Elsevier

The Lancet Oncology

Volume 8, Issue 6, June 2007, Pages 500-512
The Lancet Oncology

Fast track — Articles
Factorial phase III randomised trial of rofecoxib and prolonged constant infusion of gemcitabine in advanced non-small-cell lung cancer: the GEmcitabine-COxib in NSCLC (GECO) study

https://doi.org/10.1016/S1470-2045(07)70146-8Get rights and content

Summary

Background

The addition of cyclo-oxygenase-2 (COX-2) inhibitors and prolonged constant infusion (PCI) of gemcitabine to treatment for advanced non-small-cell lung cancer (NSCLC) might improve treatment efficacy. We aimed to assess whether the addition of rofecoxib or PCI gemcitabine could improve overall survival compared with first-line treatment with cisplatin plus gemcitabine given by standard infusion.

Methods

Patients with stage IV or IIIb (with supraclavicular nodes or pleural effusion) NSCLC who were under 70 years of age and who had performance status 0 or 1 were eligible for this multicentre, prospective, open-label, randomised phase III trial with 2×2 factorial design. Patients were randomly assigned to one of four treatment groups: group A, gemcitabine 1200 mg/m2 in a 30-min intravenous infusion on days 1 and 8 and intravenous cisplatin 80 mg/m2 on day 1, every 21 days for six cycles; group B, the same treatments as group A plus oral rofecoxib 50 mg/day until disease progression; group C, intravenous PCI gemcitabine 1200 mg/m2 in a 120-min infusion on days 1 and 8 and intravenous cisplatin 80 mg/m2 on day 1, every 21 days for six cycles; group D, the same drugs as group C plus oral rofecoxib 50 mg/day until disease progression. The primary endpoint was overall survival; secondary endpoints were progression-free survival, response rate, quality of life, and toxicity. Analyses were intention-to-treat. This trial is registered on the clinical trials site of the US National Institutes of Health website http://clinicaltrials.gov/ct/show/NCT00385606.

Findings

Between Jan 30, 2003, and May 3, 2005, 400 patients were enrolled. Median age was 60 years (range 29–71). PCI gemcitabine did not improve overall survival (median 47 weeks [95% CI 40–55] vs 44 [36–52], with standard gemcitabine infusion, hazard ratio (HR) of death 0·93 [0·74–1·17], p=0·41), progression-free survival, nor any other secondary endpoint. Vomiting and fatigue were significantly worse with PCI gemcitabine. The two rofecoxib groups were closed early (on Oct 1, 2004) due to withdrawal of the drug because of safety issues. With intention-to-treat statistical analyses limited to 240 patients (ie, those randomised before July 1, 2004) who had at least 3 months of treatment, rofecoxib did not prolong overall survival (median 44 weeks [CI 36–55] vs 44 [40–54] without rofecoxib, and HR of death 1·00 [0·75–1·34], p=0·85), or progression-free survival, but did improve response rate (41% vs 26%, p=0·02), global quality of life, physical, emotional and role functioning, fatigue, and sleeping. Rofecoxib significantly increased the incidence of diarrhoea and decreased constipation, fatigue, fever, weight loss, and pain, and analgesic consumption. Severe cardiac ischaemia was more frequent with rofecoxib than without; however, the difference was not statistically significant in the primary analysis (p=0·06) and became significant when patients who were randomised between July 1, 2004, and Sept 30, 2004, were included in the analysis (p=0·03).

Interpretation

Neither PCI gemcitabine nor rofecoxib prolonged survival in the patients in this study. Rofecoxib improved response rate and several quality-of-life items, including pain-related items and global quality of life. Further studies with less cardiotoxic COX-2 inhibitors are needed in NSCLC.

Introduction

Prognosis of patients with advanced non-small-cell lung cancer (NSCLC) is poor. Platinum-based chemotherapy is the worldwide standard treatment, and on the basis of meta-analyses, is associated with a small, but significant survival benefit at 1 year in favour of cisplatin-containing regimens compared with best supportive care.1 However, the benefit of chemotherapy is small and has to be weighed against substantial toxicity.2 Platinum-based treatment is associated with higher response rates compared with regimens that do not contain platinum, although, it does not prolong overall survival compared with regimens containing third-generation treatments (eg, taxanes, gemcitabine, and vinorelbine).3 Direct comparisons in phase III trials suggest that no major differences in efficacy exist between platinum-based treatments.4, 5

In Italy, the most commonly used treatment regimen is a combination of cisplatin and gemcitabine. Phosphorylation of gemcitabine to the monophosphate by deoxycytidine kinase is the rate-limiting step in the accumulation of the active diphosphate and triphosphate metabolites.6 Phase I studies have shown that the ability of mononuclear cells to accumulate gemcitabine triphosphate during treatment is saturable, and the optimum plasma concentration of gemcitabine that maximised the rate of formation of gemcitabine triphosphate was about 20 μmol/L.7, 8 By the use of dose rates of around 10 mg/m2/min, the target gemcitabine concentration in plasma was achieved, and the rate of gemcitabine triphosphate accumulation by mononuclear cells and leukaemia cells was optimised.9 In a phase II randomised trial in patients with pancreatic cancer, gemcitabine infused at the fixed-dose rate infusion of 10 mg/m2/min led to a median overall improvement in survival, with unusually high 1-year, 2-year, and 3-year survivorship compared with a dose-intense scheme of gemcitabine (2200 mg/m2) given in a standard 30-min infusion.10 In patients with NSCLC, the results of a randomised phase II study further showed the feasibility and activity of weekly gemcitabine at the fixed-dose rate of 10 mg/m2/min in combination with cisplatin.11 In this particular study, median progression-free survival was a promising 8 months, although overall survival was similar to that in the standard group at 13 months. These data suggested that exposure to prolonged concentrations of gemcitabine might improve its efficacy.

Preclinical evidence lends support to the association between COX-2, prostaglandins, and cancer. COX is an important enzyme in the conversion of arachidonic acid to prostaglandins, which are involved in maintenance of the gastric mucosa, regulation of renal bloodflow, platelet aggregation, and immune response.12, 13, 14 Two isoforms of COX exist: COX-1 is constitutionally expressed, and COX-2 is inducible by growth factors, oncogenes, carcinogens, and tumour-promoting phorbol esters.15 COX-2 is overexpressed in various human malignancies, and this overexpression represents an important early event in the development of some human tumours, including colon and lung cancer, and suggests that COX-2 is linked to the development of cancer.16, 17 In patients with NSCLC, overexpression of COX-2 is associated with worse prognosis and with metastasis.18, 19 Several preclinical studies have shown the in-vitro and in-vivo antitumoral activity of selective COX-2 inhibitors, which block tumour growth through many mechanisms, mainly by antiangiogenic and proapoptotic effects.20, 21 Furthermore, synergistic cytotoxicity has been reported in NSCLC cell lines with combinations of COX-2 inhibitors and several chemotherapeutic agents or radiotherapy.22, 23, 24 Based on these findings, COX-2 inhibitors have been combined with chemotherapeutic agents in cancer treatment and early trials have documented the feasibility, good tolerability, and promising activity of such combinations in patients with advanced colorectal cancer and NSCLC.25, 26 Rofecoxib is a selective COX-2 inhibitor that has ten-times greater biochemical selectivity for COX-2 than does celecoxib.27 When the current study was planned, published research suggested that a rofecoxib dose of 50 mg/day was feasible for prolonged treatment and was associated with a lower risk of gastrointestinal adverse events compared with non-steroidal anti-inflammatory drugs.28, 29, 30

The aim of this study was to assess whether the efficacy of cisplatin plus gemcitabine chemotherapy for NSCLC could be improved by the addition of rofecoxib or by a prolonged constant infusion (PCI) of gemcitabine.

Section snippets

Patients and procedures

This was a multicentre, prospective, open-label, randomised, factorial phase III trial. The study protocol was approved by the Ethics Committee of each participating institution and all patients provided written informed consent.

Patients with histologically or cytologically confirmed NSCLC, stage IV or stage IIIB disease with malignant pleural effusion or supraclavicular nodes, who were under 70 years of age, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had

Early safety analysis

The early phase II safety assessment was done according to the protocol plan, and passed the threshold for both stages. The total number of patients with unacceptable toxicity was under the threshold of 15 for all experimental groups. In group B, six patients had unacceptable toxicity consisting of febrile neutropenia (grade 3, one patient), dyspnoea (grade 4, one patient), non-neutropenic infection (grade 3, one patient), epigastralgia (grade 3, one patient), and neurological (grade 3, one

Discussion

The current study was based on a factorial design with two questions, one regarding the efficacy of a prolonged constant infusion of gemcitabine compared with standard 30-min infusion and the other regarding the effect of adding rofecoxib to chemotherapy with cisplatin and gemcitabine. For both questions, results were negative because a survival difference was not noted in either. The study was not planned to test efficacy interactions in the experimental factors. Overall, because this—to our

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