Annals of Oncology Advance Access originally published online on April 2, 2007
Annals of Oncology 2007 18(6):1037-1042; doi:10.1093/annonc/mdm084
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© 2007 European Society for Medical Oncology
lung cancer |
A phase III randomised trial comparing sequential chemotherapy using cisplatin-based regimen and paclitaxel to cisplatin-based chemotherapy alone in advanced non-small-cell lung cancer
1 Institut Jules Bordet, Department of Intensive Care and Thoracic Oncology, Brussels, Belgium
2 Département de Pneumologie, CHU de Lille, Lille, France
3 Service de Pneumologie, CHU de Charleroi, Charleroi, Belgium
4 Department of Medical Oncology, Evangelismos General Hospital, Athens, Greece
5 Service de Pneumologie, Clinique Saint-Luc, Bouge, Belgium
6 Department of Medical Oncology, Hospital de Sagunto, Avda Ramon y Cajal s/n, Valencia, Puerto de Sagunto, Spain, 46520
7 Department of Medical Oncology, Hellenic, Athens, Greece
8 Département de Pneumologie, Hôpital de Hayange, Hayange
9 Département de Pneumologie, Centre Hospitalier Intercommunal, Montfermeil
10 Département de Pneumologie, CHRU de Lille, Lille, France
11 Service de Pneumologie, Hôpital Saint-Pierre, Brussels
12 Service de Biostatistics, Institut Jules Bordet, Brussels, Belgium
* Correspondence to: Prof. J.P. Sculier, Department of Critical Care and Thoracic Oncology, Institut Jules Bordet, 1 Rue Héger-Bordet, B-1000 Brussels, Belgium. Tel: +32-2-541-31-85; Fax: +32-2-534-37-56; E-mail: sculier{at}bordet.be
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Abstract |
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Background: The purpose of this study is to determine whether in advanced non-small-cell lung cancer (NSCLC), the sequential administration of cisplatin-based chemotherapy and paclitaxel (Taxol) is superior to a cisplatin-based chemotherapy, followed by paclitaxel as salvage treatment.
Patients and methods: A total of 485 chemotherapy naive patients with advanced NSCLC were treated with three courses of GIP (gemcitibine + ifosfamide + cisplatin), consisting of cisplatin 50 mg/m2 on day 1, ifosfamide 3 g/m2 on day 1 and gemcitabine 1 g/m2 on days 1 and 8. Patients with nonprogressive disease were then randomised to further similar courses of GIP or courses of paclitaxel (225 mg/m2 over 3 h every 3 weeks).
Results: Objective response or nonprogression after induction GIP occurred in 174 and 115 patients, respectively. After randomisation, there were 140 patients in the GIP arm and 141 in the paclitaxel arm. In terms of postrandomisation survival, there was no statistically significant difference (P = 0.17) between the two arms. Median times were 9.7 [95% confidence interval (CI) 7.8–11.6] and 11.9 (95% CI 9.4–14.3) months for paclitaxel and GIP, respectively. Multivariate analysis demonstrated that sex and haemoglobin were independent prognostic factors. After adjustment for these factors, the observed hazard ratio was 0.81 (95% CI 0.63–1.04) in favour of GIP (P = 0.10). Toxicity was tolerable; there was a significantly higher rate of grades III/IV thrombocytopenia with GIP and more alopecia with paclitaxel.
Conclusion: Sequential chemotherapy using cisplatin-based regimen followed by paclitaxel does not result in better outcome than cisplatin-based chemotherapy using taxane as salvage treatment.
Key words: chemotherapy, cisplatin, non-small cell lung cancer, paclitaxel, sequential
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussioncontibutorsReferences |
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Chemotherapy is the recommended treatment of advanced non-small-cell lung cancer (NSCLC) [1–6]. Cisplatin is the main drug and it is usually combined with other drugs such as vindesine, vinblastine, mitomycin C, ifosfamide [7] and, more recently, gemcitabine, vinorelbine, paclitaxel and docetaxel [8]. In the 90s, taxanes, paclitaxel and docetaxel, emerged as important drugs for the management of NSCLC. Studies performed with docetaxel have reported consistent activity as salvage chemotherapy after cisplatin-based treatment confirmed by randomised trials [9, 10] and by implementation studies [11, 12]. Limited data also indicate that paclitaxel might have similar activity as second-line chemotherapy [13].
The activity of taxanes in patients with NSCLC resistant to or relapsing after cisplatin-based chemotherapy prompted our group to compare the effectiveness of sequential administration of cisplatin-based chemotherapy and a taxane to a common approach, i.e. cisplatin-based chemotherapy with the use of a taxane as salvage treatment. At the time the study was designed, paclitaxel was the only taxane available for academic clinical research in Europe.
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patients and methods |
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selection criteria
Patients with pathologically proven NSCLC were eligible for the study if they fulfilled all the following criteria: inoperable stage IV (or IIIB with malignant pleural effusion); presence of a measurable or assessable lesion; no prior history of malignancy except nonmelanoma skin cancer, in situ carcinoma of the cervix or ‘cured’ malignant tumour (>5-year disease-free survival); no prior chemotherapy; Karnofsky performance status (PS)
60; good renal (serum creatinine level <1.5 mg/dl and/or creatinine clearance 60 ml/min), hepatic (serum bilirubin level 
1.5 mg/dl) and haematological (neutrophils 2000/mm3 and platelets 100 000/mm3) functions; absence of perception hypoacousia or peripheral neuropathy; no recent (<3 months before the date of treatment) myocardial infarction and no active congestive heart failure or cardiac arrhythmia requiring medical treatment; no uncontrolled infectious disease; no other serious medical or psychological factors which might prevent adherence to the treatment schedule. Patients had to be available for follow-up and informed consent had to be provided. The protocol, available in details on the public website http://www.cotrec.org and the ELCWP (European Lung Cancer Working Party) website http://www.elcwp.org, had to be approved by the ethics committee of each participating centre.
treatment
Eligible patients were treated with three courses of GIP (gemcitibine + ifosfamide + cisplatin): gemcitabine (1 g/m2 on days 1 and 8) + ifosfamide (3 g/m2 on day 1) + cisplatin (50 mg/m2 on day 1). Courses were repeated every 3 weeks. The work-up performed initially, before each course, every three courses and after the completion of treatment was similar to that used in our previous trials [14]. A complete restaging was performed after three courses. Patients with nonprogressing tumour were randomised between further courses of GIP or paclitaxel (Taxol) (225 mg/m2). Response assessment was performed every three courses and responding patients were treated until best response. Patients with no further improvement went off treatment. Those with progressive disease on GIP were crossed over to paclitaxel and vice versa.
All drugs were given intravenously. Mesna was administered in order to avoid ifosfamide urotoxicity. Paclitaxel was given >3 h using dexamethasone, promethazine and cimetidine premedication.
Next course administration required haematological (neutrophils >1500/mm3 and platelets >100 000/mm3) and renal (serum creatinine <1.5 mg/dl) recovery by day 22. If the delay between two courses was >6 weeks, patient went off treatment. Gemcitabine was not administered on day 8 if neutrophils were <500/mm3 or platelets <50 000/mm3. If neutrophil nadir was <500/mm3 or platelet nadir <25 000/mm3, the dosage of the drugs was reduced to 75%. If serum creatinine peak increased between 1.5 and 3.0 mg/dl, cisplatin dosage was reduced to 50%. If creatinine peak was >3.0 mg/dl, cisplatin was discontinued. In case of hearing loss or higher World Health Organisation (WHO) grade II neurotoxicity, cisplatin was also discontinued. In case of development of anaemia with cisplatin, patient was given epoietin alpha.
criteria of evaluation
Patients were evaluated for response after the completion of three chemotherapeutic courses. Responses were assessed according to previously reported criteria [14]. Complete remission was defined as the disappearance of all signs of disease, for at least 4 weeks. In measurable disease, partial response (PR) was defined as 50% decrease of the total tumour load in two observations not <4 weeks apart, in the absence of new lesions or progression in any existing lesion. Tumour load was estimated as the tumour area calculated by the multiplication of the longest diameter by the greatest perpendicular diameter. In assessable disease, PR was defined as an estimated decrease in tumour size of 50% or more. Progression was defined as an increase of 25% in one or more measurable or assessable lesions or the appearance of new lesions. All other circumstances were classified as no change (NC). Early death due to disease progression before evaluation, toxic death due to chemotherapy or early chemotherapy discontinuation because of toxicity were considered as treatment failures and incorporated in the assessable patients.
For the comparison of the two randomised arms, survival and progression-free times were calculated from the date of randomisation. WHO criteria were used to assess toxicity.
primary end point and sample-size determination
The primary objective of the trial was to determine whether in patients with advanced NSCLC and nonprogressive disease after three courses of GIP, the sequential approach (GIP followed by paclitaxel) is associated with improved survival compared with the GIP combination. Secondary end points were the comparison of best objective response rates and toxicity between the two regimens and the activity of paclitaxel as salvage regimen.
The sample size was determined on the basis of the primary end point and of the following assumptions generated by a prior ELCWP study analysis [15]: (i) rate of randomisation was expected to be 50%–60%; (ii) 1-year survival rate after randomisation in the control arm was expected to be 20%; (iii) an increase to 35% would be considered as clinically worthwhile. This latter should be detected with an 80% probability using a two-sided log-rank test with a 5% significance level. For this purpose, the total number of events to be observed had to be 178 and it was calculated to be achieved with the randomisation of 123 patients in each arm [16].
registration and randomisation procedures
Registration and randomisation were centrally performed by calling the ELCWP central office for the study coordination and analysis in Brussels.
Randomisation was performed using the minimisation technique and patients were stratified according to the centre, initial Karnofsky PS, initial neutrophil count, type of response, sex and age.
statistical methodology
Survival curves were estimated by Kaplan and Meier's method. The log-rank test was used to compare survival curves. P values for testing differences between proportions were calculated with chi-square tests or with Fisher's exact tests. A multivariate analysis for adjustment of the treatment effect taking into account prognostic factors was performed by fitting the data with a Cox model for duration of survival. Statistical results were considered as significant when the P value level was <0.05. All reported P values are two sided.
Chemotherapy intensity was estimated by calculating relative dose intensity as previously published [17]. Comparisons were done by using Mann–Whitney tests.
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results |
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A total of 493 patients were registered from January 2000 to February 2004. Eight (1.6%) were ineligible for the following reasons: coexistence of another cancer (two), incomplete work-up (two), small-cell lung cancer histology (one), hypoacousia (one), nonadvanced disease (one), wrong protocol allocation (one). Among the 485 eligible patients, 174 demonstrated a PR and 115 NC.
A total of 281 patients were randomised: 140 to receive further GIP and 141 to receive paclitaxel. Eight were not ‘eligible’ for randomisation, four because of disease progression (documented on records review) and four because they were not assessable for response. They, nevertheless, were included in the intention-to-treat analysis. Sixteen eligible patients (10 with response and six with NC) were eventually not randomised because of physician decision (seven), loss to follow-up (three), patient's refusal (two), prolonged bone marrow aplasia (two), infection (one), peripheral neurotoxicity (one).
The characteristics of the randomised patients were well balanced between the two arms (Table 1). The median number of postrandomisation courses was three in both arms. In the paclitaxel arm, 24 patients received less than three and 36 more than three courses. Treatment was delayed in seven patients and dosage reduced in 77. In the GIP arm, 20 patients received less than three and 30 more than three courses. Treatment was delayed in three and dosage was reduced in 92. The median delivered relative dose intensity for the patients who received three postrandomisation courses was 97% for paclitaxel and 76% for GIP.
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In terms of response, 11 additional PRs were obtained by three further courses of GIP arm compared with 10 by three courses of paclitaxel. After six courses, 36% of the patients in the paclitaxel arm and 44% in the GIP arm were still in PR (P = 0.18).
There was no significant difference (P = 0.56) in progression-free survival between the two arms with a median duration of 4.0 and 4.4 months in the paclitaxel and GIP arms, respectively.
In terms of postrandomisation survival (figure 1), there was also no statistically significant difference (P = 0.17) with median times of 9.7 [95% confidence interval (CI) 7.8–11.6] and 11.9 (95% CI 9.4–14.3) months, in paclitaxel and GIP arm, respectively. One-year survival rates were 42% (34–50) and 49% (41–57), two-year 14% (8–20) and 19% (12–26) and three-year 6% (1–11) and 8% (2–14) in paclitaxel and GIP arm, respectively.
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PS, sex, age and haemoglobin level were found statistically significant prognostic factors in univariate survival analysis (Table 2). Type of response to induction GIP was not a significant factor. A multivariate model using the variables with a P value <0.30, performed on 258 patients (data were missing in 8%), identified female gender [hazard ratio (HR) = 0.55, 95% CI 0.39–0.77, P = 0.001] and anaemia (HR = 1.79, 95% CI, 1.30–2.48, P = 0.001) as independent favourable and unfavourable prognostic factors, respectively. When treatment comparison was adjusted for the above variables, the observed HR was 0.81 (95% CI 0.63–1.04) in favour of GIP (P = 0.10).
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There was a significantly higher rate of grades III/IV thrombocytopenia with the use of GIP but more alopecia with paclitaxel (Table 3).
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At the time of analysis, progression was documented in 118 patients in each arm. In the GIP arm, second-line chemotherapy was administered in 85 patients, including GIP in eight (one response observed) and paclitaxel in 69 (eight responses). In the paclitaxel arm, 66 patients were treated with second-line chemotherapy, including GIP in 40 (eight responses observed).
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discussion |
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The present phase III trial in advanced NSCLC failed to demonstrate survival improvement with sequential chemotherapy consisting of a cisplatin-based regimen followed by paclitaxel. On the contrary, in multivariate analysis, a trend for better survival was observed in favour of the nonsequential approach.
Various schedules were possible: a sequential approach with an a priori similar number of cycles in both arms (at least six), a maintenance approach by paclitaxel with a similar number of cisplatin-based chemotherapy cycles in each arm (four to six) and a maintenance approach by paclitaxel versus cisplatin-based chemotherapy after four to six cycles of induction cisplatin-based chemotherapy. We choose the sequential approach.
Sequential chemotherapy is based on the non-cross-resistant regimens theory, supported by mathematical models derived from laboratory experiments [18–20]. Although extensively investigated in various tumours, including small-cell lung cancer, breast cancer and lymphoma, sequential chemotherapy has been, so far, the topic of a few feasibility [21–25] or randomised [26] phase II trials in NSCLC. As in our protocol, those studies were using, as sequential regimens, platinum-based chemotherapy and a taxane. The rationale to use a taxane is based on results from randomised trials showing improved survival when docetaxel is given as second-line chemotherapy compared with supportive care after failure of platinum-based treatment [9].
The main reason why we used paclitaxel instead of docetaxel was that, at the time our study was designed (1999) and activated (2000), paclitaxel was the only taxane commercially available for academic clinical research in Europe. In addition, there is no data showing superiority of docetaxel over paclitaxel (or vice versa) in the treatment of NSCLC. In a phase II randomised study testing two different designs of sequential chemotherapy (carboplatin, gemcitabine followed by paclitaxel versus cisplatin/vinorelbine followed by docetaxel), results were comparable [26]. A small (71 patients) randomised trial [27] testing weekly taxane as second-line chemotherapy showed a trend for better activity of paclitaxel (PR 14%, median survival 105 days) over docetaxel (3% and 184 days).
As Feliu et al. [21], we have chosen as cisplatin-based regimen a three-drug combination (cisplatin + ifosfamide + gemcitabine) on the following considerations: (i) at the time of our study's design, triplet chemotherapy with gemcitabine, platinum and a third agent was considered promising regimen [28]; (ii) in a previous study, we had observed encouraging results when gemcitabine was combined with ifosfamide or platinum derivatives in comparison to the platinum and ifosfamide combination [14]. A recent meta-analysis has confirmed an increased activity but not improved survival of triplets although with increased toxicity [29].
There is a trend for better survival by the administration of more than three cycles of cisplatin-based chemotherapy, indicating that more cycles of GIP should have been administered before randomisation in order to avoid a bias due to cisplatin ‘undertreatment’ in the sequential arm. This bias is improbable because in two trials where patients were randomised between three and six cycles of platinum-based chemotherapy, no significant advantage in term of survival was reported by further treatment [30, 31].
A final interesting observation is that in the multivariate analysis for postrandomisation survival, there was no statistically significant difference between patients with an objective and those with NC. This indicate that disease stabilisation or minor response might be beneficial. But we have to be careful in the data interpretation, mainly because of the relatively small number of patients. Indeed, in an analysis of the trials performed by our group in the 80s and where 752 patients were assessable, an objective response to chemotherapy was found to be a predominant predictive factor for further survival [32].
In conclusion, the present phase III randomised study demonstrated that sequential chemotherapy using a cisplatin-based regimen followed by paclitaxel does not result in better outcome compared with cisplatin-based chemotherapy, reserving paclitaxel as salvage treatment. Nevertheless, the concept of sequential chemotherapy merits further investigation with different approaches such as the use of front-line taxane therapy [21] or initial combination of taxane and platinum [23]. The substitution of docetaxel for paclitaxel seems a less intriguing approach [26].
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contibutors |
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Institut Jules Bordet, Brussels, Belgium (J.P. Sculier, T. Berghmans, A.P. Meert, P. Van Houtte, M. Paesmans, P. Mommen); CHRU Calmette, Lille, France (J.J. Lafitte, A. Scherpereel); CHU de Charleroi, Charleroi, Belgium (J. Lecomte, J. Thiriaux); Hellenic Cancer Institut, St Savas Hospital, Athens, Greece (A.P. Efremidis, G. Koumakis); Clinique Saint-Luc, Bouge, Belgium (O. Van Cutsem); Hospital de Sagunto, Valencia, Spain (V. Giner); Evangelismos General Hospital, Athens, Greece (C.G. Alexopoulos, M. M. Vaslamatzis); Hôpital de Hayange, Hayange, France (M.C. Berchier, P. Botrus); CHI Le Raincy, Montfermeil, France (T. Collon); CHU Saint-Pierre, Brussels, Belgium (V. Ninane, R. Sergysels, T. Bosschaerts); CH de Douai, Douai, France (M.C. Florin, E. Maetz, S. Desurmont); CHR St-Joseph-Warquiginies, Boussu, Belgium (M. Richez); CH de Roubaix, Hôpital Victor Provo, Roubaix, France (F. Kroll, F. Steenhouwer, F. Salez, A. Strecker); Hôpital Ambroise Paré, Mons, Belgium (P. Wackenier, S. Holbrechts,); CHR Saint-Joseph, Mons, Belgium (P. Recloux); CHG de Tourcoing, Tourcoing, France (X. Ficheroulle); CHU André Vésale, Montigny-le-Tilleul, Belgium (D. Brohée); Hôpital Erasme, Brussels, Belgium (S. Luce, F. Branle); RHMS, IMC Tournai, Belgium (A. Tagnon); RHMS, Clinique Louis Caty, Baudour, Belgium (V. Richard, D. Diana, B. Vanderschueren); CH Peltzer-La Tourelle, Verviers, Belgium (J.L. Corhay, I. Louviaux); Clinique Teissier, Valenciennes, France (G. Demarcq, F. Radenne); Cabinet Médical Dampierre, Anzin, France (J.P. Roux, B. Stach); CH d'Arras, Arras, France (J.P. Bervar); Hôpital Brugmann, Brussels, Belgium (A. Drowart, T. Prigogine); CH Dr. Schaffner "Ameuille", Lens, France (J. Amourette, C. Bergoin); CH Etterbeek-Ixelles, Brussels, Belgium (G. Plat); CHI Poissy-St-Germain, St-Germain-en-Laye, France (S. Jouveshomme)
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Footnotes |
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Current address: Department of Critical Care, Institut Jules Bordet, 1 Rue Heger-Bordet, B-1000 Brussels, Belgium. 
Current address: Department of Medical Oncology, Iatriko Medical Center, 5-7 Distomou street, 151 25 Marousi, Athens, Greece.
Current address: Department of Medical Oncology, Anticancer-Oncology Hospital of Athens St Savvas, 33 Zakynthinou, 15669 Papagou, Athens, Greece.
Received for publication November 14, 2006. Revision received January 22, 2007. Accepted for publication February 6, 2007.
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