1 Hospital Germans Trias i Pujol Hospital, Badalona, Spain; 2 Grosshansdorf Hospital, Grosshansdorf, Germany; 3 Inselspital, Bern, Switzerland; 4 Fachklinik für Lungenkrankheiten, Immenhausen; 5 Lungenklinik Hemer, Hemer, Germany; 6 Department of Internal Medicine, University of Vienna, Vienna, Austria; 7 Centre François Baclesse, Caen; 8 Hopital Avicenne, Bobigny, France; 9 Hospital Universitario 12 de Octubre, Madrid, Spain; 10 Aberdeen Royal Infirmary, Aberdeen, UK; 11 Istituto dei Tumori, Genova, Italy; 12 Köln-Merheim Lungenklinik, Köln, Germany; 13 Bristol-Myers Squibb, Waterloo, Belgium; 14 Bristol-Myers Squibb, Wallingford, CT, USA
Received 27 March 2002; revised 3 June 2002; accepted 15 July 2002
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Abstract |
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The combination of paclitaxel with cisplatin or carboplatin has significant activity in non-small-cell lung cancer (NSCLC). This phase III study of chemotherapy-naïve advanced NSCLC patients was designed to assess whether response rate in patients receiving a paclitaxel/carboplatin combination was similar to that in patients receiving a paclitaxel/cisplatin combination. Paclitaxel was given at a dose of 200 mg/m2 (3-h intravenous infusion) followed by either carboplatin at an AUC of 6 or cisplatin at a dose of 80 mg/m2, all repeated every 3 weeks. Survival, toxicity and quality of life were also compared.
Patients and methods:
Patients were randomised to receive one of the two combinations, stratified according to centre, performance status, disease stage and histology. The primary analyses of response rate and survival were carried out on response-evaluable patients. Survival was also analysed for all randomised patients. Toxicity analyses were carried out on all treated patients.
Results:
A total of 618 patients were randomised. The two treatment arms were well balanced with regard to gender (83% male), age (median 58 years), performance status (83% ECOG 01), stage (68% IV, 32% IIIB) and histology (38% squamous cell carcinoma). In the paclitaxel/carboplatin arm, 306 patients received a total of 1311 courses (median four courses, range 110 courses) while in the paclitaxel/cisplatin arm, 302 patients received a total of 1321 courses (median four courses, range 110 courses). In only 76% of courses, carboplatin was administered as planned at an AUC of 6, while in 96% of courses, cisplatin was given at the planned dose of 80 mg/m2. The response rate was 25% (70 of 279) in the paclitaxel/carboplatin arm and 28% (80 of 284) in the paclitaxel/cisplatin arm (P = 0.45). Responses were reviewed by an independent radiological committee. For all randomised patients, median survival was 8.5 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm [hazard ratio 1.20, 90% confidence interval (CI) 1.031.40]; the 1-year survival rates were 33% and 38%, respectively. On the same dataset, a survival update after 22 months of additional follow-up yielded a median survival of 8.2 months in the paclitaxel/carboplatin arm and 9.8 months in the paclitaxel/cisplatin arm (hazard ratio 1.22, 90% CI 1.061.40; P = 0.019); the 2-year survival rates were 9% and 15%, respectively. Excluding neutropenia and thrombocytopenia, which were more frequent in the paclitaxel/carboplatin arm, and nausea/vomiting and nephrotoxicity, which were more frequent in the paclitaxel/cisplatin arm, the rate of severe toxicities was generally low and comparable between the two arms. Overall quality of life (EORTC QLQ-C30 and LC-13) was also similar between the two arms.
Conclusions:
This is the first trial comparing carboplatin and cisplatin in the treatment of advanced NSCLC. Although paclitaxel/carboplatin yielded a similar response rate, the significantly longer median survival obtained with paclitaxel/cisplatin indicates that cisplatin-based chemotherapy should be the first treatment option.
Key words: carboplatin, cisplatin, doublets, non-small-cell lung cancer, paclitaxel
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Introduction |
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There is ample evidence that cisplatin has a pivotal role in NSCLC management [2]. In the meta-analysis undertaken by the Non-Small-Cell Lung Cancer Collaborative Group, a hazard ratio of 0.73 was observed (27% reduction in the risk of death and 10% improvement in survival at 1 year) when cisplatin chemotherapy was compared with best supportive care [3]. A later British study was also able to confirm the benefit of cisplatin-based chemotherapy [4]. A North American meta-analysis found that only five of 33 (15%) phase III studies showed significant differences in survival in favour of the patient cohort receiving the experimental therapy. Four of these five trials included cisplatin-based regimens [5]. Vinorelbine as a single agent was the first non-cisplatin drug to show a survival advantage, with median survival of 30 weeks, compared with 22 weeks for those who were treated with fluorouracil plus leucovorin [6].
Intriguingly, paclitaxel as a single agent showed a median survival of 6.8 months, in contrast to 4.8 months for supportive care alone. The median time to disease progression was 3.9 months for patients in the paclitaxel arm and 0.5 months for supportive care alone. The Cox regression model showed a hazard ratio of 0.68 in favour of paclitaxel. No responses were observed in patients with poor performance status, which was more frequent in patients 65 years old than in younger patients [7]. Other studies have also identified older age as a prognostic factor for response and survival [810]. Phase II studies have demonstrated activity for paclitaxel as a 24-h intravenous infusion, both as a single agent and in combination with carboplatin [1114]. Paclitaxel as a 24-h intravenous infusion plus cisplatin (75 mg/m2) has been compared with cisplatin/etoposide. The response rate for paclitaxel/cisplatin was
26%, while that for cisplatin/etoposide was 12.4% (P <0.001). The median survival time was 9.9 months versus 7.6 months (P = 0.04) [15]. However, an EORTC trial of cisplatin/teniposide versus cisplatin/paclitaxel (175 mg/m2 as a 3-h intravenous infusion) found no significant difference in median survival times (9.9 versus 9.7 months respectively), although response rate was higher in the paclitaxel arm (28% versus 41%; P = 0.01) [16]. Single-agent cisplatin (100 mg/m2) has been compared with paclitaxel (175 mg/m2) plus cisplatin (80 mg/m2). Although there were differences in response rate and progression-free survival in favour of the combination arm, median survival was similar in the two arms (8.6 months in the cisplatin arm and 8.1 months in the paclitaxel/cisplatin arm) [2].
Other studies have explored the administration of paclitaxel given as a 3-h intravenous infusion in combination with carboplatin. Median survival was 30 weeks, but rose to 39 weeks when paclitaxel doses were >175 mg/m2, with carboplatin doses of 350400 mg/m2 [17]. Paclitaxel (175 versus 225 mg/m2) as a 3-h intravenous infusion has been tested in combination with carboplatin (AUC of 6), with slight differences in favour of the higher paclitaxel dose in terms of response, progression-free survival and median survival [18]. A recent trial by the Southwest Oncology Group (SWOG) epitomised the current outcomes that are achieved with chemotherapy. Vinorelbine/cisplatin (100 mg/m2) was compared with paclitaxel given as a 3-h intravenous infusion in combination with carboplatin (AUC of 6). The response rates were 28% and 25%, respectively, and median survival was the same in both arms (8 months). However, myelotoxicity and nausea and vomiting were observed more frequently in the vinorelbine/cisplatin arm [19]. In a survey of medical oncologists in the USA, the combination of paclitaxel/carboplatin was the most highly accepted therapeutic option in NSCLC. This may be explained by practical considerations, since administration is easier and toxicity milder than with cisplatin combinations [20].
The present large, randomised, multicentre European trial tested whether paclitaxel/carboplatin induces a similar benefit to paclitaxel/cisplatin in terms of objective response rate. Secondary endpoints were survival, toxicity, quality of life and the analysis of prognostic factors, including histology. Paclitaxel (200 mg/m2) was administered in both arms as a 3-h intravenous infusion with either cisplatin (80 mg/m2) or carboplatin (AUC of 6).
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Patients and methods |
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Patients were not eligible for the study if they had any of the following: (i) a history of prior or concomitant malignancy (except for curatively treated non-melanoma skin cancer or carcinoma in situ of the cervix, or other cancer for which the patient had been disease-free for 5 years); (ii) active or uncontrolled infection; (iii) significant cardiovascular disease (uncontrolled hypertension, unstable angina, active congestive heart failure, myocardial infarction within the previous year or uncontrolled serious arrhythmia); (iv) pregnancy, lactation or refusal to use effective contraception; (v) symptomatic brain metastases; (vi) evidence of peripheral neuropathy; (vii) uncontrolled diabetes mellitus; or (viii) other serious medical conditions that would impair the ability of the patient to receive protocol treatment, including prior allergic reactions to drugs containing Cremophor" EL.
Ethics review
The institutional ethics committee of each participating institution approved the study protocol. Written informed consent was obtained from each patient prior to study entry. Patients were informed that although cisplatin-based chemotherapy had been associated with survival benefit compared with best supportive care, it was unknown whether there would be a net or equal benefit from carboplatin instead of cisplatin when combined with paclitaxel.
Randomisation and treatment
Randomisation was performed centrally by Bristol-Myers Squibb Inc., Waterloo, Belgium, using a dynamic balancing algorithm of the PocockSimon type [21]. This procedure minimised imbalance in treatment assignment with respect to the following parameters: centre, performance status (ECOG 01 versus 2), disease stage (IIIB versus IV) and histology (squamous cell versus non-squamous cell carcinoma).
Paclitaxel, cisplatin and carboplatin (Bristol-Myers Squibb Inc., Princeton, NJ, USA) were provided free of charge. Patients randomised to the paclitaxel/cisplatin arm received on day 1 paclitaxel (200 mg/m2 as a 3-h intravenous infusion) followed by cisplatin (80 mg/m2 as a 30-min intravenous infusion). Patients randomised to the paclitaxel/carboplatin arm received on day 1 paclitaxel (200 mg/m2 as a 3-h intravenous infusion) followed by carboplatin (AUC of 6 as a 30-min intravenous infusion). The carboplatin dose was calculated using Calverts formula [dose (mg) = area under the concentration time curve (glomerular filtration rate + 25)]. Treatment was administered in 21-day cycles (Figure 1).
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Patients who achieved a complete response or a partial response continued treatment for a total of 10 cycles or until disease progression.
Prevention of paclitaxel reactions consisted of dexamethasone (20 mg) given orally on the evening before chemotherapy and again on the morning of treatment, intravenous diphenhydramine (50 mg), and either intravenous cimetidine (300 mg) or ranitidine (50 mg) given 30 min before paclitaxel. Intravenous administration of dexamethasone (10 mg) plus either ondansetron (2432 mg) or granisetron (10 µg/kg) plus lorazepam (12 mg) were suggested as components of the premedication with antiemetic therapy. Oral dexamethasone was used prophylactically if grade II or greater arthralgias/myalgias occurred.
Assessment of patients
The following parameters were assessed at baseline: medical history and physical examination; ECG; blood counts (haemoglobin, granulocytes and platelets); creatinine or EDTA clearance; chemistry (serum creatinine and bilirubin); pregnancy testing for women of childbearing potential; and tumour measurements. Chest X-ray and a computed tomography (CT) scan of the chest and upper abdomen were required. Patients had repeated evaluations at least every 6 weeks. Tumour response was assessed according to WHO criteria (measurable disease; complete response, partial response, stable disease and progressive disease). Tumours were re-assessed during treatment with the same imaging method used to establish baseline tumour measurement. Previously irradiated lesions were excluded from evaluation for tumour response. Quality of life was assessed with a validated, cancer-specific instrument that was self-administered at baseline and at the end of each cycle. The EORTC core quality-of-life questionnaire (QLQ-C30) was used [22], together with a lung cancer-specific quality-of-life module (QOL-LC13) [23]. These questionnaires measured global quality of life, five general cancer functional domains (physical, role, cognitive, emotional and social functioning), and 20 symptoms (fatigue, nausea/vomiting, pain, chest pain, shoulder pain, pain elsewhere, pain medication, pain medication help, dyspnea, cough, insomnia, hemoptysis, sore mouth, dysphagia, constipation, diarrhoea, peripheral neuropathy, alopecia, appetite and financial difficulties).
Statistical analysis
The primary goal of this study was to show non-inferiority in response rate for paclitaxel/carboplatin compared with paclitaxel/cisplatin. The target population size for the study was 568 patients. Under the paclitaxel/cisplatin regimen, the expected response rate was 30%. The primary test on response rate was a non-inferiority test with a null hypothesis that the paclitaxel/carboplatin combination response rate was at least 10% worse. Therefore, using a significance level of 5%, statistically significant proof of non-inferiority would be obtained if the lower limit of a two-sided 90% confidence interval (CI) of the difference in response rate between paclitaxel/cisplatin and paclitaxel/carboplatin would be 10% or more. Five hundred and twenty response-evaluable patients were needed to obtain 80% power for this test, if the two regimens had the same true response rate of 30%.
As this was a non-inferiority study, the most conservative dataset for this primary analysis was the dataset of all response evaluable patients [24]. This dataset was used for the primary analyses of response rate, survival and progression-free survival. The planned non-inferiority test of survival (as well as progression-free survival) was to conclude non-inferiority if the upper confidence level of the two-sided 90% CI of the hazard ratio (paclitaxel/cisplatin versus paclitaxel/carboplatin) was 1.27 or less. This confidence interval was obtained from a Cox regression stratified for tumour stage, performance status and histology, with treatment as the sole factor.
As a secondary analysis, all randomised patients were included in the analysis of survival and progression-free survival, which was performed strictly according to the intention-to-treat principle. The resulting confidence intervals were interpreted in the context of a non-inferiority test as well as a superiority test.
Progression-free survival was measured from the day of randomisation to the time of progression or last follow-up. In a first definition of progression-free survival, patients who received secondary therapy prior to documented disease progression were censored at the time of the secondary therapy. In a second definition, patients who received secondary radio- or chemotherapy were considered to have an event at that time.
The Cox proportional hazards regression model was used for progression-free survival and survival, stratified by tumour stage, performance status and histology. The model included the following prognostic variables: weight loss during the last 6 months prior to randomisation, gender, prior radiotherapy and baseline haemoglobin. For each of the time-to-event variables (survival, progression-free survival), KaplanMeier estimates at 1 and 2 years were calculated per treatment arm with their 95% CIs, as well as median estimates with their 95% CI.
Signs and symptoms of toxicity were reported according to their severity in frequency tables. Toxicity was evaluated considering the worst reported event per patient. For each toxicity, treatment arms were compared using Fishers exact text for 2 x 2 tables for occurrence of any toxicity and for occurrence of severe toxicity.
Quality-of-life treatment comparisons over time were assessed by longitudinal analysis curves for the median change from baseline for the global scale, for each of the five functional scales (physical, role, cognitive, social, emotional), and for the 20 symptom scales with the use of the WeiJohnson test of stochastic ordering.
The final analysis was performed on the database locked on 2 November 1998. In addition to this, a survival update analysis was performed on an updated database locked on 11 September 2001.
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Results |
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Chemotherapy administration
Of the 618 patients randomised, 10 (2%) never received any study drug. A total of 1311 courses of paclitaxel/carboplatin were administered to 306 patients, and 1321 courses of paclitaxel/cisplatin were administered to 302 patients (Table 2). The median number of courses was four (range 110) in both study arms. Twenty-six (8%) patients in the paclitaxel/carboplatin arm received more than six courses of therapy compared with 29 (10%) in the paclitaxel/cisplatin arm. One hundred and fifty-six (51%) paclitaxel/carboplatin patients and 75 (25%) paclitaxel/cisplatin patients had a dose reduction. In the paclitaxel/carboplatin arm, 71 patients had paclitaxel reduced and 144 patients had carboplatin reduced, while in the paclitaxel/cisplatin arm, 47 patients had paclitaxel reduced and 65 patients had cisplatin reduced. The median cumulative dose of paclitaxel administered was similar in both arms: 799 mg/m2 in the paclitaxel/carboplatin arm and 807 mg/m2 in the paclitaxel/cisplatin arm. The median paclitaxel dose intensity in both study arms was 65 mg/m2/week, which is very close to the planned dose intensity of 66.7 mg/m2/week. In fact, >80% of patients in this study received 90% of the scheduled paclitaxel dose intensity. The median dose intensity of platinum agents in both arms was also close to the planned dose intensity. In the paclitaxel/carboplatin arm, the median dose intensity of carboplatin was 1.9 mg/ml·min/week, compared with the planned 2 mg/ml· min/week. In the paclitaxel/cisplatin arm, the median dose intensity of cisplatin was 26 mg/m2/week, very close to the planned 26.7 mg/m2/week.
Response rate, progression-free survival and survival
Among the 618 patients randomised, 279 in the paclitaxel/carboplatin arm and 284 in the paclitaxel/cisplatin arm had response-evaluable measurable disease (Table 3). In this primary data set, the overall clinical response rate was 25% (95% CI 20% to 31%) in the paclitaxel/carboplatin arm and 28% (95% CI 23% to 34%) in the paclitaxel/cisplatin arm. Of note, four complete responses were observed in the paclitaxel/carboplatin arm and two in the paclitaxel/cisplatin arm. The two-sided 90% CI of the difference in response rate ranged from 10% to 3.4%, indicating that paclitaxel/carboplatin is statistically not inferior to paclitaxel/cisplatin. A classical superiority test to compare response rates between the two arms yielded a P value of 0.45. When all randomised patients were considered (intention-to-treat dataset), the response rates were 23% (70 of 309 patients) in the paclitaxel/carboplatin arm and 26% (80 of 309 patients) in the paclitaxel/cisplatin arm. At the time of the original analysis, 95% of patients in the paclitaxel/carboplatin arm and 93% of patients in the paclitaxel/cisplatin arm had evidence of tumour progression or had received secondary therapy prior to documentation of disease progression. On the intention-to-treat dataset, median progression-free survival was 3 months (95% CI 2.73.9 months) for the paclitaxel/carboplatin arm and 4.2 months (95% CI 3.34.4 months) for the paclitaxel/cisplatin arm (P = 0.035 by log-rank test).
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Discussion |
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This is the first large, randomised trial directly comparing paclitaxel/carboplatin with paclitaxel/cisplatin in the treatment of advanced NSCLC. The significantly superior survival achieved with cisplatin differs from results reported in similar US studies. In a recent four-arm ECOG trial [27], where 1207 patients were randomised to receive paclitaxel (as a 24-h intravenous infusion)/cisplatin, gemcitabine/cisplatin, docetaxel/cisplatin, or paclitaxel (as a 3-h intravenous infusion)/carboplatin, the response rate for all 1155 evaluable patients was 19%, with a median survival of 7.9 months, a 1-year survival rate of 33% and a 2-year survival rate of 11%. The response rate and survival did not differ significantly between patients receiving paclitaxel/cisplatin and those in any of the other three arms [27]. On the other hand, a recent large international randomised trial comparing docetaxel/carboplatin, docetaxel/cisplatin and vinorelbine/cisplatin reported a significantly superior median survival in the docetaxel/cisplatin arm (10.9 months) [28], and a European randomised study also reported a median survival of 10 months in the docetaxel/cisplatin arm [29].
Differences between paclitaxel/cisplatin and paclitaxel/carboplatin found in the present study are not due to an uneven distribution of patient characteristics (Table 1) or to the number of cycles received (Table 2). The only bias was that dose reduction of carboplatin was necessary for 96 of 279 (34%) of evaluable patients; this reduction occurred mainly at course 1, due to a miscalculation of AUC. The average AUC for these 96 patients was 4.9.
The fact that there was no difference in the ECOG study [27] between paclitaxel/carboplatin and paclitaxel/cisplatin leads us to conclude that we must be cautious with the findings of the present study. We can postulate that continuous infusion of paclitaxel could modify the therapeutic efficacy of this combination. In the prior ECOG study [15], the median survival for the paclitaxel/cisplatin arm where paclitaxel was administered by continuous infusion was 9.9 months compared with 7.6 months for the cisplatin/etoposide arm. The recommended dose for further studies was paclitaxel 135 mg/m2 by 24-h continuous infusion plus cisplatin. In the study by Schiller et al. [27], the control arm received this combination and found no differences in comparison with paclitaxel 225 mg/m2 by 3-h infusion plus carboplatin AUC 6. This study is slightly different from the present one, where patients received paclitaxel 200 mg/m2 by 3-h infusion plus carboplatin AUC 6. This point should be taken into account in future studies and meta-analyses.
This large European randomised study can contribute greatly to resolving the longstanding debate on the superiority of carboplatin- or cisplatin-based chemotherapy in lung cancer. Given the longer median survival achieved with paclitaxel/cisplatin, its use can be recommended in the treatment of patients with advanced and metastatic NSCLC. Paclitaxel/carboplatin represents a viable alternative, with a similar response rate, a good safety profile, manageable toxicity and superior ease of administration.
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Acknowledgements |
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The authors would like to acknowledge the participation of the following investigators and institutions: Dr Gatzemeier (Krankenhaus Grosshansdorf, Grosshansdorf, Germany), Dr Rosell-Costa (Hospital Germans Trias i Pujol, Badalona, Spain), Dr Betticher (Inselspital, Bern, Switzerland), Dr Goeckenjan, Dr Keppler (Fachklinik für Lungenkrankheiten, Immenhausen, Germany), Dr Macha (Lungenklinik Hemer, Hemer, Germany), Dr Pirker (Department of Internal Medicine, University of Vienna, Vienna, Austria), Dr Rivière, Dr Berthet (Centre François Baclesse, Caen, France), Dr Breau (Hôpital Avicenne, Bobigny, France), Dr Cortes-Funes, Dr Lianes (Hospital Universitario 12 de Octubre, Madrid, Spain), Dr Nicolson (Aberdeen Royal Infirmary, Aberdeen, UK), Dr Ardizzoni (Istituto dei Tumori, Genoa, Italy), Dr Chemaissani (Köln-Merheim Lungenklinik, Köln, Germany), Dr Douillard (Centre René Gauducheau, Nantes, France), Dr Moyano (Hospital Ramon y Cajal, Madrid, Spain), Dr Lopez (Txagorritxu Hospital, Vittoria, Spain), Dr Clancy (St James Hospital, Dublin, Ireland), Dr Steppert (Bezirksklinikum Kutsenberg, Ebenfeld, Germany), Dr Spaeth (Centre Alexis Vautrin, Vandoeuvre-Les-Nancy, France), Dr Hutas (Semmelweis Medical University, Budapest, Hungary), Dr Monnier (Centre anticancéreux François Baclesse, Montbéliard, France), Dr Roczkowski (Instytut Gruzucy I Chorob Pluc, Warsaw, Poland), Dr Chomy (Hôpital Haut LEvêque, Pessac, France), Dr Stahel (University Hospital, Zurich, Switzerland), Dr Van Klaveren (UZ Antwerpen, Edegem, Belgium), Dr Gottfried (Sheba Medical Center, Tel Hashomer, Israel), Dr Pesek (Faculty Hospital, Plzen, Czech Republic), Dr Testore (Ospedale Civile Asti, Italy), Dr De Grève (Akademisch Ziekenhuis-VUB, Brussels, Belgium), Dr Ojala (Tampere University Hospital, Pikonlinna, Finland), Dr Buccheri (Ospedale A. Carle, Cuneo, Italy), Dr Kolek (Soroka Medical Center, Olomouc, Czech Republic), Dr Lorsbach (Lungerklinik Ballenstedt, Ballenstedt, Germany), Dr Cohen, Dr Ariad (Faculty Hospital, Petah Tiqva, Israel), Dr Joos (UZ Gent, Gent, Belgium), Dr Van der Hoeven (Amstelveen Hospital, Amstelveen, The Netherlands), Dr Sulkes (Beilinson Medical Center, Beer Sheva, Israel), Dr Romppanen (Oulu University Central Hospital, Oulu, Finland), Dr Daly (Altnagelvin Hospital, Londonderry, UK), Dr Erdkamp (Maaslandziekenhuis Sittard, Sittard, The Netherlands), Dr Carney (Mater Hospital, Dublin, Ireland), Dr Queiroga (Hopital de S. Joao, Porto, Portugal) and Dr Rimoldi (Ospedale di Circolo, Varese, Italy). The authors would like to acknowledge the active participation of Dr Pellae-Cosset and Dr Cosaert (Paris, France), Mrs Woussen (Waterloo, Belgium), Mrs Grau (Paris, France), Dr Aloe (Rome, Italy), Dr Statuch (Uxbridge, UK), Dr Lund (Copenhagen, Denmark), Dr Lopez (Madrid, Spain), Dr Bochtler (Munich, Germany), Dr Jeynes (Hounslow, UK), Dr Schallier (Waterloo, Belgium) and Dr Frey (Baar, Switzerland).
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Footnotes |
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References |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
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2. Gatzemeier U, von Pawel J, Gottfried M et al. Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 2000; 18: 33903399.
3. 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: 899909.
4. Cullen MH, Billingham LJ, Woodroffe CM et al. Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 1999; 17: 31883194.
5. Breathnach OS, Freidlin B, Conley B et al. Twenty-two years of phase III trials for patients with advanced non-small-cell lung cancer: sobering results. J Clin Oncol 2001; 19: 17341742.
6. Crawford J, ORourke M, Schiller JH et al. Randomized trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small-cell lung cancer. J Clin Oncol 1996; 14: 27742784.[Abstract]
7. Ranson M, Davidson N, Nicolson M et al. Randomized trial of paclitaxel plus supportive care versus supportive care for patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 2000; 92: 10741080.
8. Albain KS, Crowley JJ, LeBlanc M, Livingston RB. Survival determinants in extensive-stage non-small-cell lung cancer: the Southwest Oncology Group experience. J Clin Oncol 1991; 9: 16181626.[Abstract]
9. Paesmans M, Sculier JP, Libert P et al. Prognostic factors for survival in advanced non-small-cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation algorithms in 1,052 patients. J Clin Oncol 1995; 13: 12211230.[Abstract]
10. Hickish TF, Smith IE, Ashley S, Middleton G. Chemotherapy for elderly patients with lung cancer. Lancet 1995; 346: 580.[Medline]
11. Murphy WK, Fossella FV, Win RJ et al. Phase II study of Taxol in patients with untreated advanced non-small-cell lung cancer. J Natl Cancer Inst 1993; 85: 384388.[Abstract]
12. Chang AY, Kim K, Glick J et al. Phase II study of Taxol, merbarone, and piroxantrone in stage IV non-small-cell lung cancer: the Eastern Cooperative Oncology Group results. J Natl Cancer Inst 1993; 85: 388394.[Abstract]
13. Johnson DH, Paul DM, Hande KR et al. Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol 1996; 14: 20542060.[Abstract]
14. Langer CJ, Leighton JC, Comis RL et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity, response, and survival analysis. J Clin Oncol 1995; 13: 18601870.[Abstract]
15. Bonomi P, Kim KM, Fairclough D et al. Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol 2000; 18: 623631.
16. Giaccone G, Splinter TAW, Debruyne Ch et al. Randomized study of paclitaxel-cisplatin versus cisplatinteniposide in patients with advanced non-small-cell lung cancer. J Clin Oncol 1998; 16: 21332141.[Abstract]
17. Kelly K, Pan Z, Murphy J et al. A phase I trial of paclitaxel plus carboplatin in untreated patients with advanced non-small cell lung cancer. Clin Cancer Res 1997; 3: 11171123.[Abstract]
18. Kosmidis P, Mylonakis N, Skarlos D et al. Paclitaxel (175 mg/m2) plus carboplatin (6 AUC) versus paclitaxel (225 mg/m2) plus carboplatin (6 AUC) in advanced non-small-cell lung cancer (NSCLC): a multicenter randomized trial. Ann Oncol 2000; 11: 799805.[Abstract]
19. Kelly K, Crowley J, Bunn PA et al. A randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001; 19: 32103218.
20. Shyr Y, Choy H, Cmelak A et al. Pattern of practice survey: non-small cell lung cancer in the U.S. Proc Am Soc Clin Oncol 1998; 17: 463a (Abstr 1778).
21. Pocock S, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 1975; 31: 103115.[ISI][Medline]
22. Aaronson NK, Ahmedzai S, Bergman B et al. The European organization for research and treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365376.[Abstract]
23. Bergman B, Aaronson NK, Ahmedzai S et al. The EORTC QLQ-LC13: a modular supplement to the EORTC core quality of life questionnaire (QLQ-C30) for use in lung cancer clinical trials. Eur J Cancer 1994; 30A: 635642.
24. ICH E9 Guideline: Statistical Principles for Clinical Trials, EU: CPMP/ICH/363/96, FDA: Federal Register, Vol. 63, No. 179, September 16, 1998, p. 49583.
25. Bonomi PD, Finkelstein DM, Ruckdeschel JC et al. Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: a study of the Eastern Cooperative Oncology Group. J Clin Oncol 1989; 7: 16021613.[Abstract]
26. The ICON Collaborators. ICON2: randomised trial of single-agent carboplatin against three-drug combination of CAP (cyclophosphamide, doxorubicin, and cisplatin) in women with ovarian cancer. Lancet 1998; 352: 15711576.[ISI][Medline]
27. Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346: 9298.
28. Rodriguez J, Pawel A, Pluzanska A et al. A multicenter, randomized phase III study of docetaxel + cisplatin (DC) and docetaxel + carboplatin (DCB) vs vinorelbine + cisplatin (VC) in chemotherapy-naive patients with advanced and metastatic non-small cell lung cancer. Proc Am Soc Clin Oncol 2001; 20: 314a (Abstr 1252).
29. Georgoulias V, Papadakis E, Alexopoulos A et al. Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a randomised multicentre trial. Lancet 2001; 357: 14781484.[ISI][Medline]