less than or equal to the ULN, serum ALT and AST 2 x ULN, and PaO₂ 70 mm Hg. Women who were pregnant or lactating were excluded from the study. Other exclusion criteria included patients with active infection, uncontrolled heart disease, interstitial pneumonia or active lung fibrosis, peripheral neuropathy, pleural or pericardial effusion that required drainage, past history of drug hypersensitivity, symptomatic brain metastasis, or active concomitant malignancy.

Patient eligibility was determined by the Patient Registration Center at the Tokyo Cooperative Oncology Group before patient registration. This study was approved by the institutional review boards at each participating center and all patients provided written informed consent.

Treatment Plan
Patients were randomly assigned to one of two treatment arms (Fig 1). In the experimental arm (DC), patients received docetaxel 60 mg/m² as a 1-hour intravenous infusion followed by cisplatin 80 mg/m² as a 2-hour infusion on day 1. Patients in the control arm (VdsC) received a bolus infusion of vindesine 3 mg/m² on days 1, 8, and 15, and cisplatin 80 mg/m² as a 2-hour infusion on day 1. Courses of treatment were repeated every 3 to 4 weeks in the DC arm, and once every 4 weeks in the VdsC arm.

View larger version (30K): [in this window] [in a new window]   Fig 1. Study design and patient allocation. NSCLC, non-small-cell lung cancer.

No routine premedication was given for hypersensitivity reactions during the first cycle of treatment, although in subsequent cycles this was administered if a patient experienced a reaction. All hypersensitivity reactions were identified by the patient’s physician and if deemed necessary, premedication drugs were administered by the investigator. However, recombinant human granulocyte colony-stimulating factor was administered when National Cancer Institute Common Toxicity Criteria grade 3 to 4 leukopenia or neutropenia occurred. If grade 4 neutropenia and/or leukopenia lasting for more than 3 days, grade 4 thrombocytopenia, grade 2 neuropathy, or grade 3 to 4 hepatotoxicity was observed, a 25% dose reduction of both drugs was implemented during the subsequent treatment cycle in both arms. If grade 3 stomatitis or renal toxicity occurred, the dose of cisplatin was reduced by 25%. Dose re-escalation was prohibited. Treatment was discontinued in the event of grade 3 neuropathy and again, dose re-escalation was prohibited. When leukocyte and platelet counts were less than 2,000/µL and 100,000/µL, respectively, or if infection developed at day 8 or 15, vindesine was withheld.

Patient Evaluation
Before chemotherapy, each patient underwent a complete medical history and physical examination, blood cell count determinations, biochemistry testing, chest x-ray, ECG, chest and whole-brain computed tomographic scan, abdominal ultrasound and/or computed tomographic scan, and isotope bone scan. Blood cell counts, differential WBC counts, and biochemistry testing were performed weekly during each course of chemotherapy.

Tumor responses were assessed radiographically and all responders were evaluated on extramural review. Treatment arms were blinded at the review. Standard WHO response criteria were used, and all responses were confirmed 28 days after initial documentation of the response.

QoL scores were measured using the validated instrument QoL Questionnaire for Cancer Patients Treated with Anticancer Drugs developed in Japan [27]. The instrument consists of five domains (functional, physical, mental, psychosocial, and global), and it was completed by the patient before treatment began, before the second and third therapy cycles, and 3 months after the last cycle of treatment. Evaluations were not only performed during the course of treatment but also 2 years after study treatment.

Statistical Considerations
Survival from the date of enrollment was the primary end point. The sample size was chosen on the basis of a log-rank test used to compare the two randomized groups. A sample size of 150 patients per group was estimated on the basis of a projected median survival of 42 weeks in the DC group and 30 weeks in the VdsC group, with an level of 5% (two sided) and a power of 80% to compare both groups. Dynamic balancing factors (ie, prerandomization stratification factors) included ECOG PS and institutions, and these were used to minimize any imbalance in treatment assignment.

Secondary end points included objective tumor response, response duration, rate of adverse drug reactions, and changes in QoL. The survival time and response duration were estimated for each group using the Kaplan-Meier method [28]. Response duration was calculated from the first date of a 50% reduction in the tumor to the last date that tumor reduction was documented. The difference in response duration was evaluated using the generalized Wilcoxon test. Tumor responses in both groups were compared using Fisher’s exact test. Other categoric data, such as treatment data and the incidence of adverse events, were compared between treatment groups using the ² test. QoL analyses were performed using repeated-measures analysis of variance between treatment groups on data collected before the second and third treatment cycles, and 3 months after the last cycle of treatment, adjusting for baseline QoL values.

An interim analysis on the basis of overall survival was planned for 1 year after enrollment of the last patient. The predefined early-stopping rule was based on a two-sided significance level of 0.005. The DeMets and Lan method was applied for multiple comparisons [29]. The analysis was monitored by the Independent Data Monitoring Committee. The final analysis was conducted 2 years after enrollment of the last patient and the final significance level was maintained at 0.0491.

	RESULTS

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Patient Characteristics
From April 1998 to March 2000, 311 previously untreated patients from 58 institutions were randomly assigned to treatment in the trial (Fig 1). However, six patients did not receive any protocol treatment (three in the DC arm and three in the VdsC arm). In the DC arm, one patient withdrew informed consent, another experienced a rapid increase in serum bilirubin beyond levels acceptable for inclusion into the study, and the third patient had an accident causing a thoracic spine pressure fracture; all withdrawals occurred before the first cycle of treatment. Likewise, before the first cycle of treatment, one patient in the VdsC arm had superior vena cava syndrome, one patient contracted pneumonia and the investigator decided against this patient receiving protocol treatment, and one patient (who also had pneumonia) had brain metastases and was therefore excluded from the study. An additional three patients failed to fulfill the eligibility criteria for the following reasons: stage violations (two patients, one per treatment arm) and prior treatment (one patient, DC arm). Because nine patients were deemed ineligible, 302 patients were evaluated—151 in each arm. All 302 patients were evaluated for survival, response, and toxicity. The characteristics of eligible patients are listed in Table 1.

View larger version (15K): [in this window] [in a new window]   Fig 2. Kaplan-Meier survival estimates for patients treated with docetaxel plus cisplatin and patients treated with vindesine plus cisplatin. MST, median survival time.

View larger version (29K): [in this window] [in a new window]   Fig 3. Quality-of-life assessments across four domains of the Quality of Life Questionnaire for Cancer Patients Treated with Anticancer Drugs instrument, among patients treated with docetaxel plus cisplatin and vindesine plus cisplatin. (A) Functional; (B) physical; (C) mental; and (D) psychosocial. Vertical bars represent least square means ± SE. Higher score indicates better quality of life.

	DISCUSSION

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VdsC was chosen as the control arm because this regimen showed significant survival advantage over BSC in a Canadian trial [31]. In addition, this combination has long been the standard regimen for advanced NSCLC [22,31,32]. For instance, two randomized trials conducted in Japan, which compared the more recently developed agent irinotecan plus cisplatin with VdsC, failed to show an overall survival advantage for the irinotecan-containing regimen in advanced NSCLC [33,34]. In the European study, 612 patients were randomly assigned to receive vinorelbine plus cisplatin, vindesine plus cisplatin, or vinorelbine alone. In this study, the unadjusted log-rank test comparing the survival of patients who received vinorelbine plus cisplatin versus VdsC yielded a P value of .085 in favor of vinorelbine plus cisplatin. Patients with both stage III and local recurrence (41%), or metastatic NSCLC (59%) were included, and nearly half of the patients received thoracic irradiation after chemotherapy [22]. The treatment strategy of locally advanced NSCLC is different from that of metastatic disease. Thus, the advantage of vinorelbine plus cisplatin over VdsC in patients with stage IV NSCLC has not been clearly defined.

Despite undergoing more treatment cycles, fewer patients on the DC arm experienced severe hematologic toxicities (including anemia and leukopenia) than patients treated with VdsC. Although diarrhea, nausea and vomiting, and anorexia were more frequently observed in the DC arm, such toxicities were easily managed with standard care.

DC has been evaluated in other phase III trials. In the ECOG trial, 1,207 patients were randomly assigned to paclitaxel plus cisplatin, gemcitabine plus cisplatin, docetaxel plus cisplatin, or paclitaxel plus carboplatin [35]. The response rate and median survival were similar among the four regimens for eligible patients at 19% and 7.9 months, respectively. In a large international trial (TAX-326), 1,218 chemotherapy-naive patients were randomly assigned to docetaxel plus cisplatin, docetaxel plus carboplatin, or vinorelbine plus cisplatin [36]. The DC arm favored a longer median survival time compared with the vinorelbine plus cisplatin arm (11.3 v 10.1 months) and response (31.6% v 24.5%). Although we must be careful when making retrospective comparisons, both survival figures and response data of the present study and TAX-326 were virtually identical and were better than those of the ECOG trial [35]. It is suggested that patients with more favorable prognostic factors entered in TAX-326 and the current study.

More recently, attention has focused on improving QoL as a goal of therapy for patients with advanced NSCLC [37]. One trial of docetaxel as second-line therapy versus BSC showed that chemotherapy resulted in significantly better control of pain and fatigue than did BSC [20]. In a similar comparative phase III trial, docetaxel, administered as first-line in chemotherapy-naive patients, was significantly better than BSC in controlling not only pain but also dyspnea and emotional functioning [19]. In the present study, QoL measures demonstrated that the physical domain was significantly better in the DC arm over the VdsC arm (P = .020). This finding of a QoL benefit with a docetaxel plus platinum combination is also supported by the results of TAX-326 [38]. This investigation indicated that patients in receipt of a docetaxel plus platinum combination reported greater global QoL benefit in terms of patient pain or less Karnofsky performance status deterioration than patients receiving vinorelbine plus cisplatin when the EuroQol and Lung Cancer Symptom Scale instruments were used [39,40].

In this study, we used 60 mg/m² of docetaxel on the basis of the phase II study conducted in Japan [26]. The dose of docetaxel is lower than the doses used in ECOG1594 and TAX-326 (docetaxel and cisplatin 75 mg/m²) [35,36]. In a randomized trial comparing docetaxel alone with BSC in patients previously treated with platinum-based chemotherapy, docetaxel 100 mg/m² was not tolerated but docetaxel 75 mg/m² demonstrated significant survival benefit [20]. Therapeutic index was also better for the lower dose of docetaxel in another randomized trial of second-line chemotherapy, which compared 100 or 75 mg/m² of docetaxel against a control regimen of vinorelbine or ifosfamide [21]. The docetaxel dose of 60 mg/m² might be optimal when it is combined with a standard dose of cisplatin. Additional study is warranted regarding this dose issue.

In summary, this randomized phase III trial demonstrates that DC is superior, in terms of response rate and survival, to VdsC in the treatment of previously untreated patients with stage IV NSCLC. A doubling in the 2-year survival rate is reported for DC compared with the classic standard regimen. Given the results of this trial, DC should be considered as a standard regimen for the first-line treatment of stage IV NSCLC, and it is suggested that the classic combination regimen should no longer be regarded as a suitable control arm in future randomized studies of patients with stage IV NSCLC.

	Appendix

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The Japanese Taxotere Lung Cancer Study Group comprised the authors listed and the following investigators: Y. Fujita, National Dohoku Hospital; H. Isobe, National Sapporo Hospital; Y. Nakai, Sendai Kousei Hospital; F. Shishido, Fukushima Medical University; S. Tsuchiya, National Nishigunma Hospital; K. Minato, Gunma Prefectural Cancer Center; K. Mori, Tochigi Cancer Center; Y. Takiguchi, Chiba University; T. Shinozaki, Kimitsu Central Hospital; M. Hino, Nippon Medical School Chiba Hokusoh Hospital; I. Hayashi, Cancer Institute Hospital; R. Kato, National Tokyo Medical Center; R. Ieki, Tokyo Metropolitan Komagome Hospital; K. Nakata, Toranomon Hospital; K. Yoshimori, Fukujuji Hospital; N. Horichi, Showa University; H. Saka, Nagoya National Hospital; S. Sakai, Japanese Red Cross Nagoya First Hospital; Y. Hasegawa, Nagoya University; M. Yamamoto, Nagoya Ekisaikai Hospital; A. Watanabe, Anjo Kosei Hospital; T. Sawa, Gifu Municipal Hospital; K. Shibata, Kouseiren Takaoka Hospital; M. Fujimura, Kanazawa University; Y. Idemura, Fukui Medical University; Y. Iwasaki, Kyoto Prefectural University of Medicine; F. Imamura, Osaka Medical Center for Cancer and Cardiovascular Disease; K. Nakagawa, Kinki University; M. Takada, Rinku General Medical Center; K. Obayashi, Hyogo Medical Center for Adults; H. Sakamoto, Nishi-Kobe Medical Center; H. Ueoka, Okayama University; S. Hiraki, Okayama Red Cross General Hospital; S. Kawahara, National Sanatorium Minami-Okayama Hospital; S. Sone, The University of Tokushima; T. Moritaka, Ehime Prefectural Central Hospital; N. Hara, Kyushu University; T. Rikimaru, Kurume University; M. Oka, Nagasaki University; T. Kanda, Nagasaki Municipal Hospital; S. Nagashima, Sasebo City General Hospital; A. Saito, University of the Ryukus.

	Authors’ Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have 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. Performed contract work within the last 2 years: Kaoru Kubota, Aventis Pharma Ltd; Koshiro Watanabe, Aventis Pharma Ltd; Hideo Kunitoh, Aventis Pharma Ltd; Kazumasa Noda, Aventis Pharma Ltd; Yukito Ichinose, Aventis Pharma Ltd; Nobuyuki Katakami, Aventis Pharma Ltd; Takahiko Sugiura, Aventis Pharma Ltd; Masaaki Kawahara, Aventis Pharma Ltd; Akira Yokoyama, Aventis Pharma Ltd; Soichiro Yokota, Aventis Pharma Ltd; Shuichi Yoneda, Aventis Pharma Ltd; Kaoru Matsui, Aventis Pharma Ltd; Shinzo Kudo, Aventis Pharma Ltd; Masahiko Shibuya, Aventis Pharma Ltd; Takeshi Isobe, Aventis Pharma Ltd; Yoshihiko Segawa, Aventis Pharma Ltd; Yutaka Nishiwaki, Aventis Pharma Ltd; Yasuo Ohashi, Aventis Pharma Ltd; Hisanobu Niitani, Aventis Pharma Ltd.

	NOTES

 
Supported by a grant from Aventis Pharma Ltd, Tokyo, Japan.

Previously presented in part at the Annual Meetings of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001, and Orlando, FL, May 18-21, 2002.

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

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Submitted June 24, 2003; accepted November 7, 2003.

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