Multicentre randomised phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer

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Abstract

This study compares two cytotoxic regimens comprising the same dose and schedule of cisplatin (CP) plus vinorelbine (VNR) or gemcitabine (GEM) administered under the same schedule to patients with advanced non-small cell lung cancers (NSCLC). From April 1998 to February 2003, 285 patients were randomised to receive either VNR 25 mg/m2 on days 1 and 8 as an intravenous (i.v.) bolus plus CP 75 mg/m2 on day 1 (regimen A) or GEM 1200 mg/m2 on days 1 and 8 as an i.v. 30-min infusion plus CP 75 mg/m2 on day 1 (regimen B). Both treatments were recycled every 21 days. If no progression had occurred after six cycles, the patients continued to receive VNR or GEM monochemotherapy weekly. Cross-over of the two single agents was considered if disease progression occurred. Objective response (OR), time to progression (TTP) and overall survival (OS) were analysed according to the intention-to-treat principle. 272 patients were ultimately eligible (137 on A and 135 on B). Their main characteristics were: male/female ratio 214/58; median age 63 (range 32–77) years; median Karnofsky Performance Status (PS) 80 (range 70–100); stage IIIB 34%, stage IV 61%, recurrent disease 5%; histology – epidermoid 29%, adenocarcinoma 53%, other NSCLC 18%. The characteristics of the patients in the two arms were well matched. The following response rates were observed in regimens A and B, respectively: complete response (CR) 0.7% and 3.7%, partial response (PR) 31.9% and 22.2% (P = 0.321). Median CR + PR duration was 8 months in both arms. Clinical benefit represented by an improvement in symptoms was evident in 25.7% and 28.1%, respectively. Median TTP was 5 months in both arms and median OS 11 months in both arms. Grade III–IV neutropenia occurred in 30.7% and 17.7% of the patients in arms A and B, respectively (P = 0.017); thrombocytopenia occurred in 0% and 9.3% (P = 0.004), respectively. No difference in the incidence of anaemia was observed. Non-haematological toxicity was generally mild: a higher incidence of grade 1–2 peripheral neurotoxicity and grade 1–2 local toxicity with regimen A and grade 1–2 liver toxicity with regimen B was reported. A pharmaco-economic comparison showed a difference between the two doublets, principally due to the different costs of VNR and GEM. Under the study conditions the combination of VNR or GEM with the same dose and schedule of CP produced similar OR, clinical benefits, TTP and OS in advanced NSCLC, and only mild toxicological differences were observed. Pharmaco-economic evaluation favoured the CP + VNR doublet.

Introduction

Two drug regimens containing platinum derivatives are the standard treatments for advanced non-small cell lung cancers (NSCLC) in patients with good performance status [1]. These regimens are represented by the doublets cisplatin (CP) plus gemcitabine (GEM), or vinorelbine (VNR) or paclitaxel or docetaxel, and the doublet carboplatin plus paclitaxel. As any differences in the activity of these regimens are small, their toxicological profiles and pharmaco-economic features may be important in deciding which should be administered in clinical practice.

At present, CP is considered to be the reference drug for advanced NSCLC, but the optimal dose of CP has not yet been determined, as a wide dose range between 60 and 120 mg/m2 is used. The higher doses are associated with a higher incidence of typical side-effects such as nausea/vomiting, renal impairment and cumulative neurotoxicity.

VNR is a vinca derivative whose activity in advanced NSCLC was demonstrated toward the end of the 1980s. At a weekly dose of 30 mg/m2, its combination with CP at a dose of 120 mg/m2 on day 1 proved superior to a combination of vindesine plus CP given at the same dose [2]. In these combinations the dose-limiting toxicity was neuropathy and myelosuppression, necessitating a reduction in the dose of both drugs so that the dose intensity of VNR was reduced by around 30%. Subsequently, the Southwest Oncology Group (SWOG) carried out a trial in which VNR was administered weekly at a dose of 25 mg/m2 and CP at 100 mg/m2, and that regimen was compared to single-agent CP [3]. The combination was superior to the single agent in terms of response rate, time to progression and survival. The most important side-effect was again myelosuppression. This CP + VNR regimen became the standard for SWOG and a reference regimen for clinical trials in patients with advanced NSCLC. However, in this combination also the VNR dose was reduced by around 50% on day 15, as was that of CP (a 50% reduction in courses 3 and 4).

Between 1992 and 1996 our group carried out a phase III trial to compare two doublets containing the same dose of CP (60 mg/m2) and high-dose epirubicin (on day 1) or VNR 25 mg/m2 (on days 1 and 8) in advanced NSCLC. The cycles were repeated every 21 days [4]. The trial demonstrated the same antitumour activity for both doublets but a better toxicological profile for CP + VNR. In particular, the CP + VNR combination had an overall response rate of 27% in 103 patients, with a median overall survival of 9.6 months and 1-year survival of 39%. On the basis of this trial, the regimen CP + VNR on days 1 and 8 repeated every 21 days became our standard treatment in clinical practice.

By early in 1998 many phase II trials had shown that the combination CP + GEM was very active in advanced NSCLC: the objective response rate ranged from 26% to 54%, with 1-year survival in the range 35–61% and median survival in the range 8–13 months [5], [6], [7], [8], [9], [10]. In these trials GEM was administered on a weekly basis for 3 weeks out of every 4 weeks or for 2 weeks out of every 3 weeks.

The present trial was designed to determine whether the experimental regimen of CP + GEM offers any advantages over our standard regimen of CP + VNR. The only difference between the two regimens was the presence of GEM or VNR; the CP dose and schedule (75 mg/m2 on day 1) and the GEM and VNR timing schedules (days 1 and 8) were identical in both arms. The chief aim was to compare the objective response, the time to progression and the survival.

Section snippets

Patient population

Patients had to fulfil the following criteria to be candidates for randomisation: histological or cytological diagnosis of NSCLC; stage IIIB, IV or recurrent disease after an operation for primary NSCLC; Karnofsky Performance Status (KPS) ⩾70; no prior chemotherapy or radiation therapy; adequate marrow (granulocyte count >1500/μl; platelet count of at least 100,000/μl), cardiac, hepatic and renal (serum creatinine <1.5 mg/dl) functions. Patients with the following conditions were excluded:

Results

From April 1998 to March 2003, 286 patients were enrolled on the study and were randomised to receive either regimen A (CP + VNR; 143 patients) or regimen B (CP + GEM; 143 patients). Fourteen non-eligible patients (six in regimen A and eight in regimen B) were excluded from the analysis as they did not comply with the inclusion criteria. The reasons were as follows: six did not have stage IIIB or IV, or recurrent, disease, three had had prior malignant neoplasms, one had non-NSCLC histology, one

Discussion

The combination CP + VNR was originally studied in two randomised trials in France; the planned weekly administration of VNR was at a dose of 30 mg/m2 in combination with CP administered on day 1 at a dose of 120 mg/m2 [2] or 80 mg/m2 [13], with the cycle restarting on the 28th and 21st days, respectively (Table 7). Subsequently, the SWOG performed two consecutive trials using weekly VNR at a dose of 25 mg/m2 and CP at 100 mg/m2 [3], [14]. The dose intensity of VNR with weekly administration was

Acknowledgements

This paper was previously presented in part at the Annual Meeting of the American Society of Clinical Oncology (ASCO), Chicago, 31 May–3 June 2003.

The following investigators also contributed to the study: Edera Piana, Medical Oncology Unit, S. Orsola-Malpighi Hospital, Bologna; Giorgio Lelli, Division of Medical Oncology, Casa sollievo della sofferenza, IRCCS, S.Giovanni Rotondo (Foggia); Robustelli della Cuna Gioacchino Division of Medical Oncology, Fondazione S. Maugeri IRCCS, Pavia; Luciano

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