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.
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Abstract |
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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 02). 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 cisplatinvinorelbine 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
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Introduction |
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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 cisplatinvinorelbine 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.
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Patients and methods |
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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 cisplatinvinorelbine 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 cisplatinvinorelbine, including a control group permitting determination of the response rate and survival of the study population when receiving a classical reference treatment, namely cisplatinvinorelbine.
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 KaplanMeier 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 Flemings multistep procedure design [11], with a 0.88 probability of duly asserting that the treatment had a true response rate of 30% or more ( = 0.12; ß = 0.08).
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Results |
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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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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 cisplatinvinorelbine 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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Discussion |
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Analysis of the toxicity caused by the addition of docetaxel alternating with cisplatinvinorelbine combination therapy showed predominant leukocyte toxicity equivalent to that seen with the combination cisplatinvinorelbine alone, although two treatment-related deaths occurred in the alternating treatment group following febrile neutropenia when the patients were receiving the combination cisplatinvinorelbine. 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 cisplatinvinorelbine 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 cisplatinvinorelbine). 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.
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Acknowledgements |
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Footnotes |
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References |
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