© 2005 Foundation for Promotion of Cancer Research
A Phase I/II Study Comparing Regimen Schedules of Gemcitabine and Docetaxel in Japanese Patients with Stage IIIB/IV Non-small Cell Lung Cancer
1 Medical Center for Respiratory and Allergic Diseases of Osaka Prefecture, Osaka, 2 Osaka City University Medical School, Osaka, 3 Osaka Municipal General Medical Center, Osaka, 4 Kinki University School of Medicine, Osaka and 5 Rinku General Medical Center, Osaka, Japan
For reprints and all correspondence: Kaoru Matsui, Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases. 3-7-1 Habikino, Habikino City, Osaka 583-8588, Japan. E-mail: kmatsui{at}hbk.pref.osaka.jp
Received October 7, 2004; accepted January 31, 2005
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Abstract |
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Objective: Gemcitabine and docetaxel are non-platinum agents with activity in non-small cell lung cancer (NSCLC). This study was conducted to determine and evaluate the recommended regimen of gemcitabine–docetaxel and evaluated its efficacy and safety in chemonaive Japanese NSCLC patients.
Methods: In phase I, patients with stage IIIB/IV NSCLC were randomized and received either gemcitabine on days 1 and 8 plus docetaxel on day 1 or gemcitabine on days 1 and 8 plus docetaxel on day 8. The recommended regimen was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II. Efficacy and toxicity were evaluated in all patients.
Results: Twenty-five patients were enrolled in phase I and six patients were given the recommended regimen; gemcitabine 1000 mg/m2 on days 1 and 8 plus docetaxel 50 mg/m2 on day 8. An additional 34 patients were enrolled into phase II and administered with the recommended regimen. The response rate was 32.2% [95% confidence interval (CI) 20.6–45.6%] overall and 30.0% (95% CI 16.6–46.5%) in patients with the recommended regimen (40 patients). Although grade 3 interstitial pneumonia was observed in two patients (5.0%) who received the recommended regimen, both recovered shortly after steroid treatment. No unexpected events were observed throughout this study.
Conclusions: Gemcitabine 1000 mg/m2 on days 1 and 8 plus docetaxel 50 mg/m2 on day 8 has comparable efficacy and more tolerable toxicities than previously reported platinum-based regimens. These results should be verified by a phase III study.
Key Words: docetaxel • gemcitabine • non-small cell lung cancer
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INTRODUCTION |
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Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors, progresses in a short time period, has a bleak prognosis, and represents the leading cause of cancer death in the world. The number of patients with NSCLC is increasing, and most tumors are inoperable. Despite improvements in the detection and treatment of NSCLC, long-term survival is rare. Therefore, the development of new chemotherapy treatments is essential.
The use of single-agent and combination chemotherapy against NSCLC has been studied. Platinum-based regimens have shown high efficacy but at the cost of severe toxicities (1,2). Therefore, non-platinum agents such as gemcitabine, docetaxel, paclitaxel, irinotecan and vinorelbine have been developed and have proven their efficacies. Among the new agents, the combination of gemcitabine and docetaxel has emerged as one of the most promising, showing equivalent efficacy with, and less toxicity than, cisplatin-based chemotherapies (3).
Gemcitabine (2'-deoxy-2',2'-difluorocytidine monohydrochloride) is a nucleoside antimetabolite against deoxycytidine. It is intracellularly metabolized to gemcitabine triphosphate, which inhibits DNA synthesis, and has shown potent cytocidal activity against solid tumors (4–8).
Docetaxel, an antineoplastic agent that acts on microtubules to promote formation of abnormal microtubule bundles, has also shown cytotoxicity (9–11). Gemcitabine and docetaxel have different mechanisms of action, but by combining them, there is the potential of synergistic antitumor activity (12).
Several studies have been conducted to evaluate the therapeutic benefits of gemcitabine and docetaxel (13–15). The efficacy of gemcitabine–docetaxel is similar to platinum-based regimens, but due to each drug's non-overlapping toxicities, their combination produces toxicities more tolerable than platinum-based regimens. Georgoulias et al. (16) compared gemcitabine 1100 mg/m2 on days 1 and 8 plus docetaxel 100 mg/m2 on day 8 with cisplatin 80 mg/m2 on day 2 plus docetaxel 100 mg/m2 on day 1 in 441 patients with NSCLC. They reported that the two regimens were equivalent in efficacy, but toxicities were more severe for the combination of docetaxel and cisplatin.
There has been no published report considering both administering dose and schedule for the combination of gemcitabine and docetaxel. Therefore, we conducted a phase I/II study to compare two schedules of gemcitabine–docetaxel in patients with NSCLC and determine the recommended regimen in phase II. We assessed the efficacy and safety in all 59 patients: the efficacy and detailed safety profile were also evaluated in 40 patients who were given the recommended regimen.
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SUBJECTS AND METHODS |
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ELIGIBILITY CRITERIA
Japanese patients with histologically or cytologically confirmed unresectable TNM stage IIIB or IV NSCLC who met the following criteria were eligible for the study: suitable for first-line chemotherapy with no prior chemotherapy; measurable lesions that can be accurately measured in at least one dimension; aged 20–74 years; Eastern Cooperative Oncology Group (ECOG) performance status of 0–1; a life expectancy of at least 3 months; and adequate organ functions as indicated by white blood cell count
4.0 x 109/l, absolute neutrophil count 2.0 x 109/l, platelets 100 x 109/l, hemoglobin 9.5 g/dl, aspartate aminotransferase/alanine aminotransferase 
2.5 times the upper limit of normal, total bilirubin 1.5 times the upper limit of normal, serum creatinine the upper limit of normal, PaO2 in arterial blood 60 torr. If a patient had received radiotherapy during the 3 weeks before enrollment, the measurable disease had to be outside of the radiation port. Patients were excluded from the study if they had radiologically and clinically apparent interstitial pneumonia or pulmonary fibrosis, intracavitary fluid retention requiring treatment, or grade 2–4 peripheral neuropathy or edema. Additional exclusion criteria included: superior vena cava syndrome; symptomatic brain metastasis; pregnancy or breast-feeding; active concurrent malignancy; any serious concurrent illness (e.g. uncontrolled diabetes mellitus, hepatopathy, angina pectoris, myocardial infarction within 3 months after onset, severe infection, or fever suggestive of severe infection); history of serious drug allergy; or any condition that, in the opinion of the investigator, disqualified the patient based on safety.
This study was conducted in accordance with the Declaration of Helsinki, Japanese Guidelines for Clinical Evaluation of Antineoplastic Agents (promulgated in February 1991) and good clinical practice. All patients who entered into this study were required to give written informed consent.
STUDY DESIGN AND TREATMENT
This was a multicenter, open-label, phase I/II study of gemcitabine and docetaxel in Japanese patients with advanced NSCLC.
In the phase I portion of this study, patients were randomized into two arms, each with a different treatment schedule. In both arms (Arm 1 and Arm 2), gemcitabine was administered in a 30-min infusion on days 1 and 8, every 21 days. In Arm 1, docetaxel was administered intravenously over at least 1 h on day 1; in Arm 2, docetaxel was given on day 8. The administration of docetaxel followed an intravenous infusion of dexamethasone 4 mg, and gemcitabine was given immediately after the docetaxel infusion.
Patients were discontinued from the study due to progressive disease; inability to initiate a treatment cycle even at 6 weeks after the start of the previous cycle; recurrence of a dose-limiting toxicity (DLT) after resumption of the study treatment at a reduced dose; occurrence of a serious adverse event or aggravation of a concomitant illness (e.g. interstitial pneumonia, pulmonary fibrosis, or severe infection) which caused rapid aggravation of disease and precluded continuation of the study treatment; patient's request to withdraw from the study; or any event that required discontinuation in the opinion of the investigator.
During study enrollment, the current approved maximum dosage of gemcitabine and docetaxel as single agents in Japan was 1000 mg/m2 and 60 mg/m2, respectively. In phase I, the sample size was determined to be six per cohort based on the conventional design of phase I clinical studies of antineoplastic agents. In this study, both arms were randomized according to a predetermined schedule, enrolled patients in cohorts of six, and were initially treated at dose level 1 (gemcitabine 1000 mg/m2 and docetaxel 50 mg/m2). For the first cycle of treatment, patients were treated on an inpatient basis; if their condition permitted, patients were treated on an outpatient basis thereafter. If fewer than 50% of the patients in dose level 1 experienced DLTs, patients were enrolled at dose level 2 (gemcitabine 1000 mg/m2 and docetaxel 60 mg/m2). If 50% or more of the patients in dose level 1 experienced DLTs, patients were enrolled at dose level 0 (gemcitabine 800 mg/m2 and docetaxel 50 mg/m2) (Fig. 1). The maximum tolerated dose (MTD) was defined as the dose level that produced any of the following DLTs (per the National Cancer Institute–Common Toxicity Criteria scale) in 50% or more of patients during the first treatment cycle: grade 4 leukopenia or neutropenia persisting for at least 4 days; grade 3/4 neutropenia associated with a fever 38.0°C or infection; thrombocytopenia (<20 x 109/l) or need of a platelet transfusion; or grade 3/4 non-hematological toxicities (excluding nausea/vomiting, anorexia, fatigue and hypersensitivity). G-CSFs were administrated for the treatment of grade 4 neutropenia or grade 3 neutropenic fever. A DLT was also reported if any day-8 doses were omitted and dosing requirements were not satisfied until after day 15, or if the second cycle was delayed until after day 29 because the dosing requirements were not satisfied.
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The recommended dose for phase II had to be determined from the arm that reached the highest dose level. If at dose level 2 the incidence of DLTs was less than 50%, the recommended dose was defined as dose level 2. The arm that reached the higher dose level reflected the recommended regimen for phase II. If the recommended dose level for the two arms was identical, the recommended regimen would be decided according to the following steps: (i) if frequency of DLTs was 0% in one arm and 33.3% or more in the other arm, the former was selected. If this did not occur, then (ii) if the dose intensity for evaluable patients in one arm was higher by 10% or more than the other arm, the arm with the higher dose intensity was selected. If this did not occur, then (iii) the arm with the fewer day-8 dose omissions in first and second cycles was selected. If the recommended dosage regimen still could not be decided, the sponsor (Aventis Pharma Japan and Eli Lilly Japan K.K.) and the coordinating investigator determined the recommended phase II regimen. If the MTD was dose level 0 in both arms, the study was terminated (Fig. 1).
The sample size for the recommended regimen was determined as follows. The response rate of this regimen and gemcitabine single agent was assumed to be 35 and 20%, respectively, in view of the response rates previously achieved (9,10,17,18). If the sample size of the recommended regimen was set as 40 patients, the probability for the one-sided 90% lower limit of response rate to exceed 20% was 82%. Thus, the target sample size in the recommended regimen including six patients in phase I was set at 40 patients.
The phase II study was conducted with 34 patients. Forty patients who were given the recommended regimen were evaluated for the efficacy and detailed safety profile: these patients consisted of six and 34 patients who entered into the study at phase I and II, respectively.
In this phase I/II study, patients received a minimum of two cycles of gemcitabine–docetaxel and up to four additional cycles.
DOSE MODIFICATIONS
During a cycle, dose modifications were not allowed. If not all of the following requirements were satisfied on either the day of treatment or the previous day, administrations of gemcitabine and docetaxel were delayed until the patient completely recovered. For gemcitabine and docetaxel doses administered on day 1 of Arm 1 or gemcitabine on day 1 of Arm 2, delays occurred for patients with an absolute neutrophil count <1.5 x 109/l, a platelet count <70 x 109/l, any grade 3/4 non-hematologic toxicities (except PaO2), or PaO2 <60 torr. When gemcitabine was given on day 8 of Arm 1, exceptions included leukopenia <2.0 x 109/l and an absolute neutrophil count <1.0 x 109/l, a platelet count <70 x 109/l, any grade 3/4 non-hematological toxicities. When gemcitabine was given on day 8 of Arm 2, exceptions included an absolute neutrophil count <1.5 x 109/l, a platelet count <70 x 109/l, any grade 3/4 non-hematological toxicities. If a patient developed a DLT, the subsequent doses were cancelled, and in the next cycle the patient could resume the study treatment at the next lower dose level. If a patient developed a DLT at dose level 0, gemcitabine 800 mg/m2 and docetaxel 40 mg/m2 were administered in the next cycle.
BASELINE AND TREATMENT ASSESSMENT
Assessments at baseline included tumor measurements by X-ray and computed tomography (CT) scan within 4 weeks before the day of starting the study treatment. Equally, grading performance status and physical examination were performed within a week; hematology, blood chemistries, urinalysis, arterial blood gas analysis and electrocardiogram were observed within 2 weeks.
After the start of treatment, tumor measurements were obtained every 2 weeks via X-ray and 4 weeks via CT scan. Tumor response was assessed with the World Health Organization (WHO) criteria. Safety assessments, including performance status, hematology, blood chemistries and urinalysis, were obtained weekly. Physical examination, arterial blood gas analysis and electrocardiogram were performed at any time. Adverse events were estimated according to National Cancer Institute–Common Toxicity Criteria version 2.0. All patients were assessed for efficacy and safety. An additional response rate was recorded for patients who received the recommended regimen in phase I and all phase II patients.
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RESULTS |
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PATIENT CHARACTERISTICS
Between July 2000 and July 2002, 59 chemonaive patients (43 male, 16 female) with NSCLC were enrolled in phase I and II portions from the five hospitals after approval by the IRB. Twenty-five patients were enrolled in the phase I portion of the study, and 34 patients were enrolled in phase II. Baseline patient characteristics for all patients and patients who received the recommended regimen are summarized in Table 1.
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PHASE I
Twenty-five patients were enrolled into the phase I portion of the study. The number of patients treated and the DLTs observed in the first cycle at each dose level of gemcitabine and docetaxel are shown in Table 2.
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In Arm 1, 50% of patients had DLTs at dose level 1 and dose level 0, therefore Arm 1 could not be the recommended regimen: there were 2/6 and 3/6 patients who achieved partial response (PR) at dose level 1 and 0 in Arm 1, respectively.
In Arm 2, no DLT was observed at dose level 1: 3/6 patients achieved PR. At dose level 2, one patient discontinued due to progressive disease; therefore, one patient was added. However, another patient discontinued due to grade 3 hypersensitivity (not a DLT). In this regimen, two DLTs had already been observed in five other patients, but the sponsors (Aventis Pharma Japan and Eli Lilly Japan K.K.) and investigators decided not to add one more patient to dose level 2 in Arm 2 in consideration of patients' safety. PRs were observed in 2/7 patients at dose level 2 of Arm 2.
Therefore, the recommended regimen was determined as gemcitabine 1000 mg/m2 on days 1 and 8 plus docetaxel 50 mg/m2 on day 8 due to the incidence of DLT.
DOSE ADMINISTRATION
In Arm 1, a total of 49 cycles were accomplished. One case delayed the date of administration on day 1 (defined as more than 8 days) as a matter of convenience; seven and four cases delayed their dates of administration on day 8 (defined as more than 1 day) because of adverse events and non-medical reasons, respectively; and four cases could not be treated on day 8 because of adverse events. In Arm 2, including phase I and II portions, a total of 145 cycles were accomplished. Four and five cases delayed their dates of administration on day 1 because of adverse events and non-medical reasons, respectively; 21 and nine cases delayed their dates of administration on day 8 because of adverse events and non-medical reasons, respectively; and two cases could not be treated on day 8 because of adverse events. The most common adverse event for a dose delay was neutropenia.
EFFICACY
All 59 patients were involved in the analysis for efficacy, and 19 of 59 patients achieved PR for an overall response rate of 32.2% [95% confidence interval (CI) 20.6–45.6%]. Of the 40 patients who received the recommended regimen in either phase I or phase II, 12 patients achieved PRs for a response rate of 30.0% (95% CI 16.6–46.5%).
The median time to progressive disease in all 59 patients was 111 days (95% CI 71–154 days). Median survival time was 11.9 months (95% CI 7.0–15.0 months), with 1-year survival rate at 47.1% (95% CI 34.0–60.2%).
SAFETY
All 59 patients were evaluable for safety. Grade 3 and 4 drug-related toxicities observed in all 59 patients are shown in Table 3. Grade 3 and 4 drug-related toxicities observed in 40 patients who received the recommended regimen are also shown in Table 4.
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In all 59 patients, grade 3 and 4 neutropenia were observed in 19 (32.2%) and 20 (33.9%) patients, respectively. Grade 3 and 4 leukopenia were observed in 24 (40.7%) and four (6.8%) patients, respectively. Grade 3 non-hematological toxicities included infection in four patients (6.8%), anorexia in four patients (6.8%), and nausea, diarrhea, rash and constipation in three patients (5.1%) each. After starting docetaxel administration, grade 3 interstitial pneumonia was reported in three patients (5.1%), all of whom recovered shortly after steroid treatment; grade 4 anaphylaxis was reported in two patients (3.4%). There were no toxic deaths.
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DISCUSSION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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In this phase I/II study, we examined the activity and tolerability of gemcitabine and docetaxel. In phase I, the recommended regimen was determined as gemcitabine 1000 mg/m2 on days 1 and 8 plus docetaxel 50 mg/m2 on day 8. The response rate of all 59 patients was 32.2% (95% CI 20.6–45.6%). When re-evaluated in the 40 patients who received the recommended regimen, the response rate was 30.0% (95% CI 16.6–46.5%). Although the number of patients was limited, Arm 1 (docetaxel on day 1) had a numerically better response: for the 12 patients in Arm 1, five PRs were recorded for a response rate of 42%. However, Arm 1 had more toxicities than the docetaxel on day-8 schedule.
Overall, the toxicity associated with the gemcitabine–docetaxel regimen was manageable. In Arm 1, five patients (42%) had grade 3/4 neutropenia supervened with infection or fever, while only one patient (9%) had grade 3 neutropenia with infection or fever in Arm 2. This indicated that docetaxel was better tolerated on day 8 than on day 1 in a 21-day cycle. It is speculated that the influence of time to nadir of neutropenia is different in each agent: 14–20 days with gemcitabine and 9 days with docetaxel. The time to recover from nadir is 7–8 days with gemcitabine and 8 days with docetaxel. This could explain why docetaxel on day 8 was better tolerated.
Meta-analysis studies have reported that cisplatin-based regimens produce a significant survival benefit in NSCLC (20–23), improve median survival time by 6–8 weeks and 1-year survival rate from 15% to 25% when compared with the best supportive care (24). But studies with platinum-based combinations have also reported severe toxicities, so the deterioration of patients' quality of life is a major problem to be solved (3).
New effective non-platinum-based therapies have been used in various combinations in recent years, and the combination of gemcitabine and docetaxel has been established as one of the well-examined regimens. In recent studies using gemcitabine–docetaxel in NSCLC, response rates of 25–50% (19,25–29) and time-to-progression of disease of 106–132 days (31,32) have been reported. Georgoulias et al. (16) reported that the gemcitabine–docetaxel and docetaxel–cisplatin regimens they compared were equivalent in efficacy, but toxicity was severe in the latter. While docetaxel–cisplatin regimens showed severe toxicities of grade 3 anemia (5%), grade 3/4 neutropenia (13%/21%), grade 3 nausea/vomiting (10%) and grade 3 diarrhea (8%), gemcitabine–docetaxel regimens had grade 3/4 anemia (1%/1%), grade 3/4 neutropenia (11%/11%), grade 3 nausea/vomiting (2%) and grade 3/4 diarrhea (2%/1%) in 441 patients. However, the difference of efficacy and safety by the administration schedule and dosage of gemcitabine and docetaxel has not been well documented.
There are some studies that have examined the efficacy and safety of the same schedule as the recommended regimen in our study, namely gemcitabine on days 1 and 8 plus docetaxel on day 1. In these studies dosages were various: gemcitabine was 800–1100 mg/m2 and docetaxel was 60–100 mg/m2 (18,19,27–30). Response rates in these studies also varied from 16 to 38%, which indicates that the response rate of the recommended regimen in our study (30.0%) was clinically meaningful because the dosage of docetaxel (50 mg/m2) in our study is less than that in any other studies. This might have contributed to the relatively mild toxicities of our recommended regimen.
In another study (26), a high response rate (50.0%) was achieved in patients with another administering schedule: gemcitabine 1000 mg/m2 on days 1 and 10 plus docetaxel 80 mg/m2 on day 1, administered every 21 days. The most common treatment-related toxicity was myelosuppression. Grade 3/4 leukopoenia and neutropenia occurred in only six (18%) and eight (24%) patients, respectively.
The median survival was 11.9 months in our study, being slightly better than the result from the median survival of the phase III study with gemcitabine and cisplatin, which was 8.7–9.1 months (33,34). This result suggests that the regimen we selected in the phase II portion of this study is comparable in survival with the cisplatin-based regimen.
In conclusion, the combination of gemcitabine 1000 mg/m2 on days 1 and 8 plus docetaxel 50 mg/m2 on day 8 is suggested to be better tolerated and has equivalent efficacy to cisplatin-based therapy. These results should be verified by a phase III study in Japanese patients.
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CONCLUSION |
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TOPAbstractINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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In this phase I/II study, we studied the activity and tolerability of gemcitabine and docetaxel in Japanese patients. The combination of gemcitabine 1000 mg/m2 on days 1 and 8 plus docetaxel 50 mg/m2 on day 8 is suggested to be well tolerated and has equivalent efficacy to cisplatin-based therapy.
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Acknowledgments |
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We thank Dr N. Masuda for his helpful comments with the preparation of the paper; and Drs T. Taguchi, Y. Ariyoshi, N. Hara and M. Kawahara for overseeing the management of the study. This work was supported by Eli Lilly Japan K.K.
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Notes |
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Present addresses: S. Negoro, Hyogo Medical Center for Adults, Hyogo, Japan; M. Takada, Kinki-chuo Chest Medical Center, Osaka, Japan; T. Yana, Otemae Hospital, Osaka, Japan
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References |
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1 Luedke DW, Einhorn L, Omura GA, Sarma PR, Bartolucci AA, Birch R, et al. Randomized comparison of two combination regimens versus minimal chemotherapy in non-small-cell lung cancer: a Southern Cancer Study Group trial. J Clin Oncol 1990;8:886–91.[Abstract]
2 Gridelli C, Perrone F, Palmeri S, D'Aprile M, Cognetti F, Rossi A, et al. Mitomycin plus vindesine plus etopoide (MEV) versus mitomycin plus vindesine plus cisplatin (MVP) in stage IV non-small-cell lung cancer: a phase III multicenter randomized trial. Ann Oncol 1996;7:821–6.
3 Georgoulias V, Scagliotti G, Miller V, Eckardt J, Douillard JY, Manegold C. Challenging the platinum combinations: docetaxel (Taxotere) combined with gemcitabine or vinorelbine in non-small cell lung cancer. Semin Oncol 2001;28:15–21.[Medline]
4 Fujita M, Fujita F, Inaba S, Taguchi T. Antitumor activity of LY188011, a new deoxycytidine analog, against human cancers xenografted into nude mice. Gan To Kagaku Ryoho 1994;21:517–23 (in Japanese).[Medline]
5 Fukuoka M, Negoro S, Kudo S, Furuse K, Nishikawa H, Takada Y, et al. Late phase II study of LY188011 (gemcitabine hydrochloride) in patients with non-small-cell lung cancer. Gemcitabine Late Phase II Cooperative Study Group A. Gan To Kagaku Ryoho 1996;23:1825–32 (in Japanese).[Medline]
6 Heinemann V, Hertel LW, Grindey GB, Plunkett W. Comparison of the cellular pharmacokinetics and toxicity of 2',2'-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine. Cancer Res 1988;48:4024–31.
7 Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, et al. Evaluation of the antitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine). Cancer Res 1990;50:4417–22.
8 Yokoyama A, Nakai H, Yoneda S, Kurita Y, Niitani H, Taguchi T. A late phase II study of LY188011 (gemcitabine hydrochloride) in patients with non-small-cell lung cancer. Gemcitabine Cooperative Study Group B for Late Phase II. Gan To Kagaku Ryoho 1996;23:1681–8 (in Japanese).[Medline]
9 Kudo S, Hino M, Fujita A, Igarashi T, Arita K, Niitani H, et al. Late phase II study of RP56976 (docetaxel) in patients with non-small cell lung cancer. Gan To Kagaku Ryoho 1994;21:2617–23 (in Japanese).[Medline]
10 Onoshi T, Watanabe K, Furuse K, Kurita Y, Sugiura T, Sato K, et al. Late phase II study of RP56976 (docetaxel) in patients with non-small-cell lung cancer. Gan To Kagaku Ryoho 1995;22:59–65 (in Japanese).[Medline]
11 Ringel I, Horwitz SB. Studies with RP56976 (taxotere): a semisynthetic analogue of taxol. J Natl Cancer Inst 1991;83:288–91.
12 Zoli W, Ricotti L, Dal Susino M, Barzanti F, Frassineti GL, Folli S, et al. Docetaxel and gemictabine activity in NSCLC cell lines and in primary cultures from human lung cancer. Br J Cancer 1999;81:609–15.[CrossRef][ISI][Medline]
13 Rebattu P, Quantin X, Ardiet C, Morere JF, Azarian MR, Schuller-Lebeau MP, et al. Dose-finding, pharmacokinetic and phase II study of docetaxel in combination with gemcitabine in patients with inoperable non-small cell lung cancer. Lung Cancer 2001;33:227–87.
14 Rigas JR. Non-platinum based combination chemotherapy: phase I and II trials of docetaxel plus gemcitabine, vinorelbine, or irinotecan. Semin Oncol 2001;28:15–20.[Medline]
15 Spiridonidis CH, Laufman LR, Carman L, Moore T, Blair S, Jones J, et al. Second-line chemotherapy for non-small cell lung cancer with monthly docetaxel and weekly gemcitabine: a phase II trial. Ann Oncol 2001;12:89–94.
16 Georgoulias V, Papadakis E, Alexopoulos A, Tsiafaki X, Rapti A, Veslemes M, et al. Greek Oncology Cooperative Group (GOCG) for Lung Cancer. Platinum-based and non-platinum-based chemotherapy in advanced non-small cell lung cancer: a randomised multicentre trial. Lancet 2001;357:1478–84.[CrossRef][ISI][Medline]
17 Georgoulias V, Papadakis E, Alexopoulos A, et al. Docetaxel plus cisplatin versus docetaxel plus gemcitabine chemotherapy in advanced non-small cell lung cancer: a preliminary analysis of a multicenter randomized phase II trial. Proc Am Soc Clin Oncol 1999;18:461a (Abstr).
18 Kakolyris S, Papadakis E, Tsiafaki X, Kalofonos C, Rapti A, Toubis M, et al. Doxetaxel in combination with gemcitabine plus rhG-CSF support as second-line treatment in non-small cell lung cancer. A multicenter phase II study. Lung Cancer 2001;32:179–87.[CrossRef][ISI][Medline]
19 Georgoulias V, Kouroussis C, Androulakis N, et al. Front-line treatment of advanced non-small cell lung cancer with docetaxel and gemcitabine: a multicenter phase II trial. J Clin Oncol 1999;17:914–20.
20 Grilli R, Oxman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer: how much benefit is enough? J Clin Oncol 1993;11:1866–72.
21 Marino P, Pampallona S, Preatoni A, Cantoni A, Invernizzi F. Chemotherapy vs supportive care in advanced non-small cell lung cancer. Results of a meta-analysis of the literature. Chest 1994;106:861–5.[Medline]
22 Non-small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Br Med J 1995;311:899–909.
23 Souquet PJ, Chauvin F, Boissel JP, et al. Polychemotherapy in advanced non-small cell lung cancer: a meta-analysis. Lancet 1993;342:19–21.[CrossRef][ISI][Medline]
24 ASCO Special Article. Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer. J Clin Oncol 1997;15:2996–3018.[Abstract]
25 Lizon J, Feliu J, Morales S, Dorta J, Belon J. A phase II study of gemcitabine plus docetaxel as first line treatment in non-small-cell lung cancer (NSCLC). An Oncopaz and Associated Hospitals study. Proc Am Soc Clin Oncol 2001;20:270b.
26 Hejna M, Kornek GV, Raderer M, Ulrich-Pur H, Fiebiger WC, Marosi L, et al. Treatment of patients with advanced non small cell lung carcinoma using docetaxel and gemcitabine plus granulocyte-colony stimulating factor. Cancer 2000;89:516–22.[CrossRef][ISI][Medline]
27 Kosmas C, Tsavaris N, Vadiaka M, Stavroyianni N, Koutras A, Malamos N, et al. Gemcitabine and docetaxel as second-line chemotherapy for patients with non-small cell lung carcinoma who fail prior paclitaxel plus platinum-based regimens. Cancer 2001;92:2902–10.[CrossRef][ISI][Medline]
28 Georgoulias V, Papadakis E, Alexopoulos A, Tsiafaki X, Rapti A, Veslemes M, et al. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet 2001;357:1478–84.[CrossRef][ISI][Medline]
29 Rebattu P, Quantin X, Ardiet C, Morere JF, Azarian MR, Schuller-Lebeau MP, et al. Dose-finding, pharmacokinetic and phase II study of docetaxel in combination with gemcitabine in patients with inoperable non-small cell lung cancer. Lung Cancer 2001;33:277–87.[CrossRef][ISI][Medline]
30 Niho S, Kubota K, Goto K, Ohmatsu H, Matsumoto T, Kakinuma R, et al. Combination second-line chemotherapy with gemcitabine and docetaxel for recurrent non-small-cell lung cancer after platinum-containing chemotherapy: a phase I/II trial. Cancer Chemother Pharmacol 2003;52:19–24.[CrossRef][ISI][Medline]
31 Garcia C, Milla A, Fellu J, Lorenzo A, Madronal C, Gilli F, et al. Phase II study of gemcitabine (G) in combination with docetaxel (D) in advanced non-small-cell lung cancer (NSCLC) patients (Oncopaz and Hospitals Associated). Ann Oncol 2000;11 (Suppl 4):113 (516P).
32 Amenedo M, Mel J, Huidobro G, Rodriguez M, Anton M, Constenla M, et al. Phase II multicenter clinical trial of gemcitabine (G) and docetaxel (D) in advanced non-small-cell lung cancer (NSCLC): final results. Proc Am Soc Clin Oncol 2001;20:265b.
33 Cardenal F, Lopez-Cabrerizo MP, Anton A, Alberola V, Massuti B, Carrato A, et al. Randomized phase III study of gemcitabine–cisplatin versus etoposide–cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer. J Clin Oncol 1999;17:12–8.
34 Sandler AB, Nemunaitis J, Denham C, von Pawel J, Cormier Y, Gatzemeier U, et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2000;18:122–30.
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