Phase II randomized multicenter study evaluating a treatment regimen alternating docetaxel and cisplatin–vinorelbine with a cisplatin–vinorelbine control group in patients with stage IV non-small-cell lung cancer: GFPC 97.01 study

M. Pérol1,+, H. Léna1, P. Thomas1, G. Robinet1, P. Fournel1, E Coste1, C. Belleguic1, H. Le Caer1, F. Blanchon1, A. Vergnenègre1, J.-M Vernejoux1, M.-P. Schuller-Lebeau2 and E. Pham3

1Groupe Français de Pneumo-Cancérologie, Hôpital de la Croix-Rousse, Lyon; 2Laboratoires Aventis, Paris; 3Department of Biostatistics, Université Lyon, Lyon, France

Received 16 July 2001; revised 13 November 2001; accepted 5 December 2001.


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background

The potential absence of cross-resistance between cisplatin and docetaxel in non-small-cell lung cancer (NSCLC) suggests that alternating regimens of cisplatin-based chemotherapy and docetaxel might increase the activity of chemotherapy in stage IV NSCLC.

Patients and methods

Randomized, multicenter, non-comparative phase II study in patients with stage IV NSCLC (Eastern Cooperative Oncology Group performance status of 0–2). Patients randomized to alternating treatment group (A) received docetaxel 100 mg/m2 on days (D) 1 and 43 alternating with cisplatin 100 mg/m2 on D22 and vinorelbine 30 mg/m2 on D22, D29 and D36. Those randomized to the control group (B) received cisplatin 80 mg/m2 on D1, D22 and D43 and vinorelbine 30 mg/m2 once a week from D1 to D57. Treatment was continued for a further 6 weeks in the event of objective response or stabilization.

Results

Seventy patients were enrolled (group A: 38, group B: 32). More premature treatment discontinuations due to toxicity were observed in group A (median number of cycles: 3) than in group B (median number of cycles: 5). The intention-to-treat objective response rate was 10.8% [95% confidence interval (CI) 0.8% to 20.8%] in group A compared with 25% (95% CI 10% to 40%) in group B, the median time to treatment failure being 10.2 weeks and 17.3 weeks, respectively. The median survival and 1-year survival were 29.1 weeks and 39% in group A compared with 41.6 weeks and 42% in group B. Febrile neutropenia occurred in 5.9 and 4.9% of the cycles in group A and group B, respectively. Non-hematological toxicity was moderate in the two groups.

Conclusions

The addition of docetaxel alternating with cisplatin–vinorelbine did not enhance the activity of this combination. The development of sequential regimens might be a more promising way of exploiting the absence of cross-resistance between these two drugs.

Key words: chemotherapy, metastatic disease, non-small-cell lung cancer


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Docetaxel is currently one of the most active cytostatics against non-small-cell lung cancer (NSCLC) when used as a single agent in first-line therapy, achieving a response rate in the range of 19–38% in phase II studies [1], and demonstrating superiority over palliative care [2]. The activity of docetaxel as a second-line treatment after failure of first-line platinum-based therapy has been demonstrated in two phase III studies [3, 4]. The experimental data suggest absence of cross-resistance between docetaxel and cisplatin [5]. The logical combination cisplatin–docetaxel appears to be active [6, 7], but limiting hematological toxicity requires a reduction of about 25% in the doses of both cytotoxic agents. These two opposing factors have encouraged the design of alternating therapeutic regimens, in which docetaxel is administered in alternation with platinum-based chemotherapy [8]. Alternating regimens permit the use of several active drugs, theoretically devoid of cross-resistance, in order to circumvent the mechanisms of tumor resistance to a given combination of cytostatic agents and to avoid the cumulative toxicity associated with the simultaneous administration of several drugs without any necessity for dose reduction. Viallet et al. [8] reported the results of a phase II study using a regimen alternating administration of docetaxel and the combination cisplatin–vinorelbine with an objective response rate of 43% and a median survival of 39 weeks.

Confirmation of these preliminary results seemed to be mandatory before evaluation of this alternating strategy in a phase III comparative study. The choice of a randomized, multicenter, non-comparative phase II study permitted the inclusion of a control group ‘calibrating’ the study population enrolled under the conditions of a phase III trial, in terms of response rate and survival, by the use of a classical reference treatment. The choice of the reference therapeutic regimen, namely cisplatin–vinorelbine administered in 3-week cycles, was based on the results of a phase III study [9] showing an objective response rate of 43% in a population with stage IIIB and IV NSCLC.


    Patients and methods
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 Introduction
 Patients and methods
 Results
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Eligibility criteria
The patients had to meet the following inclusion criteria: age between 18 and 70 years, histologically proven stage IV NSCLC, no brain metastasis, an Eastern Cooperative Oncology Group performance status (PS) of 2 or less, no previous chemotherapy, at least one bidimensionally measurable lesion, no peripheral neuropathy of WHO grade >1, normal hepatic function [blood bilirubin level <1.25 x upper limit of normal (ULN)], serum glutamic-oxaloacetic transaminase and glutamic-pyruvate transaminase <3 x ULN, alkaline phosphatases <2.5 x ULN), adequate hematological status (absolute granulocyte count >1.5 giga/l, platelets >100 giga/l), normal renal function (serum creatinine concentration <120 µmol/l) and signed written informed consent. Patients could not be enrolled in the study if they had a severe concomitant pathological condition or if they had experienced another type of cancer, other than in situ cervical carcinoma. Palliative radiotherapy was authorized.

The pre-enrollment evaluation systematically comprised a complete physical examination, laboratory tests including a differential blood count, platelet count, serum chemistry with creatinine and protein levels, liver function tests, chest X-ray, computed tomography scan of the chest (including adrenal areas) and brain, liver echography and/or scan and bone scintigraphy with radiographs centered on pathological areas.

Treatment
Patients fulfilling the inclusion criteria were randomized after stratification according to center and PS (PS 0 or 1 compared with 2) to one of the two treatment groups.

Patients randomized to group A (alternating treatment group) received docetaxel 100 mg/m2 as a 1-h infusion on day (D) 1, with premedication by prednisolone 100 mg orally, daily (e.g. 50 mg twice daily) for 3 days starting 1 day before the administration of docetaxel, alternating with combination chemotherapy comprising cisplatin 100 mg/m2, administered with hyperhydration on D22, and vinorelbine 30 mg/m2, administered by 20-min infusion on D22, D29 and D36. Docetaxel was administered again at the same dose on D43.

Patients randomized to group B (control group) received cisplatin 80 mg/m2 with hyperhydration every 3 weeks, i.e. on D1, D22 and D43, plus weekly vinorelbine 30 mg/m2 administered by infusion over 20 min. The doses of the cytostatic agents were adjusted during the course of treatment in accordance with hematological toxicity, i.e. according to the polynuclear neutrophil and platelet nadir during the preceding cycle and the blood count performed on the day of treatment.

Assessment of response to treatment and toxicity
The response to treatment was evaluated with WHO criteria after three cycles, i.e. on D63, at the end of 9 weeks of treatment. Both the initial staging and the response were assessed by a panel of experts independent from the investigator and blind to the assigned treatment. Treatment-related toxicities were evaluated using the WHO toxicity scale.

Second-line treatment
After the assessment on D63, treatment in both groups was continued in an identical manner by two 3-week cycles in the case of objective response or stabilization. In group A, alternating treatment was continued, starting with the combination cisplatin–vinorelbine administered as before, followed by docetaxel on D85. If progression was observed on D63, treatment was left to the discretion of the investigator in group A, whereas in group B, the patients received docetaxel at a dose of 100 mg/m2 every 3 weeks as second-line therapy, being re-evaluated after two cycles. The patients were finally assessed on D105, i.e. after 15 weeks of treatment.

Statistical analyses
This was a phase II randomized, non-comparative study with the objective of ascertaining the activity of a therapeutic regimen alternating docetaxel and the combination cisplatin–vinorelbine, including a control group permitting determination of the response rate and survival of the study population when receiving a classical reference treatment, namely cisplatin–vinorelbine.

The primary end point was the objective response rate determined in the intention-to-treat population, secondary end points being toxicity, time to treatment failure, duration of response and survival. The duration of response was defined as the interval between the first day of treatment and the onset of progression. The duration of survival was calculated from the date of randomization for all patients randomized (intention-to-treat analysis). The time to treatment failure was calculated as the interval between the date of randomization and the date of treatment discontinuation irrespective of the reason for this (progression, interruption due to toxicity, death from any cause) on the entire population of randomized patients. All these intervals were determined by the Kaplan–Meier method. The analysis of toxicity was performed on all treated patients and for each type of toxicity was based on the maximum grade of that toxicity experienced by each patient during the study [10]. The number of patients to be enrolled in each group was arbitrarily set at 50 patients according to the Fleming’s multistep procedure design [11], with a 0.88 probability of duly asserting that the treatment had a true response rate of 30% or more ({alpha} = 0.12; ß = 0.08).


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Seventy patients were enrolled in the study. The observation by the study steering committee of an imbalance between the two groups in terms of premature treatment discontinuations led to a temporary halt of enrollment during the second stage of Fleming’s multistep procedure in order to permit an unplanned interim analysis. This analysis was performed on the first 56 chronologically enrolled patients. Confirmation of the imbalance in terms of discontinuations due to toxicity and response rate led to a definite stop in the enrollment. The final results presented here consequently concern the 70 patients enrolled at that time, comprising 38 in group A and 32 in group B.

The characteristics of the patients are presented in Table 1. One patient (1.4%) was ineligible in group A due to absence of a measurable target lesion. As regards prognostic factors, the patients were evenly balanced between the two groups, except that the proportion of patients with a PS of 2 was higher in group A and more patients presented a metastasis at only one site in group B.


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Table 1. Patient characteristics
 
Treatments administered
More premature treatment discontinuations occurred in the alternating treatment group than in the control group, with a median number of cycles of three in group A and five in group B. These additional discontinuations were not due to a larger number of documented tumor progressions under treatment (31.6% in group A compared with 32.3% in group B), but followed treatment interruptions due to toxic events. Nine patients (23.7%) in the alternating treatment group discontinued chemotherapy prematurely: five due to severe infections (including two deaths related to febrile neutropenia), two due to neutropenia persisting for more than 2 weeks, one due to severe asthenia and one due to hypersensitivity to docetaxel. Three patients (9.7%) discontinued treatment prematurely in the control group: two patients due to severe infection, one of whom died after an episode of febrile neutropenia, and one patient due to ototoxicity.

The actual dose intensity calculated for each drug (taking into account the duration of each 3-week cycle in the alternating treatment group) in patients completing the first treatment phase from D1 to D63 was 32.8 mg/m2/week for docetaxel (relative dose intensity: 98%), 31.4 mg/m2/week for cisplatin (relative dose intensity: 94%) and 21.4 mg/m2/week for vinorelbine (relative dose intensity: 71%) in group A compared with 26.9 mg/m2/week for cisplatin (relative dose intensity: 100%) and 21.8 mg/m2/week for vinorelbine (relative dose intensity: 73%) in group B. In contrast, when expressed on the basis of the total duration of the first treatment phase, i.e. 9 weeks, the actual dose intensity of the drugs administered in the alternating treatment group was 16.4 mg/m2/week for docetaxel, 10.5 mg/m2/week for cisplatin and 7.1 mg/m2/week for vinorelbine.

Response to treatment
A partial response was noted in four patients in group A, corresponding to an objective response rate in the intention-to-treat population of 10.8% [95% confidence interval (CI) 0.8% to 20.8%], compared with eight patients in group B, corresponding to a response rate of 25% (95% CI 10% to 40%). The duration of response was 43.3 weeks in the alternating treatment group and 27 weeks in the control group. The number of stabilizations (11 and 10 in groups A and B, respectively) and progressions (12 in group A compared with 10 group B) were very similar in the two treatment groups. Seven patients in group B in progression under cisplatin–vinorelbine received docetaxel (100 mg/m2 administered every 3 weeks) as second-line treatment; no response was observed in any of these patients.

Survival and time to treatment failure
With a median follow-up of 103 weeks, the median survival was 29.1 weeks in group A and 41.6 weeks in group B. The survival rates at 6 months and 1 year were respectively 55.3 and 39% in group A and 67.8 and 42% in group B (Figure 1). The median time to treatment failure (treatment discontinuation irrespective of cause: toxicity, progression or death) was 10.2 weeks in group A and 17.3 weeks in group B.



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Figure 1. Overall survival (intention-to-treat, all patients).

 
Toxicity
The main toxicities (Table 2) were hematological, primarily affecting the leukocytes. No increase in toxicity was observed in group A compared with group B. There were three deaths following grade 4 febrile neutropenia, including two patients (with an initial PS of 0) in group A (death by septic shock associated with bacteremia during the second cycle of treatment, i.e. when the patients were receiving the combination cisplatin–vinorelbine) and one in group B (a patient with an initial PS of 2 who died of septic shock in the context of clear tumor progression during the fourth cycle). Non-hematological toxicities were for the most part moderate.


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Table 2. Main toxicities
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
To the best of our knowledge, this is the first randomized study assessing an alternating regimen using doxetaxel given in alternation with the combination cisplatin–vinorelbine for the treatment of patients with stage IV NSCLC. The final results on the 38 patients randomized to the alternating treatment group were disappointing. Addition of docetaxel alternating with cisplatin–vinorelbine combination therapy appeared to improve neither the response rate nor the time to treatment failure. The response rate was much lower than that observed by Viallet et al. [8], although it should be borne in mind that 15% of the patients in that study had only stage III NSCLC. This difference could also be explained by the conditions of enrollment, which were those of a multicenter phase III study, and the fact that almost a quarter of the patients enrolled had a PS of 2 [8]. Continuation of the treatment in case of stable disease after the first three cycles allowed account to be taken of late responses and consequently could not have led to underestimation of the activity of this therapeutic regimen. The median overall survival was also relatively low (29 weeks), but the survival rate at 1 year (39%) was quite comparable with the results obtained in phase III trials including only stage IV patients [6].

Analysis of the toxicity caused by the addition of docetaxel alternating with cisplatin–vinorelbine combination therapy showed predominant leukocyte toxicity equivalent to that seen with the combination cisplatin–vinorelbine alone, although two treatment-related deaths occurred in the alternating treatment group following febrile neutropenia when the patients were receiving the combination cisplatin–vinorelbine. There were in fact more premature treatment discontinuations not prompted by tumor progression in the alternating treatment group, resulting in a shorter time to treatment failure and probably contributing to an underestimation of the antitumor activity.

These poorer than expected results cannot be explained by unfavorable prognostic factors in the patient population enrolled in the study. Indeed, the results obtained for the 32 patients randomized to the control group correspond to those expected for a population with stage IV NSCLC treated by cisplatin-based chemotherapy with a survival rate at 1 year of 42%. So, the alternating regimen of docetaxel and combination cisplatin–vinorelbine chemotherapy investigated in this study did not improve the efficacy of first-line chemotherapy of metastatic NSCLC in so far as it did not permit the administration of a sufficient number of cycles of chemotherapy in nearly 30% of the patients. These results could possibly be explained on the basis of the decrease in the actual dose intensity of each component of the alternating regimen (i.e. docetaxel and cisplatin–vinorelbine). A more promising approach might consequently be to optimize the potential absence of cross-resistance between docetaxel and platinum compounds by means of sequential treatment regimens, with the possibility of maintaining a satisfactory dose intensity of each treatment component. The results obtained by the South West Oncology Group using a consolidation treatment with docetaxel following combined chemotherapy and radiotherapy in patients with locally advanced stages of NSCLC [12] also support this type of treatment sequence, which would merit being tested in patients with stage IV NSCLC.


    Acknowledgements
 
Study sponsored by Aventis Pharma, Paris, France. The authors express their thanks to Ms D. Bayrounat and Mr E. Saliba. Investigators and institutions participating in the trial were as follows: Dr H. Léna, Dr C. Belleguic, CHU Rennes; Dr P. Thomas, Professor J. P. Kleisbauer, Prof. P. Astoul, CHU Marseille; Dr G. Robinet, Dr S. Gouva, CHU Brest; Dr Pierre Fournel, CHU Saint Etienne; Dr E. Coste, Professor P. Balmes, CHU Nîmes; Dr H. Le Caer, CH Draguignan; Dr F. Blanchon, Dr M. Grivaux, CH Meaux; Dr M. Pérol, Dr S. Hominal, Professor J. C. Guérin, CHU Lyon; Professor A. Vergnenègre, Dr M. Clavel, Professor Bonnaud, CHU Limoges; Dr J. M. Vernejoux, Professor A. Taytard, CHU Bordeaux; Dr D. Paillotin, CHU Rouen, Dr R. Poirier, Dr J. Letreut, CH Aix en Provence; Dr D. Perdu, CHU Reims, Dr J. M. Chavaillon, CH Antibes.


    Footnotes
 
+ Correspondence to: Dr M. Pérol, Hôpital de la Croix-Rousse, 69317 Lyon Cedex 04, France. Tel: +33-4-72-07-17-28; Fax: +33-4-72-07-24-13; E mail: maurice.perol@chu-lyon.fr Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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8. Viallet J, Laberge F, Martins H et al. Docetaxel alternating with cisplatin and vinorelbine: early evidence of additive activity in a phase II trial of non small cell lung cancer. Proc Am Soc Clin Oncol 1996; 15: 375 (Abstr 1115).

9. Depierre P, Chastang Cl, Quoix E et al. Vinorelbine versus vinorelbine plus cisplatin in advanced non small cell cancer: a randomized trial. Ann Oncol 1994; 5: 37–42.[Abstract]

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