Elsevier

Lung Cancer

Volume 52, Issue 2, May 2006, Pages 155-163
Lung Cancer

Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: A phase III trial

https://doi.org/10.1016/j.lungcan.2006.01.006Get rights and content

Summary

Purpose

The primary objective of this randomized phase III study was to show significant difference in median time to progression (TTP) in patients with advanced NSCLC treated with single-agent gemcitabine maintenance therapy versus best supportive care following gemcitabine plus cisplatin initial first-line therapy.

Patients and methods

Chemonaive patients with stage IIIB/IV NSCLC received gemcitabine 1250 mg/m2 (days 1 and 8) plus cisplatin 80 mg/m2 (day 1) every 21 days. Patients achieving objective response or disease stabilization following initial gemcitabine plus cisplatin therapy were randomized (2:1 fashion) to receive maintenance gemcitabine (1250 mg/m2 on days 1 and 8 every 21 days) plus best supportive care (GEM arm), or best supportive care only (BSC arm).

Results

Between November 1999 and November 2002, we enrolled 352 patients (median age: 57 years; stage IV disease: 74%; Karnofsky performance status (KPS) >80: 41%). Following initial therapy, 206 patients were randomized and treated with gemcitabine (138) or best supportive care (68). TTP throughout the study period was 6.6 and 5 months for GEM and BSC arms, respectively, while values for the maintenance period were 3.6 and 2.0 months (for p < 0.001 for both). Median overall survival (OS) throughout study was 13.0 months for GEM and 11.0 months for BSC arms (p = 0.195). The toxicity profile was mild, with neutropenia being most common grade 3/4 toxicities.

Conclusion

Maintenance therapy with gemcitabine, following initial therapy with gemcitabine plus cisplatin, was feasible, and produced significantly longer TTP compared to best supportive care alone. Further studies are warranted to establish the place of maintenance chemotherapy in patients with advanced NSCLC.

Introduction

Approximately two-thirds of all patients with newly diagnosed non-small-cell lung cancer (NSCLC) have advanced disease (stage IIIB or IV) that is only amenable to palliative chemotherapy. Several randomized studies and a meta-analysis have demonstrated an advantage of chemotherapy over best supportive care alone in advanced NSCLC in terms of improvement in quality of life (QOL) and overall survival (OS) [1], [2], [3], [4], [5]. The standard primary treatment for patients with advanced NSCLC is a two-drug, platinum-based combination with one of the new-generation agents such as gemcitabine, vinorelbine, paclitaxel, or docetaxel [6].

Several phases II and III trials of gemcitabine and cisplatin combination have consistently shown high overall response rates (ORR), with improvements in time to progression (TTP) and OS [7], [8], [9], [10], [11]. However, the optimal number of initial chemotherapy cycles in advanced NSCLC is still a matter of discussion. Responses are usually seen after receiving 2–3 cycles, and several studies evaluating more prolonged initial chemotherapy have found no evidence of additional benefit [12], [13], [14]. Therefore, four treatment cycles are recommended to elicit the maximum benefit from a platinum-containing combination, with a reduced risk of toxicity caused by prolonged treatment during a relatively short period of survival.

Patients who have an objective response or disease stabilization following initial chemotherapy are likely to benefit from receiving maintenance therapy when the tumor burden is low. Since initial therapy usually involves a two-drug combination, the concept of single-agent maintenance therapy, has certain advantages for select patients. Using a drug with known single-agent activity for maintenance therapy in NSCLC, it is theoretically possible to slow disease progression and improve disease-related symptoms, with minimal side effects. Based on this rationale, investigators of the Central European Cooperative Oncology Group (CECOG) conducted a phase III, randomized, multicenter study to evaluate the effects of gemcitabine maintenance therapy following gemcitabine plus cisplatin initial therapy in patients with advanced NSCLC. The primary objective was to show a significant difference in TTP in patients treated with single-agent gemcitabine or best supportive care. The secondary efficacy end points included ORR, response duration, OS, toxicity, and symptom control.

Section snippets

Eligibility criteria

Eligible patients were required to have histologic or cytologic diagnosis of advanced NSCLC (stage IIIB disease with pleural effusion and/or positive supraclavicular nodes, or stage IV disease) not amenable to curative treatment. No prior chemotherapy was allowed and all other forms of therapy had to be completed at least 3 weeks before study enrollment. Prior radiotherapy (up to 60 Gy) was permitted if the irradiated area was not the only source of measurable disease. Other eligibility criteria

Patient characteristics

Between November 1999 and November 2002, a total of 354 patients out of 25 sites have entered the study. Respective sites included a median number of 7 (range, 1–42) patients. Two patients discontinued before the treatment, one due to disease-related death, and another due to personal decision. Baseline patient demographics and disease characteristics for the 352 patients who received induction therapy are listed in Table 1.

The patient population was predominantly male (72%), with a median age

Discussion

This randomized phase III study in patients with advanced NSCLC showed that maintenance therapy with single-agent gemcitabine following four cycles of induction gemcitabine plus cisplatin led to improved TTP with a manageable toxicity profile.

A number of studies have shown the efficacy of gemcitabine plus cisplatin combination in advanced NSCLC [7], [8], [9], [10], [11]. These findings have recently been confirmed in a meta-analysis [21]. However, the optimal duration of chemotherapy remains

Acknowledgements

We thank Dagmar Just, Reinhart Kobelt, Margit Landsgesell, Irmgard Resch and Marika Rosner for project management, Sulochana Gawande for help in preparation of this manuscript, Noelle Gasco for editorial assistance, and the following main investigators for their participation in the study: Czech Republic: Lubos Petruzelka, Charles University, Prague; Petr Prusa, Hospital Kladno; Martin Smakal, Oncological Clinic, Nova Ves pod Plesio; Boris Stastny, Faculty Hospital, Prague; Slovak Republic:

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    Preliminary results were presented as an oral presentation at the 10th world conference on lung cancer. Vancouver, BC, Canada, 10–14 August 2003 (Lung Cancer 2003;41(Suppl. 2):S29) and as a poster at the American society of clinical oncology. New Orleans, LA, 5–8 June 2004 (Proc Am Soc Clin Oncol 2004;22:630 [abstract 7067]).

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