Elsevier

Lung Cancer

Volume 53, Issue 1, July 2006, Pages 67-75
Lung Cancer

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

https://doi.org/10.1016/j.lungcan.2006.04.001Get rights and content

Summary

Purpose

Based on the promising activity of paclitaxel in small-cell lung cancer (SCLC) we conducted a randomized phase III trial to evaluate whether a combination of paclitaxel, carboplatin and etoposide phosphate (TEC) improves survival and time to progression as well as tolerability and quality of life (QoL) compared to a regimen of carboplatin, etoposide phosphate and vincristine (CEV) in SCLC patients.

Patients and methods

Six hundred and fourteen patients with stages I–IV SCLC were randomly assigned between January 1998 and December 1999 to both treatment arms. All patients were evaluated for response rate, survival, side effects and quality of life with overall survival (OS) serving as primary endpoint. A final analysis was done after a six-year follow-up. Survival curves were estimated using Kaplan–Meier curves and tested with the log-rank test. Quality of life data were assessed in using the EORTC QLQ-C30 questionnaire and evaluated by calculating and comparing the mean scores as well as applying longitudinal techniques.

Results

Six hundred and eight patients were evaluable for efficacy and toxicity. The long-term follow-up confirms the significant survival benefit for the paclitaxel, etoposide, carboplatin (TEC) regimen with a median OS of 12.5 months compared to 11.7 months for the CEV arm (HR, 1.21; 95% CI, 1.02–1.43; P = .030). The 5-year survival rates were 14% for the experimental versus 6 % for the CEV arm. Significant survival prolongation was also observed in the subgroup of patients with stage IV disease (HR, 1.27; 95% CI, 1.00–1.60; P = .047). The previously reported clinical benefit in form of an overall reduction of grade 3/4 toxicity was backed by the results of the comprehensive QoL analysis we report hereby. TEC significantly improves the relevant QoL parameters like global overall QoL or physical functioning.

Conclusion

When administered in combination with etoposide and carboplatin, paclitaxel is able to offer in SCLC patients with extensive disease a survival benefit without additional toxicities, but with gains in patient-reported quality of life. In terms of efficient palliative care, TEC might be seen as an alternative to standard cisplatin plus etoposide in patients requesting a powerful palliative regimen not compromising any survival benefit.

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.

References (35)

  • J.D. Hainsworth et al.

    Phase II randomised study of cisplatin plus etoposide phosphate or etoposide in the treatment of small-cell lung cancer

    J Clin Oncol

    (1995)
  • P.J. Loehrer et al.

    Cisplatin plus etoposide with and without ifosfamide in extensive small-cell lung cancer

    J Clin Oncol

    (1995)
  • J.H. Schiller et al.

    Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer

    J Clin Oncol

    (2001)
  • J.L. Pujol et al.

    Etoposide plus cisplatin with or without the combination of 4′-epidoxorubicin plus cyclophosphamide in the treatment of extensive small-cell lung cancer: a French Federation of Cancer Institutes multicenter phase III randomized study

    J Natl Cancer Inst

    (2001)
  • D.S. Ettinger et al.

    Phase II study of paclitaxel in patients with extensive-disease small-cell lung cancer

    J Clin Oncol

    (1995)
  • K. Kelly et al.

    Cisplatin, etoposide, and paclitaxel with granulocyte colony-stimulating factor in untreated patients with extensive-stage small cell lung cancer

    Clin Cancer Res

    (2001)
  • H.B. Niell et al.

    Randomised phase III Intergroup Trial of etoposide and cisplatin with or without paclitaxel and granulocyte colony-stimulating factor in patients with extensive stage small-cell lung cancer: Cancer and Leucemia Group B Trial 9732

    J Clin Oncol

    (2005)
  • Cited by (26)

    • A systematic review of the quality of statistical methods employed for analysing quality of life data in cancer randomised controlled trials

      2017, European Journal of Cancer
      Citation Excerpt :

      The different assessment criteria are detailed Table 1. Thirty-three studies were selected to be analysed, involving 9179 patients [13–56]. Fourteen different HRQoL questionnaires were used in all the articles studied.

    • Health-related quality of life in small-cell lung cancer: A systematic review on reporting of methods and clinical issues in randomised controlled trials

      2014, The Lancet Oncology
      Citation Excerpt :

      The increased interest of regulatory bodies into patient-reported outcomes could provide a motivating factor to improve standards for design, conduct, and reporting of health-related quality-of-life assessment in oncology trials.64 We noted several instances in which health-related quality-of-life results were reported at a much later date, and in a lower impact journal than were the main clinical results.13–15,21,22,25,26,46,47 The added value of health-related quality-of-life outcomes to the medical decision process for such trials would be limited at best.

    • Combination chemotherapy with paclitaxel and ifosfamide as the third-line regimen in patients with heavily pretreated small cell lung cancer

      2007, Lung Cancer
      Citation Excerpt :

      Whether the sequence of the regimens used for induction chemotherapy and second-line chemotherapy truly influence the response rates to salvage chemotherapy in SCLC remains to be further evaluated in future studies. Paclitaxel and ifosfamide demonstrated activity as single agents and as part of a combination regimen for SCLC, both in first-line treatment and in the setting of relapsed/refractory disease [19,20,32–37]. The triplet combination of paclitaxel, ifosfamide and platinum analogs were evaluated in several studies.

    • Small Cell Lung Cancer (SCLC); any progress?

      2007, European Journal of Cancer, Supplement
    • Case 8-2010: A 22-year-old woman with hypercalcemia and a pelvic mass

      2010, New England Journal of Medicine
      Citation Excerpt :

      The combination of etoposide and cisplatin remains the standard therapy for small-cell carcinoma of the lung. Studies have suggested that there may be a benefit to adding paclitaxel for patients with limited-stage disease, which we elected to do in this case.20 For a dosing schedule, we decided on a modification of the regimen of bleomycin, etoposide, and cisplatin that was used by the European Organisation for Research and Treatment of Cancer and the Medical Research Council in a trial (EORTC 30983/MRC TE21) for intermediate-prognosis germ-cell tumors.

    View all citing articles on Scopus
    View full text