Efficient palliation in patients with small-cell lung cancer by a combination of paclitaxel, etoposide and carboplatin: Quality of life and 6-years’-follow-up results from a randomised phase III trial
Introduction
Small-cell lung cancer (SCLC) remains a disease with a very poor outcome. Accounting for 20–25% of all lung cancers, approximately 60% of all newly diagnosed SCLC patients have already extensive stage disease (ED) with distant metastases and/or a tumor spread not confined to the hemithorax of origin [1], [2]. SCLC is a fast growing tumor compared to non-small-cell lung cancer (NSCLC). Due to the frequent spread to regional lymph nodes and extrathoracic sites, SCLC is in general regarded as a systemic disease.
In line with these characteristics, polychemotherapy is designated as a cornerstone of therapy throughout all stages of disease. For limited disease (LD), the concurrent use of thoracic radiotherapy (TRT) is common practice as well as prophylactic cranial irradiation (PCI) in LD patients with complete response.
Polychemotherapy schemes containing an alkylating agent, a topoisomerase II inhibitor and a mitotic spindle inhibitor have been proven useful for more than two decades [3]. Nevertheless, the two-drug combination of the alkylating-like agent cisplatin and the topoisomerase II inhibiting epidophyllotoxine etoposide (EP) has been demonstrated superiority mainly in terms of tolerability to the regimen of cyclophosphamide, doxo- or epirubicin and vincristine (CAV) that has long been the standard therapy for extensive disease [4], [5], [6].
Since then, several attempts have been made to overcome the therapeutic limitations seen with EP. These studies included the substitution of cisplatin by carboplatin or new platinum compounds [7], [8], the use of etoposide phosphate instead of etoposide [9] – both concepts aimed to reduce the toxicities and therapeutic inconveniences of EP – and the addition of a third, in some studies even a fourth drug to the regimen [10], [11], [12].
Among the agents appropriate to become added, paclitaxel plays a major role due to interesting phase II activity [13], [14] in SCLC and its emerging role in NSCLC. The combination of paclitaxel, etoposide and cisplatin (TEP) resulted at best in modest prolongation of failure-free survival, but showed an unfortunate toxicity profile, resulting in an early termination by one and a non-recommendation of the combination by another phase III trialists’ group [15], [16].
The disappointing results, reported by the Greek study group in LD and ED patients and by the CALGB trial including ED patients only, were recently confirmed, when TEP was used with concomitant twice-daily TRT [17] in LD patients.
Based on our extended experience with the combination of etoposide and carboplatin (EC) in SCLC [18], [19], we decided several years ago, to evaluate the combination of paclitaxel, etoposide and carboplatin (TEC) versus a combination of carboplatin, etoposide and vincristine (CEV) in a phase III study. The latter regimen had shown acceptable response rates in both, LD (90% ORR, thereof 56% CR) and ED (83% ORR, thereof 35% CR) as well as adequate median survival times (LD 13 months, ED 10 months) [18] and was considered as a standard chemotherapy. The experimental TEC arm had been evaluated before in a phase II trial [20] with a promising efficacy and a tolerable toxicity profile.
Results of this phase III study with 614 patients were previously reported [21]. Six hundred and eight patients were evaluable for all endpoints (experimental arm 301 patients, standard arm 307 patients). Hazard ratio (HR) of death after a follow up of about 3 years showed a significant difference between both arms in favour of TEC (HR, 1.22; 95% CI, 1.03–1.45; P = .024). Progression-free survival was also statistically significantly shorter for patients in the standard arm (HR, 1.21; 95% CI, 1.03–1.42). No differences in response rates were observed but significantly lower rates of grade 3/4 anaemia (1.8% versus 3.4% in all completed therapy cycles; P = .002), thrombocytopenia (2.5% versus 10.4%; P = .001) and peripheral neuropathy (0.4% versus 2.1%; P < .001) in the experimental arm. Only for grade 3/4 cough (11 versus 4 events; P = .02) and fatigue (30 versus 17 events; P = 0.02), the experimental TEC arm showed significantly higher adverse event rates.
Hereby, we report additional long-time survival data (5 and 6-year survival rates) and the quality of life (QoL) analysis of our phase III multi-centre trial.
Section snippets
Patient and methods
For this prospective phase III study, patients were randomly assigned to the two treatment groups after having provided written informed consent according to local ethics committee requirements. Patients were further stratified by a Pocock-type centralised minimization procedure for stratified randomisation [22] according to treatment centre, stage of disease (limited disease defined as tumor limited to one hemi-thorax, corresponding to stages I–IIIb versus extensive disease incorporating stage
Patients
From the 614 patients enrolled from the 19 participating centres between January 1998 and December 1999, 608 were evaluable for toxicity and survival. Five hundred and thirty four events of death were reported during the extended 6-years observation period. Forty-five patients in the TEC and 29 patients in the CEV arm were still alive, when the final analysis in January 2005 was performed (median time of follow-up: 12 months with a maximum of 80.5 months). The patient demographics were already
Discussion
By this analysis, we report the following outcome: the incorporation of paclitaxel in a platinum-etoposide-doublet leads to promising 5-year survival data long with a manageable toxicity and an acceptable quality of life in SCLC patients. When presenting the first results of this randomised study 3 years ago, certain features of our study concept were questioned [32] like the comparability and interchangeability of the platinums, the role of vincristine and the use of sequential thoracic
Acknowledgments
We acknowledge the contributions of S. Eberle and O. Verbkina in the preparation of the final statistical report and quality of life analysis. This work was supported by a restricted grant from Bristol-Myers Squibb.
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