A number of chemotherapy agents have been shown to be active in nonsmall-cell lung cancer (NSCLC).[1,2] However, the long-term prognosis for patients is still poor. After the results of a recent meta-analysis, there is wide agreement about the benefit of including cisplatin(Drug information on cisplatin) (Platinol) in first-line combination treatment of this disease.
The cisplatin and vinorelbine (Navelbine) (PV),[4,5] cisplatin (or carbo-platin) and paclitaxel(Drug information on paclitaxel) (Taxol) (PT),[6-9] or cisplatin and gemcitabine(Drug information on gemcitabine) (Gemzar) (PG)[10-11] combinations have been widely tested in the last few years. Although the addition of a new agent to cisplatin has resulted in improvement in survival when compared with cisplatin alone, there has been no statistically significant difference in survival with the use of these new regimens vs the older regimens.[9,12-16] However, there is increasing interest in testing triple-drug combinations including combinations with at least two new agents.
Our group devised the cisplatin, gemcitabine, and vinorelbine (PGV) regimen for the management of patients with advanced NSCLC. In this regimen, we scheduled all three drugs on days 1 and 8 every 3 weeks so that we were able to deliver a full dose of chemotherapy with moderate toxicity. This regimen produced more than a 50% overall response rate, and a 50-week median survival in patients with advanced NSCLC. Therefore, we embarked on a three-arm phase III trial to compare this new combination with PV and PG. An interim analysis was planned when the first 60 patients in each arm were evaluable for response.
In a parallel phase I/II study, our group also investigated the cisplatin, gemcitabine, and paclitaxel (PGT) combination administered every 3 weeks. In this regimen, we used the same doses of cisplatin and gemcitabine as in the previous trial, and split the paclitaxel dose on days 1 and 8. In view of the promising antitumor activity demonstrated by the PGT regimen in this phase II study, we decided to incorporate this combination in the phase III trial currently underway. In this article, we present the results of the interim analysis.
Chemotherapy-naive patients with histologically or cytologically proven locally advanced (stage IIIB) or metastatic (stage IV) NSCLC were eligible for this trial. Patients had to be £ 70 years of age and have adequate bone marrow function (absolute neutrophil count ³ 2 × 109/L, platelet count ³ 100 × 109/L, and hemoglobin level ³ 10.0 g/L), adequate liver function (bilirubin level < 2 times the upper limit of normal, oxaloacetic transaminase enzyme (AST) and/or alanine aminotransferase (ALT) < 3 times the upper limit of normal, prothrombin time < 1.5 times control), and creatinine clearance ³ 60 mL/min. The presence of severe cardiac arrhythmia or heart failure, second- or third-degree heart block, or acute myocardial infarction within 4 months prior to study entry were considered exclusionary. Central nervous system metastases, if asymptomatic, were not considered exclusionary.
Patients were also required to have a performance status £ 1 on the Eastern Cooperative Oncology Group (ECOG) scale, and a life expectancy of at least 12 weeks. All patients gave their written informed consent, and the trial was approved by the Ethical Committee for Biologic Research of the National Tumor Institute of Naples.
The pretreatment evaluation included a complete history and physical examination, electrocardiogram, chest x-ray, respiratory tests, fiberoptic bronchoscopy, and computed tomography (CT) of the chest, brain, and upper abdomen. A radionuclide scan of bone was also performed as necessary to document disease extent. Laboratory studies included a complete blood cell count with white blood cell differential and platelet count, full chemistry profile, prothrombin time, partial thromboplastin and thrombin time, and urinalysis.
Patients were randomized to receive: (1) cisplatin 50 mg/m², gemcitabine 1,000 mg/m², and vinorelbine 25 mg/m² on days 1 and 8, with recycling every 3 weeks (PGV arm); (2) cisplatin 100 mg/m² on day 1 and gemcitabine 1,000 mg/m² on days 1, 8, and 15 every 4 weeks (PG arm); (3) cisplatin 120 mg/m² on days 1 and 29 and vinorelbine 30 mg/m²/week for 10 weeks (PV arm), or (4) cisplatin 50 mg/m², gemcitabine 1,000 mg/m², and paclitaxel 125 mg/m² (over 1 hr) on days 1 and 8 every 3 weeks (PGT arm).
All patients received antiemetic prophylaxis consisting of HT3-receptor antagonists plus 20 mg of dexamethasone(Drug information on dexamethasone). In the PGT arm, prophylaxis for hypersensitivity to paclitaxel consisted of dexamethasone 20 mg intravenously (IV), ranitidine(Drug information on ranitidine) (Zantac) 50 mg IV, and promethazine(Drug information on promethazine) 50 mg intramuscularly (IM), administered 30 minutes before the start of paclitaxel infusion.
Response and Toxicity Evaluation
Study patients underwent assessment for tumor response after a similar period of induction chemotherapy (after three cycles in the PGV and PGT arms and two cycles in the PG and PV arms). An additional two or three cycles, respectively, were administered only in patients achieving a complete or partial response according to World Health Organization (WHO) criteria. Chest irradiation was performed (if indicated) in stage IIIB patients showing stable disease and in progressing patients when considered useful by the physician.
The WHO grade scale was also used to record toxicity. Toxicity was assessed prior to each cycle of chemotherapy, and hematologic studies were performed weekly to determine toxicity at nadir. Data showing severest toxicity for each patient in all cycles of chemotherapy were used for toxicity analysis.
Survival was the primary end point of the study. The study has a power of 80% to recognize a 50% prolongation in the median survival of patients receiving the triple-drug regimens when compared with PV and PG (12 months vs 8 months). Each arm must enroll about 120 people. An interim analysis was planned after the first 60 patients in each arm had undergone a minimum follow up at 26 weeks. The study would be concluded early if the triple-drug regimen did not demonstrate a statistically significant reduction in the risk of death (P < .44), when compared with either PV or PG (null hypothesis accepted). We also planned to close accrual early in any two-drug arm that demonstrated a significant increase in the risk of death (P < .01) as compared with one or both of the triple-drug regimens (null hypothesis rejected).
Overall survival was measured from the date of study entry to the date of death or last follow up. Survival curves were estimated using the Kaplan-Meier product-limit method, and compared by Cox analysis, with age (< 65 years vs older), performance status (0 vs 1), stage (IIIB vs IV), histology (squamous vs others), and weight loss (> 5% vs < 5% of body weight) as covariates.
Patient accrual in the PGV, PG, and PV arms began in April 1997. From October 1997 on, patients were also randomly assigned to the PGT arm. By January 16, 1999, 286 patients were enrolled in the study; 10 patients did not meet the eligibility criteria, and 9 were not evaluable because of the absence of demographics and follow-up data. On April 15, 1999, we performed an interim analysis of the survival of the first 60 evaluable patients in each arm.