288 Clinical Lung Cancer March 2003

original contribution

IntroductionNon–small-cell lung cancer (NSCLC) remains the leading

cause of cancer-related death in men and women in Westerncountries and accounts for 80% of lung cancer cases.1 The prog-nosis of patients with NSCLC is poor; only one third have re-sectable disease at diagnosis and more than half die from subse-quent relapse and metastases. Furthermore, patients with metasta-tic disease have a median survival of approximately 5-6 months.2

Docetaxel is a semisynthetic taxane derived from 10-deacetylbaccatin III3 and, like paclitaxel, promotes the in vitro assemblyof stable microtubules in the absence of guanosine triphosphate

and induces microtubule bundle formation in cells.4 Severalphase II trials have evaluated the activity of docetaxel in previ-ously untreated patients with NSCLC. Docetaxel as single-agent therapy (100 mg/m2 and 75 mg/m2 every 3 weeks) hasproduced response rates of 26%-54%.5-10 In addition, docetaxelis active in patients who are refractory or resistant to cisplatin,producing responses ranging from 18% to 25%, implying a lackof cross-resistance between docetaxel and cisplatin, probably be-cause of their different mechanisms of action.11

For > 10 years, cisplatin-based chemotherapy represented thecornerstone treatment for advanced NSCLC. A large meta-analysis of 8 randomized trials (N = 778) of cisplatin-basedchemotherapy compared with best supportive care demonstrat-ed an advantage of chemotherapy, with a 27% reduction in therisk of death and a 10% increase in 1-year survival rate.12 Fur-thermore, an analysis of survival determinants in > 2500 pa-tients proved that the use of cisplatin was an independent pre-dictor of survival.13 However, cisplatin has a low therapeuticratio and is related to severe toxicity (nausea and vomiting, renaltoxicity, neuropathy, and ototoxicity).14 Therefore, the combi-

V. Georgoulias, A.G. Pallis, C. Kourousis, A. Alexopoulos, A. Ardavanis, A. Agelidou, M. Agelidou, M. Toumbis, S. Tzannes, G. Pavlakou, P. Ziotopoulos, E. Tzelepatiotis, N. Samaras

AbstractThe purpose of this study was to compare the efficacy and safety profile of docetaxel versus the combinationof docetaxel/cisplatin as frontline treatment of patients with advanced or metastatic non–small-cell lung can-cer (NSCLC) in a multicenter, randomized, prospective phase III trial. Patients with unresectable stage IIIB ormetastatic stage IV NSCLC who had previously undergone no chemotherapy were allocated to receive eitherdocetaxel (100 mg/m2 in a 1-hour intravenous infusion; group A) or the combination of docetaxel (100 mg/m2

day 1) and cisplatin (80 mg/m2 day 2) after adequate hydration (group B). Appropriate premedication wasgiven before docetaxel infusion. All patients in group B received granulocyte colony-stimulating factor (150µg/m2 subcutaneously) support from days 3 to 9 after treatment. Response and toxicity were assessed byWorld Health Organization criteria. From March 1999 to November 2001, 302 patients were randomly assignedto receive docetaxel (group A, n = 146) or docetaxel/cisplatin (group B, n = 156). The overall response ratewas significantly higher in the combination arm (18% vs. 36%; P < 0.001). However, the 2 groups did not dif-fer in median duration of response, time to progression (TTP), median overall survival (OS), or 1-year survivalrate. Drug combination was associated with higher toxicity than single-agent therapy. Both regimens had com-parable activity in terms of TTP and OS in chemotherapy-naive patients with advanced NSCLC; however, single-agent therapy had a more favorable toxicity profile.

Clinical Lung Cancer, Vol. 4, No. 5, 288-293, 2003 Key words: Chemotherapy, Growth factors, Platinum agents, Taxanes

Docetaxel Versus Docetaxel/Cisplatin in Patients withAdvanced Non–Small-Cell Lung Cancer: PreliminaryAnalysis of a Multicenter, Randomized Phase III Study

Submitted: Dec 27, 2002; Revised: Mar 6, 2003; Accepted: Mar 14, 2003

Address for correspondence: V. Georgoulias, MD, Department of MedicalOncology, University Hospital of Heraklion, P.O. Box 1352, 71110, Heraklion, Crete, GreeceFax: 30-810-392802; e-mail: georgoul@med.uoc.gr

Lung Cancer Group, Hellenic Oncology Research Group (LCG-HORG),and Department of Medical Oncology, University Hospital of Heraklion,Crete, Greece

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289Clinical Lung Cancer March 2003

nation of cisplatin with a new-generation agent such as doce-taxel was a logical step to develop more active regimens againstNSCLC. Phase II studies of the docetaxel/cisplatin combinationreported response rates of 33.4%-45.5% and median survivaldurations of 8.4-13 months.15-17

A recently published metaanalysis compared the effect of sin-gle-agent versus combination chemotherapy on response rate,toxicity, and survival in 25 trials including 5156 patients withadvanced NSCLC. Overall, combination chemotherapy pro-duced a nearly 2-fold increase in response rate. However, sur-vival at 12 months was modestly superior with combinationchemotherapy. Additionally, combination chemotherapy alsoincreased toxicity significantly, including a 3.6-fold increase inthe risk of treatment-related death.18

Based on these data, the Lung Cancer Group of the HellenicOncology Research Group conducted a prospective, multicen-ter, randomized phase III trial comparing docetaxel versus thedocetaxel/cisplatin combination in patients with previously un-treated, unresectable, locally advanced (stage IIIB) and/ormetastatic (stage IV) NSCLC.

Patients and MethodsPatients

The inclusion criteria for this study was histologically or cy-tologically confirmed, unresectable, locally advanced (stageIIIB) and/or metastatic (stage IV) NSCLC. Additionally, eligi-ble patients were 18-75 years of age with bidimensionally meas-urable disease, life expectancy > 3 months, and a World HealthOrganization (WHO) performance status (PS) ≤ 2. All patientshad to be chemotherapy-naive. Previous radiation therapy, ei-ther in the adjuvant setting or for the treatment of bone metas-tases, was allowed provided that the measurable lesions wereoutside the radiation fields. Patients with known, symptomaticcentral nervous system metastases were ineligible. Serum biliru-bin levels had to be ≤ 1.5 times the upper normal limit (UNL);aspartate aminotransferase and alanine aminotransferase levelshad to be ≤ 2.5 times UNL in the absence of demonstrable livermetastases or ≤ 5 times UNL in the presence of liver metastases.Adequate renal function was also required (serum creatininelevel ≤ 1.5 times UNL). Neutrophil count had to be ≥ 1.5 ×109/L and platelet count ≥ 100 × 109/L. Active infection, his-tory of significant cardiac disease (ie, unstable angina, conges-tive heart failure, myocardial infarction within the previous 6months, and/or ventricular arrhythmias), and malnutrition (lossof ≥ 20% of original body weight) were criteria for exclusion.All patients gave written informed consent to participate in thestudy and the trial was approved by the ethics and scientificcommittees of the participating centers. The study was con-ducted according to the Helsinki Declaration and good clinicalpractice guidelines.

Patient EvaluationBaseline assessment was necessary for all patients and consist-

ed of complete medical history, physical examination and vitalsigns, evaluation of PS, 12-lead electrocardiography (EKG),complete blood cell count with differential and blood bio-

chemistry, chest radiography, computed tomography (CT) ofthe chest, abdomen, and brain, and whole-body radionuclidebone scan. Baseline evaluation had to be performed within 2weeks before therapy initiation. All measurable lesions wereidentified at baseline and were monitored throughout. Duringtreatment, a complete blood cell count was performed weekly;in case of grade 3 or 4 neutropenia, febrile neutropenia, orgrade 4 thrombocytopenia, the complete blood cell count wasdone daily until resolution to a grade ≤ 1. A complete medicalhistory analysis and a detailed physical examination with bloodbiochemistry, EKG, and chest radiography were performed be-fore each treatment administration to assess disease status andtreatment toxicity. Lesions were evaluated after each cycle byclinical examination or chest radiography when appropriate; allpatients were assessed for response every 3 courses of chemo-therapy. Objective tumor responses were evaluated according toWHO response criteria.19 Assessment of the lesions was per-formed by the same method on each occasion. All CT scanswere reviewed by an independent radiologist. Objective re-sponses were confirmed by repeating the CT scans 1 monthlater. After completion of study treatment, patients were fol-lowed every 2 months during the first year. Second-line thera-py included best supportive care, palliative radiation therapy, orreinduction to study treatment. Treatment with a platinum-containing regimen was not permitted in the docetaxelmonotherapy group.

Randomization and TreatmentPatients were centrally randomized by computer software to a

1:1 ratio to receive either single-agent docetaxel (group A) ordocetaxel/cisplatin (group B). The randomization to each armwas done by stratification according to PS and stage of disease.

In the single-agent arm, docetaxel was given at the dose of100 mg/m2 as a 1-hour intravenous infusion. The doses of theadministered drugs in the combination arm were based on ourprevious experience.15 We have previously shown that docetaxelat the dose of 100 mg/m2 and cisplatin at the dose of 80 mg/m2,followed by adequate hydration, administered every 3 weeks,with granulocyte colony-stimulating factor (G-CSF) support isfeasible and active in previously untreated patients with ad-vanced NSCLC.15 Therefore, docetaxel was administered onday 1 at a dose of 100 mg/m2 over a 1-hour intravenous infu-sion and cisplatin was administered on day 2 at a dose of 80mg/m2 after adequate hydration. All patients in group B re-ceived G-CSF (150 µg/m2 subcutaneously) from days 3 to 9after treatment.

The same antiemetic treatment was given to patients in bothstudy groups according to the common practice of the partici-pating centers. All patients received standard pre- and post-medication with 8 mg dexamethasone at 7 hours and 1 hour be-fore docetaxel administration and 16 mg dexamethasone in 2divided doses daily for 3 additional days to reduce the risk of al-lergic reactions and docetaxel-associated fluid retention syn-drome. Both regimens were repeated every 3 weeks. Treatmentwas continued until disease progression, the appearance of un-acceptable toxicity, or patient withdrawal of consent.

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Docetaxel Versus Docetaxel/Cisplatin in Advanced NSCLC

ToxicityAll adverse events were recorded along with a description of

the event and were graded according to WHO common toxici-ty criteria.19 In any case of grade 4 neutropenia, febrile neu-tropenia, or grade 3 or 4 thrombocytopenia, treatment was de-layed until the resolution of toxicity to grade ≤ 1, and dosagesof both drugs were reduced by 15%. In cases of grade 3/4 neu-rotoxicity and fatigue, treatment was delayed 1-2 weeks anddosages of both drugs were reduced by 25%. Dose reductionswere maintained for all subsequent cycles of treatment.

Statistical AnalysisThe primary endpoint was overall survival (OS); secondary

endpoints included overall response rate (ORR) with the 2 reg-imens, safety profile, and time to progression (TTP). The studywas designed to have 90% power to detect a difference in me-dian survival of 7 months for the single-agent docetaxel arm ver-sus 12 months for the docetaxel/cisplatin/G-CSF arm at the sta-tistically significant level of 5%. One hundred fifty evaluable pa-tients should be enrolled in each arm to achieve the statisticalrequirements of the fixed sample size design.20

Descriptive statistics for both groups are reported as mean,median, and range. Statistical comparisons between groups wereassessed by Pearson χ2 test for proportions (or Fisher Exact testwhere appropriate).20 Differences between groups in terms ofsurvival data were assessed by the log-rank and Wilcoxon tests(Kaplan-Meier analysis).21

The duration of response was calculated from the day of thefirst documentation of response to disease progression; OS wasmeasured from entry to the study until death, and the 1-yearsurvival was estimated with use of the Kaplan-Meier method.21

The TTP was measured from enrollment into the study untilthe day of the first evidence of disease progression.

ResultsPatient Characteristics

At the time of present interim analysis (March 2002), 302 pa-tients were enrolled in the study; 146 were enrolled on the doce-taxel arm and 156 on docetaxel/cisplatin/G-CSF arm. One hun-dred patients in the docetaxel group and 115 in thedocetaxel/cisplatin group were evaluable for efficacy and all pa-tients in both groups were evaluable for toxicity. Eighty-seven pa-tients were not evaluable for response for the following reasons:too early for evaluation (n = 51), disease response assessment notyet available (n = 27), or received only 1 cycle of chemotherapy(n = 9). Patient characteristics were well balanced betweengroups with respect to several prognostic factors. Patient charac-teristics are presented in Table 1.

TreatmentA total of 513 and 647 chemotherapy cycles were adminis-

tered in group A and group B, respectively. The median numberof cycles received per patient was 3.0 for the docetaxel group(range, 1-12 cycles) and 4.0 for the docetaxel/cisplatin/G-CSFgroup (range, 1-9 cycles). The median interval between cycleswas 21 days for both groups (ranges of 21-32 days and 21-34

days for single-agent and combination groups, respectively).Treatment administration was delayed in 56 cycles (11%) in thedocetaxel group and 110 cycles (17%) in the docetaxel/cispla-tin/G-CSF group (P = 0.005). Three cycles (5.4%) in the doce-taxel group and 10 cycles (9.3%) in the docetaxel/cisplatin/G-CSF group were delayed because of hematologic toxicity (P =0.038); moreover, 1 cycle (2%) in the docetaxel group and 11(10%) in the docetaxel/cisplatin/G-CSF group (P = 0.019) weredelayed because of nonhematologic toxicity. All other cycleswere delayed for reasons not related to treatment or toxicity (ie,patient request for personal reasons, pending imaging studiesfor response assessment). Dose reductions were not common,occurring in 1.2% of cycles in the single-agent arm and 4% inthe combination therapy arm. Dose reductions in the docetaxelgroup mainly resulted from hematologic toxicity; in the doce-taxel/cisplatin/G-CSF group, dose reductions resulted fromboth hematologic and nonhematologic toxicity.

Patient Characteristics in Group A (Docetaxel) and Group B (Docetaxel/Cisplatin)

Table 1

61

33-76

147 (94%)

9 (6%)

64 (41%)

80 (51%)

12 (8%)

55 (35%)

101 (65%)

57 (37%)

99 (63%)

2

1-5

9 (6%)

6 (4%)

63

41-75

131 (90%)

15 (10%)

62 (42%)

69 (47%)

15 (10%)

52 (36%)

94 (64%)

52 (36%)

94 (64%)

2

1-4

16 (11%)

4 (3%)

Group A(n = 146)

Group B(n = 156)

Abbreviation: WHO = World Health Organization

Age (Years)

Median

Range

Sex

Male

Female

WHO Performance Status

0

1

2

Histological Type

Adenocarcinoma

Nonadenocarcinoma

Stage

IIIB

IV

Number of Organs Involved

Median

Range

Previous Treatment

Surgery

Radiation therapy

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V. Georgoulias et al

Response to TreatmentThere were no complete responses in patients in the docetaxel

group; 24 patients (16%) achieved a partial response in this group.Similarly, 3 (2.0%) and 49 patients (31%) experienced completeand partial responses, respectively, in the docetaxel/cisplatin/G-CSF group. The ORRs were 18% (95% confidence interval [CI]:11.60%-24.76%) for the docetaxel group and 36% (95% CI:27.64%-43.10%) for the docetaxel/cisplatin/G-CSF group (in-tent-to-treat analysis; P < 0.001). However, no statistically signifi-cant difference was observed between the docetaxel monotherapyand combination groups regarding the median duration of re-sponse, median TTP, and median OS (Table 2). After a medianfollow-up period of 4 and 6 months for single-agent and combi-nation groups, respectively, the median OS was 10 months for thedocetaxel arm and 13 months for the docetaxel/cisplatin/G-CSFarm (P = 0.471). Thirty-two percent of the patients in the single-agent arm and 22% in the combination arm received second-linechemotherapy (P = not significant [NS]).

ToxicityThe incidence of severe hematologic toxicity (grade 3 and 4) is

presented in Figure 1. Grade 3 or 4 neutropenia was observed in30 patients (20.6%) and 39 patients (25.0%) on the docetaxel anddocetaxel/cisplatin/G-CSF arms, respectively. Eleven patients(7.5%) in the single-agent arm and 15 patients (9.5%) in the com-bination therapy arm developed febrile neutropenia. Grade 3 or 4anemia occurred relatively infrequently. Three patients (2%) in thesingle-agent arm and 3 patients (1.9%) in the combination groupdeveloped grade 3 or 4 anemia. Thrombocytopenia was morecommon in the combination group. Grade 3 or 4 thrombocy-topenia was observed in 5 patients (3.2%) in the combinationgroup; no patient in the docetaxel group developed grade 3 or 4

thrombocytopenia. However, no patient in the combination grouphad bleeding episodes or required platelet transfusions.

The incidence of grade 3 nausea and vomiting was significantlyhigher in the combination therapy group than in the single-agentgroup (7% vs. 0%; P = 0.02). Furthermore, the incidence of grade3/4 diarrhea was significantly higher in the combination group(7% vs. 2% with docetaxel alone; P = 0.04). The frequency ofgrade 2-4 nephrotoxicity was significantly lower in the docetaxelarm (0% vs. 4.5% with combination therapy; P = 0.006). Neuro-toxicity of grades 2-4 was similar between groups (docetaxel vs.docetaxel/cisplatin/G-CSF: 4.1% vs. 5.1%; P = NS). Mild hyper-sensitivity reactions were seen in 9 patients (6.0%) in the docetaxelgroup and 4 patients (2.5%) in the docetaxel/cisplatin/G-CSFgroup (P = NS). Incidence of nonhematologic toxicity is present-ed in Table 3.

There were no treatment-related deaths in the docetaxel group,whereas 5 (3.2%) treatment-related deaths (from febrile neutrope-nia, n = 2; grade 3 diarrhea and grade 3 vomiting, n = 1; grade 3anemia and non-neutropenic infection, n = 1; and acute renal fail-ure, n = 1) were observed in the docetaxel/cisplatin/G-CSF group(P = 0.02).

DiscussionThe results of the present study demonstrate that docetaxel

single-agent therapy has a more favorable toxicity profile thanthe docetaxel/cisplatin/G-CSF combination regimen in thestudied population. Granulocyte colony-stimulating factor sup-port was given in the docetaxel/cisplatin arm so the incidence ofgrade 3/4 neutropenia was similar between arms. However,thrombocytopenia and nonhematologic toxicities (Table 3)were more common in the combination group. Finally, therewere no treatment-related deaths in the docetaxel group, where-as 5 (3.2%) treatment-related deaths were observed in the doce-taxel/cisplatin/G-CSF group (P = 0.02).

The comparison of docetaxel monotherapy with the doce-taxel/cisplatin/G-CSF combination revealed that the combina-tion regimen is significantly more active than docetaxelmonotherapy in terms of response rate (18% vs. 36%; P < 0.001).Although there was a trend toward better duration of response,

Efficacy Results of Docetaxel and Docetaxel/CisplatinTable 2

Overall Response Rate

Complete response

Partial response

Stable disease

Progressive disease

Median Duration of Response, Months (Range)

TTP, Months (Range)

Median Follow-up, Months (Range)

Median Survival, Months (Range)

1-Year Survival

< 0.001

–

–

–

–

NS

0.308

NS

0.471

NS

18%

–

16%

22%

60%

8 (1-12)

7 (2-17)

4 (0.5-27.5)

10 (0.5-27.5)

40%

36%

2%

33%

22%

42%

6.5 (0.5-25)

8.5 (1-31)

6 (0.5-31)

13 (0.5-31)

45%

Result Docetaxel Docetaxel/Cisplatin

PValue

Abbreviations: NS = not significant, TTP = time to progression

Proportions of Patients with Grade 3/4 Anemia,Neutropenia, or Thrombocytopenia by Treatment Group

Figure 1

*P = 0.01

DocetaxelDocetaxel/Cisplatin

25

20

15

10

5

0Anemia Neutropenia Thrombocytopenia

Pati

ents

(%)

*

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Docetaxel Versus Docetaxel/Cisplatin in Advanced NSCLC

TTP, OS, and 1-year survival in the combination arm, this dif-ference failed to reach statistical significance. This may be at-tributed to the increased toxicity in the combination arm. TheORR of 16%, the median survival of 10 months, and the 1-yearsurvival rate of 40% observed in the single-agent arm are simi-lar to results reported in previous studies of docetaxel monother-apy, with the exception of ORR, which is slightly lower thanthose seen in earlier phase II studies.5-10 Similarly, for the doce-taxel/cisplatin/G-CSF combination, the ORR is slightly lowerthan that reported in our previous phase II study, whereas me-dian survival and 1-year survival are quite similar.15 The lowerdegree of activity observed in this study may reflect the early in-terim data analysis or may be a more accurate indication of thetrue response rate.

Some important differences were observed between the 2groups regarding toxicity. The combination of docetaxel/cispla-tin was more myelotoxic than docetaxel monotherapy, with asignificantly higher incidence of thrombocytopenia. Further-more, the incidences of grade 3 nausea and vomiting and grade3/4 diarrhea were significantly higher in the docetaxel/cisplatinarm than in the monotherapy arm, and these adverse eventswere the reason for 1 treatment-related death. As expected,nephrotoxicity was observed mainly in the combination group.Finally, significantly more treatment-related deaths occurred inthe combination arm than in the single-agent arm.

Locally advanced and metastatic NSCLC remains a fatal dis-ease. Hence, the principal goals of treatment should be pallia-tion, acceptable quality of life, and prolonged survival. There-fore, the toxicity profile of a particular chemotherapeutic regi-men should be an important issue. The toxicity of cisplatin re-mains a serious clinical problem. Nausea and emesis are oftensevere and delayed; furthermore, neurotoxicity, renal toxicity,and ototoxicity may be significant and dose-related. An impor-tant proportion of patients with NSCLC are elderly and haveconcomitant cardiac or cardiorespiratory diseases in which theadministration of cisplatin is relatively contraindicated. Addi-tionally, the administration of cisplatin requires the need for hy-

dration, leading to a prolonged hospital stay. The other platinumcompound, carboplatin, is easier to administer but producesmore severe myelosuppression, especially thrombocytopenia. Allthese factors bring up the issue of whether a platinum compoundshould be a mandatory component of chemotherapy in NSCLC.

There are very few published randomized trials comparingplatinum-based combinations with the corresponding non-plat-inum monotherapies. In one of these studies that comparedgemcitabine versus gemcitabine/cisplatin, there was no differ-ence in OS.22 The comparison of single-agent paclitaxel versuspaclitaxel/carboplatin demonstrated a higher response rate anda higher OS in favor of the combination arm.23 Similarly, a re-cent report on 332 patients treated with gemcitabine alone orthe gemcitabine/carboplatin combination also demonstrated ahigher response rate (30% vs. 12%) and median survival (6months vs. 4 months) in favor of the combination arm.24 Drugcombination was associated with higher toxicity rates than sin-gle-agent therapy in all trials.

Based on these preliminary results, we can propose that sin-gle-agent docetaxel may offer an alternative in the first-linetreatment of patients with advanced NSCLC, especially thosewho cannot tolerate platinum-based regimens.

Participating InstitutionsParticipating Centers in the Lung Cancer Group of the Hel-

lenic Oncology Research Group are as follows:Department of Medical Oncology, University Hospital of

Crete (V. Georgoulias, A.G. Pallis, C. Kourousis, N. An-droulakis); 1st Department of Pulmonary Diseases (F. Apos-tolopoulou, X. Tsiafiaki, M. Agelidou) and 2nd Department ofPulmonary Diseases (P. Ziotopoulos, F. Palamidas), Sisman-ogleion Hospital, Athens; Department of Medical Oncology,General Hospital of Larisa (A. Athanasiadis); 1st Department ofPulmonary Diseases (E. Papadakis, A. Agelidou), 3rd Depart-ment of Pulmonary Diseases (O. Anagnostopoulos, F. Pavlakas,A. Rapti), 6th Department of Pulmonary Diseases (M.Toumbis), 7th Department of Pulmonary Diseases (S. Tzannes,E. Grigoratou), Department of Internal Medicine, Medical On-cology Unit (K. Syrigos), and University Department of Pul-monary Diseases (M. Veslemes), Sotiria Hospital, Athens; 1stDepartment of Internal Medicine, Agios Savvas Cancer Hospi-tal, Athens (A. Alexopoulos, A. Ardavanis); Department of In-ternal Medicine, Laiko Hospital, Athens (A. Polyzos); Depart-ment of Internal Medicine, Medical Oncology Unit, PatisionHospital, Athens (E. Tselepatiotis); 1st Department of Pul-monary Diseases (N. Samaras) and 2nd Department of Pul-monary Diseases (N. Galanis), Papanikolaou Hospital, Thessa-loniki; and 2nd Department of Pulmonary Diseases,Theageneio Hospital, Thessaloniki (J. Stergiou, P. Papakotoulas,P. Makrantonakis, I. Boukovinas).

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Grade 3/4 Nonhematologic Toxicity by Treatment GroupTable 3

Nausea/Vomiting

Diarrhea

Mucositis

Nephrotoxicity*

Neurotoxicity*

Fatigue

Fluid Retention Syndrome

0.02

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* Grades 2-4.Abbreviation: NS = not significant.

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