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Docetaxel Versus Docetaxel Plus Cisplatin As Front-Line Treatment of Patients With Advanced Non—Small-Cell Lung Cancer: A Randomized, Multicenter Phase III Trial

From the Department of Medical Oncology, University General Hospital of Heraklion, Crete; 1st Department of Medical Oncology, Agios Savas Anticancer Hospital; 1st, 8th, and 7th Departments of Pulmonary Diseases, Sotiria Hospital; 1st and 2nd Departments of Pulmonary Diseases, Sismanoglion Hospital; Medical Oncology Unit, 3rd Department of Internal Medicine and Oncology Unit, Department of Propedeutic Medicine, School of Medicine, University of Athens; Medical Oncology Unit, 401 Military Hospital; 2nd Department of Medical Oncology, Metaxa Anticancer Hospital of Athens, Athens; 2nd Department of Pulmonary Diseases, Papanikolaou Hospital, Thessaloniki; 2nd Department of Medical Oncology, Theagenion Anticancer Hospital, Thessaloniki; Department of Medical Statistics, School of Medicine, University of Crete, Heraklion, Greece

Address reprint requests to V. Georgoulias, MD, PhD, Department of Medical Oncology, University General Hospital of Heraklion, PO Box 1352, 711 10 Heraklion, Crete, Greece; e-mail: georgoul{at}med.uoc.gr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
PURPOSE: To compare the overall survival (OS) of patients with advanced non–small-cell lung cancer (NSCLC) treated with docetaxel plus cisplatin (DC) or docetaxel (D) alone.

PATIENTS AND METHODS: Chemotherapy-naïve patients with advanced/metastatic NSCLC were randomly assigned to receive either DC (n = 167; docetaxel 100 mg/m² on day 1, cisplatin 80 mg/m² on day 2, and recombinant human granulocyte colony-stimulating factor (rhG-CSF) 150 µg/m²/d on days 3 to 9) or D (n = 152; 100 mg/m² on day 1 without rhG-CSF) every 3 weeks.

RESULTS: The overall response rates were 36.5% for DC (three complete responses and 58 partial responses) and 21.7% for D (one complete response and 32 partial responses; P = .004). The median OS was 10.5 months (range, 0.5 to 41 months) and 8.0 months (range, 0.5 to 41 months) for DC and D, respectively (P = .200). The 1- and 2-year survival rates were 44% and 19% for DC and 43% and 15% for D, respectively. Median times to tumor progression were 4.0 and 2.5 months for DC and D, respectively (P = .580). Grade 2/3 anemia was significantly higher with DC than with D (33% v 16%; P = .0001). Fifteen (9%) DC and 12 (8%) D patients developed febrile neutropenia. Grade 3/4 nausea/vomiting (P = .0001), diarrhea (P = .007), neurotoxicity (P = .017), and nephroroxicity (P = .006) were significantly more common with DC than with D. There were five treatment-related deaths in the DC group and one in the D (P = .098).

CONCLUSION: DC regimen resulted in a higher response rate but without improvement in median time to tumor progession or OS compared with D. D could be a reasonable front-line chemotherapy for patients who cannot tolerate cisplatin.

	INTRODUCTION

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Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of cases of lung cancer.^1–4 Most patients are diagnosed with metastatic disease and without systemic chemotherapy, their median survival is 5 to 6 months and less than 10% are alive at 1 year.⁵ Platinum-based regimens confer a small but statistically significant survival benefit in patients with metastatic NSCLC,^6,7 and cisplatin use is considered to be an independent predictor of survival.⁸

Docetaxel, a semi-synthetic taxoid,⁹ promotes the assembly of stable microtubules in vitro and blocks mitosis in proliferating cells. Objective response rates ranging from 26% to 54% and from 7% to 10% have been achieved with docetaxel in chemotherapy-naïve^10–15 and refractory or resistant^16,17 patients with advanced NSCLC, respectively. The combination of docetaxel and cisplatin has resulted in objective response rates of 33.4% to 45.5% and a median survival time of 8.4 to 13 months.^18–20

Randomized studies have shown that cisplatin-containing regimens are significantly more toxic than those without cisplatin^21,22 due to the low therapeutic index of cisplatin. Indeed, a comparison of the docetaxel plus cisplatin (DC) versus docetaxel plus gemcitabine in patients with advanced NSCLC failed to demonstrate any difference in terms of response rate, duration of response, time to tumor progression, and overall survival; however, the incidence of grade 3/4 nausea/vomiting, neutropenia, and diarrhea was significantly higher with DC than with docetaxel plus gemcitabine.²³ A recent meta-analysis demonstrated that combination chemotherapy produced a nearly two-fold increase in response rate, a modest improvement in 1-year survival, and a 3.6-fold increase in the risk of treatment-related death compared with single-agent treatment in patients with NSCLC.²⁴

Based on these data, the Lung Cancer Working Group of the Hellenic Oncology Research Group conducted a prospective, multicenter, randomized phase III trial to evaluate the activity and toxicity of single-agent docetaxel (D) versus DC in untreated patients with advanced or metastatic NSCLC.

	PATIENTS AND METHODS

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Eligibility Criteria
Chemotherapy-naïve patients aged 75 years with histologically or cytologically documented unresectable (with pleural effusion) stage IIIB and IV NSCLC and bidimensionally measurable disease were enrolled. Other eligibility criteria included: WHO performance status (PS) of 0 to 2; a life expectancy of at least 3 months; adequate bone marrow (absolute granulocyte count [AGC] > 1,500/µL; platelet count > 120,000 µL), renal (serum creatinine concentration < 132.6 µmol/L) and hepatic (serum bilirubin concentrations < 0.015 g/dL) function; absence of active infection, history of cardiac disease, or malnutrition (loss of > 20% of body weight); and absence of second primary tumor except in basal carcinoma of the skin or carcinoma-in-situ of the cervix. Previous radiotherapy, either in the adjuvant setting or for the treatment of bone metastases, was allowed provided that the measurable lesions were outside the radiation fields. Brain metastases were also allowed if they had been previously irradiated and there was clinical and radiologic improvement. Women of childbearing age were required to have a negative pregnancy test within 48 hours of study enrollment. The trial was approved by the Ethics and Scientific Committees of the participating hospitals, and all patients gave written informed consent to participate in the study.

Assessment of Patients
Pretreatment assessment included a complete medical history and physical examination, CBC with differential and platelet count, standard biochemical evaluation, ECG, chest radiographs, a whole-body bone scan and computed tomography (CT) scans of the chest, abdomen, and brain. During treatment, a blood-cell count with differential and platelet count was performed weekly, except in cases of grade 3 or 4 neutropenia, thrombocytopenia, or febrile neutropenia where the CBC was performed daily until the AGC was 1,200 µL and the platelet count 50 x 10³ µL. A detailed medical history was taken and a complete physical examination was performed before each course of treatment to assess disease symptoms and treatment toxicity. Biochemical tests, ECG, and chest radiographs were done every 3 weeks. A clinical neurologic assessment was performed every 3 weeks, and motor and sensory nerve-conduction velocity tests were performed in patients with grade 3 or 4 neurotoxicity. Lesions were measured after each cycle if they were assessable by physical examination or by chest radiograph; all patients were assessed for response by ultrasonography or CT scans after every three cycles of chemotherapy.

Standard WHO toxicity and response criteria were used.²⁵ All objective responses had to be maintained for at least 4 weeks and were validated by two independent radiologists.

Randomization and Treatment
Patients were centrally randomly assigned in a 1:1 ratio to receive either DC or D. Randomly assigned patients were stratified according to age, PS, and stage of the disease. In the DC regimen, docetaxel (Taxotere; Aventis Pharma, Bridgewater, NJ) was given at the dose of 100 mg/m² on day 1 and cisplatin (Platinol; Bristol-Meyers Squibb, Princeton, NJ) at the dose of 80 mg/m² on day 2 after appropriate hydration; recombinant human granulocyte colony-stimulating factor (rhG-CSF) was given prophylactically (150 µg/m²/d subcutaneously from day 3 to day 9, or until the AGC was 1,200 µL on two consecutive measurements after the nadir). Cycles were repeated every 3 weeks. In the monotherapy (D) arm, patients received docetaxel (100 mg/m² on day 1, every 3 weeks) without rhG-CSF support. Standard antiemetic treatment in the DC arm consisted of 8 mg ondansetron intravenously on day 1, before the administration of docetaxel, and 8 mg ondansetron plus 4 mg dexamethasone intravenously on day 2, before the administration of cisplatin, followed by 8 mg oral ondansetron three times a day for 3 days. Patients in the D arm received 8 mg ondansetron intravenously before treatment and 8 mg oral ondansetron three times a day for 2 to 3 days. All patients received standard pre- and postmedication with oral dexamethasone.^18–23 Monotherapy was given on an outpatient basis, whereas patients receiving DC required a 24-hour hospitalization for hydration. Treatment was administered until disease progression, unacceptable toxicity, or consent withdrawal.

Treatment Modifications
Dose adjustments were mainly based on the hematologic parameters. In the DC arm, doses of both drugs were reduced by 25% in subsequent cycles if chemotherapy-induced febrile neutropenia or grade 4 neutropenia or thrombocytopenia occurred. Prophylactic administration of rhG-CSF was given in subsequent cycles in patients treated with D who developed grade 3 or 4 neutropenia without fever; if myelosuppession or febrile neutropenia persisted, despite rhG-CSF administration, the dose of D was reduced by 25% in subsequent cycles. Dose reductions were maintained for all subsequent cycles. The doses of DC were reduced by 25% in case of grade 3 or 4 nonhematologic toxicity; in addition, the dose of docetaxel was reduced by 25% in patients with massive liver involvement (alkaline phosphatase and -glutamyl transferase serum concentrations 5 times the upper normal values).

Quality of Life (QoL) Assessment
Tumor-related symptoms and QoL were evaluated and scored at baseline and after three and six cycles of chemotherapy by completing the Lung Cancer Symptom Scale questionnaire.^26,27

Statistical Analysis
The primary end point was overall survival (OS). Secondary end points included overall response rate (ORR), time to tumor progression (TTP) and toxicity. The study was designed to have 90% power to detect a difference in median survival of 7 months for single-agent D^12,15 versus 12 months for DC^18,23 at the statistically significant level of 5%.²⁸ To achieve these statistical requirements, 150 patients/arm were needed.

Responses were analyzed on an intent-to-treat basis, and all patients who received at least one cycle were assessed for toxicity. The duration of response was calculated from the day of the first documented response to disease progression; TTP was measured from the enrollment until the day of the first evidence of disease progression; OS was measured from study entry until death. All clinical data were held centrally and analyzed with the SPSS (version 10.0; SPSS, Inc, Chicago, IL) program.

Differences between rates of the two groups of patients were tested using the Pearson's ²-test or the Fisher's test where appropriate. Furthermore, risks were assessed and compared using the odds ratio (OR).^28,29 For time events, the actuarial survival function was estimated by the method of Kaplan-Meier; differences between survival functions of the two groups were tested using the log-rank and Wilcoxon test. The former test is appropriate under the assumption of "proportional hazards" (informally assessed by survival functions that do not cross); otherwise, the latter test is more appropriate.³⁰ The independent influence of several prognostic factors on the risk of the primary and secondary binary end points was assessed by logistic regression analysis,³¹ whereas those on the survival or time to progression were assessed using the Cox's proportional hazards model.³⁰

	RESULTS

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Patient Characteristics
Between March 1999 and July 2002, a total of 339 patients with NSCLC (172 DC and 167 D) were enrolled in the study from 15 institutions. Twenty patients were not assessable for the following reasons: five patients (two DC and three D) for major violation of entry criteria; fifteen patients (three DC and 12 D) were randomly assigned but not treated. All 319 patients (167 DC and 152 D) were assessable for toxicity and response. Patient characteristics are presented in Table 1. The majority of patients were male smokers; approximately 90% had a PS of 0 to 1, and two-thirds had stage IV disease. Nine patients in each arm had received adjuvant chemotherapy and seven had palliative radiotherapy.

The median OS was 10.5 months (range, 0.5 to 41 months) for DC and 8.0 months (range, 0.5 to 41 months) for D (Wilcoxon test, P = .200). There was a trend towards a higher 6-month survival rate in favor of the combination arm (67.4% v 57.7% in DC and D arm, respectively; P = .069). However, this difference could not be maintained at 12, 18, and 24 months. Indeed, the 1- and 2-year survival rates were 44% and 19% for DC; the corresponding values for D were 43% and 15% (Fig 1).

View larger version (12K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival curves of patients treated with the docetaxel/cisplatin (DC; dotted line) regimen and docetaxel (D; continuous line) alone.

Median TTP for all patients was 4 months (range, 0.5 to 41.0 months) for DC and 2.5 months (range, 0.5 to 22.5 months) for D. Moreover, the median TTP for responders (complete response [CR], partial response [PR], stable disease [SD]) was 7.0 months (range, 1.0 to 41.0 months) for DC and 6.0 months (range, 2 to 22.5 months) for D (Fig 2; Wilcoxon test P = .580). The Cox proportional hazards regression analysis revealed that only the number of involved sites at baseline had a statistically significant (P = .045) effect on TTP (HR, 1.47; 95% CI, 1.05 to 1.95).

View larger version (12K): [in this window] [in a new window]   Fig 2. Kaplan-Meier analysis of patients' time to progression treated with docetaxel/cisplatin (DC; dotted line) regimen and docetaxel (D; continuous line) alone.

The DC regimen yielded a significantly higher response rate (CR and PR) in patients with a PS of 0 to 1, stage IIIB, and stage IV disease when compared with D (Table 4). The median duration of response was 5.0 months (range, 0.5 to 35.0 months) and 4.0 months (range, 1.0 to 20.5 months) for DC and D patients, respectively (P = .800).

Treatment Delivery
A total of 715 DC and 581 DC cycles were administered (P = .053). The median number of cycles was four (range, one to nine cycles) and three (range, one to 12 cycles) in the DC and D arms, respectively. Ninety-seven (58.1%) DC and 66 (43.4%) D patients received 4 chemotherapy cycles (P = .009). The median interval between cycles was 21 days in each group (range, 21 to 34 days in DC and 21 to 32 days in D). One hundred eleven cycles (16%) in the DC arm and 64 (11%) in the D arm were delayed (P = .018). Thirty-seven DC cycles (5.2%) were delayed because of hematologic (n = 18), nonhematologic (n = 9), and both hematologic and nonhematologic (n = 10) toxicities. Moreover, 12 DC cycles (1.7%) were delayed because of nontreatment-related events (respiratory insufficiency, n = 4; myocardial ischemia, n = 3; lower respiratory tract infection, n = 3; upper gastrointestinal bleeding, n = 1; and accident, n = 1) and 62 (8.7%) for reasons unrelated to the disease or the treatment (patients' request for personal reasons, completion of response assessment, or late admission). Twenty cycles (3.5%) were delayed in the D arm because of hematologic (n = 9), nonhematologic (n = 4), and both hematologic and nonhematologic (n = 7) toxicity; moreover, seven (1.2%) cycles were delayed because of nontreatment-related events (respiratory insufficiency, n = 2; myocardial ischemia, n = 1; lower respiratory tract infection, n = 3; and diabetic acidosis with infection, n = 1) and 37 (6.4%) for reasons unrelated to the disease or the treatment.

In the DC arm, 65 cycles (9.1%) were delayed for 7 days and 46 (6.4%) for more than 7 days. In the D arm, 36 cycles (6.2%) were delayed for 7 days and 28 (4.8%) for more than 7 days. Twenty-eight cycles (4%) in the DC arm and seven cycles (1%) in the D arm (P = .003) required dose reductions because of hematologic and/or nonhematologic toxicity.

In DC arm, the median administered dose-intensity was 32 mg/m²/wk (range, 21 to 33 mg/m²/wk) for docetaxel and 25 mg/m²/wk (range, 17 to 25 mg/m²/wk) for cisplatin corresponding to 97% and 100% of protocol planned dose. In the D arm, the median administered dose-intensity for docetaxel was 33.3 mg/m²/wk (range, 22 to 33 mg/m²/wk) corresponding to 100% of the protocol-planed dose.

One hundred-fifteen patients (68.9%) in the DC arm died during the follow-up period. Of these, 97 (80.2%) were as a result of disease progression, five (4.1%) to treatment-related toxicity, and four (3.3%) to other reasons (pulmonary embolism, n = 1; CNS stroke, n = 1; sudden death 3 months postchemotherapy, n = 1; and upper gastrointestinal bleeding as a result of nonsteroidal anti-inflammatory drugs, n = 1). Moreover, nine patients (5%) were lost to follow-up. Similarly, 113 patients (74.3%) in the D arm died during follow-up. Of these, 101 deaths (82.8%) were due to disease progression, one death (0.8%) to treatment-related toxicity, and one death (0.8%) to other reasons (acute myocardial infarction). Moreover, 10 patients (6%) were lost to follow-up.

The proportion of patients with a PS of 0 to 1 who died was 74.7%, and with PS of 2, the proportion was 93.3% (P = .022). Logistic regression analysis confirmed that PS, but not stage, histology, or extension of the disease was an independent prognostic factor (P = .037) since the estimated risk of death was about five times higher for patients with a PS of 2, compared with that of patients with a PS of 0 to 1 (OR, 4.731; 95% CI, 1.100 to 20.35).

Toxicity
Hematologic and nonhematologic toxicities are presented in Table 5. Grade 3 anemia was seen in four (3%) DC and seven (4%) D patients. However, when grade 2 anemia was taken into account, the incidence of grade 2 to 4 anemia was 31% in DC (n = 52) and 13% in D (n = 20) arms (P = .0001). All patients with grade 2/3 anemia were treated with recombinant erythropoietin and a total of 12 RBC units were transfused in patients with grade 3 anemia. Grade 3/4 neutropenia occurred in 46 (28%) DC and 38 (25%) D patients (P = .606). Fifteen (9%) DC and 12 (8%) D patients developed febrile neutropenia (P = .819); two patients in the DC and one in the D arm died because of sepsis. Grade 4 thrombocytopenia was observed only in three DC patients (2%).

There were five (3%) treatment-related deaths in DC patients (febrile neutropenia, n = 2; acute renal failure, n = 1; febrile diarrhea, n = 1; and grade 3 thrombocytopenia and pulmonary infection, n = 1) and one (0.66%; due to febrile neutropenia) in D patients (P = .098). Furthermore, 22 (13%) and 14 (9%) patients in the DC and D arm, respectively, developed non-neutropenic fever requiring hospitalization for the administration of intravenous broad-spectrum antibiotics; all patients recovered uneventfully.

QoL
Patients' compliance with QoL assessment for the D group was 97% at baseline, 80% at third cycle, and 35% at end of chemotherapy (EoC). Similarly, for the DC group, compliance was 100% at baseline, 85% at third cycle, and 41% at EoC. Baseline assessment revealed a nonsignificant difference between the two arms for appetite, fatigue, and total symptomatic distress, in favor of the DC arm. Patients treated with D but not with DC reported a significant improvement in QoL between baseline and EoC assessment for appetite (P = .048), fatigue (P = .014), cough (P = .001), dyspnea (P = .021), total symptomatic distress (P = .002), and overall QoL (P = .005). There was no difference in QoL assessments at third cycle and EoC between the two arms.

	DISCUSSION

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The results of this phase III randomized study show that DC was significantly more active in terms of objective response rate compared with D alone in patients with advanced NSCLC. Although the OS of patients treated with DC was 10.5 months compared with 8.0 months for D, this difference did not reach statistical significance. Moreover, the 1-year survival rate for patients in both groups was similar (44% for DC and 43% for D). The respective 2-year survival rates were 19% and 15%. Within each treatment group, patients with a PS of 0 to 1 had significantly longer survival than that of patients with a PS of 2 (Table 3). Regression analysis revealed that the hazard of nonsurvival for patients with a PS of 2 was about 2.5 times that of patients with a PS of 0 to 1, indicating that PS is an independent prognostic factor for survival. These results are in agreement with prior studies, which have demonstrated that cisplatin adds a modest but statistically significantly prolongation of survival obtained with single antitumor agents.⁸ Indeed, Le Chevalier et al³² reported that the combination of vinorelbine and cisplatin resulted in a significantly higher overall survival (40 weeks) than single-agent vinorelbine (31 weeks). Moreover, Sederholm³⁰ compared gemcitabine plus carboplatin with gemcitabine in 332 patients; the preliminary analysis demonstrated significantly longer OS with gemcitabine plus carboplatin than with gemcitabine. Similarly, Lilenbaum et al³¹ compared paclitaxel plus carboplatin with paclitaxel alone in 584 patients and observed a median OS of 6.5 months for paclitaxel and 8.5 months for paclitaxel plus carboplatin, a difference that was statistically significant by the Wilcoxon test (P = .0023), but not by log-rank test analysis. Another interesting finding was the observation that there was a trend towards a significant survival benefit in favor of the DC arm at 6 months, but not at 12, 18, and 24 months. This is probably as a result of the fact that the benefit of docetaxel on survival mainly appears after 6 months, as has been observed in the second-line studies;^15–17 conversely, the benefit of cisplatin on survival appears during the first 6 months of treatment.

An ORR of 36.5%, a median survival of 10.5 months, and a 1-year survival of 44% for the DC regimen in our study are similar to results already reported with the same regimen.^18–20,23 Similarly, an ORR of 21.7%, a median survival of 8.0 months, and a 1-year survival of 43% are comparable with prior reports from single-agent docetaxel phase II studies.^10,12,15 The difference in ORR between the two regimens should be attributed to cisplatin, which is active in NSCLC.³⁵ It should be mentioned that although docetaxel and cisplatin are not synergistic in vitro, they appear to be non–cross-resistant clinically.¹¹

In this study, the DC combination was also significantly more active than D in patients with a PS of 0 to 1, stage IIIB or IV disease, and adenocarcinoma. Multivariate analysis confirmed that only treatment group and histology were independent predictors of response. Previous studies have also shown the role of PS on the efficacy of chemotherapy in patients with NSCLC. In the Eastern Cooperative Oncology Group 1594 trial,³⁶ the response rate, median survival, and 1-year survival for patients with a PS of 2 who received paclitaxel and carboplatin were 13%, 4.6 months, and 13%, respectively. Similar results have also been reported in patients with advanced/metastatic NSCLC treated with either paclitaxel/carboplatin or paclitaxel/gemcitabine.³⁷ Taken together, these results clearly indicate that NSCLC patients with poor PS require a different treatment approach. Single-agent chemotherapy could be a reasonable option for these patients, but future well-controlled randomized trials should define the best anticancer drug, schedule of administration, and treatment strategy. The effect of the DC regimen in patients with adenocarcinoma should be interpreted with caution since there was no central review of the histology; in addition, histology had not been chosen as a stratification factor.

Overall, patients treated with D had a more favorable toxicity profile than patients treated with DC (Table 5). Important differences in toxicities were: (1) the incidence of grade 2 anemia was significantly higher in the DC than in the D arm; (2) there was no difference in the incidence of grade 3/4 neutropenia or febrile neutropenia between the DC and D groups; this should be atributed to the prophylactic administration of rhG-CSF in the DC arm; (3) the incidences of grade 3/4 nausea/vomiting, diarrhea, and neurotoxicity were higher with DC than with D arm; (4) eight patients in the DC arm presented grade 3/4 nephrotoxicity and one of them died; and (5) there were five treatment-related deaths in the DC arm compared with only one in the D arm. Similarly, the toxicity profile of the monotherapy arm in the Sederholm³³ and Lilenbaum³⁴ studies was more favorable compared with that of the combination arm. In our study, the incidence of toxicities in PS 2 and PS 0 to 1 patients was similar, as has been previously reported.³⁶

The QoL assessment seems to favor the monotherapy arm, since patients experienced a significant improvement of tumor-related symptoms, as well as in the global QoL score. The lack to detect a difference in the QoL assessment between the two groups should be explained by the observation that patients enrolled to the DC arm already had a better, although nonstatistically significant, QoL score at baseline.

In our study, no pharmacoeconomic studies were performed; however, the combination regimen seemed to have a higher cost than monotherapy since it required an overnight hospitalization for hydration and additional costs for treatment of severe adverse events.

In summary, our study showed that the DC regimen yielded a significantly higher ORR than D in patients with advanced NSCLC. Despite its less favorable toxicity profile, DC appears to provide a nonsignificant 2-month survival benefit compared to D. Recently, Fossella et al³⁸ reported on the results of the TAX 326 trial, which demonstrated that the DC was superior to vinorelbine plus cisplatin in terms of median survival and QoL. Therefore, although the docetaxel/platinum regimen seems to remain one of the best therapeutic options for patients with advanced NSCLC, single-agent docetaxel could be a valuable front-line chemotherapy for NSCLC patients who cannot tolerate cisplatin.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
Participating investigators and centers: V. Georgoulias, Ch. Kouroussis, Department of Medical Oncology, University General Hospital of Heraklion, Crete; A. Ardavanis, A. Alexopoulos, 1st Department of Medical Oncology, "Agios Savvas" Anticancer Hospital of Athens; M. Agelidou, X. Tsiafaki, F. Apostolopoulou, 2nd Department of Pulmonary Disease, "Sismanoglion" General Hospital of Athens; Ph. Palamidas, P. Ziotopoulos, 1st Department of Pulmonary Diseases, "Sigmanoglion" General Hospital of Athens; A. Agelidou, E. Papadakis, 1st Department of Pulmonary Diseases, "Sotiria" Hospital of Athens; A. Christou, 3rd Department of Pulmonary Diseases, "Sotiria" Hospital of Athens; M. Toubis, 6th Department of Pulmonary Diseases, "Sotiria" Hospital of Athens; S. Tzannes, A. Geroyianni, 7th Department of Pulmonary Diseases, "Sotiria" Hospital of Athens; A. Rapti, G. Pavlakou, O. Anagnostopoulou, 8th Department of Pulmonary Diseases, Hospital of Chest Diseases of Athens; K. Syrigos, Medical Oncology Unit, 3rd Department of Internal Medicine, "Sotiria" Hospital of Athens; E. Tselepatiotis, P. Kotsakis, Department of Internal Medicine, "Patision" General Hospital of Athens; A. Polyzos, Medical Oncology Unit, Propedeutiki Clinic, "Laiko" Hospital of Athens; Ch. Christofilakis, Medical Oncology Unit, "401" Military Hospital of Athens; N. Samaras, 2nd Department of Pulmonary Diseases, "Papanikolaou" Hospital of Thessaloniki; I. Boukovinas, P. Papakotoulas, P. Markantonakis, 2nd Department of Medical Oncology, "Theagenion" Anticancer Hospital of Thessaloniki.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Dr Dora Hatzidaki for the data management.

	NOTES

 
Supported partly by a grant from the Cretan Association for Biomedical Research.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... REFERENCES

 
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Submitted November 4, 2003; accepted March 30, 2004.

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